Functional evidence for a direct excitatory projection from the lateral habenula to the ventral tegmental area in the rat.

PubMed

Brown, P Leon; Shepard, Paul D

2016-09-01

The lateral habenula, a phylogenetically conserved epithalamic structure, is activated by aversive stimuli and reward omission. Excitatory efferents from the lateral habenula predominately inhibit midbrain dopamine neuronal firing through a disynaptic, feedforward inhibitory mechanism involving the rostromedial tegmental nucleus. However, the lateral habenula also directly targets dopamine neurons within the ventral tegmental area, suggesting that opposing actions may result from increased lateral habenula activity. In the present study, we tested the effect of habenular efferent stimulation on dopamine and nondopamine neurons in the ventral tegmental area of Sprague-Dawley rats using a parasagittal brain slice preparation. Single pulse stimulation of the fasciculus retroflexus excited 48% of dopamine neurons and 51% of nondopamine neurons in the ventral tegmental area of rat pups. These proportions were not altered by excision of the rostromedial tegmental nucleus and were evident in both cortical- and striatal-projecting dopamine neurons. Glutamate receptor antagonists blocked this excitation, and fasciculus retroflexus stimulation elicited evoked excitatory postsynaptic potentials with a nearly constant onset latency, indicative of a monosynaptic, glutamatergic connection. Comparison of responses in rat pups and young adults showed no significant difference in the proportion of neurons excited by fasciculus retroflexus stimulation. Our data indicate that the well-known, indirect inhibitory effect of lateral habenula activation on midbrain dopamine neurons is complemented by a significant, direct excitatory effect. This pathway may contribute to the role of midbrain dopamine neurons in processing aversive stimuli and salience. Copyright © 2016 the American Physiological Society.

Identification and validation of midbrain Kcnq4 regulation of heavy alcohol consumption in rodents.

PubMed

McGuier, Natalie S; Rinker, Jennifer A; Cannady, Reginald; Fulmer, Diana B; Jones, Sara R; Hoffman, Michaela; Mulholland, Patrick J

2018-05-24

Currently available pharmacotherapies for treating alcohol use disorder (AUD) suffer from deleterious side effects and are not efficacious in diverse populations. Clinical and preclinical studies provide evidence that the Kcnq family of genes that encode K V 7 channels influence alcohol intake and dependence. K V 7 channels are a class of slowly activating voltage-dependent K + channels that regulate neuronal excitability. Studies indicate that the K V 7 channel positive modulator retigabine can decrease dopaminergic neuron firing, alter dopamine (DA) release, and reduce alcohol intake in heavy drinking rodents. Given the critical nature of ventral tegmental area (VTA) DA to the addiction process and predominant expression of Kcnq4 in DA neurons, we investigated the role of midbrain Kcnq genes and K V 7 channels in the VTA of genetically diverse mice and long-term heavy drinking rats, respectively. Integrative bioinformatics analysis identified negative correlations between midbrain Kcnq4 expression and alcohol intake and seeking behaviors. Kcnq4 expression levels were also correlated with dopaminergic-related phenotypes in BXD strains, and Kcnq4 was present in support intervals for alcohol sensitivity and alcohol withdrawal severity QTLs in rodents. Pharmacological validation studies revealed that VTA K V 7 channels regulate excessive alcohol intake in rats with a high-drinking phenotype. Administration of a novel and selective K V 7.2/4 channel positive modulator also reduced alcohol drinking in rats. Together, these findings indicate that midbrain Kcnq4 expression regulates alcohol-related behaviors in genetically diverse mice and provide evidence that K V 7.4 channels are a critical mediator of excessive alcohol drinking. Copyright © 2018 Elsevier Ltd. All rights reserved.

Chronic methamphetamine administration causes differential regulation of transcription factors in the rat midbrain.

PubMed

Krasnova, Irina N; Ladenheim, Bruce; Hodges, Amber B; Volkow, Nora D; Cadet, Jean Lud

2011-04-25

Methamphetamine (METH) is an addictive and neurotoxic psychostimulant widely abused in the USA and throughout the world. When administered in large doses, METH can cause depletion of striatal dopamine terminals, with preservation of midbrain dopaminergic neurons. Because alterations in the expression of transcription factors that regulate the development of dopaminergic neurons might be involved in protecting these neurons after toxic insults, we tested the possibility that their expression might be affected by toxic doses of METH in the adult brain. Male Sprague-Dawley rats pretreated with saline or increasing doses of METH were challenged with toxic doses of the drug and euthanized two weeks later. Animals that received toxic METH challenges showed decreases in dopamine levels and reductions in tyrosine hydroxylase protein concentration in the striatum. METH pretreatment protected against loss of striatal dopamine and tyrosine hydroxylase. In contrast, METH challenges caused decreases in dopamine transporters in both saline- and METH-pretreated animals. Interestingly, METH challenges elicited increases in dopamine transporter mRNA levels in the midbrain in the presence but not in the absence of METH pretreatment. Moreover, toxic METH doses caused decreases in the expression of the dopamine developmental factors, Shh, Lmx1b, and Nurr1, but not in the levels of Otx2 and Pitx3, in saline-pretreated rats. METH pretreatment followed by METH challenges also decreased Nurr1 but increased Otx2 and Pitx3 expression in the midbrain. These findings suggest that, in adult animals, toxic doses of METH can differentially influence the expression of transcription factors involved in the developmental regulation of dopamine neurons. The combined increases in Otx2 and Pitx3 expression after METH preconditioning might represent, in part, some of the mechanisms that served to protect against METH-induced striatal dopamine depletion observed after METH preconditioning.

By Changing Dimensionality, Sequential Culturing of Midbrain Cells, rather than Two-Dimensional Culture, Generates a Neuron-Glia Ratio Closer to in vivo Adult Midbrain.

PubMed

Ganapathy, Kavina; Sowmithra, Sowmithra; Bhonde, Ramesh; Datta, Indrani

2016-07-16

The neuron-glia ratio is of prime importance for maintaining the physiological homeostasis of neuronal and glial cells, and especially crucial for dopaminergic neurons because a reduction in glial density has been reported in postmortem reports of brains affected by Parkinson's disease. We thus aimed at developing an in vitro midbrain culture which would replicate a similar neuron-glia ratio to that in in vivo adult midbrain while containing a similar number of dopaminergic neurons. A sequential culture technique was adopted to achieve this. Neural progenitors (NPs) were generated by the hanging-drop method and propagated as 3D neurospheres followed by the derivation of outgrowth from these neurospheres on a chosen extracellular matrix. The highest proliferation was observed in neurospheres from day in vitro (DIV) 5 through MTT and FACS analysis of Ki67 expression. FACS analysis using annexin/propidium iodide showed an increase in the apoptotic population from DIV 8. DIV 5 neurospheres were therefore selected for deriving the differentiated outgrowth of midbrain on a poly-L-lysine-coated surface. Quantitative RT-PCR showed comparable gene expressions of the mature neuronal marker β-tubulin III, glial marker GFAP and dopaminergic marker tyrosine hydroxylase (TH) as compared to in vivo adult rat midbrain. The FACS analysis showed a similar neuron-glia ratio obtained by the sequential culture in comparison to adult rat midbrain. The yield of β-tubulin III and TH was distinctly higher in the sequential culture in comparison to 2D culture, which showed a higher yield of GFAP immunopositive cells. Functional characterization indicated that both the constitutive and inducible (KCl and ATP) release of dopamine was distinctly higher in the sequential culture than the 2D culture. Thus, the sequential culture technique succeeded in the initial enrichment of NPs in 3D neurospheres, which in turn resulted in an optimal attainment of the neuron-glia ratio on outgrowth culture from these neurospheres. © 2016 S. Karger AG, Basel.

Retraction: Borroto-Escuela et al., The existence of FGFR1-5-HT1A receptor heterocomplexes in midbrain 5-HT neurons of the rat: relevance for neuroplasticity.

PubMed

2013-07-10

The Journal of Neuroscience has received a report describing an investigation by the Karolinska Institutet, which found substantial data misrepresentation in the article "The Existence of FGFR1-5-HT1A Receptor Heterocomplexes in Midbrain 5-HT Neurons of the Rat: Relevance for Neuroplasticity" by Dasiel O. Borroto-Escuela, Wilber Romero-Fernandez, Mileidys Pérez-Alea, Manuel Narvaez, Alexander O. Tarakanov, Giuseppa Mudó , Luigi F. Agnati, Francisco Ciruela, Natale Belluardo, and Kjell Fuxe, which appeared on pages 6295-6303 of the May 2, 2012 issue. Because the results cannot be considered reliable, the editors of The Journal are retracting the paper.

Cross-hemispheric dopamine projections have functional significance

PubMed Central

Fox, Megan E.; Mikhailova, Maria A.; Bass, Caroline E.; Takmakov, Pavel; Gainetdinov, Raul R.; Budygin, Evgeny A.; Wightman, R. Mark

2016-01-01

Dopamine signaling occurs on a subsecond timescale, and its dysregulation is implicated in pathologies ranging from drug addiction to Parkinson’s disease. Anatomic evidence suggests that some dopamine neurons have cross-hemispheric projections, but the significance of these projections is unknown. Here we report unprecedented interhemispheric communication in the midbrain dopamine system of awake and anesthetized rats. In the anesthetized rats, optogenetic and electrical stimulation of dopamine cells elicited physiologically relevant dopamine release in the contralateral striatum. Contralateral release differed between the dorsal and ventral striatum owing to differential regulation by D2-like receptors. In the freely moving animals, simultaneous bilateral measurements revealed that dopamine release synchronizes between hemispheres and intact, contralateral projections can release dopamine in the midbrain of 6-hydroxydopamine–lesioned rats. These experiments are the first, to our knowledge, to show cross-hemispheric synchronicity in dopamine signaling and support a functional role for contralateral projections. In addition, our data reveal that psychostimulants, such as amphetamine, promote the coupling of dopamine transients between hemispheres. PMID:27298371

Increased BOLD Activation to Predator Stressor in Subiculum and Midbrain of Amphetamine-Sensitized Maternal Rats

PubMed Central

Febo, Marcelo; Pira, Ashley S.

2011-01-01

Amphetamine, which is known to cause sensitization, potentiates the hormonal and neurobiological signatures of stress and may also increase sensitivity to stress-inducing stimuli in limbic areas. Trimethylthiazoline (5 μL TMT) is a chemical constituent of fox feces that evokes innate fear and activates the neuronal and hormonal signatures of stress in rats. We used blood oxygen level dependent (BOLD) MRI to test whether amphetamine sensitization (1 mg/kg, i.p. X 3 days) in female rats has a lasting effect on the neural response to a stress-evoking stimulus, the scent of a predator, during the postpartum period. The subiculum and dopamine-enriched midbrain VTA/SN of amphetamine-sensitized, but not control mothers showed a greater BOLD signal response to predator odor than a control putrid scent. The greater responsiveness of these two brain regions following stimulant sensitization might impact neural processing in response to stressors in the maternal brain. PMID:21134359

Increased BOLD activation to predator stressor in subiculum and midbrain of amphetamine-sensitized maternal rats.

PubMed

Febo, Marcelo; Pira, Ashley S

2011-03-25

Amphetamine, which is known to cause sensitization, potentiates the hormonal and neurobiological signatures of stress and may also increase sensitivity to stress-inducing stimuli in limbic areas. Trimethylthiazoline (5μL TMT) is a chemical constituent of fox feces that evokes innate fear and activates the neuronal and hormonal signatures of stress in rats. We used blood oxygen level dependent (BOLD) MRI to test whether amphetamine sensitization (1mg/kg, i.p. ×3days) in female rats has a lasting effect on the neural response to a stress-evoking stimulus, the scent of a predator, during the postpartum period. The subiculum and dopamine-enriched midbrain VTA/SN of amphetamine-sensitized but not control mothers showed a greater BOLD signal response to predator odor than a control putrid scent. The greater responsiveness of these two brain regions following stimulant sensitization might impact neural processing in response to stressors in the maternal brain. Copyright © 2010 Elsevier B.V. All rights reserved.

Chemogenetic Activation of Midbrain Dopamine Neurons Affects Attention, but not Impulsivity, in the Five-Choice Serial Reaction Time Task in Rats.

PubMed

Boekhoudt, Linde; Voets, Elisa S; Flores-Dourojeanni, Jacques P; Luijendijk, Mieneke Cm; Vanderschuren, Louk Jmj; Adan, Roger Ah

2017-05-01

Attentional impairments and exaggerated impulsivity are key features of psychiatric disorders, such as attention-deficit/hyperactivity disorder, schizophrenia, and addiction. These deficits in attentional performance and impulsive behaviors have been associated with aberrant dopamine (DA) signaling, but it remains unknown whether these deficits result from enhanced DA neuronal activity in the midbrain. Here, we took a novel approach by testing the impact of chemogenetically activating DA neurons in the ventral tegmental area (VTA) or substantia nigra pars compacta (SNc) on attention and impulsivity in the five-choice serial reaction time task (5-CSRTT) in rats. We found that activation of DA neurons in both the VTA and SNc impaired attention by increasing trial omissions. In addition, SNc DA neuron activation decreased attentional accuracy. Surprisingly, enhanced DA neuron activity did not affect impulsive action in this task. These results show that enhanced midbrain DA neuronal activity induces deficits in attentional performance, but not impulsivity. Furthermore, DA neurons in the VTA and SNc have different roles in regulating attention. These findings contribute to our understanding of the neural substrates underlying attention deficits and impulsivity, and provide valuable insights to improve treatment of these symptoms.

Anti-Apoptotic Protein Bcl-xL Expression in the Midbrain Raphe Region Is Sensitive to Stress and Glucocorticoids.

PubMed

Shishkina, Galina T; Kalinina, Tatyana S; Bulygina, Veta V; Lanshakov, Dmitry A; Babluk, Ekaterina V; Dygalo, Nikolay N

2015-01-01

Anti-apoptotic proteins are suggested to be important for the normal health of neurons and synapses as well as for resilience to stress. In order to determine whether stressful events may influence the expression of anti-apoptotic protein Bcl-xL in the midbrain and specifically in the midbrain serotonergic (5-HT) neurons involved in neurobehavioral responses to adverse stimuli, adult male rats were subjected to short-term or chronic forced swim stress. A short-term stress rapidly increased the midbrain bcl-xl mRNA levels and significantly elevated Bcl-xL immunoreactivity in the midbrain 5-HT cells. Stress-induced increase in glucocorticoid secretion was implicated in the observed effect. The levels of bcl-xl mRNA were decreased after stress when glucocorticoid elevation was inhibited by metyrapone (MET, 150 mg/kg), and this decrease was attenuated by glucocorticoid replacement with dexamethasone (DEX; 0.2 mg/kg). Both short-term stress and acute DEX administration, in parallel with Bcl-xL, caused a significant increase in tph2 mRNA levels and slightly enhanced tryptophan hydroxylase immunoreactivity in the midbrain. The increasing effect on the bcl-xl expression was specific to the short-term stress. Forced swim repeated daily for 2 weeks led to a decrease in bcl-xl mRNA in the midbrain without any effects on the Bcl-xL protein expression in the 5-HT neurons. In chronically stressed animals, an increase in tph2 gene expression was not associated with any changes in tryptophan hydroxylase protein levels. Our findings are the first to demonstrate that both short-term stress and acute glucocorticoid exposures induce Bcl-xL protein expression in the midbrain 5-HT neurons concomitantly with the activation of the 5-HT synthesis pathway in these neurons.

Sleep: a physiological "cerveau isolé" stage?

PubMed

Gottesmann, C; User, P; Gioanni, H

1980-01-01

Rapid or paradoxical sleep in the rat is usually preceded and often followed by a stage of short duration characterized by large spindles in the frontal cortex and theta rhythm in the hippocampus. The midbrain transection induces for hours the same electrophysiological patterns suggesting the existence in the rat of a short physiologically isolated, forebrain stage during sleep.

Combined prenatal and postnatal butyl paraben exposure produces autism-like symptoms in offspring: comparison with valproic acid autistic model.

PubMed

Ali, Elham H A; Elgoly, Amany H Mahmoud

2013-10-01

The aim of this work is to evaluate the impact of butyl paraben (BP) in brain of the pups developed for mothers administered BP from early pregnancy till weaning and its effect on studying the behavior, brain neurotransmitters and brain derived neurotrophic factor BDNF via comparing the results with valproic acid (VA) autistic-rat model preparing by a single oral injection dose of VA (800 mg/kg b.wt) at the 12.5 days of gestation. Butyl paraben was orally and subcutaneously administered (200 mg/kg b.wt) to pregnant rats from gestation day 1 to lactation day 21. The offspring male rats were subjected at the last 3 days of lactation to Morris water maze and three chamber sociability test then decapitated and the brain was excised and dissected to the cortex, hippocampus, cerebellum, midbrain and pons for the determination of norepinephrine, dopamine and serotonin (NE, DA and 5-HT) and cortex amino acids and whole brain BDNF. The results showed similar social and learning and memory behavioral deficits in VA rat model and the butyl paraben offspring in comparison with the controls. Also, some similar alterations were observed in monoamine content, amino acids and BDNF factor in the autistic-like model and butyl paraben offspring in comparison with the controls. The alterations were recorded notably in hippocampus and pons NE, midbrain DA, hippocampus and midbrain 5-HT, and frontal cortex GABA and asparagine. These data suggest that prenatal exposure to butyl paraben induced neuro-developmental disorders similar to some of the neurodevelopmental disorders observed in the VA model of autism. © 2013 Elsevier Inc. All rights reserved.

nNOS expression in the brain of rats after burn and the effect of the ACE inhibitor captopril.

PubMed

Demiralay, Ebru; Saglam, Ibrahim Yaman; Ozdamar, Emine Nur; Sehirli, Ahmet Ozer; Sener, Goksel; Saglam, Esra

2013-08-01

To investigate the role of endogenous neuronal nitric oxide synthase (nNOS) on brain injury after burn and the effects of the captopril. Wistar albino rats (200-250 g) were exposed on the dorsal surface to 90°C (burn) or 25°C (sham) water for 10 s. The ACE group was treated with intraperitoneal 10 mg/kg captopril immediately after burn and this treatment was repeated twice daily. At the end of the 24 h brain samples were taken. nNOS was studied in brain areas by immunohistochemistry. There was no difference between the cerebellar and hypothalamic areas the nNOS expression of all groups. nNOS expression increased in the frontal cortex, striatum and midbrain in the burn group compared to the control group. In the frontal cortex, nNOS expression significantly decreased after ACE inhibitor treatment (p<0.05). The striatal nNOS of the ACE group significantly increased when compared to the control group (p=0.001). In the midbrain of the animals, nNOS decreased in the ACE group. Hippocampal nNOS expression did not change after burn and significantly increased after ACE inhibitor therapy (p<0.05). Our data showed that the pathophysiological events following burn appear to be related to an acute inflammatory reaction which is associated with nNOS in the frontal cortex, striatum and midbrain, and captopril treatment abrogates the nNOS response in the frontal cortex and midbrain. Copyright © 2012 Elsevier Ltd and ISBI. All rights reserved.

Differential numbers of foci of lymphocytes within the brains of Lewis rats exposed to weak complex nocturnal magnetic fields during development of experimental allergic encephalomyelitis.

PubMed

Persinger, Michael A

2009-01-01

To discern if specific structures of the rat brain contained more foci of lymphocytes following induction of experimental allergic encephalomyelitis and exposures to weak, amplitude-modulated magnetic fields for 6 min once per hour during the scotophase, the residuals between the observed and predicted values for the numbers of foci for 320 structures were obtained. Compared to the brains of sham-field exposed rats, the brains of rats exposed to 7-Hz 50 nT (0.5 mG) amplitude-modulated fields showed more foci within hippocampal structures and the dorsal central grey of the midbrain while those exposed to 7-Hz 500 nT (5 mG) fields showed greater densities within the hypothalamus and optic chiasm. The brains of rats exposed to either the 50 nT or 500 nT amplitude-modulated 40-Hz fields displayed greater densities of foci within the midbrain structures related to rapid eye movement. Most of the enhancements of infiltrations within the magnetic field-exposed rats occurred in structures within periventricular or periaqueductal regions and were both frequency- and intensity-dependent. The specificity and complexity of the configurations of the residuals of the numbers of infiltrated foci following exposures to the different fields suggest that the brain itself may be a "sensory organ" for the detection of these stimuli.

Programming of Dopaminergic Neurons by Neonatal Sex Hormone Exposure: Effects on Dopamine Content and Tyrosine Hydroxylase Expression in Adult Male Rats

PubMed Central

Espinosa, Pedro; Silva, Roxana A.; Sanguinetti, Nicole K.; Venegas, Francisca C.; Riquelme, Raul; González, Luis F.; Cruz, Gonzalo; Renard, Georgina M.; Moya, Pablo R.; Sotomayor-Zárate, Ramón

2016-01-01

We sought to determine the long-term changes produced by neonatal sex hormone administration on the functioning of midbrain dopaminergic neurons in adult male rats. Sprague-Dawley rats were injected subcutaneously at postnatal day 1 and were assigned to the following experimental groups: TP (testosterone propionate of 1.0 mg/50 μL); DHT (dihydrotestosterone of 1.0 mg/50 μL); EV (estradiol valerate of 0.1 mg/50 μL); and control (sesame oil of 50 μL). At postnatal day 60, neurochemical studies were performed to determine dopamine content in substantia nigra-ventral tegmental area and dopamine release in nucleus accumbens. Molecular (mRNA expression of tyrosine hydroxylase) and cellular (tyrosine hydroxylase immunoreactivity) studies were also performed. We found increased dopamine content in substantia nigra-ventral tegmental area of TP and EV rats, in addition to increased dopamine release in nucleus accumbens. However, neonatal exposure to DHT, a nonaromatizable androgen, did not affect midbrain dopaminergic neurons. Correspondingly, compared to control rats, levels of tyrosine hydroxylase mRNA and protein were significantly increased in TP and EV rats but not in DHT rats, as determined by qPCR and immunohistochemistry, respectively. Our results suggest an estrogenic mechanism involving increased tyrosine hydroxylase expression, either by direct estrogenic action or by aromatization of testosterone to estradiol in substantia nigra-ventral tegmental area. PMID:26904299

Programming of Dopaminergic Neurons by Neonatal Sex Hormone Exposure: Effects on Dopamine Content and Tyrosine Hydroxylase Expression in Adult Male Rats.

PubMed

Espinosa, Pedro; Silva, Roxana A; Sanguinetti, Nicole K; Venegas, Francisca C; Riquelme, Raul; González, Luis F; Cruz, Gonzalo; Renard, Georgina M; Moya, Pablo R; Sotomayor-Zárate, Ramón

2016-01-01

We sought to determine the long-term changes produced by neonatal sex hormone administration on the functioning of midbrain dopaminergic neurons in adult male rats. Sprague-Dawley rats were injected subcutaneously at postnatal day 1 and were assigned to the following experimental groups: TP (testosterone propionate of 1.0 mg/50 μL); DHT (dihydrotestosterone of 1.0 mg/50 μL); EV (estradiol valerate of 0.1 mg/50 μL); and control (sesame oil of 50 μL). At postnatal day 60, neurochemical studies were performed to determine dopamine content in substantia nigra-ventral tegmental area and dopamine release in nucleus accumbens. Molecular (mRNA expression of tyrosine hydroxylase) and cellular (tyrosine hydroxylase immunoreactivity) studies were also performed. We found increased dopamine content in substantia nigra-ventral tegmental area of TP and EV rats, in addition to increased dopamine release in nucleus accumbens. However, neonatal exposure to DHT, a nonaromatizable androgen, did not affect midbrain dopaminergic neurons. Correspondingly, compared to control rats, levels of tyrosine hydroxylase mRNA and protein were significantly increased in TP and EV rats but not in DHT rats, as determined by qPCR and immunohistochemistry, respectively. Our results suggest an estrogenic mechanism involving increased tyrosine hydroxylase expression, either by direct estrogenic action or by aromatization of testosterone to estradiol in substantia nigra-ventral tegmental area.

Anti-Apoptotic Protein Bcl-xL Expression in the Midbrain Raphe Region Is Sensitive to Stress and Glucocorticoids

PubMed Central

Kalinina, Tatyana S.; Bulygina, Veta V.; Lanshakov, Dmitry A.; Babluk, Ekaterina V.

2015-01-01

Anti-apoptotic proteins are suggested to be important for the normal health of neurons and synapses as well as for resilience to stress. In order to determine whether stressful events may influence the expression of anti-apoptotic protein Bcl-xL in the midbrain and specifically in the midbrain serotonergic (5-HT) neurons involved in neurobehavioral responses to adverse stimuli, adult male rats were subjected to short-term or chronic forced swim stress. A short-term stress rapidly increased the midbrain bcl-xl mRNA levels and significantly elevated Bcl-xL immunoreactivity in the midbrain 5-HT cells. Stress-induced increase in glucocorticoid secretion was implicated in the observed effect. The levels of bcl-xl mRNA were decreased after stress when glucocorticoid elevation was inhibited by metyrapone (MET, 150 mg/kg), and this decrease was attenuated by glucocorticoid replacement with dexamethasone (DEX; 0.2 mg/kg). Both short-term stress and acute DEX administration, in parallel with Bcl-xL, caused a significant increase in tph2 mRNA levels and slightly enhanced tryptophan hydroxylase immunoreactivity in the midbrain. The increasing effect on the bcl-xl expression was specific to the short-term stress. Forced swim repeated daily for 2 weeks led to a decrease in bcl-xl mRNA in the midbrain without any effects on the Bcl-xL protein expression in the 5-HT neurons. In chronically stressed animals, an increase in tph2 gene expression was not associated with any changes in tryptophan hydroxylase protein levels. Our findings are the first to demonstrate that both short-term stress and acute glucocorticoid exposures induce Bcl-xL protein expression in the midbrain 5-HT neurons concomitantly with the activation of the 5-HT synthesis pathway in these neurons. PMID:26624017

Expression of dopamine D2 receptor and choline acetyltransferase mRNA in the dopamine deafferented rat caudate-putamen.

PubMed

Brené, S; Lindefors, N; Herrera-Marschitz, M; Persson, H

1990-01-01

In situ hybridization was used to study dopamine D2 receptor (D2R) and choline acetyltransferase (ChAT) mRNA expression in neurons of the rat forebrain, both on control animals and after a unilateral 6-hydroxydopamine (6-OHDA) lesion of midbrain dopamine neurons. D2R mRNA expressing neurons were seen in regions which are known to be heavily innervated by midbrain dopamine fibers such as caudate-putamen, nucleus accumbens and olfactory tubercle. ChAT mRNA expressing neurons were seen in caudate-putamen, nucleus accumbens and septal regions including vertical limb of the diagonal band. In caudate-putamen, approximately 55% of the medium sized neurons, which is the predominating neuronal cell-size in this region, were specifically labeled with the D2R probe. In addition, approximately 95% of the large size neurons in caudate-putamen were specifically labeled with both the D2R and ChAT probes, suggesting that most cholinergic neurons in the caudate-putamen express D2R mRNA. After a unilateral lesion of midbrain dopamine neurons, no change in the level of either D2R or ChAT mRNA were seen in the large size intrinsic cholinergic neurons in caudate-putamen. Similarly, no evidence was obtained for altered levels of D2R mRNA in medium size neurons in medial caudate-putamen, or nucleus accumbens. However, an increase in the number of medium size neurons expressing D2R mRNA was observed in the lateral part of the dopamine deafferented caudate-putamen. Thus, it appears that midbrain dopamine deafferentation causes an increase in D2R mRNA expression in a subpopulation of medium size neurons in the lateral caudate-putamen.

The rostromedial tegmental nucleus is essential for non-rapid eye movement sleep.

PubMed

Yang, Su-Rong; Hu, Zhen-Zhen; Luo, Yan-Jia; Zhao, Ya-Nan; Sun, Huan-Xin; Yin, Dou; Wang, Chen-Yao; Yan, Yu-Dong; Wang, Dian-Ru; Yuan, Xiang-Shan; Ye, Chen-Bo; Guo, Wei; Qu, Wei-Min; Cherasse, Yoan; Lazarus, Michael; Ding, Yu-Qiang; Huang, Zhi-Li

2018-04-01

The rostromedial tegmental nucleus (RMTg), also called the GABAergic tail of the ventral tegmental area, projects to the midbrain dopaminergic system, dorsal raphe nucleus, locus coeruleus, and other regions. Whether the RMTg is involved in sleep-wake regulation is unknown. In the present study, pharmacogenetic activation of rat RMTg neurons promoted non-rapid eye movement (NREM) sleep with increased slow-wave activity (SWA). Conversely, rats after neurotoxic lesions of 8 or 16 days showed decreased NREM sleep with reduced SWA at lights on. The reduced SWA persisted at least 25 days after lesions. Similarly, pharmacological and pharmacogenetic inactivation of rat RMTg neurons decreased NREM sleep. Electrophysiological experiments combined with optogenetics showed a direct inhibitory connection between the terminals of RMTg neurons and midbrain dopaminergic neurons. The bidirectional effects of the RMTg on the sleep-wake cycle were mimicked by the modulation of ventral tegmental area (VTA)/substantia nigra compacta (SNc) dopaminergic neuronal activity using a pharmacogenetic approach. Furthermore, during the 2-hour recovery period following 6-hour sleep deprivation, the amount of NREM sleep in both the lesion and control rats was significantly increased compared with baseline levels; however, only the control rats showed a significant increase in SWA compared with baseline levels. Collectively, our findings reveal an essential role of the RMTg in the promotion of NREM sleep and homeostatic regulation.

The rostromedial tegmental nucleus is essential for non-rapid eye movement sleep

PubMed Central

Hu, Zhen-Zhen; Luo, Yan-Jia; Zhao, Ya-Nan; Sun, Huan-Xin; Yin, Dou; Wang, Chen-Yao; Yan, Yu-Dong; Wang, Dian-Ru; Yuan, Xiang-Shan; Ye, Chen-Bo; Guo, Wei; Qu, Wei-Min; Cherasse, Yoan; Lazarus, Michael; Ding, Yu-Qiang; Huang, Zhi-Li

2018-01-01

The rostromedial tegmental nucleus (RMTg), also called the GABAergic tail of the ventral tegmental area, projects to the midbrain dopaminergic system, dorsal raphe nucleus, locus coeruleus, and other regions. Whether the RMTg is involved in sleep–wake regulation is unknown. In the present study, pharmacogenetic activation of rat RMTg neurons promoted non-rapid eye movement (NREM) sleep with increased slow-wave activity (SWA). Conversely, rats after neurotoxic lesions of 8 or 16 days showed decreased NREM sleep with reduced SWA at lights on. The reduced SWA persisted at least 25 days after lesions. Similarly, pharmacological and pharmacogenetic inactivation of rat RMTg neurons decreased NREM sleep. Electrophysiological experiments combined with optogenetics showed a direct inhibitory connection between the terminals of RMTg neurons and midbrain dopaminergic neurons. The bidirectional effects of the RMTg on the sleep–wake cycle were mimicked by the modulation of ventral tegmental area (VTA)/substantia nigra compacta (SNc) dopaminergic neuronal activity using a pharmacogenetic approach. Furthermore, during the 2-hour recovery period following 6-hour sleep deprivation, the amount of NREM sleep in both the lesion and control rats was significantly increased compared with baseline levels; however, only the control rats showed a significant increase in SWA compared with baseline levels. Collectively, our findings reveal an essential role of the RMTg in the promotion of NREM sleep and homeostatic regulation. PMID:29652889

Apoptotic natural cell death in developing primate dopamine midbrain neurons occurs during a restricted period in the second trimester of gestation

PubMed Central

Morrow, Bret A.; Roth, Robert H.; Redmond, D. Eugene; Sladek, John R.; Elsworth, John D.

2012-01-01

Natural cell death (NCD) by apoptosis is a normal developmental event in most neuronal populations, and is a determinant of the eventual size of a population. We decided to examine the timing and extent of NCD of the midbrain dopamine system in a primate species, as dopamine deficiency or excess has been implicated in several disorders. Genetic or environmental differences may alter the extent of NCD and predispose individuals to neurological or psychiatric diseases. In developing rats, NCD in the midbrain dopamine system has been observed to start at the end of gestation and peak in the postnatal period. In fetal monkey brains, apoptosis in midbrain DA neurons was identified histologically by chromatin clumping in tyrosine hydroxylase-positive cells, and confirmed by TUNEL and active caspase-3 staining. A distinct peak of NCD occurred at about E80, midway through gestation in this species. We estimate that at least 50% of the population may be lost in this process. In other brains we determined biochemically that the onset of apoptosis coincides with the time of greatest rate of increase of striatal DA concentration. Thus, marked apoptotic NCD occurs in the primate midbrain dopamine system half-way through gestation, and appears to be associated with the rapid developmental increase in striatal dopamine innervation. PMID:17313945

Omega-3 Fatty Acid Deficient Male Rats Exhibit Abnormal Behavioral Activation in the Forced Swim Test Following Chronic Fluoxetine Treatment: Association with Altered 5-HT1A and Alpha2A Adrenergic Receptor Expression

PubMed Central

Able, Jessica A.; Liu, Yanhong; Jandacek, Ronald; Rider, Therese; Tso, Patrick; McNamara, Robert K.

2014-01-01

Omega-3 fatty acid deficiency during development leads to enduing alterations in central monoamine neurotransmission in rat brain. Here we investigated the effects of omega-3 fatty acid deficiency on behavioral and neurochemical responses to chronic fluoxetine (FLX) treatment. Male rats were fed diets with (CON, n=34) or without (DEF, n=30) the omega-3 fatty acid precursor alpha-linolenic acid (ALA) during peri-adolescent development (P21-P90). A subset of CON (n=14) and DEF (n=12) rats were administered FLX (10 mg/kg/d) through their drinking water for 30 d beginning on P60. The forced swimming test (FST) was initiated on P90, and regional brain mRNA markers of serotonin and noradrenaline neurotransmission were determined. Dietary ALA depletion led to significant reductions in frontal cortex docosahexaenoic acid (DHA, 22:6n-3) composition in DEF (−26%, p=0.0001) and DEF+FLX (−32%, p=0.0001) rats. Plasma FLX and norfluoxetine concentrations did not different between FLX-treated DEF and CON rats. During the 15-min FST pretest, DEF+FLX rats exhibited significantly greater climbing behavior compared with CON+FLX rats. During the 5-min test trial, FLX treatment reduced immobility and increased swimming in CON and DEF rats, and only DEF+FLX rats exhibited significant elevations in climbing behavior. DEF+FLX rats exhibited greater midbrain, and lower frontal cortex, 5-HT1A mRNA expression compared with all groups including CON+FLX rats. DEF+FLX rats also exhibited greater midbrain alpha2A adrenergic receptor mRNA expression which was positively correlated with climbing behavior in the FST. These preclinical data demonstrate that low omega-3 fatty acid status leads to abnormal behavioral and neurochemical responses to chronic FLX treatment in male rats. PMID:24360505

[N(omega)-nitro-L-arginine methyl ester inhibits the up-regulated expression of neuronal nitric oxide synthase/NMDA receptor in the morphine analgesia tolerance rats].

PubMed

Yu, Ling; Xue, Fu-Shan; Li, Cheng-Wen; Xu, Ya-Chao; Zhang, Guo-Hua; Liu, Kun-Peng; Liu, Yi; Sun, Hai-Tao

2006-12-25

The effect of systemic administration of nonspecific nitric oxide synthase inhibitor (N(omega)-nitro-L-arginine methyl ester, L-NAME) on morphine analgesia tolerance was observed by using the thermal tail-flick method, and the roles of NO and NMDA receptors in morphine analgesia tolerance were evaluated on the basis of the expressions of nNOS mRNA, NR1A mRNA and NR2A mRNA in spinal cord and midbrain. Thirty-six healthy adult Sprague-Dawley rats were randomly divided into six groups (6 rats per group). Group 1, control group, received a subcutaneous (s.c.) injection of normal saline (1 ml); Groups 2, 3, 4, 5 and 6, the treatment groups received s.c. injection of L-NAME 10 mg/kg, L-NAME 20 mg/kg, morphine 10 mg/kg, L-NAME 10 mg/kg + morphine 10 mg/kg, and L-NAME 20 mg/kg + morphine 10 mg/kg, respectively. All rats received s.c. injections twice per day (8:00 and 17:00). The tail-flick latency (TFL) was measured in each rat before the injection as a baseline value, and then TFL at 50 min after the 1st injection every day as the measuring values. The animals (except for groups 2 and 5) were decapitated at 80 min after the last injection on the 8th day. The spinal segments and midbrain were removed for analysis of nNOS mRNA, NR1A mRNA and NR2A mRNA expressions by the RT-PCR method. The results showed that TFL remained unchangeable in group 2 compared with baseline value during the 7-day observation, while increased significantly on the 7th day in group 3. In group 4, TFL was longest on the 1st day, then decreased gradually from the 2nd day to the 6th day, and restored to the baseline value on the 6th day. In group 5, TFL showed a decreasing tendency during the 7-day observation, but was still significantly longer than the baseline value on the 7th day. The changes of TFL obtained in group 6 were similar to those in group 5. The results of RT-PCR showed that as compared with group 1, nNOS mRNA expressions in spinal cord and midbrain were significantly down-regulated in group 3, but the expressions of the NR1A mRNA and NR2A mRNA in both groups were similar, while the nNOS mRNA, NR(1A) mRNA and NR(2A) mRNA expressions were all significantly up-regulated in group 4. As compared with group 4, the expressions of nNOS mRNA, NR(1A) mRNA and NR(2A) mRNA were significantly inhibited in group 6. These results suggest that the expressions of nNOS and NMDA receptors in spinal cord and midbrain were significantly up-regulated in the rats with morphine analgesia tolerance. Chronic co-administration of L-NAME could effectively inhibit the morphine-induced overexpressions of nNOS and NMDA receptors, and postpone the development of morphine analgesia tolerance. Based on the results of this study, it is concluded that NO/NMDA receptor in spinal cord and midbrain is closely related to the development of morphine analgesia tolerance.

Proof of mechanism study of a novel serotonin transporter blocker, DA-8031, using [11C]DASB positron emission tomography and in vivo microdialysis.

PubMed

Park, Hyun Soo; Jung, In Soon; Lim, Nam Hee; Sung, Ji Hyun; Lee, Sukhyang; Moon, Byung Seok; Lee, Byung Chul; Kang, Kyung Koo; Kim, Sang Eun

2014-07-01

To investigate the efficacy of DA-8031, a novel compound for the treatment of premature ejaculation, we measured serotonin transporter (SERT) occupancy by DA-8031, as well as DA-8031-induced changes in extracellular serotonin levels, in the rat brain using positron emission tomography (PET) and 11C-N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine ([11C]DASB) and in vivo microdialysis, respectively. [11C]DASB PET scans were performed in rats with graded doses of DA-8031 (vehicle: 10, 30, and 100 mg/kg). SERT occupancy in the midbrain was determined using binding potentials for [11C]DASB calculated by the multilinear reference tissue model. Extracellular serotonin levels were monitored in the dorsal raphe nucleus of rats after the administration of DA-8031 (10-100 mg/kg) using in vivo microdialysis. PET data indicated a reduction of [11C]DASB binding to SERTs in the midbrain as a function of DA-8031 dose. SERT occupancy for each DA-8031 dose (10-100 mg/kg) ranged between 31% and 84%. The drug dose required for 50% occupancy of SERT was 13.5 mg/kg in the midbrain, comparable with previous preclinical behavioral data (∼10-30 mg/kg). In vivo microdialysis showed that DA-8031 produced a dose-dependent increase in extracellular serotonin levels in the dorsal raphe nucleus (33%-81% increase for doses of 10-100 mg/kg). These preclinical data provide a proof of mechanism for DA-8031 as a novel compound of targeting the SERT for the treatment of premature ejaculation, warranting further clinical trials. They also offer insight into the optimal drug dose needed to exert therapeutic effects while minimizing adverse effects in humans. Copyright © 2014 Elsevier Inc. All rights reserved.

Isolation of Human Induced Pluripotent Stem Cell-Derived Dopaminergic Progenitors by Cell Sorting for Successful Transplantation

PubMed Central

Doi, Daisuke; Samata, Bumpei; Katsukawa, Mitsuko; Kikuchi, Tetsuhiro; Morizane, Asuka; Ono, Yuichi; Sekiguchi, Kiyotoshi; Nakagawa, Masato; Parmar, Malin; Takahashi, Jun

2014-01-01

Summary Human induced pluripotent stem cells (iPSCs) can provide a promising source of midbrain dopaminergic (DA) neurons for cell replacement therapy for Parkinson’s disease. However, iPSC-derived donor cells inevitably contain tumorigenic or inappropriate cells. Here, we show that human iPSC-derived DA progenitor cells can be efficiently isolated by cell sorting using a floor plate marker, CORIN. We induced DA neurons using scalable culture conditions on human laminin fragment, and the sorted CORIN+ cells expressed the midbrain DA progenitor markers, FOXA2 and LMX1A. When transplanted into 6-OHDA-lesioned rats, the CORIN+ cells survived and differentiated into midbrain DA neurons in vivo, resulting in significant improvement of the motor behavior, without tumor formation. In particular, the CORIN+ cells in a NURR1+ cell-dominant stage exhibited the best survival and function as DA neurons. Our method is a favorable strategy in terms of scalability, safety, and efficiency and may be advantageous for clinical application. PMID:24672756

DNA microarray unravels rapid changes in transcriptome of MK-801 treated rat brain

PubMed Central

Kobayashi, Yuka; Kulikova, Sofya P; Shibato, Junko; Rakwal, Randeep; Satoh, Hiroyuki; Pinault, Didier; Masuo, Yoshinori

2015-01-01

AIM: To investigate the impact of MK-801 on gene expression patterns genome wide in rat brain regions. METHODS: Rats were treated with an intraperitoneal injection of MK-801 [0.08 (low-dose) and 0.16 (high-dose) mg/kg] or NaCl (vehicle control). In a first series of experiment, the frontoparietal electrocorticogram was recorded 15 min before and 60 min after injection. In a second series of experiments, the whole brain of each animal was rapidly removed at 40 min post-injection, and different regions were separated: amygdala, cerebral cortex, hippocampus, hypothalamus, midbrain and ventral striatum on ice followed by DNA microarray (4 × 44 K whole rat genome chip) analysis. RESULTS: Spectral analysis revealed that a single systemic injection of MK-801 significantly and selectively augmented the power of baseline gamma frequency (30-80 Hz) oscillations in the frontoparietal electroencephalogram. DNA microarray analysis showed the largest number (up- and down- regulations) of gene expressions in the cerebral cortex (378), midbrain (376), hippocampus (375), ventral striatum (353), amygdala (301), and hypothalamus (201) under low-dose (0.08 mg/kg) of MK-801. Under high-dose (0.16 mg/kg), ventral striatum (811) showed the largest number of gene expression changes. Gene expression changes were functionally categorized to reveal expression of genes and function varies with each brain region. CONCLUSION: Acute MK-801 treatment increases synchrony of baseline gamma oscillations, and causes very early changes in gene expressions in six individual rat brain regions, a first report. PMID:26629322

Omega-3 fatty acid deficient male rats exhibit abnormal behavioral activation in the forced swim test following chronic fluoxetine treatment: association with altered 5-HT1A and alpha2A adrenergic receptor expression.

PubMed

Able, Jessica A; Liu, Yanhong; Jandacek, Ronald; Rider, Therese; Tso, Patrick; McNamara, Robert K

2014-03-01

Omega-3 fatty acid deficiency during development leads to enduing alterations in central monoamine neurotransmission in rat brain. Here we investigated the effects of omega-3 fatty acid deficiency on behavioral and neurochemical responses to chronic fluoxetine (FLX) treatment. Male rats were fed diets with (CON, n = 34) or without (DEF, n = 30) the omega-3 fatty acid precursor alpha-linolenic acid (ALA) during peri-adolescent development (P21-P90). A subset of CON (n = 14) and DEF (n = 12) rats were administered FLX (10 mg/kg/d) through their drinking water for 30 d beginning on P60. The forced swimming test (FST) was initiated on P90, and regional brain mRNA markers of serotonin and noradrenaline neurotransmission were determined. Dietary ALA depletion led to significant reductions in frontal cortex docosahexaenoic acid (DHA, 22:6n-3) composition in DEF (-26%, p = 0.0001) and DEF + FLX (-32%, p = 0.0001) rats. Plasma FLX and norfluoxetine concentrations did not different between FLX-treated DEF and CON rats. During the 15-min FST pretest, DEF + FLX rats exhibited significantly greater climbing behavior compared with CON + FLX rats. During the 5-min test trial, FLX treatment reduced immobility and increased swimming in CON and DEF rats, and only DEF + FLX rats exhibited significant elevations in climbing behavior. DEF + FLX rats exhibited greater midbrain, and lower frontal cortex, 5-HT1A mRNA expression compared with all groups including CON + FLX rats. DEF + FLX rats also exhibited greater midbrain alpha2A adrenergic receptor mRNA expression which was positively correlated with climbing behavior in the FST. These preclinical data demonstrate that low omega-3 fatty acid status leads to abnormal behavioral and neurochemical responses to chronic FLX treatment in male rats. Copyright © 2013 Elsevier Ltd. All rights reserved.

Dopamine D3 Receptor Availability Is Associated with Inflexible Decision Making.

PubMed

Groman, Stephanie M; Smith, Nathaniel J; Petrullli, J Ryan; Massi, Bart; Chen, Lihui; Ropchan, Jim; Huang, Yiyun; Lee, Daeyeol; Morris, Evan D; Taylor, Jane R

2016-06-22

Dopamine D2/3 receptor signaling is critical for flexible adaptive behavior; however, it is unclear whether D2, D3, or both receptor subtypes modulate precise signals of feedback and reward history that underlie optimal decision making. Here, PET with the radioligand [(11)C]-(+)-PHNO was used to quantify individual differences in putative D3 receptor availability in rodents trained on a novel three-choice spatial acquisition and reversal-learning task with probabilistic reinforcement. Binding of [(11)C]-(+)-PHNO in the midbrain was negatively related to the ability of rats to adapt to changes in rewarded locations, but not to the initial learning. Computational modeling of choice behavior in the reversal phase indicated that [(11)C]-(+)-PHNO binding in the midbrain was related to the learning rate and sensitivity to positive, but not negative, feedback. Administration of a D3-preferring agonist likewise impaired reversal performance by reducing the learning rate and sensitivity to positive feedback. These results demonstrate a previously unrecognized role for D3 receptors in select aspects of reinforcement learning and suggest that individual variation in midbrain D3 receptors influences flexible behavior. Our combined neuroimaging, behavioral, pharmacological, and computational approach implicates the dopamine D3 receptor in decision-making processes that are altered in psychiatric disorders. Flexible decision-making behavior is dependent upon dopamine D2/3 signaling in corticostriatal brain regions. However, the role of D3 receptors in adaptive, goal-directed behavior has not been thoroughly investigated. By combining PET imaging with the D3-preferring radioligand [(11)C]-(+)-PHNO, pharmacology, a novel three-choice probabilistic discrimination and reversal task and computational modeling of behavior in rats, we report that naturally occurring variation in [(11)C]-(+)-PHNO receptor availability relates to specific aspects of flexible decision making. We confirm these relationships using a D3-preferring agonist, thus identifying a unique role of midbrain D3 receptors in decision-making processes. Copyright © 2016 the authors 0270-6474/16/366732-10$15.00/0.

Expression of APG-2 protein, a member of the heat shock protein 110 family, in developing rat brain.

PubMed

Okui, M; Ito, F; Ogita, K; Kuramoto, N; Kudoh, J; Shimizu, N; Ide, T

2000-01-01

APG-2 protein is a member of the heat shock protein 110 family, and it is thought to play an important role in the maintenance of neuronal functions under physiological and stress conditions. However, neither the tissue-distribution of APG-2 protein nor developmental change of its expression has been studied at the protein level. Therefore, we generated an antiserum against APG-2 protein and studied expression of this protein in rat brain and other tissues by use of the Western blot method. The results showed a high expression of APG-2 protein in various regions of the central nervous system (cerebral cortex, hippocampus, striatum, midbrain, hypothalamus, cerebellum, medulla pons, and spinal cord) throughout the entire postnatal stage. Similarly, a high level of APG-2 protein was detected in the whole brain of rat embryos and in adult rat tissues such as liver, lung, spleen, and kidney. In contrast, its expression in heart was high at postnatal days 1 and 3, but thereafter drastically decreased to a low level. Furthermore, APG-2 protein was detected in neuronal primary cultures prepared from rat cerebral cortex, and its level did not change notably during neuronal differentiation. These results show that APG-2 protein is constitutively expressed in various tissues and also in neuronal cells throughout the entire embryonic and postnatal period. suggesting that it might play an important role in these tissues under non-stress conditions.

Optimization of Peripheral Vision.

DTIC Science & Technology

1986-11-01

2 References * . . . . . . . . . . . . . . . . . . . . . . . 3 2.* ANATOMICAL FOUNDATIONS OF THE TWO SUBSYSTEMS Primary visualp...athways .......... 6 Retinal layers . . . . . . . . . . . .... ....... 7 Nerves, tracts, and midbrain structures . . . . . . . . . 7 Primary cortaara...perhaps the ambient system can be used as a second primary source of information. One reason that its use in this respect is limited is that the

LIN28A enhances the therapeutic potential of cultured neural stem cells in a Parkinson's disease model.

PubMed

Rhee, Yong-Hee; Kim, Tae-Ho; Jo, A-Young; Chang, Mi-Yoon; Park, Chang-Hwan; Kim, Sang-Mi; Song, Jae-Jin; Oh, Sang-Min; Yi, Sang-Hoon; Kim, Hyeon Ho; You, Bo-Hyun; Nam, Jin-Wu; Lee, Sang-Hun

2016-10-01

The original properties of tissue-specific stem cells, regardless of their tissue origins, are inevitably altered during in vitro culturing, lessening the clinical and research utility of stem cell cultures. Specifically, neural stem cells derived from the ventral midbrain lose their dopamine neurogenic potential, ventral midbrain-specific phenotypes, and repair capacity during in vitro cell expansion, all of which are critical concerns in using the cultured neural stem cells in therapeutic approaches for Parkinson's disease. In this study, we observed that the culture-dependent changes of neural stem cells derived from the ventral midbrain coincided with loss of RNA-binding protein LIN28A expression. When LIN28A expression was forced and sustained during neural stem cell expansion using an inducible expression-vector system, loss of dopamine neurogenic potential and midbrain phenotypes after long-term culturing was blocked. Furthermore, dopamine neurons that differentiated from neural stem cells exhibited remarkable survival and resistance against toxic insults. The observed effects were not due to a direct action of LIN28A on the differentiated dopamine neurons, but rather its action on precursor neural stem cells as exogene expression was switched off in the differentiating/differentiated cultures. Remarkable and reproducible behavioural recovery was shown in all Parkinson's disease rats grafted with neural stem cells expanded with LIN28A expression, along with extensive engraftment of dopamine neurons expressing mature neuronal and midbrain-specific markers. These findings suggest that LIN28A expression during stem cell expansion could be used to prepare therapeutically competent donor cells. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Neonatal exposure to estradiol increases dopaminergic transmission in Nucleus Accumbens and morphine-induced conditioned place preference in adult female rats.

PubMed

Bonansco, Christian; Martínez-Pinto, Jonathan; Silva, Roxana A; Velásquez, Victoria B; Martorell, Andrés; Selva, Mónica V; Espinosa, Pedro; Moya, Pablo R; Cruz, Gonzalo; Andrés, María Estela; Sotomayor-Zárate, Ramón

2018-01-29

Steroid sex hormones produce physiological effects in reproductive tissues and also in non-reproductive tissues such as the brain, particularly in cortical, limbic and midbrain areas. Dopamine (DA) neurons involved in processes such as prolactin secretion (tuberoinfundibular system), motor circuit regulation (nigrostriatal system) and driving of motivated behavior (mesocorticolimbic system), are specially regulated by sex hormones. Indeed, sex hormones promote neurochemical and behavioral effects induced by drugs of abuse by tuning midbrain DA neurons in adult animals. However, the long-term effects induced by neonatal exposure to sex hormones on dopaminergic neurotransmission have not been fully studied. The focus of this work was to reveal if a single neonatal exposure with estradiol valerate (EV) results in a programming of dopaminergic neurotransmission in the nucleus accumbens (NAcc) of adult female rats. To answer this question, electrophysiological, neurochemical, cellular, molecular and behavioral techniques were used. The data show that frequency but not amplitude of the spontaneous excitatory postsynaptic current (sEPSC) is significantly increased in NAcc medium spiny neurons (MSNs) of EV-treated rats. In addition, DA content and release are both increased in the NAcc of EV-treated rats, caused by an increased synthesis of this neurotransmitter. These results are functionally associated with a higher percentage of EV-treated rats conditioned to morphine, a drug of abuse, compared with controls. In conclusion, neonatal programming with estradiol increases NAcc dopaminergic neurotransmission in the adulthood, which may be associated with increased reinforcing effects of drugs of abuse. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Changes in the Serum Urate Level Can Predict the Development of Parkinsonism in the 6-Hydroxydopamine Animal Model.

PubMed

Sarukhani, Mohammad Reza; Haghdoost-Yazdi, Hashem; Khandan-Chelarci, Gilda

2018-05-01

Epidemiological studies indicate that a higher plasma level of uric acid (UA) associates with the reduced risk of Parkinson's disease (PD). To confirm the role of UA as a biomarker for PD, we evaluated changes in the serum UA level in the 6-hydroxydopamine (6-OHDA)-induced hemiparkinsonism in rat. For this purpose, 6-OHDA was administered in the medial forebrain bundle by stereotaxic surgery. According to the apomorphine-induced rotational test, the increased intensity of behavioral symptoms as a function of time was associated with the further reduction of UA level. On the other hand, the level of UA increased in the midbrain of the injured hemisphere. The level of reduction in the serum UA level of rats with severe and moderate symptoms was significantly higher than that of rats with mild symptoms. The immunohistofluorescence and biochemical analyses showed that the serum UA level was also correlated with the death of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra pars compacta (SNc), reduced level of striatal dopamine, and severity of oxidative stress in the midbrain. The rats with mild symptoms also showed a significant decrease in TH-positive neurons and striatal dopamine level. These findings suggest a positive correlation between the level of reduction in the serum urate level and severity of 6-OHDA-induced Parkinsonism. In addition, our findings indicated that UA had no marked neuroprotective effects, at least at concentrations obtained in this study. On the other hand, UA was introduced as a biomarker for PD, as a significant decline was observed in the serum UA level of rats with mild behavioral symptoms but with significant dopaminergic cell death in the SNc.

Co-treatment with imipramine averted haloperidol-instigated tardive dyskinesia: Association with serotonin in brain regions.

PubMed

Samad, Noreen; Yasmin, Farzana; Haleem, Darakhshan Jabeen

2016-11-01

Outcome of imipramine (IMI) treatment was scrutinized on progression of haloperidol instigated tardive dyskinesia (TD). 0.2 mg/kg/rat dosage of haloperidol provided orally to rats for 2 weeks enhanced vacuous chewing movements that escalated when the process proceeded for 5 weeks. Following 2 weeks co-injection 5 mg/kg dosage of IMI was diminished haloperidol-instigated VCMs and fully averted following five weeks. The potency of 8-OH-DPAT-instigated locomotor activity exhibited higher in saline+haloperidol treated rats while not observed in IMI+ haloperidol treated rats. 8-OH-DPAT-instigated low 5-hydroxytryptamine (5-HT; serotonin) metabolism was higher in saline+ haloperidol treated rats when compare to IMI+ haloperidol treated rats in both regions of brain (striatum and midbrain). It is recommended that IMI possibly competent in averting TD, in cases receiving treatment to antipsychotics.

Immunoreactive dynorphin in pituitary and brain.

PubMed Central

Goldstein, A; Ghazarossian, V E

1980-01-01

Distribution of the potent opioid peptide dynorphin has been determined in pituitary gland (pig, beef, rat), in the various regions of rat brain, and in rat spinal cord, by using a highly specific antiserum. By gel permeation chromatography in 4 M guanidine, the porcine pituitary immunoreactivity is found in a major peak of apparent molecular weight about 1700 and a minor peak of about 3400. Similar peaks are found in rat pituitary extracts, whereas rat brain contains, in addition, two peaks of larger apparent molecular weight. In the pituitary, immunoreactive dynorphin is found predominantly in pars nervosa. In the central nervous system, it is distributed widely, with highest concentrations in hypothalamus, medulla-pons, midbrain, and spinal cord. Although dynorphin contains leucine-enkephalin, the regional distribution of dynorphin is different from that of enkephalin or of any other known opioid peptide. PMID:6108564

Motherhood and infant contact regulate neuroplasticity in the serotonergic midbrain dorsal raphe.

PubMed

Holschbach, M Allie; Lonstein, Joseph S

2017-02-01

The adult brain shows remarkable neuroplasticity in response to hormones and the socioemotional modifications that they influence. In females with reproductive and maternal experience, this neuroplasticity includes the birth and death of cells in several forebrain regions involved in maternal caregiving and postpartum affective state. Such plasticity in midbrain sites critical for these behavioral and emotional processes has never been examined, though. By visualizing bromodeoxyuridine (BrdU) to label mitotic cells, NeuroD for neuronal precursors, and TUNEL to identify dying cells, we found that the midbrain dorsal raphe nucleus (DR, the source of most ascending serotoninergic projections) exhibited significant neuroplasticity in response to motherhood. Specifically, BrdU analyses revealed that DR newborn cell survival (but not proliferation) was regulated by reproductive state, such that cells born early postpartum were less likely to survive 12 days to reach the late postpartum period compared to cells born during late pregnancy that survived 12 days to reach the early postpartum period. Many of the surviving cells in the DR were NeuN immunoreactive, suggesting a neuronal phenotype. Consistent with these findings, late postpartum rats had fewer NeuroD-immunoreactive DR cells than early postpartum rats. Maternal experience contributed to the late postpartum reduction in DR newborn cell survival because removing the litter at parturition increased cell survival as well as reduced cell death. Unlike cytogenesis in the maternal hippocampus, which is reduced by circulating glucocorticoids, DR newborn cell survival was unaffected by postpartum adrenalectomy. These effects of reproductive state and motherhood on DR plasticity were associated with concurrent changes in DR levels of serotonin's precursor, 5-HTP, and its metabolite, 5-HIAA. Our results demonstrate for the first time that cytogenesis occurs in the midbrain DR of any adult mammal, that DR plasticity is influenced by female reproductive state and maternal experience, and that this plasticity is accompanied by changes in DR serotonergic function. Because serotonin is critical for postpartum caregiving behaviors and maternal affective state, plasticity in the DR may contribute to the neurochemical changes necessary for successful motherhood. Copyright © 2016 Elsevier Ltd. All rights reserved.

Derivation of mouse embryonic stem cell lines from tyrosine hydroxylase reporter mice crossed with a human SNCA transgenic mouse model of Parkinson's disease.

PubMed

Chumarina, Margarita; Azevedo, Carla; Bigarreau, Julie; Vignon, Clémentine; Kim, Kwang-Soo; Li, Jia-Yi; Roybon, Laurent

2017-03-01

Mouse embryonic stem cell (mESC) lines were derived by crossing heterozygous transgenic (tg) mice expressing green fluorescent protein (GFP) under the control of the rat tyrosine hydroxylase (TH) promoter, with homozygous alpha-synuclein (aSYN) mice expressing human mutant SNCA A53T under the control of the mouse Prion promoter (MoPrP), or wildtype (WT) mice. The expression of GFP and human aSYN was validated by immunocytochemistry in midbrain neuron cultures upon differentiation of mESC lines using stromal cell-derived inducing activity. These mESC lines can help to study the impact of human aSYN expression in neurons and oligodendrocytes, and also trace GFP-expressing midbrain neurons. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Effect of time period after boric acid injection on 10B absorption in different regions of adult male rat's brain.

PubMed

Khojasteh, Nasrin Baghban; Pazirandeh, Ali; Jameie, Behnam; Goodarzi, Samereh

2012-06-01

Distribution of (10)B in different regions of rat normal brain was studied. Two groups were chosen as control and trial. Trial group received 2 ml of neutral boron compound. 2, 4 and 6 h after the injection brain removed, coronal sections of forebrain, midbrain and hindbrain were sandwiched between two pieces of polycarbonate. Autoradiography plots of (10)B distribution showed significant differences in three regions with the highest (10)B concentration in the forebrain during 4 h after injection. Copyright © 2012 Elsevier Ltd. All rights reserved.

A variant of WEBINO syndrome after top of the basilar artery stroke.

PubMed

Sierra-Hidalgo, Fernando; Moreno-Ramos, Teresa; Villarejo, Alberto; Martín-Gil, Leticia; de Pablo-Fernández, Eduardo; Correas-Callero, Elisa; Ramos, Ana; Benito-León, Julián

2010-11-01

Wall-eyed bilateral internuclear ophthalmoplegia (WEBINO) is an uncommon neuro-ophthalmologic syndrome consisting of both eyes primary position exotropia and bilateral internuclear ophthalmoplegia. It is thought to be caused by medial midbrain lesions involving both bilateral medial longitudinal fasciculi and medial rectus subnuclei. We report the clinical and neuroimaging findings of a WEBINO syndrome associated to bilateral ptosis, non-reactive mydriasis and complete vertical gaze palsy in a 55-year-old man who suffered a top of the basilar artery stroke causing tegmental midbrain infarction. Copyright © 2010 Elsevier B.V. All rights reserved.

Air pollution & the brain: Subchronic diesel exhaust exposure causes neuroinflammation and elevates early markers of neurodegenerative disease.

PubMed

Levesque, Shannon; Surace, Michael J; McDonald, Jacob; Block, Michelle L

2011-08-24

Increasing evidence links diverse forms of air pollution to neuroinflammation and neuropathology in both human and animal models, but the effects of long-term exposures are poorly understood. We explored the central nervous system consequences of subchronic exposure to diesel exhaust (DE) and addressed the minimum levels necessary to elicit neuroinflammation and markers of early neuropathology. Male Fischer 344 rats were exposed to DE (992, 311, 100, 35 and 0 μg PM/m³) by inhalation over 6 months. DE exposure resulted in elevated levels of TNFα at high concentrations in all regions tested, with the exception of the cerebellum. The midbrain region was the most sensitive, where exposures as low as 100 μg PM/m³ significantly increased brain TNFα levels. However, this sensitivity to DE was not conferred to all markers of neuroinflammation, as the midbrain showed no increase in IL-6 expression at any concentration tested, an increase in IL-1β at only high concentrations, and a decrease in MIP-1α expression, supporting that compensatory mechanisms may occur with subchronic exposure. Aβ42 levels were the highest in the frontal lobe of mice exposed to 992 μg PM/m³ and tau [pS199] levels were elevated at the higher DE concentrations (992 and 311 μg PM/m³) in both the temporal lobe and frontal lobe, indicating that proteins linked to preclinical Alzheimer's disease were affected. α Synuclein levels were elevated in the midbrain in response to the 992 μg PM/m³ exposure, supporting that air pollution may be associated with early Parkinson's disease-like pathology. Together, the data support that the midbrain may be more sensitive to the neuroinflammatory effects of subchronic air pollution exposure. However, the DE-induced elevation of proteins associated with neurodegenerative diseases was limited to only the higher exposures, suggesting that air pollution-induced neuroinflammation may precede preclinical markers of neurodegenerative disease in the midbrain.

Regulation of the neurotensin NT1 receptor in the developing rat brain following chronic treatment with the antagonist SR 48692

PubMed Central

Lépée-Lorgeoux, Isabelle; Betancur, Catalina; Souazé, Frédérique; Rostène, William; Bérod, Anne; Pélaprat, Didier

2000-01-01

The aim of the present study was to investigate the role of neurotensin in the regulation of NT1 receptors during postnatal development in the rat brain. Characterization of the ontogeny of neurotensin concentration and [125I]neurotensin binding to NT1 receptors in the brain at different embryonic and postnatal stages showed that neurotensin was highly expressed at birth, reaching peak levels at postnatal day 5 (P5), and decreasing thereafter. The transient rise in neurotensin levels preceded the maximal expression of NT1 receptors, observed at P10, suggesting that neurotensin may influence the developmental profile of NT1 receptors. Using primary cultures of cerebral cortex neurons from fetal rats, we showed that exposure to the neurotensin agonist JMV 449 (1 nM) decreased (−43%) the amount of NT1 receptor mRNA measured by reverse transcription-PCR, an effect that was abolished by the non-peptide NT1 receptor antagonist SR 48692 (1 μM). However, daily injection of SR 48692 to rat pups from birth for 5, 9 or 15 days, did not modify [125I]neurotensin binding in brain membrane homogenates. Moreover, postnatal blockade of neurotensin transmission did not alter the density and distribution of NT1 receptors assessed by quantitative autoradiography nor NT1 receptor mRNA expression measured by in situ hybridization in the cerebral cortex, caudate-putamen and midbrain. These results suggest that although NT1 receptor expression can be regulated in vitro by the agonist at an early developmental stage, neurotensin is not a major factor in the establishment of the ontogenetic pattern of these receptors in the rat brain. PMID:10797539

Astrocyte Hypertrophy and Microglia Activation in the Rat Auditory Midbrain Is Induced by Electrical Intracochlear Stimulation.

PubMed

Rosskothen-Kuhl, Nicole; Hildebrandt, Heika; Birkenhäger, Ralf; Illing, Robert-Benjamin

2018-01-01

Neuron-glia interactions contribute to tissue homeostasis and functional plasticity in the mammalian brain, but it remains unclear how this is achieved. The potential of central auditory brain tissue for stimulation-dependent cellular remodeling was studied in hearing-experienced and neonatally deafened rats. At adulthood, both groups received an intracochlear electrode into the left cochlea and were continuously stimulated for 1 or 7 days after waking up from anesthesia. Normal hearing and deafness were assessed by auditory brainstem responses (ABRs). The effectiveness of stimulation was verified by electrically evoked ABRs as well as immunocytochemistry and in situ hybridization for the immediate early gene product Fos on sections through the auditory midbrain containing the inferior colliculus (IC). Whereas hearing-experienced animals showed a tonotopically restricted Fos response in the IC contralateral to electrical intracochlear stimulation, Fos-positive neurons were found almost throughout the contralateral IC in deaf animals. In deaf rats, the Fos response was accompanied by a massive increase of GFAP indicating astrocytic hypertrophy, and a local activation of microglial cells identified by IBA1. These glia responses led to a noticeable increase of neuron-glia approximations. Moreover, staining for the GABA synthetizing enzymes GAD65 and GAD67 rose significantly in neuronal cell bodies and presynaptic boutons in the contralateral IC of deaf rats. Activation of neurons and glial cells and tissue re-composition were in no case accompanied by cell death as would have been apparent by a Tunel reaction. These findings suggest that growth and activity of glial cells is crucial for the local adjustment of neuronal inhibition to neuronal excitation.

Astrocyte Hypertrophy and Microglia Activation in the Rat Auditory Midbrain Is Induced by Electrical Intracochlear Stimulation

PubMed Central

Rosskothen-Kuhl, Nicole; Hildebrandt, Heika; Birkenhäger, Ralf; Illing, Robert-Benjamin

2018-01-01

Neuron–glia interactions contribute to tissue homeostasis and functional plasticity in the mammalian brain, but it remains unclear how this is achieved. The potential of central auditory brain tissue for stimulation-dependent cellular remodeling was studied in hearing-experienced and neonatally deafened rats. At adulthood, both groups received an intracochlear electrode into the left cochlea and were continuously stimulated for 1 or 7 days after waking up from anesthesia. Normal hearing and deafness were assessed by auditory brainstem responses (ABRs). The effectiveness of stimulation was verified by electrically evoked ABRs as well as immunocytochemistry and in situ hybridization for the immediate early gene product Fos on sections through the auditory midbrain containing the inferior colliculus (IC). Whereas hearing-experienced animals showed a tonotopically restricted Fos response in the IC contralateral to electrical intracochlear stimulation, Fos-positive neurons were found almost throughout the contralateral IC in deaf animals. In deaf rats, the Fos response was accompanied by a massive increase of GFAP indicating astrocytic hypertrophy, and a local activation of microglial cells identified by IBA1. These glia responses led to a noticeable increase of neuron–glia approximations. Moreover, staining for the GABA synthetizing enzymes GAD65 and GAD67 rose significantly in neuronal cell bodies and presynaptic boutons in the contralateral IC of deaf rats. Activation of neurons and glial cells and tissue re-composition were in no case accompanied by cell death as would have been apparent by a Tunel reaction. These findings suggest that growth and activity of glial cells is crucial for the local adjustment of neuronal inhibition to neuronal excitation. PMID:29520220

MicroRNA profiling and the role of microRNA-132 in neurodegeneration using a rat model.

PubMed

Lungu, Gina; Stoica, George; Ambrus, Andy

2013-10-11

MicroRNAs (miRs) are endogenous small RNAs that regulate gene expression at the post-transcriptional level by mediating mRNA degradation or transcriptional inhibition. MiRs were implicated in the pathogenesis of numerous neurodegenerative diseases, including Parkinson's disease (PD). In this study we analyzed the possible role of miRs in the neurodegenerative process in a spontaneous autosomal recessive rat model for neurodegeneration developed in our laboratory. To investigate the role of miRs in the etiology of PD, we conducted miR expression profiling using microarrays. We found 20 miRs that are deregulated in affected rats and many of these are implicated in neurodegenerative disease, including PD. In this study we were particularly interested in the expression of miR-132, a miR that has been reported to be highly expressed in neurons, and to have a potential role in neurodegenerative diseases. We found a significant increase in miR-132 in affected rats by microarray and the result was confirmed by qPCR. Next we analyzed one of the known downstream targets of miR-132, nuclear receptor related 1 protein (Nurr1), which is essential in neurogenesis of midbrain dopaminergic neurons. Western blot analysis and immunohistochemistry revealed a significant decrease in Nurr1 protein expression in the mesencephalic neurons. Finally, we found a significant decrease in both serum and mesencephalon brain tissue of brain-derived neurotrophic factor (BDNF), which is known to be a direct target of Nurr1. Taken together, our findings suggest that miR-132 can regulate Nurr1 levels and might influence the development and function of midbrain dopaminergic neurons. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Midbrain dopamine neurons regulate preprotachykinin-A mRNA expression in the rat forebrain during development.

PubMed

Brené, S; Lindefors, N; Persson, H

1992-06-01

Intracerebroventricular 6-hydroxydopamine injections were performed at postnatal days 3 and 6 in animals pretreated with the norepinephrine uptakeblocker desimipramine in order to generate a selective lesion of dopamine neurons. In situ hybridization was then used to analyze preprotachykinin-A (PPT-A) mRNA expression in the lesioned as well as in saline-injected control animals. The midbrain dopaminergic lesion caused a 22-25% increase in the level of PPT-A mRNA in cingulate cortex and frontoparietal cortex when analysed at 2 weeks of age, compared to saline-injected control animals. In contrast, the lesion caused no change in PPT-A mRNA expression in the neonatal caudate-putamen. These results indicate that dopamine neurons downregulate the expression of PPT-A mRNA specifically in cingulate cortex and frontoparietal cortex during early postnatal brain development. In the adult rat forebrain, lesioned at P3 and P6, no change in the level of PPT-A mRNA was seen in cingulate cortex and frontoparietal cortex. However, a 29% decrease in PPT-A mRNA was seen in the lateral caudate-putamen with no significant change in neurons of medial caudate-putamen. Thus, dopamine neurons appears to exert a region specific influence on PPT-A mRNA expression during brain development.

The evolution of primary progressive apraxia of speech

PubMed Central

Duffy, Joseph R.; Strand, Edythe A.; Machulda, Mary M.; Senjem, Matthew L.; Gunter, Jeffrey L.; Schwarz, Christopher G.; Reid, Robert I.; Spychalla, Anthony J.; Lowe, Val J.; Jack, Clifford R.; Whitwell, Jennifer L.

2014-01-01

Primary progressive apraxia of speech is a recently described neurodegenerative disorder in which patients present with an isolated apraxia of speech and show focal degeneration of superior premotor cortex. Little is known about how these individuals progress over time, making it difficult to provide prognostic estimates. Thirteen subjects with primary progressive apraxia of speech underwent two serial comprehensive clinical and neuroimaging evaluations 2.4 years apart [median age of onset = 67 years (range: 49–76), seven females]. All underwent detailed speech and language, neurological and neuropsychological assessments, and magnetic resonance imaging, diffusion tensor imaging and 18F-fluorodeoxyglucose positron emission tomography at both baseline and follow-up. Rates of change of whole brain, ventricle, and midbrain volumes were calculated using the boundary-shift integral and atlas-based parcellation, and rates of regional grey matter atrophy were assessed using tensor-based morphometry. White matter tract degeneration was assessed on diffusion-tensor imaging at each time-point. Patterns of hypometabolism were assessed at the single subject-level. Neuroimaging findings were compared with a cohort of 20 age, gender, and scan-interval matched healthy controls. All subjects developed extrapyramidal signs. In eight subjects the apraxia of speech remained the predominant feature. In the other five there was a striking progression of symptoms that had evolved into a progressive supranuclear palsy-like syndrome; they showed a combination of severe parkinsonism, near mutism, dysphagia with choking, vertical supranuclear gaze palsy or slowing, balance difficulties with falls and urinary incontinence, and one was wheelchair bound. Rates of whole brain atrophy (1.5% per year; controls = 0.4% per year), ventricular expansion (8.0% per year; controls = 3.3% per year) and midbrain atrophy (1.5% per year; controls = 0.1% per year) were elevated (P ≤ 0.001) in all 13, compared to controls. Increased rates of brain atrophy over time were observed throughout the premotor cortex, as well as prefrontal cortex, motor cortex, basal ganglia and midbrain, while white matter tract degeneration spread into the splenium of the corpus callosum and motor cortex white matter. Hypometabolism progressed over time in almost all subjects. These findings demonstrate that some subjects with primary progressive apraxia of speech will rapidly evolve and develop a devastating progressive supranuclear palsy-like syndrome ∼ 5 years after onset, perhaps related to progressive involvement of neocortex, basal ganglia and midbrain. These findings help improve our understanding of primary progressive apraxia of speech and provide some important prognostic guidelines. PMID:25113789

Edaravone Guards Dopamine Neurons in a Rotenone Model for Parkinson's Disease

PubMed Central

Chen, Chunnuan; Huang, Jinsha; Zhao, Ying; Zhang, Zhentao; Qiao, Xian; Feng, Yuan; Reesaul, Harrish; Zhang, Yongxue; Sun, Shenggang; Lin, Zhicheng; Wang, Tao

2011-01-01

3-methyl-1-phenyl-2-pyrazolin-5-one (edaravone), an effective free radical scavenger, provides neuroprotection in stroke models and patients. In this study, we investigated its neuroprotective effects in a chronic rotenone rat model for Parkinson's disease. Here we showed that a five-week treatment with edaravone abolished rotenone's activity to induce catalepsy, damage mitochondria and degenerate dopamine neurons in the midbrain of rotenone-treated rats. This abolishment was attributable at least partly to edaravone's inhibition of rotenone-induced reactive oxygen species production or apoptotic promoter Bax expression and its up-regulation of the vesicular monoamine transporter 2 (VMAT2) expression. Collectively, edaravone may provide novel clinical therapeutics for PD. PMID:21677777

Brain-derived neurotrophic factor (BDNF) and its precursor (proBDNF) in genetically defined fear-induced aggression.

PubMed

Ilchibaeva, Tatiana V; Kondaurova, Elena M; Tsybko, Anton S; Kozhemyakina, Rimma V; Popova, Nina K; Naumenko, Vladimir S

2015-09-01

The brain-derived neurotrophic factor (BDNF), its precursor (proBDNF) and BDNF mRNA levels were studied in the brain of wild rats selectively bred for more than 70 generations for either high level or for the lack of affective aggressiveness towards man. Significant increase of BDNF mRNA level in the frontal cortex and increase of BDNF level in the hippocampus of aggressive rats was revealed. In the midbrain and hippocampus of aggressive rats proBDNF level was increased, whereas BDNF/proBDNF ratio was reduced suggesting the prevalence and increased influence of proBDNF in highly aggressive rats. In the frontal cortex, proBDNF level in aggressive rats was decreased. Thus, considerable structure-specific differences in BDNF and proBDNF levels as well as in BDNF gene expression between highly aggressive and nonaggressive rats were shown. The data suggested the implication of BDNF and its precursor proBDNF in the mechanism of aggressiveness and in the creation of either aggressive or nonaggressive phenotype. Copyright © 2015 Elsevier B.V. All rights reserved.

Air pollution & the brain: Subchronic diesel exhaust exposure causes neuroinflammation and elevates early markers of neurodegenerative disease

PubMed Central

2011-01-01

Background Increasing evidence links diverse forms of air pollution to neuroinflammation and neuropathology in both human and animal models, but the effects of long-term exposures are poorly understood. Objective We explored the central nervous system consequences of subchronic exposure to diesel exhaust (DE) and addressed the minimum levels necessary to elicit neuroinflammation and markers of early neuropathology. Methods Male Fischer 344 rats were exposed to DE (992, 311, 100, 35 and 0 μg PM/m3) by inhalation over 6 months. Results DE exposure resulted in elevated levels of TNFα at high concentrations in all regions tested, with the exception of the cerebellum. The midbrain region was the most sensitive, where exposures as low as 100 μg PM/m3 significantly increased brain TNFα levels. However, this sensitivity to DE was not conferred to all markers of neuroinflammation, as the midbrain showed no increase in IL-6 expression at any concentration tested, an increase in IL-1β at only high concentrations, and a decrease in MIP-1α expression, supporting that compensatory mechanisms may occur with subchronic exposure. Aβ42 levels were the highest in the frontal lobe of mice exposed to 992 μg PM/m3 and tau [pS199] levels were elevated at the higher DE concentrations (992 and 311 μg PM/m3) in both the temporal lobe and frontal lobe, indicating that proteins linked to preclinical Alzheimer's disease were affected. α Synuclein levels were elevated in the midbrain in response to the 992 μg PM/m3 exposure, supporting that air pollution may be associated with early Parkinson's disease-like pathology. Conclusions Together, the data support that the midbrain may be more sensitive to the neuroinflammatory effects of subchronic air pollution exposure. However, the DE-induced elevation of proteins associated with neurodegenerative diseases was limited to only the higher exposures, suggesting that air pollution-induced neuroinflammation may precede preclinical markers of neurodegenerative disease in the midbrain. PMID:21864400

Electronical Stimulation of the Midbrain to Promote Recovery from Traumatic Forebrain Injury

DTIC Science & Technology

2010-05-01

learning in a water maze test and normalized sensorimotor performance (movements in a transparent cylinder ). Higher rates of stimulation (20 Hz) or...descending from the nucleus raphe magnus of the medulla could enhance anatomical and behavioral recovery from spinal cord injury in rats if started within...days 4 and 5) and in the cylinder sensorimotor test has been completed for groups A-D. f-h) Months 5-7. “Begin repeat behavioral testing in group

Electrophysiological effects of monoamine oxidase inhibition on rat midbrain dopaminergic neurones: an in vitro study.

PubMed Central

Mercuri, N. B.; Bonci, A.; Siniscalchi, A.; Stefani, A.; Calabresi, P.; Bernardi, G.

1996-01-01

1 The effects of the inhibition of monoamine oxidase (MAO) type A and B have been evaluated on the spontaneous firing activity of the dopaminergic (principal) neurones of the rat midbrain intracellularly recorded from a slice preparation. 2 The non-specific MAO inhibitor, pargyline, superfused at a concentration of 10-100 microM, decreased or abolished the spontaneous firing discharge of the principal neurons in the subtantia nigra pars compacta and ventral tegmental area. This effect had a slow onset and appeared to be sustained. 3 The administration of the dopamine D2/3 receptor antagonist, sulpiride (100-300 nM), antagonized the pargyline-induced effect, while the superfusion of the dopamine D1 receptor antagonist, SCH 23390 (1-3 microM) did not counteract the induced inhibition of the firing rate. 4 The inhibitor for the MAO A, clorgyline (30-100 microM), reduced the firing rate of the dopaminergic neurones. A similar depressant effect was also observed when a MAO B inhibitor, deprenyl (30-100 microM), was applied. Lower concentrations of both drugs (300 nM-10 microM) did not produce consistent effects on neuronal discharge. 5 Our data suggest that only the blockade of both types of MAO enzymes favours the inhibitory action of endogenous dopamine on somato-dendritic D2/3 autoreceptors. PMID:8821544

Cocaine-Induced Endocannabinoid Mobilization in the Ventral Tegmental Area.

PubMed

Wang, Huikun; Treadway, Tyler; Covey, Daniel P; Cheer, Joseph F; Lupica, Carl R

2015-09-29

Cocaine is a highly addictive drug that acts upon the brain's reward circuitry via the inhibition of monoamine uptake. Endogenous cannabinoids (eCB) are lipid molecules released from midbrain dopamine (DA) neurons that modulate cocaine's effects through poorly understood mechanisms. We find that cocaine stimulates release of the eCB, 2-arachidonoylglycerol (2-AG), in the rat ventral midbrain to suppress GABAergic inhibition of DA neurons, through activation of presynaptic cannabinoid CB1 receptors. Cocaine mobilizes 2-AG via inhibition of norepinephrine uptake and promotion of a cooperative interaction between Gq/11-coupled type-1 metabotropic glutamate and α1-adrenergic receptors to stimulate internal calcium stores and activate phospholipase C. The disinhibition of DA neurons by cocaine-mobilized 2-AG is also functionally relevant because it augments DA release in the nucleus accumbens in vivo. Our results identify a mechanism through which the eCB system can regulate the rewarding and addictive properties of cocaine. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Neural Processing of Target Distance by Echolocating Bats: Functional Roles of the Auditory Midbrain

PubMed Central

Wenstrup, Jeffrey J.; Portfors, Christine V.

2011-01-01

Using their biological sonar, bats estimate distance to avoid obstacles and capture moving prey. The primary distance cue is the delay between the bat's emitted echolocation pulse and the return of an echo. The mustached bat's auditory midbrain (inferior colliculus, IC) is crucial to the analysis of pulse-echo delay. IC neurons are selective for certain delays between frequency modulated (FM) elements of the pulse and echo. One role of the IC is to create these “delay-tuned”, “FM-FM” response properties through a series of spectro-temporal integrative interactions. A second major role of the midbrain is to project target distance information to many parts of the brain. Pathways through auditory thalamus undergo radical reorganization to create highly ordered maps of pulse-echo delay in auditory cortex, likely contributing to perceptual features of target distance analysis. FM-FM neurons in IC also project strongly to pre-motor centers including the pretectum and the pontine nuclei. These pathways may contribute to rapid adjustments in flight, body position, and sonar vocalizations that occur as a bat closes in on a target. PMID:21238485

Regulation of neuropeptide Y gene expression in rat brain.

PubMed

Lindefors, N; Brené, S; Herrera-Marschitz, M; Persson, H

1990-01-01

NPY mRNA expression was studied in rat brain using in situ hybridization and RNA blot analysis. Transsynaptic regulation of NPY gene expression was specifically studied in caudate-putamen and frontoparietal (somatosensory) cortex of rats with unilateral lesion of midbrain dopamine neurons and in sham-injected animals. NPY mRNA expression in these two brain regions and the regulation of midbrain dopamine neurons were compared with that of SOM, PPT, CCK and GAD mRNA expression. Neurons expressing NPY and SOM mRNA showed a similar distribution and the expression of both NPY and SOM appears to be regulated by dopamine in a similar fashion. Following a unilateral dopamine deafferentation, the numerical density of both NPY and SOM mRNA expressing neurons almost doubled in the lesioned rat caudate-putamen with no change in the average grain density over positive neurons. Hence, in the intact caudate-putamen dopamine appears to normally suppress expression of these two neuropeptide genes. An activation of both NPY and SOM mRNA expression in many non- or low-expressing neurons is seen when the level of dopamine is decreased. In the frontoparietal cortex, on the other hand, dopamine appears to stimulate NPY and SOM gene expression. RNA blot analysis shows clear-cut changes of NPY mRNA levels in both caudate-putamen and frontoparietal cortex consistent with the changes observed using in situ hybridization. No evidence was found for a change in CCK mRNA expression by the dopamine deafferentation, while PPT mRNA expression decreased in the deafferented caudate-putamen. Consequently, dopamine exerts dissimilar effects on the expression of different neuropeptide genes, that in turn do not respond in the same way in different brain regions. Indirect evidence is also presented indicating that dopamine regulates NPY mRNA expression in a subpopulation of neurons that possibly also express GAD mRNA, both in caudate-putamen and in frontoparietal cortex.

Neuromelanin imaging and midbrain volumetry in progressive supranuclear palsy and Parkinson's disease.

PubMed

Taniguchi, Daisuke; Hatano, Taku; Kamagata, Koji; Okuzumi, Ayami; Oji, Yutaka; Mori, Akio; Hori, Masaaki; Aoki, Shigeki; Hattori, Nobutaka

2018-05-14

Background Nigral degeneration patterns differ between PSP and PD. However, the relationship between nigral degeneration and midbrain atrophy in PSP remains unclear. Objective We analyzed differences and relationships between nigral degeneration and midbrain atrophy in PSP and PD. Methods Neuromelanin-sensitive MRI and midbrain volumetry were performed in 11 PSP patients, 24 PD patients, and 10 controls to measure the neuromelanin-sensitive SNpc area and midbrain volume. Results The neuromelanin-sensitive SNpc area and midbrain volume were significantly smaller in PSP patients compared with PD patients and controls. Motor deficits were inversely correlated with neuromelanin-sensitive SNpc area in PD, but not PSP patients. There was no significant correlation between neuromelanin-sensitive SNpc area and midbrain volume in either disease group. Midbrain volumetry discriminated PSP from PD. Diagnostic accuracy was improved when neuromelanin-sensitive MRI analysis was added. Conclusions Neuromelanin-sensitive MRI and midbrain volumetry may reflect the clinical and pathological characteristics of PSP and PD. Combining neuromelanin-sensitive MRI and midbrain volumetry may be useful for differentiating PSP from PD. © 2018 International Parkinson and Movement Disorder Society. © 2018 International Parkinson and Movement Disorder Society.

Electro-acupuncture stimulation acts on the basal ganglia output pathway to ameliorate motor impairment in Parkinsonian model rats.

PubMed

Jia, Jun; Li, Bo; Sun, Zuo-Li; Yu, Fen; Wang, Xuan; Wang, Xiao-Min

2010-04-01

The role of electro-acupuncture (EA) stimulation on motor symptoms in Parkinson's disease (PD) has not been well studied. In a rat hemiparkinsonian model induced by unilateral transection of the medial forebrain bundle (MFB), EA stimulation improved motor impairment in a frequency-dependent manner. Whereas EA stimulation at a low frequency (2 Hz) had no effect, EA stimulation at a high frequency (100 Hz) significantly improved motor coordination. However, neither low nor high EA stimulation could significantly enhance dopamine levels in the striatum. EA stimulation at 100 Hz normalized the MFB lesion-induced increase in midbrain GABA content, but it had no effect on GABA content in the globus pallidus. These results suggest that high-frequency EA stimulation improves motor impairment in MFB-lesioned rats by increasing GABAergic inhibition in the output structure of the basal ganglia.

The evolution of primary progressive apraxia of speech.

PubMed

Josephs, Keith A; Duffy, Joseph R; Strand, Edythe A; Machulda, Mary M; Senjem, Matthew L; Gunter, Jeffrey L; Schwarz, Christopher G; Reid, Robert I; Spychalla, Anthony J; Lowe, Val J; Jack, Clifford R; Whitwell, Jennifer L

2014-10-01

Primary progressive apraxia of speech is a recently described neurodegenerative disorder in which patients present with an isolated apraxia of speech and show focal degeneration of superior premotor cortex. Little is known about how these individuals progress over time, making it difficult to provide prognostic estimates. Thirteen subjects with primary progressive apraxia of speech underwent two serial comprehensive clinical and neuroimaging evaluations 2.4 years apart [median age of onset = 67 years (range: 49-76), seven females]. All underwent detailed speech and language, neurological and neuropsychological assessments, and magnetic resonance imaging, diffusion tensor imaging and (18)F-fluorodeoxyglucose positron emission tomography at both baseline and follow-up. Rates of change of whole brain, ventricle, and midbrain volumes were calculated using the boundary-shift integral and atlas-based parcellation, and rates of regional grey matter atrophy were assessed using tensor-based morphometry. White matter tract degeneration was assessed on diffusion-tensor imaging at each time-point. Patterns of hypometabolism were assessed at the single subject-level. Neuroimaging findings were compared with a cohort of 20 age, gender, and scan-interval matched healthy controls. All subjects developed extrapyramidal signs. In eight subjects the apraxia of speech remained the predominant feature. In the other five there was a striking progression of symptoms that had evolved into a progressive supranuclear palsy-like syndrome; they showed a combination of severe parkinsonism, near mutism, dysphagia with choking, vertical supranuclear gaze palsy or slowing, balance difficulties with falls and urinary incontinence, and one was wheelchair bound. Rates of whole brain atrophy (1.5% per year; controls = 0.4% per year), ventricular expansion (8.0% per year; controls = 3.3% per year) and midbrain atrophy (1.5% per year; controls = 0.1% per year) were elevated (P ≤ 0.001) in all 13, compared to controls. Increased rates of brain atrophy over time were observed throughout the premotor cortex, as well as prefrontal cortex, motor cortex, basal ganglia and midbrain, while white matter tract degeneration spread into the splenium of the corpus callosum and motor cortex white matter. Hypometabolism progressed over time in almost all subjects. These findings demonstrate that some subjects with primary progressive apraxia of speech will rapidly evolve and develop a devastating progressive supranuclear palsy-like syndrome ∼ 5 years after onset, perhaps related to progressive involvement of neocortex, basal ganglia and midbrain. These findings help improve our understanding of primary progressive apraxia of speech and provide some important prognostic guidelines. © The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Lumbee traditional medicine: Neuroprotective activities of medicinal plants used to treat Parkinson's disease-related symptoms.

PubMed

de Rus Jacquet, Aurélie; Timmers, Michael; Ma, Sin Ying; Thieme, Andrew; McCabe, George P; Vest, Jay Hansford C; Lila, Mary Ann; Rochet, Jean-Christophe

2017-07-12

Parkinson's disease (PD) is a neurodegenerative disorder characterized by a loss of dopaminergic neurons in the substantia nigra pars compacta and the presence in surviving neurons of Lewy body inclusions enriched with aggregated forms of the presynaptic protein α-synuclein (aSyn). Although current therapies provide temporary symptomatic relief, they do not slow the underlying neurodegeneration in the midbrain. In this study, we analyzed contemporary herbal medicinal practices used by members of the Lumbee tribe to treat PD-related symptoms, in an effort to identify safe and effective herbal medicines to treat PD. The aims of this study were to (i) document medicinal plants used by Lumbee Indians to treat PD and PD-related symptoms, and (ii) characterize a subset of plant candidates in terms of their ability to alleviate neurotoxicity elicited by PD-related insults and their potential mechanisms of neuroprotection. Interviews of Lumbee healers and local people were carried out in Pembroke, North Carolina, and in surrounding towns. Plant samples were collected and prepared as water extracts for subsequent analysis. Extracts were characterized in terms of their ability to induce activation of the nuclear factor E2-related factor 2 (Nrf2) antioxidant response in cortical astrocytes. An extract prepared from Sambucus caerulea flowers (elderflower extract) was further examined for the ability to induce Nrf2-mediated transcription in induced pluripotent stem cell (iPSC)-derived astrocytes and primary midbrain cultures, to ameliorate mitochondrial dysfunction, and to alleviate rotenone- or aSyn-mediated neurotoxicity. The ethnopharmacological interviews resulted in the documentation of 32 medicinal plants used to treat PD-related symptoms and 40 plants used to treat other disorders. A polyphenol-rich extract prepared from elderflower activated the Nrf2-mediated antioxidant response in cortical astrocytes, iPSC-derived astrocytes, and primary midbrain cultures, apparently via the inhibition of Nrf2 degradation mediated by the ubiquitin proteasome system. Furthermore, the elderflower extract rescued mitochondrial functional deficits in a neuronal cell line and alleviated neurotoxicity elicited by rotenone and aSyn in primary midbrain cultures. These results highlight potential therapeutic benefits of botanical extracts used in traditional Lumbee medicine, and they provide insight into mechanisms by which an elderflower extract could suppress neurotoxicity elicited by environmental and genetic PD-related insults. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Pathological Laughter as a Symptom of Midbrain Infarction

PubMed Central

Dabby, Ron; Watemberg, Nathan; Lampl, Yair; Eilam, Anda; Rapaport, Abraham; Sadeh, Menachem

2004-01-01

Pathological laughter is an uncommon symptom usually caused by bilateral, diffuse cerebral lesions. It has rarely been reported in association with isolated cerebral lesions. Midbrain involvement causing pathological laughter is extremely unusual. We describe three patients who developed pathological laughter after midbrain and pontine-midbrain infarction. In two patients a small infarction in the left paramedian midbrain was detected, whereas the third one sustained a massive bilateral pontine infarction extending to the midbrain. Laughter heralded stroke by one day in one patient and occurred as a delayed phenomenon three months after stroke in another. Pathological laughter ceased within a few days in two patients and was still present at a two year follow-up in the patient with delayed-onset laughter. Pathological laughter can herald midbrain infarction or follow stroke either shortly after onset of symptoms or as a delayed phenomenon. Furthermore, small unilateral midbrain infarctions can cause this rare complication. PMID:15706050

Effects of drugs of abuse on putative rostromedial tegmental neurons, inhibitory afferents to midbrain dopamine cells.

