Osthole promotes neuronal differentiation and inhibits apoptosis via Wnt/β-catenin signaling in an Alzheimer's disease model

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

Yao, Yingjia; Gao, Zhong; Liang, Wenbo

Neurogenesis is the process by which neural stem cells (NSCs) proliferate and differentiate into neurons. This is diminished in several neurodegenerative disorders such as Alzheimer's disease (AD), which is characterized by the deposition of amyloid (A)β peptides and neuronal loss. Stimulating NSCs to replace lost neurons is therefore a promising approach for AD treatment. Our previous study demonstrated that osthole modulates NSC proliferation and differentiation, and may reduce Aβ protein expression in nerve cells. Here we investigated the mechanism underlying the effects of osthole on NSCs. We found that osthole enhances NSC proliferation and neuronal differentiation while suppressing apoptosis, effectsmore » that were exerted via activation of Wnt/β-catenin signaling. These results provide evidence that osthole can potentially be used as a therapeutic agent in the treatment of AD and other neurodegenerative disorders. - Highlights: • An Alzheimer's disease model was successfully established by transfecting APP gene into neural stem cells in vitro. • Roles of osthole in experimental AD cells were studied. • Osthole promotes proliferation and differentiation into neurons and inhibits accumulation of Aβ{sub 1–42} peptide and apoptosis. • Osthole exerts protection via Wnt/β-catenin signaling pathway.« less

Cyclic AMP imaging sheds light on PDF signaling in circadian clock neurons.

PubMed

Tomchik, Seth M; Davis, Ronald L

2008-04-24

In Drosophila, the neuropeptide PDF is required for circadian rhythmicity, but it is unclear where PDF acts. In this issue of Neuron, Shafer et al. use a novel bioimaging methodology to demonstrate that PDF elevates cAMP in nearly all clock neurons. Thus, PDF apparently exerts more widespread effects on the circadian clock network than suggested by previous studies of PDF receptor expression.

Insulin-like growth factor-1 inhibits adult supraoptic neurons via complementary modulation of mechanoreceptors and glycine receptors.

PubMed

Ster, Jeanne; Colomer, Claude; Monzo, Cécile; Duvoid-Guillou, Anne; Moos, Françoise; Alonso, Gérard; Hussy, Nicolas

2005-03-02

In the CNS, insulin-like growth factor-1 (IGF-1) is mainly known for its trophic effect both during development and in adulthood. Here, we show than in adult rat supraoptic nucleus (SON), IGF-1 receptor immunoreactivity is present in neurons, whereas IGF-1 immunoreactivity is found principally in astrocytes and more moderately in neurons. In vivo application of IGF-1 within the SON acutely inhibits the activity of both vasopressin and oxytocin neurons, the two populations of SON neuroendocrine cells. Recordings of acutely isolated SON neurons showed that this inhibition occurs through two rapid and reversible mechanisms, both involving the neuronal IGF-1 receptor but different intracellular messengers. IGF-1 inhibits Gd3+-sensitive and osmosensitive mechanoreceptor cation current via phosphatidylinositol-3 (PI3) kinase activation. IGF-1 also potentiates taurine-activated glycine receptor (GlyR) Cl- currents by increasing the agonist sensitivity through a extremely rapid (within a second) PI3 kinase-independent mechanism. Both mechanoreceptor channels and GlyR, which form the excitatory and inhibitory components of SON neuron osmosensitivity, are active at rest, and their respective inhibition and potentiation will both be inhibitory, leading to strong decrease in neuronal activity. It will be of interest to determine whether IGF-1 is released by neurons, thus participating in an inhibitory autocontrol, or astrocytes, then joining the growing family of glia-to-neuron transmitters that modulate neuronal and synaptic activity. Through the opposite and complementary acute regulation of mechanoreceptors and GlyR, IGF-1 appears as a new important neuromodulator in the adult CNS, participating in the complex integration of neural messages that regulates the level of neuronal excitability.

The importance of neuronal growth factors in the ovary.

PubMed

Streiter, S; Fisch, B; Sabbah, B; Ao, A; Abir, R

2016-01-01

The neurotrophin family consists of nerve growth factor (NGF), neurotrophin 3 (NT3) and neurotrophin 4/5 (NT4/5), in addition to brain-derived neurotrophic factor (BDNF) and the neuronal growth factors, glial cell line-derived neurotrophic factor (GDNF) and vasointestinal peptide (VIP). Although there are a few literature reviews, mainly of animal studies, on the importance of neurotrophins in the ovary, we aimed to provide a complete review of neurotrophins as well as neuronal growth factors and their important roles in normal and pathological processes in the ovary. Follicular assembly is probably stimulated by complementary effects of NGF, NT4/5 and BDNF and their receptors. The neurotrophins, GDNF and VIP and their receptors have all been identified in preantral and antral follicles of mammalian species, including humans. Transgenic mice with mutations in the genes encoding for Ngf, Nt4/5 and Bdnf and their tropomyosin-related kinase β receptor showed a reduction in preantral follicles and an abnormal ovarian morphology, whereas NGF, NT3, GDNF and VIP increased the in vitro activation of primordial follicles in rats and goats. Additionally, NGF, NT3 and GDNF promoted follicular cell proliferation; NGF, BDNF and VIP were shown to be involved in ovulation; VIP inhibited follicular apoptosis; NT4/5, BDNF and GDNF promoted oocyte maturation and NGF, NT3 and VIP stimulated steroidogenesis. NGF may also exert a stimulatory effect in ovarian cancer and polycystic ovarian syndrome (PCOS). Low levels of NGF and BDNF in follicular fluid may be associated with diminished ovarian reserve and high levels with endometriosis. More knowledge of the roles of neuronal growth factors in the ovary has important implications for the development of new therapeutic drugs (such as anti-NGF agents) for ovarian cancer and PCOS as well as various infertility problems, warranting further research. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Amitriptyline Activates TrkA to Aid Neuronal Growth and Attenuate Anesthesia-Induced Neurodegeneration in Rat Dorsal Root Ganglion Neurons.

PubMed

Zheng, Xiaochun; Chen, Feng; Zheng, Ting; Huang, Fengyi; Chen, Jianghu; Tu, Wenshao

2016-05-01

Tricyclic antidepressant amitriptyline (AM) has been shown to exert neurotrophic activity on neurons. We thus explored whether AM may aid the neuronal development and protect anesthesia-induced neuro-injury in young spinal cord dorsal root ganglion (DRG) neurons.The DRG explants were prepared from 1-day-old rats. The effect of AM on aiding DRG neural development was examined by immunohistochemistry at dose-dependent manner. AM-induced changes in gene and protein expressions, and also phosphorylation states of tyrosine kinases receptor A (TrkA) and B (TrkB) in DRG, were examined by quantitative real-time polymerase chain reaction and western blot. The effect of AM on attenuating lidocaine-induced DRG neurodegeneration was examined by immunohistochemistry, and small interfering RNA (siRNA)-mediated TrkA/B down-regulation.Amitriptyline stimulated DRG neuronal development in dose-dependent manner, but exerted toxic effect at concentrations higher than 10 M. AM activated TrkA in DRG through phosphorylation, whereas it had little effect on TrkB-signaling pathway. AM reduced lidocaine-induced DRG neurodegeneration by regenerating neurites and growth cones. Moreover, the neuroprotection of AM on lidocaine-injured neurodegeneration was blocked by siRNA-mediated TrkA down-regulation, but not by TrkB down-regulation.Amitriptyline facilitated neuronal development and had protective effect on lidocaine-induced neurodegeneration, very likely through the activation of TrkA-signaling pathway in DRG.

