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Sample records for limbic forebrain noradrenergic

  1. Discrete Forebrain Neuronal Networks Supporting Noradrenergic Regulation of Sensorimotor Gating

    PubMed Central

    Alsene, Karen M; Rajbhandari, Abha K; Ramaker, Marcia J; Bakshi, Vaishali P

    2011-01-01

    Prepulse inhibition (PPI) refers to the reduction in the startle response when a startling stimulus is preceded by a weak prestimulus, and is an endophenotype of deficient sensorimotor gating in several neuropsychiatric disorders. Emerging evidence suggests that norepinephrine (NE) regulates PPI, however, the circuitry involved is unknown. We found recently that stimulation of the locus coeruleus (LC), the primary source of NE to the forebrain, induces a PPI deficit that is a result of downstream NE release. Hence, this study sought to identify LC-innervated forebrain regions that mediate this effect. Separate groups of male Sprague–Dawley rats received a cocktail solution of the α1-NE receptor agonist phenylephrine plus the β-receptor agonist isoproterenol (equal parts of each; 0, 3, 10, and 30 μg) into subregions of the medial prefrontal cortex (mPFC), nucleus accumbens (NAcc), extended amygdala, mediodorsal thalamus (MD-thalamus), or the dorsal hippocampus (DH) before PPI testing. NE agonist infusion into the posterior mPFC, NAcc shell, bed nucleus of the stria terminalis, basolateral amygdala, and the MD-thalamus disrupted PPI, with particularly strong effects in MD-thalamus. Sites in which NE receptor stimulation did not disrupt PPI (anterior mPFC, NAcc core, central amygdala, and DH) did support PPI disruptions with the dopamine D2 receptor agonist quinpirole (0, 10 μg). This pattern reveals new pathways in the regulation of PPI, and suggests that NE transmission within distinct thalamocortical and ventral forebrain networks may subserve the sensorimotor gating deficits that are seen in disorders such as schizophrenia, Tourette syndrome, and post-traumatic stress disorder. PMID:21248721

  2. Effects of lithium and aripiprazole on brain stimulation reward and neuroplasticity markers in the limbic forebrain.

    PubMed

    Mavrikaki, Maria; Schintu, Nicoletta; Kastellakis, Andreas; Nomikos, George G; Svenningsson, Per; Panagis, George

    2014-04-01

    Bipolar disorder (BD) is a severe pathological condition with impaired reward-related processing. The present study was designed to assess the effects of two commonly used BD medications, the mood stabilizer lithium chloride (LiCl) and the atypical antipsychotic and antimanic agent aripiprazole, in an animal model of reward and motivation and on markers of neuroplasticity in the limbic forebrain in rats. We utilized intracranial self-simulation (ICSS) to assess the effects of acute and chronic administration of LiCl and aripiprazole on brain stimulation reward, and phosphorylation studies to determine their effects on specific cellular neuroplasticity markers, i.e., the phosphorylation of CREB and crucial phosphorylation sites on the GluA1 subunit of AMPA receptors and the NA1 and NA2B subunits of NMDA receptors, in the limbic forebrain. Chronic LiCl induced tolerance to the anhedonic effect of the drug observed after acute administration, while chronic aripiprazole induced a sustained anhedonic effect. These distinct behavioral responses might be related to differences in molecular markers of neuroplasticity. Accordingly, we demonstrated that chronic LiCl, but not aripiprazole, decreased phosphorylation of CREB at the Ser133 site and NA1 at the Ser896 site in the prefrontal cortex and GluA1 at the Ser831 site and NA2B at the Ser1303 site in the ventral striatum. The present study provides evidence for BD medication-evoked changes in reward and motivation processes and in specific markers of neuronal plasticity in the limbic forebrain, promoting the notion that these drugs may blunt dysregulated reward processes in BD by counteracting neuronal plasticity deficits.

  3. Visualizing an emotional valence map in the limbic forebrain by TAI-FISH.

    PubMed

    Xiu, Jianbo; Zhang, Qi; Zhou, Tao; Zhou, Ting-ting; Chen, Yang; Hu, Hailan

    2014-11-01

    A fundamental problem in neuroscience is how emotional valences are represented in the brain. We know little about how appetitive and aversive systems interact and the extent to which information regarding these two opposite values segregate and converge. Here we used a new method, tyramide-amplified immunohistochemistry-fluorescence in situ hybridization, to simultaneously visualize the neural correlates of two stimuli of contrasting emotional valence across the limbic forebrain at single-cell resolution. We discovered characteristic patterns of interaction, segregated, convergent and intermingled, between the appetitive and aversive neural ensembles in mice. In nucleus accumbens, we identified a mosaic activation pattern by positive and negative emotional cues, and unraveled previously unappreciated functional heterogeneity in the D1- and D2-type medium-spiny neurons, which correspond to the Go and NoGo pathways. These results provide insights into the coding of emotional valence in the brain and act as a proof of principle of a powerful methodology for simultaneous functional mapping of two distinct behaviors.

  4. Divergent projections of catecholaminergic neurons in the nucleus of the solitary tract to limbic forebrain and medullary autonomic brain regions.

    PubMed

    Reyes, Beverly A S; Van Bockstaele, Elisabeth J

    2006-10-30

    The nucleus of the solitary tract (NTS) is a critical structure involved in coordinating autonomic and visceral activities. Previous independent studies have demonstrated efferent projections from the NTS to the nucleus paragigantocellularis (PGi) and the central nucleus of the amygdala (CNA) in rat brain. To further characterize the neural circuitry originating from the NTS with postsynaptic targets in the amygdala and medullary autonomic targets, distinct green or red fluorescent latex microspheres were injected into the PGi and the CNA, respectively, of the same rat. Thirty-micron thick tissue sections through the lower brainstem and forebrain were collected. Every fourth section through the NTS region was processed for immunocytochemical detection of tyrosine hydroxylase (TH), a marker of catecholaminergic neurons. Retrogradely labeled neurons from the PGi or CNA were distributed throughout the rostro-caudal segments of the NTS. However, the majority of neurons containing both retrograde tracers were distributed within the caudal third of the NTS. Cell counts revealed that approximately 27% of neurons projecting to the CNA in the NTS sent collateralized projections to the PGi while approximately 16% of neurons projecting to the PGi sent collateralized projections to the CNA. Interestingly, more than half of the PGi and CNA-projecting neurons in the NTS expressed TH immunoreactivity. These data indicate that catecholaminergic neurons in the NTS are poised to simultaneously coordinate activities in limbic and medullary autonomic brain regions.

  5. Topographic architecture of stress-related pathways targeting the noradrenergic locus coeruleus.

    PubMed

    Van Bockstaele, E J; Bajic, D; Proudfit, H; Valentino, R J

    2001-06-01

    Peripheral sympathetic nerves and brainstem noradrenergic neurons of the locus coeruleus (LC) respond in parallel to a variety of stress-related stimuli which results in norepinephrine release both peripherally and centrally. Elucidation of central pathways subserving modulation of LC neurons point to extranuclear noradrenergic dendrites of LC somata that extend into peri-coerulear areas as a major target of afferents that participate in behavioral and physiological responses to stress. Anterograde tract tracing combined with immunoelectron microscopic detection of the catecholamine synthesizing enzyme tyrosine hydroxylase (TH) has demonstrated that the nucleus of the solitary tract (NTS) and the ventrolateral aspect of the periaqueductal gray (PAG), regions that participate in coordinating autonomic and motor behavior in response to stress, preferentially target the rostral ventromedial aspect of the peri-LC. In contrast, limbic forebrain afferents including the central nucleus of the amygdala (CNA) and the bed nucleus of the stria terminalis (BNST), regions that coordinate emotional responses to external stressors, provide direct synaptic input to noradrenergic dendrites that extend into rostral dorsolateral peri-coerulear areas. Neurochemical identification of transmitter systems impinging on LC indicate that the CNA provides corticotropin-releasing factor (CRF), a peptide essential for integrated physiological responses to stress, to the dorsolateral LC. Endogenous opioid peptides that originate from medullary sources, however, target primarily the "core" of the LC. Our physiological data suggest that stress engages CRF and opioid afferents to the LC, which have opposing influences on this noradrenergic system. The balance between opioid and CRF influences acting in the LC may, in part, maintain the balance of active and passive coping behaviors in response to stress. Understanding the afferent and neurochemical organization of the LC may help elucidate

  6. Lesioning noradrenergic neurons of the locus coeruleus in C57Bl/6 mice with unilateral 6-hydroxydopamine injection, to assess molecular, electrophysiological and biochemical changes in noradrenergic signaling

    PubMed Central

    Szot, P.; Knight, L.; Franklin, A.; Sikkema, C.; Foster, S.; Wilkinson, C.W.; White, S.S.; Raskind, M.A.

    2012-01-01

    The locus coeruleus (LC) is the major loci of noradrenergic innervation to the forebrain. Due to the extensive central nervous system innervation of the LC noradrenergic system, a reduction in the number of LC neurons could result in significant changes in noradrenergic function in many forebrain regions. LC noradrenergic neurons were lesioned in adult male C57Bl/6 mice with the unilateral administration of 6-hydroxydopamine (6OHDA) (vehicle on the alternate side). Noradrenergic markers were measured 3 weeks later to determine the consequence of LC loss in the forebrain. Direct administration of 6OHDA into the LC results in the specific reduction of noradrenergic neurons in the LC (as measured by electrophysiology, immunoreactivity and in situ hybridization), the lateral tegmental neurons and dopaminergic neurons in the substantia nigra (SN) and ventral tegmental region were unaffected. The loss of LC noradrenergic neurons did not result in compensatory changes in the expression of mRNA for norepinephrine (NE) synthesizing enzymes. The loss of LC noradrenergic neurons is associated with reduced NE tissue concentration and NE transporter (NET) binding sites in the frontal cortex and hippocampus, as well as other forebrain regions such as the amygdala and SN. Adrenoreceptor (AR) binding sites (α1- and α2-AR) were not significantly affected on the 6OHDA-treated side compared to the vehicle-treated side, although there is a reduction of AR binding sites on both the vehicle- and 6OHDA-treated side in specific forebrain regions. These studies indicate that unilateral stereotaxic injection of 6OHDA into mice reduces noradrenergic LC neurons and reduces noradrenergic innervation to many forebrain regions, including the contralateral side. PMID:22542679

  7. The effect of chronic in vivo infusion of forskolin on noradrenergic receptor sensitivity.

    PubMed

    Suzdak, P D; Browne, R G

    1985-01-01

    Forskolin, a diterpene isolated from the plant Coleus forskolii, activates the catalytic subunit of adenylate cyclase, resulting in a hormone receptor-independent increase in the intracellular production of cyclic AMP. This study was undertaken to assess the effect of chronic in vivo infusion of forskolin on noradrenergic neuronal activity. Forskolin was infused into the right lateral ventricle of male Sprague Dawley rats via Alzet osmotic minipumps (model 2001) for 7 days. Chronic infusion of forskolin resulted in a decrease in norepinephrine-stimulated cyclic AMP accumulation in the limbic forebrain. Chronic infusion of forskolin also resulted in a decrease in the Bmax for 3H-dihydroalprenolol (3H-DHA) binding to beta-adrenergic receptors in the cerebral cortex and hippocampus, with no apparent change in the Kd values. These data suggest the possibility of a novel therapeutic approach to modulating receptor sensitivity, and that chronic infusion of forskolin may be a useful model for studying the role of cyclic AMP in the control of neuronal activity.

  8. Noradrenergic Modulation of Arousal

    PubMed Central

    Berridge, Craig W.

    2008-01-01

    Through a highly divergent efferent projection system, the locus coeruleus-noradrenergic system supplies norepinephrine throughout the central nervous system. State-dependent neuronal discharge activity of locus coeruleus neurons has long-suggested a role of this system in the induction of an alert waking state. More recent work supports this hypothesis, demonstrating robust wake-promoting actions of the locus coeruleus-noradrenergic system. Norepinephrine enhances arousal, in part, via actions of β- and α1-receptors located within multiple subcortical structures, including the general regions of the medial septal area and the medial preoptic areas. Recent anatomical studies suggest that arousal-enhancing actions of norepinephrine are not limited to the locus coeruleus system and likely include the A1 and A2 noradrenergic cell groups. Thus, noradrenergic modulation of arousal state involves multiple noradrenergic systems acting with multiple subcortical regions. Pharmacological studies indicate that the combined actions of these systems are necessary for the sustained maintenance of arousal levels associated with spontaneous waking. Enhanced arousal state is a prominent aspect of both stress and psychostimulant drug action and evidence indicates that noradrenergic systems likely play an important role in both stress-related and psychostimulant-induced arousal. These and other observations suggest that the dysregulation of noradrenergic neurotransmission could well contribute to the dysregulation of arousal associated with a variety of behavioral disorders including insomnia and stress-related disorders. PMID:18199483

  9. Prenatal exposure to MDMA alters noradrenergic neurodevelopment in the rat

    PubMed Central

    Thompson, V.B.; Koprich, J.B.; Chen, E.Y.; Kordower, J.H.; Terpstra, B.; Lipton, J.W.

    2011-01-01

    3,4-methylenedioxymethamphetamine (MDMA; ecstasy) binds with high affinity to the norepinephrine transporter (NET), making the noradrenergic system a potential target during fetal exposure. Recent data indicates that adult rats that had been prenatally exposed to MDMA display persistent deficits in working memory and attention; behaviors consistent with abnormal noradrenergic signaling in the forebrain. The present study was designed to investigate whether prenatal exposure to MDMA from embryonic days 14–20 affects the structure and/or function of the noradrenergic system of the rat on postnatal day 21. Offspring that were prenatally exposed to MDMA exhibited an increase in noradrenergic fiber density in the prelimbic region of the prefrontal cortex and the CA1 region of the hippocampus that was not accompanied by an increase in the number of noradrenergic neurons in the locus coeruleus. Direct tissue autoradiography using tritiated nisoxetine demonstrated that while NET binding was not altered in the prelimbic cortex, the dentate gyrus, or the locus coeruleus, it was increased in the CA1, CA2, and CA3 regions of the hippocampus. Basal levels of norepinephrine were increased in the prefrontal cortex and the nucleus accumbens of MDMA-exposed rats, as compared to saline-treated controls. These findings indicate that prenatal exposure to MDMA results in structural changes in the noradrenergic system as well as functional alterations in NE neurotransmission in structures that are critical in attentional processing. PMID:21978916

  10. Serotonergic modulation of the limbic system.

    PubMed

    Hensler, Julie G

    2006-01-01

    The limbic system is composed of cortical as well as subcortical structures, which are intimately interconnected. The resulting macrostructure is responsible for the generation and expression of motivational and affective states. Especially high levels of serotonin are found in limbic forebrain structures. Serotonin projections to these structures, which arise from serotonergic cell body groups in the midbrain, form a dense plexus of axonal processes. In many areas of the limbic system, serotonergic neurotransmission can best be described as paracrine or volume transmission, and thus serotonin is believed to play a neuromodulatory role in the brain. Serotonergic projections to limbic structures, arising primarily from the dorsal and median raphe nuclei, compose two distinct serotonergic systems differing in their topographic organization, electrophysiological characteristics, morphology, as well as sensitivity to neurotoxins and perhaps psychoactive or therapeutic agents. These differences may be extremely important in understanding the role of these two serotonergic systems in normal brain function and in mental illness. Central serotonergic neurons or receptors are targets for a variety of therapeutic agents used in the treatment of disorders of the limbic system.

  11. The role of the central noradrenergic system in behavioral inhibition.

    PubMed

    Stone, Eric A; Lin, Yan; Sarfraz, Yasmeen; Quartermain, David

    2011-06-24

    Although the central noradrenergic system has been shown to be involved in a number of behavioral and neurophysiological processes, the relation of these to its role in depressive illness has been difficult to define. The present review discusses the hypothesis that one of its chief functions that may be related to affective illness is the inhibition of behavioral activation, a prominent symptom of the disorder. This hypothesis is found to be consistent with most previous neuropsychopharmacological and immunohistochemical experiments on active behavior in rodents in a variety of experimental conditions using manipulation of neurotransmission at both locus coeruleus and forebrain adrenergic receptors. The findings support a mechanism in which high rates of noradrenergic neural activity suppress the neural activity of principal neurons in forebrain regions mediating active behavior. The suppression may be mediated through postsynaptic galaninergic and adrenergic receptors, and via the release of corticotrophin-releasing hormone. The hypothesis is consistent with clinical evidence for central noradrenergic system hyperactivity in depressives and with the view that this hyperactivity is a contributing etiological factor in the disorder. A similar mechanism may underlie the ability of the noradrenergic system to suppress seizure activity suggesting that inhibition of the spread of neural activation may be a unifying function.

  12. Estrogen in the limbic system.

    PubMed

    ter Horst, Gert J

    2010-01-01

    Estrogens are a group of steroid hormones that function as the primary female sex hormone. Estrogens not only have an important role in the regulation of the estrous or menstrual cycle but also control, for example, bone formation, the cardiovascular system, and cognitive functions. Estradiol (E2), the main representative of the group, is highly lipophylic and can easily pass the blood-brain barrier to modulate neuronal activity. Particularly the limbic system, a group of tightly interconnected forebrain areas controlling mood and emotion, is rich in estrogen receptors. To date two cytoplasmatic and/or nuclear estrogen receptors named ER-alpha (ERalpha) and ER-beta (ERbeta) have been identified. In the brain, ERalpha plays a critical role in regulating reproductive neuroendocrine behavior and function. ERbeta appears to play an important role in nonreproductive behaviors, such as learning and memory, anxiety, and mood. Five splice variants of ERbeta, named Erb1, Erb2, Erb1d3, Erb2d3, and Erb1d4, have been identified with possibly different biological activities. There is evidence of a thus far not definitely characterized membrane-linked ER receptor named mER-X. In this review, the anatomy of the limbic system and the distribution of estrogen receptors (ERs) are described in relation to coping with stress and the higher prevalence of stress-related psychiatric disorders in women. Effects of cyclic estrogen administration and chronic stress on recovery and neuronal plasticity are illustrated with own results. Copyright 2010 Elsevier Inc. All rights reserved.

  13. Bilateral limbic system destruction in man.

    PubMed

    Feinstein, Justin S; Rudrauf, David; Khalsa, Sahib S; Cassell, Martin D; Bruss, Joel; Grabowski, Thomas J; Tranel, Daniel

    2010-01-01

    We report here a case study of a rare neurological patient with bilateral brain damage encompassing a substantial portion of the so-called "limbic system." The patient, Roger, has been studied in our laboratory for over 14 years, and the current article presents his complete neuroanatomical and neuropsychological profiles. The brain damage occurred in 1980 following an episode of herpes simplex encephalitis. The amount of destroyed neural tissue is extensive and includes bilateral damage to core limbic and paralimbic regions, including the hippocampus, amygdala, parahippocampal gyrus, temporal poles, orbitofrontal cortex, basal forebrain, anterior cingulate cortex, and insular cortex. The right hemisphere is more extensively affected than the left, although the lesions are largely bilateral. Despite the magnitude of his brain damage, Roger has a normal IQ, average to above-average attention, working memory, and executive functioning skills, and very good speech and language abilities. In fact, his only obvious presenting deficits are a dense global amnesia and a severe anosmia and ageusia. Roger's case presents a rare opportunity to advance our understanding of the critical functions underlying the human limbic system, and the neuropsychological and neuroanatomical data presented here provide a critical foundation for such investigations.

  14. Bilateral limbic system destruction in man

    PubMed Central

    Feinstein, Justin S.; Rudrauf, David; Khalsa, Sahib S.; Cassell, Martin D.; Bruss, Joel; Grabowski, Thomas J.; Tranel, Daniel

    2010-01-01

    We report here a case study of a rare neurological patient with bilateral brain damage encompassing a substantial portion of the so-called “limbic system.” The patient, Roger, has been studied in our laboratory for over 14 years and the current article presents his complete neuroanatomical and neuropsychological profiles. The brain damage occurred in 1980 following an episode of herpes simplex encephalitis. The amount of destroyed neural tissue is extensive and includes bilateral damage to core limbic and paralimbic regions, including the hippocampus, amygdala, parahippocampal gyrus, temporal poles, orbitofrontal cortex, basal forebrain, anterior cingulate cortex, and insular cortex. The right hemisphere is more extensively affected than the left, although the lesions are largely bilateral. Despite the magnitude of his brain damage, Roger has a normal IQ, average to above average attention, working memory, and executive functioning skills, and very good speech and language abilities. In fact, his only obvious presenting deficits are a dense global amnesia and a severe anosmia and ageusia. Roger's case presents a rare opportunity to advance our understanding of the critical functions underlying the human limbic system, and the neuropsychological and neuroanatomical data presented here provide a critical foundation for such investigations. PMID:19763994

  15. Forebrain GABAergic projections to locus coeruleus in mouse.

    PubMed

    Dimitrov, Eugene L; Yanagawa, Yuchio; Usdin, Ted B

    2013-07-01

    The noradrenergic locus coeruleus (LC) regulates arousal, memory, sympathetic nervous system activity, and pain. Forebrain projections to LC have been characterized in rat, cat, and primates, but not systematically in mouse. We surveyed mouse forebrain LC-projecting neurons by examining retrogradely labeled cells following LC iontophoresis of Fluoro-Gold and anterograde LC labeling after forebrain injection of biotinylated dextran amine or viral tracer. Similar to other species, the central amygdalar nucleus (CAmy), anterior hypothalamus, paraventricular nucleus, and posterior lateral hypothalamic area (PLH) provide major LC inputs. By using mice expressing green fluorescent protein in γ-aminobutyric acid (GABA)ergic neurons, we found that more than one-third of LC-projecting CAmy and PLH neurons are GABAergic. LC colocalization of biotinylated dextran amine, following CAmy or PLH injection, with either green fluorescent protein or glutamic acid decarboxylase (GAD)65/67 immunoreactivity confirmed these GABAergic projections. CAmy injection of adeno-associated virus encoding channelrhodopsin-2-Venus showed similar fiber labeling and association with GAD65/67-immunoreactive (ir) and tyrosine hydroxylase (TH)-ir neurons. CAmy and PLH projections were densest in a pericoerulear zone, but many fibers entered the LC proper. Close apposition between CAmy GABAergic projections and TH-ir processes suggests that CAmy GABAergic neurons may directly inhibit noradrenergic principal neurons. Direct LC neuron targeting was confirmed by anterograde transneuronal labeling of LC TH-ir neurons following CAmy or PLH injection of a herpes virus that expresses red fluorescent protein following activation by Cre recombinase in mice that express Cre recombinase in GABAergic neurons. This description of GABAergic projections from the CAmy and PLH to the LC clarifies important forebrain sources of inhibitory control of central nervous system noradrenergic activity.

  16. Dopaminergic, serotonergic, and noradrenergic deficits in Parkinson disease

    PubMed Central

    Buddhala, Chandana; Loftin, Susan K; Kuley, Brandon M; Cairns, Nigel J; Campbell, Meghan C; Perlmutter, Joel S; Kotzbauer, Paul T

    2015-01-01

    Objective People with Parkinson disease (PD) frequently develop dementia, which is associated with neocortical deposition of alpha-synuclein (α-syn) in Lewy bodies and Lewy neurites. In addition, neuronal loss and deposition of aggregated α-syn also occur in multiple subcortical nuclei that project to neocortical, limbic, and basal ganglia regions. Therefore, we quantified regional deficits in innervation from these PD-affected subcortical nuclei, by measuring the neurotransmitters and neurotransmitter transporter proteins originating from projections of dopaminergic neurons in substantia nigra pars compacta, serotonergic neurons in dorsal raphé nuclei, noradrenergic neurons in locus coeruleus, and cholinergic neurons in nucleus basalis of Meynert. Methods High-performance liquid chromatography and novel enzyme-linked immunosorbent assays were performed to quantify dopaminergic, serotonergic, noradrenergic, and cholinergic innervation in postmortem brain tissue. Eight brain regions from 15 PD participants (with dementia and Braak stage 6 α-syn deposition) and six age-matched controls were tested. Results PD participants compared to controls had widespread reductions of dopamine transporter in caudate, amygdala, hippocampus, inferior parietal lobule (IPL), precuneus, and visual association cortex (VAC) that exceeded loss of dopamine, which was only significantly reduced in caudate and amygdala. In contrast, PD participants had comparable deficits of both serotonin and serotonin transporter in caudate, middle frontal gyrus, IPL, and VAC. PD participants also had significantly reduced norepinephrine levels for all eight brain regions tested. Vesicular acetylcholine transporter levels were only quantifiable in caudate and hippocampus and did not differ between PD and control groups. Interpretation These results demonstrate widespread deficits in dopaminergic, serotonergic, and noradrenergic innervation of neocortical, limbic, and basal ganglia regions in advanced

  17. Neuropathology of the limbic system.

    PubMed

    Shaw, C M; Alvord, E C

    1997-02-01

    The history and development of the fanciful terminology concerning the structures of the limbic system are discussed. The diseases involving the limbic system are divided into three groups; (1) diseases in which the limbic system is more or less selectively involved, such as limbic encephalitis, herpes simplex encephalitis, cerebral confusions by the falx and tentorium, and internal herniations through the falx and tentorium; (2) diseases in which the limbic system is predominantly involved, such as arhinencephalia, holoprosencephaly, cyst of cavum septi pellucidi, Pick's disease, Alzheimer's disease, hippocampal sclerosis, and vascular diseases of the hippocampal formation; and (3) diseases in which the limbic system is randomly involved, such as various types of neoplasms and vascular and inflammatory lesions. The relationship between destructive lesions of the hippocampus and memory also is emphasized.

  18. A Comprehensive Analysis of the Effect of DSP4 on the Locus Coeruleus Noradrenergic System in the Rat

    PubMed Central

    Szot, Patricia; Miguelez, Cristina; White, Sylvia S.; Franklin, Allyn; Sikkema, Carl; Wilkinson, Charles W.; Ugedo, Luisa; Raskind, Murray A.

    2014-01-01

    Degeneration of the noradrenergic neurons in the locus coeruleus (LC) is a major component of Alzheimer's (AD) and Parkinson's disease (PD), but the consequence of noradrenergic neuronal loss has different effects on the surviving neurons in the two disorders. Therefore, understanding the consequence of noradrenergic neuronal loss is important in determining the role of this neurotransmitter in these neurodegenerative disorders. The goal of the study was to determine if the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) could be used as a model for either (or both) AD or PD. Rats were administered DSP4 and sacrificed 3 days, 2 weeks and 3 months later. DSP4-treatment resulted in a rapid, though transient reduction in norepinephrine (NE) and NE transporter (NET) in many brain regions receiving variable innervation from the LC. Alpha1-adrenoreceptors binding site concentrations were unchanged in all brain regions at all three time points. However, an increase in α2-AR was observed in many different brain regions 2 weeks and 3 months after DSP4. These changes observed in forebrain regions occurred without a loss in LC noradrenergic neurons. Expression of synthesizing enzymes or NET did not change in amount of expression/neuron despite the reduction in NE tissue content and NET binding site concentrations at early time points, suggesting no compensatory response. In addition, DSP4 did not affect basal activity of LC at any time point in anesthetized animals, but 2 weeks after DSP4 there is a significant increase in irregular firing of noradrenergic neurons. These data indicate that DSP4 is not a selective LC noradrenergic neurotoxin, but does affect noradrenergic neuron terminals locally, as evident by the changes in transmitter and markers at terminal regions. However, since DSP4 did not result in a LOSS of noradrenergic neurons, it is not considered an adequate model for noradrenergic neuronal loss observed in AD and PD. PMID:20045445

  19. Heritability of the limbic networks

    PubMed Central

    Kawadler, Jamie M.; Dell'Acqua, Flavio; Rijsdijk, Frühling V.; Kane, Fergus; Picchioni, Marco; McGuire, Philip; Toulopoulou, Timothea; Georgiades, Anna; Kalidindi, Sridevi; Kravariti, Eugenia; Murray, Robin M.; Murphy, Declan G.; Craig, Michael C.; Catani, Marco

    2016-01-01

    Individual differences in cognitive ability and social behaviour are influenced by the variability in the structure and function of the limbic system. A strong heritability of the limbic cortex has been previously reported, but little is known about how genetic factors influence specific limbic networks. We used diffusion tensor imaging tractography to investigate heritability of different limbic tracts in 52 monozygotic and 34 dizygotic healthy adult twins. We explored the connections that contribute to the activity of three distinct functional limbic networks, namely the dorsal cingulum (‘medial default-mode network’), the ventral cingulum and the fornix (‘hippocampal-diencephalic-retrosplenial network’) and the uncinate fasciculus (‘temporo-amygdala-orbitofrontal network’). Genetic and environmental variances were mapped for multiple tract-specific measures that reflect different aspects of the underlying anatomy. We report the highest heritability for the uncinate fasciculus, a tract that underpins emotion processing, semantic cognition, and social behaviour. High to moderate genetic and shared environmental effects were found for pathways important for social behaviour and memory, for example, fornix, dorsal and ventral cingulum. These findings indicate that within the limbic system inheritance of specific traits may rely on the anatomy of distinct networks and is higher for fronto-temporal pathways dedicated to complex social behaviour and emotional processing. PMID:26714573

  20. Cell migration in the forebrain.

    PubMed

    Marín, Oscar; Rubenstein, John L R

    2003-01-01

    The forebrain comprises an intricate set of structures that are required for some of the most complex and evolved functions of the mammalian brain. As a reflection of its complexity, cell migration in the forebrain is extremely elaborated, with widespread dispersion of cells across multiple functionally distinct areas. Two general modes of migration are distinguished in the forebrain: radial migration, which establishes the general cytoarchitectonical framework of the different forebrain subdivisions; and tangential migration, which increases the cellular complexity of forebrain circuits by allowing the dispersion of multiple neuronal types. Here, we review the cellular and molecular mechanisms underlying each of these types of migrations and discuss how emerging concepts in neuronal migration are reshaping our understanding of forebrain development in normal and pathological situations.

  1. Methylphenidate and Atomoxetine Inhibit Social Play Behavior through Prefrontal and Subcortical Limbic Mechanisms in Rats

    PubMed Central

    Achterberg, E.J. Marijke; van Kerkhof, Linda W.M.; Damsteegt, Ruth; Trezza, Viviana

    2015-01-01

    Positive social interactions during the juvenile and adolescent phases of life, in the form of social play behavior, are important for social and cognitive development. However, the neural mechanisms of social play behavior remain incompletely understood. We have previously shown that methylphenidate and atomoxetine, drugs widely used for the treatment of attention-deficit hyperactivity disorder (ADHD), suppress social play in rats through a noradrenergic mechanism of action. Here, we aimed to identify the neural substrates of the play-suppressant effects of these drugs. Methylphenidate is thought to exert its effects on cognition and emotion through limbic corticostriatal systems. Therefore, methylphenidate was infused into prefrontal and orbitofrontal cortical regions as well as into several subcortical limbic areas implicated in social play. Infusion of methylphenidate into the anterior cingulate cortex, infralimbic cortex, basolateral amygdala, and habenula inhibited social play, but not social exploratory behavior or locomotor activity. Consistent with a noradrenergic mechanism of action of methylphenidate, infusion of the noradrenaline reuptake inhibitor atomoxetine into these same regions also reduced social play. Methylphenidate administration into the prelimbic, medial/ventral orbitofrontal, and ventrolateral orbitofrontal cortex, mediodorsal thalamus, or nucleus accumbens shell was ineffective. Our data show that the inhibitory effects of methylphenidate and atomoxetine on social play are mediated through a distributed network of prefrontal and limbic subcortical regions implicated in cognitive control and emotional processes. These findings increase our understanding of the neural underpinnings of this developmentally important social behavior, as well as the mechanism of action of two widely used treatments for ADHD. PMID:25568111

  2. Psychosurgery and the limbic system

    PubMed Central

    Kelly, Desmond

    1973-01-01

    The limbic system can be considered to consist of a central ‘core’ from which three well-defined circuits emerge. These are the Papez or medial circuit, the basolateral circuit and the defence reaction circuit. The functions of the primitive limbic brain are modulated by a higher order control—the frontal lobe. Emotional responses and physiological changes have been obtained by stimulation of fronto-limbic pathways and limbic circuits and these have been used for location of target sites in psychosurgery. For the relief of intractable depression and anxiety, lesions are generally made in the lower medial quadrant or posteroorbital part of the frontal lobe, where there is a concentration of fronto-limbic connections. In primary obsessional neurosis lesions at this site produce less satisfactory results, but these illnesses may be helped by lesions in the cingulate gyrus, which is part of the Papez circuit. Patients with epilepsy and aggressive outbursts may respond to temporal lobotomy, or to operations, such as amygdalotomy, where lesions are placed in the defence reaction circuit. PMID:4618902

  3. Electroencephalography of autoimmune limbic encephalopathy.

    PubMed

    Kaplan, Peter W; Sutter, Raoul

    2013-10-01

    There is an increasing recognition of autoimmune limbic encephalopathy with the hope for earlier diagnosis and expedited and improved treatment. Although antibody testing remains the definitive clinical diagnostic feature, the presentation of a rapid dementia, behavioral changes, and seizures leads to investigation using cerebral imaging, electroencephalography, and cerebrospinal fluid to confirm the diagnosis and also to exclude similar disorders. The electroencephalographer may be asked to comment on the types of electroencephalography abnormality and provide input toward the diagnosis of limbic encephalopathy. This article reviews the literature on limbic paraneoplastic and nonparaneoplastic encephalopathies, providing descriptions and examples of the electroencephalography findings. Typically, there are patterns of slow theta and delta activity and different patterns of temporal and frontal epileptic activity.

  4. Forebrain Mechanisms of Nociception and Pain: Analysis through Imaging

    NASA Astrophysics Data System (ADS)

    Casey, Kenneth L.

    1999-07-01

    Pain is a unified experience composed of interacting discriminative, affective-motivational, and cognitive components, each of which is mediated and modulated through forebrain mechanisms acting at spinal, brainstem, and cerebral levels. The size of the human forebrain in relation to the spinal cord gives anatomical emphasis to forebrain control over nociceptive processing. Human forebrain pathology can cause pain without the activation of nociceptors. Functional imaging of the normal human brain with positron emission tomography (PET) shows synaptically induced increases in regional cerebral blood flow (rCBF) in several regions specifically during pain. We have examined the variables of gender, type of noxious stimulus, and the origin of nociceptive input as potential determinants of the pattern and intensity of rCBF responses. The structures most consistently activated across genders and during contact heat pain, cold pain, cutaneous laser pain or intramuscular pain were the contralateral insula and anterior cingulate cortex, the bilateral thalamus and premotor cortex, and the cerebellar vermis. These regions are commonly activated in PET studies of pain conducted by other investigators, and the intensity of the brain rCBF response correlates parametrically with perceived pain intensity. To complement the human studies, we developed an animal model for investigating stimulus-induced rCBF responses in the rat. In accord with behavioral measures and the results of human PET, there is a progressive and selective activation of somatosensory and limbic system structures in the brain and brainstem following the subcutaneous injection of formalin. The animal model and human PET studies should be mutually reinforcing and thus facilitate progress in understanding forebrain mechanisms of normal and pathological pain.

  5. The Role of Basal Forebrain in Rat Somatosensory Cortex: Impact on Cholinergic Innervation, Sensory Information Processing, and Tactile Discrimination

    DTIC Science & Technology

    1993-05-28

    noradrenergic neurons, as well as from the cholinergic neurons of the brainstem tegmentum (Jones and Cuello , 1989). This suggests that final control over...Jones, B. E., & Cuello , A. C. (1989). Afferents to the basal forebrain cholinergic cell area from pontomesencephalic- catecholamine, serotonin, and...organization in mouse barrel cortex. Brain Research, 165, 327-332. 160 Sofroniew, M. V., Eckenstein, Fo, Thoenen, Ho, & Cuello , A. C. (1982

  6. Contribution of limbic norepinephrine to cannabinoid-induced aversion.

    PubMed

    Carvalho, Ana Franky; Reyes, Arith-Ruth S; Sterling, Robert C; Unterwald, Ellen; Van Bockstaele, Elisabeth J

    2010-09-01

    The cannabinoid system has risen to the forefront in the development of novel treatments for a number of pathophysiological processes. However, significant side effects have been observed in clinical trials raising concerns regarding the potential clinical utility of cannabinoid-based agents. Understanding the neural circuits and neurochemical substrates impacted by cannabinoids will provide a better means of gaging their actions within the central nervous system that may contribute to the expression of unwanted side effects. In the present study, we investigated whether norepinephrine (NE) in the limbic forebrain is a critical determinant of cannabinoid receptor agonist-induced aversion and anxiety in rats. An immunotoxin lesion approach was combined with behavioral analysis using a place conditioning paradigm and the elevated zero maze. Our results show that the non-selective CB1/CB2 receptor agonist, WIN 55,212-2, produced a significant place aversion in rats. Further, NE in the nucleus accumbens was critical for WIN 55,212-2-induced aversion but did not affect anxiety-like behaviors. Depletion of NE from the bed nucleus of the stria terminalis was ineffective in altering WIN 55,212-2-induced aversion and anxiety. These results indicate that limbic, specifically accumbal, NE is required for cannabinoid-induced aversion but is not essential to cannabinoid-induced anxiety.

  7. A Noradrenergic Lesion Exacerbates Neurodegeneration in a Down Syndrome Mouse Model

    PubMed Central

    Lockrow, Jason; Boger, Heather; Gerhardt, Greg; Aston-Jones, Gary; Bachman, David; Granholm, Ann-Charlotte

    2012-01-01

    Individuals with Down syndrome (DS) acquire Alzheimer’s-like dementia (AD) and associated neuropathology earlier and at significantly greater rates than age-matched normosomic individuals. However, biological mechanisms have not been discovered and there is currently limited therapy for either DS- or AD-related dementia. Segmental trisomy 16 (Ts65Dn) mice provide a useful model for many of the degenerative changes which occur with age in DS including cognitive deficits, neuroinflammation, and degeneration of basal forebrain cholinergic neurons. Loss of noradrenergic locus coeruleus (LC) neurons is an early event in AD and in DS, and may contribute to the neuropathology. We report that Ts65Dn mice exhibit progressive loss of norepinephrine (NE) phenotype in LC neurons. In order to determine whether LC degeneration contributes to memory loss and neurodegeneration in Ts65Dn mice, we administered the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4; 2 doses of 50 mg/kg, i.p.) to Ts65Dn mice at four months of age, prior to working memory loss. At eight months of age, Ts65Dn mice treated with DSP-4 exhibited an 80% reduction in hippocampal NE, coupled with a marked increase in hippocampal neuroinflammation. Noradrenergic depletion also resulted in accelerated cholinergic neuron degeneration and a further impairment of memory function in Ts65Dn mice. In contrast, DSP-4 had minimal effects on normosomic littermates, suggesting a disease-modulated vulnerability to NE loss in the DS mouse model. These data suggest that noradrenergic degeneration may play a role in the progressive memory loss, neuroinflammation, and cholinergic loss occurring in DS individuals, providing a possible therapeutic avenue for future clinical studies. PMID:21098982

  8. Forebrain Pain Mechanisms

    PubMed Central

    Neugebauer, Volker; Galhardo, Vasco; Maione, Sabatino; Mackey, Sean C.

    2009-01-01

    Emotional-affective and cognitive dimensions of pain are less well understood than nociceptive and nocifensive components, but the forebrain is believed to play an important role. Recent evidence suggests subcortical and cortical brain areas outside the traditional pain processing network contribute critically to emotional-affective responses and cognitive deficits related to pain. These brain areas include different nuclei of the amygdala and certain prefrontal cortical areas. Their roles in various aspects of pain will be discussed. Biomarkers of cortical dysfunction are being identified that may evolve into therapeutic targets to modulate pain experience and improve pain-related cognitive impairment. Supporting data from preclinical studies in neuropathic pain models will be presented. Neuroimaging analysis provides evidence for plastic changes in the pain processing brain network. Results of clinical studies in neuropathic pain patients suggest that neuroimaging may help determine mechanisms of altered brain functions in pain as well as monitor the effects of pharmacologic interventions to optimize treatment in individual patients. Recent progress in the analysis of higher brain functions emphasizes the concept of pain as a multidimensional experience and the need for integrative approaches to determine the full spectrum of harmful or protective neurobiological changes in pain. PMID:19162070

  9. Noradrenergic innervation of juvenile nasopharyngeal angiofibroma.

    PubMed

    Wang, H W; Su, W Y; Wang, J Y

    1994-01-01

    The glyoxylic catecholaminergic histofluorescence method was employed on tissues from five cases of juvenile nasopharyngeal angiofibroma in order to study the sympathetic innervation present. There was no sympathetic innervation identified in tumor parenchyma while some scant noradrenergic fibers were found in the tumor border. These findings indicate that keeping a dissection surface out of tumor during planned excisions may be very important, as vessels there have more sympathetic innervation which will then result in good vessel contraction in controlling bleeding. Non-diseased nasal mucosa from each patient was used as control tissue, with its submucosa seen to be filled with noradrenergic innervation. Some noradrenergic fibers were also found to innervate the muscle layers of arterioles or venules adjacent to the sphenopalatine foramen.

  10. Methylphenidate and atomoxetine inhibit social play behavior through prefrontal and subcortical limbic mechanisms in rats.

    PubMed

    Achterberg, E J Marijke; van Kerkhof, Linda W M; Damsteegt, Ruth; Trezza, Viviana; Vanderschuren, Louk J M J

    2015-01-07

    Positive social interactions during the juvenile and adolescent phases of life, in the form of social play behavior, are important for social and cognitive development. However, the neural mechanisms of social play behavior remain incompletely understood. We have previously shown that methylphenidate and atomoxetine, drugs widely used for the treatment of attention-deficit hyperactivity disorder (ADHD), suppress social play in rats through a noradrenergic mechanism of action. Here, we aimed to identify the neural substrates of the play-suppressant effects of these drugs. Methylphenidate is thought to exert its effects on cognition and emotion through limbic corticostriatal systems. Therefore, methylphenidate was infused into prefrontal and orbitofrontal cortical regions as well as into several subcortical limbic areas implicated in social play. Infusion of methylphenidate into the anterior cingulate cortex, infralimbic cortex, basolateral amygdala, and habenula inhibited social play, but not social exploratory behavior or locomotor activity. Consistent with a noradrenergic mechanism of action of methylphenidate, infusion of the noradrenaline reuptake inhibitor atomoxetine into these same regions also reduced social play. Methylphenidate administration into the prelimbic, medial/ventral orbitofrontal, and ventrolateral orbitofrontal cortex, mediodorsal thalamus, or nucleus accumbens shell was ineffective. Our data show that the inhibitory effects of methylphenidate and atomoxetine on social play are mediated through a distributed network of prefrontal and limbic subcortical regions implicated in cognitive control and emotional processes. These findings increase our understanding of the neural underpinnings of this developmentally important social behavior, as well as the mechanism of action of two widely used treatments for ADHD. Copyright © 2015 the authors 0270-6474/15/350161-09$15.00/0.

  11. Sleep research in space: expression of immediate early genes in forebrain structures of rats during the nasa neurolab mission (STS-90).

    PubMed

    Centini, C; Pompeiano, O

    2007-05-01

    . Some Fos staining was also present in limbic cortical areas, the septum, and the hippocampus. The main area of the forebrain of FLT rats sacrificed at R + 1, showing an increased expression of Fos, was the central nucleus of the amygdala (CeA) (cf. 127), as well as the noradrenergic locus coeruleus (LC) nucleus (cf. 122). At R + 13 Fos immunostaining was variable among FLT rats. However, none of these rats showed a significant number of Fos-positive cells in CeA. 4. Most of the rats studied for Fos expression were also tested for FRA expression. In particular, a scattered amount of FRA expression occurred at FD14 in different areas of the neocortex and in limbic forebrain regions (such as the cingulate, retrosplenial and entorhinal cortex). It included also the hippocampus, the lateral septum, the caudate/putamen, as well as some hypothalamic regions. At the reentry (R + 1) it was previously shown that a prominent increase in FRA expression occurred in the LC of FLT rats (cf. 122). This finding was associated with an increase in FRA expression which affected not only the nucleus paragigantocellularis lateralis of the medulla, which sends excitatory glutamatergic afferents to the LC (cf. 31 for ref.), but also structures which are known to produce corticotropin-releasing factor (CRF), a neuropeptide which activates the noradrenergic LC neurons during stress. 5. These findings which result from acceleration stress were followed by REMS episodes, which probably occurred after a long period of sleep deprivation following exposure to microgravity. It was previously shown that an increase in Fos and FRA expression occurred at the reentry in some pontine and medullary reticular structures (cf. 128), which are likely to be involved in both the descending (postural atonia) and the ascending manifestations of PS. These findings can be integrated by results of the present experiments showing that at the reentry high levels of FRA expression occurred in the hippocampus and the

  12. The forebrain of the ferret.

    PubMed

    Lockard, B I

    1985-06-01

    The basic neuroanatomy of the forebrain, mainly of the telencephalon, of the adult ferret (Mustela furo), is reviewed and illustrated with special references to the features that distinguish this animal from other carnivores. References to the pertinent literature describing similar regions of other carnivores are cited.

  13. LIMBIC CIRCUITRY OF THE MIDLINE THALAMUS

    PubMed Central

    Vertes, Robert P.; Linley, Stephanie B.; Hoover, Walter B.

    2016-01-01

    The thalamus was subdivided into three major groups: sensorimotor nuclei (or principal/relay nuclei), limbic nuclei and nuclei bridging these two domains. Limbic nuclei of thalamus (or ‘limbic thalamus’) consist of the anterior nuclei, midline nuclei, medial division of the mediodorsal nucleus (MDm) and central medial nucleus (CM) of the intralaminar complex. The midline nuclei include the paraventricular (PV) and paratenial (PT) nuclei, dorsally, and the reuniens (RE) and rhomboid (RH) nuclei, ventrally. The ‘limbic’ thalamic nuclei predominantly connect with limbic-related structures and serve a direct role in limbic–associated functions. Regarding the midline nuclei, RE/RH mainly target limbic cortical structures, particularly the hippocampus and the medial prefrontal cortex. Accordingly, RE/RH participate in functions involving interactions of the HF and mPFC. By contrast, PV/PT mainly project to limbic subcortical structures, particularly the amygdala and nucleus accumbens, and hence are critically involved in affective behaviors such as stress/anxiety, feeding behavior, and drug seeking activities. The anatomical/functional characteristics of MDm and CM are very similar to those of the midline nuclei and hence the collection of nuclei extending dorsoventrally along the midline/paramidline of the thalamus constitute the core of the ‘limbic thalamus’. PMID:25616182

  14. Loss of the tailless gene affects forebrain development and emotional behavior

    PubMed Central

    Roy, Kristine; Thiels, Edda; Monaghan, A. Paula

    2009-01-01

    We are studying the role of the evolutionarily conserved tlx gene in forebrain development in mice. Tlx is expressed in the ventricular zone that gives rise to neurons and glia of the forebrain. We have shown by mutating the tlx gene in mice, that in the absence of this transcription factor, mutant animals survive, but suffer specific anatomical defects in the limbic system. Because of these developmentally induced structural changes, mice with a mutation in the tlx gene can function, but exhibit extreme behavioral pathology. Mice show heightened aggressiveness, excitability, and poor cognition. In this article, we present a summary of our findings on the cellular and behavioral changes in the forebrain of mutant animals. We show that absence of the tlx gene leads to abnormal proliferation and differentiation of progenitor cells (PCs) in the forebrain from embryonic day 9 (E9). These abnormalities lead to hypoplasia of superficial cortical layers and subsets of GABAergic interneurons in the neocortex. We examined the behavior of mutant animals in three tests for anxiety/fear: the open field, the elevated plus maze, and fear conditioning. Mutant animals are less anxious and less fearful when assessed in the elevated plus and open-field paradigm. In addition, mutant animals do not condition to either the tone or the context in the fear-conditioning paradigm. These animals, therefore, provide a genetic tool to delineate structure/function relationships in defined regions of the brain and decipher how their disruption leads to behavioral abnormalities. PMID:12527005

  15. Measurement and Regulation of Central Noradrenergic Receptors

    DTIC Science & Technology

    1993-01-11

    vivo. We have found that an increase in beta adrenoreceptor activation during stress can be detected from measurement of extra cellular levels of...problems associated with the measurement of noradrenergic neurotransmission in vivo. We have found that an increase in beta adrenoreceptor activation...increase in beta adrenoreceptor activation during stress can be detected from measurement of extracellular levels of cyclic AMP by microdialysis. These

  16. Evidence for a specialized role of the locus coeruleus noradrenergic system in cortical circuitries and behavioral operations.

    PubMed

    Chandler, Daniel J

    2016-06-15

    The brainstem nucleus locus coeruleus (LC) innervates the entire central nervous system and is the primary source of norepinephrine (NE) to the neocortex. While classically considered a homogenous modulator of forebrain activity by virtue of highly widespread and divergent axons, recent behavioral and pharmacological evidence suggest this nucleus may execute distinct operations within functionally distinct terminal fields. Summarized in this review are the anatomical and physiological properties of the nucleus within a historical context that led to the interpretation of the nucleus as a homogeneous entity with uniform and simultaneous actions throughout its terminal fields. Also included are findings from several laboratories which point to a more nuanced model of LC/NE function that parallels that seen in other forebrain-projecting monoaminergic nuclei. Such compartmentalized models of the nucleus promote the idea that specific LC circuits are involved in discrete behavioral operations, and therefore, by identifying the networks that are engaged by LC, the substrates for these behaviors can be identified and manipulated. Perturbations in the functional anatomy and physiology of this system may be related to neuropsychiatric conditions associated with dysregulation of the LC-noradrenergic system such as attention deficit hyperactivity disorder. Recent findings regarding the organization and operation of the LC/NE system collectively challenge the classical view of the nucleus as a relatively homogenous modulator of forebrain activity and provide the basis for a renewed scientific interest in this region of the brain. This article is part of a Special Issue entitled SI: Noradrenergic System. Copyright © 2015 Elsevier B.V. All rights reserved.

  17. Sequential Loss of LC Noradrenergic and Dopaminergic Neurons Results in a Correlation of Dopaminergic Neuronal Number to Striatal Dopamine Concentration.

    PubMed

    Szot, Patricia; Franklin, Allyn; Sikkema, Carl; Wilkinson, Charles W; Raskind, Murray A

    2012-01-01

    Noradrenergic neurons in the locus coeruleus (LC) are significantly reduced in Parkinson's disease (PD) and the LC exhibits neuropathological changes early in the disease process. It has been suggested that a loss of LC neurons can enhance the susceptibility of dopaminergic neurons to damage. To determine if LC noradrenergic innervation protects dopaminergic neurons from damage, the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was administered to adult male C57Bl/6 mice 3 days after bilateral LC administration of 6-hydroxydopamine (6OHDA), a time when there is a significant reduction in LC neuronal number and innervation to forebrain regions. To assess if LC loss can affect dopaminergic loss four groups of animals were studied: control, 6OHDA, MPTP, and 6OHDA + MPTP; animals sacrificed 3 weeks after MPTP administration. The number of dopaminergic neurons in the substantia nigra (SN) and ventral tegmental area (VTA), and noradrenergic neurons in the LC were determined. Catecholamine levels in striatum were measured by high-pressure liquid chromatography. The loss of LC neurons did not affect the number of dopaminergic neurons in the SN and VTA compared to control; however, LC 6OHDA significantly reduced striatal dopamine (DA; 29% reduced) but not norepinephrine (NE) concentration. MPTP significantly reduced SN and VTA neuronal number and DA concentration in the striatum compared to control; however, there was not a correlation of striatal DA concentration with SN or VTA neuronal number. Administration of 6OHDA prior to MPTP did not enhance MPTP-induced damage despite an effect of LC loss on striatal DA concentration. However, the loss of LC neurons before MPTP resulted now in a correlation between SN and VTA neuronal number to striatal DA concentration. These results demonstrate that the loss of either LC or DA neurons can affect the function of each others systems, indicating the importance of both the noradrenergic and

  18. Sequential Loss of LC Noradrenergic and Dopaminergic Neurons Results in a Correlation of Dopaminergic Neuronal Number to Striatal Dopamine Concentration

    PubMed Central

    Szot, Patricia; Franklin, Allyn; Sikkema, Carl; Wilkinson, Charles W.; Raskind, Murray A.

    2012-01-01

    Noradrenergic neurons in the locus coeruleus (LC) are significantly reduced in Parkinson’s disease (PD) and the LC exhibits neuropathological changes early in the disease process. It has been suggested that a loss of LC neurons can enhance the susceptibility of dopaminergic neurons to damage. To determine if LC noradrenergic innervation protects dopaminergic neurons from damage, the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was administered to adult male C57Bl/6 mice 3 days after bilateral LC administration of 6-hydroxydopamine (6OHDA), a time when there is a significant reduction in LC neuronal number and innervation to forebrain regions. To assess if LC loss can affect dopaminergic loss four groups of animals were studied: control, 6OHDA, MPTP, and 6OHDA + MPTP; animals sacrificed 3 weeks after MPTP administration. The number of dopaminergic neurons in the substantia nigra (SN) and ventral tegmental area (VTA), and noradrenergic neurons in the LC were determined. Catecholamine levels in striatum were measured by high-pressure liquid chromatography. The loss of LC neurons did not affect the number of dopaminergic neurons in the SN and VTA compared to control; however, LC 6OHDA significantly reduced striatal dopamine (DA; 29% reduced) but not norepinephrine (NE) concentration. MPTP significantly reduced SN and VTA neuronal number and DA concentration in the striatum compared to control; however, there was not a correlation of striatal DA concentration with SN or VTA neuronal number. Administration of 6OHDA prior to MPTP did not enhance MPTP-induced damage despite an effect of LC loss on striatal DA concentration. However, the loss of LC neurons before MPTP resulted now in a correlation between SN and VTA neuronal number to striatal DA concentration. These results demonstrate that the loss of either LC or DA neurons can affect the function of each others systems, indicating the importance of both the noradrenergic and

  19. Pulmonary noradrenergic innervation of rat and monkey: a comparative study

    PubMed Central

    El-Bermani, Al-Walid I.

    1978-01-01

    El-Bermani, Al-Walid I. (1978).Thorax, 33, 167-174. Pulmonary noradrenergic innervation of rat and monkey: a comparative study. The noradrenergic innervation of rat and monkey lungs was studied using the fluorescence histochemical method for norepinephrine of Falck (1962). In both species the noradrenergic nerves enter the lung at the hilum in association with the bronchial arteries. Major differences were noted in the distribution and pattern of these nerves, the most important of which are as follows: (1) Noradrenergic nerves have terminal varicosities in all divisions of the rat bronchial artery but are varicose in only the medium and small bronchial arteries of the monkey. (2) Noradrenergic terminals (varicosities) are in direct association with the bronchial smooth muscle in the monkey, but in the rat most of the noradrenergic nerves pass through the smooth muscle layer without forming terminal varicosities. Smooth muscle noradrenergic innervation is seen only at bifurcation points. (3) In the monkey pulmonary artery, noradrenergic terminals are restricted to the adventitio-medial junction while they appear in the media of the rat pulmonary artery. (4) Noradrenergic terminals are present in all pulmonary vein divisions of the monkey whereas in the rat the large pulmonary veins lack noradrenergic nerves. Both rat and monkey bronchial arteries and pulmonary veins were found to have adrenergic terminal varicosities deep in the medial layer. The rat pulmonary artery also has such medial terminations. In both species there is a preponderance of noradrenergic terminals in the vasa vasorum, and we think that this may be important in regulating the delivery of humoral substances to vascular walls. Images PMID:96545

  20. Seronegative Paraneoplastic Limbic Encephalitis Associated with Thymoma.

    PubMed

    Toro, Jaime; Cuellar-Giraldo, David; Duque, Alejandra; Minota, Karla; Patiño, Jorge; García, Manuel

    2017-09-01

    Paraneoplastic limbic encephalitis is an autoimmune syndrome characterized by the acute or subacute onset of encephalopathy, memory loss, confusion, temporal lobe seizures, and behavioral and mood changes. Although most patients with paraneoplastic limbic encephalitis have antineuronal antibodies, advances in the field now permit the diagnosis without autoantibody test results. In this case illustrating the new diagnostic criteria, we report a 70-year-old woman who was brought to the emergency room after the acute onset of cognitive impairment, altered mental status, and choreoathetoid movements. Brain magnetic resonance imaging showed hyperintense signals in both temporal lobes, and a chest computed tomogram revealed a thymoma. Because the patient met current diagnostic criteria for autoimmune limbic encephalitis, we were able to start treatment before her antibody tests were processed. The patient received immunotherapy and her tumor was resected. Her choreoathetoid movements disappeared and her other neurologic symptoms improved. Her cerebrospinal fluid proved to be negative for paraneoplastic limbic encephalitis antibodies. Most but not all patients with paraneoplastic limbic encephalitis associated with thymoma have evidence of paraneoplastic antibodies. Prompt management of the underlying malignancy determines whether patients survive and may minimize future cognitive and functional impairment. Practicing neurologists and psychiatrists should be aware of this diagnosis.

  1. Crocodilian Forebrain: Evolution and Development

    PubMed Central

    Pritz, Michael B.

    2015-01-01

    Organization and development of the forebrain in crocodilians are reviewed. In juvenile Caiman crocodilus, the following features were examined: identification and classification of dorsal thalamic nuclei and their respective connections with the telencephalon, presence of local circuit neurons in the dorsal thalamic nuclei, telencephalic projections to the dorsal thalamus, and organization of the thalamic reticular nucleus. These results document many similarities between crocodilians and other reptiles and birds. While crocodilians, as well as other sauropsids, demonstrate several features of neural circuitry in common with mammals, certain striking differences in organization of the forebrain are present. These differences are the result of evolution. To explore a basis for these differences, embryos of Alligator misissippiensis were examined to address the following. First, very early development of the brain in Alligator is similar to that of other amniotes. Second, the developmental program for individual vesicles of the brain differs between the secondary prosencephalon, diencephalon, midbrain, and hindbrain in Alligator. This is likely to be the case for other amniotes. Third, initial development of the diencephalon in Alligator is similar to that in other amniotes. In Alligator, alar and basal parts likely follow a different developmental scheme. PMID:25829019

  2. Functional neuroanatomy of the central noradrenergic system.

    PubMed

    Szabadi, Elemer

    2013-08-01

    The central noradrenergic neurone, like the peripheral sympathetic neurone, is characterized by a diffusely arborizing terminal axonal network. The central neurones aggregate in distinct brainstem nuclei, of which the locus coeruleus (LC) is the most prominent. LC neurones project widely to most areas of the neuraxis, where they mediate dual effects: neuronal excitation by α₁-adrenoceptors and inhibition by α₂-adrenoceptors. The LC plays an important role in physiological regulatory networks. In the sleep/arousal network the LC promotes wakefulness, via excitatory projections to the cerebral cortex and other wakefulness-promoting nuclei, and inhibitory projections to sleep-promoting nuclei. The LC, together with other pontine noradrenergic nuclei, modulates autonomic functions by excitatory projections to preganglionic sympathetic, and inhibitory projections to preganglionic parasympathetic neurones. The LC also modulates the acute effects of light on physiological functions ('photomodulation'): stimulation of arousal and sympathetic activity by light via the LC opposes the inhibitory effects of light mediated by the ventrolateral preoptic nucleus on arousal and by the paraventricular nucleus on sympathetic activity. Photostimulation of arousal by light via the LC may enable diurnal animals to function during daytime. LC neurones degenerate early and progressively in Parkinson's disease and Alzheimer's disease, leading to cognitive impairment, depression and sleep disturbance.

  3. Noradrenergic Stimulation Impairs Memory Generalization in Women.

    PubMed

    Kluen, Lisa Marieke; Agorastos, Agorastos; Wiedemann, Klaus; Schwabe, Lars

    2017-03-02

    Memory generalization is essential for adaptive decision-making and action. Our ability to generalize across past experiences relies on medial-temporal lobe structures, known to be highly sensitive to stress. Recent evidence suggests that stressful events may indeed interfere with memory generalization. Yet, the mechanisms involved in this generalization impairment are unknown. We tested here whether a pharmacological elevation of major stress mediators, noradrenaline, and glucocorticoids is sufficient to disrupt memory generalization. In a double-blind, placebo-controlled design, healthy men and women received orally a placebo, hydrocortisone, the α2-adrenoceptor antagonist yohimbine that leads to increased noradrenergic stimulation, or both drugs, before they completed an associative learning task probing memory generalization. Drugs left learning performance intact. Yohimbine, however, led to a striking generalization impairment in women, but not in men. Hydrocortisone, in turn, had no effect on memory generalization, neither in men nor in women. The present findings indicate that increased noradrenergic activity, but not cortisol, is sufficient to disrupt memory generalization in a sex-specific manner, with relevant implications for stress-related mental disorders characterized by generalization deficits.

  4. Neurocircuitry of limbic dysfunction in anorexia nervosa.

    PubMed

    Lipsman, Nir; Woodside, D Blake; Lozano, Andres M

    2015-01-01

    Anorexia Nervosa (AN) is a serious psychiatric condition marked by firmly entrenched and maladaptive behaviors and beliefs about body, weight and food, as well as high rates of psychiatric comorbidity. The neural roots of AN are now beginning to emerge, and appear to be related to dysfunctional, primarily limbic, circuits driving pathological thoughts and behaviors. As a result, the significant physical symptoms of AN are increasingly being understood at least partially as a result of abnormal or dysregulated emotional processing. This paper reviews the nature of limbic dysfunction in AN, and how structural and functional imaging has implicated distinct emotional and perceptual neural circuits driving AN symptoms. We propose that top-down and bottom-up influences converge on key limbic modulatory structures, such as the subcallosal cingulate and insula, whose normal functioning is critical to affective regulation and emotional homeostasis. Dysfunctional activity in these structures, as is seen in AN, may lead to emotional processing deficits and psychiatric symptoms, which then drive maladaptive behaviors. Modulating limbic dysregulation may therefore be a potential treatment strategy in some AN patients. Copyright © 2014 Elsevier Ltd. All rights reserved.

  5. Paraneoplastic limbic encephalitis: clinico-pathological correlations.

    PubMed Central

    Bakheit, A M; Kennedy, P G; Behan, P O

    1990-01-01

    Three new cases of limbic encephalitis in association with malignancy are reported. The literature on this condition is reviewed and the clinical, laboratory and histopathological features of cases proven at necropsy are correlated. The possible pathogenic mechanism of this disorder is discussed. PMID:1963440

  6. Evidence for alterations in central noradrenergic signaling in irritable bowel syndrome*, **

    PubMed Central

    Berman, Steven; Suyenobu, Brandall; Naliboff, Bruce D.; Bueller, Joshua; Stains, Jean; Wong, Heng; Mandelkern, Mark; Fitzgerald, Leah; Ohning, Gordon; Gupta, Arpana; Labus, Jennifer S.; Tillisch, Kirsten; Mayer, Emeran A.

    2014-01-01

    Background/aims Alterations in noradrenergic (NE) signaling have been implicated in the pathophysiology of irritable bowel syndrome (IBS), and adrenergic receptors are potential treatment targets. Methods To characterize central NE signaling in IBS, 11 patients and 11 healthy controls (HCs) were studied 3 times during an auditory oddball vigilance task after double-blind ingestion of the α2-adrenoreceptor (α2AR) antagonist yohimbine (YOH), the α2AR agonist clonidine (CLO), or placebo (PLA). Regional cerebral glucose metabolism was measured with [18F] fluorodeoxyglucose (FDG) positron emission tomography (PET). Measures of anxiety, early-life trauma, plasma NE and blood pressure were acquired. Results Patients had higher plasma NE levels than HCs before and after ingestion of all drugs (all p <0.05). YOH increased plasma NE and more anxiety in patients than in HCs. After YOH, NE levels directly correlated with drug-induced increases in anxiety in IBS patients (r=0.61), but not in HCs. IBS patients showed less YOH-mediated reduction of activity in a central arousal circuit, consistent with fewer functional presynaptic α2AR. In HCs, but not in patients, activation of amygdala and subgenual anterior cingulate cortex (sgACC) was inversely correlated with activation of anterior mid cingulate cortex (aMCC), and state anxiety covaried directly with activity in limbic and right frontotemporal cortices, but indirectly with activity in the left frontotemporal cortex. YOH-mediated reduction of activity in brainstem and amygdala inversely correlated with early life trauma. Conclusions IBS patients showed evidence for increased noradrenergic activity consistent with downregulation of presynaptic inhibitory α2ARs. Activity within central arousal circuits was biased toward greater excitability and reduced corticolimbic inhibition in IBS. Early life trauma may be one mediator of these abnormalities. PMID:22917679

  7. GABAergic synchronization in the limbic system and its role in the generation of epileptiform activity

    PubMed Central

    Avoli, Massimo; de Curtis, Marco

    2016-01-01

    GABA is the main inhibitory neurotransmitter in the adult forebrain, where it activates ionotropic type A and metabotropic type B receptors. Early studies have shown that GABAA receptor-mediated inhibition controls neuronal excitability and thus the occurrence of seizures. However, more complex, and at times unexpected, mechanisms of GABAergic signaling have been identified during epileptiform discharges over the last few years. Here, we will review experimental data that point at the paradoxical role played by GABAA receptor-mediated mechanisms in synchronizing neuronal networks, and in particular those of limbic structures such as the hippocampus, the entorhinal and perirhinal cortices, or the amygdala. After having summarized the fundamental characteristics of GABAA receptor-mediated mechanisms, we will analyze their role in the generation of network oscillations and their contribution to epileptiform synchronization. Whether and how GABAA receptors influence the interaction between limbic networks leading to ictogenesis will be also reviewed. Finally, we will consider the role of altered inhibition in the human epileptic brain along with the ability of GABAA receptor-mediated conductances to generate synchronous depolarizing events that may lead to ictogenesis in human epileptic disorders as well. PMID:21802488

  8. Chlordiazepoxide-induced released responding in extinction and punishment-conflict procedures is not altered by neonatal forebrain norepinephrine depletion.

    PubMed

    Bialik, R J; Pappas, B A; Pusztay, W

    1982-02-01

    The effects of chlordiazepoxide (CDZ) in extinction and punishment-conflict tasks were examined in rats after neonatal systemic administration of 6-hydroxydopamine (6-OHDA) to deplete forebrain norepinephrine (NE). At about 70 days of age the rats were water deprived and trained for three days to drink in a novel apparatus. On the fourth day (test day) drinking was either extinguished by elimination of water from the drinking tube or punished by lick-contingent shock. Just prior to this test session half of the vehicle and half of the 6-OHDA treated rats were given an injection of CDZ (8 mg/kg IP). Both the injection of CDZ and forebrain NE depletion prolonged responding during extinction and reduced the suppressant effects of punishment in male rats, and these effects were of similar magnitude. Furthermore, CDZ was as effective in neonatal 6-OHDA treated male rats as in vehicle treated rats indicating that decreased transmission is ascending NE fibers caused by CDZ is not solely responsible for its behavioral effects in extinction and conflict tasks. Rather, these effects may involve cooperative mediation by both noradrenergic and serotonergic forebrain terminals. Unexpectedly, CDZ's anti-extinction effect was absent in female rats and its anti-conflict effect observed only in NE depleted females.

  9. Basal Forebrain Cholinergic Modulation of Sleep Transitions

    PubMed Central

    Ozen Irmak, Simal; de Lecea, Luis

    2014-01-01

    Objectives: The basal forebrain cholinergic system is involved in cognitive processes that require an attentive state, an increased level of arousal, and/or cortical activation associated with low amplitude fast EEG activity. The activity of most neurons in the basal forebrain cholinergic space is tightly correlated with the cortical EEG and the activity state. While most cholinergic neurons fire maximally during waking and REM sleep, the activity of other types of basal forebrain neurons vastly differs across different arousal and sleep states. Numerous studies have suggested a role for the basal forebrain cholinergic neurons in eliciting cortical activation and arousal. However, the intricate local connectivity within the region requires the use of cell-specific manipulation methods to demonstrate such a causal relationship. Design and Measurements: Here we have combined optogenetics with surface EEG recordings in freely moving mice in order to investigate the effects of acute cholinergic activation on the dynamics of sleep-to-wake transitions. We recorded from naturally sleeping animals and analyzed transitions from NREM sleep to REM sleep and/or wakefulness in response to photo-stimulation of cholinergic neurons in substantia innominata. Results and Conclusions: Our results show that optogenetic activation of basal forebrain cholinergic neurons during NREM sleep is sufficient to elicit cortical activation and facilitate state transitions, particularly transitions to wakefulness and arousal, at a time scale similar to the activation induced by other subcortical systems. Our results provide in vivo cell-specific demonstration for the role of basal forebrain cholinergic system in induction of wakefulness and arousal. Citation: Ozen Irmak S, de Lecea L. Basal forebrain cholinergic modulation of sleep transitions. SLEEP 2014;37(12):1941-1951. PMID:25325504

  10. Low dose naltrexone administration in morphine dependent rats attenuates withdrawal-induced norepinephrine efflux in forebrain.

    PubMed

    Van Bockstaele, Elisabeth J; Qian, Yaping; Sterling, Robert C; Page, Michelle E

    2008-05-15

    , animals were transcardially perfused and the brains were removed for verification of probe placement. Low dose naltrexone pre-treatment significantly attenuated withdrawal-induced increases of extracellular norepinephrine in the BNST, with a smaller effect in the FC. These findings suggest that alterations in norepinephrine release associated with withdrawal may be attenuated in forebrain targets of noradrenergic brainstem neurons that may underlie reduced behavioral signs of withdrawal following low dose naltrexone administration.

  11. Low dose naltrexone administration in morphine dependent rats attenuates withdrawal-induced norepinephrine efflux in forebrain

    PubMed Central

    Van Bockstaele, Elisabeth J.; Qian, Yaping; Sterling, Robert C.; Page, Michelle E.

    2009-01-01

    experiment, animals were transcardially perfused and the brains were removed for verification of probe placement. Low dose naltrexone pre-treatment significantly attenuated withdrawal-induced increases of extracellular norepinephrine in the BNST, with a smaller effect in the FC. These findings suggest that alterations in norepinephrine release associated with withdrawal may be attenuated in forebrain targets of noradrenergic brainstem neurons that may underlie reduced behavioral signs of withdrawal following low dose naltrexone administration. PMID:18367303

  12. Noradrenergic antagonists mitigate amphetamine-induced recovery.

    PubMed

    Hylin, M J; Brenneman, M M; Corwin, J V

    2017-09-15

    Brain injury, including that due to stroke, leaves individuals with cognitive deficits that can disrupt daily aspect of living. As of now there are few treatments that shown limited amounts of success in improving functional outcome. The use of stimulants such as amphetamine have shown some success in improving outcome following brain injury. While the pharmacological mechanisms for amphetamine are known; the specific processes responsible for improving behavioral outcome following injury remain unknown. Understanding these mechanisms can help to refine the use of amphetamine as a potential treatment or lead to the use of other methods that share the same pharmacological properties. One proposed mechanism is amphetamine's impact upon noradrenaline (NA). In the current, study noradrenergic antagonists were administered prior to amphetamine to pharmacologically block α- and β-adrenergic receptors. The results demonstrated that the blockade of these receptors disrupted amphetamines ability to induce recovery from hemispatial neglect using an established aspiration lesion model. This suggests that amphetamine's ability to ameliorate neglect deficits may be due in part to noradrenaline. These results further support the role of noradrenaline in functional recovery. Finally, the development of polytherapies and combined therapeutics, while promising, may need to consider the possibility that drug interactions can negate the effectiveness of treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Basal Forebrain Cholinergic System and Memory.

    PubMed

    Blake, M G; Boccia, M M

    2017-02-18

    Basal forebrain cholinergic neurons constitute a way station for many ascending and descending pathways. These cholinergic neurons have a role in eliciting cortical activation and arousal. It is well established that they are mainly involved in cognitive processes requiring increased levels of arousal, attentive states and/or cortical activation with desynchronized activity in the EEG. These cholinergic neurons are modulated by several afferents of different neurotransmitter systems. Of particular importance within the cortical targets of basal forebrain neurons is the hippocampal cortex. The septohippocampal pathway is a bidirectional pathway constituting the main septal efferent system, which is widely known to be implicated in every memory process investigated. The present work aims to review the main neurotransmitter systems involved in modulating cognitive processes related to learning and memory through modulation of basal forebrain neurons.

  14. Descending motor pathways and the spinal motor system - Limbic and non-limbic components

    NASA Technical Reports Server (NTRS)

    Holstege, Gert

    1991-01-01

    Research on descending motor pathways to caudal brainstem and spinal cord in the spinal motor system is reviewed. Particular attention is given to somatic and autonomic motoneurons in the spinal cord and brainstem, local projections to motoneurons, bulbospinal interneurons projecting to motoneurons, descending pathways of somatic motor control systems, and descending pathways involved in limbic motor control systems.

  15. Descending motor pathways and the spinal motor system - Limbic and non-limbic components

    NASA Technical Reports Server (NTRS)

    Holstege, Gert

    1991-01-01

    Research on descending motor pathways to caudal brainstem and spinal cord in the spinal motor system is reviewed. Particular attention is given to somatic and autonomic motoneurons in the spinal cord and brainstem, local projections to motoneurons, bulbospinal interneurons projecting to motoneurons, descending pathways of somatic motor control systems, and descending pathways involved in limbic motor control systems.

  16. Limbic systems for emotion and for memory, but no single limbic system.

    PubMed

    Rolls, Edmund T

    2015-01-01

    The concept of a (single) limbic system is shown to be outmoded. Instead, anatomical, neurophysiological, functional neuroimaging, and neuropsychological evidence is described that anterior limbic and related structures including the orbitofrontal cortex and amygdala are involved in emotion, reward valuation, and reward-related decision-making (but not memory), with the value representations transmitted to the anterior cingulate cortex for action-outcome learning. In this 'emotion limbic system' a computational principle is that feedforward pattern association networks learn associations from visual, olfactory and auditory stimuli, to primary reinforcers such as taste, touch, and pain. In primates including humans this learning can be very rapid and rule-based, with the orbitofrontal cortex overshadowing the amygdala in this learning important for social and emotional behaviour. Complementary evidence is described showing that the hippocampus and limbic structures to which it is connected including the posterior cingulate cortex and the fornix-mammillary body-anterior thalamus-posterior cingulate circuit are involved in episodic or event memory, but not emotion. This 'hippocampal system' receives information from neocortical areas about spatial location, and objects, and can rapidly associate this information together by the different computational principle of autoassociation in the CA3 region of the hippocampus involving feedback. The system can later recall the whole of this information in the CA3 region from any component, a feedback process, and can recall the information back to neocortical areas, again a feedback (to neocortex) recall process. Emotion can enter this memory system from the orbitofrontal cortex etc., and be recalled back to the orbitofrontal cortex etc. during memory recall, but the emotional and hippocampal networks or 'limbic systems' operate by different computational principles, and operate independently of each other except insofar as an

  17. Basal forebrain projections to the lateral habenula modulate aggression reward

    PubMed Central

    Golden, Sam A.; Heshmati, Mitra; Flanigan, Meghan; Christoffel, Dan J.; Guise, Kevin; Pfau, Madeline L.; Aleyasin, Hossein; Menard, Caroline; Zhang, Hongxing; Hodes, Georgia E.; Bregman, Dana; Khibnik, Lena; Tai, Jonathan; Rebusi, Nicole; Krawitz, Brian; Chaudhury, Dipesh; Walsh, Jessica J.; Han, Ming-Hu; Shapiro, Matt L.; Russo, Scott J.

    2016-01-01

    Maladaptive aggressive behavior is associated with a number of neuropsychiatric disorders1 and is thought to partly result from inappropriate activation of brain reward systems in response to aggressive or violent social stimuli2. Nuclei within the ventromedial hypothalamus3–5, extended amygdala6 and limbic7 circuits are known to encode initiation of aggression; however, little is known about the neural mechanisms that directly modulate the motivational component of aggressive behavior8. To address this, we established a mouse model to measure the valence of aggressive inter-male social interaction with a smaller subordinate intruder as reinforcement for the development of conditioned place preference (CPP). Aggressors (AGG) develop a CPP, while non-aggressors (NON) develop a conditioned place aversion (CPA), to the intruder-paired context. Further, we identify a functional GABAergic projection from the basal forebrain (BF) to the lateral habenula (lHb) that bi-directionally controls the valence of aggressive interactions. Circuit-specific silencing of GABAergic BF-lHb terminals of AGG with halorhodopsin (NpHR3.0) increases lHb neuronal firing and abolishes CPP to the intruder-paired context. Activation of GABAergic BF-lHb terminals of NON with channelrhodopsin (ChR2) decreases lHb neuronal firing and promotes CPP to the intruder-paired context. Lastly, we show that altering inhibitory transmission at BF-lHb terminals does not control the initiation of aggressive behavior. These results demonstrate that the BF-lHb circuit plays a critical role in regulating the valence of inter-male aggressive behavior and provide novel mechanistic insight into the neural circuits modulating aggression reward processing. PMID:27357796

  18. Ontogeny of noradrenergic effects on ultrasonic vocalizations in rat pups.

    PubMed

    Kehoe, P; Harris, J C

    1989-10-01

    The ontogeny of noradrenergic effects and the interaction of opioid and noradrenergic systems on vocalizations in rat pups from Day 10 to Day 18 were evaluated. Day 10 pups given clonidine (0.05 or 0.5 mg/kg) ip showed a sustained high level of calling throughout a 25-min isolation period that was reversed with yohimbine (0.1 mg/kg). Day 15 pups showed identical profiles with a lower baseline rate. Day 17 pups' calls were differentially affected according to dose; Day 18 pups reduced vocalizing with clonidine. In addition, it was found that at all ages when clonidine increased calling during isolation, the pups vocalized in the nest as well. Naltrexone, an opioid antagonist, lost its effectiveness to increase vocalizations after Day 15 unless it was given subsequent to clonidine. These results suggest that pups' vocalizations are differentially affected by noradrenergic and opioid stimulation or inhibition with developmental changes.

  19. Developmental specification of forebrain cholinergic neurons.

    PubMed

    Allaway, Kathryn C; Machold, Robert

    2017-01-01

    Striatal cholinergic interneurons and basal forebrain cholinergic projection neurons, which together comprise the forebrain cholinergic system, regulate attention, memory, reward pathways, and motor activity through the neuromodulation of multiple brain circuits. The importance of these neurons in the etiology of neurocognitive disorders has been well documented, but our understanding of their specification during embryogenesis is still incomplete. All forebrain cholinergic projection neurons and interneurons appear to share a common developmental origin in the embryonic ventral telencephalon, a region that also gives rise to GABAergic projection neurons and interneurons. Significant progress has been made in identifying the key intrinsic and extrinsic factors that promote a cholinergic fate in this precursor population. However, how cholinergic interneurons and projection neurons differentiate from one another during development, as well as how distinct developmental programs contribute to heterogeneity within those two classes, is not yet well understood. In this review we summarize the transcription factors and signaling molecules known to play a role in the specification and early development of striatal and basal forebrain cholinergic neurons. We also discuss the heterogeneity of these populations and its possible developmental origins. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Ontogenetic noradrenergic lesion alters histaminergic activity in adult rats.

    PubMed

    Nowak, Przemyslaw; Jochem, Jerzy; Zwirska-Korczala, Krystyna; Josko, Jadwiga; Noras, Lukasz; Kostrzewa, Richard M; Brus, Ryszard

    2008-04-01

    To determine whether noradrenergic nerves might have a modulatory role on the sensitivity or reactivity of histaminergic receptor systems in brain, behavioral effects of the respective histamine H1, H2 and H3 antagonists S(+)chlorpheniramine, cimetidine and thioperimide in control adult rats were compared to the effects in adult rats that had been lesioned as neonates with the noradrenergic neurotoxin DSP-4. On the 1st and 3rd days after birth rat pups were treated with either saline or DSP-4 (50 mg/kg sc), then returned to their home cages with the dam. At 8 weeks when rats were tested, S(+)chlorpheniramine (10 mg/kg ip) was found to increase locomotor activity in intact and DSP-4 lesioned rats, while cimetidine (5 mg/kg, ip) and thioperimide (5 mg/kg, ip) increased activity several-fold solely in the DSP-4 group. Exploratory activity, nociceptive activity, and irritability were little altered by the histamine antagonists, although oral activity was increased by thioperimide in intact and lesioned rats, and by cimetidine or S(+)chlorpheniramine in DSP-4 rats. High performance liquid chromatography with electrochemical detection was used to determine that DSP-4 produced a 90% reduction in frontal cortex, hippocampus and hypothalamus, with a 90% elevation of NE in cerebellum--reflecting reactive sprouting of noradrenergic fibers consequent to lesion of noradrenergic tracts projecting to proximal brain regions. These findings indicate that perinatal noradrenergic fiber lesioning in rat brain is associated with an altered behavioral spectrum by histamine H1, H2 and H3 receptor antagonists, thereby implicating histaminergic systems as modulators of noradrenergic systems in brain.