PubMed

Lecca, Salvatore; Melis, Miriam; Luchicchi, Antonio; Ennas, Maria Grazia; Castelli, Maria Paola; Muntoni, Anna Lisa; Pistis, Marco

2011-02-01

Recent findings have underlined the rostromedial tegmental nucleus (RMTg), a structure located caudally to the ventral tegmental area, as an important site involved in the mechanisms of aversion. RMTg contains γ-aminobutyric acid neurons responding to noxious stimuli, densely innervated by the lateral habenula and providing a major inhibitory projection to reward-encoding midbrain dopamine (DA) neurons. One of the key features of drug addiction is the perseverance of drug seeking in spite of negative and unpleasant consequences, likely mediated by response suppression within neural pathways mediating aversion. To investigate whether the RMTg has a function in the mechanisms of addicting drugs, we studied acute effects of morphine, cocaine, the cannabinoid agonist WIN55212-2 (WIN), and nicotine on putative RMTg neurons. We utilized single unit extracellular recordings in anesthetized rats and whole-cell patch-clamp recordings in brain slices to identify and characterize putative RMTg neurons and their responses to drugs of abuse. Morphine and WIN inhibited both firing rate in vivo and excitatory postsynaptic currents (EPSCs) evoked by stimulation of rostral afferents in vitro, whereas cocaine inhibited discharge activity without affecting EPSC amplitude. Conversely, nicotine robustly excited putative RMTg neurons and enhanced EPSCs, an effect mediated by α7-containing nicotinic acetylcholine receptors. Our results suggest that activity of RMTg neurons is profoundly influenced by drugs of abuse and, as important inhibitory afferents to midbrain DA neurons, they might take place in the complex interplay between the neural circuits mediating aversion and reward.

The sleep-modulating peptide orexin-B protects midbrain dopamine neurons from degeneration, alone or in cooperation with nicotine.

PubMed

Guerreiro, Serge; Florence, Clélia; Rousseau, Erwann; Hamadat, Sabah; Hirsch, Etienne C; Michel, Patrick P

2015-01-01

To determine whether orexinergic hypothalamic peptides can influence the survival of brainstem dopamine (DA) neurons, we used a model system of rat midbrain cultures in which DA neurons degenerate spontaneously and progressively as they mature. We established that orexin (OX)-B provides partial but significant protection to spontaneously dying DA neurons, whereas the homologous peptide OXA has only marginal effects. Importantly, DA neurons rescued by OXB accumulated DA efficiently by active transport, suggesting that they were functional. G-protein-coupled OX1 and OX2 receptors were both present on DA neurons, but the protective effect of OXB was attributable solely to OX2 receptors; a selective inhibitor of this receptor subtype, N-ethyl-2-[(6-methoxy-3-pyridinyl)[(2-methylphenyl)sulfonyl]amino]-N-(3-pyridinylmethyl)-acetamide (EMPA), suppressed this effect, whereas a selective agonist, [Ala(11), d-Leu(15)]OXB, reproduced it. Survival promotion by OXB required intracellular calcium mobilization via inositol-1,4,5-triphosphate and ryanodine receptors. Nicotine, a well known neuroprotective molecule for DA neurons, improved OXB-mediated rescue through the activation of α-bungarotoxin-sensitive (presumably α7) nicotinic receptors, although nicotine had no effect on its own. Altogether, our data suggest that the loss of hypothalamic orexinergic neurons that occurs in Parkinson's disease might confer an increased vulnerability to midbrain DA neurons in this disorder. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Time-dependent effects of repeated THC treatment on dopamine D2/3 receptor-mediated signalling in midbrain and striatum.

PubMed

Tournier, Benjamin B; Tsartsalis, Stergios; Dimiziani, Andrea; Millet, Philippe; Ginovart, Nathalie

2016-09-15

This study examined the time-course of alterations in levels and functional sensitivities of dopamine D2/3 receptors (D2/3R) during the course and up to 6 weeks following cessation of chronic treatment with Delta(9)-Tetrahydrocannabinol (THC) in rats. THC treatment led to an increase in D2/3R levels in striatum, as assessed using [(3)H]-(+)-PHNO, that was readily observable after one week of treatment, remained stably elevated during the subsequent 2 weeks of treatment, but fully reversed within 2 weeks of THC discontinuation. THC-induced D2/3R alterations were more pronounced and longer lasting in the dopamine cell body regions of the midbrain, wherein [(3)H]-(+)-PHNO binding was still elevated at 2 weeks but back to control values at 6 weeks after THC cessation. Parallel analyses of the psychomotor effects of pre- and post-synaptic doses of quinpirole also showed a pattern of D2/3R functional supersensitivity indicative of more rapid subsidence in striatum than in midbrain following drug cessation. These results indicate that chronic THC is associated with a biochemical and functional sensitization of D2/3R signaling, that these responses show a region-specific temporal pattern and are fully reversible following drug discontinuation. These results suggest that an increased post-synaptic D2/3R function and a decreased DA presynaptic signaling, mediated by increased D2/3R autoinhibition, may predominate during distinct phases of withdrawal and may contribute both to the mechanisms leading to relapse and to cannabinoid withdrawal symptoms. The different rates of normalization of D2/3R function in striatum and midbrain may be critical information for the development of new pharmacotherapies for cannabis dependence. Copyright © 2016 Elsevier B.V. All rights reserved.

Semaphorin 3C Released from a Biocompatible Hydrogel Guides and Promotes Axonal Growth of Rodent and Human Dopaminergic Neurons

PubMed Central

Carballo-Molina, Oscar A.; Sánchez-Navarro, Andrea; López-Ornelas, Adolfo; Lara-Rodarte, Rolando; Salazar, Patricia; Campos-Romo, Aurelio; Ramos-Mejía, Verónica

2016-01-01

Cell therapy in experimental models of Parkinson's disease replaces the lost dopamine neurons (DAN), but we still need improved methods to guide dopaminergic axons (DAx) of grafted neurons to make proper connections. The protein Semaphorin 3C (Sema3C) attracts DAN axons and enhances their growth. In this work, we show that the hydrogel PuraMatrix, a self-assembling peptide-based matrix, incorporates Sema3C and releases it steadily during 4 weeks. We also tested if hydrogel-delivered Sema3C attracts DAx using a system of rat midbrain explants embedded in collagen gels. We show that Sema3C released by this hydrogel attracts DAx, in a similar way to pretectum, which is known to attract growing DAN axons. We assessed the effect of Sema3C on the growth of DAx using microfluidic devices. DAN from rat midbrain or those differentiated from human embryonic stem cells showed enhanced axonal extension when exposed to hydrogel-released Sema3C, similar to soluble Sema3C. Notably, DAN of human origin express the cognate Sema3C receptors, Neuropilin1 and Neuropilin2. These results show that PuraMatrix is able to incorporate and release Sema3C, and such delivery guides and promotes the axonal growth of DAN. This biocompatible hydrogel might be useful as a Sema3C carrier for in vivo studies in parkinsonian animal models. PMID:27174503

Lipopolysaccharide-induced dopaminergic cell death in rat midbrain slice cultures: role of inducible nitric oxide synthase and protection by indomethacin.

PubMed

Shibata, Haruki; Katsuki, Hiroshi; Nishiwaki, Mayumi; Kume, Toshiaki; Kaneko, Shuji; Akaike, Akinori

2003-09-01

Glial cell activation associated with inflammatory reaction may contribute to pathogenic processes of neurodegenerative disorders, through production of several cytotoxic molecules. We investigated the consequences of glial activation by interferon-gamma (IFN-gamma)/lipopolysaccharide (LPS) in rat midbrain slice cultures. Application of IFN-gamma followed by LPS caused dopaminergic cell death and accompanying increases in nitrite production and lactate dehydrogenase release. Aminoguanidine, an inhibitor of inducible nitric oxide synthase (iNOS), or SB203580, an inhibitor of p38 mitogen-activated protein kinase, prevented dopaminergic cell loss as well as nitrite production. SB203580 also suppressed expression of iNOS and cyclooxygenase-2 (COX-2) induced by IFN-gamma/LPS. A COX inhibitor indomethacin protected dopaminergic neurons from IFN-gamma/LPS-induced injury, whereas selective COX-2 inhibitors such as NS-398 and nimesulide did not. Notably, indomethacin was able to attenuate neurotoxicity of a nitric oxide (NO) donor. Neutralizing antibodies against tumour necrosis factor-alpha and interleukin-1beta did not inhibit dopaminergic cell death caused by IFN-gamma/LPS, although combined application of these antibodies blocked lactate dehydrogenase release and decrease in the number of non-dopaminergic neurons. These results indicate that iNOS-derived NO plays a crucial role in IFN-gamma/LPS-induced dopaminergic cell death, and that indomethacin exerts protective effect by mechanisms probably related to NO neurotoxicity rather than through COX inhibition.

VMAT2-mediated neurotransmission from midbrain leptin receptor neurons in feeding regulation

USDA-ARS?s Scientific Manuscript database

Leptin receptors (LepRs) expressed in the midbrain contribute to the action of leptin on feeding regulation. The midbrain neurons release a variety of neurotransmitters including dopamine (DA), glutamate and GABA. However, which neurotransmitter mediates midbrain leptin action on feeding remains unc...

Modulation of the activity of midbrain central gray substance neurons by calcium channel agonists and antagonists in vitro.

PubMed

Yakhnitsa, V A; Pilyavskii, A I; Limansky, Y P; Bulgakova, N V

1996-01-01

Changes in the background impulse activity of midbrain central gray substance neurons have been studied on slice preparations from the rat midbrain upon application of calcium-free solution, an activator of calcium channels, BAY-K 8644 (10 nM), organic (verapamil, 40 microM; D600, 10 microM; nifedipine, 1-10 microM; amiloride, 1 microM) and inorganic (Co2+, 1.5 mM) calcium channel blockers. Besides BAY-K 8644, all the substances inhibited most of the neurons studied. Verapamil, BAY-K 8644 and Co2+ also revealed facilitatory effects. Facilitatory action of BAY-K was most effective in silent neurons and in those previously inhibited by amiloride. Latent period values of inhibition in calcium-free solution and upon application of organic and inorganic blockers have the following sequence: D600 > amiloride > verapamil > Co2+ > nifedipine > calcium-free solution. Maximum rise time had the following order: amiloride > D600 > nifedipine > verapamil > Co2+ > calcium-free solution. Complete suppression of the neuronal activity induced by amiloride lasted twice as long as that induced by calcium-free solution, Co2+ and nifedipine, and six times as long as verapamil-induced suppression. Preliminary application of calcium channel blockers reduced facilitatory and increased inhibitory effects of serotonin and substance P. Data obtained are discussed with the supposition in mind that inhibition of the function of calcium channels in central gray substance neurons could be one of the mechanisms underlying the analgesic effect of a series of neurotropic agents after their introduction into this structure.

Conditioned fear in low- and high-anxious rats is differentially regulated by cortical subcortical and midbrain 5-HT(1A) receptors.

PubMed

Ferreira, R; Nobre, M J

2014-05-30

Interactions between the prelimbic cortex and the basolateral amygdala underlie fear memory processing, mostly through acquiring and consolidating the learning of a conditioned fear. More recently, studies highlighted the role of the dorsal periaqueductal gray (DPAG) in the modulation of learning fear responses. In addition, extensive data in the literature have signaled the importance of serotonin (5-HT) on fear and anxiety. In the present study, the role of 5-HT neurotransmission of the prelimbic cortex, basolateral amygdala or the DPAG on the unconditioned and conditioned fear responses in rats previously selected as low- (LA) or high-anxious (HA) were assessed through local infusions of 5-HT itself (10nmol/0.2μl) or the selective 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT - 0.3μg/0.2μl). Behavioral analysis was conducted using the fear-potentiated startle (FPS) procedure. Dependent variables recorded were the latency and amplitude of the unconditioned startle response and FPS. Our findings suggest that, on the prelimbic cortex, 5-HT modulates the expression of conditioned fear response in HA rats and this modulation is dependent on 5-HT1A receptors. This is not true, however, for the basolateral amygdala or the DPAG. In these regions LA but not HA rats were susceptible to the anxiolytic-like effect of 5-HT1A receptor activation. It is thought that the expression of conditioned fear in HA subjects may be dependent on other 5-HT receptors, as the 5-HT1B subtype, and/or changes in other systems such as the GABA and glutamate neurotransmitters. These results increase our understanding of the rostrocaudal influence of 5-HT on the unconditioned and conditioned fear responses in LA and HA subjects and, to some extent, are in disagreement with the theoretical current that emphasizes the role of 5-HT on anxiety, mainly at the subcortical and midbrain levels. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

Effects of sarizotan in animal models of ADHD: challenging pharmacokinetic-pharmacodynamic relationships.

PubMed

Danysz, Wojciech; Flik, Gunnar; McCreary, Andrew; Tober, Carsten; Dimpfel, Wilfried; Bizot, Jean C; Kostrzewa, Richard; Brown, Russell W; Jatzke, Claudia C; Greco, Sergio; Jenssen, Ann-Kristin; Parsons, Christopher G

2015-09-01

Sarizotan 1-[(2R)-3,4-dihydro-2H-chromen-2-yl]-N-[[5-(4-fluorophenyl) pyridin-3-yl]methyl] methenamine, showed an in vivo pharmaco-EEG profile resembling that of methylphenidate which is used in attention deficit/hyperactivity disorder (ADHD). In turn, we tested sarizotan against impulsivity in juvenile rats measuring the choice for large delayed vs. a small immediate reward in a T-maze and obtained encouraging results starting at 0.03 mg/kg (plasma levels of ~11 nM). Results from rats treated neonatally with 6-hydroxydopamine (6-OHDA), also supported anti-ADHD activity although starting at 0.3 mg/kg. However, microdialysis studies revealed that free brain concentration of sarizotan at active doses were below its affinity for 5-HT1A receptors, the assumed primary target. In contrast, electrophysiological experiments in mid-brain Raphé serotonergic cells paralleled by plasma sampling showed that there was ~60% inhibition of firing rate—indicating significant activation of 5-HT1A receptors—at a plasma concentration of 76 nM. In line with this, we observed that sarizotan concentrations in brain homogenates were similar to total blood levels but over 500 fold higher than free extracellular fluid (ECF) concentrations as measured using brain microdialysis. These data suggest that sarizotan may have potential anti-ADHD effects at low doses free of the previously reported side-effects. Moreover, in this case a classical pharmacokinetic-pharmacodynamic relationship based on free brain concentrations seems to be less appropriate than target engagement pharmacodynamic readouts.

On the role of brain serotonin in expression of genetic predisposition to catalepsy in animal models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Popova, N.K.; Kulikov, A.V.

1995-06-19

The activity of the rate-limiting enzyme of serotonin biosynthesis, tryptophan hydroxylase, in the striatum but not in the hippocampus and midbrain of rats bred for predisposition to catalepsy was higher than in nonselected rats. Mice of the highly susceptible to catalepsy CBA strain also differed from other noncataleptic mouse strains by the highest tryptophan hydroxylase activity in the striatum. Inhibition of tryptophan hydroxylase with p-chlorophenylalanine and p-chloromethamphetamine drastically decreased immobility time in hereditary predisposed to catalepsy animals. A decrease in the {sup 3}H-ketanserin specific binding in the striatum of cataleptic rats and CBA mice was found. It was suggested thatmore » this decrease in 5-HT2A serotonin receptor density represented a down regulation of the receptors due to an activation of serotonergic transmission in striatum. It is suggested that hereditary catalepsy may be resulted from genetic changes in the regulation of serotonin metabolism in striatum. 32 refs., 6 figs.« less

Bilateral lesions of the medial frontal cortex disrupt recognition of social hierarchy during antiphonal communication in naked mole-rats (Heterocephalus glaber).

PubMed

Yosida, Shigeto; Okanoya, Kazuo

2012-02-01

Generation of the motor patterns of emotional sounds in mammals occurs in the periaqueductal gray matter of the midbrain and is not directly controlled by the cortex. The medial frontal cortex indirectly controls vocalizations, based on the recognition of social context. We examined whether the medial frontal cortex was responsible for antiphonal vocalization, or turn-taking, in naked mole-rats. In normal turn-taking, naked mole-rats vocalize more frequently to dominant individuals than to subordinate ones. Bilateral lesions of the medial frontal cortex disrupted differentiation of call rates to the stimulus animals, which had varied social relationships to the subject. However, medial frontal cortex lesions did not affect either the acoustic properties of the vocalizations or the timing of the vocal exchanges. This suggests that the medial frontal cortex may be involved in social cognition or decision making during turn-taking, while other regions of the brain regulate when animals vocalize and the vocalizations themselves.

Ameliorative effect of Sida cordifolia in rotenone induced oxidative stress model of Parkinson's disease.

PubMed

Khurana, Navneet; Gajbhiye, Asmita

2013-12-01

Present study focused on the evaluation of aqueous extract of Sida cordifolia (AESC), and its different fractions; hexane (HFSC), chloroform (CFSC) and aqueous (AFSC), against rotenone induced biochemical, neurochemical, histopathological and behavioral alterations in a rat model of Parkinson's disease (PD). An estimation of the level of thiobarbituric acid reactive substances (TBARS), glutathione (GSH) and catalase (CAT) along with superoxide anion generation (SAG) in different brain regions (cortex, midbrain and cerebellum) was carried out to assess biochemical changes. Behavioral evaluation tests (catalepsy, rearing behavior and posture instability) and neurochemical estimations (norepinephrine, dopamine and serotonin level) along with histopathological evaluations of different brain regions were also performed. The varying doses (50, 100, 250mg/kg; p.o.) of different test treatments (AESC, HFSC, CFSC and AFSC) were co-administered along with rotenone (2mg/kg; s.c.), for a period of 35 days to rats of various groups and compared with rotenone per se (negative control) and l-deprenyl (positive control; 10mg/kg; p.o.) treated groups for the above mentioned parameters. The increase in catalepsy and posture instability along with decrease in rearing behavior observed due to rotenone treatment was significantly attenuated by co-treatment with varying doses of AESC and AFSC. Results of the histopathological studies of different brain regions of rats showed eosinophilic lesions in the mid brain region due to rotenone treatment. The eosinophilic lesions were significantly attenuated in co-treated groups of AESC-100mg/kg and AFSC-100mg/kg. Rotenone induced oxidative damage, revealed by increased level of TBARS, SAG and decreased level of GSH and CAT in mid brain region of rats, was attenuated by the co-treatment of AESC and AFSC. The rotenone induced decrease of dopamine level in the midbrain region of rats was also attenuated by co-treatment of AESC-100mg/kg and AFSC-100mg/kg. The maximum effect in all the above activities was observed in AFSC (100mg/kg) treated group, which was comparable to l-deprenyl treated group. The HFSC and CFSC co-treatment failed to show significant attenuation of rotenone induced damage. These results indicate the possible therapeutic potential of most polar fraction of AESC i.e. AFSC in PD by virtue of its antioxidative actions. Copyright © 2013 Elsevier Inc. All rights reserved.

Effect of ginsenoside Rg3 on tyrosine hydroxylase and related mechanisms in the forced swimming-induced fatigue rats.

PubMed

Xu, Yuxia; Zhang, Peng; Wang, Chu; Shan, Ye; Wang, Dandan; Qian, Fenglei; Sun, Mengwei; Zhu, Cuiqing

2013-10-28

Ginsenoside Rg3 has shown multiple pharmacological activities and been considered as one of the most promising approaches for fatigue treatment. However, little is known about the cellular and molecular mechanisms of Rg3 on anti-fatigue and the effect of Rg3 on dopaminergic system has not been reported yet. The major aim of this study is to investigate the effect of Rg3 on TH expression and the related biochemical parameters, such as PKAα, ERK1/2, Akt and α-synuclein in brain of fatigue rats. Weight-loaded forced swimming was performed to establish an animal model of fatigue. Rg3 (10mg/kg, 50mg/kg and 100mg/kg) was intragastrically administrated before swimming. The effect of Rg3 on the expression and phosphorylation of TH and TH-related proteins in fatigue rats or in SH-SY5Y cells was assessed with western blotting. HPLC was used to examine the level of DA and DOPAC in the fatigue rats tissues. TH and phosphorylated TH were decreased in different brain regions of which ventral midbrain were less affected in weight-loaded forced swimming rats. Pretreatment with Rg3 significantly suppressed fatigue-induced decrease expression of TH and TH phosphorylation. Also treatment with Rg3 reversed the decrease expression of PKAα as well as the phosphorylation of ERK1/2 and Akt which were induced by weight-loaded forced swimming. Moreover, weight-loaded swimming could induce the increase expression of α-synuclein in hippocampus and midbrain, while suppressed α-synuclein expression in striatum and prefrontal cortex. Furthermore, Rg3 could induce the increase of TH expression and phosphorylation which was accompanied with elevated expression and phosphorylation of related kinase proteins in vitro, while the inhibitors of kinase proteins could suppress these effects of Rg3. In addition, HPLC results showed that Rg3 could reverse the weight-loaded swimming-induced increase of DOPAC/DA ratio. Our data suggest that fatigue can induce the decrease of DA which might partially result from the change of TH expression and phosphorylation, and Rg3 can reverse these fatigue-induced changes. The underling mechanisms may include the activity changes of PKAα, ERK1/2, Akt and α-synuclein. © 2013 Published by Elsevier Ireland Ltd.

The effect of pulsed electromagnetic radiation from mobile phone on the levels of monoamine neurotransmitters in four different areas of rat brain.

PubMed

Aboul Ezz, H S; Khadrawy, Y A; Ahmed, N A; Radwan, N M; El Bakry, M M

2013-07-01

The use of mobile phones is rapidly increasing all over the world. Few studies deal with the effect of electromagnetic radiation (EMR) on monoamine neurotransmitters in the different brain areas of adult rat. The aim of the present study was to investigate the effect of EMR on the concentrations of dopamine (DA), norepinephrine (NE) and serotonin (5-HT) in the hippocampus, hypothalamus, midbrain and medulla oblongata of adult rats. Adult rats were exposed daily to EMR (frequency 1800 MHz, specific absorption rate 0.843 W/kg, power density 0.02 mW/cm2, modulated at 217 Hz) and sacrificed after 1, 2 and 4 months of daily EMR exposure as well as after stopping EMR for 1 month (after 4 months of daily EMR exposure). Monoamines were determined by high performance liquid chromatography coupled with fluorescence detection (HPLC-FD) using their native properties. The exposure to EMR resulted in significant changes in DA, NE and 5-HT in the four selected areas of adult rat brain. The exposure of adult rats to EMR may cause disturbances in monoamine neurotransmitters and this may underlie many of the adverse effects reported after EMR including memory, learning, and stress.

The efficacy of an antioxidant cocktail on lipid peroxide level and superoxide dismutase activity in aged rat brain and DNA damage in iron-induced epileptogenic foci.

PubMed

Komatsu, M; Hiramatsu, M

2000-08-07

Mixed natural antioxidants can be combined in a prophylactic food against age related disease involving reactive oxygen species. beta-Catechin is an antioxidant drink, having free radical scavenging activities. It contains green tea extract as a main component as well as ascorbic acid, sunflower seed extract, dunaliella carotene and natural vitamin E. In the present study, we examined the effect of beta-catechin on lipid peroxide formation and superoxide dismutase (SOD) activity in aged rat brain and the effect on 8-hydroxy-2'-deoxyguanosine (8-OHdG) in ipsilateral cortex, 30 min after ferric chloride solution was injected into the left cortex of rats. beta-Catechin solution was orally administered to aged rats and normal rats for 1 month. One-month administration of beta-catechin solution increased SOD activity in the mitochondria fraction of striatum and midbrain and decreased thiobarbiturate reactive substance formation in the cortex and cerebellum of aged rats. It also inhibited 8-OHdG formation in the ipsilateral cortex 30 min after injection of ferric chloride solution. These results suggest that beta-catechin is a suitable prophylactic beverage against age-related neurological diseases associated with reactive oxygen species.

The Effects of a Midbrain Glioma on Memory and Other Functions: A Longitudinal Single Case Study

ERIC Educational Resources Information Center

Weddell, Rodger A.

2008-01-01

Our understanding of the effects of midbrain damage on cognition is largely based on animal studies, though there have been occasional investigations of the effects of human midbrain lesions on cognition. This investigation of a rare case of a glioma initially confined to the dorsal midbrain explores the effects of disease progression on IQ,…

Midbrain-like Organoids from Human Pluripotent Stem Cells Contain Functional Dopaminergic and Neuromelanin-Producing Neurons.

PubMed

Jo, Junghyun; Xiao, Yixin; Sun, Alfred Xuyang; Cukuroglu, Engin; Tran, Hoang-Dai; Göke, Jonathan; Tan, Zi Ying; Saw, Tzuen Yih; Tan, Cheng-Peow; Lokman, Hidayat; Lee, Younghwan; Kim, Donghoon; Ko, Han Seok; Kim, Seong-Oh; Park, Jae Hyeon; Cho, Nam-Joon; Hyde, Thomas M; Kleinman, Joel E; Shin, Joo Heon; Weinberger, Daniel R; Tan, Eng King; Je, Hyunsoo Shawn; Ng, Huck-Hui

2016-08-04

Recent advances in 3D culture systems have led to the generation of brain organoids that resemble different human brain regions; however, a 3D organoid model of the midbrain containing functional midbrain dopaminergic (mDA) neurons has not been reported. We developed a method to differentiate human pluripotent stem cells into a large multicellular organoid-like structure that contains distinct layers of neuronal cells expressing characteristic markers of human midbrain. Importantly, we detected electrically active and functionally mature mDA neurons and dopamine production in our 3D midbrain-like organoids (MLOs). In contrast to human mDA neurons generated using 2D methods or MLOs generated from mouse embryonic stem cells, our human MLOs produced neuromelanin-like granules that were structurally similar to those isolated from human substantia nigra tissues. Thus our MLOs bearing features of the human midbrain may provide a tractable in vitro system to study the human midbrain and its related diseases. Copyright © 2016 Elsevier Inc. All rights reserved.

Effects of neurosteroid actions at N-methyl-D-aspartate and GABA A receptors in the midbrain ventral tegmental area for anxiety-like and mating behavior of female rats.

PubMed

Frye, Cheryl A; Paris, Jason J

2011-01-01

In the midbrain ventral tegmental area (VTA), actions of neurosteroids, such as the progesterone metabolite, 5α-pregnan-3α-ol-20-one (3α,5α-THP), can facilitate mating and influence stress-related processes. Some actions of 3α,5α-THP may occur via positive modulation of GABA(A) receptors (GBRs), or negative modulation of N-methyl-D: -aspartate receptors (NMDARs), to influence anxiety-like behavior; but this is not known. We aimed to assess the role that neurosteroids and stress factors play on intra-VTA NMDAR- and/or GBR-mediated anxiety-like and mating behavior. Estradiol-primed, ovariectomized rats, which were partially or completely adrenalectomized (ADX), received infusions of vehicle, an NMDAR blocker (MK-801; 200 ng), or a GBR antagonist (bicuculline, 100 ng) to the VTA. Rats then received intra-VTA vehicle or a neurosteroidogenesis enhancer (N,N-Dihexyl-2-(4-fluorophenyl)indole-3-acetamide, FGIN 1-27, 5 μg) and anxiety-like and sexual behavior was assessed. Complete, compared to partial, ADX significantly reduced open arm exploration on an elevated plus maze, the proportion of females that engaged in mating, lordosis quotients, pacing of sexual contacts, and defensive aggression towards a sexually vigorous male. Intra-VTA MK-801 enhanced open arm investigation and the proportion of females that engaged in mating. Infusions of either, MK-801 or FGIN 1-27, enhanced lordosis and, when co-administered, FGIN 1-27 attenuated MK-801's lordosis-enhancing effects. Intra-VTA infusions of bicuculline, prior to FGIN 1-27, blocked FGIN 1-27's effects to enhance lordosis. Together, these data suggest that reduced NMDAR activity in the VTA may influence motivation to explore and engage in sexual behavior. These data suggest that neurosteroid actions at NMDARs and GBRs in the VTA are important for exploration and/or sexual behavior.

Effects of neurosteroid actions at N-methyl-D-aspartate and GABAA receptors in the midbrain ventral tegmental area for anxiety-like and mating behavior of female rats

PubMed Central

Paris, Jason J.

2013-01-01

Rationale In the midbrain ventral tegmental area (VTA), actions of neurosteroids, such as the progesterone metabolite, 5α-pregnan-3α-ol-20-one (3α,5α-THP), can facilitate mating and influence stress-related processes. Some actions of 3α,5α-THP may occur via positive modulation of GABAA receptors (GBRs), or negative modulation of N-methyl-D-aspartate receptors (NMDARs), to influence anxiety-like behavior; but this is not known. Objectives We aimed to assess the role that neurosteroids and stress factors play on intra-VTA NMDAR- and/or GBR-mediated anxiety-like and mating behavior. Methods Estradiol-primed, ovariectomized rats, which were partially or completely adrenalectomized (ADX), received infusions of vehicle, an NMDAR blocker (MK-801; 200 ng), or a GBR antagonist (bicuculline, 100 ng) to the VTA. Rats then received intra-VTA vehicle or a neurosteroidogenesis enhancer (N,N-Dihexyl-2-(4-fluorophenyl)indole-3-acetamide, FGIN 1-27, 5 μg) and anxiety-like and sexual behavior was assessed. Results Complete, compared to partial, ADX significantly reduced open arm exploration on an elevated plus maze, the proportion of females that engaged in mating, lordosis quotients, pacing of sexual contacts, and defensive aggression towards a sexually vigorous male. Intra-VTA MK-801 enhanced open arm investigation and the proportion of females that engaged in mating. Infusions of either, MK-801 or FGIN 1-27, enhanced lordosis and, when co-administered, FGIN 1-27 attenuated MK-801’s lordosis-enhancing effects. Intra-VTA infusions of bicuculline, prior to FGIN 1-27, blocked FGIN 1-27’s effects to enhance lordosis. Conclusions Together, these data suggest that reduced NMDAR activity in the VTA may influence motivation to explore and engage in sexual behavior. These data suggest that neurosteroid actions at NMDARs and GBRs in the VTA are important for exploration and/or sexual behavior. PMID:20878318

Region specific regulation of glutamic acid decarboxylase mRNA expression by dopamine neurons in rat brain.

PubMed

Lindefors, N; Brene, S; Herrera-Marschitz, M; Persson, H

1989-01-01

In situ hybridization histochemistry and RNA blots were used to study the expression of glutamic acid decarboxylase (GAD) mRNA in rats with or without a unilateral lesion of midbrain dopamine neurons. Two populations of GAD mRNA positive neurons were found in the intact caudate-putamen, substantia nigra and fronto-parietal cortex. In caudate-putamen, only one out of ten of the GAD mRNA positive neurons expressed high levels, while in substantia nigra every second of the positive neurons expressed high levels of GAD mRNA. Relatively few, but intensively labelled neurons were found in the intact fronto-parietal cerebral cortex. In addition, one out of six of the GAD mRNA positive neurons in the fronto-parietal cortex showed a low labeling. On the ipsilateral side, the forebrain dopamine deafferentation induced an increase in the number of neurons expressing high levels of GAD mRNA in caudate-putamen, and a decrease in fronto-parietal cortex. A smaller decrease was also seen in substantia nigra. However, the total number of GAD mRNA positive neurons were not significantly changed in any of these brain regions. The changes in the levels of GAD mRNA after the dopamine lesion were confirmed by RNA blot analysis. Hence, midbrain dopamine neurons appear to control neuronal expression of GAD mRNA by a tonic down-regulation in a fraction of GAD mRNA positive neurons in caudate-putamen, and a tonic up-regulation in a fraction of GAD mRNA positive neurons in fronto-parietal cortex and substantia nigra.

Periaqueductal Gray Afferents Synapse onto Dopamine and GABA Neurons In the Rat Ventral Tegmental Area

PubMed Central

Omelchenko, Natalia; Sesack, Susan R.

2009-01-01

The midbrain central gray (periaqueductal gray; PAG) mediates defensive behaviors and is implicated in the rewarding effects of opiate drugs. Projections from the PAG to the ventral tegmental area (VTA) suggest that this region might also regulate behaviors involving motivation and cognition. However, studies have not yet examined the morphological features of PAG axons in the VTA or whether they synapse onto dopamine (DA) or GABA neurons. In this study, we injected anterograde tracers into the rat PAG and used immunoperoxidase to visualize the projections to the VTA. Immunogold-silver labeling for tyrosine hydroxylase (TH) or GABA was then used to identify the phenotype of innervated cells. Electron microscopic examination of the VTA revealed axons labeled anterogradely from the PAG, including myelinated and unmyelinated fibers and axon varicosities, some of which formed identifiable synapses. Approximately 55% of these synaptic contacts were of the symmetric (presumably inhibitory) type; the rest were asymmetric (presumably excitatory). These findings are consistent with the presence of both GABA and glutamate projection neurons in the PAG. Some PAG axons contained dense-cored vesicles indicating the presence of neuropeptides in addition to classical neurotransmitters. PAG projections synapsed onto both DA and GABA cells with no obvious selectivity, providing the first anatomical evidence for these direct connections. The results suggest a diverse nature of PAG physiological actions on midbrain neurons. Moreover, as both the VTA and PAG are implicated in the reinforcing actions of opiates, our findings provide a potential substrate for some of the rewarding effects of these drugs. PMID:19885830

The anorexic agents, sibutramine and fenfluramine, depress GABAB-induced inhibitory postsynaptic potentials in rat mesencephalic dopaminergic cells

PubMed Central

Ledonne, Ada; Sebastianelli, Luca; Federici, Mauro; Bernardi, Giorgio; Mercuri, Nicola Biagio

2009-01-01

Background and purpose Nutrition is the result of a complex interaction among environmental, homeostatic and reward-related processes. Accumulating evidence supports key roles for the dopaminergic neurons of the ventral midbrain in regulating feeding behaviour. For this reason, in the present study, we have investigated the electrophysiological effects of two centrally acting anorexic agents, fenfluramine and sibutramine, on these cells. Experimental approach Rat midbrain slices were used to make intracellular recordings from dopaminergic neurons of the substantia nigra and the ventral tegmental area. Gamma-aminobutyric acid (GABA)-mediated synaptic transmission was assessed from the inhibitory postsynaptic potentials (IPSPs) mediated by GABAA and GABAB receptors. Key results Fenfluramine and sibutramine reduced, concentration-dependently, the GABAB IPSPs, without affecting the GABAA-mediated potentials. This effect is presynaptic, as postsynaptic membrane responses induced by application of a GABAB receptor agonist, baclofen, were not affected by the two drugs. Furthermore, the selective 5-hydroxytriptamine 1B (5-HT1B) receptor antagonist, SB216641, blocked the reduction of GABAB IPSPs caused by fenfluramine and sibutramine, indicating that the receptor mediating this effect is 5-HT1B. Conclusions and implications Two anorexic agents, fenfluramine and sibutramine, induced the activation of 5-HT1B receptors located on presynaptic GABAergic terminals, thus reducing the release of GABA. This action can alter the strength of synaptic afferents that modify the activity of dopaminergic neurons, inducing neuronal excitation. Our results reveal an additional mechanism of action for fenfluramine and sibutramine that might contribute to reducing food intake, by influencing the pleasurable and motor aspects of feeding behaviour. PMID:19298257

The Role of the Lateral Habenula in Punishment

PubMed Central

Jean-Richard Dit Bressel, Philip; McNally, Gavan P.

2014-01-01

The lateral habenula (LHb) is a small epithalamic structure that projects via the fasciculus retroflexus to the midbrain. The LHb is known to modulate midbrain dopamine (DA) neurons, including inhibition of ventral tegmental area (VTA) neurons via glutamatergic excitation of the GABAergic rostromedial tegmental nucleus (RMTg). A variety of lines of evidence show activity in LHb and the LHb-RMTg pathway is correlated with, and is sufficient to support, punishment learning. However, it is not immediately clear whether LHb is necessary for punishment. Here we used a within-subjects punishment task to assess the role of LHb in the acquisition and expression of punishment as well as in aversive choice. Rats that pressed two individually presented levers for pellet rewards rapidly suppressed responding to one lever if it also caused footshock deliveries (punished lever) but continued pressing a second lever that did not cause footshock (unpunished lever). Infusions of an AMPA receptor antagonist (NBQX) into LHb had no effect on the acquisition or expression of this punishment, or on aversive choice, but did increase locomotion. Infusion of the sodium channel blocker bupivacaine likewise had no effect on expression of punishment. However, infusion of the calcium channel blocker mibefradil did affect expression of punishment by significantly decreasing the latency with which rats responded on the punished lever and significantly increasing unpunished lever-pressing. Taken together, these findings indicate that the LHb plays a limited role in punishment, influencing only latency to respond. This role is linked to calcium channel permeability and not AMPA receptor or sodium channel permeability. PMID:25365401

The role of the lateral habenula in punishment.

PubMed

Jean-Richard Dit Bressel, Philip; McNally, Gavan P

2014-01-01

The lateral habenula (LHb) is a small epithalamic structure that projects via the fasciculus retroflexus to the midbrain. The LHb is known to modulate midbrain dopamine (DA) neurons, including inhibition of ventral tegmental area (VTA) neurons via glutamatergic excitation of the GABAergic rostromedial tegmental nucleus (RMTg). A variety of lines of evidence show activity in LHb and the LHb-RMTg pathway is correlated with, and is sufficient to support, punishment learning. However, it is not immediately clear whether LHb is necessary for punishment. Here we used a within-subjects punishment task to assess the role of LHb in the acquisition and expression of punishment as well as in aversive choice. Rats that pressed two individually presented levers for pellet rewards rapidly suppressed responding to one lever if it also caused footshock deliveries (punished lever) but continued pressing a second lever that did not cause footshock (unpunished lever). Infusions of an AMPA receptor antagonist (NBQX) into LHb had no effect on the acquisition or expression of this punishment, or on aversive choice, but did increase locomotion. Infusion of the sodium channel blocker bupivacaine likewise had no effect on expression of punishment. However, infusion of the calcium channel blocker mibefradil did affect expression of punishment by significantly decreasing the latency with which rats responded on the punished lever and significantly increasing unpunished lever-pressing. Taken together, these findings indicate that the LHb plays a limited role in punishment, influencing only latency to respond. This role is linked to calcium channel permeability and not AMPA receptor or sodium channel permeability.

Compensatory Effort Parallels Midbrain Deactivation during Mental Fatigue: An fMRI Study

PubMed Central

Nakagawa, Seishu; Sugiura, Motoaki; Akitsuki, Yuko; Hosseini, S. M. Hadi; Kotozaki, Yuka; Miyauchi, Carlos Makoto; Yomogida, Yukihito; Yokoyama, Ryoichi; Takeuchi, Hikaru; Kawashima, Ryuta

2013-01-01

Fatigue reflects the functioning of our physiological negative feedback system, which prevents us from overworking. When fatigued, however, we often try to suppress this system in an effort to compensate for the resulting deterioration in performance. Previous studies have suggested that the effect of fatigue on neurovascular demand may be influenced by this compensatory effort. The primary goal of the present study was to isolate the effect of compensatory effort on neurovascular demand. Healthy male volunteers participated in a series of visual and auditory divided attention tasks that steadily increased fatigue levels for 2 hours. Functional magnetic resonance imaging scans were performed during the first and last quarter of the study (Pre and Post sessions, respectively). Tasks with low and high attentional load (Low and High conditions, respectively) were administrated in alternating blocks. We assumed that compensatory effort would be greater under the High-attentional-load condition compared with the Low-load condition. The difference was assessed during the two sessions. The effect of compensatory effort on neurovascular demand was evaluated by examining the interaction between load (High vs. Low) and time (Pre vs. Post). Significant fatigue-induced deactivation (i.e., Pre>Post) was observed in the frontal, temporal, occipital, and parietal cortices, in the cerebellum, and in the midbrain in both the High and Low conditions. The interaction was significantly greater in the High than in the Low condition in the midbrain. Neither significant fatigue-induced activation (i.e., Pre[PreE– PostE]) may reflect suppression of the negative feedback system that normally triggers recuperative rest to maintain homeostasis. PMID:23457592

Dorsal-to-Ventral Shift in Midbrain Dopaminergic Projections and Increased Thalamic/Raphe Serotonergic Function in Early Parkinson Disease.

PubMed

Joutsa, Juho; Johansson, Jarkko; Seppänen, Marko; Noponen, Tommi; Kaasinen, Valtteri

2015-07-01

Loss of nigrostriatal neurons leading to dopamine depletion in the dorsal striatum is the pathologic hallmark of Parkinson disease contributing to the primary motor symptoms of the disease. However, Parkinson pathology is more widespread in the brain, affecting also other dopaminergic pathways and neurotransmitter systems, but these changes are less well characterized. This study aimed to investigate the mesencephalic striatal and extrastriatal dopaminergic projections together with extrastriatal serotonin transporter binding in Parkinson disease. Two hundred sixteen patients with Parkinson disease and 204 control patients (patients without neurodegenerative parkinsonism syndromes and normal SPECT imaging) were investigated with SPECT using the dopamine/serotonin transporter ligand (123)I-N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane ((123)I-FP-CIT) in the clinical setting. The group differences and midbrain correlations were analyzed voxel by voxel over the entire brain. We found that Parkinson patients had lower (123)I-FP-CIT uptake in the striatum and ventral midbrain but higher uptake in the thalamus and raphe nuclei than control patients. In patients with Parkinson disease, the correlation of the midbrain tracer uptake was shifted from the putamen to widespread corticolimbic areas. All findings were highly significant at the voxel level familywise error-corrected P value of less than 0.05. Our findings show that Parkinson disease is associated not only with the degeneration of the nigrostriatal dopamine neurotransmission, but also with a parallel shift toward mesolimbic and mesocortical function. Furthermore, Parkinson disease patients seem to have upregulation of brain serotonin transporter function at the early phase of the disease. © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

VMAT2-Mediated Neurotransmission from Midbrain Leptin Receptor Neurons in Feeding Regulation

PubMed Central

Lu, Yungang; Xu, Pingwen; Isingrini, Elsa; Xu, Yong

2017-01-01

Abstract Leptin receptors (LepRs) expressed in the midbrain contribute to the action of leptin on feeding regulation. The midbrain neurons release a variety of neurotransmitters including dopamine (DA), glutamate and GABA. However, which neurotransmitter mediates midbrain leptin action on feeding remains unclear. Here, we showed that midbrain LepR neurons overlap with a subset of dopaminergic, GABAergic and glutamatergic neurons. Specific removal of vesicular monoamine transporter 2 (VMAT2) in midbrain LepR neurons (KO mice) disrupted DA accumulation in vesicles, but failed to cause a significant change in the evoked release of either glutamate or GABA to downstream neurons. While KO mice showed no differences on chow, they presented a reduced high-fat diet (HFD) intake and resisted to HFD-induced obesity. Specific activation of midbrain LepR neurons promoted VMAT2-dependent feeding on chow and HFD. When tested with an intermittent access to HFD where first 2.5-h HFD eating (binge-like) and 24-h HFD feeding were measured, KO mice exhibited more binge-like, but less 24-h HFD feeding. Interestingly, leptin inhibited 24-h HFD feeding in controls but not in KO mice. Thus, VMAT2-mediated neurotransmission from midbrain LepR neurons contributes to both binge-like eating and HFD feeding regulation. PMID:28560316

Dickkopf 3 Promotes the Differentiation of a Rostrolateral Midbrain Dopaminergic Neuronal Subset In Vivo and from Pluripotent Stem Cells In Vitro in the Mouse.

PubMed

Fukusumi, Yoshiyasu; Meier, Florian; Götz, Sebastian; Matheus, Friederike; Irmler, Martin; Beckervordersandforth, Ruth; Faus-Kessler, Theresa; Minina, Eleonora; Rauser, Benedict; Zhang, Jingzhong; Arenas, Ernest; Andersson, Elisabet; Niehrs, Christof; Beckers, Johannes; Simeone, Antonio; Wurst, Wolfgang; Prakash, Nilima

2015-09-30

Wingless-related MMTV integration site 1 (WNT1)/β-catenin signaling plays a crucial role in the generation of mesodiencephalic dopaminergic (mdDA) neurons, including the substantia nigra pars compacta (SNc) subpopulation that preferentially degenerates in Parkinson's disease (PD). However, the precise functions of WNT1/β-catenin signaling in this context remain unknown. Stem cell-based regenerative (transplantation) therapies for PD have not been implemented widely in the clinical context, among other reasons because of the heterogeneity and incomplete differentiation of the transplanted cells. This might result in tumor formation and poor integration of the transplanted cells into the dopaminergic circuitry of the brain. Dickkopf 3 (DKK3) is a secreted glycoprotein implicated in the modulation of WNT/β-catenin signaling. Using mutant mice, primary ventral midbrain cells, and pluripotent stem cells, we show that DKK3 is necessary and sufficient for the correct differentiation of a rostrolateral mdDA neuron subset. Dkk3 transcription in the murine ventral midbrain coincides with the onset of mdDA neurogenesis and is required for the activation and/or maintenance of LMX1A (LIM homeobox transcription factor 1α) and PITX3 (paired-like homeodomain transcription factor 3) expression in the corresponding mdDA precursor subset, without affecting the proliferation or specification of their progenitors. Notably, the treatment of differentiating pluripotent stem cells with recombinant DKK3 and WNT1 proteins also increases the proportion of mdDA neurons with molecular SNc DA cell characteristics in these cultures. The specific effects of DKK3 on the differentiation of rostrolateral mdDA neurons in the murine ventral midbrain, together with its known prosurvival and anti-tumorigenic properties, make it a good candidate for the improvement of regenerative and neuroprotective strategies in the treatment of PD. Significance statement: We show here that Dickkopf 3 (DKK3), a secreted modulator of WNT (Wingless-related MMTV integration site)/β-catenin signaling, is both necessary and sufficient for the proper differentiation and survival of a rostrolateral (parabrachial pigmented nucleus and dorsomedial substantia nigra pars compacta) mesodiencephalic dopaminergic neuron subset, using Dkk3 mutant mice and murine primary ventral midbrain and pluripotent stem cells. The progressive loss of these dopamine-producing mesodiencephalic neurons is a hallmark of human Parkinson's disease, which can up to now not be halted by clinical treatments of this disease. Thus, the soluble DKK3 protein might be a promising new agent for the improvement of current protocols for the directed differentiation of pluripotent and multipotent stem cells into mesodiencephalic dopaminergic neurons and for the promotion of their survival in situ. Copyright © 2015 the authors 0270-6474/15/3513386-17$15.00/0.

Comparison of (/sup 14/C)glucose and (/sup 14/C)deoxyglucose as tracers of brain glucose use

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hawkins, R.A.; Mans, A.M.; Davis, D.W.

1988-03-01

Because glucose metabolism and functional activity in brain regions are normally coupled, knowledge of regional brain glucose use can yield insights into regional functional activity. The deoxyglucose (DG) method is widely used for this purpose in experimental animals and humans but questions have arisen regarding its limits and accuracy. Therefore an experiment was designed to compare the DG method on a structure-by-structure basis with another tracer of glucose use, (6-/sup 14/C)glucose, in normal rats. The cerebral metabolic rates obtained using the two tracers were similar in the telencephalon, but the results using DG were substantially lower in the midbrain andmore » hindbrain (diencephalon, 18%; mesencephalon, 20%; metencephalon, 29%; and myelencephalon, 35%). The primary DG metabolite, DG 6-phosphate (DG-6-P) was found to disappear in a non-uniform manner from the major brain structures: telencephalon less than diencephalon less than mesencephalon = metencephalon less than myelencephalon. Thus a correlation was found between the rate of DG-6-P loss and the extent to which the DG method gave lower values of glucose use. Thus this may explain, at least in part, the discrepancies between the two methods.« less

Regulatory gene expression patterns reveal transverse and longitudinal subdivisions of the embryonic zebrafish forebrain.

PubMed

Hauptmann, G; Gerster, T

2000-03-01

To shed light on the organization of the rostral embryonic brain of a lower vertebrate, we have directly compared the expression patterns of dlx, fgf, hh, hlx, otx, pax, POU, winged helix and wnt gene family members in the fore- and midbrain of the zebrafish. We show that the analyzed genes are expressed in distinct transverse and longitudinal domains and share expression boundaries at stereotypic positions within the fore- and midbrain. Some of these shared expression boundaries coincide with morphological landmarks like the pathways of primary axon tracts. We identified a series of eight transverse diencephalic domains suggestive of neuromeric subdivisions within the rostral brain. In addition, we identified four molecularly distinct longitudinal subdivisions and provide evidence for a strong bending of the longitudinal rostral brain axis at the cephalic flexure. Our data suggest a strong conservation of early forebrain organization between lower and higher vertebrates.

[Pathophysiological aspects of the brain stem in closed head injuries (author's transl)].

PubMed

Lausberg, G

1981-07-01

In a case of severe head injury, there is a disturbance of the functional cycle between hypothalamus/mesencephalon and the cortex cerebri. In this article, the causes and the pathophysiological, functional disturbances of primary and secondary unconsciousness will be discussed. In a case of a posttraumatic intracranial hypertension, the following causes are to be considered: cerebral oedema, intracerebral haematomas and the so-called pneumatocephalus: the collection of air in the ventricle system when open head injuries of the base of the skull occur. The midbrain syndrome which is caused by the compression of the midbrain is characterized by the disturbed reaction of the pupils, convulsive seizures and vegetative dysregulation of respiration, circulation and temperature. When the above-mentioned syndrome persists, it can develop into bulbar syndrome. This is recognized through a severe functional disturbance, which can lead to central brain if the cause of the rise of intracranial pressure is not overcome within one hour.

A Wnt1-regulated genetic network controls the identity and fate of midbrain-dopaminergic progenitors in vivo.

PubMed

Prakash, Nilima; Brodski, Claude; Naserke, Thorsten; Puelles, Eduardo; Gogoi, Robindra; Hall, Anita; Panhuysen, Markus; Echevarria, Diego; Sussel, Lori; Weisenhorn, Daniela M Vogt; Martinez, Salvador; Arenas, Ernest; Simeone, Antonio; Wurst, Wolfgang

2006-01-01

Midbrain neurons synthesizing the neurotransmitter dopamine play a central role in the modulation of different brain functions and are associated with major neurological and psychiatric disorders. Despite the importance of these cells, the molecular mechanisms controlling their development are still poorly understood. The secreted glycoprotein Wnt1 is expressed in close vicinity to developing midbrain dopaminergic neurons. Here, we show that Wnt1 regulates the genetic network, including Otx2 and Nkx2-2, that is required for the establishment of the midbrain dopaminergic progenitor domain during embryonic development. In addition, Wnt1 is required for the terminal differentiation of midbrain dopaminergic neurons at later stages of embryogenesis. These results identify Wnt1 as a key molecule in the development of midbrain dopaminergic neurons in vivo. They also suggest the Wnt1-controlled signaling pathway as a promising target for new therapeutic strategies in the treatment of Parkinson's disease.

Oxygen Tension Within the Neurogenic Niche Regulates Dopaminergic Neurogenesis in the Developing Midbrain

PubMed Central

Wagenführ, Lisa; Meyer, Anne Karen; Marrone, Lara

2016-01-01

Oxygen tension is an important factor controlling stem cell proliferation and maintenance in various stem cell populations with a particular relevance in midbrain dopaminergic progenitors. Further studies have shown that the oxygen-dependent transcription factor hypoxia-inducible factor 1α (HIF-1α) is involved in these processes. However, all available studies on oxygen effects in dopaminergic neuroprogenitors were performed in vitro and thus it remains unclear whether tissue oxygen tension in the embryonic midbrain is also relevant for the regulation of dopaminergic neurogenesis in vivo. We thus dissect here the effects of oxygen tension in combination with HIF-1α conditional knockout on dopaminergic neurogenesis by using a novel experimental design allowing for the control of oxygen tension within the microenvironment of the neurogenic niche of the murine fetal midbrain in vivo. The microenvironment of the midbrain dopaminergic neurogenic niche was detected as hypoxic with oxygen tensions below 1.1%. Maternal oxygen treatment of 10%, 21%, and 75% atmospheric oxygen tension for 48 h translates into robust changes in fetal midbrain oxygenation. Fetal midbrain hypoxia hampered the generation of dopaminergic neurons and is accompanied with restricted fetal midbrain development. In contrast, induced hyperoxia stimulated proliferation and differentiation of dopaminergic progenitors during early and late embryogenesis. Oxygen effects were not directly mediated through HIF-1α signaling. These data—in agreement with in vitro data—indicate that oxygen is a crucial regulator of developmental dopaminergic neurogenesis. Our study provides the initial framework for future studies on molecular mechanisms mediating oxygen regulation of dopaminergic neurogenesis within the fetal midbrain as its natural environment. PMID:26577812

Frequency-specific adaptation and its underlying circuit model in the auditory midbrain.

PubMed

Shen, Li; Zhao, Lingyun; Hong, Bo

2015-01-01

Receptive fields of sensory neurons are considered to be dynamic and depend on the stimulus history. In the auditory system, evidence of dynamic frequency-receptive fields has been found following stimulus-specific adaptation (SSA). However, the underlying mechanism and circuitry of SSA have not been fully elucidated. Here, we studied how frequency-receptive fields of neurons in rat inferior colliculus (IC) changed when exposed to a biased tone sequence. Pure tone with one specific frequency (adaptor) was presented markedly more often than others. The adapted tuning was compared with the original tuning measured with an unbiased sequence. We found inhomogeneous changes in frequency tuning in IC, exhibiting a center-surround pattern with respect to the neuron's best frequency. Central adaptors elicited strong suppressive and repulsive changes while flank adaptors induced facilitative and attractive changes. Moreover, we proposed a two-layer model of the underlying network, which not only reproduced the adaptive changes in the receptive fields but also predicted novelty responses to oddball sequences. These results suggest that frequency-specific adaptation in auditory midbrain can be accounted for by an adapted frequency channel and its lateral spreading of adaptation, which shed light on the organization of the underlying circuitry.

Glucose modulates food-related salience coding of midbrain neurons in humans.

PubMed

Ulrich, Martin; Endres, Felix; Kölle, Markus; Adolph, Oliver; Widenhorn-Müller, Katharina; Grön, Georg

2016-12-01

Although early rat studies demonstrated that administration of glucose diminishes dopaminergic midbrain activity, evidence in humans has been lacking so far. In the present functional magnetic resonance imaging study, glucose was intravenously infused in healthy human male participants while seeing images depicting low-caloric food (LC), high-caloric food (HC), and non-food (NF) during a food/NF discrimination task. Analysis of brain activation focused on the ventral tegmental area (VTA) as the origin of the mesolimbic system involved in salience coding. Under unmodulated fasting baseline conditions, VTA activation was greater during HC compared with LC food cues. Subsequent to infusion of glucose, this difference in VTA activation as a function of caloric load leveled off and even reversed. In a control group not receiving glucose, VTA activation during HC relative to LC cues remained stable throughout the course of the experiment. Similar treatment-specific patterns of brain activation were observed for the hypothalamus. The present findings show for the first time in humans that glucose infusion modulates salience coding mediated by the VTA. Hum Brain Mapp 37:4376-4384, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Frequency-specific adaptation and its underlying circuit model in the auditory midbrain

PubMed Central

Shen, Li; Zhao, Lingyun; Hong, Bo

2015-01-01

Receptive fields of sensory neurons are considered to be dynamic and depend on the stimulus history. In the auditory system, evidence of dynamic frequency-receptive fields has been found following stimulus-specific adaptation (SSA). However, the underlying mechanism and circuitry of SSA have not been fully elucidated. Here, we studied how frequency-receptive fields of neurons in rat inferior colliculus (IC) changed when exposed to a biased tone sequence. Pure tone with one specific frequency (adaptor) was presented markedly more often than others. The adapted tuning was compared with the original tuning measured with an unbiased sequence. We found inhomogeneous changes in frequency tuning in IC, exhibiting a center-surround pattern with respect to the neuron's best frequency. Central adaptors elicited strong suppressive and repulsive changes while flank adaptors induced facilitative and attractive changes. Moreover, we proposed a two-layer model of the underlying network, which not only reproduced the adaptive changes in the receptive fields but also predicted novelty responses to oddball sequences. These results suggest that frequency-specific adaptation in auditory midbrain can be accounted for by an adapted frequency channel and its lateral spreading of adaptation, which shed light on the organization of the underlying circuitry. PMID:26483641

Endocannabinoids control vesicle release mode at midbrain periaqueductal grey inhibitory synapses.

PubMed

Aubrey, Karin R; Drew, Geoffrey M; Jeong, Hyo-Jin; Lau, Benjamin K; Vaughan, Christopher W

2017-01-01

The midbrain periaqueductal grey (PAG) forms part of an endogenous analgesic system which is tightly regulated by the neurotransmitter GABA. The role of endocannabinoids in regulating GABAergic control of this system was examined in rat PAG slices. Under basal conditions GABAergic neurotransmission onto PAG output neurons was multivesicular. Activation of the endocannabinoid system reduced GABAergic inhibition by reducing the probability of release and by shifting release to a univesicular mode. Blockade of endocannabinoid system unmasked a tonic control over the probability and mode of GABA release. These findings provides a mechanistic foundation for the control of the PAG analgesic system by disinhibition. The midbrain periaqueductal grey (PAG) has a crucial role in coordinating endogenous analgesic responses to physiological and psychological stressors. Endocannabinoids are thought to mediate a form of stress-induced analgesia within the PAG by relieving GABAergic inhibition of output neurons, a process known as disinhibition. This disinhibition is thought to be achieved by a presynaptic reduction in GABA release probability. We examined whether other mechanisms have a role in endocannabinoid modulation of GABAergic synaptic transmission within the rat PAG. The group I mGluR agonist DHPG ((R,S)-3,5-dihydroxyphenylglycine) inhibited evoked IPSCs and increased their paired pulse ratio in normal external Ca 2+ , and when release probability was reduced by lowering Ca 2+ . However, the effect of DHPG on the coefficient of variation and kinetics of evoked IPSCs differed between normal and low Ca 2+ . Lowering external Ca 2+ had a similar effect on evoked IPSCs to that observed for DHPG in normal external Ca 2+ . The low affinity GABA A receptor antagonist TPMPA ((1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid) inhibited evoked IPSCs to a greater extent in low than in normal Ca 2+ . Together these findings indicate that the normal mode of GABA release is multivesicular within the PAG, and that DHPG and lowering external Ca 2+ switch this to a univesicular mode. The effects of DHPG were mediated by mGlu5 receptor engagement of the retrograde endocannabinoid system. Blockade of endocannabinoid breakdown produced a similar shift in the mode of release. We conclude that endocannabinoids control both the mode and the probability of GABA release within the PAG. © 2016 The Authors. The Journal of Physiology © 2016 The Physiological Society.

Brain Hemispheric Differences in the Neurochemical Effects of Lead, Prenatal Stress, and the Combination and Their Amelioration by Behavioral Experience

PubMed Central

Cory-Slechta, Deborah A.

2013-01-01

Brain lateralization, critical to mediation of cognitive functions and to “multitasking,” is disrupted in conditions such as attention deficit disorder and schizophrenia. Both low-level lead (Pb) exposure and prenatal stress (PS) have been associated with mesocorticolimbic system–mediated executive-function cognitive and attention deficits. Mesocorticolimbic systems demonstrate significant laterality. Thus, altered brain lateralization could play a role in this behavioral toxicity. This study examined laterality of mesocorticolimbic monoamines (frontal cortex, nucleus accumbens, striatum, midbrain) and amino acids (frontal cortex) in male and female rats subjected to lifetime Pb exposure (0 or 50 ppm in drinking water), PS (restraint stress on gestational days 16–17), or the combination with and without repeated learning behavioral experience. Control males exhibited prominent laterality, particularly in midbrain and also in frontal cortex and striatum; females exhibited less laterality, and this was primarily striatal. Lateralized Pb ± PS induced neurotransmitter changes were assessed only in males because of limited sample sizes of Pb + PS females. In males, Pb ± PS changes occurred in left hemisphere of frontal cortex and right hemisphere of midbrain. Behavioral experience modified the laterality of Pb ± PS–induced neurotransmitter changes in a region-dependent manner. Notably, behavioral experience eliminated Pb ± PS neurotransmitter changes in males. These findings underscore the critical need to evaluate both sexes and brain hemispheres for the mechanistic understanding of sex-dependent differences in neuro- and behavioral toxicity. Furthermore, assessment of central nervous system mechanisms in the absence of behavioral experience, shown here for males, may constitute less relevant models of human health effects. PMID:23358193

The noble gas xenon provides protection and trophic stimulation to midbrain dopamine neurons.

PubMed

Lavaur, Jérémie; Le Nogue, Déborah; Lemaire, Marc; Pype, Jan; Farjot, Géraldine; Hirsch, Etienne C; Michel, Patrick P

2017-07-01

Despite its low chemical reactivity, the noble gas xenon possesses a remarkable spectrum of biological effects. In particular, xenon is a strong neuroprotectant in preclinical models of hypoxic-ischemic brain injury. In this study, we wished to determine whether xenon retained its neuroprotective potential in experimental settings that model the progressive loss of midbrain dopamine (DA) neurons in Parkinson's disease. Using rat midbrain cultures, we established that xenon was partially protective for DA neurons through either direct or indirect effects on these neurons. So, when DA neurons were exposed to l-trans-pyrrolidine-2,4-dicarboxylic acid so as to increase ambient glutamate levels and generate slow and sustained excitotoxicity, the effect of xenon on DA neurons was direct. The vitamin E analog Trolox also partially rescued DA neurons in this setting and enhanced neuroprotection by xenon. However, in the situation where DA cell death was spontaneous, the protection of DA neurons by xenon appeared indirect as it occurred through the repression of a mechanism mediated by proliferating glial cells, presumably astrocytes and their precursor cells. Xenon also exerted trophic effects for DA neurons in this paradigm. The effects of xenon were mimicked and improved by the N-methyl-d-aspartate glutamate receptor antagonist memantine and xenon itself appeared to work by antagonizing N-methyl-d-aspartate receptors. Note that another noble gas argon could not reproduce xenon effects. Overall, present data indicate that xenon can provide protection and trophic support to DA neurons that are vulnerable in Parkinson's disease. This suggests that xenon might have some therapeutic value for this disorder. © 2017 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.

Menthol enhances phasic and tonic GABAA receptor-mediated currents in midbrain periaqueductal grey neurons

PubMed Central

Lau, Benjamin K; Karim, Shafinaz; Goodchild, Ann K; Vaughan, Christopher W; Drew, Geoffrey M

2014-01-01

Background and Purpose Menthol, a naturally occurring compound in the essential oil of mint leaves, is used for its medicinal, sensory and fragrant properties. Menthol acts via transient receptor potential (TRPM8 and TRPA1) channels and as a positive allosteric modulator of recombinant GABAA receptors. Here, we examined the actions of menthol on GABAA receptor-mediated currents in intact midbrain slices. Experimental Approach Whole-cell voltage-clamp recordings were made from periaqueductal grey (PAG) neurons in midbrain slices from rats to determine the effects of menthol on GABAA receptor-mediated phasic IPSCs and tonic currents. Key Results Menthol (150–750 μM) produced a concentration-dependent prolongation of spontaneous GABAA receptor-mediated IPSCs, but not non-NMDA receptor-mediated EPSCs throughout the PAG. Menthol actions were unaffected by TRPM8 and TRPA1 antagonists, tetrodotoxin and the benzodiazepine antagonist, flumazenil. Menthol also enhanced a tonic current, which was sensitive to the GABAA receptor antagonists, picrotoxin (100 μM), bicuculline (30 μM) and Zn2+ (100 μM), but unaffected by gabazine (10 μM) and a GABAC receptor antagonist, 1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid hydrate (TPMPA; 50 μM). In addition, menthol potentiated currents induced by the extrasynaptic GABAA receptor agonist THIP/gaboxadol (10 μM). Conclusions and Implications These results suggest that menthol positively modulates both synaptic and extrasynaptic populations of GABAA receptors in native PAG neurons. The development of agents that potentiate GABAA-mediated tonic currents and phasic IPSCs in a manner similar to menthol could provide a basis for novel GABAA-related pharmacotherapies. PMID:24460753

The effects of lesions of the superior colliculus on locomotor orientation and the orienting reflex in the rat.

PubMed

Goodale, M A; Murison, R C

1975-05-02

The effects of bilateral removal of the superior colliculus or visual cortex on visually guided locomotor movements in rats performing a brightness discrimination task were investigated directly with the use of cine film. Rats with collicular lesions showed patterns of locomotion comparable to or more efficient than those of normal animals when approaching one of 5 small doors located at one end of a large open area. In contrast, animals with large but incomplete lesions of visual cortex were distinctly impaired in their visual control of approach responses to the same stimuli. On the other hand, rats with collicular damage showed no orienting reflex or evidence of distraction in the same task when novel visual or auditory stimuli were presented. However, both normal and visual-decorticate rats showed various components of the orienting reflex and disturbance in task performance when the same novel stimuli were presented. These results suggest that although the superior colliculus does not appear to be essential to the visual control of locomotor orientation, this midbrain structure might participate in the mediation of shifts in visual fixation and attention. Visual cortex, while contributing to visuospatial guidance of locomotor movements, might not play a significant role in the control and integration of the orienting reflex.

Dopamine D1-like receptor in lateral habenula nucleus affects contextual fear memory and long-term potentiation in hippocampal CA1 in rats.

PubMed

Chan, Jiangping; Guan, Xin; Ni, Yiling; Luo, Lilu; Yang, Liqiang; Zhang, Pengyue; Zhang, Jichuan; Chen, Yanmei

2017-03-15

The Lateral Habenula (LHb) plays an important role in emotion and cognition. Recent experiments suggest that LHb has functional interaction with the hippocampus and plays an important role in spatial learning. LHb is reciprocally connected with midbrain monoaminergic brain areas such as the ventral tegmental area (VTA). However, the role of dopamine type 1 receptor (D1R) in LHb in learning and memory is not clear yet. In the present study, D1R agonist or antagonist were administered bilaterally into the LHb in rats. We found that both D1R agonist and antagonist impaired the acquisition of contextual fear memory in rats. D1R agonist or antagonist also impaired long term potentiation (LTP) in hippocampal CA3-CA1 synapses in freely moving rats and attenuated learning induced phosphorylation of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR) subunit 1 (GluA1) at Ser831 and Ser845 in hippocampus. Taken together, our results suggested that dysfunction of D1R in LHb affected the function of hippocampus. Copyright © 2016 Elsevier B.V. All rights reserved.

Neuroanatomy-based matrix-guided trimming protocol for the rat brain.

PubMed

Defazio, Rossella; Criado, Ana; Zantedeschi, Valentina; Scanziani, Eugenio

2015-02-01

Brain trimming through defined neuroanatomical landmarks is recommended to obtain consistent sections in rat toxicity studies. In this article, we describe a matrix-guided trimming protocol that uses channels to reproduce coronal levels of anatomical landmarks. Both setup phase and validation study were performed on Han Wistar male rats (Crl:WI(Han)), 10-week-old, with bodyweight of 298 ± 29 (SD) g, using a matrix (ASI-Instruments(®), Houston, TX) fitted for brains of rats with 200 to 400 g bodyweight. In the setup phase, we identified eight channels, that is, 6, 8, 10, 12, 14, 16, 19, and 21, matching the recommended landmarks midway to the optic chiasm, frontal pole, optic chiasm, infundibulum, mamillary bodies, midbrain, middle cerebellum, and posterior cerebellum, respectively. In the validation study, we trimmed the immersion-fixed brains of 60 rats using the selected channels to determine how consistently the channels reproduced anatomical landmarks. Percentage of success (i.e., presence of expected targets for each level) ranged from 89 to 100%. Where 100% success was not achieved, it was noted that the shift in brain trimming was toward the caudal pole. In conclusion, we developed and validated a trimming protocol for the rat brain that allow comparable extensiveness, homology, and relevance of coronal sections as the landmark-guided trimming with the advantage of being quickly learned by technicians. © 2014 by The Author(s).

The progestin etonogestrel enhances the respiratory response to metabolic acidosis in newborn rats. Evidence for a mechanism involving supramedullary structures.

PubMed

Loiseau, Camille; Osinski, Diane; Joubert, Fanny; Straus, Christian; Similowski, Thomas; Bodineau, Laurence

2014-05-01

Central congenital hypoventilation syndrome is a neuro-respiratory disease characterized by the dysfunction of the CO2/H(+) chemosensitive neurons of the retrotrapezoid nucleus/parafacial respiratory group. A recovery of CO2/H(+) chemosensitivity has been observed in some central congenital hypoventilation syndrome patients coincidental with contraceptive treatment by a potent progestin, desogestrel (Straus et al., 2010). The mechanisms of this progestin effect remain unknown, although structures of medulla oblongata, midbrain or diencephalon are known to be targets for progesterone. In the present study, on ex vivo preparations of central nervous system of newborn rats, we show that acute exposure to etonogestrel (active metabolite of desogestrel) enhanced the increased respiratory frequency induced by metabolic acidosis via a mechanism involving supramedullary structures located in pontine, mesencephalic or diencephalic regions. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Neonatal injury rapidly alters markers of pain and stress in rat pups.

PubMed

Victoria, Nicole C; Karom, Mary C; Eichenbaum, Hila; Murphy, Anne Z

2014-01-01

Less than 60% of infants undergoing invasive procedures in the neonatal intensive care unit receive analgesic therapy. These infants show long-term decreases in pain sensitivity and cortisol reactivity. In rats, we have previously shown that inflammatory pain experienced on the day of birth significantly decreases adult somatosensory thresholds and responses to anxiety- and stress-provoking stimuli. These long-term changes in pain and stress responsiveness are accompanied by two-fold increases in central met-enkephalin and β-endorphin expression. However, the time course over which these changes in central opioid peptide expression occur, relative to the time of injury, are not known. The present studies were conducted to determine whether the observed changes in adult opioid peptide expression were present within the first postnatal week following injury. The impact of neonatal inflammation on plasma corticosterone, a marker for stress reactivity, was also determined. Brain, spinal cord, and trunk blood were harvested at 24 h, 48 h, and 7 d following intraplantar administration of the inflammatory agent carrageenan on the day of birth. Radioimmunoassay was used to determine plasma corticosterone and met-enkephalin and β-endorphin levels within the forebrain, cortex, midbrain, and spinal cord. Within 24 h of injury, met-enkephalin levels were significantly increased in the midbrain, but decreased in the spinal cord and cortex; forebrain β-endorphin levels were significantly increased as a result of early life pain. Corticosterone levels were also significantly increased. At 7 d post-injury, opioid peptides remained elevated relative to controls, suggesting a time point by which injury-induced changes become programmed and permanent. Copyright © 2013 Wiley Periodicals, Inc.

Involvement of cholinergic mechanisms in the behavioral effects of dietary fat consumption

PubMed Central

Morganstern, Irene; Ye, Zhiy; Liang, Sherry; Fagan, Shawn; Leibowitz, Sarah F.

2012-01-01

Clinical reports suggest a positive association between fat consumption and the incidence of hyperactivity, impulsivity and cognitive abnormalities. To investigate possible mechanisms underlying these disturbances under short-term conditions, we examined in Sprague-Dawley rats the influence of 7-day consumption of a high-fat diet (HFD) compared to chow on anxiety, novelty-seeking and exploratory behaviors and also on acetylcholine (ACh) neurotransmission that may mediate these behaviors. The HFD consumption, which elevated circulating fatty acids but produced no change in caloric intake or body weight, stimulated novelty-seeking and exploration in an open field, while reducing anxiety in an elevated plus maze. Using the Ellman assay to measure ACh esterase (AChE) activity that breaks down ACh, the second experiment showed HFD consumption to significantly reduce AChE activity in the frontal cortex, hypothalamus and midbrain. With measurements of [125I]-epibatidine or [125I]-bungarotoxin binding to nicotinic ACh receptors (nAChRs) containing β2 or α7 subunits, respectively, the results also showed HFD consumption to increase both β2-nAChR binding in the medial prefrontal cortex and substantia nigra and α7-nAChR binding in the lateral and ventromedial hypothalamus. When treated with an acute dose of the nicotinic antagonist, mecamylamine (0.5 mg/kg, sc), the HFD animals responded with significantly reduced exploratory and novelty-seeking behaviors, whereas the chow-consuming rats exhibited no response. These findings suggest that the exploratory and novelty-seeking behaviors induced by dietary fat may be mediated by enhanced nicotinic cholinergic activity, which is accompanied by increased density of β2-nAChRs in cortical and midbrain regions associated with impulsivity and locomotor activity and of α7-nAChRs in hypothalamic regions associated with arousal and energy balance. PMID:22765913

Electrical stimulation of the midbrain excites the auditory cortex asymmetrically.

PubMed

Quass, Gunnar Lennart; Kurt, Simone; Hildebrandt, Jannis; Kral, Andrej

2018-05-17

Auditory midbrain implant users cannot achieve open speech perception and have limited frequency resolution. It remains unclear whether the spread of excitation contributes to this issue and how much it can be compensated by current-focusing, which is an effective approach in cochlear implants. The present study examined the spread of excitation in the cortex elicited by electric midbrain stimulation. We further tested whether current-focusing via bipolar and tripolar stimulation is effective with electric midbrain stimulation and whether these modes hold any advantage over monopolar stimulation also in conditions when the stimulation electrodes are in direct contact with the target tissue. Using penetrating multielectrode arrays, we recorded cortical population responses to single pulse electric midbrain stimulation in 10 ketamine/xylazine anesthetized mice. We compared monopolar, bipolar, and tripolar stimulation configurations with regard to the spread of excitation and the characteristic frequency difference between the stimulation/recording electrodes. The cortical responses were distributed asymmetrically around the characteristic frequency of the stimulated midbrain region with a strong activation in regions tuned up to one octave higher. We found no significant differences between monopolar, bipolar, and tripolar stimulation in threshold, evoked firing rate, or dynamic range. The cortical responses to electric midbrain stimulation are biased towards higher tonotopic frequencies. Current-focusing is not effective in direct contact electrical stimulation. Electrode maps should account for the asymmetrical spread of excitation when fitting auditory midbrain implants by shifting the frequency-bands downward and stimulating as dorsally as possible. Copyright © 2018 Elsevier Inc. All rights reserved.

Mitogen-activated protein kinase phosphatase (MKP)-1 as a neuroprotective agent: promotion of the morphological development of midbrain dopaminergic neurons.

PubMed

Collins, Louise M; O'Keeffe, Gerard W; Long-Smith, Caitriona M; Wyatt, Sean L; Sullivan, Aideen M; Toulouse, André; Nolan, Yvonne M

2013-06-01

A greater understanding of the mechanisms that promote the survival and growth of dopaminergic neurons is essential for the advancement of cell replacement therapies for Parkinson's disease (PD). Evidence supports a role for the mitogen-activated protein kinase p38 in the demise of dopaminergic neurons, while mitogen-activated protein kinase phosphatase-1 (MKP-1), which negatively regulates p38 activity, has not yet been investigated in this context. Here, we show that MKP-1 is expressed in dopaminergic neurons cultured from E14 rat ventral mesencephalon (VM). When dopaminergic neurons were transfected to overexpress MKP-1, they displayed a more complex morphology than their control counterparts in vitro. Specifically, MKP-1-transfection induced significant increases in neurite length and branching with a maximum increase observed in primary branches. We demonstrate that inhibition of dopaminergic neurite growth induced by treatment of rat VM neurons with the dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA) in vitro is mediated by p38 and is concomitant with a significant and selective decrease in MKP-1 expression in these neurons. We further show that overexpression of MKP-1 in dopaminergic neurons contributes to neuroprotection against the effects of 6-OHDA. Collectively, we report that MKP-1 can promote the growth and elaboration of dopaminergic neuronal processes and can help protect them from the neurotoxic effects of 6-OHDA. Thus, we propose that strategies aimed at augmenting MKP-1 expression or activity may be beneficial in protecting dopaminergic neurons and may provide potential therapeutic approaches for PD.

Integrity of the midbrain region is required to maintain the diencephalic-mesencephalic boundary in zebrafish no isthmus/pax2.1 mutants.

PubMed

Scholpp, Steffen; Brand, Michael

2003-11-01

Initial anterior-posterior patterning of the neural tube into forebrain, midbrain, and hindbrain primordia occurs already during gastrulation, in response to signals patterning the gastrula embryo. After the initial establishment, further development within each brain part is thought to proceed largely independently of the others. However, mechanisms should exist that ensure proper delineation of brain subdivisions also at later stages; such mechanisms are, however, poorly understood. In zebrafish no isthmus mutant embryos, inactivation of the pax2.1 gene leads to a failure of the midbrain and isthmus primordium to develop normally from the gastrula stage onward (Lun and Brand [1998] Development 125:3049-3062). Here, we report that, after the initially correct establishment during gastrulation stages, the neighbouring forebrain primordium and, partially, the hindbrain primordium expand into the misspecified midbrain territory in no isthmus mutant embryos. The expansion is particularly evident for the posterior part of the diencephalon and less so for the first rhombomeric segment, the territories immediately abutting the midbrain/isthmus primordium. The nucleus of the posterior commissure is expanded in size, and marker genes of the forebrain and rhombomere 1 expand progressively into the misspecified midbrain primordium, eventually resulting in respecification of the midbrain primordium. We therefore suggest that the genetic program controlled by Pax2.1 is not only involved in initiating but also in maintaining the identity of midbrain and isthmus cells to prevent them from assuming a forebrain or hindbrain fate. Copyright 2003 Wiley-Liss, Inc.

The Transcription Factor Orthodenticle Homeobox 2 Influences Axonal Projections and Vulnerability of Midbrain Dopaminergic Neurons

ERIC Educational Resources Information Center

Chung, Chee Yeun; Licznerski, Pawel; Alavian, Kambiz N.; Simeone, Antonio; Lin, Zhicheng; Martin, Eden; Vance, Jeffery; Isacson, Ole

2010-01-01

Two adjacent groups of midbrain dopaminergic neurons, A9 (substantia nigra pars compacta) and A10 (ventral tegmental area), have distinct projections and exhibit differential vulnerability in Parkinson's disease. Little is known about transcription factors that influence midbrain dopaminergic subgroup phenotypes or their potential role in disease.…

Specification of posterior midbrain region in zebrafish neuroepithelium.

PubMed

Miyagawa, T; Amanuma, H; Kuroiwa, A; Takeda, H

1996-04-01

The developing vertebrate nervous system displays a pronounced anterior-posterior (A-P) pattern, but the mechanism that generates this pattern is poorly understood. We examined through cell-transplantation experiments, when and how the cells in the zebrafish posterior midbrain acquire regional specificity along the A-P axis as shown by pax[b] gene expression. Labelled donor cells from the presumptive midbrain region at various stages were transplanted into more anterior part of unlabelled host embryos of the same developmental stage, and the expression of pax[b] in the donor cells were examined by in situ hybridization. The results indicated that, in the cells from the presumptive midbrain region, expression of pax[b] was determined as early as the 55%-epiboly (6.5 h, early gastrulation) when the underlying hypoblastic layer reached the presumptive midbrain region. We also found that when transplanted heterotopically, anterior, but not posterior, hypoblast cells induced expression of pax[b] in the overlying ectoderm. Expression of a midbrain specific gene is determined during early gastrulation and the hypoblastic layer plays an important role in this determination process.

9-Methyl-beta-carboline has restorative effects in an animal model of Parkinson's disease.

PubMed

Wernicke, Catrin; Hellmann, Julian; Zieba, Barbara; Kuter, Katarzyna; Ossowska, Krystyna; Frenzel, Monika; Dencher, Norbert A; Rommelspacher, Hans

2010-01-01

In a previous study, a primary culture of midbrain cells was exposed to 9-methyl-beta-carboline for 48 h, which caused an increase in the number of tyrosine hydroxylase-positive cells. Quantitative RT-PCR revealed increased transcription of genes participating in the maturation of dopaminergic neurons. These in vitro findings prompted us to investigate the restorative actions of 9-methyl-beta-carboline in vivo. The compound was delivered for 14 days into the left cerebral ventricle of rats pretreated with the neurotoxin 1-methyl-4-phenyl-pyridinium ion (MPP+) for 28 days applying a dose which lowered dopamine by approximately 50%. Interestingly, 9-methyl-beta-carboline reversed the dopamine-lowering effect of the neurotoxin in the left striatum. Stereological counts of tyrosine hydroxylase-immunoreactive cells in the substantia nigra revealed that the neurotoxin caused a decrease in the number of those cells. However, when treated subsequently with 9-methyl-beta-carboline, the number reached normal values. In search of an explanation for the restorative activity, we analyzed the complexes that compose the respiratory chain in striatal mitochondria by 2-dimension gel electrophoresis followed by MALDI-TOF peptide mass fingerprinting.We found no changes in the overall composition of the complexes. However, the activity of complex I was increased by approximately 80% in mitochondria from rats treated with MPP+ and 9-methyl-beta-carboline compared to MPP+ and saline and to sham-operated rats, as determined by measurements of nicotinamide adenine dinucleotide dehydrogenase activity. Microarray technology and single RT-PCR revealed the induction of neurotrophins: brain-derived neurotrophic factor, conserved dopamine neurotrophic factor, cerebellin 1 precursor protein, and ciliary neurotrophic factor. Selected western blots yielded consistent results. The findings demonstrate restorative effects of 9-methyl-beta-carboline in an animal model of Parkinson's disease that improve the effectiveness of the respiratory chain and promote the transcription and expression of neurotrophin-related genes.

Midbrain-Driven Emotion and Reward Processing in Alcoholism

PubMed Central

Müller-Oehring, E M; Jung, Y-C; Sullivan, E V; Hawkes, W C; Pfefferbaum, A; Schulte, T

2013-01-01

Alcohol dependence is associated with impaired control over emotionally motivated actions, possibly associated with abnormalities in the frontoparietal executive control network and midbrain nodes of the reward network associated with automatic attention. To identify differences in the neural response to alcohol-related word stimuli, 26 chronic alcoholics (ALC) and 26 healthy controls (CTL) performed an alcohol-emotion Stroop Match-to-Sample task during functional MR imaging. Stroop contrasts were modeled for color-word incongruency (eg, word RED printed in green) and for alcohol (eg, BEER), positive (eg, HAPPY) and negative (eg, MAD) emotional word content relative to congruent word conditions (eg, word RED printed in red). During color-Stroop processing, ALC and CTL showed similar left dorsolateral prefrontal activation, and CTL, but not ALC, deactivated posterior cingulate cortex/cuneus. An interaction revealed a dissociation between alcohol-word and color-word Stroop processing: ALC activated midbrain and parahippocampal regions more than CTL when processing alcohol-word relative to color-word conditions. In ALC, the midbrain region was also invoked by negative emotional Stroop words thereby showing significant overlap of this midbrain activation for alcohol-related and negative emotional processing. Enhanced midbrain activation to alcohol-related words suggests neuroadaptation of dopaminergic midbrain systems. We speculate that such tuning is normally associated with behavioral conditioning to optimize responses but here contributed to automatic bias to alcohol-related stimuli. PMID:23615665

Midbrain-driven emotion and reward processing in alcoholism.

PubMed

Müller-Oehring, E M; Jung, Y-C; Sullivan, E V; Hawkes, W C; Pfefferbaum, A; Schulte, T

2013-09-01

Alcohol dependence is associated with impaired control over emotionally motivated actions, possibly associated with abnormalities in the frontoparietal executive control network and midbrain nodes of the reward network associated with automatic attention. To identify differences in the neural response to alcohol-related word stimuli, 26 chronic alcoholics (ALC) and 26 healthy controls (CTL) performed an alcohol-emotion Stroop Match-to-Sample task during functional MR imaging. Stroop contrasts were modeled for color-word incongruency (eg, word RED printed in green) and for alcohol (eg, BEER), positive (eg, HAPPY) and negative (eg, MAD) emotional word content relative to congruent word conditions (eg, word RED printed in red). During color-Stroop processing, ALC and CTL showed similar left dorsolateral prefrontal activation, and CTL, but not ALC, deactivated posterior cingulate cortex/cuneus. An interaction revealed a dissociation between alcohol-word and color-word Stroop processing: ALC activated midbrain and parahippocampal regions more than CTL when processing alcohol-word relative to color-word conditions. In ALC, the midbrain region was also invoked by negative emotional Stroop words thereby showing significant overlap of this midbrain activation for alcohol-related and negative emotional processing. Enhanced midbrain activation to alcohol-related words suggests neuroadaptation of dopaminergic midbrain systems. We speculate that such tuning is normally associated with behavioral conditioning to optimize responses but here contributed to automatic bias to alcohol-related stimuli.

The effect of exercise frequency on neuropathic pain and pain-related cellular reactions in the spinal cord and midbrain in a rat sciatic nerve injury model

PubMed Central

Sumizono, Megumi; Otsuka, Shotaro; Terashi, Takuto; Nakanishi, Kazuki; Ueda, Koki; Takada, Seiya; Kikuchi, Kiyoshi

2018-01-01

Background Exercise regimens are established methods that can relieve neuropathic pain. However, the relationship between frequency and intensity of exercise and multiple cellular responses of exercise-induced alleviation of neuropathic pain is still unclear. We examined the influence of exercise frequency on neuropathic pain and the intracellular responses in a sciatic nerve chronic constriction injury (CCI) model. Materials and methods Rats were assigned to four groups as follows: CCI and high-frequency exercise (HFE group), CCI and low-frequency exercise (LFE group), CCI and no exercise (No-Ex group), and naive animals (control group). Rats ran on a treadmill, at a speed of 20 m/min, for 30 min, for 5 (HFE) or 3 (LFE) days a week, for a total of 5 weeks. The 50% withdrawal threshold was evaluated for mechanical sensitivity. The activation of glial cells (microglia and astrocytes), expression of brain-derived neurotrophic factor (BDNF) and μ-opioid receptor in the spinal dorsal horn and endogenous opioid in the midbrain were examined using immunohistochemistry. Opioid receptor antagonists (naloxone) were administered using intraperitoneal injection. Results The development of neuropathic pain was related to the activation of glial cells, increased BDNF expression, and downregulation of the μ-opioid receptor in the ipsilateral spinal dorsal horn. In the No-Ex group, neuropathic pain showed the highest level of mechanical hypersensitivity at 2 weeks, which improved slightly until 5 weeks after CCI. In both exercise groups, the alleviation of neuropathic pain was accelerated through the regulation of glial activation, BDNF expression, and the endogenous opioid system. The expression of BDNF and endogenous opioid in relation to exercise-induced alleviation of neuropathic pain differed in the HFE and LFE groups. The effects of exercise-induced alleviation of mechanical hypersensitivity were reversed by the administration of naloxone. Conclusion The LFE and HFE program reduced neuropathic pain. Our findings indicated that aerobic exercise-induced alleviated neuropathic pain through the regulation of glial cell activation, expression of BDNF in the ipsilateral spinal dorsal horn, and the endogenous opioid system. PMID:29445295

Activation of Midbrain Structures by Associative Novelty and the Formation of Explicit Memory in Humans

ERIC Educational Resources Information Center

Schott, Bjorn H.; Sellner, Daniela B.; Lauer, Corinna-J.; Habib, Reza; Frey, Julietta U.; Guderian, Sebastian; Heinze, Hans-Jochen; Duzel, Emrah

2004-01-01

Recent evidence suggests a close functional relationship between memory formation in the hippocampus and dopaminergic neuromodulation originating in the ventral tegmental area and medial substantia nigra of the midbrain. Here we report midbrain activation in two functional MRI studies of visual memory in healthy young adults. In the first study,…

Dorsal Striatal-Midbrain Connectivity in Humans Predicts How Reinforcements Are Used to Guide Decisions

ERIC Educational Resources Information Center

Kahnt, Thorsten; Park, Soyoung Q.; Cohen, Michael X.; Beck, Anne; Heinz, Andreas; Wrase, Jana

2009-01-01

It has been suggested that the target areas of dopaminergic midbrain neurons, the dorsal (DS) and ventral striatum (VS), are differently involved in reinforcement learning especially as actor and critic. Whereas the critic learns to predict rewards, the actor maintains action values to guide future decisions. The different midbrain connections to…

A novel therapeutic approach to 6-OHDA-induced Parkinson's disease in rats via supplementation of PTD-conjugated tyrosine hydroxylase.

PubMed

Wu, Shao Ping; Fu, Ai Ling; Wang, Yu Xia; Yu, Lei Ping; Jia, Pei Yuan; Li, Qian; Jin, Guo Zhang; Sun, Man Ji

2006-07-21

The present study aimed to evaluate whether the protein transduction domain (PTD)-conjugated human tyrosine hydroxylase (TH) fusion protein was effective on the 6-hydroxydopamine (6-OHDA)-induced Parkinson's disease (PD) model rats. An expression vector pET-PTD-TH harbouring the PTD-TH gene was constructed and transformed to the Escherichia coli BL21 cells for expression. The expressed recombinant PTD-TH with a molecular weight of 61 kD was successfully transduced (1 microM) into the dopaminergic SH-sy5y human neuroblastoma cells in vitro and visualized by immunohistochemical assay. An in vivo experiment in rats showed that the iv administered PTD-TH protein (8 mg/kg) permeated across the blood-brain barrier, penetrated into the striatum and midbrain, and peaked at 5-8 h after the injection. The behavioral effects of PTD-TH on the apomorphine-induced rotations in the PD model rats 8 weeks after the 6-OHDA lesion showed that a single bolus of PTD-TH (8 mg/kg) iv injection caused a decrement of 60% of the contralateral turns on day 1 and 40% on days 5-17. The results imply that iv delivery of PTD-TH is therapeutically effective on the 6-OHDA-induced PD in rats, the PTD-mediated human TH treatment opening a promising therapeutic direction in treatment of PD.

Coordinated Recruitment of Cortical-Subcortical Circuits and Ascending Dopamine and Serotonin Neurons During Inhibitory Control of Cocaine Seeking in Rats.

PubMed

Navailles, Sylvia; Guillem, Karine; Vouillac-Mendoza, Caroline; Ahmed, Serge H

2015-09-01

People with cocaine addiction retain some degree of prefrontal cortex (PFC) inhibitory control of cocaine craving, a brain capacity that may underlie the efficacy of cognitive behavioral therapy for addiction. Similar findings were recently found in rats after extended access to and escalation of cocaine self-administration. Rats' inhibitory control of cocaine seeking was flexible, sufficiently strong to suppress cocaine-primed reinstatement and depended, at least in part, on neuronal activity within the prelimbic (PL) PFC. Here, we used a large-scale and high-resolution Fos mapping approach to identify, beyond the PL PFC, how top-down and/or bottom-up PFC-subcortical circuits are recruited during inhibition of cocaine seeking. Overall, we found that effective inhibitory control of cocaine seeking is associated with the coordinated recruitment of different top-down cortical-striatal circuits originating from different PFC territories, and of different bottom-up dopamine (DA) and serotonin (5-HT) midbrain subsystems that normally modulate activity in these circuits. This integrated brain response suggests that rats concomitantly engage and experience intricate cognitive and affective processes when they have to inhibit intense cocaine seeking. Thus, even after extended drug use, rats can be successfully trained to engage whole-brain inhibitory control mechanisms to suppress cocaine seeking. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Spatial cue reliability drives frequency tuning in the barn Owl's midbrain

PubMed Central

Cazettes, Fanny; Fischer, Brian J; Pena, Jose L

2014-01-01

The robust representation of the environment from unreliable sensory cues is vital for the efficient function of the brain. However, how the neural processing captures the most reliable cues is unknown. The interaural time difference (ITD) is the primary cue to localize sound in horizontal space. ITD is encoded in the firing rate of neurons that detect interaural phase difference (IPD). Due to the filtering effect of the head, IPD for a given location varies depending on the environmental context. We found that, in barn owls, at each location there is a frequency range where the head filtering yields the most reliable IPDs across contexts. Remarkably, the frequency tuning of space-specific neurons in the owl's midbrain varies with their preferred sound location, matching the range that carries the most reliable IPD. Thus, frequency tuning in the owl's space-specific neurons reflects a higher-order feature of the code that captures cue reliability. DOI: http://dx.doi.org/10.7554/eLife.04854.001 PMID:25531067

Human inferior colliculus activity relates to individual differences in spoken language learning.

PubMed

Chandrasekaran, Bharath; Kraus, Nina; Wong, Patrick C M

2012-03-01

A challenge to learning words of a foreign language is encoding nonnative phonemes, a process typically attributed to cortical circuitry. Using multimodal imaging methods [functional magnetic resonance imaging-adaptation (fMRI-A) and auditory brain stem responses (ABR)], we examined the extent to which pretraining pitch encoding in the inferior colliculus (IC), a primary midbrain structure, related to individual variability in learning to successfully use nonnative pitch patterns to distinguish words in American English-speaking adults. fMRI-A indexed the efficiency of pitch representation localized to the IC, whereas ABR quantified midbrain pitch-related activity with millisecond precision. In line with neural "sharpening" models, we found that efficient IC pitch pattern representation (indexed by fMRI) related to superior neural representation of pitch patterns (indexed by ABR), and consequently more successful word learning following sound-to-meaning training. Our results establish a critical role for the IC in speech-sound representation, consistent with the established role for the IC in the representation of communication signals in other animal models.

Efficient generation of hPSC-derived midbrain dopaminergic neurons in a fully defined, scalable, 3D biomaterial platform

PubMed Central

Adil, Maroof M.; Rodrigues, Gonçalo M. C.; Kulkarni, Rishikesh U.; Rao, Antara T.; Chernavsky, Nicole E.; Miller, Evan W.; Schaffer, David V.