Ghrelin Induces Leptin Resistance by Activation of Suppressor of Cytokine Signaling 3 Expression in Male Rats: Implications in Satiety Regulation

PubMed Central

Heldsinger, Andrea; Grabauskas, Gintautas; Wu, Xiaoyin; Zhou, ShiYi; Lu, Yuanxu; Song, Il

2014-01-01

The anorexigenic adipocyte-derived hormone leptin and the orexigenic hormone ghrelin act in opposition to regulate feeding behavior via the vagal afferent pathways. The mechanisms by which ghrelin exerts its inhibitory effects on leptin are unknown. We hypothesized that ghrelin activates the exchange protein activated by cAMP (Epac), inducing increased SOCS3 expression, which negatively affects leptin signal transduction and neuronal firing in nodose ganglia (NG) neurons. We showed that 91 ± 3% of leptin receptor (LRb) –bearing neurons contained ghrelin receptors (GHS-R1a) and that ghrelin significantly inhibited leptin-stimulated STAT3 phosphorylation in rat NG neurons. Studies of the signaling cascades used by ghrelin showed that ghrelin caused a significant increase in Epac and suppressor of cytokine signaling 3 (SOCS3) expression in cultured rat NG neurons. Transient transfection of cultured NG neurons to silence SOCS3 and Epac genes reversed the inhibitory effects of ghrelin on leptin-stimulated STAT3 phosphorylation. Patch-clamp studies and recordings of single neuronal discharges of vagal primary afferent neurons showed that ghrelin markedly inhibited leptin-stimulated neuronal firing, an action abolished by silencing SOCS3 expression in NG. Plasma ghrelin levels increased significantly during fasting. This was accompanied by enhanced SOCS3 expression in the NG and prevented by treatment with a ghrelin antagonist. Feeding studies showed that silencing SOCS3 expression in the NG reduced food intake evoked by endogenous leptin. We conclude that ghrelin exerts its inhibitory effects on leptin-stimulated neuronal firing by increasing SOCS3 expression. The SOCS3 signaling pathway plays a pivotal role in ghrelin's inhibitory effect on STAT3 phosphorylation, neuronal firing, and feeding behavior. PMID:25060362

Mesencephalic neuron death induced by congeners of nitrogen monoxide is prevented by the lazaroid U-83836E.

PubMed

Grasbon-Frodl, E M; Brundin, P

1997-01-01

We explored the effects of congeners of nitrogen monoxide (NO) on cultured mesencephalic neurons. Sodium nitroprusside (SNP) was used as a donor of NO, the congeners of which have been found to exert either neurotoxic or neuroprotective effects depending on the surrounding redox milieu. In contrast to a previous report that suggests that the nitrosonium ion (NO+) is neuroprotective to cultured cortical neurons, we found that the nitrosonium ion reduces the survival of cultured dopamine neurons to 32% of control. There was a trend for further impairment of dopamine neuron survival, to only 7% of untreated control, when the cultures were treated with SNP plus ascorbate, i.e. when the nitric oxide radical (NO.) had presumably been formed. We also evaluated the effects of an inhibitor of lipid peroxidation, the lazaroid U-83836E, against SNP toxicity. U-83836E exerted marked neuroprotective effects in both insult models. More than twice as many dopamine neurons (75% of control) survived when the lazaroid was added to SNP-treated cultures and the survival was increased eight-fold (to 55% of control) when U-83836E was added to cultures treated with SNP plus ascorbate. We conclude that the congeners of NO released by SNP are toxic to mesencephalic neurons in vitro and that the lazaroid U-83836E significantly increases the survival of dopamine neurons in situations where congeners of NO are generated.

Chromatic aberration and the roles of double-opponent and color-luminance neurons in color vision.

PubMed

Vladusich, Tony

2007-03-01

How does the visual cortex encode color? I summarize a theory in which cortical double-opponent color neurons perform a role in color constancy and a complementary set of color-luminance neurons function to selectively correct for color fringes induced by chromatic aberration in the eye. The theory may help to resolve an ongoing debate concerning the functional properties of cortical receptive fields involved in color coding.

Telomerase activity-independent function of telomerase reverse transcriptase is involved in acrylamide-induced neuron damage.

PubMed

Zhang, P; Pan, H; Wang, J; Liu, X; Hu, X

2014-07-01

Polyacrylamide is used widely in industry, and its decomposition product, acrylamide (ACR), readily finds its way into commonly consumed cosmetics and baked and fried foods. ACR exerts potent neurotoxic effects in human and animal models. Telomerase reverse transcriptase (TERT), the catalytic subunit of telomerase, traditionally has been considered to play an important role in maintaining telomere length. Emerging evidence has shown, however, that TERT plays an important role in neuroprotection by inhibiting apoptosis and excitotoxicity, and by promoting angiogenesis, neuronal survival and neurogenesis, which are closely related to the telomere-independent functions of TERT. We investigated whether and how the TERT pathway is involved in ACR induced neurotoxicity in rat cortical neurons. We found that ACR 1) significantly reduced the viability of cortical neurons as measured by MTT assay, 2) induced neuron apoptosis as revealed by FITC-conjugated Annexin V/PI double staining and flow cytometry (FACS) analysis, 3) elevated expression of cleaved caspase-3, and 4) decreased bcl-2 expression of cortical neurons. ACR also increased intracellular ROS levels in cortical neurons, increased MDA levels and reduced GSH, SOD and GSH-Px levels in mitochondria in a dose-dependent manner. We found that TERT expression in mitochondria was increased by ACR at concentrations of 2.5 and 5.0 mM, but TERT expression was decreased by 10 mM ACR. Telomerase activity, however, was undetectable in rat cortical neurons. Our results suggest that the TERT pathway is involved in ACR induced apoptosis of cortical neurons. TERT also may exert its neuroprotective role in a telomerase activity-independent way, especially in mitochondria.

Neuroprotective Potential of Mesenchymal Stem Cell-Based Therapy in Acute Stages of TNBS-Induced Colitis in Guinea-Pigs

PubMed Central

Robinson, Ainsley M.; Miller, Sarah; Payne, Natalie; Boyd, Richard; Sakkal, Samy; Nurgali, Kulmira

2015-01-01

Background & Aims The therapeutic benefits of mesenchymal stem cells (MSCs), such as homing ability, multipotent differentiation capacity and secretion of soluble bioactive factors which exert neuroprotective, anti-inflammatory and immunomodulatory properties, have been attributed to attenuation of autoimmune, inflammatory and neurodegenerative disorders. In this study, we aimed to determine the earliest time point at which locally administered MSC-based therapies avert enteric neuronal loss and damage associated with intestinal inflammation in the guinea-pig model of colitis. Methods At 3 hours after induction of colitis by 2,4,6-trinitrobenzene-sulfonate (TNBS), guinea-pigs received either human bone marrow-derived MSCs, conditioned medium (CM), or unconditioned medium by enema into the colon. Colon tissues were collected 6, 24 and 72 hours after administration of TNBS. Effects on body weight, gross morphological damage, immune cell infiltration and myenteric neurons were evaluated. RT-PCR, flow cytometry and antibody array kit were used to identify neurotrophic and neuroprotective factors released by MSCs. Results MSC and CM treatments prevented body weight loss, reduced infiltration of leukocytes into the colon wall and the myenteric plexus, facilitated repair of damaged tissue and nerve fibers, averted myenteric neuronal loss, as well as changes in neuronal subpopulations. The neuroprotective effects of MSC and CM treatments were observed as early as 24 hours after induction of inflammation even though the inflammatory reaction at the level of the myenteric ganglia had not completely subsided. Substantial number of neurotrophic and neuroprotective factors released by MSCs was identified in their secretome. Conclusion MSC-based therapies applied at the acute stages of TNBS-induced colitis start exerting their neuroprotective effects towards enteric neurons by 24 hours post treatment. The neuroprotective efficacy of MSC-based therapies can be exerted independently to their anti-inflammatory effects. PMID:26397368

Novel antiepileptic drug lacosamide exerts neuroprotective effects by decreasing glial activation in the hippocampus of a gerbil model of ischemic stroke.