  1. Conditional corticotropin-releasing hormone overexpression in the mouse forebrain enhances rapid eye movement sleep

    PubMed Central

    Kimura, M; Müller-Preuss, P; Lu, A; Wiesner, E; Flachskamm, C; Wurst, W; Holsboer, F; Deussing, J M

    2009-01-01

    Impaired sleep and enhanced stress hormone secretion are the hallmarks of stress-related disorders, including major depression. The central neuropeptide, corticotropin-releasing hormone (CRH), is a key hormone that regulates humoral and behavioral adaptation to stress. Its prolonged hypersecretion is believed to play a key role in the development and course of depressive symptoms, and is associated with sleep impairment. To investigate the specific effects of central CRH overexpression on sleep, we used conditional mouse mutants that overexpress CRH in the entire central nervous system (CRH-COE-Nes) or only in the forebrain, including limbic structures (CRH-COE-Cam). Compared with wild-type or control mice during baseline, both homozygous CRH-COE-Nes and -Cam mice showed constantly increased rapid eye movement (REM) sleep, whereas slightly suppressed non-REM sleep was detected only in CRH-COE-Nes mice during the light period. In response to 6-h sleep deprivation, elevated levels of REM sleep also became evident in heterozygous CRH-COE-Nes and -Cam mice during recovery, which was reversed by treatment with a CRH receptor type 1 (CRHR1) antagonist in heterozygous and homozygous CRH-COE-Nes mice. The peripheral stress hormone levels were not elevated at baseline, and even after sleep deprivation they were indistinguishable across genotypes. As the stress axis was not altered, sleep changes, in particular enhanced REM sleep, occurring in these models are most likely induced by the forebrain CRH through the activation of CRHR1. CRH hypersecretion in the forebrain seems to drive REM sleep, supporting the notion that enhanced REM sleep may serve as biomarker for clinical conditions associated with enhanced CRH secretion. PMID:19455148

  2. Conditional corticotropin-releasing hormone overexpression in the mouse forebrain enhances rapid eye movement sleep.

    PubMed

    Kimura, M; Müller-Preuss, P; Lu, A; Wiesner, E; Flachskamm, C; Wurst, W; Holsboer, F; Deussing, J M

    2010-02-01

    Impaired sleep and enhanced stress hormone secretion are the hallmarks of stress-related disorders, including major depression. The central neuropeptide, corticotropin-releasing hormone (CRH), is a key hormone that regulates humoral and behavioral adaptation to stress. Its prolonged hypersecretion is believed to play a key role in the development and course of depressive symptoms, and is associated with sleep impairment. To investigate the specific effects of central CRH overexpression on sleep, we used conditional mouse mutants that overexpress CRH in the entire central nervous system (CRH-COE-Nes) or only in the forebrain, including limbic structures (CRH-COE-Cam). Compared with wild-type or control mice during baseline, both homozygous CRH-COE-Nes and -Cam mice showed constantly increased rapid eye movement (REM) sleep, whereas slightly suppressed non-REM sleep was detected only in CRH-COE-Nes mice during the light period. In response to 6-h sleep deprivation, elevated levels of REM sleep also became evident in heterozygous CRH-COE-Nes and -Cam mice during recovery, which was reversed by treatment with a CRH receptor type 1 (CRHR1) antagonist in heterozygous and homozygous CRH-COE-Nes mice. The peripheral stress hormone levels were not elevated at baseline, and even after sleep deprivation they were indistinguishable across genotypes. As the stress axis was not altered, sleep changes, in particular enhanced REM sleep, occurring in these models are most likely induced by the forebrain CRH through the activation of CRHR1. CRH hypersecretion in the forebrain seems to drive REM sleep, supporting the notion that enhanced REM sleep may serve as biomarker for clinical conditions associated with enhanced CRH secretion.

  3. Increased central noradrenergic activity during benzodiazepine withdrawal: an electrophysiological study.

    PubMed

    Bell, J; Bickford-Wimer, P C; de la Garza, R; Egan, M; Freedman, R

    1988-11-01

    Spontaneous discharge rates of cerebellar Purkinje neurons were decreased in rats withdrawn from chronic treatment with alprazolam, diazepam, and lorazepam relative to discharge rates recorded from control rats. Prior treatment with 6-hydroxydopamine to deplete cerebellar levels of norepinephrine significantly reduced this effect of diazepam upon Purkinje cell firing rates. The data suggest that increased noradrenergic activity may be occurring during withdrawal from benzodiazepines.

  4. Physical Exercise Affects Attentional Orienting Behavior through Noradrenergic Mechanisms

    PubMed Central

    Robinson, Andrea M.; Buttolph, Thomas; Green, John T.; Bucci, David J.

    2015-01-01

    Spontaneously Hypertensive Rats (SHRs), a commonly-used animal model of ADHD, exhibit little habituation of the orienting response to repeated presentations of a non-reinforced visual stimulus. However, SHRs that have access to a running wheel for 5, 10, or 21 days exhibit robust habituation that is indistinguishable from normo-active rats. Two days of exercise, in comparison, was not sufficient to affect habituation. Here we tested the hypothesis that the effect of exercise on orienting behavior in SHRs is mediated by changes in noradrenergic function. In Experiment 1, we found that 5, 10, or 21 days of access to a running wheel, but not 2 days, significantly reduced levels of the norepinephrine transporter (NET) in medial prefrontal cortex. In Experiment 2, we tested for a causal relationship between changes in noradrenergic function and orienting behavior by blocking noradrenergic receptors during exercise. Rats that received propranolol (beta adrenergic/noradrenergic receptor blocker) during 10 days of exercise failed to exhibit an exercise-induced reduction in orienting behavior. The results inform a growing literature regarding the effects of exercise on behavior and the potential use of exercise as a treatment for mental disorders. PMID:26030434

  5. Limbic but not non-limbic kindling impairs conditioned fear and promotes plasticity of NPY and its Y2 receptor.

    PubMed

    Botterill, J J; Guskjolen, A J; Marks, W N; Caruncho, H J; Kalynchuk, L E

    2015-11-01

    Epileptic seizures negatively affect cognition. However, the mechanisms that contribute to cognitive impairments after seizures are largely unknown. Here, we examined the effects of long-term kindling (i.e., 99 stimulations) of limbic (basolateral amygdala, dorsal hippocampus) and non-limbic (caudate nucleus) brain sites on conditioned fear and hippocampal plasticity. We first showed that kindling had no effect on acquisition of a hippocampal-dependent trace fear-conditioning task but limbic kindling impaired the retrieval of these fear memories. To determine the relationship between memory and hippocampal neuronal activity, we examined the expression of Fos protein 90 min after memory retrieval (i.e., 4 days after the last kindling stimulation). We found that limbic kindling, but not non-limbic kindling, decreased Fos expression in the granule cell layer, hilus, CA3 pyramidal cell layer, and CA1 pyramidal cell layer. Next, to investigate a mechanism that could contribute to dampen hippocampal neuronal activity in limbic-kindled rats, we focused on the endogenous anticonvulsant neuropeptide Y (NPY), which is expressed in a subset of GABAergic interneurons and can prevent glutamate release through interactions with its Y2 receptor. We found that limbic kindling significantly decreased the number of NPY-immunoreactive cells in several hippocampal subfields despite minimal staining of the neurodegenerative marker Fluoro-Jade B. However, we also noted that limbic kindling enhanced NPY immunoreactivity throughout the mossy fiber pathway. In these same regions, we observed limbic kindling-induced de novo expression of the NPY Y2 receptor. These novel findings demonstrate the site-specific effects of kindling on cognition and NPY plasticity, and they provide evidence that altered hippocampal NPY after limbic seizures coincides with dampened neural activity and cognitive impairments.

  6. Alpha-2 noradrenergic receptor activation inhibits the hyperpolarization-activated cation current (Ih ) in neurons of the ventral tegmental area

    PubMed Central

    Inyushin, Mikhail U.; Arencibia-Albite, Francisco; Vázquez-Torres, Rafael; Vélez-Hernández, María E.; Jiménez-Rivera, Carlos A.

    2010-01-01

    The ventral tegmental area (VTA) is the source of dopaminergic projections innervating cortical structures and ventral forebrain. Dysfunction of this mesocorticolimbic system is critically involved in psychiatric disorders such as addiction and schizophrenia. Changes in VTA dopamine (DA) neuronal activity can alter neurotransmitter release at target regions which modify information processing in the reward circuit. Here we studied the effect of α-2 noradrenergic receptor activation on the hyperpolarization-activated cation current (Ih ) in DA neurons of the rat VTA. Brain slice preparations using whole-cell current and voltage-clamp techniques were employed. Clonidine and UK14304 (α-2 receptor selective agonists) were found to decrease Ih amplitude and to slow its rate of activation indicating a negative shift in the current’s voltage dependence. Two non-subtype-selective α-2 receptor antagonists, yohimbine and RS79948, prevented the effects of α-2 receptor activation. RX821002, a noradrenergic antagonist specific for α-2A and α-2D did not prevent Ih inhibition. This result suggests that clonidine might be acting via an α-2C subtype since this receptor is the most abundant variant in the VTA. Analysis of a second messenger system associated with the α-2 receptor revealed that Ih inhibition is independent of cyclic adenosine monophosphate (cAMP) and resulted from the activation of protein kinase C. It is suggested that the α-2 mediated hyperpolarizing shift in Ih voltage dependence can facilitate the transition from pacemaker firing to afferent-driven burst activity. This transition may play a key role on the changes in synaptic plasticity that occurs in the mesocorticolimbic system under pathological conditions. PMID:20122999

  7. A2 noradrenergic neurons regulate forced swim test immobility.

    PubMed

    Nam, Hyungwoo; Kerman, Ilan A

    2016-10-15

    The Wistar-Kyoto (WKY) rat is a widely used animal model of depression, which is characterized by dysregulation of noradrenergic signaling. We previously demonstrated that WKY rats show a unique behavioral profile on the forced swim test (FST), characterized by high levels of immobility upon initial exposure and a greater learning-like response by further increasing immobility upon re-exposure than the genetically related Wistar rats. In the current study we aimed to determine whether altered activation of brainstem noradrenergic cell groups contributes to this behavioral profile. We exposed WKY and Wistar rats, to either 5min of forced swim or to the standard two-day FST (i.e. 15min forced swim on Day 1, followed by 5min on Day 2). We then stained their brains for FOS/tyrosine hydroxylase double-immunocytochemistry to determine potential differences in the activation of the brainstem noradrenergic cell groups. We detected a relative hyperactivation in the locus coeruleus of WKY rats when compared to Wistars in response to both one- and two-day forced swim. In contrast, within the A2 noradrenergic cell group, WKY rats exhibited diminished levels of FOS across both days of the FST, suggesting their lesser activation. We followed up these observations by selectively lesioning the A2 neurons, using anti-dopamine-β-hydroxylase-conjugated saporin, in Wistar rats, which resulted in increased FST immobility on both days of the test. Together these data indicate that the A2 noradrenergic cell group regulates FST behavior, and that its hypoactivation may contribute to the unique behavioral phenotype of WKY rats.

  8. Effects of abstinence from chronic cocaine self-administration on nonhuman primate dorsal and ventral noradrenergic bundle terminal field structures.

    PubMed

    Smith, Hilary R; Beveridge, Thomas J R; Nader, Michael A; Porrino, Linda J

    2016-06-01

    Repeated exposure to cocaine is known to dysregulate the norepinephrine system, and norepinephrine has also been implicated as having a role in abstinence and withdrawal. The goal of this study was to determine the effects of exposure to cocaine self-administration and subsequent abstinence on regulatory elements of the norepinephrine system in the nonhuman primate brain. Rhesus monkeys self-administered cocaine (0.3 mg/kg/injection, 30 reinforcers/session) under a fixed-interval 3-min schedule of reinforcement for 100 sessions. Animals in the abstinence group then underwent a 30-day period during which no operant responding was conducted, followed by a final session of operant responding. Control animals underwent identical schedules of food reinforcement and abstinence. This duration of cocaine self-administration has been shown previously to increase levels of norepinephrine transporters (NET) in the ventral noradrenergic bundle terminal fields. In contrast, in the current study, abstinence from chronic cocaine self-administration resulted in elevated levels of [(3)H]nisoxetine binding to the NET primarily in dorsal noradrenergic bundle terminal field structures. As compared to food reinforcement, chronic cocaine self-administration resulted in decreased binding of [(3)H]RX821002 to α2-adrenoceptors primarily in limbic-related structures innervated by both dorsal and ventral bundles, as well as elevated binding in the striatum. However, following abstinence from responding for cocaine binding to α2-adrenoceptors was not different than in control animals. These data demonstrate the dynamic nature of the regulation of norepinephrine during cocaine use and abstinence, and provide further evidence that the norepinephrine system should not be overlooked in the search for effective pharmacotherapies for cocaine dependence.

  9. Forebrain neurogenesis: From embryo to adult

    PubMed Central

    Dennis, Daniel; Picketts, David; Slack, Ruth S.; Schuurmans, Carol

    2017-01-01

    A satellite symposium to the Canadian Developmental Biology Conference 2016 was held on March 16–17, 2016 in Banff, Alberta, Canada, entitled Forebrain Neurogenesis: From embryo to adult. The Forebrain Neurogenesis symposium was a focused, high-intensity meeting, bringing together the top Canadian and international researchers in the field. This symposium reported the latest breaking news, along with ‘state of the art’ techniques to answer fundamental questions in developmental neurobiology. Topics covered ranged from stem cell regulation to neurocircuitry development, culminating with a session focused on neuropsychiatric disorders. Understanding the underlying causes of neurodevelopmental disorders such as autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD) is of great interest as diagnoses of these conditions are climbing at alarming rates. For instance, in 2012, the Centers for Disease Control reported that the prevalence rate of ASD in the U.S. was 1 in 88; while more recent data indicate that the number is as high as 1 in 68 (Centers for Disease Control and Prevention MMWR Surveillance Summaries. Vol. 63. No. 2). Similarly, the incidence of ASD is on the rise in Canada, increasing from 1 in 150 in 2000 to 1 in 63 in 2012 in southeastern Ontario (Centers for Disease Control and Prevention). Currently very little is known regarding the deficits underlying these neurodevelopmental conditions. Moreover, the development of effective therapies is further limited by major gaps in our understanding of the fundamental processes that regulate forebrain development and adult neurogenesis. The Forebrain Neurogenesis satellite symposium was thus timely, and it played a key role in advancing research in this important field, while also fostering collaborations between international leaders, and inspiring young researchers.

  10. Pre-frontal control of closed-loop limbic neurostimulation by rodents using a brain-computer interface

    NASA Astrophysics Data System (ADS)

    Widge, Alik S.; Moritz, Chet T.

    2014-04-01

    Objective. There is great interest in closed-loop neurostimulators that sense and respond to a patient's brain state. Such systems may have value for neurological and psychiatric illnesses where symptoms have high intraday variability. Animal models of closed-loop stimulators would aid preclinical testing. We therefore sought to demonstrate that rodents can directly control a closed-loop limbic neurostimulator via a brain-computer interface (BCI). Approach. We trained rats to use an auditory BCI controlled by single units in prefrontal cortex (PFC). The BCI controlled electrical stimulation in the medial forebrain bundle, a limbic structure involved in reward-seeking. Rigorous offline analyses were performed to confirm volitional control of the neurostimulator. Main results. All animals successfully learned to use the BCI and neurostimulator, with closed-loop control of this challenging task demonstrated at 80% of PFC recording locations. Analysis across sessions and animals confirmed statistically robust BCI control and specific, rapid modulation of PFC activity. Significance. Our results provide a preliminary demonstration of a method for emotion-regulating closed-loop neurostimulation. They further suggest that activity in PFC can be used to control a BCI without pre-training on a predicate task. This offers the potential for BCI-based treatments in refractory neurological and mental illness.

  11. Pre-frontal control of closed-loop limbic neurostimulation by rodents using a brain-computer interface.

    PubMed

    Widge, Alik S; Moritz, Chet T

    2014-04-01

    There is great interest in closed-loop neurostimulators that sense and respond to a patient's brain state. Such systems may have value for neurological and psychiatric illnesses where symptoms have high intraday variability. Animal models of closed-loop stimulators would aid preclinical testing. We therefore sought to demonstrate that rodents can directly control a closed-loop limbic neurostimulator via a brain-computer interface (BCI). We trained rats to use an auditory BCI controlled by single units in prefrontal cortex (PFC). The BCI controlled electrical stimulation in the medial forebrain bundle, a limbic structure involved in reward-seeking. Rigorous offline analyses were performed to confirm volitional control of the neurostimulator. All animals successfully learned to use the BCI and neurostimulator, with closed-loop control of this challenging task demonstrated at 80% of PFC recording locations. Analysis across sessions and animals confirmed statistically robust BCI control and specific, rapid modulation of PFC activity. Our results provide a preliminary demonstration of a method for emotion-regulating closed-loop neurostimulation. They further suggest that activity in PFC can be used to control a BCI without pre-training on a predicate task. This offers the potential for BCI-based treatments in refractory neurological and mental illness.

  12. Regulatory functions of limbic Y1 receptors in body weight and anxiety uncovered by conditional knockout and maternal care

    PubMed Central

    Bertocchi, Ilaria; Oberto, Alessandra; Longo, Angela; Mele, Paolo; Sabetta, Marianna; Bartolomucci, Alessandro; Palanza, Paola; Sprengel, Rolf; Eva, Carola

    2011-01-01

    Neuropeptide Y (NPY) plays an important role in stress, anxiety, obesity, and energy homeostasis via activation of NPY-Y1 receptors (Y1Rs) in the brain. However, global knockout of the Npy1r gene has low or no impact on anxiety and body weight. To uncover the role of limbic Y1Rs, we generated conditional knockout mice in which the inactivation of the Npy1r gene was restricted to excitatory neurons of the forebrain, starting from juvenile stages (Npy1rrfb). Npy1rrfb mice exhibited increased anxiety and reduced body weight, less adipose tissue, and lower serum leptin levels. Npy1rrfb mutants also had a hyperactive hypothalamic–pituitary–adrenocortical axis, as indicated by higher peripheral corticosterone and higher density of NPY immunoreactive fibers and corticotropin releasing hormone immunoreactive cell bodies in the paraventricular hypothalamic nucleus. Importantly, through fostering experiments, we determined that differences in phenotype between Npy1rrfb and Npy1r2lox mice became apparent when both genotypes were raised by FVB/J but not by C57BL/6J dams, suggesting that limbic Y1Rs are key targets of maternal care-induced programming of anxiety and energy homeostasis. PMID:22084082

  13. Constrained spherical deconvolution analysis of the limbic network in human, with emphasis on a direct cerebello-limbic pathway

    PubMed Central

    Arrigo, Alessandro; Mormina, Enricomaria; Anastasi, Giuseppe Pio; Gaeta, Michele; Calamuneri, Alessandro; Quartarone, Angelo; De Salvo, Simona; Bruschetta, Daniele; Rizzo, Giuseppina; Trimarchi, Fabio; Milardi, Demetrio

    2014-01-01

    The limbic system is part of an intricate network which is involved in several functions like memory and emotion. Traditionally the role of the cerebellum was considered mainly associated to motion control; however several evidences are raising about a role of the cerebellum in learning skills, emotions control, mnemonic and behavioral processes involving also connections with limbic system. In 15 normal subjects we studied limbic connections by probabilistic Constrained Spherical Deconvolution (CSD) tractography. The main result of our work was to prove for the first time in human brain the existence of a direct cerebello-limbic pathway which was previously hypothesized but never demonstrated. We also extended our analysis to the other limbic connections including cingulate fasciculus, inferior longitudinal fasciculus, uncinated fasciculus, anterior thalamic connections and fornix. Although these pathways have been already described in the tractographic literature we provided reconstruction, quantitative analysis and Fractional Anisotropy (FA) right-left symmetry comparison using probabilistic CSD tractography that is known to provide a potential improvement compared to previously used Diffusion Tensor Imaging (DTI) techniques. The demonstration of the existence of cerebello-limbic pathway could constitute an important step in the knowledge of the anatomic substrate of non-motor cerebellar functions. Finally the CSD statistical data about limbic connections in healthy subjects could be potentially useful in the diagnosis of pathological disorders damaging this system. PMID:25538606

  14. Noradrenergic modulation of space exploration in visual neglect.

    PubMed

    Malhotra, Paresh A; Parton, Andrew D; Greenwood, Richard; Husain, Masud

    2006-01-01

    Visual neglect after stroke is often associated with a failure to explore contralesional space. Here, we show that guanfacine, a noradrenergic agonist that modulates dorsolateral prefrontal cortex, improves leftward space exploration in selected right-hemisphere patients with neglect. The positive effects of guanfacine were associated with extended ability to maintain attention on task. The results suggest that neuropharmacological targeting of intact frontal areas might be one way to enhance cognitive function after damage to posterior brain regions in selected individuals.

  15. Noradrenergic regulation of fear and drug-associated memory reconsolidation.

    PubMed

    Otis, James M; Werner, Craig T; Mueller, Devin

    2015-03-01

    Emotional and traumatic experiences lead to the development of particularly strong memories that can drive neuropsychiatric disorders, such as posttraumatic stress disorder (PTSD) and drug addiction. Disruption of these memories would therefore serve as a powerful treatment option, and targeting the pathologic emotional, but not declarative, component of a memory would be ideal for clinical intervention. Research reveals that after retrieval of a consolidated memory, the memory can be destabilized, and must then be reconsolidated through synaptic plasticity to allow subsequent retrieval. Disruption of reconsolidation-related plasticity would therefore impair specific, reactivated memories. Noradrenergic signaling strengthens synaptic plasticity and is essential for encoding the emotional components of memory. Consistent with this, investigations have now revealed that noradrenergic signaling is a critical mechanism for reconsolidation of emotional memories in rodent and human models. Here, we discuss these investigations and promising clinical trials indicating that disruption of noradrenergic signaling during reconsolidation may abolish the pathologic emotional, but not declarative, component of memories allowing alleviation of neuropsychiatric disorders including PTSD and drug addiction.

  16. Noradrenergic Regulation of Fear and Drug-Associated Memory Reconsolidation

    PubMed Central

    Otis, James M; Werner, Craig T; Mueller, Devin

    2015-01-01

    Emotional and traumatic experiences lead to the development of particularly strong memories that can drive neuropsychiatric disorders, such as posttraumatic stress disorder (PTSD) and drug addiction. Disruption of these memories would therefore serve as a powerful treatment option, and targeting the pathologic emotional, but not declarative, component of a memory would be ideal for clinical intervention. Research reveals that after retrieval of a consolidated memory, the memory can be destabilized, and must then be reconsolidated through synaptic plasticity to allow subsequent retrieval. Disruption of reconsolidation-related plasticity would therefore impair specific, reactivated memories. Noradrenergic signaling strengthens synaptic plasticity and is essential for encoding the emotional components of memory. Consistent with this, investigations have now revealed that noradrenergic signaling is a critical mechanism for reconsolidation of emotional memories in rodent and human models. Here, we discuss these investigations and promising clinical trials indicating that disruption of noradrenergic signaling during reconsolidation may abolish the pathologic emotional, but not declarative, component of memories allowing alleviation of neuropsychiatric disorders including PTSD and drug addiction. PMID:25315025

  17. A Basal Forebrain Site Coordinates the Modulation of Endocrine and Behavioral Stress Responses via Divergent Neural Pathways

    PubMed Central

    Johnson, Shane B.; Emmons, Eric B.; Anderson, Rachel M.; Glanz, Ryan M.; Romig-Martin, Sara A.; Narayanan, Nandakumar S.; LaLumiere, Ryan T.

    2016-01-01

    The bed nuclei of the stria terminalis (BST) are critically important for integrating stress-related signals between the limbic forebrain and hypothalamo-pituitary-adrenal (HPA) effector neurons in the paraventricular hypothalamus (PVH). Nevertheless, the circuitry underlying BST control over the stress axis and its role in depression-related behaviors has remained obscure. Utilizing optogenetic approaches in rats, we have identified a novel role for the anteroventral subdivision of BST in the coordinated inhibition of both HPA output and passive coping behaviors during acute inescapable (tail suspension, TS) stress. Follow-up experiments probed axonal pathways emanating from the anteroventral BST which accounted for separable endocrine and behavioral functions subserved by this cell group. The PVH and ventrolateral periaqueductal gray were recipients of GABAergic outputs from the anteroventral BST that were necessary to restrain stress-induced HPA activation and passive coping behavior, respectively, during TS and forced swim tests. In contrast to other BST subdivisions implicated in anxiety-like responses, these results direct attention to the anteroventral BST as a nodal point in a stress-modulatory network for coordinating neuroendocrine and behavioral coping responses, wherein impairment could account for core features of stress-related mood disorders. SIGNIFICANCE STATEMENT Dysregulation of the neural pathways modulating stress-adaptive behaviors is implicated in stress-related psychiatric illness. While aversive situations activate a network of limbic forebrain regions thought to mediate such changes, little is known about how this information is integrated to orchestrate complex stress responses. Here we identify novel roles for the anteroventral bed nuclei of the stria terminalis in inhibiting both stress hormone output and passive coping behavior via divergent projections to regions of the hypothalamus and midbrain. Inhibition of these projections

  18. Estradiol replacement enhances sleep deprivation-induced c-Fos immunoreactivity in forebrain arousal regions of ovariectomized rats.

    PubMed

    Deurveilher, S; Cumyn, E M; Peers, T; Rusak, B; Semba, K

    2008-10-01

    To understand how female sex hormones influence homeostatic mechanisms of sleep, we studied the effects of estradiol (E(2)) replacement on c-Fos immunoreactivity in sleep/wake-regulatory brain areas after sleep deprivation (SD) in ovariectomized rats. Adult rats were ovariectomized and implanted subcutaneously with capsules containing 17beta-E(2) (10.5 microg; to mimic diestrous E(2) levels) or oil. After 2 wk, animals with E(2) capsules received a single subcutaneous injection of 17beta-E(2) (10 microg/kg; to achieve proestrous E(2) levels) or oil; control animals with oil capsules received an oil injection. Twenty-four hours later, animals were either left undisturbed or sleep deprived by "gentle handling" for 6 h during the early light phase, and killed. E(2) treatment increased serum E(2) levels and uterus weights dose dependently, while attenuating body weight gain. Regardless of hormonal conditions, SD increased c-Fos immunoreactivity in all four arousal-promoting areas and four limbic and neuroendocrine nuclei studied, whereas it decreased c-Fos labeling in the sleep-promoting ventrolateral preoptic nucleus (VLPO). Low and high E(2) treatments enhanced the SD-induced c-Fos immunoreactivity in the laterodorsal subnucleus of the bed nucleus of stria terminalis and the tuberomammillary nucleus, and in orexin-containing hypothalamic neurons, with no effect on the basal forebrain and locus coeruleus. The high E(2) treatment decreased c-Fos labeling in the VLPO under nondeprived conditions. These results indicate that E(2) replacement modulates SD-induced or spontaneous c-Fos expression in sleep/wake-regulatory and limbic forebrain nuclei. These modulatory effects of E(2) replacement on neuronal activity may be, in part, responsible for E(2)'s influence on sleep/wake behavior.

  19. Principles of rat subcortical forebrain organization: a study using histological techniques and multiple fluorescence labeling.

    PubMed

    Riedel, A; Härtig, W; Seeger, G; Gärtner, U; Brauer, K; Arendt, Th

    2002-02-01

    In the present study, we introduce new views on neuro- and chemoarchitectonics of the rat forebrain subcortex deduced from traditional and current concepts of anatomical organization and from our own results. It is based on double and triple immunofluorescence of markers for transmitter-related enzymes, calcium-binding proteins, receptor proteins, myelin basic protein (MBP) and neuropeptides, and on histological cell/myelin stains. The main findings can be summarized as follows: (i) the dorsal striatum of rat and other myomorph rodents reveals a small caudate equivalent homotopic to the caudate nucleus (C) of other mammals, and a large putamen (Pu). (ii) Shell and core can be distinguished also in the 'rostral pole' of nucleus accumbens (ACC) with the calretinin/calbindin and neuropeptide Y (NPY) immunostaining. The shell reveals characteristics of a genuine striatal but not of an extended amygdala (EA) subunit. (iii) EA and lateral septum show striking similarities in structure and fiber connections and may therefore represent a separate parastriatal complex. (iv) The meandering dense layer (DL) of olfactory tubercle (OT) forms longitudinal gyrus- and sulcus-like structures converging in its rostral pole. (v) The core regions of the islands of Calleja that border the ventral pallidum (VP) sharing some of its features are invaded by myelinated fibers of the medial forebrain bundle (MFB). The island of Calleja magna is also apposed to an inconspicuous, slender dorsal appendage of VP. (vi) The VP is composed of a large dorsal reticulated part traversed by the myelinated GABAergic parvalbumin-immunoreactive axons of the MFB and a slender ventral non-reticulate part close to the islands of Calleja. (vii) Considering their close association to the limbic system, ventral striatum (VS) and VP may represent the oldest part of basal ganglia, whereas dorsal striatopallidal subunits were progressively developed in parallel to the growing neocortical influence on motor

  20. Enhanced limbic/impaired cortical-loop connection onto the hippocampus of NHE rats: Application of resting-state functional connectivity in a preclinical ADHD model.

    PubMed

    Zoratto, F; Palombelli, G M; Ruocco, L A; Carboni, E; Laviola, G; Sadile, A G; Adriani, W; Canese, R

    2017-08-30

    Due to a hyperfunctioning mesocorticolimbic system, Naples-High-Excitability (NHE) rats have been proposed to model for the meso-cortical variant of attention deficit/hyperactivity disorder (ADHD). Compared to Naples Random-Bred (NRB) controls, NHE rats show hyperactivity, impaired non-selective attention (Aspide et al., 1998), and impaired selective spatial attention (Ruocco et al., 2009a, 2014). Alteration in limbic functions has been proposed; however, resulting unbalance among forebrain areas has not been assessed yet. By resting-state functional Magnetic-Resonance Imaging (fMRI) in vivo, we investigated the connectivity of neuronal networks belonging to limbic vs. cortical loops in NHE and NRB rats (n=10 each). Notably, resting-state fMRI was applied using a multi-slice sagittal, gradient-echo sequence. Voxel-wise connectivity maps at rest, based on temporal correlation among fMRI time-series, were computed by seeding the hippocampus (Hip), nucleus accumbens (NAcc), dorsal striatum (dStr), amygdala (Amy) and dorsal/medial prefrontal cortex (PFC), both hemispheres. To summarize patterns of altered connection, clearly directional connectivity was evident within the cortical loop: bilaterally and specularly, from orbital and dorsal PFCs through dStr and hence towards Hip. Such network communication was reduced in NHE rats (also, with less mesencephalic/pontine innervation). Conversely, enhanced network activity emerged within the limbic loop of NHE rats: from left PFC, both through the NAcc and directly, to the Hip (all of which received greater ventral tegmental innervation, likely dopamine). Together with tuned-down cortical loop, this potentiated limbic loop may serve a major role in controlling ADHD-like behavioral symptoms in NHE rats. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. Paraneoplastic limbic encephalitis presenting as acute viral encephalitis.

    PubMed

    Kararizou, E; Markou, I; Zalonis, I; Gkiatas, K; Triantafyllou, N; Kararizos, G; Likomanos, D; Zambelis, T; Vassilopoulos, D

    2005-11-01

    To describe a case of limbic encephalitis which initially presented as viral limbic encephalitis and during the clinical evaluation a renal carcinoma was diagnosed. Patient with history of peripheral paresis of right facial nerve, 1 month after symptoms appearance and treatment, developed fever, vomiting, grand mal seizure, decreased level of consciousness, confusion, hallucinations and agitation. The patient initially presented a clinical picture of viral LE. which confirmed by CSF. MRI brain showed areas with pathological intensity signal in the region of limbic system unilateral. During the clinical evaluation a renal carcinoma was discovered and a nephrectomy has been performed. Although PLE typically presents as a chronic or subacute disease, it may be fulminant and clinically indistinguishable from an acute HSVE. This association pose the problem of a possible relation between this two syndromes and the correct diagnosis is very important, because there are effective treatments.

  2. Nicotine alters limbic function in adolescent rat by a 5-HT1A receptor mechanism.

    PubMed

    Dao, Jasmin M; McQuown, Susan C; Loughlin, Sandra E; Belluzzi, James D; Leslie, Frances M

    2011-06-01

    Epidemiological studies have shown that adolescent smoking is associated with health risk behaviors, including high-risk sexual activity and illicit drug use. Using rat as an animal model, we evaluated the behavioral and biochemical effects of a 4-day, low-dose nicotine pretreatment (60 μg/kg; intravenous) during adolescence and adulthood. Nicotine pretreatment significantly increased initial acquisition of cocaine self-administration, quinpirole-induced locomotor activity, and penile erection in adolescent rats, aged postnatal day (P)32. These effects were long lasting, remaining evident 10 days after the last nicotine treatment, and were observed when nicotine pretreatment was administered during early adolescence (P28-31), but not late adolescence (P38-41) or adulthood (P86-89). Neurochemical analyses of c-fos mRNA expression, and of monoamine transmitter and transporter levels, showed that forebrain limbic systems are continuing to develop during early adolescence, and that this maturation is critically altered by brief nicotine exposure. Nicotine selectively increased c-fos mRNA expression in the nucleus accumbens shell and basolateral amygdala in adolescent, but not adult animals, and altered serotonin markers in these regions as well as the prefrontal cortex. Nicotine enhancement of cocaine self-administration and quinpirole-induced locomotor activity was blocked by co-administration of WAY 100 635 (N-{2-[4-(2-methoxyphenyl)-1-piperazinyl] ethyl}-N-(2-pyridinyl)cyclohexanecarboxamide), a selective serotonin 1A (5-HT1A) receptor antagonist. Early adolescent pretreatment with the mixed autoreceptor/heteroceptor 5-HT1A receptor agonist, 8-OH-DPAT, but not the autoreceptor-selective agonist, S-15535, also enhanced quinpirole-induced locomotor activation. Nicotine enhancement of quinpirole-induced penile erection was not blocked by WAY 100 635 nor mimicked by 8-OH-DPAT. These findings indicate that early adolescent nicotine exposure uniquely alters limbic

  3. Improvement of the noradrenergic symptom cluster following treatment with milnacipran.

    PubMed

    Kasper, Siegfried; Meshkat, Diana; Kutzelnigg, Alexandra

    2011-01-01

    Depression has a major impact on social functioning. Decreased concentration, mental and physical slowing, loss of energy, lassitude, tiredness, and reduced self-care are all symptoms related to reduced noradrenergic activity. Depressed mood; loss of interest or pleasure; sleep disturbances; and feelings of worthlessness, pessimism, and anxiety are related to reduced activity of both serotonergic and noradrenergic neurotransmission. The importance of noradrenergic neurotransmission in social functioning is supported by studies with the specific norepinephrine reuptake inhibitor reboxetine. In healthy volunteers, reboxetine increases cooperative social behavior and social drive. A placebo-controlled study in depressed patients comparing reboxetine with the selective serotonin reuptake inhibitor (SSRI) fluoxetine showed significantly greater improvement in social adaptation with reboxetine. Two recent studies have examined the effect of the serotonin and norepinephrine reuptake inhibitor milnacipran on social adaptation. A study in depressed patients found that at the end of 8 weeks of treatment with milnacipran, 42.2% patients were in remission on the Social Adaptation Self-evaluation Scale (SASS). Another study in depressed workers or homemakers found that mean depression scores were significantly reduced after 2 weeks, whereas the SASS scores were significantly improved after 4 weeks. A preliminary study comparing depressed patients treated with milnacipran or the SSRI paroxetine showed that milnacipran treatment resulted in a greater number of patients in social remission. The available data thus suggest that milnacipran may improve social functioning, with a possibly greater effect than the SSRI paroxetine. These preliminary data suggest further evaluation of social dysfunction and its treatment outcome in future trials of milnacipran.

  4. Forebrain connectivity of the prefrontal cortex in the marmoset monkey (Callithrix jacchus): an anterograde and retrograde tract-tracing study.

    PubMed

    Roberts, Angela C; Tomic, Davorka L; Parkinson, Caroline H; Roeling, Tom A; Cutter, David J; Robbins, Trevor W; Everitt, Barry J

    2007-05-01

    The cortical and subcortical forebrain connections of the marmoset prefrontal cortex (PFC) were examined by injecting the retrograde tracer, choleratoxin, and the anterograde tracer, biotin dextran amine, into four sites within the PFC. Two of the sites, the lateral and orbital regions, had previously been shown to provide functionally dissociable contributions to distinct forms of behavioral flexibility, attentional set-shifting and discrimination reversal learning, respectively. The dysgranular and agranular regions lying on the orbital and medial surfaces of the frontal lobes were most closely connected with limbic structures including cingulate cortex, amygdala, parahippocampal cortex, subiculum, hippocampus, hypothalamus, medial caudate nucleus, and nucleus accumbens as well as the magnocellular division of the mediodorsal nucleus of the thalamus and midline thalamic nuclei, consistent with findings in the rhesus monkey. In contrast, the granular region on the dorsal surface closely resembled area 8Ad in macaques and had connections restricted to posterior parietal cortex primarily associated with visuospatial functions. However, it also had connections with limbic cortex, including retrosplenial and caudal cingulate cortex as well as auditory processing regions in the superior temporal cortex. The granular region on the lateral convexity had the most extensive connections. Based on its architectonics and functionality, it resembled areas 12/45 in macaques. It had connections with high-order visual processing regions in the inferotemporal cortex and posterior parietal cortex, higher-order auditory and polymodal processing regions in the superior temporal cortex. In addition it had extensive connections with limbic regions including the amygdala, parahippocampal cortex, cingulate, and retrosplenial cortex.

  5. The bilaterian forebrain: an evolutionary chimaera.

    PubMed

    Tosches, Maria Antonietta; Arendt, Detlev

    2013-12-01

    The insect, annelid and vertebrate forebrains harbour two major centres of output control, a sensory-neurosecretory centre releasing hormones and a primordial locomotor centre that controls the initiation of muscular body movements. In vertebrates, both reside in the hypothalamus. Here, we review recent comparative neurodevelopmental evidence indicating that these centres evolved from separate condensations of neurons on opposite body sides ('apical nervous system' versus 'blastoporal nervous system') and that their developmental specification involved distinct regulatory networks (apical six3 and rx versus mediolateral nk and pax gene-dependent patterning). In bilaterian ancestors, both systems approached each other and became closely intermingled, physically, functionally and developmentally. Our 'chimeric brain hypothesis' sheds new light on the vast success and rapid diversification of bilaterian animals in the Cambrian and revises our understanding of brain architecture.

  6. Clonidine and Cortical Plasticity: Possible Evidence for Noradrenergic Involvement.

    DTIC Science & Technology

    1984-10-31

    D 616 CLONIDINE AND CORTICAL PLASTICITY POSSIBLE EVIDENCE / FOR NORADRENERGIC IN..(U) BROWIN UNIV PROVIDENCE RICENTER FOR NEURAL SCIENCE S B NELSON...plasticity in kitten visual cortex, we monocularly deprived kittens while administering the at-2 adrenergic agonist clonidine (CLON). To avoid bias in...Distribution/ AvailabilitY Codes Avail and/or Dist Special I. S N 0102- LF. 014- 6601 SECuRITY CLASSIVrCATION OF TMIS PA*S St’e DOI@ MAIN Clonidine and Cortical

  7. Genomic Perspectives of Transcriptional Regulation in Forebrain Development

    PubMed Central

    Nord, Alex S.; Pattabiraman, Kartik; Visel, Axel; Rubenstein, John L. R.

    2015-01-01

    The forebrain is the seat of higher order brain functions, and many human neuropsychiatric disorders are due to genetic defects affecting forebrain development, making it imperative to understand the underlying genetic circuitry. Recent progress now makes it possible to begin fully elucidating the genomic regulatory mechanisms that control forebrain gene expression. Herein, we discuss the current knowledge of how transcription factors drive gene expression programs through their interactions with cis-acting genomic elements, such as enhancers; how analyses of chromatin and DNA modifications provide insights into gene expression states; and how these approaches yield insights into the evolution of the human brain. PMID:25569346

  8. Genomic perspectives of transcriptional regulation in forebrain development.

    PubMed

    Nord, Alex S; Pattabiraman, Kartik; Visel, Axel; Rubenstein, John L R

    2015-01-07

    The forebrain is the seat of higher-order brain functions, and many human neuropsychiatric disorders are due to genetic defects affecting forebrain development, making it imperative to understand the underlying genetic circuitry. Recent progress now makes it possible to begin fully elucidating the genomic regulatory mechanisms that control forebrain gene expression. Herein, we discuss the current knowledge of how transcription factors drive gene expression programs through their interactions with cis-acting genomic elements, such as enhancers; how analyses of chromatin and DNA modifications provide insights into gene expression states; and how these approaches yield insights into the evolution of the human brain. Copyright © 2015 Elsevier Inc. All rights reserved.

  9. The memory function of noradrenergic activity in non-REM sleep.

    PubMed

    Gais, Steffen; Rasch, Björn; Dahmen, Johannes C; Sara, Susan; Born, Jan

    2011-09-01

    There is a long-standing assumption that low noradrenergic activity during sleep reflects mainly the low arousal during this brain state. Nevertheless, recent research has demonstrated that the locus coeruleus, which is the main source of cortical noradrenaline, displays discrete periods of intense firing during non-REM sleep, without any signs of awakening. This transient locus coeruleus activation during sleep seems to occur in response to preceding learning-related episodes. In the present study, we manipulate noradrenergic activity during sleep in humans with either the α2-autoreceptor agonist clonidine or the noradrenaline reuptake inhibitor reboxetine. We show that reducing noradrenergic activity during sleep, but not during wakefulness, impairs subsequent memory performance in an odor recognition task. Increasing noradrenergic availability during sleep, in contrast, enhances memory retention. We conclude that noradrenergic activity during non-REM sleep interacts with other sleep-related mechanisms to functionally contribute to off-line memory consolidation.

  10. Interaction of basal forebrain cholinergic neurons with the glucocorticoid system in stress regulation and cognitive impairment.

    PubMed

    Paul, Saswati; Jeon, Won Kyung; Bizon, Jennifer L; Han, Jung-Soo

    2015-01-01

    A substantial number of studies on basal forebrain (BF) cholinergic neurons (BFCN) have provided compelling evidence for their role in the etiology of stress, cognitive aging, Alzheimer's disease (AD), and other neurodegenerative diseases. BFCN project to a broad range of cortical sites and limbic structures, including the hippocampus, and are involved in stress and cognition. In particular, the hippocampus, the primary target tissue of the glucocorticoid stress hormones, is associated with cognitive function in tandem with hypothalamic-pituitary-adrenal (HPA) axis modulation. The present review summarizes glucocorticoid and HPA axis research to date in an effort to establish the manner in which stress affects the release of acetylcholine (ACh), glucocorticoids, and their receptor in the context of cognitive processes. We attempt to provide the molecular interactive link between the glucocorticoids and cholinergic system that contributes to BFCN degeneration in stress-induced acceleration of cognitive decline in aging and AD. We also discuss the importance of animal models in facilitating such studies for pharmacological use, to which could help decipher disease states and propose leads for pharmacological intervention.

  11. Interaction of basal forebrain cholinergic neurons with the glucocorticoid system in stress regulation and cognitive impairment

    PubMed Central

    Paul, Saswati; Jeon, Won Kyung; Bizon, Jennifer L.; Han, Jung-Soo

    2015-01-01

    A substantial number of studies on basal forebrain (BF) cholinergic neurons (BFCN) have provided compelling evidence for their role in the etiology of stress, cognitive aging, Alzheimer’s disease (AD), and other neurodegenerative diseases. BFCN project to a broad range of cortical sites and limbic structures, including the hippocampus, and are involved in stress and cognition. In particular, the hippocampus, the primary target tissue of the glucocorticoid stress hormones, is associated with cognitive function in tandem with hypothalamic-pituitary-adrenal (HPA) axis modulation. The present review summarizes glucocorticoid and HPA axis research to date in an effort to establish the manner in which stress affects the release of acetylcholine (ACh), glucocorticoids, and their receptor in the context of cognitive processes. We attempt to provide the molecular interactive link between the glucocorticoids and cholinergic system that contributes to BFCN degeneration in stress-induced acceleration of cognitive decline in aging and AD. We also discuss the importance of animal models in facilitating such studies for pharmacological use, to which could help decipher disease states and propose leads for pharmacological intervention. PMID:25883567

  12. Atomoxetine modulates spontaneous and sensory-evoked discharge of locus coeruleus noradrenergic neurons

    PubMed Central

    Bari, A.; Aston-Jones, G.

    2012-01-01

    Atomoxetine (ATM) is a potent norepinephrine (NE) uptake inhibitor and increases both NE and dopamine synaptic levels in prefrontal cortex, where it is thought to exert its beneficial effects on attention and impulsivity. At the behavioral level, ATM has been shown to cause improvements on measures of executive functions, such as response inhibition, working memory and attentional set shifting across different species. However, the exact mechanism of action for ATM’s effects on cognition is still not clear. One possible target for the cognitive enhancing effects of ATM is the noradrenergic locus coeruleus (LC), the only source of NE to key forebrain areas such as cerebral cortex and hippocampus. Although it is known that ATM increases NE availability overall by blocking reuptake of NE, the effects of this agent on impulse activity of LC neurons have not been reported. Here, the effect of ATM (0.1 – 1 mg/kg, ip) on NE-LC neurons was investigated by recording extracellular activity of LC neurons in isoflurane-anesthetized rats. ATM caused a significant decrease of the tonic activity of LC single-units, although leaving intact the sensory-evoked excitatory component of LC phasic response. Moreover, the magnitude of the inhibitory component of LC response to paw stimulation was increased after 1 mg/kg of ATM and its duration was prolonged at 0.3 mg/kg. Together, these effects of ATM produced an increase in the phasic-to-tonic ratio of LC phasic response to sensory stimulation. ATM also modulated the average sensory-evoked local field potential (LFP) and spike-field coherence in LC depending on the dose tested. The lower dose (0.1 mg/kg) significantly decreased early positive and negative components of the sensory-evoked LFP response. Higher doses (0.3–1 mg/kg) initially increased and then decreased the amplitude of components of the evoked fields, whereas the spike-field coherence was enhanced by 1 mg/kg ATM across frequency bands. Finally, coherence between LC

  13. Locus Coeruleus Kappa-Opioid Receptors Modulate Reinstatement of Cocaine Place Preference Through a Noradrenergic Mechanism

    PubMed Central

    Al-Hasani, Ream; McCall, Jordan G; Foshage, Audra M; Bruchas, Michael R

    2013-01-01

    Activation of kappa-opioid receptors (KORs) in monoamine circuits results in dysphoria-like behaviors and stress-induced reinstatement of drug seeking in both conditioned place preference (CPP) and self-administration models. Noradrenergic (NA) receptor systems have also been implicated in similar behaviors. Dynorphinergic projections terminate within the locus coeruleus (LC), a primary source of norepinephrine in the forebrain, suggesting a possible link between the NA and dynorphin/kappa opioid systems, yet the implications of these putative interactions have not been investigated. We isolated the necessity of KORs in the LC in kappa opioid agonist (U50,488)-induced reinstatement of cocaine CPP by blocking KORs in the LC with NorBNI (KOR antagonist). KOR-induced reinstatement was significantly attenuated in mice injected with NorBNI in the LC. To determine the sufficiency of KORs in the LC on U50,488-induced reinstatement of cocaine CPP, we virally re-expressed KORs in the LC of KOR knockout mice. We found that KORs expression in the LC alone was sufficient to partially rescue KOR-induced reinstatement. Next we assessed the role of NA signaling in KOR-induced reinstatement of cocaine CPP in the presence and absence of a α2-agonist (clonidine), β-adrenergic receptor antagonist (propranolol), and β1- and β2-antagonist (betaxolol and ICI-118,551 HCl). Both the blockade of postsynaptic β1-adrenergic receptors and the activation of presynaptic inhibitory adrenergic autoreceptors selectively potentiated the magnitude of KOR-induced reinstatement of cocaine CPP but not cocaine-primed CPP reinstatement. Finally, viral restoration of KORs in the LC together with β-adrenergic receptor blockade did not potentiate KOR-induced reinstatement to cocaine CPP, suggesting that adrenergic receptor interactions occur at KOR-expressing regions external to the LC. These results identify a previously unknown interaction between KORs and NA systems and suggest a NA regulation of

  14. Locus coeruleus kappa-opioid receptors modulate reinstatement of cocaine place preference through a noradrenergic mechanism.

    PubMed

    Al-Hasani, Ream; McCall, Jordan G; Foshage, Audra M; Bruchas, Michael R

    2013-11-01

    Activation of kappa-opioid receptors (KORs) in monoamine circuits results in dysphoria-like behaviors and stress-induced reinstatement of drug seeking in both conditioned place preference (CPP) and self-administration models. Noradrenergic (NA) receptor systems have also been implicated in similar behaviors. Dynorphinergic projections terminate within the locus coeruleus (LC), a primary source of norepinephrine in the forebrain, suggesting a possible link between the NA and dynorphin/kappa opioid systems, yet the implications of these putative interactions have not been investigated. We isolated the necessity of KORs in the LC in kappa opioid agonist (U50,488)-induced reinstatement of cocaine CPP by blocking KORs in the LC with NorBNI (KOR antagonist). KOR-induced reinstatement was significantly attenuated in mice injected with NorBNI in the LC. To determine the sufficiency of KORs in the LC on U50,488-induced reinstatement of cocaine CPP, we virally re-expressed KORs in the LC of KOR knockout mice. We found that KORs expression in the LC alone was sufficient to partially rescue KOR-induced reinstatement. Next we assessed the role of NA signaling in KOR-induced reinstatement of cocaine CPP in the presence and absence of a α2-agonist (clonidine), β-adrenergic receptor antagonist (propranolol), and β(1)- and β(2)-antagonist (betaxolol and ICI-118,551 HCl). Both the blockade of postsynaptic β(1)-adrenergic receptors and the activation of presynaptic inhibitory adrenergic autoreceptors selectively potentiated the magnitude of KOR-induced reinstatement of cocaine CPP but not cocaine-primed CPP reinstatement. Finally, viral restoration of KORs in the LC together with β-adrenergic receptor blockade did not potentiate KOR-induced reinstatement to cocaine CPP, suggesting that adrenergic receptor interactions occur at KOR-expressing regions external to the LC. These results identify a previously unknown interaction between KORs and NA systems and suggest a NA

  15. Angiotensin II-noradrenergic interactions in renovascular hypertensive rats.

    PubMed Central

    Zimmerman, J B; Robertson, D; Jackson, E K

    1987-01-01

    This study tested the hypothesis that interactions of endogenous angiotensin II (AII) with the noradrenergic neuroeffector junction are important in renin-dependent hypertension. In the in situ blood-perfused rat mesentery, in normal rats exogenous AII potentiated mesenteric vascular responses to periarterial (sympathetic) nerve stimulation (PNS) more than vascular responses to exogenous norepinephrine (NE). In 2-kidney-1-clip (2K-1C) rats with renovascular hypertension mesenteric vascular responses to PNS and NE were greater than in sham-operated rats, and renovascular hypertension mimicked the effects of exogenous AII with respect to enhancing responses to PNS more than responses to NE. In 2K-1C rats, but not in sham-operated rats, 1-Sar-8-Ile-AII markedly suppressed vascular responses to PNS, without influencing responses to NE. Finally, 1-Sar-8-Ile-AII attenuated sympathetic nerve stimulation-induced neuronal spillover of NE in 2K-1C rats, but not in sham-operated rats. These data indicate that renovascular hypertension enhances noradrenergic neurotransmission, and that this enhancement is mediated in part by AII-induced facilitation of NE release. PMID:3301900

  16. Mirtazapine: an antidepressant with noradrenergic and specific serotonergic effects.

    PubMed

    Stimmel, G L; Dopheide, J A; Stahl, S M

    1997-01-01

    Mirtazapine is a unique antidepressant that refines the specificity of effects on noradrenergic and serotonergic systems. It is an antagonist of presynaptic alpha 2-adrenergic autoreceptors and heteroreceptors on both norepinephrine and serotonin (5-HT) presynaptic axons, plus is a potent antagonist of postsynaptic 5-HT2 and 5-HT3 receptors. The net outcome of these effects is increased noradrenergic activity together with specific increased serotonergic activity, especially at 5-HT1A receptors. This mechanism of action maintains equivalent antidepressant efficacy but minimizes many of the adverse effects common to both tricyclic antidepressants and selective serotonin reuptake inhibitors. Mirtazapine has an onset of clinical effect in 2-4 weeks similar to other antidepressants, although sleep disturbances and anxiety symptoms may improve in the first week of treatment. It has minimal cardiovascular and anticholinergic effects, and essentially lacks serotonergic effects such as gastrointestinal symptoms, insomnia, and sexual dysfunction. Sedation, increased appetite, and weight gain are more common with mirtazapine than with placebo. An elimination half-life of 20-40 hours enables once-daily bedtime dosing. The recommended initial dosage is 15 mg once/day at bedtime, with an effective daily dosage range of 15-45 mg. Cases of overdose of up to 975 mg caused significant sedation but no cardiovascular or respiratory effects or seizures.

  17. Histamine excites noradrenergic neurons in locus coeruleus in rats.

    PubMed

    Korotkova, Tatiana M; Sergeeva, Olga A; Ponomarenko, Alexei A; Haas, Helmut L

    2005-07-01

    Histamine is implicated in the control of many brain functions, in particular the control of arousal. Histaminergic neurons send dense projections through the entire brain, including the locus coeruleus (LC)--the main noradrenergic (NAergic) nucleus. In this study, we have examined the effect of bath-applied histamine on cells in the LC by single-unit recordings in slices and the expression of histamine receptors in this area by single-cell RT-PCR. Histamine (10 microM) increased the firing of NAergic cells to 130+/-9% of control, 100 microM to 256+/-58% of control. This excitation was unaffected by blocking synaptic transmission. Histamine-mediated excitation was blocked by an H1 receptor antagonist, mepyramine, in 78% of cells and by cimetidine, an H2 receptor antagonist, in 42% of cells, but not by the H3 receptor antagonist, thioperamide. RT-PCR revealed that mRNA for the H1 receptor was expressed in 77% of isolated LC neurons, mRNA for the H2 receptor in 41% of LC neurons and H3 receptors in 29%. These findings underline the coordination between aminergic systems and suggest that the arousal induced by the histamine system could involve excitation of noradrenergic neurons in the locus coeruleus.

  18. Amphetamine and cocaine induce drug-specific activation of the c-fos gene in striosome-matrix compartments and limbic subdivisions of the striatum.

    PubMed Central

    Graybiel, A M; Moratalla, R; Robertson, H A

    1990-01-01

    Amphetamine and cocaine are stimulant drugs that act on central monoaminergic neurons to produce both acute psychomotor activation and long-lasting behavioral effects including addiction and psychosis. Here we report that single doses of these drugs induce rapid expression of the nuclear proto-oncogene c-fos in the forebrain and particularly in the striatum, an extrapyramidal structure implicated in addiction and in long-term drug-induced changes in motor function. The two drugs induce strikingly different patterns of c-fos expression in the striosome-matrix compartments and limbic subdivisions of the striatum, and their effects are pharmacologically distinct, although both are sensitive to dopamine receptor blockade. We propose that differential activation of immediate-early genes by psychostimulants may be an early step in drug-specific molecular cascades contributing to acute and long-lasting psychostimulant-induced changes in behavior. Images PMID:2118661

  19. Expression and role of Roundabout-1 in embryonic Xenopus forebrain.

    PubMed

    Connor, R M; Key, B

    2002-09-01

    The receptor Roundabout-1 (Robo1) and its ligand Slit are known to influence axon guidance and central nervous system (CNS) patterning in both vertebrate and nonvertebrate systems. Although Robo-Slit interactions mediate axon guidance in the Drosophila CNS, their role in establishing the early axon scaffold in the embryonic vertebrate brain remains unclear. We report here the identification and expression of a Xenopus Robo1 orthologue that is highly homologous to mammalian Robo1. By using overexpression studies and immunohistochemical and in situ hybridization techniques, we have investigated the role of Robo1 in the development of a subset of neurons and axon tracts in the Xenopus forebrain. Robo1 is expressed in forebrain nuclei and in neuroepithelial cells underlying the main axon tracts. Misexpression of Robo1 led to aberrant development of axon tracts as well as the ectopic differentiation of forebrain neurons. These results implicate Robo1 in both neuronal differentiation and axon guidance in embryonic vertebrate forebrain.

  20. Connections of the limbic network: a corticocortical evoked potentials study.

    PubMed

    Enatsu, Rei; Gonzalez-Martinez, Jorge; Bulacio, Juan; Kubota, Yuichi; Mosher, John; Burgess, Richard C; Najm, Imad; Nair, Dileep R

    2015-01-01

    Papez proposed a network for higher brain function, which is termed the limbic network. However, the in vivo human limbic network has not been established. We investigated the connectivity of the human limbic system using corticocortical evoked potential (CCEP). This retrospective analysis included 28 patients with medically intractable focal epilepsy who underwent stereoelectroencephalography (SEEG) and CCEP. Alternating 1 Hz electrical stimuli were delivered to parts of the limbic system [anterior and posterior hippocampus, temporal pole, parahippocampal gyrus (PHG), amygdala, anterior (ACG) and posterior cingulate gyrus (PCG), medial and lateral orbitofrontal cortex (OF)]. A total of 40-60 stimuli were averaged in each trial to obtain CCEP responses. CCEP distributions were evaluated by calculating the root mean square (RMS) of CCEP responses. Anterior hippocampal stimulation elicited prominent CCEP responses in medial and lateral temporal structures, PCG, medial OF and insula over the ipsilateral hemisphere. Posterior hippocampal stimulation induced CCEP responses in the ipsilateral medial and lateral temporal structures and PCG. The findings also revealed connections from temporal pole to the ipsilateral medial temporal structures, and connections from PHG to the ipsilateral hippocampus and PCG. The amygdala projected to broad areas including the ipsilateral medial and lateral temporal structures, medial and lateral frontal areas, the cingulate gyrus, insula and inferior parietal lobule. ACG and PCG showed connections to the ipsilateral medial fronto-parietal areas and connections to bilateral medial temporo-parieto-occipital and lateral parieto-occipital areas, respectively. Medial and lateral OF stimulation induced responses in the adjacent cortices. This study revealed that various regions within the limbic network are intimately connected in reverberating circuits and are linked to specific ipsilateral and contralateral regions, which may reflect

  1. Mosaic Subventricular Origins of Forebrain Oligodendrogenesis

    PubMed Central

    Azim, Kasum; Berninger, Benedikt; Raineteau, Olivier

    2016-01-01

    In the perinatal as well as the adult CNS, the subventricular zone (SVZ) of the forebrain is the largest and most active source of neural stem cells (NSCs) that generates neurons and oligodendrocytes (OLs), the myelin forming cells of the CNS. Recent advances in the field are beginning to shed light regarding SVZ heterogeneity, with the existence of spatially segregated microdomains that are intrinsically biased to generate phenotypically distinct neuronal populations. Although most research has focused on this regionalization in the context of neurogenesis, newer findings underline that this also applies for the genesis of OLs under the control of specific patterning molecules. In this mini review, we discuss the origins as well as the mechanisms that induce and maintain SVZ regionalization. These come in the flavor of specific signaling ligands and subsequent initiation of transcriptional networks that provide a basis for subdividing the SVZ into distinct lineage-specific microdomains. We further emphasize canonical Wnts and FGF2 as essential signaling pathways for the regional genesis of OL progenitors from NSCs of the dorsal SVZ. This aspect of NSC biology, which has so far received little attention, may unveil new avenues for appropriately recruiting NSCs in demyelinating diseases. PMID:27047329

  2. Behavioral models in mice. Implication of the alpha noradrenergic system.

    PubMed

    Hascoët, M; Bourin, M; Bradwejn, J

    1991-01-01

    1. The mechanism of action of drugs might change according to the test used. Several noradrenergic drugs were tested in order to understand their implication in the mobility tests. 2. It was found that clonidine, an Alpha 2 agonist, acted differently according to the test used. It provoked sedation in spontaneous activity test, and anti-immobility effects in the other tests. 3. Tail suspension test is able to show the double acting of clonidine. 4. Idazoxan might act either as an alpha 2 antagonist or as partial alpha 2 agonist. TST shown the unexpected partial alpha agonist effect of the molecule. 5. Forced swimming test is more specific for predicting antidepressant activity than tail suspension test which is close to a spontaneous activity model.

  3. Noradrenergic mechanisms of arousal's bidirectional effects on episodic memory.

    PubMed

    Clewett, David; Sakaki, Michiko; Nielsen, Shawn; Petzinger, Giselle; Mather, Mara

    2017-01-01

    Arousal's selective effects on cognition go beyond the simple enhancement of emotional stimuli, sometimes enhancing and other times impairing processing of proximal neutral information. Past work shows that arousal impairs encoding of subsequent neutral stimuli regardless of their top-down priority via the engagement of β-adrenoreceptors. In contrast, retrograde amnesia induced by emotional arousal can flip to enhancement when preceding neutral items are prioritized in top-down attention. Whether β-adrenoreceptors also contribute to this retrograde memory enhancement of goal-relevant neutral stimuli is unclear. In this pharmacological study, we administered 40mg of propranolol or 40mg of placebo to healthy young adults to examine whether emotional arousal's bidirectional effects on declarative memory relies on β-adrenoreceptor activation. Following pill intake, participants completed an emotional oddball task in which they were asked to prioritize a neutral object appearing just before an emotional or neutral oddball image within a sequence of 7 neutral objects. Under placebo, emotional oddballs impaired memory for lower priority oddball+1 objects but had no effect on memory for high priority oddball-1 objects. Propranolol blocked this anterograde amnesic effect of arousal. Emotional oddballs also enhanced selective memory trade-offs significantly more in the placebo than drug condition, such that high priority oddball-1 objects were more likely to be remembered at the cost of their corresponding lower priority oddball+1 objects under arousal. Lastly, those who recalled more high priority oddball-1 objects preceding an emotional versus neutral oddball image showed greater increases in salivary alpha-amylase, a biomarker of noradrenergic system activation, across the task. Together these findings suggest that different noradrenergic mechanisms contribute to the anterograde and retrograde mnemonic effects of arousal on proximal neutral memoranda. Copyright © 2016

  4. Selective noradrenergic vulnerability in α-synuclein transgenic mice.

    PubMed

    Sotiriou, Evangelos; Vassilatis, Demetrios K; Vila, Miquel; Stefanis, Leonidas

    2010-12-01

    Classical pathological signs of Parkinson's disease (PD) include loss of dopaminergic neurons in substantia nigra (SN) and noradrenergic neurons in locus coeruleus (LC), and deposition of Lewy bodies rich in the presynaptic protein alpha-synuclein (ASYN). Mammalian genetic models based on ASYN overexpression, however, have generally not reproduced the profound dopaminergic deficit of PD and do not display classical PD phenotypes. In the current study we examined these catecholaminergic systems in transgenic (Tg) mice expressing the A53T mutant of human ASYN under the Prion promoter. Surprisingly we detected a substantial reduction in norepinephrine (NE), but not dopamine (DA), levels in spinal cord, olfactory bulb and striatum of aged (15-month-old), but not young (4-month-old) transgenic compared to control mice. In spinal cord and olfactory bulb of 15-month-old Tg mice there was an age-dependent decrease in tyrosine hydroxylase (TH) protein levels, which in spinal cord was accompanied by a decrease in TH-positive terminals detected by immunohistochemistry. There was no difference in the number of TH-positive neuron cell bodies in SN or LC between Tg and control mice. We conclude that aberrant ASYN, expressed in both SN and LC, induces preferential degeneration of noradrenergic terminals. These observations suggest that in mice the NE may be more vulnerable than the DA system to the toxic effects of aberrant alpha-synuclein, and are in line with the major damage to the NE system that occurs in patients with PD. Copyright © 2008 Elsevier Inc. All rights reserved.

  5. Noradrenergic antidepressants increase cortical dopamine: potential use in augmentation strategies.

    PubMed

    Masana, Mercè; Castañé, Anna; Santana, Noemí; Bortolozzi, Analía; Artigas, Francesc

    2012-09-01

    Most antidepressant treatments, based on serotonin (5-HT) and/or norepinephrine (NE) transporter blockade, show limited efficacy and slow onset of action, requiring the use of augmentation strategies. Here we report on a novel antidepressant strategy to selectively increase DA function in prefrontal cortex (PFC) without the potential tolerance problems associated to DA transporter blockade. This approach is based on previous observations indicating that extracellular DA in rat medial PFC (mPFC) - but not in nucleus accumbens (NAc) - arises from noradrenergic terminals and is sensitive to noradrenergic drugs. A low dose of reboxetine (3 mg/kg i.p.; NE reuptake inhibitor) non-significantly increased extracellular DA in mPFC. Interestingly, its combined administration with 5 mg/kg s.c. mirtazapine (non-selective α₂-adrenoceptor antagonist) increased extracellular DA in mPFC (264 ± 28%), but not in NAc. Extracellular NE (but not 5-HT) in mPFC was also enhanced by the combined treatment (472 ± 70%). Repeated (×3) reboxetine + mirtazapine administration produced a moderate additional increase in mPFC DA and markedly reduced the immobility time (-51%) in the forced-swim test. Neurochemical and behavioral effects of the reboxetine + mirtazapine combination persisted in rats pretreated with citalopram (3 mg/kg, s.c.), suggesting its potential usefulness to augment SSRI effects. In situ hybridization c-fos studies were performed to examine the brain areas involved in the above antidepressant-like effects, showing changes in c-fos expression in hippocampal and cortical areas. BDNF expression was also increased in the hippocampal formation. Overall, these results indicate a synergistic effect of the reboxetine + mirtazapine combination to increase DA and NE function in mPFC and to evoke robust antidepressant-like responses.

  6. The mRNA expression and histological integrity in rat forebrain motor and sensory regions are minimally affected by acrylamide exposure through drinking water

    SciTech Connect

    Bowyer, John F.; Latendresse, John R.; Delongchamp, Robert R.; Warbritton, Alan R.; Thomas, Monzy; Divine, Becky; Doerge, Daniel R.

    2009-11-01

    A study was undertaken to determine whether alterations in the gene expression or overt histological signs of neurotoxicity in selected regions of the forebrain might occur from acrylamide exposure via drinking water. Gene expression at the mRNA level was evaluated by cDNA array and/or RT-PCR analysis in the striatum, substantia nigra and parietal cortex of rat after a 2-week acrylamide exposure. The highest dose tested (maximally tolerated) of approximately 44 mg/kg/day resulted in a significant decreased body weight, sluggishness, and locomotor activity reduction. These physiological effects were not accompanied by prominent changes in gene expression in the forebrain. All the expression changes seen in the 1200 genes that were evaluated in the three brain regions were <= 1.5-fold, and most not significant. Very few, if any, statistically significant changes were seen in mRNA levels of the more than 50 genes directly related to the cholinergic, noradrenergic, GABAergic or glutamatergic neurotransmitter systems in the striatum, substantia nigra or parietal cortex. All the expression changes observed in genes related to dopaminergic function were less than 1.5-fold and not statistically significant and the 5HT1b receptor was the only serotonin-related gene affected. Therefore, gene expression changes were few and modest in basal ganglia and sensory cortex at a time when the behavioral manifestations of acrylamide toxicity had become prominent. No histological evidence of axonal, dendritic or neuronal cell body damage was found in the forebrain due to the acrylamide exposure. As well, microglial activation was not present. These findings are consistent with the absence of expression changes in genes related to changes in neuroinflammation or neurotoxicity. Over all, these data suggest that oral ingestion of acrylamide in drinking water or food, even at maximally tolerable levels, induced neither marked changes in gene expression nor neurotoxicity in the motor and

  7. The mRNA expression and histological integrity in rat forebrain motor and sensory regions are minimally affected by acrylamide exposure through drinking water.

    PubMed

    Bowyer, John F; Latendresse, John R; Delongchamp, Robert R; Warbritton, Alan R; Thomas, Monzy; Divine, Becky; Doerge, Daniel R

    2009-11-01

    A study was undertaken to determine whether alterations in the gene expression or overt histological signs of neurotoxicity in selected regions of the forebrain might occur from acrylamide exposure via drinking water. Gene expression at the mRNA level was evaluated by cDNA array and/or RT-PCR analysis in the striatum, substantia nigra and parietal cortex of rat after a 2-week acrylamide exposure. The highest dose tested (maximally tolerated) of approximately 44 mg/kg/day resulted in a significant decreased body weight, sluggishness, and locomotor activity reduction. These physiological effects were not accompanied by prominent changes in gene expression in the forebrain. All the expression changes seen in the 1200 genes that were evaluated in the three brain regions were < or =1.5-fold, and most not significant. Very few, if any, statistically significant changes were seen in mRNA levels of the more than 50 genes directly related to the cholinergic, noradrenergic, GABAergic or glutamatergic neurotransmitter systems in the striatum, substantia nigra or parietal cortex. All the expression changes observed in genes related to dopaminergic function were less than 1.5-fold and not statistically significant and the 5HT1b receptor was the only serotonin-related gene affected. Therefore, gene expression changes were few and modest in basal ganglia and sensory cortex at a time when the behavioral manifestations of acrylamide toxicity had become prominent. No histological evidence of axonal, dendritic or neuronal cell body damage was found in the forebrain due to the acrylamide exposure. As well, microglial activation was not present. These findings are consistent with the absence of expression changes in genes related to changes in neuroinflammation or neurotoxicity. Over all, these data suggest that oral ingestion of acrylamide in drinking water or food, even at maximally tolerable levels, induced neither marked changes in gene expression nor neurotoxicity in the motor and

  8. Understanding the links between vestibular and limbic systems regulating emotions.

    PubMed

    Rajagopalan, Archana; Jinu, K V; Sailesh, Kumar Sai; Mishra, Soumya; Reddy, Udaya Kumar; Mukkadan, Joseph Kurien

    2017-01-01

    Vestibular system, which consists of structures in the inner ear and brainstem, plays a vital role is body balance and patient well-being. In recent years, modulating this system by vestibular stimulation techniques are reported to be effective in stress relief and possibly patient's emotional well-being. Emotions refer to an aroused state involving intense feeling, autonomic activation, and related change in behavior, which accompany many of our conscious experiences. The limbic system is primarily involved in the regulation of emotions. Considering the extensive networks between vestibular and limbic system, it is likely that vestibular stimulation techniques may be useful in influencing emotions. Hence, we review here, the possible mechanisms through which vestibular system can influence emotions and highlight the necessary knowledge gaps, which warrants further research to develop vestibular stimulation techniques as a means to treat health conditions associated with emotional disturbances.

  9. Understanding the links between vestibular and limbic systems regulating emotions

    PubMed Central

    Rajagopalan, Archana; Jinu, K. V.; Sailesh, Kumar Sai; Mishra, Soumya; Reddy, Udaya Kumar; Mukkadan, Joseph Kurien

    2017-01-01

    Vestibular system, which consists of structures in the inner ear and brainstem, plays a vital role is body balance and patient well-being. In recent years, modulating this system by vestibular stimulation techniques are reported to be effective in stress relief and possibly patient's emotional well-being. Emotions refer to an aroused state involving intense feeling, autonomic activation, and related change in behavior, which accompany many of our conscious experiences. The limbic system is primarily involved in the regulation of emotions. Considering the extensive networks between vestibular and limbic system, it is likely that vestibular stimulation techniques may be useful in influencing emotions. Hence, we review here, the possible mechanisms through which vestibular system can influence emotions and highlight the necessary knowledge gaps, which warrants further research to develop vestibular stimulation techniques as a means to treat health conditions associated with emotional disturbances. PMID:28250668

  10. Limbic grey matter changes in early Parkinson's disease.

    PubMed

    Li, Xingfeng; Xing, Yue; Schwarz, Stefan T; Auer, Dorothee P

    2017-05-02

    The purpose of this study was to investigate local and network-related changes of limbic grey matter in early Parkinson's disease (PD) and their inter-relation with non-motor symptom severity. We applied voxel-based morphometric methods in 538 T1 MRI images retrieved from the Parkinson's Progression Markers Initiative website. Grey matter densities and cross-sectional estimates of age-related grey matter change were compared between subjects with early PD (n = 366) and age-matched healthy controls (n = 172) within a regression model, and associations of grey matter density with symptoms were investigated. Structural brain networks were obtained using covariance analysis seeded in regions showing grey matter abnormalities in PD subject group. Patients displayed focally reduced grey matter density in the right amygdala, which was present from the earliest stages of the disease without further advance in mild-moderate disease stages. Right amygdala grey matter density showed negative correlation with autonomic dysfunction and positive with cognitive performance in patients, but no significant interrelations were found with anxiety scores. Patients with PD also demonstrated right amygdala structural disconnection with less structural connectivity of the right amygdala with the cerebellum and thalamus but increased covariance with bilateral temporal cortices compared with controls. Age-related grey matter change was also increased in PD preferentially in the limbic system. In conclusion, detailed brain morphometry in a large group of early PD highlights predominant limbic grey matter deficits with stronger age associations compared with controls and associated altered structural connectivity pattern. This provides in vivo evidence for early limbic grey matter pathology and structural network changes that may reflect extranigral disease spread in PD. Hum Brain Mapp, 2017. © 2017 The Authors Human Brain Mapping Published by Wiley Periodicals, Inc. © 2017 The

  11. Cortical deactivation induced by subcortical network dysfunction in limbic seizures

    PubMed Central

    Englot, Dario J.; Modi, Badri; Mishra, Asht M.; DeSalvo, Matthew; Hyder, Fahmeed; Blumenfeld, Hal

    2009-01-01

    Normal human consciousness may be impaired by two possible routes: direct reduced function in widespread cortical regions, or indirect disruption of subcortical activating systems. The route through which temporal lobe limbic seizures impair consciousness is not known. We recently developed an animal model which, like human limbic seizures, exhibits neocortical deactivation including cortical slow waves and reduced cortical cerebral blood flow (CBF). We now find through functional MRI (fMRI) that electrically-stimulated hippocampal seizures in rats cause increased activity in subcortical structures including the septal area and mediodorsal thalamus, along with reduced activity in frontal, cingulate, and retrosplenial cortex. Direct recordings from the hippocampus, septum, and medial thalamus demonstrated fast poly-spike activity associated with increased neuronal firing and CBF, while frontal cortex showed slow oscillations with decreased neuronal firing and CBF. Stimulation of septal area, but not hippocampus or medial thalamus, in the absence of a seizure resulted in cortical deactivation with slow oscillations and behavioral arrest, resembling changes seen during limbic seizures. Transecting the fornix, the major route from hippocampus to subcortical structures, abolished the negative cortical and behavioral effects of seizures. Cortical slow oscillations and behavioral arrest could be reconstituted in fornix-lesioned animals by inducing synchronous activity in the hippocampus and septal area, implying involvement of a downstream region converged upon by both structures. These findings suggest that limbic seizures may cause neocortical deactivation indirectly, through impaired subcortical function. If confirmed, subcortical networks may represent a target for therapies aimed at preserving consciousness in human temporal lobe seizures. PMID:19828814

  12. sup 125 I-(Tyr0,D-Trp8)somatostatin-14 binding sites in the locus coeruleus of the rat are located on both ascending and descending projecting noradrenergic cells

    SciTech Connect

    Epelbaum, J.; Bluet-Pajot, M.T.; Llorens-Cortes, C.; Kordon, C.; Mounier, F.; Senut, M.C.; Videau, C. )

    1990-01-01

    Radioautographic determinations of 125I-(Tyr0,D-Trp8)somatostatin-14 (125I-SRIF) binding sites were performed on frozen serial sections of the locus coeruleus (LC) of control rats and of rats subjected to either bilateral microinjections of 6 hydroxydopamine (6-OHDA) into the LC or unilateral microinjection into the ascending noradrenergic bundles. These experiments were performed in order to determine whether 125I-SRIF binding was localized to noradrenergic-containing cells and in which regions the cells which contain the binding sites are projecting. The extent of the lesions was assessed by measuring norepinephrine (NE) levels in the hippocampus (88% decrease as compared to sham-operated animals) for bilateral LC lesions and in the frontal cortex (87% reduction vs. contralateral side) for unilateral bundle lesions. In control rats, 125I-SRIF binding sites were restricted to the boundaries of the LC and followed closely the distribution of tyrosine hydroxylase-labeled cells. Three weeks after bilateral injections of 6-OHDA, 125I-SRIF binding decreased by 79% in all regions of the LC. In contrast, unilateral destruction of the ascending noradrenergic bundles resulted in a moderate decrease only in the middle part of the LC with a more important effect in the dorsal (55%) than in the ventral (24%) portion of the nucleus. These data demonstrate that: (1) most SRIF receptors in the LC are located in the vicinity of NE-containing cell bodies and (2) NE-containing cells bearing SRIF receptors project to the forebrain as well as to other terminal areas located more caudally in the brain. These data suggest a general role for SRIF in the control of the multiple functions of the LC.

  13. Disgust and fear recognition in paraneoplastic limbic encephalitis.

    PubMed

    Sprengelmeyer, Reiner; Atkinson, Anthony P; Sprengelmeyer, Anke; Mair-Walther, Johanna; Jacobi, Christian; Wildemann, Brigitte; Dittrich, Winand H; Hacke, Werner

    2010-05-01

    Paraneoplastic limbic encephalitis (PNLE) affects limbic portions of the brain associated with recognition of social signals of emotions. Yet it is not known whether this perceptual ability is impaired in individuals with PNLE. We therefore conducted a single case study to explore possible impairments in recognising facially, vocally and bodily expressed emotions, using standardised emotion recognition tests. Facial expression recognition was tested with two forced-choice emotion-labelling tasks using static faces with either prototypical or morphed blends of basic emotions. Recognition of vocally and bodily expressed emotions was also tested with forced-choice labelling tasks, one based on prosodic cues, the other on whole-body movement cues. We found a deficit in fear and disgust recognition from both face and voice, while recognition of bodily expressed emotions was unaffected. These findings are consistent with data from previous studies demonstrating critical roles for certain brain regions - particularly the amygdala and insular cortex - in processing facially and vocally displayed basic emotions, and furthermore, suggest that recognition of bodily expressed emotions may not depend on neural structures involved in facial and vocal emotion recognition. Impaired facial and vocal emotion recognition may form a further neuropsychological marker of limbic encephalitis, in addition to the already well-described mnestic deficits.

  14. Limbic Interference During Social Action Planning in Schizophrenia.

    PubMed

    Stegmayer, Katharina; Bohlhalter, Stephan; Vanbellingen, Tim; Federspiel, Andrea; Wiest, Roland; Müri, René M; Strik, Werner; Walther, Sebastian

    2017-05-30

    Schizophrenia is characterized by social interaction deficits contributing to poor functional outcome. Hand gesture use is particularly impaired, linked to frontal lobe dysfunction and frontal grey matter deficits. The functional neural correlates of impaired gesturing are currently unclear. We therefore investigated aberrant brain activity during impaired gesturing in schizophrenia. We included 22 patients with schizophrenia and 25 healthy control participants matched for age, gender, and education level. We obtained functional magnetic resonance imaging data using an event-related paradigm to assess brain activation during gesture planning and execution. Group differences in whole brain effects were calculated using factorial designs. Gesture ratings were performed by a single rater, blind to diagnoses and clinical presentation. During gesture planning and execution both groups activated brain areas of the praxis network. However, patients had reduced dorsolateral prefrontal cortex (DLPFC) and increased inferior parietal lobe (IPL) activity. Performance accuracy was associated with IPL activity in patients. Furthermore, patients activated temporal poles, amygdala and hippocampus during gesture planning, which was associated with delusion severity. Finally, patients demonstrated increased dorsomedial prefrontal cortex activity during planning of novel gestures. We demonstrate less prefrontal, but more IPL and limbic activity during gesturing in schizophrenia. IPL activity was associated with performance accuracy, whereas limbic activity was linked to delusion severity. These findings may reflect impaired social action planning and a limbic interference with gestures in schizophrenia contributing to poor gesture performance and consequently poor social functioning in schizophrenia. © The Author 2017. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.

  15. Evolution of vertebrate forebrain development: how many different mechanisms?

    PubMed Central

    FOLEY, ANN C.; STERN, CLAUDIO D.

    2001-01-01

    Over the past 50 years and more, many models have been proposed to explain how the nervous system is initially induced and how it becomes subdivided into gross regions such as forebrain, midbrain, hindbrain and spinal cord. Among these models is the 2-signal model of Nieuwkoop & Nigtevecht (1954), who suggested that an initial signal (‘activation’) from the organiser both neuralises and specifies the forebrain, while later signals (‘transformation’) from the same region progressively caudalise portions of this initial territory. An opposing idea emerged from the work of Otto Mangold (1933) and other members of the Spemann laboratory: 2 or more distinct organisers, emitting different signals, were proposed to be responsible for inducing the head, trunk and tail regions. Since then, evidence has accumulated that supports one or the other model, but it has been very difficult to distinguish between them. Recently, a considerable body of work from mouse embryos has been interpreted as favouring the latter model, and as suggesting that a ‘head organiser’, required for the induction of the forebrain, is spatially separate from the classic organiser (Hensen's node). An extraembryonic tissue, the ‘anterior visceral endoderm’ (AVE), was proposed to be the source of forebrain-inducing signals. It is difficult to find tissues that are directly equivalent embryologically or functionally to the AVE in other vertebrates, which led some (e.g. Kessel, 1998) to propose that mammals have evolved a new way of patterning the head. We will present evidence from the chick embryo showing that the hypoblast is embryologically and functionally equivalent to the mouse AVE. Like the latter, the hypoblast also plays a role in head development. However, it does not act like a true organiser. It induces pre-neural and pre-forebrain markers, but only transiently. Further development of neural and forebrain phenotypes requires additional signals not provided by the hypoblast. In

  16. A review of the adverse effects and safety of noradrenergic antidepressants.

    PubMed

    Whiskey, Eromona; Taylor, David

    2013-08-01

    There are a variety of noradrenergic antidepressants available, most of which act by inhibiting neuronal noradrenaline re-uptake, although few drugs are specific for this action. Where drugs have numerous actions the adverse effects of noradrenaline reuptake may be difficult to isolate, although in this respect the adverse effects of reboxetine, a specific noradrenaline re-uptake inhibitor, are illuminating. Noradrenergic antidepressants typically cause minor changes in blood and heart rate, sweating and insomnia. Other pharmacological actions shown by non-specific antidepressants may act to worsen or mitigate these adverse effects. Noradrenergic drugs are less likely than selective serotonin reuptake inhibitors (SSRIs) to cause sexual dysfunction but more likely to cause urinary hesitancy. Doubts remain over the relative propensity for antidepressants with different modes of action to cause diabetes and hyponatraemia. Noradrenergic actions do not seem to confer a risk of death in overdose.