2017-01-01

Pluripotent stem cells (PSCs) have major potential as an unlimited source of functional cells for many biomedical applications; however, the development of cell manufacturing systems to enable this promise faces many challenges. For example, there have been major recent advances in the generation of midbrain dopaminergic (mDA) neurons from stem cells for Parkinson’s Disease (PD) therapy; however, production of these cells typically involves undefined components and difficult to scale 2D culture formats. Here, we used a fully defined, 3D, thermoresponsive biomaterial platform to rapidly generate large numbers of action-potential firing mDA neurons after 25 days of differentiation (~40% tyrosine hydroxylase (TH) positive, maturing into 25% cells exhibiting mDA neuron-like spiking behavior). Importantly, mDA neurons generated in 3D exhibited a 30-fold increase in viability upon implantation into rat striatum compared to neurons generated on 2D, consistent with the elevated expression of survival markers FOXA2 and EN1 in 3D. A defined, scalable, and resource-efficient cell culture platform can thus rapidly generate high quality differentiated cells, both neurons and potentially other cell types, with strong potential to accelerate both basic and translational research. PMID:28091566

Aminochrome decreases NGF, GDNF and induces neuroinflammation in organotypic midbrain slice cultures.

PubMed

de Araújo, Fillipe M; Ferreira, Rafael S; Souza, Cleide S; Dos Santos, Cleonice Creusa; Rodrigues, Tácio L R S; E Silva, Juliana Helena C; Gasparotto, Juciano; Gelain, Daniel Pens; El-Bachá, Ramon S; D Costa, Maria de Fátima; Fonseca, José Claudio M; Segura-Aguilar, Juan; Costa, Silvia L; Silva, Victor Diogenes A

2018-05-01

Recent evidence shows that aminochrome induces glial activation related to neuroinflammation. This dopamine derived molecule induces formation and stabilization of alpha-synuclein oligomers, mitochondria dysfunction, oxidative stress, dysfunction of proteasomal and lysosomal systems, endoplasmic reticulum stress and disruption of the microtubule network, but until now there has been no evidence of effects on production of cytokines and neurotrophic factors, that are mechanisms involved in neuronal loss in Parkinson's disease (PD). This study examines the potential role of aminochrome on the regulation of NGF, GDNF, TNF-α and IL-1β production and microglial activation in organotypic midbrain slice cultures from P8 - P9 Wistar rats. We demonstrated aminochrome (25 μM, for 24 h) induced reduction of GFAP expression, reduction of NGF and GDNF mRNA levels, morphological changes in Iba1 + cells, and increase of both TNF-α, IL-1β mRNA and protein levels. Moreover, aminochrome (25 μM, for 48 h) induced morphological changes in the edge of slices and reduction of TH expression. These results demonstrate neuroinflammation, as well as negative regulation of neurotrophic factors (GDNF and NGF), may be involved in aminochrome-induced neurodegeneration, and they contribute to a better understanding of PD pathogenesis. Copyright © 2018 Elsevier B.V. All rights reserved.

Environment- and activity-dependent dopamine neurotransmitter plasticity in the adult substantia nigra.

PubMed

Aumann, Tim D

2016-04-01

The ability of neurons to change the amount or type of neurotransmitter they use, or 'neurotransmitter plasticity', is an emerging new form of adult brain plasticity. For example, it has recently been shown that neurons in the adult rat hypothalamus up- or down-regulate dopamine (DA) neurotransmission in response to the amount of light the animal receives (photoperiod), and that this in turn affects anxiety- and depressive-like behaviors (Dulcis et al., 2013). In this Chapter I consolidate recent evidence from my laboratory suggesting neurons in the adult mouse substantia nigra pars compacta (SNc) also undergo DA neurotransmitter plasticity in response to persistent changes in their electrical activity, including that driven by the mouse's environment or behavior. Specifically, we have shown that the amounts of tyrosine hydroxylase (TH, the rate-limiting enzyme in DA synthesis) gene promoter activity, TH mRNA and TH protein in SNc neurons increases or decreases after ∼20h of altered electrical activity. Also, infusion of ion-channel agonists or antagonists into the midbrain for 2 weeks results in ∼10% (∼500 neurons) more or fewer TH immunoreactive (TH+) SNc neurons, with no change in the total number of SNc neurons (TH+ and TH-). Targeting ion-channels mediating cell-autonomous pacemaker activity in, or synaptic input and afferent pathways to, SNc neurons are equally effective in this regard. In addition, exposing mice to different environments (sex pairing or environment enrichment) for 1-2 weeks induces ∼10% more or fewer TH+ SNc (and ventral tegmental area or VTA) neurons and this is abolished by concurrent blockade of synaptic transmission in midbrain. Although further research is required to establish SNc (and VTA) DA neurotransmitter plasticity, and to determine whether it alters brain function and behavior, it is an exciting prospect because: (1) It may play important roles in movement, motor learning, reward, motivation, memory and cognition; and (2) Imbalances in midbrain DA cause symptoms associated with several prominent brain and behavioral disorders such as schizophrenia, addiction, obsessive-compulsive disorder, depression, Parkinson's disease and attention-deficit and hyperactivity disorder. Midbrain DA neurotransmitter plasticity may therefore play a role in the etiology of these symptoms, and might also offer new treatment options. Copyright © 2015 Elsevier B.V. All rights reserved.

Gray-matter volume, midbrain dopamine D2/D3 receptors and drug craving in methamphetamine users.

PubMed

Morales, A M; Kohno, M; Robertson, C L; Dean, A C; Mandelkern, M A; London, E D

2015-06-01

Dysfunction of the mesocorticolimbic system has a critical role in clinical features of addiction. Despite evidence suggesting that midbrain dopamine receptors influence amphetamine-induced dopamine release and that dopamine is involved in methamphetamine-induced neurotoxicity, associations between dopamine receptors and gray-matter volume have been unexplored in methamphetamine users. Here we used magnetic resonance imaging and [(18)F]fallypride positron emission tomography, respectively, to measure gray-matter volume (in 58 methamphetamine users) and dopamine D2/D3 receptor availability (binding potential relative to nondisplaceable uptake of the radiotracer, BPnd) (in 31 methamphetamine users and 37 control participants). Relationships between these measures and self-reported drug craving were examined. Although no difference in midbrain D2/D3 BPnd was detected between methamphetamine and control groups, midbrain D2/D3 BPnd was positively correlated with gray-matter volume in the striatum, prefrontal cortex, insula, hippocampus and temporal cortex in methamphetamine users, but not in control participants (group-by-midbrain D2/D3 BPnd interaction, P<0.05 corrected for multiple comparisons). Craving for methamphetamine was negatively associated with gray-matter volume in the insula, prefrontal cortex, amygdala, temporal cortex, occipital cortex, cerebellum and thalamus (P<0.05 corrected for multiple comparisons). A relationship between midbrain D2/D3 BPnd and methamphetamine craving was not detected. Lower midbrain D2/D3 BPnd may increase vulnerability to deficits in gray-matter volume in mesocorticolimbic circuitry in methamphetamine users, possibly reflecting greater dopamine-induced toxicity. Identifying factors that influence prefrontal and limbic volume, such as midbrain BPnd, may be important for understanding the basis of drug craving, a key factor in the maintenance of substance-use disorders.

Gray-Matter Volume, Midbrain Dopamine D2/D3 Receptors and Drug Craving in Methamphetamine Users

PubMed Central

Morales, Angelica A.; Kohno, Milky; Robertson, Chelsea L.; Dean, Andy C.; Mandelkern, Mark A.; London, Edythe D.

2015-01-01

Dysfunction of the mesocorticolimbic system plays a critical role in clinical features of addiction. Despite evidence suggesting that midbrain dopamine receptors influence amphetamine-induced dopamine release and that dopamine is involved in methamphetamine-induced neurotoxicity, associations between dopamine receptors and gray-matter volume have been unexplored in methamphetamine users. Here we used magnetic resonance imaging and [18F]fallypride positron emission tomography, respectively, to measure gray-matter volume (in 58 methamphetamine users) and dopamine D2/D3 receptor availability (binding potential relative to nondisplaceable uptake of the radiotracer, BPnd) (in 31 methamphetamine users and 37 control participants). Relationships between these measures and self-reported drug craving were examined. Although no difference in midbrain D2/D3 BPnd was detected between methamphetamine and control groups, midbrain D2/D3 BPnd was positively correlated with gray-matter volume in the striatum, prefrontal cortex, insula, hippocampus and temporal cortex in methamphetamine users, but not in control participants (group-by-midbrain D2/D3 BPnd interaction, p<0.05 corrected for multiple comparisons). Craving for methamphetamine was negatively associated with gray-matter volume in the insula, prefrontal cortex, amygdala, temporal cortex, occipital cortex, cerebellum, and thalamus (p<0.05 corrected for multiple comparisons). A relationship between midbrain D2/D3 BPnd and methamphetamine craving was not detected. Lower midbrain D2/D3 BPnd may increase vulnerability to deficits in gray-matter volume in mesocorticolimbic circuitry in methamphetamine users, possibly reflecting greater dopamine-induced toxicity. Identifying factors that influence prefrontal and limbic volume, such as midbrain BPnd, may be important for understanding the basis of drug craving, a key factor in the maintenance of substance use disorders. PMID:25896164

Putative presynaptic dopamine dysregulation in schizophrenia is supported by molecular evidence from post-mortem human midbrain

PubMed Central

Purves-Tyson, T D; Owens, S J; Rothmond, D A; Halliday, G M; Double, K L; Stevens, J; McCrossin, T; Shannon Weickert, C

2017-01-01

The dopamine hypothesis of schizophrenia posits that increased subcortical dopamine underpins psychosis. In vivo imaging studies indicate an increased presynaptic dopamine synthesis capacity in striatal terminals and cell bodies in the midbrain in schizophrenia; however, measures of the dopamine-synthesising enzyme, tyrosine hydroxylase (TH), have not identified consistent changes. We hypothesise that dopamine dysregulation in schizophrenia could result from changes in expression of dopamine synthesis enzymes, receptors, transporters or catabolic enzymes. Gene expression of 12 dopamine-related molecules was examined in post-mortem midbrain (28 antipsychotic-treated schizophrenia cases/29 controls) using quantitative PCR. TH and the synaptic dopamine transporter (DAT) proteins were examined in post-mortem midbrain (26 antipsychotic-treated schizophrenia cases per 27 controls) using immunoblotting. TH and aromatic acid decarboxylase (AADC) mRNA and TH protein were unchanged in the midbrain in schizophrenia compared with controls. Dopamine receptor D2 short, vesicular monoamine transporter (VMAT2) and DAT mRNAs were significantly decreased in schizophrenia, with no change in DRD3 mRNA, DRD3nf mRNA and DAT protein between diagnostic groups. However, DAT protein was significantly increased in putatively treatment-resistant cases of schizophrenia compared to putatively treatment-responsive cases. Midbrain monoamine oxidase A (MAOA) mRNA was increased, whereas MAOB and catechol-O-methyl transferase mRNAs were unchanged in schizophrenia. We conclude that, whereas some mRNA changes are consistent with increased dopamine action (decreased DAT mRNA), others suggest reduced dopamine action (increased MAOA mRNA) in the midbrain in schizophrenia. Here, we identify a molecular signature of dopamine dysregulation in the midbrain in schizophrenia that mainly includes gene expression changes of molecules involved in dopamine synthesis and in regulating the time course of dopamine action. PMID:28094812

Extra-prostatic Transgene-associated Neoplastic Lesions in Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) Mice

PubMed Central

Berman-Booty, Lisa D.; Thomas-Ahner, Jennifer M.; Bolon, Brad; Oglesbee, Michael J.; Clinton, Steven K.; Kulp, Samuel K.; Chen, Ching-Shih; La Perle, Krista

2014-01-01

Male transgenic adenocarcinoma of the mouse prostate (TRAMP) mice are frequently used in prostate cancer research because their prostates consistently develop a series of pre-neoplastic and neoplastic lesions. Disease progression in TRAMP mouse prostates culminates in metastatic, poorly differentiated carcinomas with neuroendocrine features. The androgen dependence of the rat probasin promoter largely limits transgene expression to the prostatic epithelium. However, extra-prostatic transgene-positive lesions have been described in TRAMP mice, including renal tubulo-acinar carcinomas, neuroendocrine carcinomas of the urethra, and phyllodes-like tumors of the seminal vesicle. Here we describe the histologic and immunohistochemical features of two novel extra-prostatic lesions in TRAMP mice: primary anaplastic tumors of uncertain cell origin in the midbrain, and poorly differentiated adenocarcinomas of the submandibular salivary gland. These newly characterized tumors apparently result from transgene expression in extra-prostatic locations rather than representing metastatic prostate neoplasms because lesions were identified in both male and female mice as well as in male TRAMP mice without histologically apparent prostate tumors. In this paper we also calculate the incidences of the urethral carcinomas and renal tubulo-acinar carcinomas, further elucidate the biological behavior of the urethral carcinomas, and demonstrate the critical importance of complete necropsies even when evaluating presumably well characterized phenotypes in genetically engineered mice. PMID:24742627

Extra-prostatic transgene-associated neoplastic lesions in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice.

PubMed

Berman-Booty, Lisa D; Thomas-Ahner, Jennifer M; Bolon, Brad; Oglesbee, Michael J; Clinton, Steven K; Kulp, Samuel K; Chen, Ching-Shih; La Perle, Krista M D

2015-02-01

Male transgenic adenocarcinoma of the mouse prostate (TRAMP) mice are frequently used in prostate cancer research because their prostates consistently develop a series of preneoplastic and neoplastic lesions. Disease progression in TRAMP mouse prostates culminates in metastatic, poorly differentiated carcinomas with neuroendocrine features. The androgen dependence of the rat probasin promoter largely limits transgene expression to the prostatic epithelium. However, extra-prostatic transgene-positive lesions have been described in TRAMP mice, including renal tubuloacinar carcinomas, neuroendocrine carcinomas of the urethra, and phyllodes-like tumors of the seminal vesicle. Here, we describe the histologic and immunohistochemical features of 2 novel extra-prostatic lesions in TRAMP mice: primary anaplastic tumors of uncertain cell origin in the midbrain and poorly differentiated adenocarcinomas of the submandibular salivary gland. These newly characterized tumors apparently result from transgene expression in extra-prostatic locations rather than representing metastatic prostate neoplasms because lesions were identified in both male and female mice and in male TRAMP mice without histologically apparent prostate tumors. In this article, we also calculate the incidences of the urethral carcinomas and renal tubuloacinar carcinomas, further elucidate the biological behavior of the urethral carcinomas, and demonstrate the critical importance of complete necropsies even when evaluating presumably well characterized phenotypes in genetically engineered mice. © 2014 by The Author(s).

Identification and characterisation of midbrain nuclei using optimised functional magnetic resonance imaging

PubMed Central

Limbrick-Oldfield, Eve H.; Brooks, Jonathan C.W.; Wise, Richard J.S.; Padormo, Francesco; Hajnal, Jo V.; Beckmann, Christian F.; Ungless, Mark A.

2012-01-01

Localising activity in the human midbrain with conventional functional MRI (fMRI) is challenging because the midbrain nuclei are small and located in an area that is prone to physiological artefacts. Here we present a replicable and automated method to improve the detection and localisation of midbrain fMRI signals. We designed a visual fMRI task that was predicted would activate the superior colliculi (SC) bilaterally. A limited number of coronal slices were scanned, orientated along the long axis of the brainstem, whilst simultaneously recording cardiac and respiratory traces. A novel anatomical registration pathway was used to optimise the localisation of the small midbrain nuclei in stereotactic space. Two additional structural scans were used to improve registration between functional and structural T1-weighted images: an echo-planar image (EPI) that matched the functional data but had whole-brain coverage, and a whole-brain T2-weighted image. This pathway was compared to conventional registration pathways, and was shown to significantly improve midbrain registration. To reduce the physiological artefacts in the functional data, we estimated and removed structured noise using a modified version of a previously described physiological noise model (PNM). Whereas a conventional analysis revealed only unilateral SC activity, the PNM analysis revealed the predicted bilateral activity. We demonstrate that these methods improve the measurement of a biologically plausible fMRI signal. Moreover they could be used to investigate the function of other midbrain nuclei. PMID:21867762

Influence of Oxygen Tension on Dopaminergic Differentiation of Human Fetal Stem Cells of Midbrain and Forebrain Origin

PubMed Central

Krabbe, Christina; Bak, Sara Thornby; Jensen, Pia; von Linstow, Christian; Martínez Serrano, Alberto; Hansen, Claus; Meyer, Morten

2014-01-01

Neural stem cells (NSCs) constitute a promising source of cells for transplantation in Parkinson's disease (PD), but protocols for controlled dopaminergic differentiation are not yet available. Here we investigated the influence of oxygen on dopaminergic differentiation of human fetal NSCs derived from the midbrain and forebrain. Cells were differentiated for 10 days in vitro at low, physiological (3%) versus high, atmospheric (20%) oxygen tension. Low oxygen resulted in upregulation of vascular endothelial growth factor and increased the proportion of tyrosine hydroxylase-immunoreactive (TH-ir) cells in both types of cultures (midbrain: 9.1±0.5 and 17.1±0.4 (P<0.001); forebrain: 1.9±0.4 and 3.9±0.6 (P<0.01) percent of total cells). Regardless of oxygen levels, the content of TH-ir cells with mature neuronal morphologies was higher for midbrain as compared to forebrain cultures. Proliferative Ki67-ir cells were found in both types of cultures, but the relative proportion of these cells was significantly higher for forebrain NSCs cultured at low, as compared to high, oxygen tension. No such difference was detected for midbrain-derived cells. Western blot analysis revealed that low oxygen enhanced β-tubulin III and GFAP expression in both cultures. Up-regulation of β-tubulin III was most pronounced for midbrain cells, whereas GFAP expression was higher in forebrain as compared to midbrain cells. NSCs from both brain regions displayed less cell death when cultured at low oxygen tension. Following mictrotransplantation into mouse striatal slice cultures predifferentiated midbrain NSCs were found to proliferate and differentiate into substantial numbers of TH-ir neurons with mature neuronal morphologies, particularly at low oxygen. In contrast, predifferentiated forebrain NSCs microtransplanted using identical conditions displayed little proliferation and contained few TH-ir cells, all of which had an immature appearance. Our data may reflect differences in dopaminergic differentiation capacity and region-specific requirements of NSCs, with the dopamine-depleted striatum cultured at low oxygen offering an attractive micro-environment for midbrain NSCs. PMID:24788190

Sustained expression of PGC-1α in the rat nigrostriatal system selectively impairs dopaminergic function

PubMed Central

Ciron, C.; Lengacher, S.; Dusonchet, J.; Aebischer, P.; Schneider, B.L.

2012-01-01

Mitochondrial dysfunction and oxidative stress have been implicated in the etiology of Parkinson's disease. Therefore, pathways controlling mitochondrial activity rapidly emerge as potential therapeutic targets. Here, we explore the neuronal response to prolonged overexpression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), a transcriptional regulator of mitochondrial function, both in vitro and in vivo. In neuronal primary cultures from the ventral midbrain, PGC-1α induces mitochondrial biogenesis and increases basal respiration. Over time, we observe an increasing proportion of the oxygen consumed by neurons which are dedicated to adenosine triphosphate production. In parallel to enhanced oxidative phosphorylation, PGC-1α progressively leads to a decrease in mitochondrial polarization. In the adult rat nigrostriatal system, adeno-associated virus (AAV)-mediated overexpression of PGC-1α induces the selective loss of dopaminergic markers and increases dopamine (DA) catabolism, leading to a reduction in striatal DA content. In addition, PGC-1α prevents the labeling of nigral neurons following striatal injection of the fluorogold retrograde tracer. When PGC-1α is expressed at higher levels following intranigral AAV injection, it leads to overt degeneration of dopaminergic neurons. Finally, PGC-1α overexpression does not prevent nigrostriatal degeneration in pathologic conditions induced by α-synuclein overexpression. Overall, we find that lasting overexpression of PGC-1α leads to major alterations in the metabolic activity of neuronal cells which dramatically impair dopaminergic function in vivo. These results highlight the central role of PGC-1α in the function and survival of dopaminergic neurons and the critical need for maintaining physiological levels of PGC-1α activity. PMID:22246294

The effects of extreme nutritional conditions on the neurochemistry of reward and addiction

NASA Astrophysics Data System (ADS)

Pothos, Emmanuel N.

2001-08-01

Weight loss is a frequent problem in space flights. We now claim that it may affect performance and drug-seeking behavior by altering midbrain neurochemistry. In food-deprived rats (20-30% underweight) basal extracellular dopamine levels in the nucleus accumbens decrease to 40-50% of normal and locomotion is depressed. However, amphetamine-induced dopamine release and locomotion are higher than in controls (1825% vs. 595% after a 25 μM d-amphetamine intraaccumbens infusion). The lower basal and the higher stimulated dopamine levels suggest that the neurotransmitter accumulates presynaptically in the accumbens of the underweight rats due to subnormal basal release. Psychostimulants are more rewarding for underweight subjects possibly because they release significantly more dopamine from elevated presynaptic stores into the accumbens. Consequently, weight loss can lead both to depression of performance and propensity to substance abuse. These effects should be considered when providing nutritional resources for space flights so that weight loss is limited.

In a rat model of panic, corticotropin responses to dorsal periaqueductal gray stimulation depend on physical exertion.

PubMed

de Souza Armini, Rubia; Bernabé, Cristian Setúbal; Rosa, Caroline Azevedo; Siller, Carlos Antônio; Schimitel, Fagna Giacomin; Tufik, Sérgio; Klein, Donald Franklin; Schenberg, Luiz Carlos

2015-03-01

Panic disorder patients are exquisitely and specifically sensitive to hypercapnia. The demonstration that carbon dioxide provokes panic in fear-unresponsive amygdala-calcified Urbach-Wiethe patients emphasizes that panic is not fear nor does it require the activation of the amygdala. This is consonant with increasing evidence suggesting that panic is mediated caudally at midbrain's dorsal periaqueductal gray matter (DPAG). Another startling feature of the apparently spontaneous clinical panic is the counterintuitive lack of increments in corticotropin, cortisol and prolactin, generally considered 'stress hormones'. Here we show that the stress hormones are not changed during DPAG-evoked panic when escape is prevented by stimulating the rat in a small compartment. Neither did the corticotropin increase when physical exertion was statistically adjusted to the same degree as non-stimulated controls, as measured by lactate plasma levels. Conversely, neuroendocrine responses to foot-shocks were independent from muscular effort. Data are consonant with DPAG mediation of panic attacks. Copyright © 2015 Elsevier Ltd. All rights reserved.

Facilitation of the arterial baroreflex by the preoptic area in anaesthetized rats.

PubMed Central

Inui, K; Nomura, J; Murase, S; Nosaka, S

1995-01-01

1. Activation of cell bodies in the ventrolateral part of the midbrain periaqueductal grey matter (PAG) facilitates the arterial baroreflex via the nucleus raphe magnus. The facilitatory effects of stimulation within the hypothalamus on the arterial baroreflex and their relation to the PAG and nucleus raphe magnus were studied in urethane- and chloralose-anaesthetized rats. 2. Systematic mapping experiments revealed that the preoptic area (POA) is the principal location in the hypothalamus of neuronal cell bodies that are responsible for the potentiation of the baroreflex. In addition to provoking hypotension and vagal bradycardia, both electrical and chemical stimulation of the POA produced facilitation of baroreflex vagal bradycardia (BVB) that was evoked by electrical stimulation of the aortic depressor nerve. Baroreflex hypotension was slightly augmented during activation of the POA in vagotomized rats. 3. Selective destruction of cell bodies either in the ventrolateral PAG or in the nucleus raphe magnus reduced facilitation of BVB by the POA. Hypotension and bradycardia due to POA stimulation were also markedly attenuated after such selective destruction. 4. In conclusion, the POA, the ventrolateral PAG and the nucleus raphe magnus constitute a functional complex that produces cardiovascular trophotropic effects including hypotension, vagal bradycardia and baroreflex facilitation. PMID:8568691

Neuroprotective Effects of Filgrastim in Rotenone-Induced Parkinson's Disease in Rats: Insights into its Anti-Inflammatory, Neurotrophic, and Antiapoptotic Effects.

PubMed

Azmy, Mariama S; Menze, Esther T; El-Naga, Reem N; Tadros, Mariane G

2018-01-11

All current treatments of Parkinson's disease (PD) focus on enhancing the dopaminergic effects and providing symptomatic relief; however, they cannot delay the disease progression. Filgrastim, a recombinant methionyl granulocyte colony-stimulating factor, demonstrated neuroprotection in many neurodegenerative and neurological diseases. This study aimed to assess the neuroprotective effects of filgrastim in rotenone-induced rat model of PD and investigate the potential underlying mechanisms of filgrastim actions. The effects of two doses of filgrastim (20 and 40 μg/kg) on spontaneous locomotion, catalepsy, body weight, histology, and striatal dopamine (DA) content, as well as tyrosine hydroxylase (TH) and α-synuclein expression, were evaluated. Then, the effective dose was further tested for its potential anti-inflammatory, neurotrophic, and antiapoptotic effects. Filgrastim (40 μg/kg) prevented rotenone-induced motor deficits, weight reduction, striatal DA depletion, and histological damage. Besides, it significantly inhibited rotenone-induced decrease in TH expression and increase in α-synuclein immunoreactivity in the midbrains and striata of the rats. These effects were associated with reduction of rotenone-induced neuroinflammation, apoptosis, and brain-derived neurotrophic factor depletion. Collectively, these results suggest that filgrastim might be a good candidate for management of PD.

Midbrain Raphe Stimulation Improves Behavioral and Anatomical Recovery from Fluid-Percussion Brain Injury

PubMed Central

Carballosa Gonzalez, Melissa M.; Blaya, Meghan O.; Alonso, Ofelia F.; Bramlett, Helen M.

2013-01-01

Abstract The midbrain median raphe (MR) and dorsal raphe (DR) nuclei were tested for their capacity to regulate recovery from traumatic brain injury (TBI). An implanted, wireless self-powered stimulator delivered intermittent 8-Hz pulse trains for 7 days to the rat's MR or DR, beginning 4–6 h after a moderate parasagittal (right) fluid-percussion injury. MR stimulation was also examined with a higher frequency (24 Hz) or a delayed start (7 days after injury). Controls had sham injuries, inactive stimulators, or both. The stimulation caused no apparent acute responses or adverse long-term changes. In water-maze trials conducted 5 weeks post-injury, early 8-Hz MR and DR stimulation restored the rate of acquisition of reference memory for a hidden platform of fixed location. Short-term spatial working memory, for a variably located hidden platform, was restored only by early 8-Hz MR stimulation. All stimulation protocols reversed injury-induced asymmetry of spontaneous forelimb reaching movements tested 6 weeks post-injury. Post-mortem histological measurement at 8 weeks post-injury revealed volume losses in parietal-occipital cortex and decussating white matter (corpus callosum plus external capsule), but not hippocampus. The cortical losses were significantly reversed by early 8-Hz MR and DR stimulation, the white matter losses by all forms of MR stimulation. The generally most effective protocol, 8-Hz MR stimulation, was tested 3 days post-injury for its acute effect on forebrain cyclic adenosine monophosphate (cAMP), a key trophic signaling molecule. This procedure reversed injury-induced declines of cAMP levels in both cortex and hippocampus. In conclusion, midbrain raphe nuclei can enduringly enhance recovery from early disseminated TBI, possibly in part through increased signaling by cAMP in efferent targets. A neurosurgical treatment for TBI using interim electrical stimulation in raphe repair centers is suggested. PMID:22963112

The value of midbrain morphology in predicting prognosis in chronic disorders of consciousness: A preliminary ultrasound study.

PubMed

Chillura, Antonino; Naro, Antonino; Micchia, Katia; Bramanti, Alessia; Bramanti, Placido; Calabrò, Rocco Salvatore

2017-09-15

Transcranial sonography (TCS) of the brainstem is currently used to support the clinical diagnosis of movement disorders. The aim of the study was to assess the usefulness of midbrain TCS in assessing outcome in patients with Chronic Disorders of Consciousness (DOC). Eleven patients with Minimally Conscious State (MCS) and Unresponsive Wakefulness Syndrome (UWS) were included in the study. We measured the area and echogenicity of the midbrain by encoding and digitally analyzing the corresponding images from the orbitomeatal plane, the morphology of brain parenchyma from the thalamic and cella media plane, and the intracranial circulation. All the patients showed an increase of pulsatility index and numerous morphological alterations on all the scan planes. In particular, we found a loss of the characteristic butterfly-shape of the midbrain, which appeared hypoechoic in the UWS but not in the MCS patients. After six months, the patients were clinically assessed by using Glasgow Outcome Scale Extended (GOSE). We found that a higher increase in GOSE scoring at follow-up was correlated with larger area and higher echogenicity of the midbrain at baseline. The present study suggests that TCS data of the midbrain may support clinical assessment of patients with chronic DOC to estimate their outcome. Copyright © 2017 Elsevier B.V. All rights reserved.

Distinct Correlation Structure Supporting a Rate-Code for Sound Localization in the Owl’s Auditory Forebrain

PubMed Central

2017-01-01

Abstract While a topographic map of auditory space exists in the vertebrate midbrain, it is absent in the forebrain. Yet, both brain regions are implicated in sound localization. The heterogeneous spatial tuning of adjacent sites in the forebrain compared to the midbrain reflects different underlying circuitries, which is expected to affect the correlation structure, i.e., signal (similarity of tuning) and noise (trial-by-trial variability) correlations. Recent studies have drawn attention to the impact of response correlations on the information readout from a neural population. We thus analyzed the correlation structure in midbrain and forebrain regions of the barn owl’s auditory system. Tetrodes were used to record in the midbrain and two forebrain regions, Field L and the downstream auditory arcopallium (AAr), in anesthetized owls. Nearby neurons in the midbrain showed high signal and noise correlations (RNCs), consistent with shared inputs. As previously reported, Field L was arranged in random clusters of similarly tuned neurons. Interestingly, AAr neurons displayed homogeneous monotonic azimuth tuning, while response variability of nearby neurons was significantly less correlated than the midbrain. Using a decoding approach, we demonstrate that low RNC in AAr restricts the potentially detrimental effect it can have on information, assuming a rate code proposed for mammalian sound localization. This study harnesses the power of correlation structure analysis to investigate the coding of auditory space. Our findings demonstrate distinct correlation structures in the auditory midbrain and forebrain, which would be beneficial for a rate-code framework for sound localization in the nontopographic forebrain representation of auditory space. PMID:28674698

A novel role for FOXA2 and SHH in organizing midbrain signaling centers.

PubMed

Bayly, Roy D; Brown, Charmaine Y; Agarwala, Seema

2012-09-01

The floor plate (FP) is a midline signaling center, known to direct ventral cell fates and axon guidance in the neural tube. The recent identification of midbrain FP as a source of dopaminergic neurons has renewed interest in its specification and organization, which remain poorly understood. In this study, we have examined the chick midbrain and spinal FP and show that both can be partitioned into medial (MFP) and lateral (LFP) subdivisions. Although Hedgehog (HH) signaling is necessary and sufficient for LFP specification, it is not sufficient for MFP induction. By contrast, the transcription factor FOXA2 can execute the full midbrain and spinal cord FP program via HH-independent and dependent mechanisms. Interestingly, although HH-independent FOXA2 activity is necessary and sufficient for inducing MFP-specific gene expression (e.g., LMX1B, BMP7), it cannot confer ventral identity to midline cells without also turning on Sonic hedgehog (SHH). We also note that the signaling centers of the midbrain, the FP, roof plate (RP) and the midbrain-hindbrain boundary (MHB) are physically contiguous, with each expressing LMX1B and BMP7. Possibly as a result, SHH or FOXA2 misexpression can transform the MHB into FP and also suppress RP induction. Conversely, HH or FOXA2 knockdown expands the endogenous RP and transforms the MFP into a RP and/or MHB fate. Finally, combined HH blockade and FOXA2 misexpression in ventral midbrain induces LMX1B expression, which triggers the specification of the RP, rather than the MFP. Thus we identify HH-independent and dependent roles for FOXA2 in specifying the FP. In addition, we elucidate for the first time, a novel role for SHH in determining whether a midbrain signaling center will become the FP, MHB or RP. Copyright © 2012 Elsevier Inc. All rights reserved.

Frequency-specific attentional modulation in human primary auditory cortex and midbrain.

PubMed

Riecke, Lars; Peters, Judith C; Valente, Giancarlo; Poser, Benedikt A; Kemper, Valentin G; Formisano, Elia; Sorger, Bettina

2018-07-01

Paying selective attention to an audio frequency selectively enhances activity within primary auditory cortex (PAC) at the tonotopic site (frequency channel) representing that frequency. Animal PAC neurons achieve this 'frequency-specific attentional spotlight' by adapting their frequency tuning, yet comparable evidence in humans is scarce. Moreover, whether the spotlight operates in human midbrain is unknown. To address these issues, we studied the spectral tuning of frequency channels in human PAC and inferior colliculus (IC), using 7-T functional magnetic resonance imaging (FMRI) and frequency mapping, while participants focused on different frequency-specific sounds. We found that shifts in frequency-specific attention alter the response gain, but not tuning profile, of PAC frequency channels. The gain modulation was strongest in low-frequency channels and varied near-monotonically across the tonotopic axis, giving rise to the attentional spotlight. We observed less prominent, non-tonotopic spatial patterns of attentional modulation in IC. These results indicate that the frequency-specific attentional spotlight in human PAC as measured with FMRI arises primarily from tonotopic gain modulation, rather than adapted frequency tuning. Moreover, frequency-specific attentional modulation of afferent sound processing in human IC seems to be considerably weaker, suggesting that the spotlight diminishes toward this lower-order processing stage. Our study sheds light on how the human auditory pathway adapts to the different demands of selective hearing. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Specificity and impact of adrenergic projections to the midbrain dopamine system

PubMed Central

Mejias-Aponte, Carlos A.

2016-01-01

Dopamine (DA) is a neuromodulator that regulates different brain circuits involved in cognitive functions, motor coordination, and emotions. Dysregulation of DA is associated with many neurological and psychiatric disorders such as Parkinson’s disease and substance abuse. Several lines of research have shown that the midbrain DA system is regulated by the central adrenergic system. This review focuses on adrenergic interactions with midbrain DA neurons. It discusses the current neuroanatomy including source of adrenergic innervation, type of synapses, and adrenoceptors expression. It also discusses adrenergic regulation of DA cell activity and neurotransmitter release. Finally, it reviews several neurological and psychiatric disorders where changes in adrenergic system are associated with dysregulation of the midbrain DA system. PMID:26820641

The distribution of the orphan bombesin receptor subtype-3 in the rat CNS.

PubMed

Jennings, C A; Harrison, D C; Maycox, P R; Crook, B; Smart, D; Hervieu, G J

2003-01-01

Bombesin receptor subtype 3 (BRS-3) is an orphan G-protein coupled receptor that shares between 47 and 51% homology with other known bombesin receptors. The natural ligand for BRS-3 is currently unknown and little is known about the mechanisms regulating BRS-3 gene expression. Unlike other mammalian bombesin receptors that have been shown to be predominantly expressed in the CNS and gastrointestinal tract, expression of the BRS-3 receptor in the rat brain has previously not been observed. To gain further understanding of the biology of BRS-3, we have studied the distribution of BRS-3 mRNA and protein in the rat CNS. The mRNA expression pattern was studied using reverse transcription followed by quantitative polymerase chain reaction. Using immunohistological techniques, the distribution of BRS-3 protein in the rat brain was investigated using a rabbit affinity-purified polyclonal antiserum raised against an N-terminal peptide. The BRS-3 receptor was found to be widely expressed in the rat brain at both mRNA and protein levels. Particularly strong immunosignals were observed in the cerebral cortex, hippocampal formation, hypothalamus and thalamus. Other regions of the brain such as the basal ganglia, midbrain and reticular formation were also immunopositive for BRS-3. In conclusion, our neuroanatomical data provide evidence that BRS-3 is as widely expressed in the rat brain as other bombesin-like peptide receptors and suggest that this receptor may also have important roles in the CNS, mediating the functions of a so far unidentified ligand.

Vertical diplopia and oscillopsia due to midbrain keyhole aqueduct syndrome associated with severe cough.

PubMed

Oh, Angela Jinsook; Lanzman, Bryan Alexander; Liao, Yaping Joyce

2018-06-01

Midline structural defects in the neural axis can give rise to neuro-ophthalmic symptoms. We report a rare case of keyhole aqueduct syndrome presenting after two years of severe cough due to gastroesophageal reflux disease. A 58-year-old woman with a 2-year history of daily, severe cough presented to the neuro-ophthalmology clinic with progressive diplopia and oscillopsia. Examination revealed a 1-2 Hz down-beating nystagmus in primary gaze that worsened with left, right, and down gazes. Gaze evoked nystagmus and mild paresis were also seen with up gaze. There was an incomitant left hypertropia due to skew deviation that worsened with right and up gazes and improved with down gaze. She also had a right-sided ptosis and a 3 mm anisocoria not due to cranial nerve 3 paresis or Horner's syndrome. Brain magnetic resonance imaging showed a 1.5 mm × 11.7 mm × 6 mm midline cleft in the ventral midbrain communicating with the cerebral aqueduct, consistent with keyhole aqueduct syndrome. Her nystagmus and diplopia improved with oral acetazolamide treatment, at high doses of 2500-3000 mg per day. We report the first case of midbrain keyhole aqueduct syndrome with ocular motor and other neuro-ophthalmic manifestations associated with severe cough. Although her cough was effectively treated and intracranial pressure measurement was normal, her ophthalmic symptoms continued to progress, which is common in previous cases reported. Treatment with acetazolamide led to significant improvement, supporting the use of acetazolamide in this rare condition.

Protection of dopaminergic neurons by 5-lipoxygenase inhibitor.

PubMed

Kang, Kai-Hsiang; Liou, Horng-Hui; Hour, Mann-Jen; Liou, Houng-Chi; Fu, Wen-Mei

2013-10-01

Neuroinflammation and oxidative stress are important factors that induce neurodegeneration in age-related neurological disorders. 5-Lipoxygenase (5-LOX) is the enzyme responsible for catalysing the synthesis of leukotriene or 5-HETE from arachidonic acid. 5-LOX is expressed in the central nervous system and may cause neurodegenerative disease. In this study, we investigated the effect of the pharmacological inhibition of 5-lipoxygenase on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/MPP(+)-induced dopaminergic neuronal death in midbrain neuron-glia co-cultures and in mice. It was found that 5-LOX was over-expressed in astrocytes after the injection of MPTP into C57BL6 mice. MK-886, a specific inhibitor of 5-LOX activating protein (FLAP), significantly increased [(3)H]-dopamine uptake, a functional indicator of the integrity of dopaminergic neurons, in midbrain cultures or the SH-SY5Y human dopaminergic cell line following MPP(+) treatment. In addition, LTB₄, one of 5-LOX's downstream products, was increased in the striatum and substantia nigra following MPTP injection in mice. LTB₄ but not LTD₄ and 5-HETE enhanced MPP(+)-induced neurotoxicity in primary midbrain cultures. MK-886 administration increased the number of tyrosine hydroxylase-positive neurons in the substantia nigra and the dopamine content in the striatum in MPTP-induced parkinsonian mice. Furthermore, the MPTP-induced upregulation of LTB₄ in the striatum and substantia nigra was antagonised by MK-886. These results suggest that 5-LOX inhibitors may be developed as novel neuroprotective agents and LTB₄ may play an important pathological role in Parkinson's disease. Copyright © 2013 Elsevier Ltd. All rights reserved.

Suppression and facilitation of auditory neurons through coordinated acoustic and midbrain stimulation: investigating a deep brain stimulator for tinnitus

NASA Astrophysics Data System (ADS)

Offutt, Sarah J.; Ryan, Kellie J.; Konop, Alexander E.; Lim, Hubert H.

2014-12-01

Objective. The inferior colliculus (IC) is the primary processing center of auditory information in the midbrain and is one site of tinnitus-related activity. One potential option for suppressing the tinnitus percept is through deep brain stimulation via the auditory midbrain implant (AMI), which is designed for hearing restoration and is already being implanted in deaf patients who also have tinnitus. However, to assess the feasibility of AMI stimulation for tinnitus treatment we first need to characterize the functional connectivity within the IC. Previous studies have suggested modulatory projections from the dorsal cortex of the IC (ICD) to the central nucleus of the IC (ICC), though the functional properties of these projections need to be determined. Approach. In this study, we investigated the effects of electrical stimulation of the ICD on acoustic-driven activity within the ICC in ketamine-anesthetized guinea pigs. Main Results. We observed ICD stimulation induces both suppressive and facilitatory changes across ICC that can occur immediately during stimulation and remain after stimulation. Additionally, ICD stimulation paired with broadband noise stimulation at a specific delay can induce greater suppressive than facilitatory effects, especially when stimulating in more rostral and medial ICD locations. Significance. These findings demonstrate that ICD stimulation can induce specific types of plastic changes in ICC activity, which may be relevant for treating tinnitus. By using the AMI with electrode sites positioned with the ICD and the ICC, the modulatory effects of ICD stimulation can be tested directly in tinnitus patients.

Neural Correlates of Hostile Jokes: Cognitive and Motivational Processes in Humor Appreciation.

PubMed

Chan, Yu-Chen; Liao, Yi-Jun; Tu, Cheng-Hao; Chen, Hsueh-Chih

2016-01-01

Hostile jokes (HJs) provide aggressive catharsis and a feeling of superiority. Behavioral research has found that HJs are perceived as funnier than non-hostile jokes (NJs). The purpose of the present study was to identify the neural correlates of the interaction between type and humor by comparing HJs, NJs, and their corresponding hostile sentences (HSs) and non-hostile sentences (NSs). HJs primarily showed activation in the dorsomedial prefrontal cortex (dmPFC) and midbrain compared with the corresponding hostile baseline. Conversely, NJs primarily revealed activation in the ventromedial PFC (vmPFC), amygdala, midbrain, ventral anterior cingulate cortex, and nucleus accumbens (NAcc) compared with the corresponding non-hostile baseline. These results support the critical role of the medial PFC (mPFC) for the neural correlates of social cognition and socio-emotional processing in response to different types of jokes. Moreover, the processing of HJs showed increased activation in the dmPFC, which suggested cognitive operations of social motivation, whereas the processing of NJs displayed increased activation in the vmPFC, which suggested social-affective engagement. HJs versus NJs primarily showed increased activation in the dmPFC and midbrain, whereas NJs versus HJs primarily displayed greater activation in the amygdala and midbrain. The psychophysiological interaction (PPI) analysis demonstrated functional coupling of the dmPFC-dlPFC and midbrain-dmPFC for HJs and functional coupling of the vmPFC-midbrain and amygdala-midbrain-NAcc for NJs. Surprisingly, HJs were not perceived as funnier than NJs. Future studies could further investigate the neural correlates of potentially important traits of high-hostility tendencies in humor appreciation based on the psychoanalytic and superiority theories of humor.

Long-term oral kinetin does not protect against α-synuclein-induced neurodegeneration in rodent models of Parkinson's disease.

PubMed

Orr, Adam L; Rutaganira, Florentine U; de Roulet, Daniel; Huang, Eric J; Hertz, Nicholas T; Shokat, Kevan M; Nakamura, Ken

2017-10-01

Mutations in the mitochondrial kinase PTEN-induced putative kinase 1 (PINK1) cause Parkinson's disease (PD), likely by disrupting PINK1's kinase activity. Although the mechanism(s) underlying how this loss of activity causes degeneration remains unclear, increasing PINK1 activity may therapeutically benefit some forms of PD. However, we must first learn whether restoring PINK1 function prevents degeneration in patients harboring PINK1 mutations, or whether boosting PINK1 function can offer protection in more common causes of PD. To test these hypotheses in preclinical rodent models of PD, we used kinetin triphosphate, a small-molecule that activates both wild-type and mutant forms of PINK1, which affects mitochondrial function and protects neural cells in culture. We chronically fed kinetin, the precursor of kinetin triphosphate, to PINK1-null rats in which PINK1 was reintroduced into their midbrain, and also to rodent models overexpressing α-synuclein. The highest tolerated dose of oral kinetin increased brain levels of kinetin for up to 6 months, without adversely affecting the survival of nigrostriatal dopamine neurons. However, there was no degeneration of midbrain dopamine neurons lacking PINK1, which precluded an assessment of neuroprotection and raised questions about the robustness of the PINK1 KO rat model of PD. In two rodent models of α-synuclein-induced toxicity, boosting PINK1 activity with oral kinetin provided no protective effects. Our results suggest that oral kinetin is unlikely to protect against α-synuclein toxicity, and thus fail to provide evidence that kinetin will protect in sporadic models of PD. Kinetin may protect in cases of PINK1 deficiency, but this possibility requires a more robust PINK1 KO model that can be validated by proof-of-principle genetic correction in adult animals. Copyright © 2017 Elsevier Ltd. All rights reserved.

Glutamate synaptic inputs to ventral tegmental area neurons in the rat derive primarily from subcortical sources.

PubMed

Omelchenko, N; Sesack, S R

2007-05-25

Dopamine and GABA neurons in the ventral tegmental area project to the nucleus accumbens and prefrontal cortex and modulate locomotor and reward behaviors as well as cognitive and affective processes. Both midbrain cell types receive synapses from glutamate afferents that provide an essential control of behaviorally-linked activity patterns, although the sources of glutamate inputs have not yet been completely characterized. We used antibodies against the vesicular glutamate transporter subtypes 1 and 2 (VGlut1 and VGlut2) to investigate the morphology and synaptic organization of axons containing these proteins as putative markers of glutamate afferents from cortical versus subcortical sites, respectively, in rats. We also characterized the ventral tegmental area cell populations receiving VGlut1+ or VGlut2+ synapses according to their transmitter phenotype (dopamine or GABA) and major projection target (nucleus accumbens or prefrontal cortex). By light and electron microscopic examination, VGlut2+ as opposed to VGlut1+ axon terminals were more numerous, had a larger average size, synapsed more proximally, and were more likely to form convergent synapses onto the same target. Both axon types formed predominantly asymmetric synapses, although VGlut2+ terminals more often formed synapses with symmetric morphology. No absolute selectivity was observed for VGlut1+ or VGlut2+ axons to target any particular cell population. However, the synapses onto mesoaccumbens neurons more often involved VGlut2+ terminals, whereas mesoprefrontal neurons received relatively equal synaptic inputs from VGlut1+ and VGlut2+ profiles. The distinct morphological features of VGlut1 and VGlut2 positive axons suggest that glutamate inputs from presumed cortical and subcortical sources, respectively, differ in the nature and intensity of their physiological actions on midbrain neurons. More specifically, our findings imply that subcortical glutamate inputs to the ventral tegmental area expressing VGlut2 predominate over cortical sources of excitation expressing VGlut1 and are more likely to drive the behaviorally-linked bursts in dopamine cells that signal future expectancy or attentional shifting.

Pbx proteins cooperate with Engrailed to pattern the midbrain-hindbrain and diencephalic-mesencephalic boundaries

PubMed Central

Erickson, Timothy; Scholpp, Steffen; Brand, Michael; Moens, Cecilia B.; Waskiewicz, Andrew Jan

2007-01-01

Pbx proteins are a family of TALE-class transcription factors that are well characterized as Hox co-factors acting to impart segmental identity to the hindbrain rhombomeres. However, no role for Pbx in establishing more anterior neural compartments has been demonstrated. Studies done in Drosophila show that Engrailed requires Exd (Pbx orthologue) for its biological activity. Here, we present evidence that zebrafish Pbx proteins cooperate with Engrailed to compartmentalize the midbrain by regulating the maintenance of the midbrain-hindbrain boundary (MHB) and the diencephalic-mesencephalic boundary (DMB). Embryos lacking Pbx function correctly initiate midbrain patterning, but fail to maintain eng2a, pax2a, fgf8, gbx2, and wnt1 expression at the MHB. Formation of the DMB is also defective as shown by a caudal expansion of diencephalic epha4a and pax6a expression into midbrain territory. These phenotypes are similar to the phenotype of an Engrailed loss-of-function embryo, supporting the hypothesis that Pbx and Engrailed act together on a common genetic pathway. Consistent with this model, we demonstrate that zebrafish Engrailed and Pbx interact in vitro, and that this interaction is required for both the eng2a overexpression phenotype and Engrailed’s role in patterning the MHB. Our data support a novel model of midbrain development in which Pbx and Engrailed proteins cooperatively pattern the mesencephalic region of the neural tube. PMID:16959235

Pbx proteins cooperate with Engrailed to pattern the midbrain-hindbrain and diencephalic-mesencephalic boundaries.

PubMed

Erickson, Timothy; Scholpp, Steffen; Brand, Michael; Moens, Cecilia B; Waskiewicz, Andrew Jan

2007-01-15

Pbx proteins are a family of TALE-class transcription factors that are well characterized as Hox co-factors acting to impart segmental identity to the hindbrain rhombomeres. However, no role for Pbx in establishing more anterior neural compartments has been demonstrated. Studies done in Drosophila show that Engrailed requires Exd (Pbx orthologue) for its biological activity. Here, we present evidence that zebrafish Pbx proteins cooperate with Engrailed to compartmentalize the midbrain by regulating the maintenance of the midbrain-hindbrain boundary (MHB) and the diencephalic-mesencephalic boundary (DMB). Embryos lacking Pbx function correctly initiate midbrain patterning, but fail to maintain eng2a, pax2a, fgf8, gbx2, and wnt1 expression at the MHB. Formation of the DMB is also defective as shown by a caudal expansion of diencephalic epha4a and pax6a expression into midbrain territory. These phenotypes are similar to the phenotype of an Engrailed loss-of-function embryo, supporting the hypothesis that Pbx and Engrailed act together on a common genetic pathway. Consistent with this model, we demonstrate that zebrafish Engrailed and Pbx interact in vitro and that this interaction is required for both the eng2a overexpression phenotype and Engrailed's role in patterning the MHB. Our data support a novel model of midbrain development in which Pbx and Engrailed proteins cooperatively pattern the mesencephalic region of the neural tube.

Genetic disruption of the nuclear receptor Nur77 (Nr4a1) in rat reduces dopamine cell loss and l-Dopa-induced dyskinesia in experimental Parkinson's disease.

PubMed

Rouillard, Claude; Baillargeon, Joanie; Paquet, Brigitte; St-Hilaire, Michel; Maheux, Jérôme; Lévesque, Catherine; Darlix, Noémie; Majeur, Simon; Lévesque, Daniel

2018-06-01

Parkinson's disease (PD) is an idiopathic progressive neurodegenerative disorder characterized by the loss of midbrain dopamine neurons. Levodopa (l-dopa) is the main pharmacological approach to relieve PD motor symptoms. However, chronic treatment with l-Dopa is inevitably associated with the generation of abnormal involuntary movements (l-Dopa-induced dyskinesia). We have previously shown that Nr4a1 (Nur77), a transcription factor of the nuclear receptor family, is closely associated with dopamine neurotransmission in the mature brain. However, the role of Nr4a1 in the etiology of PD and its treatment remain elusive. We report here that the neurotoxin 6-hydroxydopamine in rat lead to a rapid up-regulation of Nr4a1 in the substantia nigra. Genetic disruption of Nr4a1 in rat reduced neurotoxin-induced dopamine cell loss and l-Dopa-induced dyskinesia, whereas virally-driven striatal overexpression of Nr4a1 enhanced or partially restored involuntary movements induced by chronic l-Dopa in wild type and Nr4a1-deficient rats, respectively. Collectively, these results suggest that Nr4a1 is involved in dopamine cell loss and l-Dopa-induced dyskinesia in experimental PD. Copyright © 2018 Elsevier Inc. All rights reserved.

Amodal brain activation and functional connectivity in response to high-energy-density food cues in obesity.

PubMed

Carnell, Susan; Benson, Leora; Pantazatos, Spiro P; Hirsch, Joy; Geliebter, Allan

2014-11-01

The obesogenic environment is pervasive, yet only some people become obese. The aim was to investigate whether obese individuals show differential neural responses to visual and auditory food cues, independent of cue modality. Obese (BMI 29-41, n = 10) and lean (BMI 20-24, n = 10) females underwent fMRI scanning during presentation of auditory (spoken word) and visual (photograph) cues representing high-energy-density (ED) and low-ED foods. The effect of obesity on whole-brain activation, and on functional connectivity with the midbrain/VTA, was examined. Obese compared with lean women showed greater modality-independent activation of the midbrain/VTA and putamen in response to high-ED (vs. low-ED) cues, as well as relatively greater functional connectivity between the midbrain/VTA and cerebellum (P < 0.05 corrected). Heightened modality-independent responses to food cues within the midbrain/VTA and putamen, and altered functional connectivity between the midbrain/VTA and cerebellum, could contribute to excessive food intake in obese individuals. © 2014 The Obesity Society.

Human inferior colliculus activity relates to individual differences in spoken language learning

PubMed Central

Chandrasekaran, Bharath; Kraus, Nina

2012-01-01

A challenge to learning words of a foreign language is encoding nonnative phonemes, a process typically attributed to cortical circuitry. Using multimodal imaging methods [functional magnetic resonance imaging-adaptation (fMRI-A) and auditory brain stem responses (ABR)], we examined the extent to which pretraining pitch encoding in the inferior colliculus (IC), a primary midbrain structure, related to individual variability in learning to successfully use nonnative pitch patterns to distinguish words in American English-speaking adults. fMRI-A indexed the efficiency of pitch representation localized to the IC, whereas ABR quantified midbrain pitch-related activity with millisecond precision. In line with neural “sharpening” models, we found that efficient IC pitch pattern representation (indexed by fMRI) related to superior neural representation of pitch patterns (indexed by ABR), and consequently more successful word learning following sound-to-meaning training. Our results establish a critical role for the IC in speech-sound representation, consistent with the established role for the IC in the representation of communication signals in other animal models. PMID:22131377

Evidence of degraded representation of speech in noise, in the aging midbrain and cortex

PubMed Central

Simon, Jonathan Z.; Anderson, Samira

2016-01-01

Humans have a remarkable ability to track and understand speech in unfavorable conditions, such as in background noise, but speech understanding in noise does deteriorate with age. Results from several studies have shown that in younger adults, low-frequency auditory cortical activity reliably synchronizes to the speech envelope, even when the background noise is considerably louder than the speech signal. However, cortical speech processing may be limited by age-related decreases in the precision of neural synchronization in the midbrain. To understand better the neural mechanisms contributing to impaired speech perception in older adults, we investigated how aging affects midbrain and cortical encoding of speech when presented in quiet and in the presence of a single-competing talker. Our results suggest that central auditory temporal processing deficits in older adults manifest in both the midbrain and in the cortex. Specifically, midbrain frequency following responses to a speech syllable are more degraded in noise in older adults than in younger adults. This suggests a failure of the midbrain auditory mechanisms needed to compensate for the presence of a competing talker. Similarly, in cortical responses, older adults show larger reductions than younger adults in their ability to encode the speech envelope when a competing talker is added. Interestingly, older adults showed an exaggerated cortical representation of speech in both quiet and noise conditions, suggesting a possible imbalance between inhibitory and excitatory processes, or diminished network connectivity that may impair their ability to encode speech efficiently. PMID:27535374

Neural correlates of behavioral amplitude modulation sensitivity in the budgerigar midbrain

PubMed Central

Neilans, Erikson G.; Abrams, Kristina S.; Idrobo, Fabio; Carney, Laurel H.

2016-01-01

Amplitude modulation (AM) is a crucial feature of many communication signals, including speech. Whereas average discharge rates in the auditory midbrain correlate with behavioral AM sensitivity in rabbits, the neural bases of AM sensitivity in species with human-like behavioral acuity are unexplored. Here, we used parallel behavioral and neurophysiological experiments to explore the neural (midbrain) bases of AM perception in an avian speech mimic, the budgerigar (Melopsittacus undulatus). Behavioral AM sensitivity was quantified using operant conditioning procedures. Neural AM sensitivity was studied using chronically implanted microelectrodes in awake, unrestrained birds. Average discharge rates of multiunit recording sites in the budgerigar midbrain were insufficient to explain behavioral sensitivity to modulation frequencies <100 Hz for both tone- and noise-carrier stimuli, even with optimal pooling of information across recording sites. Neural envelope synchrony, in contrast, could explain behavioral performance for both carrier types across the full range of modulation frequencies studied (16–512 Hz). The results suggest that envelope synchrony in the budgerigar midbrain may underlie behavioral sensitivity to AM. Behavioral AM sensitivity based on synchrony in the budgerigar, which contrasts with rate-correlated behavioral performance in rabbits, raises the possibility that envelope synchrony, rather than average discharge rate, might also underlie AM perception in other species with sensitive AM detection abilities, including humans. These results highlight the importance of synchrony coding of envelope structure in the inferior colliculus. Furthermore, they underscore potential benefits of devices (e.g., midbrain implants) that evoke robust neural synchrony. PMID:26843608

Midbrain response to milkshake correlates with ad libitum milkshake intake in the absence of hunger.

PubMed

Nolan-Poupart, Sarah; Veldhuizen, Maria G; Geha, Paul; Small, Dana M

2013-01-01

There is now widespread agreement that individual variation in the neural circuits representing the reinforcing properties of foods may be associated with risk for overeating and obesity. What is currently unknown is how and whether brain response to a food is related to immediate subsequent intake of that food. Here we used functional magnetic resonance imaging (fMRI) to test whether response to a palatable milkshake is associated with subsequent ad libitum milkshake consumption. We predicted that enhanced responses in key reward regions (insula, striatum, midbrain, medial orbitofrontal cortex) and decreased responses in regions implicated in self-control (lateral prefrontal and lateral orbitofrontal cortex) would be associated with greater intake. We found a significant positive association between response to milkshake in the periaqueductal gray region of the midbrain and ad libitum milkshake intake. Although strong bilateral insular responses were observed during consumption of the milkshake this response did not correlate with subsequent intake. The associations observed in the midbrain and orbitofrontal cortex were uninfluenced by ratings of hunger, which were near neutral. We conclude that midbrain response to a palatable food is related to eating in the absence of hunger. Copyright © 2012 Elsevier Ltd. All rights reserved.

Representation of particle motion in the auditory midbrain of a developing anuran.

PubMed

Simmons, Andrea Megela

2015-07-01

In bullfrog tadpoles, a "deaf period" of lessened responsiveness to the pressure component of sounds, evident during the end of the late larval period, has been identified in the auditory midbrain. But coding of underwater particle motion in the vestibular medulla remains stable over all of larval development, with no evidence of a "deaf period." Neural coding of particle motion in the auditory midbrain was assessed to determine if a "deaf period" for this mode of stimulation exists in this brain area in spite of its absence from the vestibular medulla. Recording sites throughout the developing laminar and medial principal nuclei show relatively stable thresholds to z-axis particle motion, up until the "deaf period." Thresholds then begin to increase from this point up through the rest of metamorphic climax, and significantly fewer responsive sites can be located. The representation of particle motion in the auditory midbrain is less robust during later compared to earlier larval stages, overlapping with but also extending beyond the restricted "deaf period" for pressure stimulation. The decreased functional representation of particle motion in the auditory midbrain throughout metamorphic climax may reflect ongoing neural reorganization required to mediate the transition from underwater to amphibious life.

Neural correlates of appetitive-aversive interactions in Pavlovian fear conditioning.

PubMed

Nasser, Helen M; McNally, Gavan P

2013-03-19

We used Pavlovian counterconditioning in rats to identify the neural mechanisms for appetitive-aversive motivational interactions. In Stage I, rats were trained on conditioned stimulus (CS)-food (unconditioned stimulus [US]) pairings. In Stage II, this appetitive CS was transformed into a fear CS via pairings with footshock. The development of fear responses was retarded in rats that had received Stage I appetitive training. This counterconditioning was associated with increased levels of phosphorylated mitogen activated protein kinase immunoreactivity (pMAPK-IR) in several brain regions, including midline thalamus, rostral agranular insular cortex (RAIC), lateral amygdala, and nucleus accumbens core and shell, but decreased expression in the ventrolateral quadrant of the midbrain periaqueductal gray. These brain regions showing differential pMAPK-IR have previously been identified as part of the fear prediction error circuit. We then examined the causal role of RAIC MAPK in fear learning and showed that Stage II fear learning was prevented by RAIC infusions of the MEK inhibitor PD098059 (0.5 µg/hemisphere). Taken together, these results show that there are opponent interactions between the appetitive and aversive motivational systems during fear learning and that the transformation of a reward CS into a fear CS is linked to heightened activity in the fear prediction error circuit.

The Cytoarchitecture of the Inferior Colliculus Revisited

PubMed Central

Loftus, William C.; Malmierca, Manuel S.; Bishop, Deborah C.; Oliver, Douglas L.

2008-01-01

The inferior colliculus (IC) is the major component of the auditory midbrain and contains three major subdivisions: a central nucleus, a dorsal cortex, and a lateral cortex (LC). Discrepancies in the nomenclature and parcellation of the LC in the rat and cat seem to imply different, species-specific functions for this region. To establish a comparable parcellation of the LC for both rat and cat, we investigated the histochemistry and inputs of the LC. In both species, the deep lateral cortex is marked by a transition between the NADPH-d rich superficial cortex and a cytochrome oxidase rich central nucleus. In both species, focal injections of anterograde tracers in the cochlear nucleus at sites of known best frequency produced bands of labeled inputs in two different subdivisions of the IC. A medial band of axons terminated in the central nucleus, while shorter bands were located laterally and oriented nearly perpendicularly to the medial bands. In the rat, these lateral bands were located in the third, deepest layer of the lateral (external) cortex. In the cat, the bands were located in a region that was previously ascribed to the central nucleus, but now considered to belong to the third, deepest layer of the LC, the ventrolateral nucleus. In both species, the LC inputs had a tonotopic organization. In view of this parallel organization, we propose a common parcellation of the IC for rat and cat with a new nomenclature. The deep layer of the LC, previously referred to as layer 3 in the rat, is designated as the ‘ventrolateral nucleus’ of the LC, making it clear that this region is thought to be homologous with the ventrolateral nucleus in the cat. The similar organization of the LC implies that this subdivision of the IC has similar functions in cats and rats. PMID:18313229

Rehabilitative skilled forelimb training enhances axonal remodeling in the corticospinal pathway but not the brainstem-spinal pathways after photothrombotic stroke in the primary motor cortex.

PubMed

Okabe, Naohiko; Himi, Naoyuki; Maruyama-Nakamura, Emi; Hayashi, Norito; Narita, Kazuhiko; Miyamoto, Osamu

2017-01-01

Task-specific rehabilitative training is commonly used for chronic stroke patients. Axonal remodeling is believed to be one mechanism underlying rehabilitation-induced functional recovery, and significant roles of the corticospinal pathway have previously been demonstrated. Brainstem-spinal pathways, as well as the corticospinal tract, have been suggested to contribute to skilled motor function and functional recovery after brain injury. However, whether axonal remodeling in the brainstem-spinal pathways is a critical component for rehabilitation-induced functional recovery is not known. In this study, rats were subjected to photothrombotic stroke in the caudal forelimb area of the primary motor cortex and received rehabilitative training with a skilled forelimb reaching task for 4 weeks. After completion of the rehabilitative training, the retrograde tracer Fast blue was injected into the contralesional lower cervical spinal cord. Fast blue-positive cells were counted in 32 brain areas located in the cerebral cortex, hypothalamus, midbrain, pons, and medulla oblongata. Rehabilitative training improved motor performance in the skilled forelimb reaching task but not in the cylinder test, ladder walk test, or staircase test, indicating that rehabilitative skilled forelimb training induced task-specific recovery. In the histological analysis, rehabilitative training significantly increased the number of Fast blue-positive neurons in the ipsilesional rostral forelimb area and secondary sensory cortex. However, rehabilitative training did not alter the number of Fast blue-positive neurons in any areas of the brainstem. These results indicate that rehabilitative skilled forelimb training enhances axonal remodeling selectively in the corticospinal pathway, which suggests a critical role of cortical plasticity, rather than brainstem plasticity, in task-specific recovery after subtotal motor cortex destruction.

Rehabilitative skilled forelimb training enhances axonal remodeling in the corticospinal pathway but not the brainstem-spinal pathways after photothrombotic stroke in the primary motor cortex

PubMed Central

Himi, Naoyuki; Maruyama-Nakamura, Emi; Hayashi, Norito; Narita, Kazuhiko; Miyamoto, Osamu

2017-01-01

Task-specific rehabilitative training is commonly used for chronic stroke patients. Axonal remodeling is believed to be one mechanism underlying rehabilitation-induced functional recovery, and significant roles of the corticospinal pathway have previously been demonstrated. Brainstem-spinal pathways, as well as the corticospinal tract, have been suggested to contribute to skilled motor function and functional recovery after brain injury. However, whether axonal remodeling in the brainstem-spinal pathways is a critical component for rehabilitation-induced functional recovery is not known. In this study, rats were subjected to photothrombotic stroke in the caudal forelimb area of the primary motor cortex and received rehabilitative training with a skilled forelimb reaching task for 4 weeks. After completion of the rehabilitative training, the retrograde tracer Fast blue was injected into the contralesional lower cervical spinal cord. Fast blue-positive cells were counted in 32 brain areas located in the cerebral cortex, hypothalamus, midbrain, pons, and medulla oblongata. Rehabilitative training improved motor performance in the skilled forelimb reaching task but not in the cylinder test, ladder walk test, or staircase test, indicating that rehabilitative skilled forelimb training induced task-specific recovery. In the histological analysis, rehabilitative training significantly increased the number of Fast blue-positive neurons in the ipsilesional rostral forelimb area and secondary sensory cortex. However, rehabilitative training did not alter the number of Fast blue-positive neurons in any areas of the brainstem. These results indicate that rehabilitative skilled forelimb training enhances axonal remodeling selectively in the corticospinal pathway, which suggests a critical role of cortical plasticity, rather than brainstem plasticity, in task-specific recovery after subtotal motor cortex destruction. PMID:29095902

Fos-defined activity in rat brainstem following centripetal acceleration.

PubMed

Kaufman, G D; Anderson, J H; Beitz, A J

1992-11-01

To identify rat brainstem nuclei involved in the initial, short-term response to a change in gravito-inertial force, adult Long-Evans rats were rotated in the horizontal plane for 90 min in complete darkness after they were eccentrically positioned off the axis of rotation (off-axis) causing a centripetal acceleration of 2 g. Neural activation was defined by the brainstem distribution of the c-fos primary response gene protein, Fos, using immunohistochemistry. The Fos labeling in off-axis animals was compared with that of control animals who were rotated on the axis of rotation (on-axis) with no centripetal acceleration, or who were restrained but not rotated. In the off-axis animals there was a significant labeling of neurons: in the inferior, medial, and y-group subnuclei of the vestibular complex; in subnuclei of the inferior olive, especially the dorsomedial cell column; in midbrain nuclei, including the interstitial nucleus of Cajal, nucleus of Darkschewitsch, Edinger-Westphal nucleus, and dorsolateral periaqueductal gray; in autonomic centers including the solitary nucleus, area postrema, and locus coeruleus; and in reticular nuclei including the lateral reticular nucleus and the lateral parabrachial nucleus. Also, there was greater Fos expression in the dorsomedial cell column, the principal inferior olive subnuclei, inferior vestibular nucleus, the dorsolateral central gray, and the locus coeruleus in animals who had their heads restrained compared to animals whose heads were not restrained. As one control, the vestibular neuroepithelium was destroyed by injecting sodium arsanilate into the middle ear, bilaterally. This resulted in a complete lack of Fos labeling in the vestibular nuclei and the inferior olive, and a significant reduction in labeling in other nuclei in the off-axis condition, indicating that these nuclei have a significant labyrinth-sensitive component to their Fos labeling. The data indicate that several novel brainstem regions, including the dorsomedial cell column of the inferior olive and the periaqueductal gray, as well as more traditional brainstem nuclei including vestibular and oculomotor related nuclei, respond to otolith activation during a sustained centripetal acceleration.

Combinatorial Wnt control of zebrafish midbrain-hindbrain boundary formation.

PubMed

Buckles, Gerri R; Thorpe, Christopher J; Ramel, Marie-Christine; Lekven, Arne C

2004-05-01

Wnt signaling is known to be required for the normal development of the vertebrate midbrain and hindbrain, but genetic loss of function analyses in the mouse and zebrafish yield differing results regarding the relative importance of specific Wnt loci. In the zebrafish, Wnt1 and Wnt10b functionally overlap in their control of gene expression in the ventral midbrain-hindbrain boundary (MHB), but they are not required for the formation of the MHB constriction. Whether other wnt loci are involved in zebrafish MHB development is unclear, although the expression of at least two wnts, wnt3a and wnt8b, is maintained in wnt1/wnt10b mutants. In order to address the role of wnt3a in zebrafish, we have isolated a full length cDNA and examined its expression and function via knockdown by morpholino antisense oligonucleotide (MO)-mediated knockdown. The expression pattern of wnt3a appears to be evolutionarily conserved between zebrafish and mouse, and MO knockdown shows that Wnt3a, while not uniquely required for MHB development, is required in the absence of Wnt1 and Wnt10b for the formation of the MHB constriction. In zebrafish embryos lacking Wnt3a, Wnt1 and Wnt10b, the expression of engrailed orthologs, pax2a and fgf8 is not maintained after mid-somitogenesis. In contrast to acerebellar and no isthmus mutants, in which midbrain and hindbrain cells acquire new fates but cell number is not significantly affected until late in embryogenesis, zebrafish embryos lacking Wnt3a, Wnt1 and Wnt10b undergo extensive apoptosis in the midbrain and cerebellum anlagen beginning in mid-somitogenesis, which results in the absence of a significant portion of the midbrain and cerebellum. Thus, the requirement for Wnt signaling in forming the MHB constriction is evolutionarily conserved in vertebrates and it is possible in zebrafish to dissect the relative impact of multiple Wnt loci in midbrain and hindbrain development.

Acute administration of fluoxetine normalizes rapid eye movement sleep abnormality, but not depressive behaviors in olfactory bulbectomized rats.

PubMed

Wang, Yi-Qun; Tu, Zhi-Cai; Xu, Xing-Yuan; Li, Rui; Qu, Wei-Min; Urade, Yoshihiro; Huang, Zhi-Li

2012-01-01

In humans, depression is associated with altered rapid eye movement (REM) sleep. However, the exact nature of the relationship between depressive behaviors and sleep abnormalities is debated. In this study, bilateral olfactory bulbectomy (OBX) was carried out to create a model of depression in rats. The sleep-wake profiles were assayed using a cutting-edge sleep bioassay system, and depressive behaviors were evaluated by open field and forced swimming tests. The monoamine content and monoamine metabolite levels in the brain were determined by a HPLC-electrochemical detection system. OBX rats exhibited a significant increase in REM sleep, especially between 15:00 and 18:00 hours during the light period. Acute treatment with fluoxetine (10 mg/kg, i.p.) immediately abolished the OBX-induced increase in REM sleep, but hyperactivity in the open field test and the time spent immobile in the forced swimming test remained unchanged. Neurochemistry studies revealed that acute administration of fluoxetine increased serotonin (5-HT) levels in the hippocampus, thalamus, and midbrain and decreased levels of the 5-HT metabolite 5-hydroxyindoleacetic acid (5-HIAA). The ratio of 5-HIAA to 5-HT decreased in almost all regions of the brain. These results indicate that acute administration of fluoxetine can reduce the increase in REM sleep but does not change the depressive behaviors in OBX rats, suggesting that there was no causality between REM sleep abnormalities and depressive behaviors in OBX rats. © 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.

Neuroanatomy and sex differences of the lordosis-inhibiting system in the lateral septum

PubMed Central

Tsukahara, Shinji; Kanaya, Moeko; Yamanouchi, Korehito

2014-01-01

Female sexual behavior in rodents, termed lordosis, is controlled by facilitatory and inhibitory systems in the brain. It has been well demonstrated that a neural pathway from the ventromedial hypothalamic nucleus (VMN) to the midbrain central gray (MCG) is essential for facilitatory regulation of lordosis. The neural pathway from the arcuate nucleus to the VMN, via the medial preoptic nucleus, in female rats mediates transient suppression of lordosis, until female sexual receptivity is induced. In addition to this pathway, other regions are involved in inhibitory regulation of lordosis in female rats. The lordosis-inhibiting systems exist not only in the female brain but also in the male brain. The systems contribute to suppression of heterotypical sexual behavior in male rats, although they have the potential ability to display lordosis. The lateral septum (LS) exerts an inhibitory influence on lordosis in both female and male rats. This review focuses on the neuroanatomy and sex differences of the lordosis-inhibiting system in the LS. The LS functionally and anatomically links to the MCG to exert suppression of lordosis. Neurons of the intermediate part of the LS (LSi) serve as lordosis-inhibiting neurons and project axons to the MCG. The LSi-MCG neural connection is sexually dimorphic, and formation of the male-like LSi-MCG neural connection is affected by aromatized testosterone originating from the testes in the postnatal period. The sexually dimorphic LSi-MCG neural connection may reflect the morphological basis of sex differences in the inhibitory regulation of lordosis in rats. PMID:25278832

Expression patterns of ion channels and structural proteins in a multimodal cell type of the avian optic tectum.

PubMed

Lischka, Katharina; Ladel, Simone; Luksch, Harald; Weigel, Stefan

2018-02-15

The midbrain is an important subcortical area involved in distinct functions such as multimodal integration, movement initiation, bottom-up, and top-down attention. Our group is particularly interested in cellular computation of multisensory integration. We focus on the visual part of the avian midbrain, the optic tectum (TeO, counterpart to mammalian superior colliculus). This area has a layered structure with the great advantage of distinct input and output regions. In chicken, the TeO is organized in 15 layers where visual input targets the superficial layers while auditory input terminates in deeper layers. One specific cell type, the Shepherd's crook neuron (SCN), extends dendrites in both input regions. The characteristic feature of these neurons is the axon origin at the apical dendrite. The molecular identity of this characteristic region and thus, the site of action potential generation are of particular importance to understand signal flow and cellular computation in this neuron. We present immunohistochemical data of structural proteins (NF200, Ankyrin G, and Myelin) and ion channels (Pan-Na v , Na v 1.6, and K v 3.1b). NF200 is strongly expressed in the axon. Ankyrin G is mainly expressed at the axon initial segment (AIS). Myelination starts after the AIS as well as the distribution of Na v channels on the axon. The subtype Na v 1.6 has a high density in this region. K v 3.1b is restricted to the soma, the primary neurite and the axon branch. The distribution of functional molecules in SCNs provides insight into the information flow and the integration of sensory modalities in the TeO of the avian midbrain. © 2017 Wiley Periodicals, Inc.

Disrupted Functional Connectivity with Dopaminergic Midbrain in Cocaine Abusers

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tomasi, D.; Tomasi, D.; Volkow, N.D.

Chronic cocaine use is associated with disrupted dopaminergic neurotransmission but how this disruption affects overall brain function (other than reward/motivation) is yet to be fully investigated. Here we test the hypothesis that cocaine addicted subjects will have disrupted functional connectivity between the midbrain (where dopamine neurons are located) and cortical and subcortical brain regions during the performance of a sustained attention task. We measured brain activation and functional connectivity with fMRI in 20 cocaine abusers and 20 matched controls. When compared to controls, cocaine abusers had lower positive functional connectivity of midbrain with thalamus, cerebellum, and rostral cingulate, and thismore » was associated with decreased activation in thalamus and cerebellum and enhanced deactivation in rostral cingulate. These findings suggest that decreased functional connectivity of the midbrain interferes with the activation and deactivation signals associated with sustained attention in cocaine addicts.« less

Reward modulation of hippocampal subfield activation during successful associative encoding and retrieval

PubMed Central

Wolosin, Sasha M.; Zeithamova, Dagmar; Preston, Alison R.

2012-01-01

Emerging evidence suggests that motivation enhances episodic memory formation through interactions between medial temporal lobe (MTL) structures and dopaminergic midbrain. In addition, recent theories propose that motivation specifically facilitates hippocampal associative binding processes, resulting in more detailed memories that are readily reinstated from partial input. Here, we used high-resolution functional magnetic resonance imaging to determine how motivation influences associative encoding and retrieval processes within human MTL subregions and dopaminergic midbrain. Participants intentionally encoded object associations under varying conditions of reward and performed a retrieval task during which studied associations were cued from partial input. Behaviorally, cued recall performance was superior for high-value relative to low-value associations; however, participants differed in the degree to which rewards influenced memory. The magnitude of behavioral reward modulation was associated with reward-related activation changes in dentate gyrus/CA2,3 during encoding and enhanced functional connectivity between dentate gyrus/CA2,3 and dopaminergic midbrain during both the encoding and retrieval phases of the task. These findings suggests that within the hippocampus, reward-based motivation specifically enhances dentate gyrus/CA2,3 associative encoding mechanisms through interactions with dopaminergic midbrain. Furthermore, within parahippocampal cortex and dopaminergic midbrain regions, activation associated with successful memory formation was modulated by reward across the group. During the retrieval phase, we also observed enhanced activation in hippocampus and dopaminergic midbrain for high-value associations that occurred in the absence of any explicit cues to reward. Collectively, these findings shed light on fundamental mechanisms through which reward impacts associative memory formation and retrieval through facilitation of MTL and VTA/SN processing. PMID:22524296

Conserved mechanisms of vocalization coding in mammalian and songbird auditory midbrain.

PubMed

Woolley, Sarah M N; Portfors, Christine V

2013-11-01

The ubiquity of social vocalizations among animals provides the opportunity to identify conserved mechanisms of auditory processing that subserve communication. Identifying auditory coding properties that are shared across vocal communicators will provide insight into how human auditory processing leads to speech perception. Here, we compare auditory response properties and neural coding of social vocalizations in auditory midbrain neurons of mammalian and avian vocal communicators. The auditory midbrain is a nexus of auditory processing because it receives and integrates information from multiple parallel pathways and provides the ascending auditory input to the thalamus. The auditory midbrain is also the first region in the ascending auditory system where neurons show complex tuning properties that are correlated with the acoustics of social vocalizations. Single unit studies in mice, bats and zebra finches reveal shared principles of auditory coding including tonotopy, excitatory and inhibitory interactions that shape responses to vocal signals, nonlinear response properties that are important for auditory coding of social vocalizations and modulation tuning. Additionally, single neuron responses in the mouse and songbird midbrain are reliable, selective for specific syllables, and rely on spike timing for neural discrimination of distinct vocalizations. We propose that future research on auditory coding of vocalizations in mouse and songbird midbrain neurons adopt similar experimental and analytical approaches so that conserved principles of vocalization coding may be distinguished from those that are specialized for each species. This article is part of a Special Issue entitled "Communication Sounds and the Brain: New Directions and Perspectives". Copyright © 2013 Elsevier B.V. All rights reserved.

Development and initial characterization of a novel ghrelin receptor CRISPR/Cas9 knockout wistar rat model.

PubMed

Zallar, L J; Tunstall, B J; Richie, C T; Zhang, Y J; You, Z B; Gardner, E L; Heilig, M; Pickel, J; Koob, G F; Vendruscolo, L F; Harvey, B K; Leggio, L

2018-01-30

Ghrelin, a stomach-derived hormone implicated in numerous behaviors including feeding, reward, stress, and addictive behaviors, acts by binding to the growth hormone secretagogue receptor (GHSR). Here, we present the development, verification, and initial characterization of a novel GHSR knockout (KO) Wistar rat model created with CRISPR genome editing. Using CRISPR/Cas9, we developed a GHSR KO in a Wistar background. Loss of GHSR mRNA expression was histologically verified using RNAscope in wild-type (WT; n = 2) and KO (n = 2) rats. We tested the effects of intraperitoneal acyl-ghrelin administration on food consumption and plasma growth hormone (GH) concentrations in WT (n = 8) and KO (n = 8) rats. We also analyzed locomotion, food consumption, and body fat composition in these animals. Body weight was monitored from early development to adulthood. The RNAscope analysis revealed an abundance of GHSR mRNA expression in the hypothalamus, midbrain, and hippocampus in WTs, and no observed probe binding in KOs. Ghrelin administration increased plasma GH levels (p = 0.0067) and food consumption (p = 0.0448) in WT rats but not KOs. KO rats consumed less food overall at basal conditions and weighed significantly less compared with WTs throughout development (p = 0.0001). Compared with WTs, KOs presented higher concentrations of brown adipose tissue (BAT; p = 0.0322). We have verified GHSR deletion in our KO model using histological, physiological, neuroendocrinological, and behavioral measures. Our findings indicate that GHSR deletion in rats is not only associated with a lack of response to ghrelin, but also associated with decreases in daily food consumption and body growth, and increases in BAT. This GHSR KO Wistar rat model provides a novel tool for studying the role of the ghrelin system in obesity and in a wide range of medical and neuropsychiatric disorders.

Obstructive sleep apnea is associated with altered midbrain chemical concentrations.

PubMed

Macey, Paul M; Sarma, Manoj K; Prasad, Janani P; Ogren, Jennifer A; Aysola, Ravi; Harper, Ronald M; Thomas, M Albert

2017-11-05

Obstructive sleep apnea (OSA) is accompanied by altered structure and function in cortical, limbic, brainstem, and cerebellar regions. The midbrain is relatively unexamined, but contains many integrative nuclei which mediate physiological functions that are disrupted in OSA. We therefore assessed the chemistry of the midbrain in OSA in this exploratory study. We used a recently developed accelerated 2D magnetic resonance spectroscopy (2D-MRS) technique, compressed sensing-based 4D echo-planar J-resolved spectroscopic imaging (4D-EP-JRESI), to measure metabolites in the midbrain of 14 OSA (mean age±SD:54.6±10.6years; AHI:35.0±19.4; SAO 2 min:83±7%) and 26 healthy control (50.7±8.5years) subjects. High-resolution T1-weighted scans allowed voxel localization. MRS data were processed with custom MATLAB-based software, and metabolite ratios calculated with respect to the creatine peak using a prior knowledge fitting (ProFit) algorithm. The midbrain in OSA showed decreased N-acetylaspartate (NAA; OSA:1.24±0.43, Control:1.47±0.41; p=0.03; independent samples t-test), a marker of neuronal viability. Increased levels in OSA over control subjects appeared in glutamate (Glu; OSA:1.23±0.57, Control:0.98±0.33; p=0.03), ascorbate (Asc; OSA:0.56±0.28, Control:0.42±0.20; (50.7±8.5years; p=0.03), and myo-inositol (mI; OSA:0.96±0.48, Control:0.72±0.35; p=0.03). No differences between groups appeared in γ-aminobutyric acid (GABA) or taurine. The midbrain in OSA patients shows decreased NAA, indicating neuronal injury or dysfunction. Higher Glu levels may reflect excitotoxic processes and astrocyte activation, and higher mI is also consistent with glial activation. Higher Asc levels may result from oxidative stress induced by intermittent hypoxia in OSA. Additionally, Asc and Glu are involved with glutamatergic processes, which are likely upregulated in the midbrain nuclei of OSA patients. The altered metabolite levels help explain dysfunction and structural deficits in the midbrain of OSA patients. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

A role for midline and intralaminar thalamus in the associative blocking of Pavlovian fear conditioning.

PubMed

Sengupta, Auntora; McNally, Gavan P

2014-01-01

Fear learning occurs in response to positive prediction error, when the expected outcome of a conditioning trial exceeds that predicted by the conditioned stimuli present. This role for error in Pavlovian association formation is best exemplified by the phenomenon of associative blocking, whereby prior fear conditioning of conditioned stimulus (CS) A is able to prevent learning to CSB when they are conditioned in compound. The midline and intralaminar thalamic nuclei (MIT) are well-placed to contribute to fear prediction error because they receive extensive projections from the midbrain periaqueductal gray-which has a key role in fear prediction error-and project extensively to prefrontal cortex and amygdala. Here we used an associative blocking design to study the role of MIT in fear learning. In Stage I rats were trained to fear CSA via pairings with shock. In Stage II rats received compound fear conditioning of CSAB paired with shock. On test, rats that received Stage I training expressed less fear to CSB relative to control rats that did not receive this training. Microinjection of bupivacaine into MIT prior to Stage II training had no effect on the expression of fear during Stage II and had no effect on fear learning in controls, but prevented associative blocking and so enabled fear learning to CSB. These results show an important role for MIT in predictive fear learning and are discussed with reference to previous findings implicating the midline and posterior intralaminar thalamus in fear learning and fear responding.

N,N-dimethyl-2-(2-amino-4-(18)F-fluorophenylthio)-benzylamine (4-(18)F-ADAM): an improved PET radioligand for serotonin transporters.

PubMed

Shiue, Grace G; Choi, Seok-Rye; Fang, Ping; Hou, Catherine; Acton, Paul D; Cardi, Chris; Saffer, Janet R; Greenberg, Joel H; Karp, Joel S; Kung, Hank F; Shiue, Chyng-Yann

2003-12-01

There has been considerable interest in the development of PET radioligands that are useful for imaging serotonin transporter (SERT) in the living human brain. For the last decade, (11)C-(+)McN5652 has been the most promising PET agent for studying SERT in humans. However, this agent has some limitations. Recently, a new promising SERT PET radioligand, 3-(11)C-amino-4-(2-dimethylaminomethylphenylsulfanyl)benzonitrile, has been reported. We recently reported the synthesis of a new (18)F-labeled SERT PET radioligand, N,N-dimethyl-2-(2-amino-4-(18)F-fluorophenylthio)benzylamine (4-(18)F-ADAM), which may have advantages over (11)C-labeled radioligands. The purpose of this study was to evaluate this newly developed (18)F-labeled PET radioligand as a promising agent for studying SERT in the living human brain. This agent was evaluated by studying its in vitro binding to different monoamine transporters, its in vivo biodistributions in rats, its integrity and pharmacologic profiles in rat brain, and its distribution in a female baboon brain. In vitro binding assays showed that 4-F-ADAM displayed high affinity to SERT sites (inhibition constant = 0.081 nmol/L, using membrane preparations of LLC-PK1 cells expressing the specific transporter) and showed more than 1,000- and 28,000-fold selectivity for SERT over norepinephrine transporter and dopamine transporter, respectively. Biodistribution of 4-(18)F-ADAM in rats showed a high initial uptake and slow clearance in the brain (2.13%, 1.90%, and 0.95% injected dose per organ at 2, 30, and 60 min after intravenous injection, respectively), with the specific binding peaking at 2 h after injection (hypothalamus/cerebellum = 12.49). The uptake in blood, muscle, lung, kidney, and liver was also initially high but cleared rapidly. The radioactivity in the femur increases with time for 4-(18)F-ADAM, indicating that in vivo defluorination may occur. In vivo metabolism studies in rats showed that 4-(18)F-ADAM was not metabolized in rat brain (>96% of radioactivity was recovered as parent compound at 1 h after injection). However, it metabolized rapidly in the blood. Less than 7% of the radioactivity recovered from plasma was the parent compound, with the majority of radioactivity in the plasma not extractable by ethyl acetate. Blocking studies showed significant decreases in the uptake of 4-(18)F-ADAM in the brain regions (hypothalamus, hippocampus, and striatum) where SERT concentrations are high when rats were pretreated with (+)McN5652 (2 mg/kg 5 min before intravenous injection of 4-(18)F-ADAM). However, changes in the uptake of 4-(18)F-ADAM in these brain regions were less significant when rats were pretreated with either methylphenidate or nisoxetine. The baboon study showed that uptake of 4-(18)F-ADAM in the midbrain peaked at approximately 1 h after injection and then declined slowly. The ratios of the radioactivity in the midbrain to that in the cerebellum (where the concentration of SERT is low) at 2 and 3 h after injection were 3.2 and 4.2, respectively. 4-(18)F-ADAM is suitable as a PET radioligand for studying SERT in the living brain. Further characterization of this new radioligand in humans is warranted.

Comparisons of MRI images, and auditory-related and vocal-related protein expressions in the brain of echolocation bats and rodents.

PubMed

Hsiao, Chun-Jen; Hsu, Chih-Hsiang; Lin, Ching-Lung; Wu, Chung-Hsin; Jen, Philip Hung-Sun

2016-08-17

Although echolocating bats and other mammals share the basic design of laryngeal apparatus for sound production and auditory system for sound reception, they have a specialized laryngeal mechanism for ultrasonic sound emissions as well as a highly developed auditory system for processing species-specific sounds. Because the sounds used by bats for echolocation and rodents for communication are quite different, there must be differences in the central nervous system devoted to producing and processing species-specific sounds between them. The present study examines the difference in the relative size of several brain structures and expression of auditory-related and vocal-related proteins in the central nervous system of echolocation bats and rodents. Here, we report that bats using constant frequency-frequency-modulated sounds (CF-FM bats) and FM bats for echolocation have a larger volume of midbrain nuclei (inferior and superior colliculi) and cerebellum relative to the size of the brain than rodents (mice and rats). However, the former have a smaller volume of the cerebrum and olfactory bulb, but greater expression of otoferlin and forkhead box protein P2 than the latter. Although the size of both midbrain colliculi is comparable in both CF-FM and FM bats, CF-FM bats have a larger cerebrum and greater expression of otoferlin and forkhead box protein P2 than FM bats. These differences in brain structure and protein expression are discussed in relation to their biologically relevant sounds and foraging behavior.

The dorsal tectal longitudinal column (TLCd): a second longitudinal column in the paramedian region of the midbrain tectum.

PubMed

Aparicio, M-Auxiliadora; Saldaña, Enrique

2014-03-01

The tectal longitudinal column (TLC) is a longitudinally oriented, long and narrow nucleus that spans the paramedian region of the midbrain tectum of a large variety of mammals (Saldaña et al. in J Neurosci 27:13108-13116, 2007). Recent analysis of the organization of this region revealed another novel nucleus located immediately dorsal, and parallel, to the TLC. Because the name "tectal longitudinal column" also seems appropriate for this novel nucleus, we suggest the TLC described in 2007 be renamed the "ventral tectal longitudinal column (TLCv)", and the newly discovered nucleus termed the "dorsal tectal longitudinal column (TLCd)". This work represents the first characterization of the rat TLCd. A constellation of anatomical techniques was used to demonstrate that the TLCd differs from its surrounding structures (TLCv and superior colliculus) cytoarchitecturally, myeloarchitecturally, neurochemically and hodologically. The distinct expression of vesicular amino acid transporters suggests that TLCd neurons are GABAergic. The TLCd receives major projections from various areas of the cerebral cortex (secondary visual mediomedial area, and granular and dysgranular retrosplenial cortices) and from the medial pretectal nucleus. It densely innervates the ipsilateral lateral posterior and laterodorsal nuclei of the thalamus. Thus, the TLCd is connected with vision-related neural centers. The TLCd may be unique as it constitutes the only known nucleus made of GABAergic neurons dedicated to providing massive inhibition to higher order thalamic nuclei of a specific sensory modality.

Differential distribution of the sodium‐activated potassium channels slick and slack in mouse brain

PubMed Central

Knaus, Hans‐Günther; Schwarzer, Christoph

2015-01-01

ABSTRACT The sodium‐activated potassium channels Slick (Slo2.1, KCNT2) and Slack (Slo2.2, KCNT1) are high‐conductance potassium channels of the Slo family. In neurons, Slick and Slack channels are involved in the generation of slow afterhyperpolarization, in the regulation of firing patterns, and in setting and stabilizing the resting membrane potential. The distribution and subcellular localization of Slick and Slack channels in the mouse brain have not yet been established in detail. The present study addresses this issue through in situ hybridization and immunohistochemistry. Both channels were widely distributed and exhibited distinct distribution patterns. However, in some brain regions, their expression overlapped. Intense Slick channel immunoreactivity was observed in processes, varicosities, and neuronal cell bodies of the olfactory bulb, granular zones of cortical regions, hippocampus, amygdala, lateral septal nuclei, certain hypothalamic and midbrain nuclei, and several regions of the brainstem. The Slack channel showed primarily a diffuse immunostaining pattern, and labeling of cell somata and processes was observed only occasionally. The highest Slack channel expression was detected in the olfactory bulb, lateral septal nuclei, basal ganglia, and distinct areas of the midbrain, brainstem, and cerebellar cortex. In addition, comparing our data obtained from mouse brain with a previously published study on rat brain revealed some differences in the expression and distribution of Slick and Slack channels in these species. J. Comp. Neurol. 524:2093–2116, 2016. © 2015 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc. PMID:26587966

Encoding of natural and artificial stimuli in the auditory midbrain

NASA Astrophysics Data System (ADS)

Lyzwa, Dominika

How complex acoustic stimuli are encoded in the main center of convergence in the auditory midbrain is not clear. Here, the representation of neural spiking responses to natural and artificial sounds across this subcortical structure is investigated based on neurophysiological recordings from the mammalian midbrain. Neural and stimulus correlations of neuronal pairs are analyzed with respect to the neurons' distance, and responses to different natural communication sounds are discriminated. A model which includes linear and nonlinear neural response properties of this nucleus is presented and employed to predict temporal spiking responses to new sounds. Supported by BMBF Grant 01GQ0811.

Development and function of the midbrain dopamine system: what we know and what we need to.

PubMed

Bissonette, G B; Roesch, M R

2016-01-01

The past two decades have seen an explosion in our understanding of the origin and development of the midbrain dopamine system. Much of this work has been focused on the aspects of dopamine neuron development related to the onset of movement disorders such as Parkinson's disease, with the intent of hopefully delaying, preventing or fixing symptoms. While midbrain dopamine degeneration is a major focus for treatment and research, many other human disorders are impacted by abnormal dopamine, including drug addiction, autism and schizophrenia. Understanding dopamine neuron ontogeny and how dopamine connections and circuitry develops may provide us with key insights into potentially important avenues of research for other dopamine-related disorders. This review will provide a brief overview of the major molecular and genetic players throughout the development of midbrain dopamine neurons and what we know about the behavioral- and disease-related implications associated with perturbations to midbrain dopamine neuron development. We intend to combine the knowledge of two broad fields of neuroscience, both developmental and behavioral, with the intent on fostering greater discussion between branches of neuroscience in the service of addressing complex cognitive questions from a developmental perspective and identifying important gaps in our knowledge for future study. © 2015 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Lateral suboccipital retrosigmoid approach with tentorial incision for petroclival meningiomas: technical note.