PubMed

Ahn, Ji Yun; Yan, Bing Chun; Park, Joon Ha; Ahn, Ji Hyeon; Lee, Dae Hwan; Kim, In Hye; Cho, Jeong-Hwi; Chen, Bai Hui; Lee, Jae-Chul; Cho, Young Shin; Shin, Myoung Chul; Cho, Jun Hwi; Hong, Seongkweon; Won, Moo-Ho; Kim, Sung Koo

2015-12-01

Lacosamide, which is a novel antiepileptic drug, has been reported to exert various additional therapeutic effects. The present study investigated the neuroprotective effects of lacosamide against transient cerebral ischemia-induced neuronal cell damage in the hippocampal cornu ammonis (CA)-1 region of a gerbil model. Neuronal Nuclei immunohistochemistry demonstrated that pre- and post-surgical treatment (5 min ischemia) with 25 mg/kg lacosamide protected CA1 pyramidal neurons in the lacosamide-treated-ischemia-operated group from ischemic injury 5 days post-ischemia, as compared with gerbils in the vehicle-treated-ischemia-operated group. Furthermore, treatment with 25 mg/kg lacosamide markedly attenuated the activation of astrocytes and microglia in the ischemic CA1 region at 5 days post-ischemia. The results of the present study suggested that pre- and post-surgical treatment of the gerbils with lacosamide was able to protect against transient cerebral ischemic injury-induced CA1 pyramidal neuronal cell death in the hippocampus. In addition, the neuroprotective effects of lacosamide may be associated with decreased activation of glial cells in the ischemic CA1 region.

Amitriptyline Activates TrkA to Aid Neuronal Growth and Attenuate Anesthesia-Induced Neurodegeneration in Rat Dorsal Root Ganglion Neurons

PubMed Central

Zheng, Xiaochun; Chen, Feng; Zheng, Ting; Huang, Fengyi; Chen, Jianghu; Tu, Wenshao

2016-01-01

Abstract Tricyclic antidepressant amitriptyline (AM) has been shown to exert neurotrophic activity on neurons. We thus explored whether AM may aid the neuronal development and protect anesthesia-induced neuro-injury in young spinal cord dorsal root ganglion (DRG) neurons. The DRG explants were prepared from 1-day-old rats. The effect of AM on aiding DRG neural development was examined by immunohistochemistry at dose-dependent manner. AM-induced changes in gene and protein expressions, and also phosphorylation states of tyrosine kinases receptor A (TrkA) and B (TrkB) in DRG, were examined by quantitative real-time polymerase chain reaction and western blot. The effect of AM on attenuating lidocaine-induced DRG neurodegeneration was examined by immunohistochemistry, and small interfering RNA (siRNA)-mediated TrkA/B down-regulation. Amitriptyline stimulated DRG neuronal development in dose-dependent manner, but exerted toxic effect at concentrations higher than 10 M. AM activated TrkA in DRG through phosphorylation, whereas it had little effect on TrkB-signaling pathway. AM reduced lidocaine-induced DRG neurodegeneration by regenerating neurites and growth cones. Moreover, the neuroprotection of AM on lidocaine-injured neurodegeneration was blocked by siRNA-mediated TrkA down-regulation, but not by TrkB down-regulation. Amitriptyline facilitated neuronal development and had protective effect on lidocaine-induced neurodegeneration, very likely through the activation of TrkA-signaling pathway in DRG. PMID:27149473

Energy expenditure: a critical determinant of energy balance with key hypothalamic controls.

PubMed

Richard, D

2007-09-01

Energy stores are regulated through complex neural controls exerted on both food intake and energy expenditure. These controls are insured by interconnected neurons that produce different peptides or classic neurotransmitters, which have been regrouped into anabolic' and catabolic' systems. While the control of energy intake has been addressed in numerous investigations, that of energy expenditure has, as yet, only received a moderate interest, even though energy expenditure represents a key determinant of energy balance. In laboratory rodents, in particular, a strong regulatory control is exerted on brown adipose tissue (BAT), which represent an efficient thermogenic effector. BAT thermogenesis is governed by the sympathetic nervous system (SNS), whose activity is controlled by neurons comprised in various brain regions, which include the paraventricular hypothalamic nucleus (PVH), the arcuate nucleus (ARC) and the lateral hypothalamus (LH). Proopiomelanocortin neurons from the ARC project to the PVH and terminate in the vicinity of the melanocortin-4 receptors, which are concentrated in the descending division of the PVH, which comprise neurons controlling the SNS outflow to BAT. The LH contains neurons producing melanin-concentrating hormone or orexins, which also are important peptides in the control of energy expenditure. These neurons are not only polysynaptically connected to BAT, but also linked to brains regions controlling motivated behaviors and locomotor activity and, consequently, their role in the control of energy expenditure could go beyond BAT thermogenesis.

Synergy optimization and operation management on syndicate complementary knowledge cooperation

NASA Astrophysics Data System (ADS)

Tu, Kai-Jan

2014-10-01

The number of multi enterprises knowledge cooperation has grown steadily, as a result of global innovation competitions. I have conducted research based on optimization and operation studies in this article, and gained the conclusion that synergy management is effective means to break through various management barriers and solve cooperation's chaotic systems. Enterprises must communicate system vision and access complementary knowledge. These are crucial considerations for enterprises to exert their optimization and operation knowledge cooperation synergy to meet global marketing challenges.

Quercetin Exerts Differential Neuroprotective Effects Against H2O2 and Aβ Aggregates in Hippocampal Neurons: the Role of Mitochondria.