  17. Neurotoxic effects of DSP-4 on the central noradrenergic system in male zebra finches.

    PubMed

    Waterman, Susanna A; Harding, Cheryl F

    2008-04-09

    When administered systemically, the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) appears to target the noradrenergic innervation originating in the locus coeruleus causing long-term decrements in noradrenergic function. In songbirds, DSP-4-treatment decreased female-directed singing by males and copulation solicitation responses of females to male songs. However, DSP-4 treatment in songbirds did not lower measures of NE function in the brain to the same extent as it does in mammals. The current study had two goals: determining if two DSP-4 treatments 10 days apart would cause significant decrements in noradrenergic function in male zebra finches and determining if, as in other species, the noradrenergic innervation of midbrain and cortical areas would be profoundly affected while hypothalamic areas were spared. Dopamine-beta-hydroxylase immunoreactivity (DBH-ir) was quantified in thirteen brain regions (five vocal control nuclei, one auditory nucleus, two hypothalamic nuclei, and five additional areas that demonstrated high DBH labeling in controls). Within 20 days, DSP-4 treatment profoundly reduced the number of DBH-ir cells in both the locus coeruleus and ventral subcoeruleus. Unlike a previous study, DBH labeling delineated four out of five vocal control nuclei and an auditory nucleus. As expected, DSP-4 treatment significantly decreased DBH labeling in all areas examined in the mesencephalon and telencephalon without significantly affecting DBH-ir in hypothalamic areas. This double treatment regime appears to be much more effective in decreasing noradrenergic function in songbirds than the single treatment typically used.

  18. Targeting the Noradrenergic System for Gender-Sensitive Medication Development for Tobacco Dependence

    PubMed Central

    Verplaetse, Terril L.; Weinberger, Andrea H.; Smith, Philip H.; Cosgrove, Kelly P.; Mineur, Yann S.; Picciotto, Marina R.; Mazure, Carolyn M.

    2015-01-01

    Introduction: Tobacco use remains the leading cause of morbidity and mortality for both women and men in the United States, and women often experience poorer smoking cessation outcomes than men. Preliminary evidence suggests there are sex differences in medication effectiveness for smoking cessation. However, current medications do not take into account gender-sensitive treatment development and efficacy, underscoring the importance of this underdeveloped area of research. Methods: We reviewed preclinical and clinical evidence for gender differences in the inability to quit smoking by examining (a) the effect of increased negative affect and stress reactivity on smoking outcomes in women and (b) smoking for nicotine reinforcement in men. We also reviewed the current literature targeting the noradrenergic system as a novel gender-sensitive treatment strategy for tobacco dependence. Results: We hypothesize that noradrenergic agents that normalize noradrenergic activity may differentially attenuate stress reactivity in women and nicotine-related reinforcement in men, indicating that targeting the noradrenergic system for smoking cessation may be effective for both genders, with benefits operating through sex-specific mechanisms. Conclusions: Converging lines of preclinical and clinical evidence suggest that gender-sensitive approaches to medication development for smoking cessation are a critical next step for addressing low quit rates and exacerbated health risks among women. Evidence reviewed indicates that smoking activates different brain systems modulated by noradrenergic activity in women versus men, and noradrenergic compounds may preferentially target these gender-sensitive systems. PMID:25762760

  19. Genomic Perspectives of Transcriptional Regulation in Forebrain Development

    DOE PAGES

    Nord, Alex S.; Pattabiraman, Kartik; Visel, Axel; ...

    2015-01-07

    The forebrain is the seat of higher-order brain functions, and many human neuropsychiatric disorders are due to genetic defects affecting forebrain development, making it imperative to understand the underlying genetic circuitry. We report that recent progress now makes it possible to begin fully elucidating the genomic regulatory mechanisms that control forebrain gene expression. Here, we discuss the current knowledge of how transcription factors drive gene expression programs through their interactions with cis-acting genomic elements, such as enhancers; how analyses of chromatin and DNA modifications provide insights into gene expression states; and how these approaches yield insights into the evolution ofmore » the human brain.« less

  20. Intracranial Metastatic Disease Spares the Limbic Circuit: A Review of 697 Metastatic Lesions in 107 Patients

    SciTech Connect

    Marsh, James C.; Herskovic, Arnold M.; Gielda, Benjamin T.; Hughes, Frank F.; Hoeppner, Thomas; Turian, Julius; Abrams, Ross A.

    2010-02-01

    Purpose: We report the incidence of metastatic involvement of the limbic circuit in a retrospective review of patients treated at our institution. This review was performed to assess the feasibility of selectively sparing the limbic system during whole-brain radiotherapy and prophylactic cranial irradiation. Methods and Materials: We identified 697 intracranial metastases in 107 patients after reviewing contrast-enhanced CT and/or MR image sets for each patient. Lesions were localized to the limbic circuit or to the rest of the brain/brain stem. Patients were categorized by tumor histology (e.g., non-small-cell lung cancer, small-cell lung cancer, breast cancer, and other) and by total number of intracranial metastases (1-3, oligometastatic; 4 or more, nonoligometastatic). Results: Thirty-six limbic metastases (5.2% of all metastases) were identified in 22 patients who had a median of 16.5 metastases/patient (limbic metastases accounted for 9.9% of their lesions). Sixteen metastases (2.29%) involved the hippocampus, and 20 (2.86%) involved the rest of the limbic circuit; 86.2% of limbic metastases occurred in nonoligometastatic patients, and 13.8% occurred in oligometastatic patients. The incidence of limbic metastases by histologic subtype was similar. The incidence of limbic metastases in oligometastatic patients was 4.9% (5/103): 0.97%, hippocampus; 3.9%, remainder of the limbic circuit. One of 53 oligometastatic patients (1.9%) had hippocampal metastases, while 4/53 (7.5%) had other limbic metastases. Conclusions: Metastatic involvement of the limbic circuit is uncommon and limited primarily to patients with nonoligometastatic disease, supporting our hypothesis that it is reasonable to selectively exclude or reduce the dose to the limbic circuit when treating patients with prophylactic cranial irradiation or whole-brain radiotherapy for oligometastatic disease not involving these structures.

  1. Antagonism of Muscarinic Acetylcholine Receptors Alters Synaptic ERK Phosphorylation in the Rat Forebrain.

    PubMed

    Mao, Li-Min; Wang, Henry H; Wang, John Q

    2016-12-28

    Acetylcholine (ACh) is a key transmitter in the mesocorticolimbic circuit. By interacting with muscarinic ACh receptors (mAChR) enriched in the circuit, ACh actively regulates various neuronal and synaptic activities. The extracellular signal-regulated kinase (ERK) is one of members of the mitogen-activated protein kinase family and is subject to the regulation by dopamine receptors, although the regulation of ERKs by limbic mAChRs is poorly understood. In this study, we investigated the role of mAChRs in the regulation of ERK phosphorylation (activation) in the mesocorticolimbic system of adult rat brains in vivo. We targeted a sub-pool of ERKs at synaptic sites. We found that a systemic injection of the mAChR antagonist scopolamine increased phosphorylation of synaptic ERKs in the striatum (caudate putamen and nucleus accumbens) and medial prefrontal cortex (mPFC). Increases in ERK phosphorylation in both forebrain regions were rapid and transient. Notably, pretreatment with a dopamine D1 receptor (D1R) antagonist SCH23390 blocked the scopolamine-stimulated ERK phosphorylation in these brain regions, while a dopamine D2 receptor antagonist eticlopride did not. Scopolamine and SCH23390 did not change the amount of total ERK proteins. These results demonstrate that mAChRs inhibit synaptic ERK phosphorylation in striatal and mPFC neurons under normal conditions. Blockade of this inhibitory mAChR tone leads to the upregulation of ERK phosphorylation likely through a mechanism involving the level of D1R activity.

  2. Dynamic expression of MEIS1 homeoprotein in E14.5 forebrain and differentiated forebrain-derived neural stem cells.

    PubMed

    Barber, Benjamin A; Liyanage, Vichithra R B; Zachariah, Robby M; Olson, Carl O; Bailey, Melissa A G; Rastegar, Mojgan

    2013-10-01

    Central nervous system development is controlled by highly conserved homeoprotein transcription factors including HOX and TALE (Three Amino acid Loop Extension). TALE proteins are primarily known as HOX-cofactors and play key roles in cell proliferation, differentiation and organogenesis. MEIS1 is a TALE member with established expression in the developing central nervous system. MEIS1 is essential for embryonic development and Meis1 knockout mice dies at embryonic day (E) 14.5. However, Meis1/MEIS1 expression in the devolving forebrain, at this critical time-point has not been studied. Here, for the first time we characterize the region-specific expression of MEIS1 in E14.5 mouse forebrain, filling the gap of MEIS1 expression profile between E12.5 and E16.5. Previously, we reported MEIS1 transcriptional regulatory role in neuronal differentiation and established forebrain-derived neural stem cells (NSC) for gene therapy application of neuronal genes. Here, we show the dynamic expression of Meis1/MEIS1 during the differentiation of forebrain-derived NSC toward a glial lineage. Our results show that Meis1/MEIS1 expression is induced during NSC differentiation and is expressed in both differentiated neurons and astrocytes. Confirming these results, we detected MEIS1 expression in primary cultures of in vivo differentiated cortical neurons and astrocytes. We further demonstrate Meis1/MEIS1 expression relative to other TALE family members in the forebrain-derived NSC in the absence of Hox genes. Our data provide evidence that forebrain-derived NSC can be used as an accessible in vitro model to study the expression and function of TALE proteins, supporting their potential role in modulating NSC self-renewal and differentiation.

  3. Evidence for evolutionary specialization in human limbic structures

    PubMed Central

    Barger, Nicole; Hanson, Kari L.; Teffer, Kate; Schenker-Ahmed, Natalie M.; Semendeferi, Katerina

    2014-01-01

    Increasingly, functional and evolutionary research has highlighted the important contribution emotion processing makes to complex human social cognition. As such, it may be asked whether neural structures involved in emotion processing, commonly referred to as limbic structures, have been impacted in human brain evolution. To address this question, we performed an extensive evolutionary analysis of multiple limbic structures using modern phylogenetic tools. For this analysis, we combined new volumetric data for the hominoid (human and ape) amygdala and 4 amygdaloid nuclei, hippocampus, and striatum, collected using stereological methods in complete histological series, with previously published datasets on the amygdala, orbital and medial frontal cortex, and insula, as well as a non-limbic structure, the dorsal frontal cortex, for contrast. We performed a parallel analysis using large published datasets including many anthropoid species (human, ape, and monkey), but fewer hominoids, for the amygdala and 2 amygdaloid subdivisions, hippocampus, schizocortex, striatum, and septal nuclei. To address evolutionary change, we compared observed human values to values predicted from regressions run through (a) non-human hominoids and (b) non-human anthropoids, assessing phylogenetic influence using phylogenetic generalized least squares regression. Compared with other hominoids, the volumes of the hippocampus, the lateral nucleus of the amygdala, and the orbital frontal cortex were, respectively, 50, 37, and 11% greater in humans than predicted for an ape of human hemisphere volume, while the medial and dorsal frontal cortex were, respectively, 26 and 29% significantly smaller. Compared with other anthropoids, only human values for the striatum fell significantly below predicted values. Overall, the data present support for the idea that regions involved in emotion processing are not necessarily conserved or regressive, but may even be enhanced in recent human evolution

  4. Norepinephrine deficiency in Parkinson's disease: the case for noradrenergic enhancement.

    PubMed

    Espay, Alberto J; LeWitt, Peter A; Kaufmann, Horacio

    2014-12-01

    The dramatic response of most motor and some nonmotor symptoms to dopaminergic therapies has contributed to maintaining the long-established identity of Parkinson's disease (PD) as primarily a nigrostriatal dopamine (DA) deficiency syndrome. However, DA neurotransmission may be neither the first nor the major neurotransmitter casualty in the neurodegenerative sequence of PD. Growing evidence supports earlier norepinephrine (NE) deficiency resulting from selective degeneration of neurons of the locus coeruleus and sympathetic ganglia. Dopaminergic replacement therapy therefore would seem to neglect some of the motor, behavioral, cognitive, and autonomic impairments that are directly or indirectly associated with the marked deficiency of NE in the brain and elsewhere. Therapeutic strategies to enhance NE neurotransmission have undergone only limited pharmacological testing. Currently, these approaches include selective NE reuptake inhibition, presynaptic α2 -adrenergic receptor blockade, and an NE prodrug, the artificial amino acid L-threo-3,4-dihydroxyphenylserine. In addition to reducing the consequences of deficient noradrenergic signaling, enhancement strate gies have the potential for augmenting the effects of dopaminergic therapies in PD. Furthermore, early recognition of the various clinical manifestations associated with NE deficiency, which may precede development of motor symptoms, could provide a window of opportunity for neuroprotective interventions.

  5. Brainstem and limbic encephalitis with paraneoplastic neuromyelitis optica.

    PubMed

    Moussawi, Khaled; Lin, David J; Matiello, Marcelo; Chew, Sheena; Morganstern, Daniel; Vaitkevicius, Henrikas

    2016-01-01

    The spectrum of disorders associated with anti-neuromyelitis optica (NMO) antibody is being extended to include infrequent instances associated with cancer. We describe a patient with brainstem and limbic encephalitis from NMO-immunoglobulin G in serum and cerebrospinal fluid in the context of newly diagnosed breast cancer. The neurological features markedly improved with excision of her breast cancer and immune suppressive therapy. This case further broadens the NMO spectrum disorders (NMOSD) by an association between NMOSD and cancer and raises the question of coincidental occurrence and the appropriate circumstances to search for a tumor in certain instances of NMO. Copyright © 2015 Elsevier Ltd. All rights reserved.

  6. Drugs of abuse specifically sensitize noradrenergic and serotonergic neurons via a non-dopaminergic mechanism.

    PubMed

    Lanteri, Christophe; Salomon, Lucas; Torrens, Yvette; Glowinski, Jacques; Tassin, Jean-Pol

    2008-06-01

    A challenge in drug dependence is to delineate long-term neurochemical modifications induced by drugs of abuse. Repeated d-amphetamine was recently shown to disrupt a mutual regulatory link between noradrenergic and serotonergic neurons, thus inducing long-term increased responses to d-amphetamine and para-chloroamphetamine, respectively. We show here that such a sensitization of noradrenergic and serotonergic neurons also occurs following repeated treatment with cocaine, morphine, or alcohol, three compounds belonging to main groups of addictive substances. In all cases, this sensitization is prevented by alpha 1b-adrenergic and 5-HT2A receptors blockade, indicating the critical role of these receptors on long-term effects of drugs of abuse. However, repeated treatments with two non-addictive antidepressants, venlafaxine, and clorimipramine, which nevertheless inhibit noradrenergic and serotonergic reuptake, do not induce noradrenergic and serotonergic neurons sensitization. Similarly, this sensitization does not occur following repeated treatments with a specific inhibitor of dopamine (DA) reuptake, GBR12783. Moreover, we show that the effects of SCH23390, a D1 receptor antagonist known to inhibit development of d-amphetamine behavioral sensitization, are due to its 5-HT2C receptor agonist property. SCH23390 blocks amphetamine-induced release of norepinephrine and RS102221, a 5-HT2C antagonist, can reverse this inhibition as well as inhibition of noradrenergic sensitization and development of behavioral sensitization induced by repeated d-amphetamine. We propose that noradrenergic/serotonergic uncoupling is a common neurochemical consequence of repeated consumption of drugs of abuse, unrelated with DA release. Our data also suggest that compounds able to restore the link between noradrenergic and serotonergic modulatory systems could represent important therapeutic targets for investigation.

  7. Adult forebrain NMDA receptors gate social motivation and social memory.

    PubMed

    Jacobs, Stephanie; Tsien, Joe Z

    2017-02-01

    Motivation to engage in social interaction is critical to ensure normal social behaviors, whereas dysregulation in social motivation can contribute to psychiatric diseases such as schizophrenia, autism, social anxiety disorders and post-traumatic stress disorder (PTSD). While dopamine is well known to regulate motivation, its downstream targets are poorly understood. Given the fact that the dopamine 1 (D1) receptors are often physically coupled with the NMDA receptors, we hypothesize that the NMDA receptor activity in the adult forebrain principal neurons are crucial not only for learning and memory, but also for the proper gating of social motivation. Here, we tested this hypothesis by examining sociability and social memory in inducible forebrain-specific NR1 knockout mice. These mice are ideal for exploring the role of the NR1 subunit in social behavior because the NR1 subunit can be selectively knocked out after the critical developmental period, in which NR1 is required for normal development. We found that the inducible deletion of the NMDA receptors prior to behavioral assays impaired, not only object and social recognition memory tests, but also resulted in profound deficits in social motivation. Mice with ablated NR1 subunits in the forebrain demonstrated significant decreases in sociability compared to their wild type counterparts. These results suggest that in addition to its crucial role in learning and memory, the NMDA receptors in the adult forebrain principal neurons gate social motivation, independent of neuronal development.

  8. VENTROMEDIAN FOREBRAIN DYSGENESIS FOLLOWS EARLY PRENATAL ETHANOL EXPOSURE IN MICE

    PubMed Central

    Godin, Elizabeth A.; Dehart, Deborah B.; Parnell, Scott E.; O'Leary-Moore, Shonagh K.; Sulik, Kathleen K.

    2010-01-01

    Ethanol exposure on gestational day (GD) 7 in the mouse has previously been shown to result in ventromedian forebrain deficits along with facial anomalies characteristic of fetal alcohol syndrome (FAS). To further explore ethanol's teratogenic effect on the ventromedian forebrain in this mouse model, scanning electron microscopic and histological analyses were conducted. For this, time mated C57Bl/6J mice were injected with 2.9 g/kg ethanol or saline twice, at a four hour interval, on their 7th day of pregnancy. On GD 12.5, 13 and 17, control and ethanol-exposed specimens were collected and processed for light and scanning electron microscopic analyses. Gross morphological changes present in the forebrains of ethanol-exposed embryos included cerebral hemispheres that were too close in proximity or rostrally united, enlarged foramina of Monro, enlarged or united lateral ventricles, and varying degrees of hippocampal and ventromedian forebrain deficiency. In GD 12.5 control and ethanol-exposed embryos, in situ hybridization employing probes for Nkx2.1 or Fzd8 to distinguish the preoptic area and medial ganglionic eminences (MGE) from the lateral ganglionic eminences, respectively, confirmed the selective loss of ventromedian tissues. Immunohistochemical labeling of oligodendrocyte progenitors with Olig2, a transcription factor necessary for their specification, and of GABA, an inhibitory neurotransmitter, showed ethanol-induced reductions in both. To investigate later consequences of ventromedian forebrain loss, MGE-derived somatostatin-expressing interneurons in the subpallial region of GD 17 fetal mice were examined, with results showing that the somatostatin-expressing interneurons that were present were dysmorphic in the ethanol-exposed fetuses. The potential functional consequences of this insult are discussed. PMID:21074610

  9. The Subthalamic Nucleus, Limbic Function, and Impulse Control.

    PubMed

    Rossi, P Justin; Gunduz, Aysegul; Okun, Michael S

    2015-12-01

    It has been well documented that deep brain stimulation (DBS) of the subthalamic nucleus (STN) to address some of the disabling motor symptoms of Parkinson's disease (PD) can evoke unintended effects, especially on non-motor behavior. This observation has catalyzed more than a decade of research concentrated on establishing trends and identifying potential mechanisms for these non-motor effects. While many issues remain unresolved, the collective result of many research studies and clinical observations has been a general recognition of the role of the STN in mediating limbic function. In particular, the STN has been implicated in impulse control and the related construct of valence processing. A better understanding of STN involvement in these phenomena could have important implications for treating impulse control disorders (ICDs). ICDs affect up to 40% of PD patients on dopamine agonist therapy and approximately 15% of PD patients overall. ICDs have been reported to be associated with STN DBS. In this paper we will focus on impulse control and review pre-clinical, clinical, behavioral, imaging, and electrophysiological studies pertaining to the limbic function of the STN.

  10. Chronic stress disrupts neural coherence between cortico-limbic structures

    PubMed Central

    Oliveira, João Filipe; Dias, Nuno Sérgio; Correia, Mariana; Gama-Pereira, Filipa; Sardinha, Vanessa Morais; Lima, Ana; Oliveira, Ana Filipa; Jacinto, Luís Ricardo; Ferreira, Daniela Silva; Silva, Ana Maria; Reis, Joana Santos; Cerqueira, João José; Sousa, Nuno

    2013-01-01

    Chronic stress impairs cognitive function, namely on tasks that rely on the integrity of cortico-limbic networks. To unravel the functional impact of progressive stress in cortico-limbic networks we measured neural activity and spectral coherences between the ventral hippocampus (vHIP) and the medial prefrontal cortex (mPFC) in rats subjected to short term stress (STS) and chronic unpredictable stress (CUS). CUS exposure consistently disrupted the spectral coherence between both areas for a wide range of frequencies, whereas STS exposure failed to trigger such effect. The chronic stress-induced coherence decrease correlated inversely with the vHIP power spectrum, but not with the mPFC power spectrum, which supports the view that hippocampal dysfunction is the primary event after stress exposure. Importantly, we additionally show that the variations in vHIP-to-mPFC coherence and power spectrum in the vHIP correlated with stress-induced behavioral deficits in a spatial reference memory task. Altogether, these findings result in an innovative readout to measure, and follow, the functional events that underlie the stress-induced reference memory impairments. PMID:23390414

  11. [Spatial Cognition and Episodic Memory Formation in the Limbic Cortex].

    PubMed

    Kobayashi, Yasushi

    2017-04-01

    The limbic lobe defined by Broca is a cortical region with highly diverse structure and functions, and comprises the paleo-, archi-, and neocortices as well as their transitional zones. In the limbic lobe, Brodmann designated areas 27, 28, 34, 35, and 36 adjacent to the hippocampus, and areas 23, 24, 25, 26, 29, 30, 31, 32, and 33 around the corpus callosum. In the current literature, areas 27 and 28 correspond to the presubiculum and entorhinal cortex, respectively. Area 34 represents the cortico-medial part of the amygdaloid complex. Areas 35 and 36 roughly cover the perirhinal and parahippocampal cortices. Areas 24, 25, 32, and 33 belong to the anterior cingulate gyrus, while areas 23, 26, 29, 30, and 31 to the posterior cingulate gyrus. Areas 25, 32, and the anteroinferior portion of area 24 are deeply involved in emotional responses, particularly in their autonomic functions, through reciprocal connections with the amygdaloid complex, anterior thalamus and projections to the brainstem and spinal visceral centers. Areas 29 and 30 have dense reciprocal connections with areas 23 and 31, the dorsolateral prefrontal areas, and the regions related to the hippocampus. They play pivotal roles in mediating spatial cognition, working memory processing, and episodic memory formation.

  12. Compulsive sexual behavior: Prefrontal and limbic volume and interactions

    PubMed Central

    Schmidt, Casper; Morris, Laurel S.; Kvamme, Timo L.; Hall, Paula; Birchard, Thaddeus

    2016-01-01

    Abstract Background Compulsive sexual behaviors (CSB) are relatively common and associated with significant personal and social dysfunction. The underlying neurobiology is still poorly understood. The present study examines brain volumes and resting state functional connectivity in CSB compared with matched healthy volunteers (HV). Methods Structural MRI (MPRAGE) data were collected in 92 subjects (23 CSB males and 69 age‐matched male HV) and analyzed using voxel‐based morphometry. Resting state functional MRI data using multi‐echo planar sequence and independent components analysis (ME‐ICA) were collected in 68 subjects (23 CSB subjects and 45 age‐matched HV). Results CSB subjects showed greater left amygdala gray matter volumes (small volume corrected, Bonferroni adjusted P < 0.01) and reduced resting state functional connectivity between the left amygdala seed and bilateral dorsolateral prefrontal cortex (whole brain, cluster corrected FWE P < 0.05) compared with HV. Conclusions CSB is associated with elevated volumes in limbic regions relevant to motivational salience and emotion processing, and impaired functional connectivity between prefrontal control regulatory and limbic regions. Future studies should aim to assess longitudinal measures to investigate whether these findings are risk factors that predate the onset of the behaviors or are consequences of the behaviors. Hum Brain Mapp 38:1182–1190, 2017. © 2016 Wiley Periodicals, Inc. PMID:27787929

  13. [Limbic ictus as a condition for anxiety attacks].

    PubMed

    Gallinat, J; Hegerl, U

    1999-03-01

    Episodes of anxiety have been reported to be the most common psychological symptoms in patients with partial seizures. They may occur before, during and after seizures and can also appear in isolation without any convulsive symptoms. The epileptic anxiety syndrome is strikingly similar to panic attacks, and panic disorder is an important differential diagnosis. The close relationship between epileptic seizures and panic attacks is of special interest for a better pathophysiological understanding of panic attacks. In the literature an epileptiform neuronal activity is discussed as a possible underlying mechanism for panic disorder. The finding that anxiety was the most common experiential phenomenon produced by electrical stimulation of amygdala and hippocampus with depth electrodes points in this direction. PET has demonstrated abnormalities of hippocampal structures during the nonpanic state of patients with panic disorder. In addition, some EEG studies have demonstrated a high incidence of epileptiform EEG patterns in patients with panic disorder with or without agoraphobia. This was the reason why several investigators proposed that a subset of panic attacks may be related to abnormal epileptiform neuronal activity in the limbic system. The size of this subset is difficult to determine because discharges in the depth of the limbic system often cannot be seen in the scalp EEG. Concerning the hypothetical pathophysiological mechanism of panic disorder therapeutic measures were taken with antiepileptic agents. The best results were obtained for valproic acid. It seems to be reasonable to make a therapeutic trial with antiepileptic medication after nonresponse to standard pharmacotherapy.

  14. Intrinsic Limbic and Paralimbic Networks Are Associated With Criminal Psychopathy

    PubMed Central

    Juárez, Michelle; Kiehl, Kent A.; Calhoun, Vince D.

    2014-01-01

    Background Psychopathy is a personality disorder associated with impairments in decision-making, empathy, and impulsivity. Recent brain imaging studies suggest that psychopathy is associated with abnormalities in limbic/paralimbic brain regions. To date, no studies have examined functional brain connectivity measures using independent component analyses (ICA) in adults with psychopathy. Here, we test hypotheses regarding paralimbic connectivity in adult incarcerated individuals stratified by psychopathy scores. Methods One hundred and two prison inmates were rated using the Hare Psychopathy Checklist-Revised (PCL-R). FMRI data were collected while subjects performed an auditory target detection “oddball” task. FMRI data were analyzed using group ICA to identify functional networks responding to the oddball task correlating with psychopathy scores. Results Components demonstrating significant correlations with psychopathy included a default mode network, a frontoparietal component, and a visual/posterior cingulate component. Modulation trends correlated strongly with factor 2 (impulsivity) and total PCL-R scores in the frontoparietal and visual/posterior cingulate networks, and with factor 1 (affective) scores within the default mode network. The posterior cingulate region factored significantly in the modulation trends observed. Conclusion Consistent with the hypothesis of limbic/paralimbic abnormalities associated with psychopathy, modulation trends correlated strongly with PCL-R scores. There is strong evidence to implicate the posterior cingulate in aberrant functional connectivity associated with the manifestation of psychopathic symptoms. Future investigations comparing functional trends associated with the posterior cingulate in psychopathic subjects may provide further insight into the manifestation of this disorder. PMID:22431294

  15. Volume of the human septal forebrain region is a predictor of source memory accuracy.

    PubMed

    Butler, Tracy; Blackmon, Karen; Zaborszky, Laszlo; Wang, Xiuyuan; DuBois, Jonathan; Carlson, Chad; Barr, William B; French, Jacqueline; Devinsky, Orrin; Kuzniecky, Ruben; Halgren, Eric; Thesen, Thomas

    2012-01-01

    Septal nuclei, components of basal forebrain, are strongly and reciprocally connected with hippocampus, and have been shown in animals to play a critical role in memory. In humans, the septal forebrain has received little attention. To examine the role of human septal forebrain in memory, we acquired high-resolution magnetic resonance imaging scans from 25 healthy subjects and calculated septal forebrain volume using recently developed probabilistic cytoarchitectonic maps. We indexed memory with the California Verbal Learning Test-II. Linear regression showed that bilateral septal forebrain volume was a significant positive predictor of recognition memory accuracy. More specifically, larger septal forebrain volume was associated with the ability to recall item source/context accuracy. Results indicate specific involvement of septal forebrain in human source memory, and recall the need for additional research into the role of septal nuclei in memory and other impairments associated with human diseases.

  16. Neuropeptide S interacts with the basolateral amygdala noradrenergic system in facilitating object recognition memory consolidation.

    PubMed

    Han, Ren-Wen; Xu, Hong-Jiao; Zhang, Rui-San; Wang, Pei; Chang, Min; Peng, Ya-Li; Deng, Ke-Yu; Wang, Rui

    2014-01-01

    The noradrenergic activity in the basolateral amygdala (BLA) was reported to be involved in the regulation of object recognition memory. As the BLA expresses high density of receptors for Neuropeptide S (NPS), we investigated whether the BLA is involved in mediating NPS's effects on object recognition memory consolidation and whether such effects require noradrenergic activity. Intracerebroventricular infusion of NPS (1nmol) post training facilitated 24-h memory in a mouse novel object recognition task. The memory-enhancing effect of NPS could be blocked by the β-adrenoceptor antagonist propranolol. Furthermore, post-training intra-BLA infusions of NPS (0.5nmol/side) improved 24-h memory for objects, which was impaired by co-administration of propranolol (0.5μg/side). Taken together, these results indicate that NPS interacts with the BLA noradrenergic system in improving object recognition memory during consolidation.

  17. Interaction of noradrenergic pharmacological manipulation and subthalamic stimulation on movement initiation control in Parkinson's disease.

    PubMed

    Albares, Marion; Thobois, Stéphane; Favre, Emilie; Broussolle, Emmanuel; Polo, Gustavo; Domenech, Philippe; Boulinguez, Philippe; Ballanger, Bénédicte

    2015-01-01

    Slowness in movement initiation (akinesia) is a cardinal feature of Parkinson's disease (PD), which is still poorly understood. Notably, akinesia is restored by subthalamic nucleus deep brain stimulation (STN-DBS) but not fully reversed by current dopaminergic treatments. It was recently suggested that this disorder is of executive nature (related to inhibitory control of response) and of non-dopaminergic origin (possibly noradrenergic). To test the double hypothesis that: 1) the ability to control movement initiation is modified by noradrenergic neurotransmission modulation, and 2) this effect is mediated by the regulation of STN activity. Sixteen STN-DBS PD patients were enrolled in a placebo-controlled study investigating the effects of noradrenergic attenuation by clonidine (∝2-adrenergic receptor agonist). Movement initiation latency was assessed by means of a cue-target reaction time task. Patients, who remained on their chronic dopaminergic medication, were tested on four sessions: two with placebo (ON- or OFF-DBS), and two with a 150 μg oral dose of clonidine (ON- or OFF-DBS). In the OFF stimulation condition, patients were locked into a mode of control maintaining inappropriate response inhibition. This dysfunctional executive setting was overcome by STN-DBS. Clonidine, however, was found to impair specifically the ability to release inhibitory control in the ON-DBS state. Overall our results suggest an important implication of the noradrenergic system in the pathophysiology of akinesia in PD. Reducing the noradrenergic "tonus" may even block the positive action of STN-DBS on akinesia, suggesting, at least by part, a noradrenergic-dependent STN-DBS efficiency. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. Differential modulation of emotion processing brain regions by noradrenergic and serotonergic antidepressants.

    PubMed

    Brühl, Annette Beatrix; Jäncke, Lutz; Herwig, Uwe

    2011-08-01

    Most widely used antidepressant drugs affect the serotonergic and noradrenergic pathways. However, there are currently no neurobiological criteria for selecting between these targets and predicting the treatment response in individual depressed patients. The current study is aimed at differentiating brain regions known to be pathophysiologically and functionally involved in depression-related emotion processing with respect to their susceptibility to serotonergic and noradrenergic modulation. In a single-blind pseudo-randomized crossover study, 16 healthy subjects (out of 21 enrolled) were included in analysis after ingesting a single dose of citalopram (a selective serotonin-reuptake inhibitor, 40 mg), reboxetine (a selective noradrenaline-reuptake inhibitor, 8 mg), or placebo at three time points prior to functional magnetic resonance imaging (fMRI). During fMRI, subjects anticipated and subsequently viewed emotional pictures. Effects of serotonergic and noradrenergic modulation versus placebo on brain activity during the perception of negative pictures were analyzed with a repeated measures ANOVA in the whole brain and in specific regions of interest relevant to depression. Noradrenergic modulation by reboxetine increased brain activity in the thalamus, right dorsolateral prefrontal cortex and occipital regions during the perception of negative emotional stimuli. Citalopram primarily affected the ventrolateral prefrontal cortical regions. The brain regions involved in the processing of negative emotional stimuli were differentially modulated by selective noradrenergic and serotonergic drugs: thalamic activity was increased by reboxetine, whereas citalopram primarily affected ventrolateral prefrontal regions. Thus, dysfunction in these regions, which could be identified in depressed patients, may predict treatment responses to either noradrenergic or serotonergic antidepressants.

  19. Targeting the noradrenergic system for gender-sensitive medication development for tobacco dependence.

    PubMed

    Verplaetse, Terril L; Weinberger, Andrea H; Smith, Philip H; Cosgrove, Kelly P; Mineur, Yann S; Picciotto, Marina R; Mazure, Carolyn M; McKee, Sherry A

    2015-04-01

    Tobacco use remains the leading cause of morbidity and mortality for both women and men in the United States, and women often experience poorer smoking cessation outcomes than men. Preliminary evidence suggests there are sex differences in medication effectiveness for smoking cessation. However, current medications do not take into account gender-sensitive treatment development and efficacy, underscoring the importance of this underdeveloped area of research. We reviewed preclinical and clinical evidence for gender differences in the inability to quit smoking by examining (a) the effect of increased negative affect and stress reactivity on smoking outcomes in women and (b) smoking for nicotine reinforcement in men. We also reviewed the current literature targeting the noradrenergic system as a novel gender-sensitive treatment strategy for tobacco dependence. We hypothesize that noradrenergic agents that normalize noradrenergic activity may differentially attenuate stress reactivity in women and nicotine-related reinforcement in men, indicating that targeting the noradrenergic system for smoking cessation may be effective for both genders, with benefits operating through sex-specific mechanisms. Converging lines of preclinical and clinical evidence suggest that gender-sensitive approaches to medication development for smoking cessation are a critical next step for addressing low quit rates and exacerbated health risks among women. Evidence reviewed indicates that smoking activates different brain systems modulated by noradrenergic activity in women versus men, and noradrenergic compounds may preferentially target these gender-sensitive systems. © The Author 2015. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  20. Cortico-limbic circuitry and the airways: Insights from functional neuroimaging of respiratory afferents and efferents

    PubMed Central

    Evans, Karleyton C.

    2010-01-01

    After nearly two decades of active research, functional neuroimaging has demonstrated utility in the identification of cortical, limbic, and paralimbic (cortico-limbic) brain regions involved in respiratory control and respiratory perception. Before the recent boon of human neuroimaging studies, the location of the principal components of respiratory-related cortico-limbic circuitry had been unknown and their function had been poorly understood. Emerging neuroimaging evidence in both healthy and patient populations suggests that cognitive and emotional/affective processing within cortico-limbic circuitry modulates respiratory control and respiratory perception. This paper will review functional neuroimaging studies of respiration with a focus on whole brain investigations of sensorimotor pathways that have identified respiratory-related neural circuitry known to overlap emotional/affective cortico-limbic circuitry. To aid the interpretation of present and future findings, the complexities and challenges underlying neuroimaging methodologies will also be reviewed as applied to the study of respiration physiology. PMID:20211221

  1. Purkinje cell loss and the noradrenergic system in the cerebellum of pcd mutant mice.

    PubMed

    Ghetti, B; Fuller, R W; Sawyer, B D; Hemrick-Luecke, S K; Schmidt, M J

    1981-12-01

    Purkinje cells in the cerebellum receive inhibitory noradrenergic input from the locus coeruleus. In pcd mutant mice all Purkinje cells degenerate by 45 days of age. The purpose of the present studies was to determine if the loss of these cerebellar neurons affects the amounts of norepinephrine in the cerebellum of mice 25-280 days of age. No significant changes in norepinephrine content were detected during or after Purkinje cell degeneration. However, since degeneration led to a reduction in cerebellar weight, the norepinephrine concentration was increased in pcd mutants. These results indicate that despite the loss of a major postsynaptic target (Purkinje cells), the cerebellar noradrenergic input remains stable.

  2. Development of axonal pathways in the human fetal fronto-limbic brain: histochemical characterization and diffusion tensor imaging.

    PubMed

    Vasung, Lana; Huang, Hao; Jovanov-Milošević, Nataša; Pletikos, Mihovil; Mori, Susumu; Kostović, Ivica

    2010-10-01

    The development of cortical axonal pathways in the human brain begins during the transition between the embryonic and fetal period, happens in a series of sequential events, and leads to the establishment of major long trajectories by the neonatal period. We have correlated histochemical markers (acetylcholinesterase (AChE) histochemistry, antibody against synaptic protein SNAP-25 (SNAP-25-immunoreactivity) and neurofilament 200) with the diffusion tensor imaging (DTI) database in order to make a reconstruction of the origin, growth pattern and termination of the pathways in the period between 8 and 34 postconceptual weeks (PCW). Histological sections revealed that the initial outgrowth and formation of joined trajectories of subcortico-frontal pathways (external capsule, cerebral stalk-internal capsule) and limbic bundles (fornix, stria terminalis, amygdaloid radiation) occur by 10 PCW. As early as 11 PCW, major afferent fibers invade the corticostriatal junction. At 13-14 PCW, axonal pathways from the thalamus and basal forebrain approach the deep moiety of the cortical plate, causing the first lamination. The period between 15 and 18 PCW is dominated by elaboration of the periventricular crossroads, sagittal strata and spread of fibers in the subplate and marginal zone. Tracing of fibers in the subplate with DTI is unsuccessful due to the isotropy of this zone. Penetration of the cortical plate occurs after 24-26 PCW. In conclusion, frontal axonal pathways form the periventricular crossroads, sagittal strata and 'waiting' compartments during the path-finding and penetration of the cortical plate. Histochemistry is advantageous in the demonstration of a growth pattern, whereas DTI is unique for demonstrating axonal trajectories. The complexity of fibers is the biological substrate of selective vulnerability of the fetal white matter.

  3. Pilomotor seizures: an autonomic semiology of limbic encephalitis?

    PubMed

    Rocamora, Rodrigo; Becerra, Juan L; Fossas, Pilar; Gomez, María; Vivanco-Hidalgo, Rosa M; Mauri, José A; Molins, Albert

    2014-09-01

    Ictal piloerection is an infrequent seizure semiology that is commonly overlooked as an ictal epileptic manifestation. Piloerection is considered to be principally caused by temporal lobe activity although frontal and hypothalamic seizure origins have been reported. The described etiology has shown a wide variety of structural causes such as mesial temporal sclerosis, tumors, posttraumatic, cavernomas and cryptogenic epilepsies. We retrospectively reviewed the incidence of ictal piloerection in the clinical records of patients who underwent video-EEG monitoring (VEEGM) between 2007 and 2013 in a multicenter cooperative study. All patients presented refractory epilepsies and were evaluated with a protocol that included brain MRI, neuropsychology and VEEGM. A total of 766 patients were evaluated in four tertiary centers in Spain. Five patients showed piloerection as principal seizure semiology (prevalence 0.65%). The mean age at seizure onset was 39.6 years and the average epilepsy duration was 5.2 years (range 2-14) before diagnosis. Four patients were additionally examined with FDG-PET and/or SPECT-SISCOM. All presented temporal lobe epilepsy (TLE), three right-sided and two left-sided. A typical unilateral hippocampal sclerosis was described in 3 cases. The etiology detected in all cases was limbic encephalitis. Three had LGI1, one anti-Hu, and another Ma2 antibodies. Our series describes a so far not well-recognized autoimmune association of pilomotor seizures to limbic encephalitis. This etiology should be ruled out through a comprehensive diagnostic work-up even in cases of long-lasting TLE with typical hippocampal atrophy on MRI. Copyright © 2014 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

  4. Fronto-limbic volumetric changes in major depressive disorder.

    PubMed

    Malykhin, Nikolai V; Carter, Rawle; Hegadoren, Kathleen M; Seres, Peter; Coupland, Nicholas J

    2012-02-01

    Fronto-limbic dysregulation in major depressive disorder (MDD) may be influenced by early life stress and antidepressant treatment. The present structural MRI study aimed to determine the relationship between amygdala, cingulate and subgenual prefrontal cortex volumes in MDD and their associations with child abuse and antidepressants. Right-handed subjects (21-50 years), meeting DSM-IV criteria for MDD, either with (n=19) or without (n=20) childhood sexual or physical abuse. Healthy controls (n=34) were matched for age, sex, education and smoking. 3D-MPRAGE images with a spatial resolution of 1.5 mm×1.0 mm×1.0 mm were acquired with a Siemens Sonata 1.5 T system. Volumes of subgenual prefrontal cortex, amygdala and affective, cognitive, superior and posterior divisions of cingulate cortex were analyzed using DISPLAY software using reliable volumetric protocols. Groups were compared using ANCOVA, with intracranial volume as a covariate. MDD subjects had low cingulate (cognitive division) and high amygdala volumes. Low cingulate volume was related to abuse and treatment history. Amygdala volume was predicted by subgenual prefrontal and cingulate (cognitive division) volumes and the presence of paracingulate cortex. This study was cross sectional and the sample size was limited for subgroup and correlational analyses. Our data suggest that MDD may be associated with alterations in anterior cingulate cortex and amygdala. Morphological variation, early stress and stress-protective factors may contribute to differences in fronto-limbic structures in MDD. Copyright © 2011 Elsevier B.V. All rights reserved.

  5. Alcoholism and Dampened Temporal Limbic Activation to Emotional Faces

    PubMed Central

    Marinkovic, Ksenija; Oscar-Berman, Marlene; Urban, Trinity; O’Reilly, Cara E.; Howard, Julie A.; Sawyer, Kayle; Harris, Gordon J.

    2013-01-01

    Background Excessive chronic drinking is accompanied by a broad spectrum of emotional changes ranging from apathy and emotional flatness to deficits in comprehending emotional information, but their neural bases are poorly understood. Methods Emotional abnormalities associated with alcoholism were examined with functional magnetic resonance imaging in abstinent long-term alcoholic men in comparison to healthy demographically matched controls. Participants were presented with emotionally valenced words and photographs of faces during deep (semantic) and shallow (perceptual) encoding tasks followed by recognition. Results Overall, faces evoked stronger activation than words, with the expected material-specific laterality (left hemisphere for words, and right for faces) and depth of processing effects. However, whereas control participants showed stronger activation in the amygdala and hippocampus when viewing faces with emotional (relative to neutral) expressions, the alcoholics responded in an undifferentiated manner to all facial expressions. In the alcoholic participants, amygdala activity was inversely correlated with an increase in lateral prefrontal activity as a function of their behavioral deficits. Prefrontal modulation of emotional function as a compensation for the blunted amygdala activity during a socially relevant face appraisal task is in agreement with a distributed network engagement during emotional face processing. Conclusions Deficient activation of amygdala and hippocampus may underlie impaired processing of emotional faces associated with long-term alcoholism and may be a part of the wide array of behavioral problems including disinhibition, concurring with previously documented interpersonal difficulties in this population. Furthermore, the results suggest that alcoholics may rely on prefrontal rather than temporal limbic areas in order to compensate for reduced limbic responsivity and to maintain behavioral adequacy when faced with emotionally

  6. Basal forebrain control of wakefulness and cortical rhythms

    PubMed Central

    Anaclet, Christelle; Pedersen, Nigel P.; Ferrari, Loris L.; Venner, Anne; Bass, Caroline E.; Arrigoni, Elda; Fuller, Patrick M.

    2015-01-01

    Wakefulness, along with fast cortical rhythms and associated cognition, depend on the basal forebrain (BF). BF cholinergic cell loss in dementia and the sedative effect of anti-cholinergic drugs have long implicated these neurons as important for cognition and wakefulness. The BF also contains intermingled inhibitory GABAergic and excitatory glutamatergic cell groups whose exact neurobiological roles are unclear. Here we show that genetically targeted chemogenetic activation of BF cholinergic or glutamatergic neurons in behaving mice produced significant effects on state consolidation and/or the electroencephalogram but had no effect on total wake. Similar activation of BF GABAergic neurons produced sustained wakefulness and high-frequency cortical rhythms, whereas chemogenetic inhibition increased sleep. Our findings reveal a major contribution of BF GABAergic neurons to wakefulness and the fast cortical rhythms associated with cognition. These findings may be clinically applicable to manipulations aimed at increasing forebrain activation in dementia and the minimally conscious state. PMID:26524973

  7. Abnormal development of the locus coeruleus in Ear2(Nr2f6)-deficient mice impairs the functionality of the forebrain clock and affects nociception

    PubMed Central

    Warnecke, Marei; Oster, Henrik; Revelli, Jean-Pierre; Alvarez-Bolado, Gonzalo; Eichele, Gregor

    2005-01-01

    The orphan nuclear receptor Ear2 (Nr2f6) is transiently expressed in the rostral part of the rhombic lip in which the locus coeruleus (LC) arises. LC development, regulated by a signaling cascade (Mash1 → Phox2b → Phox2a), is disrupted in Ear2-/- embryos as revealed by an approximately threefold reduction in the number of Phox2a- and Phox2b-expressing LC progenitor cells. Mash1 expression in the rhombic lip, however, is unaffected, placing Ear2 in between Mash1 and Phox2a/b. Dopamine-β-hydroxylase and tyrosine hydroxylase staining demonstrate that >70% of LC neurons are absent in the adult with agenesis affecting primarily the dorsal division of the LC. Normally, this division projects noradrenergic efferents to the cortex that appear to be diminished in Ear2-/- since the cortical concentration of noradrenaline is four times lower in these mice. The rostral region of the cortex is known to contain a circadian pacemaker regulating adaptability to light- and restricted food-driven entrainment. In situ hybridization establishes that the circadian expression pattern of the clock gene Period1 is abolished in the Ear2-/- forebrain. Behavioral experiments reveal that Ear2 mutants have a delayed entrainment to shifted light-dark cycles and adapt less efficiently to daytime feeding schedules. We propose that neurons in the dorsal division of LC contribute to the regulation of the forebrain clock, at least in part, through targeted release of noradrenaline into the cortical area. PMID:15741322

  8. Developmentally defined forebrain circuits regulate appetitive and aversive olfactory learning

    PubMed Central

    Muthusamy, Nagendran; Zhang, Xuying; Johnson, Caroline A.; Yadav, Prem N.; Ghashghaei, H. Troy

    2016-01-01

    Postnatal and adult neurogenesis are region- and modality-specific, but the significance of developmentally distinct neuronal populations remains unclear. We demonstrate that chemogenetic inactivation of a subset of forebrain and olfactory neurons generated at birth disrupts responses to an aversive odor. In contrast, novel appetitive odor learning is sensitive to inactivation of adult born neurons, unveiling that developmentally defined sets of neurons may differentially participate in hedonic aspects of sensory learning. PMID:27918532

  9. Necdin promotes tangential migration of neocortical interneurons from basal forebrain.

    PubMed

    Kuwajima, Takaaki; Hasegawa, Koichi; Yoshikawa, Kazuaki

    2010-03-10

    Necdin is a pleiotropic protein that promotes neuronal differentiation and survival. In mammals, the necdin gene on the maternal chromosome is silenced by genomic imprinting, and only the paternal necdin gene is expressed in virtually all postmitotic neurons. Necdin forms a complex with the homeodomain protein Dlx2 to enhance its transcriptional activity. Dlx2 plays a major role in controlling tangential migration of GABAergic interneurons from the basal forebrain to the neocortex. Here, we examined whether Dlx2-expressing interneurons migrate properly in vivo in mutant mice lacking the paternal necdin gene. In necdin-deficient mice at birth, the population of Dlx2-expressing cells significantly decreased in the neocortex but increased in the preoptic area. DiI-labeled cell migration assay using organotypic forebrain slice cultures revealed that the number of cells migrating from the medial ganglionic eminence into the neocortex was significantly reduced in necdin-deficient embryos. Furthermore, necdin-deficient mice had a decreased population of neocortical GABA-containing neurons and were highly susceptible to pentylenetetrazole-induced seizures. These results suggest that necdin promotes tangential migration of neocortical GABAergic interneurons during mammalian forebrain development.

  10. Shh and forebrain evolution in the blind cavefish Astyanax mexicanus.

    PubMed

    Rétaux, Sylvie; Pottin, Karen; Alunni, Alessandro

    2008-03-01

    The blind cavefish and its surface counterpart of the teleost species Astyanax mexicanus constitute an excellent model to study the evolution of morphological features. During adaptation to their lives in perpetual darkness, the cave population has lost eyes (and pigmentation), but has gained several constructive traits. Recently, the demonstration that an increase in Shh (Sonic Hedgehog) midline signalling was indirectly responsible for the loss of eyes in cavefish led to new ways to search for possible modifications in the forebrain of these cavefish, as this anterior-most region of the vertebrate central nervous system develops under close control of the powerful Shh morphogen. In this review, we summarize the recent progress in the understanding of forebrain and eye modifications in cavefish. These include major changes in cell death, cell proliferation and cell migration in various parts of the forebrain when compared with their surface counterparts with eyes. The outcome of these modifications, in terms of neuronal circuitry, morphological and behavioral adaptations are discussed.

  11. Corelease of acetylcholine and GABA from cholinergic forebrain neurons

    PubMed Central

    Saunders, Arpiar; Granger, Adam J; Sabatini, Bernardo L

    2015-01-01

    Neurotransmitter corelease is emerging as a common theme of central neuromodulatory systems. Though corelease of glutamate or GABA with acetylcholine has been reported within the cholinergic system, the full extent is unknown. To explore synaptic signaling of cholinergic forebrain neurons, we activated choline acetyltransferase expressing neurons using channelrhodopsin while recording post-synaptic currents (PSCs) in layer 1 interneurons. Surprisingly, we observed PSCs mediated by GABAA receptors in addition to nicotinic acetylcholine receptors. Based on PSC latency and pharmacological sensitivity, our results suggest monosynaptic release of both GABA and ACh. Anatomical analysis showed that forebrain cholinergic neurons express the GABA synthetic enzyme Gad2 and the vesicular GABA transporter (Slc32a1). We confirmed the direct release of GABA by knocking out Slc32a1 from cholinergic neurons. Our results identify GABA as an overlooked fast neurotransmitter utilized throughout the forebrain cholinergic system. GABA/ACh corelease may have major implications for modulation of cortical function by cholinergic neurons. DOI: http://dx.doi.org/10.7554/eLife.06412.001 PMID:25723967

  12. Ascending connections to the forebrain in the Tegu lizard.

    PubMed

    Lohman, A H; van Woerden-Verkley, I

    1978-12-01

    The ascending connections to the striatum and the cortex of the Tegu lizard, Tupinambis nigropunctatus, were studied by means of anterograde fiber degeneration and retrograde axonal transport. The striatum receives projections by way of the dorsal peduncle of the lateral forebrain bundle from four dorsal thalamic nuclei: nucleus rotundus, nucleus reuniens, the posterior part of the dorsal lateral geniculate nucleus and nucleus dorsomedialis. The former three nuclei project to circumscribed areas of the dorsal striatum, whereas nucleus dorsomedialis has a distribution to the whole dorsal striatum. Other sources of origin to the striatum are the mesencephalic reticular formation, substantia nigra and nucleus cerebelli lateralis. With the exception of the latter afferentation all these projections are ipsilateral. The ascending connections to the pallium originate for the major part from nucleus dorsolateralis anterior of the dorsal thalamus. The fibers course in both the medial forebrain bundle and the dorsal peduncle of the lateral forebrain bundle and terminate ipsilaterally in the middle of the molecular layer of the small-celled part of the mediodorsal cortex and bilaterally above the intermediate region of the dorsal cortex. The latter area is reached also by fibers from the septal area. The large-celled part of the mediodorsal cortex receives projections from nucleus raphes superior and the corpus mammillare.

  13. Basal forebrain degeneration precedes and predicts the cortical spread of Alzheimer's pathology

    PubMed Central

    Schmitz, Taylor W.; Nathan Spreng, R.; Weiner, Michael W.; Aisen, Paul; Petersen, Ronald; Jack, Clifford R.; Jagust, William; Trojanowki, John Q.; Toga, Arthur W.; Beckett, Laurel; Green, Robert C.; Saykin, Andrew J.; Morris, John; Shaw, Leslie M.; Khachaturian, Zaven; Sorensen, Greg; Kuller, Lew; Raichle, Marc; Paul, Steven; Davies, Peter; Fillit, Howard; Hefti, Franz; Holtzman, Davie; Mesulam, M Marcel; Potter, William; Snyder, Peter; Schwartz, Adam; Montine, Tom; Thomas, Ronald G.; Donohue, Michael; Walter, Sarah; Gessert, Devon; Sather, Tamie; Jiminez, Gus; Harvey, Danielle; Bernstein, Matthew; Fox, Nick; Thompson, Paul; Schuff, Norbert; Borowski, Bret; Gunter, Jeff; Senjem, Matt; Vemuri, Prashanthi; Jones, David; Kantarci, Kejal; Ward, Chad; Koeppe, Robert A.; Foster, Norm; Reiman, Eric M.; Chen, Kewei; Mathis, Chet; Landau, Susan; Cairns, Nigel J.; Householder, Erin; Taylor-Reinwald, Lisa; Lee, Virginia; Korecka, Magdalena; Figurski, Michal; Crawford, Karen; Neu, Scott; Foroud, Tatiana M.; Potkin, Steven; Shen, Li; Faber, Kelley; Kim, Sungeun; Nho, Kwangsik; Thal, Leon; Buckholtz, Neil; Albert, Marylyn; Frank, Richard; Hsiao, John; Kaye, Jeffrey; Quinn, Joseph; Lind, Betty; Carter, Raina; Dolen, Sara; Schneider, Lon S.; Pawluczyk, Sonia; Beccera, Mauricio; Teodoro, Liberty; Spann, Bryan M.; Brewer, James; Vanderswag, Helen; Fleisher, Adam; Heidebrink, Judith L.; Lord, Joanne L.; Mason, Sara S.; Albers, Colleen S.; Knopman, David; Johnson, Kris; Doody, Rachelle S.; Villanueva-Meyer, Javier; Chowdhury, Munir; Rountree, Susan; Dang, Mimi; Stern, Yaakov; Honig, Lawrence S.; Bell, Karen L.; Ances, Beau; Carroll, Maria; Leon, Sue; Mintun, Mark A.; Schneider, Stacy; Oliver, Angela; Marson, Daniel; Griffith, Randall; Clark, David; Geldmacher, David; Brockington, John; Roberson, Erik; Grossman, Hillel; Mitsis, Effie; de Toledo-Morrell, Leyla; Shah, Raj C.; Duara, Ranjan; Varon, Daniel; Greig, Maria T.; Roberts, Peggy; Albert, Marilyn; Onyike, Chiadi; D'Agostino, Daniel; Kielb, Stephanie; Galvin, James E.; Cerbone, Brittany; Michel, Christina A.; Rusinek, Henry; de Leon, Mony J.; Glodzik, Lidia; De Santi, Susan; Doraiswamy, P. Murali; Petrella, Jeffrey R.; Wong, Terence Z.; Arnold, Steven E.; Karlawish, Jason H.; Wolk, David; Smith, Charles D.; Jicha, Greg; Hardy, Peter; Sinha, Partha; Oates, Elizabeth; Conrad, Gary; Lopez, Oscar L.; Oakley, MaryAnn; Simpson, Donna M.; Porsteinsson, Anton P.; Goldstein, Bonnie S.; Martin, Kim; Makino, Kelly M.; Ismail, M. Saleem; Brand, Connie; Mulnard, Ruth A.; Thai, Gaby; Mc-Adams-Ortiz, Catherine; Womack, Kyle; Mathews, Dana; Quiceno, Mary; Diaz-Arrastia, Ramon; King, Richard; Weiner, Myron; Martin-Cook, Kristen; DeVous, Michael; Levey, Allan I.; Lah, James J.; Cellar, Janet S.; Burns, Jeffrey M.; Anderson, Heather S.; Swerdlow, Russell H.; Apostolova, Liana; Tingus, Kathleen; Woo, Ellen; Silverman, Daniel H. S.; Lu, Po H.; Bartzokis, George; Graff-Radford, Neill R.; Parfitt, Francine; Kendall, Tracy; Johnson, Heather; Farlow, Martin R.; Hake, AnnMarie; Matthews, Brandy R.; Herring, Scott; Hunt, Cynthia; van Dyck, Christopher H.; Carson, Richard E.; MacAvoy, Martha G.; Chertkow, Howard; Bergman, Howard; Hosein, Chris; Black, Sandra; Stefanovic, Bojana; Caldwell, Curtis; Robin Hsiung, Ging-Yuek; Feldman, Howard; Mudge, Benita; Assaly, Michele; Kertesz, Andrew; Rogers, John; Bernick, Charles; Munic, Donna; Kerwin, Diana; Mesulam, Marek-Marsel; Lipowski, Kristine; Wu, Chuang-Kuo; Johnson, Nancy; Sadowsky, Carl; Martinez, Walter; Villena, Teresa; Turner, Raymond Scott; Johnson, Kathleen; Reynolds, Brigid; Sperling, Reisa A.; Johnson, Keith A.; Marshall, Gad; Frey, Meghan; Lane, Barton; Rosen, Allyson; Tinklenberg, Jared; Sabbagh, Marwan N.; Belden, Christine M.; Jacobson, Sandra A.; Sirrel, Sherye A.; Kowall, Neil; Killiany, Ronald; Budson, Andrew E.; Norbash, Alexander; Johnson, Patricia Lynn; Allard, Joanne; Lerner, Alan; Ogrocki, Paula; Hudson, Leon; Fletcher, Evan; Carmichael, Owen; Olichney, John; DeCarli, Charles; Kittur, Smita; Borrie, Michael; Lee, T.-Y.; Bartha, Rob; Johnson, Sterling; Asthana, Sanjay; Carlsson, Cynthia M.; Potkin, Steven G.; Preda, Adrian; Nguyen, Dana; Tariot, Pierre; Reeder, Stephanie; Bates, Vernice; Capote, Horacio; Rainka, Michelle; Scharre, Douglas W.; Kataki, Maria; Adeli, Anahita; Zimmerman, Earl A.; Celmins, Dzintra; Brown, Alice D.; Pearlson, Godfrey D.; Blank, Karen; Anderson, Karen; Santulli, Robert B.; Kitzmiller, Tamar J.; Schwartz, Eben S.; Sink, Kaycee M.; Williamson, Jeff D.; Garg, Pradeep; Watkins, Franklin; Ott, Brian R.; Querfurth, Henry; Tremont, Geoffrey; Salloway, Stephen; Malloy, Paul; Correia, Stephen; Rosen, Howard J.; Miller, Bruce L.; Mintzer, Jacobo; Spicer, Kenneth; Bachman, David; Finger, Elizabether; Pasternak, Stephen; Rachinsky, Irina; Drost, Dick; Pomara, Nunzio; Hernando, Raymundo; Sarrael, Antero; Schultz, Susan K.; Boles Ponto, Laura L.; Shim, Hyungsub; Smith, Karen Elizabeth; Relkin, Norman; Chaing, Gloria; Raudin, Lisa; Smith, Amanda; Fargher, Kristin; Raj, Balebail Ashok; Neylan, Thomas; Grafman, Jordan; Davis, Melissa; Morrison, Rosemary; Hayes, Jacqueline; Finley, Shannon; Friedl, Karl; Fleischman, Debra; Arfanakis, Konstantinos; James, Olga; Massoglia, Dino; Fruehling, J. Jay; Harding, Sandra; Peskind, Elaine R.; Petrie, Eric C.; Li, Gail; Yesavage, Jerome A.; Taylor, Joy L.; Furst, Ansgar J.

    2016-01-01

    There is considerable debate whether Alzheimer's disease (AD) originates in basal forebrain or entorhinal cortex. Here we examined whether longitudinal decreases in basal forebrain and entorhinal cortex grey matter volume were interdependent and sequential. In a large cohort of age-matched older adults ranging from cognitively normal to AD, we demonstrate that basal forebrain volume predicts longitudinal entorhinal degeneration. Models of parallel degeneration or entorhinal origin received negligible support. We then integrated volumetric measures with an amyloid biomarker sensitive to pre-symptomatic AD pathology. Comparison between cognitively matched normal adult subgroups, delineated according to the amyloid biomarker, revealed abnormal degeneration in basal forebrain, but not entorhinal cortex. Abnormal degeneration in both basal forebrain and entorhinal cortex was only observed among prodromal (mildly amnestic) individuals. We provide evidence that basal forebrain pathology precedes and predicts both entorhinal pathology and memory impairment, challenging the widely held belief that AD has a cortical origin. PMID:27811848

  14. Noradrenergic Control of Odor Recognition in a Nonassociative Olfactory Learning Task in the Mouse

    ERIC Educational Resources Information Center

    Veyrac, Alexandra; Nguyen, Veronique; Marien, Marc; Didier, Anne; Jourdan, Francois

    2007-01-01

    The present study examined the influence of pharmacological modulations of the locus coeruleus noradrenergic system on odor recognition in the mouse. Mice exposed to a nonrewarded olfactory stimulation (training) were able to memorize this odor and to discriminate it from a new odor in a recall test performed 15 min later. At longer delays (30 or…

  15. Facilitation of Learning by Social-Emotional Feedback in Humans Is Beta-Noradrenergic-Dependent

    ERIC Educational Resources Information Center

    Mihov, Yoan; Mayer, Simon; Musshoff, Frank; Maier, Wolfgang; Kendrick, Keith M.; Hurlemann, Rene

    2010-01-01

    Adaptive behavior in dynamic environments critically depends on the ability to learn rapidly and flexibly from the outcomes of prior choices. In social environments, facial expressions of emotion often serve as performance feedback and thereby guide declarative learning. Abundant evidence implicates beta-noradrenergic signaling in the modulatory…

  16. Orphanin FQ/Nociceptin Interacts with the Basolateral Amygdala Noradrenergic System in Memory Consolidation

    ERIC Educational Resources Information Center

    Roozendaal, Benno; Lengvilas, Ray; McGaugh, James L.; Civelli, Olivier; Reinscheid, Rainer K.

    2007-01-01

    Extensive evidence indicates that the basolateral complex of the amygdala (BLA) mediates hormonal and neurotransmitter effects on the consolidation of emotionally influenced memory and that such modulatory influences involve noradrenergic activation of the BLA. As the BLA also expresses a high density of receptors for orphanin FQ/nociceptin…

  17. Facilitation of Learning by Social-Emotional Feedback in Humans Is Beta-Noradrenergic-Dependent

    ERIC Educational Resources Information Center

    Mihov, Yoan; Mayer, Simon; Musshoff, Frank; Maier, Wolfgang; Kendrick, Keith M.; Hurlemann, Rene

    2010-01-01

    Adaptive behavior in dynamic environments critically depends on the ability to learn rapidly and flexibly from the outcomes of prior choices. In social environments, facial expressions of emotion often serve as performance feedback and thereby guide declarative learning. Abundant evidence implicates beta-noradrenergic signaling in the modulatory…

  18. Complementary neural correlates of motivation in dopaminergic and noradrenergic neurons of monkeys

    PubMed Central

    Bouret, Sebastien; Ravel, Sabrina; Richmond, Barry J.

    2012-01-01

    Rewards have many influences on learning, decision-making, and performance. All seem to rely on complementary actions of two closely related catecholaminergic neuromodulators, dopamine (DA), and noradrenaline (NA). We compared single unit activity of dopaminergic neurons of the substantia nigra pars compacta (SNc) and noradrenergic neurons of the locus coeruleus (LC) in monkeys performing a reward schedule task. Their motivation, indexed using operant performance, increased as they progressed through schedules ending in reward delivery. The responses of dopaminergic and noradrenergic neurons around the time of major task events, visual cues predicting trial outcome and operant action to complete a trial were similar in that they occurred at the same time. They were also similar in that they both responded most strongly to the first cues in schedules, which are the most informative cues. The neuronal responses around the time of the monkeys' actions were different, in that the response intensity profiles changed in opposite directions. Dopaminergic responses were stronger around predictably rewarded correct actions whereas noradrenergic responses were greater around predictably unrewarded correct actions. The complementary response profiles related to the monkeys operant actions suggest that DA neurons might relate to the value of the current action whereas the noradrenergic neurons relate to the psychological cost of that action. PMID:22822392

  19. The Memory Function of Noradrenergic Activity in Non-REM Sleep

    ERIC Educational Resources Information Center

    Gais, Steffen; Rasch, Bjorn; Dahmen, Johannes C.; Sara, Susan; Born, Jan

    2011-01-01

    There is a long-standing assumption that low noradrenergic activity during sleep reflects mainly the low arousal during this brain state. Nevertheless, recent research has demonstrated that the locus coeruleus, which is the main source of cortical noradrenaline, displays discrete periods of intense firing during non-REM sleep, without any signs of…

  20. Resilience to chronic stress is mediated by noradrenergic regulation of dopamine neurons.

    PubMed

    Isingrini, Elsa; Perret, Léa; Rainer, Quentin; Amilhon, Bénédicte; Guma, Elisa; Tanti, Arnaud; Martin, Garance; Robinson, Jennifer; Moquin, Luc; Marti, Fabio; Mechawar, Naguib; Williams, Sylvain; Gratton, Alain; Giros, Bruno

    2016-04-01

    Dopamine (DA) neurons in the ventral tegmental area (VTA) help mediate stress susceptibility and resilience. However, upstream mechanisms controlling these neurons remain unknown. Noradrenergic (NE) neurons in the locus coeruleus, implicated in the pathophysiology of depression, have direct connections within the VTA. Here we demonstrate that NE neurons regulate vulnerability to social defeat through inhibitory control of VTA DA neurons.

  1. Orphanin FQ/Nociceptin Interacts with the Basolateral Amygdala Noradrenergic System in Memory Consolidation

    ERIC Educational Resources Information Center

    Roozendaal, Benno; Lengvilas, Ray; McGaugh, James L.; Civelli, Olivier; Reinscheid, Rainer K.

    2007-01-01

    Extensive evidence indicates that the basolateral complex of the amygdala (BLA) mediates hormonal and neurotransmitter effects on the consolidation of emotionally influenced memory and that such modulatory influences involve noradrenergic activation of the BLA. As the BLA also expresses a high density of receptors for orphanin FQ/nociceptin…

  2. The Memory Function of Noradrenergic Activity in Non-REM Sleep

    ERIC Educational Resources Information Center

    Gais, Steffen; Rasch, Bjorn; Dahmen, Johannes C.; Sara, Susan; Born, Jan

    2011-01-01

    There is a long-standing assumption that low noradrenergic activity during sleep reflects mainly the low arousal during this brain state. Nevertheless, recent research has demonstrated that the locus coeruleus, which is the main source of cortical noradrenaline, displays discrete periods of intense firing during non-REM sleep, without any signs of…

  3. Restoring Spinal Noradrenergic Inhibitory Tone Attenuates Pain Hypersensitivity in a Rat Model of Parkinson's Disease

    PubMed Central

    Wang, Bing; Chen, Li-Hua

    2016-01-01

    In the present study, we investigated whether restoring descending noradrenergic inhibitory tone can attenuate pain in a PD rat model, which was established by stereotaxic infusion of 6-hydroxydopamine (6-OHDA) into the bilateral striatum (CPu). PD rats developed thermal and mechanical hypersensitivity at the 4th week after surgery. HPLC analysis showed that NE content, but not dopamine or 5-HT, significantly decreased in lumbar spinal cord in PD rats. Additional noradrenergic depletion by injection of N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) aggravated pain hypersensitivity in PD rats. At the 5th week after injection of 6-OHDA, systemic treatment with pharmacological norepinephrine (NE) precursor droxidopa (L-DOPS) or α2 adrenoceptor agonist clonidine significantly attenuated thermal and mechanical pain hypersensitivity in PD rats. Furthermore, application of norepinephrine (NE) and 5-hydroxytryptamine (5-HT) reuptake inhibitors duloxetine, but not 5-HT selective reuptake inhibitors sertraline, significantly inhibited thermal and mechanical pain hypersensitivity in PD rats. Systemic administration of Madopar (L-DOPA) or the D2/D3 agonist pramipexole slightly inhibited the thermal, but not mechanical, hypersensitivity in PD rats. Thus, our study revealed that impairment of descending noradrenergic system may play a key role in PD-associated pain and restoring spinal noradrenergic inhibitory tone may serve as a novel strategy to manage PD-associated pain. PMID:27747105

  4. Noradrenergic Control of Odor Recognition in a Nonassociative Olfactory Learning Task in the Mouse

    ERIC Educational Resources Information Center

    Veyrac, Alexandra; Nguyen, Veronique; Marien, Marc; Didier, Anne; Jourdan, Francois

    2007-01-01

    The present study examined the influence of pharmacological modulations of the locus coeruleus noradrenergic system on odor recognition in the mouse. Mice exposed to a nonrewarded olfactory stimulation (training) were able to memorize this odor and to discriminate it from a new odor in a recall test performed 15 min later. At longer delays (30 or…

  5. Noradrenergic Action in Prefrontal Cortex in the Late Stage of Memory Consolidation

    ERIC Educational Resources Information Center

    Tronel, Sophie; Feenstra, Matthijs G. P.; Sara, Susan J.

    2004-01-01

    These experiments investigated the role of the noradrenergic system in the late stage of memory consolidation and in particular its action at beta receptors in the prelimbic region (PL) of the prefrontal cortex in the hours after training. Rats were trained in a rapidly acquired, appetitively motivated foraging task based on olfactory…

  6. Repeated Administration of Amitriptyline in Neuropathic Pain: Modulation of the Noradrenergic Descending Inhibitory System.

    PubMed

    Hiroki, Tadanao; Suto, Takashi; Saito, Shigeru; Obata, Hideaki

    2017-10-01

    The tricyclic antidepressant amitriptyline, the serotonin and noradrenaline reuptake inhibitor duloxetine, and gabapentinoids are first-line drugs for treatment of neuropathic pain. The analgesic effect of these drugs relates to brainstem-spinal descending noradrenergic systems. However, amitriptyline utilizes a variety of mechanisms for analgesia in neuropathic pain, and it is unclear which mechanism is most important. In the present study, we investigated the role of descending noradrenergic systems in the analgesic effect of these drugs for treatment of neuropathic pain. We also examined whether amitriptyline modifies the descending noradrenergic systems. Seven days after L5 spinal nerve ligation (SNL), rats received N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4, 50 mg/kg) to degenerate noradrenergic fibers. The rats then received 5 daily intraperitoneal injections of amitriptyline (10 mg/kg), duloxetine (10 mg/kg), pregabalin (10 mg/kg), or gabapentin (50 mg/kg) from 21 days after SNL surgery. Paw withdrawal thresholds were determined to assess the effect of the drugs on hyperalgesia after SNL. To determine whether 5 daily injections of amitriptyline activated noradrenergic neurons in the locus coeruleus (LC) and spinal cord with or without DSP-4 treatment, we performed immunohistochemistry using antibodies for c-Fos and dopamine beta-hydroxylase (DβH). Five daily injections of amitriptyline, duloxetine, pregabalin, and gabapentin exerted antihyperalgesic effects in SNL rats (P < .001; estimated treatment effect of amitriptyline [99% confidence interval]: 59.9 [35.1-84.7] g). The antihyperalgesic effects of duloxetine, pregabalin, and gabapentin were reversed by pretreatment with DSP-4 (P < .001, respectively). However, antihyperalgesia was still observed after treatment of amitriptyline in SNL rats with DSP-4 pretreatment (P < .001, 59.7 [30.0-89.3] g), and this analgesic effect was not reversed by the α2-adrenoceptor antagonist idazoxan (30

  7. The noradrenergic paradox: implications in the management of depression and anxiety

    PubMed Central

    Montoya, Alonso; Bruins, Robert; Katzman, Martin A; Blier, Pierre

    2016-01-01

    Both major depressive disorder and the anxiety disorders are major causes of disability and markedly contribute to a significant global burden of the disease worldwide. In part because of the significant socioeconomic burden associated with these disorders, theories have been developed to specifically build clinical treatment approaches. One such theory, the monoaminergic hypothesis, has led to the development of several generations of selective and nonselective inhibitors of transporters of serotonin and norepinephrine, with the goal of augmenting monoaminergic transmission. These efforts have led to considerable success in the development of antidepressant therapeutics. However, there is a strong correlation between enhanced noradrenergic activity and fear and anxiety. Consequently, some physicians have expressed concerns that the same enhanced noradrenergic activity that alleviates depression could also promote anxiety. The fact that the serotonergic and noradrenergic reuptake inhibitors are successfully used in the treatment of anxiety and panic disorders seems paradoxical. This review was undertaken to determine if any clinical evidence exists to show that serotonergic and noradrenergic reuptake inhibitors can cause anxiety. The PubMed, EMBASE, and Cochrane Library databases were searched, and the results limited to randomized, double-blind, placebo-controlled studies performed in nongeriatric adults and with clear outcome measures were reported. Based on these criteria, a total of 52 studies were examined. Patients in these studies suffered from depression or anxiety disorders (generalized and social anxiety disorders, panic disorder, and posttraumatic stress disorder). The large majority of these studies employed venlafaxine or duloxetine, and the remainder used tri-cyclic antidepressants, atomoxetine, or reboxetine. All the studies reported clinically significant alleviation of depressive and/or anxious symptoms by these therapeutics. In none of these

  8. The noradrenergic paradox: implications in the management of depression and anxiety.

    PubMed

    Montoya, Alonso; Bruins, Robert; Katzman, Martin A; Blier, Pierre

    2016-01-01

    Both major depressive disorder and the anxiety disorders are major causes of disability and markedly contribute to a significant global burden of the disease worldwide. In part because of the significant socioeconomic burden associated with these disorders, theories have been developed to specifically build clinical treatment approaches. One such theory, the monoaminergic hypothesis, has led to the development of several generations of selective and nonselective inhibitors of transporters of serotonin and norepinephrine, with the goal of augmenting monoaminergic transmission. These efforts have led to considerable success in the development of antidepressant therapeutics. However, there is a strong correlation between enhanced noradrenergic activity and fear and anxiety. Consequently, some physicians have expressed concerns that the same enhanced noradrenergic activity that alleviates depression could also promote anxiety. The fact that the serotonergic and noradrenergic reuptake inhibitors are successfully used in the treatment of anxiety and panic disorders seems paradoxical. This review was undertaken to determine if any clinical evidence exists to show that serotonergic and noradrenergic reuptake inhibitors can cause anxiety. The PubMed, EMBASE, and Cochrane Library databases were searched, and the results limited to randomized, double-blind, placebo-controlled studies performed in nongeriatric adults and with clear outcome measures were reported. Based on these criteria, a total of 52 studies were examined. Patients in these studies suffered from depression or anxiety disorders (generalized and social anxiety disorders, panic disorder, and posttraumatic stress disorder). The large majority of these studies employed venlafaxine or duloxetine, and the remainder used tri-cyclic antidepressants, atomoxetine, or reboxetine. All the studies reported clinically significant alleviation of depressive and/or anxious symptoms by these therapeutics. In none of these

  9. Fear conditioning selectively disrupts noradrenergic facilitation of GABAergic inhibition in the basolateral amygdala.

    PubMed

    Skelly, M J; Ariwodola, O J; Weiner, J L

    2017-02-01

    Inappropriate fear memory formation is symptomatic of many psychopathologies, and delineating the neurobiology of non-pathological fear learning may provide critical insight into treating these disorders. Fear memory formation is associated with decreased inhibitory signaling in the basolateral amygdala (BLA), and disrupted noradrenergic signaling may contribute to this decrease. BLA noradrenergic neurotransmission has been implicated in fear memory formation, and distinct adrenoreceptor (AR) subtypes modulate excitatory and inhibitory neurotransmission in this region. For example, α1-ARs promote GABA release from local inhibitory interneurons, while β3-ARs potentiate neurotransmission at lateral paracapsular (LPC) GABAergic synapses. Conversely, β1/2-ARs amplify excitatory signaling at glutamatergic synapses in the BLA. As increased BLA excitability promotes fear memory formation, we hypothesized that fear learning shifts the balanced regional effects of noradrenergic signaling toward excitation. To test this hypothesis, we used the fear-potentiated startle paradigm in combination with whole cell patch clamp electrophysiology to examine the effects of AR activation on BLA synaptic transmission following fear conditioning in male Long-Evans rats. We first demonstrated that inhibitory neurotransmission is decreased at both local and LPC synapses following fear conditioning. We next measured noradrenergic facilitation of BLA inhibitory signaling at local and LPC synapses using α1-and β3-AR agonists (1 μM A61603 and 10 μM BRL37344), and found that the ability of these agents to facilitate inhibitory neurotransmission is disrupted following fear conditioning. Conversely, we found that fear learning does not disrupt noradrenergic modulation of glutamatergic signaling via a β1/2-AR agonist (1 μM isoproterenol). Taken together, these studies suggest that fear learning increases BLA excitability by selectively disrupting the inhibitory effects of noradrenaline

  10. Immunohistochemical localization of the D1 dopamine receptor in rat brain reveals its axonal transport, pre- and postsynaptic localization, and prevalence in the basal ganglia, limbic system, and thalamic reticular nucleus.

    PubMed Central

    Huang, Q; Zhou, D; Chase, K; Gusella, J F; Aronin, N; DiFiglia, M

    1992-01-01

    D1 dopamine receptor localization was examined by immunohistochemistry using a polyclonal anti-peptide antibody which (i) immunoprecipitated a protein fragment encoded by a D1 receptor cDNA and (ii) on Western blots of solubilized striatal and hippocampal membranes recognized two proteins of approximately 50 kDa and 75 kDa, corresponding to reported sizes of D1 receptor proteins. Immunoreactivity overlapped with dopamine-containing pathways, patterns of D1 receptor binding, and mRNA expression. Staining was concentrated in prefrontal, cingulate, parietal, piriform, entorhinal, and hippocampal cortical areas and subcortically in the basal ganglia, amygdala, septal area, substantia inominata, thalamus, hypothalamus, and neurohypophysis. Prominent labeling was seen in the thalamic reticular nucleus, a region known to integrate ascending basal forebrain inputs with thalamocortical and corticothalamic pathways and in fiber bundles interconnecting limbic areas. In striatal neuropil, staining appeared in spines (heads and necks), at postsynaptic sites in dendrites, and in axon terminals; in the pars reticulata of the substantia nigra, labeling was prevalent in myelinated and unmyelinated axons and dendrites. These data provide direct evidence for the regional and subcellular distribution of D1 receptor protein in the brain and for its pre- and postsynaptic localization in the basal ganglia. The prominent immunoreactivity seen in the limbic system and thalamic reticular nucleus supports an important role for this receptor subtype in mediating integrative processes involved with learning, memory, and cognition. Images PMID:1281547

  11. Co-localization of the cannabinoid type 1 receptor with corticotropin-releasing factor-containing afferents in the noradrenergic nucleus locus coeruleus: implications for the cognitive limb of the stress response.

    PubMed

    R Wyrofsky, Ryan; Reyes, Beverly A S; Van Bockstaele, Elisabeth J

    2017-03-02

    The noradrenergic system has been shown to play a key role in the regulation of stress responses, arousal, mood, and emotional states. Corticotropin-releasing factor (CRF) is a primary mediator of stress-induced activation of noradrenergic neurons in the nucleus locus coeruleus (LC). The endocannabinoid (eCB) system also plays a key role in modulating stress responses, acting as an "anti-stress" neuro-mediator. In the present study, we investigated the cellular sites for interactions between the cannabinoid receptor type 1 (CB1r) and CRF in the LC. Immunofluorescence and high-resolution immunoelectron microscopy showed co-localization of CB1r and CRF in both the core and peri-LC areas. Semi-quantitative analysis revealed that 44% (208/468) of CRF-containing axon terminals in the core and 35% (104/294) in the peri-LC expressed CB1r, while 18% (85/468) of CRF-containing axon terminals in the core and 6.5% (19/294) in the peri-LC were presynaptic to CB1r-containing dendrites. In the LC core, CB1r + CRF axon terminals were more frequently of the symmetric (inhibitory) type; while in the peri-LC, a majority were of the asymmetric (excitatory) type. Triple label immunofluorescence results supported the ultrastructural analysis indicating that CB1r + CRF axon terminals contained either gamma amino butyric acid or glutamate. Finally, anterograde transport from the central nucleus of the amygdala revealed that CRF-amygdalar afferents projecting to the LC contain CB1r. Taken together, these results indicate that the eCB system is poised to directly modulate stress-integrative heterogeneous CRF afferents in the LC, some of which arise from limbic sources.

  12. Age-related changes in the noradrenergic innervation of the coronary arteries in old rats: a fluorescent histochemical study.

    PubMed

    Amenta, F; Mione, M C

    1988-04-01

    Age-related changes in the density of the noradrenergic perivascular plexus supplying the coronary vessels in the rat were studied using the glyoxylic acid fluorescence technique. A marked decrease in the density of the noradrenergic innervation of large, medium and small size coronary arteries was observed in 25-month-old rats. In contrast, the fluorescent nerves supplying the coronary veins were not decreased in old animals. The present data are indicative of an age-related reduction of fluorescent noradrenergic nerves in the rat coronary arteries.

  13. Regenerations of the noradrenergic innervation of the cardiovascular system of the chick following treatment with 6-hydroxydopamine

    PubMed Central

    Bennett, T.; Malmfors, T.