PubMed

Yamahata, Hitoshi; Tokimura, Hiroshi; Hirahara, Kazuho; Ishii, Takeshi; Mori, Masanao; Hanaya, Ryosuke; Arita, Kazunori

2014-08-01

Introduction The resection of petroclival meningiomas presents great neurosurgical challenges. Although multiple surgical approaches have been developed, the retrosigmoid route tends to be used to address tumors that are predominantly located in the posterior fossa. Our modification of the lateral suboccipital retrosigmoid approach with the placement of a tentorial incision yields good visualization of the supratentorial part of the tumor around the midbrain. Methods We treated four patients, one with primary and three with recurrent petroclival meningioma, by our modified approach. After lateral suboccipital craniotomy, the infratentorial part of the tumor was removed after detaching it from the tentorial surface. The cerebellar tentorium was then carefully incised from the supracerebellar angle, taking care not to damage the superior cerebellar artery and trochlear nerve. Results The operative field surrounding the midbrain was widened by this procedure, and safe dissection of the tumor from the brainstem and other neurovascular structures was performed with direct observation of the interface. Conclusions Our approach is a useful modification of the retrosigmoid approach to petroclival meningiomas. It facilitates the safe resection of the supratentorial part of the tumor in the ambient cistern behind the tentorium.

Navigation-supported diagnosis of the substantia nigra by matching midbrain sonography and MRI

NASA Astrophysics Data System (ADS)

Salah, Zein; Weise, David; Preim, Bernhard; Classen, Joseph; Rose, Georg

2012-03-01

Transcranial sonography (TCS) is a well-established neuroimaging technique that allows for visualizing several brainstem structures, including the substantia nigra, and helps for the diagnosis and differential diagnosis of various movement disorders, especially in Parkinsonian syndromes. However, proximate brainstem anatomy can hardly be recognized due to the limited image quality of B-scans. In this paper, a visualization system for the diagnosis of the substantia nigra is presented, which utilizes neuronavigated TCS to reconstruct tomographical slices from registered MRI datasets and visualizes them simultaneously with corresponding TCS planes in realtime. To generate MRI tomographical slices, the tracking data of the calibrated ultrasound probe are passed to an optimized slicing algorithm, which computes cross sections at arbitrary positions and orientations from the registered MRI dataset. The extracted MRI cross sections are finally fused with the region of interest from the ultrasound image. The system allows for the computation and visualization of slices at a near real-time rate. Primary tests of the system show an added value to the pure sonographic imaging. The system also allows for reconstructing volumetric (3D) ultrasonic data of the region of interest, and thus contributes to enhancing the diagnostic yield of midbrain sonography.

[Comparative characteristics of the functioning of brain structures exposed to morphine and D-phenylalanine].

PubMed

Iarosh, A K; Goruk, P S; Luk'ianov, E A

1987-01-01

In experiments on rats it was shown that morphine and D-phenylalanine in doses of 5 and 100 mg/kg, respectively, produce a similar by the degree increase of pain reaction thresholds at stimulation of paws through the electrified floor of the chamber. Experiments on rabbits demonstrated that the main factor in morphine action is a decrease of excitability and blood filling of the reticular formation of the midbrain and the central gray matter and an increase of excitability of the dorsal hippocamp without significant changes in the frontal cortex excitability. D-phenylalanine also caused a decrease of excitability of the reticular formation but in contrast to morphine failed to change excitability of the dorsal hippocamp and enhanced excitability of the central gray matter.

Enhanced midbrain response at 6-month follow-up in cocaine addiction, association with reduced drug-related choice: Midbrain in drug choice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moeller, Scott J.; Tomasi, Dardo; Woicik, Patricia A.

Drug addiction is characterized by dysregulated dopamine neurotransmission. Although dopamine functioning appears to partially recover with abstinence, the specific regions that recover and potential impact on drug seeking remain to be determined. Here we used functional magnetic resonance imaging (fMRI) to study an ecologically valid sample of 15 treatment-seeking cocaine addicted individuals at baseline and 6-month follow-up. At both study sessions, we collected fMRI scans during performance of a drug Stroop task, clinical self-report measures of addiction severity and behavioral measures of cocaine seeking (simulated cocaine choice); actual drug use in between the two study sessions was also monitored. Atmore » 6-month follow-up (compared with baseline), we predicted functional enhancement of dopaminergically innervated brain regions, relevant to the behavioral responsiveness toward salient stimuli. Consistent with predictions, whole-brain analyses revealed responses in the midbrain (encompassing the ventral tegmental area/substantia nigra complex) and thalamus (encompassing the mediodorsal nucleus) that were higher (and more positively correlated) at follow-up than baseline. Increased midbrain activity from baseline to follow-up correlated with reduced simulated cocaine choice, indicating that heightened midbrain activations in this context may be marking lower approach motivation for cocaine. Normalization of midbrain function at follow-up was also suggested by exploratory comparisons with active cocaine users and healthy controls (who were assessed only at baseline). Enhanced self-control at follow-up was suggested by a trend for the commonly hypoactive dorsal anterior cingulate cortex to increase response during a drug-related context. Together, these results suggest that fMRI could be useful in sensitively tracking follow-up outcomes in drug addiction.« less

Graded levels of FGF protein span the midbrain and can instruct graded induction and repression of neural mapping labels

PubMed Central

Chen, Yao; Mohammadi, Moosa; Flanagan, John G.

2009-01-01

Summary Graded guidance labels are widely used in neural map formation, but it is not well understood which potential strategy leads to their graded expression. In midbrain tectal map development, FGFs can induce an entire midbrain, but their protein distribution is unclear, nor is it known whether they may act instructively to produce graded gene expression. Using a receptor-alkaline phosphatase fusion probe, we find a long-range posterior>anterior FGF protein gradient spanning the midbrain. Heparan sulfate proteoglycan (HSPG) is required for this gradient. To test whether graded FGF concentrations can instruct graded gene expression, a quantitative tectal explant assay was developed. Engrailed-2 and ephrin-As, normally in posterior>anterior tectal gradients, showed graded upregulation. Moreover, EphAs, normally in anterior>posterior countergradients, showed coordinately graded downregulation. These results provide a mechanism to establish graded mapping labels, and more generally provide a developmental strategy to coordinately induce a structure and pattern its cell properties in gradients. PMID:19555646

Does the Superior Colliculus Control Perceptual Sensitivity or Choice Bias during Attention? Evidence from a Multialternative Decision Framework

PubMed Central

Steinmetz, Nicholas A.; Moore, Tirin; Knudsen, Eric I.

2017-01-01

Distinct networks in the forebrain and the midbrain coordinate to control spatial attention. The critical involvement of the superior colliculus (SC)—the central structure in the midbrain network—in visuospatial attention has been shown by four seminal, published studies in monkeys (Macaca mulatta) performing multialternative tasks. However, due to the lack of a mechanistic framework for interpreting behavioral data in such tasks, the nature of the SC's contribution to attention remains unclear. Here we present and validate a novel decision framework for analyzing behavioral data in multialternative attention tasks. We apply this framework to re-examine the behavioral evidence from these published studies. Our model is a multidimensional extension to signal detection theory that distinguishes between two major classes of attentional mechanisms: those that alter the quality of sensory information or “sensitivity,” and those that alter the selective gating of sensory information or “choice bias.” Model-based simulations and model-based analyses of data from these published studies revealed a converging pattern of results that indicated that choice-bias changes, rather than sensitivity changes, were the primary outcome of SC manipulation. Our results suggest that the SC contributes to attentional performance predominantly by generating a spatial choice bias for stimuli at a selected location, and that this bias operates downstream of forebrain mechanisms that enhance sensitivity. The findings lead to a testable mechanistic framework of how the midbrain and forebrain networks interact to control spatial attention. SIGNIFICANCE STATEMENT Attention involves the selection of the most relevant information for differential sensory processing and decision making. While the mechanisms by which attention alters sensory encoding (sensitivity control) are well studied, the mechanisms by which attention alters decisional weighting of sensory evidence (choice-bias control) are poorly understood. Here, we introduce a model of multialternative decision making that distinguishes bias from sensitivity effects in attention tasks. With our model, we simulate experimental data from four seminal studies that microstimulated or inactivated a key attention-related midbrain structure, the superior colliculus (SC). We demonstrate that the experimental effects of SC manipulation are entirely consistent with the SC controlling attention by changing choice bias, thereby shedding new light on how the brain mediates attention. PMID:28100734

Does the Superior Colliculus Control Perceptual Sensitivity or Choice Bias during Attention? Evidence from a Multialternative Decision Framework.

PubMed

Sridharan, Devarajan; Steinmetz, Nicholas A; Moore, Tirin; Knudsen, Eric I

2017-01-18

Distinct networks in the forebrain and the midbrain coordinate to control spatial attention. The critical involvement of the superior colliculus (SC)-the central structure in the midbrain network-in visuospatial attention has been shown by four seminal, published studies in monkeys (Macaca mulatta) performing multialternative tasks. However, due to the lack of a mechanistic framework for interpreting behavioral data in such tasks, the nature of the SC's contribution to attention remains unclear. Here we present and validate a novel decision framework for analyzing behavioral data in multialternative attention tasks. We apply this framework to re-examine the behavioral evidence from these published studies. Our model is a multidimensional extension to signal detection theory that distinguishes between two major classes of attentional mechanisms: those that alter the quality of sensory information or "sensitivity," and those that alter the selective gating of sensory information or "choice bias." Model-based simulations and model-based analyses of data from these published studies revealed a converging pattern of results that indicated that choice-bias changes, rather than sensitivity changes, were the primary outcome of SC manipulation. Our results suggest that the SC contributes to attentional performance predominantly by generating a spatial choice bias for stimuli at a selected location, and that this bias operates downstream of forebrain mechanisms that enhance sensitivity. The findings lead to a testable mechanistic framework of how the midbrain and forebrain networks interact to control spatial attention. Attention involves the selection of the most relevant information for differential sensory processing and decision making. While the mechanisms by which attention alters sensory encoding (sensitivity control) are well studied, the mechanisms by which attention alters decisional weighting of sensory evidence (choice-bias control) are poorly understood. Here, we introduce a model of multialternative decision making that distinguishes bias from sensitivity effects in attention tasks. With our model, we simulate experimental data from four seminal studies that microstimulated or inactivated a key attention-related midbrain structure, the superior colliculus (SC). We demonstrate that the experimental effects of SC manipulation are entirely consistent with the SC controlling attention by changing choice bias, thereby shedding new light on how the brain mediates attention. Copyright © 2017 the authors 0270-6474/17/370480-32$15.00/0.

Protection of Primary Dopaminergic Midbrain Neurons by GPR139 Agonists Supports Different Mechanisms of MPP+ and Rotenone Toxicity

PubMed Central

Bayer Andersen, Kirsten; Leander Johansen, Jens; Hentzer, Morten; Smith, Garrick Paul; Dietz, Gunnar P. H.

2016-01-01

The G-protein coupled receptor 139 (GPR139) is expressed specifically in the brain in areas of relevance for motor control. GPR139 function and signal transduction pathways are elusive, and results in the literature are even contradictory. Here, we examined the potential neuroprotective effect of GPR139 agonism in primary culture models of dopaminergic (DA) neuronal degeneration. We find that in vitro GPR139 agonists protected primary mesencephalic DA neurons against 1-methyl-4-phenylpyridinium (MPP+)-mediated degeneration. Protection was concentration-dependent and could be blocked by a GPR139 antagonist. However, the protection of DA neurons was not found against rotenone or 6-hydroxydopamine (6-OHDA) mediated degeneration. Our results support differential mechanisms of toxicity for those substances commonly used in Parkinson’s disease (PD) models and potential for GPR139 agonists in neuroprotection. PMID:27445691

Parkinson's disease candidate gene prioritization based on expression profile of midbrain dopaminergic neurons

PubMed Central

2010-01-01

Background Parkinson's disease is the second most common neurodegenerative disorder. The pathological hallmark of the disease is degeneration of midbrain dopaminergic neurons. Genetic association studies have linked 13 human chromosomal loci to Parkinson's disease. Identification of gene(s), as part of the etiology of Parkinson's disease, within the large number of genes residing in these loci can be achieved through several approaches, including screening methods, and considering appropriate criteria. Since several of the indentified Parkinson's disease genes are expressed in substantia nigra pars compact of the midbrain, expression within the neurons of this area could be a suitable criterion to limit the number of candidates and identify PD genes. Methods In this work we have used the combination of findings from six rodent transcriptome analysis studies on the gene expression profile of midbrain dopaminergic neurons and the PARK loci in OMIM (Online Mendelian Inheritance in Man) database, to identify new candidate genes for Parkinson's disease. Results Merging the two datasets, we identified 20 genes within PARK loci, 7 of which are located in an orphan Parkinson's disease locus and one, which had been identified as a disease gene. In addition to identifying a set of candidates for further genetic association studies, these results show that the criteria of expression in midbrain dopaminergic neurons may be used to narrow down the number of genes in PARK loci for such studies. PMID:20716345

Retinal input to efferent target amacrine cells in the avian retina

PubMed Central

Lindstrom, Sarah H.; Azizi, Nason; Weller, Cynthia; Wilson, Martin

2012-01-01

The bird visual system includes a substantial projection, of unknown function, from a midbrain nucleus to the contralateral retina. Every centrifugal, or efferent, neuron originating in the midbrain nucleus makes synaptic contact with the soma of a single, unique amacrine cell, the target cell (TC). By labeling efferent neurons in the midbrain we have been able to identify their terminals in retinal slices and make patch clamp recordings from TCs. TCs generate Na+ based action potentials triggered by spontaneous EPSPs originating from multiple classes of presynaptic neurons. Exogenously applied glutamate elicited inward currents having the mixed pharmacology of NMDA, kainate and inward rectifying AMPA receptors. Exogenously applied GABA elicited currents entirely suppressed by GABAzine, and therefore mediated by GABAA receptors. Immunohistochemistry showed the vesicular glutamate transporter, vGluT2, to be present in the characteristic synaptic boutons of efferent terminals, whereas the GABA synthetic enzyme, GAD, was present in much smaller processes of intrinsic retinal neurons. Extracellular recording showed that exogenously applied GABA was directly excitatory to TCs and, consistent with this, NKCC, the Cl− transporter often associated with excitatory GABAergic synapses, was identified in TCs by antibody staining. The presence of excitatory retinal input to TCs implies that TCs are not merely slaves to their midbrain input; instead, their output reflects local retinal activity and descending input from the midbrain. PMID:20650017

Midbrain Gene Screening Identifies a New Mesoaccumbal Glutamatergic Pathway and a Marker for Dopamine Cells Neuroprotected in Parkinson’s Disease

PubMed Central

Viereckel, Thomas; Dumas, Sylvie; Smith-Anttila, Casey J. A.; Vlcek, Bianca; Bimpisidis, Zisis; Lagerström, Malin C.; Konradsson-Geuken, Åsa; Wallén-Mackenzie, Åsa

2016-01-01

The ventral tegmental area (VTA) and substantia nigra pars compacta (SNc) of the midbrain are associated with Parkinson’s disease (PD), schizophrenia, mood disorders and addiction. Based on the recently unraveled heterogeneity within the VTA and SNc, where glutamate, GABA and co-releasing neurons have been found to co-exist with the classical dopamine neurons, there is a compelling need for identification of gene expression patterns that represent this heterogeneity and that are of value for development of human therapies. Here, several unique gene expression patterns were identified in the mouse midbrain of which NeuroD6 and Grp were expressed within different dopaminergic subpopulations of the VTA, and TrpV1 within a small heterogeneous population. Optogenetics-coupled in vivo amperometry revealed a previously unknown glutamatergic mesoaccumbal pathway characterized by TrpV1-Cre-expression. Human GRP was strongly detected in non-melanized dopaminergic neurons within the SNc of both control and PD brains, suggesting GRP as a marker for neuroprotected neurons in PD. This study thus unravels markers for distinct subpopulations of neurons within the mouse and human midbrain, defines unique anatomical subregions within the VTA and exposes an entirely new glutamatergic pathway. Finally, both TRPV1 and GRP are implied in midbrain physiology of importance to neurological and neuropsychiatric disorders. PMID:27762319

Phosphodiesterase 7 Inhibition Induces Dopaminergic Neurogenesis in Hemiparkinsonian Rats

PubMed Central

Morales-Garcia, Jose A.; Alonso-Gil, Sandra; Gil, Carmen; Martinez, Ana; Santos, Angel

2015-01-01

Parkinson’s disease is characterized by a loss of dopaminergic neurons in a specific brain region, the ventral midbrain. Parkinson’s disease is diagnosed when approximately 50% of the dopaminergic neurons of the substantia nigra pars compacta (SNpc) have degenerated and the others are already affected by the disease. Thus, it is conceivable that all therapeutic strategies, aimed at neuroprotection, start too late. Therefore, an urgent medical need exists to discover new pharmacological targets and novel drugs with disease-modifying properties. In this regard, modulation of endogenous adult neurogenesis toward a dopaminergic phenotype might provide a new strategy to target Parkinson’s disease by partially ameliorating the dopaminergic cell loss that occurs in this disorder. We have previously shown that a phosphodiesterase 7 (PDE7) inhibitor, S14, exerts potent neuroprotective and anti-inflammatory effects in different rodent models of Parkinson’s disease, indicating that this compound could represent a novel therapeutic agent to stop the dopaminergic cell loss that occurs during the progression of the disease. In this report we show that, in addition to its neuroprotective effect, the PDE7 inhibitor S14 is also able to induce endogenous neuroregenerative processes toward a dopaminergic phenotype. We describe a population of actively dividing cells that give rise to new neurons in the SNpc of hemiparkinsonian rats after treatment with S14. In conclusion, our data identify S14 as a novel regulator of dopaminergic neuron generation. Significance Parkinson’s disease is a neurodegenerative disorder characterized by the loss of dopaminergic neurons in the ventral midbrain. Currently, no cure and no effective disease-modifying therapy are available for Parkinson’s disease; therefore, an urgent medical need exists to discover new pharmacological targets and novel drugs for the treatment of this disorder. The present study reports that an inhibitor of the enzyme phosphodiesterase 7 (S14) induces proliferation in vitro and in vivo of neural stem cells, promoting its differentiation toward a dopaminergic phenotype and therefore enhancing dopaminergic neuron generation. Because this drug is also able to confer neuroprotection of these cells in animal models of Parkinson’s disease, S14 holds great promise as a therapeutic new strategy for this disorder. PMID:25925836

Glutamate spillover modulates GABAergic synaptic transmission in the rat midbrain periaqueductal grey via metabotropic glutamate receptors and endocannabinoid signaling.

PubMed

Drew, Geoffrey M; Mitchell, Vanessa A; Vaughan, Christopher W

2008-01-23

Glutamate spillover regulates GABAergic synaptic transmission at several CNS synapses via presynaptic ionotropic and metabotropic glutamate receptors (mGluRs). We have previously demonstrated that activation of group I-III mGluRs inhibits GABAergic transmission in the midbrain periaqueductal gray (PAG), a region involved in organizing behavioral responses to threat, stress, and pain. Here, we examined the role of glutamate spillover in the modulation of GABAergic transmission in the PAG. Using whole-cell recordings from rat PAG slices, we found that evoked IPSCs were reduced by the nonspecific glutamate transport blockers DL-threo-beta-benzyloxyaspartic acid (TBOA) and L-trans-pyrrolidine-2,4-dicarboxylic acid, but not by the glial GLT1-specific blocker dihydrokainate. In contrast, TBOA had no effect on evoked IPSCs when glutamate uptake into the postsynaptic neuron was selectively impaired. TBOA increased the paired-pulse ratio of evoked IPSCs and reduced the rate but not the amplitude of spontaneous miniature IPSCs. The effect of TBOA on evoked IPSCs was abolished by the broad-spectrum mGluR antagonist (2S)-2-amino-2-[(1S,2S)-2-carboxycycloprop-1-yl]-3-(xanth-9-yl) propanoic acid (100 microM), reduced by the mGluR5-specific antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) and mimicked by the mGluR1/5 agonist (RS)-3,5-dihydroxyphenylglycine (DHPG). Furthermore, the effects of both TBOA and DHPG were reduced by the cannabinoid CB1 receptor antagonist 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-1-piperidinyl-1H-pyrazole-3-carboxamide (AM251). Finally, although MPEP and AM251 had no effect on single evoked IPSCs, they increased evoked IPSCs during repetitive stimulation. These results indicate that neuronal glutamate transporters limit mGluR5 activation and endocannabinoid signaling, but may be overwhelmed during conditions of elevated glutamate release. Thus, neuronal glutamate transporters play a key role in regulating endocannabinoid-mediated cross talk between glutamatergic and GABAergic synapses within the PAG.

Mitochondrial uncoupling agents antagonize rotenone actions in rat substantia nigra dopamine neurons.

PubMed

Wu, Yan-Na; Munhall, Adam C; Johnson, Steven W

2011-06-13

Mild uncoupling of oxidative phosphorylation has been reported to reduce generation of reactive oxygen species (ROS) and therefore may be neuroprotective. We reported previously that the mitochondrial poison rotenone enhanced currents evoked by N-methyl-D-aspartate (NMDA) by a ROS-dependent mechanism in rat midbrain dopamine neurons. Thus, rotenone, which produces a model of Parkinson's disease in rodents, may increase the risk of dopamine neuron excitotoxicity. The purpose of this study was to test the hypothesis that oxidative phosphorylation uncoupling agents would antagonize the effect of rotenone on NMDA current. We used patch pipettes to record whole-cell currents under voltage-clamp (-60 mV) in substantia nigra dopamine neurons in slices of rat brain. Rotenone, NMDA and uncoupling agents were added to the brain slice superfusate. Inward currents evoked by NMDA (30 μM) more than doubled in amplitude after slices were superfused for 30 min with 100 nM rotenone. Continuous superfusion with the uncoupling agent carbonyl cyanide-p-trifluoromethoxy-phenylhydrazone (1-3 nM) or 2,4-dinitrophenol (100 nM) significantly antagonized and delayed the ability of rotenone to potentiate NMDA currents. Coenzyme Q₁₀ (1-10 nM), which has been reported to facilitate uncoupling protein activity, also antagonized this action of rotenone. These results suggest that mild uncoupling of oxidative phosphorylation may protect dopamine neurons against injury from mitochondrial poisons such as rotenone. Published by Elsevier B.V.

Reducing Ventral Tegmental Dopamine D2 Receptor Expression Selectively Boosts Incentive Motivation

PubMed Central

de Jong, Johannes W; Roelofs, Theresia J M; Mol, Frédérique M U; Hillen, Anne E J; Meijboom, Katharina E; Luijendijk, Mieneke C M; van der Eerden, Harrie A M; Garner, Keith M; Vanderschuren, Louk J M J; Adan, Roger A H

2015-01-01

Altered mesolimbic dopamine signaling has been widely implicated in addictive behavior. For the most part, this work has focused on dopamine within the striatum, but there is emerging evidence for a role of the auto-inhibitory, somatodendritic dopamine D2 receptor (D2R) in the ventral tegmental area (VTA) in addiction. Thus, decreased midbrain D2R expression has been implicated in addiction in humans. Moreover, knockout of the gene encoding the D2R receptor (Drd2) in dopamine neurons has been shown to enhance the locomotor response to cocaine in mice. Therefore, we here tested the hypothesis that decreasing D2R expression in the VTA of adult rats, using shRNA knockdown, promotes addiction-like behavior in rats responding for cocaine or palatable food. Rats with decreased VTA D2R expression showed markedly increased motivation for both sucrose and cocaine under a progressive ratio schedule of reinforcement, but the acquisition or maintenance of cocaine self-administration were not affected. They also displayed enhanced cocaine-induced locomotor activity, but no change in basal locomotion. This robust increase in incentive motivation was behaviorally specific, as we did not observe any differences in fixed ratio responding, extinction responding, reinstatement or conditioned suppression of cocaine, and sucrose seeking. We conclude that VTA D2R knockdown results in increased incentive motivation, but does not directly promote other aspects of addiction-like behavior. PMID:25735756

GABA(A) receptor antagonism in the ventrocaudal periaqueductal gray increases anxiety in the anxiety-resistant postpartum rat.

PubMed

Miller, Stephanie M; Piasecki, Christopher C; Peabody, Mitchell F; Lonstein, Joseph S

2010-06-01

Postpartum mammals show suppressed anxiety, which is necessary for their ability to appropriately care for offspring. It is parsimonious to suggest that the neurobiological basis of this reduced anxiety is similar to that of non-parturient animals, involving GABA(A) receptor activity in sites including the midbrain periaqueductal gray (PAG). In Experiment 1, postpartum and diestrous virgin female rats received an intraperitoneal injection of the GABA(A) receptor antagonist (+)-bicuculline (0, 2 and 4 mg/kg) and anxiety-related behavior was assessed with an elevated plus maze. The 4 mg/kg dose of (+)-bicuculline significantly increased anxiety-related behavior, particularly in the postpartum females. Experiment 2 revealed that bicuculline's action was within the central nervous system, because anxiety in neither dams nor virgins was significantly affected by intraperitoneal injection of bicuculline methiodide (0, 2 and 6 mg/kg), which does not readily cross the blood-brain-barrier. In Experiment 3, bicuculline methiodide (2.5 ng/side) was directly infused into the ventrocaudal PAG (cPAGv) and significantly increased dams' anxiety compared to saline-infused controls. These studies expand our knowledge of how GABA(A) receptor modulators affect anxiety behaviors in postpartum rats to the widely-used elevated plus maze, and indicate that the postpartum suppression of anxiety is in part a consequence of elevated GABAergic neurotransmission in the cPAGv. Copyright 2010 Elsevier Inc. All rights reserved.

Viral vector-mediated downregulation of RhoA increases survival and axonal regeneration of retinal ganglion cells

PubMed Central

Koch, Jan Christoph; Tönges, Lars; Michel, Uwe; Bähr, Mathias; Lingor, Paul

2014-01-01

The Rho/ROCK pathway is a promising therapeutic target in neurodegenerative and neurotraumatic diseases. Pharmacological inhibition of various pathway members has been shown to promote neuronal regeneration and survival. However, because pharmacological inhibitors are inherently limited in their specificity, shRNA-mediated approaches can add more information on the function of each single kinase involved. Thus, we generated adeno-associated viral vectors (AAV) to specifically downregulate Ras homologous member A (RhoA) via shRNA. We found that specific knockdown of RhoA promoted neurite outgrowth of retinal ganglion cells (RGC) grown on the inhibitory substrate chondroitin sulfate proteoglycan (CSPG) as well as neurite regeneration of primary midbrain neurons (PMN) after scratch lesion. In the rat optic nerve crush (ONC) model in vivo, downregulation of RhoA significantly enhanced axonal regeneration compared to control. Moreover, survival of RGC transduced with AAV expressing RhoA-shRNA was substantially increased at 2 weeks after optic nerve axotomy. Compared to previous data using pharmacological inhibitors to target RhoA, its upstream regulator Nogo or its main downstream target ROCK, the specific effects of RhoA downregulation shown here were most pronounced in regard to promoting RGC survival but neurite outgrowth and axonal regeneration were also increased significantly. Taken together, we show here that specific knockdown of RhoA substantially increases neuronal survival after optic nerve axotomy and modestly increases neurite outgrowth in vitro and axonal regeneration after optic nerve crush. PMID:25249936

Holmes Tremor Secondary to a Stabbing Lesion in the Midbrain.

PubMed

Cury, Rubens Gisbert; Barbosa, Egberto Reis; Freitas, Christian; de Souza Godoy, Luis Filipe; Paiva, Wellingson Silva

2017-01-01

The development of Holmes tremor (HT) after a direct lesion of the midbrain has rarely been reported in the literature, although several etiologies have been linked with HT, such as stroke, brainstem tumors, multiple sclerosis, head trauma, or infections. A 31-year-old male, having been stabbed in the right eye, presented with a rest and action tremor in the left upper limb associated with left hemiparesis with corresponding post-contrast volumetric magnetic resonance imaging T1 with sagittal oblique reformation showing the knife trajectory reaching the right midbrain. Despite the rarity of the etiology of HT in the present case, clinicians working with persons with brain injuries should be aware of this type of situation.

Neuroprotective Effect of Exogenous Melatonin on Dopaminergic Neurons of the Substantia Nigra in Ovariectomized Rats

PubMed Central

Mehraein, Fereshteh; Talebi, Reza; Jameie, Behnamedin; Joghataie, Mohammad Taghi; Madjd, Zahra

2011-01-01

Background: Melatonin has receptors in substantia nigra pars compacta (SNc) and regulates development of dopaminergic (DA) neurons. This study was undertaken to determine ability of melatonin to protect SNc dopaminergic neuron loss induced by estrogen deficiency in ovariectomized rats. Methods: Female rats were randomized into four groups of seven each: control, ethanol sham, ovariectomy (ovx) and ovx with melatonin (ovx + m). In ovx, ovaries were removed. Ovx + m group was intraperitoneally injected with melatonin for 10 days, while the ethanol sham group received only ethanol. All rats were perfused with 4% paraformaldehyde, midbrains removed, fixed and paraffin embedded, then processed for Nissl and tyrosine hydroxylase staining (IHC). Ten sections of SNc in Nissl and IHC staining were analyzed in each animal, Nissl stained and tyrosine hydroxylase (TH) immunoreactive cells were counted in five experimental groups randomly. Data was analyzed using SPSS by ANOVA and t-test. Differences were considered significant for P<0.05. Results: There was less cell number in ovx compared to control and ethanol sham groups significantly (P<0.001). The ovx + m group had more cells than the ovx group in the SNc significantly (P<0.001). Furthermore, there was significant decrease of TH positive cell number in the ovx group compared to control and ethanol sham groups (P<0.05). The number of TH immunoreactive cells was higher in ovx + m compared to the ovx group (P<0.05). Conclusion: These findings can be compared with human and used in clinical application for prevention of DA neuron death of SNc after ovariectomy. PMID:21725499

Developmental PCB Exposure Increases Audiogenic Seizures and Decreases Glutamic Acid Decarboxylase in the Inferior Colliculus

PubMed Central

Bandara, Suren B.; Eubig, Paul A.; Sadowski, Renee N.; Schantz, Susan L.

2016-01-01

Previously, we observed that developmental polychlorinated biphenyl (PCB) exposure resulted in an increase in audiogenic seizures (AGSs) in rats. However, the rats were exposed to loud noise in adulthood, and were not tested for AGS until after 1 year of age, either of which could have interacted with early PCB exposure to increase AGS susceptibility. This study assessed susceptibility to AGS in young adult rats following developmental PCB exposure alone (without loud noise exposure) and investigated whether there was a decrease in GABA inhibitory neurotransmission in the inferior colliculus (IC) that could potentially explain this effect. Female Long-Evans rats were dosed orally with 0 or 6 mg/kg/day of an environmentally relevant PCB mixture from 28 days prior to breeding until the pups were weaned at postnatal day 21. One male-female pair from each litter was retained for the AGS study whilst another was retained for Western blot analysis of glutamic acid decarboxylase (GAD) and GABAAα1 receptor in the IC, the site in the auditory midbrain where AGS are initiated. There was a significant increase in the number and severity of AGSs in the PCB groups, with females somewhat more affected than males. GAD65 was decreased but there was no change in GAD67 or GABAAα1 in the IC indicating decreased inhibitory regulation in the PCB group. These results confirm that developmental PCB exposure alone is sufficient to increase susceptibility to AGS, and provide the first evidence for a possible mechanism of action at the level of the IC. PMID:26543103

Ebf2 is required for development of dopamine neurons in the midbrain periaqueductal gray matter of mouse.

PubMed

Yang, Qiaoqiao; Liu, Shuxi; Yin, Min; Yin, Yanqing; Zhou, Guomin; Zhou, Jiawei

2015-11-01

Dopaminergic (DA) neurons in the midbrain ventral periaqueductal gray matter (PAG) play critical roles in various physiological and pathophysiological processes including sleep-wake rhyme, antinociception, and drug addiction. However, the molecular mechanisms underlying their development are poorly understood. Here, we showed that PAG DA neurons arose as early as E15.5 in mouse embryos. During the prenatal period, the majority of PAG DA neurons was distributed in the intermediate and caudal regions of the PAG. In the postnatal brain, ∼50% of PAG DA neurons were preferentially located in the caudal portion of the PAG. Moreover, transcription factor early B-cell factor 2 (Ebf2) was transiently expressed in a subset of DA neurons in embryonic ventral mesencephalon. Functional analysis revealed that loss of Ebf2 in vivo caused a marked reduction in the number of DA neurons in the midbrain PAG but not in the substantia nigra and ventral tegmental area. Thus, Ebf2 is identified as a novel and important regulator selectively required for midbrain PAG DA neuron development. © 2015 Wiley Periodicals, Inc.

Utility of a tripolar stimulating electrode for eliciting dopamine release in the rat striatum.

PubMed

Bergstrom, B P; Garris, P A

1999-03-01

The present study evaluated tripolar stimulating electrodes for eliciting dopamine release in the rat brain in vivo. Stimulating electrodes were placed either in the medial forebrain bundle or in the ventral mesencephalon associated with the ventral tegmental area and substantia nigra. The concentration of extracellular dopamine was monitored in dopamine terminal fields at 100-ms intervals using fast-scan cyclic voltammetry at carbon-fiber microelectrodes. To characterize the stimulated area, recordings were collected in several striatal regions including the caudate putamen and the core and shell of the nucleus accumbens. The tripolar electrode was equally effective in stimulating dopamine release in medial and lateral regions of the striatum. In contrast, responses evoked by a bipolar electrode were typically greater in one mediolateral edge versus the other. The added size of the tripolar electrode did not appear to cause complications as signals were stable over the course of the experiment (3 h). Subsets of mesostriatal dopamine neurons could also be selectively activated using the tripolar electrode in excellent agreement with previously described topography. Taken together, these results suggested that the tripolar stimulating electrode is well suited for studying the regulation of midbrain dopamine neurons in vivo.

Alteration in the level of endogenous hypothalamic prostaglandins induced by delta 9-tetrahydrocannabinol in the rat.

PubMed Central

Coupar, I. M.; Taylor, D. A.

1982-01-01

1 Whole brain and regional brain levels of prostaglandin E2 (PGE2)-like material have been determined following administration of delta 9-tetrahydrocannabinol (delta 9 -THC) in rats. 2 Intravenous administration of delta 9-THC 2 mg/kg, resulted in marked behavioural changes and hypothermia. The behavioural changes consisted mainly of catatonia (most apparent at 30 min after administration of delta 9-THC), followed by sedation (most evident at 60 min). Hypothermia was marked from 30 min after administration of delta 9-THC. 3 delta 9-THC did not after the whole brain levels of PGE2-like material 30, 60 or 120 min after administration. 4 delta 9-THC did not alter the levels of PGE2-like material in the medulla oblongata/pons, midbrain, cortex and cerebellum, 30 min after administration. However, there was a significant reduction of PGE2-like material in the hypothalamus, 30 min after delta 9-THC. 5 It is suggested that the delta 9-THC-induced decrease in hypothalamic PGE2-like material may contribute to the hypothermia observed following delta 9-THC administration. PMID:6282371

MORIN MITIGATES OXIDATIVE STRESS, APOPTOSIS AND INFLAMMATION IN CEREBRAL ISCHEMIC RATS

PubMed Central

Chen, Yanrong; Li, Yanke; Xu, Huali; Li, Gang; Ma, Yunxia; Pang, Yu Jun

2017-01-01

Background: Morin is a flavanoid which exhibits potent antioxidant activity in various oxidative stress related diseases. The current study was attempted to scrutinize the preclinical bio-efficacy of morin on focal ischemia. Methods: The animal model of focal cerebral ischemic injury was done by midbrain carotid artery occlusion (MCAO) method, followed by Morin (30mg/kg) administration for seven days. Results: The outcome of the study showed that treatment with morin displayed positive effects in reducing the focal cerebral ischemia. This effect was evident with the improvements in neurological deficits, reduction in MDA content and elevation of antioxidant levels (SOD, GSH and Gpx). Furthermore, protein expression of Bax and caspase-3 were effectively down-regulated, whilst the expression of Bcl-2 was significantly elevated. On the other hand, the mRNA expression of proinflammatory cytokines was significantly reduced in focal cerebral ischemic rats upon morin intervention. Conclusion: Thus, the beneficial effects of morin on cerebral ischemia assault may result from the reduction of oxidative stress, inhibition of apoptosis and inflammation. The neuroprotective effects of morin supplement may serve as potent adjuvant in the amelioration of ischemic stroke. PMID:28573251

Neuropeptide gene expression in brain is differentially regulated by midbrain dopamine neurons.

PubMed

Lindefors, N; Brené, S; Herrera-Marschitz, M; Persson, H

1990-01-01

In situ hybridization was used to study the expression of prepro-neuropeptide Y (NPY), preprosomatostatin (SOM), preprotachykinin (PPT) and preprocholecystokinin (CCK) mRNA in caudate-putamen and frontoparietal cortex of rat brain with unilateral lesion of midbrain dopamine neurons. Neurons expressing NPY and SOM mRNA showed a similar distribution and the expression of both NPY and SOM appears to be regulated by dopamine in a similar fashion. Following a dopamine deafferentation, the numerical density of both NPY and SOM mRNA producing neurons almost doubled in the lesioned caudate-putamen with no change in the average grain density over positive neurons. Hence, in the intact caudate-putamen dopamine appears to suppress expression of these two neuropeptide genes leading to an activation of both NPY and SOM mRNA expression in many non- or low-expressing neurons when the level of dopamine is decreased. In the fronto-parietal cortex, on the other hand, dopamine appears to stimulate NPY and SOM gene expression. Thus, in the absence of dopamine about half of the NPY positive neurons disappeared. However, for SOM the number of positive neurons did not change, but rather most positive neurons appeared to have down-regulated their SOM mRNA expression. No evidence was found for a change in CCK mRNA expression by the dopamine deafferentation, while PPT mRNA expression decreased in the deafferented caudate-putamen. Consequently, dopamine exerts dissimilar effects on the expression of different neuropeptide genes, that in turn do not respond in the same way in different brain regions.

Reassessment of the structural basis of the ascending arousal system

PubMed Central

Fuller, Patrick M.; Sherman, David; Pedersen, Nigel P.; Saper, Clifford B.; Lu, Jun

2011-01-01

The “ascending reticular activating system” theory proposed that neurons in the upper brainstem reticular formation projected to forebrain targets that promoted wakefulness. More recent formulations have emphasized that most neurons at the pontomesencepahlic junction that participate in these pathways are actually in monoaminergic and cholinergic cell groups. However, cell-specific lesions of these cell groups have never been able to reproduce the deep coma seen after acute paramedian midbrain lesions that transect ascending axons at the caudal midbrain level. To determine whether the cortical afferents from the thalamus or the basal forebrain were more important in maintaining arousal, we first place large cell-body specific lesions in these targets. Surprisingly, extensive thalamic lesions had little effect on EEG or behavioral measures of wakefulness or on c-Fos expression by cortical neurons during wakefulness. In contrast, animals with large basal forebrain lesions were behaviorally unresponsive, had a monotonous sub-1 Hz EEG, and little cortical c-Fos expression during continuous gentle handling. We then retrogradely labeled inputs to the basal forebrain from the upper brainstem, and found a substantial input from glutamatergic neurons in the parabrachial nucleus and adjacent pre-coeruleus area. Cell specific lesions of the parabrachial-precoeruleus complex produced behavioral unresponsiveness, a monotonous sub-1Hz cortical EEG, and loss of cortical c-Fos expression during gentle handling. These experiments indicate that in rats the reticulo-thalamo-cortical pathway may play a very limited role in behavioral or electrocortical arousal, while the projection from the parabrachial nucleus and precoeruleus region, relayed by the basal forebrain to the cerebral cortex, may be critical for this process. PMID:21280045

Differential distribution of the sodium-activated potassium channels slick and slack in mouse brain.

PubMed

Rizzi, Sandra; Knaus, Hans-Günther; Schwarzer, Christoph

2016-07-01

The sodium-activated potassium channels Slick (Slo2.1, KCNT2) and Slack (Slo2.2, KCNT1) are high-conductance potassium channels of the Slo family. In neurons, Slick and Slack channels are involved in the generation of slow afterhyperpolarization, in the regulation of firing patterns, and in setting and stabilizing the resting membrane potential. The distribution and subcellular localization of Slick and Slack channels in the mouse brain have not yet been established in detail. The present study addresses this issue through in situ hybridization and immunohistochemistry. Both channels were widely distributed and exhibited distinct distribution patterns. However, in some brain regions, their expression overlapped. Intense Slick channel immunoreactivity was observed in processes, varicosities, and neuronal cell bodies of the olfactory bulb, granular zones of cortical regions, hippocampus, amygdala, lateral septal nuclei, certain hypothalamic and midbrain nuclei, and several regions of the brainstem. The Slack channel showed primarily a diffuse immunostaining pattern, and labeling of cell somata and processes was observed only occasionally. The highest Slack channel expression was detected in the olfactory bulb, lateral septal nuclei, basal ganglia, and distinct areas of the midbrain, brainstem, and cerebellar cortex. In addition, comparing our data obtained from mouse brain with a previously published study on rat brain revealed some differences in the expression and distribution of Slick and Slack channels in these species. J. Comp. Neurol. 524:2093-2116, 2016. © 2015 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc. © 2015 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc.

Childhood trauma, midbrain activation and psychotic symptoms in borderline personality disorder

PubMed Central

Nicol, K; Pope, M; Romaniuk, L; Hall, J

2015-01-01

Childhood trauma is believed to contribute to the development of borderline personality disorder (BPD), however the mechanism by which childhood trauma increases risk for specific symptoms of the disorder is not well understood. Here, we explore the relationship between childhood trauma, brain activation in response to emotional stimuli and psychotic symptoms in BPD. Twenty individuals with a diagnosis of BPD and 16 healthy controls were recruited to undergo a functional MRI scan, during which they viewed images of faces expressing the emotion of fear. Participants also completed the childhood trauma questionnaire (CTQ) and a structured clinical interview. Between-group differences in brain activation to fearful faces were limited to decreased activation in the BPD group in the right cuneus. However, within the BPD group, there was a significant positive correlation between physical abuse scores on the CTQ and BOLD signal in the midbrain, pulvinar and medial frontal gyrus to fearful (versus neutral) faces. In addition there was a significant correlation between midbrain activation and reported psychotic symptoms in the BPD group (P<0.05). These results show that physical abuse in childhood is, in individuals with BPD, associated with significantly increased activation of a network of brain regions including the midbrain in response to emotional stimuli. Sustained differences in the response of the midbrain to emotional stimuli in individuals with BPD who suffered childhood physical abuse may underlie the vulnerability of these patients to developing psychotic symptoms. PMID:25942040

Anatomic location and somatotopic arrangement of the corticospinal tract at the cerebral peduncle in the human brain.

PubMed

Kwon, H G; Hong, J H; Jang, S H

2011-12-01

Little is known about the detailed anatomic location and somatotopic arrangement at the CP. Using DTT with FSL tools, we conducted an investigation of the anatomic location and somatotopic arrangement of the CST at the CP in the human brain. We recruited 43 healthy volunteers for this study. DTI was obtained by using 1.5T, and CSTs for the hand and leg were obtained by using the FSL tool. The somatotopic location of the CST was evaluated as the highest probabilistic location at the upper and lower midbrain. The posterior boundary was determined as the line between the interpeduncular fossa and the lateral sulcus; we then drew a rectangle on the basis of the boundary of the CP. In the mediolateral direction, the highest probabilistic locations for the hand and leg were an average of 60.46% and 69.98% from the medial boundary at the upper midbrain level and 53.44% and 62.76% at the lower midbrain level, respectively. As for the anteroposterior direction, the highest probabilistic locations for the hand and leg were an average of 28.26% and 32.03% from the anterior boundary at the upper midbrain level and 30.19% and 33.59% at the lower midbrain level, respectively. We found that the hand somatotopy for the CST is located at the middle portion of the CP and the leg somatotopy is located lateral to the hand somatotopy.

Midbrain dopamine receptor availability is inversely associated with novelty-seeking traits in humans.

PubMed

Zald, David H; Cowan, Ronald L; Riccardi, Patrizia; Baldwin, Ronald M; Ansari, M Sib; Li, Rui; Shelby, Evan S; Smith, Clarence E; McHugo, Maureen; Kessler, Robert M

2008-12-31

Novelty-seeking personality traits are a major risk factor for the development of drug abuse and other unsafe behaviors. Rodent models of temperament indicate that high novelty responding is associated with decreased inhibitory autoreceptor control of midbrain dopamine neurons. It has been speculated that individual differences in dopamine functioning also underlie the personality trait of novelty seeking in humans. However, differences in the dopamine system of rodents and humans, as well as the methods for assessing novelty responding/seeking across species leave unclear to what extent the animal models inform our understanding of human personality. In the present study we examined the correlation between novelty-seeking traits in humans and D(2)-like (D(2)/D(3)) receptor availability in the substantia nigra/ventral tegmental area. Based on the rodent literature we predicted that novelty seeking would be characterized by lowered levels of D(2)-like (auto)receptor availability in the midbrain. Thirty-four healthy adults (18 men, 16 women) completed the Tridimensional Personality Questionnaire-Novelty-Seeking Scale and PET scanning with the D(2)/D(3) ligand [(18)F]fallypride. Novelty-Seeking personality traits were inversely associated with D(2)-like receptor availability in the ventral midbrain, an effect that remained significant after controlling for age. We speculate that the lower midbrain (auto)receptor availability seen in high novelty seekers leads to accentuated dopaminergic responses to novelty and other conditions that induce dopamine release.

Midbrain dopamine receptor availability is inversely associated with novelty seeking traits in humans

PubMed Central

Zald, David H.; Cowan, Ronald L.; Riccardi, Patrizia; Baldwin, Ronald M.; Ansari, M. Sib; Li, Rui; Shelby, Evan S.; Smith, Clarence E.; McHugo, Maureen; Kessler, Robert M.

2009-01-01

Novelty seeking personality traits are a major risk factor for the development of drug abuse and other unsafe behaviors. Rodent models of temperament indicate that high novelty responding is associated with decreased inhibitory autoreceptor control of midbrain dopamine neurons. It has been speculated that individual differences in dopamine functioning also underlie the personality trait of novelty seeking in humans. However, differences in the dopamine system of rodents and humans, as well as the methods for assessing novelty responding/seeking across species leave unclear to what extent the animal models inform our understanding of human personality. In the present study we examined the correlation between novelty seeking traits in humans and D2-like (D2/D3) receptor availability in the substantia nigra/ventral tegmental area. Based on the rodent literature we predicted that novelty seeking would be characterized by lowered levels of D2-like (auto)receptor availability in the midbrain. 34 healthy adults (18 men, 16 women) completed the Tridimensional Personality Questionnaire-Novelty Seeking Scale and PET scanning with the D2/D3 ligand [18F]fallypride. Novelty seeking personality traits were inversely associated with D2-like receptor availability in the ventral midbrain, an effect that remained significant after controlling for age. We speculate that the lower midbrain (auto)receptor availability seen in high novelty seekers leads to accentuated dopaminergic responses to novelty and other conditions that induce DA release. PMID:19118170

Passive stimulation and behavioral training differentially transform temporal processing in the inferior colliculus and primary auditory cortex

PubMed Central

Beitel, Ralph E.; Schreiner, Christoph E.; Leake, Patricia A.

2016-01-01

In profoundly deaf cats, behavioral training with intracochlear electric stimulation (ICES) can improve temporal processing in the primary auditory cortex (AI). To investigate whether similar effects are manifest in the auditory midbrain, ICES was initiated in neonatally deafened cats either during development after short durations of deafness (8 wk of age) or in adulthood after long durations of deafness (≥3.5 yr). All of these animals received behaviorally meaningless, “passive” ICES. Some animals also received behavioral training with ICES. Two long-deaf cats received no ICES prior to acute electrophysiological recording. After several months of passive ICES and behavioral training, animals were anesthetized, and neuronal responses to pulse trains of increasing rates were recorded in the central (ICC) and external (ICX) nuclei of the inferior colliculus. Neuronal temporal response patterns (repetition rate coding, minimum latencies, response precision) were compared with results from recordings made in the AI of the same animals (Beitel RE, Vollmer M, Raggio MW, Schreiner CE. J Neurophysiol 106: 944–959, 2011; Vollmer M, Beitel RE. J Neurophysiol 106: 2423–2436, 2011). Passive ICES in long-deaf cats remediated severely degraded temporal processing in the ICC and had no effects in the ICX. In contrast to observations in the AI, behaviorally relevant ICES had no effects on temporal processing in the ICC or ICX, with the single exception of shorter latencies in the ICC in short-deaf cats. The results suggest that independent of deafness duration passive stimulation and behavioral training differentially transform temporal processing in auditory midbrain and cortex, and primary auditory cortex emerges as a pivotal site for behaviorally driven neuronal temporal plasticity in the deaf cat. NEW & NOTEWORTHY Behaviorally relevant vs. passive electric stimulation of the auditory nerve differentially affects neuronal temporal processing in the central nucleus of the inferior colliculus (ICC) and the primary auditory cortex (AI) in profoundly short-deaf and long-deaf cats. Temporal plasticity in the ICC depends on a critical amount of electric stimulation, independent of its behavioral relevance. In contrast, the AI emerges as a pivotal site for behaviorally driven neuronal temporal plasticity in the deaf auditory system. PMID:27733594

Menthol Alone Upregulates Midbrain nAChRs, Alters nAChR Subtype Stoichiometry, Alters Dopamine Neuron Firing Frequency, and Prevents Nicotine Reward

PubMed Central

Henderson, Brandon J.; Wall, Teagan R.; Henley, Beverley M.; Kim, Charlene H.; Nichols, Weston A.; Moaddel, Ruin; Xiao, Cheng

2016-01-01

Upregulation of β2 subunit-containing (β2*) nicotinic acetylcholine receptors (nAChRs) is implicated in several aspects of nicotine addiction, and menthol cigarette smokers tend to upregulate β2* nAChRs more than nonmenthol cigarette smokers. We investigated the effect of long-term menthol alone on midbrain neurons containing nAChRs. In midbrain dopaminergic (DA) neurons from mice containing fluorescent nAChR subunits, menthol alone increased the number of α4 and α6 nAChR subunits, but this upregulation did not occur in midbrain GABAergic neurons. Thus, chronic menthol produces a cell-type-selective upregulation of α4* nAChRs, complementing that of chronic nicotine alone, which upregulates α4 subunit-containing (α4*) nAChRs in GABAergic but not DA neurons. In mouse brain slices and cultured midbrain neurons, menthol reduced DA neuron firing frequency and altered DA neuron excitability following nAChR activation. Furthermore, menthol exposure before nicotine abolished nicotine reward-related behavior in mice. In neuroblastoma cells transfected with fluorescent nAChR subunits, exposure to 500 nm menthol alone also increased nAChR number and favored the formation of (α4)3(β2)2 nAChRs; this contrasts with the action of nicotine itself, which favors (α4)2(β2)3 nAChRs. Menthol alone also increases the number of α6β2 receptors that exclude the β3 subunit. Thus, menthol stabilizes lower-sensitivity α4* and α6 subunit-containing nAChRs, possibly by acting as a chemical chaperone. The abolition of nicotine reward-related behavior may be mediated through menthol's ability to stabilize lower-sensitivity nAChRs and alter DA neuron excitability. We conclude that menthol is more than a tobacco flavorant: administered alone chronically, it alters midbrain DA neurons of the nicotine reward-related pathway. SIGNIFICANCE STATEMENT Menthol, the most popular flavorant for tobacco products, has been considered simply a benign flavor additive. However, as we show here, menthol alone exerts several neurobiological changes. We are among the first to show that menthol, by itself, increases the number of nicotinic acetylcholine receptors (nAChRs) in the mouse brain. It does so at a dose that matches nicotine in its ability to increase nAChR number. At this same dose, menthol also alters midbrain dopamine neuron function and prevents nicotine reward-related behavior. Together, our data show that menthol is more than an “inert” flavor additive and is able to change the function of midbrain dopamine neurons that are part of the mesolimbic reward pathway. PMID:26961950

5-HT1A receptor gene silencers Freud-1 and Freud-2 are differently expressed in the brain of rats with genetically determined high level of fear-induced aggression or its absence.

PubMed

Kondaurova, Elena M; Ilchibaeva, Tatiana V; Tsybko, Anton S; Kozhemyakina, Rimma V; Popova, Nina K; Naumenko, Vladimir S

2016-09-01

Serotonin 5-HT1A receptor is known to play a crucial role in the mechanisms of genetically defined aggression. In its turn, 5-HT1A receptor functional state is under control of multiple factors. Among others, transcriptional factors Freud-1 and Freud-2 are known to be involved in the repression of 5-HT1A receptor gene expression. However, implication of these factors in the regulation of behavior is unclear. Here, we investigated the expression of 5-HT1A receptor and silencers Freud-1 and Freud-2 in the brain of rats selectively bred for 85 generations for either high level of fear-induced aggression or its absence. It was shown that Freud-1 and Freud-2 levels were different in aggressive and nonaggressive animals. Freud-1 protein level was decreased in the hippocampus, whereas Freud-2 protein level was increased in the frontal cortex of highly aggressive rats. There no differences in 5-HT1A receptor gene expression were found in the brains of highly aggressive and nonaggressive rats. However, 5-HT1A receptor protein level was decreased in the midbrain and increased in the hippocampus of highly aggressive rats. These data showed the involvement of Freud-1 and Freud-2 in the regulation of genetically defined fear-induced aggression. However, these silencers do not affect transcription of the 5-HT1A receptor gene in the investigated rats. Our data indicate the implication of posttranscriptional rather than transcriptional regulation of 5-HT1A receptor functional state in the mechanisms of genetically determined aggressive behavior. On the other hand, the implication of other transcriptional regulators for 5-HT1A receptor gene in the mechanisms of genetically defined aggression could be suggested. Copyright © 2016 Elsevier B.V. All rights reserved.

Relationship of gonadal hormone administration, sex, reproductive status and age to monoamine oxidase activity within the hypothalamus.

PubMed

Luine, V; Hearns, M

1990-08-01

Abstract Activity of Type A monoamine oxidase (MAO) was measured in microdissected samples from preoptic-hypothalamic and hindbrain areas of young male and female rats, and aged female rats. Administration of estradiol and progesterone, in doses sufficient to facilitate lordosis behavior and induce a luteinizing hormone surge in ovariectomized, but not castrated rats, was associated with sexually dimorphic changes of MAO activity within the hypothalamus. Forty-two h following estradiol benzoate administration, increased MAO activity was measured in the ventromedial nucleus (VML) and midbrain central gray of females, while decreased MAO activity was measured in the VML and arcuate-median eminence (ArME) of males. Progesterone administration to estradiol benzoate-primed rats was associated with decreased MAO activity in the VML and medial preoptic nucleus (mPOA) of females and decreased activity in the dorsal raphe nucleus of males. Activity of MAO on diestrus, proestrus and estrus was assessed in ten preoptic-hypothalamic and hindbrain sites. Differences between days of the cycle were limited to the mPOA, ArME and VML. While activities were generally lowest at estrus, these areas exhibited different patterns of activity across the cycle. Activity was highest at proestrus in the mPOA and highest at diestrus in the VML and ArME. Activity of MAO in some areas of 25-month old, diestrus rats was altered as compared to young, cycling rats; however, ageing was not associated with widespread changes in MAO activity. In the suprachiasmatic nucleus, aged rats showed approximately 30% less activity than young rats. In the mPOA, VML and ArME, activity in aged females was different from some, but not all, days of the estrous cycle. These results show that MAO activity changes within specific hypothalamic sites when the neuroendocrine axis is altered. Since the changes are present in areas where activity of rnonoaminergic systems is critical for initiating gonadotrophin surges and inducing lordosis behavior, these results provide initial evidence that catabolism of monoamines by MAO may contribute to rnonoaminergic regulation of reproductive function.

[Role of the midbrain reticular formation in hormonal supply to the body in conditions of chronic emotional stress].

PubMed

Amiragova, M G; Arakhangel'skaia, M I

1983-08-01

Chronic animal experiments were made to study the endocrine and electroencephalographic responses of the cortico-subcortical structures to stress before and after coagulation of the midbrain reticular formation. The operation entailed dramatic changes in both the bioelectrical responses and thyroid and adrenal responses, which were found to be differentiated.

Holmes Tremor Secondary to a Stabbing Lesion in the Midbrain

PubMed Central

Cury, Rubens Gisbert; Barbosa, Egberto Reis; Freitas, Christian; de Souza Godoy, Luis Filipe; Paiva, Wellingson Silva

2017-01-01

Background The development of Holmes tremor (HT) after a direct lesion of the midbrain has rarely been reported in the literature, although several etiologies have been linked with HT, such as stroke, brainstem tumors, multiple sclerosis, head trauma, or infections. Phenomenology Shown A 31-year-old male, having been stabbed in the right eye, presented with a rest and action tremor in the left upper limb associated with left hemiparesis with corresponding post-contrast volumetric magnetic resonance imaging T1 with sagittal oblique reformation showing the knife trajectory reaching the right midbrain. Educational Value Despite the rarity of the etiology of HT in the present case, clinicians working with persons with brain injuries should be aware of this type of situation. PMID:29226021

Tonic effects of the dopaminergic ventral midbrain on the auditory cortex of awake macaque monkeys.

PubMed

Huang, Ying; Mylius, Judith; Scheich, Henning; Brosch, Michael

2016-03-01

This study shows that ongoing electrical stimulation of the dopaminergic ventral midbrain can modify neuronal activity in the auditory cortex of awake primates for several seconds. This was reflected in a decrease of the spontaneous firing and in a bidirectional modification of the power of auditory evoked potentials. We consider that both effects are due to an increase in the dopamine tone in auditory cortex induced by the electrical stimulation. Thus, the dopaminergic ventral midbrain may contribute to the tonic activity in auditory cortex that has been proposed to be involved in associating events of auditory tasks (Brosch et al. Hear Res 271:66-73, 2011) and may modulate the signal-to-noise ratio of the responses to auditory stimuli.

Serotonin regulates the phase of the rat suprachiasmatic circadian pacemaker in vitro only during the subjective day.

PubMed

Medanic, M; Gillette, M U

1992-05-01

1. The suprachiasmatic nucleus (SCN) of the hypothalamus is the primary pacemaker for circadian rhythms in mammals. The 24 h pacemaker is endogenous to the SCN and persists for multiple cycles in the suprachiasmatic brain slice. 2. While serotonin is not endogenous to the SCN, a major midbrain hypothalamic afferent pathway is serotonergic. Within this tract the dorsal raphe nucleus sends direct projections to the ventrolateral portions of the SCN. We investigated a possible regulatory role for serotonin in the mammalian circadian system by examining its effect, when applied at projection sites, on the circadian rhythm of neuronal activity in rat SCN in vitro. 3. Eight-week-old male rats from our inbred colony, housed on a 12 h light: 12 h dark schedule, were used. Hypothalamic brain slices containing the paired SCN were prepared in the day and maintained in glucose and bicarbonate-supplemented balanced salt solution for up to 53 h. 4. A 10(-11) ml drop of 10(-6) M-serotonin (5-hydroxytryptamine (5-HT) creatinine sulphate complex) in medium was applied to the ventrolateral portion of one of the SCN for 5 min on the first day in vitro. The effect of the treatment at each of seven time points across the circadian cycle was examined. The rhythm of spontaneous neuronal activity was recorded extracellularly on the second and third days in vitro. Phase shifts were determined by comparing the time-of-peak of neuronal activity in serotonin- vs. media-treated slices. 5. Application of serotonin during the subjective day induced significant advances in the phase of the electrical activity rhythm (n = 11). The most sensitive time of treatment was CT 7 (circadian time 7 is 7 h after 'lights on' in the animal colony), when a 7.0 +/- 0.1 h phase advance was observed (n = 3). This phase advance was perpetuated on day 3 in vitro without decrement. Serotonin treatment during the subjective night had no effect on the timing of the electrical activity rhythm (n = 9). 6. The specificity of the serotonin-induced phase change was assessed by treating slices in the same manner with a microdrop of serotonergic agonists, 5-carboxamidotryptamine, that targets the 5-HT1 class of receptors, or 8-hydroxy-dipropylaminotetralin (8-OH DPAT), that acts on the 5-HT1A receptor subtype.(ABSTRACT TRUNCATED AT 400 WORDS)

Fetal diffusion tensor quantification of brainstem pathology in Chiari II malformation.

PubMed

Woitek, Ramona; Prayer, Daniela; Weber, Michael; Amann, Gabriele; Seidl, Rainer; Bettelheim, Dieter; Schöpf, Veronika; Brugger, Peter C; Furtner, Julia; Asenbaum, Ulrika; Kasprian, Gregor

2016-05-01

This prenatal MRI study evaluated the potential of diffusion tensor imaging (DTI) metrics to identify changes in the midbrain of fetuses with Chiari II malformations compared to fetuses with mild ventriculomegaly, hydrocephalus and normal CNS development. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were calculated from a region of interest (ROI) in the midbrain of 46 fetuses with normal CNS, 15 with Chiari II malformations, eight with hydrocephalus and 12 with mild ventriculomegaly. Fetuses with different diagnoses were compared group-wise after age-matching. Axial T2W-FSE sequences and single-shot echo planar DTI sequences (16 non-collinear diffusion gradient-encoding directions, b-values of 0 and 700 s/mm(2), 1.5 Tesla) were evaluated retrospectively. In Chiari II malformations, FA was significantly higher than in age-matched fetuses with a normal CNS (p = .003), while ADC was not significantly different. No differences in DTI metrics between normal controls and fetuses with hydrocephalus or vetriculomegaly were detected. DTI can detect and quantify parenchymal alterations of the fetal midbrain in Chiari II malformations. Therefore, in cases of enlarged fetal ventricles, FA of the fetal midbrain may contribute to the differentiation between Chiari II malformation and other entities. • FA in the fetal midbrain is elevated in Chiari II malformations. • FA is not elevated in hydrocephalus and mild ventriculomegaly without Chiari II. • Measuring FA may help distinguish different causes for enlarged ventricles prenatally. • Elevated FA may aid in the diagnosis of open neural tube defects. • Elevated FA might contribute to stratification for prenatal surgery in Chiari II.

Selective increase of in vivo firing frequencies in DA SN neurons after proteasome inhibition in the ventral midbrain.

PubMed

Subramaniam, Mahalakshmi; Kern, Beatrice; Vogel, Simone; Klose, Verena; Schneider, Gaby; Roeper, Jochen

2014-09-01

The impairment of protein degradation via the ubiquitin-proteasome system (UPS) is present in sporadic Parkinson's disease (PD), and might play a key role in selective degeneration of vulnerable dopamine (DA) neurons in the substantia nigra pars compacta (SN). Further evidence for a causal role of dysfunctional UPS in familial PD comes from mutations in parkin, which results in a loss of function of an E3-ubiquitin-ligase. In a mouse model, genetic inactivation of an essential component of the 26S proteasome lead to widespread neuronal degeneration including DA midbrain neurons and the formation of alpha-synuclein-positive inclusion bodies, another hallmark of PD. Studies using pharmacological UPS inhibition in vivo had more mixed results, varying from extensive degeneration to no loss of DA SN neurons. However, it is currently unknown whether UPS impairment will affect the neurophysiological functions of DA midbrain neurons. To answer this question, we infused a selective proteasome inhibitor into the ventral midbrain in vivo and recorded single DA midbrain neurons 2 weeks after the proteasome challenge. We found a selective increase in the mean in vivo firing frequencies of identified DA SN neurons in anesthetized mice, while those in the ventral tegmental area (VTA) were unaffected. Our results demonstrate that a single-hit UPS inhibition is sufficient to induce a stable and selective hyperexcitability phenotype in surviving DA SN neurons in vivo. This might imply that UPS dysfunction sensitizes DA SN neurons by enhancing 'stressful pacemaking'. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Neurosurgical treatment of pediatric low-grade midbrain tumors: a single consecutive institutional series of 15 patients.

PubMed

Lundar, Tryggve; Due-Tønnessen, Bernt Johan; Egge, Arild; Scheie, David; Brandal, Petter; Stensvold, Einar; Due-Tønnessen, Paulina

2014-12-01

The authors delineate the long-term results of surgical treatment for pediatric low-grade midbrain glioma. A series of 15 consecutive patients (age range 0-15 years) who underwent primary tumor resection for a low-grade midbrain glioma during the years 1989-2010 were included in this retrospective study on surgical morbidity, mortality rate, academic achievement, and/or work participation. Gross motor function and activities of daily living were scored according to the Barthel Index. Of the 15 patients, 10 were in their 1st decade (age 0-9 years) and 5 were in their 2nd decade of life (age 10-15 years) at the time of surgery. The male/female ratio was 0.50 (5:10). No patients were lost to follow-up. One patient died in the postoperative period (32 days posttreatment). Another 2 patients died during follow-up. One patient succumbed to acute bleeding in the resection cavity 8 months after surgery, and the other died of shunt failure 21 years after initial treatment. Twelve patients are alive at the time of this writing, with follow-up periods from 3 to 24 years (median 8 years). Among the 12 survivors, the Barthel Index scores were normal (100) in 11 patients and 80 in 1 patient. A total of 25 tumor resections were performed. In 1 patient, further resection was performed 5 days after initial resection due to MRI-confirmed residual tumor. Another 5 patients underwent repeat tumor resection after MRI-confirmed progressive tumor disease and clinical deterioration ranging from 3 months to 4 years after the initial operation. Three of these 5 patients also underwent a third resection, and 1 of the 3 underwent a fourth operation. Six children received adjuvant therapy: local radiotherapy in 2 patients, chemotherapy in 3 patients, and both in 1 patient. Twelve (80%) of the 15 patients needed treatment for persistent hydrocephalus. Selected cases of low-grade midbrain gliomas may clearly benefit from resection with favorable results, even for prolonged periods. Three patients in the present series died, one of whom had a prolonged survival period of 21 years. Among the 12 survivors, stable long-term results appeared obtainable in at least 9. One patient died of acute hemorrhage 8 months after initial resection; otherwise, rapid tumor progression and death were not observed. Forty percent of the patients received adjuvant treatment, with local radiotherapy, chemotherapy, or both.

Long-Term Impairment of Sound Processing in the Auditory Midbrain by Daily Short-Term Exposure to Moderate Noise.

PubMed

Cheng, Liang; Wang, Shao-Hui; Peng, Kang; Liao, Xiao-Mei

2017-01-01

Most citizen people are exposed daily to environmental noise at moderate levels with a short duration. The aim of the present study was to determine the effects of daily short-term exposure to moderate noise on sound level processing in the auditory midbrain. Sound processing properties of auditory midbrain neurons were recorded in anesthetized mice exposed to moderate noise (80 dB SPL, 2 h/d for 6 weeks) and were compared with those from age-matched controls. Neurons in exposed mice had a higher minimum threshold and maximum response intensity, a longer first spike latency, and a higher slope and narrower dynamic range for rate level function. However, these observed changes were greater in neurons with the best frequency within the noise exposure frequency range compared with those outside the frequency range. These sound processing properties also remained abnormal after a 12-week period of recovery in a quiet laboratory environment after completion of noise exposure. In conclusion, even daily short-term exposure to moderate noise can cause long-term impairment of sound level processing in a frequency-specific manner in auditory midbrain neurons.

The Significance of Brain Transcranial Sonography in Burning Mouth Syndrome: a Pilot Study.

PubMed

Zavoreo, Iris; Vučićević, Vanja; Boras; Zadravec, Dijana; Bašić, Vanja; Kes; Ciliga, Dubravka; Gabrić, Dragana

2017-03-01

Burning mouth syndrome (BMS) is a chronic disorder which is affecting mostly postmenopausal women and is characterized by burning symptoms in the oral cavity on the clinically healthy oral mucosa. Also, the results of previous studies suggested a possible role of peripheral and/or central neurological disturbances in these patients. The aim of this study was to analyze patients with burning mouth syndrome using transcranial sonography. By use of transcranial sonography of the brain parenchyma, substantia nigra , midbrain raphe and brain nucleus were evaluated in 20 patients with BMS (64.7±12.3 years) and 20 controls with chronic pain in the lumbosacral region (61.5±15). Statistical analysis was performed by use of Student t test with significance set at p<0.05. The results of this study have shown hypoechogenicity of the substantia nigra and midbrain raphe as well as hyperechogenicity of the brain nucleus in BMS patients (p<0,05) as compared to controls. Altered transcranial sonography findings of the brain parenchyma , midbrain raphe and brain nucl eus in patients with burning mouth syndrome might reflect central disturbances within this syndrome. Burning Mouth Syndrome; Transcranial Sonography; substantia nigra; Midbrain Raphe Nuclei; Red Nucleus.

Long-Term Impairment of Sound Processing in the Auditory Midbrain by Daily Short-Term Exposure to Moderate Noise

PubMed Central

Cheng, Liang; Wang, Shao-Hui; Peng, Kang

2017-01-01

Most citizen people are exposed daily to environmental noise at moderate levels with a short duration. The aim of the present study was to determine the effects of daily short-term exposure to moderate noise on sound level processing in the auditory midbrain. Sound processing properties of auditory midbrain neurons were recorded in anesthetized mice exposed to moderate noise (80 dB SPL, 2 h/d for 6 weeks) and were compared with those from age-matched controls. Neurons in exposed mice had a higher minimum threshold and maximum response intensity, a longer first spike latency, and a higher slope and narrower dynamic range for rate level function. However, these observed changes were greater in neurons with the best frequency within the noise exposure frequency range compared with those outside the frequency range. These sound processing properties also remained abnormal after a 12-week period of recovery in a quiet laboratory environment after completion of noise exposure. In conclusion, even daily short-term exposure to moderate noise can cause long-term impairment of sound level processing in a frequency-specific manner in auditory midbrain neurons. PMID:28589040

UV-laser microdissection and mRNA expression analysis of individual neurons from postmortem Parkinson's disease brains.

PubMed

Gründemann, Jan; Schlaudraff, Falk; Liss, Birgit

2011-01-01

Cell specificity of gene expression analysis is essential to avoid tissue sample related artifacts, in particular when the relative number of target cells present in the compared tissues varies dramatically, e.g., when comparing dopamine neurons in midbrain tissues from control subjects with those from Parkinson's disease (PD) cases. Here, we describe a detailed protocol that combines contact-free UV-laser microdissection and quantitative PCR of reverse-transcribed RNA of individual neurons from postmortem human midbrain tissue from PD patients and unaffected controls. Among expression changes in a variety of dopamine neuron marker, maintenance, and cell-metabolism genes, we found that α-synuclein mRNA levels were significantly elevated in individual neuromelanin-positive dopamine midbrain neurons from PD brains when compared to those from matched controls.

Prospect theory does not describe the feedback-related negativity value function.

PubMed

Sambrook, Thomas D; Roser, Matthew; Goslin, Jeremy

2012-12-01

Humans handle uncertainty poorly. Prospect theory accounts for this with a value function in which possible losses are overweighted compared to possible gains, and the marginal utility of rewards decreases with size. fMRI studies have explored the neural basis of this value function. A separate body of research claims that prediction errors are calculated by midbrain dopamine neurons. We investigated whether the prospect theoretic effects shown in behavioral and fMRI studies were present in midbrain prediction error coding by using the feedback-related negativity, an ERP component believed to reflect midbrain prediction errors. Participants' stated satisfaction with outcomes followed prospect theory but their feedback-related negativity did not, instead showing no effect of marginal utility and greater sensitivity to potential gains than losses. Copyright © 2012 Society for Psychophysiological Research.

Neuroprotective potential of spermidine against rotenone induced Parkinson's disease in rats.

PubMed

Sharma, Sunaina; Kumar, Puneet; Deshmukh, Rahul

2018-06-01

Parkinson's disease is a leading hypokinetic disorder characterized by selective loss of dopaminergic neurons in substantia nigra pars compacta (SNpc) region of mid-brain. Degeneration of dopaminergic neurons is considered to be due to oxidative stress, neuroinflammation, disturbed calcium homeostasis and glutamate excitotoxicity etc. Spermidine is a polyamine which counteracts age associated cell death by scavenging free radical formation, activates authophagic machinery by enhancing formation of autophagosome, and antagonizes NMDA receptor. In the current study we investigated the neuroprotective potential of spermidine against rotenone induced PD in rats. Rats were treated subcutaneously with rotenone 1.5 mg/kg daily for 28 days. Spermidine 5&10 mg/kg was administered orally 1 h prior to rotenone administration from 15 to 28. Rotenone caused significant reduction in motor functioning and elevated levels of oxidative stress markers and proinflammatory cytokines levels (IL-1β, IL6 and TNF-α). The neurochemical analysis revealed a significant decrease in serotonin, norepinephrine, dopamine and their metabolites accompanied by a significant loss of dopaminergic neurons in the SNpc following ROT injection. However, treatment with spermidine rescued DAergic neurons in SNpc and nerve terminals in the striatum following ROT insult. Spermidine treatment also attenuated oxidative stress, neuroinflammation and restored striatal neurochemistry. Results of our study suggest that spermidine has promising neuroprotective effect against degenerative changes in experimental PD, and the protective effects are mediated through its antioxidant and anti-inflammatory properties. Copyright © 2018 Elsevier Ltd. All rights reserved.

Pulmonary toxicity and extrapulmonary tissue distribution of metals after repeated exposure to different welding fumes.

PubMed

Antonini, James M; Roberts, Jenny R; Chapman, Rebecca S; Soukup, Joleen M; Ghio, Andrew J; Sriram, Krishnan

2010-08-01

Welders are exposed to fumes with different metal profiles. The goals of this study were to compare lung responses in rats after treatment with chemically different welding fumes and to examine the extrapulmonary fate of metals after deposition in the lungs. Rats were treated by intratracheal instillation (0.5 mg/rat, once a week for 7 weeks) with gas metal arc-mild steel (GMAW-MS) or manual metal arc-hardsurfacing (MMAW-HS) welding fumes. Controls were treated with saline. At 1, 4, 35, and 105 days after the last treatment, lung injury and inflammation were measured, and elemental analysis of different organs was determined to assess metal clearance. The MMAW-HS fume was highly water-soluble and chemically more complex with higher levels of soluble Mn and Cr compared to the GMAW-MS fume. Treatments with the GMAW-MS fume had no effect on toxicity when compared with controls. The MMAW-HS fume induced significant lung damage early after treatment that remained elevated until 35 days. Metals associated with each fume sample was cleared at different rates from the lungs. Mn was cleared from the lungs at a faster rate and to a greater extent compared to the other metals over the 105-day recovery period. Mn and Cr in the MMAW-HS fume translocated from the respiratory tract and deposited in other organs. Importantly, increased deposition of Mn, but not other metals, was observed in discrete brain regions, including dopamine-rich areas (e.g., striatum and midbrain).

Acute and chronic head-down tail suspension diminishes cerebral perfusion in rats

NASA Technical Reports Server (NTRS)

Wilkerson, M. Keith; Colleran, Patrick N.; Delp, Michael D.

2002-01-01

The purpose of this study was to test the hypothesis that regional brain blood flow and vascular resistance are altered by acute and chronic head-down tail suspension (HDT). Regional cerebral blood flow, arterial pressure, heart rate, and vascular resistance were measured in a group of control rats during normal standing and following 10 min of HDT and in two other groups of rats after 7 and 28 days of HDT. Heart rate was not different among conditions, whereas mean arterial pressure was elevated at 10 min of HDT relative to the other conditions. Total brain blood flow was reduced from that during standing by 48, 24, and 27% following 10 min and 7 and 28 days of HDT, respectively. Regional blood flows to all cerebral tissues and the eyes were reduced with 10 min of HDT and remained lower in the eye, olfactory bulbs, left and right cerebrum, thalamic region, and the midbrain with 7 and 28 days of HDT. Total brain vascular resistance was 116, 44, and 38% greater following 10 min and 7 and 28 days of HDT, respectively, relative to that during control standing. Vascular resistance was elevated in all cerebral regions with 10 min of HDT and remained higher than control levels in most brain regions. These results demonstrate that HDT results in chronic elevations in total and regional cerebral vascular resistance, and this may be the underlying stimulus for the HDT-induced smooth muscle hypertrophy of cerebral resistance arteries.

Comparison of histamine and hyperosmotic arabinose infusion on brain capillary permeability to hydrophilic solutes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lucchesi, K.J.

1986-03-01

The effect of bilateral intracarotid infusion of histamine (HA) on capillary permeability-surface area products (PS) of two metabolically inert tracers was determined and compared to that of L(+)arabinose (ARAB) in rat brain. Ringer's solution alone, or with 1 mg/kg HA diphosphate or 1.6M ARAB added, was infused (0.9 ml over 0.5 min) into each external carotid artery (CA). Five minutes later, a bolus of /sup 14/C-sucrose and /sup 3/H-L-glucose was injected i.v. Estimates of PS for both tracers were computed by the method of Ohno et al after brain concentration was corrected for tracer within cerebral blood vessels. Brain bloodmore » volume, based on the /sup 14/C-dextran space, was the same (.016 ml/g) in discrete cortical and midbrain regions of all rats except those treated with ARAB. The latter yielded .033 ml/g, presumably due to dextran extravasation. Infusion of ARAB, HA and Ringer's increased the PS's of sucrose and L-glucose by 10x, 8x, and 3x in brain regions perfused by the internal CA's. The ratio, PS-sucrose/PS-L-glucose was unchanged by any treatment. Both ARAB and HA caused transient falls in arterial pressure, but only ARAB caused deaths (3 of 9 rats). While as effective as ARAB in opening the blood-brain barrier, HA may be safer than hyperosmotic shock to enhance delivery of chemotherapeutic agents to brain tumors.« less

Cholinergic mechanisms of analgesia produced by physostigmine, morphine and cold water swimming.

PubMed

Romano, J A; Shih, T M

1983-07-01

This study concerns the cholinergic involvement in three experimental procedures which produce analgesia. Rats were given one of seven treatments: saline (1.0 ml/kg, i.p.); morphine sulfate (3.5, 6.0 or 9.0 mg/kg, i.p.); physostigmine salicylate (0.65 mg/kg, i.p.); warm water swim (3.5 min at 28 degrees C); and cold water swim (3.5 min at 2 degrees C). Each rat was tested on a hot plate (59.1 degrees C) once prior to and 30 min after treatment. Immediately after the last test the rats were killed with focussed microwave radiation. Levels of acetylcholine (ACh) and choline (Ch) in six brain areas (brain stem, cerebral cortex, hippocampus, midbrain, cerebellum and striatum) were analyzed by gas chromatograph-mass spectrometer. Morphine (9.0 mg/kg), physostigmine and cold water swimming caused significant analgesia. Morphine elevated the levels of ACh in the cerebellum and striatum, cold water swimming--in the cerebellum, striatum and cortex, and physostigmine--in the striatum and hippocampus. Levels of choline were elevated by morphine in the cerebellum, cortex and hippocampus, while cold water swimming elevated levels of choline in the cerebellum, cortex, striatum and hippocampus. Physostigmine did not change levels of choline in any of the brain areas studied. These data suggest that the analgetic effects of morphine or cold water swimming may be mediated by components of the cholinergic system that differ from those involved in the analgetic effects of physostigmine.

High-Frequency Stimulation of the Subthalamic Nucleus Activates Motor Cortex Pyramidal Tract Neurons by a Process Involving Local Glutamate, GABA and Dopamine Receptors in Hemi-Parkinsonian Rats.

PubMed

Chuang, Chi-Fen; Wu, Chen-Wei; Weng, Ying; Hu, Pei-San; Yeh, Shin-Rung; Chang, Yen-Chung

2018-04-30

Deep brain stimulation (DBS) is widely used to treat advanced Parkinson’s disease (PD). Here, we investigated how DBS applied on the subthalamic nucleus (STN) influenced the neural activity in the motor cortex. Rats, which had the midbrain dopaminergic neurons partially depleted unilaterally, called the hemi-Parkinsonian rats, were used as a study model. c-Fos expression in the neurons was used as an indicator of neural activity. Application of high-frequency stimulation (HFS) upon the STN was used to mimic the DBS treatment. The motor cortices in the two hemispheres of hemi-Parkinsonian rats were found to contain unequal densities of c-Fos-positive (Fos+) cells, and STN-HFS rectified this bilateral imbalance. In addition, STN-HFS led to the intense c-Fos expression in a group of motor cortical neurons which exhibited biochemical and anatomical characteristics resembling those of the pyramidal tract (PT) neurons sending efferent projections to the STN. The number of PT neurons expressing high levels of c-Fos was significantly reduced by local application of the antagonists of non-N-methyl-D-aspartate (non-NMDA) glutamate receptors, gammaaminobutyric acid A (GABAA) receptors and dopamine receptors in the upper layers of the motor cortex. The results indicate that the coincident activations of synapses and dopamine receptors in the motor cortex during STN-HFS trigger the intense expression of c-Fos of the PT neurons. The implications of the results on the cellular mechanism underlying the therapeutic effects of STN-DBS on the movement disorders of PD are also discussed.

Developmental PCB Exposure Increases Audiogenic Seizures and Decreases Glutamic Acid Decarboxylase in the Inferior Colliculus.

PubMed

Bandara, Suren B; Eubig, Paul A; Sadowski, Renee N; Schantz, Susan L

2016-02-01

Previously, we observed that developmental polychlorinated biphenyl (PCB) exposure resulted in an increase in audiogenic seizures (AGSs) in rats. However, the rats were exposed to loud noise in adulthood, and were not tested for AGS until after 1 year of age, either of which could have interacted with early PCB exposure to increase AGS susceptibility. This study assessed susceptibility to AGS in young adult rats following developmental PCB exposure alone (without loud noise exposure) and investigated whether there was a decrease in GABA inhibitory neurotransmission in the inferior colliculus (IC) that could potentially explain this effect. Female Long-Evans rats were dosed orally with 0 or 6 mg/kg/day of an environmentally relevant PCB mixture from 28 days prior to breeding until the pups were weaned at postnatal day 21. One male-female pair from each litter was retained for the AGS study whilst another was retained for Western blot analysis of glutamic acid decarboxylase (GAD) and GABAAα1 receptor in the IC, the site in the auditory midbrain where AGS are initiated. There was a significant increase in the number and severity of AGSs in the PCB groups, with females somewhat more affected than males. GAD65 was decreased but there was no change in GAD67 or GABAAα1 in the IC indicating decreased inhibitory regulation in the PCB group. These results confirm that developmental PCB exposure alone is sufficient to increase susceptibility to AGS, and provide the first evidence for a possible mechanism of action at the level of the IC. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Acute Noxious Stimulation Modifies Morphine Effect in Serotonergic but not Dopaminergic Midbrain Areas

PubMed Central

Bajic, Dusica; Commons, Kathryn G.

2010-01-01

It is poorly understood if and how pain may modify the effect of opioids on neural systems that contribute to reward and addictive behavior. We hypothesized that the activation of ascending dopaminergic and serotonergic nuclei by morphine is modified by the presence of noxious stimulation. Immunohistochemical double-labeling technique with Fos was used to examine if an intraplantar formalin injection, an acute noxious input, changed the effect of morphine on dopaminergic neurons of the ventral tegmental area (VTA), and serotonergic neurons of the dorsal raphe nucleus (DR). Four groups of rats were analyzed: (1) CONTROL injected with normal saline subcutaneously, (2) rats treated with FORMALIN into the hind paw 30 minutes after normal saline injection, (3) rats injected with MORPHINE sulfate subcutaneously, and (4) rats treated with formalin into the hind paw 30 minutes after morphine injection (MORPHINE/FORMALIN). Following morphine injection, there was an increase in the number of dopaminergic neurons in the VTA with Fos immunolabeling. However, noxious stimulation did not detectably change morphine's effect on Fos expression in VTA dopamine neurons. In contrast, the number of serotonergic neurons containing Fos was increased in the morphine/formalin group compared to all other groups and this effect was topographically selective for the dorsal area of the DR at mid rostro-caudal levels. Therefore, morphine's activation of the VTA, which is associated with motivated behavior and reward seeking, appears similar in the context of pain. However, activation of the ascending serotonin system, which influences mood and has the capacity to modify reward pathways, appears different. In addition, these findings reveal interactions between nociceptive signaling and opioids that contrasts with the notion that opioids simply block access of nociceptive signaling to supraspinal structures. PMID:20026253

Effects of molindone on central dopaminergic neuronal activity and metabolism: similarity to other neuroleptics.

PubMed

Bunney, B S; Roth, R H; Aghajanian, G K

1975-01-01

The effect of molindone on the activity of dopaminergic (DA) neurons in the rat midbrain and on DA metabolism in the striatum and olfactory tubercles was studied using extracellular single unit recording and biochemical techniques respectively. Molindone in low intravenous doses (0.4-0.8 mg/kg) was found to reverse d-amphetamine and apomorphine induced depression of DA neurons and to block apomorphine induced depression of these cells. Molindone was also found to increase dopamine synthesis and dihydroxyphenylactic acid levels in the striatum and olfacotry tubercles. In all of these respects molindone behaves identically to most classical neuroleptics. However, unlike most antipsychotic drugs previously tested, molindone failed to increase the baseline firing rate of DA cells and blocked haloperidol induced increases in DA neuron activity. In this regard molindone most closely resembles thioridazine and clozapine. Possible mechanisms of action of molindone are discussed based on these findings.

Synaptosomal degradation of substance P and some other neuropeptides.

PubMed

Arzumanyan, A M; Arutunyan, A A; Akopyan, T N

1985-12-01

Synaptosomes purified from spinal cord and from different rat brain areas exhibit peptide hydrolase activity, cleaving substance P (SP), bradykinin, THRH, LHRH, and neurotensin. The lowest activity for all the peptides tested was found in spinal cord, while the region with the highest degrading activity depended on the substrate: for substance P, it was striatum and cortex; for bradykinin, hypothalamus, and medulla oblongata; for THRH, striatum; for LHRH, midbrain; and for neurotensin, hippocampus. Degradation of substance P takes place at the plasma membrane of synaptosomes. Synaptosome ghosts cleave substance P (pH optimum 7-9, Km-2.5 X 10(-5) M, Vmax-130 nmol . hr-1 . mg protein-1) and also a number of its C-terminal fragments. Effects of the inhibitors show that several different classes of peptidases and proteases are involved in the degradation process. Peptide cleavage represents the probable pathway of synaptosomal inactivation of substance P.

[The influence of L-glutamate and carbachol on burst firing of dopaminergic neurons in ventral tegmental area].

PubMed

Wang, Shan-shan; Wei, Chun-ling; Liu, Zhi-qiang; Ren, Wei

2011-02-25

Burst firing of dopaminergic neurons in ventral tegmental area (VTA) induces a large transient increase in synaptic dopamine (DA) release and thus is considered the reward-related signal. But the mechanisms of burst generation of dopaminergic neuron still remain unclear. This experiment investigated the burst firing of VTA dopaminergic neurons in rat midbrain slices perfused with carbachol and L-glutamate individually or simultaneously to understand the neurotransmitter mechanism underlying burst generation. The results showed that bath application of carbachol (10 μmol/L) and pulse application of L-glutamate (3 mmol/L) both induced burst firing in dopaminergic neuron. Co-application of carbachol and L-glutamate induced burst firing in VTA dopaminergic cells which couldn't be induced to burst by the two chemicals separately. The result indicates that carbachol and L-glutamate co-regulate burst firing of dopaminergic neuron.

Cell type-specific gene expression of midbrain dopaminergic neurons reveals molecules involved in their vulnerability and protection.

PubMed

Chung, Chee Yeun; Seo, Hyemyung; Sonntag, Kai Christian; Brooks, Andrew; Lin, Ling; Isacson, Ole

2005-07-01

Molecular differences between dopamine (DA) neurons may explain why the mesostriatal DA neurons in the A9 region preferentially degenerate in Parkinson's disease (PD) and toxic models, whereas the adjacent A10 region mesolimbic and mesocortical DA neurons are relatively spared. To characterize innate physiological differences between A9 and A10 DA neurons, we determined gene expression profiles in these neurons in the adult mouse by laser capture microdissection, microarray analysis and real-time PCR. We found 42 genes relatively elevated in A9 DA neurons, whereas 61 genes were elevated in A10 DA neurons [> 2-fold; false discovery rate (FDR) < 1%]. Genes of interest for further functional analysis were selected by criteria of (i) fold differences in gene expression, (ii) real-time PCR validation and (iii) potential roles in neurotoxic or protective biochemical pathways. Three A9-elevated molecules [G-protein coupled inwardly rectifying K channel 2 (GIRK2), adenine nucleotide translocator 2 (ANT-2) and the growth factor IGF-1] and three A10-elevated peptides (GRP, CGRP and PACAP) were further examined in both alpha-synuclein overexpressing PC12 (PC12-alphaSyn) cells and rat primary ventral mesencephalic (VM) cultures exposed to MPP+ neurotoxicity. GIRK2-positive DA neurons were more vulnerable to MPP+ toxicity and overexpression of GIRK2 increased the vulnerability of PC12-alphaSyn cells to the toxin. Blocking of ANT decreased vulnerability to MPP+ in both cell culture systems. Exposing cells to IGF-1, GRP and PACAP decreased vulnerability of both cell types to MPP+, whereas CGRP protected PC12-alphaSyn cells but not primary VM DA neurons. These results indicate that certain differentially expressed molecules in A9 and A10 DA neurons may play key roles in their relative vulnerability to toxins and PD.

Menthol Alone Upregulates Midbrain nAChRs, Alters nAChR Subtype Stoichiometry, Alters Dopamine Neuron Firing Frequency, and Prevents Nicotine Reward.

PubMed

Henderson, Brandon J; Wall, Teagan R; Henley, Beverley M; Kim, Charlene H; Nichols, Weston A; Moaddel, Ruin; Xiao, Cheng; Lester, Henry A

2016-03-09

Upregulation of β2 subunit-containing (β2*) nicotinic acetylcholine receptors (nAChRs) is implicated in several aspects of nicotine addiction, and menthol cigarette smokers tend to upregulate β2* nAChRs more than nonmenthol cigarette smokers. We investigated the effect of long-term menthol alone on midbrain neurons containing nAChRs. In midbrain dopaminergic (DA) neurons from mice containing fluorescent nAChR subunits, menthol alone increased the number of α4 and α6 nAChR subunits, but this upregulation did not occur in midbrain GABAergic neurons. Thus, chronic menthol produces a cell-type-selective upregulation of α4* nAChRs, complementing that of chronic nicotine alone, which upregulates α4 subunit-containing (α4*) nAChRs in GABAergic but not DA neurons. In mouse brain slices and cultured midbrain neurons, menthol reduced DA neuron firing frequency and altered DA neuron excitability following nAChR activation. Furthermore, menthol exposure before nicotine abolished nicotine reward-related behavior in mice. In neuroblastoma cells transfected with fluorescent nAChR subunits, exposure to 500 nm menthol alone also increased nAChR number and favored the formation of (α4)3(β2)2 nAChRs; this contrasts with the action of nicotine itself, which favors (α4)2(β2)3 nAChRs. Menthol alone also increases the number of α6β2 receptors that exclude the β3 subunit. Thus, menthol stabilizes lower-sensitivity α4* and α6 subunit-containing nAChRs, possibly by acting as a chemical chaperone. The abolition of nicotine reward-related behavior may be mediated through menthol's ability to stabilize lower-sensitivity nAChRs and alter DA neuron excitability. We conclude that menthol is more than a tobacco flavorant: administered alone chronically, it alters midbrain DA neurons of the nicotine reward-related pathway. Copyright © 2016 the authors 0270-6474/16/362957-18$15.00/0.