PubMed

Godoy, Juan A; Lindsay, Carolina B; Quintanilla, Rodrigo A; Carvajal, Francisco J; Cerpa, Waldo; Inestrosa, Nibaldo C

2017-11-01

Amyloid-β peptide (Aβ) is one of the major players in the pathogenesis of Alzheimer's disease (AD). Despite numerous studies, the mechanisms by which Aβ induces neurodegeneration are not completely understood. Oxidative stress is considered a major contributor to the pathogenesis of AD, and accumulating evidence indicates that high levels of reactive oxygen species (ROS) are involved in Aβ-induced neurodegeneration. Moreover, Aβ can induce the deregulation of calcium homeostasis, which also affects mitochondrial function and triggers neuronal cell death. In the present study, we analyzed the effects of quercetin, a plant flavonoid with antioxidant properties, on oxidative stress- and Aβ-induced degeneration. Our results indicate that quercetin efficiently protected against H 2 O 2 -induced neuronal toxicity; however, this protection was only partial in rat hippocampal neurons that were treated with Aβ. Treatment with quercetin decreased ROS levels, recovered the normal morphology of mitochondria, and prevented mitochondrial dysfunction in neurons that were treated with H 2 O 2 . By contrast, quercetin treatment partially rescued hippocampal neurons from Aβ-induced mitochondrial injury. Most importantly, quercetin treatment prevented the toxic effects that are induced by H 2 O 2 in hippocampal neurons and, to a lesser extent, the Aβ-induced toxicity that is associated with the superoxide anion, which is a precursor of ROS production in mitochondria. Collectively, these results indicate that quercetin exerts differential effects on the prevention of H 2 O 2 - and Aβ-induced neurotoxicity in hippocampal neurons and may be a powerful tool for dissecting the molecular mechanisms underlying Aβ neurotoxicity.

Lacosamide protects striatal and hippocampal neurons from in vitro ischemia without altering physiological synaptic plasticity.

PubMed

Mazzocchetti, Petra; Tantucci, Michela; Bastioli, Guendalina; Calabrese, Valeria; Di Filippo, Massimiliano; Tozzi, Alessandro; Calabresi, Paolo; Costa, Cinzia

2018-06-01

Lacosamide ([(R)-2-acetamido-N-benzyl-3-methoxypropanamide], LCM), is an antiepileptic that exerts anticonvulsant activity by selectively enhancing slow sodium channel inactivation. By inhibiting seizures and neuronal excitability it might therefore be a good candidate to stabilize neurons and protect them from energetic insults. Using electrophysiological analyses, we have investigated in mice the possible neuroprotective effect of LCM against in vitro ischemia obtained by oxygen and glucose deprivation (ODG), in striatal and hippocampal tissues, two brain structures particularly susceptible to ischemic injury and of pivotal importance for different form of learning and memory. We also explored in these regions the influence of LCM on firing discharge and on long-term synaptic plasticity. We found that in both areas LCM reduced the neuronal firing activity in a use-dependent manner without influencing the physiological synaptic transmission, confirming its anticonvulsant effects. Moreover, we found that this AED is able to protect, in a dose dependent manner, striatal and hippocampal neurons from energy metabolism failure produced by OGD. This neuroprotective effect does not imply impairment of long-term potentiation of striatal and hippocampal synapses and suggests that LCM might exert additional beneficial therapeutic effects beyond its use as antiepileptic. Copyright © 2018 Elsevier Ltd. All rights reserved.

Immunolocalization of vesicular glutamate transporters 1 and 2 in the rat inferior colliculus.

PubMed

Altschuler, R A; Tong, L; Holt, A G; Oliver, D L

2008-06-12

The inferior colliculus is a major relay nucleus in the ascending auditory pathways that receives multiple glutamatergic inputs. Vesicular glutamate transporters 1 and 2 (VGLUT1, VGLUT2) most often have complementary non-overlapping distributions and can be used to differentiate glutamatergic inputs. The present study therefore examined co-immunolabeling of VGLUT1 and VGLUT2 in three divisions of the rat inferior colliculus. Additional co-immunolabeling of microtubule-associated protein 2 and neuronal class III beta-tubulin provided visualization of neuronal soma and processes and allowed identification of axo-somatic versus axo-dendritic contacts. Results showed numerous VGLUT1 and 2 immunolabeled terminals in the central nucleus, lateral cortex and dorsal cortex. In all three divisions there was little to no co-containment of the two vesicular glutamate transporters indicating a complementary distribution. VGLUT1 made predominantly axo-dendritic connections in the neuropil, while VGLUT2 had many axo-somatic contacts in addition to axo-dendritic contacts. VGLUT2 immunolabeled terminals were numerous on the soma and proximal dendrites of many medium-to-large and large neurons in the central nucleus and medium to large neurons in the dorsal cortex. There were more VGLUT2 terminals than VGLUT1 in all divisions and more VGLUT2 terminals in dorsal and lateral cortices than in the central nucleus. This study shows that VGLUT1 and VGLUT2 differentiate complementary patterns of glutamatergic inputs into the central nucleus, lateral and dorsal cortex of the inferior colliculus with VGLUT1 endings predominantly on the dendrites and VGLUT2 on both dendrites and somas.

Transient inactivation of the anterior cingulate cortex in rats disrupts avoidance of a dynamic object.

PubMed

Svoboda, Jan; Lobellová, Veronika; Popelíková, Anna; Ahuja, Nikhil; Kelemen, Eduard; Stuchlík, Aleš

2017-03-01

Although animals often learn and monitor the spatial properties of relevant moving objects such as conspecifics and predators to properly organize their own spatial behavior, the underlying brain substrate has received little attention and hence remains elusive. Because the anterior cingulate cortex (ACC) participates in conflict monitoring and effort-based decision making, and ACC neurons respond to objects in the environment, it may also play a role in the monitoring of moving cues and exerting the appropriate spatial response. We used a robot avoidance task in which a rat had to maintain at least a 25cm distance from a small programmable robot to avoid a foot shock. In successive sessions, we trained ten Long Evans male rats to avoid a fast-moving robot (4cm/s), a stationary robot, and a slow-moving robot (1cm/s). In each condition, the ACC was transiently inactivated by bilateral injections of muscimol in the penultimate session and a control saline injection was given in the last session. Compared to the corresponding saline session, ACC-inactivated rats received more shocks when tested in the fast-moving condition, but not in the stationary or slow robot conditions. Furthermore, ACC-inactivated rats less frequently responded to an approaching robot with appropriate escape responses although their response to shock stimuli remained preserved. Since we observed no effect on slow or stationary robot avoidance, we conclude that the ACC may exert cognitive efforts for monitoring dynamic updating of the position of an object, a role complementary to the dorsal hippocampus. Copyright © 2017 Elsevier Inc. All rights reserved.

Neurons for hunger and thirst transmit a negative-valence teaching signal.

PubMed

Betley, J Nicholas; Xu, Shengjin; Cao, Zhen Fang Huang; Gong, Rong; Magnus, Christopher J; Yu, Yang; Sternson, Scott M

2015-05-14

Homeostasis is a biological principle for regulation of essential physiological parameters within a set range. Behavioural responses due to deviation from homeostasis are critical for survival, but motivational processes engaged by physiological need states are incompletely understood. We examined motivational characteristics of two separate neuron populations that regulate energy and fluid homeostasis by using cell-type-specific activity manipulations in mice. We found that starvation-sensitive AGRP neurons exhibit properties consistent with a negative-valence teaching signal. Mice avoided activation of AGRP neurons, indicating that AGRP neuron activity has negative valence. AGRP neuron inhibition conditioned preference for flavours and places. Correspondingly, deep-brain calcium imaging revealed that AGRP neuron activity rapidly reduced in response to food-related cues. Complementary experiments activating thirst-promoting neurons also conditioned avoidance. Therefore, these need-sensing neurons condition preference for environmental cues associated with nutrient or water ingestion, which is learned through reduction of negative-valence signals during restoration of homeostasis.