    1974-01-01

    1. Fluorescence histochemical and pharmacological studies were made of the noradrenergic innervation of inferior venae cavae and left atria from 2- and 6-week-old chicks before, and following, treatment with 6-hydroxydopamine. 2. Noradrenergic nerves in the younger animals appeared to be relatively resistant to the toxic effects of 6-hydroxydopamine. 3. In the older animals, the time course of recovery from the effects of 6-hydroxydopamine appeared to reflect the rate of regeneration of destroyed noradrenergic nerves. 4. Marked presynaptic supersensitivity to adrenaline and noradrenaline was observed in left atria and inferior venae cavae following treatment with 6-hydroxydopamine. PMID:4455832

  14. Limbic hyperactivity associated to verbal memory deficit in schizophrenia.

    PubMed

    Suazo, Vanessa; Díez, Álvaro; Tamayo, Pilar; Montes, Carlos; Molina, Vicente

    2013-06-01

    In schizophrenia there seems to be an inefficient activation of prefrontal and hippocampal regions. Patients tend to show worse cognitive performance in functions subserved by those regions as compared to healthy controls in spite of higher regional activation. However, the association between activation abnormalities and cognitive deficits remains without being understood. In the present study, we compared cerebral perfusion using single-photon emission tomography (SPECT) in patients and controls to study the association between activation patterns and cognitive performance in this disease. The SPECT studies were simultaneously obtained with an electrophysiological recording during a P300 paradigm to elicit P3a and P3b components. We included 23 stable patients with paranoid schizophrenia and 29 healthy controls that underwent clinical and cognitive assessments. Patients with schizophrenia showed an increased perfusion in the right hippocampus with respect to healthy controls, they also displayed a statistically significant inverse association between perfusion in the left hippocampus and verbal memory performance. Healthy controls showed an inverse association between perfusion in the left dorsolateral prefrontal (DLPFC) region and working memory performance. P3b but not P3a amplitude was significantly lower in patients. The limbic overactivation in the patients may contribute to their cognitive deficits in verbal memory. Copyright © 2013 Elsevier Ltd. All rights reserved.

  15. Basal Forebrain Cholinergic System and Orexin Neurons: Effects on Attention

    PubMed Central

    Villano, Ines; Messina, Antonietta; Valenzano, Anna; Moscatelli, Fiorenzo; Esposito, Teresa; Monda, Vincenzo; Esposito, Maria; Precenzano, Francesco; Carotenuto, Marco; Viggiano, Andrea; Chieffi, Sergio; Cibelli, Giuseppe; Monda, Marcellino; Messina, Giovanni

    2017-01-01

    The basal forebrain (BF) cholinergic system has an important role in attentive functions. The cholinergic system can be activated by different inputs, and in particular, by orexin neurons, whose cell bodies are located within the postero-lateral hypothalamus. Recently the orexin-producing neurons have been proved to promote arousal and attention through their projections to the BF. The aim of this review article is to summarize the evidence showing that the orexin system contributes to attentional processing by an increase in cortical acetylcholine release and in cortical neurons activity. PMID:28197081

  16. Treatment of limbic encephalitis with anti-glioma-inactivated 1 (LGI1) antibodies.

    PubMed

    Krastinova, E; Vigneron, M; Le Bras, P; Gasnault, J; Goujard, C

    2012-11-01

    We report a 72-year-old patient who developed acute limbic encephalitis initially considered of uncertain aetiology. Detailed information on clinical presentation, MRI appearance, antibody levels, cognitive impairment assessment, treatment and evolution of the patient is reported here. Since the early 2000s, many antibodies implied in central nervous system autoimmune disorders have been identified. Anti-glioma-inactivated 1 (LGI1) antibodies have been recently identified as associated with limbic encephalitis, as was the case in our patient.

  17. In vivo magnetic resonance imaging of the human limbic white matter

    PubMed Central

    Mori, Susumu; Aggarwal, Manisha

    2014-01-01

    The limbic system mediates memory, behavior, and emotional output in the human brain, and is implicated in the pathology of Alzheimer’s disease and a wide spectrum of related neurological disorders. In vivo magnetic resonance imaging (MRI) of structural components comprising the limbic system and their interconnections via white matter pathways in the human brain has helped define current understanding of the limbic model based on the classical circuit proposed by Papez. MRI techniques, including diffusion MR imaging, provide a non-invasive method to characterize white matter tracts of the limbic system, and investigate pathological changes that affect these pathways in clinical settings. This review focuses on delineation of the anatomy of major limbic tracts in the human brain, namely, the cingulum, the fornix and fimbria, and the stria terminalis, based on in vivo MRI contrasts. The detailed morphology and intricate trajectories of these pathways that can be identified using relaxometry-based and diffusion-weighted MRI provide an important anatomical reference for evaluation of clinical disorders commonly associated with limbic pathology. PMID:25505883

  18. Interruption of central noradrenergic pathways and morphine withdrawal excitation of oxytocin neurones in the rat

    PubMed Central

    Brown, C H; Murphy, N P; Munro, G; Ludwig, M; Bull, P M; Leng, G; Russell, J A

    1998-01-01

    We have tested the hypothesis that morphine withdrawal excitation of oxytocin neurones that follows from administration of naloxone to morphine-dependent rats is a consequence of excitation of noradrenergic neurones. Female rats were made morphine dependent by intracerebroventricular (i.c.v.) infusion of the opioid at increasing doses over 5 days. On the sixth day, the rats were anaesthetized with urethane or pentobarbitone and prepared for blood sampling to determine plasma oxytocin by radioimmunoassay or for in vivo extracellular recording of the firing rate of identified oxytocin neurones from the supraoptic nucleus. Morphine withdrawal was induced by intravenous (i.v.) injection of the opioid antagonist naloxone (5 mg kg−1). In one group of rats the noradrenergic projections to the hypothalamus were lesioned by i.c.v. injection of 6-hydroxydopamine immediately prior to the induction of morphine dependence. In these rats the oxytocin secretion induced by i.v. cholecystokinin was reduced to 9% of that seen in sham-lesioned rats but in contrast, no attenuation of morphine withdrawal-induced oxytocin secretion was observed. i.c.v. infusion of the α1-adrenoreceptor antagonist benoxathian, at up to 5.3 μg min−1, dose-dependently inhibited the withdrawal excitation of oxytocin neurones in morphine-dependent rats under urethane anaesthesia, and benoxathian reduced withdrawal-induced oxytocin secretion to 37% of that of vehicle-infused rats. i.c.v. benoxathian also inhibited the activity of oxytocin neurones in morphine-naïve rats. Similarly, microdialysis administration of 2 mm benoxathian directly onto the surface of the supraoptic nucleus reduced the activity of oxytocin neurones by 53%. Thus noradrenergic systems are not essential for the expression of morphine withdrawal excitation, since chronic neurotoxic destruction of the noradrenergic inputs to the hypothalamus did not affect the magnitude of withdrawal-induced oxytocin secretion. However, tonically

  19. Noradrenergic function and the mechanism of action of antianxiety treatment. I. The effect of long-term alprazolam treatment.

    PubMed

    Charney, D S; Heninger, G R

    1985-05-01

    There is preclinical and clinical evidence suggesting that one neural mechanism responsible for antipanic efficacy is a reduction in brain noradrenergic function. Alprazolam, a triazolobenzodiazepine, has been demonstrated to have antipanic properties; however, to our knowledge, its effects on noradrenergic function have not been established. To assess whether alprazolam alters noradrenergic function, the effects of alprazolam on baseline plasma free 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG), and yohimbine-induced increases in plasma MHPG level, anxiety-nervousness, blood pressure, and somatic symptoms were studied in 14 patients with agoraphobia and panic disorder. Long-term alprazolam treatment significantly reduced plasma MHPG baseline and blunted the yohimbine-induced increases in plasma MHPG, anxiety-nervousness, and sitting systolic blood pressure. These observations suggest that the antipanic mechanism of action of alprazolam may be due in part to an interaction between benzodiazepine-sensitive and noradrenergic neural systems.

  20. Environmental enrichment delays limbic epileptogenesis and restricts pathologic synaptic plasticity.

    PubMed

    Yang, Meng; Ozturk, Ezgi; Salzberg, Michael R; Rees, Sandra; Morris, Margaret; O'Brien, Terence J; Jones, Nigel C

    2016-03-01

    Environmental exposures impart powerful effects on vulnerability to many brain diseases, including epilepsy. Mesial temporal lobe epilepsy (MTLE) is a common form of epilepsy, and it is often accompanied by neuropsychiatric comorbidities. This study tests the hypothesis that environmental enrichment (EE) confers antiepileptogenic, psychoprotective, and neuroprotective effects in the amygdala kindling model of MTLE, and explores potential neurobiologic mechanisms. At weaning, male Wistar rats were allocated into either EE (large cages containing running wheels and toys; n = 43) or standard housing (SH; standard laboratory cages; n = 39) conditions. At P56, a bipolar electrode was implanted into the left amygdala, and rats underwent rapid amygdala kindling until experiencing five class V seizures (Racine scale, fully kindled). The elevated plus maze was used to assess anxiety. Postmortem histologic and molecular analyses investigated potential biologic mediators of effects. EE significantly delayed kindling epileptogenesis, with EE rats requiring a significantly greater number of kindling stimulations to reach a fully kindled state compared to SH rats (p < 0.05). EE and kindling both reduced anxiety (p < 0.05). Timm's staining revealed significant reductions in aberrant mossy fiber sprouting in EE rats (p < 0.05), and these effects of EE were accompanied by reduced expression of TrkB and CRH genes. We identify beneficial effects of EE on vulnerability to limbic epileptogenesis and anxiety, and identify reduced pathologic neuroplasticity and plasticity-related gene expression as potential underlying mechanisms. Enhanced environmental stimulation represents a potential antiepileptogenic strategy that might also mitigate the common psychiatric comorbidities of MTLE. Wiley Periodicals, Inc. © 2016 International League Against Epilepsy.

  1. Dynamic variation in forebrain estradiol levels during song learning

    PubMed Central

    Chao, Andrew; Paon, Ashley; Remage-Healey, Luke

    2014-01-01

    Estrogens shape brain circuits during development, and the capacity to synthesize estrogens locally has consequences for both sexual differentiation and the acute modulation of circuits during early learning. A recently-optimized method to detect and quantify fluctuations in brain estrogens in vivo provides a direct means to explore how brain estrogen production contributes to both differentiation and neuromodulation during development. Here, we use this method to test the hypothesis that neuroestrogens are sexually-differentiated as well as dynamically responsive to song tutoring (via passive video/audio playback) during the period of song learning in juvenile zebra finches. Our results show that baseline neuroestradiol levels in the caudal forebrain do not differ between males and females during an early critical masculinization window. Instead, we observe a prominent difference between males and females in baseline neuroestradiol that emerges during the subadult stage as animals approach sexual maturity. Second, we observe that fluctuating neuroestradiol levels during periods of passive song tutoring exhibit a markedly different profile in juveniles as compared to adults. Specifically, neuroestrogens in the caudal forebrain are elevated following (rather than during) tutor song exposure in both juvenile males and females, suggesting an important role for the early consolidation of tutor song memories. These results further reveal a circadian influence on the fluctuations in local neuroestrogens during sensory/cognitive tasks. Taken together, these findings uncover several unexpected features of brain estrogen synthesis in juvenile animals that may have implications for secondary masculinization as well as the consolidation of recent sensory experiences. PMID:25205304

  2. Learning and the motivation to eat: Forebrain circuitry

    PubMed Central

    Petrovich, Gorica D.

    2011-01-01

    Appetite and eating are not only controlled by energy needs, but also by extrinsic factors that are not directly related to energy balance. Environmental signals that acquire motivational properties through associative learning—learned cues—can override homeostatic signals and stimulate eating in sated states, or inhibit eating in states of hunger. Such influences are important, as environmental factors are believed to contribute to the increased susceptibility to overeating and the rise in obesity in the developed world. Similarly, environmental and social factors contribute to the onset and maintenance of anorexia nervosa and other eating disorders through interactions with the individual genetic background. Nevertheless, how learning enables environmental signals to control feeding, and the underlying brain mechanisms are poorly understood. We developed two rodent models to study how learned cues are integrated with homeostatic signals within functional forebrain networks, and how these networks are modulated by experience. In one model, a cue previously paired with food when an animal was hungry induces eating in sated rats. In the other model, food-deprived rats inhibit feeding when presented with a cue that signals danger, a tone previously paired with footshocks. Here evidence will be reviewed that the forebrain network formed by the amygdala, lateral hypothalamus and medial prefrontal cortex mediates cue-driven feeding, while a parallel amygdalar circuitry mediates suppression of eating by the fear cue. Findings from the animal models may be relevant for understanding aspects of human appetite and eating, and maladaptive mechanisms that could lead to overeating and anorexia. PMID:21549730

  3. Learning and the motivation to eat: forebrain circuitry.

    PubMed

    Petrovich, Gorica D

    2011-09-26

    Appetite and eating are not only controlled by energy needs, but also by extrinsic factors that are not directly related to energy balance. Environmental signals that acquire motivational properties through associative learning-learned cues-can override homeostatic signals and stimulate eating in sated states, or inhibit eating in states of hunger. Such influences are important, as environmental factors are believed to contribute to the increased susceptibility to overeating and the rise in obesity in the developed world. Similarly, environmental and social factors contribute to the onset and maintenance of anorexia nervosa and other eating disorders through interactions with the individual genetic background. Nevertheless, how learning enables environmental signals to control feeding, and the underlying brain mechanisms are poorly understood. We developed two rodent models to study how learned cues are integrated with homeostatic signals within functional forebrain networks, and how these networks are modulated by experience. In one model, a cue previously paired with food when an animal was hungry induces eating in sated rats. In the other model, food-deprived rats inhibit feeding when presented with a cue that signals danger, a tone previously paired with footshocks. Here evidence will be reviewed that the forebrain network formed by the amygdala, lateral hypothalamus and medial prefrontal cortex mediates cue-driven feeding, while a parallel amygdalar circuitry mediates suppression of eating by the fear cue. Findings from the animal models may be relevant for understanding aspects of human appetite and eating, and maladaptive mechanisms that could lead to overeating and anorexia.

  4. A cholinergic basal forebrain feeding circuit modulates appetite suppression.

    PubMed

    Herman, Alexander M; Ortiz-Guzman, Joshua; Kochukov, Mikhail; Herman, Isabella; Quast, Kathleen B; Patel, Jay M; Tepe, Burak; Carlson, Jeffrey C; Ung, Kevin; Selever, Jennifer; Tong, Qingchun; Arenkiel, Benjamin R

    2016-10-13

    Atypical food intake is a primary cause of obesity and other eating and metabolic disorders. Insight into the neural control of feeding has previously focused mainly on signalling mechanisms associated with the hypothalamus, the major centre in the brain that regulates body weight homeostasis. However, roles of non-canonical central nervous system signalling mechanisms in regulating feeding behaviour have been largely uncharacterized. Acetylcholine has long been proposed to influence feeding owing in part to the functional similarity between acetylcholine and nicotine, a known appetite suppressant. Nicotine is an exogenous agonist for acetylcholine receptors, suggesting that endogenous cholinergic signalling may play a part in normal physiological regulation of feeding. However, it remains unclear how cholinergic neurons in the brain regulate food intake. Here we report that cholinergic neurons of the mouse basal forebrain potently influence food intake and body weight. Impairment of cholinergic signalling increases food intake and results in severe obesity, whereas enhanced cholinergic signalling decreases food consumption. We found that cholinergic circuits modulate appetite suppression on downstream targets in the hypothalamus. Together our data reveal the cholinergic basal forebrain as a major modulatory centre underlying feeding behaviour.

  5. Distribution of vasopressin in the forebrain of spotted hyenas.

    PubMed

    Rosen, Greta J; De Vries, Geert J; Villalba, Constanza; Weldele, Mary L; Place, Ned J; Coscia, Elizabeth M; Glickman, Steve E; Forger, Nancy G

    2006-09-01

    The extreme virilization of the female spotted hyena raises interesting questions with respect to sexual differentiation of the brain and behavior. Females are larger and more aggressive than adult, non-natal males and dominate them in social encounters; their external genitalia also are highly masculinized. In many vertebrates, the arginine vasopressin (VP) innervation of the forebrain, particularly that of the lateral septum, is associated with social behaviors such as aggression and dominance. Here, we used immunohistochemistry to examine the distribution of VP cells and fibers in the forebrains of adult spotted hyenas. We find the expected densely staining VP immunoreactive (VP-ir) neurons in the paraventricular and supraoptic nuclei, as well as an unusually extensive distribution of magnocelluar VP-ir neurons in accessory regions. A small number of VP-ir cell bodies are present in the suprachiasmatic nucleus and bed nucleus of the stria terminalis; however, there are extensive VP-ir fiber networks in presumed projection areas of these nuclei, for example, the subparaventricular zone and lateral septum, respectively. No significant sex differences were detected in the density of VP-ir fibers in any area examined. In the lateral septum, however, marked variability was observed. Intact females exhibited a dense fiber network, as did two of the four males examined; the two other males had almost no VP-ir septal fibers. This contrasts with findings in many other vertebrate species, in which VP innervation of the lateral septum is consistently greater in males than in females.

  6. Distribution of Fos-immunoreactive cells in rat forebrain and midbrain following social defeat stress and diazepam treatment.

    PubMed

    Lkhagvasuren, B; Oka, T; Nakamura, Y; Hayashi, H; Sudo, N; Nakamura, K

    2014-07-11

    The anxiolytic diazepam selectively inhibits psychological stress-induced autonomic and behavioral responses without causing noticeable suppression of other central performances. This pharmacological property of diazepam led us to the idea that neurons that exhibit diazepam-sensitive, psychological stress-induced activation are potentially those recruited for stress responses. To obtain neuroanatomical clues for the central stress circuitries, we examined the effects of diazepam on psychological stress-induced neuronal activation in broad brain regions. Rats were exposed to a social defeat stress, which caused an abrupt increase in body temperature by up to 2°C. Pretreatment with diazepam (4mg/kg, i.p.) attenuated the stress-induced hyperthermia, confirming an inhibitory physiological effect of diazepam on the autonomic stress response. Subsequently, the distribution of cells expressing Fos, a marker of neuronal activation, was examined in 113 forebrain and midbrain regions of these rats after the stress exposure and diazepam treatment. The stress following vehicle treatment markedly increased Fos-immunoreactive (IR) cells in most regions of the cerebral cortex, limbic system, thalamus, hypothalamus and midbrain, which included parts of the autonomic, neuroendocrine, emotional and arousal systems. The diazepam treatment significantly reduced the stress-induced Fos expression in many brain regions including the prefrontal, sensory and motor cortices, septum, medial amygdaloid nucleus, medial and lateral preoptic areas, parvicellular paraventricular hypothalamic nucleus, dorsomedial hypothalamus, perifornical nucleus, tuberomammillary nucleus, association, midline and intralaminar thalami, and median and dorsal raphe nuclei. In contrast, diazepam increased Fos-IR cells in the central amygdaloid nucleus, medial habenular nucleus, ventromedial hypothalamic nucleus and magnocellular lateral hypothalamus. These results provide important information for elucidating the

  7. Localization of myocyte enhancer factor 2 in the rodent forebrain: regionally-specific cytoplasmic expression of MEF2A.

    PubMed

    Neely, M Diana; Robert, Elizabeth M; Baucum, Anthony J; Colbran, Roger J; Muly, E Chris; Deutch, Ariel Y

    2009-06-05

    The transcription factor myocyte enhancer factor 2 (MEF2) is expressed throughout the central nervous system, where four MEF2 isoforms play important roles in neuronal survival and differentiation and in synapse formation and maintenance. It is therefore somewhat surprising that there is a lack of detailed information on the localization of MEF2 isoforms in the mammalian brain. We have analyzed the regional, cellular, and subcellular expression of MEF2A and MEF2D in the rodent brain. These two MEF2 isoforms were co-expressed in virtually all neurons in the cortex and the striatum, but were not detected in astrocytes. MEF2A and MEF2D were localized to the nuclei of neurons in many forebrain areas, consistent with their roles as transcriptional regulators. However, in several subcortical sites we observed extensive cytoplasmic expression of MEF2A but not MEF2D. MEF2A was particularly enriched in processes of neurons in the lateral septum and bed nucleus of the stria terminalis, as well as in several other limbic sites, including the central amygdala and paraventricular nuclei of the hypothalamus and thalamus. Ultrastructural examination similarly revealed MEF2A-ir in axons and dendrites as well as MEF2A-ir nuclei in the lateral septum and bed nucleus of the stria terminalis neurons. This study demonstrates for the first time extensive cytoplasmic localization of a MEF2 transcription factor in the mammalian brain in vivo. The extranuclear localization of MEF2A suggests novel roles for MEF2A in specific neuronal populations.

  8. Orally administrated dipeptide Ser-Tyr efficiently stimulates noradrenergic turnover in the mouse brain.

    PubMed

    Ichinose, Takashi; Moriyasu, Kazuki; Nakahata, Akane; Tanaka, Mitsuru; Matsui, Toshiro; Furuya, Shigeki

    2015-01-01

    In this study, we examined the effect of orally administrated dipeptides containing Tyr (Y) on the metabolism of catecholamines in mouse brains. We found that among eight synthetic dipeptides whose sequences are present frequently in soy proteins, Ser-Tyr (SY), Ile-Tyr, and Tyr-Pro had the highest apparent permeability coefficients in monolayers of human intestinal epithelial Caco-2 cells. When administrated orally, SY markedly increased tyrosine content in the cerebral cortex compared to the vehicle control, Ile-Tyr, Tyr-Pro, and Y alone. The oral administration of SY more effectively increased 3-methoxy-4-hydroxyphenylethyleneglycol, the principal metabolite of noradrenaline, in the cerebral cortex and hippocampus than did Ile-Tyr, Tyr-Pro, or Y alone. Central noradrenergic turnover was also markedly stimulated by SY administration. These in vivo observations strongly suggest that SY is more potent in boosting central catecholamine transmission, particularly the noradrenergic system, than Y alone or other dipeptides that include Y.

  9. Noradrenergic lesioning with an anti-dopamine beta-hydroxylase immunotoxin

    NASA Technical Reports Server (NTRS)

    Picklo, M. J.; Wiley, R. G.; Lappi, D. A.; Robertson, D.

    1994-01-01

    Sympathectomy has been achieved by a variety of methods but each has its limitations. These include lack of tissue specificity, incomplete lesioning, and the age range of susceptibility to the lesioning. To circumvent these drawbacks, an immunotoxin was constructed using a monoclonal antibody against the noradrenergic specific enzyme dopamine beta-hydroxylase (D beta H) coupled via a disulfide bond to saporin, a ribosomal inactivating protein. Three days after intravenous injection of the anti-D beta H immunotoxin (50 micrograms) into adult Sprague-Dawley rats, 66% of neurons in the superior cervical ganglia were chromatolytic. Superior cervical ganglia neurons were poisoned in 1 day old and 1 week old (86% of neurons) neonatal rats following subcutaneous injection of 3.75 and 15 micrograms, respectively. The anti-D beta H immunotoxin will be a useful tool in the study of the peripheral noradrenergic system in adult and neonatal animals.

  10. Noradrenergic blockade stabilizes prefrontal activity and enables fear extinction under stress

    PubMed Central

    Fitzgerald, Paul J.; Giustino, Thomas F.; Seemann, Jocelyn R.; Maren, Stephen

    2015-01-01

    Stress-induced impairments in extinction learning are believed to sustain posttraumatic stress disorder (PTSD). Noradrenergic signaling may contribute to extinction impairments by modulating medial prefrontal cortex (mPFC) circuits involved in fear regulation. Here we demonstrate that aversive fear conditioning rapidly and persistently alters spontaneous single-unit activity in the prelimbic and infralimbic subdivisions of the mPFC in behaving rats. These conditioning-induced changes in mPFC firing were mitigated by systemic administration of propranolol (10 mg/kg, i.p.), a β-noradrenergic receptor antagonist. Moreover, propranolol administration dampened the stress-induced impairment in extinction observed when extinction training is delivered shortly after fear conditioning. These findings suggest that β-adrenoceptors mediate stress-induced changes in mPFC spike firing that contribute to extinction impairments. Propranolol may be a helpful adjunct to behavioral therapy for PTSD, particularly in patients who have recently experienced trauma. PMID:26124100

  11. Noradrenergic blockade stabilizes prefrontal activity and enables fear extinction under stress.

    PubMed

    Fitzgerald, Paul J; Giustino, Thomas F; Seemann, Jocelyn R; Maren, Stephen

    2015-07-14

    Stress-induced impairments in extinction learning are believed to sustain posttraumatic stress disorder (PTSD). Noradrenergic signaling may contribute to extinction impairments by modulating medial prefrontal cortex (mPFC) circuits involved in fear regulation. Here we demonstrate that aversive fear conditioning rapidly and persistently alters spontaneous single-unit activity in the prelimbic and infralimbic subdivisions of the mPFC in behaving rats. These conditioning-induced changes in mPFC firing were mitigated by systemic administration of propranolol (10 mg/kg, i.p.), a β-noradrenergic receptor antagonist. Moreover, propranolol administration dampened the stress-induced impairment in extinction observed when extinction training is delivered shortly after fear conditioning. These findings suggest that β-adrenoceptors mediate stress-induced changes in mPFC spike firing that contribute to extinction impairments. Propranolol may be a helpful adjunct to behavioral therapy for PTSD, particularly in patients who have recently experienced trauma.

  12. The role of brain noradrenergic system in the regulation of liver cytochrome P450 expression.

    PubMed

    Sadakierska-Chudy, Anna; Haduch, Anna; Rysz, Marta; Gołembiowska, Krystyna; Daniel, Władysława A

    2013-09-15

    The aim of the present study was to examine the effect of the brain noradrenergic system on the expression of cytochrome P450 in the liver. The experiment was carried out on male Wistar rats. Intracerebroventricular injection of the noradrenergic neurotoxin DSP-4 diminished noradrenaline level in the brain. Simultaneously, significant decreases in the serum concentration of the growth hormone, testosterone and the thyroid hormone thyroxine, as well as an increase in corticosterone level were observed. The concentrations of triiodothyronine and the cytokines interleukine 2 (IL-2) and 6 (IL-6) were not changed by DSP-4. The neurotoxin produced complex changes in the functioning of cytochrome P450. Significant decreases in the activity of liver CYP2C11 (measured as a rate of the 2α- and 16α-hydroxylation of testosterone) and CYP3A (measured as a rate of the 2β- and 6β-hydroxylation of testosterone) were found. In contrast, the activity of CYP1A (measured as a rate of caffeine metabolism) rose, while that of CYP2A (measured as a rate of the 7α-hydroxylation of testosterone), CYP2C6 (measured as a rate of the 7-hydroxylation of warfarin) and CYP2D (the 1'-hydroxylation of bufuralol) remained unchanged. The changes in the activity of CYP1A, CYP2C11 and CYP3A correlated positively with those in CYP protein levels and with the CYP mRNA levels of CYP1A1, CYP2C11 and CYP3A1/2 genes, respectively. The obtained results indicate an important role of the brain noradrenergic system in the neuroendocrine regulation of liver cytochrome P450 expression, which may be of significance in pathological states involving this system, or during pharmacotherapy with drugs affecting noradrenergic transmission.

  13. Histamine in the locus coeruleus promotes descending noradrenergic inhibition of neuropathic hypersensitivity.

    PubMed

    Wei, Hong; Jin, Cong-Yu; Viisanen, Hanna; You, Hao-Jun; Pertovaara, Antti

    2014-12-01

    Among brain structures receiving efferent projections from the histaminergic tuberomammillary nucleus is the pontine locus coeruleus (LC) involved in descending noradrenergic control of pain. Here we studied whether histamine in the LC is involved in descending regulation of neuropathic hypersensitivity. Peripheral neuropathy was induced by unilateral spinal nerve ligation in the rat with a chronic intracerebral and intrathecal catheter for drug administrations. Mechanical hypersensitivity in the injured limb was assessed by monofilaments. Heat nociception was assessed by determining radiant heat-induced paw flick. Histamine in the LC produced a dose-related (1-10μg) mechanical antihypersensitivity effect (maximum effect at 15min and duration of effect 30min), without influence on heat nociception. Pretreatment of LC with zolantidine (histamine H2 receptor antagonist), but not with pyrilamine (histamine H1 receptor antagonist), and spinal administration of atipamezole (an α2-adrenoceptor antagonist), prazosine (an α1-adrenoceptor antagonist) or bicuculline (a GABAA receptor antagonist) attenuated the antihypersensitivity effect of histamine. The histamine-induced antihypersensitivity effect was also reduced by pretreatment of LC with fadolmidine, an α2-adrenoceptor agonist inducing autoinhibition of noradrenergic cell bodies. Zolantidine or pyrilamine alone in the LC failed to influence pain behavior, while A-960656 (histamine H3 receptor antagonist) suppressed hypersensitivity. A plausible explanation for these findings is that histamine, due to excitatory action mediated by the histamine H2 receptor on noradrenergic cell bodies, promotes descending spinal α1/2-adrenoceptor-mediated inhibition of neuropathic hypersensitivity. Blocking the autoinhibitory histamine H3 receptor on histaminergic nerve terminals in the LC facilitates release of histamine and thereby, increases descending noradrenergic pain inhibition.

  14. Noradrenergic α1 Receptors as a Novel Target for the Treatment of Nicotine Addiction

    PubMed Central

    Forget, Benoit; Wertheim, Carrie; Mascia, Paola; Pushparaj, Abhiram; Goldberg, Steven R; Le Foll, Bernard

    2010-01-01

    Nicotine is the main psychoactive ingredient in tobacco and its rewarding effects are considered primarily responsible for persistent tobacco smoking and relapse. Although dopamine has been extensively implicated in the rewarding effects of nicotine, noradrenergic systems may have a larger role than previously suspected. This study evaluated the role of noradrenergic α1 receptors in nicotine and food self-administration and relapse, nicotine discrimination, and nicotine-induced dopamine release in the nucleus accumbens in rats. We found that the noradrenergic α1 receptor antagonist prazosin (0.25–1 mg/kg) dose dependently reduced the self-administration of nicotine (0.03 mg/kg), an effect that was maintained over consecutive daily sessions; but did not reduce food self-administration. Prazosin also decreased reinstatement of extinguished nicotine seeking induced by either a nicotine prime (0.15 mg/kg) or nicotine-associated cues, but not food-induced reinstatement of food-seeking, and decreased nicotine-induced (0.15 mg/kg) dopamine release in the nucleus accumbens shell. However, prazosin did not have nicotine-like discriminative effects and did not alter the dose-response curve for nicotine discrimination. These findings suggest that stimulation of noradrenergic α1 receptors is involved in nicotine self-administration and relapse, possibly via facilitation of nicotine-induced activation of the mesolimbic dopaminergic system. The findings point to α1 adrenoceptor blockade as a potential new approach to the treatment of tobacco dependence in humans. PMID:20357760

  15. Childhood maltreatment, altered limbic neurobiology, and substance use relapse severity via trauma-specific reductions in limbic gray matter volume.

    PubMed

    Van Dam, Nicholas T; Rando, Kenneth; Potenza, Marc N; Tuit, Keri; Sinha, Rajita

    2014-08-01

    Substance use disorders (SUDs) are among the most common sequelae of childhood maltreatment, yet the independent contributions of SUDs and childhood maltreatment to neurobiological changes and the effect of the latter on relapse risk (a critical variable in addiction treatment) are relatively unknown. To identify structural neural characteristics independently associated with childhood maltreatment (CM; a common type of childhood adversity), comparing a sample with SUD with a demographically comparable control sample, and to examine the relationship between CM-related structural brain changes and subsequent relapse. Structural magnetic resonance imaging study comparing 79 treatment-engaged participants with SUD in acute remission in inpatient treatment at a community mental health center vs 98 healthy control participants at an outpatient research center at an academic medical center. Both groups included individuals with a range of CM experiences. Participants with SUD were followed up prospectively for 90 days to assess relapse and relapse severity. Standard 12-step, recovery-based, inpatient addiction treatment for all participants with SUD. Gray matter volume (GMV), subsequent substance use relapse, days to relapse, and severity of relapse. Controlling for SUD and psychiatric comorbidity, CM (dichotomously classified) was uniquely associated with lower GMV across all participants in the left hippocampus (cornu ammonis 1-3, dentate gyrus), parahippocampus (presubiculum, parasubiculum, prosubiculum, subiculum, and entorhinal cortex), and anterior fusiform gyrus (corrected P < .05; uncorrected P = .001). Among the sample with SUD, CM prospectively predicted a shorter relapse to use of any drug (P = .048), while CM-related GMV reductions predicted severity of substance use relapse (P = .04). Findings indicate that CM was related to decreased GMV in limbic regions, which in turn predicted increased risk of relapse in SUD. These results suggest that

  16. Childhood Maltreatment, Altered Limbic Neurobiology, and Substance Use Relapse Severity via Trauma-Specific Reductions in Limbic Gray Matter Volume

    PubMed Central

    Van Dam, Nicholas T.; Rando, Kenneth; Potenza, Marc N.; Tuit, Keri; Sinha, Rajita

    2015-01-01

    decreased GMV in limbic regions, which in turn predicted increased risk of relapse in SUD. These results suggest that CM may significantly affect the course of SUD treatment outcomes and that SUD treatment planning may benefit from identifying and addressing CM. PMID:24920451

  17. Enhanced assymetrical noradrenergic transmission in the olfactory bulb of deoxycorticosterone acetate-salt hypertensive rats.

    PubMed

    Abramoff, Tamara; Guil, María J; Morales, Vanina P; Hope, Sandra I; Soria, Celeste; Bianciotti, Liliana G; Vatta, Marcelo S

    2013-10-01

    The ablation of olfactory bulb induces critical changes in dopamine, and monoamine oxidase activity in the brain stem. Growing evidence supports the participation of this telencephalic region in the regulation blood pressure and cardiovascular activity but little is known about its contribution to hypertension. We have previously reported that in the olfactory bulb of normotensive rats endothelins enhance noradrenergic activity by increasing tyrosine hydroxylase activity and norepinephrine release. In the present study we sought to establish the status of noradrenergic activity in the olfactory bulb of deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Different steps in norepinephrine transmission including tyrosine hydroxylase activity, neuronal norepinephrine release and uptake were assessed in the left and right olfactory bulb of DOCA-salt hypertensive rats. Increased tyrosine hydroxylase activity, and decreased neuronal norepinephrine uptake were observed in the olfactory bulb of DOCA-salt hypertensive rats. Furthermore the expression of tyrosine hydroxylase and its phosphorylated forms were also augmented. Intriguingly, asymmetrical responses between the right and left olfactory bulb of normotensive and hypertensive rats were observed. Neuronal norepinephrine release was increased in the right but not in the left olfactory bulb of DOCA-salt hypertensive rats, whereas non asymmetrical differences were observed in normotensive animals. Present findings indicate that the olfactory bulb of hypertensive rats show an asymmetrical increase in norepinephrine activity. The observed changes in noradrenergic transmission may likely contribute to the onset and/or progression of hypertension in this animal model.

  18. Facilitation of learning by social-emotional feedback in humans is beta-noradrenergic-dependent.

    PubMed

    Mihov, Yoan; Mayer, Simon; Musshoff, Frank; Maier, Wolfgang; Kendrick, Keith M; Hurlemann, René

    2010-08-01

    Adaptive behavior in dynamic environments critically depends on the ability to learn rapidly and flexibly from the outcomes of prior choices. In social environments, facial expressions of emotion often serve as performance feedback and thereby guide declarative learning. Abundant evidence implicates beta-noradrenergic signaling in the modulatory influence of emotion on declarative learning. It is currently unclear whether a similar mechanism also mediates a guidance of declarative learning by social-emotional feedback administered in the form of facial expressions. We therefore conducted a double-blind randomized placebo-controlled trial to test the effects of a 40-mg single oral dose of the nonspecific beta-noradrenergic antagonist propranolol in a behavioral task that required gradual declarative learning of item-category associations from either social-emotional (happy vs. angry faces) or nonsocial (green vs. red color signals) trial-by-trial feedback. As predicted on the basis of our previous experiments, learning from social-emotional feedback was more effective than learning from nonsocial feedback in placebo-treated subjects. This advantage of social-emotional over nonsocial feedback was abolished by propranolol treatment. Propranolol had no effect on learning during the nonsocial feedback condition. Our findings suggest that a facilitation of declarative learning by social-emotional feedback critically involves signaling via beta-noradrenergic receptors. Copyright (c) 2010 Elsevier Ltd. All rights reserved.

  19. NORADRENERGIC, BUT NOT CHOLINERGIC, DEAFFERENTATION OF PREFRONTAL CORTEX IMPAIRS ATTENTIONAL SET-SHIFTING

    PubMed Central

    McGAUGHY, J.; ROSS, R. S.; EICHENBAUM, H.

    2008-01-01

    Both norepinephrine and acetylcholine have been shown to be critically involved in mediating attention but there remains debate about whether they serve similar or unique functions. Much of what is known about the role of these neurochemicals in cognition is based on manipulations done at the level of the cell body but these findings are difficult to reconcile with data regarding the unique contribution of cortical subregions, e.g. the dorsolateral prefrontal cortex, to attention. In the current study, we directly compared the effects of noradrenergic and cholinergic deafferentation of the rat medial prefrontal cortex, the homologue of primate dorsolateral prefrontal cortex, using an intradimensional/extradimensional attentional set shifting task, a task previously shown to be able to dissociate the function of the primate dorsolateral prefrontal cortex from orbitofrontal cortex. We found that noradrenergic, but not cholinergic, deafferentation produces specific impairments in the ability to shift attentional set. We also clarified the nature of the attentional deficits by assessing the ability of rats to disregard irrelevant stimuli. Noradrenergic lesions did not alter the ability of rats to ignore irrelevant stimuli, suggesting that the attentional deficit results from an overly focused attentional state that retards learning that a new stimulus dimension predicts reward. PMID:18355972

  20. A central neuropathic pain model by DSP-4 induced lesion of noradrenergic neurons: preliminary report.

    PubMed

    Kudo, Takashi; Kushikata, Tetsuya; Kudo, Mihoko; Kudo, Tsuyoshi; Hirota, Kazuyoshi

    2010-09-06

    Neuropathic pain models are classified as central and peripheral pain models. Although various peripheral neuropathic pain models are established, central pain models are based only on spinal cord injury. DSP-4 is a competitive inhibitor of norepinephrine uptake that selectively degenerates the locus coeruleus (LC)-noradrenergic neurons projection to the cerebral cortex and hippocampus. In the present study, we have tested whether lesion of LC-noradrenergic neurons by ip DSP-4 (0, 10, 30, 50 mg/kg, n=7 each) could provide a new central neuropathic pain model in rats using a hot-plate and tail-flick tests. DSP-4 significantly reduced the hot-plate latency and norepinephrine contents especially in the coerulean regions. However, DSP-4 did not change tail-flick latency. There are significant correlations of the latency in the hot-plate test with norepinephrine contents in the cerebral cortex (r=0.432, p=0.022), the hippocampus (r=0.465, p=0.013) and the pons (r=0.400, p=0.035) but not with those in the hypothalamus and the spinal cord. As response to hot-plate and tail-flick implies supra-spinal process and spinal reflex, respectively, central neuropathic pain may be facilitated by DSP-4 depleting LC-noradrenergic neurons although the present data are preliminary.

  1. Nasal Respiration Entrains Human Limbic Oscillations and Modulates Cognitive Function

    PubMed Central

    Jiang, Heidi; Zhou, Guangyu; Arora, Nikita; Schuele, Stephan; Rosenow, Joshua; Gottfried, Jay A.

    2016-01-01

    The need to breathe links the mammalian olfactory system inextricably to the respiratory rhythms that draw air through the nose. In rodents and other small animals, slow oscillations of local field potential activity are driven at the rate of breathing (∼2–12 Hz) in olfactory bulb and cortex, and faster oscillatory bursts are coupled to specific phases of the respiratory cycle. These dynamic rhythms are thought to regulate cortical excitability and coordinate network interactions, helping to shape olfactory coding, memory, and behavior. However, while respiratory oscillations are a ubiquitous hallmark of olfactory system function in animals, direct evidence for such patterns is lacking in humans. In this study, we acquired intracranial EEG data from rare patients (Ps) with medically refractory epilepsy, enabling us to test the hypothesis that cortical oscillatory activity would be entrained to the human respiratory cycle, albeit at the much slower rhythm of ∼0.16–0.33 Hz. Our results reveal that natural breathing synchronizes electrical activity in human piriform (olfactory) cortex, as well as in limbic-related brain areas, including amygdala and hippocampus. Notably, oscillatory power peaked during inspiration and dissipated when breathing was diverted from nose to mouth. Parallel behavioral experiments showed that breathing phase enhances fear discrimination and memory retrieval. Our findings provide a unique framework for understanding the pivotal role of nasal breathing in coordinating neuronal oscillations to support stimulus processing and behavior. SIGNIFICANCE STATEMENT Animal studies have long shown that olfactory oscillatory activity emerges in line with the natural rhythm of breathing, even in the absence of an odor stimulus. Whether the breathing cycle induces cortical oscillations in the human brain is poorly understood. In this study, we collected intracranial EEG data from rare patients with medically intractable epilepsy, and found evidence

  2. Nasal Respiration Entrains Human Limbic Oscillations and Modulates Cognitive Function.

    PubMed

    Zelano, Christina; Jiang, Heidi; Zhou, Guangyu; Arora, Nikita; Schuele, Stephan; Rosenow, Joshua; Gottfried, Jay A

    2016-12-07

    The need to breathe links the mammalian olfactory system inextricably to the respiratory rhythms that draw air through the nose. In rodents and other small animals, slow oscillations of local field potential activity are driven at the rate of breathing (∼2-12 Hz) in olfactory bulb and cortex, and faster oscillatory bursts are coupled to specific phases of the respiratory cycle. These dynamic rhythms are thought to regulate cortical excitability and coordinate network interactions, helping to shape olfactory coding, memory, and behavior. However, while respiratory oscillations are a ubiquitous hallmark of olfactory system function in animals, direct evidence for such patterns is lacking in humans. In this study, we acquired intracranial EEG data from rare patients (Ps) with medically refractory epilepsy, enabling us to test the hypothesis that cortical oscillatory activity would be entrained to the human respiratory cycle, albeit at the much slower rhythm of ∼0.16-0.33 Hz. Our results reveal that natural breathing synchronizes electrical activity in human piriform (olfactory) cortex, as well as in limbic-related brain areas, including amygdala and hippocampus. Notably, oscillatory power peaked during inspiration and dissipated when breathing was diverted from nose to mouth. Parallel behavioral experiments showed that breathing phase enhances fear discrimination and memory retrieval. Our findings provide a unique framework for understanding the pivotal role of nasal breathing in coordinating neuronal oscillations to support stimulus processing and behavior. Animal studies have long shown that olfactory oscillatory activity emerges in line with the natural rhythm of breathing, even in the absence of an odor stimulus. Whether the breathing cycle induces cortical oscillations in the human brain is poorly understood. In this study, we collected intracranial EEG data from rare patients with medically intractable epilepsy, and found evidence for respiratory entrainment

  3. Maternal sensitivity, infant limbic structure volume and functional connectivity: a preliminary study

    PubMed Central

    Rifkin-Graboi, A; Kong, L; Sim, L W; Sanmugam, S; Broekman, B F P; Chen, H; Wong, E; Kwek, K; Saw, S-M; Chong, Y-S; Gluckman, P D; Fortier, M V; Pederson, D; Meaney, M J; Qiu, A

    2015-01-01

    Mechanisms underlying the profound parental effects on cognitive, emotional and social development in humans remain poorly understood. Studies with nonhuman models suggest variations in parental care affect the limbic system, influential to learning, autobiography and emotional regulation. In some research, nonoptimal care relates to decreases in neurogenesis, although other work suggests early-postnatal social adversity accelerates the maturation of limbic structures associated with emotional learning. We explored whether maternal sensitivity predicts human limbic system development and functional connectivity patterns in a small sample of human infants. When infants were 6 months of age, 20 mother–infant dyads attended a laboratory-based observational session and the infants underwent neuroimaging at the same age. After considering age at imaging, household income and postnatal maternal anxiety, regression analyses demonstrated significant indirect associations between maternal sensitivity and bilateral hippocampal volume at six months, with the majority of associations between sensitivity and the amygdala demonstrating similar indirect, but not significant results. Moreover, functional analyses revealed direct associations between maternal sensitivity and connectivity between the hippocampus and areas important for emotional regulation and socio-emotional functioning. Sensitivity additionally predicted indirect associations between limbic structures and regions related to autobiographical memory. Our volumetric results are consistent with research indicating accelerated limbic development in response to early social adversity, and in combination with our functional results, if replicated in a larger sample, may suggest that subtle, but important, variations in maternal care influence neuroanatomical trajectories important to future cognitive and emotional functioning. PMID:26506054

  4. [Paraneoplastic limbic encephalitis with positive anti-RI antibodies and mediastinal seminoma].

    PubMed

    Launay, M; Bozzolo, E; Venissac, N; Delmont, E; Fredenrich, A; Thomas, P

    2008-01-01

    We report the case of a 49-year-old man who was admitted for progressive behaviorial disorders with frontal elements. There was no sensorial nor motor deficiency. Clinical examination revealed android obesity, cutaneous and mucous paleness, pubic and axillary depilation and gynecomastia. Encephalic MRI found a lesion of the left amygdalian region with high T2 intensity and low T1 intensity associated with gadolinium-enhancement. Cerebrospinal fluid analysis showed a lymphocytic meningitis. Panhypopituitarism was found on the endocrine investigations. Anti-RI antibodies were positive, leading to the diagnosis of paraneoplastic limbic encephalitis. The CT-scan showed a node of the lower part of the thymic area. Surgical resection revealed an ectopic mediastinal seminoma. The evolution consisted of paraneoplastic fever and crossed-syndrome with right hemiparesia and left common oculomotor nerve paralysis. Treatment was completed by two cycles of carboplatin, corticosteroids and substitutive opotherapy. Paraneoplastic fever disappeared, but behavioral disorders and palsy remain unchanged. The patient died two years later in a bedridden state. This case of paraneoplastic limbic encephalitis associated with positive anti-RI antibodies and mediastinal seminoma is exceptional and has not to our knowledge been described in the literature. Cancers usually associated with anti-RI antibody are breast and lung cancer. Paraneoplastic limbic encephalitis is not the classical clinical presentation, which usually is brainstem encephalitis. Hypothalamic involvement, uncommon in paraneoplastic limbic encephalitis is mainly associated with positive antineuronal anti-Ma2 antibodies. Finally, the gadolinium enhancement on encephalic MRI is unusual in paraneoplastic limbic encephalitis.

  5. Aberrant hippocampal neurogenesis after limbic kindling: Relationship to BDNF and hippocampal-dependent memory.

    PubMed

    Botterill, J J; Brymer, K J; Caruncho, H J; Kalynchuk, L E

    2015-06-01

    Seizures dramatically increase the number of adult generated neurons in the hippocampus. However, it is not known whether this effect depends on seizures that originate in specific brain regions or whether it is nonspecific to seizure activity regardless of origin. We used kindling of different brain sites to address this question. Rats received 99 kindling stimulations of the basolateral amygdala, dorsal hippocampus, or caudate nucleus over a 6-week period. After kindling, we counted the number of adult generated hippocampal neurons that were birth-dated with the proliferative marker bromodeoxyuridine (BrdU) to evaluate cell proliferation and survival under conditions of repeated seizures. Next, we counted the number of doublecortin immunoreactive (DCX-ir) cells and evaluated their dendritic complexity to determine if limbic and nonlimbic seizures have differential effects on neuronal maturation. We also quantified hippocampal brain-derived neurotrophin factor (BDNF) protein levels using an ELISA kit and assessed memory performance using a hippocampal-dependent fear conditioning paradigm. We found that limbic, but not nonlimbic, seizures dramatically increased hippocampal cell proliferation and the number of hilar-CA3 ectopic granule cells. Further, limbic kindling promoted dendritic outgrowth of DCX-ir cells and the number of DCX-ir cells containing basal dendrites. Limbic kindling also enhanced BDNF protein levels throughout the entire hippocampus and impaired the retrieval of fear memories. Collectively, our results suggest a relationship between limbic seizures, neurogenesis, BDNF protein, and cognition.

  6. Dynamic behaviour of human neuroepithelial cells in the developing forebrain

    PubMed Central

    Subramanian, Lakshmi; Bershteyn, Marina; Paredes, Mercedes F.; Kriegstein, Arnold R.

    2017-01-01

    To understand how diverse progenitor cells contribute to human neocortex development, we examined forebrain progenitor behaviour using timelapse imaging. Here we find that cell cycle dynamics of human neuroepithelial (NE) cells differ from radial glial (RG) cells in both primary tissue and in stem cell-derived organoids. NE cells undergoing proliferative, symmetric divisions retract their basal processes, and both daughter cells regrow a new process following cytokinesis. The mitotic retraction of the basal process is recapitulated by NE cells in cerebral organoids generated from human-induced pluripotent stem cells. In contrast, RG cells undergoing vertical cleavage retain their basal fibres throughout mitosis, both in primary tissue and in older organoids. Our findings highlight developmentally regulated changes in mitotic behaviour that may relate to the role of RG cells to provide a stable scaffold for neuronal migration, and suggest that the transition in mitotic dynamics can be studied in organoid models. PMID:28139695

  7. The dopaminergic projection system, basal forebrain macrosystems, and conditioned stimuli

    PubMed Central

    Zahm, Daniel S.

    2011-01-01

    This review begins with a description of some problems that in recent years have beset an influential circuit model of fear-conditioning and goes on to look at neuroanatomy that might subserve conditioning viewed in a broader perspective, including not only fear, but also appetitive, conditioning. The paper then focuses on basal forebrain functional-anatomical systems, or macrosystems, as they have come to be called, which Lennart Heimer and colleagues described beginning in the 1970’s. Yet more specific attention is then given to the relationships of the dorsal and ventral striatopallidal systems and extended amygdala with the dopaminergic mesotelencephalic projection systems, culminating with the hypothesis that all macrosystems contribute to behavioral conditioning. PMID:18204412

  8. Basal Forebrain Atrophy Contributes to Allocentric Navigation Impairment in Alzheimer's Disease Patients.

    PubMed

    Kerbler, Georg M; Nedelska, Zuzana; Fripp, Jurgen; Laczó, Jan; Vyhnalek, Martin; Lisý, Jiří; Hamlin, Adam S; Rose, Stephen; Hort, Jakub; Coulson, Elizabeth J

    2015-01-01

    The basal forebrain degenerates in Alzheimer's disease (AD) and this process is believed to contribute to the cognitive decline observed in AD patients. Impairment in spatial navigation is an early feature of the disease but whether basal forebrain dysfunction in AD is responsible for the impaired navigation skills of AD patients is not known. Our objective was to investigate the relationship between basal forebrain volume and performance in real space as well as computer-based navigation paradigms in an elderly cohort comprising cognitively normal controls, subjects with amnestic mild cognitive impairment and those with AD. We also tested whether basal forebrain volume could predict the participants' ability to perform allocentric- vs. egocentric-based navigation tasks. The basal forebrain volume was calculated from 1.5 T magnetic resonance imaging (MRI) scans, and navigation skills were assessed using the human analog of the Morris water maze employing allocentric, egocentric, and mixed allo/egocentric real space as well as computerized tests. When considering the entire sample, we found that basal forebrain volume correlated with spatial accuracy in allocentric (cued) and mixed allo/egocentric navigation tasks but not the egocentric (uncued) task, demonstrating an important role of the basal forebrain in mediating cue-based spatial navigation capacity. Regression analysis revealed that, although hippocampal volume reflected navigation performance across the entire sample, basal forebrain volume contributed to mixed allo/egocentric navigation performance in the AD group, whereas hippocampal volume did not. This suggests that atrophy of the basal forebrain contributes to aspects of navigation impairment in AD that are independent of hippocampal atrophy.

  9. Differential effects of unilateral olfactory deprivation on noradrenergic and cholinergic systems in the main olfactory bulb of the rat.

    PubMed

    Gómez, C; Briñón, J G; Colado, M I; Orio, L; Vidal, M; Barbado, M V; Alonso, J R

    2006-09-15

    The lack of environmental olfactory stimulation produced by sensory deprivation causes significant changes in the deprived olfactory bulb. Olfactory transmission in the main olfactory bulb (MOB) is strongly modulated by centrifugal systems. The present report examines the effects of unilateral deprivation on the noradrenergic and cholinergic centrifugal systems innervating the MOB. The morphology, distribution, and density of positive axons were studied in the MOBs of control and deprived rats, using dopamine-beta-hydroxylase (DBH)-immunohistochemistry and acetylcholinesterase (AChE) histochemistry in serial sections. Catecholamine content was compared among the different groups of MOBs (control, contralateral, and ipsilateral to the deprivation) using high-performance liquid chromatography analysis. Sensory deprivation revealed that the noradrenergic system developed adaptive plastic changes after olfactory deprivation, including important modifications in its fiber density and distribution, while no differences in cholinergic innervation were observed under the same conditions. The noradrenergic system underwent an important alteration in the glomerular layer, in which some glomeruli showed a dense noradrenergic innervation that was not detected in control animals. The DBH-positive glomeruli with the highest noradrenergic fiber density were compared with AChE-stained sections and it was observed that the strongly noradrenergic-innervated glomeruli were always atypical glomeruli (characterized by their strong degree of cholinergic innervation). In addition to the morphological findings, our biochemical data revealed that olfactory deprivation caused a decrease in the content of dopamine and its metabolite 3,4-dihydroxyphenylacetic acid in the ipsilateral MOB in comparison to the contralateral and control MOBs, together with an increase in noradrenaline levels in both the ipsilateral and contralateral MOBs. Our results show that regulation of the noradrenergic

  10. Dynamic variation in forebrain estradiol levels during song learning.

    PubMed

    Chao, Andrew; Paon, Ashley; Remage-Healey, Luke

    2015-03-01

    Estrogens shape brain circuits during development, and the capacity to synthesize estrogens locally has consequences for both sexual differentiation and the acute modulation of circuits during early learning. A recently optimized method to detect and quantify fluctuations in brain estrogens in vivo provides a direct means to explore how brain estrogen production contributes to both differentiation and neuromodulation during development. Here, we use this method to test the hypothesis that neuroestrogens are sexually differentiated as well as dynamically responsive to song tutoring (via passive video/audio playback) during the period of song learning in juvenile zebra finches. Our results show that baseline neuroestradiol levels in the caudal forebrain do not differ between males and females during an early critical masculinization window. Instead, we observe a prominent difference between males and females in baseline neuroestradiol that emerges during the subadult stage as animals approach sexual maturity. Second, we observe that fluctuating neuroestradiol levels during periods of passive song tutoring exhibit a markedly different profile in juveniles as compared to adults. Specifically, neuroestrogens in the caudal forebrain are elevated following (rather than during) tutor song exposure in both juvenile males and females, suggesting an important role for the early consolidation of tutor song memories. These results further reveal a circadian influence on the fluctuations in local neuroestrogens during sensory/cognitive tasks. Taken together, these findings uncover several unexpected features of brain estrogen synthesis in juvenile animals that may have implications for secondary masculinization as well as the consolidation of recent sensory experiences. © 2014 Wiley Periodicals, Inc.

  11. Patterns of cell death in the perinatal mouse forebrain.

    PubMed

    Mosley, Morgan; Shah, Charisma; Morse, Kiriana A; Miloro, Stephen A; Holmes, Melissa M; Ahern, Todd H; Forger, Nancy G

    2017-01-01

    The importance of cell death in brain development has long been appreciated, but many basic questions remain, such as what initiates or terminates the cell death period. One obstacle has been the lack of quantitative data defining exactly when cell death occurs. We recently created a "cell death atlas," using the detection of activated caspase-3 (AC3) to quantify apoptosis in the postnatal mouse ventral forebrain and hypothalamus, and found that the highest rates of cell death were seen at the earliest postnatal ages in most regions. Here we have extended these analyses to prenatal ages and additional brain regions. We quantified cell death in 16 forebrain regions across nine perinatal ages from embryonic day (E) 17 to postnatal day (P) 11 and found that cell death peaks just after birth in most regions. We found greater cell death in several regions in offspring delivered vaginally on the day of parturition compared with those of the same postconception age but still in utero at the time of collection. We also found massive cell death in the oriens layer of the hippocampus on P1 and in regions surrounding the anterior crossing of the corpus callosum on E18 as well as the persistence of large numbers of cells in those regions in adult mice lacking the pro-death Bax gene. Together these findings suggest that birth may be an important trigger of neuronal cell death and identify transient cell groups that may undergo wholesale elimination perinatally. J. Comp. Neurol. 525:47-64, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  12. Forebrain neurogenesis after focal Ischemic and traumatic brain injury.

    PubMed

    Kernie, Steven G; Parent, Jack M

    2010-02-01

    Neural stem cells persist in the adult mammalian forebrain and are a potential source of neurons for repair after brain injury. The two main areas of persistent neurogenesis, the subventricular zone (SVZ)-olfactory bulb pathway and hippocampal dentate gyrus, are stimulated by brain insults such as stroke or trauma. Here we focus on the effects of focal cerebral ischemia on SVZ neural progenitor cells in experimental stroke, and the influence of mechanical injury on adult hippocampal neurogenesis in models of traumatic brain injury (TBI). Stroke potently stimulates forebrain SVZ cell proliferation and neurogenesis. SVZ neuroblasts are induced to migrate to the injured striatum, and to a lesser extent to the peri-infarct cortex. Controversy exists as to the types of neurons that are generated in the injured striatum, and whether adult-born neurons contribute to functional restoration remains uncertain. Advances in understanding the regulation of SVZ neurogenesis in general, and stroke-induced neurogenesis in particular, may lead to improved integration and survival of adult-born neurons at sites of injury. Dentate gyrus cell proliferation and neurogenesis similarly increase after experimental TBI. However, pre-existing neuroblasts in the dentate gyrus are vulnerable to traumatic insults, which appear to stimulate neural stem cells in the SGZ to proliferate and replace them, leading to increased numbers of new granule cells. Interventions that stimulate hippocampal neurogenesis appear to improve cognitive recovery after experimental TBI. Transgenic methods to conditionally label or ablate neural stem cells are beginning to further address critical questions regarding underlying mechanisms and functional significance of neurogenesis after stroke or TBI. Future therapies should be aimed at directing appropriate neuronal replacement after ischemic or traumatic injury while suppressing aberrant integration that may contribute to co-morbidities such as epilepsy or

  13. Limbic Encephalitis: Potential Impact of Adaptive Autoimmune Inflammation on Neuronal Circuits of the Amygdala.

    PubMed

    Melzer, Nico; Budde, Thomas; Stork, Oliver; Meuth, Sven G

    2015-01-01

    Limbic encephalitis is characterized by adaptive autoimmune inflammation of the gray matter structures of the limbic system. It has recently been identified as a major cause of temporal lobe epilepsy accompanied by progressive declarative - mainly episodic - -memory disturbance as well as a variety of rather poorly defined emotional and behavioral changes. While autoimmune inflammation of the hippocampus is likely to be responsible for declarative memory disturbance, consequences of autoimmune inflammation of the amygdala are largely unknown. The amygdala is central for the generation of adequate homoeostatic behavioral responses to emotionally significant external stimuli following processing in a variety of parallel neuronal circuits. Here, we hypothesize that adaptive cellular and humoral autoimmunity may target and modulate distinct inhibitory or excitatory neuronal networks within the amygdala, and thereby strongly impact processing of emotional stimuli and corresponding behavioral responses. This may explain some of the rather poorly understood neuropsychiatric symptoms in limbic encephalitis.

  14. Noradrenergic transmission in the central medial thalamic nucleus modulates the electroencephalographic activity and emergence from propofol anesthesia in rats.

    PubMed

    Fu, Bao; Yu, Tian; Yuan, Jie; Gong, Xingrui; Zhang, Mazhong

    2017-03-01

    At present, the mechanisms by which general anesthetics causing loss of consciousness remain unclear. The central medial thalamic nucleus (CMT) is a rarely studied component of the midline thalamic complex, which is deemed to be a part of the nonspecific arousal system. Although the CMT participates in modulating arousal and receives excitatory noradrenergic projections from locus coeruleus, it remains unknown whether the noradrenergic pathway in the CMT takes part in modulating the arousal system. Therefore, we hypothesized that noradrenergic transmission in the CMT is involved in modulating induction and emergence of propofol anesthesia. First, we infused norepinephrine (NE) into the CMT to observe the role of CMT noradrenergic pathway in modulating the anesthetic state induced by propofol. The results showed that microinjection of NE into the CMT accelerated emergence from propofol anesthesia, but had no impact on the induction of or sensitivity to propofol anesthesia in rats. In addition, infusion of NE into the CMT caused electroencephalography changes in the prefrontal cortex and the anterior cingulate cortex. Finally, we used a whole-cell patch clamp to examine the effects of NE on neuronal excitability and GABAergic transmission in the CMT. In the CMT slices, propofol suppressed neuronal excitability and enhanced GABAergic transmission, while application of NE partly reversed these effects. These findings support the hypothesis that the CMT noradrenergic pathway plays an important role in modulating the emergence from general anesthesia. © 2017 International Society for Neurochemistry.

  15. Action of the noradrenergic system on adult-born cells is required for olfactory learning in mice.

    PubMed

    Moreno, Melissa M; Bath, Kevin; Kuczewski, Nicola; Sacquet, Joëlle; Didier, Anne; Mandairon, Nathalie

    2012-03-14

    We have previously shown that an experience-driven improvement in olfactory discrimination (perceptual learning) requires the addition of newborn neurons in the olfactory bulb (OB). Despite this advance, the mechanisms which govern the selective survival of newborn OB neurons following learning remain largely unknown. We propose that activity of the noradrenergic system is a critical mediator providing a top-down signal to control the selective survival of newly born cells and support perceptual learning. In adult mice, we used pharmacological means to manipulate the noradrenergic system and neurogenesis and to assess their individual and additive effects on behavioral performance on a perceptual learning task. We then looked at the effects of these manipulations on regional survival of adult-born cells in the OB. Finally, using confocal imaging and electrophysiology, we investigated potential mechanisms by which noradrenaline could directly influence the survival of adult-born cells. Consistent with our hypotheses, direct manipulation of noradrenergic transmission significantly effect on adult-born cell survival and perceptual learning. Specifically, learning required both the presence of adult-born cell and noradrenaline. Finally, we provide a mechanistic link between these effects by showing that adult-born neurons receive noradrenergic projections and are responsive to noradrenaline. Based upon these data we argue that noradrenergic transmission is a key mechanism selecting adult-born neurons during learning and demonstrate that top-down neuromodulation acts on adult-born neuron survival to modulate learning performance.

  16. Opsoclonus-myoclonus and anti-Hu positive limbic encephalitis in a patient with neuroblastoma.

    PubMed

    Morales La Madrid, Andres; Rubin, Charles M; Kohrman, Michael; Pytel, Peter; Cohn, Susan L

    2012-03-01

    Opsoclonus-myoclonus syndrome (OMS) is seen in 2-3% of children with neuroblastoma and is believed to be caused by an autoimmune process elicited by the tumor. Although long-term neurologic sequelae are common in children with OMS, limbic encephalitis has not previously been reported. We report a child who developed limbic encephalitis associated with anti-Hu antibodies, 6 years after her initial diagnosis of neuroblastoma and OMS. This case demonstrates that patients with neuroblastoma and OMS are at risk for developing new paraneoplastic symptoms years after their original diagnosis and emphasizes the need for careful long-term follow-up.

  17. Lesion analysis for cingulotomy and limbic leucotomy: comparison and correlation with clinical outcomes

    PubMed Central

    Yang, Jimmy C.; Ginat, Daniel T.; Dougherty, Darin D.

    2014-01-01

    Object Cingulotomy and limbic leucotomy are lesioning surgeries with demonstrated benefit for medically intractable psychiatric illnesses. They represent significant refinements of the prefrontal lobotomy used from the 1930s through the 1950s. However, the associations between anatomical characterization of these lesions and outcome data are not well understood. To elucidate these procedures and associations, the authors sought to define and compare the neuroanatomy of cingulotomy and limbic leucotomy and to test a method that uses neuroanatomical data and voxel-based lesion–symptom mapping (VLSM) to reveal potential refinements to modern psychiatric neurosurgical procedures. Methods T1-weighted MR images of patients who had undergone cingulotomy and limbic leucotomy were segmented and registered onto the Montreal Neurological Institute T1-weighted template brain MNI152. Using an atlas-based approach, the authors calculated, by case, the percentage of each anatomical structure affected by the lesion. Because of the infrequency of modern lesion procedures and the requirement for higher-resolution clinical imaging, the sample size was small. The pilot study correlated cingulotomy and limbic leucotomy lesion characteristics with clinical outcomes for patients with obsessive-compulsive disorder. For this study, preoperative and postoperative Yale-Brown Obsessive Compulsive Scale scores for 11 cingulotomy patients and 8 limbic leucotomy patients were obtained, and lesion masks were defined and compared anatomically by using an atlas-based method. Statistically significant voxels were additionally calculated by using VLSM techniques that correlated lesion characteristics with postoperative scores. Results Mean lesion volumes were 13.3 ml for cingulotomy and 11.8 ml for limbic leucotomy. As expected, cingulotomy was isolated to the anterior cingulum. The subcaudate tractotomy portion of limbic leucotomy additionally affected Brodmann area 25, the medial orbitofrontal

  18. Neurodevelopment Genes in Lampreys Reveal Trends for Forebrain Evolution in Craniates

    PubMed Central

    Guérin, Adèle; d'Aubenton-Carafa, Yves; Marrakchi, Emna; Da Silva, Corinne; Wincker, Patrick; Mazan, Sylvie; Rétaux, Sylvie

    2009-01-01

    The forebrain is the brain region which has undergone the most dramatic changes through vertebrate evolution. Analyses conducted in lampreys are essential to gain insight into the broad ancestral characteristics of the forebrain at the dawn of vertebrates, and to understand the molecular basis for the diversifications that have taken place in cyclostomes and gnathostomes following their splitting. Here, we report the embryonic expression patterns of 43 lamprey genes, coding for transcription factors or signaling molecules known to be involved in cell proliferation, stemcellness, neurogenesis, patterning and regionalization in the developing forebrain. Systematic expression patterns comparisons with model organisms highlight conservations likely to reflect shared features present in the vertebrate ancestors. They also point to changes in signaling systems –pathways which control the growth and patterning of the neuroepithelium-, which may have been crucial in the evolution of forebrain anatomy at the origin of vertebrates. PMID:19399187

  19. Neurodevelopment genes in lampreys reveal trends for forebrain evolution in craniates.

    PubMed

    Guérin, Adèle; d'Aubenton-Carafa, Yves; Marrakchi, Emna; Da Silva, Corinne; Wincker, Patrick; Mazan, Sylvie; Rétaux, Sylvie

    2009-01-01

    The forebrain is the brain region which has undergone the most dramatic changes through vertebrate evolution. Analyses conducted in lampreys are essential to gain insight into the broad ancestral characteristics of the forebrain at the dawn of vertebrates, and to understand the molecular basis for the diversifications that have taken place in cyclostomes and gnathostomes following their splitting. Here, we report the embryonic expression patterns of 43 lamprey genes, coding for transcription factors or signaling molecules known to be involved in cell proliferation, stemcellness, neurogenesis, patterning and regionalization in the developing forebrain. Systematic expression patterns comparisons with model organisms highlight conservations likely to reflect shared features present in the vertebrate ancestors. They also point to changes in signaling systems -pathways which control the growth and patterning of the neuroepithelium-, which may have been crucial in the evolution of forebrain anatomy at the origin of vertebrates.

  20. Midbrain and forebrain patterning delivers immunocytochemically and functionally similar populations of neuropeptide Y containing GABAergic neurons.

    PubMed

    Khaira, S K; Nefzger, C M; Beh, S J; Pouton, C W; Haynes, J M

    2011-09-01

    Neurons differentiated in vitro from embryonic stem cells (ESCs) have the potential to serve both as models of disease states and in drug discovery programs. In this study, we use sonic hedgehog (SHH) and fibroblast growth factor 8 (FGF-8) to enrich for forebrain and midbrain phenotypes from mouse ESCs. We then investigate, using Ca(2+) imaging and [(3)H]-GABA release studies, whether the GABAergic neurons produced exhibit distinct functional phenotypes. At day 24 of differentiation, reverse transcriptase-PCR showed the presence of both forebrain (Bf-1, Hesx1, Pgc-1α, Six3) and midbrain (GATA2, GATA3) selective mRNA markers in developing forebrain-enriched cultures. All markers were present in midbrain cultures except for Bf-1 and Pgc-1α. Irrespective of culture conditions all GABA immunoreactive neurons were also immunoreactive to neuropeptide Y (NPY) antibodies. Forebrain and midbrain GABAergic neurons responded to ATP (1 mM), L-glutamate (30 μM), noradrenaline (30 μM), acetylcholine (30 μM) and dopamine (30 μM), with similar elevations of intracellular Ca(2+)([Ca(2+)](i)). The presence of GABA(A) and GABA(B) antagonists, bicuculline (30 μM) and CGP55845 (1 μM), increased the elevation of [Ca(2+)](i) in response to dopamine (30 μM) in midbrain, but not forebrain GABAergic neurons. All agonists, except dopamine, elicited similar [(3)H]-GABA release from forebrain and midbrain cultures. Dopamine (30 μM) did not stimulate significant [(3)H]-GABA release in midbrain cultures, although it was effective in forebrain cultures. This study shows that differentiating neurons toward a midbrain fate restricts the expression of forebrain markers. Forebrain differentiation results in the expression of forebrain and midbrain markers. All GABA(+) neurons contain NPY, and show similar agonist-induced elevations of [Ca(2+)](i) and [(3)H]-GABA release. This study indicates that the pharmacological phenotype of these particular neurons may be independent of the addition of

  1. Forebrain glucocorticoid receptor gene deletion attenuates behavioral changes and antidepressant responsiveness during chronic stress.

    PubMed

    Jacobson, Lauren

    2014-10-02

    Stress is an important risk factor for mood disorders. Stress also stimulates the secretion of glucocorticoids, which have been found to influence mood. To determine the role of forebrain glucocorticoid receptors (GR) in behavioral responses to chronic stress, the present experiments compared behavioral effects of repeated social defeat in mice with forebrain GR deletion and in floxed GR littermate controls. Repeated defeat produced alterations in forced swim and tail suspension immobility in floxed GR mice that did not occur in mice with forebrain GR deletion. Defeat-induced changes in immobility in floxed GR mice were prevented by chronic antidepressant treatment, indicating that these behaviors were dysphoria-related. In contrast, although mice with forebrain GR deletion exhibited antidepressant-induced decreases in tail suspension immobility in the absence of stress, this response did not occur in mice with forebrain GR deletion after defeat. There were no marked differences in plasma corticosterone between genotypes, suggesting that behavioral differences depended on forebrain GR rather than on abnormal glucocorticoid secretion. Defeat-induced gene expression of the neuronal activity marker c-fos in the ventral hippocampus, paraventricular thalamus and lateral septum correlated with genotype-related differences in behavioral effects of defeat, whereas c-fos induction in the nucleus accumbens and central and basolateral amygdala correlated with genotype-related differences in behavioral responses to antidepressant treatment. The dependence of both negative (dysphoria-related) and positive (antidepressant-induced) behaviors on forebrain GR is consistent with the contradictory effects of glucocorticoids on mood, and implicates these or other forebrain regions in these effects. Copyright © 2014 Elsevier B.V. All rights reserved.

  2. Forebrain glucocorticoid receptor gene deletion attenuates behavioral changes and antidepressant responsiveness during chronic stress

    PubMed Central

    Jacobson, Lauren

    2014-01-01

    Stress is an important risk factor for mood disorders. Stress also stimulates the secretion of glucocorticoids, which have been found to influence mood. To determine the role of forebrain glucocorticoid receptors (GR) in behavioral responses to chronic stress, the present experiments compared behavioral effects of repeated social defeat in mice with forebrain GR deletion and in floxed GR littermate controls. Repeated defeat produced alterations in forced swim and tail suspension immobility in floxed GR mice that did not occur in mice with forebrain GR deletion. Defeat-induced changes in immobility in floxed GR mice were prevented by chronic antidepressant treatment, indicating that these behaviors were dysphoria-related. In contrast, although mice with forebrain GR deletion exhibited antidepressant-induced decreases in tail suspension immobility in the absence of stress, this response did not occur in mice with forebrain GR deletion after defeat. There were no marked differences in plasma corticosterone between genotypes, suggesting that behavioral differences depended on forebrain GR rather than on abnormal glucocorticoid secretion. Defeat-induced gene expression of the neuronal activity marker c-fos in the ventral hippocampus, paraventricular thalamus and lateral septum correlated with genotype-related differences in behavioral effects of defeat, whereas c-fos induction in the nucleus accumbens and central and basolateral amygdala correlated with genotype-related differences in behavioral responses to antidepressant treatment. The dependence of both negative (dysphoria-related) and positive (antidepressant-induced) behaviors on forebrain GR is consistent with the contradictory effects of glucocorticoids on mood, and implicates these or other forebrain regions in these effects. PMID:25168761

  3. Behavioral reactivity to a noradrenergic challenge after chronic oral methylphenidate (ritalin) in rats.

    PubMed

    Leblanc-Duchin, Denise; Taukulis, Harald K

    2004-12-01

    Methylphenidate (Ritalin) is routinely used for the treatment of attention-deficit/hyperactivity disorder (ADHD). It is a psychomotor stimulant with pharmacodynamics similar to those established for cocaine and amphetamine with primary activation of the noradrenergic and dopaminergic systems. Long-term exposure to psychostimulants including methylphenidate (MPD) is believed to result in enduring functional changes along both these pathways and various behaviors mediated by these systems may be affected. In the present experiment, the effects of intermittent oral administration of methylphenidate (10 mg/kg) to rats over a 4-week period were subsequently (after a drug washout interval) assessed in three animal models sensitive to noradrenergic manipulation: the elevated plus-maze, predator odor avoidance, and social interaction tests. The behaviors of methylphenidate-experienced animals were compared with untreated controls. Thirty minutes prior to testing, half the animals with each of these histories received an injection of yohimbine hydrochloride (2.0 mg/kg), an alpha2-adrenoreceptor blocker intended to evoke noradrenergic system activation, while the remainder received a saline injection. Yohimbine was expected to reduce both exploration of novel stimuli and interaction with conspecifics, and it was predicted that methylphenidate would potentiate these effects. Relative to saline-tested controls, rats that received both the methylphenidate treatment and the yohimbine challenge exhibited the least exploration in the predator odor test and the lowest duration of interaction with an unfamiliar conspecific partner in the social interaction test. The behavior patterns observed in this group of rats suggest heightened emotionality and defensiveness that are typically seen when rats are administered drugs known to be anxiogenic in human subjects. In the plus-maze, exploratory locomotor activities remained unaltered by either drug while yohimbine decreased risk

  4. The Sensory Impact of Nicotine on Noradrenergic and Dopaminergic Neurons of the Nicotine Reward - Addiction Neurocircuitry

    PubMed Central

    Rose, Jed E; Dehkordi, Ozra; Manaye, Kebreten F; Millis, Richard M; Cianaki, Salman Ameri; Jayam-Trouth, Annapurni

    2016-01-01

    The sensory experience of smoking is a key component of nicotine addiction known to result, in part, from stimulation of nicotinic acetylcholine receptors (nAChRs) at peripheral sensory nerve endings. Such stimulation of nAChRs is followed by activation of neurons at multiple sites in the mesocorticolimbic reward pathways. However, the neurochemical profiles of CNS cells that mediate the peripheral sensory impact of nicotine remain unknown. In the present study in mice, we first used c-Fos immunohistochemistry to identify CNS cells stimulated by nicotine (NIC, 40 μg/kg, IP) and by a peripherally-acting analog of nicotine, nicotine pyrrolidine methiodide (NIC-PM, 30 μg/kg, IP). Sequential double-labelling was then performed to determine whether noradrenergic and dopaminergic neurons of the nicotine reward-addiction circuitry were primary targets of NIC and NIC-PM. Double-labelling of NIC and/or NIC-PM activated c-Fos immunoreactive cells with tyrosine hydroxylase (TH) showed no apparent c-Fos expression by the dopaminergic cells of the ventral tegmental area (VTA). With the exception of sparse numbers of TH immunoreactive D11 cells, dopamine-containing neurons in other areas of the reward-addiction circuitry, namely periaqueductal gray, and dorsal raphe, were also devoid of c-Fos immunoreactivity. Noradrenergic neurons of locus coeruleus (LC), known to innervate VTA, were activated by both NIC and NIC-PM. These results demonstrate that noradrenergic neurons of LC are among the first structures that are stimulated by single acute IP injection of NIC and NIC-PM. Dopaminergic neurons of VTA and other CNS sites, did not respond to acute IP administration of NIC or NIC-PM by induction of c-Fos. PMID:27347434

  5. The Sensory Impact of Nicotine on Noradrenergic and Dopaminergic Neurons of the Nicotine Reward - Addiction Neurocircuitry.

    PubMed

    Rose, Jed E; Dehkordi, Ozra; Manaye, Kebreten F; Millis, Richard M; Cianaki, Salman Ameri; Jayam-Trouth, Annapurni

    2016-04-01

    The sensory experience of smoking is a key component of nicotine addiction known to result, in part, from stimulation of nicotinic acetylcholine receptors (nAChRs) at peripheral sensory nerve endings. Such stimulation of nAChRs is followed by activation of neurons at multiple sites in the mesocorticolimbic reward pathways. However, the neurochemical profiles of CNS cells that mediate the peripheral sensory impact of nicotine remain unknown. In the present study in mice, we first used c-Fos immunohistochemistry to identify CNS cells stimulated by nicotine (NIC, 40 μg/kg, IP) and by a peripherally-acting analog of nicotine, nicotine pyrrolidine methiodide (NIC-PM, 30 μg/kg, IP). Sequential double-labelling was then performed to determine whether noradrenergic and dopaminergic neurons of the nicotine reward-addiction circuitry were primary targets of NIC and NIC-PM. Double-labelling of NIC and/or NIC-PM activated c-Fos immunoreactive cells with tyrosine hydroxylase (TH) showed no apparent c-Fos expression by the dopaminergic cells of the ventral tegmental area (VTA). With the exception of sparse numbers of TH immunoreactive D11 cells, dopamine-containing neurons in other areas of the reward-addiction circuitry, namely periaqueductal gray, and dorsal raphe, were also devoid of c-Fos immunoreactivity. Noradrenergic neurons of locus coeruleus (LC), known to innervate VTA, were activated by both NIC and NIC-PM. These results demonstrate that noradrenergic neurons of LC are among the first structures that are stimulated by single acute IP injection of NIC and NIC-PM. Dopaminergic neurons of VTA and other CNS sites, did not respond to acute IP administration of NIC or NIC-PM by induction of c-Fos.

  6. Prenatal Drug Exposures Sensitize Noradrenergic Circuits to Subsequent Disruption by Chlorpyrifos

    PubMed Central

    Slotkin, Theodore A.; Skavicus, Samantha; Seidler, Frederic J.

    2015-01-01

    We examined whether nicotine or dexamethasone, common prenatal drug exposures, sensitize the developing brain to chlorpyrifos. We gave nicotine to pregnant rats throughout gestation at a dose (3 mg/kg/day) producing plasma levels typical of smokers; offspring were then given chlorpyrifos on postnatal days 1–4, at a dose (1 mg/kg) that produces minimally-detectable inhibition of brain cholinesterase activity. In a parallel study, we administered dexamethasone to pregnant rats on gestational days 17–19 at a standard therapeutic dose (0.2 mg/kg) used in the management of preterm labor, followed by postnatal chlorpyrifos. We evaluated cerebellar noradrenergic projections, a known target for each agent, and contrasted the effects with those in the cerebral cortex. Either drug augmented the effect of chlorpyrifos, evidenced by deficits in cerebellar β-adrenergic receptors; the receptor effects were not due to increased systemic toxicity or cholinesterase inhibition, nor to altered chlorpyrifos pharmacokinetics. Further, the deficits were not secondary adaptations to presynaptic hyperinnervation/hyperactivity, as there were significant deficits in presynaptic norepinephrine levels that would serve to augment the functional consequence of receptor deficits. The pretreatments also altered development of cerebrocortical noradrenergic circuits, but with a different overall pattern, reflecting the dissimilar developmental stages of the regions at the time of exposure. However, in each case the net effects represented a change in the developmental trajectory of noradrenergic circuits, rather than simply a continuation of an initial injury. Our results point to the ability of prenatal drug exposure to create a subpopulation with heightened vulnerability to environmental neurotoxicants. PMID:26419632

  7. Prenatal drug exposures sensitize noradrenergic circuits to subsequent disruption by chlorpyrifos.

    PubMed

    Slotkin, Theodore A; Skavicus, Samantha; Seidler, Frederic J

    2015-12-02

    We examined whether nicotine or dexamethasone, common prenatal drug exposures, sensitize the developing brain to chlorpyrifos. We gave nicotine to pregnant rats throughout gestation at a dose (3mg/kg/day) producing plasma levels typical of smokers; offspring were then given chlorpyrifos on postnatal days 1-4, at a dose (1mg/kg) that produces minimally-detectable inhibition of brain cholinesterase activity. In a parallel study, we administered dexamethasone to pregnant rats on gestational days 17-19 at a standard therapeutic dose (0.2mg/kg) used in the management of preterm labor, followed by postnatal chlorpyrifos. We evaluated cerebellar noradrenergic projections, a known target for each agent, and contrasted the effects with those in the cerebral cortex. Either drug augmented the effect of chlorpyrifos, evidenced by deficits in cerebellar β-adrenergic receptors; the receptor effects were not due to increased systemic toxicity or cholinesterase inhibition, nor to altered chlorpyrifos pharmacokinetics. Further, the deficits were not secondary adaptations to presynaptic hyperinnervation/hyperactivity, as there were significant deficits in presynaptic norepinephrine levels that would serve to augment the functional consequence of receptor deficits. The pretreatments also altered development of cerebrocortical noradrenergic circuits, but with a different overall pattern, reflecting the dissimilar developmental stages of the regions at the time of exposure. However, in each case the net effects represented a change in the developmental trajectory of noradrenergic circuits, rather than simply a continuation of an initial injury. Our results point to the ability of prenatal drug exposure to create a subpopulation with heightened vulnerability to environmental neurotoxicants.