Quantitative Susceptibility Mapping of the Midbrain in Parkinson’s Disease

PubMed Central

Du, Guangwei; Liu, Tian; Lewis, Mechelle M.; Kong, Lan; Wang, Yi; Connor, James; Mailman, Richard B.; Huang, Xuemei

2017-01-01

Background Parkinson’s disease (PD) is marked pathologically by dopamine neuron loss and iron overload in the substantia nigra pars compacta. Midbrain iron content is reported to be increased in PD based on magnetic resonance imaging (MRI) R2* changes. Because quantitative susceptibility mapping is a novel MRI approach to measure iron content, we compared it with R2* for assessing midbrain changes in PD. Methods Quantitative susceptibility mapping and R2* maps were obtained from 47 PD patients and 47 healthy controls. Midbrain susceptibility and R2* values were analyzed by using both voxel-based and region-of-interest approaches in normalized space, and analyzed along with clinical data, including disease duration, Unified Parkinson’s Disease Rating Scale (UPDRS) I, II, and III sub-scores, and levodopa-equivalent daily dosage. All studies were done while PD patients were “on drug.” Results Compared with controls, PD patients showed significantly increased susceptibility values in both right (cluster size = 106 mm3) and left (164 mm3) midbrain, located ventrolateral to the red nucleus that corresponded to the substantia nigra pars compacta. Susceptibility values in this region were correlated significantly with disease duration, UPDRS II, and levodopa-equivalent daily dosage. Conversely, R2* was increased significantly only in a much smaller region (62 mm3) of the left lateral substantia nigra pars compacta and was not significantly correlated with clinical parameters. Conclusion The use of quantitative susceptibility mapping demonstrated marked nigral changes that correlated with clinical PD status more sensitively than R2*. These data suggest that quantitative susceptibility mapping may be a superior imaging biomarker to R2* for estimating brain iron levels in PD. PMID:26362242

Amphetamine Self-Administration Attenuates Dopamine D2 Autoreceptor Function

PubMed Central

Calipari, Erin S; Sun, Haiguo; Eldeeb, Khalil; Luessen, Deborah J; Feng, Xin; Howlett, Allyn C; Jones, Sara R; Chen, Rong

2014-01-01

Dopamine D2 autoreceptors located on the midbrain dopaminergic neurons modulate dopamine (DA) neuron firing, DA release, and DA synthesis through a negative-feedback mechanism. Dysfunctional D2 autoreceptors following repeated drug exposure could lead to aberrant DA activity in the ventral tegmental area (VTA) and projection areas such as nucleus accumbens (NAcc), promoting drug-seeking and -taking behavior. Therefore, it is important to understand molecular mechanisms underlying drug-induced changes in D2 autoreceptors. Here, we reported that 5 days of amphetamine (AMPH) self-administration reduced the ability of D2 autoreceptors to inhibit DA release in the NAcc as determined by voltammetry. Using the antibody-capture [35S]GTPγS scintillation proximity assay, we demonstrated for the first time that midbrain D2/D3 receptors were preferentially coupled to Gαi2, whereas striatal D2/D3 receptors were coupled equally to Gαi2 and Gαo for signaling. Importantly, AMPH abolished the interaction between Gαi2 and D2/D3 receptors in the midbrain while leaving striatal D2/D3 receptors unchanged. The disruption of the coupling between D2/D3 receptors and Gαi2 by AMPH is at least partially explained by the enhanced RGS2 (regulator of G-protein signaling 2) activity resulting from an increased RGS2 trafficking to the membrane. AMPH had no effects on the midbrain expression and trafficking of other RGS proteins such as RGS4 and RGS8. Our data suggest that midbrain D2/D3 receptors are more susceptible to AMPH-induced alterations. Reduced D2 autoreceptor function could lead to enhanced DA signaling and ultimately addiction-related behavior. RGS2 may be a potential non-dopaminergic target for pharmacological intervention of dysfunctional DA transmission and drug addiction. PMID:24513972

A Sensitive Membrane-Targeted Biosensor for Monitoring Changes in Intracellular Chloride in Neuronal Processes

PubMed Central

Watts, Spencer D.; Suchland, Katherine L.; Amara, Susan G.; Ingram, Susan L.

2012-01-01

Background Regulation of chloride gradients is a major mechanism by which excitability is regulated in neurons. Disruption of these gradients is implicated in various diseases, including cystic fibrosis, neuropathic pain and epilepsy. Relatively few studies have addressed chloride regulation in neuronal processes because probes capable of detecting changes in small compartments over a physiological range are limited. Methodology/Principal Findings In this study, a palmitoylation sequence was added to a variant of the yellow fluorescent protein previously described as a sensitive chloride indicator (YFPQS) to target the protein to the plasma membrane (mbYFPQS) of cultured midbrain neurons. The reporter partitions to the cytoplasmic face of the cellular membranes, including the plasma membrane throughout the neurons and fluorescence is stable over 30–40 min of repeated excitation showing less than 10% decrease in mbYFPQS fluorescence compared to baseline. The mbYFPQS has similar chloride sensitivity (k50 =  41 mM) but has a shifted pKa compared to the unpalmitoylated YFPQS variant (cytYFPQS) that remains in the cytoplasm when expressed in midbrain neurons. Changes in mbYFPQS fluorescence were induced by the GABAA agonist muscimol and were similar in the soma and processes of the midbrain neurons. Amphetamine also increased mbYFPQS fluorescence in a subpopulation of cultured midbrain neurons that was reversed by the selective dopamine transporter (DAT) inhibitor, GBR12909, indicating that mbYFPQS is sensitive enough to detect endogenous DAT activity in midbrain dopamine (DA) neurons. Conclusions/Significance The mbYFPQS biosensor is a sensitive tool to study modulation of intracellular chloride levels in neuronal processes and is particularly advantageous for simultaneous whole-cell patch clamp and live-cell imaging experiments. PMID:22506078

Amphetamine self-administration attenuates dopamine D2 autoreceptor function.

PubMed

Calipari, Erin S; Sun, Haiguo; Eldeeb, Khalil; Luessen, Deborah J; Feng, Xin; Howlett, Allyn C; Jones, Sara R; Chen, Rong

2014-07-01

Dopamine D2 autoreceptors located on the midbrain dopaminergic neurons modulate dopamine (DA) neuron firing, DA release, and DA synthesis through a negative-feedback mechanism. Dysfunctional D2 autoreceptors following repeated drug exposure could lead to aberrant DA activity in the ventral tegmental area (VTA) and projection areas such as nucleus accumbens (NAcc), promoting drug-seeking and -taking behavior. Therefore, it is important to understand molecular mechanisms underlying drug-induced changes in D2 autoreceptors. Here, we reported that 5 days of amphetamine (AMPH) self-administration reduced the ability of D2 autoreceptors to inhibit DA release in the NAcc as determined by voltammetry. Using the antibody-capture [(35)S]GTPγS scintillation proximity assay, we demonstrated for the first time that midbrain D2/D3 receptors were preferentially coupled to Gαi2, whereas striatal D2/D3 receptors were coupled equally to Gαi2 and Gαo for signaling. Importantly, AMPH abolished the interaction between Gαi2 and D2/D3 receptors in the midbrain while leaving striatal D2/D3 receptors unchanged. The disruption of the coupling between D2/D3 receptors and Gαi2 by AMPH is at least partially explained by the enhanced RGS2 (regulator of G-protein signaling 2) activity resulting from an increased RGS2 trafficking to the membrane. AMPH had no effects on the midbrain expression and trafficking of other RGS proteins such as RGS4 and RGS8. Our data suggest that midbrain D2/D3 receptors are more susceptible to AMPH-induced alterations. Reduced D2 autoreceptor function could lead to enhanced DA signaling and ultimately addiction-related behavior. RGS2 may be a potential non-dopaminergic target for pharmacological intervention of dysfunctional DA transmission and drug addiction.

Neural Correlates of Hostile Jokes: Cognitive and Motivational Processes in Humor Appreciation

PubMed Central

Chan, Yu-Chen; Liao, Yi-Jun; Tu, Cheng-Hao

2016-01-01

Hostile jokes (HJs) provide aggressive catharsis and a feeling of superiority. Behavioral research has found that HJs are perceived as funnier than non-hostile jokes (NJs). The purpose of the present study was to identify the neural correlates of the interaction between type and humor by comparing HJs, NJs, and their corresponding hostile sentences (HSs) and non-hostile sentences (NSs). HJs primarily showed activation in the dorsomedial prefrontal cortex (dmPFC) and midbrain compared with the corresponding hostile baseline. Conversely, NJs primarily revealed activation in the ventromedial PFC (vmPFC), amygdala, midbrain, ventral anterior cingulate cortex, and nucleus accumbens (NAcc) compared with the corresponding non-hostile baseline. These results support the critical role of the medial PFC (mPFC) for the neural correlates of social cognition and socio-emotional processing in response to different types of jokes. Moreover, the processing of HJs showed increased activation in the dmPFC, which suggested cognitive operations of social motivation, whereas the processing of NJs displayed increased activation in the vmPFC, which suggested social-affective engagement. HJs versus NJs primarily showed increased activation in the dmPFC and midbrain, whereas NJs versus HJs primarily displayed greater activation in the amygdala and midbrain. The psychophysiological interaction (PPI) analysis demonstrated functional coupling of the dmPFC–dlPFC and midbrain–dmPFC for HJs and functional coupling of the vmPFC–midbrain and amygdala–midbrain–NAcc for NJs. Surprisingly, HJs were not perceived as funnier than NJs. Future studies could further investigate the neural correlates of potentially important traits of high-hostility tendencies in humor appreciation based on the psychoanalytic and superiority theories of humor. PMID:27840604

Differences in Number of Midbrain Dopamine Neurons Associated with Summer and Winter Photoperiods in Humans

PubMed Central

Aumann, Tim D.; Raabus, Mai; Tomas, Doris; Prijanto, Agustinus; Churilov, Leonid; Spitzer, Nicholas C.; Horne, Malcolm K.

2016-01-01

Recent evidence indicates the number of dopaminergic neurons in the adult rodent hypothalamus and midbrain is regulated by environmental cues, including photoperiod, and that this occurs via up- or down-regulation of expression of genes and proteins that are important for dopamine (DA) synthesis in extant neurons (‘DA neurotransmitter switching’). If the same occurs in humans, it may have implications for neurological symptoms associated with DA imbalances. Here we tested whether there are differences in the number of tyrosine hydroxylase (TH, the rate-limiting enzyme in DA synthesis) and DA transporter (DAT) immunoreactive neurons in the midbrain of people who died in summer (long-day photoperiod, n = 5) versus winter (short-day photoperiod, n = 5). TH and DAT immunoreactivity in neurons and their processes was qualitatively higher in summer compared with winter. The density of TH immunopositive (TH+) neurons was significantly (~6-fold) higher whereas the density of TH immunonegative (TH-) neurons was significantly (~2.5-fold) lower in summer compared with winter. The density of total neurons (TH+ and TH- combined) was not different. The density of DAT+ neurons was ~2-fold higher whereas the density of DAT- neurons was ~2-fold lower in summer compared with winter, although these differences were not statistically significant. In contrast, midbrain nuclear volume, the density of supposed glia (small TH- cells), and the amount of TUNEL staining were the same in summer compared with winter. This study provides the first evidence of an association between environmental stimuli (photoperiod) and the number of midbrain DA neurons in humans, and suggests DA neurotransmitter switching underlies this association. PMID:27428306

Expression of mRNAs encoding dopamine receptors in striatal regions is differentially regulated by midbrain and hippocampal neurons.

PubMed

Brené, S; Herrera-Marschitz, M; Persson, H; Lindefors, N

1994-02-01

The glutamate analogue kainic acid was injected into the hippocampus of intact or 6-hydroxydopamine deafferented rats to investigate the influence of hippocampal neurons on the expression of dopamine D1 and D2 receptor mRNAs in subregions of the striatal complex and possible modulation by dopaminergic neurons. Quantitative in situ hybridization using 35S-labeled oligonucleotide probes specific for dopamine D1 and D2 receptor mRNAs, respectively, were used. It was found that an injection of kainic acid into the hippocampal formation had alone no significant effect on dopamine D1 or D2 receptor mRNA levels in any of the analyzed striatal subregions in animals analyzed 4 h after the injections. Kainic acid stimulation in the hippocampus ipsilateral to the dopamine lesion produced an increase in D1 receptor mRNA levels in the ipsilateral medial caudate-putamen, and a bilateral increase in core and shell of nucleus accumbens (ventral striatal limbic regions). A unilateral 6-hydroxydopamine lesion alone caused an increase in D2 receptor mRNA in the lateral caudate-putamen (dorsal striatal motor region) ipsilateral to the lesion and an increase in D1 receptor mRNA in the accumbens core ipsilateral to the lesion. However, in dopamine-lesioned animals, dopamine D1 receptor mRNA levels were increased bilaterally in nucleus accumbens core and shell and in the ipsilateral medial caudate-putamen following kainic acid stimulation in the hippocampus ipsilateral to the dopamine lesion. These results indicate a differential regulation of the expression of dopamine D1 and D2 receptor mRNAs by midbrain and hippocampal neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

Stress and combined exposure to low doses of pyridostigmine bromide, DEET, and permethrin produce neurochemical and neuropathological alterations in cerebral cortex, hippocampus, and cerebellum.

PubMed

Abdel-Rahman, A; Abou-Donia, Suzanne; El-Masry, Eman; Shetty, Ashok; Abou-Donia, Mohamed

2004-01-23

Exposure to a combination of stress and low doses of the chemicals pyridostigmine bromide (PB), DEET, and permethrin in adult rats, a model of Gulf War exposure, produces blood-brain barrier (BBB) disruption and neuronal cell death in the cingulate cortex, dentate gyrus, thalamus, and hypothalamus. In this study, neuropathological alterations in other areas of the brain where no apparent BBB disruption was observed was studied following such exposure. Animals exposed to both stress and chemical exhibited decreased brain acetylcholinesterase (AChE) activity in the midbrain, brainstem, and cerebellum and decreased m2 muscarinic acetylcholine (ACh) receptor ligand binding in the midbrain and cerebellum. These alterations were associated with significant neuronal cell death, reduced microtubule-associated protein (MAP-2) expression, and increased glial fibrillary acidic protein (GFAP) expression in the cerebral cortex and the hippocampal subfields CA1 and CA3. In the cerebellum, the neurochemical alterations were associated with Purkinje cell loss and increased GFAP immunoreactivity in the white matter. However, animals subjected to either stress or chemicals alone did not show any of these changes in comparison to vehicle-treated controls. Collectively, these results suggest that prolonged exposure to a combination of stress and the chemicals PB, DEET, and permethrin can produce significant damage to the cerebral cortex, hippocampus, and cerebellum, even in the absence of apparent BBB damage. As these areas of the brain are respectively important for the maintenance of motor and sensory functions, learning and memory, and gait and coordination of movements, such alterations could lead to many physiological, pharmacological, and behavioral abnormalities, particularly motor deficits and learning and memory dysfunction.

Modulation of cue-induced firing of ventral tegmental area dopamine neurons by leptin and ghrelin

PubMed Central

van der Plasse, G; van Zessen, R; Luijendijk, M C M; Erkan, H; Stuber, G D; Ramakers, G M J; Adan, R A H

2015-01-01

Background/objectives: The rewarding value of palatable foods contributes to overconsumption, even in satiated subjects. Midbrain dopaminergic activity in response to reward-predicting environmental stimuli drives reward-seeking and motivated behavior for food rewards. This mesolimbic dopamine (DA) system is sensitive to changes in energy balance, yet it has thus far not been established whether reward signaling of DA neurons in vivo is under control of hormones that signal appetite and energy balance such as ghrelin and leptin. Subjects/methods: We trained rats (n=11) on an operant task in which they could earn two different food rewards. We then implanted recording electrodes in the ventral tegmental area (VTA), and recorded from DA neurons during behavior. Subsequently, we assessed the effects of mild food restriction and pretreatment with the adipose tissue-derived anorexigenic hormone leptin or the orexigenic hormone ghrelin on VTA DA reward signaling. Results: Animals showed an increase in performance following mild food restriction (P=0.002). Importantly, food-cue induced DA firing increased when animals were food restricted (P=0.02), but was significantly attenuated after leptin pretreatment (P=0.00). While ghrelin did affect baseline DA activity (P=0.025), it did not affect cue-induced firing (P⩾0.353). Conclusions: Metabolic signals, such as leptin, affect food seeking, a process that is dependent on the formation of cue-reward outcomes and involves midbrain DA signaling. These data show that food restriction engages the encoding of food cues by VTA DA neurons at a millisecond level and leptin suppresses this activity. This suggests that leptin is a key in linking metabolic information to reward signaling. PMID:26183405

Parkin Deficiency Reduces Hippocampal Glutamatergic Neurotransmission by Impairing AMPA Receptor Endocytosis.

PubMed

Cortese, Giuseppe P; Zhu, Mei; Williams, Damian; Heath, Sarah; Waites, Clarissa L

2016-11-30

Mutations in the gene encoding Parkin, an E3 ubiquitin ligase, lead to juvenile-onset Parkinson's disease by inducing the selective death of midbrain dopaminergic neurons. Accumulating evidence indicates that Parkin also has an important role in excitatory glutamatergic neurotransmission, although its precise mechanism of action remains unclear. Here, we investigate Parkin's role at glutamatergic synapses of rat hippocampal neurons. We find that Parkin-deficient neurons exhibit significantly reduced AMPA receptor (AMPAR)-mediated currents and cell-surface expression, and that these phenotypes result from decreased postsynaptic expression of the adaptor protein Homer1, which is necessary for coupling AMPAR endocytic zones with the postsynaptic density. Accordingly, Parkin loss of function leads to the reduced density of postsynaptic endocytic zones and to impaired AMPAR internalization. These findings demonstrate a novel and essential role for Parkin in glutamatergic neurotransmission, as a stabilizer of postsynaptic Homer1 and the Homer1-linked endocytic machinery necessary for maintaining normal cell-surface AMPAR levels. Mutations in Parkin, a ubiquitinating enzyme, lead to the selective loss of midbrain dopaminergic neurons and juvenile-onset Parkinson's disease (PD). Parkin loss of function has also been shown to alter hippocampal glutamatergic neurotransmission, providing a potential explanation for PD-associated cognitive impairment. However, very little is known about Parkin's specific sites or mechanisms of action at glutamatergic synapses. Here, we show that Parkin deficiency leads to decreased AMPA receptor-mediated activity due to disruption of the postsynaptic endocytic zones required for maintaining proper cell-surface AMPA receptor levels. These findings demonstrate a novel role for Parkin in synaptic AMPA receptor internalization and suggest a Parkin-dependent mechanism for hippocampal dysfunction that may explain cognitive deficits associated with some forms of PD. Copyright © 2016 the authors 0270-6474/16/3612243-16$15.00/0.

Dopamine Promotes Motor Cortex Plasticity and Motor Skill Learning via PLC Activation

PubMed Central

Rioult-Pedotti, Mengia-Seraina; Pekanovic, Ana; Atiemo, Clement Osei; Marshall, John; Luft, Andreas Rüdiger

2015-01-01

Dopaminergic neurons in the ventral tegmental area, the major midbrain nucleus projecting to the motor cortex, play a key role in motor skill learning and motor cortex synaptic plasticity. Dopamine D1 and D2 receptor antagonists exert parallel effects in the motor system: they impair motor skill learning and reduce long-term potentiation. Traditionally, D1 and D2 receptor modulate adenylyl cyclase activity and cyclic adenosine monophosphate accumulation in opposite directions via different G-proteins and bidirectionally modulate protein kinase A (PKA), leading to distinct physiological and behavioral effects. Here we show that D1 and D2 receptor activity influences motor skill acquisition and long term synaptic potentiation via phospholipase C (PLC) activation in rat primary motor cortex. Learning a new forelimb reaching task is severely impaired in the presence of PLC, but not PKA-inhibitor. Similarly, long term potentiation in motor cortex, a mechanism involved in motor skill learning, is reduced when PLC is inhibited but remains unaffected by the PKA inhibitor. Skill learning deficits and reduced synaptic plasticity caused by dopamine antagonists are prevented by co-administration of a PLC agonist. These results provide evidence for a role of intracellular PLC signaling in motor skill learning and associated cortical synaptic plasticity, challenging the traditional view of bidirectional modulation of PKA by D1 and D2 receptors. These findings reveal a novel and important action of dopamine in motor cortex that might be a future target for selective therapeutic interventions to support learning and recovery of movement resulting from injury and disease. PMID:25938462

Expression pattern of the thrombopoietin receptor (Mpl) in the murine central nervous system.

PubMed

Ivanova, Anna; Wuerfel, Jens; Zhang, Juan; Hoffmann, Olaf; Ballmaier, Matthias; Dame, Christof

2010-07-28

Thrombopoietin (Thpo) and its receptor (Mpl), which regulate megakaryopoiesis, are expressed in the central nervous system (CNS), where Thpo is thought to exert pro-apoptotic effects on newly generated neurons. Mpl expression has been analysed in brain tissue on transcript level and in cultured primary rat neurons and astrocytes on protein level. Herein, we analysed Mpl expression in the developing and adult murine CNS by immunohistochemistry and investigated the brain of mice with homozygous Mpl deficiency (Mpl-/-) by MRI. Mpl was not detectable at developmental stages E12 to E15 in any resident cells of the CNS. From E18 onwards, robust Mpl expression was found in various brain areas, including cerebral cortex, olfactory bulb, thalamus, hypothalamus, medulla, pons, and the grey matter of spinal cord. However, major developmental changes became obvious: In the subventricular zone of the cerebral cortex Mpl expression occurred only during late gestation, while in the hippocampus Mpl expression was detectable for first time at stage P4. In the white matter of the cerebellum Mpl expression was restricted to the perinatal period. In the adult cerebellum, Mpl expression switched to Purkinje cell. The majority of other Mpl-positive cells were NeuN-positive neurons. None of the cells could be double-labelled with astrocyte marker GFAP. Mpl-/- mice showed no gross abnormalities of the brain. Our data locate Mpl expression to neurons at different subdivisions of the spinal cord, rhombencephalon, midbrain and prosencephalon. Besides neuronal cells Mpl protein is also expressed in Purkinje cells of the adult cerebellum.

Resveratrol Protects Dopamine Neurons Against Lipopolysaccharide-Induced Neurotoxicity through Its Anti-Inflammatory Actions

PubMed Central

Zhang, Feng; Shi, Jing-Shan; Zhou, Hui; Wilson, Belinda; Hong, Jau-Shyong

2010-01-01

Parkinson's disease (PD) is the second most common neurodegenerative disease characterized by a progressive loss of dopamine (DA) neurons in the substantia nigra. Accumulating evidence indicates that inhibition of microglia-mediated neuroinflammation may become a reliable protective strategy for PD. Resveratrol, a nonflavonoid polyphenol naturally found in red wine and grapes, has been known to possess antioxidant, anticancer, and anti-inflammatory properties. Although recent studies have shown that resveratrol provided neuroprotective effects against ischemia, seizure, and neurodegenerative disorders, the mechanisms underlying its beneficial effects on dopaminergic neurodegeneration are poorly defined. In this study, rat primary midbrain neuron-glia cultures were used to elucidate the molecular mechanisms underlying resveratrol-mediated neuroprotection. The results clearly demonstrated that resveratrol protected DA neurons against lipopolysaccharide (LPS)-induced neurotoxicity in concentration- and time-dependent manners through the inhibition of microglial activation and the subsequent reduction of proinflammatory factor release. Mechanistically, resveratrol-mediated neuroprotection was attributed to the inhibition of NADPH oxidase. This conclusion is supported by the following observations. First, resveratrol reduced NADPH oxidase-mediated generation of reactive oxygen species. Second, LPS-induced translocation of NADPH oxidase cytosolic subunit p47 to the cell membrane was significantly attenuated by resveratrol. Third and most importantly, resveratrol failed to exhibit neuroprotection in cultures from NADPH oxidase-deficient mice. Furthermore, this neuroprotection was also related to an attenuation of the activation of mitogen-activated protein kinases and nuclear factor-κB signaling pathways in microglia. These findings suggest that resveratrol exerts neuroprotection against LPS-induced dopaminergic neurodegeneration, and NADPH oxidase may be a major player in resveratrol-mediated neuroprotection. PMID:20554604

Weak reward source memory in depression reflects blunted activation of VTA/SN and parahippocampus

PubMed Central

Dobbins, Ian G.; Pizzagalli, Diego A.

2014-01-01

Reward responses in the medial temporal lobes and dopaminergic midbrain boost episodic memory formation in healthy adults, and weak memory for emotionally positive material in depression suggests this mechanism may be dysfunctional in major depressive disorder (MDD). To test this hypothesis, we performed a study in which unmedicated adults with MDD and healthy controls encoded drawings paired with reward or zero tokens during functional magnetic resonance imaging. In a recognition test, participants judged whether drawings were previously associated with the reward token (‘reward source’) or the zero token (‘zero source’). Unlike controls, depressed participants failed to show better memory for drawings from the reward source vs the zero source. Consistent with predictions, controls also showed a stronger encoding response to reward tokens vs zero tokens in the right parahippocampus and dopaminergic midbrain, whereas the MDD group showed the opposite pattern—stronger responses to zero vs reward tokens—in these regions. Differential activation of the dopaminergic midbrain by reward vs zero tokens was positively correlated with the reward source memory advantage in controls, but not depressed participants. These data suggest that weaker memory for positive material in depression reflects blunted encoding responses in the dopaminergic midbrain and medial temporal lobes. PMID:24078019

The Significance of Brain Transcranial Sonography in Burning Mouth Syndrome: a Pilot Study

PubMed Central

Zavoreo, Iris; Vučićević, Vanja; Zadravec, Dijana; Bašić, Vanja; Kes; Ciliga, Dubravka; Gabrić, Dragana

2017-01-01

Objective Burning mouth syndrome (BMS) is a chronic disorder which is affecting mostly postmenopausal women and is characterized by burning symptoms in the oral cavity on the clinically healthy oral mucosa. Also, the results of previous studies suggested a possible role of peripheral and/or central neurological disturbances in these patients. The aim of this study was to analyze patients with burning mouth syndrome using transcranial sonography. Methods By use of transcranial sonography of the brain parenchyma, substantia nigra, midbrain raphe and brain nucleus were evaluated in 20 patients with BMS (64.7±12.3 years) and 20 controls with chronic pain in the lumbosacral region (61.5±15). Statistical analysis was performed by use of Student t test with significance set at p<0.05. Results The results of this study have shown hypoechogenicity of the substantia nigra and midbrain raphe as well as hyperechogenicity of the brain nucleus in BMS patients (p<0,05) as compared to controls. Conclusions Altered transcranial sonography findings of the brain parenchyma, midbrain raphe and brain nucleus in patients with burning mouth syndrome might reflect central disturbances within this syndrome. Key words Burning Mouth Syndrome; Transcranial Sonography; substantia nigra; Midbrain Raphe Nuclei; Red Nucleus PMID:28740270

Midbrain interaction with the hypothalamus in expression of aggressive behavior in cats.

PubMed

Romaniuk, A; Golebiewski, H

1977-01-01

The effects of injections of M- and N-cholinergic blocking agents into the antero-medial hypothalamus (HM) and the midbrain central gray (GC) on the aggressive behavior of cats, evoked by microinjections of carbachol into those areas, were investigated in chronic experiments. The influence of pharmacological suppression of the M-cholinergic system in HM on the carbachol-induced aggression response from GC and vice versa was also studied. In the experiments a quantitative method was applied for measuring the specific vocalization - growling, which is a characteristic of aggressive behavior. In the HM and GC areas of the cat the N- and the M-cholinergic systems participated in the control of aggressive behavior, but the M-component dominated in the process. The suppression of M-cholinergic system in GC prevented the appearance of aggressive behavior evoked by injections of carbachol into HM, and the M-cholinergic blockade in HM reduced (by 90 percent) the aggression response evoked by the injections of carbachol into GC. It is concluded that a concurrent action of the hypothalamic and the midbrain cholinergic systems is necessary for the appearance of a fully expressed aggressive behavior. The hypothalamus and the midbrain are probably links of the same functional circuit, and that the control of aggressive behavior is based on a circulatory action between these structures.

The neural correlates of priming emotion and reward systems for conflict processing in alcoholics.

PubMed

Schulte, T; Jung, Y-C; Sullivan, E V; Pfefferbaum, A; Serventi, M; Müller-Oehring, E M

2017-12-01

Emotional dysregulation in alcoholism (ALC) may result from disturbed inhibitory mechanisms. We therefore tested emotion and alcohol cue reactivity and inhibitory processes using negative priming. To test the neural correlates of cue reactivity and negative priming, 26 ALC and 26 age-matched controls underwent functional MRI performing a Stroop color match-to-sample task. In cue reactivity trials, task-irrelevant emotion and alcohol-related pictures were interspersed between color samples and color words. In negative priming trials, pictures primed the semantic content of an alcohol or emotion Stroop word. Behaviorally, both groups showed response facilitation to picture cue trials and response inhibition to primed trials. For cue reactivity to emotion and alcohol pictures, ALC showed midbrain-limbic activation. By contrast, controls activated frontoparietal executive control regions. Greater midbrain-hippocampal activation in ALC correlated with higher amounts of lifetime alcohol consumption and higher anxiety. With negative priming, ALC exhibited frontal cortical but not midbrain-hippocampal activation, similar to the pattern observed in controls. Higher frontal activation to alcohol-priming correlated with less craving and to emotion-priming with fewer depressive symptoms. The findings suggest that neurofunctional systems in ALC can be primed to deal with upcoming emotion- and alcohol-related conflict and can overcome the prepotent midbrain-limbic cue reactivity response.

Bone marrow-derived mesenchymal stem cells ameliorate sodium nitrite-induced hypoxic brain injury in a rat model

PubMed Central

Ali, Elham H.A.; Ahmed-Farid, Omar A.; Osman, Amany A. E.

2017-01-01

Sodium nitrite (NaNO2) is an inorganic salt used broadly in chemical industry. NaNO2 is highly reactive with hemoglobin causing hypoxia. Mesenchymal stem cells (MSCs) are capable of differentiating into a variety of tissue specific cells and MSC therapy is a potential method for improving brain functions. This work aims to investigate the possible therapeutic role of bone marrow-derived MSCs against NaNO2 induced hypoxic brain injury. Rats were divided into control group (treated for 3 or 6 weeks), hypoxic (HP) group (subcutaneous injection of 35 mg/kg NaNO2 for 3 weeks to induce hypoxic brain injury), HP recovery groups N-2wR and N-3wR (treated with the same dose of NaNO2 for 2 and 3 weeks respectively, followed by 4-week or 3-week self-recovery respectively), and MSCs treated groups N-2wSC and N-3wSC (treated with the same dose of NaNO2 for 2 and 3 weeks respectively, followed by one injection of 2 × 106 MSCs via the tail vein in combination with 4 week self-recovery or intravenous injection of NaNO2 for 1 week in combination with 3 week self-recovery). The levels of neurotransmitters (norepinephrine, dopamine, serotonin), energy substances (adenosine monophosphate, adenosine diphosphate, adenosine triphosphate), and oxidative stress markers (malondialdehyde, nitric oxide, 8-hydroxy-2′-deoxyguanosine, glutathione reduced form, and oxidized glutathione) in the frontal cortex and midbrain were measured using high performance liquid chromatography. At the same time, hematoxylin-eosin staining was performed to observe the pathological change of the injured brain tissue. Compared with HP group, pathological change of brain tissue was milder, the levels of malondialdehyde, nitric oxide, oxidized glutathione, 8-hydroxy-2′-deoxyguanosine, norepinephrine, serotonin, glutathione reduced form, and adenosine triphosphate in the frontal cortex and midbrain were significantly decreased, and glutathione reduced form/oxidized glutathione and adenosine monophosphate/adenosine triphosphate ratio were significantly increased in the MSCs treated groups. These findings suggest that bone marrow-derived MSCs exhibit neuroprotective effects against NaNO2-induced hypoxic brain injury through exerting anti-oxidative effects and providing energy to the brain. PMID:29323037

Increased expression of c-fos in the medial preoptic area after mating in male rats: role of afferent inputs from the medial amygdala and midbrain central tegmental field.

PubMed

Baum, M J; Everitt, B J

1992-10-01

Immunocytochemical methods were used to localize the protein product of the immediate-early gene, c-fos, in male rats after exposure to, or direct physical interaction with, oestrous females. Increasing amounts of physical contact with a female, with resultant olfactory-vomeronasal and/or genital-somatosensory inputs, caused corresponding increments in c-fos expression in the medial preoptic area, the caudal part of the bed nucleus of the stria terminalis, the medial amygdala, and the midbrain central tegmental field. Males bearing unilateral electrothermal lesions of the olfactory peduncle showed a significant reduction in c-fos expression in the ipsilateral medial amygdala, but not in other structures, provided their coital interaction with oestrous females was restricted to mount-thrust and occasional intromissive patterns due to repeated application of lidocaine anaesthetic to the penis. No such lateralization of c-fos expression occurred in other males with unilateral olfactory lesions which were allowed to intromit and ejaculate with a female. These results suggest that olfactory inputs, possibly of vomeronasal origin, contribute to the activation of c-fos in the medial amygdala. However, lesion-induced deficits in this type of afferent input to the nervous system appear to be readily compensated for by the genital somatosensory input derived from repeated intromissions. Unilateral excitotoxic lesions of the medial preoptic area, made by infusing quinolinic acid, failed to reduce c-fos expression in the ipsilateral or contralateral medial amygdala or central tegmental field following ejaculation. By contrast, combined, unilateral excitotoxic lesions of the medial amygdala and the central tegmental field significantly reduced c-fos expression in the ipsilateral bed nucleus of the stria terminalis and medial preoptic area after mating; no such asymmetry in c-fos expression occurred when lesions were restricted to either the medial amygdala or central tegmental field. This suggests that afferent inputs from the central tegmental field (probably of genital-somatosensory origin) and from the medial amygdala (probably of olfactory-vomeronasal origin) interact to promote cellular activity, and the resultant induction of c-fos, in the ipsilateral bed nucleus of the stria terminalis and medial preoptic area. The monitoring of neuronal c-fos expression provides an effective means of studying the role of sensory factors in governing the activity of integrated neural structures which control the expression of a complex social behaviour.

A QUICK Screen for Lrrk2 Interaction Partners – Leucine-rich Repeat Kinase 2 is Involved in Actin Cytoskeleton Dynamics*

PubMed Central

Meixner, Andrea; Boldt, Karsten; Van Troys, Marleen; Askenazi, Manor; Gloeckner, Christian J.; Bauer, Matthias; Marto, Jarrod A.; Ampe, Christophe; Kinkl, Norbert; Ueffing, Marius

2011-01-01

Mutations in human leucine-rich repeat kinase 2 (Lrrk2), a protein of yet unknown function, are linked to Parkinson's disease caused by degeneration of midbrain dopaminergic neurons. The protein comprises several domains including a GTPase and a kinase domain both affected by several pathogenic mutations. To elucidate the molecular interaction network of endogenous Lrrk2 under stoichiometric constraints, we applied QUICK (quantitative immunoprecipitation combined with knockdown) in NIH3T3 cells. The identified interactome reveals actin isoforms as well as actin-associated proteins involved in actin filament assembly, organization, rearrangement, and maintenance, suggesting that the biological function of Lrrk2 is linked to cytoskeletal dynamics. In fact, we demonstrate Lrrk2 de novo binding to F-actin and its ability to modulate its assembly in vitro. When tested in intact cells, knockdown of Lrrk2 causes morphological alterations in NIH3T3 cells. In developing dopaminergic midbrain primary neurons, Lrrk2 knockdown results in shortened neurite processes, indicating a physiological role of Lrrk2 in cytoskeletal organization and dynamics of dopaminergic neurons. Hence, our results demonstrate that molecular interactions as well as the physiological function of Lrrk2 are closely related to the organization of the actin-based cytoskeleton, a crucial feature of neuronal development and neuron function. PMID:20876399

Brain circuits mediating baroreflex bradycardia inhibition in rats: an anatomical and functional link between the cuneiform nucleus and the periaqueductal grey

PubMed Central

Netzer, Florence; Bernard, Jean-François; Verberne, Anthony J M; Hamon, Michel; Camus, Françoise; Benoliel, Jean-Jacques; Sévoz-Couche, Caroline

2011-01-01

Abstract Defence responses triggered experimentally in rats by stimulation of the dorsomedial nucleus of the hypothalamus (DMH) and the dorsolateral periaqueductal grey matter (PAG) inhibit the cardiac baroreflex response (i.e. bradycardia). It has also been proposed that the midbrain cuneiform nucleus (CnF) is involved in active responses. Our aim was to identify the neurocircuitry involved in defence-induced baroreflex inhibition, with a particular focus on the link between DMH, CnF and dorsolateral PAG. Microinjection of the anterograde tracer Phaseolus vulgaris leucoaggutinin into the CnF revealed a dense projection to the dorsolateral PAG. Moreover, activation of neurons in the CnF induced increased expression of Fos protein in the dorsolateral PAG. Inhibition of neurons of the CnF or dorsolateral PAG prevented the inhibition of baroreflex bradycardia induced by DMH or CnF stimulation, respectively. These results provide a detailed description of the brain circuitry underlying acute baroreflex modulation by neurons of the DMH. Our data have shown for the first time that the CnF plays a key role in defence reaction-associated cardiovascular changes; its stimulation, from the DMH, activates the dorsolateral PAG, which, in turn, inhibits baroreflex bradycardia. PMID:21486808

Hypothalamic self-stimulation and stimulation escape in relation to feeding and mating.

PubMed

Hoebel, B G

1979-10-01

This review begins with James Olds' discovery that self-stimulation at various brain sites can be influenced by food intake or androgen treatment. It then describes our research designed to reveal the functional significance of self-stimulation. The evidence suggests that lateral hypothalamic self-stimulation is controlled by many of the same factors that control feeding. We believe this control is exerted by at least two neural mechanisms. One is the classical, medial hypothalamic satiety system. Another is an adrenergic system ascending from the midbrain to the lateral hypothalamus. Damage to either one can disinhibit self-stimulation and feeding, thus contributing to obesity. Some of our studies use rats with two electrodes, one that induces feeding and one that induces mating. There are two response levers in the test cage, one for self-stimulation and one for escape from automatic stimulation. With the feeding electrode, rats self-stimulated less and escaped more after a meal than before. The same shift occurred after an anorectic dose of insulin or the commercial appetite suppressant phenylpropanolamine. With the sex electrode the shift from reward to aversion occurred after ejaculation. The review ends with credit to James Olds for pioneering this line of research into the neuropsychology of reinforcement.

Protein-based human iPS cells efficiently generate functional dopamine neurons and can treat a rat model of Parkinson disease.

PubMed

Rhee, Yong-Hee; Ko, Ji-Yun; Chang, Mi-Yoon; Yi, Sang-Hoon; Kim, Dohoon; Kim, Chun-Hyung; Shim, Jae-Won; Jo, A-Young; Kim, Byung-Woo; Lee, Hyunsu; Lee, Suk-Ho; Suh, Wonhee; Park, Chang-Hwan; Koh, Hyun-Chul; Lee, Yong-Sung; Lanza, Robert; Kim, Kwang-Soo; Lee, Sang-Hun

2011-06-01

Parkinson disease (PD) involves the selective loss of midbrain dopamine (mDA) neurons and is a possible target disease for stem cell-based therapy. Human induced pluripotent stem cells (hiPSCs) are a potentially unlimited source of patient-specific cells for transplantation. However, it is critical to evaluate the safety of hiPSCs generated by different reprogramming methods. Here, we compared multiple hiPSC lines derived by virus- and protein-based reprogramming to human ES cells (hESCs). Neuronal precursor cells (NPCs) and dopamine (DA) neurons delivered from lentivirus-based hiPSCs exhibited residual expression of exogenous reprogramming genes, but those cells derived from retrovirus- and protein-based hiPSCs did not. Furthermore, NPCs derived from virus-based hiPSCs exhibited early senescence and apoptotic cell death during passaging, which was preceded by abrupt induction of p53. In contrast, NPCs derived from hESCs and protein-based hiPSCs were highly expandable without senescence. DA neurons derived from protein-based hiPSCs exhibited gene expression, physiological, and electrophysiological properties similar to those of mDA neurons. Transplantation of these cells into rats with striatal lesions, a model of PD, significantly rescued motor deficits. These data support the clinical potential of protein-based hiPSCs for personalized cell therapy of PD.

Pyroglutamic acid stimulates DNA synthesis in rat primary hepatocytes through the mitogen-activated protein kinase pathway.

PubMed

Inoue, Shinjiro; Okita, Yoichi; de Toledo, Andreia; Miyazaki, Hiroyuki; Hirano, Eiichi; Morinaga, Tetsuo

2015-01-01

We purified pyroglutamic acid from human placental extract and identified it as a potent stimulator of rat primary hepatocyte DNA synthesis. Pyroglutamic acid dose-dependently stimulated DNA synthesis, and this effect was inhibited by PD98059, a dual specificity mitogen-activated protein kinase kinase 1 (MAP2K1) inhibitor. Therefore, pyroglutamic acid stimulated DNA synthesis in rat primary hepatocytes via MAPK signaling.

LIVER REGENERATION STUDIES WITH RAT HEPATOCYTES IN PRIMARY CULTURE

EPA Science Inventory

Adult rat parenchymal hepatocytes in primary culture can be induced to enter into DNA synthesis and mitosis. The optimal conditions for hepatocyte replication are low plating density (less than 10,000 cells/sq cm) and 50% serum from two-thirds partially hepatectomized rats (48 hr...

Hepatoprotective effects of Poly-[hemoglobin-superoxide dismutase-catalase-carbonic anhydrase] on alcohol-damaged primary rat hepatocyte culture in vitro.

PubMed

Jiang, Wenhua; Bian, Yuzhu; Wang, Zhenghui; Chang, Thomas Ming Swi

2017-02-01

We have prepared a novel nanobiotherapeutic, Poly-[hemoglobin-superoxide dismutase-catalase-carbonic anhydrase], which not only transports both oxygen and carbon dioxide but also a therapeutic antioxidant. Our previous study in a severe sustained 90 min hemorrhagic shock rat model shows that it has a hepatoprotective effect. We investigate its hepatoprotective effect further in this present report using an alcohol-damaged primary hepatocyte culture model. Results show that it significantly reduced ethanol-induced AST release, lipid peroxidation, and ROS production in rat primary hepatocytes culture. It also significantly enhanced the viability of ethanol-treated hepatocytes. Thus, the result shows that Poly-[hemoglobin-superoxide dismutase-catalase-carbonic anhydrase] also has some hepatoprotective effects against alcohol-induced injury in in vitro rat primary hepatocytes cell culture. This collaborate our previous observation of its hepatoprotective effect in a severe sustained 90-min hemorrhagic shock rat model.

Accurate Sound Localization in Reverberant Environments is Mediated by Robust Encoding of Spatial Cues in the Auditory Midbrain

PubMed Central

Devore, Sasha; Ihlefeld, Antje; Hancock, Kenneth; Shinn-Cunningham, Barbara; Delgutte, Bertrand

2009-01-01

In reverberant environments, acoustic reflections interfere with the direct sound arriving at a listener’s ears, distorting the spatial cues for sound localization. Yet, human listeners have little difficulty localizing sounds in most settings. Because reverberant energy builds up over time, the source location is represented relatively faithfully during the early portion of a sound, but this representation becomes increasingly degraded later in the stimulus. We show that the directional sensitivity of single neurons in the auditory midbrain of anesthetized cats follows a similar time course, although onset dominance in temporal response patterns results in more robust directional sensitivity than expected, suggesting a simple mechanism for improving directional sensitivity in reverberation. In parallel behavioral experiments, we demonstrate that human lateralization judgments are consistent with predictions from a population rate model decoding the observed midbrain responses, suggesting a subcortical origin for robust sound localization in reverberant environments. PMID:19376072

Cholinergic Mesopontine Signals Govern Locomotion and Reward Through Dissociable Midbrain Pathways

PubMed Central

Xiao, Cheng; Cho, Jounhong Ryan; Zhou, Chunyi; Treweek, Jennifer B.; Chan, Ken; McKinney, Sheri L.; Yang, Bin; Gradinaru, Viviana

2016-01-01

The mesopontine tegmentum, including the pedunculopontine and laterodorsal tegmental nuclei (PPN and LDT), provides major cholinergic inputs to midbrain and regulates locomotion and reward. To delineate the underlying projection-specific circuit mechanisms we employed optogenetics to control mesopontine cholinergic neurons at somata and at divergent projections within distinct midbrain areas. Bidirectional manipulation of PPN cholinergic cell bodies exerted opposing effects on locomotor behavior and reinforcement learning. These motor and reward effects were separable via limiting photostimulation to PPN cholinergic terminals in the ventral substantia nigra pars compacta (vSNc) or to the ventral tegmental area (VTA), respectively. LDT cholinergic neurons also form connections with vSNc and VTA neurons, however although photo-excitation of LDT cholinergic terminals in the VTA caused positive reinforcement, LDT-to-vSNc modulation did not alter locomotion or reward. Therefore, the selective targeting of projection-specific mesopontine cholinergic pathways may offer increased benefit in treating movement and addiction disorders. PMID:27100197

Reward and aversion in a heterogeneous midbrain dopamine system.

PubMed

Lammel, Stephan; Lim, Byung Kook; Malenka, Robert C

2014-01-01

The ventral tegmental area (VTA) is a heterogeneous brain structure that serves a central role in motivation and reward processing. Abnormalities in the function of VTA dopamine (DA) neurons and the targets they influence are implicated in several prominent neuropsychiatric disorders including addiction and depression. Recent studies suggest that the midbrain DA system is composed of anatomically and functionally heterogeneous DA subpopulations with different axonal projections. These findings may explain a number of previously confusing observations that suggested a role for DA in processing both rewarding as well as aversive events. Here we will focus on recent advances in understanding the neural circuits mediating reward and aversion in the VTA and how stress as well as drugs of abuse, in particular cocaine, alter circuit function within a heterogeneous midbrain DA system. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. Copyright © 2013 Elsevier Ltd. All rights reserved.

Role and Mechanism of Microglial Activation in Iron-Induced Selective and Progressive Dopaminergic Neurodegeneration

PubMed Central

Yan, Zhao-fen; Gao, Jun-hua; Sun, Li; Huang, Xi-yan; Liu, Zhuo; Yu, Shu-yang; Cao, Chen-Jie; Zuo, Li-jun; Chen, Ze-Jie; Hu, Yang; Wang, Fang; Hong, Jau-shyong; Wang, Xiao-min

2016-01-01

Parkinson’s disease (PD) patients have excessive iron depositions in substantia nigra (SN). Neuroinflammation characterized by microglial activation is pivotal for dopaminergic neurodegeneration in PD. However, the role and mechanism of microglial activation in iron-induced dopaminergic neurodegeneration in SN remain unclear yet. This study aimed to investigate the role and mechanism of microglial β-nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) activation in iron-induced selective and progressive dopaminergic neurodegeneration. Multiple primary midbrain cultures from rat, NOX2+/+ and NOX2−/− mice were used. Dopaminergic neurons, total neurons, and microglia were visualized by immunostainings. Cell viability was measured by MTT assay. Superoxide (O2·−) and intracellular reactive oxygen species (iROS) were determined by measuring SOD-inhibitable reduction of tetrazolium salt WST-1 and DCFH-DA assay. mRNA and protein were detected by real-time PCR and Western blot. Iron induces selective and progressive dopaminergic neurotoxicity in rat neuron–microglia–astroglia cultures and microglial activation potentiates the neurotoxicity. Activated microglia produce a magnitude of O2·− and iROS, and display morphological alteration. NOX2 inhibitor diphenylene iodonium protects against iron-elicited dopaminergic neurotoxicity through decreasing microglial O2·− generation, and NOX2−/− mice are resistant to the neurotoxicity by reducing microglial O2·− production, indicating that iron-elicited dopaminergic neurotoxicity is dependent of NOX2, a O2·−-generating enzyme. NOX2 activation is indicated by the increased mRNA and protein levels of subunits P47 and gp91. Molecules relevant to NOX2 activation include PKC-σ, P38, ERK1/2, JNK, and NF-ΚBP65 as their mRNA and protein levels are enhanced by NOX2 activation. Iron causes selective and progressive dopaminergic neurodegeneration, and microglial NOX2 activation potentiates the neurotoxicity. PKC-σ, P38, ERK1/2, JNK, and NF-ΚBP65 are the potential molecules relevant to microglial NOX2 activation. PMID:24277523

Methyllycaconitine: a non-radiolabeled ligand for mapping α7 neuronal nicotinic acetylcholine receptors - in vivo target localization and biodistribution in rat brain.

PubMed

Nirogi, Ramakrishna; Kandikere, Vishwottam; Bhyrapuneni, Gopinadh; Saralaya, Ramanatha; Muddana, Nageswararao; Komarneni, Prashanth

2012-07-01

Reduction of cerebral cortical and hippocampal α7 neuronal nicotinic acetylcholine receptor (nAChR) density was observed in the Alzheimer's disease (AD) and other neurodegenerative diseases. Mapping the subtypes of nAChRs with selective ligand by viable, quick and consistent method in preclinical drug discovery may lead to rapid development of more effective therapeutic agents. The objective of this study was to evaluate the use of methyllycaconitine (MLA) in non-radiolabeled form for mapping α7 nAChRs in rat brain. MLA pharmacokinetic and brain penetration properties were assessed in male Wistar rats. The tracer properties of MLA were evaluated in rat brain by dose and time dependent differential regional distribution studies. Target specificity was validated after blocking with potent α7 nAChR agonists ABBF, PNU282987 and nicotine. High performance liquid chromatography combined with triple quad mass spectral detector (LC-MS/MS) was used to measure the plasma and brain tissue concentrations of MLA. MLA has shown rapid brain uptake followed by a 3-5 fold higher specific binding in regions containing the α7 nAChRs (hypothalamus - 1.60 ng/g), when compared to non-specific regions (striatum - 0.53 ng/g, hippocampus - 0.46 ng/g, midbrain - 0.37 ng/g, frontal cortex - 0.35 ng/g and cerebellum - 0.30 ng/g). Pretreatment with potent α7 nAChR agonists significantly blocked the MLA uptake in hypothalamus. The non-radiolabeled MLA binding to brain region was comparable with the α7 mRNA localization and receptor distribution reported for [(3)H] MLA in rat brain. The rat pharmacokinetic, brain penetration and differential brain regional distribution features favor that MLA is suitable to use in preclinical stage for mapping α7 nAChRs. Hence, this approach can be employed as an essential tool for quicker development of novel selective ligand to map variation in the α7 receptor densities, as well as to evaluate potential new chemical entities targeting neurodegenerative diseases. Copyright © 2012 Elsevier Inc. All rights reserved.

Manganese-enhanced magnetic resonance imaging (MEMRI) reveals brain circuitry involved in responding to an acute novel stress in rats with a history of repeated social stress.

PubMed

Bangasser, Debra A; Lee, Catherine S; Cook, Philip A; Gee, James C; Bhatnagar, Seema; Valentino, Rita J

2013-10-02

Responses to acute stressors are determined in part by stress history. For example, a history of chronic stress results in facilitated responses to a novel stressor and this facilitation is considered to be adaptive. We previously demonstrated that repeated exposure of rats to the resident-intruder model of social stress results in the emergence of two subpopulations that are characterized by different coping responses to stress. The submissive subpopulation failed to show facilitation to a novel stressor and developed a passive strategy in the Porsolt forced swim test. Because a passive stress coping response has been implicated in the propensity to develop certain psychiatric disorders, understanding the unique circuitry engaged by exposure to a novel stressor in these subpopulations would advance our understanding of the etiology of stress-related pathology. An ex vivo functional imaging technique, manganese-enhanced magnetic resonance imaging (MEMRI), was used to identify and distinguish brain regions that are differentially activated by an acute swim stress (15 min) in rats with a history of social stress compared to controls. Specifically, Mn(2+) was administered intracerebroventricularly prior to swim stress and brains were later imaged ex vivo to reveal activated structures. When compared to controls, all rats with a history of social stress showed greater activation in specific striatal, hippocampal, hypothalamic, and midbrain regions. The submissive subpopulation of rats was further distinguished by significantly greater activation in amygdala, bed nucleus of the stria terminalis, and septum, suggesting that these regions may form a circuit mediating responses to novel stress in individuals that adopt passive coping strategies. The finding that different circuits are engaged by a novel stressor in the two subpopulations of rats exposed to social stress implicates a role for these circuits in determining individual strategies for responding to stressors. Finally, these data underscore the utility of ex vivo MEMRI to identify and distinguish circuits engaged in behavioral responses. Copyright © 2013 Elsevier Inc. All rights reserved.

Microwave hyperthermia-induced blood-brain barrier alterations

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lin, J.C.; Lin, M.F.

We have studied the interaction of microwaves with the blood-brain barrier in Wistar rats. Indwelling catheters were placed in the femoral vein. Evans blue in isotonic saline was used as a visual indicator of barrier permeation. Irradiation with pulsed 2450-MHz microwaves for 20 min at average power densities of 0.5 to 2600 mW/cm/sup 2/, which resulted in average specific absorption rages (SARs) of 0.04 to 200 mW/g in the brain, did not produce staining, except in regions that normally are highly permeable. When the incident power density was increased to 3000 mW/cm/sup 2/ (SAR of 240 mW/g), extravasation of Evansmore » blue could be seen in the cortex, hippocampus, and midbrain. The rectal temperature, as monitored by a copper-constantan thermocouple, showed a maximum increase of less than 1.0/sup o/C. the brain temperature recorded in a similar group of animals using a non-field-perturbing thermistor exceeded 43/sup o/C. At the higher power density the extravasation depended on the irradition and euthanization times. In one series of experiments, rats were irradiated at 3000 mW/cm/sup 2/ for 5, 10, 15, and 20 min. Immediately after irradiation all except the 5-min animals exhibited increased permeability in some regions of the brain. Brains of rats euthanized 30 min after irradiation were free of Evans blue, while those euthanized 10 and 20 min postirradiation showed significant dye staining but with less intensity than those euthanized immediately after irradiation.« less

Participation of the dorsal periaqueductal grey matter in the hypoxic ventilatory response in unanaesthetized rats.

PubMed

Lopes, L T; Biancardi, V; Vieira, E B; Leite-Panissi, C; Bícego, K C; Gargaglioni, L H

2014-07-01

Although periaqueductal grey matter activation is known to elicit respiratory and cardiovascular responses, the role of this midbrain area in the compensatory responses to hypoxia is still unknown. To test the participation of the periaqueductal grey matter in cardiorespiratory and thermal responses to hypoxia in adult male Wistar rats, we performed a chemical lesion of the dorsolateral/dorsomedial or the ventrolateral/lateral periaqueductal grey matter using ibotenic acid. Pulmonary ventilation, mean arterial pressure, heart rate and body temperature were measured in unanaesthetized rats during normoxic and hypoxic exposure (5, 15, 30 min, 7% O2). An ibotenic acid lesion of the dorsolateral/dorsomedial periaqueductal grey matter caused a higher increase in pulmonary ventilation (67.1%, 1730±282.5 mL kg(-1) min(-1)) compared to the Sham group (991.4±194 mL kg(-1) min(-1)) after 15 min in hypoxia, whereas for the ventrolateral/Lateral periaqueductal grey matter lesion, no differences were observed between groups. Mean arterial pressure, heart rate and body temperature were not affected by a dorsolateral/dorsomedial or ventrolateral/lateral periaqueductal grey matter lesion. Middle to caudal portions of the dorsolateral/dorsomedial periaqueductal grey matter neurones modulate the hypoxic ventilatory response, exerting an inhibitory modulation during low O2 situations. In addition, the middle to caudal portions of the dorsolateral/dorsomedial or ventrolateral/lateral periaqueductal grey matter do not appear to exert a tonic role on cardiovascular or thermal parameters during normoxic and hypoxic conditions. © 2014 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

Human olfactory bulb neural stem cells mitigate movement disorders in a rat model of Parkinson's disease.

PubMed

Marei, Hany E S; Lashen, Samah; Farag, Amany; Althani, Asmaa; Afifi, Nahla; A, Abd-Elmaksoud; Rezk, Shaymaa; Pallini, Roberto; Casalbore, Patrizia; Cenciarelli, Carlo

2015-07-01

Parkinson's disease (PD) is a neurological disorder characterized by the loss of midbrain dopaminergic (DA) neurons. Neural stem cells (NSCs) are multipotent stem cells that are capable of differentiating into different neuronal and glial elements. The production of DA neurons from NSCs could potentially alleviate behavioral deficits in Parkinsonian patients; timely intervention with NSCs might provide a therapeutic strategy for PD. We have isolated and generated highly enriched cultures of neural stem/progenitor cells from the human olfactory bulb (OB). If NSCs can be obtained from OB, it would alleviate ethical concerns associated with the use of embryonic tissue, and provide an easily accessible cell source that would preclude the need for invasive brain surgery. Following isolation and culture, olfactory bulb neural stem cells (OBNSCs) were genetically engineered to express hNGF and GFP. The hNFG-GFP-OBNSCs were transplanted into the striatum of 6-hydroxydopamin (6-OHDA) Parkinsonian rats. The grafted cells survived in the lesion environment for more than eight weeks after implantation with no tumor formation. The grafted cells differentiated in vivo into oligodendrocyte-like (25 ± 2.88%), neuron-like (52.63 ± 4.16%), and astrocyte -like (22.36 ± 1.56%) lineages, which we differentiated based on morphological and immunohistochemical criteria. Transplanted rats exhibited a significant partial correction in stepping and placing in non-pharmacological behavioral tests, pole and rotarod tests. Taken together, our data encourage further investigations of the possible use of OBNSCs as a promising cell-based therapeutic strategy for Parkinson's disease. © 2014 Wiley Periodicals, Inc.

Dopamine is produced in the rat spinal cord and regulates micturition reflex after spinal cord injury

PubMed Central

Hou, Shaoping; Carson, David M.; Wu, Di; Klaw, Michelle C.; Houlé, John D.; Tom, Veronica J.

2016-01-01

Dopamine (DA) neurons in the mammalian central nervous system are thought to be restricted to the brain. DA-mediated regulation of urinary activity is considered to occur through an interaction between midbrain DA neurons and the pontine micturition center. Here we show that DA is produced in the rat spinal cord and modulates the bladder reflex. We observed numerous tyrosine hydroxylase (TH)+ neurons in the autonomic nuclei and superficial dorsal horn in L6–S3 spinal segments. These neurons are dopamine-β-hydroxylase (DBH)− and some contain detectable dopamine decarboxylase (DDC), suggesting their capacity to produce DA. Interestingly, following a complete thoracic spinal cord injury (SCI) to interrupt supraspinal projections, more TH+ neurons emerged in the lumbosacral spinal cord, coincident with a sustained, low level of DA expression there and a partially recovered micturition reflex. Non-selective blockade of spinal DA receptors reduced bladder activity whereas activation of spinal D2-like receptors increased bladder activity and facilitated voiding. Additionally, depletion of lumbosacral TH+ neurons with 6-hydroxydopamine (6-OHDA) decreased bladder non-voiding contractions and voiding efficiency. Furthermore, injecting the transsynaptic neuronal tracer pseudorabies virus (PRV) into the bladder detrusor labeled TH+ cells in the lumbosacral cord, confirming their involvement in spinal micturition reflex circuits. These results illustrate that DA is synthesized in the rat spinal cord; plasticity of lumbosacral TH+ neurons following SCI may contribute to DA expression and modulate the spinal bladder reflex. Thus, spinally-derived DA and receptors could be a novel therapeutic target to improve micturition recovery after SCI. PMID:26655672

Dopamine is produced in the rat spinal cord and regulates micturition reflex after spinal cord injury.

PubMed

Hou, Shaoping; Carson, David M; Wu, Di; Klaw, Michelle C; Houlé, John D; Tom, Veronica J

2016-11-01

Dopamine (DA) neurons in the mammalian central nervous system are thought to be restricted to the brain. DA-mediated regulation of urinary activity is considered to occur through an interaction between midbrain DA neurons and the pontine micturition center. Here we show that DA is produced in the rat spinal cord and modulates the bladder reflex. We observed numerous tyrosine hydroxylase (TH) + neurons in the autonomic nuclei and superficial dorsal horn in L6-S3 spinal segments. These neurons are dopamine-β-hydroxylase (DBH) - and some contain detectable dopamine decarboxylase (DDC), suggesting their capacity to produce DA. Interestingly, following a complete thoracic spinal cord injury (SCI) to interrupt supraspinal projections, more TH + neurons emerged in the lumbosacral spinal cord, coincident with a sustained, low level of DA expression there and a partially recovered micturition reflex. Non-selective blockade of spinal DA receptors reduced bladder activity whereas activation of spinal D 2 -like receptors increased bladder activity and facilitated voiding. Additionally, depletion of lumbosacral TH + neurons with 6-hydroxydopamine (6-OHDA) decreased bladder non-voiding contractions and voiding efficiency. Furthermore, injecting the transsynaptic neuronal tracer pseudorabies virus (PRV) into the bladder detrusor labeled TH + cells in the lumbosacral cord, confirming their involvement in spinal micturition reflex circuits. These results illustrate that DA is synthesized in the rat spinal cord; plasticity of lumbosacral TH + neurons following SCI may contribute to DA expression and modulate the spinal bladder reflex. Thus, spinally-derived DA and receptors could be a novel therapeutic target to improve micturition recovery after SCI. Published by Elsevier Inc.

Microinjection of muscimol into caudal periaqueductal gray lowers body temperature and attenuates increases in temperature and activity evoked from the dorsomedial hypothalamus.

PubMed

de Menezes, Rodrigo C A; Zaretsky, Dmitry V; Fontes, Marco A P; DiMicco, Joseph A

2006-05-30

Microinjection of the neuronal inhibitor muscimol into the midbrain lateral/dorsolateral periaqueductal gray (l/dlPAG) suppresses increases in heart rate (HR) and mean arterial pressure (MAP) evoked by microinjection of the GABA(A) receptor antagonist bicuculline methiodide (BMI) into the dorsomedial hypothalamus (DMH) in rats. Injection of BMI into the DMH also increases body temperature (Tco) and motor activity. Here, our goal was to extend previous findings by examining the effect of microinjection of muscimol into the PAG on these thermogenic and behavioral responses in conscious freely moving rats. Microinjection of muscimol (300 pmol and 1 nmol) alone into the l/dlPAG reduced baseline Tco without affecting activity, HR, or MAP. Similar injection of a dose that failed to alter baseline Tco (100 pmol) suppressed the increases in Tco evoked from the DMH and significantly attenuated DMH-induced increases in locomotor activity. Whereas microinjection of 1 nmol muscimol into the ldlPAG abolished the increases in Tco evoked from the DMH and in fact lowered body temperature to a degree similar to that seen after this dose of muscimol alone, 1 nmol muscimol at adjacent sites outside the targeted region of the PAG had no significant effect on DMH-induced increases in Tco or any other parameter. These results indicate a role for neuronal activity in the l/dlPAG in (1) the temperature and behavioral responses to disinhibition of neurons in the DMH, and (2) the maintenance of basal body temperature in conscious freely moving rats.

Isolated Medial Rectus Nuclear Palsy as a Rare Presentation of Midbrain Infarction.

PubMed

Al-Sofiani, Mohammed; Lee Kwen, Peterkin

2015-10-08

Diplopia is a common subjective complaint that can be the first manifestation of a serious pathology. Here, we report a rare case of midbrain infarction involving the lateral subnucleus of the oculomotor nuclear complex presenting as diplopia, with no other stroke manifestations. An 83-year-old right-handed white man with past medical history of diabetes mellitus, hypertension, dyslipidemia, and coronary artery disease presented to the emergency department (ED) with diplopia and unsteadiness. Two days prior to admission, the patient woke up with constant horizontal diplopia and unsteadiness, which limited his daily activities and led to a fall at home. He denied any weakness, clumsiness, nausea, vomiting, photophobia, fever, or chills. Ocular exam showed a disconjugate gaze at rest, weakness of the left medial rectus muscle, impaired convergence test, and bilateral 3-mm reactive pupils. The diplopia resolved by closing either eye. The remaining extraocular muscles and other cranial nerves were normal. There was no nystagmus, ptosis, or visual field deficit. Sensation, muscle tone, and strength were normal in all extremities. Magnetic resonance imaging (MRI) of the brain revealed a tiny focus of restricted diffusion in the left posterior lateral midbrain. A thorough history and physical examination is essential to diagnose and manage diplopia. Isolated extraocular palsy is usually thought to be caused by orbital lesions or muscular diseases. Here, we report a case of midbrain infarction manifested as isolated medial rectus palsy.

Safety and tolerability of MRI-guided infusion of AAV2-hAADC into the mid-brain of nonhuman primate

PubMed Central

Sebastian, Waldy San; Kells, Adrian P; Bringas, John; Samaranch, Lluis; Hadaczek, Piotr; Ciesielska, Agnieszka; Macayan, Michael J; Pivirotto, Phillip J; Forsayeth, John; Osborne, Sheryl; Wright, J Fraser; Green, Foad; Heller, Gregory; Bankiewicz, Krystof S

2014-01-01

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare, autosomal-recessive neurological disorder caused by mutations in the DDC gene that leads to an inability to synthesize catecholamines and serotonin. As a result, patients suffer compromised development, particularly in motor function. A recent gene replacement clinical trial explored putaminal delivery of recombinant adeno-associated virus serotype 2 vector encoding human AADC (AAV2-hAADC) in AADC-deficient children. Unfortunately, patients presented only modest amelioration of motor symptoms, which authors acknowledged could be due to insufficient transduction of putamen. We hypothesize that, with the development of a highly accurate MRI-guided cannula placement technology, a more effective approach might be to target the affected mid-brain neurons directly. Transduction of AADC-deficient dopaminergic neurons in the substantia nigra and ventral tegmental area with locally infused AAV2-hAADC would be expected to lead to restoration of normal dopamine levels in affected children. The objective of this study was to assess the long-term safety and tolerability of bilateral AAV2-hAADC MRI-guided pressurized infusion into the mid-brain of nonhuman primates. Animals received either vehicle, low or high AAV2-hAADC vector dose and were euthanized 1, 3, or 9 months after surgery. Our data indicate that effective mid-brain transduction was achieved without untoward effects. PMID:25541617

Effects of phenobarbital on aniline metabolism in primary liver cell culture of rats with ethionine-induced liver disorder.

PubMed

Noguchi, M; Nitoh, S; Mabuchi, M; Kawai, Y

1996-04-01

In experiment 1, the amount of aniline (AN) metabolites in the primary cell culture medium of the liver cells obtained from ethionine (ET)-treated rats was compared with that of the control (normal) rats. Although the metabolites detected in both groups were p-aminophenol (p-AP), N-acetyl-p-AP (AAP), acetoanilide (AAN), AAP-glucuronide (AAPG), phenylhydroxylamine sulfate (PHAS) and p-AP-glucuronide (p-APG), the amount of AAP was lower and that of p-APG was markedly higher in the ET-treated rats than in the control rats. In experiment 2, phenobarbital (PB) was orally administered to the ET-treated and control rats at a dose of 100 mg/kg. The time course changes in AN metabolites in the primary cell culture medium of liver cells obtained at 2 or 48 hr after PB treatment were compared with those without PB treatment. In the ET-treated rats, the amount of PHAS was slightly higher at 2 hr after PB treatment, and that of AAP was lower and that of p-APG was higher at 48 hr after PB treatment as compared with those without PB treatment. In the control rats, the amounts of AAP, AAN, p-AP and p-APG at 2 hr after PB treatment remained lower than those without PB treatment, and that of AAP was markedly lower and that of p-APG was higher at 48 hr after PB treatment as compared with those without PB treatment. These findings indicated greater detoxication in the primary liver cell culture in the ET-treated rats than in the control rats. Furthermore, detoxication was greater in the primary cell culture of liver cell obtained from the ET-treated rats after PB treatment than from those without PB treatment, because the production of acetylates (AAP) decreased and p-APG increased (induction of conjugated enzyme) in the PB treatment group.

Effects of Korean Red Ginseng extract on tissue plasminogen activator and plasminogen activator inhibitor-1 expression in cultured rat primary astrocytes

PubMed Central

Ko, Hyun Myung; Joo, So Hyun; Kim, Pitna; Park, Jin Hee; Kim, Hee Jin; Bahn, Geon Ho; Kim, Hahn Young; Lee, Jongmin; Han, Seol-Heui; Shin, Chan Young; Park, Seung Hwa

2013-01-01

Korean Red Ginseng (KRG) is an oriental herbal preparation obtained from Panax ginseng Meyer (Araliaceae). To expand our understanding of the action of KRG on central nervous system (CNS) function, we examined the effects of KRG on tissue plasminogen activator (tPA)/plasminogen activator inhibitor-1 (PAI-1) expression in rat primary astrocytes. KRG extract was treated in cultured rat primary astrocytes and neuron in a concentration range of 0.1 to 1.0 mg/mL and the expression of functional tPA/PAI-1 was examined by casein zymography, Western blot and reverse transcription-polymerase chain reaction. KRG extracts increased PAI-1 expression in rat primary astrocytes in a concentration dependent manner (0.1 to 1.0 mg/mL) without affecting the expression of tPA itself. Treatment of 1.0 mg/mL KRG increased PAI-1 protein expression in rat primary astrocytes to 319.3±65.9% as compared with control. The increased PAI-1 expression mediated the overall decrease in tPA activity in rat primary astrocytes. Due to the lack of PAI-1 expression in neuron, KRG did not affect tPA activity in neuron. KRG treatment induced a concentration dependent activation of PI3K, p38, ERK1/2, and JNK in rat primary astrocytes and treatment of PI3K or MAPK inhibitors such as LY294002, U0126, SB203580, and SP600125 (10 μM each), significantly inhibited 1.0 mg/mL KRG-induced expression of PAI- 1 and down-regulation of tPA activity in rat primary astrocytes. Furthermore, compound K but not other ginsenosides such as Rb1 and Rg1 induced PAI-1 expression. KRG-induced up-regulation of PAI-1 in astrocytes may play important role in the regulation of overall tPA activity in brain, which might underlie some of the beneficial effects of KRG on CNS such as neuroprotection in ischemia and brain damaging condition as well as prevention or recovery from addiction. PMID:24235858

spiel ohne grenzen/pou2 is required during establishment of the zebrafish midbrain-hindbrain boundary organizer.

PubMed

Belting, H G; Hauptmann, G; Meyer, D; Abdelilah-Seyfried, S; Chitnis, A; Eschbach, C; Söll, I; Thisse, C; Thisse, B; Artinger, K B; Lunde, K; Driever, W

2001-11-01

The vertebrate midbrain-hindbrain boundary (MHB) organizes patterning and neuronal differentiation in the midbrain and anterior hindbrain. Formation of this organizing center involves multiple steps, including positioning of the MHB within the neural plate, establishment of the organizer and maintenance of its regional identity and signaling activities. Juxtaposition of the Otx2 and Gbx2 expression domains positions the MHB. How the positional information is translated into activation of Pax2, Wnt1 and Fgf8 expression during MHB establishment remains unclear. In zebrafish spiel ohne grenzen (spg) mutants, the MHB is not established, neither isthmus nor cerebellum form, the midbrain is reduced in size and patterning abnormalities develop within the hindbrain. In spg mutants, despite apparently normal expression of otx2, gbx1 and fgf8 during late gastrula stages, the initial expression of pax2.1, wnt1 and eng2, as well as later expression of fgf8 in the MHB primordium are reduced. We show that spg mutants have lesions in pou2, which encodes a POU-domain transcription factor. Maternal pou2 transcripts are distributed evenly in the blastula, and zygotic expression domains include the midbrain and hindbrain primordia during late gastrulation. Microinjection of pou2 mRNA can rescue pax2.1 and wnt1 expression in the MHB of spg/pou2 mutants without inducing ectopic expression. This indicates an essential but permissive role for pou2 during MHB establishment. pou2 is expressed normally in noi/pax2.1 and ace/fgf8 zebrafish mutants, which also form no MHB. Thus, expression of pou2 does not depend on fgf8 and pax2.1. Our data suggest that pou2 is required for the establishment of the normal expression domains of wnt1 and pax2.1 in the MHB primordium.

Contralateral migration of oculomotor neurons is regulated by Slit/Robo signaling.

PubMed

Bjorke, Brielle; Shoja-Taheri, Farnaz; Kim, Minkyung; Robinson, G Eric; Fontelonga, Tatiana; Kim, Kyung-Tai; Song, Mi-Ryoung; Mastick, Grant S

2016-10-22

Oculomotor neurons develop initially like typical motor neurons, projecting axons out of the ventral midbrain to their ipsilateral targets, the extraocular muscles. However, in all vertebrates, after the oculomotor nerve (nIII) has reached the extraocular muscle primordia, the cell bodies that innervate the superior rectus migrate to join the contralateral nucleus. This motor neuron migration represents a unique strategy to form a contralateral motor projection. Whether migration is guided by diffusible cues remains unknown. We examined the role of Slit chemorepellent signals in contralateral oculomotor migration by analyzing mutant mouse embryos. We found that the ventral midbrain expresses high levels of both Slit1 and 2, and that oculomotor neurons express the repellent Slit receptors Robo1 and Robo2. Therefore, Slit signals are in a position to influence the migration of oculomotor neurons. In Slit 1/2 or Robo1/2 double mutant embryos, motor neuron cell bodies migrated into the ventral midbrain on E10.5, three days prior to normal migration. These early migrating neurons had leading projections into and across the floor plate. In contrast to the double mutants, embryos which were mutant for single Slit or Robo genes did not have premature migration or outgrowth on E10.5, demonstrating a cooperative requirement of Slit1 and 2, as well as Robo1 and 2. To test how Slit/Robo midline repulsion is modulated, we found that the normal migration did not require the receptors Robo3 and CXCR4, or the chemoattractant, Netrin 1. The signal to initiate contralateral migration is likely autonomous to the midbrain because oculomotor neurons migrate in embryos that lack either nerve outgrowth or extraocular muscles, or in cultured midbrains that lacked peripheral tissue. Overall, our results demonstrate that a migratory subset of motor neurons respond to floor plate-derived Slit repulsion to properly control the timing of contralateral migration.

Reduced noradrenergic innervation of ventral midbrain dopaminergic cell groups and the subthalamic nucleus in MPTP-treated parkinsonian monkeys.

PubMed

Masilamoni, Gunasingh Jeyaraj; Groover, Olivia; Smith, Yoland

2017-04-01

There is anatomical and functional evidence that ventral midbrain dopaminergic (DA) cell groups and the subthalamic nucleus (STN) receive noradrenergic innervation in rodents, but much less is known about these interactions in primates. Degeneration of NE neurons in the locus coeruleus (LC) and related brainstem NE cell groups is a well-established pathological feature of Parkinson's disease (PD), but the development of such pathology in animal models of PD has been inconsistent across species and laboratories. We recently demonstrated 30-40% neuronal loss in the LC, A5 and A6 NE cell groups of rhesus monkeys rendered parkinsonian by chronic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In this study, we used dopamine-beta-hydroxylase (DβH) immunocytochemistry to assess the impact of this neuronal loss on the number of NE terminal-like varicosities in the substantia nigra pars compacta (SNC), ventral tegmental area (VTA), retrorubral field (RRF) and STN of MPTP-treated parkinsonian monkeys. Our findings reveal that the NE innervation of the ventral midbrain and STN of normal monkeys is heterogeneously distributed being far more extensive in the VTA, RRF and dorsal tier of the SNC than in the ventral SNC and STN. In parkinsonian monkeys, all regions underwent a significant (~50-70%) decrease in NE innervation. At the electron microscopic level, some DβH-positive terminals formed asymmetric axo-dendritic synapses in VTA and STN. These findings demonstrate that the VTA, RRF and SNCd are the main ventral midbrain targets of ascending NE inputs, and that these connections undergo a major break-down in chronically MPTP-treated parkinsonian monkeys. This severe degeneration of the ascending NE system may contribute to the pathophysiology of ventral midbrain and STN neurons in PD. Copyright © 2017 Elsevier Inc. All rights reserved.

In Vitro Transformation of Rat and Mouse Cells by DNA from Simian Virus 40

PubMed Central

Abrahams, P. J.; van der Eb, A. J.

1975-01-01

Primary rat kidney cells and mouse 3T3 cells can be transformed by DNA of simian virus 40 when use is made of the calcium technique (Graham and van der Eb, 1973). The transformation assay in primary rat cells is reproducible, but the dose response is not linear. PMID:166204

Features of morfological changes in primary thyroid gland CTLL cultures of rats descendants prenatally exposed by radioisotopes of iodine-131.

PubMed

Boiko, O A; Lavrenchuk, H Yo; Lypska, A I; Talko, V V; Asmolkov, V S

2017-12-01

to investigate morphological changes in the primary thyroid cell culture of rat infants whose parents were prenatally exposed by radioisotope iodine 131. obtaining and culturing of thyroid tissue primary cell cultures of newborn rats, cytological (receipt and analysis of cell cultures agents for optical microscopy), biophysical (flow cytometry), statistics. It was shown that cells in thyroid primary culture of offspring rats prenatally exposed by radioisotopes of iodine 131 signs of destructive degenerative changes were observed mostly when animals of both sexes were irra diated. Increased number of two and three nuclear cells and induction of ring like cells is an evidence of signifi cant genotoxic violation and points to the genome instability in offspring of animals exposed by radioisotope iodine 131. Analysis and quantitative morphological parameters of cells in thyroid primary culture of newborn rats whose parents were exposed prenatally by radioisotopes of iodine 131 showed that upon exposure to radiation thy roid undergoes destructive changes at the cellular level and, even in the second generation of offspring, leads to disruption of its functions. O. A. Boiko, H. Yo. Lavrenchuk, A. I. Lypska, V. V. Talko, V. S. Asmolkov.

Arctigenin Increases Hemeoxygenase-1 Gene Expression by Modulating PI3K/AKT Signaling Pathway in Rat Primary Astrocytes.

PubMed

Jeong, Yeon-Hui; Park, Jin-Sun; Kim, Dong-Hyun; Kim, Hee-Sun

2014-11-01

In the present study, we found that the natural compound arctigenin inhibited hydrogen peroxide-induced reactive oxygen species (ROS) production in rat primary astrocytes. Since hemeoxygenase-1 (HO-1) plays a critical role as an antioxidant defense factor in the brain, we examined the effect of arctigenin on HO-1 expression in rat primary astrocytes. We found that arctigenin increased HO-1 mRNA and protein levels. Arctigenin also increases the nuclear translocation and DNA binding of Nrf2/c-Jun to the antioxidant response element (ARE) on HO-1 promoter. In addition, arctigenin increased ARE-mediated transcriptional activities in rat primary astrocytes. Further mechanistic studies revealed that arctigenin increased the phosphorylation of AKT, a downstream substrate of phosphatidylinositol 3-kinase (PI3K). Treatment of cells with a PI3K-specific inhibitor, LY294002, suppressed the HO-1 expression, Nrf2 DNA binding and ARE-mediated transcriptional activities in arctigenin-treated astrocyte cells. The results collectively suggest that PI3K/AKT signaling pathway is at least partly involved in HO-1 expression by arctigenin via modulation of Nrf2/ARE axis in rat primary astrocytes.

Arctigenin Increases Hemeoxygenase-1 Gene Expression by Modulating PI3K/AKT Signaling Pathway in Rat Primary Astrocytes

PubMed Central

Jeong, Yeon-Hui; Park, Jin-Sun; Kim, Dong-Hyun; Kim, Hee-Sun

2014-01-01

In the present study, we found that the natural compound arctigenin inhibited hydrogen peroxide-induced reactive oxygen species (ROS) production in rat primary astrocytes. Since hemeoxygenase-1 (HO-1) plays a critical role as an antioxidant defense factor in the brain, we examined the effect of arctigenin on HO-1 expression in rat primary astrocytes. We found that arctigenin increased HO-1 mRNA and protein levels. Arctigenin also increases the nuclear translocation and DNA binding of Nrf2/c-Jun to the antioxidant response element (ARE) on HO-1 promoter. In addition, arctigenin increased ARE-mediated transcriptional activities in rat primary astrocytes. Further mechanistic studies revealed that arctigenin increased the phosphorylation of AKT, a downstream substrate of phosphatidylinositol 3-kinase (PI3K). Treatment of cells with a PI3K-specific inhibitor, LY294002, suppressed the HO-1 expression, Nrf2 DNA binding and ARE-mediated transcriptional activities in arctigenin-treated astrocyte cells. The results collectively suggest that PI3K/AKT signaling pathway is at least partly involved in HO-1 expression by arctigenin via modulation of Nrf2/ARE axis in rat primary astrocytes. PMID:25489416

The effects of hyaluronic acid hydrogels with tunable mechanical properties on neural progenitor cell differentiation.

PubMed

Seidlits, Stephanie K; Khaing, Zin Z; Petersen, Rebecca R; Nickels, Jonathan D; Vanscoy, Jennifer E; Shear, Jason B; Schmidt, Christine E

2010-05-01

We report the ability to direct the differentiation pathway of neural progenitor cells (NPCs) within hydrogels having tunable mechanical properties. By modifying the polymeric sugar hyaluronic acid (HA), a major extracellular matrix component in the fetal mammalian brain, with varying numbers of photocrosslinkable methacrylate groups, hydrogels could be prepared with bulk compressive moduli spanning the threefold range measured for neonatal brain and adult spinal cord. Ventral midbrain-derived NPCs were photoencapsulated into HA hydrogels and remained viable after encapsulation. After three weeks, the majority of NPCs cultured in hydrogels with mechanical properties comparable to those of neonatal brain had differentiated into neurons (ss-III tubulin-positive), many of which had extended long, branched processes, indicative of a relatively mature phenotype. In contrast, NPCs within stiffer hydrogels, with mechanical properties comparable to those of adult brain, had differentiated into mostly astrocytes (glial fibrillary acidic protein (GFAP)-positive). Primary spinal astrocytes cultured in the hydrogel variants for two weeks acquired a spread and elongated morphology only in the stiffest hydrogels evaluated, with mechanical properties similar to adult tissue. Results demonstrate that the mechanical properties of these scaffolds can assert a defining influence on the differentiation of ventral midbrain-derived NPCs, which have strong clinical relevance because of their ability to mature into dopaminergic neurons of the substantia nigra, cells that idiopathically degenerate in individuals suffering from Parkinson's disease. Copyright 2010 Elsevier Ltd. All rights reserved.

Somnolence and Stuttering as the Primary Manifestations of a Midbrain Stroke

PubMed Central

Karakis, Ioannis; Ellenstein, Aviva; Roselló, Gemma R; Romero, José R

2008-01-01

Background: Stroke can occasionally manifest with non-lateralizing findings such as somnolence and stuttering. We describe a case and discuss the anatomical and physiological implications of this rare combination of symptoms. Case report: A 51-year-old woman presented with 3 days of “feeling drunk”. She could further specify her symptoms as blurry vision, slurred speech, and gait instability. She had a history of hypertension and hyperlipidemia. Her examination at presentation was remarkable only for marked somnolence. Over the next several hours she developed mild upgaze limitation and vertical nystagmus. Non-enhanced computed tomography of the brain was normal. Brain magnetic resonance imaging (MRI) revealed a 5 mm acute infarct in the caudal midbrain. The first week the patient remained somnolent and manifested marked stuttering. The patient improved gradually with speech therapy. Conclusion: Strokes affecting the diencephalic-mesencephalic junction can manifest with stuttering. Defective projections of the reticular formation to the supplementary motor area, damaged extrapyramidal circuits, and/or aberrant propioceptive feedback due to involvement of the mesencephalic nucleus of the trigeminal nerve are the proposed pathophysiological mechanisms. Somnolence can also be part of the presentation and is likely due to disruptions of sleep pathways subserved by the reticular activating system. The accurate diagnosis of these cases depends on careful clinical assessment and high index of suspicion for stroke, especially in lieu of preexisting vascular risk factors and lack of an alternative explanation such as toxic-metabolic encephalopathy. PMID:22518226

Subdiaphragmatic vagotomy increases the sensitivity of lumbar Aδ primary afferent neurons along with voltage-dependent potassium channels in rats.

PubMed

Furuta, Sadayoshi; Watanabe, Lisa; Doi, Seira; Horiuchi, Hiroshi; Matsumoto, Kenjiro; Kuzumaki, Naoko; Suzuki, Tsutomu; Narita, Minoru

2012-02-01

Subdiaphragmatic vagal dysfunction causes chronic pain. To verify whether this chronic pain is accompanied by enhanced peripheral nociceptive sensitivity, we evaluated primary afferent neuronal excitability in subdiaphragmatic vagotomized (SDV) rats. SDV rats showed a decrease in the electrical stimuli-induced hind limb-flexion threshold at 250 Hz, but showed no similar effect at 5 or 2000 Hz, which indicated that lumbar primary afferent Aδ sensitivity was enhanced in SDV rats. The whole-cell patch-clamp technique also revealed the hyper-excitability of acutely dissociated medium-sized lumbar dorsal root ganglion (DRG) neurons isolated from SDV rats. The contribution of changes in voltage-dependent potassium (Kv) channels was assessed, and transient A-type K(+) (I(A) ) current density was apparently decreased. Moreover, Kv4.3 immunoreactivity in medium-sized DRG neurons was significantly reduced in SDV rats compared to sham. These results indicate that SDV causes hyper-excitability of lumbar primary Aδ afferent neurons, which may be induced along with suppressing I(A) currents via the decreased expression of Kv4.3. Thus, peripheral Aδ neuroplasticity may contribute to the chronic lower limb pain caused by SDV. Copyright © 2011 Wiley Periodicals, Inc.

Midbrain adaptation may set the stage for the perception of musical beat

PubMed Central

2017-01-01

The ability to spontaneously feel a beat in music is a phenomenon widely believed to be unique to humans. Though beat perception involves the coordinated engagement of sensory, motor and cognitive processes in humans, the contribution of low-level auditory processing to the activation of these networks in a beat-specific manner is poorly understood. Here, we present evidence from a rodent model that midbrain preprocessing of sounds may already be shaping where the beat is ultimately felt. For the tested set of musical rhythms, on-beat sounds on average evoked higher firing rates than off-beat sounds, and this difference was a defining feature of the set of beat interpretations most commonly perceived by human listeners over others. Basic firing rate adaptation provided a sufficient explanation for these results. Our findings suggest that midbrain adaptation, by encoding the temporal context of sounds, creates points of neural emphasis that may influence the perceptual emergence of a beat. PMID:29118141

Aldehyde dehydrogenase 1a1 mediates a GABA synthesis pathway in midbrain dopaminergic neurons.

PubMed

Kim, Jae-Ick; Ganesan, Subhashree; Luo, Sarah X; Wu, Yu-Wei; Park, Esther; Huang, Eric J; Chen, Lu; Ding, Jun B

2015-10-02

Midbrain dopamine neurons are an essential component of the basal ganglia circuitry, playing key roles in the control of fine movement and reward. Recently, it has been demonstrated that γ-aminobutyric acid (GABA), the chief inhibitory neurotransmitter, is co-released by dopamine neurons. Here, we show that GABA co-release in dopamine neurons does not use the conventional GABA-synthesizing enzymes, glutamate decarboxylases GAD65 and GAD67. Our experiments reveal an evolutionarily conserved GABA synthesis pathway mediated by aldehyde dehydrogenase 1a1 (ALDH1a1). Moreover, GABA co-release is modulated by ethanol (EtOH) at concentrations seen in blood alcohol after binge drinking, and diminished ALDH1a1 leads to enhanced alcohol consumption and preference. These findings provide insights into the functional role of GABA co-release in midbrain dopamine neurons, which may be essential for reward-based behavior and addiction. Copyright © 2015, American Association for the Advancement of Science.

Parkin loss leads to PARIS-dependent declines in mitochondrial mass and respiration

PubMed Central

Stevens, Daniel A.; Lee, Yunjong; Kang, Ho Chul; Lee, Byoung Dae; Lee, Yun-Il; Bower, Aaron; Jiang, Haisong; Kang, Sung-Ung; Andrabi, Shaida A.; Dawson, Valina L.; Shin, Joo-Ho; Dawson, Ted M.

2015-01-01

Mutations in parkin lead to early-onset autosomal recessive Parkinson’s disease (PD) and inactivation of parkin is thought to contribute to sporadic PD. Adult knockout of parkin in the ventral midbrain of mice leads to an age-dependent loss of dopamine neurons that is dependent on the accumulation of parkin interacting substrate (PARIS), zinc finger protein 746 (ZNF746), and its transcriptional repression of PGC-1α. Here we show that adult knockout of parkin in mouse ventral midbrain leads to decreases in mitochondrial size, number, and protein markers consistent with a defect in mitochondrial biogenesis. This decrease in mitochondrial mass is prevented by short hairpin RNA knockdown of PARIS. PARIS overexpression in mouse ventral midbrain leads to decreases in mitochondrial number and protein markers and PGC-1α–dependent deficits in mitochondrial respiration. Taken together, these results suggest that parkin loss impairs mitochondrial biogenesis, leading to declining function of the mitochondrial pool and cell death. PMID:26324925

Oxidant and enzymatic antioxidant status (gene expression and activity) in the brain of chickens with cold-induced pulmonary hypertension

NASA Astrophysics Data System (ADS)

Hassanpour, Hossein; Khalaji-Pirbalouty, Valiallah; Nasiri, Leila; Mohebbi, Abdonnaser; Bahadoran, Shahab

2015-11-01

To evaluate oxidant and antioxidant status of the brain (hindbrain, midbrain, and forebrain) in chickens with cold-induced pulmonary hypertension, the measurements of lipid peroxidation, protein oxidation, antioxidant capacity, enzymatic activity, and gene expression (for catalase, glutathione peroxidase, and superoxide dismutases) were done. There were high lipid peroxidation/protein oxidation and low antioxidant capacity in the hindbrain of cold-induced pulmonary hypertensive chickens compared to control ( P < 0.05). In the hypertensive chickens, superoxide dismutase activity was decreased (forebrain, midbrain, and hindbrain), while catalase activity was increased (forebrain and midbrain) ( P < 0.05). Glutathione peroxidase activity did not change. Relative gene expression of catalase and superoxide dismutases (1 and 2) was downregulated, while glutathione peroxidase was upregulated in the brain of the cold-induced pulmonary hypertensive chickens. Probably, these situations in the oxidant and antioxidant status of the brain especially hindbrain may change its function at cardiovascular center and sympathetic nervous system to exacerbate pulmonary hypertension.

Menthol Enhances Nicotine Reward-Related Behavior by Potentiating Nicotine-Induced Changes in nAChR Function, nAChR Upregulation, and DA Neuron Excitability.

PubMed

Henderson, Brandon J; Wall, Teagan R; Henley, Beverley M; Kim, Charlene H; McKinney, Sheri; Lester, Henry A

2017-11-01

Understanding why the quit rate among smokers of menthol cigarettes is lower than non-menthol smokers requires identifying the neurons that are altered by nicotine, menthol, and acetylcholine. Dopaminergic (DA) neurons in the ventral tegmental area (VTA) mediate the positive reinforcing effects of nicotine. Using mouse models, we show that menthol enhances nicotine-induced changes in nicotinic acetylcholine receptors (nAChRs) expressed on midbrain DA neurons. Menthol plus nicotine upregulates nAChR number and function on midbrain DA neurons more than nicotine alone. Menthol also enhances nicotine-induced changes in DA neuron excitability. In a conditioned place preference (CPP) assay, we observed that menthol plus nicotine produces greater reward-related behavior than nicotine alone. Our results connect changes in midbrain DA neurons to menthol-induced enhancements of nicotine reward-related behavior and may help explain how smokers of menthol cigarettes exhibit reduced cessation rates.

Nucleus accumbens controls wakefulness by a subpopulation of neurons expressing dopamine D1 receptors.

PubMed

Luo, Yan-Jia; Li, Ya-Dong; Wang, Lu; Yang, Su-Rong; Yuan, Xiang-Shan; Wang, Juan; Cherasse, Yoan; Lazarus, Michael; Chen, Jiang-Fan; Qu, Wei-Min; Huang, Zhi-Li

2018-04-20

Nucleus accumbens (NAc) is involved in behaviors that depend on heightened wakefulness, but its impact on arousal remains unclear. Here, we demonstrate that NAc dopamine D 1 receptor (D 1 R)-expressing neurons are essential for behavioral arousal. Using in vivo fiber photometry in mice, we find arousal-dependent increases in population activity of NAc D 1 R neurons. Optogenetic activation of NAc D 1 R neurons induces immediate transitions from non-rapid eye movement sleep to wakefulness, and chemogenetic stimulation prolongs arousal, with decreased food intake. Patch-clamp, tracing, immunohistochemistry, and electron microscopy reveal that NAc D 1 R neurons project to the midbrain and lateral hypothalamus, and might disinhibit midbrain dopamine neurons and lateral hypothalamus orexin neurons. Photoactivation of terminals in the midbrain and lateral hypothalamus is sufficient to induce wakefulness. Silencing of NAc D 1 R neurons suppresses arousal, with increased nest-building behaviors. Collectively, our data indicate that NAc D 1 R neuron circuits are essential for the induction and maintenance of wakefulness.

Midbrain adaptation may set the stage for the perception of musical beat.

PubMed

Rajendran, Vani G; Harper, Nicol S; Garcia-Lazaro, Jose A; Lesica, Nicholas A; Schnupp, Jan W H

2017-11-15

The ability to spontaneously feel a beat in music is a phenomenon widely believed to be unique to humans. Though beat perception involves the coordinated engagement of sensory, motor and cognitive processes in humans, the contribution of low-level auditory processing to the activation of these networks in a beat-specific manner is poorly understood. Here, we present evidence from a rodent model that midbrain preprocessing of sounds may already be shaping where the beat is ultimately felt. For the tested set of musical rhythms, on-beat sounds on average evoked higher firing rates than off-beat sounds, and this difference was a defining feature of the set of beat interpretations most commonly perceived by human listeners over others. Basic firing rate adaptation provided a sufficient explanation for these results. Our findings suggest that midbrain adaptation, by encoding the temporal context of sounds, creates points of neural emphasis that may influence the perceptual emergence of a beat. © 2017 The Authors.

The rostromedial tegmental nucleus (RMTg), a major GABAergic afferent to midbrain dopamine neurons, selectively encodes aversive stimuli and promotes behavioral inhibition

PubMed Central

Jhou, Thomas C.; Fields, Howard L.; Baxter, Mark G.; Saper, Clifford B.; Holland, Peter C.