Prolactin receptor in regulation of neuronal excitability and channels

PubMed Central

Patil, Mayur J; Henry, Michael A; Akopian, Armen N

2014-01-01

Prolactin (PRL) activates PRL receptor isoforms to exert regulation of specific neuronal circuitries, and to control numerous physiological and clinically-relevant functions including; maternal behavior, energy balance and food intake, stress and trauma responses, anxiety, neurogenesis, migraine and pain. PRL controls these critical functions by regulating receptor potential thresholds, neuronal excitability and/or neurotransmission efficiency. PRL also influences neuronal functions via activation of certain neurons, resulting in Ca2+ influx and/or electrical firing with subsequent release of neurotransmitters. Although PRL was identified almost a century ago, very little specific information is known about how PRL regulates neuronal functions. Nevertheless, important initial steps have recently been made including the identification of PRL-induced transient signaling pathways in neurons and the modulation of neuronal transient receptor potential (TRP) and Ca2+-dependent K+ channels by PRL. In this review, we summarize current knowledge and recent progress in understanding the regulation of neuronal excitability and channels by PRL. PMID:24758841

Novel antiepileptic drug lacosamide exerts neuroprotective effects by decreasing glial activation in the hippocampus of a gerbil model of ischemic stroke

PubMed Central

AHN, JI YUN; YAN, BING CHUN; PARK, JOON HA; AHN, JI HYEON; LEE, DAE HWAN; KIM, IN HYE; CHO, JEONG-HWI; CHEN, BAI HUI; LEE, JAE-CHUL; CHO, YOUNG SHIN; SHIN, MYOUNG CHUL; CHO, JUN HWI; HONG, SEONGKWEON; WON, MOO-HO; KIM, SUNG KOO

2015-01-01

Lacosamide, which is a novel antiepileptic drug, has been reported to exert various additional therapeutic effects. The present study investigated the neuroprotective effects of lacosamide against transient cerebral ischemia-induced neuronal cell damage in the hippocampal cornu ammonis (CA)-1 region of a gerbil model. Neuronal Nuclei immunohistochemistry demonstrated that pre- and post-surgical treatment (5 min ischemia) with 25 mg/kg lacosamide protected CA1 pyramidal neurons in the lacosamide-treated-ischemia-operated group from ischemic injury 5 days post-ischemia, as compared with gerbils in the vehicle-treated-ischemia-operated group. Furthermore, treatment with 25 mg/kg lacosamide markedly attenuated the activation of astrocytes and microglia in the ischemic CA1 region at 5 days post-ischemia. The results of the present study suggested that pre- and post-surgical treatment of the gerbils with lacosamide was able to protect against transient cerebral ischemic injury-induced CA1 pyramidal neuronal cell death in the hippocampus. In addition, the neuroprotective effects of lacosamide may be associated with decreased activation of glial cells in the ischemic CA1 region. PMID:26668588

Enriched Endogenous Omega-3 Polyunsaturated Fatty Acids Protect Cortical Neurons from Experimental Ischemic Injury.

PubMed

Shi, Zhe; Ren, Huixia; Luo, Chuanming; Yao, Xiaoli; Li, Peng; He, Chengwei; Kang, Jing-X; Wan, Jian-Bo; Yuan, Ti-Fei; Su, Huanxing

2016-11-01

Omega-3 polyunsaturated fatty acids (n-3 PUFAs) exert therapeutic potential in a variety of neurological disorders, including ischemic stroke. However, the underlying mechanisms still lack investigation. Here, we report that cultured cortical neurons isolated from fat-1 mice with high endogenous n-3 PUFAs were tolerant to oxygen-glucose deprivation/reperfusion (OGD/R) injury. Fat-1 neurons exhibited significantly attenuated reactive oxygen species (ROS) activation induced by OGD/R injury, upregulated antiapoptotic proteins Bcl-2 and Bcl-xL, and reduced cleaved caspase-3. Exogenous administration of docosahexaenoic acid (DHA), a major component of the n-3 PUFA family, resulted in similar protective effects on cultured cortex neurons. We further verified the protective effects of n-3 PUFAs in vivo, using a mini ischemic model with a reproducible cortical infarct and manifest function deficits by occlusion of the distal branch of the middle cerebral artery with focused femtosecond laser pulses. The Fat-1 animals showed decreased ROS expression and higher level of glutathione in the injured brain, associated with improved functional recovery. We therefore provide evidence that n-3 PUFAs exert their protective effects against ischemic injury both in vitro and in vivo, partly through inhibiting ROS activation.

Metformin Protects Neurons against Oxygen-Glucose Deprivation/Reoxygenation -Induced Injury by Down-Regulating MAD2B.

PubMed

Meng, Xianfang; Chu, Guangpin; Yang, Zhihua; Qiu, Ping; Hu, Yue; Chen, Xiaohe; Peng, Wenpeng; Ye, Chen; He, Fang-Fang; Zhang, Chun

2016-01-01

Metformin, the common medication for type II diabetes, has protective effects on cerebral ischemia. However, the molecular mechanisms are far from clear. Mitotic arrest deficient 2-like protein 2 (MAD2B), an inhibitor of the anaphase-promoting complex (APC), is widely expressed in hippocampal and cortical neurons and plays an important role in mediating high glucose-induced neurotoxicity. The present study investigated whether metformin modifies the expression of MAD2B and to exert its neuroprotective effects in primary cultured cortical neurons during oxygen-glucose deprivation/reoxygenation (OGD/R), a widely used in vitro model of ischemia/reperfusion. Primary cortical neurons were cultured, deprived of oxygen-glucose for 1 h, and then recovered with oxygen-glucose for 12 h and 24 h. Cell viability was measured by detecting the levels of lactate dehydrogenase (LDH) in culture medium. The levels of MAD2B, cyclin B and p-histone 3 were measured by Western blot. Cell viability of neurons was reduced under oxygen-glucose deprivation/reoxygenation (OGD/R). The expression of MAD2B was increased under OGD/R. The levels of cyclin B1, which is a substrate of APC, were also increased. Moreover, OGD/R up-regulated the phosphorylation levels of histone 3, which is the induction of aberrant re-entry of post-mitotic neurons. However, pretreatment of neurons with metformin alleviated OGD/R-induced injury. Metformin further decreased the expression of MAD2B, cyclin B1 and phosphorylation levels of histone 3. Metformin exerts its neuroprotective effect through regulating the expression of MAD2B in neurons under OGD/R. © 2016 The Author(s) Published by S. Karger AG, Basel.

SCG postnatal remodelling--hypertrophy and neuron number stability--in Spix's yellow-toothed cavies (Galea spixii).

PubMed

Ladd, Aliny A B Lobo; Ladd, Fernando V Lobo; da Silva, Andrea A P; Oliveira, Moacir F; de Souza, Romeu R; Coppi, Antonio A

2012-04-01

Whilst a fall in neuron numbers seems a common pattern during postnatal development, several authors have nonetheless reported an increase in neuron number, which may be associated with any one of a number of possible processes encapsulating either neurogenesis or late maturation and incomplete differentiation. Recent publications have thus added further fuel to the notion that a postnatal neurogenesis may indeed exist in sympathetic ganglia. In the light of these uncertainties surrounding the effects exerted by postnatal development on the number of superior cervical ganglion (SCG) neurons, we have used state-of-the-art design-based stereology to investigate the quantitative structure of SCG at four distinct timepoints after birth, viz., 1-3 days, 1 month, 12 months and 36 months. The main effects exerted by ageing on the SCG structure were: (i) a 77% increase in ganglion volume; (ii) stability in the total number of the whole population of SCG nerve cells (no change--either increase or decrease) during post-natal development; (iii) a higher proportion of uninucleate neurons to binucleate neurons only in newborn animals; (iv) a 130% increase in the volume of uninucleate cell bodies; and (v) the presence of BrdU positive neurons in animals at all ages. At the time of writing our results support the idea that neurogenesis takes place in the SCG of preás, albeit it warrants confirmation by further markers. We also hypothesise that a portfolio of other mechanisms: cell repair, maturation, differentiation and death may be equally intertwined and implicated in the numerical stability of SCG neurons during postnatal development. Copyright © 2011 ISDN. Published by Elsevier Ltd. All rights reserved.