  8. Activation of histamine H3 receptors inhibits renal noradrenergic neurotransmission in anesthetized dogs.

    PubMed

    Yamasaki, T; Tamai, I; Matsumura, Y

    2001-05-01

    To investigate the possible involvement of histamine H(3) receptors in renal noradrenergic neurotransmission, effects of (R)alpha-methylhistamine (R-HA), a selective H3-receptor agonist, and thioperamide (Thiop), a selective H3-receptor antagonist, on renal nerve stimulation (RNS)-induced changes in renal function and norepinephrine (NE) overflow in anesthetized dogs were examined. RNS (0.5-2.0 Hz) produced significant decreases in urine flow and urinary sodium excretion and increases in NE overflow rate (NEOR), without affecting renal hemodynamics. When R-HA (1 microg x kg(-1) x min(-1)) was infused intravenously, mean arterial pressure and heart rate were significantly decreased, and there was a tendency to reduce basal values of urine flow and urinary sodium excretion. During R-HA infusion, RNS-induced antidiuretic action and increases in NEOR were markedly attenuated. Thiop infusion (5 microg x kg(-1) x min(-1)) did not affect basal hemodynamic and excretory parameters. Thiop infusion caused RNS-induced antidiuretic action and increases in NEOR similar to the basal condition. When R-HA was administered concomitantly with Thiop infusion, R-HA failed to attenuate the RNS-induced antidiuretic action and increases in NEOR. However, in the presence of pyrilamine (a selective H1-receptor antagonist) or cimetidine (a selective H2-receptor antagonist) infusion, R-HA attenuated the RNS-induced actions, similarly to the case without these antagonists. Thus functional histamine H3 receptors, possibly located on renal noradrenergic nerve endings, may play the role of inhibitory modulators of renal noradrenergic neurotransmission.

  9. The effects of periaqueductally injected transmitter antagonists on forebrain-elicited vocalization in the squirrel monkey.

    PubMed

    Jürgens, U; Lu, C L

    1993-06-01

    In 15 squirrel monkeys, vocalization-eliciting electrodes were implanted into the following forebrain structures: anterior cingulate cortex, genu of the internal capsule, amygdala, bed nucleus of the stria terminalis, hypothalamus, midline thalamus, inferior thalamic peduncle and periventricular grey. Then, injections of 29 transmitter antagonists were made into the midbrain periaqueductal grey (PAG) and their effects tested on the elicitability of vocalization from the forebrain. Vocalization could be blocked completely with glutamate antagonists. NMDA receptor antagonists as well as kainate/quisqualate receptor antagonists were effective. Facilitatory effects, i.e. a decrease in threshold of forebrain-elicited vocalization, was obtained with GABA-A receptor, glycine and opioid antagonists. The facilitatory effect of the opioid antagonist naloxone was limited to vocalizations expressing aversive emotional states. GABA-A receptor antagonists not only facilitated forebrain-induced vocalization but also produced vocalization themselves, i.e. without concomitant forebrain stimulation. No effects were obtained with antagonists of muscarinic and nicotinic receptors, with the GABA-B receptor antagonist phaclofen and antagonists of the monoamines dopamine, noradrenaline, adrenaline, serotonin and histamine. It is concluded that the PAG represents a crucial relay station of the vocalization-controlling system. In this station, transmission of vocalization-relevant information depends upon the activation of glutamatergic synapses. Inhibitory control is exerted by GABA, glycine and endogenous opioids. Acetylcholine, dopamine, noradrenaline, adrenaline, serotonin and histamine may play a transient modulatory role; forebrain-induced vocalization, however, does not depend upon the cholinergic or monoaminergic activation of PAG neurons.

  10. From pluripotency to forebrain patterning: an in vitro journey astride embryonic stem cells.

    PubMed

    Lupo, Giuseppe; Bertacchi, Michele; Carucci, Nicoletta; Augusti-Tocco, Gabriella; Biagioni, Stefano; Cremisi, Federico

    2014-08-01

    Embryonic stem cells (ESCs) have been used extensively as in vitro models of neural development and disease, with special efforts towards their conversion into forebrain progenitors and neurons. The forebrain is the most complex brain region, giving rise to several fundamental structures, such as the cerebral cortex, the hypothalamus, and the retina. Due to the multiplicity of signaling pathways playing different roles at distinct times of embryonic development, the specification and patterning of forebrain has been difficult to study in vivo. Research performed on ESCs in vitro has provided a large body of evidence to complement work in model organisms, but these studies have often been focused more on cell type production than on cell fate regulation. In this review, we systematically reassess the current literature in the field of forebrain development in mouse and human ESCs with a focus on the molecular mechanisms of early cell fate decisions, taking into consideration the specific culture conditions, exogenous and endogenous molecular cues as described in the original studies. The resulting model of early forebrain induction and patterning provides a useful framework for further studies aimed at reconstructing forebrain development in vitro for basic research or therapy.

  11. Roof plate mediated morphogenesis of the forebrain: New players join the game.

    PubMed

    Gupta, Sandeep; Sen, Jonaki

    2016-05-15

    The roof plate is a crucial signaling center located at the dorsal midline of the developing central nervous system (CNS) along its rostro-caudal axis. By virtue of secreting multiple signaling molecules, it regulates diverse processes such as specification of dorsal fate, proliferation and axon guidance. In the forebrain, the roof plate is not only involved in patterning but is also involved in the division of the single forebrain vesicle into the two cerebral hemispheres, the failure of which leads to certain forms of holoprosencephaly. Although several molecular players such as Fgfs, BMPs, Wnts and Shh have been identified as crucial regulators of development of the forebrain, little is known about how they interact to bring about the morphological changes associated with the division of the forebrain vesicle into the cerebral hemispheres. Recent studies have now identified the dorsal mesenchyme as an additional source of signaling cues, which is likely to influence the division of the forebrain vesicle into cerebral hemispheres. In this review, we discuss the current understanding about the molecular mechanisms of roof plate mediated patterning and morphogenesis of the forebrain including some recently identified factors that influence this process and also highlight the gaps in our knowledge that remain.

  12. Activation of noradrenergic neurons projecting to the diencephalon following central administration of histamine is mediated by H1 receptors.

    PubMed

    Fleckenstein, A E; Lookingland, K J; Moore, K E

    1994-02-28

    The effect of histamine on the activity of noradrenergic neurons terminating in discrete regions of the diencephalon was examined in male rats. Noradrenergic neuronal activity was estimated by measuring the concentration of norepinephrine and its metabolite 3-methoxy-4-hydroxyphenylethyleneglycol [MHPG] in the medial zona incerta [MZI] and in the dorsomedial [DMN], periventricular [PeVN] and medial preoptic hypothalamic nuclei [MPN]. The intracerebroventricular administration of histamine effected a time-related increase in MHPG concentrations in the MZI, DMN, PeVN and MPN; these effects were blocked by the H1 antagonist mepyramine but not the H2 antagonist zolantidine. Neither mepyramine nor zolantidine affected basal MHPG concentrations in any of the brain regions examined. These results indicate that central administration of histamine increases the activity of noradrenergic neurons projecting to the diencephalon via an action at H1 but not H2 receptors.

  13. Noradrenergic interactions via autonomic nervous system: a promising target for extinction-based exposure therapy?

    PubMed

    Calişkan, Gürsel; Albrecht, Anne

    2013-12-01

    Fearful associations can be replaced by neutral associations through repetitive exposure of an individual to the fearful situation without the aversive component. Recently, Peña and colleagues (Peña DF, Engineer ND, McIntyre CK. Biol Psychiatry 73: 1071-1077, 2013) demonstrated that pairing activation of noradrenergic (NA) pathways through vagus nerve stimulation (VNS) with extinction learning accelerates consolidation of extinction memories in rats. Their findings stress the importance of activating the NA system through VNS in treatment of anxiety disorders such as PTSD or phobia.

  14. Degeneration of the locus ceruleus noradrenergic neurons in the stress-induced depression of rats.

    PubMed

    Kitayama, Isao T; Otani, Masato; Murase, Sumio

    2008-12-01

    We produced a model of depression in rats which have been exposed to 2-weeks forced walking stress. Electron microscopic observation on the locus ceruleus (LC) cells of the model rats disclosed low dense areas, destroyed membranes, aggregation of intracellular organs, and increased microglia. Density of LC axon terminals in the frontal cortex stained with dopamine beta-hydroxylase antiserum and percentage of LC cells stained with horseradish peroxidase or activated by electrical stimulation antidromically were low in the model. These indices increased in the model treated with imipramine. These findings suggest that the LC noradrenergic neurons degenerate in depression, but regenerate in remission.

  15. Autoradiographic analysis of alpha 1-noradrenergic receptors in the human brain postmortem. Effect of suicide

    SciTech Connect

    Gross-Isseroff, R.; Dillon, K.A.; Fieldust, S.J.; Biegon, A. )

    1990-11-01

    In vitro quantitative autoradiography of alpha 1-noradrenergic receptors, using tritiated prazosin as a ligand, was performed on 24 human brains postmortem. Twelve brains were obtained from suicide victims and 12 from matched controls. We found significant lower binding to alpha 1 receptors in several brain regions of the suicide group as compared with matched controls. This decrease in receptor density was evident in portions of the prefrontal cortex, as well as the temporal cortex and in the caudate nucleus. Age, sex, presence of alcohol, and time of death to autopsy did not affect prazosin binding, in our sample, as measured by autoradiography.

  16. Pharmacologic reduction of CNS noradrenergic activity in PTSD: the case for clonidine and prazosin.

    PubMed

    Boehnlein, James K; Kinzie, J David

    2007-03-01

    This article reviews the neurobiologic rationale for and presents clinical guidance concerning the use of medications that reduce central nervous system noradrenergic activity in the treatment of intrusive symptoms of posttraumatic stress disorder. The authors reviewed neurobiological studies, nonclinical studies using animal models, clinical case reports, open-label drug studies, and blinded, placebo-controlled drug studies. This review of the basic science and clinical literature, and the authors' clinical experience with culturally and demographically diverse populations, indicate that clonidine and prazosin can play a useful role in treating sleep disturbance and hyperarousal in posttraumatic stress disorder, with minimal adverse effects and low financial cost.

  17. Forebrain commissures and visual memory: a new approach.

    PubMed

    Doty, R W; Ringo, J L; Lewine, J D

    1988-08-01

    The primary purpose of these exploratory experiments was to determine: (1) whether the forebrain commissures can provide full accessibility of the mnemonic store to either hemisphere when the taks involves memory for 'events' (images) rather than, as in essentially all previous tests on split-brain animals, memory for 'rules' (discrimination habits); and (2) whether the anterior commissure (AC) alone is capable of such function. Macaques, with optic chiasm transected to allow limitation of direct visual input to one or the other hemisphere, were trained on tasks requiring recognition of previously viewed photographic slides. For one task, delayed-matching-to-sample (DMTS), the animal was presented with a 'sample' image, and then 0-15s later was required to choose that image in preference to a second image concurrently displayed. On the other task, running recognition (RR), a series of images was presented, some of which were repetitions of images previously seen in that session, and the animal was required to signal its recognition of these repetitions. For either task the initial presentation could be made to one eye and hemisphere, and subsequent recognition required of the other. In such circumstance, if all forebrain commissures were divided, such interhemispheric recognition was no longer possible. For the DMTS task if either the AC or 5 mm of the splenium of the corpus callosum were available, interhemispheric recognition was basically equivalent to that using the same eye and hemisphere. However, interhemispheric accuracy with the RR task, while well above chance levels, was consistently inferior to that achieved intrahemispherically when complex scenes or objects were viewed. This is probably a consequence mostly of the differing visual fields of the two eyes, since interhemispheric accuracy was greatly improved by use of images having approximately identical right and left halves. No consistent hemispheric specialization nor difference in direction of

  18. Baseline frontostriatal-limbic connectivity predicts reward-based memory formation.

    PubMed

    Hamann, Janne M; Dayan, Eran; Hummel, Friedhelm C; Cohen, Leonardo G

    2014-12-01

    Reward mediates the acquisition and long-term retention of procedural skills in humans. Yet, learning under rewarded conditions is highly variable across individuals and the mechanisms that determine interindividual variability in rewarded learning are not known. We postulated that baseline functional connectivity in a large-scale frontostriatal-limbic network could predict subsequent interindividual variability in rewarded learning. Resting-state functional MRI was acquired in two groups of subjects (n = 30) who then trained on a visuomotor procedural learning task with or without reward feedback. We then tested whether baseline functional connectivity within the frontostriatal-limbic network predicted memory strength measured immediately, 24 h and 1 month after training in both groups. We found that connectivity in the frontostriatal-limbic network predicted interindividual variability in the rewarded but not in the unrewarded learning group. Prediction was strongest for long-term memory. Similar links between connectivity and reward-based memory were absent in two control networks, a fronto-parieto-temporal language network and the dorsal attention network. The results indicate that baseline functional connectivity within the frontostriatal-limbic network successfully predicts long-term retention of rewarded learning.

  19. Early life stress modulates oxytocin effects on limbic system during acute psychosocial stress.

    PubMed

    Grimm, Simone; Pestke, Karin; Feeser, Melanie; Aust, Sabine; Weigand, Anne; Wang, Jue; Wingenfeld, Katja; Pruessner, Jens C; La Marca, Roberto; Böker, Heinz; Bajbouj, Malek

    2014-11-01

    Early life stress (ELS) is associated with altered stress responsivity, structural and functional brain changes and an increased risk for the development of psychopathological conditions in later life. Due to its behavioral and physiological effects, the neuropeptide oxytocin (OXT) is a useful tool to investigate stress responsivity, even though the neurobiological underpinnings of its effects are still unknown. Here we investigate the effects of OXT on cortisol stress response and neural activity during psychosocial stress. Using functional magnetic resonance imaging in healthy subjects with and without a history of ELS, we found attenuated hormonal reactivity and significantly reduced limbic deactivation after OXT administration in subjects without a history of ELS. Subjects who experienced ELS showed both blunted stress reactivity and limbic deactivation during stress. Furthermore, in these subjects OXT had opposite effects with increased hormonal reactivity and increased limbic deactivation. Our results might implicate that reduced limbic deactivation and hypothalamic-pituitary-adrenal axis responsivity during psychosocial stress are markers for biological resilience after ELS. Effects of OXT in subjects with a history of maltreatment could therefore be considered detrimental and suggest careful consideration of OXT administration in such individuals. © The Author (2014). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  20. Early life stress as an influence on limbic epilepsy: an hypothesis whose time has come?

    PubMed

    Koe, Amelia S; Jones, Nigel C; Salzberg, Michael R

    2009-01-01

    The pathogenesis of mesial temporal lobe epilepsy (MTLE), the most prevalent form of refractory focal epilepsy in adults, is thought to begin in early life, even though seizures may not commence until adolescence or adulthood. Amongst the range of early life factors implicated in MTLE causation (febrile seizures, traumatic brain injury, etc.), stress may be one important contributor. Early life stress is an a priori agent deserving study because of the large amount of neuroscientific data showing enduring effects on structure and function in hippocampus and amygdala, the key structures involved in MTLE. An emerging body of evidence directly tests hypotheses concerning early life stress and limbic epilepsy: early life stressors, such as maternal separation, have been shown to aggravate epileptogenesis in both status epilepticus and kindling models of limbic epilepsy. In addition to elucidating its influence on limbic epileptogenesis itself, the study of early life stress has the potential to shed light on the psychiatric disorder that accompanies MTLE. For many years, psychiatric comorbidity was viewed as an effect of epilepsy, mediated psychologically and/or neurobiologically. An alternative - or complementary - perspective is that of shared causation. Early life stress, implicated in the pathogenesis of several psychiatric disorders, may be one such causal factor. This paper aims to critically review the body of experimental evidence linking early life stress and epilepsy; to discuss the direct studies examining early life stress effects in current models of limbic seizures/epilepsy; and to suggest priorities for future research.

  1. Opsoclonus-myoclonus syndrome and limbic encephalitis associated with GABAB receptor antibodies in CSF.

    PubMed

    DeFelipe-Mimbrera, Alicia; Masjuan, Jaime; Corral, Íñigo; Villar, Luisa Maria; Graus, Francesc; García-Barragán, Nuria

    2014-07-15

    We report a case of a woman who had two consecutive autoimmune neurological disorders, including an opsoclonus-myoclonus syndrome (OMS) and limbic encephalitis (LE), with positive titers of GABAB receptor antibodies. The patient never developed seizures or had an underlying tumor after 4 years of follow-up.

  2. Excitatory Amplification Through Divergent-Convergent Circuits: The Role of the Midline Thalamus in Limbic Seizures

    PubMed Central

    Sloan, David M; Zhang, DeXing; Bertram, Edward H

    2014-01-01

    Introduction The midline thalamic nuclei are an important component of limbic seizures. Although the anatomic connections and excitatory influences of the midline thalamus are well known, its physiological role in limbic seizures is unclear. We examined the role of the midline thalamus on two circuits that are involved in limbic seizures: (a) the subiculum-prefrontal cortex (SB-PFC), and (b) the piriform cortex-entorhinal cortex (PC-EC). Methods Evoked field potentials for both circuits were obtained in anesthetized rats, and the likely direct monosynaptic and polysynaptic contributions to the responses were identified. Seizures were generated in both circuits by 20 Hz stimulus trains. Once stable seizures and evoked potentials were established, the midline thalamus was inactivated through an injection of the sodium channel blocker tetrodotoxin (TTX), and the effects on the evoked responses and seizures were analyzed. Results Inactivation of the midline thalamus suppressed seizures in both circuits. Seizure suppression was associated with a significant reduction in the late thalamic component but no significant change in the early direct monosynaptic component. Injections that did not suppress the seizures did not alter the evoked potentials. Conclusions Suppression of the late thalamic component of the evoked potential at the time of seizure suppression suggests that the thalamus facilitates seizure induction by extending the duration of excitatory drive through a divergent-convergent excitatory amplification system. This work may have broader implications for understanding signaling in the limbic system. PMID:21554957

  3. Fronto-limbic effective connectivity as possible predictor of antidepressant response to SSRI administration.

    PubMed

    Vai, Benedetta; Bulgarelli, Chiara; Godlewska, Beata R; Cowen, Philip J; Benedetti, Francesco; Harmer, Catherine J

    2016-12-01

    The timely selection of the optimal treatment for depressed patients is critical to improve remission rates. The detection of pre-treatment variables able to predict differential treatment response may provide novel approaches for treatment selection. Selective serotonin reuptake inhibitors (SSRIs) modulate the fronto-limbic functional response and connectivity, an effect preceding the overt clinical antidepressant effects. Here we investigated whether the cortico-limbic connectivity associated with emotional bias measured before SSRI administration predicts the efficacy of antidepressant treatment in MDD patients. fMRI and Dynamic Causal Modeling (DCM) were combined to study if effective connectivity might differentiate healthy controls (HC) and patients affected by major depression who later responded (RMDD, n=21), or failed to respond (nRMDD, n=12), to 6 weeks of escitalopram administration. Sixteen DCMs exploring connectivity between anterior cingulate cortex (ACC), ventrolateral prefrontal cortex (VLPFC), Amygdala (Amy), and fusiform gyrus (FG) were constructed. Analyses revealed that nRMDD had reduced endogenous connectivity from Amy to VLPFC and to ACC, with an increased connectivity and modulation of the ACC to Amy connectivity when processing of fearful emotional stimuli compared to HC. RMDD and HC did not significantly differ among themselves. Pre-treatment effective connectivity in fronto-limbic circuitry could be an important factor affecting antidepressant response, and highlight the mechanisms which may be involved in recovery from depression. These results suggest that fronto-limbic connectivity might provide a neural biomarker to predict the clinical outcome to SSRIs administration in major depression.

  4. Wired for behaviors: from development to function of innate limbic system circuitry

    PubMed Central

    Sokolowski, Katie; Corbin, Joshua G.

    2012-01-01

    The limbic system of the brain regulates a number of behaviors that are essential for the survival of all vertebrate species including humans. The limbic system predominantly controls appropriate responses to stimuli with social, emotional, or motivational salience, which includes innate behaviors such as mating, aggression, and defense. Activation of circuits regulating these innate behaviors begins in the periphery with sensory stimulation (primarily via the olfactory system in rodents), and is then processed in the brain by a set of delineated structures that primarily includes the amygdala and hypothalamus. While the basic neuroanatomy of these connections is well-established, much remains unknown about how information is processed within innate circuits and how genetic hierarchies regulate development and function of these circuits. Utilizing innovative technologies including channel rhodopsin-based circuit manipulation and genetic manipulation in rodents, recent studies have begun to answer these central questions. In this article we review the current understanding of how limbic circuits regulate sexually dimorphic behaviors and how these circuits are established and shaped during pre- and post-natal development. We also discuss how understanding developmental processes of innate circuit formation may inform behavioral alterations observed in neurodevelopmental disorders, such as autism spectrum disorders, which are characterized by limbic system dysfunction. PMID:22557946

  5. One-single physical exercise session after object recognition learning promotes memory persistence through hippocampal noradrenergic mechanisms.

    PubMed

    da Silva de Vargas, Liane; Neves, Ben-Hur Souto das; Roehrs, Rafael; Izquierdo, Iván; Mello-Carpes, Pâmela

    2017-06-30

    Previously we showed the involvement of the hippocampal noradrenergic system in the consolidation and persistence of object recognition (OR) memory. Here we show that one-single physical exercise session performed immediately after learning promotes OR memory persistence and increases norepinephrine levels in the hippocampus. Additionally, effects of exercise on memory are avoided by an intra-hippocampal beta-adrenergic antagonist infusion. Taken together, these results suggest that exercise effects on memory can be related to noradrenergic mechanisms and acute physical exercise can be a non-pharmacological intervention to assist memory consolidation and persistence, with few or no side effects. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Probing forebrain to hindbrain circuit functions in Xenopus.

    PubMed

    Kelley, Darcy B; Elliott, Taffeta M; Evans, Ben J; Hall, Ian C; Leininger, Elizabeth C; Rhodes, Heather J; Yamaguchi, Ayako; Zornik, Erik

    2017-01-01

    The vertebrate hindbrain includes neural circuits that govern essential functions including breathing, blood pressure and heart rate. Hindbrain circuits also participate in generating rhythmic motor patterns for vocalization. In most tetrapods, sound production is powered by expiration and the circuitry underlying vocalization and respiration must be linked. Perception and arousal are also linked; acoustic features of social communication sounds-for example, a baby's cry-can drive autonomic responses. The close links between autonomic functions that are essential for life and vocal expression have been a major in vivo experimental challenge. Xenopus provides an opportunity to address this challenge using an ex vivo preparation: an isolated brain that generates vocal and breathing patterns. The isolated brain allows identification and manipulation of hindbrain vocal circuits as well as their activation by forebrain circuits that receive sensory input, initiate motor patterns and control arousal. Advances in imaging technologies, coupled to the production of Xenopus lines expressing genetically encoded calcium sensors, provide powerful tools for imaging neuronal patterns in the entire fictively behaving brain, a goal of the BRAIN Initiative. Comparisons of neural circuit activity across species (comparative neuromics) with distinctive vocal patterns can identify conserved features, and thereby reveal essential functional components. © 2017 Wiley Periodicals, Inc.

  7. Basal forebrain dynamics during nonassociative and associative olfactory learning

    PubMed Central

    Devore, Sasha; Pender-Morris, Nathaniel; Dean, Owen; Smith, David

    2015-01-01

    Cholinergic and GABAergic projections from the horizontal diagonal band (HDB) and medial preoptic area (MCPO) of the basal forebrain to the olfactory system are associated with odor discrimination and odor learning, as well as modulation of neural responses in olfactory structures. Whereas pharmacological and lesion studies give insights into the functional role of these modulatory inputs on a slow timescale, the response dynamics of neurons in the HDB/MCPO during olfactory behaviors have not been investigated. In this study we examined how these neurons respond during two olfactory behaviors: spontaneous investigation of odorants and odor-reward association learning. We observe rich heterogeneity in the response dynamics of individual HDB/MCPO neurons, with a substantial fraction of neurons exhibiting task-related modulation. HDB/MCPO neurons show both rapid and transient responses during bouts of odor investigation and slow, long-lasting modulation of overall response rate based on behavioral demands. Specifically, baseline rates were higher during the acquisition phase of an odor-reward association than during spontaneous investigation or the recall phase of an odor reward association. Our results suggest that modulatory projections from the HDB/MCPO are poised to influence olfactory processing on multiple timescales, from hundreds of milliseconds to minutes, and are therefore capable of rapidly setting olfactory network dynamics during odor processing and learning. PMID:26561601

  8. Basal forebrain dynamics during nonassociative and associative olfactory learning.

    PubMed

    Devore, Sasha; Pender-Morris, Nathaniel; Dean, Owen; Smith, David; Linster, Christiane

    2016-01-01

    Cholinergic and GABAergic projections from the horizontal diagonal band (HDB) and medial preoptic area (MCPO) of the basal forebrain to the olfactory system are associated with odor discrimination and odor learning, as well as modulation of neural responses in olfactory structures. Whereas pharmacological and lesion studies give insights into the functional role of these modulatory inputs on a slow timescale, the response dynamics of neurons in the HDB/MCPO during olfactory behaviors have not been investigated. In this study we examined how these neurons respond during two olfactory behaviors: spontaneous investigation of odorants and odor-reward association learning. We observe rich heterogeneity in the response dynamics of individual HDB/MCPO neurons, with a substantial fraction of neurons exhibiting task-related modulation. HDB/MCPO neurons show both rapid and transient responses during bouts of odor investigation and slow, long-lasting modulation of overall response rate based on behavioral demands. Specifically, baseline rates were higher during the acquisition phase of an odor-reward association than during spontaneous investigation or the recall phase of an odor reward association. Our results suggest that modulatory projections from the HDB/MCPO are poised to influence olfactory processing on multiple timescales, from hundreds of milliseconds to minutes, and are therefore capable of rapidly setting olfactory network dynamics during odor processing and learning.

  9. Adherent neural stem (NS) cells from fetal and adult forebrain.

    PubMed

    Pollard, Steven M; Conti, Luciano; Sun, Yirui; Goffredo, Donato; Smith, Austin

    2006-07-01

    Stable in vitro propagation of central nervous system (CNS) stem cells would offer expanded opportunities to dissect basic molecular, cellular, and developmental processes and to model neurodegenerative disease. CNS stem cells could also provide a source of material for drug discovery assays and cell replacement therapies. We have recently reported the generation of adherent, symmetrically expandable, neural stem (NS) cell lines derived both from mouse and human embryonic stem cells and from fetal forebrain (Conti L, Pollard SM, Gorba T, Reitano E, Toselli M, Biella G, Sun Y, Sanzone S, Ying QL, Cattaneo E, Smith A. 2005. Niche-independent symmetrical self-renewal of a mammalian tissue stem cell. PLoS Biol 3(9):e283). These NS cells retain neuronal and glial differentiation potential after prolonged passaging and are transplantable. NS cells are likely to comprise the resident stem cell population within heterogeneous neurosphere cultures. Here we demonstrate that similar NS cell cultures can be established from the adult mouse brain. We also characterize the growth factor requirements for NS cell derivation and self-renewal. We discuss our current understanding of the relationship of NS cell lines to physiological progenitor cells of fetal and adult CNS.

  10. Unique spatiotemporal requirements for intraflagellar transport genes during forebrain development

    PubMed Central

    Chang, Ching-Fang; Cionni, Megan; Brugmann, Samantha A.

    2017-01-01

    Primary cilia are organelles extended from virtually all cells and are required for the proper regulation of a number of canonical developmental pathways. The role in cortical development of proteins important for ciliary form and function is a relatively understudied area. Here we have taken a genetic approach to define the role in forebrain development of three intraflagellar transport proteins known to be important for primary cilia function. We have genetically ablated Kif3a, Ift88, and Ttc21b in a series of specific spatiotemporal domains. The resulting phenotypes allow us to draw several conclusions. First, we conclude that the Ttc21b cortical phenotype is not due to the activity of Ttc21b within the brain itself. Secondly, some of the most striking phenotypes are from ablations in the neural crest cells and the adjacent surface ectoderm indicating that cilia transduce critical tissue—tissue interactions in the developing embryonic head. Finally, we note striking differences in phenotypes from ablations only one embryonic day apart, indicating very discrete spatiotemporal requirements for these three genes in cortical development. PMID:28291836

  11. Basal forebrain circuit for sleep-wake control.

    PubMed

    Xu, Min; Chung, Shinjae; Zhang, Siyu; Zhong, Peng; Ma, Chenyan; Chang, Wei-Cheng; Weissbourd, Brandon; Sakai, Noriaki; Luo, Liqun; Nishino, Seiji; Dan, Yang

    2015-11-01

    The mammalian basal forebrain (BF) has important roles in controlling sleep and wakefulness, but the underlying neural circuit remains poorly understood. We examined the BF circuit by recording and optogenetically perturbing the activity of four genetically defined cell types across sleep-wake cycles and by comprehensively mapping their synaptic connections. Recordings from channelrhodopsin-2 (ChR2)-tagged neurons revealed that three BF cell types, cholinergic, glutamatergic and parvalbumin-positive (PV+) GABAergic neurons, were more active during wakefulness and rapid eye movement (REM) sleep (wake/REM active) than during non-REM (NREM) sleep, and activation of each cell type rapidly induced wakefulness. By contrast, activation of somatostatin-positive (SOM+) GABAergic neurons promoted NREM sleep, although only some of them were NREM active. Synaptically, the wake-promoting neurons were organized hierarchically by glutamatergic→cholinergic→PV+ neuron excitatory connections, and they all received inhibition from SOM+ neurons. Together, these findings reveal the basic organization of the BF circuit for sleep-wake control.

  12. Evolution and development of interhemispheric connections in the vertebrate forebrain

    PubMed Central

    Suárez, Rodrigo; Gobius, Ilan; Richards, Linda J.

    2014-01-01

    Axonal connections between the left and right sides of the brain are crucial for bilateral integration of lateralized sensory, motor, and associative functions. Throughout vertebrate species, forebrain commissures share a conserved developmental plan, a similar position relative to each other within the brain and similar patterns of connectivity. However, major events in the evolution of the vertebrate brain, such as the expansion of the telencephalon in tetrapods and the origin of the six-layered isocortex in mammals, resulted in the emergence and diversification of new commissural routes. These new interhemispheric connections include the pallial commissure, which appeared in the ancestors of tetrapods and connects the left and right sides of the medial pallium (hippocampus in mammals), and the corpus callosum, which is exclusive to eutherian (placental) mammals and connects both isocortical hemispheres. A comparative analysis of commissural systems in vertebrates reveals that the emergence of new commissural routes may have involved co-option of developmental mechanisms and anatomical substrates of preexistent commissural pathways. One of the embryonic regions of interest for studying these processes is the commissural plate, a portion of the early telencephalic midline that provides molecular specification and a cellular scaffold for the development of commissural axons. Further investigations into these embryonic processes in carefully selected species will provide insights not only into the mechanisms driving commissural evolution, but also regarding more general biological problems such as the role of developmental plasticity in evolutionary change. PMID:25071525

  13. Forebrain neurocircuitry associated with human reflex cardiovascular control

    PubMed Central

    Shoemaker, J. Kevin; Goswami, Ruma

    2015-01-01

    Physiological homeostasis depends upon adequate integration and responsiveness of sensory information with the autonomic nervous system to affect rapid and effective adjustments in end organ control. Dysregulation of the autonomic nervous system leads to cardiovascular disability with consequences as severe as sudden death. The neural pathways involved in reflexive autonomic control are dependent upon brainstem nuclei but these receive modulatory inputs from higher centers in the midbrain and cortex. Neuroimaging technologies have allowed closer study of the cortical circuitry related to autonomic cardiovascular adjustments to many stressors in awake humans and have exposed many forebrain sites that associate strongly with cardiovascular arousal during stress including the medial prefrontal cortex, insula cortex, anterior cingulate, amygdala and hippocampus. Using a comparative approach, this review will consider the cortical autonomic circuitry in rodents and primates with a major emphasis on more recent neuroimaging studies in awake humans. A challenge with neuroimaging studies is their interpretation in view of multiple sensory, perceptual, emotive and/or reflexive components of autonomic responses. This review will focus on those responses related to non-volitional baroreflex control of blood pressure and also on the coordinated responses to non-fatiguing, non-painful volitional exercise with particular emphasis on the medial prefrontal cortex and the insula cortex. PMID:26388780

  14. Emergence of learned categorical representations within an auditory forebrain circuit

    PubMed Central

    Jeanne, James M.; Thompson, Jason V.; Sharpee, Tatyana O.; Gentner, Timothy Q.

    2011-01-01

    Many learned behaviors are thought to require the activity of high-level neurons that represent categories of complex signals, such as familiar faces or native speech sounds. How these complex, experience-dependent neural responses emerge within the brain’s circuitry is not well understood. The caudomedial mesopallium (CMM), a secondary auditory region in the songbird brain, contains neurons that respond to specific combinations of song components and respond preferentially to the songs that birds have learned to recognize. Here, we examine the transformation of these learned responses across a broader forebrain circuit that includes the caudolateral mesopallium (CLM), an auditory region that provides input to CMM. We recorded extracellular single-unit activity in CLM and CMM in European starlings trained to recognize sets of conspecific songs and compared multiple encoding properties of neurons between these regions. We find that the responses of CMM neurons are more selective between song components, convey more information about song components, and are more variable over repeated components than the responses of CLM neurons. While learning enhances neural encoding of song components in both regions, CMM neurons encode more information about the learned categories associated with songs than CLM neurons. Collectively, these data suggest that CLM and CMM are part of a functional sensory hierarchy that is modified by learning to yield representations of natural vocal signals that are increasingly informative with respect to behavior. PMID:21325527

  15. Basal Forebrain Thermoregulatory Mechanism Modulates Auto-Regulated Sleep

    PubMed Central

    Mallick, Hruda Nanda; Kumar, Velayudhan Mohan

    2012-01-01

    Regulation of body temperature and sleep are two physiological mechanisms that are vital for our survival. Interestingly neural structures implicated in both these functions are common. These areas include the medial preoptic area (POA), the lateral POA, the ventrolateral POA, the median preoptic nucleus, and the medial septum, which form part of the basal forebrain (BF). When given a choice, rats prefer to stay at an ambient temperature of 27°C, though the maximum sleep was observed when they were placed at 30°C. Ambient temperature around 27°C should be considered as the thermoneutral temperature for rats in all sleep studies. At this temperature the diurnal oscillations of sleep and body temperature are properly expressed. The warm sensitive neurons of the POA mediate the increase in sleep at 30°C. Promotion of sleep during the rise in ambient temperature from 27 to 30°C, serve a thermoregulatory function. Autonomous thermoregulatory changes in core body temperature and skin temperature could act as an input signal to modulate neuronal activity in sleep-promoting brain areas. The studies presented here show that the neurons of the BF play a key role in regulating sleep. BF thermoregulatory system is a part of the global homeostatic sleep regulatory mechanism, which is auto-regulated. PMID:22754548

  16. Dopamine receptor gene expression by enkephalin neurons in rat forebrain

    SciTech Connect

    Le Moine, C.; Normand, E.; Guitteny, A.F.; Fouque, B.; Teoule, R.; Bloch, B. )

    1990-01-01

    In situ hybridization experiments were performed with brain sections from normal, control and haloperidol-treated rats to identify and map the cells expressing the D2 dopamine receptor gene. D2 receptor mRNA was detected with radioactive or biotinylated oligonucleotide probes. D2 receptor mRNA was present in glandular cells of the pituitary intermediate lobe and in neurons of the substantia nigra, ventral tegmental area, and forebrain, especially in caudate putamen, nucleus accumbens, olfactory tubercle, and piriform cortex. Hybridization with D2 and preproenkephalin A probes in adjacent sections, as well as combined hybridization with the two probes in the same sections, demonstrated that all detectable enkephalin neurons in the striatum contained the D2 receptor mRNA. Large neurons in caudate putamen, which were unlabeled with the preproenkephalin A probe and which may have been cholinergic, also expressed the D2 receptor gene. Haloperidol treatment (14 or 21 days) provoked an increase in mRNA content for D2 receptor and preproenkephalin A in the striatum. This suggests that the increase in D2 receptor number observed after haloperidol treatment is due to increased activity of the D2 gene. These results indicate that in the striatum, the enkephalin neurons are direct targets for dopamine liberated from mesostriatal neurons.

  17. Habituation and extinction of fear recruit overlapping forebrain structures.

    PubMed

    Furlong, Teri M; Richardson, Rick; McNally, Gavan P

    2016-02-01

    Establishing the neurocircuitry involved in inhibiting fear is important for understanding and treating anxiety disorders. To date, extinction procedures have been predominately used to examine the inhibition of learned fear, where fear is reduced to a conditioned stimulus (CS) by presenting it in the absence of the unconditioned stimulus (US). However, learned fear can also be reduced by habituation procedures where the US is presented in the absence of the CS. Here we used expression of the activity marker c-Fos in rats to compare the recruitment of several forebrain structures following fear habituation and extinction. Following fear conditioning where a tone CS was paired with a loud noise US, fear was then reduced the following day by either presentation of the CS or US alone (i.e. CS extinction or US habituation, respectively). This extinction and habituation training recruited several common structures, including infralimbic cortex, basolateral amygdala, midline thalamus and medial hypothalamus (orexin neurons). Moreover, this overlap was shared when examining the neural correlates of the expression of habituation and extinction, with common recruitment of infralimbic cortex and midline thalamus. However, there were also important differences. Specifically, acquisition of habituation was associated with greater recruitment of prelimbic cortex whereas expression of habituation was associated with greater recruitment of paraventricular thalamus. There was also less recruitment of central amygdala for habituation compared to extinction in the retention phase. These findings indicate that largely overlapping neurocircuitries underlie habituation and fear extinction and imply common mechanisms for reducing fear across different inhibitory treatments.

  18. Common modulation of limbic network activation underlies musical emotions as they unfold.

    PubMed

    Singer, Neomi; Jacoby, Nori; Lin, Tamar; Raz, Gal; Shpigelman, Lavi; Gilam, Gadi; Granot, Roni Y; Hendler, Talma

    2016-11-01

    Music is a powerful means for communicating emotions among individuals. Here we reveal that this continuous stream of affective information is commonly represented in the brains of different listeners and that particular musical attributes mediate this link. We examined participants' brain responses to two naturalistic musical pieces using functional Magnetic Resonance imaging (fMRI). Following scanning, as participants listened to the musical pieces for a second time, they continuously indicated their emotional experience on scales of valence and arousal. These continuous reports were used along with a detailed annotation of the musical features, to predict a novel index of Dynamic Common Activation (DCA) derived from ten large-scale data-driven functional networks. We found an association between the unfolding music-induced emotionality and the DCA modulation within a vast network of limbic regions. The limbic-DCA modulation further corresponded with continuous changes in two temporal musical features: beat-strength and tempo. Remarkably, this "collective limbic sensitivity" to temporal features was found to mediate the link between limbic-DCA and the reported emotionality. An additional association with the emotional experience was found in a left fronto-parietal network, but only among a sub-group of participants with a high level of musical experience (>5years). These findings may indicate two processing-levels underlying the unfolding of common music emotionality; (1) a widely shared core-affective process that is confined to a limbic network and mediated by temporal regularities in music and (2) an experience based process that is rooted in a left fronto-parietal network that may involve functioning of the 'mirror-neuron system'.

  19. Network and pharmacological mechanisms leading to epileptiform synchronization in the limbic system in vitro.

    PubMed

    Avoli, Massimo; D'Antuono, Margherita; Louvel, Jacques; Köhling, Rüdiger; Biagini, Giuseppe; Pumain, René; D'Arcangelo, Giovanna; Tancredi, Virginia

    2002-10-01

    Seizures in patients presenting with mesial temporal lobe epilepsy result from the interaction among neuronal networks in limbic structures such as the hippocampus, amygdala and entorhinal cortex. Mesial temporal lobe epilepsy, one of the most common forms of partial epilepsy in adulthood, is generally accompanied by a pattern of brain damage known as mesial temporal sclerosis. Limbic seizures can be mimicked in vitro using preparations of combined hippocampus-entorhinal cortex slices perfused with artificial cerebrospinal fluid containing convulsants or nominally zero Mg(2+), in order to produce epileptiform synchronization. Here, we summarize experimental evidence obtained in such slices from rodents. These data indicate that in control animals: (i) prolonged, NMDA receptor-dependent epileptiform discharges, resembling electrographic limbic seizures, originate in the entorhinal cortex from where they propagate to the hippocampus via the perforant path-dentate gyrus route; (ii) the initiation and maintenance of these ictal discharges is paradoxically contributed by GABA (mainly type A) receptor-mediated mechanisms; and (iii) CA3 outputs, which relay a continuous pattern of interictal discharge at approximately 1Hz, control rather than sustain ictal discharge generation in entorhinal cortex. Recent work indicates that such a control is weakened in the pilocarpine model of epilepsy (presumably as a result of CA3 cell damage). In addition, in these experiments electrographic seizure activity spreads directly to the CA1-subiculum regions through the temporoammonic pathway. Studies reviewed here indicate that these changes in network interactions, along with other mechanisms of synaptic plasticity (e.g. axonal sprouting, decreased activation of interneurons, upregulation of bursting neurons) can confer to the epileptic, damaged limbic system, the ability to produce recurrent limbic seizures as seen in patients with mesial temporal lobe epilepsy.

  20. The anatomy of extended limbic pathways in Asperger syndrome: a preliminary diffusion tensor imaging tractography study.

    PubMed

    Pugliese, Luca; Catani, Marco; Ameis, Stephanie; Dell'Acqua, Flavio; Thiebaut de Schotten, Michel; Murphy, Clodagh; Robertson, Dene; Deeley, Quinton; Daly, Eileen; Murphy, Declan G M

    2009-08-15

    It has been suggested that people with autistic spectrum disorder (ASD) have altered development (and connectivity) of limbic circuits. However, direct evidence of anatomical differences specific to white matter pathways underlying social behaviour and emotions in ASD is lacking. We used Diffusion Tensor Imaging Tractography to compare, in vivo, the microstructural integrity and age-related differences in the extended limbic pathways between subjects with Asperger syndrome and healthy controls. Twenty-four males with Asperger syndrome (mean age 23+/-12 years, age range: 9-54 years) and 42 age-matched male controls (mean age 25+/-10 years, age range: 9-54 years) were studied. We quantified tract-specific diffusivity measurements as indirect indexes of microstructural integrity (e.g. fractional anisotropy, FA; mean diffusivity, MD) and tract volume (e.g. number of streamlines) of the main limbic tracts. The dissected limbic pathways included the inferior longitudinal fasciculus, inferior frontal occipital fasciculus, uncinate, cingulum and fornix. There were no significant between-group differences in FA and MD. However, compared to healthy controls, individuals with Asperger syndrome had a significantly higher number of streamlines in the right (p=.003) and left (p=.03) cingulum, and in the right (p=.03) and left (p=.04) inferior longitudinal fasciculus. In contrast, people with Asperger syndrome had a significantly lower number of streamlines in the right uncinate (p=.02). Within each group there were significant age-related differences in MD and number of streamlines, but not FA. However, the only significant age-related between-group difference was in mean diffusivity of the left uncinate fasciculus (Z(obs)=2.05) (p=.02). Our preliminary findings suggest that people with Asperger syndrome have significant differences in the anatomy, and maturation, of some (but not all) limbic tracts.

  1. Concurrent glucocorticoid and noradrenergic activity shifts instrumental behavior from goal-directed to habitual control.

    PubMed

    Schwabe, Lars; Tegenthoff, Martin; Höffken, Oliver; Wolf, Oliver T

    2010-06-16

    Stress modulates instrumental action in favor of habitual stimulus-response processes that are insensitive to changes in outcome value and at the expense of goal-directed action-outcome processes. The neuroendocrine mechanism underlying this phenomenon is unknown. Here, we tested the hypothesis that concurrent glucocorticoid and noradrenergic activity bias instrumental behavior toward habitual performance. To this end, healthy men and women received hydrocortisone, the alpha2-adrenoceptor antagonist yohimbine or both orally before they were trained in two instrumental actions leading to two distinct food outcomes. After training, one of the outcomes was devalued by inviting participants to eat that food to satiety. A subsequent extinction test revealed whether instrumental performance was goal-directed or habitual. Participants that received hydrocortisone or yohimbine alone decreased responding to the devalued action in the extinction test, i.e., they behaved goal-directed. The combined administration of hydrocortisone and yohimbine, however, rendered participants' behavior insensitive to changes in the value of the goal (i.e., habitual). These findings demonstrate that the concerted action of glucocorticoids and noradrenergic activity shifts instrumental behavior from goal-directed to habitual control.

  2. Nortriptyline Enhances Morphine-Conditioned Place Preference in Neuropathic Rats: Role of the Central Noradrenergic System.

    PubMed

    Mi, Wenli; Wang, Shuxing; You, Zerong; Lim, Grewo; McCabe, Michael F; Kim, Hyangin; Chen, Lucy; Mao, Jianren

    2017-09-01

    Combination drug therapy is commonly used to treat chronic pain conditions such as neuropathic pain, and antidepressant is often used together with opioid analgesics. While rewarding is an intrinsic property of opioid analgesics, it is unknown whether the use of an antidepressant would influence opioid reward, which may contribute to opioid addiction. In this study, we examined whether nortriptyline (a tricyclic antidepressant and a first-line medication for neuropathic pain) would enhance the morphine rewarding property in both naive and chronic constriction sciatic nerve injury (CCI) rats. The rewarding effect of these drugs was assessed using conditioned place preference (CPP). The real-time polymerase chain reaction, western blot, and enzyme-linked immunosorbent assay analysis were used to investigate the function of central noradrenergic system. In naive rats, coadministration of nortriptyline with morphine did not change the acquisition of morphine-induced CPP. However, nortriptyline enhanced the acquisition, delayed the extinction, and augmented the reinstatement of morphine-induced CPP in CCI rats. In CCI rats treated with both nortriptyline and morphine, the expression of α2A-adrenergic receptors, norepinephrine transporter, and tyrosine hydroxylase was markedly decreased in the locus coeruleus, whereas the norepinephrine concentration in the nucleus accumbens was remarkably increased. These results demonstrate that nortriptyline enhanced morphine reward when both drugs were used to treat neuropathic pain in rats and that this behavioral phenotype is likely to be mediated by upregulation of the central noradrenergic system. These findings may have implications in opioid therapy commonly used for chronic pain management.

  3. Blood--brain barrier sodium/potassium pump: modulation by central noradrenergic innervation.

    PubMed

    Harik, S I

    1986-06-01

    The active transport of Na+ and K+ across the blood--brain barrier by the membrane-bound enzyme Na+/K+-activated ATPase of brain microvessel endothelial cells has a major role in the maintenance of brain water and electrolyte homeostasis. To test whether the putative noradrenergic innervation of cerebral microvessels from the nucleus locus ceruleus contributes to the regulation of Na+/K+-ATPase activity of the blood--brain barrier, specific [3H]ouabain-binding studies were performed on cerebral microvessels and crude cortical membranes obtained from Wistar rats with unilateral 6-hydroxydopamine lesion of the nucleus locus ceruleus. Such lesion depleted norepinephrine by about 90% in the ipsilateral cerebral cortex without affecting the contralateral cortex. [3H]Ouabain binding to membranes of cerebral cortex and the cerebral microvessels was specific and saturable. The maximal ouabain-binding capacity in microvessels of the ipsilateral, norepinephrine-depleted, cerebral cortex was reduced by about 40%, without change in the affinity of binding. [3H]Ouabain binding to crude membrane fractions of the cerebral cortex was not significantly affected by locus ceruleus lesion. The results suggest that Na+/K+-ATPase activity of cerebral microvessels, and the consequent transport of Na+ and K+ across the blood--brain barrier, is modulated by noradrenergic innervation from the locus ceruleus.

  4. Noradrenergic refinement of glutamatergic neuronal circuits in the lateral superior olivary nucleus before hearing onset.

    PubMed

    Hirao, Kenzo; Eto, Kei; Nakahata, Yoshihisa; Ishibashi, Hitoshi; Nagai, Taku; Nabekura, Junichi

    2015-09-01

    Neuronal circuit plasticity during development is fundamental for precise network formation. Pioneering studies of the developmental visual cortex indicated that noradrenaline (NA) is crucial for ocular dominance plasticity during the critical period in the visual cortex. Recent research demonstrated tonotopic map formation by NA during the critical period in the auditory system, indicating that NA also contributes to synaptic plasticity in this system. The lateral superior olive (LSO) in the auditory system receives glutamatergic input from the ventral cochlear nucleus (VCN) and undergoes circuit remodeling during postnatal development. LSO is innervated by noradrenergic afferents and is therefore a suitable model to study the function of NA in refinement of neuronal circuits. Chemical lesions of the noradrenergic system and chronic inhibition of α2-adrenoceptors in vivo during postnatal development in mice disrupted functional elimination and strengthening of VCN-LSO afferents. This was potentially mediated by activation of presynaptic α2-adrenoceptors and inhibition of glutamate release because NA presynaptically suppressed excitatory postsynaptic current (EPSC) through α2-adrenoceptors during the first two postnatal weeks in an in vitro study. Furthermore, NA and α2-adrenoceptor agonist induced long-term suppression of EPSCs and decreased glutamate release. These results suggest that NA has a critical role in synaptic refinement of the VCN-LSO glutamatergic pathway through failure of synaptic transmission. Because of the ubiquitous distribution of NA afferents and the extensive expression of α2-adrenoceptors throughout the immature brain, this phenomenon might be widespread in the developing central nervous system.

  5. Noradrenergic-Dopaminergic Interactions Due to DSP-4-MPTP Neurotoxin Treatments: Iron Connection.

    PubMed

    Archer, Trevor

    2016-01-01

    The investigations of noradrenergic lesions and dopaminergic lesions have established particular profiles of functional deficits and accompanying alterations of biomarkers in brain regions and circuits. In the present account, the focus of these lesions is directed toward the effects upon dopaminergic neurotransmission and expression that are associated with the movement disorders and psychosis-like behavior. In this context, it was established that noradrenergic denervation, through administration of the selective noradrenaline (NA) neurotoxin, DSP-4, should be performed prior to the depletion of dopamine (DA) with the selective neurotoxin, MPTP. Employing this regime, it was shown that (i) following DSP-4 (50 mg/kg) pretreatment of C57/Bl6 mice, both the functional and neurochemical (DA loss) effects of MPTP (2 × 20 and 2 × 40 mg/kg) were markedly exacerbated, and (ii) following postnatal iron (Fe(2+), 7.5 mg/kg, on postnatal days 19-12), pretreatment with DSP-4 followed by the lower 2 × 20 mg/kg MPTP dose induced even greater losses of motor behavior and striatal DA. As yet, the combination of NA-DA depletions, and even more so Fe(2+)-NA-DA depletion, has been considered to present a movement disorder aspect although studies exploring cognitive domains are lacking. With intrusion of iron overload into this formula, the likelihood of neuropsychiatric disorder, as well, unfolds.

  6. [Intraventricular yohimbine infusion induces noradrenergic changes in motor cerebral injured rats and enhances motor recovery].

    PubMed

    González-Piña, Rigoberto; Alfaro-Rodríguez, Alfonso; Bueno-Nava, Antonio; Ávila-Luna, Alberto

    2013-01-01

    It has been proposed that noradrenaline is one of the neurotransmitters involved in the functional recovery. In this sense, it has been proposed that the alpha-2 noradrenergic receptors play an important role in the functional reinstatement. the aim of this work was to study the role of the alpha-2 noradrenergic receptors on the noradrenaline contents in cerebellum and pons of rats iron-injured in the motor cortex. Fifteen male Wistar rats were allocated in three groups: control (n = 5) with intracortical infusion of saline (0.9%), injured (n = 5) with intracortical infusion of dextran iron and intraventricular infusion of saline, and injured + yohimbine (alpha-2 receptor antagonist; n = 5) that received an intracortical infusion of dextran iron and also an intraventricular infusion of yohimbine. Motor behavior was assessed by means of the beam-walking paradigm. Three days after surgeries, the animals were sacrificed and the left and right sides of the pons and the cerebellar hemispheres were extracted. Tissues were prepared for noradrenaline analysis by means of high performance liquid chromatography. We observed that the yohimbine-treated animals had a noradrenaline increase in the right side of the pons and a decrease in the right cerebellar hemisphere. It is concluded that the blockage of the alpha-2 receptors leads to an increase of noradrenaline in the locus coeruleus, which retards the effects of the cerebral injury.

  7. Power based association analysis (PBAT) of serotonergic and noradrenergic polymorphisms in bipolar patients with suicidal behaviour.

    PubMed

    De Luca, Vincenzo; Strauss, John; Kennedy, James L

    2008-01-01

    Suicidality is a major health concern worldwide particularly in affective disorder patients. Attempted suicide is familial. There is strong neurobiological evidence showing that serotonergic and noradrenergic dysfunction is implicated in suicidal behaviours. We will apply now a new family based association strategy aimed to explain the genetic influence in suicidal behaviour by power based association test statistics (PBAT) in 336 bipolar patients assessed for suicidality within nuclear families. By use of conditional power calculations, the approach screens all possible null hypotheses without biasing the nominal significance level, and it identifies the subset of phenotypes that has optimal power when tested for association by either univariate or multivariate family based association test (FBAT). Using this statistical approach (PBAT) we investigated polymorphisms in serotonergic and noradrenergic genes, considering suicidal behaviour severity instead of the dichotomous phenotype (presence of suicide attempt). COMT Val/Met polymorphism was not associated with suicide with high confidence (power=91%). On the other hand, the analysis of the other 12 markers in the adrenergic and serotonergic genes revealed that the TH allele tended towards association with higher severity of suicidal behaviour (p=0.060) but the power obtained was very low. The marginal finding of association between TH and severe suicidal behaviour are convergent with previous reports. On the other hand, our sample has enough power to exclude the other polymorphisms investigated as major candidate for suicidality in bipolar disorder.

  8. Association of basal forebrain volumes and cognition in normal aging.

    PubMed

    Wolf, D; Grothe, M; Fischer, F U; Heinsen, H; Kilimann, I; Teipel, S; Fellgiebel, A

    2014-01-01

    The basal forebrain cholinergic system (BFCS) is known to undergo moderate neurodegenerative alterations during normal aging and severe atrophy in Alzheimer's disease (AD). It has been suggested that functional and structural alterations of the BFCS mediate cognitive performance in normal aging and AD. But, it is still unclear to what extend age-associated cognitive decline can be related to BFCS in normal aging. We analyzed the relationship between BFCS volume and cognition using MRI and a comprehensive neuropsychological test battery in a cohort of 43 healthy elderly subjects spanning the age range from 60 to 85 years. Most notably, we found significant associations between general intelligence and BFCS volumes, specifically within areas corresponding to posterior nuclei of the nucleus basalis of Meynert (Ch4p) and the nucleus subputaminalis (NSP). Associations between specific cognitive domains and BFCS volumes were less pronounced. Supplementary analyses demonstrated that especially the volume of NSP but also the volume of Ch4p was related to the volume of widespread temporal, frontal, and parietal gray and white matter regions. Volumes of these gray and white matter regions were also related to general intelligence. Higher volumes of Ch4p and NSP may enhance the effectiveness of acetylcholine supply in related gray and white matter regions underlying general intelligence and hence explain the observed association between the volume of Ch4p as well as NSP and general intelligence. Since general intelligence is known to attenuate the degree of age-associated cognitive decline and the risk of developing late-onset AD, the BFCS might, besides the specific contribution to the pathophysiology in AD, constitute a mechanism of brain resilience in normal aging.

  9. Visualization of the medial forebrain bundle using diffusion tensor imaging

    PubMed Central

    Hana, Ardian; Hana, Anisa; Dooms, Georges; Boecher-Schwarz, Hans; Hertel, Frank

    2015-01-01

    Diffusion tensor imaging is a technique that enables physicians the portrayal of white matter tracts in vivo. We used this technique in order to depict the medial forebrain bundle (MFB) in 15 consecutive patients between 2012 and 2015. Men and women of all ages were included. There were six women and nine men. The mean age was 58.6 years (39–77). Nine patients were candidates for an eventual deep brain stimulation. Eight of them suffered from Parkinson‘s disease and one had multiple sclerosis. The remaining six patients suffered from different lesions which were situated in the frontal lobe. These were 2 metastasis, 2 meningiomas, 1 cerebral bleeding, and 1 glioblastoma. We used a 3DT1-sequence for the navigation. Furthermore T2- and DTI- sequences were performed. The FOV was 200 × 200 mm2, slice thickness 2 mm, and an acquisition matrix of 96 × 96 yielding nearly isotropic voxels of 2 × 2 × 2 mm. 3-Tesla-MRI was carried out strictly axial using 32 gradient directions and one b0-image. We used Echo-Planar-Imaging (EPI) and ASSET parallel imaging with an acceleration factor of 2. b-value was 800 s/mm2. The maximal angle was 50°. Additional scanning time was < 9 min. We were able to visualize the MFB in 12 of our patients bilaterally and in the remaining three patients we depicted the MFB on one side. It was the contralateral side of the lesion. These were 2 meningiomas and one metastasis. Portrayal of the MFB is possible for everyday routine for neurosurgical interventions. As part of the reward circuitry it might be of substantial importance for neurosurgeons during deep brain stimulation in patients with psychiatric disorders. Surgery in this part of the brain should always take the preservation of this white matter tract into account. PMID:26581828

  10. Cholinergic Neurons Excite Cortically Projecting Basal Forebrain GABAergic Neurons

    PubMed Central

    Yang, Chun; McKenna, James T.; Zant, Janneke C.; Winston, Stuart; Basheer, Radhika

    2014-01-01

    The basal forebrain (BF) plays an important role in the control of cortical activation and attention. Understanding the modulation of BF neuronal activity is a prerequisite to treat disorders of cortical activation involving BF dysfunction, such as Alzheimer's disease. Here we reveal the interaction between cholinergic neurons and cortically projecting BF GABAergic neurons using immunohistochemistry and whole-cell recordings in vitro. In GAD67-GFP knock-in mice, BF cholinergic (choline acetyltransferase-positive) neurons were intermingled with GABAergic (GFP+) neurons. Immunohistochemistry for the vesicular acetylcholine transporter showed that cholinergic fibers apposed putative cortically projecting GABAergic neurons containing parvalbumin (PV). In coronal BF slices from GAD67-GFP knock-in or PV-tdTomato mice, pharmacological activation of cholinergic receptors with bath application of carbachol increased the firing rate of large (>20 μm diameter) BF GFP+ and PV (tdTomato+) neurons, which exhibited the intrinsic membrane properties of cortically projecting neurons. The excitatory effect of carbachol was blocked by antagonists of M1 and M3 muscarinic receptors in two subpopulations of BF GABAergic neurons [large hyperpolarization-activated cation current (Ih) and small Ih, respectively]. Ion substitution experiments and reversal potential measurements suggested that the carbachol-induced inward current was mediated mainly by sodium-permeable cation channels. Carbachol also increased the frequency of spontaneous excitatory and inhibitory synaptic currents. Furthermore, optogenetic stimulation of cholinergic neurons/fibers caused a mecamylamine- and atropine-sensitive inward current in putative GABAergic neurons. Thus, cortically projecting, BF GABAergic/PV neurons are excited by neighboring BF and/or brainstem cholinergic neurons. Loss of cholinergic neurons in Alzheimer's disease may impair cortical activation, in part, through disfacilitation of BF cortically

  11. Visualization of the medial forebrain bundle using diffusion tensor imaging.

    PubMed

    Hana, Ardian; Hana, Anisa; Dooms, Georges; Boecher-Schwarz, Hans; Hertel, Frank

    2015-01-01

    Diffusion tensor imaging is a technique that enables physicians the portrayal of white matter tracts in vivo. We used this technique in order to depict the medial forebrain bundle (MFB) in 15 consecutive patients between 2012 and 2015. Men and women of all ages were included. There were six women and nine men. The mean age was 58.6 years (39-77). Nine patients were candidates for an eventual deep brain stimulation. Eight of them suffered from Parkinson's disease and one had multiple sclerosis. The remaining six patients suffered from different lesions which were situated in the frontal lobe. These were 2 metastasis, 2 meningiomas, 1 cerebral bleeding, and 1 glioblastoma. We used a 3DT1-sequence for the navigation. Furthermore T2- and DTI- sequences were performed. The FOV was 200 × 200 mm(2), slice thickness 2 mm, and an acquisition matrix of 96 × 96 yielding nearly isotropic voxels of 2 × 2 × 2 mm. 3-Tesla-MRI was carried out strictly axial using 32 gradient directions and one b0-image. We used Echo-Planar-Imaging (EPI) and ASSET parallel imaging with an acceleration factor of 2. b-value was 800 s/mm(2). The maximal angle was 50°. Additional scanning time was < 9 min. We were able to visualize the MFB in 12 of our patients bilaterally and in the remaining three patients we depicted the MFB on one side. It was the contralateral side of the lesion. These were 2 meningiomas and one metastasis. Portrayal of the MFB is possible for everyday routine for neurosurgical interventions. As part of the reward circuitry it might be of substantial importance for neurosurgeons during deep brain stimulation in patients with psychiatric disorders. Surgery in this part of the brain should always take the preservation of this white matter tract into account.

  12. Mechanisms of action of CHF3381 in the forebrain

    PubMed Central

    Barbieri, Mario; Bregola, Gianni; Buzzi, Andrea; Marino, Silvia; Zucchini, Silvia; Stables, James P; Bergamaschi, Marco; Pietra, Claudio; Villetti, Gino; Simonato, Michele

    2003-01-01

    Aim of this study was to gain insight into the mechanism of action of CHF3381, a novel putative antiepileptic and neuroprotective drug. CHF3381 blocked NMDA currents in primary cultures of cortical neurons: maximal effect was nearly −80% of the NMDA-evoked current, with EC50 of approximately 5 μM. This effect was selective, reversible, use-dependent and elicited at the concentrations reached in the rodent brain after peripheral administration of therapeutic doses. CHF3381 also inhibited voltage-gated Na+ currents in an apparently voltage-dependent manner. However, this effect could be obtained only at relatively high concentrations (100 μM). Consistent with the mild effects on voltage-gated Na+ channels, CHF3381 (100 μM) failed to affect electrical stimulation-evoked glutamate overflow in hippocampal slices. In contrast, the anti-convulsant agent and Na+ channel blocker lamotrigine (100 μM) inhibited stimulation-evoked glutamate overflow by approximately 50%. CHF3381 reduced kindled seizure-induced c-fos mRNA levels within the same brain regions, and to a similar level, as the selective NMDA receptor antagonist MK801, providing circumstantial evidence to the idea that CHF3381 blocks NMDA receptors in vivo. The present mechanistic studies suggest that the primary mechanism of action of CHF3381 in the forebrain is blockade of NMDA receptors. On this basis, this compound may have a potential use in other diseases caused by or associated with a pathologically high level of NMDA receptor activation. PMID:12890713

  13. Glucocorticoids interact with noradrenergic activation at encoding to enhance long-term memory for emotional material in women.

    PubMed

    Segal, S K; Simon, R; McFarlin, S; Alkire, M; Desai, A; Cahill, L F

    2014-09-26

    Evidence from the animal literature suggests that post-training glucocorticoids (GCs) interact with noradrenergic activation at acquisition to enhance memory consolidation for emotional stimuli. While there is evidence that GCs enhance memory for emotional material in humans, the extent to which this depends on noradrenergic activation at encoding has not been explored. In this study, 20-mg hydrocortisone was administered to healthy young women (18-35 yrs old) in a double-blind fashion 10 min prior to viewing a series of emotional and neutral images. Saliva samples were taken at baseline, 10 min after drug or placebo administration, immediately after viewing the images, 10, 20, and 30 min after viewing the images. Participants returned 1 week later for a surprise recall test. Results suggest that, hydrocortisone administration resulted in emotional memory enhancement only in participants who displayed an increase in endogenous noradrenergic activation, measured via salivary alpha-amylase at encoding. These results support findings in the animal literature, and suggest that GC-induced memory enhancement relies on noradrenergic activation at encoding in women.

  14. Disrupting spinal noradrenergic activation delays recovery of acute incision induced hypersensitivity and increases spinal glial activation in the rat

    PubMed Central

    Arora, Vipin; Morado-Urbina, Carlos Eduardo; Aschenbrenner, Carol A.; Hayashida, Ken-ichiro; Wang, FuZhou; Martin, Thomas J.; Eisenach, James C.; Peters, Christopher M.

    2016-01-01

    Clinical studies suggest that descending inhibitory controls from the brainstem are important for speeding recovery from pain following surgery. We examined the effects of destroying spinally projecting noradrenergic neurons via intrathecally administered antibody to dopamine β-hydroxylase conjugated to saporin (DβH-saporin) on recovery in an acute incisional pain model. Mechanical and thermal paw withdrawal thresholds and non-evoked spontaneous guarding scores were tested for several weeks postoperatively and analyzed using mixed effects growth curve modeling. DβH-saporin treatment resulted in a significant prolongation in the duration of mechanical and to a lesser degree thermal hypersensitivity in the ipsilateral paw of incised rats but did not increase the duration of spontaneous guarding. DβH-saporin treatment was also associated with increased microglial and astrocyte activation in the ipsilateral spinal cord 21 days post-incision compared to IgG-saporin treated controls. Chronic intrathecal administration of the α2 adrenergic receptor antagonist atipamezole (50-200 μg/day) produced similar effects. These data suggest that spinally projecting noradrenergic pathways and spinal α2 adrenergic receptor activation are important for speeding recovery from hypersensitivity following surgical incision possibly by reducing spinal glial activation. Interventions that augment the noradrenergic system may be important to speed recovery from pain after surgery. Perspective Endogenous descending spinal noradrenergic activation promotes resolution of incision induced hypersensitivity and inhibits spinal microglial and astrocyte activation in part through α2 adrenergic receptors. PMID:26545342

  15. Glutamate input to noradrenergic neurons plays an essential role in the development of morphine dependence and psychomotor sensitization.

    PubMed

    Parkitna, Jan Rodriguez; Solecki, Wojciech; Gołembiowska, Krystyna; Tokarski, Krzysztof; Kubik, Jakub; Gołda, Sławomir; Novak, Martin; Parlato, Rosanna; Hess, Grzegorz; Sprengel, Rolf; Przewłocki, Ryszard

    2012-11-01

    The brain's noradrenergic system is involved in the development of behaviours induced by drugs of abuse, e.g. dependence and withdrawal, and also reward or psychomotor effects. To investigate how noradrenergic system activity is controlled in the context associated with drug-induced behaviours, we generated a Cre/loxP mouse model in which the essential glutamate NMDA receptor subunit NR1 is ablated in cells expressing dopamine β-hydroxylase (Dbh). As a result, the noradrenergic cells in NR1DbhCre mice lack the NMDA receptor-dependent component of excitatory post-synaptic currents. The mutant mice displayed no obvious behavioural alterations, had unchanged noradrenaline content and mild increase in dopamine levels in the nucleus accumbens. Interestingly, NR1DbhCre animals did not develop morphine-induced psychomotor sensitization. However, when the morphine injections were preceded by treatment with RX821002, an antagonist of α2-adrenergic receptors, the development of sensitization was restored. Conversely, pretreatment with clonidine, an agonist of α2-adrenergic receptors, blocked development of sensitization in wild-type mice. We also found that while the development of tolerance to morphine was normal in mutant mice, withdrawal symptoms were attenuated. These data reveal that NMDA receptors on noradrenergic neurons regulate development of opiate dependence and psychomotor sensitization, by controlling drug-induced noradrenaline signalling.

  16. Effects of the noradrenergic neurotoxin DSP-4 on the expression of α1-adrenoceptor subtypes after antidepressant treatment.

    PubMed

    Kreiner, Grzegorz; Zelek-Molik, Agnieszka; Kowalska, Marta; Bielawski, Adam; Antkiewicz-Michaluk, Lucyna; Nalepa, Irena

    2011-01-01

    We have previously reported that chronic imipramine and electroconvulsive treatments increase the α(1A)-adrenoceptor (but not the α(1B) subtype) mRNA level and the receptor density in the rat cerebral cortex. Furthermore, we have also shown that chronic treatment with citalopram does not affect the expression of either the α(1A)- or the α(1B)-adrenoceptor, indicating that the previously observed up-regulation of α(1A)-adrenoceptor may depend on the noradrenergic component of the pharmacological mechanism of action of these antidepressants. Here, we report that previous noradrenergic depletion with DSP-4 (50 mg/kg) (a neurotoxin selective for the noradrenergic nerve terminals) significantly attenuated the increase of α(1A)-adrenoceptor mRNA induced by a 14-day treatment with imipramine (IMI, 20 mg/kg, ip) and abolished the effect of electroconvulsive shock (ECS, 150 mA, 0.5 s) in the prefrontal cortex of the rat brain. The changes in the receptor protein expression (as reflected by its density) that were induced by IMI and ECS treatments were differently modulated by DSP-4 lesioning, and only the ECS-induced increase in α(1A)-adrenoceptor level was abolished. This study provides further evidence corroborating our initial hypothesis that the noradrenergic component of the action of antidepressant agents plays an essential role in the modulation of α(1A)-adrenoceptor in the rat cerebral cortex.

  17. Both a Nicotinic Single Nucleotide Polymorphism (SNP) and a Noradrenergic SNP Modulate Working Memory Performance when Attention Is Manipulated

    ERIC Educational Resources Information Center

    Greenwood, Pamela M.; Sundararajan, Ramya; Lin, Ming-Kuan; Kumar, Reshma; Fryxell, Karl J.; Parasuraman, Raja

    2009-01-01

    We investigated the relation between the two systems of visuospatial attention and working memory by examining the effect of normal variation in cholinergic and noradrenergic genes on working memory performance under attentional manipulation. We previously reported that working memory for location was impaired following large location precues,…

  18. Both a Nicotinic Single Nucleotide Polymorphism (SNP) and a Noradrenergic SNP Modulate Working Memory Performance when Attention Is Manipulated

    ERIC Educational Resources Information Center

    Greenwood, Pamela M.; Sundararajan, Ramya; Lin, Ming-Kuan; Kumar, Reshma; Fryxell, Karl J.; Parasuraman, Raja

    2009-01-01

    We investigated the relation between the two systems of visuospatial attention and working memory by examining the effect of normal variation in cholinergic and noradrenergic genes on working memory performance under attentional manipulation. We previously reported that working memory for location was impaired following large location precues,…

  19. Clinically Anxious Individuals Show Disrupted Feedback between Inferior Frontal Gyrus and Prefrontal-Limbic Control Circuit.

    PubMed

    Cha, Jiook; DeDora, Daniel; Nedic, Sanja; Ide, Jaime; Greenberg, Tsafrir; Hajcak, Greg; Mujica-Parodi, Lilianne Rivka

    2016-04-27

    Clinical anxiety is associated with generalization of conditioned fear, in which innocuous stimuli elicit alarm. Using Pavlovian fear conditioning (electric shock), we quantify generalization as the degree to which subjects' neurobiological responses track perceptual similarity gradients to a conditioned stimulus. Previous studies show that the ventromedial prefrontal cortex (vmPFC) inversely and ventral tegmental area directly track the gradient of perceptual similarity to the conditioned stimulus in healthy individuals, whereas clinically anxious individuals fail to discriminate. Here, we extend this work by identifying specific functional roles within the prefrontal-limbic circuit. We analyzed fMRI time-series acquired from 57 human subjects during a fear generalization task using entropic measures of circuit-wide regulation and feedback (power spectrum scale invariance/autocorrelation), in combination with structural (diffusion MRI-probabilistic tractography) and functional (stochastic dynamic causal modeling) measures of prefrontal-limbic connectivity within the circuit. Group comparison and correlations with anxiety severity across 57 subjects revealed dysregulatory dynamic signatures within the inferior frontal gyrus (IFG), which our prior work has linked to impaired feedback within the circuit. Bayesian model selection then identified a fully connected prefrontal-limbic model comprising the IFG, vmPFC, and amygdala. Dysregulatory IFG dynamics were associated with weaker reciprocal excitatory connectivity between the IFG and the vmPFC. The vmPFC exhibited inhibitory influence on the amygdala. Our current results, combined with our previous work across a threat-perception spectrum of 137 subjects and a meta-analysis of 366 fMRI studies, dissociate distinct roles for three prefrontal-limbic regions, wherein the IFG provides evaluation of stimulus meaning, which then informs the vmPFC in inhibiting the amygdala. Affective neuroscience has generally treated

  20. Orexin A-induced enhancement of attentional processing in rats: role of basal forebrain neurons

    PubMed Central

    Zajo, Kristin N.; Fadel, Jim R.; Burk, Joshua A.

    2015-01-01

    Rationale Orexins are neuropeptides released in multiple brain regions from neurons that originate within the lateral hypothalamus and contiguous perfornical area. The basal forebrain, a structure implicated in attentional processing, receives orexinergic inputs. Our previous work demonstrated that administration of an orexin-1 receptor antagonist, SB-334867, systemically or via infusion directly into the basal forebrain, can disrupt performance in a task that places explicit demands on attentional processing. Objectives Given that the orexin-1 receptor binds orexin A with high affinity, we tested whether orexin A could enhance attention in rats. Methods Attentional performance was assessed using a task that required discrimination of variable duration visual signals from trials when no signal was presented. We also tested whether infusions of orexin A into the lateral ventricle could attenuate deficits following lesions of medial prefrontal cortical cholinergic projections that arise from the basal forebrain. Results Infusions of orexin A into the basal forebrain attenuated distracter-induced decreases in attentional performance. Orexin A attenuated deficits in lesioned animals when a visual distracter was presented. Conclusion The present results support the view that orexin A can enhance attentional performance via actions in the basal forebrain and may be beneficial for some conditions characterized by attentional dysfunction due to disruption of cortical cholinergic inputs. PMID:26534765

  1. Brain atrophy in primary progressive aphasia involves the cholinergic basal forebrain and Ayala’s nucleus

    PubMed Central

    Teipel, Stefan J.; Flatz, Wilhelm; Ackl, Nibal; Grothe, Michel; Kilimann, Ingo; Bokde, Arun L.W.; Grinberg, Lea; Amaro, Edson; Kljajevic, Vanja; Alho, Eduardo; Knels, Christina; Ebert, Anne; Heinsen, Helmut; Danek, Adrian

    2014-01-01

    Primary progressive aphasia (PPA) is characterized by left hemispheric frontotemporal cortical atrophy. Evidence from anatomical studies suggests that the nucleus subputaminalis (NSP), a subnucleus of the cholinergic basal forebrain, may be involved in the pathological process of PPA. Therefore, we studied the pattern of cortical and basal forebrain atrophy in 10 patients with a clinical diagnosis of PPA and 18 healthy age-matched controls using high-resolution magnetic resonance imaging (MRI). We determined the cholinergic basal forebrain nuclei according to Mesulam’s nomenclature and the NSP in MRI reference space based on histological sections and the MRI scan of a post-mortem brain in cranio. Using voxel-based analysis, we found left hemispheric cortical atrophy in PPA patients compared with controls, including prefrontal, lateral temporal and medial temporal lobe areas. We detected cholinergic basal forebrain atrophy in left predominant localizations of Ch4p, Ch4am, Ch4al, Ch3 and NSP. For the first time, we have described the pattern of basal forebrain atrophy in PPA and confirmed the involvement of NSP that had been predicted based on theoretical considerations. Our findings may enhance understanding of the role of cholinergic degeneration for the regional specificity of the cortical destruction leading to the syndrome of PPA. PMID:24434193

  2. Consequential apoptosis in the cerebellum following injury to the developing rat forebrain.

    PubMed

    Taylor, Deanna L; Joashi, Umesh C; Sarraf, Catherine; Edwards, A David; Mehmet, Huseyin

    2006-07-01

    In focal brain lesions, alterations in blood flow and cerebral metabolism can be detected in brain areas remote from the primary injury. The cellular consequences of this phenomenon, originally termed diaschisis, are not fully understood. Here, we report that in two distinct models of forebrain injury, neuronal death in the cerebellum, a site distant to the primary injury, results as consequence of neuronal loss in the forebrain. Fourteen-day-old rats were subjected to unilateral forebrain injury, achieved by either hypoxia-ischemia (right carotid artery ligation and hypoxia) or direct needle injury to brain tissue. At defined times after injury, the presence of apoptosis was investigated by cell morphology, in situ end labeling, electron microscopy and poly-ADP-ribose polymerase (PARP) cleavage. Injury to the rat forebrain following hypoxia-ischemia increased apoptosis in the internal granular and Purkinje cell layers of the cerebellum, a site distant to that of the primary injury. The number of apoptotic cells in the cerebellum was significantly related to cell death in the hippocampus. Similarly, direct needle injury to the forebrain resulted in extensive apoptotic cell death in the cerebellum. These results emphasize the intimate relationship between defined neuronal populations in relatively distant brain areas and suggest a cellular basis for diaschisis.

  3. Prosomeric map of the lamprey forebrain based on calretinin immunocytochemistry, Nissl stain, and ancillary markers.

    PubMed

    Pombal, M A; Puelles, L

    1999-11-22

    The structural organization of the lamprey extratelencephalic forebrain is re-examined from the perspective of the prosomeric segmental paradigm. The question asked was whether the prosomeric forebrain model used for gnathostomes is of material advantage for interpreting subdivisions in the lamprey forebrain. To this aim, the main longitudinal and transverse landmarks recognized by the prosomeric model in other vertebrates were identified in Nissl-stained lamprey material. Lines of cytoarchitectural discontinuity and contours of migrated neuronal groups were mapped in a two-dimensional sagittal representation and were also classified according to their radial position. Immunocytochemical mapping of calretinin expression in adjacent sections served to define particular structural units better, in particular, the dorsal thalamus. These data were complemented by numerous other chemoarchitectonic observations obtained with ancillary markers, which identified additional specific formations, subdivisions, or boundaries. Emphasis was placed on studying whether such chemically defined neuronal groups showed boundaries aligned with the postulated inter- or intraprosomeric boundaries. The course of diverse axonal tracts was studied also with regard to their prosomeric topography. This analysis showed that the full prosomeric model applies straightforwardly to the lamprey forebrain. This finding implies that a common segmental and longitudinal organization of the neural tube may be primitive for all vertebrates. Interesting novel aspects appear in the interpretation of the lamprey pretectum, the dorsal and ventral thalami, and the hypothalamus. The topologic continuity of the prosomeric forebrain regions with evaginated or non-evaginated portions of the telencephalon was also examined.