2009-01-01

Summary Separate studies have implicated the lateral habenula (LHb) or amygdala-related regions in processing aversive stimuli, but their relationships to each other and to appetitive motivational systems are poorly understood. We show that neurons in the recently identified GABAergic rostromedial tegmental nucleus (RMTg), which receive a major LHb input, project heavily to midbrain dopamine neurons, and show phasic activations and/or Fos induction after aversive stimuli (footshocks, shock-predictive cues, food deprivation, or reward omission) and inhibitions after rewards or reward-predictive stimuli. RMTg lesions markedly reduce passive fear behaviors (freezing, open-arm avoidance) dependent on the extended amygdala, periaqueductal gray, or septum, all regions that project directly to the RMTg. In contrast, RMTg lesions spare or enhance active fear responses (treading, escape) in these same paradigms. These findings suggest that aversive inputs from widespread brain regions and stimulus modalities converge onto the RMTg, which opposes reward and motor-activating functions of midbrain dopamine neurons PMID:19285474

Menthol Enhances Nicotine Reward-Related Behavior by Potentiating Nicotine-Induced Changes in nAChR Function, nAChR Upregulation, and DA Neuron Excitability

PubMed Central

Henderson, Brandon J; Wall, Teagan R; Henley, Beverley M; Kim, Charlene H; McKinney, Sheri; Lester, Henry A

2017-01-01

Understanding why the quit rate among smokers of menthol cigarettes is lower than non-menthol smokers requires identifying the neurons that are altered by nicotine, menthol, and acetylcholine. Dopaminergic (DA) neurons in the ventral tegmental area (VTA) mediate the positive reinforcing effects of nicotine. Using mouse models, we show that menthol enhances nicotine-induced changes in nicotinic acetylcholine receptors (nAChRs) expressed on midbrain DA neurons. Menthol plus nicotine upregulates nAChR number and function on midbrain DA neurons more than nicotine alone. Menthol also enhances nicotine-induced changes in DA neuron excitability. In a conditioned place preference (CPP) assay, we observed that menthol plus nicotine produces greater reward-related behavior than nicotine alone. Our results connect changes in midbrain DA neurons to menthol-induced enhancements of nicotine reward-related behavior and may help explain how smokers of menthol cigarettes exhibit reduced cessation rates. PMID:28401925

Selective updating of working memory content modulates meso-cortico-striatal activity.

PubMed

Murty, Vishnu P; Sambataro, Fabio; Radulescu, Eugenia; Altamura, Mario; Iudicello, Jennifer; Zoltick, Bradley; Weinberger, Daniel R; Goldberg, Terry E; Mattay, Venkata S

2011-08-01

Accumulating evidence from non-human primates and computational modeling suggests that dopaminergic signals arising from the midbrain (substantia nigra/ventral tegmental area) mediate striatal gating of the prefrontal cortex during the selective updating of working memory. Using event-related functional magnetic resonance imaging, we explored the neural mechanisms underlying the selective updating of information stored in working memory. Participants were scanned during a novel working memory task that parses the neurophysiology underlying working memory maintenance, overwriting, and selective updating. Analyses revealed a functionally coupled network consisting of a midbrain region encompassing the substantia nigra/ventral tegmental area, caudate, and dorsolateral prefrontal cortex that was selectively engaged during working memory updating compared to the overwriting and maintenance of working memory content. Further analysis revealed differential midbrain-dorsolateral prefrontal interactions during selective updating between low-performing and high-performing individuals. These findings highlight the role of this meso-cortico-striatal circuitry during the selective updating of working memory in humans, which complements previous research in behavioral neuroscience and computational modeling. Published by Elsevier Inc.

DLP1-Dependent Mitochondrial Fragmentation Mediates 1-methyl-4-phenylpyridinium Toxicity in Neurons: Implications for Parkinson's Disease

PubMed Central

Wang, Xinglong; Su, Bo; Liu, Wanhong; He, Xiaohua; Gao, Yuan; Castellani, Rudy J.; Perry, George; Smith, Mark A.; Zhu, Xiongwei

2011-01-01

SUMMARY Selective degeneration of nigrostriatal dopaminergic neurons in Parkinson disease (PD) can be modeled by the administration of the neurotoxin 1-methyl-4-phenylpyridinium (MPP+). Since abnormal mitochondrial dynamics are increasingly implicated in the pathogenesis of PD, in this study, we investigated the effect of MPP+ on mitochondrial dynamics and assessed temporal and causal relationship with other toxic effects induced by MPP+ in neuronal cells. In SH-SY5Y cells, MPP+ causes a rapid increase in mitochondrial fragmentation followed by a second wave of increase in mitochondrial fragmentation, along with increased DLP1 expression and mitochondrial translocation. Genetic inactivation of DLP1 completely blocks MPP+-induced mitochondrial fragmentation. Notably, this approach partially rescues MPP+-induced decline in ATP levels and ATP/ADP ratio and increased [Ca2+]i and almost completely prevents increased reactive oxygen species production, loss of mitochondrial membrane potential, enhanced autophagy and cell death, suggesting that mitochondria fragmentation is an upstream event that mediates MPP+-induced toxicity. On the other hand, thiol antioxidant NAC or glutamate receptor antagonist D-AP5 also partially alleviate MPP+-induced mitochondrial fragmentation, suggesting a vicious spiral of events contributes to MPP+-induced toxicity. We further validated our findings in primary rat midbrain dopaminergic neurons that 0.5 μM MPP+ induced mitochondrial fragmentation only in TH-positive dopaminergic neurons in a similar pattern to that in SH-SY5Y cells but had no effects on these mitochondrial parameters in TH-negative neurons. Overall, these findings suggest that DLP1-dependent mitochondrial fragmentation plays a crucial role in mediating MPP+-induced mitochondria abnormalities and cellular dysfunction and may represent a novel therapeutic target for PD. PMID:21615675

Brain Circuits of Methamphetamine Place Reinforcement Learning: The Role of the Hippocampus-VTA Loop.

PubMed

Keleta, Yonas B; Martinez, Joe L

2012-03-01

The reinforcing effects of addictive drugs including methamphetamine (METH) involve the midbrain ventral tegmental area (VTA). VTA is primary source of dopamine (DA) to the nucleus accumbens (NAc) and the ventral hippocampus (VHC). These three brain regions are functionally connected through the hippocampal-VTA loop that includes two main neural pathways: the bottom-up pathway and the top-down pathway. In this paper, we take the view that addiction is a learning process. Therefore, we tested the involvement of the hippocampus in reinforcement learning by studying conditioned place preference (CPP) learning by sequentially conditioning each of the three nuclei in either the bottom-up order of conditioning; VTA, then VHC, finally NAc, or the top-down order; VHC, then VTA, finally NAc. Following habituation, the rats underwent experimental modules consisting of two conditioning trials each followed by immediate testing (test 1 and test 2) and two additional tests 24 h (test 3) and/or 1 week following conditioning (test 4). The module was repeated three times for each nucleus. The results showed that METH, but not Ringer's, produced positive CPP following conditioning each brain area in the bottom-up order. In the top-down order, METH, but not Ringer's, produced either an aversive CPP or no learning effect following conditioning each nucleus of interest. In addition, METH place aversion was antagonized by coadministration of the N-methyl-d-aspartate (NMDA) receptor antagonist MK801, suggesting that the aversion learning was an NMDA receptor activation-dependent process. We conclude that the hippocampus is a critical structure in the reward circuit and hence suggest that the development of target-specific therapeutics for the control of addiction emphasizes on the hippocampus-VTA top-down connection.

Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite

PubMed Central

Abizaid, Alfonso; Liu, Zhong-Wu; Andrews, Zane B.; Shanabrough, Marya; Borok, Erzsebet; Elsworth, John D.; Roth, Robert H.; Sleeman, Mark W.; Picciotto, Marina R.; Tschöp, Matthias H.; Gao, Xiao-Bing; Horvath, Tamas L.

2006-01-01

The gut hormone ghrelin targets the brain to promote food intake and adiposity. The ghrelin receptor growth hormone secretagogue 1 receptor (GHSR) is present in hypothalamic centers controlling energy metabolism as well as in the ventral tegmental area (VTA), a region important for motivational aspects of multiple behaviors, including feeding. Here we show that in mice and rats, ghrelin bound to neurons of the VTA, where it triggered increased dopamine neuronal activity, synapse formation, and dopamine turnover in the nucleus accumbens in a GHSR-dependent manner. Direct VTA administration of ghrelin also triggered feeding, while intra-VTA delivery of a selective GHSR antagonist blocked the orexigenic effect of circulating ghrelin and blunted rebound feeding following fasting. In addition, ghrelin- and GHSR-deficient mice showed attenuated feeding responses to restricted feeding schedules. Taken together, these data suggest that the mesolimbic reward circuitry is targeted by peripheral ghrelin to influence physiological mechanisms related to feeding. PMID:17060947

The preliminary evaluation of degradation of substance P(SP) fragment's analogue less than Glu SP6-11 in the subcellular fractions from different areas of rat brain.

PubMed

Turski, W A; Lachowicz, L; Koziołkiewicz, W

1985-01-01

Peptidase(s) activity of different subcellular fractions isolated from cortex, hippocampus, midbrain, thalamus with hypothalamus, cerebellum and medulla oblongata exerted against less than Glu SP6-11 (3H-Phen8) was evaluated in "low-ionic" and similar (in composition) to both extracellular and intracellular conditions. The incubation of less than Glu SP6-11 with different fractions leaves the hexapeptide undegraded in the studied conditions in most cases. Peptidases activity results in the formation of the first of all C-terminal and exceptionally "internal" labelled products. Labelled N-terminal products were not seen. The most effective degradation in vitro of less than Glu SP6-11 takes place, in the majority of cases, in "low ionic" conditions when compared to those similar to extra or intracellular ones. The biggest total (per 1 g of wet mass) and specific activities against less than Glu SP6-11 can be shown in the hippocampus areas.

Destruction of the medial forebrain bundle caudal to the site of stimulation reduces rewarding efficacy but destruction rostrally does not.

PubMed

Gallistel, C R; Leon, M; Lim, B T; Sim, J C; Waraczynski, M

1996-08-01

Rats with an electrode in the medial forebrain bundle (MFB) in or near the ventral tegmental area and another at the level of the rostral hypothalamus sustained large electrolytic lesions at either the rostral or the caudal electrode. The rewarding efficacy of stimulation through the other electrode was determined before and after the lesion. Massive damage to the MFB in the rostral lateral hypothalamus (LH) generally had little effect on the rewarding efficacy of more caudal stimulation, whereas large lesions in the caudal MFB generally reduced the rewarding efficacy of LH stimulation by 35-60%. Similar reductions were produced by knife cuts in the caudal MFB. These results appear to be inconsistent with the hypothesis that the reward fibers consist either of descending or ascending fibers coursing in or near the MFB. It is suggested that the reward fibers are collaterals from neurons with both their somata and their behaviorally significant terminals located primarily in the midbrain.

Midbrain stimulation-evoked lumbar spinal activity in the adult decerebrate mouse.

PubMed

Stecina, Katinka

2017-08-15

Genetic techniques rendering murine models a popular choice for neuroscience research has led to important insights on neural networks controlling locomotor function. Using genetically altered mouse models for in vivo, electrophysiological studies in the adult state could validate key principles of locomotor network organization that have been described in neonatal, in vitro preparations. The experimental model presented here describes a decerebrate, in vivo adult mouse preparation in which focal, electrical midbrain stimulation was combined with monitoring lumbar neural activity and motor output after pre-collicular decerebration and neuromuscular blockade. Lumbar cord dorsum potentials (in 9/10 animals) and motoneuron output (in 3/5 animals) including fictive locomotion, was achieved by focal midbrain stimulation. The stimulation electrode locations could be reconstructed (in 6/7 animals) thereby allowing anatomical identification of the stimulated supraspinal regions. This preparation allows for concomitant recording or stimulation in the spinal cord and in the mid/hindbrain of adult mice. It differs from other methods used in the past with adult mice as it does not require pharmacological manipulation of neural excitability in order to generate motor output. Midbrain stimulation can consistently be used for inducing lumbar neural activity in adult mice under neuromuscular blockade. This model is suited for examination of brain-spinal connectivity and it may benefit a wide range of fields depending on the features of the genetically modified mouse models used in combination with the presented methods. Copyright © 2017 Elsevier B.V. All rights reserved.

Auditory midbrain implant: a review.

PubMed

Lim, Hubert H; Lenarz, Minoo; Lenarz, Thomas

2009-09-01

The auditory midbrain implant (AMI) is a new hearing prosthesis designed for stimulation of the inferior colliculus in deaf patients who cannot sufficiently benefit from cochlear implants. The authors have begun clinical trials in which five patients have been implanted with a single shank AMI array (20 electrodes). The goal of this review is to summarize the development and research that has led to the translation of the AMI from a concept into the first patients. This study presents the rationale and design concept for the AMI as well a summary of the animal safety and feasibility studies that were required for clinical approval. The authors also present the initial surgical, psychophysical, and speech results from the first three implanted patients. Overall, the results have been encouraging in terms of the safety and functionality of the implant. All patients obtain improvements in hearing capabilities on a daily basis. However, performance varies dramatically across patients depending on the implant location within the midbrain with the best performer still not able to achieve open set speech perception without lip-reading cues. Stimulation of the auditory midbrain provides a wide range of level, spectral, and temporal cues, all of which are important for speech understanding, but they do not appear to sufficiently fuse together to enable open set speech perception with the currently used stimulation strategies. Finally, several issues and hypotheses for why current patients obtain limited speech perception along with several feasible solutions for improving AMI implementation are presented.

Forebrain pathway for auditory space processing in the barn owl.

PubMed

Cohen, Y E; Miller, G L; Knudsen, E I

1998-02-01

The forebrain plays an important role in many aspects of sound localization behavior. Yet, the forebrain pathway that processes auditory spatial information is not known for any species. Using standard anatomic labeling techniques, we used a "top-down" approach to trace the flow of auditory spatial information from an output area of the forebrain sound localization pathway (the auditory archistriatum, AAr), back through the forebrain, and into the auditory midbrain. Previous work has demonstrated that AAr units are specialized for auditory space processing. The results presented here show that the AAr receives afferent input from Field L both directly and indirectly via the caudolateral neostriatum. Afferent input to Field L originates mainly in the auditory thalamus, nucleus ovoidalis, which, in turn, receives input from the central nucleus of the inferior colliculus. In addition, we confirmed previously reported projections of the AAr to the basal ganglia, the external nucleus of the inferior colliculus (ICX), the deep layers of the optic tectum, and various brain stem nuclei. A series of inactivation experiments demonstrated that the sharp tuning of AAr sites for binaural spatial cues depends on Field L input but not on input from the auditory space map in the midbrain ICX: pharmacological inactivation of Field L eliminated completely auditory responses in the AAr, whereas bilateral ablation of the midbrain ICX had no appreciable effect on AAr responses. We conclude, therefore, that the forebrain sound localization pathway can process auditory spatial information independently of the midbrain localization pathway.

Lung granulomatous response induced by infection with the intestinal nematode Nippostrongylusbrasiliensis is suppressed in mast cell-deficient Ws/Ws rats

PubMed Central

ARIZONO, N; NISHIDA, M; UCHIKAWA, R; YAMADA, M; MATSUDA, S; TEGOSHI, T; KITAMURA, Y; SASABE, M

1996-01-01

Certain nematode infections induce eosinophil infiltration and granulomatous responses in the lungs. To examine the role of mast cells in the development of lung lesions, normal +/+ and genetically mast cell-deficient Ws/Ws rats were infected with the nematode Nippostrongylusbrasiliensis. In +/+ rats, numbers of eosinophils in bronchoalveolar lavage fluid (BALF) increased significantly 3–7 days after infection, and granulomatous responses composed of histiocytes/macrophages and multinucleate giant cells were triggered in the lungs 3–14 days after infection. Challenge infection, which was carried out on day 28 after primary infection, induced much higher levels of granulomatous response than after primary infection, suggesting that the response is mediated at least in part by an immunological mechanism. In Ws/Ws rats, both the eosinophil percentage in BALF and the size of the granulomas in the lungs were significantly smaller than in +/+ rats after primary as well as after challenge infection. The amount of rat mast cell protease (RMCP) II in +/+ rat BALF was increased 1 day after primary infection and more significantly after challenge infection, suggesting that lung mucosal mast cells were activated more markedly after the challenge infection. In Ws/Ws rats, RMCP II was undetectable throughout the observation period. The time course of nematode migration in the lungs did not differ in +/+ and Ws/Ws rats. These results suggest that mast cell activation might be relevant to eosinophil infiltration and granulomatous response in the lungs, although the responses do not affect lung migration of the nematode. PMID:8870698

Activation of the reticulothalamic cholinergic pathway by the major metabolites of aniracetam.

PubMed

Nakamura, K; Shirane, M

1999-09-10

The aim of the study was to further investigate the effects of aniracetam, a cognition enhancer, and its metabolites on the brain cholinergic system. We measured choline acetyltransferase activity and acetylcholine release using in vivo brain microdialysis in stroke-prone spontaneously hypertensive rats (SHRSP). The enzyme activity in the pons-midbrain and hippocampus, and basal acetylcholine release in the nucleus reticularis thalami were lower in SHRSP than in age-matched Wistar Kyoto rats, indicating central cholinergic deficits in SHRSP. Repeated treatment of aniracetam (50 mg/kg p.o. x 11 for 6 days) preferentially increased the enzyme activity in the thalamus, whereas decreased it in the striatum. Among the metabolites of aniracetam, local perfusion of N-anisoyl-gamma-aminobutyric acid (GABA, 0.1 and/or 1 microM) and p-anisic acid (1 microM) into the nucleus reticularis thalami, dorsal hippocampus and prefrontal cortex of SHRSP produced a significant but delayed increase of acetylcholine release. We failed, however, to find any effect of aniracetam itself. A direct injection of N-anisoyl-GABA (1 nmol) into the pedunculopontine tegmental nucleus of SHRSP enhanced the release in the nucleus reticularis thalami. Thus, these data prove that aniracetam can facilitate central cholinergic neurotransmission via both metabolites. Based on its pharmacokinetic profile, N-anisoyl-GABA may contribute to the clinical effects of aniracetam, mainly by acting on the reticulothalamic cholinergic pathway.

Enhanced proliferation and dopaminergic differentiation of ventral mesencephalic precursor cells by synergistic effect of FGF2 and reduced oxygen tension

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jensen, Pia; Department of Neurosurgery, University of Bern, CH-3010 Bern; Gramsbergen, Jan-Bert

Effective numerical expansion of dopaminergic precursors might overcome the limited availability of transplantable cells in replacement strategies for Parkinson's disease. Here we investigated the effect of fibroblast growth factor-2 (FGF2) and FGF8 on expansion and dopaminergic differentiation of rat embryonic ventral mesencephalic neuroblasts cultured at high (20%) and low (3%) oxygen tension. More cells incorporated bromodeoxyuridine in cultures expanded at low as compared to high oxygen tension, and after 6 days of differentiation there were significantly more neuronal cells in low than in high oxygen cultures. Low oxygen during FGF2-mediated expansion resulted also in a significant increase in tyrosine hydroxylase-immunoreactivemore » (TH-ir) dopaminergic neurons as compared to high oxygen tension, but no corresponding effect was observed for dopamine release into the culture medium. However, switching FGF2-expanded cultures from low to high oxygen tension during the last two days of differentiation significantly enhanced dopamine release and intracellular dopamine levels as compared to all other treatment groups. In addition, the short-term exposure to high oxygen enhanced in situ assessed TH enzyme activity, which may explain the elevated dopamine levels. Our findings demonstrate that modulation of oxygen tension is a recognizable factor for in vitro expansion and dopaminergic differentiation of rat embryonic midbrain precursor cells.« less

Effect of MDMA-Induced Axotomy on the Dorsal Raphe Forebrain Tract in Rats: An In Vivo Manganese-Enhanced Magnetic Resonance Imaging Study

PubMed Central

Chiu, Chuang-Hsin; Siow, Tiing-Yee; Weng, Shao-Ju; Hsu, Yi-Hua; Huang, Yuahn-Sieh; Chang, Kang-Wei; Cheng, Cheng-Yi; Ma, Kuo-Hsing

2015-01-01

3,4-Methylenedioxymethamphetamine (MDMA), also known as “Ecstasy”, is a common recreational drug of abuse. Several previous studies have attributed the central serotonergic neurotoxicity of MDMA to distal axotomy, since only fine serotonergic axons ascending from the raphe nucleus are lost without apparent damage to their cell bodies. However, this axotomy has never been visualized directly in vivo. The present study examined the axonal integrity of the efferent projections from the midbrain raphe nucleus after MDMA exposure using in vivo manganese-enhanced magnetic resonance imaging (MEMRI). Rats were injected subcutaneously six times with MDMA (5 mg/kg) or saline once daily. Eight days after the last injection, manganese ions (Mn2+) were injected stereotactically into the raphe nucleus, and a series of MEMRI images was acquired over a period of 38 h to monitor the evolution of Mn2+-induced signal enhancement across the ventral tegmental area, the medial forebrain bundle (MFB), and the striatum. The MDMA-induced loss of serotonin transporters was clearly evidenced by immunohistological staining consistent with the Mn2+-induced signal enhancement observed across the MFB and striatum. MEMRI successfully revealed the disruption of the serotonergic raphe-striatal projections and the variable effect of MDMA on the kinetics of Mn2+ accumulation in the MFB and striatum. PMID:26378923

Mixed microencapsulation of rat primary hepatocytes and Sertoli cells improves the metabolic function in a D-galactosamine and lipopolysaccharide-induced rat model of acute liver failure.

PubMed

Zheng, Ming-Hua; Lin, Hai-Long; Qiu, Li-Xin; Cui, Yao-Li; Sun, Qing-Feng; Chen, Yong-Ping

2009-01-01

Hepatocyte transplantation is an alternative to transplantation of the whole liver. Compared with xenogeneic hepatocytes, primary hepatocytes have some advantages, such as a more powerful function and a smaller frequency of rejection caused by the host. Cell microencapsulation prevents direct access of host cells to the graft but cannot impede transfer of transplant-derived peptides, which can cross the physical barrier. Sertoli cells are central to the immune privilege demonstrated in the testis, and their actions have been utilized to protect cell transplants. Co-microencapsulating Sertoli cells with HepG2 cells has proved to be a valuable strategy in hepatocyte transplantation. Thus mixed microcapsules of primary rat hepatocytes and primary Sertoli cells may improve metabolic function in a d-galactosamine and lipopolysaccharide-induced rat model of acute liver failure.

Focal atrophy in Dementia with Lewy Bodies on MRI: a distinct pattern from Alzheimer's disease

PubMed Central

Whitwell, Jennifer L; Weigand, Stephen D; Shiung, Maria M; Boeve, Bradley F; Ferman, Tanis J; Smith, Glenn E; Knopman, David S; Petersen, Ronald C; Benarroch, Eduardo E; Josephs, Keith A; Jack, Clifford R

2009-01-01

SUMMARY Dementia with Lewy Bodies (DLB) is the second most common cause of degenerative dementia after Alzheimer's disease (AD). However, unlike in AD the patterns of cerebral atrophy associated with DLB have not been well established. The aim of this study was to identify a signature pattern of cerebral atrophy in DLB and to compare it to the pattern found in AD. Seventy-two patients that fulfilled clinical criteria for probable DLB were age and gender-matched to 72 patients with probable AD and 72 controls. Voxel-based morphometry (VBM) was used to assess patterns of grey matter atrophy in the DLB and AD groups, relative to controls, after correction for multiple comparisons (p<0.05). Study specific templates and prior probability maps were used to avoid normalization and segmentation bias. Region-of-interest (ROI) analyses were also performed comparing loss of the midbrain, substantia innominata (SI), temporoparietal cortex and hippocampus between the groups. The DLB group showed very little cortical involvement on VBM with regional grey matter loss observed primarily in the dorsal midbrain, SI and hypothalamus. In comparison, the AD group showed a widespread pattern of grey matter loss involving the temporoparietal association cortices and the medial temporal lobes. The SI and dorsal midbrain were involved in AD however they were not identified as a cluster of loss discrete from uninvolved surrounding areas, as observed in the DLB group. On direct comparison between the two groups, the AD group showed greater loss in the medial temporal lobe and inferior temporal regions than the DLB group. The ROI analysis showed reduced SI and midbrain grey matter in both the AD and DLB groups. The SI grey matter was reduced more in AD than DLB, yet the midbrain was reduced more in DLB than AD. The hippocampus and temporoparietal cortex showed significantly greater loss in the AD group compared to the DLB group. A pattern of relatively focused atrophy of the midbrain, hypothalamus and SI, with a relative sparing of the hippocampus and temporoparietal cortex, is therefore suggestive of DLB and may aid in the differentiation of DLB from AD. These findings support recent pathological studies showing an ascending pattern of Lewy Body progression from brainstem to basal areas of the brain. Damage to this network of structures in DLB may affect a number of different neurotransmitter systems which in turn may contribute to a number of the core clinical features of DLB. PMID:17267521

Three cases of communication syringomyelia secondary to midbrain gliomas.

PubMed Central

Williams, B; Timperley, W R

1977-01-01

Three cases of midbrain gliomas are descrbied clinically and pathologically. In each case high pressure symptoms were followed by visual disturbance and the onset of syringomyelia symptoms before death. All the patients had hydrocephalus. In one case with concomitant syringobulbia, the syrinx appeared to due to CSF communicating with the cord cavity through the tissues of the brain stem. In the other cases the communication between the CSF pathways and the syrinx was at the usual site, through the central canal at the obex. Images PMID:845611

Evaluation of brain SERT occupancy by resveratrol against MDMA-induced neurobiological and behavioral changes in rats: A 4-[¹⁸F]-ADAM/small-animal PET study.

PubMed

Shih, Jui-Hu; Ma, Kuo-Hsing; Chen, Chien-Fu F; Cheng, Cheng-Yi; Pao, Li-Heng; Weng, Shao-Ju; Huang, Yuahn-Sieh; Shiue, Chyng-Yann; Yeh, Ming-Kung; Li, I-Hsun

2016-01-01

The misuse of 3,4-methylenedioxymethamphetamine (MDMA) has drawn a growing concern worldwide for its psychophysiological impacts on humans. MDMA abusers are often accompanied by long-term serotonergic neurotoxicity, which is associated with reduced density of cerebral serotonin transporters (SERT) and depressive disorders. Resveratrol (RSV) is a natural polyphenolic phytoalexin that has been known for its antidepressant and neuroprotective effects. However, biological targets of RSV as well as its neuroprotective effects against MDMA remained largely unknown. In this study, we examined binding potency of RSV and MDMA to SERT using small-animal positron emission tomography (PET) with the SERT radioligand, N,N-dimethyl-2-(2-amino-4-[(18)F]fluorophenylthio)benzylamine (4-[(18)F]-ADAM) and investigated the protection of RSV against the acute and long-term adverse effects of MDMA. We found that RSV exhibit binding potentials to SERT in vivo in a dose-dependent manner with variation among brain regions. When the MDMA-treated rats (10mg/kg, s.c.) were co-injected with RSV (20mg/kg, i.p.) twice daily for 4 consecutive days, MDMA-induced acute elevation in plasma corticosterone was significantly reduced. Further, 4-[(18)F]-ADAM PET imaging revealed that RSV protected against the MDMA-induced decrease in SERT availability in the midbrain and the thalamus 2 weeks following the co-treatment. The PET data were comparable to the observation from the forced swim test that RSV sufficiently ameliorated the depressive-like behaviors of the MDMA-treated rats. Together, these findings suggest that RSV is a potential antidepressant and may confer protection against neurobiological and behavioral changes induced by MDMA. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

Altered brainstem auditory evoked potentials in a rat central sensitization model are similar to those in migraine

PubMed Central

Arakaki, Xianghong; Galbraith, Gary; Pikov, Victor; Fonteh, Alfred N.; Harrington, Michael G.

2014-01-01

Migraine symptoms often include auditory discomfort. Nitroglycerin (NTG)-triggered central sensitization (CS) provides a rodent model of migraine, but auditory brainstem pathways have not yet been studied in this example. Our objective was to examine brainstem auditory evoked potentials (BAEPs) in rat CS as a measure of possible auditory abnormalities. We used four subdermal electrodes to record horizontal (h) and vertical (v) dipole channel BAEPs before and after injection of NTG or saline. We measured the peak latencies (PLs), interpeak latencies (IPLs), and amplitudes for detectable waveforms evoked by 8, 16, or 32 KHz auditory stimulation. At 8 KHz stimulation, vertical channel positive PLs of waves 4, 5, and 6 (vP4, vP5, and vP6), and related IPLs from earlier negative or positive peaks (vN1-vP4, vN1-vP5, vN1-vP6; vP3-vP4, vP3-vP6) increased significantly 2 hours after NTG injection compared to the saline group. However, BAEP peak amplitudes at all frequencies, PLs and IPLs from the horizontal channel at all frequencies, and the vertical channel stimulated at 16 and 32 KHz showed no significant/consistent change. For the first time in the rat CS model, we show that BAEP PLs and IPLs ranging from putative bilateral medial superior olivary nuclei (P4) to the more rostral structures such as the medial geniculate body (P6) were prolonged 2 hours after NTG administration. These BAEP alterations could reflect changes in neurotransmitters and/or hypoperfusion in the midbrain. The similarity of our results with previous human studies further validates the rodent CS model for future migraine research. PMID:24680742

Long-term dysregulation of brain corticotrophin and glucocorticoid receptors and stress reactivity by single early-life pain experience in male and female rats.

PubMed

Victoria, Nicole C; Inoue, Kiyoshi; Young, Larry J; Murphy, Anne Z

2013-12-01

Inflammatory pain experienced on the day of birth (postnatal day 0: PD0) significantly dampens behavioral responses to stress- and anxiety-provoking stimuli in adult rats. However, to date, the mechanisms by which early life pain permanently alters adult stress responses remain unknown. The present studies examined the impact of inflammatory pain, experienced on the day of birth, on adult expression of receptors or proteins implicated in the activation and termination of the stress response, including corticotrophin releasing factor receptors (CRFR1 and CRFR2) and glucocorticoid receptor (GR). Using competitive receptor autoradiography, we show that Sprague Dawley male and female rat pups administered 1% carrageenan into the intraplantar surface of the hindpaw on the day of birth have significantly decreased CRFR1 binding in the basolateral amygdala and midbrain periaqueductal gray in adulthood. In contrast, CRFR2 binding, which is associated with stress termination, was significantly increased in the lateral septum and cortical amygdala. GR expression, measured with in situ hybridization and immunohistochemistry, was significantly increased in the paraventricular nucleus of the hypothalamus and significantly decreased in the hippocampus of neonatally injured adults. In parallel, acute stress-induced corticosterone release was significantly attenuated and returned to baseline more rapidly in adults injured on PD0 in comparison to controls. Collectively, these data show that early life pain alters neural circuits that regulate responses to and neuroendocrine recovery from stress, and suggest that pain experienced by infants in the Neonatal Intensive Care Unit may permanently alter future responses to anxiety- and stress-provoking stimuli. Published by Elsevier Ltd.

STIMULATION OF NICOTINE REWARD AND CENTRAL CHOLINERGIC ACTIVITY IN SPRAGUE-DAWLEY RATS EXPOSED PERINATALLY TO A FAT-RICH DIET

PubMed Central

Morganstern, Irene; Lukatskaya, Olga; Moon, Sang-Ho; Guo, Wei-Ran; Shaji, Jane; Karatayev, Olga; Leibowitz, Sarah F.

2014-01-01

Rationale While clinical studies show maternal consumption of palatable fat-rich diets during pregnancy to negatively impact the children’s behaviors and increase their vulnerability to drug abuse, the precise behavioral and neurochemical mechanisms mediating these phenomena have yet to be examined. Objective The study examined in rats whether gestational exposure to a high-fat diet (HFD) can increase the offspring’s propensity to use nicotine and whether disturbances in central nicotinic cholinergic signaling accompany this behavioral effect. Methods Rat offspring exposed perinatally to a HFD or Chow diet were characterized in terms of their nicotine self-administration behavior in a series of operant response experiments and the activity of acetylcholinesterase (AChE) and density of nicotinic ACh receptors (nAChRs) in different brain areas. Result Perinatal HFD compared to Chow exposure increased nicotine-self administration behavior during fixed-ratio and dose-response testing and caused an increase in breakpoint using progressive ratio testing, while nicotine-seeking in response to nicotine prime-induced reinstatement was reduced. This behavioral change induced by the HFD was associated with a significant reduction in activity of AChE in the midbrain, hypothalamus and striatum and increased density of β2-nAChRs in the ventral tegmental area and substantia nigra and of α7-nAChRs in the lateral and ventromedial hypothalamus. Conclusions Perinatal exposure to a HFD increases the vulnerability of the offspring to excessive nicotine use by enhancing its reward potential, and these behavioral changes are accompanied by a stimulation of nicotinic cholinergic signaling in mesostriatal and hypothalamic brain areas important for reinforcement and consummatory behavior. PMID:23836027

Evidence That the Periaqueductal Gray Matter Mediates the Facilitation of Panic-Like Reactions in Neonatally-Isolated Adult Rats

PubMed Central

Quintino-dos-Santos, Jeyce Willig; Müller, Cláudia Janaína Torres; Bernabé, Cristie Setúbal; Rosa, Caroline Azevedo; Tufik, Sérgio; Schenberg, Luiz Carlos

2014-01-01

Plenty of evidence suggests that childhood separation anxiety (CSA) predisposes the subject to adult-onset panic disorder (PD). As well, panic is frequently comorbid with both anxiety and depression. The brain mechanisms whereby CSA predisposes to PD are but completely unknown in spite of the increasing evidence that panic attacks are mediated at midbrain's dorsal periaqueductal gray matter (DPAG). Accordingly, here we examined whether the neonatal social isolation (NSI), a model of CSA, facilitates panic-like behaviors produced by electrical stimulations of DPAG of rats as adults. Eventual changes in anxiety and depression were also assessed in the elevated plus-maze (EPM) and forced-swimming test (FST) respectively. Male pups were subjected to 3-h daily isolations from post-natal day 2 (PN2) until weaning (PN21) allotting half of litters in individual boxes inside a sound-attenuated chamber (NSI, n = 26) whilst siblings (sham-isolated rats, SHAM, n = 27) and dam were moved to another box in a separate room. Non-handled controls (CTRL, n = 18) remained undisturbed with dams until weaning. As adults, rats were implanted with electrodes into the DPAG (PN60) and subjected to sessions of intracranial stimulation (PN65), EPM (PN66) and FST (PN67-PN68). Groups were compared by Fisher's exact test (stimulation sites), likelihood ratio chi-square tests (stimulus-response threshold curves) and Bonferroni's post hoc t-tests (EPM and FST), for P<0.05. Notably, DPAG-evoked panic-like responses of immobility, exophthalmus, trotting, galloping and jumping were markedly facilitated in NSI rats relative to both SHAM and CTRL groups. Conversely, anxiety and depression scores either did not change or were even reduced in neonatally-handled groups relative to CTRL, respectively. Data are the first behavioral evidence in animals that early-life separation stress produces the selective facilitation of panic-like behaviors in adulthood. Most importantly, results implicate the DPAG not only in panic attacks but also in separation-anxious children's predispositions to the late development of PD. PMID:24594924

Oxidative deamination of alicyclic primary amines by liver microsomes from rats and rabbits.

PubMed

Kurebayashi, H; Tanaka, A; Yamaha, T; Tatahashi, A

1988-09-01

1. Substrate selectivity and species difference in the oxidative deamination of the alicyclic primary amines, cyclopentylamine, cyclohexylamine, cycloheptylamine, 1- and 2-aminoindane, and 1- and 2-aminotetralin were studied using liver microsomes from rats and rabbits. 2. The deamination rates of the amines were much greater with liver microsomes from rabbits than from rats. Substrate selectivity resulted in much faster deamination of 1-aminoindane and 1-aminotetralin than of the corresponding 2-amino compounds, especially in rats. 3. When 1-aminoindane and 1-aminotetralin were incubated with rat liver microsomes and NADPH under 18O2, oxygen-18 was incorporated into the deaminated products, 1-indanone and 1-tetralone. The carbinolamine is a key intermediate in the oxidative deamination by rat liver microsomes, indicating the contribution of cytochrome P-450-dependent alpha-C-oxidation to the reaction. 4. Alicyclic primary amines gave type II binding spectra with rat and rabbit liver microsomes, but the spectra appeared to contain type I components. 5. The ratios of the alcohols, cyclohexanol, 2-tetralol and 2-indanol in the deaminated products were high in both rats and rabbits. The ketones were precursors of the alcohols, and substrate selectivity in reduction of the alicyclic ketones with NADPH was similar in both species.

Improved cell therapy protocol for Parkinson’s disease based on differentiation efficiency and safety of hESC-, hiPSC and non-human primate iPSC-derived DA neurons

PubMed Central

Maria, Sundberg; Helle, Bogetofte; Tristan, Lawson; Gaynor, Smith; Arnar, Astradsson; Michele, Moore; Teresia, Osborn; Oliver, Cooper; Roger, Spealman; Penelope, Hallett; Ole, Isacson

2013-01-01

The main motor symptoms of Parkinson’s disease are due to the loss of dopaminergic (DA) neurons in the ventral midbrain (VM). For the future treatment of Parkinson’s disease with cell transplantation it is important to develop efficient differentiation methods for production of human iPSCs and hESCs-derived midbrain-type DA neurons. Here we describe an efficient differentiation and sorting strategy for DA-neurons from both human ES/iPS cells and non-human primate iPSCs. The use of non-human primate iPSCs for neuronal differentiation and autologous transplantation is important for pre-clinical evaluation of safety and efficacy of stem cell-derived DA neurons. The aim of this study was to improve the safety of human- and non-human primate-iPSC (PiPSC)-derived DA neurons. According to our results, NCAM+/CD29low sorting enriched VM DA-neurons from pluripotent stem cell-derived neural cell populations. NCAM+/CD29low DA-neurons were positive for FOXA2/TH and EN1/TH and this cell population had increased expression levels of FOXA2, LMX1A, TH, GIRK2, PITX3, EN1, NURR1 mRNA compared to unsorted neural cell populations. PiPSC-derived NCAM+/CD29low DA-neurons were able to restore motor function of 6-OHDA lesioned rats 16 weeks after transplantation. The transplanted sorted cells also integrated in the rodent brain tissue, with robust TH+/hNCAM+ neuritic innervation of the host striatum. One year after autologous transplantation, the primate iPSC-derived neural cells survived in the striatum of one primate without any immunosuppression. These neural cell grafts contained FOXA2/TH-positive neurons in the graft site. This is an important proof of concept for the feasibility and safety of iPSC-derived cell transplantation therapies in the future. PMID:23666606

Effects and Mechanisms of 3α,5α,-THP on Emotion, Motivation, and Reward Functions Involving Pregnane Xenobiotic Receptor

PubMed Central

Frye, Cheryl A.; Paris, J. J.; Walf, A. A.; Rusconi, J. C.

2011-01-01

Progestogens [progesterone (P4) and its products] play fundamental roles in the development and/or function of the central nervous system during pregnancy. We, and others, have investigated the role of pregnane neurosteroids for a plethora of functional effects beyond their pro-gestational processes. Emerging findings regarding the effects, mechanisms, and sources of neurosteroids have challenged traditional dogma about steroid action. How the P4 metabolite and neurosteroid, 3α-hydroxy-5α-pregnan-20-one (3α,5α-THP), influences cellular functions and behavioral processes involved in emotion/affect, motivation, and reward, is the focus of the present review. To further understand these processes, we have utilized an animal model assessing the effects, mechanisms, and sources of 3α,5α-THP. In the ventral tegmental area (VTA), 3α,5α-THP has actions to facilitate affective, and motivated, social behaviors through non-traditional targets, such as GABA, glutamate, and dopamine receptors. 3α,5α-THP levels in the midbrain VTA both facilitate, and/or are enhanced by, affective and social behavior. The pregnane xenobiotic receptor (PXR) mediates the production of, and/or metabolism to, various neurobiological factors. PXR is localized to the midbrain VTA of rats. The role of PXR to influence 3α,5α-THP production from central biosynthesis, and/or metabolism of peripheral P4, in the VTA, as well as its role to facilitate, or be increased by, affective/social behaviors is under investigation. Investigating novel behavioral functions of 3α,5α-THP extends our knowledge of the neurobiology of progestogens, relevant for affective/social behaviors, and their connections to systems that regulate affect and motivated processes, such as those important for stress regulation and neuropsychiatric disorders (anxiety, depression, schizophrenia, drug dependence). Thus, further understanding of 3α,5α-THP’s role and mechanisms to enhance affective and motivated processes is essential. PMID:22294977

Intralaminar stimulation of the inferior colliculus facilitates frequency-specific activation in the auditory cortex

NASA Astrophysics Data System (ADS)

Allitt, B. J.; Benjaminsen, C.; Morgan, S. J.; Paolini, A. G.

2013-08-01

Objective. Auditory midbrain implants (AMI) provide inadequate frequency discrimination for open set speech perception. AMIs that can take advantage of the tonotopic laminar of the midbrain may be able to better deliver frequency specific perception and lead to enhanced performance. Stimulation strategies that best elicit frequency specific activity need to be identified. This research examined the characteristic frequency (CF) relationship between regions of the auditory cortex (AC), in response to stimulated regions of the inferior colliculus (IC), comparing monopolar, and intralaminar bipolar electrical stimulation. Approach. Electrical stimulation using multi-channel micro-electrode arrays in the IC was used to elicit AC responses in anaesthetized male hooded Wistar rats. The rate of activity in AC regions with CFs within 3 kHz (CF-aligned) and unaligned CFs was used to assess the frequency specificity of responses. Main results. Both monopolar and bipolar IC stimulation led to CF-aligned neural activity in the AC. Altering the distance between the stimulation and reference electrodes in the IC led to changes in both threshold and dynamic range, with bipolar stimulation with 400 µm spacing evoking the lowest AC threshold and widest dynamic range. At saturation, bipolar stimulation elicited a significantly higher mean spike count in the AC at CF-aligned areas than at CF-unaligned areas when electrode spacing was 400 µm or less. Bipolar stimulation using electrode spacing of 400 µm or less also elicited a higher rate of elicited activity in the AC in both CF-aligned and CF-unaligned regions than monopolar stimulation. When electrodes were spaced 600 µm apart no benefit over monopolar stimulation was observed. Furthermore, monopolar stimulation of the external cortex of the IC resulted in more localized frequency responses than bipolar stimulation when stimulation and reference sites were 200 µm apart. Significance. These findings have implications for the future development of AMI, as a bipolar stimulation strategy may improve the ability of implant users to discriminate between frequencies.

CRISPR/Cas9-Mediated Zebrafish Knock-in as a Novel Strategy to Study Midbrain-Hindbrain Boundary Development

PubMed Central

Kesavan, Gokul; Chekuru, Avinash; Machate, Anja; Brand, Michael

2017-01-01

The midbrain-hindbrain boundary (MHB) acts as an organizer and controls the fate of neighboring cells to develop into either mesencephalic (midbrain) or metencephalic (hindbrain) cells by secreting signaling molecules like Wnt1 and Fgf8. The zebrafish is an excellent vertebrate model for studying MHB development due to the ease of gene manipulation and the possibility of following cellular dynamics and morphogenetic processes using live imaging. Currently, only very few reporter and/or Cre-driver lines are available to study gene expression at the MHB, hampering the understanding of MHB development, and traditional transgenic technologies using promoter/enhancer fragments or bacterial artificial chromosome (BAC)-mediated transgenesis often do not faithfully recapitulate endogenous expression patterns. In contrast, CRISPR/Cas9-mediated genome editing technology now provides a great opportunity to efficiently knock-in or knock-out genes. We have generated four CRISPR/Cas9-based knock-in fluorescent reporter lines for two crucial genes involved in MHB development, namely otx2 and pax2a. The coding sequences of the reporters were knocked-in upstream of the corresponding ATG and are, thus, under the control of the endogenous promoter/enhancer elements. Interestingly, this strategy does not disturb endogenous gene expression. Using the fast maturing fluorescent protein reporter, Venus, enabled us to follow MHB development using cell tracking and live imaging. In addition, we show that these reporter lines label various neuronal and glial cell types in the adult zebrafish brain, making them highly suitable for investigating embryonic and adult midbrain, hindbrain, and MHB development. PMID:28713249

From Threat to Fear: The neural organization of defensive fear systems in humans

PubMed Central

Mobbs, Dean; Marchant, Jennifer L; Hassabis, Demis; Seymour, Ben; Tan, Geoffrey; Gray, Marcus; Petrovic, Predrag; Dolan, Raymond J.; Frith, Christopher D.

2009-01-01

Post-encounter and circa-strike defensive contexts represent two adaptive responses to potential and imminent danger. In the context of a predator, the post-encounter reflects the initial detection of the potential threat, whilst the circa-strike is associated with direct predatory attack. We used fMRI to investigate the neural organization of anticipation and avoidance of artificial predators with high or low probability of capturing the subject across analogous post-encounter and circa-strike contexts of threat. Consistent with defense systems models, post-encounter threat elicited activity in forebrain areas including subgenual anterior cingulate cortex (sgACC), hippocampus and amygdala. Conversely, active avoidance during circa-strike threat increased activity in mid-dorsal ACC and midbrain areas. During the circa-strike condition, subjects showed increased coupling between the midbrain and mid-dorsal ACC and decreased coupling with the sgACC, amygdala and hippocampus. Greater activity was observed in the right pregenual ACC for high compared to low probability of capture during circa-strike threat. This region showed decreased coupling with the amygdala, insula and ventromedial prefrontal cortex. Finally, we found that locomotor errors correlated with subjective reports of panic for the high compared to low probability of capture during the circa-strike threat and these panic-related locomotor errors were correlated with midbrain activity. These findings support models suggesting that higher forebrain areas are involved in early threat responses, including the assignment and control of fear, whereas as imminent danger results in fast, likely “hard-wired”, defensive reactions mediated by the midbrain. PMID:19793982

There's more than one way to scan a cat: imaging cat auditory cortex with high-field fMRI using continuous or sparse sampling.

PubMed

Hall, Amee J; Brown, Trecia A; Grahn, Jessica A; Gati, Joseph S; Nixon, Pam L; Hughes, Sarah M; Menon, Ravi S; Lomber, Stephen G

2014-03-15

When conducting auditory investigations using functional magnetic resonance imaging (fMRI), there are inherent potential confounds that need to be considered. Traditional continuous fMRI acquisition methods produce sounds >90 dB which compete with stimuli or produce neural activation masking evoked activity. Sparse scanning methods insert a period of reduced MRI-related noise, between image acquisitions, in which a stimulus can be presented without competition. In this study, we compared sparse and continuous scanning methods to identify the optimal approach to investigate acoustically evoked cortical, thalamic and midbrain activity in the cat. Using a 7 T magnet, we presented broadband noise, 10 kHz tones, or 0.5 kHz tones in a block design, interleaved with blocks in which no stimulus was presented. Continuous scanning resulted in larger clusters of activation and more peak voxels within the auditory cortex. However, no significant activation was observed within the thalamus. Also, there was no significant difference found, between continuous or sparse scanning, in activations of midbrain structures. Higher magnitude activations were identified in auditory cortex compared to the midbrain using both continuous and sparse scanning. These results indicate that continuous scanning is the preferred method for investigations of auditory cortex in the cat using fMRI. Also, choice of method for future investigations of midbrain activity should be driven by other experimental factors, such as stimulus intensity and task performance during scanning. Copyright © 2014 Elsevier B.V. All rights reserved.

Midbrain functional connectivity and ventral striatal dopamine D2-type receptors: Link to impulsivity in methamphetamine users

PubMed Central

Kohno, Milky; Okita, Kyoji; Morales, Angelica M.; Robertson, Chelsea; Dean, Andy C.; Ghahremani, Dara G.; Sabb, Fred; Mandelkern, Mark A.; Bilder, Robert M.; London, Edythe D.

2015-01-01

Stimulant use disorders are associated with deficits in striatal dopamine receptor availability, abnormalities in mesocorticolimbic resting-state functional connectivity (RSFC), and impulsivity. In methamphetamine-dependent research participants, impulsivity is correlated negatively with striatal D2-type receptor availability, and mesocorticolimbic RSFC is stronger than in controls. The extent to which these features of methamphetamine dependence are interrelated, however, is unknown. This question was addressed in two studies. In Study 1, 19 methamphetamine-dependent and 26 healthy control subjects underwent [18F]fallypride positron emission tomography to measure ventral striatal dopamine D2-type receptor availability, indexed by binding potential (BPND), and functional magnetic resonance imaging (fMRI) to assess mesocorticolimbic RSFC, using a midbrain seed. In Study 2, an independent sample of 20 methamphetamine-dependent and 18 control subjects completed the Barratt Impulsiveness Scale in addition to fMRI. Study 1 showed a significant group by ventral striatal BPND interaction effect on RSFC, reflecting a negative relationship between ventral striatal BPND and RSFC between midbrain and striatum, orbitofrontal cortex, and insula in methamphetamine-dependent participants but a positive relationship in the control group. In Study 2, an interaction of group with RSFC on impulsivity was observed. Methamphetamine-dependent participants users exhibited a positive relationship of midbrain RSFC to the left ventral striatum with cognitive impulsivity, whereas a negative relationship was observed in healthy controls. The results indicate that ventral striatal D2-type receptor signaling may affect system-level activity within the mesocorticolimbic system, providing a functional link that may help explain high impulsivity in methamphetamine-dependent individuals. PMID:26830141

Intrinsic functional connectivity alterations in progressive supranuclear palsy: Differential effects in frontal cortex, motor, and midbrain networks.

PubMed

Rosskopf, Johannes; Gorges, Martin; Müller, Hans-Peter; Lulé, Dorothée; Uttner, Ingo; Ludolph, Albert C; Pinkhardt, Elmar; Juengling, Freimut D; Kassubek, Jan

2017-07-01

The topography of functional network changes in progressive supranuclear palsy can be mapped by intrinsic functional connectivity MRI. The objective of this study was to study functional connectivity and its clinical and behavioral correlates in dedicated networks comprising the cognition-related default mode and the motor and midbrain functional networks in patients with PSP. Whole-brain-based "resting-state" functional MRI and high-resolution T1-weighted magnetic resonance imaging data together with neuropsychological and video-oculographic data from 34 PSP patients (22 with Richardson subtype and 12 with parkinsonian subtype) and 35 matched healthy controls were subjected to network-based functional connectivity and voxel-based morphometry analysis. After correction for global patterns of brain atrophy, the group comparison between PSP patients and controls revealed significantly decreased functional connectivity (P < 0.05, corrected) in the prefrontal cortex, which was significantly correlated with cognitive performance (P = 0.006). Of note, midbrain network connectivity in PSP patients showed increased connectivity with the thalamus, on the one hand, whereas, on the other hand, lower functional connectivity within the midbrain was significantly correlated with vertical gaze impairment, as quantified by video-oculography (P = 0.004). PSP Richardson subtype showed significantly increased functional motor network connectivity with the medial prefrontal gyrus. PSP-associated neurodegeneration was attributed to both decreased and increased functional connectivity. Decreasing functional connectivity was associated with worse behavioral performance (ie, dementia severity and gaze palsy), whereas the pattern of increased functional connectivity may be a potential adaptive mechanism. © 2017 International Parkinson and Movement Disorder Society. © 2017 International Parkinson and Movement Disorder Society.

Intrinsic Properties Guide Proximal Abducens and Oculomotor Nerve Outgrowth in Avian Embryos

PubMed Central

Lance-Jones, Cynthia; Shah, Veeral; Noden, Drew M.; Sours, Emily

2012-01-01

Proper movement of the vertebrate eye requires the formation of precisely patterned axonal connections linking cranial somatic motoneurons, located at defined positions in the ventral midbrain and hindbrain, with extraocular muscles. The aim of this research was to assess the relative contributions of intrinsic, population-specific properties and extrinsic, outgrowth site-specific cues during the early stages of abducens and oculomotor nerve development in avian embryos. This was accomplished by surgically transposing midbrain and caudal hindbrain segments, which had been pre-labeled by electroporation with an EGFP construct. Graft-derived EGFP+ oculomotor axons entering a hindbrain microenvironment often mimicked an abducens initial pathway and coursed cranially. Similarly, some EGFP+ abducens axons entering a midbrain microenvironment mimicked an oculomotor initial pathway and coursed ventrally. Many but not all of these axons subsequently projected to extraocular muscles that they would not normally innervate. Strikingly, EGFP+ axons also took initial paths atypical for their new location. Upon exiting from a hindbrain position, most EGFP+ oculomotor axons actually coursed ventrally and joined host branchiomotor nerves, whose neurons share molecular features with oculomotor neurons. Similarly, upon exiting from a midbrain position, some EGFP+ abducens axons turned caudally, elongated parallel to the brainstem, and contacted the lateral rectus muscle, their originally correct target. These data reveal an interplay between intrinsic properties that are unique to oculomotor and abducens populations and shared ability to recognize and respond to extrinsic directional cues. The former play a prominent role in initial pathway choices, whereas the latter appear more instructive during subsequent directional choices. PMID:21739615

Synchrony of corticostriatal-midbrain activation enables normal inhibitory control and conflict processing in recovering alcoholic men.

PubMed

Schulte, Tilman; Müller-Oehring, Eva M; Sullivan, Edith V; Pfefferbaum, Adolf

2012-02-01

Alcohol dependence is associated with inhibitory control deficits, possibly related to abnormalities in frontoparietal cortical and midbrain function and connectivity. We examined functional connectivity and microstructural fiber integrity between frontoparietal and midbrain structures using a Stroop Match-to-Sample task with functional magnetic resonance imaging and diffusion tensor imaging in 18 alcoholic and 17 control subjects. Manipulation of color cues and response repetition sequences modulated cognitive demands during Stroop conflict. Despite similar lateral frontoparietal activity and functional connectivity in alcoholic and control subjects when processing conflict, control subjects deactivated the posterior cingulate cortex (PCC), whereas alcoholic subjects did not. Posterior cingulum fiber integrity predicted the degree of PCC deactivation in control but not alcoholic subjects. Also, PCC activity was modulated by executive control demands: activated during response switching and deactivated during response repetition. Alcoholics showed the opposite pattern: activation during repetition and deactivation during switching. Here, in alcoholic subjects, greater deviations from the normal PCC activity correlated with higher amounts of lifetime alcohol consumption. A functional dissociation of brain network connectivity between the groups further showed that control subjects exhibited greater corticocortical connectivity among middle cingulate, posterior cingulate, and medial prefrontal cortices than alcoholic subjects. In contrast, alcoholic subjects exhibited greater midbrain-orbitofrontal cortical network connectivity than control subjects. Degree of microstructural fiber integrity predicted robustness of functional connectivity. Thus, even subtle compromise of microstructural connectivity in alcoholism can influence modulation of functional connectivity and underlie alcohol-related cognitive impairment. Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Parallel Coding of First- and Second-Order Stimulus Attributes by Midbrain Electrosensory Neurons

PubMed Central

McGillivray, Patrick; Vonderschen, Katrin; Fortune, Eric S.; Chacron, Maurice J.

2015-01-01

Natural stimuli often have time-varying first-order (i.e., mean) and second-order (i.e., variance) attributes that each carry critical information for perception and can vary independently over orders of magnitude. Experiments have shown that sensory systems continuously adapt their responses based on changes in each of these attributes. This adaptation creates ambiguity in the neural code as multiple stimuli may elicit the same neural response. While parallel processing of first- and second-order attributes by separate neural pathways is sufficient to remove this ambiguity, the existence of such pathways and the neural circuits that mediate their emergence have not been uncovered to date. We recorded the responses of midbrain electrosensory neurons in the weakly electric fish Apteronotus leptorhynchus to stimuli with first- and second-order attributes that varied independently in time. We found three distinct groups of midbrain neurons: the first group responded to both first- and second-order attributes, the second group responded selectively to first-order attributes, and the last group responded selectively to second-order attributes. In contrast, all afferent hindbrain neurons responded to both first- and second-order attributes. Using computational analyses, we show how inputs from a heterogeneous population of ON- and OFF-type afferent neurons are combined to give rise to response selectivity to either first- or second-order stimulus attributes in midbrain neurons. Our study thus uncovers, for the first time, generic and widely applicable mechanisms by which parallel processing of first- and second-order stimulus attributes emerges in the brain. PMID:22514313

CRISPR/Cas9-Mediated Zebrafish Knock-in as a Novel Strategy to Study Midbrain-Hindbrain Boundary Development.

PubMed

Kesavan, Gokul; Chekuru, Avinash; Machate, Anja; Brand, Michael

2017-01-01

The midbrain-hindbrain boundary (MHB) acts as an organizer and controls the fate of neighboring cells to develop into either mesencephalic (midbrain) or metencephalic (hindbrain) cells by secreting signaling molecules like Wnt1 and Fgf8. The zebrafish is an excellent vertebrate model for studying MHB development due to the ease of gene manipulation and the possibility of following cellular dynamics and morphogenetic processes using live imaging. Currently, only very few reporter and/or Cre-driver lines are available to study gene expression at the MHB, hampering the understanding of MHB development, and traditional transgenic technologies using promoter/enhancer fragments or bacterial artificial chromosome (BAC)-mediated transgenesis often do not faithfully recapitulate endogenous expression patterns. In contrast, CRISPR/Cas9-mediated genome editing technology now provides a great opportunity to efficiently knock-in or knock-out genes. We have generated four CRISPR/Cas9-based knock-in fluorescent reporter lines for two crucial genes involved in MHB development, namely otx2 and pax2a . The coding sequences of the reporters were knocked-in upstream of the corresponding ATG and are, thus, under the control of the endogenous promoter/enhancer elements. Interestingly, this strategy does not disturb endogenous gene expression. Using the fast maturing fluorescent protein reporter, Venus, enabled us to follow MHB development using cell tracking and live imaging. In addition, we show that these reporter lines label various neuronal and glial cell types in the adult zebrafish brain, making them highly suitable for investigating embryonic and adult midbrain, hindbrain, and MHB development.

Alpha6-Containing Nicotinic Acetylcholine Receptors Mediate Nicotine-Induced Structural Plasticity in Mouse and Human iPSC-Derived Dopaminergic Neurons.

PubMed

Collo, Ginetta; Cavalleri, Laura; Zoli, Michele; Maskos, Uwe; Ratti, Emiliangelo; Merlo Pich, Emilio

2018-01-01

Midbrain dopamine (DA) neurons are considered a critical substrate for the reinforcing and sensitizing effects of nicotine and tobacco dependence. While the role of the α4 and β2 subunit containing nicotinic acetylcholine receptors (α4β2 ∗ nAChRs) in mediating nicotine effects on DA release and DA neuron activity has been widely explored, less information is available on their role in the morphological adaptation of the DA system to nicotine, eventually leading to dysfunctional behaviors observed in nicotine dependence. In particular, no information is available on the role of α6 ∗ nAChRs in nicotine-induced structural plasticity in rodents and no direct evidence exists regarding the occurrence of structural plasticity in human DA neurons exposed to nicotine. To approach this problem, we used two parallel in vitro systems, mouse primary DA neuron cultures from E12.5 embryos and human DA neurons differentiated from induced pluripotent stem cells (iPSCs) of healthy donors, identified using TH + immunoreactivity. In both systems, nicotine 1-10 μM produced a dose-dependent increase of maximal dendrite length, number of primary dendrites, and soma size when measured after 3 days in culture. These effects were blocked by pretreatments with the α6 ∗ nAChR antagonists α-conotoxin MII and α-conotoxin PIA, as well as by the α4β2nAChR antagonist dihydro-β-erythroidine (DHβE) in both mouse and human DA neurons. Nicotine was also ineffective when the primary DA neurons were obtained from null mutant mice for either the α6 subunit or both the α4 and α6 subunits of nAChR. When pregnant mice were exposed to nicotine from gestational day 15, structural plasticity was also observed in the midbrain DA neurons of postnatal day 1 offspring only in wild-type mice and not in both null mutant mice. This study confirmed the critical role of α4α6 ∗ nAChRs in mediating nicotine-induced structural plasticity in both mouse and human DA neurons, supporting the translational relevance of neurons differentiated from human iPSCs for pharmacological studies.

Diversity of bilateral synaptic assemblies for binaural computation in midbrain single neurons.

PubMed

He, Na; Kong, Lingzhi; Lin, Tao; Wang, Shaohui; Liu, Xiuping; Qi, Jiyao; Yan, Jun

2017-11-01

Binaural hearing confers many beneficial functions but our understanding of its underlying neural substrates is limited. This study examines the bilateral synaptic assemblies and binaural computation (or integration) in the central nucleus of the inferior colliculus (ICc) of the auditory midbrain, a key convergent center. Using in-vivo whole-cell patch-clamp, the excitatory and inhibitory postsynaptic potentials (EPSPs/IPSPs) of single ICc neurons to contralateral, ipsilateral and bilateral stimulation were recorded. According to the contralateral and ipsilateral EPSP/IPSP, 7 types of bilateral synaptic assemblies were identified. These include EPSP-EPSP (EE), E-IPSP (EI), E-no response (EO), II, IE, IO and complex-mode (CM) neurons. The CM neurons showed frequency- and/or amplitude-dependent EPSPs/IPSPs to contralateral or ipsilateral stimulation. Bilateral stimulation induced EPSPs/IPSPs that could be larger than (facilitation), similar to (ineffectiveness) or smaller than (suppression) those induced by contralateral stimulation. Our findings have allowed our group to characterize novel neural circuitry for binaural computation in the midbrain. Copyright © 2017 Elsevier B.V. All rights reserved.

Electrosensory Midbrain Neurons Display Feature Invariant Responses to Natural Communication Stimuli.

PubMed

Aumentado-Armstrong, Tristan; Metzen, Michael G; Sproule, Michael K J; Chacron, Maurice J

2015-10-01

Neurons that respond selectively but in an invariant manner to a given feature of natural stimuli have been observed across species and systems. Such responses emerge in higher brain areas, thereby suggesting that they occur by integrating afferent input. However, the mechanisms by which such integration occurs are poorly understood. Here we show that midbrain electrosensory neurons can respond selectively and in an invariant manner to heterogeneity in behaviorally relevant stimulus waveforms. Such invariant responses were not seen in hindbrain electrosensory neurons providing afferent input to these midbrain neurons, suggesting that response invariance results from nonlinear integration of such input. To test this hypothesis, we built a model based on the Hodgkin-Huxley formalism that received realistic afferent input. We found that multiple combinations of parameter values could give rise to invariant responses matching those seen experimentally. Our model thus shows that there are multiple solutions towards achieving invariant responses and reveals how subthreshold membrane conductances help promote robust and invariant firing in response to heterogeneous stimulus waveforms associated with behaviorally relevant stimuli. We discuss the implications of our findings for the electrosensory and other systems.

Age-related changes in glial cells of dopamine midbrain subregions in rhesus monkeys.

PubMed

Kanaan, Nicholas M; Kordower, Jeffrey H; Collier, Timothy J

2010-06-01

Aging remains the strongest risk factor for developing Parkinson's disease (PD), and there is selective vulnerability in midbrain dopamine (DA) neuron degeneration in PD. By tracking normal aging-related changes with an emphasis on regional specificity, factors involved in selective vulnerability and resistance to degeneration can be studied. Towards this end, we sought to determine whether age-related changes in microglia and astrocytes in rhesus monkeys are region-specific, suggestive of involvement in regional differences in vulnerability to degeneration that may be relevant to PD pathogenesis. Gliosis in midbrain DA subregions was measured by estimating glia number using unbiased stereology, assessing fluorescence intensity for proteins upregulated during activation, and rating morphology. With normal aging, microglia exhibited increased staining intensity and a shift to more activated morphologies preferentially in the vulnerable substantia nigra-ventral tier (vtSN). Astrocytes did not exhibit age-related changes consistent with an involvement in regional vulnerability in any measure. Our results suggest advancing age is associated with chronic mild inflammation in the vtSN, which may render these DA neurons more vulnerable to degeneration. Copyright 2008 Elsevier Inc. All rights reserved.

Dopamine Induces Oscillatory Activities in Human Midbrain Neurons with Parkin Mutations.

PubMed

Zhong, Ping; Hu, Zhixing; Jiang, Houbo; Yan, Zhen; Feng, Jian

2017-05-02

Locomotor symptoms in Parkinson's disease (PD) are accompanied by widespread oscillatory neuronal activities in basal ganglia. Here, we show that activation of dopamine D1-class receptors elicits a large rhythmic bursting of spontaneous excitatory postsynaptic currents (sEPSCs) in midbrain neurons differentiated from induced pluripotent stem cells (iPSCs) of PD patients with parkin mutations, but not normal subjects. Overexpression of wild-type parkin, but not its PD-causing mutant, abolishes the oscillatory activities in patient neurons. Dopamine induces a delayed enhancement in the amplitude of spontaneous, but not miniature, EPSCs, thus increasing quantal content. The results suggest that presynaptic regulation of glutamatergic transmission by dopamine D1-class receptors is significantly potentiated by parkin mutations. The aberrant dopaminergic regulation of presynaptic glutamatergic transmission in patient-specific iPSC-derived midbrain neurons provides a mechanistic clue to PD pathophysiology, and it demonstrates the usefulness of this model system in understanding how mutations of parkin cause movement symptoms in Parkinson's disease. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Inhibiting effects of rhynchophylline on methamphetamine-dependent zebrafish are related with the expression of tyrosine hydroxylase (TH).

PubMed

Zhu, Chen; Liu, Wei; Luo, Chaohua; Liu, Yi; Li, Chan; Fang, Miao; Lin, Yingbo; Ou, Jinying; Chen, Minting; Zhu, Daoqi; Yung, Ken Kin-Lam; Mo, Zhixian

2017-03-01

In this study, to study the effect of rhynchophylline on TH in midbrain of methamphetamine-induced conditioned place preference (CPP) adult zebrafish, place preference adult zebrafish models were established by methamphetamine (40μg/g) and the expression of TH was observed by immunohistochemistry technique and Western blot. Ketamine (150μg/g), high dose of rhynchophylline (100μg/g) group can significantly reduce the place preference; immunohistochemistry results showed that the number of TH-positive neurons in midbrain was increased in the methamphetamine model group, whereas less TH-positive neurons were found in the ketamine group and high dosage rhynchophylline group. Western blot results showed that the expression of TH protein was significantly increased in the model group, whereas less expression was found in the ketamine group, high dosage rhynchophylline group. Our data pointed out that TH plays an important role in the formation of methamphetamine-induced place preference in adult zebrafish. Rhynchophylline reversed the expression of TH in the midbrain demonstrates the potential effect of mediates methamphetamine induced rewarding effect. Copyright © 2017 Elsevier B.V. All rights reserved.

Intrinsic monitoring of learning success facilitates memory encoding via the activation of the SN/VTA-Hippocampal loop.

PubMed

Ripollés, Pablo; Marco-Pallarés, Josep; Alicart, Helena; Tempelmann, Claus; Rodríguez-Fornells, Antoni; Noesselt, Toemme

2016-09-20

Humans constantly learn in the absence of explicit rewards. However, the neurobiological mechanisms supporting this type of internally-guided learning (without explicit feedback) are still unclear. Here, participants who completed a task in which no external reward/feedback was provided, exhibited enhanced fMRI-signals within the dopaminergic midbrain, hippocampus, and ventral striatum (the SN/VTA-Hippocampal loop) when successfully grasping the meaning of new-words. Importantly, new-words that were better remembered showed increased activation and enhanced functional connectivity between the midbrain, hippocampus, and ventral striatum. Moreover, enhanced emotion-related physiological measures and subjective pleasantness ratings during encoding were associated with remembered new-words after 24 hr. Furthermore, increased subjective pleasantness ratings were also related to new-words remembered after seven days. These results suggest that intrinsic-potentially reward-related-signals, triggered by self-monitoring of correct performance, can promote the storage of new information into long-term memory through the activation of the SN/VTA-Hippocampal loop, possibly via dopaminergic modulation of the midbrain.

Intrinsic monitoring of learning success facilitates memory encoding via the activation of the SN/VTA-Hippocampal loop

PubMed Central

Ripollés, Pablo; Marco-Pallarés, Josep; Alicart, Helena; Tempelmann, Claus; Rodríguez-Fornells, Antoni; Noesselt, Toemme

2016-01-01

Humans constantly learn in the absence of explicit rewards. However, the neurobiological mechanisms supporting this type of internally-guided learning (without explicit feedback) are still unclear. Here, participants who completed a task in which no external reward/feedback was provided, exhibited enhanced fMRI-signals within the dopaminergic midbrain, hippocampus, and ventral striatum (the SN/VTA-Hippocampal loop) when successfully grasping the meaning of new-words. Importantly, new-words that were better remembered showed increased activation and enhanced functional connectivity between the midbrain, hippocampus, and ventral striatum. Moreover, enhanced emotion-related physiological measures and subjective pleasantness ratings during encoding were associated with remembered new-words after 24 hr. Furthermore, increased subjective pleasantness ratings were also related to new-words remembered after seven days. These results suggest that intrinsic—potentially reward-related—signals, triggered by self-monitoring of correct performance, can promote the storage of new information into long-term memory through the activation of the SN/VTA-Hippocampal loop, possibly via dopaminergic modulation of the midbrain. DOI: http://dx.doi.org/10.7554/eLife.17441.001 PMID:27644419

Loss of Mitochondrial Fission Depletes Axonal Mitochondria in Midbrain Dopamine Neurons

PubMed Central

Berthet, Amandine; Margolis, Elyssa B.; Zhang, Jue; Hsieh, Ivy; Zhang, Jiasheng; Hnasko, Thomas S.; Ahmad, Jawad; Edwards, Robert H.; Sesaki, Hiromi; Huang, Eric J.

2014-01-01

Disruptions in mitochondrial dynamics may contribute to the selective degeneration of dopamine (DA) neurons in Parkinson's disease (PD). However, little is known about the normal functions of mitochondrial dynamics in these neurons, especially in axons where degeneration begins, and this makes it difficult to understand the disease process. To study one aspect of mitochondrial dynamics—mitochondrial fission—in mouse DA neurons, we deleted the central fission protein dynamin-related protein 1 (Drp1). Drp1 loss rapidly eliminates the DA terminals in the caudate–putamen and causes cell bodies in the midbrain to degenerate and lose α-synuclein. Without Drp1, mitochondrial mass dramatically decreases, especially in axons, where the mitochondrial movement becomes uncoordinated. However, in the ventral tegmental area (VTA), a subset of midbrain DA neurons characterized by small hyperpolarization-activated cation currents (Ih) is spared, despite near complete loss of their axonal mitochondria. Drp1 is thus critical for targeting mitochondria to the nerve terminal, and a disruption in mitochondrial fission can contribute to the preferential death of nigrostriatal DA neurons. PMID:25339743

Loss of mitochondrial fission depletes axonal mitochondria in midbrain dopamine neurons.

PubMed

Berthet, Amandine; Margolis, Elyssa B; Zhang, Jue; Hsieh, Ivy; Zhang, Jiasheng; Hnasko, Thomas S; Ahmad, Jawad; Edwards, Robert H; Sesaki, Hiromi; Huang, Eric J; Nakamura, Ken

2014-10-22

Disruptions in mitochondrial dynamics may contribute to the selective degeneration of dopamine (DA) neurons in Parkinson's disease (PD). However, little is known about the normal functions of mitochondrial dynamics in these neurons, especially in axons where degeneration begins, and this makes it difficult to understand the disease process. To study one aspect of mitochondrial dynamics-mitochondrial fission-in mouse DA neurons, we deleted the central fission protein dynamin-related protein 1 (Drp1). Drp1 loss rapidly eliminates the DA terminals in the caudate-putamen and causes cell bodies in the midbrain to degenerate and lose α-synuclein. Without Drp1, mitochondrial mass dramatically decreases, especially in axons, where the mitochondrial movement becomes uncoordinated. However, in the ventral tegmental area (VTA), a subset of midbrain DA neurons characterized by small hyperpolarization-activated cation currents (Ih) is spared, despite near complete loss of their axonal mitochondria. Drp1 is thus critical for targeting mitochondria to the nerve terminal, and a disruption in mitochondrial fission can contribute to the preferential death of nigrostriatal DA neurons. Copyright © 2014 the authors 0270-6474/14/3414304-14$15.00/0.

SELENIUM MODIFIES THE METABOLISM AND TOXICITY OF ARSENIC IN PRIMARY RAT HEPATOCYTES

EPA Science Inventory

ABSTRACT
Selenium Modifies the Metabolism and Toxicity of Arsenic in Primary Rat Hepatocytes. Miroslav Styblo, David J. Thomas (2000) Toxicol. Appl. Pharmacol.
Arsenic and selenium are metalloids with similar chemical properties and metabolic fates. Inorganic arsenic (iAs...

Expression of the mRNAs encoding the limbic system-associated membrane protein (LAMP): II. Fetal rat brain.

PubMed

Pimenta, A F; Reinoso, B S; Levitt, P

1996-11-11

The limbic system-associated membrane protein (LAMP) is a 64-68 kDa neuronal surface glycoprotein expressed in cortical and subcortical regions of the limbic system of the adult and developing rat central nervous system (CNS). LAMP is a member of the immunoglobulin superfamily of cell adhesion molecules with three Ig domains and is highly conserved between rat and human. In this study, the temporal and spatial pattern of lamp gene expression during fetal rat development was analyzed by using Northern blot analysis and in situ hybridization. In Northern blot analysis, two lamp mRNA transcripts, 1.6 kb and 8.0 kb, identical in size to those present in the adult rat nervous system, were detected in developing neural tissue. In situ hybridization analysis showed close correlation, though not identity, between the expression of lamp mRNAs and the distribution of LAMP in limbic regions of the developing rat CNS, indicative of a more complex regulation of gene expression than was previously thought to be the case. The expression of lamp mRNAs is first detected on about embryonic day (E) 13. The hybridization signal is not seen in the proliferative ventricular zone at any level of the neuraxis, indicating that lamp is expressed in postmitotic neurons. In the cerebral cortex, lamp mRNAs are expressed in limbic cortical regions, such as the perirhinal cortex, prefrontal cortex, and cingulate cortex. In the hippocampus, the hybridization signal is observed in Ammon's horn by E18. The neostriatum, amygdaloid complex, and most hypothalamic areas express lamp mRNAs from early stages (E13-E14) in a pattern consistent with the onset of neurogenesis. The emerging patterns of lamp expression at the outset are similar to those seen in adult hypothalamus and dorsal thalamus. Although the hybridization signal is observed in some nonlimbic areas, including midbrain and hindbrain structures, intense labeling is evident in more classic limbic regions. The high levels of expression of lamp in limbic regions, beginning in early developmental stages, combined with the results of previous functional in vitro and in vivo studies, support a role for LAMP as a recognition molecule involved in the formation of limbic connections.

Characterization of Rat Meibomian Gland Ion and Fluid Transport

PubMed Central

Yu, Dongfang; Davis, Richard M.; Aita, Megumi; Burns, Kimberlie A.; Clapp, Phillip W.; Gilmore, Rodney C.; Chua, Michael; O'Neal, Wanda K.; Schlegel, Richard; Randell, Scott H.; C. Boucher, Richard

2016-01-01

Purpose We establish novel primary rat meibomian gland (MG) cell culture systems and explore the ion transport activities of the rat MG. Methods Freshly excised rat MG tissues were characterized as follows: (1) mRNA expression of selected epithelial ion channels/transporters were measured by RT-PCR, (2) localization of epithelial sodium channel (ENaC) mRNAs was performed by in situ hybridization, and (3) protein expression and localization of βENaC, the Na+/K+/Cl− cotransporter (NKCC), and the Na+/K+ ATPase were evaluated by immunofluorescence. Primary isolated rat MG cells were cocultured with 3T3 feeder cells and a Rho-associated kinase (ROCK) inhibitor (Y-27632) for expansion. Passaged rat MG cells were cultured as planar sheets under air-liquid interface (ALI) conditions for gene expression and electrophysiologic studies. Passaged rat MG cells also were cultured in matrigel matrices to form spheroids, which were examined ultrastructurally by transmission electron microscopy (TEM) and functionally using swelling assays. Results Expression of multiple ion channel/transporter genes was detected in rat MG tissues. β-ENaC mRNA and protein were localized more to MG peripheral acinar cells than central acinar cells or ductular epithelial cells. Electrophysiologic studies of rat MG cell planar cultures demonstrated functional sodium, chloride, and potassium channels, and cotransporters activities. Transmission electron microscopic analyses of rat MG spheroids revealed highly differentiated MG cells with abundant lysosomal lamellar bodies. Rat MG spheroids culture-based measurements demonstrated active volume regulation by ion channels. Conclusions This study demonstrates the presence and function of ion channels and volume transport by rat MG. Two novel primary MG cell culture models that may be useful for MG research were established. PMID:27127933

Regional volumes in brain stem and cerebellum are associated with postural impairments in young brain-injured patients.

PubMed

Drijkoningen, David; Leunissen, Inge; Caeyenberghs, Karen; Hoogkamer, Wouter; Sunaert, Stefan; Duysens, Jacques; Swinnen, Stephan P

2015-12-01

Many patients with traumatic brain injury (TBI) suffer from postural control impairments that can profoundly affect daily life. The cerebellum and brain stem are crucial for the neural control of posture and have been shown to be vulnerable to primary and secondary structural consequences of TBI. The aim of this study was to investigate whether morphometric differences in the brain stem and cerebellum can account for impairments in static and dynamic postural control in TBI. TBI patients (n = 18) and healthy controls (n = 30) completed three challenging postural control tasks on the EquiTest® system (Neurocom). Infratentorial grey matter (GM) and white matter (WM) volumes were analyzed with cerebellum-optimized voxel-based morphometry using the spatially unbiased infratentorial toolbox. Volume loss in TBI patients was revealed in global cerebellar GM, global infratentorial WM, middle cerebellar peduncles, pons and midbrain. In the TBI group and across both groups, lower postural control performance was associated with reduced GM volume in the vermal/paravermal regions of lobules I-IV, V and VI. Moreover, across all participants, worse postural control performance was associated with lower WM volume in the pons, medulla, midbrain, superior and middle cerebellar peduncles and cerebellum. This is the first study in TBI patients to demonstrate an association between postural impairments and reduced volume in specific infratentorial brain areas. Volumetric measures of the brain stem and cerebellum may be valuable prognostic markers of the chronic neural pathology, which complicates rehabilitation of postural control in TBI. © 2015 Wiley Periodicals, Inc.

Optogenetic fMRI and electrophysiological identification of region-specific connectivity between the cerebellar cortex and forebrain.

PubMed

Choe, Katrina Y; Sanchez, Carlos F; Harris, Neil G; Otis, Thomas S; Mathews, Paul J

2018-06-01

Complex animal behavior is produced by dynamic interactions between discrete regions of the brain. As such, defining functional connections between brain regions is critical in gaining a full understanding of how the brain generates behavior. Evidence suggests that discrete regions of the cerebellar cortex functionally project to the forebrain, mediating long-range communication potentially important in motor and non-motor behaviors. However, the connectivity map remains largely incomplete owing to the challenge of driving both reliable and selective output from the cerebellar cortex, as well as the need for methods to detect region specific activation across the entire forebrain. Here we utilize a paired optogenetic and fMRI (ofMRI) approach to elucidate the downstream forebrain regions modulated by activating a region of the cerebellum that induces stereotypical, ipsilateral forelimb movements. We demonstrate with ofMRI, that activating this forelimb motor region of the cerebellar cortex results in functional activation of a variety of forebrain and midbrain areas of the brain, including the hippocampus and primary motor, retrosplenial and anterior cingulate cortices. We further validate these findings using optogenetic stimulation paired with multi-electrode array recordings and post-hoc staining for molecular markers of activated neurons (i.e. c-Fos). Together, these findings demonstrate that a single discrete region of the cerebellar cortex is capable of influencing motor output and the activity of a number of downstream forebrain as well as midbrain regions thought to be involved in different aspects of behavior. Copyright © 2018 Elsevier Inc. All rights reserved.

Response Properties of Neighboring Neurons in the Auditory Midbrain for Pure-Tone Stimulation: A Tetrode Study

PubMed Central

Seshagiri, Chandran V.; Delgutte, Bertrand

2007-01-01

The complex anatomical structure of the central nucleus of the inferior colliculus (ICC), the principal auditory nucleus in the midbrain, may provide the basis for functional organization of auditory information. To investigate this organization, we used tetrodes to record from neighboring neurons in the ICC of anesthetized cats and studied the similarity and difference among the responses of these neurons to pure-tone stimuli using widely used physiological characterizations. Consistent with the tonotopic arrangement of neurons in the ICC and reports of a threshold map, we found a high degree of correlation in the best frequencies (BFs) of neighboring neurons, which were mostly <3 kHz in our sample, and the pure-tone thresholds among neighboring neurons. However, width of frequency tuning, shapes of the frequency response areas, and temporal discharge patterns showed little or no correlation among neighboring neurons. Because the BF and threshold are measured at levels near the threshold and the characteristic frequency (CF), neighboring neurons may receive similar primary inputs tuned to their CF; however, at higher levels, additional inputs from other frequency channels may be recruited, introducing greater variability in the responses. There was also no correlation among neighboring neurons' sensitivity to interaural time differences (ITD) measured with binaural beats. However, the characteristic phases (CPs) of neighboring neurons revealed a significant correlation. Because the CP is related to the neural mechanisms generating the ITD sensitivity, this result is consistent with segregation of inputs to the ICC from the lateral and medial superior olives. PMID:17671101

Response properties of neighboring neurons in the auditory midbrain for pure-tone stimulation: a tetrode study.

PubMed

Seshagiri, Chandran V; Delgutte, Bertrand

2007-10-01

The complex anatomical structure of the central nucleus of the inferior colliculus (ICC), the principal auditory nucleus in the midbrain, may provide the basis for functional organization of auditory information. To investigate this organization, we used tetrodes to record from neighboring neurons in the ICC of anesthetized cats and studied the similarity and difference among the responses of these neurons to pure-tone stimuli using widely used physiological characterizations. Consistent with the tonotopic arrangement of neurons in the ICC and reports of a threshold map, we found a high degree of correlation in the best frequencies (BFs) of neighboring neurons, which were mostly <3 kHz in our sample, and the pure-tone thresholds among neighboring neurons. However, width of frequency tuning, shapes of the frequency response areas, and temporal discharge patterns showed little or no correlation among neighboring neurons. Because the BF and threshold are measured at levels near the threshold and the characteristic frequency (CF), neighboring neurons may receive similar primary inputs tuned to their CF; however, at higher levels, additional inputs from other frequency channels may be recruited, introducing greater variability in the responses. There was also no correlation among neighboring neurons' sensitivity to interaural time differences (ITD) measured with binaural beats. However, the characteristic phases (CPs) of neighboring neurons revealed a significant correlation. Because the CP is related to the neural mechanisms generating the ITD sensitivity, this result is consistent with segregation of inputs to the ICC from the lateral and medial superior olives.

Regional cerebral blood flow changes associated with clitorally induced orgasm in healthy women.

PubMed

Georgiadis, Janniko R; Kortekaas, Rudie; Kuipers, Rutger; Nieuwenburg, Arie; Pruim, Jan; Reinders, A A T Simone; Holstege, Gert

2006-12-01

There is a severe lack of knowledge regarding the brain regions involved in human sexual performance in general, and female orgasm in particular. We used [15O]-H2O positron emission tomography to measure regional cerebral blood flow (rCBF) in 12 healthy women during a nonsexual resting state, clitorally induced orgasm, sexual clitoral stimulation (sexual arousal control) and imitation of orgasm (motor output control). Extracerebral markers of sexual performance and orgasm were rectal pressure variability (RPstd) and perceived level of sexual arousal (PSA). Sexual stimulation of the clitoris (compared to rest) significantly increased rCBF in the left secondary and right dorsal primary somatosensory cortex, providing the first account of neocortical processing of sexual clitoral information. In contrast, orgasm was mainly associated with profound rCBF decreases in the neocortex when compared with the control conditions (clitoral stimulation and imitation of orgasm), particularly in the left lateral orbitofrontal cortex, inferior temporal gyrus and anterior temporal pole. Significant positive correlations were found between RPstd and rCBF in the left deep cerebellar nuclei, and between PSA and rCBF in the ventral midbrain and right caudate nucleus. We propose that decreased blood flow in the left lateral orbitofrontal cortex signifies behavioural disinhibition during orgasm in women, and that deactivation of the temporal lobe is directly related to high sexual arousal. In addition, the deep cerebellar nuclei may be involved in orgasm-specific muscle contractions while the involvement of the ventral midbrain and right caudate nucleus suggests a role for dopamine in female sexual arousal and orgasm.

A universal role of the ventral striatum in reward-based learning: Evidence from human studies

PubMed Central

Daniel, Reka; Pollmann, Stefan

2014-01-01

Reinforcement learning enables organisms to adjust their behavior in order to maximize rewards. Electrophysiological recordings of dopaminergic midbrain neurons have shown that they code the difference between actual and predicted rewards, i.e., the reward prediction error, in many species. This error signal is conveyed to both the striatum and cortical areas and is thought to play a central role in learning to optimize behavior. However, in human daily life rewards are diverse and often only indirect feedback is available. Here we explore the range of rewards that are processed by the dopaminergic system in human participants, and examine whether it is also involved in learning in the absence of explicit rewards. While results from electrophysiological recordings in humans are sparse, evidence linking dopaminergic activity to the metabolic signal recorded from the midbrain and striatum with functional magnetic resonance imaging (fMRI) is available. Results from fMRI studies suggest that the human ventral striatum (VS) receives valuation information for a diverse set of rewarding stimuli. These range from simple primary reinforcers such as juice rewards over abstract social rewards to internally generated signals on perceived correctness, suggesting that the VS is involved in learning from trial-and-error irrespective of the specific nature of provided rewards. In addition, we summarize evidence that the VS can also be implicated when learning from observing others, and in tasks that go beyond simple stimulus-action-outcome learning, indicating that the reward system is also recruited in more complex learning tasks. PMID:24825620

Lactoferrin promote primary rat osteoblast proliferation and differentiation via up-regulation of insulin-like growth factor-1 expression.

PubMed

Hou, Jian-ming; Wu, Man; Lin, Qing-ming; Lin, Fan; Xue, Ying; Lan, Xu-hua; Chen, En-yu; Wang, Mei-li; Yang, Hai-yan; Wang, Feng-xiong

2014-08-01

The aim of this study was to explore the effect of lactoferrin (LF) in primary fetal rat osteoblasts proliferation and differentiation and investigate the underlying molecular mechanisms. Primary rat osteoblasts were obtained from the calvarias of neonatal rats. Osteoblasts were treated with LF (0.1-1000 μg/mL), or OSI-906 [a selective inhibitor of insulin-like growth factor 1 (IGF-1) receptor and insulin receptor]. The IGF-1 was then knocked down by small hairpin RNA (shRNA) technology and then was treated with recombinant human IGF-1 or LF. Cell proliferation and differentiation were measured by MTT assay and alkaline phosphatase (ALP) assay, respectively. The expression of IGF-1 and IGF binding protein 2 (IGFBP2) mRNA were analyzed using real-time PCR. LF promotes the proliferation and differentiation of osteoblasts in a certain range (1-100 μg/mL) in time- and dose-dependent manner. The mRNA level of IGF-1 was significantly increased, while the expression of IGFBP2 was suppressed by LF treatment. Knockdown of IGF-1 by shRNA in primary rat osteoblast dramatically decreased the abilities of proliferation and differentiation of osteoblasts and blocked the proliferation and differentiation effect of LF in osteoblasts. OSI906 (5 μM) blocked the mitogenic and differentiation of LF in osteoblasts. Proliferation and differentiation of primary rat osteoblasts in response to LF are mediated in part by stimulating of IGF-1 gene expression and alterations in the gene expression of IGFBP2.

Lignans from Opuntia ficus-indica seeds protect rat primary hepatocytes and HepG2 cells against ethanol-induced oxidative stress.

PubMed

Kim, Jung Wha; Yang, Heejung; Kim, Hyeon Woo; Kim, Hong Pyo; Sung, Sang Hyun

2017-01-01

Bioactivity-guided isolation of Opuntia ficus-indica (Cactaceae) seeds against ethanol-treated primary rat hepatocytes yielded six lignan compounds. Among the isolates, furofuran lignans 4-6, significantly protected rat hepatocytes against ethanol-induced oxidative stress by reducing intracellular reactive oxygen species levels, preserving antioxidative defense enzyme activities, and maintaining the glutathione content. Moreover, 4 dose-dependently induced the heme oxygenase-1 expression in HepG2 cells.

Comparative effects on rat primary astrocytes and C6 rat glioma cells cultures after 24-h exposure to silver nanoparticles (AgNPs)

NASA Astrophysics Data System (ADS)

Salazar-García, Samuel; Silva-Ramírez, Ana Sonia; Ramirez-Lee, Manuel A.; Rosas-Hernandez, Hector; Rangel-López, Edgar; Castillo, Claudia G.; Santamaría, Abel; Martinez-Castañon, Gabriel A.; Gonzalez, Carmen

2015-11-01

The aim of this work was to compare the effects of 24-h exposure of rat primary astrocytes and C6 rat glioma cells to 7.8 nm AgNPs. Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor and current treatments lead to diverse side-effects; for this reason, it is imperative to investigate new approaches, including those alternatives provided by nanotechnology, like nanomaterials (NMs) such as silver nanoparticles. Herein, we found that C6 rat glioma cells, but no primary astrocytes, decreased cell viability after AgNPs treatment; however, both cell types diminished their proliferation. The decrease of glioma C6 cells proliferation was related with necrosis, while in primary astrocytes, the decreased proliferation was associated with the induction of apoptosis. The ionic control (AgNO3) exerted a different profile than AgNPs; the bulk form did not modify the basal effect in each determination, whereas cisplatin, a well-known antitumoral drug used as a comparative control, promoted cytotoxicity in both cell types at specific concentrations. Our findings prompt the need to determine the fine molecular and cellular mechanisms involved in the differential biological responses to AgNPs in order to develop new tools or alternatives based on nanotechnology that may contribute to the understanding, impact and use of NMs in specific targets, like glioblastoma cells.

The generation of NGF-secreting primary rat monocytes: a comparison of different transfer methods.

PubMed

Hohsfield, Lindsay A; Geley, Stephan; Reindl, Markus; Humpel, Christian

2013-05-31

Nerve growth factor (NGF), a member of the neurotrophin family, is responsible for the maintenance and survival of cholinergic neurons in the basal forebrain. The degeneration of cholinergic neurons and reduced acetycholine levels are hallmarks of Alzheimer's disease (AD) as well as associated with learning and memory deficits. Thus far, NGF has proven the most potent neuroprotective molecule against cholinergic neurodegeneration. However, delivery of this factor into the brain remains difficult. Recent studies have begun to elucidate the potential use of monocytes as vehicles for therapeutic delivery into the brain. In this study, we employed different transfection and transduction methods to generate NGF-secreting primary rat monocytes. Specifically, we compared five methods for generating NGF-secreting monocytes: (1) cationic lipid-mediated transfection (Effectene and FuGene), (2) classical electroporation, (3) nucleofection, (4) protein delivery (Bioporter) and (5) lentiviral vectors. Here, we report that classical transfection methods (lipid-mediated transfection, electroporation, nucleofection) are inefficient tools for proper gene transfer into primary rat monocytes. We demonstrate that lentiviral infection and Bioporter can successfully transduce/load primary rat monocytes and produce effective NGF secretion. Furthermore, our results indicate that NGF is bioactive and that Bioporter-loaded monocytes do not appear to exhibit any functional disruptions (i.e. in their ability to differentiate and phagocytose beta-amyloid). Taken together, our results show that primary monocytes can be effectively loaded or transduced with NGF and provides information on the most effective method for generating NGF-secreting primary rat monocytes. This study also provides a basis for further development of primary monocytes as therapeutic delivery vehicles to the diseased AD brain. Copyright © 2013 Elsevier B.V. All rights reserved.

Assessment of mitochondrial dysfunction-related, drug-induced hepatotoxicity in primary rat hepatocytes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Cong; Sekine, Shuichi, E-mail: ssekine@facult

Evidence that mitochondrial dysfunction plays a central role in drug-induced liver injury is rapidly accumulating. In contrast to physiological conditions, in which almost all adenosine triphosphate (ATP) in hepatocytes is generated in mitochondria via aerobic respiration, the high glucose content and limited oxygen supply of conventional culture systems force primary hepatocytes to generate most ATP via cytosolic glycolysis. Thus, such anaerobically poised cells are resistant to xenobiotics that impair mitochondrial function, and are not suitable to identify drugs with mitochondrial liabilities. In this study, primary rat hepatocytes were cultured in galactose-based medium, instead of the conventional glucose-based medium, and inmore » hyperoxia to improve the reliance of energy generation on aerobic respiration. Activation of mitochondria was verified by diminished cellular lactate release and increased oxygen consumption. These conditions improved sensitivity to the mitochondrial complex I inhibitor rotenone. Since oxidative stress is also a general cause of mitochondrial impairment, cells were exposed to test compounds in the presence of transferrin to increase the generation of reactive oxygen species via increased uptake of iron. Finally, 14 compounds with reported mitochondrial liabilities were tested to validate this new drug-induced mitochondrial toxicity assay. Overall, the culture of primary rat hepatocytes in galactose, hyperoxia and transferrin is a useful model for the identification of mitochondrial dysfunction-related drug-induced hepatotoxicity. - Highlights: • Drug-induced mitochondrial toxicity was evaluated using primary rat hepatocytes. • Galactose and hyperoxia could activate OXPHOS in primary rat hepatocytes. • Cells with enhanced OXPHOS exhibit improved sensitivity to mitochondrial toxins. • Transferrin potentiate mitochondrial toxicity via increased ROS production.« less

Striatal and midbrain connectivity with the hippocampus selectively boosts memory for contextual novelty

PubMed Central

Kafkas, Alexandros; Montaldi, Daniela

2015-01-01

The role of contextual expectation in processing familiar and novel stimuli was investigated in a series of experiments combining eye tracking, functional magnetic resonance imaging, and behavioral methods. An experimental paradigm emphasizing either familiarity or novelty detection at retrieval was used. The detection of unexpected familiar and novel stimuli, which were characterized by lower probability, engaged activity in midbrain and striatal structures. Specifically, detecting unexpected novel stimuli, relative to expected novel stimuli, produced greater activity in the substantia nigra/ventral tegmental area (SN/VTA), whereas the detection of unexpected familiar, relative to expected, familiar stimuli, elicited activity in the striatum/globus pallidus (GP). An effective connectivity analysis showed greater functional coupling between these two seed areas (GP and SN/VTA) and the hippocampus, for unexpected than for expected stimuli. Within this network of midbrain/striatal–hippocampal interactions two pathways are apparent; the direct SN–hippocampal pathway sensitive to unexpected novelty and the perirhinal–GP–hippocampal pathway sensitive to unexpected familiarity. In addition, increased eye fixations and pupil dilations also accompanied the detection of unexpected relative to expected familiar and novel stimuli, reflecting autonomic activity triggered by the functioning of these two pathways. Finally, subsequent memory for unexpected, relative to expected, familiar, and novel stimuli was characterized by enhanced recollection, but not familiarity, accuracy. Taken together, these findings suggest that a hippocampal–midbrain network, characterized by two distinct pathways, mediates encoding facilitation and most critically, that this facilitation is driven by contextual novelty, rather than by the absolute novelty of a stimulus. This contextually sensitive neural mechanism appears to elicit increased exploratory behavior, leading subsequently to greater recollection of the unexpected stimulus. © 2015 The Authors Hippocampus Published by Wiley Periodicals, Inc. PMID:25708843

Proliferation of murine midbrain neural stem cells depends upon an endogenous sonic hedgehog (Shh) source.