Melanin-concentrating hormone neurons discharge in a reciprocal manner to orexin neurons across the sleep–wake cycle

PubMed Central

Hassani, Oum Kaltoum; Lee, Maan Gee; Jones, Barbara E.

2009-01-01

Neurons containing melanin-concentrating hormone (MCH) are codistributed with neurons containing orexin (Orx or hypocretin) in the lateral hypothalamus, a peptide and region known to be critical for maintaining wakefulness. Evidence from knockout and c-Fos studies suggests, however, that the MCH neurons might play a different role than Orx neurons in regulating activity and sleep–wake states. To examine this possibility, neurons were recorded across natural sleep–wake states in head-fixed rats and labeled by using the juxtacellular technique for subsequent immunohistochemical identification. Neurons identified as MCH+ did not fire during wake (W); they fired selectively during sleep, occasionally during slow wave sleep (SWS) and maximally during paradoxical sleep (PS). As W-Off/Sleep-On, the MCH neurons discharged in a reciprocal manner to the W-On/Sleep-Off Orx neurons and could accordingly play a complementary role to Orx neurons in sleep–wake state regulation and contribute to the pathophysiology of certain sleep disorders, such as narcolepsy with cataplexy. PMID:19188611

Double dissociation of value computations in orbitofrontal and anterior cingulate neurons

PubMed Central

Kennerley, Steven W.; Behrens, Timothy E. J.; Wallis, Jonathan D.

2011-01-01

Damage to prefrontal cortex (PFC) impairs decision-making, but the underlying value computations that might cause such impairments remain unclear. Here we report that value computations are doubly dissociable within PFC neurons. While many PFC neurons encoded chosen value, they used opponent encoding schemes such that averaging the neuronal population eliminated value coding. However, a special population of neurons in anterior cingulate cortex (ACC) - but not orbitofrontal cortex (OFC) - multiplex chosen value across decision parameters using a unified encoding scheme, and encoded reward prediction errors. In contrast, neurons in OFC - but not ACC - encoded chosen value relative to the recent history of choice values. Together, these results suggest complementary valuation processes across PFC areas: OFC neurons dynamically evaluate current choices relative to recent choice values, while ACC neurons encode choice predictions and prediction errors using a common valuation currency reflecting the integration of multiple decision parameters. PMID:22037498

Sub-millisecond closed-loop feedback stimulation between arbitrary sets of individual neurons

PubMed Central

Müller, Jan; Bakkum, Douglas J.; Hierlemann, Andreas

2012-01-01

We present a system to artificially correlate the spike timing between sets of arbitrary neurons that were interfaced to a complementary metal–oxide–semiconductor (CMOS) high-density microelectrode array (MEA). The system features a novel reprogrammable and flexible event engine unit to detect arbitrary spatio-temporal patterns of recorded action potentials and is capable of delivering sub-millisecond closed-loop feedback of electrical stimulation upon trigger events in real-time. The relative timing between action potentials of individual neurons as well as the temporal pattern among multiple neurons, or neuronal assemblies, is considered an important factor governing memory and learning in the brain. Artificially changing timings between arbitrary sets of spiking neurons with our system could provide a “knob” to tune information processing in the network. PMID:23335887

Tissue-specific activities of the Fat1 cadherin cooperate to control neuromuscular morphogenesis

PubMed Central

2018-01-01

Muscle morphogenesis is tightly coupled with that of motor neurons (MNs). Both MNs and muscle progenitors simultaneously explore the surrounding tissues while exchanging reciprocal signals to tune their behaviors. We previously identified the Fat1 cadherin as a regulator of muscle morphogenesis and showed that it is required in the myogenic lineage to control the polarity of progenitor migration. To expand our knowledge on how Fat1 exerts its tissue-morphogenesis regulator activity, we dissected its functions by tissue-specific genetic ablation. An emblematic example of muscle under such morphogenetic control is the cutaneous maximus (CM) muscle, a flat subcutaneous muscle in which progenitor migration is physically separated from the process of myogenic differentiation but tightly associated with elongating axons of its partner MNs. Here, we show that constitutive Fat1 disruption interferes with expansion and differentiation of the CM muscle, with its motor innervation and with specification of its associated MN pool. Fat1 is expressed in muscle progenitors, in associated mesenchymal cells, and in MN subsets, including the CM-innervating pool. We identify mesenchyme-derived connective tissue (CT) as a cell type in which Fat1 activity is required for the non–cell-autonomous control of CM muscle progenitor spreading, myogenic differentiation, motor innervation, and for motor pool specification. In parallel, Fat1 is required in MNs to promote their axonal growth and specification, indirectly influencing muscle progenitor progression. These results illustrate how Fat1 coordinates the coupling of muscular and neuronal morphogenesis by playing distinct but complementary actions in several cell types. PMID:29768404

Resonance Properties of Class I and Class II Neurons Differentially Modulated by Channel Noise

NASA Astrophysics Data System (ADS)

Wang, Lei

2018-01-01

Resonance properties of two different neuron types (Class I and Class II) induced by channel noise are investigated in this study. It is found that for Class I neuron, spiking activity is enhanced when certain noise intensity is presented, especially under weak current stimuli -- a typical phenomenon of stochastic resonance (SR); while for Class II neuron, in addition to perform the SR, certain noise intensity would inhibit neuronal activity under some current stimuli -- a typical phenomenon of inverse stochastic resonance (ISR). Moreover, we show that only sodium channel noise or potassium channel noise variation can achieve the similar phenomena. Consequently, the model results suggest that channel noise may exert differential roles in modulating the resonance properties of Class I and Class II neurons.

The allosteric citalopram binding site differentially interferes with neuronal firing rate and SERT trafficking in serotonergic neurons.

PubMed

Matthäus, Friederike; Haddjeri, Nasser; Sánchez, Connie; Martí, Yasmina; Bahri, Senda; Rovera, Renaud; Schloss, Patrick; Lau, Thorsten

2016-11-01

Citalopram is a clinically applied selective serotonin re-uptake inhibitor for antidepressant pharmacotherapy. It consists of two enantiomers, S-citalopram (escitalopram) and R-citalopram, of which escitalopram exerts the antidepressant therapeutic effect and has been shown to be one of the most efficient antidepressants, while R-citalopram antagonizes escitalopram via an unknown molecular mechanism that may depend on binding to a low-affinity allosteric binding site of the serotonin transporter. However, the precise mechanism of antidepressant regulation of the serotonin transporter by citalopram enantiomers still remains elusive. Here we investigate escitalopram׳s acute effect on (1) serotonergic neuronal firing in transgenic mice that express the human serotonin transporter without and with a mutation that disables the allosteric binding site, and (2) regulation of the serotonin transporter׳s cell surface localization in stem cell-derived serotonergic neurons. Our results demonstrate that escitalopram inhibited neuronal firing less potently in the mouse line featuring a mutation that abolishes the function of the allosteric binding site and induced serotonin transporter internalization independently of the allosteric binding site mechanism. Furthermore, citalopram enantiomers dose-dependently induced serotonin transporter internalization. In conclusion, this study provides new insight into antidepressant effects exerted by citalopram enantiomers in presence and absence of a functional allosteric binding site. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

β-Amyloid-acetylcholine molecular interaction: new role of cholinergic mediators in anti-Alzheimer therapy?