  4. Ilex paraguariensis Promotes Orofacial Pain Relief After Formalin Injection: Involvement of Noradrenergic Pathway

    PubMed Central

    de Carvalho, Eudislaine Fonseca; de Oliveira, Simone Kobe; Nardi, Viviane Koepp; Gelinski, Tathiana Carla; Bortoluzzi, Marcelo Carlos; Maraschin, Marcelo; Nardi, Geisson Marcos

    2016-01-01

    Background: Drinking mate or chimarrão, a hot infusion of Ilex paraguariensis (ILEX) leaves, is a common habit in Southern South America that has a social and almost ritualistic role. It has been used as a stimulant beverage in South America and analgesic in regions of Argentina for treatment of headache and others painful inflammatory conditions such as arthritis and rheumatism. Objective: The aim of this study was to evaluate the pharmacological activity of I. paraguariensis infusion (ILEX) on orofacial nociception model induced by formalin, and study its mechanism of action. Materials and Methods: The analgesic effect of ILEX was assessed through writhing test, paw formalin test, paw edema induced by carrageenan, and orofacial pain induced by formalin. To study the action mechanism of ILEX, opioidergic, dopaminergic, nitrergic, and adrenergic pathways were investigated. Results: The high-performance liquid chromatography analysis of ILEX infusion revealed caffeine and theobromine. The treatment with ILEX reduced the number of writhing. However, it was effective neither in the formalin paw test nor in the paw edema induced by carrageenan. Different from formalin paw test, ILEX was able to reduce the orofacial reactivity to formalin in 31.8% (70.4 ± 2.5 s; first phase), and 20% (127.3 ± 18.9 s; second phase). The analgesic effect of ILEX results from the modulation of noradrenergic pathways since prazosin (α1-adrenoceptor antagonist, 0.15 mg/kg; intraperitoneal) reversed the analgesic effect of ILEX. Conclusions: The present report demonstrates that analgesic effect of ILEX in orofacial formalin test is due mainly to modulation of noradrenergic pathways. SUMMARY Ilex paraguariensis (ILEX) has been used as a stimulant beverage in South America and analgesic in regions of Argentina for the treatment of headache and others painful inflammatory conditions such arthritis and rheumatism.The aim of this study was to evaluate the pharmacological activity of ILEX on

  5. Ilex paraguariensis Promotes Orofacial Pain Relief After Formalin Injection: Involvement of Noradrenergic Pathway.

    PubMed

    de Carvalho, Eudislaine Fonseca; de Oliveira, Simone Kobe; Nardi, Viviane Koepp; Gelinski, Tathiana Carla; Bortoluzzi, Marcelo Carlos; Maraschin, Marcelo; Nardi, Geisson Marcos

    2016-03-01

    Drinking mate or chimarrão, a hot infusion of Ilex paraguariensis (ILEX) leaves, is a common habit in Southern South America that has a social and almost ritualistic role. It has been used as a stimulant beverage in South America and analgesic in regions of Argentina for treatment of headache and others painful inflammatory conditions such as arthritis and rheumatism. The aim of this study was to evaluate the pharmacological activity of I. paraguariensis infusion (ILEX) on orofacial nociception model induced by formalin, and study its mechanism of action. The analgesic effect of ILEX was assessed through writhing test, paw formalin test, paw edema induced by carrageenan, and orofacial pain induced by formalin. To study the action mechanism of ILEX, opioidergic, dopaminergic, nitrergic, and adrenergic pathways were investigated. The high-performance liquid chromatography analysis of ILEX infusion revealed caffeine and theobromine. The treatment with ILEX reduced the number of writhing. However, it was effective neither in the formalin paw test nor in the paw edema induced by carrageenan. Different from formalin paw test, ILEX was able to reduce the orofacial reactivity to formalin in 31.8% (70.4 ± 2.5 s; first phase), and 20% (127.3 ± 18.9 s; second phase). The analgesic effect of ILEX results from the modulation of noradrenergic pathways since prazosin (α1-adrenoceptor antagonist, 0.15 mg/kg; intraperitoneal) reversed the analgesic effect of ILEX. The present report demonstrates that analgesic effect of ILEX in orofacial formalin test is due mainly to modulation of noradrenergic pathways. Ilex paraguariensis (ILEX) has been used as a stimulant beverage in South America and analgesic in regions of Argentina for the treatment of headache and others painful inflammatory conditions such arthritis and rheumatism.The aim of this study was to evaluate the pharmacological activity of ILEX on orofacial nociception model induced by formalin, and study its mechanism of

  6. Stimulation of the Noradrenergic System during Memory Formation Impairs Extinction Learning but not the Disruption of Reconsolidation

    PubMed Central

    Soeter, Marieke; Kindt, Merel

    2012-01-01

    The noradrenergic system plays a critical role in the ‘consolidation' of emotional memory. If we are to target ‘reconsolidation' in patients with anxiety disorders, the noradrenergic strengthening of fear memory should not impair the disruption of reconsolidation. In Experiment I, we addressed this issue using a differential fear conditioning procedure allowing selective reactivation of one of two fear associations. First, we strengthened fear memory by administering an α2-adrenergic receptor antagonist (ie, yohimbine HCl; double-blind placebo-controlled study) 30 min before acquisition (time for peak value yohimbine HCl <1 h). Next, the reconsolidation of one of the fear associations was manipulated by administering a β-adrenergic receptor antagonist (ie, propranolol HCl) 90 min before its selective reactivation (time for peak value propranolol HCl <2 h). In Experiment II, we administered propranolol HCl after reactivation of the memory to rule out a possible effect of the pharmacological manipulation on the memory retrieval itself. The excessive release of noradrenaline during memory formation not only delayed the process of extinction 48 h later, but also triggered broader fear generalization. Yet, the β-adrenergic receptor blocker during reconsolidation selectively ‘neutralized' the fear-arousing aspects of the noradrenergic-strengthened memory and undermined the generalization of fear. We observed a similar reduction in fear responding when propranolol HCl was administered after reactivation of the memory. The present findings demonstrate the involvement of noradrenergic modulation in the formation as well as generalization of human fear memory. Given that the noradrenergic strengthening of fear memory impaired extinction learning but not the disruption of reconsolidation, our findings may have implications for the treatment of anxiety disorders. PMID:22169947

  7. Optogenetic stimulation of cholinergic brainstem neurons during focal limbic seizures: Effects on cortical physiology.

    PubMed

    Furman, Moran; Zhan, Qiong; McCafferty, Cian; Lerner, Benjamin A; Motelow, Joshua E; Meng, Jin; Ma, Chanthia; Buchanan, Gordon F; Witten, Ilana B; Deisseroth, Karl; Cardin, Jessica A; Blumenfeld, Hal

    2015-12-01

    Focal temporal lobe seizures often cause impaired cortical function and loss of consciousness. Recent work suggests that the mechanism for depressed cortical function during focal seizures may depend on decreased subcortical cholinergic arousal, which leads to a sleep-like state of cortical slow-wave activity. To test this hypothesis, we sought to directly activate subcortical cholinergic neurons during focal limbic seizures to determine the effects on cortical function. Here we used an optogenetic approach to selectively stimulate cholinergic brainstem neurons in the pedunculopontine tegmental nucleus during focal limbic seizures induced in a lightly anesthetized rat model. We found an increase in cortical gamma activity and a decrease in delta activity in response to cholinergic stimulation. These findings support the mechanistic role of reduced subcortical cholinergic arousal in causing cortical dysfunction during seizures. Through further work, electrical or optogenetic stimulation of subcortical arousal networks may ultimately lead to new treatments aimed at preventing cortical dysfunction during seizures.

  8. Limbic Metabolic Abnormalities in Remote Traumatic Brain Injury and Correlation With Psychiatric Morbidity and Social Functioning

    PubMed Central

    Capizzano, Arístides A.; Jorge, Ricardo E.; Robinson, Robert G.

    2013-01-01

    The aim of this study was to investigate limbic metabolic abnormalities in remote traumatic brain injury (TBI) and their psychiatric correlates. Twenty patients and 13 age-matched comparison subjects received complete psychiatric evaluation and brain MRI and MR spectroscopy at 3 Tesla. Patients had reduced NAA to creatine ratio in the left hippocampus relative to comparison subjects (mean=1.3 [SD=0.21] compared with mean=1.55 [SD=0.21]; F=10.73, df=1, 30, p=0.003), which correlated with the Social Functioning Examination scores (rs=−0.502, p=0.034). Furthermore, patients with mood disorders had reduced NAA to creatine ratio in the left cingulate relative to patients without mood disorders (1.47 compared with 1.68; F=3.393, df=3, 19, p=0.044). Remote TBI displays limbic metabolic abnormalities, which correlate to social outcome and psychiatric status. PMID:21037120

  9. The role of the periaqueductal grey in limbic and neocortical vocal fold control.

    PubMed

    Jürgens, U; Zwirner, P

    1996-11-25

    The effects of a pharmacological blockade of the periaqueductal grey of the midbrain (PAG) on the elicitability of vocal fold movements from the facial motor cortex on the one hand and the anterior cingulate cortex and dorsomedial hypothalamus on the other were studied in the squirrel monkey. PAG blockade abolished vocal fold activity induced by the cingulate cortex and hypothalamus, but not that induced by the neocortex. These results point to the existence of two separate vocal fold control pathways at midbrain level: one limbic, responsible for non-verbal emotional vocal utterances, and one neocortical, responsible for the production of learned vocal patterns. The PAG represents a crucial relay station of the limbic but not the neocortical vocal control pathway.

  10. Limbic, associative, and motor territories within the targets for deep brain stimulation: potential clinical implications.

    PubMed

    Sudhyadhom, Atchar; Bova, Frank J; Foote, Kelly D; Rosado, Christian A; Kirsch-Darrow, Lindsey; Okun, Michael S

    2007-07-01

    The use of deep brain stimulation (DBS) has recently been expanding for the treatment of many neurologic disorders such as Parkinson disease, dystonia, essential tremor, Tourette's syndrome, cluster headache, epilepsy, depression, and obsessive compulsive disorder. The target structures for DBS include specific segregated territories within limbic, associative, or motor regions of very small subnuclei. In this review, we summarize current clinical techniques for DBS, the cognitive/mood/motor outcomes, and the relevant neuroanatomy with respect to functional territories within specific brain targets. Future development of new techniques and technology that may include a more direct visualization of "motor" territories within target structures may prove useful for avoiding side effects that may result from stimulation of associative and limbic regions. Alternatively, newer procedures may choose and specifically target non-motor territories for chronic electrical stimulation.

  11. Gut-brain peptides in corticostriatal-limbic circuitry and alcohol use disorders

    PubMed Central

    Vadnie, Chelsea A.; Park, Jun Hyun; Abdel Gawad, Noha; Ho, Ada Man Choi; Hinton, David J.; Choi, Doo-Sup

    2014-01-01

    Peptides synthesized in endocrine cells in the gastrointestinal tract and neurons are traditionally considered regulators of metabolism, energy intake, and appetite. However, recent work has demonstrated that many of these peptides act on corticostriatal-limbic circuitry and, in turn, regulate addictive behaviors. Given that alcohol is a source of energy and an addictive substance, it is not surprising that increasing evidence supports a role for gut-brain peptides specifically in alcohol use disorders (AUD). In this review, we discuss the effects of several gut-brain peptides on alcohol-related behaviors and the potential mechanisms by which these gut-brain peptides may interfere with alcohol-induced changes in corticostriatal-limbic circuitry. This review provides a summary of current knowledge on gut-brain peptides focusing on five peptides: neurotensin, glucagon-like peptide 1, ghrelin, substance P, and neuropeptide Y. Our review will be helpful to develop novel therapeutic targets for AUD. PMID:25278825

  12. The Limbic-Prefrontal Network Modulated by Electroacupuncture at CV4 and CV12

    PubMed Central

    Fang, Jiliang; Wang, Xiaoling; Liu, Hesheng; Wang, Yin; Zhou, Kehua; Hong, Yang; Liu, Jun; Wang, Lei; Xue, Chao; Song, Ming; Liu, Baoyan; Zhu, Bing

    2012-01-01

    fMRI studies showed that acupuncture could induce hemodynamic changes in brain networks. Many of these studies focused on whether specific acupoints could activate specific brain regions and were often limited to manual acupuncture at acupoints on the limbs. In this fMRI study, we investigated acupuncture's modulation effects on brain functional networks by electroacupuncture (EA) at acupoints on the midline of abdomen. Acupoints Guanyuan (CV4) and Zhongwan (CV12) were stimulated in 21 healthy volunteers. The needling sensations, brain activation, and functional connectivity were studied. We found that the limbic-prefrontal functional network was deactivated by EA at CV4 and CV12. More importantly, the local functional connectivity was significantly changed during EA stimulation, and the change persisted during the period after the stimulation. Although minor differences existed, both acupoints similarly modulated the limbic-prefrontal functional network, which is overlapped with the functional circuits associated with emotional and cognitive regulation. PMID:22291848

  13. A Primary Role for Nucleus Accumbens and Related Limbic Network in Vocal Tics.

    PubMed

    McCairn, Kevin W; Nagai, Yuji; Hori, Yukiko; Ninomiya, Taihei; Kikuchi, Erika; Lee, Ju-Young; Suhara, Tetsuya; Iriki, Atsushi; Minamimoto, Takafumi; Takada, Masahiko; Isoda, Masaki; Matsumoto, Masayuki

    2016-01-20

    Inappropriate vocal expressions, e.g., vocal tics in Tourette syndrome, severely impact quality of life. Neural mechanisms underlying vocal tics remain unexplored because no established animal model representing the condition exists. We report that unilateral disinhibition of the nucleus accumbens (NAc) generates vocal tics in monkeys. Whole-brain PET imaging identified prominent, bilateral limbic cortico-subcortical activation. Local field potentials (LFPs) developed abnormal spikes in the NAc and the anterior cingulate cortex (ACC). Vocalization could occur without obvious LFP spikes, however, when phase-phase coupling of alpha oscillations were accentuated between the NAc, ACC, and the primary motor cortex. These findings contrasted with myoclonic motor tics induced by disinhibition of the dorsolateral putamen, where PET activity was confined to the ipsilateral sensorimotor system and LFP spikes always preceded motor tics. We propose that vocal tics emerge as a consequence of dysrhythmic alpha coupling between critical nodes in the limbic and motor networks. VIDEO ABSTRACT.

  14. Diurnal cortisol amplitude and fronto-limbic activity in response to stressful stimuli.

    PubMed

    Cunningham-Bussel, Amy C; Root, James C; Butler, Tracy; Tuescher, Oliver; Pan, Hong; Epstein, Jane; Weisholtz, Daniel S; Pavony, Michelle; Silverman, Michael E; Goldstein, Martin S; Altemus, Margaret; Cloitre, Marylene; Ledoux, Joseph; McEwen, Bruce; Stern, Emily; Silbersweig, David

    2009-06-01

    The development and exacerbation of many psychiatric and neurologic conditions are associated with dysregulation of the hypothalamic pituitary adrenal (HPA) axis as measured by aberrant levels of cortisol secretion. Here we report on the relationship between the amplitude of diurnal cortisol secretion, measured across 3 typical days in 18 healthy individuals, and blood oxygen level dependant (BOLD) response in limbic fear/stress circuits, elicited by in-scanner presentation of emotionally negative stimuli, specifically, images of the World Trade Center (WTC) attack. Results indicate that subjects who secrete a greater amplitude of cortisol diurnally demonstrate less brain activation in limbic regions, including the amygdala and hippocampus/parahippocampus, and hypothalamus during exposure to traumatic WTC-related images. Such initial findings can begin to link our understanding, in humans, of the relationship between the diurnal amplitude of a hormone integral to the stress response, and those neuroanatomical regions that are implicated as both modulating and being modulated by that response.

  15. Opposing regulation of dopaminergic activity and exploratory motor behavior by forebrain and brainstem cholinergic circuits.

    PubMed

    Patel, Jyoti C; Rossignol, Elsa; Rice, Margaret E; Machold, Robert P

    2012-01-01

    Dopamine transmission is critical for exploratory motor behaviour. A key regulator is acetylcholine; forebrain acetylcholine regulates striatal dopamine release, whereas brainstem cholinergic inputs regulate the transition of dopamine neurons from tonic to burst firing modes. How these sources of cholinergic activity combine to control dopamine efflux and exploratory motor behaviour is unclear. Here we show that mice lacking total forebrain acetylcholine exhibit enhanced frequency-dependent striatal dopamine release and are hyperactive in a novel environment, whereas mice lacking rostral brainstem acetylcholine are hypoactive. Exploratory motor behaviour is normalized by the removal of both cholinergic sources. Involvement of dopamine in the exploratory motor phenotypes observed in these mutants is indicated by their altered sensitivity to the dopamine D2 receptor antagonist raclopride. These results support a model in which forebrain and brainstem cholinergic systems act in tandem to regulate striatal dopamine signalling for proper control of motor activity.

  16. Cortico-limbic connectivity in MAOA-L carriers is vulnerable to acute tryptophan depletion.

    PubMed

    Eisner, Patrick; Klasen, Martin; Wolf, Dhana; Zerres, Klaus; Eggermann, Thomas; Eisert, Albrecht; Zvyagintsev, Mikhail; Sarkheil, Pegah; Mathiak, Krystyna A; Zepf, Florian; Mathiak, Klaus

    2017-03-01

    A gene-environment interaction between expression genotypes of the monoamine oxidase A (MAOA) and adverse childhood experience increases the risk of antisocial behavior. However, the neural underpinnings of this interaction remain uninvestigated. A cortico-limbic circuit involving the prefrontal cortex (PFC) and the amygdala is central to the suppression of aggressive impulses and is modulated by serotonin (5-HT). MAOA genotypes may modulate the vulnerability of this circuit and increase the risk for emotion regulation deficits after specific life events. Acute tryptophan depletion (ATD) challenges 5-HT regulation and may identify vulnerable neuronal circuits, contributing to the gene-environment interaction. Functional magnetic resonance imaging measured the resting-state state activity in 64 healthy males in a double-blind, placebo-controlled study. Cortical maps of amygdala correlation identified the impact of ATD and its interaction with low- (MAOA-L) and high-expression variants (MAOA-H) of MAOA on cortico-limbic connectivity. Across all Regions of Interest (ROIs) exhibiting an ATD effect on cortico-limbic connectivity, MAOA-L carriers were more susceptible to ATD than MAOA-H carriers. In particular, the MAOA-L group exhibited a larger reduction of amygdala connectivity with the right prefrontal cortex and a larger increase of amygdala connectivity with the insula and dorsal PCC. MAOA-L carriers were more susceptable to a central 5-HT challenge in cortico-limbic networks. Such vulnerability of the cortical serotonergic system may contribute to the emergence of antisocial behavior after systemic challenges, observed as gene-environment interaction. Hum Brain Mapp 38:1622-1635, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  17. Opposing roles of nucleus accumbens core and shell dopamine in the modulation of limbic information processing

    PubMed Central

    Ito, Rutsuko; Hayen, Anja

    2011-01-01

    The dopaminergic innervation of the nucleus accumbens (NAc) is implicated in the selection and integration of motivationally relevant cortico-limbic information that governs behavioral output. However, it is unknown if the dopaminergic innervations of two anatomically distinct subregions of the NAc, core and shell, have differential roles in this gating process, and whether dopaminergic mechanisms are important in regulating the balance of limbic control over appetitive behavior at the point of learning. Having previously shown that repeated systemic pre-treatment with amphetamine disrupts the regulation of competing limbic control over appetitive behavior in mice, we hereby examined the effects of repeated pre-training intra-NAc shell or core microinfusions of d-amphetamine, general dopamine (DA) receptor antagonist cis-flupenthixol (FLU), or vehicle solution (saline) upon a simultaneously acquired conditioned cue and place preference task in rats. Repeated infusions of amphetamine into the NAc shell and core had opposite effects on the acquisition of conditioned place preference by significantly enhancing, and attenuating hippocampal-dependent place conditioning respectively. In contrast, direct infusions of flupenthixol into the NAc shell attenuated place conditioning, while NAc core flupenthixol infusions not only attenuated cue conditioning, but also enhanced conditioned place preference. These findings implicate the NAc shell DA as being necessary for enabling hippocampal-dependent spatial information to gain control over appetitive learning, and the NAc core DA as being important for allowing basolateral amygdala-dependent information to gain control over appetitive learning. It is further proposed that NAc core DA may be critical in regulating limbic information flow through the NAc shell. PMID:21508225

  18. Hypothalamic tumors impact gray and white matter volumes in fronto-limbic brain areas.

    PubMed

    Özyurt, Jale; Müller, Hermann L; Warmuth-Metz, Monika; Thiel, Christiane M

    2017-04-01

    Patients with hypothalamic involvement of a sellar/parasellar tumor often suffer from cognitive and social-emotional deficits that a lesion in the hypothalamus cannot fully explain. It is conceivable that these deficits are partly due to distal changes in hypothalamic networks, evolving secondary to a focal lesion. Focusing on childhood-onset craniopharyngioma patients, we aimed at investigating the impact of hypothalamic lesions on gray and white matter areas densely connected to the hypothalamus, and to relate structural changes to neuropsychological deficits frequently observed in patients. We performed a voxel-based morphometric analysis based on data of 11 childhood-onset craniopharyngioma patients with hypothalamic tumor involvement, and 18 healthy controls (median age: 17.2 and 17.4 yrs.). Whole-brain analyses were used to test for volumetric differences between the groups (T-tests) and subsequent regression analyses were used to correlate neuropsychological performance with gray and white matter volumes within the patient group. Patients compared to controls had significantly reduced gray matter volumes in areas of the anterior and posterior limbic subsystems which are densely connected with the hypothalamus. In addition, a reduction in white matter volumes was observed in tracts connecting the hypothalamus to other limbic areas. Worse long-term memory retrieval was correlated with smaller gray matter volumes in the posterior cingulate cortex. Our data provide the first evidence that hypothalamic tumor involvement impacts gray and white matter volumes in limbic areas, outside the area of tumor growth. Notably, the functional range of the two limbic subsystems affected, strikingly parallels the two major domains of psychological complaints in patients i.e., deficits in episodic memory and in socio-emotional functioning. We suggest that focal hypothalamic lesions may trigger distal changes in connected brain areas, which then contribute to the impairments in

  19. Methylphenidate attenuates limbic brain inhibition after cocaine-cues exposure in cocaine abusers.

    SciTech Connect

    Volkow, N.D.; Wang, G.; Volkow, N.D.; Wang, G.-J.; Tomasi, D.; Telang, F.; Fowler, J.S.; Pradhan, K.; Jayne, M.; Logan, J.; Goldstein, R.Z.; Alia-Klein, N.; Wong, C.T.

    2010-07-01

    Dopamine (phasic release) is implicated in conditioned responses. Imaging studies in cocaine abusers show decreases in striatal dopamine levels, which we hypothesize may enhance conditioned responses since tonic dopamine levels modulate phasic dopamine release. To test this we assessed the effects of increasing tonic dopamine levels (using oral methylphenidate) on brain activation induced by cocaine-cues in cocaine abusers. Brain metabolism (marker of brain function) was measured with PET and {sup 18}FDG in 24 active cocaine abusers tested four times; twice watching a Neutral video (nature scenes) and twice watching a Cocaine-cues video; each video was preceded once by placebo and once by methylphenidate (20 mg). The Cocaine-cues video increased craving to the same extent with placebo (68%) and with methylphenidate (64%). In contrast, SPM analysis of metabolic images revealed that differences between Neutral versus Cocaine-cues conditions were greater with placebo than methylphenidate; whereas with placebo the Cocaine-cues decreased metabolism (p<0.005) in left limbic regions (insula, orbitofrontal, accumbens) and right parahippocampus, with methylphenidate it only decreased in auditory and visual regions, which also occurred with placebo. Decreases in metabolism in these regions were not associated with craving; in contrast the voxel-wise SPM analysis identified significant correlations with craving in anterior orbitofrontal cortex (p<0.005), amygdala, striatum and middle insula (p<0.05). This suggests that methylphenidate's attenuation of brain reactivity to Cocaine-cues is distinct from that involved in craving. Cocaine-cues decreased metabolism in limbic regions (reflects activity over 30 minutes), which contrasts with activations reported by fMRI studies (reflects activity over 2-5 minutes) that may reflect long-lasting limbic inhibition following activation. Studies to evaluate the clinical significance of methylphenidate's blunting of cue-induced limbic

  20. The metabolic effects of limbic leucotomy in Gilles de la Tourette syndrome.

    PubMed Central

    Sawle, G V; Lees, A J; Hymas, N F; Brooks, D J; Frackowiak, R S

    1993-01-01

    Regional cerebral oxygen metabolism was measured before and after limbic leucotomy in a patient with Gilles de la Tourette syndrome, obsessive compulsive disorder, and obsessional slowness. The preoperative scan showed hypermetabolism in the caudate nuclei, which normalised after operation. It is proposed that the beneficial effects of this operation on both tics and obsessive compulsive behaviour are mediated by disruption of abnormal neural activity in basal ganglia-thalamocortical loops. Images PMID:8410025

  1. Methylphenidate attenuates limbic brain inhibition after cocaine-cues exposure in cocaine abusers.

    PubMed

    Volkow, Nora D; Wang, Gene-Jack; Tomasi, Dardo; Telang, Frank; Fowler, Joanna S; Pradhan, Kith; Jayne, Millard; Logan, Jean; Goldstein, Rita Z; Alia-Klein, Nelly; Wong, Christopher

    2010-07-09

    Dopamine (phasic release) is implicated in conditioned responses. Imaging studies in cocaine abusers show decreases in striatal dopamine levels, which we hypothesize may enhance conditioned responses since tonic dopamine levels modulate phasic dopamine release. To test this we assessed the effects of increasing tonic dopamine levels (using oral methylphenidate) on brain activation induced by cocaine-cues in cocaine abusers. Brain metabolism (marker of brain function) was measured with PET and (18)FDG in 24 active cocaine abusers tested four times; twice watching a Neutral video (nature scenes) and twice watching a Cocaine-cues video; each video was preceded once by placebo and once by methylphenidate (20 mg). The Cocaine-cues video increased craving to the same extent with placebo (68%) and with methylphenidate (64%). In contrast, SPM analysis of metabolic images revealed that differences between Neutral versus Cocaine-cues conditions were greater with placebo than methylphenidate; whereas with placebo the Cocaine-cues decreased metabolism (p<0.005) in left limbic regions (insula, orbitofrontal, accumbens) and right parahippocampus, with methylphenidate it only decreased in auditory and visual regions, which also occurred with placebo. Decreases in metabolism in these regions were not associated with craving; in contrast the voxel-wise SPM analysis identified significant correlations with craving in anterior orbitofrontal cortex (p<0.005), amygdala, striatum and middle insula (p<0.05). This suggests that methylphenidate's attenuation of brain reactivity to Cocaine-cues is distinct from that involved in craving. Cocaine-cues decreased metabolism in limbic regions (reflects activity over 30 minutes), which contrasts with activations reported by fMRI studies (reflects activity over 2-5 minutes) that may reflect long-lasting limbic inhibition following activation. Studies to evaluate the clinical significance of methylphenidate's blunting of cue-induced limbic

  2. Synchronous inhibitory potentials precede seizure-like events in acute models of focal limbic seizures.

    PubMed

    Uva, Laura; Breschi, Gian Luca; Gnatkovsky, Vadym; Taverna, Stefano; de Curtis, Marco

    2015-02-18

    Interictal spikes in models of focal seizures and epilepsies are sustained by the synchronous activation of glutamatergic and GABAergic networks. The nature of population spikes associated with seizure initiation (pre-ictal spikes; PSs) is still undetermined. We analyzed the networks involved in the generation of both interictal and PSs in acute models of limbic cortex ictogenesis induced by pharmacological manipulations. Simultaneous extracellular and intracellular recordings from both principal cells and interneurons were performed in the medial entorhinal cortex of the in vitro isolated guinea pig brain during focal interictal and ictal discharges induced in the limbic network by intracortical and brief arterial infusions of either bicuculline methiodide (BMI) or 4-aminopyridine (4AP). Local application of BMI in the entorhinal cortex did not induce seizure-like events (SLEs), but did generate periodic interictal spikes sensitive to the glutamatergic non-NMDA receptor antagonist DNQX. Unlike local applications, arterial perfusion of either BMI or 4AP induced focal limbic SLEs. PSs just ahead of SLE were associated with hyperpolarizing potentials coupled with a complete blockade of firing in principal cells and burst discharges in putative interneurons. Interictal population spikes recorded from principal neurons between two SLEs correlated with a depolarizing potential. We demonstrate in two models of acute limbic SLE that PS events are different from interictal spikes and are sustained by synchronous activation of inhibitory networks. Our findings support a prominent role of synchronous network inhibition in the initiation of a focal seizure. Copyright © 2015 the authors 0270-6474/15/353048-08$15.00/0.

  3. Close Vicinity of PrP Expressing Cells (FDC) with Noradrenergic Fibers in Healthy Sheep Spleen

    PubMed Central

    Lezmi, S.; Hunsmann, G.; Baron, T.

    2001-01-01

    In naturally and experimentally occurring scrapie in sheep, prions invade the immune system and replicate in lymphoid organs. Here we analysed immunohistochemically, in seven spleens of 6-month-old healthy sheep, the nature of the cells expressing prion protein (PrP) potentially supporting prion replication, as well as their relationship with autonomic innervation. PrP was identified using either RB1 rabbit antiserum or 4F2 monoclonal antibody directed against AA 108–123 portion of the bovine and AA 79–92 of human prion protein respectively. Using double labelling analysis, we demonstrated that PrPc is expressed by follicular dendritic cells using a specific monoclonal antibody (CNA42). We also showed the close vicinity of these PrP expressing cells with noradrenergic fibers, using a polyclonal tyrosine hydroxylase antibody. Our results may help the study of the cellular requirements for the possible neuroinvasion from the spleen. PMID:11785673

  4. Effect of cocaine on ion channels and glutamatergic EPSCs in noradrenergic locus coeruleus neurons.

    PubMed

    Liu, L N; Zhu, F P; Song, M Y; Kang, X J; Shang, S J; Zhang, X Y; Xu, H D; Teng, S S; Liu, B; Kuo, S T; Liu, W; Li, M L; Zhou, L; Jiao, R Y; Wang, C H; Wang, S R; Yang, H; Zhang, B; Zhou, Z; Xu, Z Q D

    2014-07-01

    The locus coeruleus (LC) is an important brainstem area involved in cocaine addiction. However, evidence to elucidate how cocaine modulates the activity of LC neurons remains incomplete. Here, we performed whole recordings in brain slices to evaluate the effects of cocaine on the sodium (Na(+)), potassium (K(+)), calcium (Ca(2+)) channels, and glutamatergic synaptic transmission in the locus coeruleus neurons. Local application of cocaine significantly and reversibly reduced the spontaneous firing rate but did not affect action potential amplitude, rising time, decay time, or half width of noradrenergic locus coeruleus neurons. Moreover, cocaine attenuated the sodium current but did not affect potassium and calcium currents. The N-methyl-D-aspartate receptor mediated excitatory postsynaptic currents were reduced by neuropeptide galanin but not cocaine. All those data demonstrate that cocaine has inhibitory effect on the spontaneous activities and sodium current in locus coeruleus neurons. Therefore, neuromodulation of sodium channel in locus coeruleus neurons may play an important role in drug addiction.

  5. Coordinated forms of noradrenergic plasticity in the locus coeruleus and primary auditory cortex

    PubMed Central

    Martins, Ana Raquel O.; Froemke, Robert C.

    2015-01-01

    The cerebral cortex is plastic and represents the world according to the significance of sensory stimuli. However, cortical networks are embodied within complex circuits including neuromodulatory systems such as the noradrenergic locus coeruleus, providing information about internal state and behavioral relevance. While norepinephrine is important for cortical plasticity, it is unknown how modulatory neurons themselves respond to changes of sensory input. Here we examine how locus coeruleus neurons are modified by experience, and the consequences of locus coeruleus plasticity on cortical representations and sensory perception. We made whole-cell recordings from rat locus coeruleus and primary auditory cortex (AI), pairing sounds with locus coeruleus activation. Although initially unresponsive, locus coeruleus neurons developed and maintained auditory responses afterwards. Locus coeruleus plasticity induced changes in AI responses lasting at least hours and improved auditory perception for days to weeks. Our results demonstrate that locus coeruleus is highly plastic, leading to substantial changes in regulation of brain state by norepinephrine. PMID:26301326

  6. Stress-related noradrenergic activity prompts large-scale neural network reconfiguration.

    PubMed

    Hermans, Erno J; van Marle, Hein J F; Ossewaarde, Lindsey; Henckens, Marloes J A G; Qin, Shaozheng; van Kesteren, Marlieke T R; Schoots, Vincent C; Cousijn, Helena; Rijpkema, Mark; Oostenveld, Robert; Fernández, Guillén

    2011-11-25

    Acute stress shifts the brain into a state that fosters rapid defense mechanisms. Stress-related neuromodulators are thought to trigger this change by altering properties of large-scale neural populations throughout the brain. We investigated this brain-state shift in humans. During exposure to a fear-related acute stressor, responsiveness and interconnectivity within a network including cortical (frontoinsular, dorsal anterior cingulate, inferotemporal, and temporoparietal) and subcortical (amygdala, thalamus, hypothalamus, and midbrain) regions increased as a function of stress response magnitudes. β-adrenergic receptor blockade, but not cortisol synthesis inhibition, diminished this increase. Thus, our findings reveal that noradrenergic activation during acute stress results in prolonged coupling within a distributed network that integrates information exchange between regions involved in autonomic-neuroendocrine control and vigilant attentional reorienting.

  7. Noradrenergic innervation of the human adrenal cortex as revealed by dopamine-beta-hydroxylase immunohistochemistry.

    PubMed Central

    Charlton, B G; McGadey, J; Russell, D; Neal, D E

    1992-01-01

    Noradrenergic innervation of the human adrenal cortex was investigated using immunohistochemistry directed at dopamine-beta-hydroxylase. Nerves were present as slender trunks and individual varicose fibres in the capsule and all cortical zones except the inner zona reticularis. Some fibres were located adjacent to blood vessels and in the muscular tunics of arterioles; others were apparently adjacent to parenchymal cells. These results in the human confirm and extend previous animal studies and suggest a possible anatomical substrate for regulation of adrenal blood flow, and also for the direct action of noradrenaline on zona fasciculata cells to stimulate glucocorticoid secretion via beta-1-adrenoceptors. Images Fig. 1 Fig. 2 Fig. 3 Fig. 4 Fig. 5 PMID:1336772

  8. Limbic system pathologies associated with deficiencies and excesses of the trace elements iron, zinc, copper, and selenium.

    PubMed

    Torres-Vega, Adriana; Pliego-Rivero, Bernardo F; Otero-Ojeda, Gloria A; Gómez-Oliván, Leobardo M; Vieyra-Reyes, Patricia

    2012-12-01

    Deficiencies of nutrients such as amino acids, vitamins, lipids, and trace elements during gestation and early infanthood have strong deleterious effects on the development of the limbic system; these effects may be irreversible, even when adequate supplementation is provided at later developmental stages. Recent advances in the neurochemistry of biometals are increasingly establishing the roles of the trace elements iron, copper, zinc, and selenium in a variety of cell functions and are providing insight into the repercussions of deficiencies and excesses of these elements on the development of the central nervous system, especially the limbic system. The limbic system comprises diverse areas with high metabolic demands and differential storage of iron, copper, zinc, and selenium. This review summarizes available evidence suggesting the involvement of these trace elements in pathological disorders of the limbic system. © 2012 International Life Sciences Institute.

  9. Interactive effects of BDNF Val66Met genotype and trauma on limbic brain anatomy in childhood

    PubMed Central

    Marusak, Hilary A.; Kuruvadi, Nisha; Vila, Angela M.; Shattuck, David W.; Joshi, Shantanu H.; Joshi, Anand A.; Jella, Pavan K.; Thomason, Moriah E.

    2015-01-01

    Childhood trauma is a major precipitating factor in psychiatric disease. Emerging data suggest that stress susceptibility is genetically determined, and that risk is mediated by changes in limbic brain circuitry. There is a need to identify markers of disease vulnerability, and it is critical that these markers be investigated in childhood and adolescence, a time when neural networks are particularly malleable and when psychiatric disorders frequently emerge. In this preliminary study, we evaluated whether a common variant in the brain-derived neurotrophic factor (BDNF) gene (Val66Met; rs6265) interacts with childhood trauma to predict limbic gray matter volume in a sample of 55 youth high in sociodemographic risk. We found trauma-by-BDNF interactions in the right subcallosal area and right hippocampus, wherein BDNF-related gray matter changes were evident in youth without histories of trauma. In youth without trauma exposure, lower hippocampal volume was related to higher symptoms of anxiety. These data provide preliminary evidence for a contribution of a common BDNF gene variant to the neural correlates of childhood trauma among high-risk urban youth. Altered limbic structure in early life may lay the foundation for longer-term patterns of neural dysfunction, and hold implications for understanding the psychiatric and psychobiological consequences of traumatic stress on the developing brain. PMID:26286685

  10. Effects of isomers of apomorphines on dopamine receptors in striatal and limbic tissue of rat brain

    SciTech Connect

    Kula, N.S.; Baldessarini, R.J.; Bromley, S.; Neumeyer, J.L.

    1985-09-16

    The optical isomers of apomorphine (APO) and N-propylnorapomorphine (NPA) were interacted with three biochemical indices of dopamine (Da) receptors in extrapyramidal and limbic preparations of rat brain tissues. There were consistent isomeric preferences for the R(-) configuration of both DA analogs in stimulation adenylate cyclase (D-1 sites) and in competing for high affinity binding of /sup 3/H-spiroperidol (D-2 sites) and of /sup 3/H-ADTN (DA agonist binding sites) in striatal tissue, with lesser isomeric differences in the limbic tissue. The S(+) apomorphines did not inhibit stimulation of adenylate cyclase by DA. The tendency for greater activity of higher apparent affinity of R(-) apomorphines in striatum may reflect the evidently greater abundance of receptor sites in that region. There were only small regional differences in interactions of the apomorphine isomers with all three receptor sites, except for a strong preference of (-)NPA for striatal D-2 sites. These results do not parallel our recent observations indicating potent and selective antidopaminergic actions of S(+) apomorphines in the rat limbic system. They suggest caution in assuming close parallels between current biochemical functional, especially behavioral, methods of evaluating dopamine receptors of mammalian brain.

  11. Restoring Conscious Arousal During Focal Limbic Seizures with Deep Brain Stimulation.

    PubMed

    Kundishora, Adam J; Gummadavelli, Abhijeet; Ma, Chanthia; Liu, Mengran; McCafferty, Cian; Schiff, Nicholas D; Willie, Jon T; Gross, Robert E; Gerrard, Jason; Blumenfeld, Hal

    2016-03-03

    Impaired consciousness occurs suddenly and unpredictably in people with epilepsy, markedly worsening quality of life and increasing risk of mortality. Focal seizures with impaired consciousness are the most common form of epilepsy and are refractory to all current medical and surgical therapies in about one-sixth of cases. Restoring consciousness during and following seizures would be potentially transformative for these individuals. Here, we investigate deep brain stimulation to improve level of conscious arousal in a rat model of focal limbic seizures. We found that dual-site stimulation of the central lateral nucleus of the intralaminar thalamus (CL) and the pontine nucleus oralis (PnO) bilaterally during focal limbic seizures restored normal-appearing cortical electrophysiology and markedly improved behavioral arousal. In contrast, single-site bilateral stimulation of CL or PnO alone was insufficient to achieve the same result. These findings support the "network inhibition hypothesis" that focal limbic seizures impair consciousness through widespread inhibition of subcortical arousal. Driving subcortical arousal function would be a novel therapeutic approach to some forms of refractory epilepsy and may be compatible with devices already in use for responsive neurostimulation. Multisite deep brain stimulation of subcortical arousal structures may benefit not only patients with epilepsy but also those with other disorders of consciousness.

  12. Brain tissue properties differentiate between motor and limbic basal ganglia circuits

    PubMed Central

    Accolla, Ettore A; Dukart, Juergen; Helms, Gunther; Weiskopf, Nikolaus; Kherif, Ferath; Lutti, Antoine; Chowdhury, Rumana; Hetzer, Stefan; Haynes, John-Dylan; Kühn, Andrea A; Draganski, Bogdan

    2014-01-01

    Despite advances in understanding basic organizational principles of the human basal ganglia, accurate in vivo assessment of their anatomical properties is essential to improve early diagnosis in disorders with corticosubcortical pathology and optimize target planning in deep brain stimulation. Main goal of this study was the detailed topological characterization of limbic, associative, and motor subdivisions of the subthalamic nucleus (STN) in relation to corresponding corticosubcortical circuits. To this aim, we used magnetic resonance imaging and investigated independently anatomical connectivity via white matter tracts next to brain tissue properties. On the basis of probabilistic diffusion tractography we identified STN subregions with predominantly motor, associative, and limbic connectivity. We then computed for each of the nonoverlapping STN subregions the covariance between local brain tissue properties and the rest of the brain using high-resolution maps of magnetization transfer (MT) saturation and longitudinal (R1) and transverse relaxation rate (R2*). The demonstrated spatial distribution pattern of covariance between brain tissue properties linked to myelin (R1 and MT) and iron (R2*) content clearly segregates between motor and limbic basal ganglia circuits. We interpret the demonstrated covariance pattern as evidence for shared tissue properties within a functional circuit, which is closely linked to its function. Our findings open new possibilities for investigation of changes in the established covariance pattern aiming at accurate diagnosis of basal ganglia disorders and prediction of treatment outcome. PMID:24777915

  13. Limbic irritability and chaotic neural response during conflicting stroop task in the patients with unipolar depression.

    PubMed

    Bob, P; Susta, M; Procházková-Vecerová, A; Kukleta, M; Pavlát, J; Jagla, F; Raboch, J

    2006-01-01

    According to recent findings activation of anterior cingulate cortex (ACC) is related to detecting cognitive conflict. This conflict related activation elicits autonomic responses which can be assessed by psychophysiological measures such as heart rate variability calculated as beat to beat R-R intervals (RRI). Recent findings in neuroscience also suggest that cognitive conflict is related to specific nonlinear chaotic changes of the signal generated by neural systems. The present study used Stroop word-color test as an experimental approach to psychophysiological study of cognitive conflict in connection with RRI measurement, psychometric measurement of limbic irritability (LSCL-33), depression (BDI-II) and calculation of largest Lyapunov exponents in nonlinear data analysis of RRI time series. Significant correlation 0.61 between largest Lyapunov exponents and LSCL-33 found in this study indicate that a defect of neural inhibition during conflicting Stroop task is closely related to limbic irritability. Because limbic irritability is probably closely related to epileptiform abnormalities in the temporolimbic structures, this result might represent useful instrument for indication of anticonvulsant treatment in depressive patients who are resistant to antidepressant medication.

  14. Interactive effects of BDNF Val66Met genotype and trauma on limbic brain anatomy in childhood.

    PubMed

    Marusak, Hilary A; Kuruvadi, Nisha; Vila, Angela M; Shattuck, David W; Joshi, Shantanu H; Joshi, Anand A; Jella, Pavan K; Thomason, Moriah E

    2016-05-01

    Childhood trauma is a major precipitating factor in psychiatric disease. Emerging data suggest that stress susceptibility is genetically determined, and that risk is mediated by changes in limbic brain circuitry. There is a need to identify markers of disease vulnerability, and it is critical that these markers be investigated in childhood and adolescence, a time when neural networks are particularly malleable and when psychiatric disorders frequently emerge. In this preliminary study, we evaluated whether a common variant in the brain-derived neurotrophic factor (BDNF) gene (Val66Met; rs6265) interacts with childhood trauma to predict limbic gray matter volume in a sample of 55 youth high in sociodemographic risk. We found trauma-by-BDNF interactions in the right subcallosal area and right hippocampus, wherein BDNF-related gray matter changes were evident in youth without histories of trauma. In youth without trauma exposure, lower hippocampal volume was related to higher symptoms of anxiety. These data provide preliminary evidence for a contribution of a common BDNF gene variant to the neural correlates of childhood trauma among high-risk urban youth. Altered limbic structure in early life may lay the foundation for longer term patterns of neural dysfunction, and hold implications for understanding the psychiatric and psychobiological consequences of traumatic stress on the developing brain.

  15. Can memories kindle nonconvulsive behavioral seizures in humans? Case report exemplifying the "limbic psychotic trigger reaction".

    PubMed

    Pontius, Anneliese A; Wieser, Heinz-Gregor

    2004-10-01

    We present three hypotheses-(1) the limbic psychotic trigger reaction (LPTR) is a form of nonconvulsive behavioral seizures (NCBS), (2) kindling may occur in the LPTR, and (3) kindling may occur with memory stimuli-and report a case that may exemplify a LPTR kindled by memory and triggered by light and smell. The LPTR has a primate model, in which NCBS are kindled by intermittent exposure to actual subthreshold stimuli. In humans, we propose that such triggering stimuli can be revived by memory alone. Thus, individualized stimuli can trigger partial limbic seizures or seizure-like bizarre episodes with a transient loss of frontal control functions. We present a case of paroxysmal episodes of out-of-character, bizarre, unplanned nonvoluntary acts that occurred with flat affect and without drive motivation (e.g., "fire setting"). Implicated is a transient state of limbic "paleo-consciousness" with preserved memory, autonomic arousal, and first-time brief psychosis (e.g., olfactory, visual hallucinations and depersonalization with olfactory attributes). As in kindled primates, LPTR patients do not show a consistent pattern of morphological brain abnormality; half have had an abnormal electroencephalogram, computed tomography scan, or magnetic resonance image at some time during their lives, and half (including the new patient) have had closed head injuries.

  16. Regulation of fear responses by striatal and extrastriatal adenosine A2A receptors in forebrain.

    PubMed

    Wei, Catherine J; Augusto, Elisabete; Gomes, Catarina A; Singer, Philipp; Wang, Yumei; Boison, Detlev; Cunha, Rodrigo A; Yee, Benjamin K; Chen, Jiang-Fan

    2014-06-01

    Adenosine A2A receptors (A2ARs) are enriched in the striatum but are also present at lower levels in the extrastriatal forebrain (i.e., hippocampus, cortex), integrating dopamine, glutamate, and brain-derived neurotrophic factor (BDNF) signaling, and are thus essential for striatal neuroplasticity and fear and anxiety behavior. We tested two brain region-specific A2AR knockout lines with A2ARs selectively deleted either in the striatum (st-A2AR KO) or the entire forebrain (striatum, hippocampus, and cortex [fb-A2AR KO]) on fear and anxiety-related responses. We also examined the effect of hippocampus-specific A2AR deletion by local injection of adeno-associated virus type 5 (AAV5)-Cre into floxed-A2AR knockout mice. Selectively deleting A2ARs in the striatum increased Pavlovian fear conditioning (both context and tone) in st-A2AR KO mice, but extending the deletion to the rest of the forebrain apparently spared context fear conditioning and attenuated tone fear conditioning in fb-A2AR KO mice. Moreover, focal deletion of hippocampal A2ARs by AAV5-Cre injection selectively attenuated context (but not tone) fear conditioning. Deletion of A2ARs in the entire forebrain in fb-A2AR KO mice also produced an anxiolytic phenotype in both the elevated plus maze and open field tests, and increased the startle response. These extrastriatal forebrain A2AR behavioral effects were associated with reduced BDNF levels in the fb-A2AR KO hippocampus. This study provides evidence that inactivation of striatal A2ARs facilitates Pavlovian fear conditioning, while inactivation of extrastriatal A2ARs in the forebrain inhibits fear conditioning and also affects anxiety-related behavior. Copyright © 2014. Published by Elsevier Inc.

  17. Effects of hypocretin (orexin) neuronal loss on sleep and extracellular adenosine levels in the basal forebrain

    PubMed Central

    Murillo-Rodriguez, Eric; Liu, Meng; Blanco-Centurion, Carlos; Shiromani, Priyattam J.

    2009-01-01

    Neurons containing the neuropeptide hypocretin (orexin) are localized only in the lateral hypothalamus from where they innervate multiple regions implicated in arousal, including the basal forebrain. HCRT activation of downstream arousal neurons is likely to stimulate release of endogenous factors. One such factor is adenosine (AD), which in the basal forebrain increases with waking and decreases with sleep, and is hypothesized to regulate the waxing and waning of sleep drive. Does loss of HCRT neurons affect AD levels in the basal forebrain? Is the increased sleep that accompanies HCRT loss a consequence of higher AD levels in the basal forebrain? In the present study, we investigate these questions by lesioning the HCRT neurons (hypocretin-2-saporin) and measuring sleep and extracellular levels of AD in the basal forebrain. In separate groups of rats, the neurotoxin HCRT2-SAP or saline were administered locally to the lateral hypothalamus and 80 days later AD and sleep were assessed. Rats given the neurotoxin had a 94% loss of the HCRT neurons. These rats awake less at night, and had more REM sleep, which is consistent with a HCRT hypofunction. These rats also had more sleep after brief periods of sleep deprivation. However, in the lesioned rats, AD levels did not increase with 6h sleep deprivation, whereas such an increase in AD occurred in rats without lesion of the HCRT neurons. These findings indicate that AD levels do not increase with waking in rats with a HCRT lesion, and that the increased sleep in these rats occurs independently of AD levels in the basal forebrain. PMID:18783368

  18. Organization of the avian basal forebrain: chemical anatomy in the parrot (Melopsittacus undulatus).

    PubMed

    Roberts, Todd Freeman; Hall, William Sterling; Brauth, Steven Earle

    2002-12-23

    Hodological, electrophysiological, and ablation studies indicate a role for the basal forebrain in telencephalic vocal control; however, to date the organization of the basal forebrain has not been extensively studied in any nonmammal or nonhuman vocal learning species. To this end the chemical anatomy of the avian basal forebrain was investigated in a vocal learning parrot, the budgerigar (Melopsittacus undulatus). Immunological and histological stains, including choline acetyltransferase, acetylcholinesterase, tyrosine hydroxylase, dopamine and cAMP-regulated phosphoprotein (DARPP)-32, the calcium binding proteins calbindin D-28k and parvalbumin, calcitonin gene-related peptide, iron, substance P, methionine enkephalin, nicotinamide adenine dinucleotide phosphotase diaphorase, and arginine vasotocin were used in the present study. We conclude that the ventral paleostriatum (cf. Kitt and Brauth [1981] Neuroscience 6:1551-1566) and adjacent archistriatal regions can be subdivided into several distinct subareas that are chemically comparable to mammalian basal forebrain structures. The nucleus accumbens is histochemically separable into core and shell regions. The nucleus taeniae (TN) is theorized to be homologous to the medial amygdaloid nucleus. The archistriatum pars ventrolateralis (Avl; comparable to the pigeon archistriatum pars dorsalis) is theorized to be a possible homologue of the central amygdaloid nucleus. The TN and Avl are histochemically continuous with the medial aspects of the bed nucleus of the stria terminalis and the ventromedial striatum, forming an avian analogue of the extended amygdala. The apparent counterpart in budgerigars of the mammalian nucleus basalis of Meynert consists of a field of cholinergic neurons spanning the basal forebrain. The budgerigar septal region is theorized to be homologous as a field to the mammalian septum. Our results are discussed with regard to both the evolution of the basal forebrain and its role in vocal

  19. Parallel changes in brain flunitrazepam binding and density of noradrenergic innervation.

    PubMed

    Medina, J H; Novas, M L

    1983-04-08

    The neonatal injection of neurotoxic compounds such as 6-hydroxydopa (6-OH-DOPA) and DSP 4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride) produces marked changes in the development of central noradrenergic neurons, i.e. permanent denervation of the cerebral cortex and hyperinnervation of the brain stem and the cerebellum. Adult animals treated at birth with both neurotoxins were used to study the binding of [3H]flunitrazepam (FNZ) to membranes isolated from these regions. The administration of both toxins produced a marked and similar increase in the number of FNZ binding sites in the cerebellum. In the brain stem, 6-OH-DOPA increased the density of these receptors much more than DSP 4 (33% vs. 13%), a difference similar to that observed between the effects of both compounds on brain stem NA. In the cerebral cortex, both compounds reduced the maximal number of FNZ binding sites. No changes were observed in the affinity of FNZ binding sites in the different structures. When adult rats treated at birth with 6-OH-DOPA received an injection of DSP 4 7 days later, the number of FNZ binding sites was reduced by 43% in the cerebellum, 53% in the brain stem and 11% in the cerebral cortex. In these structures, DSP 4 reduced the absolute number of FNZ binding sites to the same level both in rats treated at birth with 6-OH-DOPA and in non-treated animals receiving DSP 4 7 days before killing. These results are further support for the existence of close parallelism between the density of benzodiazepine receptors, as demonstrated by FNZ binding, and the density of brain noradrenergic innervation.

  20. Is the Noradrenergic Symptom Cluster a Valid Construct in Adjunctive Treatment of Major Depressive Disorder?

    PubMed

    Stauffer, Virginia L; Liu, Peng; Goldberger, Celine; Marangell, Lauren B; Nelson, Craig; Gorwood, Philip; Fava, Maurizio

    2017-03-01

    To identify symptoms potentially representative of a noradrenergic symptom cluster as possible predictors of response to the selective norepinephrine reuptake inhibitor (NRI) edivoxetine when used as monotherapy or adjunctive treatment in patients with DSM-IV-TR major depressive disorder (MDD). Pooled data from 4 adjunctive treatment trials (selective serotonin reuptake inhibitor [SSRI] + edivoxetine 6-18 mg/d vs SSRI + placebo; N = 2,066) and data from 1 monotherapy trial (edivoxetine 6-18 mg/d versus placebo; N = 495) were used to identify predictors of response related to noradrenergic symptoms using a resampling-based ensemble tree method. The trials were conducted from 2008 to 2013. In the pooled adjunctive trials, no subgroup was identified that demonstrated a greater edivoxetine-placebo treatment difference than the overall patient cohort. In the edivoxetine monotherapy trial, no subgroup showing greater mean edivoxetine-placebo differences on the Montgomery-Asberg Depression Rating Scale versus the overall patient cohort was identified; a subgroup (67%) with high b​aseline Massachusetts General Hospital Cognitive and Physical Functioning Questionnaire (CPFQ) total score (≥ 28) showed statistically significantly (P = .02) greater mean edivoxetine-placebo differences on the Sheehan Disability Scale versus the overall patient cohort, and subgroups with baseline CPFQ total score ≥ 28 (65%), CPFQ cognition dimension score ≥ 16 (63%), or CPFQ physical dimension score ≥ 13 (59%) showed statistically significantly (P ≤ .025) greater mean edivoxetine-placebo differences on the CPFQ total score versus the overall patient cohort. While we could not identify symptoms predictive of response to the selective NRI edivoxetine used as adjunctive treatment, impaired cognition and physical symptoms may predict greater improvement during monotherapy. ClinicalTrials.gov identifiers: NCT00840034, NCT01173601, NCT01187407, NCT01185340, NCT00795821.

  1. CXCR4 and NMDA Receptors Are Functionally Coupled in Rat Hippocampal Noradrenergic and Glutamatergic Nerve Endings.

    PubMed

    Di Prisco, Silvia; Olivero, Guendalina; Merega, Elisa; Bonfiglio, Tommaso; Marchi, Mario; Pittaluga, Anna

    2016-12-01

    Previous studies had shown that the HIV-1 capsidic glycoprotein gp120 (strain IIIB) modulates presynaptic release-regulating NMDA receptors on noradrenergic and glutamatergic terminals. This study aims to assess whether the chemokine CXC4 receptors (CXCR4s) has a role in the gp120-mediated effects. The effect of CXCL12, the endogenous ligand at CXCR4, on the NMDA-mediated releasing activity was therefore investigated. Rat hippocampal synaptosomes were preloaded with [(3)H]noradrenaline ([(3)H]NA) or [(3)H]D-aspartate ([(3)H]D-Asp) and acutely exposed to CXCL12, to NMDA or to both agonists. CXCL12, inactive on its own, facilitated the NMDA-evoked tritium release. The NMDA antagonist MK-801 abolished the NMDA/CXCL12-evoked tritium release of both radiolabelled tracers, while the CXCR4 antagonist AMD 3100 halved it, suggesting that rat hippocampal nerve endings possess presynaptic release-regulating CXCR4 receptors colocalized with NMDA receptors. Accordingly, Western blot analysis confirmed the presence of CXCR4 proteins in synaptosomal plasmamembranes. In both synaptosomal preparations, CXCL12-induced facilitation of NMDA-mediated release was dependent upon PLC-mediated src-induced events leading to mobilization of Ca(2+) from intraterminal IP3-sensitive stores Finally, the gp120-induced facilitation of NMDA-mediated release of [(3)H]NA and [(3)H]D-Asp was prevented by AMD 3100. We propose that CXCR4s are functionally coupled to NMDA receptors in rat hippocampal noradrenergic and glutamatergic terminals and account for the gp120-induced modulation of the NMDA-mediated central effects. The NMDA/CXCR4 cross-talk could have a role in the neuropsychiatric symptoms often observed in HIV-1 positive patients.

  2. Noradrenergic regulation of plasticity marker expression in the adult rodent piriform cortex.

    PubMed

    Vadodaria, Krishna C; Yanpallewar, Sudhirkumar U; Vadhvani, Mayur; Toshniwal, Devyani; Liles, L Cameron; Rommelfanger, Karen S; Weinshenker, David; Vaidya, Vidita A

    2017-02-23

    The adult rodent piriform cortex has been reported to harbor immature neurons that express markers associated with neurodevelopment and plasticity, namely polysialylated neural cell adhesion molecule (PSA-NCAM) and doublecortin (DCX). We characterized the expression of PSA-NCAM and DCX across the rostrocaudal axis of the rat piriform cortex and observed higher numbers of PSA-NCAM and DCX positive cells in the posterior subdivision. As observed in the rat piriform cortex, Nestin-GFP reporter mice also revealed a similar gradient of GFP-positive cells with an increasing rostro-caudal gradient of expression. Given the extensive noradrenergic innervation of the piriform cortex and its role in regulating piriform cortex function and synaptic plasticity, we addressed the influence of norepinephrine (NE) on piriform cortex plasticity marker expression. Depletion of NE by treatment with the noradrenergic neurotoxin DSP-4 significantly increased the number of DCX and PSA-NCAM immunopositive cells in the piriform cortex of adult rats. Similarly, DSP-4 treated Nestin-GFP reporter mice revealed a robust induction of GFP-positive cells within the piriform cortex following NE depletion. Genetic loss of NE in dopamine β-hydroxylase knockout (Dbh -/-) mice phenocopied the effects of DSP-4, with an increase noted in PSA-NCAM and DCX positive cells in the piriform cortex. Further, chronic α2-adrenergic receptor stimulation with the agonist guanabenz increased PSA-NCAM and DCX positive cells in the piriform cortex of adult rats and GFP-positive cells in the piriform cortex of Nestin-GFP mice. By contrast, chronic α2-adrenergic receptor blockade with the antagonist yohimbine reduced PSA-NCAM and DCX positive cells in the piriform cortex of adult rats. Our results provide novel evidence for a role of NE in regulating the expression of plasticity markers, including PSA-NCAM, DCX, and nestin, within the adult mouse and rat piriform cortex.

  3. Bisphenol A exposure disrupts the development of the locus coeruleus-noradrenergic system in mice.

    PubMed

    Tando, So; Itoh, Kyoko; Yaoi, Takeshi; Ogi, Hiroshi; Goto, Shoko; Mori, Miyuki; Fushiki, Shinji

    2014-12-01

    It has been reported that bisphenol A (BPA), a widespread xenoestrogen employed in the production of polycarbonate plastics, affects brain development in both humans and rodents. In the present study employing mice, we examined the effects of exposure to BPA (500 μg/kg/day) during fetal and lactational periods on the development of the locus coeruleus (LC) at the age of embryonic day 18 (E18), postnatal 3 weeks (P3W), P8W and P16W. The number of tyrosine hydroxylase-immunoreactive cells (TH-IR cells) in females exposed to BPA was decreased, compared with the control females at P3W. At P8W, the number of TH-IR cells in females exposed to BPA was significantly decreased, compared with the control females, whereas the number of TH-IR cells in males exposed to BPA was significantly increased, compared with the control males, which resulted in reversed transient sexual differences in the numbers of TH-IR cells observed in the controls at P8W. However, no significant changes were demonstrated at E18 or P16W. Next, we examined the density of the fibers containing norepinephrine transporter (NET) in the anterior cingulate cortex (ACC) and prefrontal cortex, at P3W, P8W and P16W, because NET would be beneficial in identifying the targets of the LC noradrenergic neurons. There were no significant differences shown in the density of the NET-positive fibers, between the control and the groups exposed to BPA. These results suggested that BPA might disrupt the development of physiological sexual differences in the LC-noradrenergic system in mice, although further studies are necessary to clarify the underlying mechanisms. © 2014 Japanese Society of Neuropathology.

  4. Noradrenergic activation of the basolateral amygdala maintains hippocampus-dependent accuracy of remote memory.

    PubMed

    Atucha, Erika; Vukojevic, Vanja; Fornari, Raquel V; Ronzoni, Giacomo; Demougin, Philippe; Peter, Fabian; Atsak, Piray; Coolen, Marcel W; Papassotiropoulos, Andreas; McGaugh, James L; de Quervain, Dominique J-F; Roozendaal, Benno

    2017-08-22

    Emotional enhancement of memory by noradrenergic mechanisms is well-described, but the long-term consequences of such enhancement are poorly understood. Over time, memory traces are thought to undergo a neural reorganization, that is, a systems consolidation, during which they are, at least partly, transferred from the hippocampus to neocortical networks. This transfer is accompanied by a decrease in episodic detailedness. Here we investigated whether norepinephrine (NE) administration into the basolateral amygdala after training on an inhibitory avoidance discrimination task, comprising two distinct training contexts, alters systems consolidation dynamics to maintain episodic-like accuracy and hippocampus dependency of remote memory. At a 2-d retention test, both saline- and NE-treated rats accurately discriminated the training context in which they had received footshock. Hippocampal inactivation with muscimol before retention testing disrupted discrimination of the shock context in both treatment groups. At 28 d, saline-treated rats showed hippocampus-independent retrieval and lack of discrimination. In contrast, NE-treated rats continued to display accurate memory of the shock-context association. Hippocampal inactivation at this remote retention test blocked episodic-like accuracy and induced a general memory impairment. These findings suggest that the NE treatment altered systems consolidation dynamics by maintaining hippocampal involvement in the memory. This shift in systems consolidation was paralleled by time-regulated DNA methylation and transcriptional changes of memory-related genes, namely Reln and Pkmζ, in the hippocampus and neocortex. The findings provide evidence suggesting that consolidation of emotional memories by noradrenergic mechanisms alters systems consolidation dynamics and, as a consequence, influences the maintenance of long-term episodic-like accuracy of memory.

  5. Role of noradrenergic pathways in sneeze-induced urethral continence reflex in rats.

    PubMed

    Kaiho, Yasuhiro; Kamo, Izumi; Chancellor, Michael B; Arai, Yoichi; de Groat, William C; Yoshimura, Naoki

    2007-02-01

    To clarify the role of noradrenergic pathways in preventing stress urinary incontinence (SUI) during sneezing, we investigated the effect of the norepinephrine reuptake inhibitor nisoxetine and alpha-adrenoceptor antagonists phentolamine (nonspecific blocker) and prazosin (alpha(1)-receptor-selective blocker) on the neurally evoked urethral continence reflex induced by sneezing in rats. The amplitude of urethral pressure responses during sneezing (A-URS), urethral baseline pressure (UBP) at the midurethra, and sneeze-induced leak point pressure (S-LPP) were measured in normal female adult rats and rats with SUI induced by vaginal distention (VD). In normal rats, intrathecal (it) phentolamine (0.02 nmol) and prazosin (0.02 nmol) decreased A-URS by 11.9 and 15.7%, respectively, without affecting UBP. In both normal and VD rats, intravenous (iv) application of nisoxetine (1 mg/kg) increased A-URS by 17.2 and 18.3% and UBP by 23.7 and 32.7%, respectively. Phentolamine or prazosin (both it) eliminated nisoxetine-induced increases in A-URS, but not the increases in UBP, which were, however, suppressed by iv phentolamine (5 mg/kg) or prazosin (1 mg/kg). Sneezing induced fluid leakage from the urethral orifice in VD rats, but not in normal rats. In VD rats, S-LPP was increased by 30.2% by iv nisoxetine. Application of phentolamine and prazosin (both it) decreased S-LPP by 15.7 and 20.6%, respectively, and nisoxetine induced increases in S-LPP to 13.2 and 12.3%, respectively. These results indicate that activation of the noradrenergic system by a norepinephrine reuptake inhibitor can prevent SUI via alpha(1-)adrenoceptors by enhancing the sneeze-induced active urethral closure mechanism at the spinal level and augmenting UBP at the periphery.

  6. Inferior frontal gyrus preserves working memory and emotional learning under conditions of impaired noradrenergic signaling

    PubMed Central

    Becker, Benjamin; Androsch, Lucas; Jahn, Ralph T.; Alich, Therese; Striepens, Nadine; Markett, Sebastian; Maier, Wolfgang; Hurlemann, René

    2013-01-01

    Compensation has been widely applied to explain neuroimaging findings in neuropsychiatric patients. Functional compensation is often invoked when patients display equal performance and increased neural activity in comparison to healthy controls. According to the compensatory hypothesis increased activity allows the brain to maintain cognitive performance despite underlying neuropathological changes. Due to methodological and pathology-related issues, however, the functional relevance of the increased activity and the specific brain regions involved in the compensatory response remain unclear. An experimental approach that allows a transient induction of compensatory responses in the healthy brain could help to overcome these issues. To this end we used the non-selective beta-blocker propranolol to pharmacologically induce sub-optimal noradrenergic signaling in healthy participants. In two independent functional MRI (fMRI) experiments participants received either placebo or propranolol before they underwent a cognitive challenge (Experiment 1: working memory; Experiment 2: emotional learning: Pavlovian fear conditioning). In Experiment 1 propranolol had no effects on working memory performance, but evoked stronger activity in the left inferior frontal gyrus (IFG). In Experiment 2 propranolol produced no effects on emotional memory formation, but evoked stronger activity in the right IFG. The present finding that sub-optimal beta-adrenergic signaling did not disrupt performance and concomitantly increased IFG activity is consistent with, and extends, current perspectives on functional compensation. Together, our findings suggest that under conditions of impaired noradrenergic signaling, heightened activity in brain regions located within the cognitive control network, particularly the IFG, may reflect compensatory operations subserving the maintenance of behavioral performance. PMID:24381546

  7. Modulation of Limbic and Prefrontal Connectivity by Electroconvulsive Therapy in Treatment-resistant Depression: A Preliminary Study.

    PubMed

    Cano, Marta; Cardoner, Narcís; Urretavizcaya, Mikel; Martínez-Zalacaín, Ignacio; Goldberg, Ximena; Via, Esther; Contreras-Rodríguez, Oren; Camprodon, Joan; de Arriba-Arnau, Aida; Hernández-Ribas, Rosa; Pujol, Jesús; Soriano-Mas, Carles; Menchón, José M

    2016-01-01

    Although current models of depression suggest that a sequential modulation of limbic and prefrontal connectivity is needed for illness recovery, neuroimaging studies of electroconvulsive therapy (ECT) have focused on assessing functional connectivity (FC) before and after an ECT course, without characterizing functional changes occurring at early treatment phases. To assess sequential changes in limbic and prefrontal FC during the course of ECT and their impact on clinical response. Longitudinal intralimbic and limbic-prefrontal networks connectivity study. We assessed 15 patients with treatment-resistant depression at four different time-points throughout the entire course of an ECT protocol and 10 healthy participants at two functional neuroimaging examinations. Furthermore, a path analysis to test direct and indirect predictive effects of limbic and prefrontal FC changes on clinical response measured with the Hamilton Rating Scale for Depression was also performed. An early significant intralimbic FC decrease significantly predicted a later increase in limbic-prefrontal FC, which in turn significantly predicted clinical improvement at the end of an ECT course. Our data support that treatment response involves sequential changes in FC within regions of the intralimbic and limbic-prefrontal networks. This approach may help in identifying potential early biomarkers of treatment response. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Childhood trauma and the limbic network: a multimodal MRI study in patients with bipolar disorder and controls.

    PubMed

    Souza-Queiroz, Julia; Boisgontier, Jennifer; Etain, Bruno; Poupon, Cyril; Duclap, Delphine; d'Albis, Marc-Antoine; Daban, Claire; Hamdani, Nora; Le Corvoisier, Philippe; Delavest, Marine; Bellivier, Frank; Guevara, Pamela; Leboyer, Marion; Henry, Chantal; Houenou, Josselin

    2016-08-01

    Childhood trauma (CT) is a major risk factor for psychiatric conditions. It is hypothesized that CT effects are mediated by the limbic system. Few multimodal neuroimaging studies allow an integrated perspective of this impact. Our goal was thus to study the effects of CT on the limbic network. We acquired multimodal MRI (T1, diffusion weighted, and resting state fMRI) data from 79 subjects (47 healthy controls and 32 patients with bipolar disorder, BD). We performed correlational analyses between Childhood Trauma Questionnaire (sub)scores (physical and emotional abuse/neglect and sexual abuse) and anatomo-functional measurements of the limbic network (hippocampal and amygdala volumes, prefronto-limbic functional connectivity, uncinate fractional anisotropy). We found CTQ total scores to be negatively correlated with amygdala volume, prefronto-limbic functional connectivity (FC) and uncinate fractional anisotropy in our sample. Considering subscores, neglects (physical and emotional) were the only to affect neural parameters. The patients with BD drove most of the results. Small sample size and low level of trauma in controls. Our multimodal approach enabled an integrated view of the long-term effects of CT on the limbic system. Copyright © 2016 Elsevier B.V. All rights reserved.

  9. Short-term ethanol exposure causes imbalanced neurotrophic factor allocation in the basal forebrain cholinergic system: a novel insight into understanding the initial processes of alcohol addiction.

    PubMed

    Miki, Takanori; Kusaka, Takashi; Yokoyama, Toshifumi; Ohta, Ken-ichi; Suzuki, Shingo; Warita, Katsuhiko; Jamal, Mostofa; Wang, Zhi-Yu; Ueki, Masaaki; Liu, Jun-Qian; Yakura, Tomiko; Tamai, Motoki; Sumitani, Kazunori; Hosomi, Naohisa; Takeuchi, Yoshiki

    2014-02-01

    Alcohol ingestion affects both motor and cognitive functions. One brain system that is influenced by ethanol is the basal forebrain (BF) cholinergic projection system, which projects to diverse neocortical and limbic areas. The BF is associated with memory and cognitive function. Our primary interest is the examination of how regions that receive BF cholinergic projections are influenced by short-term ethanol exposure through alterations in the mRNA levels of neurotrophic factors [nerve growth factor/TrkA, brain-derived neurotrophic factor/TrkB, and glial-derived neurotrophic factor (GDNF)/GDNF family receptor α1]. Male BALB/C mice were fed a liquid diet containing 5 % (v/v) ethanol. Pair-fed control mice were maintained on an identical liquid diet, except that the ethanol was isocalorically substituted with sucrose. Mice exhibiting signs of ethanol intoxication (stages 1-2) were used for real-time reverse transcription-polymerase chain reaction analyses. Among the BF cholinergic projection regions, decreased levels of GDNF mRNA and increased levels of TrkB mRNA were observed in the basal nucleus, and increased levels of TrkB mRNA were observed in the cerebral cortex. There were no significant alterations in the levels of expression of relevant neurotrophic factors in the septal nucleus and hippocampus. Given that neurotrophic factors function in retrograde/anterograde or autocrine/paracrine mechanisms and that BF cholinergic projection regions are neuroanatomically connected, these findings suggested that an imbalanced allocation of neurotrophic factor ligands and receptors is an initial phenomenon in alcohol addiction. The exact mechanisms underlying this phenomenon in the BF cholinergic system are unknown. However, our results provide a novel notion for the understanding of the initial processes in alcohol addiction.

  10. Involvement of endothelins in deoxycorticosterone acetate-salt hypertension through the modulation of noradrenergic transmission in the rat posterior hypothalamus.

    PubMed

    Abramoff, Tamara; Guil, María J; Morales, Vanina P; Hope, Sandra I; Höcht, Christian; Bianciotti, Liliana G; Vatta, Marcelo S

    2015-06-01

    What is the central question of this study? Does ex vivo administration of endothelin-1 and endothelin-3 regulate noradrenergic transmission in the posterior hypothalamus of deoxycorticosterone acetate-salt hypertensive rats compared with normotensive rats? What is the main finding and its importance? Endothelin-1 and endothelin-3 enhanced diverse mechanisms leading to increased noradrenergic transmission in the posterior hypothalamus of deoxycorticosterone acetate-salt hypertensive rats. Unveiling the role of brain endothelins in hypertension would probably favour the development of new therapeutic targets for the treatment of essential hypertension, which still represents a challenging disease with high mortality. Brain catecholamines participate in diverse biological functions regulated by the hypothalamus. We have previously reported that endothelin-1 and endothelin-3 (ET-1 and ET-3) modulate catecholaminergic activity in the anterior and posterior hypothalamus of normotensive rats. The aim of the present study was to evaluate the interaction between endothelins and noradrenergic transmission in the posterior hypothalamus of deoxycorticosterone acetate (DOCA)-salt hypertensive rats. We assessed the effects of ET-1 and ET-3 on tyrosine hydroxylase activity and expression, neuronal noradrenaline (NA) release, neuronal NA transporter (NAT) activity and expression, monoamine oxidase activity and NA endogenous content and utilization (as a marker of turnover) in the posterior hypothalamus of DOCA-salt hypertensive rats. In addition, levels of ETA and ETB receptors were assayed in normotensive and hypertensive rats. Results showed that tyrosine hydroxylase activity and total and phosphorylated levels, NAT activity and content, NA release, monoamine oxidase activity and NA utilization were increased in DOCA-salt rats. Both ET-1 and ET-3 further enhanced all noradrenergic parameters except for total tyrosine hydroxylase level and NA endogenous content and utilization

  11. Lesion of the bulbospinal noradrenergic pathways blocks desipramine-induced inhibition of the C-fiber evoked nociceptive reflex in rats.

    PubMed

    Hernández, A; Laurido, C; Mondaca, M; Pelissier, T; Burgos, H; Soto-Moyano, R

    2001-04-13

    Desipramine-induced inhibition of spinal cord nociceptive transmission was studied in rats with or without lesion of the bulbospinal noradrenergic system by recording the C-fiber evoked nociceptive reflex from a hind limb. Bulbospinal noradrenergic projections were lesioned by injecting intrathecally 20 microg of 6-hydroxydopamine 2 weeks before the electrophysiological experiments. Results show that desipramine (5, 10 and 20 mg/kg intraperitoneally) produced dose-dependent inhibition of the C reflex response duration in rats having intact noradrenergic bulbospinal systems. The inhibitory effect of desipramine was reduced or even abolished in rats pre-treated with 6-hydroxydopamine. In addition, [3H]-noradrenaline uptake was significantly lower in spinal cord slices arising from 6-hydroxydopamine lesioned animals, as compared to that from intact rats. These observations support the notion that the antinociceptive activity of antidepressants with noradrenergic selectivity depends on a normal rate of endogenous noradrenaline released by bulbospinal neurons.

  12. Noradrenergic afferents and receptors in the medial preoptic area: neuroanatomical and neurochemical links between the regulation of sleep and body temperature.

    PubMed

    Kumar, Velayudhan Mohan; Vetrivelan, Ramalingam; Mallick, Hruda Nanda

    2007-05-01

    Several studies have shown the importance of the medial preoptic area in the regulation of sleep-wakefulness and of body temperature. The medial preoptic area has a rich noradrenergic innervation, coming mostly from the lateral tegmental noradrenergic system. The accumulating evidences show that the noradrenergic afferents to the medial preoptic area are involved in the induction of sleep. This hypnogenic mechanism operates through the postsynaptic alpha1 and alpha2-adrenergic receptors. Noradrenergic afferents are also involved in the thermoregulatory mechanisms, and the activation of these fibers brings about a fall in body temperature. Though the body temperature changes are brought about by the same receptor subtypes as those involved in hypnogenesis, observations suggest the possibility of separate sets of noradrenergic afferents in the medial preoptic area for sleep regulation and thermoregulation. In this review, we present the compelling evidences, which showed that the noradrenergic afferents of the medial preoptic area bring about a fall in body temperature and other thermoregulatory behavioral alterations associated with sleep.

  13. Eph/Ephrin signalling maintains eye field segregation from adjacent neural plate territories during forebrain morphogenesis

    PubMed Central

    Cavodeassi, Florencia; Ivanovitch, Kenzo; Wilson, Stephen W.

    2013-01-01

    During forebrain morphogenesis, there is extensive reorganisation of the cells destined to form the eyes, telencephalon and diencephalon. Little is known about the molecular mechanisms that regulate region-specific behaviours and that maintain the coherence of cell populations undergoing specific morphogenetic processes. In this study, we show that the activity of the Eph/Ephrin signalling pathway maintains segregation between the prospective eyes and adjacent regions of the anterior neural plate during the early stages of forebrain morphogenesis in zebrafish. Several Ephrins and Ephs are expressed in complementary domains in the prospective forebrain and combinatorial abrogation of their activity results in incomplete segregation of the eyes and telencephalon and in defective evagination of the optic vesicles. Conversely, expression of exogenous Ephs or Ephrins in regions of the prospective forebrain where they are not usually expressed changes the adhesion properties of the cells, resulting in segregation to the wrong domain without changing their regional fate. The failure of eye morphogenesis in rx3 mutants is accompanied by a loss of complementary expression of Ephs and Ephrins, suggesting that this pathway is activated downstream of the regional fate specification machinery to establish boundaries between domains undergoing different programmes of morphogenesis. PMID:24026122

  14. Basal forebrain moderates the magnitude of task-dependent amygdala functional connectivity

    PubMed Central

    Knodt, Annchen R.; Hariri, Ahmad R.

    2015-01-01

    Animal studies reveal that the amygdala promotes attention and emotional memory, in part, by driving activity in downstream target regions including the prefrontal cortex (PFC) and hippocampus. Prior work has demonstrated that the amygdala influences these regions directly through monosynaptic glutamatergic signaling, and indirectly by driving activity of the cholinergic basal forebrain and subsequent downstream acetylcholine release. Yet to date, no work has addressed the functional relevance of the cholinergic basal forebrain in facilitating signaling from the amygdala in humans. We set out to determine how blood oxygen level-dependent signal within the amygdala and cholinergic basal forebrain interact to predict neural responses within downstream targets. Here, we use functional connectivity analyses to demonstrate that the cholinergic basal forebrain moderates increased amygdala connectivity with both the PFC and the hippocampus during the processing of biologically salient stimuli in humans. We further demonstrate that functional variation within the choline transporter gene predicts the magnitude of this modulatory effect. Collectively, our results provide novel evidence for the importance of cholinergic signaling in modulating neural pathways supporting arousal, attention and memory in humans. Further, our results may shed light on prior association studies linking functional variation within the choline transporter gene and diagnoses of major depression and attention-deficit hyperactivity disorder. PMID:24847112

  15. Identification of the optic recess region as a morphogenetic entity in the zebrafish forebrain.

    PubMed

    Affaticati, Pierre; Yamamoto, Kei; Rizzi, Barbara; Bureau, Charlotte; Peyriéras, Nadine; Pasqualini, Catherine; Demarque, Michaël; Vernier, Philippe

    2015-03-04

    Regionalization is a critical, highly conserved step in the development of the vertebrate brain. Discrepancies exist in how regionalization of the anterior vertebrate forebrain is conceived since the "preoptic area" is proposed to be a part of the telencephalon in tetrapods but not in teleost fish. To gain insight into this complex morphogenesis, formation of the anterior forebrain was analyzed in 3D over time in zebrafish embryos, combining visualization of proliferation and differentiation markers, with that of developmental genes. We found that the region containing the preoptic area behaves as a coherent morphogenetic entity, organized around the optic recess and located between telencephalon and hypothalamus. This optic recess region (ORR) makes clear borders with its neighbor areas and expresses a specific set of genes (dlx2a, sim1a and otpb). We thus propose that the anterior forebrain (secondary prosencephalon) in teleosts contains three morphogenetic entities (telencephalon, ORR and hypothalamus), instead of two (telencephalon and hypothalamus). The ORR in teleosts could correspond to "telencephalic stalk area" and "alar hypothalamus" in tetrapods, resolving current inconsistencies in the comparison of basal forebrain among vertebrates.

  16. TrkA Gene Ablation in Basal Forebrain Results in Dysfunction of the Cholinergic Circuitry

    PubMed Central

    Sanchez-Ortiz, Efrain; Yui, Daishi; Song, Dongli; Li, Yun; Rubenstein, John L.; Reichardt, Louis F.; Parada, Luis F.

    2012-01-01

    Dysfunction of basal forebrain cholinergic neurons (BFCNs) is an early pathological hallmark of Alzheimer's disease (AD). Numerous studies have indicated that nerve growth factor (NGF) supports survival and phenotypic differentiation of BFCNs. Consistent with a potential link to AD pathogenesis, TrkA, a NGF receptor, is expressed in cholinergic forebrain neuronal populations including those in basal forebrain (BF) and striatum, and is markedly reduced in individuals with mild cognitive impairment (MCI) without dementia and early-stage AD. To investigate the role of TrkA in the development, connectivity, and function of the BF cholinergic system and its contribution to AD pathology, we have generated a forebrain-specific conditional TrkA knockout mouse line. Our findings show a key role for TrkA signaling in establishing the BF cholinergic circuitry through the ERK pathway, and demonstrate that the normal developmental increase of choline acetyltransferase (ChAT) expression becomes critically dependent on TrkA signaling before neuronal connections are established. Moreover, the anatomical and physiological deficits caused by lack of TrkA signaling in BFCNs have selective impact on cognitive activity. These data demonstrate that TrkA loss results in cholinergic BF dysfunction and cognitive decline that is reminiscent of MCI and early AD. PMID:22442072

  17. Fgf19 regulated by Hh signaling is required for zebrafish forebrain development.

    PubMed

    Miyake, Ayumi; Nakayama, Yoshiaki; Konishi, Morichika; Itoh, Nobuyuki

    2005-12-01

    Fibroblast growth factor (Fgf) signaling plays important roles in brain development. Fgf3 and Fgf8 are crucial for the formation of the forebrain and hindbrain. Fgf8 is also required for the midbrain to form. Here, we identified zebrafish Fgf19 and examined its roles in brain development by knocking down Fgf19 function. We found that Fgf19 expressed in the forebrain, midbrain and hindbrain was involved in cell proliferation and cell survival during embryonic brain development. Fgf19 was also essential for development of the ventral telencephalon and diencephalon. Regional specification is linked to cell type specification. Fgf19 was also essential for the specification of gamma-aminobutyric acid (GABA)ergic interneurons and oligodendrocytes generated in the ventral telencephalon and diencephalon. The cross talk between Fgf and Hh signaling is critical for brain development. In the forebrain, Fgf19 expression was down-regulated on inhibition of Hh but not of Fgf3/Fgf8, and overexpression of Fgf19 rescued partially the phenotype on inhibition of Hh. The present findings indicate that Fgf19 signaling is crucial for forebrain development by interacting with Hh and provide new insights into the roles of Fgf signaling in brain development.

  18. GABAergic terminals are a source of galanin to modulate cholinergic neuron development in the neonatal forebrain.

    PubMed

    Keimpema, Erik; Zheng, Kang; Barde, Swapnali Shantaram; Berghuis, Paul; Dobszay, Márton B; Schnell, Robert; Mulder, Jan; Luiten, Paul G M; Xu, Zhiqing David; Runesson, Johan; Langel, Ülo; Lu, Bai; Hökfelt, Tomas; Harkany, Tibor

    2014-12-01

    The distribution and (patho-)physiological role of neuropeptides in the adult and aging brain have been extensively studied. Galanin is an inhibitory neuropeptide that can coexist with γ-aminobutyric acid (GABA) in the adult forebrain. However, galanin's expression sites, mode of signaling, impact on neuronal morphology, and colocalization with amino acid neurotransmitters during brain development are less well understood. Here, we show that galaninergic innervation of cholinergic projection neurons, which preferentially express galanin receptor 2 (GalR2) in the neonatal mouse basal forebrain, develops by birth. Nerve growth factor (NGF), known to modulate cholinergic morphogenesis, increases GalR2 expression. GalR2 antagonism (M871) in neonates reduces the in vivo expression and axonal targeting of the vesicular acetylcholine transporter (VAChT), indispensable for cholinergic neurotransmission. During cholinergic neuritogenesis in vitro, GalR2 can recruit Rho-family GTPases to induce the extension of a VAChT-containing primary neurite, the prospective axon. In doing so, GalR2 signaling dose-dependently modulates directional filopodial growth and antagonizes NGF-induced growth cone differentiation. Galanin accumulates in GABA-containing nerve terminals in the neonatal basal forebrain, suggesting its contribution to activity-driven cholinergic development during the perinatal period. Overall, our data define the cellular specificity and molecular complexity of galanin action in the developing basal forebrain. © The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  19. Extensive Lesions of Cholinergic Basal Forebrain Neurons Do Not Impair Spatial Working Memory

    ERIC Educational Resources Information Center

    Vuckovich, Joseph A.; Semel, Mara E.; Baxter, Mark G.