PubMed

Martínez, Constanza; Cornejo, Víctor Hugo; Lois, Pablo; Ellis, Tammy; Solis, Natalia P; Wainwright, Brandon J; Palma, Verónica

2013-01-01

The Sonic Hedgehog (Shh) pathway is responsible for critical patterning events early in development and for regulating the delicate balance between proliferation and differentiation in the developing and adult vertebrate brain. Currently, our knowledge of the potential role of Shh in regulating neural stem cells (NSC) is largely derived from analyses of the mammalian forebrain, but for dorsal midbrain development it is mostly unknown. For a detailed understanding of the role of Shh pathway for midbrain development in vivo, we took advantage of mouse embryos with cell autonomously activated Hedgehog (Hh) signaling in a conditional Patched 1 (Ptc1) mutant mouse model. This animal model shows an extensive embryonic tectal hypertrophy as a result of Hh pathway activation. In order to reveal the cellular and molecular origin of this in vivo phenotype, we established a novel culture system to evaluate neurospheres (nsps) viability, proliferation and differentiation. By recreating the three-dimensional (3-D) microenvironment we highlight the pivotal role of endogenous Shh in maintaining the stem cell potential of tectal radial glial cells (RGC) and progenitors by modulating their Ptc1 expression. We demonstrate that during late embryogenesis Shh enhances proliferation of NSC, whereas blockage of endogenous Shh signaling using cyclopamine, a potent Hh pathway inhibitor, produces the opposite effect. We propose that canonical Shh signaling plays a central role in the control of NSC behavior in the developing dorsal midbrain by acting as a niche factor by partially mediating the response of NSC to epidermal growth factor (EGF) and fibroblast growth factor (FGF) signaling. We conclude that endogenous Shh signaling is a critical mechanism regulating the proliferation of stem cell lineages in the embryonic dorsal tissue.

Insights into the central pathways involved in the emetic and behavioural responses to exendin-4 in the ferret.

PubMed

Lu, Zengbing; Yeung, Chi-Kong; Lin, Ge; Yew, David T W; Andrews, P L R; Rudd, John A

2017-01-01

GLP-1 receptor agonists are utilised for the treatment of Type-2 diabetes but can be associated with undesirable effects of nausea and vomiting. To investigate the role of GLP-1 receptors in mechanisms of emesis, behaviours indicative of nausea (BIN) and food intake in the ferret. Exendin-4 (10 and 30nmol, i.c.v.) induced emesis, inhibited food intake, and increased the frequency of BIN. Increases in c-Fos in the brainstem, midbrain and forebrain occurred in animals exhibiting emesis; no activation of the brainstem occurred in animals not vomiting. Exendin-4 (10nmol, i.c.v.) when preceded by i.c.v. saline (15μl), was not emetic but induced BIN and inhibited food intake; exendin (9-39) (100nmol) reduced BIN only. c-Fos showed that consistent with the absence of emesis in saline/exendin-4 treated animals there was no increase in c-Fos in the brainstem, but it increased in midbrain and forebrain nuclei. Excepting the amygdala, exendin (9-39) was without efffect on the increases in c-Fos. Analysis of c-Fos data showed a positive linear relationship between midbrain and forebrain areas irrespective of the occurrence of emesis induced by exendin-4. In contrast, brainstem and midbrain c-Fos levels were positively correlated, but only in animals with emesis. The brainstem is critical for exendin-4-induced emesis but suppression of food intake and BIN involves more rostral brain sites. Exendin-4-induced BIN and c-Fos activation of the amygdala are sensitive to exendin (9-39), whereas the suppression of food intake is not implicating separate control mechanisms for emesis and BIN. Copyright © 2016 Elsevier B.V. All rights reserved.

Loss of NCB5OR in the cerebellum disturbs iron pathways, potentiates behavioral abnormalities, and exacerbates harmaline-induced tremor in mice.

PubMed

Stroh, Matthew A; Winter, Michelle K; Swerdlow, Russell H; McCarson, Kenneth E; Zhu, Hao

2016-08-01

Iron dyshomeostasis has been implicated in many diseases, including a number of neurological conditions. Cytosolic NADH cytochrome b5 oxidoreductase (NCB5OR) is ubiquitously expressed in animal tissues and is capable of reducing ferric iron in vitro. We previously reported that global gene ablation of NCB5OR resulted in early-onset diabetes and altered iron homeostasis in mice. To further investigate the specific effects of NCB5OR deficiency on neural tissue without contributions from known phenotypes, we generated a conditional knockout (CKO) mouse that lacks NCB5OR only in the cerebellum and midbrain. Assessment of molecular markers in the cerebellum of CKO mice revealed changes in pathways associated with cellular and mitochondrial iron homeostasis. (59)Fe pulse-feeding experiments revealed cerebellum-specific increased or decreased uptake of iron by 7 and 16 weeks of age, respectively. Additionally, we characterized behavioral changes associated with loss of NCB5OR in the cerebellum and midbrain in the context of dietary iron deprivation-evoked generalized iron deficiency. Locomotor activity was reduced and complex motor task execution was altered in CKO mice treated with an iron deficient diet. A sucrose preference test revealed that the reward response was intact in CKO mice, but that iron deficient diet consumption altered sucrose preference in all mice. Detailed gait analysis revealed locomotor changes in CKO mice associated with dysfunctional proprioception and locomotor activation independent of dietary iron deficiency. Finally, we demonstrate that loss of NCB5OR in the cerebellum and midbrain exacerbated harmaline-induced tremor activity. Our findings suggest an essential role for NCB5OR in maintaining both iron homeostasis and the proper functioning of various locomotor pathways in the mouse cerebellum and midbrain.

Comparison of brain serotonin transporter using [I-123]-ADAM between obese and non-obese young adults without an eating disorder

PubMed Central

Wu, Chih-Hsing; Chang, Chin-Sung; Yang, Yen Kuang; Shen, Lie-Hang; Yao, Wei-Jen

2017-01-01

Cerebral serotonin metabolism has an important but controversial role in obesity. However, it is not given enough attention in morbidly obese young adults. We used single photon emission computed tomography (SPECT) with [I-123]-labeled 2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine (ADAM) to investigate changes in serotonin transporter (SERT) availability in 10 morbidly obese young adults without an eating disorder (M/F = 5/5, body mass index (BMI): 40.3 ± 4.1 kg/m2, percentage of body fat (BF%): 46.0 ± 3.9%) and 10 age- and sex-matched non-obese controls (BMI: 20.3 ± 1.2 kg/m2, BF%: 20.6 ± 8.9%). All participants underwent SPECT at 10 min and 6 h after an injection of 200 MBq of [I-123]-ADAM. The SERT binding site (midbrain) was drawn with cerebellum normalization. The BF% and fat distribution were measured using dual-energy X-ray absorptiometry. The midbrain/cerebellum SERT binding ratios (2.49 ± 0.46 vs. 2.47 ± 0.47; p = 0.912) at 6 h were not significantly different between groups, nor was the distribution of the summed images at 10 min (1.36 ± 0.14 vs. 1.35 ± 0.11; p = 0.853). There were no significant correlations between midbrain/cerebellum SERT binding ratio and age, BMI, BF%, or fat distribution. No significant difference in SERT availability in the midbrain between morbidly obese and non-obese young adults without an eating disorder indicates an unmet need for investigating the role of cerebral serotonin in obesity. PMID:28182708

Tyrosine hydroxylase down-regulation after loss of Abelson helper integration site 1 (AHI1) promotes depression via the circadian clock pathway in mice.

PubMed

Guo, Dongkai; Zhang, Shun; Sun, Hongyang; Xu, Xingyun; Hao, Zongbing; Mu, Chenchen; Xu, Xingshun; Wang, Guanghui; Ren, Haigang

2018-04-06

Abelson helper integration site 1 (AHI1) is associated with several neuropsychiatric and brain developmental disorders, such as schizophrenia, depression, autism, and Joubert syndrome. Ahi1 deficiency in mice leads to behaviors typical of depression. However, the mechanisms by which AHI1 regulates behavior remain to be elucidated. Here, we found that down-regulation of expression of the rate-limiting enzyme in dopamine biosynthesis, tyrosine hydroxylase (TH), in the midbrains of Ahi1- knockout (KO) mice is responsible for Ahi1 -deficiency-mediated depressive symptoms. We also found that Rev-Erbα, a TH transcriptional repressor and circadian regulator, is up-regulated in the Ahi1- KO mouse midbrains and Ahi1 -knockdown Neuro-2a cells. Moreover, brain and muscle Arnt-like protein 1 (BMAL1), the Rev-Erb α transcriptional regulator, is also increased in the Ahi1- KO mouse midbrains and Ahi1 -knockdown cells. Our results further revealed that AHI1 decreases BMAL1/Rev-Erbα expression by interacting with and repressing retinoic acid receptor-related orphan receptor α, a nuclear receptor and transcriptional regulator of circadian genes. Of note, Bmal1 deficiency reversed the reduction in TH expression induced by Ahi1 deficiency. Moreover, microinfusion of the Rev-Erbα inhibitor SR8278 into the ventral midbrain of Ahi1- KO mice significantly increased TH expression in the ventral tegmental area and improved their depressive symptoms. These findings provide a mechanistic explanation for a link between AHI1-related behaviors and the circadian clock pathway, indicating an involvement of circadian regulatory proteins in AHI1-regulated mood and behavior. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

The zebrafish orphan nuclear receptor genes nr2e1 and nr2e3 are expressed in developing eye and forebrain.

PubMed

Kitambi, Satish Srinivas; Hauptmann, Giselbert

2007-02-01

Mammalian Nr2e1 (Tailless, Mtll or Tlx) and Nr2e3 (photoreceptor-specific nuclear receptor, Pnr) are highly related orphan nuclear receptors, that are expressed in eye and forebrain-derived structures. In this study, we analyzed the developmental expression patterns of zebrafish nr2e1 and nr2e3. RT-PCR analysis showed that nr2e1 and nr2e3 are both expressed during embryonic and post-embryonic development. To examine the spatial distribution of nr2e1 and nr2e3 during development whole-mount in situ hybridization was performed. At tailbud stage, initial nr2e1 expression was localized to the rostral brain rudiment anterior to pax2.1 and eng2 expression at the prospective midbrain-hindbrain boundary. During subsequent stages, nr2e1 became widely expressed in fore- and midbrain primordia, eye and olfactory placodes. At 24hpf, strong nr2e1 expression was detected in telencephalon, hypothalamus, dorsal thalamus, pretectum, midbrain tectum, and retina. At 2dpf, the initially widespread nr2e1 expression became more restricted to distinct regions within the fore- and midbrain and to the retinal ciliary margin, the germinal zone which gives rise to retina and presumptive iris. Expression of nr2e3 was exclusively found in the developing retina and epiphysis. In both structures, nr2e3 expression was found in photoreceptor cells. The developmental expression profile of zebrafish nr2e1 and nr2e3 is consistent with evolutionary conserved functions in eye and rostral brain structures.

Loss of NCB5OR in the cerebellum disturbs iron pathways, potentiates behavioral abnormalities, and exacerbates harmaline-induced tremor in mice

PubMed Central

Stroh, Matthew A.; Winter, Michelle K.; Swerdlow, Russell H.; McCarson, Kenneth E.; Zhu, Hao

2018-01-01

Iron dyshomeostasis has been implicated in many diseases, including a number of neurological conditions. Cytosolic NADH cytochrome b5 oxidoreductase (NCB5OR) is ubiquitously expressed in animal tissues and is capable of reducing ferric iron in vitro. We previously reported that global gene ablation of NCB5OR resulted in early-onset diabetes and altered iron homeostasis in mice. To further investigate the specific effects of NCB5OR deficiency on neural tissue without contributions from known phenotypes, we generated a conditional knockout (CKO) mouse that lacks NCB5OR only in the cerebellum and midbrain. Assessment of molecular markers in the cerebellum of CKO mice revealed changes in pathways associated with cellular and mitochondrial iron homeostasis. 59Fe pulse-feeding experiments revealed cerebellum-specific increased or decreased uptake of iron by 7 weeks and 16 weeks of age, respectively. Additionally, we characterized behavioral changes associated with loss of NCB5OR in the cerebellum and midbrain in the context of dietary iron deprivation-evoked generalized iron deficiency. Locomotor activity was reduced and complex motor task execution was altered in CKO mice treated with an iron deficient diet. A sucrose preference test revealed that the reward response was intact in CKO mice, but that iron deficient diet consumption altered sucrose preference in all mice. Detailed gait analysis revealed locomotor changes in CKO mice associated with dysfunctional proprioception and locomotor activation independent of dietary iron deficiency. Finally, we demonstrate that loss of NCB5OR in the cerebellum and midbrain exacerbated harmaline-induced tremor activity. Our findings suggest an essential role for NCB5OR in maintaining both iron homeostasis and the proper functioning of various locomotor pathways in the mouse cerebellum and midbrain. PMID:27188291

Positron emission tomography quantification of serotonin transporter in suicide attempters with major depressive disorder.

PubMed

Miller, Jeffrey M; Hesselgrave, Natalie; Ogden, R Todd; Sullivan, Gregory M; Oquendo, Maria A; Mann, J John; Parsey, Ramin V

2013-08-15

Several lines of evidence implicate abnormal serotonergic function in suicidal behavior and completed suicide, including low serotonin transporter binding in postmortem studies of completed suicide. We have also reported low in vivo serotonin transporter binding in major depressive disorder (MDD) during a major depressive episode using positron emission tomography (PET) with [(11)C]McN5652. We quantified regional brain serotonin transporter binding in vivo in depressed suicide attempters, depressed nonattempters, and healthy controls using PET and a superior radiotracer, [(11)C]DASB. Fifty-one subjects with DSM-IV current MDD, 15 of whom were past suicide attempters, and 32 healthy control subjects underwent PET scanning with [(11)C]DASB to quantify in vivo regional brain serotonin transporter binding. Metabolite-corrected arterial input functions and plasma free-fraction were acquired to improve quantification. Depressed suicide attempters had lower serotonin transporter binding in midbrain compared with depressed nonattempters (p = .031) and control subjects (p = .0093). There was no difference in serotonin transporter binding comparing all depressed subjects with healthy control subjects considering six a priori regions of interest simultaneously (p = .41). Low midbrain serotonin transporter binding appears to be related to the pathophysiology of suicidal behavior rather than of major depressive disorder. This is consistent with postmortem work showing low midbrain serotonin transporter binding capacity in depressed suicides and may partially explain discrepant in vivo findings quantifying serotonin transporter in depression. Future studies should investigate midbrain serotonin transporter binding as a predictor of suicidal behavior in MDD and determine the cause of low binding. Copyright © 2013 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Activation of Tyrosine Hydroxylase mRNA Translation by cAMP in Midbrain Dopaminergic Neurons

PubMed Central

Chen, Xiqun; Xu, Lu; Radcliffe, Pheona; Sun, Baoyong; Tank, A. William

2009-01-01

During prolonged stress or chronic treatment with neurotoxins, robust compensatory mechanisms occur which maintain sufficient levels of catecholamine neurotransmitters in terminal regions. One of these mechanisms is the up-regulation of tyrosine hydroxylase (TH), the enzyme that controls catecholamine biosynthesis. In neurons of the periphery and locus coeruleus, this up-regulation is associated with an initial induction of TH mRNA. In contrast, this induction either does not occur or is nominal in mesencephalic dopamine neurons. The reasons for this lack of compensatory TH mRNA induction remain obscure, because so little is known about the regulation of TH expression in these neurons. In this report we test whether activation of the cAMP signaling pathway regulates TH gene expression in two rodent models of midbrain dopamine neurons, ventral midbrain organotypic slice cultures and MN9D cells. Our results demonstrate that elevation of cAMP leads to induction of TH protein and TH activity in both model systems; however, TH mRNA levels are not up-regulated by cAMP. The induction of TH protein is the result of a novel post-transcriptional mechanism that activates TH mRNA translation. This translational activation is mediated by sequences within the 3′UTR of TH mRNA. Our results support a model in which cAMP induces or activates trans-factors that interact with the TH mRNA 3′UTR to increase TH protein synthesis. An understanding of this novel regulatory mechanism may help to explain the control of TH gene expression and consequently dopamine biosynthesis in midbrain neurons under different physiological and pathological conditions. PMID:18349104

Discrimination of dementia with Lewy bodies from Alzheimer's disease using voxel-based morphometry of white matter by statistical parametric mapping 8 plus diffeomorphic anatomic registration through exponentiated Lie algebra.

PubMed

Nakatsuka, Tomoya; Imabayashi, Etsuko; Matsuda, Hiroshi; Sakakibara, Ryuji; Inaoka, Tsutomu; Terada, Hitoshi

2013-05-01

The purpose of this study was to identify brain atrophy specific for dementia with Lewy bodies (DLB) and to evaluate the discriminatory performance of this specific atrophy between DLB and Alzheimer's disease (AD). We retrospectively reviewed 60 DLB and 30 AD patients who had undergone 3D T1-weighted MRI. We randomly divided the DLB patients into two equal groups (A and B). First, we obtained a target volume of interest (VOI) for DLB-specific atrophy using correlation analysis of the percentage rate of significant whole white matter (WM) atrophy calculated using the Voxel-based Specific Regional Analysis System for Alzheimer's Disease (VSRAD) based on statistical parametric mapping 8 (SPM8) plus diffeomorphic anatomic registration through exponentiated Lie algebra, with segmented WM images in group A. We then evaluated the usefulness of this target VOI for discriminating the remaining 30 DLB patients in group B from the 30 AD patients. Z score values in this target VOI obtained from VSRAD were used as the determinant in receiver operating characteristic (ROC) analysis. Specific target VOIs for DLB were determined in the right-side dominant dorsal midbrain, right-side dominant dorsal pons, and bilateral cerebellum. ROC analysis revealed that the target VOI limited to the midbrain exhibited the highest area under the ROC curves of 0.75. DLB patients showed specific atrophy in the midbrain, pons, and cerebellum. Midbrain atrophy demonstrated the highest power for discriminating DLB and AD. This approach may be useful for determining the contributions of DLB and AD pathologies to the dementia syndrome.

K(v) channel interacting protein 3 expression and regulation by haloperidol in midbrain dopaminergic neurons.

PubMed

Duncan, Carlotta E; Schofield, Peter R; Weickert, Cynthia Shannon

2009-12-22

Antipsychotic drugs are the main treatment for schizophrenia, despite their adverse side effects and uncertain mode of action. Gene expression studies in the brains of rodents treated with antipsychotic drugs aim to uncover this mechanism and elucidate more specific targets for schizophrenia treatment. Previous expression profiling analyses showed that K(v) channel interacting protein 3 (KChIP3) was down-regulated in the mouse brain following treatment with multiple antipsychotic drugs. In this study, we used in situ hybridization to anatomically define the expression of KChIP3 mRNA in the mouse brain and to quantify its regulation by 7-day haloperidol treatment. We used immunohistochemistry to localize KChIP3 protein expression in the midbrain, dorsal and ventral striatum and the prefrontal cortex. We found KChIP3 mRNA throughout the grey matter of the brain, with high expression in the hippocampus, specific thalamic nuclei, deeper cortical layers and in the midbrain. KChIP3 mRNA was significantly down-regulated in the dorsal striatum and the ventral tegmental area following haloperidol treatment. KChIP3 protein is expressed in the neuropil in the cortex and striatum, as well as in the soma of deeper layer cortical and striatal neurons. This study, for the first time, also localized KChIP3 protein in the cell bodies and processes of dopaminergic neurons in the midbrain. These findings indicate that regulation of KChIP3, particularly in mesocortical dopamine neurons, may be part of the action of antipsychotic drugs and that prolonged and more specific targeting of ion channel subunits may enhance the therapeutic effects of antipsychotic drugs.

Effort-based cost-benefit valuation and the human brain

PubMed Central

Croxson, Paula L; Walton, Mark E; O'Reilly, Jill X; Behrens, Timothy EJ; Rushworth, Matthew FS

2010-01-01

In both the wild and the laboratory, animals' preferences for one course of action over another reflect not just reward expectations but also the cost in terms of effort that must be invested in pursuing the course of action. The ventral striatum and dorsal anterior cingulate cortex (ACCd) are implicated in the making of cost-benefit decisions in the rat but there is little information about how effort costs are processed and influence calculations of expected net value in other mammals including the human. We carried out a functional magnetic resonance imaging (fMRI) study to determine whether and where activity in the human brain was available to guide effort-based cost-benefit valuation. Subjects were scanned while they performed a series of effortful actions to obtain secondary reinforcers. At the beginning of each trial, subjects were presented with one of eight different visual cues which they had learned indicated how much effort the course of action would entail and how much reward could be expected at its completion. Cue-locked activity in the ventral striatum and midbrain reflected the net value of the course of action, signaling the expected amount of reward discounted by the amount of effort to be invested. Activity in ACCd also reflected the interaction of both expected reward and effort costs. Posterior orbitofrontal and insular activity, however, only reflected the expected reward magnitude. The ventral striatum and anterior cingulate cortex may be the substrate of effort-based cost-benefit valuation in primates as well as in rats. PMID:19357278

AAV-Mediated Gene Transfer of the Obesity-Associated Gene Etv5 in Rat Midbrain Does Not Affect Energy Balance or Motivated Behavior

PubMed Central

Boender, Arjen J.; Koning, Nivard A.; van den Heuvel, José K.; Luijendijk, Mieneke C. M.; van Rozen, Andrea J.; la Fleur, Susanne E.; Adan, Roger A. H.

2014-01-01

Several genome-wide association studies have implicated the transcription factor E-twenty- six version 5 (Etv5) in the regulation of body mass index. Further substantiating the role of Etv5 in feeding behavior are the findings that targeted disruption of Etv5 in mice leads to decreased body weight gain and that expression of Etv5 is decreased in the ventral tegmental area and substantia nigra pars compacta (VTA/SNpc) after food restriction. As Etv5 has been suggested to influence dopaminergic neurotransmission by driving the expression of genes that are responsible for the synthesis and release of dopamine, we investigated if expression levels of Etv5 are dependent on nutritional state and subsequently influence the expression levels of tyrosine hydroxylase. While it was shown that Etv5 expression in the VTA/SNpc increases after central administration of leptin and that Etv5 was able to drive expression of tyrosine hydroxylase in vitro, AAV-mediated gene transfer of Etv5 into the VTA/SNpc of rats did not alter expression of tyrosine hydroxylase in vivo. Moreover, AAV-mediated gene transfer of Etv5 in the VTA/SNpc did not affect measures of energy balance or performances in a progressive ratio schedule. Thus, these data do not support a role for increased expression of Etv5 in the VTA/SNpc in the regulation of feeding behavior. PMID:24710089

Acute food deprivation reverses morphine-induced locomotion deficits in M5 muscarinic receptor knockout mice.

PubMed

Steidl, Stephan; Lee, Esther; Wasserman, David; Yeomans, John S

2013-09-01

Lesions of the pedunculopontine tegmental nucleus (PPT), one of two sources of cholinergic input to the ventral tegmental area (VTA), block conditioned place preference (CPP) for morphine in drug-naïve rats. M5 muscarinic cholinergic receptors, expressed by midbrain dopamine neurons, are critical for the ability of morphine to increase nucleus accumbens dopamine levels and locomotion, and for morphine CPP. This suggests that M5-mediated PPT cholinergic inputs to VTA dopamine neurons critically contribute to morphine-induced dopamine activation, reward and locomotion. In the current study we tested whether food deprivation, which reduces PPT contribution to morphine CPP in rats, could also reduce M5 contributions to morphine-induced locomotion in mice. Acute 18-h food deprivation reversed the phenotypic differences usually seen between non-deprived wild-type and M5 knockout mice. That is, food deprivation increased morphine-induced locomotion in M5 knockout mice but reduced morphine-induced locomotion in wild-type mice. Food deprivation increased saline-induced locomotion equally in wild-type and M5 knockout mice. Based on these findings, we suggest that food deprivation reduces the contribution of M5-mediated PPT cholinergic inputs to the VTA in morphine-induced locomotion and increases the contribution of a PPT-independent pathway. The contributions of cholinergic, dopaminergic and GABAergic neurons to the effects of acute food deprivation are discussed. Copyright © 2013 Elsevier B.V. All rights reserved.

Serotonin regulates brain-derived neurotrophic factor expression in select brain regions during acute psychological stress

PubMed Central

Jiang, De-guo; Jin, Shi-li; Li, Gong-ying; Li, Qing-qing; Li, Zhi-ruo; Ma, Hong-xia; Zhuo, Chuan-jun; Jiang, Rong-huan; Ye, Min-jie

2016-01-01

Previous studies suggest that serotonin (5-HT) might interact with brain-derived neurotrophic factor (BDNF) during the stress response. However, the relationship between 5-HT and BDNF expression under purely psychological stress is unclear. In this study, one hour before psychological stress exposure, the 5-HT1A receptor agonist 8-OH-DPAT or antagonist MDL73005, or the 5-HT2A receptor agonist DOI or antagonist ketanserin were administered to rats exposed to psychological stress. Immunohistochemistry and in situ hybridization revealed that after psychological stress, with the exception of the ventral tegmental area, BDNF protein and mRNA expression levels were higher in the 5-HT1A and the 5-HT2A receptor agonist groups compared with the solvent control no-stress or psychological stress group in the CA1 and CA3 of the hippocampus, prefrontal cortex, central amygdaloid nucleus, dorsomedial hypothalamic nucleus, dentate gyrus, shell of the nucleus accumbens and the midbrain periaqueductal gray. There was no significant difference between the two agonist groups. In contrast, after stress exposure, BDNF protein and mRNA expression levels were lower in the 5-HT1A and 5-HT2A receptor antagonist groups than in the solvent control non-stress group, with the exception of the ventral tegmental area. Our findings suggest that 5-HT regulates BDNF expression in a rat model of acute psychological stress. PMID:27857753

Prolonged maternal separation disturbs the serotonergic system during early brain development.

PubMed

Ohta, Ken-Ichi; Miki, Takanori; Warita, Katsuhiko; Suzuki, Shingo; Kusaka, Takashi; Yakura, Tomiko; Liu, Jun-Qian; Tamai, Motoki; Takeuchi, Yoshiki

2014-04-01

Early life stress interrupts brain development through the disturbance of various neurotransmitter and neurotrophic factor activities, but the details remain unclear. In the current study, we focused on the serotonergic system, which plays a critical role in brain development, and examined the time-dependent influence of prolonged maternal separation on male Sprague-Dawley rats. The rats were separated from their dams for 3h twice-daily during postnatal days (PDs) 2-20. The influence of prolonged maternal separation was analyzed on PDs 7, 14, 21, and 28 using HPLC to assess concentrations of serotonin and 5-hydroxyindoleacetic acid and using real-time RT-PCR to measure mRNA expression of the serotonin 1A and 2A receptors in various brain regions. HPLC revealed imbalance between serotonin and 5-hydroxyindoleacetic acid in midbrain raphe nuclei, the amygdala, the hippocampus, and the medial prefrontal cortex (mPFC) on PDs 7 and 14. Furthermore, real-time RT-PCR showed attenuation of mRNA expression of the serotonin 1A receptor in the hippocampus and the mPFC and of the serotonin 2A receptor only in the mPFC on PDs 7 and 14. The observed alterations returned to control levels after maternal separation ended. These findings suggest that the early life stress of prolonged maternal separation disturbs the serotonergic system during a crucial period of brain development, which might in part be responsible for emotional abnormalities later in life. Copyright © 2013 ISDN. Published by Elsevier Ltd. All rights reserved.

Microinjection of procaine and electrolytic lesion in the ventral tegmental area suppresses hippocampal theta rhythm in urethane-anesthetized rats.

PubMed

Orzeł-Gryglewska, Jolanta; Jurkowlaniec, Edyta; Trojniar, Weronika

2006-01-30

The midbrain ventral tegmental area (VTA), a key structure of the mesocorticolimbic system is anatomically connected with the hippocampal formation. In addition mesocortical dopamine was found to influence hippocampus-related memory and hippocampal synaptic plasticity, both being linked to the theta rhythm. Therefore, the aim of the present study was to evaluate the possible role of the VTA in the regulation of the hippocampal theta activity. The study was performed on urethane-anesthetized male Wistar rats in which theta rhythm was evoked by tail pinch. It was found that unilateral, temporal inactivation of the VTA by means of direct procaine injection resulted in bilateral suppression of the hippocampal theta which manifested as a loss of synchronization of hippocampal EEG and respective reduction of the power and also the frequency of the 3-6 Hz theta band. Depression of the power of the 3-6 Hz component of the EEG signal was also seen in spontaneous hippocampal EEG after procaine. The permanent destruction of the VTA by means of unilateral electrocoagulation evoked a long-lasting, mainly ipsilateral depression of the power of the theta with some influence on its frequency. Simultaneously, there was a substantial increase of the power in higher frequency bands indicating decrease of a synchrony of the hippocampal EEG activity. On the basis of these results indicating impairment of synchronization of the hippocampal activity the VTA may be considered as another part of the brainstem theta synchroning system.

Histopathological effects of fibrin glue on penile fracture in a rat model.

PubMed

Tasdemir, Cemal; Samdanci, Emine T; Turtay, Muhammet G; Firat, Cemal; Oguzturk, Hakan; Ozdemir, Hulya

2011-12-01

To evaluate both histopathological effects and potential clinical application of fibrin glue on the penile cavernosal tissue. Experimental penile fracture was formed by incising from the proximal dorsal side of the penis in 32 Wistar Albino rats. The rats were randomly assigned to four main groups of eight animals each. In the control group, the incision was not repaired and it was left to secondary healing. In the primary repair group, the incision was primarily repaired. In the fibrin glue group, glue was applied only to the incision. In the final group, fibrin glue was applied to the incision following primary repair. Three weeks later, penectomy tissue was examined histopathologically. When the control group was compared with primary repair+fibrin glue group, the differences in cavernous tissue healing with fibrosis and inflammation were statistically significant (p = 0.04 and 0.01, respectively). The primary repair+fibrin glue group, showed the best cavernous healing with fibrosis observed in only one rat. . There was no significant difference between the control group and the other groups according to cavernous tissue healing with fibrosis and inflammation (p = 0.11 and 0.12). Hyperemia was observed in the all groups of rats. Fibrin glue can be used in cavernoseal surgeries due to its adhesive and potentially anti-inflammatory features.

Pathological and immunohistochemical study of lethal primary brain stem injuries

PubMed Central

2012-01-01

Background Many of the deaths that occur shortly after injury or in hospitals are caused by mild trauma. Slight morphological changes are often found in the brain stems of these patients during autopsy. The purpose of this study is to investigate the histopathological changes involved in primary brain stem injuries (PBSI) and their diagnostic significance. Methods A total of 65 patients who had died of PBSI and other conditions were randomly selected. They were divided into 2 groups, an injury group (25 cases) and a control group (20 cases). Slides of each patient’s midbrain, pons, and medulla oblongata were prepared and stained with HE, argentaffin, and immunohistochemical agents (GFAP, NF, amyloid-ß, MBP). Under low power (×100) and NF staining, the diameter of the thickest longitudinal axon was measured at its widest point. Ten such diameters were collected for each part of the brain (midbrain, pons, and medulla oblongata). Data were recorded and analyzed statistically. Results Brain stem contusions, astrocyte activity, edema, and pathological changes in the neurons were visibly different in the injury and control groups (P < 0.05). Characteristic changes occurred in the neural axons, axon diameter varied from axon to axon and even over different segments of one axon, and several pathological phenomena were observed. These included segmental thickening and curving, wave-like processing, disarrangement, and irregular swelling. A few axons ruptured and intumesced into retraction balls. Immunohistochemical MBP staining showed enlargement and curving of spaces between the myelin sheaths and axons in certain areas. The myelin sheaths lining the surfaces of the axons were in some cases incomplete and even exfoliated, and segmentation disappeared. These pathological changes increased in severity over time (P < 0.05). Conclusions These histopathological changes may prove beneficial to the pathological diagnosis of PBSI during autopsy. The measurement of axon diameters provides a referent quantitative index for the diagnosis of the specific causes of death involved in PBSI. Virtual Slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1345298818712204 PMID:22613041

Neural substrates of defensive reactivity in two subtypes of specific phobia

PubMed Central

Hilbert, Kevin; Stolyar, Veronika; Maslowski, Nina I.; Beesdo-Baum, Katja; Wittchen, Hans-Ulrich

2014-01-01

Depending on threat proximity, different defensive behaviours are mediated by a descending neural network involving forebrain (distal threat) vs midbrain areas (proximal threat). Compared to healthy subjects, it can be assumed that phobics are characterized by shortened defensive distances on a behavioural and neural level. This study aimed at characterizing defensive reactivity in two subtypes of specific phobia [snake (SP) and dental phobics (DP)]. Using functional magnetic resonance imaging (fMRI), n = 39 subjects (13 healthy controls, HC; 13 SP; 13 DP) underwent an event-related fMRI task employing an anticipation (5–10 s) and immediate perception phase (phobic pictures and matched neutral stimuli; 1250 ms) to modulate defensive distance. Although no differential brain activity in any comparisons was observed in DP, areas associated with defensive behaviours (e.g. amygdala, hippocampus, midbrain) were activated in SP. Decreasing defensive distance in SP was characterized by a shift to midbrain activity. Present findings substantiate differences between phobia types in their physiological and neural organization that can be expanded to early stages of defensive behaviours. Findings may contribute to a better understanding of the dynamic organization of defensive reactivity in different types of phobic fear. PMID:24174207

Zebrafish mab21l2 is specifically expressed in the presumptive eye and tectum from early somitogenesis onwards.

PubMed

Kudoh, T; Dawid, I B

2001-11-01

Random screening for tissue specific genes in zebrafish by in situ hybridization led us to isolate a gene which showed highly restricted expression in the developing eyes and midbrain at somitogenesis stages. This gene was very similar to mouse and human mab21l2. The characteristic expression pattern of mab21l2 facilitates a detailed description of the morphogenesis of the eyes and midbrain in the zebrafish. In the eye field, mab21l2 expression illustrates the transformation of the eye field to form two separate eyes in the anterior neural plate. Mab21l2 staining in the cyclopic mutants, cyc and oep, exhibited incomplete splitting of the eye primodium. In the midbrain, mab21l2 is expressed in the tectum, and its expression follows the expansion of the tectal region. In mutants affecting the mid-hindbrain boundary (MHB), mab21l2 expression is affected differentially. In the noi/pax2.1 mutant, mab21l2 is down-regulated and the size of the tectum remains small, whereas in the ace/fgf8 mutant, mab21l2 expression persists although the shape of the tectum is altered.

Homozygous ARHGEF2 mutation causes intellectual disability and midbrain-hindbrain malformation.

PubMed

Ravindran, Ethiraj; Hu, Hao; Yuzwa, Scott A; Hernandez-Miranda, Luis R; Kraemer, Nadine; Ninnemann, Olaf; Musante, Luciana; Boltshauser, Eugen; Schindler, Detlev; Hübner, Angela; Reinecker, Hans-Christian; Ropers, Hans-Hilger; Birchmeier, Carmen; Miller, Freda D; Wienker, Thomas F; Hübner, Christoph; Kaindl, Angela M

2017-04-01

Mid-hindbrain malformations can occur during embryogenesis through a disturbance of transient and localized gene expression patterns within these distinct brain structures. Rho guanine nucleotide exchange factor (ARHGEF) family members are key for controlling the spatiotemporal activation of Rho GTPase, to modulate cytoskeleton dynamics, cell division, and cell migration. We identified, by means of whole exome sequencing, a homozygous frameshift mutation in the ARHGEF2 as a cause of intellectual disability, a midbrain-hindbrain malformation, and mild microcephaly in a consanguineous pedigree of Kurdish-Turkish descent. We show that loss of ARHGEF2 perturbs progenitor cell differentiation and that this is associated with a shift of mitotic spindle plane orientation, putatively favoring more symmetric divisions. The ARHGEF2 mutation leads to reduction in the activation of the RhoA/ROCK/MLC pathway crucial for cell migration. We demonstrate that the human brain malformation is recapitulated in Arhgef2 mutant mice and identify an aberrant migration of distinct components of the precerebellar system as a pathomechanism underlying the midbrain-hindbrain phenotype. Our results highlight the crucial function of ARHGEF2 in human brain development and identify a mutation in ARHGEF2 as novel cause of a neurodevelopmental disorder.

Homozygous ARHGEF2 mutation causes intellectual disability and midbrain-hindbrain malformation

PubMed Central

Yuzwa, Scott A.; Hernandez-Miranda, Luis R.; Musante, Luciana; Boltshauser, Eugen; Schindler, Detlev; Hübner, Angela; Reinecker, Hans-Christian; Ropers, Hans-Hilger; Miller, Freda D.; Hübner, Christoph; Kaindl, Angela M.

2017-01-01

Mid-hindbrain malformations can occur during embryogenesis through a disturbance of transient and localized gene expression patterns within these distinct brain structures. Rho guanine nucleotide exchange factor (ARHGEF) family members are key for controlling the spatiotemporal activation of Rho GTPase, to modulate cytoskeleton dynamics, cell division, and cell migration. We identified, by means of whole exome sequencing, a homozygous frameshift mutation in the ARHGEF2 as a cause of intellectual disability, a midbrain-hindbrain malformation, and mild microcephaly in a consanguineous pedigree of Kurdish-Turkish descent. We show that loss of ARHGEF2 perturbs progenitor cell differentiation and that this is associated with a shift of mitotic spindle plane orientation, putatively favoring more symmetric divisions. The ARHGEF2 mutation leads to reduction in the activation of the RhoA/ROCK/MLC pathway crucial for cell migration. We demonstrate that the human brain malformation is recapitulated in Arhgef2 mutant mice and identify an aberrant migration of distinct components of the precerebellar system as a pathomechanism underlying the midbrain-hindbrain phenotype. Our results highlight the crucial function of ARHGEF2 in human brain development and identify a mutation in ARHGEF2 as novel cause of a neurodevelopmental disorder. PMID:28453519

α-Synuclein-induced lysosomal dysfunction occurs through disruptions in protein trafficking in human midbrain synucleinopathy models.

PubMed

Mazzulli, Joseph R; Zunke, Friederike; Isacson, Ole; Studer, Lorenz; Krainc, Dimitri

2016-02-16

Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by the accumulation of protein aggregates comprised of α-synuclein (α-syn). A major barrier in treatment discovery for PD is the lack of identifiable therapeutic pathways capable of reducing aggregates in human neuronal model systems. Mutations in key components of protein trafficking and cellular degradation machinery represent important risk factors for PD; however, their precise role in disease progression and interaction with α-syn remains unclear. Here, we find that α-syn accumulation reduced lysosomal degradation capacity in human midbrain dopamine models of synucleinopathies through disrupting hydrolase trafficking. Accumulation of α-syn at the cell body resulted in aberrant association with cis-Golgi-tethering factor GM130 and disrupted the endoplasmic reticulum-Golgi localization of rab1a, a key mediator of vesicular transport. Overexpression of rab1a restored Golgi structure, improved hydrolase trafficking and activity, and reduced pathological α-syn in patient neurons. Our work suggests that enhancement of lysosomal hydrolase trafficking may prove beneficial in synucleinopathies and indicates that human midbrain disease models may be useful for identifying critical therapeutic pathways in PD and related disorders.

Somatodendritic dopamine release: recent mechanistic insights

PubMed Central

Rice, Margaret E.; Patel, Jyoti C.

2015-01-01

Dopamine (DA) is a key transmitter in motor, reward and cogitative pathways, with DA dysfunction implicated in disorders including Parkinson's disease and addiction. Located in midbrain, DA neurons of the substantia nigra pars compacta project via the medial forebrain bundle to the dorsal striatum (caudate putamen), and DA neurons in the adjacent ventral tegmental area project to the ventral striatum (nucleus accumbens) and prefrontal cortex. In addition to classical vesicular release from axons, midbrain DA neurons exhibit DA release from their cell bodies and dendrites. Somatodendritic DA release leads to activation of D2 DA autoreceptors on DA neurons that inhibit their firing via G-protein-coupled inwardly rectifying K+ channels. This helps determine patterns of DA signalling at distant axonal release sites. Somatodendritically released DA also acts via volume transmission to extrasynaptic receptors that modulate local transmitter release and neuronal activity in the midbrain. Thus, somatodendritic release is a pivotal intrinsic feature of DA neurons that must be well defined in order to fully understand the physiology and pathophysiology of DA pathways. Here, we review recent mechanistic aspects of somatodendritic DA release, with particular emphasis on the Ca2+ dependence of release and the potential role of exocytotic proteins. PMID:26009764

Characterization of three novel members of the zebrafish Pax2/5/8 family: dependency of Pax5 and Pax8 expression on the Pax2.1 (noi) function.

PubMed

Pfeffer, P L; Gerster, T; Lun, K; Brand, M; Busslinger, M

1998-08-01

The mammalian Pax2, Pax5 and Pax8 genes code for highly related transcription factors, which play important roles in embryonic development and organogenesis. Here we report the characterization of all members of the zebrafish Pax2/5/8 family. These genes have arisen by duplications before or at the onset of vertebrate evolution. Due to an additional genome amplification in the fish lineage, the zebrafish contains two Pax2 genes, the previously known Pax[b] gene (here renamed as Pax2.1) and a novel Pax2.2 gene. The zebrafish Pax2.1 gene most closely resembles the mammalian Pax2 gene in its expression pattern, as it is transcribed first in the midbrain-hindbrain boundary region, then in the optic stalk, otic system, pronephros and nephric ducts, and lastly in specific interneurons of the hindbrain and spinal cord. Pax2.2 differs from Pax2.1 by the absence of expression in the nephric system and by a delayed onset of transcription in other Pax2.1 expession domains. Pax8 is also expressed in the same domains as Pax2.1, but its transcription is already initiated during gastrulation in the primordia of the otic placode and pronephric anlage, thus identifying Pax8 as the earliest developmental marker of these structures. The zebrafish Pax5 gene, in contrast to its mouse orthologue, is transcribed in the otic system in addition to its prominent expression at the midbrain-hindbrain boundary. The no isthmus (noi) mutation is known to inactivate the Pax2.1 gene, thereby affecting the development of the midbrain-hindbrain boundary region, pronephric system, optic stalk and otic region. Although the different members of the Pax2/5/8 family may potentially compensate for the loss of Pax2.1 function, we demonstrate here that only the expression of the Pax2.2 gene remains unaffected in noi mutant embryos. The expression of Pax5 and Pax8 is either not initiated at the midbrain-hindbrain boundary or is later not maintained in other expression domains. Consequently, the noi mutation of zebrafish is equivalent to combined inactivation of the mouse Pax2 and Pax5 genes with regard to the loss of midbrain-hindbrain boundary development.

The zebrafish spiel-ohne-grenzen (spg) gene encodes the POU domain protein Pou2 related to mammalian Oct4 and is essential for formation of the midbrain and hindbrain, and for pre-gastrula morphogenesis.

PubMed

Burgess, Shawn; Reim, Gerlinde; Chen, Wenbiao; Hopkins, Nancy; Brand, Michael

2002-02-01

In early embryonic development, the brain is divided into three main regions along the anteroposterior axis: the forebrain, midbrain and hindbrain. Through retroviral insertional mutagenesis and chemical mutagenesis experiments in zebrafish, we have isolated mutations that cause abnormal hindbrain organization and a failure of the midbrain-hindbrain boundary (MHB) to form, a region that acts as an organizer for the adjacent brain regions. The mutations fail to complement the spiel-ohne-grenzen (spg) mutation, which causes a similar phenotype, but for which the affected gene is unknown. We show through genetic mapping, cloning of the proviral insertion site and allele sequencing that spg mutations disrupt pou2, a gene encoding the Pou2 transcription factor. Based on chromosomal synteny, phylogenetic sequence comparison, and expression and functional data, we suggest that pou2 is the zebrafish ortholog of mouse Oct3/Oct4 and human POU5F1. For the mammalian genes, a function in brain development has so far not been described. In the absence of functional pou2, expression of markers for the midbrain, MHB and the hindbrain primordium (pax2.1, wnt1, krox20) are severely reduced, correlating with the neuroectoderm-specific expression phase of pou2. Injection of pou2 mRNA restores these defects in spg mutant embryos, but does not activate these markers ectopically, demonstrating a permissive role for pou2. Injections of pou2-morpholinos phenocopy the spg phenotype at low concentration, further proving that spg encodes pou2. Two observations suggest that pou2 has an additional earlier function: higher pou2-morpholino concentrations specifically cause a pre-gastrula arrest of cell division and morphogenesis, and expression of pou2 mRNA itself is reduced in spg-homozygous embryos at this stage. These experiments suggest two roles for pou2. Initially, Pou2 functions during early proliferation and morphogenesis of the blastomeres, similar to Oct3/4 in mammals during formation of the inner cell mass. During zebrafish brain formation, Pou2 then functions a second time to activate gene expression in the midbrain and hindbrain primordium, which is reflected at later stages in the specific lack in spg embryos of the MHB and associated defects in the mid- and hindbrain.

A Wnt1 regulated Frizzled-1/β-Catenin signaling pathway as a candidate regulatory circuit controlling mesencephalic dopaminergic neuron-astrocyte crosstalk: Therapeutical relevance for neuron survival and neuroprotection

PubMed Central

2011-01-01

Background Dopamine-synthesizing (dopaminergic, DA) neurons in the ventral midbrain (VM) constitute a pivotal neuronal population controlling motor behaviors, cognitive and affective brain functions, which generation critically relies on the activation of Wingless-type MMTV integration site (Wnt)/β-catenin pathway in their progenitors. In Parkinson's disease, DA cell bodies within the substantia nigra pars compacta (SNpc) progressively degenerate, with causes and mechanisms poorly understood. Emerging evidence suggests that Wnt signaling via Frizzled (Fzd) receptors may play a role in different degenerative states, but little is known about Wnt signaling in the adult midbrain. Using in vitro and in vivo model systems of DA degeneration, along with functional studies in both intact and SN lesioned mice, we herein highlight an intrinsic Wnt1/Fzd-1/β-catenin tone critically contributing to the survival and protection of adult midbrain DA neurons. Results In vitro experiments identifie Fzd-1 receptor expression at a mRNA and protein levels in dopamine transporter (DAT) expressing neurons, and demonstrate the ability of exogenous Wnt1 to exert robust neuroprotective effects against Caspase-3 activation, the loss of tyrosine hydroxylase-positive (TH+) neurons and [3H] dopamine uptake induced by different DA-specific insults, including serum and growth factor deprivation, 6-hydroxydopamine and MPTP/MPP+. Co-culture of DA neurons with midbrain astrocytes phenocopies Wnt1 neuroprotective effects, whereas RNA interference-mediated knockdown of Wnt1 in midbrain astrocytes markedly reduces astrocyte-induced TH+ neuroprotection. Likewise, silencing β-catenin mRNA or knocking down Fzd-1 receptor expression in mesencephalic neurons counteract astrocyte-induced TH+ neuroprotection. In vivo experiments document Fzd-1 co-localization with TH+ neurons within the intact SNpc and blockade of Fzd/β-catenin signaling by unilateral infusion of a Fzd/β-catenin antagonist within the SN induces reactive astrocytosis and acutely inhibits TH+ neuron survival in ipsilateral SNpc, an effect efficiently prevented by pharmacological activation of β-catenin signaling within the SNpc. Conclusion These results defining a novel Wnt1/Fzd-1/β-catenin astrocyte-DA autoprotective loop provide a new mechanistic inside into the regulation of pro-survival processes, with potentially relevant consequences for drug design or drug action in Parkinson's disease. PMID:21752258

Early handling, but not maternal separation, decreases emotional responses in two paradigms of fear without changes in mesolimbic dopamine.

PubMed

Madruga, Clarice; Xavier, Léder L; Achaval, Matilde; Sanvitto, Gilberto L; Lucion, Aldo B

2006-01-30

This study aimed at identifying the effects of neonatal handling (H) and maternal separation (MS) on two paradigms of fear, learned and innate, and on the tyrosine hydroxylase (TH) immunoreactive cells in adult life. Wistar rats were daily handled with a brief maternal separation, maternal separated for 3 h or left undisturbed during the first 10 days of life. Behavioural responses in the open-field (innate fear) and conditioned fear (learned fear) were evaluated. Moreover, a semi-quantitative analysis of TH immunoreactivity in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNpc) was performed using optical densitometry and confirmed by planar measurements of neuronal density. Early handling decreased behaviour responses of innate and learned fear in adult life, while maternal separation had no significant long-lasting effect on these responses compared to the non-handled group. The behavioural effects of early handling could not be explained by changes in the density of midbrain dopaminergic cells, which were not affected by handling or maternal separation.

IAP-Based Cell Sorting Results in Homogeneous Transplantable Dopaminergic Precursor Cells Derived from Human Pluripotent Stem Cells.

PubMed

Lehnen, Daniela; Barral, Serena; Cardoso, Tiago; Grealish, Shane; Heuer, Andreas; Smiyakin, Andrej; Kirkeby, Agnete; Kollet, Jutta; Cremer, Harold; Parmar, Malin; Bosio, Andreas; Knöbel, Sebastian

2017-10-10

Human pluripotent stem cell (hPSC)-derived mesencephalic dopaminergic (mesDA) neurons can relieve motor deficits in animal models of Parkinson's disease (PD). Clinical translation of differentiation protocols requires standardization of production procedures, and surface-marker-based cell sorting is considered instrumental for reproducible generation of defined cell products. Here, we demonstrate that integrin-associated protein (IAP) is a cell surface marker suitable for enrichment of hPSC-derived mesDA progenitor cells. Immunomagnetically sorted IAP + mesDA progenitors showed increased expression of ventral midbrain floor plate markers, lacked expression of pluripotency markers, and differentiated into mature dopaminergic (DA) neurons in vitro. Intrastriatal transplantation of IAP + cells sorted at day 16 of differentiation in a rat model of PD resulted in functional recovery. Grafts from sorted IAP + mesDA progenitors were more homogeneous in size and DA neuron density. Thus, we suggest IAP-based sorting for reproducible prospective enrichment of mesDA progenitor cells in clinical cell replacement strategies. Copyright © 2017 Miltenyi Biotec GmbH. Published by Elsevier Inc. All rights reserved.

Brain reward circuitry beyond the mesolimbic dopamine system: a neurobiological theory.

PubMed

Ikemoto, Satoshi

2010-11-01

Reductionist attempts to dissect complex mechanisms into simpler elements are necessary, but not sufficient for understanding how biological properties like reward emerge out of neuronal activity. Recent studies on intracranial self-administration of neurochemicals (drugs) found that rats learn to self-administer various drugs into the mesolimbic dopamine structures-the posterior ventral tegmental area, medial shell nucleus accumbens and medial olfactory tubercle. In addition, studies found roles of non-dopaminergic mechanisms of the supramammillary, rostromedial tegmental and midbrain raphe nuclei in reward. To explain intracranial self-administration and related effects of various drug manipulations, I outlined a neurobiological theory claiming that there is an intrinsic central process that coordinates various selective functions (including perceptual, visceral, and reinforcement processes) into a global function of approach. Further, this coordinating process for approach arises from interactions between brain structures including those structures mentioned above and their closely linked regions: the medial prefrontal cortex, septal area, ventral pallidum, bed nucleus of stria terminalis, preoptic area, lateral hypothalamic areas, lateral habenula, periaqueductal gray, laterodorsal tegmental nucleus and parabrachical area. Published by Elsevier Ltd.

A novel GABAergic afferent input to the pontine reticular formation: the mesopontine GABAergic column.

PubMed

Liang, Chang-Lin; Marks, Gerald A

2009-11-10

Pharmacological manipulations of gamma-aminobutyric acid (GABA) neurotransmission in the nucleus pontis oralis (PnO) of the rat brainstem produce alterations in sleep/wake behavior. Local applications of GABA(A) receptor antagonists and agonists increase REM sleep and wake, respectively. These findings support a role for GABAergic mechanisms of the PnO in the control of arousal state. We have been investigating sources of GABA innervation of the PnO that may interact with local GABA(A) receptors in the control of state. Utilizing a retrograde tracer, cholera toxin-B subunit (CTb), injected into the PnO and dual-label immunohistochemistry with an antibody against glutamic acid decarboxalase-67 (GAD67), we report on a previously unidentified GABAergic neuronal population projecting to the contralateral PnO appearing as a column of cells, with long-axis in the sagittal plane, extending through the midbrain and pons. We refer to these neurons as the mesopontine GABAergic column (MPGC). The contiguous, columnar, anatomical distribution suggests operation as a functional neural system, which may influence expression of REM sleep, wake and other behaviors subserved by the PnO.

The intralaminar thalamus—an expressway linking visual stimuli to circuits determining agency and action selection

PubMed Central

Fisher, Simon D.; Reynolds, John N. J.

2014-01-01

Anatomical investigations have revealed connections between the intralaminar thalamic nuclei and areas such as the superior colliculus (SC) that receive short latency input from visual and auditory primary sensory areas. The intralaminar nuclei in turn project to the major input nucleus of the basal ganglia, the striatum, providing this nucleus with a source of subcortical excitatory input. Together with a converging input from the cerebral cortex, and a neuromodulatory dopaminergic input from the midbrain, the components previously found necessary for reinforcement learning in the basal ganglia are present. With this intralaminar sensory input, the basal ganglia are thought to play a primary role in determining what aspect of an organism’s own behavior has caused salient environmental changes. Additionally, subcortical loops through thalamic and basal ganglia nuclei are proposed to play a critical role in action selection. In this mini review we will consider the anatomical and physiological evidence underlying the existence of these circuits. We will propose how the circuits interact to modulate basal ganglia output and solve common behavioral learning problems of agency determination and action selection. PMID:24765070

Effects of electroacupuncture on metabolic changes in motor cortex and striatum of 6-hydroxydopamine-induced Parkinsonian rats.

PubMed

Li, Min; Wang, Ke; Su, Wen-Ting; Jia, Jun; Wang, Xiao-Min

2017-10-06

To explore the possible underlying mechanism by investigating the effect of electroacupuncture (EA) treatment on the primary motor cortex and striatum in a unilateral 6-hydroxydopamine (6-OHDA) induced rat Parkinson's disease (PD) model. Male Sprague-Dawley rats were randomly divided into sham group (n=16), model group (n=14), and EA group (n=14). EA stimulation at Dazhui (GV 14) and Baihui (GV20) was applied to PD rats in the EA group for 4 weeks. Behavioral tests were conducted to evaluate the effectiveness of EA treatment. Metabolites were detected by 7.0 T proton nuclear magnetic resonance. Following 4 weeks of EA treatment in PD model rats, the abnormal behavioral impairment induced by 6-OHDA was alleviated. In monitoring changes in metabolic activity, ratios of myoinositol/creatine (Cr) and N-acetyl aspartate (NAA)/Cr in the primary motor cortex were significantly lower at the injected side than the non-injected side in PD rats (P=0.024 and 0.020). The ratios of glutamate + glutamine (Glx)/Cr and NAA/Cr in the striatum were higher and lower, respectively, at the injected side than the non-injected side (P=0.046 and 0.008). EA treatment restored the balance of metabolic activity in the primary motor cortex and striatum. In addition, the taurine/Cr ratio and Glx/Cr ratio were elevated in the striatum of PD model rats compared to sham-lesioned rats (P=0.026 and 0.000). EA treatment alleviated the excessive glutamatergic transmission by down-regulating the striatal Glx/Cr ratio (P=0.001). The Glx/Cr ratio was negatively correlated with floor plane spontaneous locomotion in PD rats (P=0.027 and P=0.0007). EA treatment is able to normalize the metabolic balance in the primary motor cortex and striatum of PD rats, which may contribute to its therapeutic effect on motor deficits. The striatal Glx/Cr ratio may serve as a potential indicator of PD and a therapeutic target of EA treatment.

Reticular influences on primary and augmenting responses in the somatosensory cortex.

PubMed

Steriade, M; Morin, D

1981-01-26

The effects of brief, conditioning trains of high-frequency pulses to the midbrain reticular formation (RF) on primary and augmenting responses of somatosensory (SI) cortex were investigated. Testing stimulation was applied to the ventrobasal (VB) thalamus or to the white matter (WM) beneath SI in VB-lesioned animals. The RF-elicited EEG activation was associated with increased firing rates of SI neurons, enhanced probability of early synaptic discharges to VB or WM stimuli, and significantly reduced duration of the suppressed firing period following an afferent VB or WM volley. The diminished latency of the postinhibitory rebound under RF stimulation had the consequence that, within 10/sec shock-train, the second stimulus was delivered following completion of the rebound component and, instead of an augmented potential, generated a field response of primary-type. The dependence of the RF-induced change in augmenting potentials upon the sharpening effect exerted on the preceding inhibitory-rebound sequence was corroborated by analyzing the RF influence on neurons with different time-course of recovery from inhibition. The replacement of augmenting potentials by primary responses under RF stimulation is advanced as the mechanism behind the obliteration of spontaneously developing 'type I' spindle-waves during EEG arousal. The demonstration of RF influences on SI responses to WM stimulation in VB-lesioned animals points out the cortical level of the effects. The reticulo-thalamo-cortical pathways underlying these influences are discussed.

GENE EXPRESSION ALTERATIONS OBSERVED IN PRIMARY CULTURED RAT HEPATOCYTES AFTER TREATMENT WITH CHLORINATED OR CHLORINATED AND OZONATED DRINKING WATER FROM EAST FORK LAKE, OHIO

EPA Science Inventory

Drinking water from East Fork Lake was spiked with iodide and bromide, disinfected with chlorine or ozone + chlorine, concentrated ~100-fold using reverse osmosis, and volatile disinfection by-products (DBPs) added back. Primary rat hepatocytes were exposed to full-strength, 1:10...

Rescue from dwarfism by thyroid function compensation in rdw rats.

PubMed

Furudate, Sen-ichi; Ono, Masao; Shibayama, Keiko; Ohyama, Yoshihide; Kuwada, Masahiro; Kimura, Toshimi; Kameya, Toru

2005-10-01

The rdw rat was initially reported as having hereditary dwarfism caused by pituitary dysfunction. Subsequent studies on the rdw rat, however, have demonstrated that the primary cause of rdw dwarfism is present in the thyroid gland but not in the pituitary gland. The primary cause of rdw rat disorders is a missense mutation of the thyroglobulin (Tg) gene by a one-point mutation. In the present study, we attempted to rescue the dwarfism of the rdw rats using a diet supplemented with thyroid powder (T-powder) and a thyroid graft (T-graft). The infants of the rdw rat were successfully raised to a mature stage body weight, accompanied by elevation of serum growth hormone (GH) and prolactin (PRL), by the T-powder. Furthermore, the T-graft successfully increased the body weight with fertility. The serum GH and PRL levels in the T-graft rdw rat significantly increased. The serum thyroid-stimulating hormone (TSH) levels in the T-graft rdw rat were significantly decreased but were significantly higher than those in the control rat. The GH and PRL mRNA expression in the rdw rat with the T-graft was virtually the same as that of the control, but the TSH beta mRNA differed from that of the control rats. Thus, the dwarfism in the rdw rat is rescued by thyroid function compensation, such as that afforded by T-powder and T-graft.

A Phase III Study of Conventional Radiation Therapy Plus Thalidomide Versus Conventional Radiation Therapy for Multiple Brain Metastases (RTOG 0118)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Knisely, Jonathan P.S.; Berkey, Brian; Chakravarti, Arnab

2008-05-01

Purpose: To compare whole-brain radiation therapy (WBRT) with WBRT combined with thalidomide for patients with brain metastases not amenable to resection or radiosurgery. Patients and Methods: Patients with Zubrod performance status 0-1, MRI-documented multiple (>3), large (>4 cm), or midbrain brain metastases arising from a histopathologically confirmed extracranial primary tumor, and an anticipated survival of >8 weeks were randomized to receive WBRT to a dose of 37.5 Gy in 15 fractions with or without thalidomide during and after WBRT. Prerandomization stratification used Radiation Therapy Oncology Group (RTOG) Recursive Partitioning Analysis (RPA) Class and whether post-WBRT chemotherapy was planned. Endpoints includedmore » overall survival, progression-free survival, time to neurocognitive progression, the cause of death, toxicities, and quality of life. A protocol-planned interim analysis documented that the trial had an extremely low probability of ever showing a significant difference favoring the thalidomide arm given the results at the time of the analysis, and it was therefore closed on the basis of predefined statistical guidelines. Results: Enrolled in the study were 332 patients. Of 183 accrued patients, 93 were randomized to receive WBRT alone and 90 to WBRT and thalidomide. Median survival was 3.9 months for both arms. No novel toxicities were seen, but thalidomide was not well tolerated in this population. Forty-eight percent of patients discontinued thalidomide because of side effects. Conclusion: Thalidomide provided no survival benefit for patients with multiple, large, or midbrain metastases when combined with WBRT; nearly half the patients discontinued thalidomide due to side effects.« less

Cortical modulation of auditory processing in the midbrain

PubMed Central

Bajo, Victoria M.; King, Andrew J.

2013-01-01

In addition to their ascending pathways that originate at the receptor cells, all sensory systems are characterized by extensive descending projections. Although the size of these connections often outweighs those that carry information in the ascending auditory pathway, we still have a relatively poor understanding of the role they play in sensory processing. In the auditory system one of the main corticofugal projections links layer V pyramidal neurons with the inferior colliculus (IC) in the midbrain. All auditory cortical fields contribute to this projection, with the primary areas providing the largest outputs to the IC. In addition to medium and large pyramidal cells in layer V, a variety of cell types in layer VI make a small contribution to the ipsilateral corticocollicular projection. Cortical neurons innervate the three IC subdivisions bilaterally, although the contralateral projection is relatively small. The dorsal and lateral cortices of the IC are the principal targets of corticocollicular axons, but input to the central nucleus has also been described in some studies and is distinctive in its laminar topographic organization. Focal electrical stimulation and inactivation studies have shown that the auditory cortex can modify almost every aspect of the response properties of IC neurons, including their sensitivity to sound frequency, intensity, and location. Along with other descending pathways in the auditory system, the corticocollicular projection appears to continually modulate the processing of acoustical signals at subcortical levels. In particular, there is growing evidence that these circuits play a critical role in the plasticity of neural processing that underlies the effects of learning and experience on auditory perception by enabling changes in cortical response properties to spread to subcortical nuclei. PMID:23316140

VGLUT2 mRNA and protein expression in the visual thalamus and midbrain of prosimian galagos (Otolemur garnetti).

PubMed

Balaram, Pooja; Takahata, Toru; Kaas, Jon H

2011-03-01

Vesicular glutamate transporters (VGLUTs) control the storage and presynaptic release of glutamate in the central nervous system, and are involved in the majority of glutamatergic transmission in the brain. Two VGLUT isoforms, VGLUT1 and VGLUT2, are known to characterize complementary distributions of glutamatergic neurons in the rodent brain, which suggests that they are each responsible for unique circuits of excitatory transmission. In rodents, VGLUT2 is primarily utilized in thalamocortical circuits, and is strongly expressed in the primary sensory nuclei, including all areas of the visual thalamus. The distribution of VGLUT2 in the visual thalamus and midbrain has yet to be characterized in primate species. Thus, the present study describes the expression of VGLUT2 mRNA and protein across the visual thalamus and superior colliculus of prosimian galagos to provide a better understanding of glutamatergic transmission in the primate brain. VGLUT2 is strongly expressed in all six layers of the dorsal lateral geniculate nucleus, and much less so in the intralaminar zones, which correspond to retinal and superior collicular inputs, respectively. The parvocellular and magnocellular layers expressed VGLUT2 mRNA more densely than the koniocellular layers. A patchy distribution of VGLUT2 positive terminals in the pulvinar complex possibly reflects inputs from the superior colliculus. The upper superficial granular layers of the superior colliculus, with inputs from the retina, most densely expressed VGLUT2 protein, while the lower superficial granular layers, with projections to the pulvinar, most densely expressed VGLUT2 mRNA. The results are consistent with the conclusion that retinal and superior colliculus projections to the thalamus depend highly on the VGLUT2 transporter, as do cortical projections from the magnocellular and parvocellular layers of the lateral geniculate nucleus and neurons of the pulvinar complex.

Brain alpha-ketoglutarate dehydrogenase complex: kinetic properties, regional distribution, and effects of inhibitors.

PubMed

Lai, J C; Cooper, A J

1986-11-01

The substrate and cofactor requirements and some kinetic properties of the alpha-ketoglutarate dehydrogenase complex (KGDHC; EC 1.2.4.2, EC 2.3.1.61, and EC 1.6.4.3) in purified rat brain mitochondria were studied. Brain mitochondrial KGDHC showed absolute requirement for alpha-ketoglutarate, CoA and NAD, and only partial requirement for added thiamine pyrophosphate, but no requirement for Mg2+ under the assay conditions employed in this study. The pH optimum was between 7.2 and 7.4, but, at pH values below 7.0 or above 7.8, KGDHC activity decreased markedly. KGDHC activity in various brain regions followed the rank order: cerebral cortex greater than cerebellum greater than or equal to midbrain greater than striatum = hippocampus greater than hypothalamus greater than pons and medulla greater than olfactory bulb. Significant inhibition of brain mitochondrial KGDHC was noted at pathological concentrations of ammonia (0.2-2 mM). However, the purified bovine heart KGDHC and KGDHC activity in isolated rat heart mitochondria were much less sensitive to inhibition. At 5 mM both beta-methylene-D,L-aspartate and D,L-vinylglycine (inhibitors of cerebral glucose oxidation) inhibited the purified heart but not the brain mitochondrial enzyme complex. At approximately 10 microM, calcium slightly stimulated (by 10-15%) the brain mitochondrial KGDHC. At concentrations above 100 microM, calcium (IC50 = 1 mM) inhibited both brain mitochondrial and purified heart KGDHC. The present results suggest that some of the kinetic properties of the rat brain mitochondrial KGDHC differ from those of the purified bovine heart and rat heart mitochondrial enzyme complexes. They also suggest that the inhibition of KGDHC by ammonia and the consequent effect on the citric acid cycle fluxes may be of pathophysiological and/or pathogenetic importance in hyperammonemia and in diseases (e.g., hepatic encephalopathy, inborn errors of urea metabolism, Reye's syndrome) where hyperammonemia is a consistent feature. Brain accumulation of calcium occurs in a number of pathological conditions. Therefore, it is possible that such a calcium accumulation may have a deleterious effect on KGDHC activity.

The endocannabinoid system in the rat dorsolateral periaqueductal grey mediates fear-conditioned analgesia and controls fear expression in the presence of nociceptive tone

PubMed Central

Olango, WM; Roche, M; Ford, GK; Harhen, B; Finn, DP

2012-01-01

BACKGROUND AND PURPOSE Endocannabinoids in the midbrain periaqueductal grey (PAG) modulate nociception and unconditioned stress-induced analgesia; however, their role in fear-conditioned analgesia (FCA) has not been examined. The present study examined the role of the endocannabinoid system in the dorsolateral (dl) PAG in formalin-evoked nociceptive behaviour, conditioned fear and FCA in rats. EXPERIMENTAL APPROACH Rats received intra-dlPAG administration of the CB1 receptor antagonist/inverse agonist rimonabant, or vehicle, before re-exposure to a context paired 24 h previously with foot shock. Formalin-evoked nociceptive behaviour and fear-related behaviours (freezing and 22 kHz ultrasonic vocalization) were assessed. In a separate cohort, levels of endocannabinoids [2-arachidonoyl glycerol (2-AG) and N-arachidonoyl ethanolamide (anandamide; AEA)] and the related N-acylethanolamines (NAEs) [N-palmitoyl ethanolamide (PEA) and N-oleoyl ethanolamide (OEA)] were measured in dlPAG tissue following re-exposure to conditioned context in the presence or absence of formalin-evoked nociceptive tone. KEY RESULTS Re-exposure of rats to the context previously associated with foot shock resulted in FCA. Intra-dlPAG administration of rimonabant significantly attenuated FCA and fear-related behaviours expressed in the presence of nociceptive tone. Conditioned fear without formalin-evoked nociceptive tone was associated with increased levels of 2-AG, AEA, PEA and OEA in the dlPAG. FCA was specifically associated with an increase in AEA levels in the dlPAG. CONCLUSIONS AND IMPLICATIONS Conditioned fear to context mobilises endocannabinoids and NAEs in the dlPAG. These data support a role for endocannabinoids in the dlPAG in mediating the potent suppression of pain responding which occurs during exposure to conditioned aversive contexts. LINKED ARTICLES This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue-7 PMID:21564082

Evidence that primary visual cortex is required for image, orientation, and motion discrimination by rats.

PubMed

Petruno, Sarah K; Clark, Robert E; Reinagel, Pamela

2013-01-01

The pigmented Long-Evans rat has proven to be an excellent subject for studying visually guided behavior including quantitative visual psychophysics. This observation, together with its experimental accessibility and its close homology to the mouse, has made it an attractive model system in which to dissect the thalamic and cortical circuits underlying visual perception. Given that visually guided behavior in the absence of primary visual cortex has been described in the literature, however, it is an empirical question whether specific visual behaviors will depend on primary visual cortex in the rat. Here we tested the effects of cortical lesions on performance of two-alternative forced-choice visual discriminations by Long-Evans rats. We present data from one highly informative subject that learned several visual tasks and then received a bilateral lesion ablating >90% of primary visual cortex. After the lesion, this subject had a profound and persistent deficit in complex image discrimination, orientation discrimination, and full-field optic flow motion discrimination, compared with both pre-lesion performance and sham-lesion controls. Performance was intact, however, on another visual two-alternative forced-choice task that required approaching a salient visual target. A second highly informative subject learned several visual tasks prior to receiving a lesion ablating >90% of medial extrastriate cortex. This subject showed no impairment on any of the four task categories. Taken together, our data provide evidence that these image, orientation, and motion discrimination tasks require primary visual cortex in the Long-Evans rat, whereas approaching a salient visual target does not.

DIFFERENTIAL GENE EXPRESSION PROFILES IN RAT TRACHAEL EPITHELIAL (RTE) CELLS IN RESPONSE TO COMBUSTION-SOURCE PARTICULATE MATTER (PM) AND VANADIUM (V) A PRIMARY METAL CONSTITUENT

EPA Science Inventory

Differential gene expression profiles in rat tracheal epithelial (RTE) cells in response to combustion-source particulate matter (PM) and vanadium (V) a primary metal constituent
Srikanth S. Nadadur, Janice A. Dye and Daniel L. Costa, US EPA, ORD, NHEERL (ETD, Pulmonary Toxico...

ANIMAL MODELS OF DYSTONIA: LESSONS FROM A MUTANT RAT

PubMed Central

LeDoux, Mark S.

2010-01-01

Dystonia is a motor sign characterized by involuntary muscle contractions which produce abnormal postures. Genetic factors contribute significantly to primary dystonia. In comparison, secondary dystonia can be caused by a wide variety of metabolic, structural, infectious, toxic and inflammatory insults to the nervous system. Although classically ascribed to dysfunction of the basal ganglia, studies of diverse animal models have pointed out that dystonia is a network disorder with important contributions from abnormal olivocerebellar signaling. In particular, work with the dystonic (dt) rat has engendered dramatic paradigm shifts in dystonia research. The dt rat manifests generalized dystonia caused by deficiency of the neuronally-restricted protein caytaxin. Electrophysiological and biochemical studies have shown that defects at the climbing fiber-Purkinje cell synapse in the dt rat lead to abnormal bursting firing patterns in the cerebellar nuclei, which increases linearly with postnatal age. In a general sense, the dt rat has shown the scientific and clinical communities that dystonia can arise from dysfunctional cerebellar cortex. Furthermore, work with the dt rat has provided evidence that dystonia (1) is a neurodevelopmental network disorder and (2) can be driven by abnormal cerebellar output. In large part, work with other animal models has expanded upon studies in the dt rat and shown that primary dystonia is a multi-nodal network disorder associated with defective sensorimotor integration. In addition, experiments in genetically-engineered models have been used to examine the underlying cellular pathologies that drive primary dystonia. PMID:21081162

GIRK Channels Modulate Opioid-Induced Motor Activity in a Cell Type- and Subunit-Dependent Manner

PubMed Central

Kotecki, Lydia; Hearing, Matthew; McCall, Nora M.; Marron Fernandez de Velasco, Ezequiel; Pravetoni, Marco; Arora, Devinder; Victoria, Nicole C.; Munoz, Michaelanne B.; Xia, Zhilian; Slesinger, Paul A.; Weaver, C. David

2015-01-01

G-protein-gated inwardly rectifying K+ (GIRK/Kir3) channel activation underlies key physiological effects of opioids, including analgesia and dependence. GIRK channel activation has also been implicated in the opioid-induced inhibition of midbrain GABA neurons and consequent disinhibition of dopamine (DA) neurons in the ventral tegmental area (VTA). Drug-induced disinhibition of VTA DA neurons has been linked to reward-related behaviors and underlies opioid-induced motor activation. Here, we demonstrate that mouse VTA GABA neurons express a GIRK channel formed by GIRK1 and GIRK2 subunits. Nevertheless, neither constitutive genetic ablation of Girk1 or Girk2, nor the selective ablation of GIRK channels in GABA neurons, diminished morphine-induced motor activity in mice. Moreover, direct activation of GIRK channels in midbrain GABA neurons did not enhance motor activity. In contrast, genetic manipulations that selectively enhanced or suppressed GIRK channel function in midbrain DA neurons correlated with decreased and increased sensitivity, respectively, to the motor-stimulatory effect of systemic morphine. Collectively, these data support the contention that the unique GIRK channel subtype in VTA DA neurons, the GIRK2/GIRK3 heteromer, regulates the sensitivity of the mouse mesolimbic DA system to drugs with addictive potential. PMID:25948263

Neural substrates of defensive reactivity in two subtypes of specific phobia.

PubMed

Lueken, Ulrike; Hilbert, Kevin; Stolyar, Veronika; Maslowski, Nina I; Beesdo-Baum, Katja; Wittchen, Hans-Ulrich

2014-11-01

Depending on threat proximity, different defensive behaviours are mediated by a descending neural network involving forebrain (distal threat) vs midbrain areas (proximal threat). Compared to healthy subjects, it can be assumed that phobics are characterized by shortened defensive distances on a behavioural and neural level. This study aimed at characterizing defensive reactivity in two subtypes of specific phobia [snake (SP) and dental phobics (DP)]. Using functional magnetic resonance imaging (fMRI), n = 39 subjects (13 healthy controls, HC; 13 SP; 13 DP) underwent an event-related fMRI task employing an anticipation (5-10 s) and immediate perception phase (phobic pictures and matched neutral stimuli; 1250 ms) to modulate defensive distance. Although no differential brain activity in any comparisons was observed in DP, areas associated with defensive behaviours (e.g. amygdala, hippocampus, midbrain) were activated in SP. Decreasing defensive distance in SP was characterized by a shift to midbrain activity. Present findings substantiate differences between phobia types in their physiological and neural organization that can be expanded to early stages of defensive behaviours. Findings may contribute to a better understanding of the dynamic organization of defensive reactivity in different types of phobic fear. © The Author (2013). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Tracking brain damage in progressive supranuclear palsy: a longitudinal MRI study.

PubMed

Agosta, Federica; Caso, Francesca; Ječmenica-Lukić, Milica; Petrović, Igor N; Valsasina, Paola; Meani, Alessandro; Copetti, Massimiliano; Kostić, Vladimir S; Filippi, Massimo

2018-01-18

In this prospective, longitudinal, multiparametric MRI study, we investigated clinical as well as brain grey matter and white matter (WM) regional changes in patients with progressive supranuclear palsy-Richardson's syndrome (PSP-RS). Twenty-one patients with PSP-RS were evaluated at baseline relative to 36 healthy controls and after a mean follow-up of 1.4 years with clinical rating scales, neuropsychological tests and MRI scans. Relative to controls, patients with PSP-RS showed at baseline a typical pattern of brain damage, including midbrain atrophy, frontal cortical thinning and widespread WM involvement of the main infratentorial and supratentorial tracts that exceeded cortical damage. Longitudinal study showed that PSP-RS exhibited no further changes in cortical thinning, which remained relatively focal, while midbrain atrophy and WM damage significantly progressed. Corpus callosum and frontal WM tract changes correlated with the progression of both disease severity and behavioural dysfunction. This study demonstrated the feasibility of carrying out longitudinal diffusion tensor MRI in patients with PSP-RS and its sensitivity to identifying the progression of pathology. Longitudinal midbrain volume loss and WM changes are associated with PSP disease course. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Glutamate neurons are intermixed with midbrain dopamine neurons in nonhuman primates and humans

PubMed Central

Root, David H.; Wang, Hui-Ling; Liu, Bing; Barker, David J.; Mód, László; Szocsics, Péter; Silva, Afonso C.; Maglóczky, Zsófia; Morales, Marisela

2016-01-01

The rodent ventral tegmental area (VTA) and substantia nigra pars compacta (SNC) contain dopamine neurons intermixed with glutamate neurons (expressing vesicular glutamate transporter 2; VGluT2), which play roles in reward and aversion. However, identifying the neuronal compositions of the VTA and SNC in higher mammals has remained challenging. Here, we revealed VGluT2 neurons within the VTA and SNC of nonhuman primates and humans by simultaneous detection of VGluT2 mRNA and tyrosine hydroxylase (TH; for identification of dopamine neurons). We found that several VTA subdivisions share similar cellular compositions in nonhuman primates and humans; their rostral linear nuclei have a high prevalence of VGluT2 neurons lacking TH; their paranigral and parabrachial pigmented nuclei have mostly TH neurons, and their parabrachial pigmented nuclei have dual VGluT2-TH neurons. Within nonhuman primates and humans SNC, the vast majority of neurons are TH neurons but VGluT2 neurons were detected in the pars lateralis subdivision. The demonstration that midbrain dopamine neurons are intermixed with glutamate or glutamate-dopamine neurons from rodents to humans offers new opportunities for translational studies towards analyzing the roles that each of these neurons play in human behavior and in midbrain-associated illnesses such as addiction, depression, schizophrenia, and Parkinson’s disease. PMID:27477243

Altered top-down and bottom-up processing of fear conditioning in panic disorder with agoraphobia.

PubMed

Lueken, U; Straube, B; Reinhardt, I; Maslowski, N I; Wittchen, H-U; Ströhle, A; Wittmann, A; Pfleiderer, B; Konrad, C; Ewert, A; Uhlmann, C; Arolt, V; Jansen, A; Kircher, T

2014-01-01

Although several neurophysiological models have been proposed for panic disorder with agoraphobia (PD/AG), there is limited evidence from functional magnetic resonance imaging (fMRI) studies on key neural networks in PD/AG. Fear conditioning has been proposed to represent a central pathway for the development and maintenance of this disorder; however, its neural substrates remain elusive. The present study aimed to investigate the neural correlates of fear conditioning in PD/AG patients. The blood oxygen level-dependent (BOLD) response was measured using fMRI during a fear conditioning task. Indicators of differential conditioning, simple conditioning and safety signal processing were investigated in 60 PD/AG patients and 60 matched healthy controls. Differential conditioning was associated with enhanced activation of the bilateral dorsal inferior frontal gyrus (IFG) whereas simple conditioning and safety signal processing were related to increased midbrain activation in PD/AG patients versus controls. Anxiety sensitivity was associated positively with the magnitude of midbrain activation. The results suggest changes in top-down and bottom-up processes during fear conditioning in PD/AG that can be interpreted within a neural framework of defensive reactions mediating threat through distal (forebrain) versus proximal (midbrain) brain structures. Evidence is accumulating that this network plays a key role in the aetiopathogenesis of panic disorder.

Midbrain dopamine neurons associated with reward processing innervate the neurogenic subventricular zone.

PubMed

Lennington, Jessica B; Pope, Sara; Goodheart, Anna E; Drozdowicz, Linda; Daniels, Stephen B; Salamone, John D; Conover, Joanne C

2011-09-14

Coordinated regulation of the adult neurogenic subventricular zone (SVZ) is accomplished by a myriad of intrinsic and extrinsic factors. The neurotransmitter dopamine is one regulatory molecule implicated in SVZ function. Nigrostriatal and ventral tegmental area (VTA) midbrain dopamine neurons innervate regions adjacent to the SVZ, and dopamine synapses are found on SVZ cells. Cell division within the SVZ is decreased in humans with Parkinson's disease and in animal models of Parkinson's disease following exposure to toxins that selectively remove nigrostriatal neurons, suggesting that dopamine is critical for SVZ function and nigrostriatal neurons are the main suppliers of SVZ dopamine. However, when we examined the aphakia mouse, which is deficient in nigrostriatal neurons, we found no detrimental effect to SVZ proliferation or organization. Instead, dopamine innervation of the SVZ tracked to neurons at the ventrolateral boundary of the VTA. This same dopaminergic neuron population also innervated the SVZ of control mice. Characterization of these neurons revealed expression of proteins indicative of VTA neurons. Furthermore, exposure to the neurotoxin MPTP depleted neurons in the ventrolateral VTA and resulted in decreased SVZ proliferation. Together, these results reveal that dopamine signaling in the SVZ originates from a population of midbrain neurons more typically associated with motivational and reward processing.

Hierarchical prediction errors in midbrain and septum during social learning.

PubMed

Diaconescu, Andreea O; Mathys, Christoph; Weber, Lilian A E; Kasper, Lars; Mauer, Jan; Stephan, Klaas E

2017-04-01

Social learning is fundamental to human interactions, yet its computational and physiological mechanisms are not well understood. One prominent open question concerns the role of neuromodulatory transmitters. We combined fMRI, computational modelling and genetics to address this question in two separate samples (N = 35, N = 47). Participants played a game requiring inference on an adviser's intentions whose motivation to help or mislead changed over time. Our analyses suggest that hierarchically structured belief updates about current advice validity and the adviser's trustworthiness, respectively, depend on different neuromodulatory systems. Low-level prediction errors (PEs) about advice accuracy not only activated regions known to support 'theory of mind', but also the dopaminergic midbrain. Furthermore, PE responses in ventral striatum were influenced by the Met/Val polymorphism of the Catechol-O-Methyltransferase (COMT) gene. By contrast, high-level PEs ('expected uncertainty') about the adviser's fidelity activated the cholinergic septum. These findings, replicated in both samples, have important implications: They suggest that social learning rests on hierarchically related PEs encoded by midbrain and septum activity, respectively, in the same manner as other forms of learning under volatility. Furthermore, these hierarchical PEs may be broadcast by dopaminergic and cholinergic projections to induce plasticity specifically in cortical areas known to represent beliefs about others. © The Author (2017). Published by Oxford University Press.

Anesthetic state modulates excitability but not spectral tuning or neural discrimination in single auditory midbrain neurons

PubMed Central

Schumacher, Joseph W.; Schneider, David M.

2011-01-01

The majority of sensory physiology experiments have used anesthesia to facilitate the recording of neural activity. Current techniques allow researchers to study sensory function in the context of varying behavioral states. To reconcile results across multiple behavioral and anesthetic states, it is important to consider how and to what extent anesthesia plays a role in shaping neural response properties. The role of anesthesia has been the subject of much debate, but the extent to which sensory coding properties are altered by anesthesia has yet to be fully defined. In this study we asked how urethane, an anesthetic commonly used for avian and mammalian sensory physiology, affects the coding of complex communication vocalizations (songs) and simple artificial stimuli in the songbird auditory midbrain. We measured spontaneous and song-driven spike rates, spectrotemporal receptive fields, and neural discriminability from responses to songs in single auditory midbrain neurons. In the same neurons, we recorded responses to pure tone stimuli ranging in frequency and intensity. Finally, we assessed the effect of urethane on population-level representations of birdsong. Results showed that intrinsic neural excitability is significantly depressed by urethane but that spectral tuning, single neuron discriminability, and population representations of song do not differ significantly between unanesthetized and anesthetized animals. PMID:21543752

Hierarchical prediction errors in midbrain and septum during social learning

PubMed Central

Mathys, Christoph; Weber, Lilian A. E.; Kasper, Lars; Mauer, Jan; Stephan, Klaas E.

2017-01-01

Abstract Social learning is fundamental to human interactions, yet its computational and physiological mechanisms are not well understood. One prominent open question concerns the role of neuromodulatory transmitters. We combined fMRI, computational modelling and genetics to address this question in two separate samples (N = 35, N = 47). Participants played a game requiring inference on an adviser’s intentions whose motivation to help or mislead changed over time. Our analyses suggest that hierarchically structured belief updates about current advice validity and the adviser’s trustworthiness, respectively, depend on different neuromodulatory systems. Low-level prediction errors (PEs) about advice accuracy not only activated regions known to support ‘theory of mind’, but also the dopaminergic midbrain. Furthermore, PE responses in ventral striatum were influenced by the Met/Val polymorphism of the Catechol-O-Methyltransferase (COMT) gene. By contrast, high-level PEs (‘expected uncertainty’) about the adviser’s fidelity activated the cholinergic septum. These findings, replicated in both samples, have important implications: They suggest that social learning rests on hierarchically related PEs encoded by midbrain and septum activity, respectively, in the same manner as other forms of learning under volatility. Furthermore, these hierarchical PEs may be broadcast by dopaminergic and cholinergic projections to induce plasticity specifically in cortical areas known to represent beliefs about others. PMID:28119508

INTEGRATED DISINFECTION BY-PRODUCTS (DBP) MIXTURES RESEARCH: GENE EXPRESSION ALTERATIONS IN PRIMARY RAT HEPATOCYTE CULTURES EXPOSED TO DBP MIXTURES FORMED BY CHLORINATION AND OZONATION/POSTCHLORINATION

EPA Science Inventory

What is the study?
This study was designed to provide data on the in vitro toxicity of water concentrates containing complex mixtures of DBPs. Rat hepatocytes in primary culture were exposed for 24 hr to full strength, 1:10 or 1:20 dilutions of chlorination or ozonation/chl...

Zebrafish aussicht mutant embryos exhibit widespread overexpression of ace (fgf8) and coincident defects in CNS development.

PubMed

Heisenberg, C P; Brennan, C; Wilson, S W

1999-05-01

During the development of the zebrafish nervous system both noi, a zebrafish pax2 homolog, and ace, a zebrafish fgf8 homolog, are required for development of the midbrain and cerebellum. Here we describe a dominant mutation, aussicht (aus), in which the expression of noi and ace is upregulated. In aus mutant embryos, ace is upregulated at many sites in the embryo, while noi expression is only upregulated in regions of the forebrain and midbrain which also express ace. Subsequent to the alterations in noi and ace expression, aus mutants exhibit defects in the differentiation of the forebrain, midbrain and eyes. Within the forebrain, the formation of the anterior and postoptic commissures is delayed and the expression of markers within the pretectal area is reduced. Within the midbrain, En and wnt1 expression is expanded. In heterozygous aus embryos, there is ectopic outgrowth of neural retina in the temporal half of the eyes, whereas in putative homozygous aus embryos, the ventral retina is reduced and the pigmented retinal epithelium is expanded towards the midline. The observation that aus mutant embryos exhibit widespread upregulation of ace raised the possibility that aus might represent an allele of the ace gene itself. However, by crossing carriers for both aus and ace, we were able to generate homozygous ace mutant embryos that also exhibited the aus phenotype. This indicated that aus is not tightly linked to ace and is unlikely to be a mutation directly affecting the ace locus. However, increased Ace activity may underly many aspects of the aus phenotype and we show that the upregulation of noi in the forebrain of aus mutants is partially dependent upon functional Ace activity. Conversely, increased ace expression in the forebrain of aus mutants is not dependent upon functional Noi activity. We conclude that aus represents a mutation involving a locus normally required for the regulation of ace expression during embryogenesis.

CT-angiography source images indicate less fatal outcome despite coma of patients in the Basilar Artery International Cooperation Study.

PubMed

Pallesen, Lars P; Khomenko, Andrei; Dzialowski, Imanuel; Barlinn, Jessica; Barlinn, Kristian; Zerna, Charlotte; van der Hoeven, Erik Jrj; Algra, Ale; Kapelle, L Jaap; Michel, Patrik; Bodechtel, Ulf; Demchuk, Andrew M; Schonewille, Wouter; Puetz, Volker

2017-02-01

Background Coma is associated with poor outcome in patients with basilar artery occlusion. Aims We sought to assess whether the posterior circulation Acute Stroke Prognosis Early CT Score and the Pons-Midbrain Index applied to CT angiography source images predict the outcome of comatose patients in the Basilar Artery International Cooperation Study. Methods Basilar Artery International Cooperation Study was a prospective, observational registry of patients with acute basilar artery occlusion with 48 recruiting centers worldwide. We applied posterior circulation Acute Stroke Prognosis Early CT Score and Pons-Midbrain Index to CT angiography source images of Basilar Artery International Cooperation Study patients who presented with coma. We calculated adjusted risk ratios to assess the association of dichotomized posterior circulation Acute Stroke Prognosis Early CT Score (≥8 vs. <8) and Pons-Midbrain Index (<3 vs. ≥3) with mortality and favourable outcome (modified Rankin Scale score 0-3) at one month. Results Of 619 patients in the Basilar Artery International Cooperation Study registry, CT angiography source images were available for review in 158 patients. Among these, 78 patients (49%) presented with coma. Compared to non-comatose patients, comatose patients were more likely to die (risk ratios 2.34; CI 95% 1.56-3.52) and less likely to have a favourable outcome (risk ratios 0.44; CI 95% 0.24-0.80). Among comatose patients, a Pons-Midbrain Index < 3 was related to reduced mortality (adjusted RR 0.66; 95% CI 0.46-0.96), but not to favourable outcome (adjusted RR 1.19; 95% CI 0.39-3.62). Posterior circulation Acute Stroke Prognosis Early CT Score dichotomized at ≥ 8 vs. <8 was not significantly associated with death (adjusted RR 0.70; 95% CI 0.46-1.05). Conclusion In comatose patients with basilar artery occlusion, the extent of brainstem ischemia appears to be related to mortality but not to favourable outcome.

COMPARATIVE IMMUNOSUPPRESSION OF VARIOUS GLYCOL ETHERS ORALLY ADMINISTERED TO FISCHER 344 RATS

EPA Science Inventory

Oral dosing of adult rats F344 rats with the glycol ether 2-methoxyethanol (ME) or its principal metabolite 2-methoxyacetic acid (MAA) results in the suppression of the primary plaque-forming cell (PFC) response to trinitrophenyl-lipopolysaccharide (TNP_LPS). n the present study,...

Rotenone induces oxidative stress and dopaminergic neuron damage in organotypic substantia nigra cultures.

PubMed

Testa, Claudia M; Sherer, Todd B; Greenamyre, J Timothy

2005-03-24

Rotenone, a pesticide and complex I inhibitor, causes nigrostriatal degeneration similar to Parkinson disease pathology in a chronic, systemic, in vivo rodent model [M. Alam, W.J. Schmidt, Rotenone destroys dopaminergic neurons and induces parkinsonian symptoms in rats, Behav. Brain Res. 136 (2002) 317-324; R. Betarbet, T.B. Sherer, G. MacKenzie, M. Garcia-Osuna, A.V. Panov, J.T. Greenamyre, Chronic systemic pesticide exposure reproduces features of Parkinson's disease, Nat. Neurosci. 3 (2000) 1301-1306; S.M. Fleming, C. Zhu, P.O. Fernagut, A. Mehta, C.D. DiCarlo, R.L. Seaman, M.F. Chesselet, Behavioral and immunohistochemical effects of chronic intravenous and subcutaneous infusions of varying doses of rotenone, Exp. Neurol. 187 (2004) 418-429; T.B. Sherer, J.H. Kim, R. Betarbet, J.T. Greenamyre, Subcutaneous rotenone exposure causes highly selective dopaminergic degeneration and alpha-synuclein aggregation, Exp. Neurol. 179 (2003) 9-16.]. To better investigate the role of mitochondria and complex I inhibition in chronic, progressive neurodegenerative disease, we developed methods for long-term culture of rodent postnatal midbrain organotypic slices. Chronic complex I inhibition over weeks by low dose (10-50 nM) rotenone in this system lead to dose- and time-dependent destruction of substantia nigra pars compacta neuron processes, morphologic changes, some neuronal loss, and decreased tyrosine hydroxylase (TH) protein levels. Chronic complex I inhibition also caused oxidative damage to proteins, measured by protein carbonyl levels. This oxidative damage was blocked by the antioxidant alpha-tocopherol (vitamin E). At the same time, alpha-tocopherol also blocked rotenone-induced reductions in TH protein and TH immunohistochemical changes. Thus, oxidative damage is a primary mechanism of mitochondrial toxicity in intact dopaminergic neurons. The organotypic culture system allows close study of this and other interacting mechanisms over a prolonged time period in mature dopaminergic neurons with intact processes, surrounding glia, and synaptic connections.