PubMed

Grimaldi, Manuela; Marino, Sara Di; Florenzano, Fulvio; Ciotta, Maria Teresa; Nori, Stefania Lucia; Rodriquez, Manuela; Sorrentino, Giuseppe; D'Ursi, Anna Maria; Scrima, Mario

2016-07-01

For long time Alzheimer's disease has been attributed to a cholinergic deficit. More recently, it has been considered dependent on the accumulation of the amyloid beta peptide (Aβ), which promotes neuronal loss and impairs neuronal function. Results/methodology: In the present study, using biophysical and biochemical experiments we tested the hypothesis that in addition to its role as a neurotransmitter, acetylcholine may exert its action as an anti-Alzheimer agent through a direct interaction with Aβ. Our data provide evidence that acetylcholine favors the soluble peptide conformation and exerts a neuroprotective effect against the neuroinflammatory and toxic effects of Aβ. The present paper paves the way toward the development of new polyfunctional anti-Alzheimer therapeutics capable of intervening on both the cholinergic transmission and the Aβ aggregation.

Supraphysiological doses of performance enhancing anabolic-androgenic steroids exert direct toxic effects on neuron-like cells

PubMed Central

Basile, John R.; Binmadi, Nada O.; Zhou, Hua; Yang, Ying-Hua; Paoli, Antonio; Proia, Patrizia

2013-01-01

Anabolic-androgenic steroids (AAS) are lipophilic hormones often taken in excessive quantities by athletes and bodybuilders to enhance performance and increase muscle mass. AAS exert well known toxic effects on specific cell and tissue types and organ systems. The attention that androgen abuse has received lately should be used as an opportunity to educate both athletes and the general population regarding their adverse effects. Among numerous commercially available steroid hormones, very few have been specifically tested for direct neurotoxicity. We evaluated the effects of supraphysiological doses of methandienone and 17-α-methyltestosterone on sympathetic-like neuron cells. Vitality and apoptotic effects were analyzed, and immunofluorescence staining and western blot performed. In this study, we demonstrate that exposure of supraphysiological doses of methandienone and 17-α-methyltestosterone are toxic to the neuron-like differentiated pheochromocytoma cell line PC12, as confirmed by toxicity on neurite networks responding to nerve growth factor and the modulation of the survival and apoptosis-related proteins ERK, caspase-3, poly (ADP-ribose) polymerase and heat-shock protein 90. We observe, in contrast to some previous reports but in accordance with others, expression of the androgen receptor (AR) in neuron-like cells, which when inhibited mitigated the toxic effects of AAS tested, suggesting that the AR could be binding these steroid hormones to induce genomic effects. We also note elevated transcription of neuritin in treated cells, a neurotropic factor likely expressed in an attempt to resist neurotoxicity. Taken together, these results demonstrate that supraphysiological exposure to the AAS methandienone and 17-α-methyltestosterone exert neurotoxic effects by an increase in the activity of the intrinsic apoptotic pathway and alterations in neurite networks. PMID:23675320

Sonic Hedgehog Expression in Corticofugal Projection Neurons Directs Cortical Microcircuit Formation

PubMed Central

Harwell, Corey C.; Parker, Philip R.L.; Gee, Steven M.; Okada, Ami; McConnell, Susan K.; Kreitzer, Anatol C.; Kriegstein, Arnold R.

2012-01-01

SUMMARY The precise connectivity of inputs and outputs is critical for cerebral cortex function; however, the cellular mechanisms that establish these connections are poorly understood. Here, we show that the secreted molecule Sonic Hedgehog (Shh) is involved in synapse formation of a specific cortical circuit. Shh is expressed in layer V corticofugal projection neurons and the Shh receptor, Brother of CDO (Boc), is expressed in local and callosal projection neurons of layer II/III that synapse onto the subcortical projection neurons. Layer V neurons of mice lacking functional Shh exhibit decreased synapses. Conversely, the loss of functional Boc leads to a reduction in the strength of synaptic connections onto layer Vb, but not layer II/III, pyramidal neurons. These results demonstrate that Shh is expressed in postsynaptic target cells while Boc is expressed in a complementary population of presynaptic input neurons, and they function to guide the formation of cortical microcircuitry. PMID:22445340

Cell-Specific Cholinergic Modulation of Excitability of Layer 5B Principal Neurons in Mouse Auditory Cortex

PubMed Central

Joshi, Ankur; Kalappa, Bopanna I.; Anderson, Charles T.

2016-01-01

The neuromodulator acetylcholine (ACh) is crucial for several cognitive functions, such as perception, attention, and learning and memory. Whereas, in most cases, the cellular circuits or the specific neurons via which ACh exerts its cognitive effects remain unknown, it is known that auditory cortex (AC) neurons projecting from layer 5B (L5B) to the inferior colliculus, corticocollicular neurons, are required for cholinergic-mediated relearning of sound localization after occlusion of one ear. Therefore, elucidation of the effects of ACh on the excitability of corticocollicular neurons will bridge the cell-specific and cognitive properties of ACh. Because AC L5B contains another class of neurons that project to the contralateral cortex, corticocallosal neurons, to identify the cell-specific mechanisms that enable corticocollicular neurons to participate in sound localization relearning, we investigated the effects of ACh release on both L5B corticocallosal and corticocollicular neurons. Using in vitro electrophysiology and optogenetics in mouse brain slices, we found that ACh generated nicotinic ACh receptor (nAChR)-mediated depolarizing potentials and muscarinic ACh receptor (mAChR)-mediated hyperpolarizing potentials in AC L5B corticocallosal neurons. In corticocollicular neurons, ACh release also generated nAChR-mediated depolarizing potentials. However, in contrast to the mAChR-mediated hyperpolarizing potentials in corticocallosal neurons, ACh generated prolonged mAChR-mediated depolarizing potentials in corticocollicular neurons. These prolonged depolarizing potentials generated persistent firing in corticocollicular neurons, whereas corticocallosal neurons lacking mAChR-mediated depolarizing potentials did not show persistent firing. We propose that ACh-mediated persistent firing in corticocollicular neurons may represent a critical mechanism required for learning-induced plasticity in AC. SIGNIFICANCE STATEMENT Acetylcholine (ACh) is crucial for cognitive functions. Whereas in most cases the cellular circuits or the specific neurons via which ACh exerts its cognitive effects remain unknown, it is known that auditory cortex (AC) corticocollicular neurons projecting from layer 5B to the inferior colliculus are required for cholinergic-mediated relearning of sound localization after occlusion of one ear. Therefore, elucidation of the effects of ACh on the excitability of corticocollicular neurons will bridge the cell-specific and cognitive properties of ACh. Our results suggest that cell-specific ACh-mediated persistent firing in corticocollicular neurons may represent a critical mechanism required for learning-induced plasticity in AC. Moreover, our results provide synaptic mechanisms via which ACh may mediate its effects on AC receptive fields. PMID:27511019

ENHANCED 5-HT1A RECEPTOR-DEPENDENT FEEDBACK CONTROL OVER DORSAL RAPHE SEROTONIN NEURONS IN THE SERT KNOCKOUT MOUSE

PubMed Central

Soiza-Reilly, Mariano; Goodfellow, Nathalie M.; Lambe, Evelyn K.; Commons, Kathryn G.