    2004-01-01

    A recent study suggests that lesions to all major areas of the cholinergic basal forebrain in the rat (medial septum, horizontal limb of the diagonal band of Broca, and nucleus basalis magnocellularis) impair a spatial working memory task. However, this experiment used a surgical technique that may have damaged cerebellar Purkinje cells. The…

  20. Forebrain metabolic activation induced by the repetition of audiogenic seizures in Wistar rats.

    PubMed

    Pereira de Vasconcelos, A; Vergnes, M; Boyet, S; Marescaux, C; Nehlig, A

    1997-07-11

    In Wistar rats susceptible to audiogenic seizures (Wistar AS) inbred in our laboratory, the exposure to an intense sound induces an epileptic seizure characterized by a running episode followed by a tonic phase showing the major involvement of brainstem structures. After 10-20 sound-induced seizures, development of facial and forelimb clonus and/or tonic-clonic seizures characterize the generalization from brainstem to the forebrain as a result of seizure repetition. In order to specify the anatomical substrates of repeated audiogenic seizures in Wistar AS, we used the 2-deoxyglucose (2DG) technique over a 5 min period to map the midbrain and forebrain structures activated by audiogenic seizures before and after seizure repetition. In naive Wistar AS, six of the 22 structures showed a significant 20-56% increase in relative optical densities compared to non-epileptic controls; these were central and medial amygdala nuclei, perirhinal cortex, medial septum, subthalamic and caudate nuclei. In kindled Wistar AS, 12 additional structures showed a significant 16-121% increase in 2DG labeling. These structures were the substantia nigra, all layers of the hippocampus, the basolateral amygdala, three thalamic nuclei, the frontal motor and prefrontal cortices. In conclusion, the metabolic activation of midbrain and forebrain areas in kindled versus naive Wistar AS rats reflects the changes in the nature of the seizures and the involvement of these structures in the spread of seizure activity from the brainstem to the forebrain during seizure repetition.

  1. Extensive Lesions of Cholinergic Basal Forebrain Neurons Do Not Impair Spatial Working Memory

    ERIC Educational Resources Information Center

    Vuckovich, Joseph A.; Semel, Mara E.; Baxter, Mark G.

    2004-01-01

    A recent study suggests that lesions to all major areas of the cholinergic basal forebrain in the rat (medial septum, horizontal limb of the diagonal band of Broca, and nucleus basalis magnocellularis) impair a spatial working memory task. However, this experiment used a surgical technique that may have damaged cerebellar Purkinje cells. The…

  2. TASK Channels on Basal Forebrain Cholinergic Neurons Modulate Electrocortical Signatures of Arousal by Histamine

    PubMed Central

    Vu, Michael T.; Du, Guizhi; Bayliss, Douglas A.

    2015-01-01

    Basal forebrain cholinergic neurons are the main source of cortical acetylcholine, and their activation by histamine elicits cortical arousal. TWIK-like acid-sensitive K+ (TASK) channels modulate neuronal excitability and are expressed on basal forebrain cholinergic neurons, but the role of TASK channels in the histamine-basal forebrain cholinergic arousal circuit is unknown. We first expressed TASK channel subunits and histamine Type 1 receptors in HEK cells. Application of histamine in vitro inhibited the acid-sensitive K+ current, indicating a functionally coupled signaling mechanism. We then studied the role of TASK channels in modulating electrocortical activity in vivo using freely behaving wild-type (n = 12) and ChAT-Cre:TASKf/f mice (n = 12), the latter lacking TASK-1/3 channels on cholinergic neurons. TASK channel deletion on cholinergic neurons significantly altered endogenous electroencephalogram oscillations in multiple frequency bands. We then identified the effect of TASK channel deletion during microperfusion of histamine into the basal forebrain. In non-rapid eye movement sleep, TASK channel deletion on cholinergic neurons significantly attenuated the histamine-induced increase in 30–50 Hz activity, consistent with TASK channels contributing to histamine action on basal forebrain cholinergic neurons. In contrast, during active wakefulness, histamine significantly increased 30–50 Hz activity in ChAT-Cre:TASKf/f mice but not wild-type mice, showing that the histamine response depended upon the prevailing cortical arousal state. In summary, we identify TASK channel modulation in response to histamine receptor activation in vitro, as well as a role of TASK channels on cholinergic neurons in modulating endogenous oscillations in the electroencephalogram and the electrocortical response to histamine at the basal forebrain in vivo. SIGNIFICANCE STATEMENT Attentive states and cognitive function are associated with the generation of γ EEG activity

  3. Exercise-induced noradrenergic activation enhances memory consolidation in both normal aging and patients with amnestic mild cognitive impairment.

    PubMed

    Segal, Sabrina K; Cotman, Carl W; Cahill, Lawrence F

    2012-01-01

    Post-trial pharmacological activation of the noradrenergic system can facilitate memory consolidation. Because exercise activates the locus coeruleus and increases brain norepinephrine release, we hypothesized that post-trial exercise could function as a natural stimulus to enhance memory consolidation. We investigated this in amnestic mild cognitive impairment (aMCI) and cognitively normal elderly individuals by examining the effects of an acute bout of post-learning, aerobic exercise (6 minutes at 70% VO2 max on a stationary bicycle) on memory for some emotional images. Exercise significantly elevated endogenous norepinephrine (measured via the biomarker, salivary alpha-amylase) in both aMCI patients and controls. Additionally, exercise retrogradely enhanced memory in both aMCI patients and controls. Acute exercise that activates the noradrenergic system may serve as a beneficial, natural, and practical therapeutic intervention for cognitive decline in the aging population.

  4. Ultrastructural evidence for synaptic contacts between cortical noradrenergic afferents and endocannabinoid-synthesizing post-synaptic neurons

    PubMed Central

    Reyes, Beverly A. S.; Heldt, Nathan A.; Mackie, Ken; Van Bockstaele, Elisabeth J.

    2015-01-01

    Endocannabinoids (eCBs) are involved in a myriad of physiological processes that are mediated through the activation of cannabinoid receptors, which are ubiquitously distributed within the nervous system. One neurochemical target at which cannabinoids interact to have global effects on behavior is brain noradrenergic circuitry. We, and others, have previously shown that CB type 1 receptors (CB1r) are positioned to pre-synaptically modulate norepinephrine (NE) release in the rat frontal cortex (FC). Diacylglycerol lipase (DGL) is a key enzyme in the biosynthesis of the endocannabinoid 2-arachidonoylglycerol (2-AG). While DGL-α is expressed in the FC in the rat brain, it is not known whether noradrenergic afferents target neurons expressing synthesizing enzymes for the endocannabinoid, 2-AG. In the present study, we employed high-resolution neuroanatomical approaches to better define cellular sites for interactions between noradrenergic afferents and FC neurons expressing DGL-α. Immunofluorescence microscopy showed close appositions between processes containing the norepinephrine transporter (NET) or dopamine-β-hydroxylase (DβH) and cortical neurons expressing DGL-α-immunoreactivity. Ultrastructural analysis using immunogold-silver labeling for DGL-α and immunoperoxidase labeling for NET or DβH confirmed that NET-labeled axon terminals were directly apposed to FC somata and dendritic processes that exhibited DGL-α-immunoreactivity. Finally, tissue sections were processed for immunohistochemical detection of DGL-α , CB1r and DβH. Triple label immunofluorescence revealed that CB1r and DβH were co-localized in common cellular profiles and these were in close association with DGL-α. Taken together, these data provide anatomical evidence for direct synaptic associations between noradrenergic afferents and cortical neurons exhibiting endocannabinoid synthesizing machinery. PMID:26162236

  5. Central noradrenergic lesion induced by DSP-4 impairs the acquisition of avoidance reactions and prevents molecular changes in the amygdala.

    PubMed

    Radwanska, Kasia; Nikolaev, Evgenij; Kaczmarek, Leszek

    2010-10-01

    The noradrenergic system plays and an important modulatory role in memory consolidation of emotionally arousing tasks. However, the molecular cascades regulated in the brain by norepinephrine and involved in memory formation are still largely unknown. The purpose of the present study was to evaluate the role of the noradrenergic system on the acquisition of a highly emotionally arousing task-two-way active avoidance training-and its molecular and cellular substrates. The selective norepinephrine neurotoxin N-(2-chloroethyl)-N-ethyl-2 bromobenzylamine (DSP-4, 50mg/kg) was used. DSP-4-treated rats were trained in a shuttle box to avoid a footshock signaled by an auditory stimulus. Immunohistochemical mapping of the neuronal plasticity-related molecules c-Fos protein and the activated form of extracellular signal-regulated kinase (phosphorylated ERK [pERK]) was then employed. We found that DSP-4 treatment depleted the expression of the norepinephrine marker dopamine -hydroxylase (DBH) in the locus coeruleus and its projection area, the basolateral nucleus of the amygdala, confirming locus coeruleus noradrenergic lesion in the experimental animals. Furthermore, DSP-4 treatment impaired the acquisition of the avoidance reaction. We also found that acquisition of the active avoidance reaction induced c-Fos expression and ERK activation in the amygdala and piriform cortex. This upregulation was prevented by DSP-4 treatment. Thus, our data suggest that the noradrenergic system is involved in the acquisition of the active avoidance reaction by regulating ERK pathway activity and c-Fos expression in the amygdala and piriform cortex.

  6. Monosynaptic Glutamatergic Activation of Locus Coeruleus and Other Lower Brainstem Noradrenergic Neurons by the C1 Cells in Mice

    PubMed Central

    Holloway, Benjamin B.; Stornetta, Ruth L.; Bochorishvili, Genrieta; Erisir, Alev; Viar, Kenneth E.

    2013-01-01

    The C1 neurons, located in the rostral ventrolateral medulla (VLM), are activated by pain, hypotension, hypoglycemia, hypoxia, and infection, as well as by psychological stress. Prior work has highlighted the ability of these neurons to increase sympathetic tone, hence peripheral catecholamine release, probably via their direct excitatory projections to sympathetic preganglionic neurons. In this study, we use channelrhodopsin-2 (ChR2) optogenetics to test whether the C1 cells are also capable of broadly activating the brain's noradrenergic system. We selectively expressed ChR2(H134R) in rostral VLM catecholaminergic neurons by injecting Cre-dependent adeno-associated viral vectors into the brain of adult dopamine-β-hydroxylase (DβH)Cre/0 mice. Most ChR2-expressing VLM neurons (75%) were immunoreactive for phenylethanolamine N-methyl transferease, thus were C1 cells, and most of the ChR2-positive axonal varicosities were immunoreactive for vesicular glutamate transporter-2 (78%). We produced light microscopic evidence that the axons of rostral VLM (RVLM) catecholaminergic neurons contact locus coeruleus, A1, and A2 noradrenergic neurons, and ultrastructural evidence that these contacts represent asymmetric synapses. Using optogenetics in tissue slices, we show that RVLM catecholaminergic neurons activate the locus coeruleus as well as A1 and A2 noradrenergic neurons monosynaptically by releasing glutamate. In conclusion, activation of RVLM catecholaminergic neurons, predominantly C1 cells, by somatic or psychological stresses has the potential to increase the firing of both peripheral and central noradrenergic neurons. PMID:24285886

  7. Optogenetic Dissection of the Basal Forebrain Neuromodulatory Control of Cortical Activation, Plasticity, and Cognition.

    PubMed

    Lin, Shih-Chieh; Brown, Ritchie E; Hussain Shuler, Marshall G; Petersen, Carl C H; Kepecs, Adam

    2015-10-14

    The basal forebrain (BF) houses major ascending projections to the entire neocortex that have long been implicated in arousal, learning, and attention. The disruption of the BF has been linked with major neurological disorders, such as coma and Alzheimer's disease, as well as in normal cognitive aging. Although it is best known for its cholinergic neurons, the BF is in fact an anatomically and neurochemically complex structure. Recent studies using transgenic mouse lines to target specific BF cell types have led to a renaissance in the study of the BF and are beginning to yield new insights about cell-type-specific circuit mechanisms during behavior. These approaches enable us to determine the behavioral conditions under which cholinergic and noncholinergic BF neurons are activated and how they control cortical processing to influence behavior. Here we discuss recent advances that have expanded our knowledge about this poorly understood brain region and laid the foundation for future cell-type-specific manipulations to modulate arousal, attention, and cortical plasticity in neurological disorders. Although the basal forebrain is best known for, and often equated with, acetylcholine-containing neurons that provide most of the cholinergic innervation of the neocortex, it is in fact an anatomically and neurochemically complex structure. Recent studies using transgenic mouse lines to target specific cell types in the basal forebrain have led to a renaissance in this field and are beginning to dissect circuit mechanisms in the basal forebrain during behavior. This review discusses recent advances in the roles of basal forebrain cholinergic and noncholinergic neurons in cognition via their dynamic modulation of cortical activity. Copyright © 2015 the authors 0270-6474/15/3513896-08$15.00/0.

  8. Optogenetic Dissection of the Basal Forebrain Neuromodulatory Control of Cortical Activation, Plasticity, and Cognition

    PubMed Central

    Brown, Ritchie E.; Hussain Shuler, Marshall G.; Petersen, Carl C.H.; Kepecs, Adam

    2015-01-01

    The basal forebrain (BF) houses major ascending projections to the entire neocortex that have long been implicated in arousal, learning, and attention. The disruption of the BF has been linked with major neurological disorders, such as coma and Alzheimer's disease, as well as in normal cognitive aging. Although it is best known for its cholinergic neurons, the BF is in fact an anatomically and neurochemically complex structure. Recent studies using transgenic mouse lines to target specific BF cell types have led to a renaissance in the study of the BF and are beginning to yield new insights about cell-type-specific circuit mechanisms during behavior. These approaches enable us to determine the behavioral conditions under which cholinergic and noncholinergic BF neurons are activated and how they control cortical processing to influence behavior. Here we discuss recent advances that have expanded our knowledge about this poorly understood brain region and laid the foundation for future cell-type-specific manipulations to modulate arousal, attention, and cortical plasticity in neurological disorders. SIGNIFICANCE STATEMENT Although the basal forebrain is best known for, and often equated with, acetylcholine-containing neurons that provide most of the cholinergic innervation of the neocortex, it is in fact an anatomically and neurochemically complex structure. Recent studies using transgenic mouse lines to target specific cell types in the basal forebrain have led to a renaissance in this field and are beginning to dissect circuit mechanisms in the basal forebrain during behavior. This review discusses recent advances in the roles of basal forebrain cholinergic and noncholinergic neurons in cognition via their dynamic modulation of cortical activity. PMID:26468190

  9. TDP-43 pathology in the basal forebrain and hypothalamus of patients with amyotrophic lateral sclerosis.

    PubMed

    Cykowski, Matthew D; Takei, Hidehiro; Schulz, Paul E; Appel, Stanley H; Powell, Suzanne Z

    2014-12-24

    Amyotrophic lateral sclerosis is a neurodegenerative disease characterized clinically by motor symptoms including limb weakness, dysarthria, dysphagia, and respiratory compromise, and pathologically by inclusions of transactive response DNA-binding protein 43 kDa (TDP-43). Patients with amyotrophic lateral sclerosis also may demonstrate non-motor symptoms and signs of autonomic and energy dysfunction as hypermetabolism and weight loss that suggest the possibility of pathology in the forebrain, including hypothalamus. However, this region has received little investigation in amyotrophic lateral sclerosis. In this study, the frequency, topography, and clinical associations of TDP-43 inclusion pathology in the basal forebrain and hypothalamus were examined in 33 patients with amyotrophic lateral sclerosis: 25 men and 8 women; mean age at death of 62.7 years, median disease duration of 3.1 years (range of 1.3 to 9.8 years). TDP-43 pathology was present in 11 patients (33.3%), including components in both basal forebrain (n=10) and hypothalamus (n=7). This pathology was associated with non-motor system TDP-43 pathology (Χ2=17.5, p=0.00003) and bulbar symptoms at onset (Χ2=4.04, p=0.044), but not age or disease duration. Furthermore, TDP-43 pathology in the lateral hypothalamic area was associated with reduced body mass index (W=11, p=0.023). This is the first systematic demonstration of pathologic involvement of the basal forebrain and hypothalamus in amyotrophic lateral sclerosis. Furthermore, the findings suggest that involvement of the basal forebrain and hypothalamus has significant phenotypic associations in amyotrophic lateral sclerosis, including site of symptom onset, as well as deficits in energy metabolism with loss of body mass index.

  10. The role of the septo-hippocampal system and its noradrenergic afferents in behavioural responses to none-reward.

    PubMed

    Gray, J A; Feldon, J; Rawlins, J N; Owen, S; McNaughton, N

    1977-01-01

    Our experiments were designed with two purposes: (i) to examine the effects on one behaviour of differing interventions in the septo-hippocampal system; (ii) to compare these effects with those of minor tranquillizers. The behaviour studied (in rats) is extinction in the alley after continuous (CRF) or partial (PRF) reinforcement. Minor tranquillizers and large septal lesions produce three effects: (1) resistance to extinction is increased after CRF; (2) resistance to extinction is decreased after PRF; (3) the partial reinforcement extinction effect (PREE) is abolished. Small septal lesions fractionate this syndrome: either effect (1) or an actual increase in the size of the PREE is produced by medial septal lesions abolishing hippocampal theta; effects (2) and (3), but not (1), are produced by lateral septal lesions sparing theta. Dorso-medial fornix section, abolishing theta, reproduces the effects of medial septal lesions. Fimbrial section, sparing theta, reproduces some of the effects of lateral septal lesions. Minor tranquillizers produce a rise in the threshold for septal driving of hippocampal theta specifically at 7.7 Hz. This effect is reproduced by blockade of noradrenergic transmission or destruction of the dorsal noradrenergic bundle with 6-hydroxydopamine. This lesion reproduces all three behavioural changes listed above. These results suggest a model for the role of the septo-hippocampal system and its noradrenergic inputs in the PREE. This model is compared with other approaches to the septo-hippocampal system.

  11. Differential sensitivity of intranuclear and systemic oxytocin release to central noradrenergic receptor stimulation during mid- and late gestation in rats.

    PubMed

    Lipschitz, David L; Crowley, William R; Bealer, Steven L

    2004-09-01

    A number of changes occur in the oxytocin (OT) system during gestation, such as increases in hypothalamic OT mRNA, increased neural lobe and systemic OT, and morphological and electrophysiological changes in OT-containing magnocellular neurons, suggestive of altered neuronal sensitivity, which may be mediated by ovarian steroids. Because central norepinephrine (NE) and histamine (HA) are potent stimulators of OT release during parturition and lactation, the present study investigated the effects of central noradrenergic and histaminergic receptor activation on systemic (NE, HA) and intranuclear (NE) OT release in pregnant rats and in ovariectomized rats treated with ovarian steroids. Plasma OT levels in late gestation were significantly higher compared with all other groups, and neither adrenergic nor histaminergic receptor blockade decreased these elevated levels. Furthermore, the alpha-adrenergic agonist phenylephrine, but not histamine, stimulated systemic OT release to a significantly greater extent in late gestation than in midpregnant, ovariectomized, or steroid-treated females. Although basal extracellular OT levels in the paraventricular nucleus, as measured with microdialysis, were unchanged during pregnancy or steroid treatment, noradrenergic receptor stimulation of intranuclear OT release was significantly elevated in midgestation females compared with all other groups. These studies indicate that sensitivity of intranuclear and systemic OT release to noradrenergic receptor activation differentially varies during the course of gestation.

  12. Timing is everything: does the robust upregulation of noradrenergically regulated plasticity genes underlie the rapid antidepressant effects of sleep deprivation?

    PubMed

    Payne, Jennifer L; Quiroz, Jorge A; Zarate, Carlos A; Manji, Husseini K

    2002-11-15

    The mechanisms by which sleep deprivation brings about rapid antidepressant effects remain to be elucidated. Biological rhythms have the capacity to temporally dissociate biochemical processes, and imposing a temporal coincidence on normally dissociated events can have striking and unexpected effects. In this context, it is noteworthy that the locus coeruleus (LC) noradrenergic projection is quiescent only during rapid-eye-movement (REM) sleep, when the target tissues display their greatest sensitivity; indeed, the temporal dissociation between the firing of the LC noradrenergic neurons and the sensitivity of its postsynaptic targets in the cortex may have considerable relevance for the antidepressant effects of sleep deprivation. Sleep deprivation rapidly upregulates several plasticity-related genes, effects that are noradrenergically mediated; these are the very same genes that are upregulated by chronic antidepressants. Thus, activating the norepinephrine system during REM sleep (by infusing an alpha(2) antagonist) may allow an interaction with a primed, sensitized postsynaptic milieu, thereby rapidly increasing the expression of plasticity genes and consequently a rapid antidepressant response.

  13. REM sleep-like atonia of hypoglossal (XII) motoneurons is caused by loss of noradrenergic and serotonergic inputs.

    PubMed

    Fenik, Victor B; Davies, Richard O; Kubin, Leszek

    2005-11-15

    Studies of hypoglossal (XII) motoneurons that innervate the genioglossus muscle, an upper airway dilator, suggested that the suppression of upper airway motor tone during REM sleep is caused by withdrawal of excitation mediated by norepinephrine and serotonin. Our objectives were to determine whether antagonism of aminergic receptors located in the XII nucleus region can abolish the REM sleep-like atonia of XII motoneurons, and whether both serotonergic and noradrenergic antagonists are required to achieve this effect. REM sleep-like episodes were elicited in anesthetized rats by pontine carbachol injections before and at various times after microinjection of prazosin and methysergide combined, or of only one of the drugs, into the XII nucleus. Spontaneous XII nerve activity was significantly reduced, by 35 to 81%, by each antagonist alone and in combination, indicating that XII motoneurons were under both noradrenergic and serotonergic endogenous excitatory drives. During the 32 to 81 min after microinjections of both antagonists, pontine carbachol caused no depression of XII nerve activity, whereas other characteristic effects (activation of the hippocampal and cortical EEG, and slowing of the respiratory rate) remained intact. A partial recovery of the depressant effect of carbachol then occurred parallel to the recovery of spontaneous XII nerve activity from the depressant effect of the antagonists. Microinjections of either antagonist alone did not eliminate the depressant effect of carbachol. The REM sleep-like depression of XII motoneuronal activity induced by pontine carbachol can be fully accounted for by the combined withdrawal of noradrenergic and serotonergic effects on XII motoneurons.

  14. A2 Noradrenergic Lesions Prevent Renal Sympathoinhibition Induced by Hypernatremia in Rats

    PubMed Central

    Pedrino, Gustavo Rodrigues; Freiria-Oliveira, André Henrique; Almeida Colombari, Débora Simões; Rosa, Daniel Alves; Cravo, Sergio Luiz

    2012-01-01

    Renal vasodilation and sympathoinhibition are recognized responses induced by hypernatremia, but the central neural pathways underlying such responses are not yet entirely understood. Several findings suggest that A2 noradrenergic neurons, which are found in the nucleus of the solitary tract (NTS), play a role in the pathways that contribute to body fluid homeostasis and cardiovascular regulation. The purpose of this study was to determine the effects of selective lesions of A2 neurons on the renal vasodilation and sympathoinhibition induced by hypertonic saline (HS) infusion. Male Wistar rats (280–350 g) received an injection into the NTS of anti-dopamine-beta-hydroxylase-saporin (A2 lesion; 6.3 ng in 60 nl; n = 6) or free saporin (sham; 1.3 ng in 60 nl; n = 7). Two weeks later, the rats were anesthetized (urethane 1.2 g⋅kg−1 b.wt., i.v.) and the blood pressure, renal blood flow (RBF), renal vascular conductance (RVC) and renal sympathetic nerve activity (RSNA) were recorded. In sham rats, the HS infusion (3 M NaCl, 1.8 ml⋅kg−1 b.wt., i.v.) induced transient hypertension (peak at 10 min after HS; 9±2.7 mmHg) and increases in the RBF and RVC (141±7.9% and 140±7.9% of baseline at 60 min after HS, respectively). HS infusion also decreased the RSNA (−45±5.0% at 10 min after HS) throughout the experimental period. In the A2-lesioned rats, the HS infusion induced transient hypertension (6±1.4 mmHg at 10 min after HS), as well as increased RBF and RVC (133±5.2% and 134±6.9% of baseline at 60 min after HS, respectively). However, in these rats, the HS failed to reduce the RSNA (115±3.1% at 10 min after HS). The extent of the catecholaminergic lesions was confirmed by immunocytochemistry. These results suggest that A2 noradrenergic neurons are components of the neural pathways regulating the composition of the extracellular fluid compartment and are selectively involved in hypernatremia-induced sympathoinhibition. PMID:22629424

  15. A1 noradrenergic neurons lesions reduce natriuresis and hypertensive responses to hypernatremia in rats.

    PubMed

    da Silva, Elaine Fernanda; Freiria-Oliveira, André Henrique; Custódio, Carlos Henrique Xavier; Ghedini, Paulo César; Bataus, Luiz Artur Mendes; Colombari, Eduardo; de Castro, Carlos Henrique; Colugnati, Diego Basile; Rosa, Daniel Alves; Cravo, Sergio L D; Pedrino, Gustavo Rodrigues

    2013-01-01

    Noradrenergic neurons in the caudal ventrolateral medulla (CVLM; A1 group) contribute to cardiovascular regulation. The present study assessed whether specific lesions in the A1 group altered the cardiovascular responses that were evoked by hypertonic saline (HS) infusion in non-anesthetized rats. Male Wistar rats (280-340 g) received nanoinjections of antidopamine-β-hydroxylase-saporin (A1 lesion, 0.105 ng.nL(-1)) or free saporin (sham, 0.021 ng.nL(-1)) into their CVLMs. Two weeks later, the rats were anesthetized (2% halothane in O2) and their femoral artery and vein were catheterized and led to exit subcutaneously between the scapulae. On the following day, the animals were submitted to HS infusion (3 M NaCl, 1.8 ml • kg(-1), b.wt., for longer than 1 min). In the sham-group (n = 8), HS induced a sustained pressor response (ΔMAP: 35±3.6 and 11±1.8 mmHg, for 10 and 90 min after HS infusion, respectively; P<0.05 vs. baseline). Ten min after HS infusion, the pressor responses of the anti-DβH-saporin-treated rats (n = 11)were significantly smaller(ΔMAP: 18±1.4 mmHg; P<0.05 vs. baseline and vs. sham group), and at 90 min, their blood pressures reached baseline values (2±1.6 mmHg). Compared to the sham group, the natriuresis that was induced by HS was reduced in the lesioned group 60 min after the challenge (196±5.5 mM vs. 262±7.6 mM, respectively; P<0.05). In addition, A1-lesioned rats excreted only 47% of their sodium 90 min after HS infusion, while sham animals excreted 80% of their sodium. Immunohistochemical analysis confirmed a substantial destruction of the A1 cell group in the CVLM of rats that had been nanoinjected withanti-DβH-saporin. These results suggest that medullary noradrenergic A1 neurons are involved in the excitatory neural pathway that regulates hypertensive and natriuretic responses to acute changes in the composition of body fluid.

  16. Intrathecal immunoglobulin A and G antibodies to synapsin in a patient with limbic encephalitis

    PubMed Central

    Piepgras, Johannes; Höltje, Markus; Otto, Carolin; Harms, Hendrik; Satapathy, Annyesha; Cesca, Fabrizia; Benfenati, Fabio; Gitler, Daniel; Pich, Andreas; Zander, Johannes-Friedrich

    2015-01-01

    Objective: To report on the identification of intrathecally synthesized immunoglobulin A (IgA) and immunoglobulin G (IgG) antibodies to synapsin, a synaptic vesicle-associated protein, in a patient with limbic encephalitis. Methods: Methods included clinical characterization, indirect immunofluorescence, immunoprecipitation, mass spectrometry, immunoblots of wild-type and synapsin I/II/III knockout mice, and cell-based assays with synapsin Ia, Ib, IIa, and IIb plasmids. Results: A 69-year-old man presented with confusion, disorientation, seizures, and left hippocampal hyperintensities on MRI. CSF examinations revealed an intrathecal IgA and IgG synthesis. Except for IgG antibodies to voltage-gated potassium channels in CSF, screening for known neuronal autoantibodies in serum and CSF was negative. However, indirect immunofluorescence using the patient's CSF showed binding of IgA to mouse hippocampus, amygdala, and cerebellum. Immunoprecipitation with CSF IgA followed by mass spectrometry identified synapsin as autoantigenic target. Knockout tissues and cell-based assays confirmed that IgA and IgG in the patient's CSF and serum reacted with synapsin Ia, Ib, and IIa. Calculation of antibody indices proved intrathecal synthesis of anti-synapsin IgA and IgG. The patient responded clinically to immunotherapy but developed left hippocampal atrophy. CSF IgA or IgG of the patient did not bind to live, unfixed, and nonpermeabilized mouse hippocampal neurons, compatible with synapsin being an intracellular antigen. Conclusions: This report identifies isoforms of the synaptic vesicle-associated protein synapsin as targets of intrathecally produced IgA and IgG antibodies in a patient with limbic encephalitis. Future studies should clarify the prevalence and pathogenic relevance of anti-synapsin antibodies in limbic encephalitis. PMID:26587554

  17. Delta FosB and AP-1-mediated transcription modulate cannabinoid CB₁ receptor signaling and desensitization in striatal and limbic brain regions.

    PubMed

    Lazenka, Matthew F; David, Bethany G; Lichtman, Aron H; Nestler, Eric J; Selley, Dana E; Sim-Selley, Laura J

    2014-10-01

    Repeated Δ(9)-tetrahydrocannabinol (THC) administration produces cannabinoid type 1 receptor (CB₁R) desensitization and downregulation, as well as tolerance to its in vivo pharmacological effects. However, the magnitude of CB₁R desensitization varies by brain region, with CB₁Rs in the striatum and its output nuclei undergoing less desensitization than other regions. A growing body of data indicates that regional differences in CB₁R desensitization are produced, in part, by THC-mediated induction of the stable transcription factor, ΔFosB, and subsequent regulation of CB₁Rs. The purpose of the present study was to determine whether THC-mediated induction of ΔFosB in the striatum inhibits CB₁R desensitization in the striatum and output nuclei. This hypothesis was tested using bitransgenic mice with inducible expression of ΔFosB or ΔcJun, a dominant negative inhibitor of AP-1-mediated transcription, in specific forebrain regions. Mice were treated repeatedly with escalating doses of THC or vehicle for 6.5 days, and CB₁R-mediated G-protein activation was assessed using CP55,940-stimulated [(35)S]GTPγS autoradiography. Overexpression of ΔFosB in striatal dopamine type 1 receptor-containing (D1R) medium spiny neurons (MSNs) attenuated CB₁R desensitization in the substantia nigra, ventral tegmental area (VTA) and amygdala. Expression of ΔcJun in striatal D1R- and dopamine type 2 receptor (D2R)-containing MSNs enhanced CB₁R desensitization in the caudate-putamen and attenuated desensitization in the hippocampus and VTA. THC-mediated in vivo pharmacological effects were then assessed in ΔcJun-expressing mice. Tolerance to THC-mediated hypomotility was enhanced in ΔcJun-expressing mice. These data reveal that ΔFosB and possibly other AP-1 binding proteins regulate CB₁R signaling and adaptation in the striatum and limbic system. Copyright © 2014 Elsevier Inc. All rights reserved.

  18. [A case of acute limbic encephalitis with cerebral salt wasting syndrome].

    PubMed

    Nishio, Motonobu; Nishitani, Nobuyuki; Tanaka, Keiko

    2014-01-01

    A 37-year-old woman presented with psychiatric symptoms. Cerebrospinal fluid analysis revealed pleocytosis and increased protein. The patient was diagnosed with limbic encephalitis on the basis of the clinical course. However, remarkable hyponatremia was noted throughout the clinical course, leading to a diagnosis of cerebral salt wasting syndrome (CSWS). The hyponatremia was alleviated by supplementation with sodium and water. The findings seen in this case indicate that differentiation between syndrome of inappropriate of antidiuretic hormone and CSWS is important in cases of hyponatremia accompanied by central nervous system disease.

  19. The prefrontal-limbic system: development, neuroanatomy, function, and implications for socioemotional development.

    PubMed

    Braun, Katharina

    2011-12-01

    The knowledge that neonatal emotional experience and associated learning processes are critical in the maturation of prefronto-limbic circuits emphasizes the importance of preterm and neonatal care. The further improvement of care and intervention strategies requires a deeper understanding of epigenetic mechanisms mediating experience-induced synaptic reorganization underlying the emergence of emotional and cognitive behavioral traits. Interdisciplinary research efforts are needed in which pediatricians and developmental biologists and psychologists merge their knowledge, concepts, and methodology. The hope is that the translational relevance of research efforts can be improved through a greater interaction between basic and clinical scientists.

  20. Potassium channel antibody-associated encephalopathy: a potentially immunotherapy-responsive form of limbic encephalitis.

    PubMed

    Vincent, Angela; Buckley, Camilla; Schott, Jonathan M; Baker, Ian; Dewar, Bonnie-Kate; Detert, Niels; Clover, Linda; Parkinson, Abigail; Bien, Christian G; Omer, Salah; Lang, Bethan; Rossor, Martin N; Palace, Jackie

    2004-03-01

    Patients presenting with subacute amnesia are frequently seen in acute neurological practice. Amongst the differential diagnoses, herpes simplex encephalitis, Korsakoff's syndrome and limbic encephalitis should be considered. Limbic encephalitis is typically a paraneoplastic syndrome with a poor prognosis; thus, identifying those patients with potentially reversible symptoms is important. Voltage-gated potassium channel antibodies (VGKC-Ab) have recently been reported in three cases of reversible limbic encephalitis. Here we review the clinical, immunological and neuropsychological features of 10 patients (nine male, one female; age range 44-79 years), eight of whom were identified in two centres over a period of 15 months. The patients presented with 1-52 week histories of memory loss, confusion and seizures. Low plasma sodium concentrations, initially resistant to treatment, were present in eight out of 10. Brain MRI at onset showed signal change in the medial temporal lobes in eight out of 10 cases. Paraneoplastic antibodies were negative, but VGKC-Ab ranged from 450 to 5128 pM (neurological and healthy controls <100 pM). CSF oligoclonal bands were found in only one, but bands matched with those in the serum were found in six other patients. VGKC-Abs in the CSF, tested in five individuals, varied between <1 and 10% of serum values. Only one patient had neuromyotonia, which was excluded by electromyography in seven of the others. Formal neuropsychology testing showed severe and global impairment of memory, with sparing of general intellect in all but two patients, and of nominal functions in all but one. Variable regimes of steroids, plasma exchange and intravenous immunoglobulin were associated with variable falls in serum VGKC-Abs, to values between 2 and 88% of the initial values, together with marked improvement of neuropsychological functioning in six patients, slight improvement in three and none in one. The improvement in neuropsychological functioning in

  1. Transdermal neuromodulation of noradrenergic activity suppresses psychophysiological and biochemical stress responses in humans

    PubMed Central

    Tyler, William J.; Boasso, Alyssa M.; Mortimore, Hailey M.; Silva, Rhonda S.; Charlesworth, Jonathan D.; Marlin, Michelle A.; Aebersold, Kirsten; Aven, Linh; Wetmore, Daniel Z.; Pal, Sumon K.

    2015-01-01

    We engineered a transdermal neuromodulation approach that targets peripheral (cranial and spinal) nerves and utilizes their afferent pathways as signaling conduits to influence brain function. We investigated the effects of this transdermal electrical neurosignaling (TEN) method on sympathetic physiology under different experimental conditions. The TEN method involved delivering high-frequency pulsed electrical currents to ophthalmic and maxillary divisions of the right trigeminal nerve and cervical spinal nerve afferents. Under resting conditions, TEN significantly suppressed basal sympathetic tone compared to sham as indicated by functional infrared thermography of facial temperatures. In a different experiment, subjects treated with TEN reported significantly lower levels of tension and anxiety on the Profile of Mood States scale compared to sham. In a third experiment when subjects were experimentally stressed TEN produced a significant suppression of heart rate variability, galvanic skin conductance, and salivary α-amylase levels compared to sham. Collectively these observations demonstrate TEN can dampen basal sympathetic tone and attenuate sympathetic activity in response to acute stress induction. Our physiological and biochemical observations are consistent with the hypothesis that TEN modulates noradrenergic signaling to suppress sympathetic activity. We conclude that dampening sympathetic activity in such a manner represents a promising approach to managing daily stress. PMID:26353920

  2. A noradrenergic sensitive endogenous clock is present in the rat pineal gland.

    PubMed

    Wongchitrat, Prapimpun; Felder-Schmittbuhl, Marie-Paule; Govitrapong, Piyarat; Phansuwan-Pujito, Pansiri; Simonneaux, Valérie

    2011-01-01

    The aim of this study was to examine the occurrence of endogenous oscillations of Per1, Per2, Bmal1 and Rev-erbα genes in rat pineal explants and to investigate their regulation by adrenergic ligands. Our results show a significant and sustained rhythm of Per2,Bmal1 and Rev-erbα gene expression for up to 48 h in cultured pineal gland with a pattern similar to that observed in vivo. By contrast, the rhythms of Per1 and Aa-nat, the rate-limiting enzyme for melatonin synthesis, were strongly attenuated after 24 h in culture. Addition of the exogenous adrenergic agonist isoproterenol on cultured pineal glands induced a short-term increase in mRNA levels of Per1 and Aa-nat, but not those of Per2,Bmal1 and Rev-erbα. This study demonstrates that the rat pineal gland hosts a circadian oscillator as evidenced by the sustained, noradrenergic-independent, endogenous oscillations of Per2, Bmal1 and Rev-erbα mRNA levels in cultured tissues. Only expression of Per1 was stimulated by adrenergic ligands suggesting that, in vivo, the adrenergic input could synchronize the pineal clock by acting selectively on Per1.

  3. CRH engagement of the locus coeruleus noradrenergic system mediates stress-induced anxiety

    PubMed Central

    McCall, Jordan G.; Al-Hasani, Ream; Siuda, Edward R.; Hong, Daniel Y.; Norris, Aaron J.; Ford, Christopher P.; Bruchas, Michael R.

    2015-01-01

    Summary The locus coeruleus noradrenergic (LC-NE) system is one of the first systems engaged following a stressful event. While numerous groups have demonstrated that LC-NE neurons are activated by many different stressors, the underlying neural circuitry and the role of this activity in generating stress-induced anxiety has not been elucidated. Using a combination of in vivo chemogenetics, optogenetics, and retrograde tracing we determine that increased tonic activity of the LC-NE system is necessary and sufficient for stress-induced anxiety and aversion. Selective inhibition of LC-NE neurons during stress prevents subsequent anxiety-like behavior. Exogenously increasing tonic, but not phasic, activity of LC-NE neurons is alone sufficient for anxiety-like and aversive behavior. Furthermore, endogenous corticotropin releasing hormone+ (CRH+) LC inputs from the amygdala increase tonic LC activity, inducing anxiety-like behaviors. These studies position the LC-NE system as a critical mediator of acute stress-induced anxiety and offer a potential intervention for preventing stress-related affective disorders. PMID:26212712

  4. α1-Noradrenergic System Role in Increased Motivation for Cocaine Intake in Rats with Prolonged Access

    PubMed Central

    Wee, Sunmee; Mandyam, Chitra D.; Lekic, Dusan M; Koob, George F.

    2008-01-01

    In rodents, extended access to cocaine produces an escalation in cocaine self-administration that has face and construct validity for human compulsive drug intake. Here we report that rats with six-hour access (long access, LgA) to cocaine self-administration produced a higher breakpoint for cocaine using a progressive-ratio schedule than rats with one-hour access (short access, ShA), and prazosin (α1 receptor antagonist) reduced the higher breakpoint for cocaine in LgA rats. Additionally, the number of neurons with α1-adrenergic receptor-like immunoreactivity in the bed nucleus of stria terminalis (BNST) was found to be much lower in LgA rats than in ShA and drug-naive rats. In contrast, UK14304 (α2 receptor agonist) and betaxolol (β1 receptor antagonist) had no effect on cocaine self-administration in either group. The data suggest that activation of the α1-noradrenergic system, perhaps in the BNST, is associated with increased motivation for cocaine in rats with extended access. PMID:17920248

  5. Exercise offers anxiolytic potential: a role for stress and brain noradrenergic-galaninergic mechanisms.

    PubMed

    Sciolino, Natale R; Holmes, Philip V

    2012-10-01

    Although physical activity reduces anxiety in humans, the neural basis for this response is unclear. Rodent models are essential to understand the mechanisms that underlie the benefits of exercise. However, it is controversial whether exercise exerts anxiolytic-like potential in rodents. Evidence is reviewed to evaluate the effects of wheel running, an experimental mode of exercise in rodents, on behavior in tests of anxiety and on norepinephrine and galanin systems in neural circuits that regulate stress. Stress is proposed to account for mixed behavioral findings in this literature. Indeed, running promotes an adaptive response to stress and alters anxiety-like behaviors in a manner dependent on stress. Running amplifies galanin expression in noradrenergic locus coeruleus (LC) and suppresses stress-induced activity of the LC and norepinephrine output in LC-target regions. Thus, enhanced galanin-mediated suppression of brain norepinephrine in runners is supported by current literature as a mechanism that may contribute to the stress-protective effects of exercise. These data support the use of rodents to study the emotional and neurobiological consequences of exercise. Copyright © 2012 Elsevier Ltd. All rights reserved.

  6. Exercise offers anxiolytic potential: A role for stress and brain noradrenergic-galaninergic mechanisms

    PubMed Central

    Sciolino, Natale R.; Holmes, Philip V.

    2016-01-01

    Although physical activity reduces anxiety in humans, the neural basis for this response is unclear. Rodent models are essential to understand the mechanisms that underlie the benefits of exercise. However, it is controversial whether exercise exerts anxiolytic-like potential in rodents. Evidence is reviewed to evaluate the effects of wheel running, an experimental mode of exercise in rodents, on behavior in tests of anxiety and on norepinephrine and galanin systems in neural circuits that regulate stress. Stress is proposed to account for mixed behavioral findings in this literature. Indeed, running promotes an adaptive response to stress and alters anxiety-like behaviors in a manner dependent on stress. Running amplifies galanin expression in noradrenergic locus coeruleus (LC) and suppresses stress-induced activity of the LC and norepinephrine output in LC-target regions. Thus, enhanced galanin-mediated suppression of brain norepinephrine in runners is supported by current literature as a mechanism that may contribute to the stress-protective effects of exercise. These data support the use of rodents to study the emotional and neurobiological consequences of exercise. PMID:22771334

  7. CRH Engagement of the Locus Coeruleus Noradrenergic System Mediates Stress-Induced Anxiety.

    PubMed

    McCall, Jordan G; Al-Hasani, Ream; Siuda, Edward R; Hong, Daniel Y; Norris, Aaron J; Ford, Christopher P; Bruchas, Michael R

    2015-08-05

    The locus coeruleus noradrenergic (LC-NE) system is one of the first systems engaged following a stressful event. While numerous groups have demonstrated that LC-NE neurons are activated by many different stressors, the underlying neural circuitry and the role of this activity in generating stress-induced anxiety has not been elucidated. Using a combination of in vivo chemogenetics, optogenetics, and retrograde tracing, we determine that increased tonic activity of the LC-NE system is necessary and sufficient for stress-induced anxiety and aversion. Selective inhibition of LC-NE neurons during stress prevents subsequent anxiety-like behavior. Exogenously increasing tonic, but not phasic, activity of LC-NE neurons is alone sufficient for anxiety-like and aversive behavior. Furthermore, endogenous corticotropin-releasing hormone(+) (CRH(+)) LC inputs from the amygdala increase tonic LC activity, inducing anxiety-like behaviors. These studies position the LC-NE system as a critical mediator of acute stress-induced anxiety and offer a potential intervention for preventing stress-related affective disorders. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Dopaminergic and Noradrenergic Contributions to Functionality in ADHD: The Role of Methylphenidate

    PubMed Central

    Engert, Veronika; Pruessner, Jens C

    2008-01-01

    Attention Deficit Hyperactivity Disorder (ADHD) is a childhood psychiatric condition characterized by severe impulsiveness, inattention and overactivity. Methylphenidate (MPH), a psychostimulant affecting both the dopaminergic and the noradrenergic systems, is one of the most frequently prescribed treatments for ADHD. Despite the widespread use of MPH and its proven effectiveness, its precise neurochemical mechanisms of action are under debate. For the most part, MPH’s influence on subcortical dopamine neurotransmission is thought to play a crucial role in its behavioral and cognitive effects. In their hypothesis of biphasic MPH action, Seeman and Madras [42, 43] suggest that therapeutic doses of MPH elevate tonic dopamine while inhibiting phasic transmitter release in subcortical structures, leading to reduced postsynaptic receptor stimulation and psychomotor activation in response to salient stimuli. Volkow and colleagues [56] suggest that by amplifying a weak striatal dopamine signal, MPH increases the perception of a stimulus or task as salient. The enhanced interest for the task is thought to increase attention and improve performance. Recent animal studies have however shown that when administered at doses producing clinically relevant drug plasma levels and enhancing cognitive function, MPH preferentially activates dopamine and noradrenaline efflux within the prefrontal cortex relative to the subcortical structures [5]. Overall, we suggest that the delineated theories of MPH therapeutic action should not be discussed as exclusive. Studies are outlined that allow integrating the different findings and models. PMID:19587853

  9. Statins Promote Long-Term Recovery after Ischemic Stroke by Reconnecting Noradrenergic Neuronal Circuitry

    PubMed Central

    Cho, Kyoung Joo; Cheon, So Young; Kim, Gyung Whan

    2015-01-01

    Inhibitors of HMG-CoA reductase (statins), widely used to lower cholesterol in coronary heart and vascular disease, are effective drugs in reducing the risk of stroke and improving its outcome in the long term. After ischemic stroke, cardiac autonomic dysfunction and psychological problems are common complications related to deficits in the noradrenergic (NA) system. This study investigated the effects of statins on the recovery of NA neuron circuitry and its function after transient focal cerebral ischemia (tFCI). Using the wheat germ agglutinin (WGA) transgene technique combined with the recombinant adenoviral vector system, NA-specific neuronal pathways were labeled, and were identified in the locus coeruleus (LC), where NA neurons originate. NA circuitry in the atorvastatin-treated group recovered faster than in the vehicle-treated group. The damaged NA circuitry was partly reorganized with the gradual recovery of autonomic dysfunction and neurobehavioral deficit. Newly proliferated cells might contribute to reorganizing NA neurons and lead anatomic and functional recovery of NA neurons. Statins may be implicated to play facilitating roles in the recovery of the NA neuron and its function. PMID:26448880

  10. Noradrenergic System in Down Syndrome and Alzheimer's Disease A Target for Therapy.

    PubMed

    Phillips, Cristy; Fahimi, Atoossa; Das, Devsmita; Mojabi, Fatemeh S; Ponnusamy, Ravikumar; Salehi, Ahmad

    2016-01-01

    Locus coeruleus (LC) neurons in the brainstem send extensive noradrenergic (NE)-ergic terminals to the majority of brain regions, particularly those involved in cognitive function. Both Alzheimer's disease (AD) and Down syndrome (DS) are characterized by similar pathology including significant LC degeneration and dysfunction of the NE-ergic system. Extensive loss of NE-ergic terminals has been linked to alterations in brain regions vital for cognition, mood, and executive function. While the mechanisms by which NE-ergic abnormalities contribute to cognitive dysfunction are not fully understood, emergent evidence suggests that rescue of NE-ergic system can attenuate neuropathology and cognitive decline in both AD and DS. Therapeutic strategies to enhance NE neurotransmission have undergone limited testing. Among those deployed to date are NE reuptake inhibitors, presynaptic α-adrenergic receptor antagonists, NE prodrugs, and β-adrenergic agonists. Here we examine alterations in the NE-ergic system in AD and DS and suggest that NE-ergic system rescue is a plausible treatment strategy for targeting cognitive decline in both disorders.

  11. Triphenyl phosphate enhances adipogenic differentiation, glucose uptake and lipolysis via endocrine and noradrenergic mechanisms.

    PubMed

    Cano-Sancho, German; Smith, Anna; La Merrill, Michele A

    2017-04-01

    The use of triphenyl phosphate (TPhP) as a flame retardant or plasticizer has increased during the last decade, resulting in widespread human exposure without commensurate toxicity assessment. The main objectives of this study were to assess the in vitro effect of TPhP and its metabolite diphenyl phosphate (DPhP) on the adipogenic differentiation of 3T3-L1 cells, as well as glucose uptake and lipolysis in differentiated 3T3-L1 adipocytes. TPhP increased pre-adipocyte proliferation and subsequent adipogenic differentiation of 3T3-L1 cells, coinciding with increased transcription in the CEBP and PPARG pathway. Treatment of mature adipocytes with TPhP increased the basal- and insulin stimulated- uptake of the glucose analog 2-[N (-7-nitrobenz-2-oxa1, 3-diazol-4-yl) amino]-2-deoxy-d-glucose (2-NBDG). This effect was ablated by inhibition of PI3K, a member of the insulin signaling pathway. DPhP had no significant effect on cell proliferation and, compared to TPhP, a weaker effect on adipogenic differentiation and on 2-NBDG uptake. Both TPhP and DPhT significantly enhanced the isoproterenol-induced lipolysis, most likely by increasing the expression of lipolytic genes during and after differentiation. This study suggests that TPhP increases adipogenic differentiation, glucose uptake, and lipolysis in 3T3-L1 cells through endocrine and noradrenergic mechanisms.

  12. The roles of noradrenergic and glucocorticoid activation in the development of intrusive memories.

    PubMed

    Bryant, Richard A; McGrath, Chloe; Felmingham, Kim L

    2013-01-01

    Intrusive memories are a common feature of many psychological disorders. Recent evidence has potentially extended cognitive models of intrusions by identifying the role of biological markers of arousal at the time of consolidation in subsequent memory for emotional events. This study investigated the role of arousal during consolidation in the development of intrusive memories. Seventy-eight university students (37 men and 41 women) viewed 20 negative and 20 neutral images. Half the participants then underwent a cold pressor test (High Stress), immersing their hand in ice water, while the remaining participants immersed their hand in warm water (Low Stress). Samples of salivary alpha-amylase (sAA) and cortisol were collected from participants at baseline and following the stressor challenge. Participants completed a delayed free recall test and intrusion questionnaires two days later. Participants in the High Stress condition reported more intrusions of negative images than participants in the Low Stress condition. An interaction variable in a linear regression of increased noradrenergic and cortisol values predicted intrusive memories of emotional stimuli for men but not women. These findings are consistent with recent evidence of the combined effects of noradrenaline and corticoid responses to stress on emotional memories, and also with increasing evidence of gender differences in how stress hormones influence formation of emotional memories. These findings point to possible mechanisms by which development of intrusions may be prevented after consolidation of traumatic experiences.

  13. Noradrenergic and Serotonergic Mechanisms in the Neurobiology of Posttraumatic Stress Disorder and Resilience

    PubMed Central

    Krystal, John H.; Neumeister, Alexander

    2009-01-01

    Posttraumatic stress disorder (PTSD) is characterized mainly by symptoms of re-experiencing, avoidance and hyperarousal as a consequence of catastrophic and traumatic events that are distinguished from ordinary stressful life events. Although extensive research has already been done, the etiology of PTSD remains unclear. Research on the impact of trauma on neurobiological systems can be expected to inform the development of treatments that are directed specifically to symptoms of PTSD. During the past 25 years there has been a dramatic increase in the knowledge about noradrenergic and serotonergic mechanisms in stress response, PTSD and more recently in resilience and this knowledge has justified the use of antidepressants with monoaminergic mechanisms of action for patients with PTSD. Nevertheless, available treatments of PTSD are only to some extent effective and enhanced understanding of the neurobiology of PTSD may lead to the development of improved treatments for these patients. In the present review, we aim to close existing gaps between basic research in psychopathology, neurobiology and treatment development with the ultimate goal to translate basic research into clinically relevant findings which may directly benefit patients with PTSD. PMID:19332037

  14. Noradrenergic function in generalized anxiety disorder, major depressive disorder, and healthy subjects.

    PubMed

    Sevy, S; Papadimitriou, G N; Surmont, D W; Goldman, S; Mendlewicz, J

    1989-01-15

    Plasma norepinephrine (NE), free 3-methoxy-4-hydroxyphenethylene glycol (MHPG), and binding of tritiated yohimbine to platelet membranes were measured in 14 patients with generalized anxiety disorder (GAD), who were matched for age and sex with 14 patients with unipolar major depressive disorder (MDD) and 14 normal subjects. Plasma NE and MHPG levels were increased and the number of alpha2-adrenoreceptors (Bmax) was decreased in GAD patients compared with MDD and normal subjects. No differences were found between MDD patients and normal subjects for plasma NE, MHPG, and alpha2-adrenoreceptor binding. Plasma NE and MHPG were significantly correlated in MDD patients and tended toward a significant positive correlation in GAD patients. Plasma MHPG and affinity of binding platelet alpha2-adrenoreceptors (Kd) were significantly correlated in normal subjects. Thus, noradrenergic activity seems to be increased in patients with GAD, but not in patients with MDD. In GAD patients, higher levels of catecholamines may lead to a down-regulation of presynaptic alpha2-adrenoreceptors.

  15. Functional differentiation of cholinergic and noradrenergic modulation in a biophysical model of olfactory bulb granule cells

    PubMed Central

    Linster, Christiane

    2015-01-01

    Olfactory bulb granule cells are modulated by both acetylcholine (ACh) and norepinephrine (NE), but the effects of these neuromodulators have not been clearly distinguished. We used detailed biophysical simulations of granule cells, both alone and embedded in a microcircuit with mitral cells, to measure and distinguish the effects of ACh and NE on cellular and microcircuit function. Cholinergic and noradrenergic modulatory effects on granule cells were based on data obtained from slice experiments; specifically, ACh reduced the conductance densities of the potassium M current and the calcium-dependent potassium current, whereas NE nonmonotonically regulated the conductance density of an ohmic potassium current. We report that the effects of ACh and NE on granule cell physiology are distinct and functionally complementary to one another. ACh strongly regulates granule cell firing rates and afterpotentials, whereas NE bidirectionally regulates subthreshold membrane potentials. When combined, NE can regulate the ACh-induced expression of afterdepolarizing potentials and persistent firing. In a microcircuit simulation developed to investigate the effects of granule cell neuromodulation on mitral cell firing properties, ACh increased spike synchronization among mitral cells, whereas NE modulated the signal-to-noise ratio. Coapplication of ACh and NE both functionally improved the signal-to-noise ratio and enhanced spike synchronization among mitral cells. In summary, our computational results support distinct and complementary roles for ACh and NE in modulating olfactory bulb circuitry and suggest that NE may play a role in the regulation of cholinergic function. PMID:26334007

  16. Noradrenergic Modulation of Intrinsic and Synaptic Properties of Lumbar Motoneurons in the Neonatal Rat Spinal Cord

    PubMed Central

    Tartas, Maylis; Morin, France; Barrière, Grégory; Goillandeau, Michel; Lacaille, Jean-Claude; Cazalets, Jean-René; Bertrand, Sandrine S.

    2009-01-01

    Although it is known that noradrenaline (NA) powerfully controls spinal motor networks, few data are available regarding the noradrenergic (NAergic) modulation of intrinsic and synaptic properties of neurons in motor networks. Our work explores the cellular basis of NAergic modulation in the rat motor spinal cord. We first show that lumbar motoneurons express the three classes of adrenergic receptors at birth. Using patch-clamp recordings in the newborn rat spinal cord preparation, we characterized the effects of NA and of specific agonists of the three classes of adrenoreceptors on motoneuron membrane properties. NA increases the motoneuron excitability partly via the inhibition of a KIR like current. Methoxamine (α1), clonidine (α2) and isoproterenol (β) differentially modulate the motoneuron membrane potential but also increase motoneuron excitability, these effects being respectively inhibited by the antagonists prazosin (α1), yohimbine (α2) and propranolol (β). We show that the glutamatergic synaptic drive arising from the T13-L2 network is enhanced in motoneurons by NA, methoxamine and isoproterenol. On the other hand, NA, isoproterenol and clonidine inhibit both the frequency and amplitude of miniature glutamatergic EPSCs while methoxamine increases their frequency. The T13-L2 synaptic drive is thereby differentially modulated from the other glutamatergic synapses converging onto motoneurons and enhanced by presynaptic α1 and β receptor activation. Our data thus show that the NAergic system exerts a powerful and complex neuromodulation of lumbar motor networks in the neonatal rat spinal cord. PMID:20300468

  17. Functional differentiation of cholinergic and noradrenergic modulation in a biophysical model of olfactory bulb granule cells.

    PubMed

    Li, Guoshi; Linster, Christiane; Cleland, Thomas A

    2015-12-01

    Olfactory bulb granule cells are modulated by both acetylcholine (ACh) and norepinephrine (NE), but the effects of these neuromodulators have not been clearly distinguished. We used detailed biophysical simulations of granule cells, both alone and embedded in a microcircuit with mitral cells, to measure and distinguish the effects of ACh and NE on cellular and microcircuit function. Cholinergic and noradrenergic modulatory effects on granule cells were based on data obtained from slice experiments; specifically, ACh reduced the conductance densities of the potassium M current and the calcium-dependent potassium current, whereas NE nonmonotonically regulated the conductance density of an ohmic potassium current. We report that the effects of ACh and NE on granule cell physiology are distinct and functionally complementary to one another. ACh strongly regulates granule cell firing rates and afterpotentials, whereas NE bidirectionally regulates subthreshold membrane potentials. When combined, NE can regulate the ACh-induced expression of afterdepolarizing potentials and persistent firing. In a microcircuit simulation developed to investigate the effects of granule cell neuromodulation on mitral cell firing properties, ACh increased spike synchronization among mitral cells, whereas NE modulated the signal-to-noise ratio. Coapplication of ACh and NE both functionally improved the signal-to-noise ratio and enhanced spike synchronization among mitral cells. In summary, our computational results support distinct and complementary roles for ACh and NE in modulating olfactory bulb circuitry and suggest that NE may play a role in the regulation of cholinergic function.

  18. The mechanism of noradrenergic alpha 1 excitatory modulation of pontine reticular formation neurons.

    PubMed

    Stevens, D R; McCarley, R W; Greene, R W

    1994-11-01

    The alpha 1 adrenergic receptor occurs in all major divisions of the CNS and is thought to play a role in all behaviors influenced by norepinephrine (NE). In the medial pontine reticular formation (mPRF), the proposed site of adrenergic enhancement of startle responses (Davis, 1984), alpha 1 agonists excite most neurons (Gerber et al., 1990). We here report that alpha 1 excitation results from a reduction of a voltage- and calcium-dependent potassium current, not previously recognized as ligand-modulated. The calcium sensitivity is suggested by its antagonism with Mg2+, Cd2+, Ba2+, low concentrations of tetraethylammonium, and charybdotoxin. The voltage sensitivity of this conductance falls within the membrane potential range critical to action potential generation. Based on this voltage sensitivity, the change in repetitive firing characteristics may be predicted according to a mathematical model of the mPRF neuronal electrophysiology. The predicted response to a 50% decrease in the phenylephrine (PE)-sensitive conductance is similar to the observed responses, with respect to both the current response under voltage-clamp conditions and alterations of the AHP and frequency/current curve. In contrast, modeling a reduction of a voltage-insensitive leak current predicts none of these changes. Thus, the noradrenergic reduction of this current depolarizes the membrane, increases the likelihood of an initial response to depolarizing input, and increases firing rate during sustained depolarization in a manner consistent with an NE role as an excitatory neuromodulator of the mPRF.

  19. The inhibition of the dorsal paragigantocellular reticular nucleus induces waking and the activation of all adrenergic and noradrenergic neurons: a combined pharmacological and functional neuroanatomical study.

    PubMed

    Clément, Olivier; Valencia Garcia, Sara; Libourel, Paul-Antoine; Arthaud, Sébastien; Fort, Patrice; Luppi, Pierre-Hervé

    2014-01-01

    GABAergic neurons specifically active during paradoxical sleep (PS) localized in the dorsal paragigantocellular reticular nucleus (DPGi) are known to be responsible for the cessation of activity of the noradrenergic neurons of the locus coeruleus during PS. In the present study, we therefore sought to determine the role of the DPGi in PS onset and maintenance and in the inhibition of the LC noradrenergic neurons during this state. The effect of the inactivation of DPGi neurons on the sleep-waking cycle was examined in rats by microinjection of muscimol, a GABAA agonist, or clonidine, an alpha-2 adrenergic receptor agonist. Combining immunostaining of the different populations of wake-inducing neurons with that of c-FOS, we then determined whether muscimol inhibition of the DPGi specifically induces the activation of the noradrenergic neurons of the LC. Slow wave sleep and PS were abolished during 3 and 5 h after muscimol injection in the DPGi, respectively. The application of clonidine in the DPGi specifically induced a significant decrease in PS quantities and delayed PS appearance compared to NaCl. We further surprisingly found out that more than 75% of the noradrenergic and adrenergic neurons of all adrenergic and noradrenergic cell groups are activated after muscimol treatment in contrast to the other wake active systems significantly less activated. These results suggest that, in addition to its already know inhibition of LC noradrenergic neurons during PS, the DPGi might inhibit the activity of noradrenergic and adrenergic neurons from all groups during PS, but also to a minor extent during SWS and waking.

  20. The Inhibition of the Dorsal Paragigantocellular Reticular Nucleus Induces Waking and the Activation of All Adrenergic and Noradrenergic Neurons: A Combined Pharmacological and Functional Neuroanatomical Study

    PubMed Central

    Clément, Olivier; Valencia Garcia, Sara; Libourel, Paul-Antoine; Arthaud, Sébastien; Fort, Patrice; Luppi, Pierre-Hervé

    2014-01-01

    GABAergic neurons specifically active during paradoxical sleep (PS) localized in the dorsal paragigantocellular reticular nucleus (DPGi) are known to be responsible for the cessation of activity of the noradrenergic neurons of the locus coeruleus during PS. In the present study, we therefore sought to determine the role of the DPGi in PS onset and maintenance and in the inhibition of the LC noradrenergic neurons during this state. The effect of the inactivation of DPGi neurons on the sleep-waking cycle was examined in rats by microinjection of muscimol, a GABAA agonist, or clonidine, an alpha-2 adrenergic receptor agonist. Combining immunostaining of the different populations of wake-inducing neurons with that of c-FOS, we then determined whether muscimol inhibition of the DPGi specifically induces the activation of the noradrenergic neurons of the LC. Slow wave sleep and PS were abolished during 3 and 5 h after muscimol injection in the DPGi, respectively. The application of clonidine in the DPGi specifically induced a significant decrease in PS quantities and delayed PS appearance compared to NaCl. We further surprisingly found out that more than 75% of the noradrenergic and adrenergic neurons of all adrenergic and noradrenergic cell groups are activated after muscimol treatment in contrast to the other wake active systems significantly less activated. These results suggest that, in addition to its already know inhibition of LC noradrenergic neurons during PS, the DPGi might inhibit the activity of noradrenergic and adrenergic neurons from all groups during PS, but also to a minor extent during SWS and waking. PMID:24811249

  1. Locomotor-activated neurons of the cat. II. Noradrenergic innervation and colocalization with NEα 1a or NEα 2b receptors in the thoraco-lumbar spinal cord.

    PubMed

    Noga, Brian R; Johnson, Dawn M G; Riesgo, Mirta I; Pinzon, Alberto

    2011-04-01

    Norepinephrine (NE) is a strong modulator and/or activator of spinal locomotor networks. Thus noradrenergic fibers likely contact neurons involved in generating locomotion. The aim of the present study was to investigate the noradrenergic innervation of functionally related, locomotor-activated neurons within the thoraco-lumbar spinal cord. This was accomplished by immunohistochemical colocalization of noradrenergic fibers using dopamine-β-hydroxylase or NEα(1A) and NEα(2B) receptors with cells expressing the c-fos gene activity-dependent marker Fos. Experiments were performed on paralyzed, precollicular-postmamillary decerebrate cats, in which locomotion was induced by electrical stimulation of the mesencephalic locomotor region. The majority of Fos labeled neurons, especially abundant in laminae VII and VIII throughout the thoraco-lumbar (T13-L7) region of locomotor animals, showed close contacts with multiple noradrenergic boutons. A small percentage (10-40%) of Fos neurons in the T7-L7 segments showed colocalization with NEα(1A) receptors. In contrast, NEα(2B) receptor immunoreactivity was observed in 70-90% of Fos cells, with no obvious rostrocaudal gradient. In comparison with results obtained from our previous study on the same animals, a significantly smaller proportion of Fos labeled neurons were innervated by noradrenergic than serotonergic fibers, with significant differences observed for laminae VII and VIII in some segments. In lamina VII of the lumbar segments, the degree of monoaminergic receptor subtype/Fos colocalization examined statistically generally fell into the following order: NEα(2B) = 5-HT(2A) ≥ 5-HT(7) = 5-HT(1A) > NEα(1A). These results suggest that noradrenergic modulation of locomotion involves NEα(1A)/NEα(2B) receptors on noradrenergic-innervated locomotor-activated neurons within laminae VII and VIII of thoraco-lumbar segments. Further study of the functional role of these receptors in locomotion is warranted.

  2. Locomotor-activated neurons of the cat. II. Noradrenergic innervation and colocalization with NEα1a or NEα2b receptors in the thoraco-lumbar spinal cord

    PubMed Central

    Johnson, Dawn M. G.; Riesgo, Mirta I.; Pinzon, Alberto

    2011-01-01

    Norepinephrine (NE) is a strong modulator and/or activator of spinal locomotor networks. Thus noradrenergic fibers likely contact neurons involved in generating locomotion. The aim of the present study was to investigate the noradrenergic innervation of functionally related, locomotor-activated neurons within the thoraco-lumbar spinal cord. This was accomplished by immunohistochemical colocalization of noradrenergic fibers using dopamine-β-hydroxylase or NEα1A and NEα2B receptors with cells expressing the c-fos gene activity-dependent marker Fos. Experiments were performed on paralyzed, precollicular-postmamillary decerebrate cats, in which locomotion was induced by electrical stimulation of the mesencephalic locomotor region. The majority of Fos labeled neurons, especially abundant in laminae VII and VIII throughout the thoraco-lumbar (T13-L7) region of locomotor animals, showed close contacts with multiple noradrenergic boutons. A small percentage (10–40%) of Fos neurons in the T7-L7 segments showed colocalization with NEα1A receptors. In contrast, NEα2B receptor immunoreactivity was observed in 70–90% of Fos cells, with no obvious rostrocaudal gradient. In comparison with results obtained from our previous study on the same animals, a significantly smaller proportion of Fos labeled neurons were innervated by noradrenergic than serotonergic fibers, with significant differences observed for laminae VII and VIII in some segments. In lamina VII of the lumbar segments, the degree of monoaminergic receptor subtype/Fos colocalization examined statistically generally fell into the following order: NEα2B = 5-HT2A ≥ 5-HT7 = 5-HT1A > NEα1A. These results suggest that noradrenergic modulation of locomotion involves NEα1A/NEα2B receptors on noradrenergic-innervated locomotor-activated neurons within laminae VII and VIII of thoraco-lumbar segments. Further study of the functional role of these receptors in locomotion is warranted. PMID:21307324

  3. Neuronal amyloid-β accumulation within cholinergic basal forebrain in ageing and Alzheimer's disease.

    PubMed

    Baker-Nigh, Alaina; Vahedi, Shahrooz; Davis, Elena Goetz; Weintraub, Sandra; Bigio, Eileen H; Klein, William L; Geula, Changiz

    2015-06-01

    The mechanisms that contribute to selective vulnerability of the magnocellular basal forebrain cholinergic neurons in neurodegenerative diseases, such as Alzheimer's disease, are not fully understood. Because age is the primary risk factor for Alzheimer's disease, mechanisms of interest must include age-related alterations in protein expression, cell type-specific markers and pathology. The present study explored the extent and characteristics of intraneuronal amyloid-β accumulation, particularly of the fibrillogenic 42-amino acid isoform, within basal forebrain cholinergic neurons in normal young, normal aged and Alzheimer's disease brains as a potential contributor to the selective vulnerability of these neurons using immunohistochemistry and western blot analysis. Amyloid-β1-42 immunoreactivity was observed in the entire cholinergic neuronal population regardless of age or Alzheimer's disease diagnosis. The magnitude of this accumulation as revealed by optical density measures was significantly greater than that in cortical pyramidal neurons, and magnocellular neurons in the globus pallidus did not demonstrate a similar extent of amyloid immunoreactivity. Immunoblot analysis with a panel of amyloid-β antibodies confirmed accumulation of high concentration of amyloid-β in basal forebrain early in adult life. There was no age- or Alzheimer-related alteration in total amyloid-β content within this region. In contrast, an increase in the large molecular weight soluble oligomer species was observed with a highly oligomer-specific antibody in aged and Alzheimer brains when compared with the young. Similarly, intermediate molecular weight oligomeric species displayed an increase in aged and Alzheimer brains when compared with the young using two amyloid-β42 antibodies. Compared to cortical homogenates, small molecular weight oligomeric species were lower and intermediate species were enriched in basal forebrain in ageing and Alzheimer's disease. Regional and age

  4. Striatal-Limbic Activation is Associated with Intensity of Anticipatory Anxiety

    PubMed Central

    Yang, Hongyu; Spence, Jeffrey S.; Devous, Michael D.; Briggs, Richard W.; Goyal, Aman; Xiao, Hong; Yadav, Hardik; Adinoff, Bryon

    2013-01-01

    Anxiety experienced in anticipation of impending aversive events induces striatal-limbic activation. However, previous functional magnetic imaging (fMRI) studies of anticipatory anxiety have utilized post-test measures of anxiety, making a direct association between neural activation and distress problematic. This paradigm was designed to assess the BOLD response to an aversive conditioned stimulus while simultaneously measuring subjective anxiety. Fifteen male healthy subjects (45.5±8.5 years old) were studied. A high threat conditioned stimulus (CS) was paired with either an unpredictable, highly aversive (painful) or a non-aversive (non-painful) unconditioned stimulus and compared to a low threat CS paired with a predictable, non-aversive stimulus. Neural response was assessed with fMRI, and subjective anxiety (1 to 4) was recorded upon the presentation of each CS. High subjective ratings of real-time anticipatory anxiety (2, 3, and 4), relative to low anticipatory anxiety (1), elicited increased activation in the bilateral striatum, bilateral orbital frontal cortex, left anterior insula, and anterior cingulate cortex (ACC) and decreased activation in the posterior cingulate cortex (PCC). The amplitude of BOLD signal change generally paralleled the subjective rating of anxiety. Real-time measures of anticipatory anxiety confirm previous reports, using post-test measures of anxiety, of striatal-limbic activation during anticipatory anxiety while simultaneously demonstrating an increase in BOLD response in parallel with heightened anxiety. PMID:23137803

  5. Behavioural signs of depression and apoptosis in the limbic system following myocardial infarction: effects of sertraline.

    PubMed

    Wann, B P; Bah, T M; Kaloustian, S; Boucher, M; Dufort, A M; Le Marec, N; Godbout, R; Rousseau, G

    2009-06-01

    Depression is diagnosed in 15-30% of patients following myocardial infarction (MI) and this may also be observed in the rat. We measured the effects of the antidepressant sertraline on behavioural and biochemical events following MI in a rat model. Following surgery, MI rats and sham controls were treated with sertraline (10 mg/kg, i.p.) or saline. Subgroups of rats were tested for behavioural depression 14 days after surgery. Apoptosis was estimated in other rats by measuring caspase-3 activity and TUNEL positive cells (3 days after surgery) in limbic structures (amygdale, hippocampus, hypothalamus, frontal and prefrontal cortices). Bax/Bcl-2 ratio was measured 14 days after surgery. Behavioural signs of depression (decreased sucrose intake and forced swimming time) were found in saline-treated MI rats but not in sertraline-treated rats. Compared with controls, caspase-3 activity and TUNEL positive cells were significantly increased in most limbic structures of MI rats. High prefrontal Bax/Bcl-2 ratio in MI rats correlated with low forced swimming time. Apoptosis was not found in sertraline-treated MI rats. These results establish the bases of a rat model of depression following MI and show for the first time that a selective serotonin reuptake inhibitor prevents both behavioural and biochemical markers in this model.

  6. Functional heterogeneity of the limbic thalamus: From hippocampal to cortical functions.

    PubMed

    Wolff, Mathieu; Alcaraz, Fabien; Marchand, Alain R; Coutureau, Etienne

    2015-07-01

    Today, the idea that the integrity of the limbic thalamus is necessary for normal memory functions is well established. However, if the study of thalamic patients emphasized the anterior and the mediodorsal thalamus as the critical thalamic loci supporting cognitive functions, clinical studies have so far failed to attribute a specific role to each of these regions. In view of these difficulties, we review here the experimental data conducted in rodents harboring specific lesions of each thalamic region. These data clearly indicate a major functional dissociation within the limbic thalamus. The anterior thalamus provides critical support for hippocampal functions due to its cardinal location in the Papez circuit, while the mediodorsal thalamus may signal relevant information in a circuit encompassing the basolateral amygdala and the prefrontal cortex. Interestingly, while clinical studies have suggested that diencephalic pathologies may disconnect the medial temporal lobe from the cortex, experimental studies conducted in rodent show how this may differently affect distinct temporo-thalamo-cortical circuits, sharing the same general organization but supporting dissociable functions. Copyright © 2014 Elsevier Ltd. All rights reserved.

  7. 5HTTLPR polymorphism and enlargement of the pulvinar: unlocking the backdoor to the limbic system.

    PubMed

    Young, Keith A; Holcomb, Leigh A; Bonkale, Willy L; Hicks, Paul B; Yazdani, Umar; German, Dwight C

    2007-03-15

    The 5HTTLPR genetic variant of the serotonin transporter (SERT), which consists of a long (SERT-l) and short (SERT-s) allele, has emerged as a major factor influencing emotional behavior and brain anatomy. The pulvinar nucleus of the thalamus projects to important limbic nuclei including the amygdala and cingulate cortex, is involved in the processing of stimuli with emotional content, and contains an abundance of SERT. Stereological methods were used to measure pulvinar neuron number in postmortem tissue from major depressive disorder (n = 11), bipolar disorder (n = 11), schizophrenia (n = 12), and control (n = 15) specimens from the Stanley Foundation Neuropathology Consortium. The effect of SERT genotype on pulvinar volume and neuron number was investigated by using analysis of covariance. Analysis of covariance with diagnosis, SERT genotype, age, hemisphere, postmortem interval, and time-in-formalin covariates identified a 20% increase in pulvinar neuron number and volume in SERT-ss subjects. The elevated number of pulvinar neurons in subjects with a SERT-ss genotype may serve to enhance subcortical input of emotionally relevant stimuli to the limbic system, providing a mechanism for the 5HTTLPR genetic variant to affect predisposition to conditions such as major depression.

  8. The role of the medial temporal limbic system in processing emotions in voice and music.

    PubMed

    Frühholz, Sascha; Trost, Wiebke; Grandjean, Didier

    2014-12-01

    Subcortical brain structures of the limbic system, such as the amygdala, are thought to decode the emotional value of sensory information. Recent neuroimaging studies, as well as lesion studies in patients, have shown that the amygdala is sensitive to emotions in voice and music. Similarly, the hippocampus, another part of the temporal limbic system (TLS), is responsive to vocal and musical emotions, but its specific roles in emotional processing from music and especially from voices have been largely neglected. Here we review recent research on vocal and musical emotions, and outline commonalities and differences in the neural processing of emotions in the TLS in terms of emotional valence, emotional intensity and arousal, as well as in terms of acoustic and structural features of voices and music. We summarize the findings in a neural framework including several subcortical and cortical functional pathways between the auditory system and the TLS. This framework proposes that some vocal expressions might already receive a fast emotional evaluation via a subcortical pathway to the amygdala, whereas cortical pathways to the TLS are thought to be equally used for vocal and musical emotions. While the amygdala might be specifically involved in a coarse decoding of the emotional value of voices and music, the hippocampus might process more complex vocal and musical emotions, and might have an important role especially for the decoding of musical emotions by providing memory-based and contextual associations. Copyright © 2014 Elsevier Ltd. All rights reserved.

  9. Morphological brain measures of cortico-limbic inhibition related to resilience.

    PubMed

    Gupta, Arpana; Love, Aubrey; Kilpatrick, Lisa A; Labus, Jennifer S; Bhatt, Ravi; Chang, Lin; Tillisch, Kirsten; Naliboff, Bruce; Mayer, Emeran A

    2016-12-28

    Resilience is the ability to adequately adapt and respond to homeostatic perturbations. Although resilience has been associated with positive health outcomes, the neuro-biological basis of resilience is poorly understood. The aim of the study was to identify associations between regional brain morphology and trait resilience with a focus on resilience-related morphological differences in brain regions involved in cortico-limbic inhibition. The relationship between resilience and measures of affect were also investigated. Forty-eight healthy subjects completed structural MRI scans. Self-reported resilience was measured using the Connor and Davidson Resilience Scale. Segmentation and regional parcellation of images was performed to yield a total of 165 regions. Gray matter volume (GMV), cortical thickness, surface area, and mean curvature were calculated for each region. Regression models were used to identify associations between morphology of regions belonging to executive control and emotional arousal brain networks and trait resilience (total and subscales) while controlling for age, sex, and total GMV. Correlations were also conducted between resilience scores and affect scores. Significant associations were found between GM changes in hypothesized brain regions (subparietal sulcus, intraparietal sulcus, amygdala, anterior mid cingulate cortex, and subgenual cingulate cortex) and resilience scores. There were significant positive correlations between resilience and positive affect and negative correlations with negative affect. Resilience was associated with brain morphology of regions involved in cognitive and affective processes related to cortico-limbic inhibition. Brain signatures associated with resilience may be a biomarker of vulnerability to disease. © 2016 Wiley Periodicals, Inc.

  10. Oxidative metabolism of limbic structures after acute administration of diazepam, alprazolam and zolpidem.

    PubMed

    González-Pardo, Héctor; Conejo, Nélida M; Arias, Jorge L

    2006-08-30

    The effects of acute administration of two benzodiazepines and a non-benzodiazepine hypnotic on behavior and brain metabolism were evaluated in rats. After testing the behavioral action of the benzodiazepines on the open field and the elevated plus-maze, the effects of the three drugs on neuronal metabolism of particular limbic regions were measured using cytochrome c oxidase (CO) histochemistry. Diazepam (5 mg/kg i.p.) and alprazolam (0.5 mg/kg i.p.) induced clear anxiolytic effects and a decrease in locomotion, whereas zolpidem (2 mg/kg i.p.) caused an intense hypnotic effect. The anxiolytic effects of alprazolam were distinguishable from diazepam due to the pharmacological and clinical profile of this triazolobenzodiazepine. CO activity decreased significantly in almost all the limbic regions evaluated after zolpidem administration. However, significant prominent decreases in CO activity were found after diazepam treatment in the medial mammillary nucleus, anteroventral thalamus, cingulate cortex, dentate gyrus and basolateral amygdala. Alprazolam caused similar decreases in CO activity, with the exception of the prelimbic and cingulate cortices, where significant increases were detected. In agreement with previous studies using other functional mapping techniques, our results indicate that particular benzodiazepines and non-benzodiazepine hypnotics induce selective changes in brain oxidative metabolism.

  11. Limbic Tract Integrity Contributes to Pattern Separation Performance Across the Lifespan.

    PubMed

    Bennett, Ilana J; Huffman, Derek J; Stark, Craig E L

    2015-09-01

    Accurate memory for discrete events is thought to rely on pattern separation to orthogonalize the representations of similar events. Previously, we reported that a behavioral index of pattern separation was correlated with activity in the hippocampus (dentate gyrus, CA3) and with integrity of the perforant path, which provides input to the hippocampus. If the hippocampus operates as part of a broader neural network, however, pattern separation would likely also relate to integrity of limbic tracts (fornix, cingulum bundle, and uncinate fasciculus) that connect the hippocampus to distributed brain regions. In this study, healthy adults (20-89 years) underwent diffusion tensor imaging and completed the Behavioral Pattern Separation Task-Object Version (BPS-O) and Rey Auditory Verbal Learning Test (RAVLT). After controlling for global effects of brain aging, exploratory skeleton-wise and targeted tractography analyses revealed that fornix integrity (fractional anisotropy, mean diffusivity, and radial diffusivity; but not mode) was significantly related to pattern separation (measured using BPS-O and RAVLT tasks), but not to recognition memory. These data suggest that hippocampal disconnection, via individual- and age-related differences in limbic tract integrity, contributes to pattern separation performance. Extending our earlier work, these results also support the notion that pattern separation relies on broad neural networks interconnecting the hippocampus.

  12. Limbic Tract Integrity Contributes to Pattern Separation Performance Across the Lifespan

    PubMed Central

    Bennett, Ilana J.; Huffman, Derek J.; Stark, Craig E.L.