Nogo-receptor 1 antagonization in combination with neurotrophin-4/5 is not superior to single factor treatment in promoting survival and morphological complexity of cultured dopaminergic neurons.

PubMed

Seiler, Stefanie; Di Santo, Stefano; Sahli, Sebastian; Andereggen, Lukas; Widmer, Hans Rudolf

2017-08-01

Cell transplantation using ventral mesencephalic tissue is an experimental approach to treat Parkinson's disease. This approach is limited by poor survival of the transplants and the high number of dopaminergic neurons needed for grafting. Increasing the yield of dopaminergic neurons in donor tissue is of great importance. We have previously shown that antagonization of the Nogo-receptor 1 by NEP1-40 promoted survival of cultured dopaminergic neurons and exposure to neurotrophin-4/5 increased dopaminergic cell densities in organotypic midbrain cultures. We investigated whether a combination of both treatments offers a novel tool to further improve dopaminergic neuron survival. Rat embryonic ventral mesencephalic neurons grown as organotypic free-floating roller tube or primary dissociated cultures were exposed to neurotrophin-4/5 and NEP1-40. The combined and single factor treatment resulted in significantly higher numbers of tyrosine hydroxylase positive neurons compared to controls. Significantly stronger tyrosine hydroxylase signal intensity was detected by Western blotting in the combination-treated cultures compared to controls but not compared to single factor treatments. Neurotrophin-4/5 and the combined treatment showed significantly higher signals for the neuronal marker microtubule-associated protein 2 in Western blots compared to control while no effects were observed for the astroglial marker glial fibrillary acidic protein between groups, suggesting that neurotrophin-4/5 targets mainly neuronal cells. Finally, NEP1-40 and the combined treatment significantly augmented tyrosine hydroxylase positive neurite length. Summarizing, our findings substantiate that antagonization of the Nogo-receptor 1 promotes dopaminergic neurons but does not further increase the yield of dopaminergic neurons and their morphological complexity when combined with neurotrophin-4/5 hinting to the idea that these treatments might exert their effects by activating common downstream pathways. Copyright © 2017 Elsevier B.V. All rights reserved.

Role played by periaqueductal gray neurons in parasympathetically mediated fear bradycardia in conscious rats.

PubMed

Koba, Satoshi; Inoue, Ryo; Watanabe, Tatsuo

2016-06-01

Freezing, a characteristic pattern of defensive behavior elicited by fear, is associated with a decrease in the heart rate. Central mechanisms underlying fear bradycardia are poorly understood. The periaqueductal gray (PAG) in the midbrain is known to contribute to autonomic cardiovascular adjustments associated with various emotional behaviors observed during active or passive defense reactions. The purpose of this study was to elucidate the role played by PAG neurons in eliciting fear bradycardia. White noise sound (WNS) exposure at 90 dB induced freezing behavior and elicited bradycardia in conscious rats. The WNS exposure-elicited bradycardia was mediated parasympathetically because intravenous administration of atropine abolished the bradycardia (P < 0.05). Moreover, WNS exposure-elicited bradycardia was mediated by neuronal activation of the lateral/ventrolateral PAG (l/vlPAG) because bilateral microinjection of muscimol, a GABAA agonist, into the l/vlPAG significantly suppressed the bradycardia. It is noted that muscimol microinjected bilaterally into the dorsolateral PAG had no effect on WNS exposure-elicited bradycardia. Furthermore, retrograde neuronal tracing experiments combined with immunohistochemistry demonstrated that a number of l/vlPAG neurons that send direct projections to the nucleus ambiguus (NA) in the medulla, a major origin of parasympathetic preganglionic neurons to the heart, were activated by WNS exposure. Based on these findings, we propose that the l/vlPAG-NA monosynaptic pathway transmits fear-driven central signals, which elicit bradycardia through parasympathetic outflow. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

Interactions of ( sup 3 H)amphetamine with rat brain synaptosomes. I. Saturable sequestration

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zaczek, R.; Culp, S.; Goldberg, H.

1991-05-01

Previous studies have identified a saturable site of d-({sup 3}H)amphetamine sequestration (AMSEQ) in rat brain synaptosomes. The present study characterized AMSEQ with respect to its subcellular, neuronal and regional distributions, ontogenetic development, pharmacological specificity and factors required for its maintenance. Although AMSEQ was reduced when assays were performed in Krebs' buffer incubated at 37{degree}C as compared to assays performed in isotonic Tris-sucrose buffer incubated at room temperature, the pharmacological profiles of AMSEQ were virtually identical under both conditions. AMSEQ was negligible in tissues outside the central nervous system, enriched in synaptosomes and partially reduced by striatal kainic acid lesion, indicatingmore » neuronal localization. The distribution of AMSEQ in the central nervous system was heterogenous. Highest levels were present in hypothalamus with progressively lower levels noted in parietal cortex, frontal cortex, striatum, thalamus, hippocampus, midbrain, cerebellum, pons-medulla and spinal cord. With regard to its ontogeny, AMSEQ increased early in neonatal life, reaching adult levels by postnatal day 14. Although the effects of amphetamine to abolish the transynaptosomal pH gradient suggest a possible role for this gradient in the maintenance of AMSEQ, the pharmacological profile of AMSEQ indicates that other factors are involved. An interaction with an intrasynaptosomal acid, such as N-acetylaspartate, may account for AMSEQ maintenance. AMSEQ did not possess a stereospecific preference for either d-(IC50 = 177 microM) or I-amphetamine (IC50 = 173 microM). However, the pharmacological profile of AMSEQ indicated structural specificity with antidepressants being relatively potent inhibitors. (Abstract Truncated)« less

Ultra-high-field fMRI insights on insight: Neural correlates of the Aha!-moment.

PubMed

Tik, Martin; Sladky, Ronald; Luft, Caroline Di Bernardi; Willinger, David; Hoffmann, André; Banissy, Michael J; Bhattacharya, Joydeep; Windischberger, Christian

2018-04-17

Finding creative solutions to difficult problems is a fundamental aspect of human culture and a skill highly needed. However, the exact neural processes underlying creative problem solving remain unclear. Insightful problem solving tasks were shown to be a valid method for investigating one subcomponent of creativity: the Aha!-moment. Finding insightful solutions during a remote associates task (RAT) was found to elicit specific cortical activity changes. Considering the strong affective components of Aha!-moments, as manifested in the subjectively experienced feeling of relief following the sudden emergence of the solution of the problem without any conscious forewarning, we hypothesized the subcortical dopaminergic reward network to be critically engaged during Aha. To investigate those subcortical contributions to insight, we employed ultra-high-field 7 T fMRI during a German Version of the RAT. During this task, subjects were exposed to word triplets and instructed to find a solution word being associated with all the three given words. They were supposed to press a button as soon as they felt confident about their solution without further revision, allowing us to capture the exact event of Aha!-moment. Besides the finding on cortical involvement of the left anterior middle temporal gyrus (aMTG), here we showed for the first time robust subcortical activity changes related to insightful problem solving in the bilateral thalamus, hippocampus, and the dopaminergic midbrain comprising ventral tegmental area (VTA), nucleus accumbens (NAcc), and caudate nucleus. These results shed new light on the affective neural mechanisms underlying insightful problem solving. © 2018 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc.

Dynamic Contrast-Enhanced MRI of Gd-albumin Delivery to the Rat Hippocampus In Vivo by Convection-Enhanced Delivery

PubMed Central

Kim, Jung Hwan; Astary, Garrett W.; Nobrega, Tatiana L.; Kantorovich, Svetlana; Carney, Paul R.; Mareci, Thomas H.; Sarntinoranont, Malisa

2013-01-01

Convection enhanced delivery (CED) shows promise in treating neurological diseases due to its ability to circumvent the blood-brain barrier (BBB) and deliver therapeutics directly to the parenchyma of the central nervous system (CNS). Such a drug delivery method may be useful in treating CNS disorders involving the hippocampus such temporal lobe epilepsy and gliomas; however, the influence of anatomical structures on infusate distribution is not fully understood. As a surrogate for therapeutic agents, we used gadolinium-labeled-albumin (Gd-albumin) tagged with Evans blue dye to observe the time dependence of CED infusate distributions into the rat dorsal and ventral hippocampus in vivo with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). For finer anatomical detail, final distribution volumes (Vd) of the infusate were observed with high-resolution T1-weighted MR imaging and light microscopy of fixed brain sections. Dynamic images demonstrated that Gd-albumin preferentially distributed within the hippocampus along neuroanatomical structures with less fluid resistance and less penetration was observed in dense cell layers. Furthermore, significant leakage into adjacent cerebrospinal fluid (CSF) spaces such as the hippocampal fissure, velum interpositum and midbrain cistern occurred toward the end of infusion. Vd increased linearly with infusion volume (Vi) at a mean Vd/Vi ratio of 5.51 ± 0.55 for the dorsal hippocampus infusion and 5.30 ± 0.83 for the ventral hippocampus infusion. This study demonstrated the significant effects of tissue structure and CSF space boundaries on infusate distribution during CED. PMID:22687936

3,4-Methylenedioxymethamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of (/sup 3/H)paroxetine-labeled serotonin uptake sites

DOE Office of Scientific and Technical Information (OSTI.GOV)

Battaglia, G.; Yeh, S.Y.; O'Hearn, E.

1987-09-01

This study examines the effects of repeated systemic administration (20 mg/kg s.c., twice daily for 4 days) of 3,4-methylenedioxymethamphetamine (MDMA) and 3,4-methylenedioxyamphetamine (MDA) on levels of brain monoamines, their metabolites and on the density of monoamine uptake sites in various regions of rat brain. Marked reductions (30-60%) in the concentration of 5-hydroxyindoleacetic acid were observed in cerebral cortex, hippocampus, striatum, hypothalamus and midbrain at 2 weeks after a 4-day treatment regimen of MDMA or MDA; less consistent reductions in serotonin (5-HT) content were observed in these brain regions. In addition, both MDMA and MDA caused comparable and substantial reductions (50-75%)more » in the density of (/sup 3/H)paroxetine-labeled 5-HT uptake sites in all brain regions examined. In contrast, neither MDMA nor MDA caused any widespread or long-term changes in the content of the catecholaminergic markers (i.e., norepinephrine, dopamine, 3,4 dihydroxyphenylacetic acid and homovanillic acid) or in the number of (/sup 3/H)mazindol-labeled norepinephrine or dopamine uptake sites in the brain regions examined. These data demonstrate that MDMA and MDA cause long-lasting neurotoxic effects with respect to both the functional and structural integrity of serotonergic neurons in brain. Furthermore, our measurement of reductions in the density of 5-HT uptake sites provides a means for quantification of the neurodegenerative effects of MDMA and MDA on presynaptic 5-HT terminals.« less

Morphine regulates Argonaute 2 and TH expression and activity but not miR-133b in midbrain dopaminergic neurons.

PubMed

García-Pérez, Daniel; López-Bellido, Roger; Hidalgo, Juana M; Rodríguez, Raquel E; Laorden, Maria Luisa; Núñez, Cristina; Milanés, Maria Victoria

2015-01-01

Epigenetic changes such as microRNAs (miRs)/Ago2-induced gene silencing represent complex molecular signature that regulate cellular plasticity. Recent studies showed involvement of miRs and Ago2 in drug addiction. In this study, we show that changes in gene expression induced by morphine and morphine withdrawal occur with concomitant epigenetic modifications in the mesolimbic dopaminergic (DA) pathway [ventral tegmental area (VTA)/nucleus accumbens (NAc) shell], which is critically involved in drug-induced dependence. We found that acute or chronic morphine administration as well as morphine withdrawal did not modify miR-133b messenger RNA (mRNA) expression in the VTA, whereas Ago2 protein levels were decreased and increased in morphine-dependent rats and after morphine withdrawal, respectively. These changes were paralleled with enhanced and decreased NAc tyrosine hydroxylase (TH) protein (an early DA marker) in morphine-dependent rats and after withdrawal, respectively. We also observed changes in TH mRNA expression in the VTA that could be related to Ago2-induced translational repression of TH mRNA during morphine withdrawal. However, the VTA number of TH-positive neurons suffered no alterations after the different treatment. Acute morphine administration produced a marked increase in TH activity and DA turnover in the NAc (shell). In contrast, precipitated morphine withdrawal decreased TH activation and did not change DA turnover. These findings provide new information into the possible correlation between Ago2/miRs complex regulation and DA neurons plasticity during opiate addiction. © 2013 Society for the Study of Addiction.

Effect of background noise on neuronal coding of interaural level difference cues in rat inferior colliculus

PubMed Central

Mokri, Yasamin; Worland, Kate; Ford, Mark; Rajan, Ramesh

2015-01-01

Humans can accurately localize sounds even in unfavourable signal-to-noise conditions. To investigate the neural mechanisms underlying this, we studied the effect of background wide-band noise on neural sensitivity to variations in interaural level difference (ILD), the predominant cue for sound localization in azimuth for high-frequency sounds, at the characteristic frequency of cells in rat inferior colliculus (IC). Binaural noise at high levels generally resulted in suppression of responses (55.8%), but at lower levels resulted in enhancement (34.8%) as well as suppression (30.3%). When recording conditions permitted, we then examined if any binaural noise effects were related to selective noise effects at each of the two ears, which we interpreted in light of well-known differences in input type (excitation and inhibition) from each ear shaping particular forms of ILD sensitivity in the IC. At high signal-to-noise ratios (SNR), in most ILD functions (41%), the effect of background noise appeared to be due to effects on inputs from both ears, while for a large percentage (35.8%) appeared to be accounted for by effects on excitatory input. However, as SNR decreased, change in excitation became the dominant contributor to the change due to binaural background noise (63.6%). These novel findings shed light on the IC neural mechanisms for sound localization in the presence of continuous background noise. They also suggest that some effects of background noise on encoding of sound location reported to be emergent in upstream auditory areas can also be observed at the level of the midbrain. PMID:25865218

TRPV1 in Brain Is Involved in Acetaminophen-Induced Antinociception

PubMed Central

Eschalier, Alain; Zygmunt, Peter M.; Högestätt, Edward D.

2010-01-01

Background Acetaminophen, the major active metabolite of acetanilide in man, has become one of the most popular over-the-counter analgesic and antipyretic agents, consumed by millions of people daily. However, its mechanism of action is still a matter of debate. We have previously shown that acetaminophen is further metabolized to N-(4-hydroxyphenyl)-5Z,8Z,11Z,14Z -eicosatetraenamide (AM404) by fatty acid amide hydrolase (FAAH) in the rat and mouse brain and that this metabolite is a potent activator of transient receptor potential vanilloid 1 (TRPV1) in vitro. Pharmacological activation of TRPV1 in the midbrain periaqueductal gray elicits antinociception in rats. It is therefore possible that activation of TRPV1 in the brain contributes to the analgesic effect of acetaminophen. Methodology/Principal Findings Here we show that the antinociceptive effect of acetaminophen at an oral dose lacking hypolocomotor activity is absent in FAAH and TRPV1 knockout mice in the formalin, tail immersion and von Frey tests. This dose of acetaminophen did not affect the global brain contents of prostaglandin E2 (PGE2) and endocannabinoids. Intracerebroventricular injection of AM404 produced a TRPV1-mediated antinociceptive effect in the mouse formalin test. Pharmacological inhibition of TRPV1 in the brain by intracerebroventricular capsazepine injection abolished the antinociceptive effect of oral acetaminophen in the same test. Conclusions This study shows that TRPV1 in brain is involved in the antinociceptive action of acetaminophen and provides a strategy for developing central nervous system active oral analgesics based on the coexpression of FAAH and TRPV1 in the brain. PMID:20862299

CHROMagar Candida as the Sole Primary Medium for Isolation of Yeasts and as a Source Medium for the Rapid-Assimilation-of-Trehalose Test

PubMed Central

Murray, Melissa P.; Zinchuk, Riva; Larone, Davise H.

2005-01-01

The chromogenic medium BBL CHROMagar Candida (CAC) was evaluated as a sole primary medium for the isolation of yeasts from clinical specimens in which yeasts are the primary concern. Additionally, the reliability of the rapid-assimilation-of-trehalose (RAT) test in yielding correct results with isolates taken from CAC was assessed. A total of 270 throat, urine, and genital (TUG) specimens were streaked onto CAC, Sabouraud dextrose agar (SDA), inhibitory mold agar (IMA), and Mycosel (MYC). A total of 69 blood culture broths that were smear positive for yeast were streaked onto CAC and SDA. A 1-h RAT test (NCCLS M35-A) was performed simultaneously on isolates from CAC and SDA. A total of 112 TUG specimens yielded yeast colonies (CAC, 111 colonies; IMA, 105; SDA, 103; MYC, 91). The 69 blood culture yeasts grew on both CAC and SDA. Mixed cultures of yeasts were detected on 11 CAC plates but were unrecognized on other media. Colonies suspected of being C. glabrata on 32 CAC plates were all RAT test positive and confirmed to be C. glabrata; of 59 colonies with various characteristics of color and morphology on CAC, none were RAT positive, and all were conventionally identified as yeasts other than C. glabrata (sensitivity and specificity, 100%). The same isolates from SDA tested for RAT produced six false negatives and no false positives (sensitivity, 81%; specificity, 100%). The results show that CAC can be used as the sole primary medium for recovery of yeasts from clinical specimens. Additionally, isolates grown on CAC yield excellent results with the RAT test utilized in this study. PMID:15750085

CHROMagar Candida as the sole primary medium for isolation of yeasts and as a source medium for the rapid-assimilation-of-trehalose test.

PubMed

Murray, Melissa P; Zinchuk, Riva; Larone, Davise H

2005-03-01

The chromogenic medium BBL CHROMagar Candida (CAC) was evaluated as a sole primary medium for the isolation of yeasts from clinical specimens in which yeasts are the primary concern. Additionally, the reliability of the rapid-assimilation-of-trehalose (RAT) test in yielding correct results with isolates taken from CAC was assessed. A total of 270 throat, urine, and genital (TUG) specimens were streaked onto CAC, Sabouraud dextrose agar (SDA), inhibitory mold agar (IMA), and Mycosel (MYC). A total of 69 blood culture broths that were smear positive for yeast were streaked onto CAC and SDA. A 1-h RAT test (NCCLS M35-A) was performed simultaneously on isolates from CAC and SDA. A total of 112 TUG specimens yielded yeast colonies (CAC, 111 colonies; IMA, 105; SDA, 103; MYC, 91). The 69 blood culture yeasts grew on both CAC and SDA. Mixed cultures of yeasts were detected on 11 CAC plates but were unrecognized on other media. Colonies suspected of being C. glabrata on 32 CAC plates were all RAT test positive and confirmed to be C. glabrata; of 59 colonies with various characteristics of color and morphology on CAC, none were RAT positive, and all were conventionally identified as yeasts other than C. glabrata (sensitivity and specificity, 100%). The same isolates from SDA tested for RAT produced six false negatives and no false positives (sensitivity, 81%; specificity, 100%). The results show that CAC can be used as the sole primary medium for recovery of yeasts from clinical specimens. Additionally, isolates grown on CAC yield excellent results with the RAT test utilized in this study.

Glucose deprivation reversibly down-regulates tissue plasminogen activator via proteasomal degradation in rat primary astrocytes.

PubMed

Cho, Kyu Suk; Joo, So Hyun; Choi, Chang Soon; Kim, Ki Chan; Ko, Hyun Myung; Park, Jin Hee; Kim, Pitna; Hur, Jun; Lee, Sung Hoon; Bahn, Geon Ho; Ryu, Jong Hoon; Lee, Jongmin; Han, Seol-Heui; Kwon, Kyoung Ja; Shin, Chan Young

2013-05-20

Tissue plasminogen activator (tPA) is an essential neuromodulator whose involvement in multiple functions such as synaptic plasticity, cytokine-like immune function and regulation of cell survival mandates rapid and tight tPA regulation in the brain. We investigated the possibility that a transient metabolic challenge induced by glucose deprivation may affect tPA activity in rat primary astrocytes, the main cell type responsible for metabolic regulation in the CNS. Rat primary astrocytes were incubated in serum-free DMEM without glucose. Casein zymography was used to determine tPA activity, and tPA mRNA was measured by RT-PCR. The signaling pathways regulating tPA activity were identified by Western blotting. Glucose deprivation rapidly down-regulated the activity of tPA without affecting its mRNA level in rat primary astrocytes; this effect was mimicked by translational inhibitors. The down-regulation of tPA was accompanied by increased tPA degradation, which may be modulated by a proteasome-dependent degradation pathway. Glucose deprivation induced activation of PI3K-Akt-GSK3β, p38 and AMPK, and inhibition of these pathways using LY294002, SB203580 and compound C significantly inhibited glucose deprivation-induced tPA down-regulation, demonstrating the essential role of these pathways in tPA regulation in glucose-deprived astrocytes. Rapid and reversible regulation of tPA activity in rat primary astrocytes during metabolic crisis may minimize energy-requiring neurologic processes in stressed situations. This effect may thereby increase the opportunity to invest cellular resources in cell survival and may allow rapid re-establishment of normal cellular function after the crisis. Copyright © 2013 Elsevier Inc. All rights reserved.

[Isolation, purification and primary culture of rat pancreatic beta-cells].

PubMed

Liu, Yu-Pu; Lü, Qing-Guo; Tong, Nan-Wei

2009-01-01

To isolate and purify rat pancreatic beta-cells and to explore the best conditions for the primary culture of the pancreatic beta-cells in vitro. The pancreas of Norman Wistar rats were digested by collagenase V. The islets were purified by mesh sieve. The activity of the islets was stimulated by different concentrations of glucose and detected by dithizone dye. The purified islets were put into RPMI-1640 nutritive medium for culture overnight. The cultured islets were digested again with trypsin and DNAase to obtain the suspension containing single pancreatic cells. The beta-cells were separated and purified in a fluorescence-activated cell sorter (FACS) in the medium containing 2.8 mmol/L glucose. The purified beta-cells were identified by immunohistochemistry and glucose stimulating test. Ham's F-10 with different concentrations of glucose and 3-Isobutyl-1-methylxanthine (IBMX) were used as nutritive medium for the primary cell culture for 24 hours. The best conditions for the culture were identified. An average of 550 +/- 90 islets with fine activities were obtained per rat. The purification with FACS obtained about 5688 beta-cells per rat, with a recovery rate of (93.69 +/- 1.26)% and a purity of (85.5 +/- 1.24)%. A concentration of 10.0 mmol/L and 16.0 mmol/L glucose in primary culture for 24 hours produced the highest survival rates of beta-cells, but IBMX did not increase the survival rates of beta-cells. FACS is effective in purifying pancreatic beta-cells from the suspension with a medium containing 2.8 mmol/L glucose. Pancreatic beta-cells maintain relatively high activities in Ham's F-10 medium containing 10.0-16.0 mmol/L glucose in primary culture.

Unimodal primary sensory cortices are directly connected by long-range horizontal projections in the rat sensory cortex.

PubMed

Stehberg, Jimmy; Dang, Phat T; Frostig, Ron D

2014-01-01

Research based on functional imaging and neuronal recordings in the barrel cortex subdivision of primary somatosensory cortex (SI) of the adult rat has revealed novel aspects of structure-function relationships in this cortex. Specifically, it has demonstrated that single whisker stimulation evokes subthreshold neuronal activity that spreads symmetrically within gray matter from the appropriate barrel area, crosses cytoarchitectural borders of SI and reaches deeply into other unimodal primary cortices such as primary auditory (AI) and primary visual (VI). It was further demonstrated that this spread is supported by a spatially matching underlying diffuse network of border-crossing, long-range projections that could also reach deeply into AI and VI. Here we seek to determine whether such a network of border-crossing, long-range projections is unique to barrel cortex or characterizes also other primary, unimodal sensory cortices and therefore could directly connect them. Using anterograde (BDA) and retrograde (CTb) tract-tracing techniques, we demonstrate that such diffuse horizontal networks directly and mutually connect VI, AI and SI. These findings suggest that diffuse, border-crossing axonal projections connecting directly primary cortices are an important organizational motif common to all major primary sensory cortices in the rat. Potential implications of these findings for topics including cortical structure-function relationships, multisensory integration, functional imaging, and cortical parcellation are discussed.

Unimodal primary sensory cortices are directly connected by long-range horizontal projections in the rat sensory cortex

PubMed Central

Stehberg, Jimmy; Dang, Phat T.; Frostig, Ron D.

2014-01-01

Research based on functional imaging and neuronal recordings in the barrel cortex subdivision of primary somatosensory cortex (SI) of the adult rat has revealed novel aspects of structure-function relationships in this cortex. Specifically, it has demonstrated that single whisker stimulation evokes subthreshold neuronal activity that spreads symmetrically within gray matter from the appropriate barrel area, crosses cytoarchitectural borders of SI and reaches deeply into other unimodal primary cortices such as primary auditory (AI) and primary visual (VI). It was further demonstrated that this spread is supported by a spatially matching underlying diffuse network of border-crossing, long-range projections that could also reach deeply into AI and VI. Here we seek to determine whether such a network of border-crossing, long-range projections is unique to barrel cortex or characterizes also other primary, unimodal sensory cortices and therefore could directly connect them. Using anterograde (BDA) and retrograde (CTb) tract-tracing techniques, we demonstrate that such diffuse horizontal networks directly and mutually connect VI, AI and SI. These findings suggest that diffuse, border-crossing axonal projections connecting directly primary cortices are an important organizational motif common to all major primary sensory cortices in the rat. Potential implications of these findings for topics including cortical structure-function relationships, multisensory integration, functional imaging, and cortical parcellation are discussed. PMID:25309339

BAG3 promotes the phenotypic transformation of primary rat vascular smooth muscle cells via TRAIL.

PubMed

Fu, Yao; Chang, Ye; Chen, Shuang; Li, Yuan; Chen, Yintao; Sun, Guozhe; Yu, Shasha; Ye, Ning; Li, Chao; Sun, Yingxian

2018-05-01

Under normal physiological condition, the mature vascular smooth muscle cells (VSMCs) show differentiated phenotype. In response to various environmental stimuluses, VSMCs convert from the differentiated phenotype to dedifferentiated phenotype characterized by the increased ability of proliferation/migration and the reduction of contractile ability. The phenotypic transformation of VSMCs played an important role in atherosclerosis. Both Bcl-2-associated athanogene 3 (BAG3) and tumor necrosis factor-related apopt-osis inducing ligand (TRAIL) involved in apoptosis. The relationship between BAG3 and TRAIL and their effects the proliferation and migration in VSMCs are rarely reported. This study investigated the effects of BAG3 on the phenotypic modulation and the potential underlying mechanisms in primary rat VSMCs. Primary rat VSMCs were extracted and cultured in vitro. Cell proliferation was detected by cell counting, real-time cell analyzer (RTCA) and EdU incorporation. Cell migration was detected by wound healing, Transwell and RTCA. BAG3 and TRAIL were detected using real-time PCR and western blotting and the secreted proteins in the cultured media by dot blot. The expression of BAG3 increased with continued passages in cultured primary VSMCs. BAG3 promoted the proliferation and migration of primary rat VSMC in a time-dependent manner. BAG3 significantly increased the expression of TRAIL while had no effects on its receptors. TRAIL knockdown or blocking by neutralizing antibody inhibited the proliferation of VSMCs induced by BAG3. TRAIL knockdown exerted no obvious influence on the migration of VSMCs. Based on this study, we report for the first time that BAG3 was expressed in cultured primary rat VSMCs and the expression of BAG3 increased with continued passages. Furthermore, BAG3 promoted the proliferation of VSMCs via increasing the expression of TRAIL. In addition, we also demonstrated that BAG3 promoted the migration of VSMCs independent of TRAIL upregulation.

GABA transporter currents activated by protein kinase A excite midbrain neurons during opioid withdrawal.

PubMed

Bagley, Elena E; Gerke, Michelle B; Vaughan, Christopher W; Hack, Stephen P; Christie, MacDonald J

2005-02-03

Adaptations in neurons of the midbrain periaqueductal gray (PAG) induced by chronic morphine treatment mediate expression of many signs of opioid withdrawal. The abnormally elevated action potential rate of opioid-sensitive PAG neurons is a likely cellular mechanism for withdrawal expression. We report here that opioid withdrawal in vitro induced an opioid-sensitive cation current that was mediated by the GABA transporter-1 (GAT-1) and required activation of protein kinase A (PKA) for its expression. Inhibition of GAT-1 or PKA also prevented withdrawal-induced hyperexcitation of PAG neurons. Our findings indicate that GAT-1 currents can directly increase the action potential rates of neurons and that GAT-1 may be a target for therapy to alleviate opioid-withdrawal symptoms.

Degraded Auditory Processing in a Rat Model of Autism Limits the Speech Representation in Non-primary Auditory Cortex

PubMed Central

Engineer, C.T.; Centanni, T.M.; Im, K.W.; Borland, M.S.; Moreno, N.A.; Carraway, R.S.; Wilson, L.G.; Kilgard, M.P.

2014-01-01

Although individuals with autism are known to have significant communication problems, the cellular mechanisms responsible for impaired communication are poorly understood. Valproic acid (VPA) is an anticonvulsant that is a known risk factor for autism in prenatally exposed children. Prenatal VPA exposure in rats causes numerous neural and behavioral abnormalities that mimic autism. We predicted that VPA exposure may lead to auditory processing impairments which may contribute to the deficits in communication observed in individuals with autism. In this study, we document auditory cortex responses in rats prenatally exposed to VPA. We recorded local field potentials and multiunit responses to speech sounds in primary auditory cortex, anterior auditory field, ventral auditory field. and posterior auditory field in VPA exposed and control rats. Prenatal VPA exposure severely degrades the precise spatiotemporal patterns evoked by speech sounds in secondary, but not primary auditory cortex. This result parallels findings in humans and suggests that secondary auditory fields may be more sensitive to environmental disturbances and may provide insight into possible mechanisms related to auditory deficits in individuals with autism. PMID:24639033

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rawal, Nina; Corti, Olga; CNRS, UMR 7225, Paris

Parkinson's disease (PD) is caused by degeneration of the dopaminergic (DA) neurons of the substantia nigra but the molecular mechanisms underlying the degenerative process remain elusive. Several reports suggest that cell cycle deregulation in post-mitotic neurons could lead to neuronal cell death. We now show that Parkin, an E3 ubiquitin ligase linked to familial PD, regulates {beta}-catenin protein levels in vivo. Stabilization of {beta}-catenin in differentiated primary ventral midbrain neurons results in increased levels of cyclin E and proliferation, followed by increased levels of cleaved PARP and loss of DA neurons. Wnt3a signaling also causes death of post-mitotic DA neuronsmore » in parkin null animals, suggesting that both increased stabilization and decreased degradation of {beta}-catenin results in DA cell death. These findings demonstrate a novel regulation of Wnt signaling by Parkin and suggest that Parkin protects DA neurons against excessive Wnt signaling and {beta}-catenin-induced cell death.« less

Rat coronaviruses infect rat alveolar type I epithelial cells and induce expression of CXC chemokines

PubMed Central

Miura, Tanya A.; Wang, Jieru; Holmes, Kathryn V.; Mason, Robert J.

2007-01-01

We analyzed the ability of two rat coronavirus (RCoV) strains, sialodacryoadenitis virus (SDAV) and Parker’s RCoV (RCoV-P), to infect rat alveolar type I cells and induce chemokine expression. Primary rat alveolar type II cells were transdifferentiated into the type I cell phenotype. Type I cells were productively infected with SDAV and RCoV-P, and both live virus and UV-inactivated virus induced mRNA and protein expression of three CXC chemokines: CINC-2, CINC-3, and LIX, which are neutrophil chemoattractants. Dual immunolabeling of type I cells for viral antigen and CXC chemokines showed that chemokines were expressed primarily by uninfected cells. Virus-induced chemokine expression was reduced by the IL-1 receptor antagonist, suggesting that IL-1 produced by infected cells induces uninfected cells to express chemokines. Primary cultures of alveolar epithelial cells are an important model for the early events in viral infection that lead to pulmonary inflammation. PMID:17804032

Copper uptake and retention in liver parenchymal cells isolated from nutritionally copper-deficient rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Van den Berg, G.J.; de Goeij, J.J.; Bock, I.

1991-08-01

Copper uptake and retention were studied in primary cultures of liver parenchymal cells isolated from copper-deficient rats. Male Sprague-Dawley rats were fed a copper-deficient diet (less than 1 mg Cu/kg) for 10 wk. Copper-deficient rats were characterized by low copper concentrations in plasma and liver, anemia, low plasma ceruloplasmin oxidase activity and increased 64Cu whole-body retention. Freshly isolated liver parenchymal cells from copper-deficient rats showed a higher 64Cu influx, which was associated with a higher apparent Vmax of 45 {plus minus} 4 pmol Cu.mg protein-1.min-1 as compared with 30 {plus minus} 3 pmol Cu.mg protein-1.min-1 for cells isolated from copper-sufficientmore » rats. No significant difference in the apparent Km (approximately 30 mumol/L) was observed. Relative 64Cu efflux from cells from copper-deficient rats was significantly smaller than the efflux from cells from copper-sufficient rats after prelabeling as determined by 2-h efflux experiments. Analysis of the medium after efflux from cells from copper-deficient rats showed elevated protein-associated 64Cu, suggesting a higher incorporation of radioactive copper during metalloprotein synthesis. Effects of copper deficiency persist in primary cultures of parenchymal cells derived from copper-deficient rats, and short-term cultures of these cells offer a prospect for the study of cell biological aspects of the metabolic adaptation of the liver to copper deficiency.« less

Intracerebral transplants of primary muscle cells: a potential 'platform' for transgene expression in the brain

NASA Technical Reports Server (NTRS)

Jiao, S.; Schultz, E.; Wolff, J. A.

1992-01-01

After the transplantation of rat primary muscle cells into the caudate or cortex of recipient rats, the muscle cells were able to persist for at least 6 months. Muscle cells transfected with expression plasmids prior to transplantation were able to express reporter genes in the brains for at least 2 months. These results suggest that muscle cells might be a useful 'platform' for transgene expression in the brain.

Rat Sertoli cells acquire a beta-adrenergic response during primary culture.

PubMed Central

Kierszenbaum, A L; Spruill, W A; White, M G; Tres, L L; Perkins, J P

1985-01-01

Two-dimensional polyacrylamide gel electrophoresis and the radioligand (-)-[125I]iodopindolol (125I-Pin) have been used to study isoproterenol-dependent protein phosphorylation and beta-adrenergic receptor availability, respectively, in cultured Sertoli cells and freshly isolated seminiferous tubular segments of sexually immature and mature rats. Sertoli cells prepared from sexually immature rats show progressive 125I-Pin binding in primary cultures that correlates with isoproterenol-induced cell shape changes, redistribution of immunoreactive vimentin, and phosphorylation of this intermediate filament protein. The development of 125I-Pin binding to Sertoli cell lysates is blocked by cycloheximide. Seminiferous tubules do not show significant isoproterenol-dependent vimentin phosphorylation nor 125I-Pin binding. However, vimentin phosphorylation can be induced by follicle-stimulating hormone or a cyclic nucleotide analog. This study stresses the need for correlating pharmacological-induced responses observed in Sertoli cell primary cultures with those in the intact seminiferous tubule. Images PMID:2984678

Effects of Trichostatin A on drug uptake transporters in primary rat hepatocyte cultures

PubMed Central

Ramboer, Eva; Rogiers, Vera; Vanhaecke, Tamara; Vinken, Mathieu

2015-01-01

The present study was set up to investigate the effects of Trichostatin A (TSA), a prototypical epigenetic modifier, on the expression and activity of hepatic drug uptake transporters in primary cultured rat hepatocytes. To this end, the expression of the sinusoidal transporters sodium-dependent taurocholate cotransporting polypeptide (Ntcp) and organic anion transporting polypeptide 4 (Oatp4) was monitored by real-time quantitative reverse transcriptase polymerase chain reaction analysis and immunoblotting. The activity of the uptake transporters was analyzed using radiolabeled substrates and chemical inhibitors. Downregulation of the expression and activity of Oatp4 and Ntcp was observed as a function of the cultivation time and could not be counteracted by TSA. In conclusion, the epigenetic modifier TSA does not seem to exert a positive effect on the expression and activity of the investigated uptake transporters in primary rat hepatocyte cultures. PMID:26648816

Treatment of Partial Thickness Burns with a Novel Extracellular Matrix in Rats (Rattus norvegicus)

DTIC Science & Technology

2016-12-20

However, infections likely interfered with wound healing and prevented assessment of graft infiltration. A different animal model will be needed to...The primary outcome measure was wound area remaining after four weeks.Methods: Fifty male Sprague-Dawley rats were anesthetized. A 2-cm diameter...bandaging material were then applied to protect the wound and rats were housed on sterile bedding. The rats were examined and dressings changed at

Differentiated human midbrain-derived neural progenitor cells express excitatory strychnine-sensitive glycine receptors containing α2β subunits.

PubMed

Wegner, Florian; Kraft, Robert; Busse, Kathy; Härtig, Wolfgang; Ahrens, Jörg; Leffler, Andreas; Dengler, Reinhard; Schwarz, Johannes

2012-01-01

Human fetal midbrain-derived neural progenitor cells (NPCs) may deliver a tissue source for drug screening and regenerative cell therapy to treat Parkinson's disease. While glutamate and GABA(A) receptors play an important role in neurogenesis, the involvement of glycine receptors during human neurogenesis and dopaminergic differentiation as well as their molecular and functional characteristics in NPCs are largely unknown. Here we investigated NPCs in respect to their glycine receptor function and subunit expression using electrophysiology, calcium imaging, immunocytochemistry, and quantitative real-time PCR. Whole-cell recordings demonstrate the ability of NPCs to express functional strychnine-sensitive glycine receptors after differentiation for 3 weeks in vitro. Pharmacological and molecular analyses indicate a predominance of glycine receptor heteromers containing α2β subunits. Intracellular calcium measurements of differentiated NPCs suggest that glycine evokes depolarisations mediated by strychnine-sensitive glycine receptors and not by D-serine-sensitive excitatory glycine receptors. Culturing NPCs with additional glycine, the glycine-receptor antagonist strychnine, or the Na(+)-K(+)-Cl(-) co-transporter 1 (NKCC1)-inhibitor bumetanide did not significantly influence cell proliferation and differentiation in vitro. These data indicate that NPCs derived from human fetal midbrain tissue acquire essential glycine receptor properties during neuronal maturation. However, glycine receptors seem to have a limited functional impact on neurogenesis and dopaminergic differentiation of NPCs in vitro.

Differentiated Human Midbrain-Derived Neural Progenitor Cells Express Excitatory Strychnine-Sensitive Glycine Receptors Containing α2β Subunits

PubMed Central

Wegner, Florian; Kraft, Robert; Busse, Kathy; Härtig, Wolfgang; Ahrens, Jörg; Leffler, Andreas; Dengler, Reinhard; Schwarz, Johannes

2012-01-01

Background Human fetal midbrain-derived neural progenitor cells (NPCs) may deliver a tissue source for drug screening and regenerative cell therapy to treat Parkinson’s disease. While glutamate and GABAA receptors play an important role in neurogenesis, the involvement of glycine receptors during human neurogenesis and dopaminergic differentiation as well as their molecular and functional characteristics in NPCs are largely unknown. Methodology/Principal Findings Here we investigated NPCs in respect to their glycine receptor function and subunit expression using electrophysiology, calcium imaging, immunocytochemistry, and quantitative real-time PCR. Whole-cell recordings demonstrate the ability of NPCs to express functional strychnine-sensitive glycine receptors after differentiation for 3 weeks in vitro. Pharmacological and molecular analyses indicate a predominance of glycine receptor heteromers containing α2β subunits. Intracellular calcium measurements of differentiated NPCs suggest that glycine evokes depolarisations mediated by strychnine-sensitive glycine receptors and not by D-serine-sensitive excitatory glycine receptors. Culturing NPCs with additional glycine, the glycine-receptor antagonist strychnine, or the Na+-K+-Cl− co-transporter 1 (NKCC1)-inhibitor bumetanide did not significantly influence cell proliferation and differentiation in vitro. Conclusions/Significance These data indicate that NPCs derived from human fetal midbrain tissue acquire essential glycine receptor properties during neuronal maturation. However, glycine receptors seem to have a limited functional impact on neurogenesis and dopaminergic differentiation of NPCs in vitro. PMID:22606311

Oxytocin modulates hemodynamic responses to monetary incentives in humans

PubMed Central

Mickey, Brian J.; Heffernan, Joseph; Heisel, Curtis; Peciña, Marta; Hsu, David T.; Zubieta, Jon-Kar; Love, Tiffany M.

2016-01-01

Oxytocin is a neuropeptide widely recognized for its role in regulating social and reproductive behavior. Increasing evidence from animal models suggests that oxytocin also modulates reward circuitry in non-social contexts, but evidence in humans is lacking. Here we examined the effects of oxytocin administration on reward circuit function in 18 healthy men as they performed a monetary incentive task. The blood oxygenation level dependent (BOLD) signal was measured using functional magnetic resonance imaging in the context of a randomized, double-blind, placebo-controlled, crossover trial of intranasal oxytocin. We found that oxytocin increases the BOLD signal in the midbrain (substantia nigra and ventral tegmental area) during the late phase of the hemodynamic response to incentive stimuli. Oxytocin’s effects on midbrain responses correlated positively with its effects on positive emotional state. We did not detect an effect of oxytocin on responses in the nucleus accumbens. Whole-brain analyses revealed that oxytocin attenuated medial prefrontal cortical deactivation specifically during anticipation of loss. Our findings demonstrate that intranasal administration of oxytocin modulates human midbrain and medial prefrontal function during motivated behavior. These findings suggest that endogenous oxytocin is a neurochemical mediator of reward behaviors in humans – even in a non-social context – and that the oxytocinergic system is a potential target of pharmacotherapy for psychiatric disorders that involve dysfunction of reward circuitry. PMID:27614896

Perceptual load-dependent neural correlates of distractor interference inhibition.

PubMed

Xu, Jiansong; Monterosso, John; Kober, Hedy; Balodis, Iris M; Potenza, Marc N

2011-01-18

The load theory of selective attention hypothesizes that distractor interference is suppressed after perceptual processing (i.e., in the later stage of central processing) at low perceptual load of the central task, but in the early stage of perceptual processing at high perceptual load. Consistently, studies on the neural correlates of attention have found a smaller distractor-related activation in the sensory cortex at high relative to low perceptual load. However, it is not clear whether the distractor-related activation in brain regions linked to later stages of central processing (e.g., in the frontostriatal circuits) is also smaller at high rather than low perceptual load, as might be predicted based on the load theory. We studied 24 healthy participants using functional magnetic resonance imaging (fMRI) during a visual target identification task with two perceptual loads (low vs. high). Participants showed distractor-related increases in activation in the midbrain, striatum, occipital and medial and lateral prefrontal cortices at low load, but distractor-related decreases in activation in the midbrain ventral tegmental area and substantia nigra (VTA/SN), striatum, thalamus, and extensive sensory cortices at high load. Multiple levels of central processing involving midbrain and frontostriatal circuits participate in suppressing distractor interference at either low or high perceptual load. For suppressing distractor interference, the processing of sensory inputs in both early and late stages of central processing are enhanced at low load but inhibited at high load.

Rapid Effects of Hearing Song on Catecholaminergic Activity in the Songbird Auditory Pathway

PubMed Central

Matragrano, Lisa L.; Beaulieu, Michaël; Phillip, Jessica O.; Rae, Ali I.; Sanford, Sara E.; Sockman, Keith W.; Maney, Donna L.

2012-01-01

Catecholaminergic (CA) neurons innervate sensory areas and affect the processing of sensory signals. For example, in birds, CA fibers innervate the auditory pathway at each level, including the midbrain, thalamus, and forebrain. We have shown previously that in female European starlings, CA activity in the auditory forebrain can be enhanced by exposure to attractive male song for one week. It is not known, however, whether hearing song can initiate that activity more rapidly. Here, we exposed estrogen-primed, female white-throated sparrows to conspecific male song and looked for evidence of rapid synthesis of catecholamines in auditory areas. In one hemisphere of the brain, we used immunohistochemistry to detect the phosphorylation of tyrosine hydroxylase (TH), a rate-limiting enzyme in the CA synthetic pathway. We found that immunoreactivity for TH phosphorylated at serine 40 increased dramatically in the auditory forebrain, but not the auditory thalamus and midbrain, after 15 min of song exposure. In the other hemisphere, we used high pressure liquid chromatography to measure catecholamines and their metabolites. We found that two dopamine metabolites, dihydroxyphenylacetic acid and homovanillic acid, increased in the auditory forebrain but not the auditory midbrain after 30 min of exposure to conspecific song. Our results are consistent with the hypothesis that exposure to a behaviorally relevant auditory stimulus rapidly induces CA activity, which may play a role in auditory responses. PMID:22724011

Synaptic potentiation onto habenula neurons in the learned helplessness model of depression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, B.; Schulz, D.; Li, B

The cellular basis of depressive disorders is poorly understood. Recent studies in monkeys indicate that neurons in the lateral habenula (LHb), a nucleus that mediates communication between forebrain and midbrain structures, can increase their activity when an animal fails to receive an expected positive reward or receives a stimulus that predicts aversive conditions (that is, disappointment or anticipation of a negative outcome). LHb neurons project to, and modulate, dopamine-rich regions, such as the ventral tegmental area (VTA), that control reward-seeking behaviour and participate in depressive disorders. Here we show that in two learned helplessness models of depression, excitatory synapses ontomore » LHb neurons projecting to the VTA are potentiated. Synaptic potentiation correlates with an animal's helplessness behaviour and is due to an enhanced presynaptic release probability. Depleting transmitter release by repeated electrical stimulation of LHb afferents, using a protocol that can be effective for patients who are depressed, markedly suppresses synaptic drive onto VTA-projecting LHb neurons in brain slices and can significantly reduce learned helplessness behaviour in rats. Our results indicate that increased presynaptic action onto LHb neurons contributes to the rodent learned helplessness model of depression.« less

Complementary roles for amygdala and periaqueductal gray in temporal-difference fear learning.

PubMed

Cole, Sindy; McNally, Gavan P

2009-01-01

Pavlovian fear conditioning is not a unitary process. At the neurobiological level multiple brain regions and neurotransmitters contribute to fear learning. At the behavioral level many variables contribute to fear learning including the physical salience of the events being learned about, the direction and magnitude of predictive error, and the rate at which these are learned about. These experiments used a serial compound conditioning design to determine the roles of basolateral amygdala (BLA) NMDA receptors and ventrolateral midbrain periaqueductal gray (vlPAG) mu-opioid receptors (MOR) in predictive fear learning. Rats received a three-stage design, which arranged for both positive and negative prediction errors producing bidirectional changes in fear learning within the same subjects during the test stage. Intra-BLA infusion of the NR2B receptor antagonist Ifenprodil prevented all learning. In contrast, intra-vlPAG infusion of the MOR antagonist CTAP enhanced learning in response to positive predictive error but impaired learning in response to negative predictive error--a pattern similar to Hebbian learning and an indication that fear learning had been divorced from predictive error. These findings identify complementary but dissociable roles for amygdala NMDA receptors and vlPAG MOR in temporal-difference predictive fear learning.

Biology of GDNF and its receptors - Relevance for disorders of the central nervous system.

PubMed

Ibáñez, Carlos F; Andressoo, Jaan-Olle

2017-01-01

A targeted effort to identify novel neurotrophic factors for midbrain dopaminergic neurons resulted in the isolation of GDNF (glial cell line-derived neurotrophic factor) from the supernatant of a rat glial cell line in 1993. Over two decades and 1200 papers later, the GDNF ligand family and their different receptor systems are now recognized as one of the major neurotrophic networks in the nervous system, important for the development, maintenance and function of a variety of neurons and glial cells. The many ways in which the four members of the GDNF ligand family can signal and function allow these factors to take part in the control of multiple types of processes, from neuronal survival to axon guidance and synapse formation in the developing nervous system, to synaptic function and regenerative responses in the adult. In this review, we will briefly summarize basic aspects of GDNF signaling mechanisms and receptor systems and then review our current knowledge of the physiology of GDNF activities in the central nervous system, with an eye to its relevance for neurodegenerative and neuropsychiatric diseases. Copyright © 2016 Elsevier Inc. All rights reserved.

Lesions of the lateral habenula facilitate active avoidance learning and threat extinction.

PubMed

Song, Mihee; Jo, Yong Sang; Lee, Yeon-Kyung; Choi, June-Seek

2017-02-01

The lateral habenula (LHb) is an epithalamic brain structure that provides strong projections to midbrain monoaminergic systems that are involved in motivation, emotion, and reinforcement learning. LHb neurons are known to convey information about aversive outcomes and negative prediction errors, suggesting a role in learning from aversive events. To test this idea, we examined the effects of electrolytic lesions of the LHb on signaled two-way active avoidance learning in which rats were trained to avoid an unconditioned stimulus (US) by taking a proactive shuttling response to an auditory conditioned stimulus (CS). The lesioned animals learned the avoidance response significantly faster than the control groups. In a separate experiment, we also investigated whether the LHb contributes to Pavlovian threat (fear) conditioning and extinction. Following paired presentations of the CS and the US, LHb-lesioned animals showed normal acquisition of conditioned response (CR) measured with freezing. However, extinction of the CR in the subsequent CS-only session was significantly faster. The enhanced performance in avoidance learning and in threat extinction jointly suggests that the LHb normally plays an inhibitory role in learning driven by absence of aversive outcomes. Copyright © 2016 Elsevier B.V. All rights reserved.

Translational approach to the pathophysiology of panic disorder: Focus on serotonin and endogenous opioids.

PubMed

Graeff, Frederico G

2017-05-01

Panic patients experience recurrent panic attacks. Two main neurochemical hypotheses have been proposed to explain this vulnerability. The first suggests that panic patients have deficient serotonergic inhibition of neurons localized in the dorsal periaqueductal gray matter of the midbrain that organizes defensive reactions to cope with proximal threats as well as of sympathomotor control areas of the rostral ventrolateral medulla that generate neurovegetative symptoms of the panic attack. The second proposes that endogenous opioids buffer panic attacks in normal subjects, and their deficit results in heightened sensitivity to suffocation and separation anxiety in panic patients. Experimental results obtained in rat models of panic indicate that serotonin interacts synergistically with endogenous opioids in the dorsal periaqueductal gray through 5-HT1A and μ-opioid receptors to inhibit proximal defense and, supposedly, panic attacks. These findings allow reconciliation of the serotonergic and opioidergic hypotheses of panic pathophysiology. They also indicate that endogenous opioids are likely to participate in the panicolytic action of antidepressants and suggest that exogenous opioids may be useful for treating panic patients resistant to conventional pharmacotherapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

Progesterone from maternal circulation binds to progestin receptors in fetal brain.

PubMed

Wagner, Christine K; Quadros-Mennella, Princy

2017-06-01

Steroid hormones activate nuclear receptors which, as transcription factors, can regulate critical aspects of neural development. Many regions of the rat forebrain, midbrain and hindbrain express progestin receptors (PR) during perinatal life, suggesting that progesterone may play an important role in the development of the brain. An immunohistochemical approach using two antibodies with differential recognition of ligand-bound PR was used to examine whether fetuses are exposed to maternal progesterone during pregnancy and whether progesterone from maternal circulation can bind to PR within the fetal brain. Findings demonstrate that maternal and fetal serum progesterone levels are positively correlated at the end of gestation, suggesting a common source of progesterone in mothers and fetuses (e.g., the maternal ovary). Additional findings suggest that administration of exogenous progesterone to mothers not only increases fetal serum progesterone levels within 2 h, but appears to increase ligand-bound PR in fetal brain. These findings suggest that progesterone of maternal origin may play a previously overlooked role in neural development. In addition, there are implications for the ongoing prophylactic use of synthetic progestins in pregnant women for the prevention of premature birth. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 767-774, 2017. © 2016 Wiley Periodicals, Inc.

Synaptic potentiation onto habenula neurons in learned helplessness model of depression

PubMed Central

Li, Bo; Piriz, Joaquin; Mirrione, Martine; Chung, ChiHye; Proulx, Christophe D.; Schulz, Daniela; Henn, Fritz; Malinow, Roberto

2010-01-01

The cellular basis of depressive disorders is poorly understood1. Recent studies in monkeys indicate that neurons in the lateral habenula (LHb), a nucleus that mediates communication between forebrain and midbrain structures, can increase their activity when an animal fails to receive an expected positive reward or receives a stimulus that predicts aversive conditions (i.e. disappointment or anticipation of a negative outcome)2, 3, 4. LHb neurons project to and modulate dopamine-rich regions such as the ventral-tegmental area (VTA)2, 5 that control reward-seeking behavior6 and participate in depressive disorders7. Here we show in two learned helplessness models of depression that excitatory synapses onto LHb neurons projecting to the VTA are potentiated. Synaptic potentiation correlates with an animal’s helplessness behavior and is due to an enhanced presynaptic release probability. Depleting transmitter release by repeated electrical stimulation of LHb afferents, using a protocol that can be effective on depressed patients8, 9, dramatically suppresses synaptic drive onto VTA-projecting LHb neurons in brain slices and can significantly reduce learned helplessness behavior in rats. Our results indicate that increased presynaptic action onto LHb neurons contributes to the rodent learned helplessness model of depression. PMID:21350486

Synaptic potentiation onto habenula neurons in the learned helplessness model of depression.

PubMed

Li, Bo; Piriz, Joaquin; Mirrione, Martine; Chung, ChiHye; Proulx, Christophe D; Schulz, Daniela; Henn, Fritz; Malinow, Roberto

2011-02-24

The cellular basis of depressive disorders is poorly understood. Recent studies in monkeys indicate that neurons in the lateral habenula (LHb), a nucleus that mediates communication between forebrain and midbrain structures, can increase their activity when an animal fails to receive an expected positive reward or receives a stimulus that predicts aversive conditions (that is, disappointment or anticipation of a negative outcome). LHb neurons project to, and modulate, dopamine-rich regions, such as the ventral tegmental area (VTA), that control reward-seeking behaviour and participate in depressive disorders. Here we show that in two learned helplessness models of depression, excitatory synapses onto LHb neurons projecting to the VTA are potentiated. Synaptic potentiation correlates with an animal's helplessness behaviour and is due to an enhanced presynaptic release probability. Depleting transmitter release by repeated electrical stimulation of LHb afferents, using a protocol that can be effective for patients who are depressed, markedly suppresses synaptic drive onto VTA-projecting LHb neurons in brain slices and can significantly reduce learned helplessness behaviour in rats. Our results indicate that increased presynaptic action onto LHb neurons contributes to the rodent learned helplessness model of depression.

Accurate counting of neurons in frozen sections: some necessary precautions.

PubMed Central

Cooper, J D; Payne, J N; Horobin, R W

1988-01-01

In 30 microns frozen sections of rat midbrain the retrograde axonal transport of diamidino yellow, a fluorescent tracer, was used to demonstrate a population of neurons in the substantia nigra. However, when visualisation was carried out using the routine Nissl method a significant proportion of neurons failed to stain. As the presence of the retrograde tracer did not affect Nissl staining of such cells, such incomplete staining, with consequent underestimation of neuronal populations, is probably a common error in similar material. Further investigation revealed that the proportion of such unstained neurons was greater when the staining time was short, when stain concentration was low, or when section thickness was increased. Some stains were worse in this respect than others. Cresyl fast violet resulted in the highest proportion of unstained neurons, thionin resulted in the lowest proportion. It was concluded that the rate of diffusion of the stain into the section was the main factor limiting the staining of neurons present. Staining with pure thionin at 0.1% concentration for at least 3 minutes and with sections no thicker than 30 microns is one regime which would avoid this problem. Images Fig. 1 PMID:2461923

Beta-cell metabolic alterations under chronic nutrient overload in rat and human islets

USDA-ARS?s Scientific Manuscript database

The aim of this study was to assess multifactorial Beta-cell responses to metabolic perturbations in primary rat and human islets. Treatment of dispersed rat islet cells with elevated glucose and free fatty acids (FFAs, oleate:palmitate = 1:1 v/v) resulted in increases in the size and the number of ...

Effects and mechanisms of Shaofu-Zhuyu decoction and its major bioactive component for Cold - Stagnation and Blood - Stasis primary dysmenorrhea rats.

PubMed

Huang, Xiaochen; Su, Shulan; Duan, Jin-Ao; Sha, Xiuxiu; Zhu, Kavin Yue; Guo, Jianming; Yu, Li; Liu, Pei; Shang, Erxin; Qian, Dawei

2016-06-20

Traditional Chinese medicine (TCM) is used under the guidance of the theory of traditional Chinese medical sciences in clinical application. The Chinese herbal formula, Shaofu Zhuyu decoction (SFZYD), is considered as an effective prescription for treating Cold - Stagnation and Blood - Stasis (CSBS) primary dysmenorrhea. The previous studies showed the SFZYD exhibited significant anti-inflammation and analgesic effect. In this present study the metabolomics of CSBS primary dysmenorrhea diseased rats and the cytokine transcription in PHA stimulated-PBMC were investigated to explore the effects and mechanisms. Explore a valuable insight into the effects and mechanisms of SFZYD on Cold - Stagnation and Blood - Stasis primary dysmenorrhea rats. We established CSBS primary dysmenorrhea diseased rats according the clinical symptoms. A targeted tandem mass spectrometry (MS/MS)-based metabolomic platform was used to evaluate the metabolic profiling changes and the intervention effects by SFZYD. The PBMC cell was adopted to explore the mechanisms by analyzing the signaling pathway evaluated by expression of inflammatory cytokines, c-jun and c-fos and corresponding phosphorylation levels. Estradiol, oxytocin, progesterone, endothelin, β-endorphin and PGF2α were restored back to the normal level after the treatment of SFZYD. Total twenty-five metabolites (10 in plasma and 15 in urine), up-regulated or down-regulated, were identified. These identified biomarkers underpinning the metabolic pathway including pentose and glucuronate interconversions, steroid hormone biosynthesis, and glycerophospholipid metabolism are disturbed in model rats. Among these metabolites, twenty one potential biomarkers were regulated after SFZYD treated. The compound of paeoniflorin, a major bioactive compound in SFZYD, was proved to regulate the MAPK signaling pathway by inhibiting the expression of IL-1β, IL-2, IL-10, IL-12, TNFα, INFγ, c-jun and c-fos in PHA stimulated-PBMC. These findings indicated that SFZYD improved the metabolic profiling and biochemical indicators on CSBS primary dysmenorrhea rats. And the mechanisms were closely related with the regulation of the MAPK pathway by reduction in phosphorylated forms of the three MAPK (ERK1/2, p38 and JNK) and down regulation of c-jun and c-fos by paeoniflorin. The data could be provided the guidance for further research and new drug discovery. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The lifelong maintenance of mesencephalic dopaminergic neurons by Nurr1 and engrailed

PubMed Central

2014-01-01

Specific vulnerability and degeneration of the dopaminergic neurons in the substantia nigra pars compacta of the midbrain is the pathological hallmark of Parkinson’s disease. A number of transcription factors regulate the birth and development of this set of neurons and some remain constitutively expressed throughout life. These maintenance transcription factors are closely associated with essential neurophysiological functions and are required ultimately for the long-term survival of the midbrain dopaminergic neurons. The current review describes the role of two such factors, Nurr1 and engrailed, in differentiation, maturation, and in normal physiological functions including acquisition of neurotransmitter identity. The review will also elucidate the relationship of these factors with life, vulnerability, degeneration and death of mesencephalic dopaminergic neurons in the context of Parkinson’s disease. PMID:24685177

RMND5 from Xenopus laevis is an E3 ubiquitin-ligase and functions in early embryonic forebrain development.

PubMed

Pfirrmann, Thorsten; Villavicencio-Lorini, Pablo; Subudhi, Abinash K; Menssen, Ruth; Wolf, Dieter H; Hollemann, Thomas

2015-01-01

In Saccharomyces cerevisiae the Gid-complex functions as an ubiquitin-ligase complex that regulates the metabolic switch between glycolysis and gluconeogenesis. In higher organisms six conserved Gid proteins form the CTLH protein-complex with unknown function. Here we show that Rmnd5, the Gid2 orthologue from Xenopus laevis, is an ubiquitin-ligase embedded in a high molecular weight complex. Expression of rmnd5 is strongest in neuronal ectoderm, prospective brain, eyes and ciliated cells of the skin and its suppression results in malformations of the fore- and midbrain. We therefore suggest that Xenopus laevis Rmnd5, as a subunit of the CTLH complex, is a ubiquitin-ligase targeting an unknown factor for polyubiquitination and subsequent proteasomal degradation for proper fore- and midbrain development.

Understanding dopamine and reinforcement learning: the dopamine reward prediction error hypothesis.

PubMed

Glimcher, Paul W

2011-09-13

A number of recent advances have been achieved in the study of midbrain dopaminergic neurons. Understanding these advances and how they relate to one another requires a deep understanding of the computational models that serve as an explanatory framework and guide ongoing experimental inquiry. This intertwining of theory and experiment now suggests very clearly that the phasic activity of the midbrain dopamine neurons provides a global mechanism for synaptic modification. These synaptic modifications, in turn, provide the mechanistic underpinning for a specific class of reinforcement learning mechanisms that now seem to underlie much of human and animal behavior. This review describes both the critical empirical findings that are at the root of this conclusion and the fantastic theoretical advances from which this conclusion is drawn.

Understanding dopamine and reinforcement learning: The dopamine reward prediction error hypothesis

PubMed Central

Glimcher, Paul W.

2011-01-01

A number of recent advances have been achieved in the study of midbrain dopaminergic neurons. Understanding these advances and how they relate to one another requires a deep understanding of the computational models that serve as an explanatory framework and guide ongoing experimental inquiry. This intertwining of theory and experiment now suggests very clearly that the phasic activity of the midbrain dopamine neurons provides a global mechanism for synaptic modification. These synaptic modifications, in turn, provide the mechanistic underpinning for a specific class of reinforcement learning mechanisms that now seem to underlie much of human and animal behavior. This review describes both the critical empirical findings that are at the root of this conclusion and the fantastic theoretical advances from which this conclusion is drawn. PMID:21389268

Reverse Transcriptase-Containing Particles Induced in Rous Sarcoma Virus-Transformed Rat Cells by Arginine Deprivation

PubMed Central

Kotler, Moshe; Weinberg, Eynat; Haspel, Osnat; Becker, Yechiel

1972-01-01

Incubation of rat cells transformed by Rous sarcoma virus (RSV) in an arginine-deficient medium resulted in accumulation of particles in the culture medium. Such particles did not appear when the transformed rat cells were incubated in a complete medium nor in the medium of primary rat cells which were incubated either in arginine-deficient or complete media. The particles which were released from the arginine-deprived transformed rat cells resemble C-type particles in their properties. These particles band in sucrose gradients at a density of 1.16 g/ml and contain 35S ribonucleic acid (RNA) molecules and a reverse transcriptase activity. Analysis of the cytoplasm of transformed and primary rat cells, deprived and undeprived of arginine, revealed the presence of reverse transcriptase-containing particles which banded in sucrose gradients at a density of 1.14 g/ml. These particles differed from the particles released into the medium by the arginine-deprived RSV-transformed rat cells. The deoxyribonucleic acid (DNA) molecules synthesized in vitro by the reverse transcriptase present in the particles isolated from the medium of arginine-deprived cells hybridized to RSV RNA, whereas the DNA synthesized by the cell-bound enzyme had no homology to RSV RNA. PMID:4116137

Comparison of pharyngocutaneous fistula closure with and without bacterial cellulose in a rat model.

PubMed

Demir, Berat; Sarı, Murat; Binnetoglu, Adem; Yumusakhuylu, Ali Cemal; Filinte, Deniz; Tekin, İshak Özel; Bağlam, Tekin; Batman, Abdullah Çağlar

2018-04-01

The present study aimed to compare the effects of bacterial cellulose used for closure of pharyngocutaneous fistulae, a complication of total laryngectomy, with those of primary sutures in a rat model. Thirty female Sprague-Dawley underwent experimental pharyngoesophagotomy and were grouped depending on the material used for pharyngocutaneous fistula closure: group I, which received primary sutures alone, group II, which received bacterial cellulose alone; and group III, which received both. After 7 days, the rats were sacrificed. Pharyngocutaneous fistula development was assessed, the gross wound was inspected, and histological examination was conducted. Pharyngocutaneous fistulae developed in 12 rats (41%) in all: 6 from group I (21%), 4 from group II (14%) and 2 from group III (7%). Fibroblast density and inflammatory cell infiltration were significantly greater in group III than group I. We concluded that bacterial cellulose may be useful for pharyngocutaneous fistula closure. Copyright © 2017 Elsevier B.V. All rights reserved.

Functional characterization of apical transporters expressed in rat proximal tubular cells (PTCs) in primary culture.

PubMed

Nakanishi, Takeo; Fukushi, Akimasa; Sato, Masanobu; Yoshifuji, Mayuko; Gose, Tomoka; Shirasaka, Yoshiyuki; Ohe, Kazuyo; Kobayashi, Masato; Kawai, Keiichi; Tamai, Ikumi

2011-12-05

Since in vitro cell culture models often show altered apical transporter expression, they are not necessarily suitable for the analysis of renal transport processes. Therefore, we aimed here to investigate the usefulness of primary-cultured rat proximal tubular cells (PTCs) for this purpose. After isolation of renal cortical cells from rat kidneys, PTCs were enriched and the gene expression and function of apical transporters were analyzed by means of microarray, RT-PCR and uptake experiments. RT-PCR confirmed that the major apical transporters were expressed in rat PTCs. Na(+)-dependent uptake of α-methyl-d-glucopyranoside (αMG), ergothioneine and carnitine by the PTCs suggests functional expression of Sglts, Octn1 and Octn2, respectively. Inhibition of pH-dependent glycylsarcosine uptake by low concentration of cephalexin, which is a β-lactam antibiotics recognized by Pepts, indicates a predominant role of high affinity type Pept2, but not low affinity type Pept1, in the PTCs. Moreover, the permeability ratio of [(14)C]αMG (apical to basolateral/basolateral to apical) across PTCs was 4.3, suggesting that Sglt-mediated reabsorptive transport is characterized. In conclusion, our results indicate that rat PTCs in primary culture are found to be a promising in vitro model to evaluate reabsorption processes mediated at least by Sglts, Pept2, Octn1 and Octn2.

Anti-tumor response induced by immunologically modified carbon nanotubes and laser irradiation using rat mammary tumor model

NASA Astrophysics Data System (ADS)

Acquaviva, Joseph T.; Hasanjee, Aamr M.; Bahavar, Cody F.; Zhou, Fefian; Liu, Hong; Howard, Eric W.; Bullen, Liz C.; Silvy, Ricardo P.; Chen, Wei R.

2015-03-01

Laser immunotherapy (LIT) is being developed as a treatment modality for metastatic cancer which can destroy primary tumors and induce effective systemic anti-tumor responses by using a targeted treatment approach in conjunction with the use of a novel immunoadjuvant, glycated chitosan (GC). In this study, Non-invasive Laser Immunotherapy (NLIT) was used as the primary treatment mode. We incorporated single-walled carbon nanotubes (SWNTs) into the treatment regimen to boost the tumor-killing effect of LIT. SWNTs and GC were conjugated to create a completely novel, immunologically modified carbon nanotube (SWNT-GC). To determine the efficacy of different laser irradiation durations, 5 minutes or 10 minutes, a series of experiments were performed. Rats were inoculated with DMBA-4 cancer cells, a highly aggressive metastatic cancer cell line. Half of the treatment group of rats receiving laser irradiation for 10 minutes survived without primary or metastatic tumors. The treatment group of rats receiving laser irradiation for 5 minutes had no survivors. Thus, Laser+SWNT-GC treatment with 10 minutes of laser irradiation proved to be effective at reducing tumor size and inducing long-term anti-tumor immunity.

Unilateral nasal obstruction affects motor representation development within the face primary motor cortex in growing rats.

PubMed

Abe, Yasunori; Kato, Chiho; Uchima Koecklin, Karin Harumi; Okihara, Hidemasa; Ishida, Takayoshi; Fujita, Koichi; Yabushita, Tadachika; Kokai, Satoshi; Ono, Takashi

2017-06-01

Postnatal growth is influenced by genetic and environmental factors. Nasal obstruction during growth alters the electromyographic activity of orofacial muscles. The facial primary motor area represents muscles of the tongue and jaw, which are essential in regulating orofacial motor functions, including chewing and jaw opening. This study aimed to evaluate the effect of chronic unilateral nasal obstruction during growth on the motor representations within the face primary motor cortex (M1). Seventy-two 6-day-old male Wistar rats were randomly divided into control ( n = 36) and experimental ( n = 36) groups. Rats in the experimental group underwent unilateral nasal obstruction after cauterization of the external nostril at 8 days of age. Intracortical microstimulation (ICMS) mapping was performed when the rats were 5, 7, 9, and 11 wk old in control and experimental groups ( n = 9 per group per time point). Repeated-measures multivariate ANOVA was used for intergroup and intragroup statistical comparisons. In the control and experimental groups, the total number of positive ICMS sites for the genioglossus and anterior digastric muscles was significantly higher at 5, 7, and 9 wk, but there was no significant difference between 9 and 11 wk of age. Moreover, the total number of positive ICMS sites was significantly smaller in the experimental group than in the control at each age. It is possible that nasal obstruction induced the initial changes in orofacial motor behavior in response to the altered respiratory pattern, which eventually contributed to face-M1 neuroplasticity. NEW & NOTEWORTHY Unilateral nasal obstruction in rats during growth periods induced changes in arterial oxygen saturation (SpO 2 ) and altered development of the motor representation within the face primary cortex. Unilateral nasal obstruction occurring during growth periods may greatly affect not only respiratory function but also craniofacial function in rats. Nasal obstruction should be treated as soon as possible to avoid adverse effects on normal growth, development, and physiological functions. Copyright © 2017 the American Physiological Society.

Exploring human disease using the Rat Genome Database.

PubMed

Shimoyama, Mary; Laulederkind, Stanley J F; De Pons, Jeff; Nigam, Rajni; Smith, Jennifer R; Tutaj, Marek; Petri, Victoria; Hayman, G Thomas; Wang, Shur-Jen; Ghiasvand, Omid; Thota, Jyothi; Dwinell, Melinda R

2016-10-01

Rattus norvegicus, the laboratory rat, has been a crucial model for studies of the environmental and genetic factors associated with human diseases for over 150 years. It is the primary model organism for toxicology and pharmacology studies, and has features that make it the model of choice in many complex-disease studies. Since 1999, the Rat Genome Database (RGD; http://rgd.mcw.edu) has been the premier resource for genomic, genetic, phenotype and strain data for the laboratory rat. The primary role of RGD is to curate rat data and validate orthologous relationships with human and mouse genes, and make these data available for incorporation into other major databases such as NCBI, Ensembl and UniProt. RGD also provides official nomenclature for rat genes, quantitative trait loci, strains and genetic markers, as well as unique identifiers. The RGD team adds enormous value to these basic data elements through functional and disease annotations, the analysis and visual presentation of pathways, and the integration of phenotype measurement data for strains used as disease models. Because much of the rat research community focuses on understanding human diseases, RGD provides a number of datasets and software tools that allow users to easily explore and make disease-related connections among these datasets. RGD also provides comprehensive human and mouse data for comparative purposes, illustrating the value of the rat in translational research. This article introduces RGD and its suite of tools and datasets to researchers - within and beyond the rat community - who are particularly interested in leveraging rat-based insights to understand human diseases. © 2016. Published by The Company of Biologists Ltd.

Long-term neuroplasticity of the face primary motor cortex and adjacent somatosensory cortex induced by tooth loss can be reversed following dental implant replacement in rats.

PubMed

Avivi-Arber, Limor; Lee, Jye-Chang; Sood, Mandeep; Lakschevitz, Flavia; Fung, Michelle; Barashi-Gozal, Maayan; Glogauer, Michael; Sessle, Barry J

2015-11-01

Tooth loss is common, and exploring the neuroplastic capacity of the face primary motor cortex (face-M1) and adjacent primary somatosensory cortex (face-S1) is crucial for understanding how subjects adapt to tooth loss and their prosthetic replacement. The aim was to test if functional reorganization of jaw and tongue motor representations in the rat face-M1 and face-S1 occurs following tooth extraction, and if subsequent dental implant placement can reverse this neuroplasticity. Rats (n = 22) had the right maxillary molar teeth extracted under local and general anesthesia. One month later, seven rats had dental implant placement into healed extraction sites. Naive rats (n = 8) received no surgical treatment. Intracortical microstimulation (ICMS) and recording of evoked jaw and tongue electromyographic responses were used to define jaw and tongue motor representations at 1 month (n = 8) or 2 months (n = 7) postextraction, 1 month postimplant placement, and at 1-2 months in naive rats. There were no significant differences across study groups in the onset latencies of the ICMS-evoked responses (P > 0.05), but in comparison with naive rats, tooth extraction caused a significant (P < 0.05) and sustained (1-2 months) decreased number of ICMS-defined jaw and tongue sites within face-M1 and -S1, and increased thresholds of ICMS-evoked responses in these sites. Furthermore, dental implant placement reversed the extraction-induced changes in face-S1, and in face-M1 the number of jaw sites even increased as compared to naive rats. These novel findings suggest that face-M1 and adjacent face-S1 may play a role in adaptive mechanisms related to tooth loss and their replacement with dental implants. © 2015 Wiley Periodicals, Inc.

Evaluating the anti-fertility potential of α-chlorohydrin on testis and spermatozoa in the adult male wild Indian house rat (Rattus rattus).

PubMed

Madhu, Nithar Ranjan; Sarkar, Bhanumati; Biswas, Surjyo Jyoti; Behera, Biplab Kumar; Patra, Ashis

2011-01-01

To examine the effects of α-chlorohydrin on testis and cauda epididymis in the male house rat (Rattus rattus), 24 adult male rats were segregated into two groups. Group I rats were force-fed daily by intragastric intubation with α-chlorohydrin at a single dose of 1.0 mg/100 g body weight/d for 5, 15, and 45 days. Another group was fed with distilled water, which served as the control. The treated male rats were paired with 24 adult proestrus female rats for 5 days after the last oral treatment and fertility was tested. At the end of the experiments, all of the male rats were weighed and killed by cervical dislocation. The right testes were removed, weighed, and processed for ultrastructural changes of spermatozoa from the cauda epididymis and testis under scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The seminiferous tubular area, nuclear diameter of the Sertoli and Leydig cells, percentage of spermatogonia, primary spermatocytes, secondary spermatocytes, spermatids, spermatozoa, and Sertoli cells in each group were compared morphometrically. Our results showed that the percentages of primary spermatocytes steadily increased from 5 to 15 days, but primary and secondary spermatocytes decreased significantly at 45 days. There was a steady decline in the percentages of spermatozoa and spermatids at all fixation intervals in the treated animals, but the percentages of spermatogonia and Sertoli cells increased significantly at 15 and 45 days. Seminiferous tubular areas, nuclear diameter of Leydig and Sertoli cells, and fertility rates were reduced after 45 days of treatment. SEM and TEM studies revealed severe morphological abnormalities in the spermatozoa, including deglutination of the acrosomal part, loss of head capsules, and fragmentation of tail fibrils. There was an enhanced anti-fertility effect and a lower number of implantation sites in the rats treated for 5 days. Our results validate α-chlorohydrin as a successful anti-fertility agent that prevents spermatogenesis.

Spontaneous Trigeminal Allodynia in Rats: A Model of Primary Headache

PubMed Central

Oshinsky, Michael L.; Sanghvi, Menka M.; Maxwell, Christina R.; Gonzalez, Dorian; Spangenberg, Rebecca J.; Cooper, Marnie; Silberstein, Stephen D.

2014-01-01

Animal models are essential for studying the pathophysiology of headache disorders and as a screening tool for new therapies. Most animal models modify a normal animal in an attempt to mimic migraine symptoms. They require manipulation to activate the trigeminal nerve or dural nociceptors. At best, they are models of secondary headache. No existing model can address the fundamental question: How is a primary headache spontaneously initiated? In the process of obtaining baseline periorbital von Frey thresholds in a wild-type Sprague-Dawley rat, we discovered a rat with spontaneous episodic trigeminal allodynia (manifested by episodically changing periorbital pain threshold). Subsequent mating showed that the trait is inherited. Animals with spontaneous trigeminal allodynia allow us to study the pathophysiology of primary recurrent headache disorders. To validate this as a model for migraine, we tested the effects of clinically proven acute and preventive migraine treatments on spontaneous changes in rat periorbital sensitivity. Sumatriptan, ketorolac, and dihydroergotamine temporarily reversed the low periorbital pain thresholds. Thirty days of chronic valproic acid treatment prevented spontaneous changes in trigeminal allodynia. After discontinuation, the rats returned to their baseline of spontaneous episodic threshold changes. We also tested the effects of known chemical human migraine triggers. On days when the rats did not have allodynia and showed normal periorbital von Frey thresholds, glycerol trinitrate and calcitonin gene related peptide induced significant decreases in the periorbital pain threshold. This model can be used as a predictive model for drug development and for studies of putative biomarkers for headache diagnosis and treatment. PMID:22963523

Extended cocaine-seeking produces a shift from goal-directed to habitual responding in rats.

PubMed

Leong, Kah-Chung; Berini, Carole R; Ghee, Shannon M; Reichel, Carmela M

2016-10-01

Cocaine addiction is often characterized by a rigid pattern of behavior in which cocaine users continue seeking and taking drug despite negative consequences associated with its use. As such, full acquisition and relapse of drug-seeking behavior may be attributed to a shift away from goal-directed responding and a shift towards the maladaptive formation of rigid and habit-like responses. This rigid nature of habitual responding can be developed with extended training and is typically characterized by insensitivity to changes in outcome value. The present study determined whether cocaine (primary reinforcer) and cocaine associated cues (secondary reinforcer) could be devalued in rats with different histories of cocaine self-administration. Specifically, rats were trained on two schedules of cocaine self-administration (long-access vs. short-access). Following training the cocaine reinforcer was devalued through three separate pairings of lithium chloride with cocaine infusions. Cocaine history did not have an impact on devaluation of cocaine-associated cues. However, the reinforcing properties of cocaine were devalued only in rats on a short-access cocaine schedule but not those trained on a long-access schedule. Taken together this pattern of findings suggests that, in short access rats, devaluation is specific to the primary reinforcer and not associative stimuli such as cues. Importantly, rats that received extended training during self-administration displayed insensitivity to outcome devaluation of the primary reinforcer as well as all associative stimuli, thus displaying rigid behavioral responding similar to behavioral patterns found in addiction. Alternatively, long access cocaine exposure may have altered the devaluation threshold. Copyright © 2016 Elsevier Inc. All rights reserved.

Traditional Chinese medicine for the treatment of primary dysmenorrhea: how do Yuanhu painkillers effectively treat dysmenorrhea?

PubMed

Chen, Yuetao; Cao, Yu; Xie, Yanhua; Zhang, Xiaokai; Yang, Qian; Li, Xiaoqian; Sun, Jiyuan; Qiu, Pengcheng; Cao, Wei; Wang, Siwang

2013-09-15

To examine the efficacy of YuanHu painkillers (YHP) as a treatment for primary dysmenorrhea and to reveal YHP's principle formula. A Wistar rat uterine contraction model was utilized in this study. Rats were given 0.698g/kg YHP, 0.07g/kg tetrahydropalmatine (THP; YHP's main component), 0.02g/kg imperatorin (IMP), or THP+IMP (0.07+0.02g/kg) as polypharmacy (PG) by gavage. H&E staining and histopathological examination of the uteri tissue samples were performed. We then detected superoxide dismutase (SOD) and malondialdehyde (MDA), nitric oxide (NO), as well as inducible nitric oxide synthase (iNOS), i-κB, nuclear factor-κB (NF-κB), and cyclooxygenase-2 (COX-2) indices. PG significantly inhibited the uterine contraction of the primary dysmenorrhea rat model (p<0.05), and was significantly different than single-agent therapy (p<0.05). Histopathological examination showed inflammation in the uteri of the control group which YHP and its main constitutes alleviated. THP significantly inhibited the contraction of isolated uteri caused by Ach, PGF2α and oxytocin in a concentration-dependent fashion. THP and IMP both significantly affected the levels of NO, activation of NF-κB, up-regulated the expression of i-κB and down-regulated the expression of both iNOS and COX-2. IMP obviously decreased the level of MDA and increased the activation of SOD (p<0.05). PG obviously improved all the parameters mentioned above (p<0.05). YHP exerted protective effects on primary dysmenorrhea in rats and remarkably alleviated the severity of experimental primary dysmenorrhea. The combined strategy proved to be more effective than either THP or IMP alone and may have synergistic effects in combination in primary dysmenorrhea. Mechanisms that might account for the beneficial effects include abating oxidative stress, inhibiting over-inflammatory reaction, and alleviating the contraction of isolated rat uteri by inhibiting the influx of extracellular Ca(2+). Broad potential for future clinical practice is foreseeable. Copyright © 2013 Elsevier GmbH. All rights reserved.

Comparative study of the primary cilia in thyrocytes of adult mammals

PubMed Central

Utrilla, J C; Gordillo-Martínez, F; Gómez-Pascual, A; Fernández-Santos, J M; Garnacho, C; Vázquez-Román, V; Morillo-Bernal, J; García-Marín, R; Jiménez-García, A; Martín-Lacave, I

2015-01-01

Since their discovery in different human tissues by Zimmermann in 1898, primary cilia have been found in the vast majority of cell types in vertebrates. Primary cilia are considered to be cellular antennae that occupy an ideal cellular location for the interpretation of information both from the environment and from other cells. To date, in mammalian thyroid gland, primary cilia have been found in the thyrocytes of humans and dogs (fetuses and adults) and in rat embryos. The present study investigated whether the existence of this organelle in follicular cells is a general event in the postnatal thyroid gland of different mammals, using both immunolabeling by immunofluorescence and electron microscopy. Furthermore, we aimed to analyse the presence of primary cilia in various thyroid cell lines. According to our results, primary cilia are present in the adult thyroid gland of most mammal species we studied (human, pig, guinea pig and rabbit), usually as a single copy per follicular cell. Strikingly, they were not found in rat or mouse thyroid tissues. Similarly, cilia were also observed in all human thyroid cell lines tested, both normal and neoplastic follicular cells, but not in cultured thyrocytes of rat origin. We hypothesize that primary cilia could be involved in the regulation of normal thyroid function through specific signaling pathways. Nevertheless, further studies are needed to shed light on the permanence of these organelles in the thyroid gland of most species during postnatal life. PMID:26228270

Electrolytic lesion of the nucleus raphe magnus reduced the antinociceptive effects of bilateral morphine microinjected into the nucleus cuneiformis in rats.

PubMed

Haghparast, Abbas; Ordikhani-Seyedlar, Mehdi; Ziaei, Maryam

2008-06-27

Several lines of investigation show that the rostral ventromedial medulla is a critical relay for midbrain regions, including the nucleus cuneiformis (CnF), which control nociception at the spinal cord. There is some evidence that local stimulation or morphine administration into the CnF produces the effective analgesia through the nucleus raphe magnus (NRM). The present study tries to determine the effect of morphine-induced analgesia following microinjection into the CnF in the absence of NRM. Seven days after the cannulae implantation, morphine was microinjected bilaterally into the CnF at the doses of 0.25, 1, 2.5, 5, 7.5 and 10 microg/0.3 microl saline per side. The morphine-induced antinociceptive effect measured by tail-flick test at 30, 60, 90 and 120 min after microinjection. The results showed that bilateral microinjection of morphine into the CnF dose-dependently causes increase in tail-flick latency (TFL). The 50% effective dose of morphine was determined and microinjected into the CnF (2.5 microg/0.3 microl saline per side) in rats after NRM electrolytic lesion (1 mA, 30 s). Lesion of the NRM significantly decreased TFLs, 30 (P<0.01) and 60 (P<0.05) but not 90-120 min after morphine microinjection into the CnF, compared with sham-lesion group. We concluded that morphine induces the analgesic effects through the opioid receptors in the CnF. It is also appeared that morphine-induced antinociception decreases following the NRM lesion but it seems that there are some other descending pain modulatory pathways that activate in the absence of NRM.

Periaqueductal gray glutamatergic, cannabinoid and vanilloid receptor interplay in defensive behavior and aversive memory formation.

PubMed

Back, Franklin P; Carobrez, Antonio P

2018-06-01

Stimulation of the midbrain periaqueductal gray matter (PAG) in humans elicits sensations of fear and impending terror, and mediates predator defensive responses in rodents. In rats, pharmacological stimulation of the dorsolateral portion of the PAG (dlPAG) with N-Methyl-d-Aspartate (NMDA) induces aversive conditioning that acts as an unconditioned stimulus (US). In the present work, we investigated the interplay between the vanilloid TRPV1 and cannabinoid CB1 receptors in the NMDA-dlPAG defensive response and in subsequent aversive learning. Rats were subjected to dlPAG NMDA infusion in an olfactory conditioned stimulus (CS) task allowing the evaluation of immediate and long-term defensive behavioral responses during CS presentation. The results indicated that an intermediate dose of NMDA (50 pmol) induced both immediate and long-term effects. A sub-effective dose of NMDA (25 pmol) was potentiated by the TRPV1 receptor agonist capsaicin (CAP, 1 nmol) and the CB1 receptor antagonist, AM251 (200 pmol). CAP (10 nmol) or the combination of CAP (1 nmol) and AM251 (200 pmol) induced long-term effects without increasing immediate defensive responses. The glutamate release inhibitor riluzole (2 or 4 nmol) and the AMPA/kainate receptor antagonist DNQX (2 or 4 nmol) potentiated the immediate effects but blocked the long-term effects. The results showed that immediate defensive responses rely on NMDA receptors, and aversive learning on the fine-tuning of TRPV1, CB1, metabotropic glutamate and AMPA receptors located in pre- and postsynaptic membranes. In conclusion, the activity of the dlPAG determines core affective aspects of aversive memory formation controlled by local TRPV1/CB1 balance. Copyright © 2018 Elsevier Ltd. All rights reserved.

β-Caryophyllene, a phytocannabinoid attenuates oxidative stress, neuroinflammation, glial activation, and salvages dopaminergic neurons in a rat model of Parkinson disease.

PubMed

Ojha, Shreesh; Javed, Hayate; Azimullah, Sheikh; Haque, M Emdadul

2016-07-01

Parkinson disease (PD) is a neurodegenerative disease characterized by progressive dopaminergic neurodegeneration in the substantia nigra pars compacta (SNc) area. The present study was undertaken to evaluate the neuroprotective effect of β-caryophyllene (BCP) against rotenone-induced oxidative stress and neuroinflammation in a rat model of PD. In the present study, BCP was administered once daily for 4 weeks at a dose of 50 mg/kg body weight prior to a rotenone (2.5 mg/kg body weight) challenge to mimic the progressive neurodegenerative nature of PD. Rotenone administration results in oxidative stress as evidenced by decreased activities of superoxide dismutase, catalase, and depletion of glutathione with a concomitant rise in lipid peroxidation product, malondialdehyde. Rotenone also significantly increased pro-inflammatory cytokines in the midbrain region and elevated the inflammatory mediators such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in the striatum. Further, immunohistochemical analysis revealed loss of dopaminergic neurons in the SNc area and enhanced expression of ionized calcium-binding adaptor molecule-1 (Iba-1) and glial fibrillary acidic protein (GFAP), indicators of microglia activation, and astrocyte hypertrophy, respectively, as an index of inflammation. However, treatment with BCP rescued dopaminergic neurons and decreased microglia and astrocyte activation evidenced by reduced Iba-1 and GFAP expression. BCP in addition to attenuation of pro-inflammatory cytokines and inflammatory mediators such as COX-2 and iNOS, also restored antioxidant enzymes and inhibited lipid peroxidation as well as glutathione depletion. The findings demonstrate that BCP provides neuroprotection against rotenone-induced PD and the neuroprotective effects can be ascribed to its potent antioxidant and anti-inflammatory activities.

Reversible inactivation of interpeduncular nucleus impairs memory consolidation and retrieval but not learning in rats: A behavioral and molecular study.

PubMed

Khatami, Leila; Khodagholi, Fariba; Motamedi, Fereshteh

2018-04-16

The Interpedundular nucleus (IPN) is a small midbrain structure located deeply between the two cerebral peduncles. The strategic placement of this nucleus makes it a possible relay between structures involved in the modulation of hippocampal theta rhythm activity. In this study we aimed to investigate how reversible inactivation of IPN could affect the acquisition, consolidation and retrieval phases of memory in passive avoidance (PA) and Morris water maze (MWM) tasks. To support our data, molecular studies were performed in order to detect possible changes in the expression of proteins related to learning and memory in the hippocampus. To address this issue rats' IPN was reversibly inactivated by microinjection of lidocaine hydrochloride (4%). After the behavioral studies, the phosphorylation of CREB and P70, and c-fos expression levels in the hippocampus were determined using western blotting and immunohistochemistry respectively. Our results in the PA and MWM tasks showed that IPN reversible inactivation could impair immediate post training consolidation and retrieval while it had no effect on the acquisition phase. In addition, there was a deficit in the retention of the MWM working memory. Our data showed the ratio of pCREB/CREB, pP70/P70 and c-fos expression in the hippocampus significantly decreased after IPN reversible inactivation. Collectively, the results show that behaviorally defined changes could be due to what happens molecularly in the hippocampus after IPN reversible inactivation. It is concluded that IPN not only makes part of a network involved in the modulation of hippocampal theta rhythm activity, but also is actively engaged in hippocampal memory formation. Copyright © 2018 Elsevier B.V. All rights reserved.

Neonatal over-expression of estrogen receptor-α alters midbrain dopamine neuron development and reverses the effects of low maternal care in female offspring

PubMed Central

Peña, Catherine Jensen; Champagne, Frances A

2014-01-01

Maternal behavior is dependent on estrogen receptor-alpha (ERα; Esr1) and oxytocin receptor (OTR) signaling in the medial preoptic area (MPOA) of the hypothalamus, as well as dopamine signaling from the ventral tegmental area (VTA) to forebrain regions. Previous studies in rats indicate that low levels of maternal care, particularly licking/grooming (LG), lead to reduced levels of MPOA ERα and VTA dopamine neurons in female offspring and predict lower levels of postpartum maternal behavior by these offspring. The aim of the current study was to determine the functional impact on maternal behavior of neonatal manipulation of ERα in females that had experienced low vs. high levels of postnatal maternal LG. Adenovirus expressing ESR1 was targeted to the MPOA in female pups from low and high LG litters on postnatal day 2–3. Over-expression of ESR1 in low LG offspring elevated the level of ERα-immunoreactive cells in the MPOA and of tyrosine hydroxylase cells in the VTA to that observed in high LG females. Amongst juvenile female low LG offspring, ESR1 over-expression also decreased the latency to engage in maternal behavior toward donor pups. These results show that virally-mediated expression of ESR1 in the neonatal rat hypothalamus results in lasting changes in ESR1 expression through the juvenile period, and can “rescue” hormone receptor levels and behavior of offspring reared by low LG dams, potentially mediated by downstream alterations within reward circuitry. Thus, the transmission of maternal behavior from one generation to the next can be augmented by neonatal ERα in the MPOA. PMID:25044746

Intra-VTA infusions of the substance P analogue, DiMe-C7, and intra-accumbens infusions of amphetamine induce analgesia in the formalin test for tonic pain.

PubMed

Altier, N; Stewart, J

1993-11-19

Experiments were designed to examine the analgesic effects of SP injected into the ventral tegmental area (VTA). Rats received bilateral intra-VTA infusions of 3.0 micrograms/0.5 microliter/side of the SP analogue, DiMe-C7, or the vehicle, either immediately prior to or 25 min following an injection of 0.05 ml of 2.5% formalin into one hind paw. Formalin-induced pain responses were continuously recorded for 75 min. DiMe-C7 attenuated pain responses for approximately 30 min; the analgesia was more potent and longer-lasting when DiMe-C7 was infused after, rather than prior to, the early pain phase. In another set of experiments, rats were tested in the formalin test immediately following bilateral infusions of amphetamine (1.5 or 2.5 micrograms/0.05 microliter/side) into either the medial prefrontal cortex (mPFC) or the nucleus accumbens septi (NAS). Amphetamine failed to alter pain responses when infused into the mPFC, but both doses attenuated pain responses during 25 min when infused into the NAS. There was no evidence for pain inhibition in the tail-flick test for phasic pain following either intra-VTA DiMe-C7 or intra-NAS amphetamine. The finding that intra-VTA DiMe-C7 and intra-NAS amphetamine produces analgesia in the formalin, but not the tail-flick test, suggests that activation of mesolimbic dopamine (DA) neurons contributes to suppression of tonic pain. Because stressors attenuate tonic pain responses, and are known to cause SP release in the VTA, we speculate that SP-induced activation of midbrain DA systems may mediate a form of pain- or stress-induced pain inhibitory system.