    2015-01-01

    Accurate memory for discrete events is thought to rely on pattern separation to orthogonalize the representations of similar events. Previously, we reported that a behavioral index of pattern separation was correlated with activity in the hippocampus (dentate gyrus, CA3) and with integrity of the perforant path, which provides input to the hippocampus. If the hippocampus operates as part of a broader neural network, however, pattern separation would likely also relate to integrity of limbic tracts (fornix, cingulum bundle, and uncinate fasciculus) that connect the hippocampus to distributed brain regions. In this study, healthy adults (20–89 years) underwent diffusion tensor imaging and completed the Behavioral Pattern Separation Task-Object Version (BPS-O) and Rey Auditory Verbal Learning Test (RAVLT). After controlling for global effects of brain aging, exploratory skeleton-wise and targeted tractography analyses revealed that fornix integrity (fractional anisotropy, mean diffusivity, and radial diffusivity; but not mode) was significantly related to pattern separation (measured using BPS-O and RAVLT tasks), but not to recognition memory. These data suggest that hippocampal disconnection, via individual- and age-related differences in limbic tract integrity, contributes to pattern separation performance. Extending our earlier work, these results also support the notion that pattern separation relies on broad neural networks interconnecting the hippocampus. PMID:24825784

  13. Limbic system structures differentially contribute to exploratory trip organization of the rat.

    PubMed

    Winter, Shawn S; Köppen, Jenny R; Ebert, Tialia B N; Wallace, Douglas G

    2013-02-01

    The role of limbic system structures in spatial orientation continues to be debated. The hippocampus (HPC) has been implicated in encoding symbolic representations of environments (i.e., cognitive map), whereas entorhinal cortex (EC) function has been implicated in self-movement cue processing (i.e., dead reckoning). These distinctions largely depend on the electrophysiological characteristics of cells within these regions and behavioral tasks that typically fail to dissociate environmental and self-movement cue processing. Topographic and kinematic characteristics of exploratory trip organization have been shown to differentially depend on environmental and self-movement cue processing. The present study examines the effects of either HPC or EC lesions on exploratory trip organization under varying lighting conditions. HPC lesions selectively impaired all measures of performance under dark conditions, but spared all measures of performance under light conditions. EC lesions impaired kinematic measures related to distance estimation under all conditions and impaired all measures of performance under light conditions. These results provide evidence that the HPC is involved in processing self-movement cues but not environmental cues, and EC is involved in processing distance estimates generated from either self-movement or environmental cues. These observations provide further support for serial processing of self-movement cues through limbic system structures that converge on the HPC. Copyright © 2012 Wiley Periodicals, Inc.

  14. Dysregulation of prefrontal cortex-mediated slow evolving limbic dynamics drives stress-induced emotional pathology

    PubMed Central

    Hultman, Rainbo; Mague, Stephen D.; Li, Qiang; Katz, Brittany M.; Michel, Nadine; Lin, Lizhen; Wang, Joyce; David, Lisa K.; Blount, Cameron; Chandy, Rithi; Carlson, David; Ulrich, Kyle; Carin, Lawrence; Dunson, David; Kumar, Sunil; Deisseroth, Karl; Moore, Scott D.; Dzirasa, Kafui

    2016-01-01

    Summary Circuits distributed across cortico-limbic brain regions compose the networks that mediate emotional behavior. The prefrontal cortex (PFC) regulates ultraslow (<1Hz) dynamics across these networks, and PFC dysfunction is implicated in stress-related illnesses including major depressive disorder (MDD). To uncover the mechanism whereby stress-induced changes in PFC circuitry alter emotional networks to yield pathology, we used a multi-disciplinary approach including in vivo recordings in mice and chronic social-defeat stress. Our network model, inferred using machine learning, linked stress-induced behavioral pathology to the capacity of PFC to synchronize amygdala and VTA activity. Direct stimulation of PFC-amygdala circuitry with DREADDs normalized PFC-dependent limbic synchrony in stress-susceptible animals and restored normal behavior. In addition to providing insights into MDD mechanisms, our findings demonstrate an interdisciplinary approach that can be used to identify the large-scale network changes that underlie complex emotional pathologies and the specific network nodes that can be used to develop targeted interventions. PMID:27346529

  15. Neuregulin 1 represses limbic epileptogenesis through ErbB4 in parvalbumin-expressing interneurons.

    PubMed

    Tan, Guo-He; Liu, Yuan-Yuan; Hu, Xiao-Ling; Yin, Dong-Min; Mei, Lin; Xiong, Zhi-Qi

    2011-12-11

    Epilepsy is a common and refractory neurological disorder, but the neuronal regulatory mechanisms of epileptogenesis remain largely unclear. Activity-dependent transcription of genes for neurotrophins such as brain-derived neurotrophic factor (BDNF) has been shown to promote epileptogenesis; however, little is known about factors that may act as intrinsic, homeostatic or counterbalancing mechanisms. Using rodent models, here we show that limbic seizure activity upregulated NRG1-ErbB4 signaling and that epileptogenesis was inhibited by infusing NRG1 intracerebrally but exacerbated by neutralizing endogenous NRG1 with soluble ErbB4 extracellular domain, by inhibiting ErbB4 activation or by deleting the Erbb4 gene. Furthermore, specific depletion of ErbB4 in parvalbumin-expressing interneurons abolished NRG1-mediated inhibition of epileptogenesis and promoted kindling progression, resulting in increased spontaneous seizures and exuberant mossy fiber sprouting. In contrast, depleting ErbB4 in CaMKIIα-positive pyramidal neurons had no effect. Thus, NRG1-induced activation of ErbB4 in parvalbumin-expressing inhibitory interneurons may serve as a critical endogenous negative-feedback mechanism to suppress limbic epileptogenesis.

  16. Limbic-motor integration by neural excitations and inhibitions in the nucleus accumbens.

    PubMed

    Morrison, Sara E; McGinty, Vincent B; du Hoffmann, Johann; Nicola, Saleem M

    2017-08-09

    The nucleus accumbens (NAc) has often been described as a "limbic-motor interface," implying that the NAc integrates the value of expected rewards with the motor planning required to obtain them. However, there is little direct evidence that the signaling of individual NAc neurons combines information about predicted reward and behavioral response. Here, we report that cue-evoked neural responses in the NAc form a likely physiological substrate for its limbic-motor integration function. Across task contexts, individual NAc neurons in behaving rats robustly encode the reward-predictive qualities of a cue, as well as the probability of behavioral response to the cue, as coexisting components of the neural signal. In addition, cue-evoked activity encodes spatial and locomotor aspects of the behavioral response, including proximity to a reward-associated target and the latency and speed of approach to the target. Notably, there are important limits to the ability of NAc neurons to integrate motivational information into behavior: in particular, updating of predicted reward value appears to occur on a relatively long time scale, as NAc neurons fail to discriminate between cues with reward associations that change frequently. Overall, these findings suggest that NAc cue-evoked signals - including inhibition of firing (as noted here for the first time) - provide a mechanism for linking reward prediction and other motivationally relevant factors, such as spatial proximity, to the probability and vigor of a reward-seeking behavioral response. Copyright © 2017, Journal of Neurophysiology.

  17. Voltage-gated potassium channel antibody paraneoplastic limbic encephalitis associated with acute myeloid leukemia.

    PubMed

    Alcantara, Marion; Bennani, Omar; Verdure, Pierre; Leprêtre, Stéphane; Tilly, Hervé; Jardin, Fabrice

    2013-05-01

    Among paraneoplastic syndromes (PNS) associated with malignant hemopathies, there are few reports of PNS of the central nervous system and most of them are associated with lymphomas. Limbic encephalitis is a rare neurological syndrome classically diagnosed in the context of PNS. We report the case of a 81-year-old man who presented with a relapsed acute myeloid leukemia (AML) with minimal maturation. He was admitted for confusion with unfavorable evolution as he presented a rapidly progressive dementia resulting in death. A brain magnetic resonance imaging, performed 2 months after the onset, was considered normal. An electroencephalogram showed non-specific bilateral slow waves. We received the results of the blood screening of neuronal autoanti-bodies after the patient's death and detected the presence of anti-voltage-gated potassium channel (VGKC) antibodies at 102 pmol/l (normal at <30 pmol/l). Other etiologic studies, including the screening for another cause of rapidly progressive dementia, were negative. To our knowledge, this is the first case of anti-VGKC paraneoplastic limbic encephalitis related to AML.

  18. Voltage-Gated Potassium Channel Antibody Paraneoplastic Limbic Encephalitis Associated with Acute Myeloid Leukemia

    PubMed Central

    Alcantara, Marion; Bennani, Omar; Verdure, Pierre; Leprêtre, Stéphane; Tilly, Hervé; Jardin, Fabrice

    2013-01-01

    Among paraneoplastic syndromes (PNS) associated with malignant hemopathies, there are few reports of PNS of the central nervous system and most of them are associated with lymphomas. Limbic encephalitis is a rare neurological syndrome classically diagnosed in the context of PNS. We report the case of a 81-year-old man who presented with a relapsed acute myeloid leukemia (AML) with minimal maturation. He was admitted for confusion with unfavorable evolution as he presented a rapidly progressive dementia resulting in death. A brain magnetic resonance imaging, performed 2 months after the onset, was considered normal. An electroencephalogram showed non-specific bilateral slow waves. We received the results of the blood screening of neuronal autoanti-bodies after the patient's death and detected the presence of anti-voltage-gated potassium channel (VGKC) antibodies at 102 pmol/l (normal at <30 pmol/l). Other etiologic studies, including the screening for another cause of rapidly progressive dementia, were negative. To our knowledge, this is the first case of anti-VGKC paraneoplastic limbic encephalitis related to AML. PMID:23898271

  19. Correlations between Limbic White Matter and Cognitive Function in Temporal-Lobe Epilepsy, Preliminary Findings

    PubMed Central

    Alexander, Ryan P. D.; Concha, Luis; Snyder, Thomas J.; Beaulieu, Christian; Gross, Donald William

    2014-01-01

    The limbic system is presumed to have a central role in cognitive performance, in particular memory. The purpose of this study was to investigate the relationship between limbic white matter microstructure and neuropsychological function in temporal-lobe epilepsy (TLE) patients using diffusion tensor imaging (DTI). Twenty-one adult TLE patients, including 7 non-lesional (nlTLE) and 14 with unilateral mesial temporal sclerosis (uTLE), were studied with both DTI and hippocampal T2 relaxometry. Correlations were performed between fractional anisotropy (FA) of the bilateral fornix and cingulum, hippocampal T2, neuropsychological tests. Positive correlations were observed in the whole group for the left fornix and processing speed index. In contrast, memory tests did not show significant correlations with DTI findings. Subgroup analysis demonstrated an association between the left fornix and processing speed in nlTLE but not uTLE. No correlations were observed between hippocampal T2 and test scores in either the TLE group as a whole or after subgroup analysis. Our findings suggest that integrity of the left fornix specifically is an important anatomical correlate of cognitive function in TLE patients, in particular patients with nlTLE. PMID:25071551

  20. Disruption of TrkB-mediated PLCγ signaling inhibits limbic epileptogenesis

    PubMed Central

    He, XP; Pan, E; Sciarretta, C; Minichiello, L; McNamara, JO

    2010-01-01

    The BDNF receptor, TrkB, is critical to limbic epileptogenesis, but the responsible downstream signaling pathways are unknown. We hypothesized that TrkB-dependent activation of PLCγ1 signaling is the key pathway and tested this in trkBPLC/PLC mice carrying a mutation (Y816F) that uncouples TrkB from PLCγ1. Biochemical measures revealed activation of both TrkB and PLCγ1 in hippocampi in the pilocarpine and kindling models in WT mice. PLCγ1 activation was decreased in hippocampi isolated from trkBPLC/PLC compared to control mice. Epileptogenesis assessed by development of kindling was inhibited in trkBPLC/PLC compared to control mice. Long-term potentiation of the mossy fiber-CA3 pyramid synapse was impaired in slices of trkBPLC/PLC mice. We conclude that TrkB-dependent activation of PLCγ1 signaling is an important molecular mechanism of limbic epileptogenesis. Elucidating signaling pathways activated by a cell membrane receptor in animal models of CNS disorders promises to reveal novel targets for specific and effective therapeutic intervention. PMID:20445044

  1. Structural Plasticity of Dentate Granule Cell Mossy Fibers During the Development of Limbic Epilepsy

    PubMed Central

    Danzer, Steve C.; He, Xiaoping; Loepke, Andreas W.; McNamara, James O.

    2009-01-01

    Altered granule cell≫CA3 pyramidal cell synaptic connectivity may contribute to the development of limbic epilepsy. To explore this possibility, granule cell giant mossy fiber bouton plasticity was examined in the kindling and pilocarpine models of epilepsy using green fluorescent protein-expressing transgenic mice. These studies revealed significant increases in the frequency of giant boutons with satellite boutons 2 days and 1 month after pilocarpine status epilepticus, and increases in giant bouton area at 1 month. Similar increases in giant bouton area were observed shortly after kindling. Finally, both models exhibited plasticity of mossy fiber giant bouton filopodia, which contact GABAergic interneurons mediating feedforward inhibition of CA3 pyramids. In the kindling model, however, all changes were fleeting, having resolved by 1 month after the last evoked seizure. Together, these findings demonstrate striking structural plasticity of granule cell mossy fiber synaptic terminal structure in two distinct models of adult limbic epileptogenesis. We suggest that these plasticities modify local connectivities between individual mossy fiber terminals and their targets, inhibitory interneurons, and CA3 pyramidal cells potentially altering the balance of excitation and inhibition during the development of epilepsy. PMID:19294647

  2. Diffusion tensor imaging tractography and reliability analysis for limbic and paralimbic white matter tracts.

    PubMed

    Malykhin, Nikolai; Concha, Luis; Seres, Peter; Beaulieu, Christian; Coupland, Nicholas J

    2008-11-30

    Diffusion tensor imaging (DTI) provides the opportunity to study white matter tracts in vivo. The goal was to estimate the reliability of DTI tractography for the analysis of limbic and paralimbic white matter. Normative data from 24 healthy subjects and reliability data from four healthy and four depressed subjects were acquired at 1.5 Tesla, using twice-refocused spin-echo, echoplanar DTI and Fluid-Attenuated Inversion Recovery (FLAIR) DTI sequences. Fiber tracking was performed using the Fiber Assignment by Continuous Tracking algorithm. Fractional Anisotropy (FA), trace Apparent Diffusion Coefficient and tract volumes were calculated. The inter-rater (and intra-rater) intraclass correlation coefficients for FA values were as follows: rostral cingulum 0.89 (0.87), dorsal cingulum 0.85 (0.90), parahippocampal cingulum 0.85 (0.95), uncinate fasciculus 0.85 (0.87), medial prefrontal white matter 0.97 (0.99), ventromedial prefrontal white matter 0.92 (0.93), crus of fornix 0.80 (0.81). The reported DTI protocol provides a reliable method to analyze limbic and paralimbic white matter tracts relevant to psychiatric disorders.

  3. Diffusion tensor imaging in Alzheimer's disease: insights into the limbic-diencephalic network and methodological considerations

    PubMed Central

    Acosta-Cabronero, Julio; Nestor, Peter J.

    2014-01-01

    Glucose hypometabolism and gray matter atrophy are well known consequences of Alzheimer's disease (AD). Studies using these measures have shown that the earliest clinical stages, in which memory impairment is a relatively isolated feature, are associated with degeneration in an apparently remote group of areas—mesial temporal lobe (MTL), diencephalic structures such as anterior thalamus and mammillary bodies, and posterior cingulate. These sites are thought to be strongly anatomically inter-connected via a limbic-diencephalic network. Diffusion tensor imaging or DTI—an imaging technique capable of probing white matter tissue microstructure—has recently confirmed degeneration of the white matter connections of the limbic-diencephalic network in AD by way of an unbiased analysis strategy known as tract-based spatial statistics (TBSS). The present review contextualizes the relevance of these findings, in which the fornix is likely to play a fundamental role in linking MTL and diencephalon. An interesting by-product of this work has been in showing that alterations in diffusion behavior are complex in AD—while early studies tended to focus on fractional anisotropy, recent work has highlighted that this measure is not the most sensitive to early changes. Finally, this review will discuss in detail several technical aspects of DTI both in terms of image acquisition and TBSS analysis as both of these factors have important implications to ensure reliable observations are made that inform understanding of neurodegenerative diseases. PMID:25324775

  4. Impaired Frontal-Limbic White Matter Maturation in Children at Risk for Major Depression.

    PubMed

    Hung, Yuwen; Saygin, Zeynep M; Biederman, Joseph; Hirshfeld-Becker, Dina; Uchida, Mai; Doehrmann, Oliver; Han, Michelle; Chai, Xiaoqian J; Kenworthy, Tara; Yarmak, Pavel; Gaillard, Schuyler L; Whitfield-Gabrieli, Susan; Gabrieli, John D E

    2017-09-01

    Depression is among the most common neuropsychiatric disorders. It remains unclear whether brain abnormalities associated with depression reflect the pathological state of the disease or neurobiological traits predisposing individuals to depression. Parental history of depression is a risk factor that more than triples the risk of depression. We compared white matter (WM) microstructure cross-sectionally in 40 children ages 8-14 with versus without parental history of depression (At-Risk vs. Control). There were significant differences in age-related changes of fractional anisotropy (FA) between the groups, localized in the anterior fronto-limbic WM pathways, including the anterior cingulum and the genu of the corpus callosum. Control children exhibited typical increasing FA with age, whereas At-Risk children exhibited atypical decreasing FA with age in these fronto-limbic regions. Furthermore, dorsal cingulate FA significantly correlated with depressive symptoms for At-Risk children. The results suggest maturational WM microstructure differences in mood-regulatory neurocircuitry that may contribute to neurodevelopmental risk for depression. The study provides new insights into neurodevelopmental susceptibility to depression and related disabilities that may promote early preventive intervention approaches. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  5. Disruption of TrkB-mediated phospholipase Cgamma signaling inhibits limbic epileptogenesis.

    PubMed

    He, Xiao Ping; Pan, Enhui; Sciarretta, Carla; Minichiello, Liliana; McNamara, James O

    2010-05-05

    The BDNF receptor, TrkB, is critical to limbic epileptogenesis, but the responsible downstream signaling pathways are unknown. We hypothesized that TrkB-dependent activation of phospholipase Cgamma1 (PLCgamma1) signaling is the key pathway and tested this in trkB(PLC/PLC) mice carrying a mutation (Y816F) that uncouples TrkB from PLCgamma1. Biochemical measures revealed activation of both TrkB and PLCgamma1 in hippocampi in the pilocarpine and kindling models in wild-type mice. PLCgamma1 activation was decreased in hippocampi isolated from trkB(PLC/PLC) compared with control mice. Epileptogenesis assessed by development of kindling was inhibited in trkB(PLC/PLC) compared with control mice. Long-term potentiation of the mossy fiber-CA3 pyramid synapse was impaired in slices of trkB(PLC/PLC) mice. We conclude that TrkB-dependent activation of PLCgamma1 signaling is an important molecular mechanism of limbic epileptogenesis. Elucidating signaling pathways activated by a cell membrane receptor in animal models of CNS disorders promises to reveal novel targets for specific and effective therapeutic intervention.

  6. Neurodevelopmental marker for limbic maldevelopment in antisocial personality disorder and psychopathy

    PubMed Central

    Raine, Adrian; Lee, Lydia; Yang, Yaling; Colletti, Patrick

    2010-01-01

    Background Antisocial personality disorder and psychopathy have been hypothesised to have a neurodevelopmental basis, but this proposition has not been formally tested. Aims This study tests the hypothesis that individuals with cavum septum pellucidum (CSP), a marker of limbic neural maldevelopment, will show higher levels of psychopathy and antisocial personality. Method Cavum septum pellucidum was assessed using anatomical magnetic resonance imaging in a community sample. Those with CSP (n = 19) were compared with those lacking CSP (n = 68) on antisocial personality, psychopathy and criminal offending. Results Those with CSP had significantly higher levels of antisocial personality, psychopathy, arrests and convictions compared with controls. The pervasiveness of this association was indicated by the fact that those lacking a diagnosis of antisocial personality disorder, but who were charged or convicted for an offence, had a more extensive CSP than non-antisocial controls. Results could not be attributed to prior trauma exposure, head injury, demographic factors or comorbid psychiatric conditions. Conclusions Our findings appear to be the first to provide evidence for a neurodevelopmental brain abnormality in those with antisocial personality disorder and psychopathy, and support the hypothesis that early maldevelopment of limbic and septal structures predisposes to the spectrum of antisocial behaviours. PMID:20807962

  7. Neurodevelopmental marker for limbic maldevelopment in antisocial personality disorder and psychopathy.

    PubMed

    Raine, Adrian; Lee, Lydia; Yang, Yaling; Colletti, Patrick

    2010-09-01

    Antisocial personality disorder and psychopathy have been hypothesised to have a neurodevelopmental basis, but this proposition has not been formally tested. This study tests the hypothesis that individuals with cavum septum pellucidum (CSP), a marker of limbic neural maldevelopment, will show higher levels of psychopathy and antisocial personality. Cavum septum pellucidum was assessed using anatomical magnetic resonance imaging in a community sample. Those with CSP (n = 19) were compared with those lacking CSP (n = 68) on antisocial personality, psychopathy and criminal offending. Those with CSP had significantly higher levels of antisocial personality, psychopathy, arrests and convictions compared with controls. The pervasiveness of this association was indicated by the fact that those lacking a diagnosis of antisocial personality disorder, but who were charged or convicted for an offence, had a more extensive CSP than non-antisocial controls. Results could not be attributed to prior trauma exposure, head injury, demographic factors or comorbid psychiatric conditions. Our findings appear to be the first to provide evidence for a neurodevelopmental brain abnormality in those with antisocial personality disorder and psychopathy, and support the hypothesis that early maldevelopment of limbic and septal structures predisposes to the spectrum of antisocial behaviours.

  8. Neurophysiological responses to stressful motion and anti-motion sickness drugs as mediated by the limbic system

    NASA Technical Reports Server (NTRS)

    Kohl, R. L.; Odell, S.

    1982-01-01

    Performance is characterized in terms of attention and memory, categorizing extrinsic mechanism mediated by ACTH, norepinephrine and dopamine, and intrinsic mechanisms as cholinergic. The cholinergic role in memory and performance was viewed from within the limbic system and related to volitional influences of frontal cortical afferents and behavioral responses of hypothalamic and reticular system efferents. The inhibitory influence of the hippocampus on the autonomic and hormonal responses mediated through the hypothalamus, pituitary, and brain stem are correlated with the actions of such anti-motion sickness drugs as scopolamine and amphetamine. These drugs appear to exert their effects on motion sickness symptomatology through diverse though synergistic neurochemical mechanisms involving the septohippocampal pathway and other limbic system structures. The particular impact of the limbic system on an animal's behavioral and hormonal responses to stress is influenced by ACTH, cortisol, scopolamine, and amphetamine.

  9. Disturbed Mental Imagery of Affected Body-Parts in Patients with Hysterical Conversion Paraplegia Correlates with Pathological Limbic Activity

    PubMed Central

    Saj, Arnaud; Raz, Noa; Levin, Netta; Ben-Hur, Tamir; Arzy, Shahar

    2014-01-01

    Patients with conversion disorder generally suffer from a severe neurological deficit which cannot be attributed to a structural neurological damage. In two patients with acute conversion paraplegia, investigation with functional magnetic resonance imaging (fMRI) showed that the insular cortex, a limbic-related cortex involved in body-representation and subjective emotional experience, was activated not only during attempt to move the paralytic body-parts, but also during mental imagery of their movements. In addition, mental rotation of affected body-parts was found to be disturbed, as compared to unaffected body parts or external objects. fMRI during mental rotation of the paralytic body-part showed an activation of another limbic related region, the anterior cingulate cortex. These data suggest that conversion paraplegia is associated with pathological activity in limbic structures involved in body representation and a deficit in mental processing of the affected body-parts. PMID:24961768

  10. Development of glucocorticoid receptor regulation in the rat forebrain: Implications for adverse effects of glucocorticoids in preterm infants

    EPA Science Inventory

    Glucocorticoids are the consensus treatment to avoid respiratory distress in preterm infants but there is accumulating evidence that these agents evoke long-term neurobehavioral deficits. Earlier, we showed that the developing rat forebrain is far more sensitive to glucocorticoi...

  11. Lack of the murine homeobox gene Hesx1 leads to a posterior transformation of the anterior forebrain

    PubMed Central

    Andoniadou, Cynthia L.; Signore, Massimo; Sajedi, Ezat; Gaston-Massuet, Carles; Kelberman, Daniel; Burns, Alan J.; Itasaki, Nobue; Dattani, Mehul; Martinez-Barbera, Juan Pedro

    2008-01-01

    The homeobox gene Hesx1 is an essential repressor that is required within the anterior neural plate for normal forebrain development in mouse and humans. Combining genetic cell labelling and marker analyses, we demonstrate that the absence of Hesx1 leads to a posterior transformation of the anterior forebrain (AFB) during mouse development. Our data suggest that the mechanism underlying this transformation is the ectopic activation of Wnt/β-catenin signalling within the Hesx1 expression domain in the AFB. When ectopically expressed in the developing mouse embryo, Hesx1 alone cannot alter the normal fate of posterior neural tissue. However, conditional expression of Hesx1 within the AFB can rescue the forebrain defects observed in the Hesx1 mutants. The results presented here provide new insights into the function of Hesx1 in forebrain formation. PMID:17360769

  12. Differential effects of light and feeding on circadian organization of peripheral clocks in a forebrain Bmal1 mutant.

    PubMed

    Izumo, Mariko; Pejchal, Martina; Schook, Andrew C; Lange, Ryan P; Walisser, Jacqueline A; Sato, Takashi R; Wang, Xiaozhong; Bradfield, Christopher A; Takahashi, Joseph S

    2014-12-19

    In order to assess the contribution of a central clock in the hypothalamic suprachiasmatic nucleus (SCN) to circadian behavior and the organization of peripheral clocks, we generated forebrain/SCN-specific Bmal1 knockout mice by using floxed Bmal1 and pan-neuronal Cre lines. The forebrain knockout mice showed >90% deletion of BMAL1 in the SCN and exhibited an immediate and complete loss of circadian behavior in constant conditions. Circadian rhythms in peripheral tissues persisted but became desynchronized and damped in constant darkness. The loss of synchrony was rescued by light/dark cycles and partially by restricted feeding (only in the liver and kidney but not in the other tissues) in a distinct manner. These results suggest that the forebrain/SCN is essential for internal temporal order of robust circadian programs in peripheral clocks, and that individual peripheral clocks are affected differently by light and feeding in the absence of a functional oscillator in the forebrain.

  13. Development of glucocorticoid receptor regulation in the rat forebrain: Implications for adverse effects of glucocorticoids in preterm infants

    EPA Science Inventory

    Glucocorticoids are the consensus treatment to avoid respiratory distress in preterm infants but there is accumulating evidence that these agents evoke long-term neurobehavioral deficits. Earlier, we showed that the developing rat forebrain is far more sensitive to glucocorticoi...

  14. [Disorders of neurogenesis of cortical and subcortical structures in rat brain limbic system during fetal alcohol syndrome formation].

    PubMed

    Svanidze, I K; Museridze, D P; Didimova, E V; Sanikidze, T V; Gegenava, L G; Gvinadze, N N

    2012-01-01

    Disorders of neurogenesis of cortical and subcortical structures in rat brain limbic system were studied in the offspring of rats that received ethanol during pregnancy. The methods used included the staining of histological sections with cresyl violet, in vitro culture, and electron paramagnetic resonance. Prenatal alcohol intoxication was shown to induce the disturbances in proliferative activity of granular layer cells in the hippocampal dentate gyrus, neuron- and glioblast migration, enhancement of free NO and lipoperoxide production and cell death. This resulted in the changes in the number of neurons in cortical and subcortical structures of rat brain limbic system and in fetal alcohol syndrome formation.

  15. Distribution of glutamine synthetase in the chick forebrain: implications for passive avoidance memory formation.

    PubMed

    O'Dowd, B S; Ng, K T; Robinson, S R

    1997-01-01

    The glial enzyme glutamine synthetase (GS) converts glutamate to glutamine; the latter is used by neurons for the resynthesis of glutamate and GABA. We have used a monoclonal antibody to GS to examine the regional distribution of this enzyme in the forebrains of day-old chicks. GS was detected in glia throughout the rostral and caudal regions of the forebrain and was particularly intense in the hippocampus, area parahippocampus and parts of the hyperstriatal and paleostriatal complex, regions widely considered to be involved in memory formation. Thus, our data provide an anatomical framework for the conclusion that neurons require the support of glia in order to restock their glutamate and/or GABA transmitter supplies during memory processing.

  16. Clonally Related Forebrain Interneurons Disperse Broadly across Both Functional Areas and Structural Boundaries.

    PubMed

    Mayer, Christian; Jaglin, Xavier H; Cobbs, Lucy V; Bandler, Rachel C; Streicher, Carmen; Cepko, Constance L; Hippenmeyer, Simon; Fishell, Gord

    2015-09-02

    The medial ganglionic eminence (MGE) gives rise to the majority of mouse forebrain interneurons. Here, we examine the lineage relationship among MGE-derived interneurons using a replication-defective retroviral library containing a highly diverse set of DNA barcodes. Recovering the barcodes from the mature progeny of infected progenitor cells enabled us to unambiguously determine their respective lineal relationship. We found that clonal dispersion occurs across large areas of the brain and is not restricted by anatomical divisions. As such, sibling interneurons can populate the cortex, hippocampus striatum, and globus pallidus. The majority of interneurons appeared to be generated from asymmetric divisions of MGE progenitor cells, followed by symmetric divisions within the subventricular zone. Altogether, our findings uncover that lineage relationships do not appear to determine interneuron allocation to particular regions. As such, it is likely that clonally related interneurons have considerable flexibility as to the particular forebrain circuits to which they can contribute.

  17. The ancestral role of nodal signalling in breaking L/R symmetry in the vertebrate forebrain.

    PubMed

    Lagadec, Ronan; Laguerre, Laurent; Menuet, Arnaud; Amara, Anis; Rocancourt, Claire; Péricard, Pierre; Godard, Benoît G; Rodicio, Maria Celina; Rodriguez-Moldes, Isabel; Mayeur, Hélène; Rougemont, Quentin; Mazan, Sylvie; Boutet, Agnès

    2015-03-30

    Left-right asymmetries in the epithalamic region of the brain are widespread across vertebrates, but their magnitude and laterality varies among species. Whether these differences reflect independent origins of forebrain asymmetries or taxa-specific diversifications of an ancient vertebrate feature remains unknown. Here we show that the catshark Scyliorhinus canicula and the lampreys Petromyzon marinus and Lampetra planeri exhibit conserved molecular asymmetries between the left and right developing habenulae. Long-term pharmacological treatments in these species show that nodal signalling is essential to their generation, rather than their directionality as in teleosts. Moreover, in contrast to zebrafish, habenular left-right differences are observed in the absence of overt asymmetry of the adjacent pineal field. These data support an ancient origin of epithalamic asymmetry, and suggest that a nodal-dependent asymmetry programme operated in the forebrain of ancestral vertebrates before evolving into a variable trait in bony fish.

  18. Molecular taxonomy of major neuronal classes in the adult mouse forebrain.

    PubMed

    Sugino, Ken; Hempel, Chris M; Miller, Mark N; Hattox, Alexis M; Shapiro, Peter; Wu, Caizi; Huang, Z Josh; Nelson, Sacha B

    2006-01-01

    Identifying the neuronal cell types that comprise the mammalian forebrain is a central unsolved problem in neuroscience. Global gene expression profiles offer a potentially unbiased way to assess functional relationships between neurons. Here, we carried out microarray analysis of 12 populations of neurons in the adult mouse forebrain. Five of these populations were chosen from cingulate cortex and included several subtypes of GABAergic interneurons and pyramidal neurons. The remaining seven were derived from the somatosensory cortex, hippocampus, amygdala and thalamus. Using these expression profiles, we were able to construct a taxonomic tree that reflected the expected major relationships between these populations, such as the distinction between cortical interneurons and projection neurons. The taxonomic tree indicated highly heterogeneous gene expression even within a single region. This dataset should be useful for the classification of unknown neuronal subtypes, the investigation of specifically expressed genes and the genetic manipulation of specific neuronal circuit elements.

  19. Enriched environment influences brain-derived neurotrophic factor levels in rat forebrain after focal stroke.

    PubMed

    Zhao, L R; Risedal, A; Wojcik, A; Hejzlar, J; Johansson, B B; Kokaia, Z

    2001-06-15

    Tissue levels of brain-derived neurotrophic factor (BDNF) protein were studied using enzyme immunoassay in different forebrain regions in the ipsi- and contralateral hemispheres of rats housed under enriched or standard conditions after the middle cerebral artery ligation. BDNF levels in the ipsilateral to ligation side was significantly higher only in the frontal cortex of standard as compared to enriched rats. However, BDNF overall was more abundant in standard than in enriched group. In addition, BDNF levels detected in the hippocampus and frontal cortex on the ischemic side of standard rats was higher as compared to contralateral side. The present study shows that housing conditions after permanent middle cerebral artery ligation leads to differential regulation of BDNF protein levels in forebrain regions which might have important implication for post-ischemic recovery.

  20. Nerve growth factor corrects developmental impairments of basal forebrain cholinergic neurons in the trisomy 16 mouse.

    PubMed Central

    Corsi, P; Coyle, J T

    1991-01-01

    The trisomy 16 (Ts16) mouse, which shares genetic and phenotypic homologies with Down syndrome, exhibits impaired development of the basal forebrain cholinergic system. Basal forebrains obtained from Ts16 and euploid littermate fetuses at 15 days of gestation were dissociated and cultured in completely defined medium, with cholinergic neurons identified by choline acetyltransferase (ChAT) immunoreactivity. The Ts16 cultures exhibited fewer ChAT-immunoreactive neurons, which were smaller and emitted shorter, smoother, and more simplified neurites than those from euploid littermates. Whereas the addition of beta-nerve growth factor (100 ng/ml) augmented the specific activity of ChAT and neuritic extension for both Ts16 and euploid cholinergic neurons, only Ts16 cultures exhibited an increase in the number and size of ChAT-immunoreactive neurons. Furthermore, Ts16 ChAT-immunoreactive neurites formed varicosities only in the presence of beta-nerve growth factor. Images PMID:2000385

  1. Receptors for GRP/bombesin-like peptides in the rat forebrain

    SciTech Connect

    Wolf, S.S.; Moody, T.W.

    1985-01-01

    Binding sites in the rat forebrain were characterized using ( SVI-Tyr4)bombesin as a receptor probe. Pharmacology experiments indicate that gastrin releasing peptide (GRP) and the GRP fragments GRP as well as Ac-GRP inhibited radiolabeled (Tyr4)bombesin binding with high affinity. Biochemistry experiments indicated that heat, N-ethyl maleimide or trypsin greatly reduced radiolabeled (Tyr4)bombesin binding. Also, autoradiographic studies indicated that highest grain densities were present in the stria terminalis, periventricular and suprachiasmatic nucleus of the hypothalamus, dorsomedial and rhomboid thalamus, dentate gyrus, hippocampus and medial amygdaloid nucleus. The data suggest that CNS protein receptors, which are discretely distributed in the rat forebrain, may mediate the action of endogenous GRP/bombesin-like peptides.

  2. Brain-derived neurotrophic factor (BDNF) overexpression in the forebrain results in learning and memory impairments.

    PubMed

    Cunha, Carla; Angelucci, Andrea; D'Antoni, Angela; Dobrossy, Mate D; Dunnett, Stephen B; Berardi, Nicoletta; Brambilla, Riccardo

    2009-03-01

    In this study we analyzed the effect on behavior of a chronic exposure to brain-derived neurotrophic factor (BDNF), by analysing a mouse line overexpressing BDNF under the alphaCaMKII promoter, which drives the transgene expression exclusively to principal neurons of the forebrain. BDNF transgenic mice and their WT littermates were examined with a battery of behavioral tests, in order to evaluate motor coordination, learning, short and long-term memory formation. Our results demonstrate that chronic BDNF overexpression in the central nervous system (CNS) causes learning deficits and short-term memory impairments, both in spatial and instrumental learning tasks. This observation suggests that a widespread increase in BDNF in forebrain networks may result in adverse effects on learning and memory formation.

  3. Overexpression of the Type 1 Adenylyl Cyclase in the Forebrain Leads to Deficits of Behavioral Inhibition

    PubMed Central

    Cao, Hong; Saraf, Amit; Zweifel, Larry S.

    2015-01-01

    The type 1 adenylyl cyclase (AC1) is an activity-dependent, calcium-stimulated adenylyl cyclase expressed in the nervous system that is implicated in memory formation. We examined the locomotor activity, and impulsive and social behaviors of AC1+ mice, a transgenic mouse strain overexpressing AC1 in the forebrain. Here we report that AC1+ mice exhibit hyperactive behaviors and demonstrate increased impulsivity and reduced sociability. In contrast, AC1 and AC8 double knock-out mice are hypoactive, and exhibit increased sociability and reduced impulsivity. Interestingly, the hyperactivity of AC1+ mice can be corrected by valproate, a mood-stabilizing drug. These data indicate that increased expression of AC1 in the forebrain leads to deficits in behavioral inhibition. PMID:25568126

  4. Brain-derived neurotrophic factor signaling is altered in the forebrain of Engrailed-2 knockout mice.

    PubMed

    Zunino, G; Messina, A; Sgadò, P; Baj, G; Casarosa, S; Bozzi, Y

    2016-06-02

    Engrailed-2 (En2), a homeodomain transcription factor involved in regionalization and patterning of the midbrain and hindbrain regions has been associated to autism spectrum disorders (ASDs). En2 knockout (En2(-/-)) mice show ASD-like features accompanied by a significant loss of GABAergic subpopulations in the hippocampus and neocortex. Brain-derived neurotrophic factor (BDNF) is a crucial factor for the postnatal development of forebrain GABAergic neurons, and altered GABA signaling has been hypothesized to underlie the symptoms of ASD. Here we sought to determine whether interneuron loss in the En2(-/-) forebrain might be related to altered expression of BDNF and its signaling receptors. We first evaluated the expression of different BDNF mRNA isoforms in the neocortex and hippocampus of wild-type (WT) and En2(-/-) mice. Quantitative RT-PCR showed a marked down-regulation of several splicing variants of BDNF mRNA in the neocortex but not hippocampus of adult En2(-/-) mice, as compared to WT controls. Accordingly, levels of mature BDNF protein were lower in the neocortex but not hippocampus of En2(-/-) mice, as compared to WT. Increased levels of phosphorylated TrkB and decreased levels of p75 receptor were also detected in the neocortex of mutant mice. Accordingly, the expression of low density lipoprotein receptor (LDLR) and RhoA, two genes regulated via p75 was significantly altered in forebrain areas of mutant mice. These data indicate that BDNF signaling alterations might be involved in the anatomical changes observed in the En2(-/-) forebrain and suggest a pathogenic role of altered BDNF signaling in this mouse model of ASD.

  5. Ablation of ferroptosis regulator glutathione peroxidase 4 in forebrain neurons promotes cognitive impairment and neurodegeneration.

    PubMed

    Hambright, William Sealy; Fonseca, Rene Solano; Chen, Liuji; Na, Ren; Ran, Qitao

    2017-02-01

    Synaptic loss and neuron death are the underlying cause of neurodegenerative diseases such as Alzheimer's disease (AD); however, the modalities of cell death in those diseases remain unclear. Ferroptosis, a newly identified oxidative cell death mechanism triggered by massive lipid peroxidation, is implicated in the degeneration of neurons populations such as spinal motor neurons and midbrain neurons. Here, we investigated whether neurons in forebrain regions (cerebral cortex and hippocampus) that are severely afflicted in AD patients might be vulnerable to ferroptosis. To this end, we generated Gpx4BIKO mouse, a mouse model with conditional deletion in forebrain neurons of glutathione peroxidase 4 (Gpx4), a key regulator of ferroptosis, and showed that treatment with tamoxifen led to deletion of Gpx4 primarily in forebrain neurons of adult Gpx4BIKO mice. Starting at 12 weeks after tamoxifen treatment, Gpx4BIKO mice exhibited significant deficits in spatial learning and memory function versus Control mice as determined by the Morris water maze task. Further examinations revealed that the cognitively impaired Gpx4BIKO mice exhibited hippocampal neurodegeneration. Notably, markers associated with ferroptosis, such as elevated lipid peroxidation, ERK activation and augmented neuroinflammation, were observed in Gpx4BIKO mice. We also showed that Gpx4BIKO mice fed a diet deficient in vitamin E, a lipid soluble antioxidant with anti-ferroptosis activity, had an expedited rate of hippocampal neurodegeneration and behavior dysfunction, and that treatment with a small-molecule ferroptosis inhibitor ameliorated neurodegeneration in those mice. Taken together, our results indicate that forebrain neurons are susceptible to ferroptosis, suggesting that ferroptosis may be an important neurodegenerative mechanism in diseases such as AD.

  6. Increase in cortical endocannabinoid signaling in a rat model of basal forebrain cholinergic dysfunction.

    PubMed

    Llorente-Ovejero, Alberto; Manuel, Iván; Giralt, Maria Teresa; Rodríguez-Puertas, Rafael

    2017-08-18

    The basal forebrain cholinergic pathways progressively degenerate during the progression of Alzheimer's disease, leading to an irreversible impairment of memory and thinking skills. The stereotaxic lesion with 192IgG-saporin in the rat brain has been used to eliminate basal forebrain cholinergic neurons and is aimed at emulating the cognitive damage described in this disease in order to explore its effects on behavior and on neurotransmission. Learning and memory processes that are controlled by cholinergic neurotransmission are also modulated by the endocannabinoid (eCB) system. The objective of the present study is to evaluate the eCB signaling in relation to the memory impairment induced in adult rats following a specific cholinergic lesion of the basal forebrain. Therefore, CB1 receptor-mediated signaling was analyzed using receptor and functional autoradiography, and cellular distribution by immunofluorescence. The passive avoidance test and histochemical data revealed a relationship between impaired behavioral responses and a loss of approximately 75% of cholinergic neurons in the nucleus basalis magnocellularis (NBM), accompanied by cortical cholinergic denervation. The decrease in CB1 receptor density observed in the hippocampus, together with hyperactivity of eCB signaling in the NBM and cortex, suggest an interaction between the eCB and cholinergic systems. Moreover, following basal forebrain cholinergic denervation, the presynaptic GABAergic immunoreactivity was reduced in cortical areas. In conclusion, CB1 receptors present in presynaptic GABAergic terminals in the hippocampus are down regulated, but not those in cortical glutamatergic synapses. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

  7. Cholinergic Inputs from Basal Forebrain Add an Excitatory Bias to Odor Coding in the Olfactory Bulb

    PubMed Central

    Rothermel, Markus; Carey, Ryan M.; Puche, Adam; Shipley, Michael T.

    2014-01-01

    Cholinergic modulation of central circuits is associated with active sensation, attention, and learning, yet the neural circuits and temporal dynamics underlying cholinergic effects on sensory processing remain unclear. Understanding the effects of cholinergic modulation on particular circuits is complicated by the widespread projections of cholinergic neurons to telencephalic structures that themselves are highly interconnected. Here we examined how cholinergic projections from basal forebrain to the olfactory bulb (OB) modulate output from the first stage of sensory processing in the mouse olfactory system. By optogenetically activating their axons directly in the OB, we found that cholinergic projections from basal forebrain regulate OB output by increasing the spike output of presumptive mitral/tufted cells. Cholinergic stimulation increased mitral/tufted cell spiking in the absence of inhalation-driven sensory input and further increased spiking responses to inhalation of odorless air and to odorants. This modulation was rapid and transient, was dependent on local cholinergic signaling in the OB, and differed from modulation by optogenetic activation of cholinergic neurons in basal forebrain, which led to a mixture of mitral/tufted cell excitation and suppression. Finally, bulbar cholinergic enhancement of mitral/tufted cell odorant responses was robust and occurred independent of the strength or even polarity of the odorant-evoked response, indicating that cholinergic modulation adds an excitatory bias to mitral/tufted cells as opposed to increasing response gain or sharpening response spectra. These results are consistent with a role for the basal forebrain cholinergic system in dynamically regulating the sensitivity to or salience of odors during active sensing of the olfactory environment. PMID:24672011

  8. Extracellular signal-regulated kinase phosphorylation in forebrain neurones contributes to osmoregulatory mechanisms.

    PubMed

    Dine, Julien; Ducourneau, Vincent R R; Fénelon, Valérie S; Fossat, Pascal; Amadio, Aurélie; Eder, Matthias; Israel, Jean-Marc; Oliet, Stéphane H R; Voisin, Daniel L

    2014-04-01

    Vasopressin secretion from the magnocellular neurosecretory cells (MNCs) is crucial for body fluid homeostasis. Osmotic regulation of MNC activity involves the concerted modulation of intrinsic mechanosensitive ion channels, taurine release from local astrocytes as well as excitatory inputs derived from osmosensitive forebrain regions. Extracellular signal-regulated protein kinases (ERK) are mitogen-activated protein kinases that transduce extracellular stimuli into intracellular post-translational and transcriptional responses, leading to changes in intrinsic neuronal properties and synaptic function. Here, we investigated whether ERK activation (i.e. phosphorylation) plays a role in the functioning of forebrain osmoregulatory networks. We found that within 10 min after intraperitoneal injections of hypertonic saline (3 m, 6 m) in rats, many phosphoERK-immunopositive neurones were observed in osmosensitive forebrain regions, including the MNC containing supraoptic nuclei. The intensity of ERK labelling was dose-dependent. Reciprocally, slow intragastric infusions of water that lower osmolality reduced basal ERK phosphorylation. In the supraoptic nucleus, ERK phosphorylation predominated in vasopressin neurones vs. oxytocin neurones and was absent from astrocytes. Western blot experiments confirmed that phosphoERK expression in the supraoptic nucleus was dose dependent. Intracerebroventricular administration of the ERK phosphorylation inhibitor U 0126 before a hyperosmotic challenge reduced the number of both phosphoERK-immunopositive neurones and Fos expressing neurones in osmosensitive forebrain regions. Blockade of ERK phosphorylation also reduced hypertonically induced depolarization and an increase in firing of the supraoptic MNCs recorded in vitro. It finally reduced hypertonically induced vasopressin release in the bloodstream. Altogether, these findings identify ERK phosphorylation as a new element contributing to the osmoregulatory mechanisms of

  9. Stereotaxic probabilistic maps of the magnocellular cell groups in human basal forebrain

    PubMed Central

    Zaborszky, L.; Hoemke, L.; Mohlberg, H.; Schleicher, A.; Amunts, K.; Zilles, K.

    2008-01-01

    The basal forebrain contains several interdigitating anatomical structures, including the diagonal band of Broca, the basal nucleus of Meynert, the ventral striatum, and also cell groups underneath the globus pallidus that bridge the centromedial amygdala to the bed nucleus of the stria terminalis. Among the cell populations, the magnocellular, cholinergic corticopetal projection neurons have received particular attention due to their loss in Alzheimer’s disease. In MRI images, the precise delineation of these structures is difficult due to limited spatial resolution and contrast. Here, using microscopic delineations in ten human postmortem brains, we present stereotaxic probabilistic maps of the basal forebrain areas containing the magnocellular cell groups. Cytoarchitectonic mapping was performed in silver stained histological serial sections. The positions and the extent of the magnocellular cell groups within the septum (Ch1-2), the horizontal limb of the diagonal band (Ch3), and in the sublenticular part of the basal forebrain (Ch4) were traced in high-resolution digitized histological sections, 3D reconstructed, and warped to the reference space of the MNI single subject brain. The superposition of the cytoarchitectonic maps in the MNI brain shows the intersubject variability of the various Ch compartments and their stereotaxic position relative to other brain structures. Both the right and left Ch4 regions showed significantly smaller volumes when age was considered as a covariate. Probabilistic maps of compartments of the basal forebrain magnocellular system are now available as an open source reference for correlation with fMRI, PET, and structural MRI data of the living human brain. PMID:18585468

  10. Forebrain CRHR1 deficiency attenuates chronic stress-induced cognitive deficits and dendritic remodeling

    PubMed Central

    Wang, Xiao-Dong; Chen, Yuncai; Wolf, Miriam; Wagner, Klaus V.; Liebl, Claudia; Scharf, Sebastian H.; Harbich, Daniela; Mayer, Bianca; Wurst, Wolfgang; Holsboer, Florian; Deussing, Jan M.; Baram, Tallie Z.; Müller, Marianne B.; Schmidt, Mathias V.

    2011-01-01

    Chronic stress evokes profound structural and molecular changes in the hippocampus, which may underlie spatial memory deficits. Corticotropin-releasing hormone (CRH) and CRH receptor 1 (CRHR1) mediate some of the rapid effects of stress on dendritic spine morphology and modulate learning and memory, thus providing a potential molecular basis for impaired synaptic plasticity and spatial memory by repeated stress exposure. Using adult male mice with CRHR1 conditionally inactivated in the forebrain regions, we investigated the role of CRH-CRHR1 signaling in the effects of chronic social defeat stress on spatial memory, the dendritic morphology of hippocampal CA3 pyramidal neurons, and the hippocampal expression of nectin-3, a synaptic cell adhesion molecule important in synaptic remodeling. In chronically stressed wild-type mice, spatial memory was disrupted, and the complexity of apical dendrites of CA3 neurons reduced. In contrast, stressed mice with forebrain CRHR1 deficiency exhibited normal dendritic morphology of CA3 neurons and mild impairments in spatial memory. Additionally, we showed that the expression of nectin-3 in the CA3 area was regulated by chronic stress in a CRHR1-dependent fashion and associated with spatial memory and dendritic complexity. Moreover, forebrain CRHR1 deficiency prevented the down-regulation of hippocampal glucocorticoid receptor expression by chronic stress but induced increased body weight gain during persistent stress exposure. These findings underscore the important role of forebrain CRH-CRHR1 signaling in modulating chronic stress-induced cognitive, structural and molecular adaptations, with implications for stress-related psychiatric disorders. PMID:21296667

  11. Tyrosine hydroxylase immunoreactive neurons in the forebrain of the trout: organization, cellular features and innervation.

    PubMed

    Anadón, Ramón; Rodríguez-Moldes, Isabel; González, Agustín

    We studied the segmental distribution and cellular features of tyrosine hydroxylase-immunoreactive (TH-ir) neurons in the forebrain of trout. Large differences in cell size, general morphology, and complexity of cell processes were observed between TH-ir nuclei of different regions, and a new type of complex spiny TH-ir neurons in the ventral telencephalon is described for the first time. The distribution of TH-ir fibers was also analyzed and discussed.

  12. Time course of ischemia/reperfusion-induced oxidative modification of neural proteins in rat forebrain.

    PubMed

    Lehotský, J; Murín, R; Strapková, A; Uríková, A; Tatarková, Z; Kaplán, P

    2004-12-01

    Time course of oxidative modification of forebrain neural proteins was investigated in the rat model of global and partial cerebral ischemia/reperfusion. Animals were subjected to 4-vessel occlusion for 15 min (global ischemia). After the end of ischemia and at different reperfusion times (2, 24 and 48 h), lipoperoxidation-dependent and direct oxidative modification neural protein markers were measured in the forebrain total membrane fraction (tissue homogenate). Ischemia itself causes significant changes only in levels of tryptophan and bityrosine fluorescence when compared to controls. All tested parameters of protein modification altered significantly and were maximal at later reperfusion stage. Content of carbonyl group in re-flow period steadily increased and culminated at 48 h of reperfusion. The highest increase in the fluorescence of bityrosines was detected after 24 h of reperfusion and was statistically significant to both sham operated and ischemic groups. The changes in fluorescence intensity of tryptophan decreased during a reperfusion time dependent manner. Formation of lysine conjugates with lipoperoxidation end-products significantly increased only at later stages of reperfusion. Total forebrain membranes from animals subjected to 3-vessel occlusion model to 15 min (partial ischemia) show no altered content of oxidatively modified proteins compared to controls. Restoration of blood flow for 24 h significantly decreased only fluorescence of aromatic tryptophan. Partial forebrain ischemia/reperfusion resulted in no detectable significant changes in oxidative products formation in extracerebral tissues (liver and kidney) homogenates. Our results suggest that global ischemia/reperfusion initiates both the lipoperoxidation-dependent and direct oxidative modifications of neural proteins. The findings support the view that spatial and temporal injury at later stages of ischemic insult at least partially involves oxidative stress-induced amino acid

  13. Extracellular signal-regulated kinase phosphorylation in forebrain neurones contributes to osmoregulatory mechanisms

    PubMed Central

    Dine, Julien; Ducourneau, Vincent R R; Fénelon, Valérie S; Fossat, Pascal; Amadio, Aurélie; Eder, Matthias; Israel, Jean-Marc; Oliet, Stéphane H R; Voisin, Daniel L

    2014-01-01

    Vasopressin secretion from the magnocellular neurosecretory cells (MNCs) is crucial for body fluid homeostasis. Osmotic regulation of MNC activity involves the concerted modulation of intrinsic mechanosensitive ion channels, taurine release from local astrocytes as well as excitatory inputs derived from osmosensitive forebrain regions. Extracellular signal-regulated protein kinases (ERK) are mitogen-activated protein kinases that transduce extracellular stimuli into intracellular post-translational and transcriptional responses, leading to changes in intrinsic neuronal properties and synaptic function. Here, we investigated whether ERK activation (i.e. phosphorylation) plays a role in the functioning of forebrain osmoregulatory networks. We found that within 10 min after intraperitoneal injections of hypertonic saline (3 m, 6 m) in rats, many phosphoERK-immunopositive neurones were observed in osmosensitive forebrain regions, including the MNC containing supraoptic nuclei. The intensity of ERK labelling was dose-dependent. Reciprocally, slow intragastric infusions of water that lower osmolality reduced basal ERK phosphorylation. In the supraoptic nucleus, ERK phosphorylation predominated in vasopressin neurones vs. oxytocin neurones and was absent from astrocytes. Western blot experiments confirmed that phosphoERK expression in the supraoptic nucleus was dose dependent. Intracerebroventricular administration of the ERK phosphorylation inhibitor U 0126 before a hyperosmotic challenge reduced the number of both phosphoERK-immunopositive neurones and Fos expressing neurones in osmosensitive forebrain regions. Blockade of ERK phosphorylation also reduced hypertonically induced depolarization and an increase in firing of the supraoptic MNCs recorded in vitro. It finally reduced hypertonically induced vasopressin release in the bloodstream. Altogether, these findings identify ERK phosphorylation as a new element contributing to the osmoregulatory mechanisms of

  14. Forebrain neuropeptide regulation of pair association and behavior in cooperating cleaner fish.

    PubMed

    Cardoso, Sónia C; Grutter, Alexandra S; Paula, José R; André, Gonçalo I; Messias, João P; Gozdowska, Magdalena; Kulczykowska, Ewa; Soares, Marta C

    2015-06-01

    Animals establish privileged relationships with specific partners, which are treated differently from other conspecifics, and contribute to behavioral variation. However, there is limited information on the underlying physiological mechanisms involved in the establishment of these privileged ties and their relationship to individual cooperation levels. The Indo-Pacific bluestreak cleaner wrasse Labroides dimidiatus often forages in mixed-sex pairs when cleaning fish clients. Intra-couple conflicts often arise during a joint client inspection, which may alter the overall quality of cleaning service provided. Here we tested two hypotheses: a) whether intra-pair association (i.e. association index), measured with joint interspecific cleaning and intraspecific behavior, is correlated with neuroendocrine mechanisms involving forebrain neuropeptides arginine vasotocin (AVT) and isotocin (IT) and b) whether these neuropeptide level shifts relate to an individual's interspecific service quality. We found that partner support (number of cleaning interactions and tactile stimulation) received by male cleaners increased with association index. When cleaners inspected clients alone, cleaners' cheating decreased with association index for females but not males. AVT levels did not differ according to sex or association level. Forebrain IT levels increased with association index for males, whereas no relationship was found for females. Finally, cleaner cheating varied between sex and forebrain IT levels. Findings indicate that variation in pairs' relationships influences male and female cleaner fish differently and contributes to the variation of brain neuropeptide levels, which is linked to distinct cooperative outcomes.

  15. CBP regulates the differentiation of interneurons from ventral forebrain neural precursors during murine development.

    PubMed

    Tsui, David; Voronova, Anastassia; Gallagher, Denis; Kaplan, David R; Miller, Freda D; Wang, Jing

    2014-01-15

    The mechanisms that regulate appropriate genesis and differentiation of interneurons in the developing mammalian brain are of significant interest not only because interneurons play key roles in the establishment of neural circuitry, but also because when they are deficient, this can cause epilepsy. In this regard, one genetic syndrome that is associated with deficits in neural development and epilepsy is Rubinstein-Taybi Syndrome (RTS), where the transcriptional activator and histone acetyltransferase CBP is mutated and haploinsufficient. Here, we have asked whether CBP is necessary for the appropriate genesis and differentiation of interneurons in the murine forebrain, since this could provide an explanation for the epilepsy that is associated with RTS. We show that CBP is expressed in neural precursors within the embryonic medial ganglionic eminence (MGE), an area that generates the vast majority of interneurons for the cortex. Using primary cultures of MGE precursors, we show that knockdown of CBP causes deficits in differentiation of these precursors into interneurons and oligodendrocytes, and that overexpression of CBP is by itself sufficient to enhance interneuron genesis. Moreover, we show that levels of the neurotransmitter synthesis enzyme GAD67, which is expressed in inhibitory interneurons, are decreased in the dorsal and ventral forebrain of neonatal CBP(+/-) mice, indicating that CBP plays a role in regulating interneuron development in vivo. Thus, CBP normally acts to ensure the differentiation of appropriate numbers of forebrain interneurons, and when its levels are decreased, this causes deficits in interneuron development, providing a potential explanation for the epilepsy seen in individuals with RTS.

  16. Forebrain neuroanatomy of the neonatal and juvenile dolphin (T. truncatus and S. coeruloalba).

    PubMed

    Parolisi, Roberta; Peruffo, Antonella; Messina, Silvia; Panin, Mattia; Montelli, Stefano; Giurisato, Maristella; Cozzi, Bruno; Bonfanti, Luca

    2015-01-01

    Knowledge of dolphin functional neuroanatomy mostly derives from post-mortem studies and non-invasive approaches (i.e., magnetic resonance imaging), due to limitations in experimentation on cetaceans. As a consequence the availability of well-preserved tissues for histology is scarce, and detailed histological analyses are referred mainly to adults. Here we studied the neonatal/juvenile brain in two species of dolphins, the bottlenose dolphin (Tursiops truncatus) and the striped dolphin (Stenella coeruleoalba), with special reference to forebrain regions. We analyzed cell density in subcortical nuclei, white/gray matter ratio, and myelination in selected regions at different anterior-posterior levels of the whole dolphin brain at different ages, to better define forebrain neuroanatomy and the developmental stage of the dolphin brain around birth. The analyses were extended to the periventricular germinal layer and the cerebellum, whose delayed genesis of the granule cell layer is a hallmark of postnatal development in the mammalian nervous system. Our results establish an atlas of the young dolphin forebrain and, on the basis of occurrence/absence of delayed neurogenic layers, confirm the stage of advanced brain maturation in these animals with respect to most terrestrial mammals.

  17. The neuroprotective mechanism of ampicillin in a mouse model of transient forebrain ischemia

    PubMed Central

    Lee, Kyung-Eon; Cho, Kyung-Ok; Choi, Yun-Sik

    2016-01-01

    Ampicillin, a β-lactam antibiotic, dose-dependently protects neurons against ischemic brain injury. The present study was performed to investigate the neuroprotective mechanism of ampicillin in a mouse model of transient global forebrain ischemia. Male C57BL/6 mice were anesthetized with halothane and subjected to bilateral common carotid artery occlusion for 40 min. Before transient forebrain ischemia, ampicillin (200 mg/kg, intraperitoneally [i.p.]) or penicillin G (6,000 U/kg or 20,000 U/kg, i.p.) was administered daily for 5 days. The pretreatment with ampicillin but not with penicillin G signifi cantly attenuated neuronal damage in the hippocampal CA1 subfield. Mechanistically, the increased activity of matrix metalloproteinases (MMPs) following forebrain ischemia was also attenuated by ampicillin treatment. In addition, the ampicillin treatment reversed increased immunoreactivities to glial fibrillary acidic protein and isolectin B4, markers of astrocytes and microglia, respectively. Furthermore, the ampicillin treatment significantly increased the level of glutamate transporter-1, and dihydrokainic acid (DHK, 10 mg/kg, i.p.), an inhibitor of glutamate transporter-1 (GLT-1), reversed the neuroprotective effect of ampicillin. Taken together, these data indicate that ampicillin provides neuroprotection against ischemia-reperfusion brain injury, possibly through inducing the GLT-1 protein and inhibiting the activity of MMP in the mouse hippocampus. PMID:26937215

  18. Forebrain neuroanatomy of the neonatal and juvenile dolphin (T. truncatus and S. coeruloalba)

    PubMed Central

    Parolisi, Roberta; Peruffo, Antonella; Messina, Silvia; Panin, Mattia; Montelli, Stefano; Giurisato, Maristella; Cozzi, Bruno; Bonfanti, Luca

    2015-01-01

    Knowledge of dolphin functional neuroanatomy mostly derives from post-mortem studies and non-invasive approaches (i.e., magnetic resonance imaging), due to limitations in experimentation on cetaceans. As a consequence the availability of well-preserved tissues for histology is scarce, and detailed histological analyses are referred mainly to adults. Here we studied the neonatal/juvenile brain in two species of dolphins, the bottlenose dolphin (Tursiops truncatus) and the striped dolphin (Stenella coeruleoalba), with special reference to forebrain regions. We analyzed cell density in subcortical nuclei, white/gray matter ratio, and myelination in selected regions at different anterior–posterior levels of the whole dolphin brain at different ages, to better define forebrain neuroanatomy and the developmental stage of the dolphin brain around birth. The analyses were extended to the periventricular germinal layer and the cerebellum, whose delayed genesis of the granule cell layer is a hallmark of postnatal development in the mammalian nervous system. Our results establish an atlas of the young dolphin forebrain and, on the basis of occurrence/absence of delayed neurogenic layers, confirm the stage of advanced brain maturation in these animals with respect to most terrestrial mammals. PMID:26594155

  19. Dietary protein, energy and arginine affect LAT1 expression in forebrain white matter differently.

    PubMed

    Wu, X; Yin, Y L; Li, T J; Wang, L; Ruan, Z; Liu, Z Q; Hou, Y Q

    2010-09-01

    L-type amino acid transporter-1 (LAT1) transports large, branched-chain, aromatic and neutral amino acids. About 64 Duroc × Landrace × Yorkshire pigs were used to study the effects of dietary crude protein (CP), energy and arginine on LAT1 expression in forebrain. The results showed that LAT1 expression in forebrain was sensitive to different levels of CP, energy and arginine. On the basis of Western blot analysis, a lower level of LAT1 presented in the brain tissues of pigs fed the low dietary CP diet (P < 0.05), a higher level were found in pigs fed the higher CP diet, with moderate to intense staining seen in pigs fed the diet plus 1% arginine. In contrast, pigs fed the control-energy diet had weak LAT1 expression, and those fed the diet supplemented with 1% arginine showed lowest LAT1 expression (P < 0.05). These results showed that LAT1 was highly expressed in the forebrain, and expression of LAT1 was affected by dietary protein, energy and arginine differently.

  20. Characterization of forebrain neurons derived from late-onset Huntington's disease human embryonic stem cell lines

    PubMed Central

    Niclis, Jonathan C.; Pinar, Anita; Haynes, John M.; Alsanie, Walaa; Jenny, Robert; Dottori, Mirella; Cram, David S.

    2012-01-01

    Huntington's disease (HD) is an incurable neurodegenerative disorder caused by a CAG repeat expansion in exon 1 of the Huntingtin (HTT) gene. Recently, induced pluripotent stem cell (iPSC) lines carrying atypical and aggressive (CAG60+) HD variants have been generated and exhibit disparate molecular pathologies. Here we investigate two human embryonic stem cell (hESC) lines carrying CAG37 and CAG51 typical late-onset repeat expansions in comparison to wildtype control lines during undifferentiated states and throughout forebrain neuronal differentiation. Pluripotent HD lines demonstrate growth, viability, pluripotent gene expression, mitochondrial activity and forebrain specification that is indistinguishable from control lines. Expression profiles of crucial genes known to be dysregulated in HD remain unperturbed in the presence of mutant protein and throughout differentiation; however, elevated glutamate-evoked responses were observed in HD CAG51 neurons. These findings suggest typical late-onset HD mutations do not alter pluripotent parameters or the capacity to generate forebrain neurons, but that such progeny may recapitulate hallmarks observed in established HD model systems. Such HD models will help further our understanding of the cascade of pathological events leading to disease onset and progression, while simultaneously facilitating the identification of candidate HD therapeutics. PMID:23576953

  1. The integrity of cholinergic basal forebrain neurons depends on expression of Nkx2-1

    PubMed Central

    Magno, Lorenza; Kretz, Oliver; Bert, Bettina; Ersözlü, Sara; Vogt, Johannes; Fink, Heidrun; Kimura, Shioko; Vogt, Angelika; Monyer, Hannah; Nitsch, Robert; Naumann, Thomas

    2012-01-01

    The transcription factor Nkx2-1 belongs to the homeobox-encoding family of proteins that have essential functions in prenatal brain development. Nkx2-1 is required for the specification of cortical interneurons and several neuronal subtypes of the ventral forebrain. Moreover, this transcription factor is involved in migratory processes by regulating the expression of guidance molecules. Interestingly, Nkx2-1 expression was recently detected in the mouse brain at postnatal stages. Using two transgenic mouse lines that allow prenatal or postnatal cell type-specific deletion of Nkx2-1, we show that continuous expression of the transcription factor is essential for the maturation and maintenance of cholinergic basal forebrain neurons in mice. Notably, prenatal deletion of Nkx2-1 in GAD67-expressing neurons leads to a nearly complete loss of cholinergic neurons and parvalbumin-containing GABAergic neurons in the basal forebrain. We also show that postnatal mutation of Nkx2-1 in choline acetyltransferase-expressing cells causes a striking reduction in their number. These degenerative changes are accompanied by partial denervation of their target structures and results in a discrete impairment of spatial memory. PMID:22098391

  2. Time-lapse live imaging of clonally related neural progenitor cells in the developing zebrafish forebrain.

    PubMed

    Dong, Zhiqiang; Wagle, Mahendra; Guo, Su

    2011-04-06

    Precise patterns of division, migration and differentiation of neural progenitor cells are crucial for proper brain development and function. To understand the behavior of neural progenitor cells in the complex in vivo environment, time-lapse live imaging of neural progenitor cells in an intact brain is critically required. In this video, we exploit the unique features of zebrafish embryos to visualize the development of forebrain neural progenitor cells in vivo. We use electroporation to genetically and sparsely label individual neural progenitor cells. Briefly, DNA constructs coding for fluorescent markers were injected into the forebrain ventricle of 22 hours post fertilization (hpf) zebrafish embryos and electric pulses were delivered immediately. Six hours later, the electroporated zebrafish embryos were mounted with low melting point agarose in glass bottom culture dishes. Fluorescently labeled neural progenitor cells were then imaged for 36 hours with fixed intervals under a confocal microscope using water dipping objective lens. The present method provides a way to gain insights into the in vivo development of forebrain neural progenitor cells and can be applied to other parts of the central nervous system of the zebrafish embryo.

  3. Limbic encephalitis associated with anti-NH2-terminal of α-enolase antibodies

    PubMed Central

    Kishitani, Toru; Matsunaga, Akiko; Ikawa, Masamichi; Hayashi, Kouji; Yamamura, Osamu; Hamano, Tadanori; Watanabe, Osamu; Tanaka, Keiko; Nakamoto, Yasunari; Yoneda, Makoto

    2017-01-01

    Abstract Several types of autoantibodies have been reported in autoimmune limbic encephalitis (LE), such as antibodies against the voltage-gated potassium channel (VGKC) complex including leucine-rich glioma inactivated 1 (LGI1). We recently reported a patient with autoimmune LE and serum anti-NH2-terminal of α-enolase (NAE) antibodies, a specific diagnostic marker for Hashimoto encephalopathy (HE), who was diagnosed with HE based on the presence of antithyroid antibodies and responsiveness to immunotherapy. This case suggests that LE patients with antibodies to both the thyroid and NAE could be diagnosed with HE and respond to immunotherapy. The aim of this study was to clarify the clinicoimmunological features and efficacy of immunotherapy in LE associated with anti-NAE antibodies to determine whether the LE is a clinical subtype of HE. We examined serum anti-NAE antibodies in 78 LE patients with limbic abnormality on magnetic resonance imaging and suspected HE based on positivity for antithyroid antibodies. Nineteen of the 78 patients had anti-NAE antibodies; however, 5 were excluded because they were double positive for antibodies to the VGKC complex including LGI1. No antibodies against the N-methyl-D-aspartate receptor (NMDAR), contactin-associated protein 2 (Caspr2), γ-aminobutyric acid-B receptor (GABABR), or α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) were detected in the 19 patients. Among the remaining 14 who were positive only for anti-NAE antibodies, the median age was 62.5 (20–83) years, 9 (64%) were women, and 8 (57%) showed acute onset, with less than 2 weeks between onset and admission. Consciousness disturbance (71%) and memory disturbance (64%) were frequently observed, followed by psychiatric symptoms (50%) and seizures (43%). The frequency of these symptoms significantly differed between the acute- and subacute-onset groups. Abnormalities in cerebrospinal fluid and electroencephalogram were commonly observed (92

  4. Intrathecal reboxetine suppresses evoked and ongoing neuropathic pain behaviours by restoring spinal noradrenergic inhibitory tone.

    PubMed

    Hughes, Sam; Hickey, Louise; Donaldson, Lucy F; Lumb, Bridget M; Pickering, Anthony E

    2015-02-01

    The descending noradrenergic (NAergic) projection to the spinal cord forms part of an endogenous analgesic system. After nerve injury, a localised failure in this compensatory system has been implicated as a permissive factor in the development of neuropathic sensitisation. We investigated whether restoring descending NAergic tone with intrathecal reboxetine can oppose the development of the neuropathic pain phenotype after tibial nerve transection (TNT). Rats had a lumbar intrathecal catheter implanted at the time of nerve injury for administration of reboxetine (10 μg) in both acute and chronic dosing experiments. In acute dosing experiments, both intrathecal and systemic (30 mg/kg) reboxetine partially reversed mechanical allodynia. This antiallodynic effect of intrathecal reboxetine was blocked by prior administration of yohimbine (α2-adrenoceptor antagonist, 30 μg) but not by prazosin (α1-adrenoceptor antagonist, 30 μg) or propranolol (β-adrenoceptor antagonist, 100 μg). Chronic intrathecal reboxetine (10 μg, intrathecally, twice daily for 2 weeks) suppressed the development of cold and mechanical allodynia. Nerve-injured animals demonstrated a place preference for intrathecal reboxetine, suggesting that it also reduced spontaneous pain. In contrast, an equivalent antiallodynic dose of systemic reboxetine (30 mg/kg) was aversive in both naive and TNT rats. On cessation of chronic intrathecal reboxetine, there was a gradual development of allodynic sensitisation that was indistinguishable from control TNT animals by 7 days after the end of dosing. Our results suggest that pharmacological restoration of spinal NAergic tone with intrathecal reboxetine can suppress both allodynia and spontaneous pain in the TNT model.

  5. The metabolic syndrome in mice overexpressing neuropeptide Y in noradrenergic neurons.

    PubMed

    Ailanen, Liisa; Ruohonen, Suvi T; Vähätalo, Laura H; Tuomainen, Katja; Eerola, Kim; Salomäki-Myftari, Henriikka; Röyttä, Matias; Laiho, Asta; Ahotupa, Markku; Gylling, Helena; Savontaus, Eriika

    2017-07-01

    A gain-of-function polymorphism in human neuropeptide Y (NPY) gene (rs16139) associates with metabolic disorders and earlier onset of type 2 diabetes (T2D). Similarly, mice overexpressing NPY in noradrenergic neurons (OE-NPY(DBH)) display obesity and impaired glucose metabolism. In this study, the metabolic syndrome-like phenotype was characterized and mechanisms of impaired hepatic fatty acid, cholesterol and glucose metabolism in pre-obese (2-month-old) and obese (4-7-month-old) OE-NPY(DBH) mice were elucidated. Susceptibility to T2D was assessed by subjecting mice to high caloric diet combined with low-dose streptozotocin. Contribution of hepatic Y1-receptor to the phenotype was studied using chronic treatment with an Y1-receptor antagonist, BIBO3304. Obese OE-NPY(DBH) mice displayed hepatosteatosis and hypercholesterolemia preceded by decreased fatty acid oxidation and accelerated cholesterol synthesis. Hyperinsulinemia in early obese state inhibited pyruvate- and glucose-induced hyperglycemia, and deterioration of glucose metabolism of OE-NPY(DBH) mice developed with aging. Furthermore, streptozotocin induced T2D only in OE-NPY(DBH) mice. Hepatic inflammation was not morphologically visible, but upregulated hepatic anti-inflammatory pathways and increased 8-isoprostane combined with increased serum resistin and decreased interleukin 10 pointed to increased NPY-induced oxidative stress that may predispose OE-NPY(DBH) mice to insulin resistance. Chronic treatment with BIBO3304 did not improve the metabolic status of OE-NPY(DBH) mice. Instead, downregulation of beta-1-adrenoceptors suggests indirect actions of NPY via inhibition of sympathetic nervous system. In conclusion, changes in hepatic fatty acid, cholesterol and glucose metabolism favoring energy storage contribute to the development of NPY-induced metabolic syndrome, and the effect is likely mediated by changes in sympathetic nervous system activity. © 2017 Society for Endocrinology.

  6. Corticotropin releasing factor dose-dependently modulates excitatory synaptic transmission in the noradrenergic nucleus locus coeruleus.

    PubMed

    Prouty, Eric W; Waterhouse, Barry D; Chandler, Daniel J

    2017-03-01

    The noradrenergic nucleus locus coeruleus (LC) is critically involved in the stress response and receives afferent input from a number of corticotropin releasing factor (CRF) containing structures. Several in vivo and in vitro studies in rat have shown that CRF robustly increases the firing rate of LC neurons in a dose-dependent manner. While it is known that these increases are dependent on CRF receptor subtype 1 and mediated by effects of cAMP intracellular signaling cascades on potassium conductance, the impact of CRF on synaptic transmission within LC has not been clarified. In the present study, we used whole-cell patch clamp electrophysiology to assess how varying concentrations of bath-applied CRF affect AMPA-receptor dependent spontaneous excitatory post-synaptic currents (sEPSCs). Compared to vehicle, 10, 25, and 100 nm CRF had no significant effects on any sEPSC parameters. Fifty nanomolar CRF, however, significantly increased sEPSC amplitude, half-width, and charge transfer, while these measures were significantly decreased by 200 nm CRF. These observations suggest that stress may differentially affect ongoing excitatory synaptic transmission in LC depending on how much CRF is released from presynaptic terminals. Combined with the well-documented effects of CRF on membrane properties and spontaneous LC discharge, these observations may help explain how stress and CRF release are able to modulate the signal to noise ratio of LC neurons. These findings have implications for how stress affects the fidelity of signal transmission and information flow through LC and how it might impact norepinephrine release in the CNS.

  7. Ablation of the central noradrenergic neurons for unraveling their roles in stress and anxiety.

    PubMed

    Itoi, Keiichi

    2008-01-01

    Despite considerable evidence suggesting the relationship between the central noradrenergic (NA) system and fear/anxiety states, previous animal studies have not demonstrated sheer involvement of the locus coeruleus (LC) in mediating fear or anxiety. Following the negative results of 6-hydroexydopamine (6-OHDA)-induced LC ablation in fear-conditioning studies, most researchers dared not approach this problem using the ablation strategy. The results obtained by a limited number of endeavors, conducted later, were not consistent with the idea of LC being related to anxiety, either, with the exception of the study by Lapiz and colleagues. Since methodological problems were recognized in the neurotoxin-induced NA ablation, employed in previous studies, a novel mouse model was developed in which the LC-NA neurons were ablated selectively and thoroughly by the immunotoxin-mediated cellular targeting. The use of this model clearly demonstrated that the LC was part of the anxiety circuitry. The reason for the discrepancy between the latest study and previous ones is not clear, but it may be due either to the difference in the experimental paradigms or to the different methods for LC ablation. In any case, our findings have shed light on the LC as a locus pertaining to anxiety behavior, and may help link the apparently inconsistent results in previous studies. In addition, the novel method for the LC cell targeting, presented here may provide a potential means for studying the physiological roles of the LC including sleep/wakefulness, as well as its possible involvement in the pathogenesis of psychiatric disorders, including depression, anxiety disorders, and attention deficit/hyperactivity disorder.

  8. beta-Endorphin-induced stimulation of central sympathetic outflow: inhibitory modulation by central noradrenergic neurons.

    PubMed

    Appel, N M; Van Loon, G R

    1986-06-01

    Endorphins, a class of endogenous opioid peptides, produce a diversity of physiological effects attributable to their actions in the central nervous system. We have reported previously the effect of intracisternal (i.c.) administration of synthetic human beta-endorphin to increase plasma catecholamine concentrations, presumably by acting at opioid receptors in the brain to stimulate the central sympathetic outflow to adrenal medulla and peripheral sympathetic nerve terminals. This beta-endorphin-induced increase in plasma catecholamine concentration is dose-dependent, inhibited by naloxone and blocked by bilateral adrenal gland denervation or ganglionic blockade with chlorisondamine. We also provided evidence supporting involvement of central cholinergic, somatostatin and angiotensin II neuronal systems in modulating this beta-endorphin-induced effect. In this study we examined the possibility of central noradrenergic regulation of beta-endorphin-induced catecholamine secretion. Simultaneous i.c. administration of norepinephrine with beta-endorphin blunted the plasma epinephrine response to i.c. beta-endorphin in conscious, unrestrained rats bearing chronic i.a. cannulas. On the other hand, depletion of brain norepinephrine by prior i.c. 6-hydroxydopamine (6-OHDA) treatment potentiated the plasma epinephrine response to i.c. beta-endorphin. In addition, rats pretreated with 6-OHDA appeared supersensitive to the blunting effect of i.c. norepinephrine on beta-endorphin-induced catecholamine secretion. Specifically, i.c. norepinephrine at a dose insufficient to reduce beta-endorphin-induced catecholamine secretion in vehicle-treated rats prevented beta-endorphin-induced epinephrine and norepinephrine secretion in rats whose brains had been depleted of norepinephrine by prior 6-OHDA treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

  9. The noradrenergic innervation of the rat thymus during pregnancy and in the post partum period.

    PubMed Central

    Kendall, M D; Atkinson, B A; Muñoz, F J; de la Riva, C; Clarke, A G; von Gaudecker, B

    1994-01-01

    The noradrenergic innervation of the rat thymus during pregnancy and the post partum period was examined by a sucrose glyoxylic acid method for catecholamines, and by high pressure liquid chromatography. Fluorescent nerves decreased in number throughout pregnancy when there was an overall loss in thymic weight due to cortical involution. These changes are maximal by parturition. There was a dramatic increase in nerves between d 21 of pregnancy and d 1 after parturition, especially in the capsule and around blood vessels in the connective tissue septa. The neonates were removed at parturition and thymic weight was rapidly regained. The increased numbers of nerves remained throughout this post partum period. Noradrenaline levels in the thymus altered in a similar pattern throughout pregnancy and the post partum period, but did not parallel thymic weight changes. The mean noradrenaline concentration in the virgin thymus was 1063 +/- 107 pg/mg protein. Levels remained similar during early pregnancy and increased significantly at d 16. Virgin levels were regained by d 21. Values peaked after parturition but rapidly decreased over the next 3 days, and remained at or below virgin levels to d 28 except for a transient rise at d 10 post partum. Adrenaline values were consistently below detection levels. This study shows that there are variations in both nerves visualised, and in neurotransmitter (noradrenaline) content in the thymus during the course of pregnancy and the post partum period. Thus thymic function could be influenced by central events (levels of catecholamines in peripheral blood) as well as local events mediated by transmitter changes in nerves. Images Fig. 4 Fig. 5 Fig. 6 Fig. 7 PMID:7649797

  10. Noradrenergic and GABAB Receptor Activation Differentially Modulate Inputs to the Premotor Nucleus RA in Zebra Finches

    PubMed Central

    Sizemore, Max; Perkel, David J.

    2008-01-01

    Neuromodulators can rapidly modify neural circuits, altering behavior. Songbirds provide an excellent system for studying the role of neuromodulation in modifying circuits that underlie behavior because song learning and production are mediated by a discrete set of interconnected nuclei. We examined the neuromodulatory effects of noradrenergic and GABAB receptor activation on synaptic inputs to the premotor robust nucleus of the arcopallium (RA) in zebra finches using whole cell voltage-clamp recording in vitro. In adults, norepinephrine strongly reduced input from the lateral magnocellular nucleus of the anterior nidopallium (LMAN) but only slightly reduced the input from nucleus HVC (proper name), the excitatory input from axon collaterals of other RA neurons, and input from GABAergic interneurons. The effect of norepinephrine was mimicked by the α2 adrenoceptor agonist UK14,304 and blocked by the α2 antagonist yohimbine. Conversely, the GABAB receptor agonist baclofen strongly decreased HVC, collateral, and GABAergic inputs to RA neurons while causing little reduction in the LMAN input. In juveniles undergoing song learning, norepinephrine reduced the LMAN input, caused only a small reduction in the HVC input, and greatly reduced the collateral and GABAergic inputs. Baclofen caused similar results in juvenile and adult birds, reducing HVC, collateral, and GABAergic inputs significantly more than the LMAN input. Significant increases in paired-pulse ratio accompanied al