2014-01-01

5-HT1A receptors are widely expressed in the brain and play a critical role in feedback inhibition of serotonin (5-HT) neurons through multiple mechanisms. Yet, it remains poorly understood how these feedback mechanisms, particularly those involving long-range projections, adapt in mood disorders. Here, we examined several aspects of 5-HT1A receptor function in the 5-HT transporter knockout mouse (SERT-KO), a model of vulnerability to stress and mood disorders. We found that in comparison to wild-type (WT) mice, SERT-KO mice had more passive coping in response to acute swim stress and this was accompanied by hypo-activation of medial prefrontal cortex (mPFC) Fos expression. Both of these effects were reversed by systemically blocking 5-HT1A receptors. Ex-vivo electrophysiological experiments showed that 5-HT exerted greater 5-HT1A-mediated inhibitory effects in the mPFC of SERT-KO mice compared to WT. Since 5-HT1A receptors in the mPFC provide a key feedback regulation of the dorsal raphe nucleus (DRN), we used a disinhibition strategy to examined endogenous feedback control of 5-HT neurons. Blocking 5-HT1A receptors disinhibited several fold more 5-HT neurons in the DRN of SERT-KO than in WT mice, revealing the presence of enhanced feedback inhibition of 5-HT neurons in the SERT-KO. Taken together our results indicate that increased stress sensitivity in the SERT-KO is associated with the enhanced capacity of 5-HT1A receptors to inhibit neurons in the mPFC as well as to exert feedback inhibition of DRN 5-HT neurons. PMID:25261781

Neurons for hunger and thirst transmit a negative-valence teaching signal

PubMed Central

Gong, Rong; Magnus, Christopher J.; Yu, Yang; Sternson, Scott M.

2015-01-01

Homeostasis is a biological principle for regulation of essential physiological parameters within a set range. Behavioural responses due to deviation from homeostasis are critical for survival, but motivational processes engaged by physiological need states are incompletely understood. We examined motivational characteristics and dynamics of two separate neuron populations that regulate energy and fluid homeostasis by using cell type-specific activity manipulations in mice. We found that starvation-sensitive AGRP neurons exhibit properties consistent with a negative-valence teaching signal. Mice avoided activation of AGRP neurons, indicating that AGRP neuron activity has negative valence. AGRP neuron inhibition conditioned preference for flavours and places. Correspondingly, deep-brain calcium imaging revealed that AGRP neuron activity rapidly reduced in response to food-related cues. Complementary experiments activating thirst-promoting neurons also conditioned avoidance. Therefore, these need-sensing neurons condition preference for environmental cues associated with nutrient or water ingestion, which is learned through reduction of negative-valence signals during restoration of homeostasis. PMID:25915020

Functional Assays for Neurotoxicity Testing

EPA Science Inventory

Neurobehavioral and pathological evaluations of the nervous system are complementary components of basic research and toxicity testing of pharmaceutical and environmental chemicals. While neuropathological assessments provide insight as to cellular changes in neurons, behavioral ...

Functional Assays for Neurotoxicity Testing*

EPA Science Inventory

Neurobehavioral and pathological evaluations of the nervous system are complementary components of basic research and toxicity testing of pharmaceutical and environmental chemicals. While neuropathological assessments provide insight as to cellular changes in neurons, behavioral ...

“Listening” and “talking” to neurons: Implications of immune activation for pain control and increasing the efficacy of opioids

PubMed Central

Watkins, Linda R.; Hutchinson, Mark R.; Milligan, Erin D.; Maier, Steven F.

2008-01-01

It is recently become clear that activated immune cells and immune-like glial cells can dramatically alter neuronal function. By increasing neuronal excitability, these non-neuronal cells are now implicated in the creation and maintenance of pathological pain, such as occurs in response to peripheral nerve injury. Such effects are exerted at multiple sites along the pain pathway, including at peripheral nerves, dorsal root ganglia, and spinal cord. In addition, activated glial cells are now recognized as disrupting the pain suppressive effects of opioid drugs and contributing to opioid tolerance and opioid dependence/withdrawal. While this review focuses on regulation of pain and opioid actions, such immune-neuronal interactions are broad in their implications. Such changes in neuronal function would be expected to occur wherever immune-derived substances come in close contact with neurons. PMID:17706291

Early Correlated Network Activity in the Hippocampus: Its Putative Role in Shaping Neuronal Circuits.

PubMed

Griguoli, Marilena; Cherubini, Enrico

2017-01-01

Synchronized neuronal activity occurring at different developmental stages in various brain structures represents a hallmark of developmental circuits. This activity, which differs in its specific patterns among animal species may play a crucial role in de novo formation and in shaping neuronal networks. In the rodent hippocampus in vitro , the so-called giant depolarizing potentials (GDPs) constitute a primordial form of neuronal synchrony preceding more organized forms of activity such as oscillations in the theta and gamma frequency range. GDPs are generated at the network level by the interaction of the neurotransmitters glutamate and GABA which, immediately after birth, exert both a depolarizing and excitatory action on their targets. GDPs are triggered by GABAergic interneurons, which in virtue of their extensive axonal branching operate as functional hubs to synchronize large ensembles of cells. Intrinsic bursting activity, driven by a persistent sodium conductance and facilitated by the low expression of Kv7.2 and Kv7.3 channel subunits, responsible for I M , exerts a permissive role in GDP generation. Here, we discuss how GDPs are generated in a probabilistic way when neuronal excitability within a local circuit reaches a certain threshold and how GDP-associated calcium transients act as coincident detectors for enhancing synaptic strength at emerging GABAergic and glutamatergic synapses. We discuss the possible in vivo correlate of this activity. Finally, we debate recent data showing how, in several animal models of neuropsychiatric disorders including autism, a GDPs dysfunction is associated to morphological alterations of neuronal circuits and behavioral deficits reminiscent of those observed in patients.

Quercetin attenuates neuronal cells damage in a middle cerebral artery occlusion animal model.

PubMed

Park, Dong-Ju; Shah, Fawad-Ali; Koh, Phil-Ok

2018-04-27

Cerebral ischemia is a neurological disorder with high mortality. Quercetin is a flavonoid compound that is abundant in vegetables and fruits. It exerts anti-inflammatory and anti-apoptotic effects. This study investigated the neuroprotective effects of quercetin in focal cerebral ischemia. Male Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) to induce focal cerebral ischemia. Quercetin or vehicle was injected 30 min before the onset of ischemia. A neurological function test, brain edema measurement, and 2,3,5-triphenyltetrazolium chloride staining were performed to elucidate the neuroprotective effects of quercetin. Western blot analysis was performed to observe caspase-3 and poly ADP-ribose polymerase (PARP) protein expression. MCAO leads to severe neuronal deficits and increases brain edema and infarct volume. However, quercetin administration attenuated the MCAO-induced neuronal deficits and neuronal degeneration. We observed increases in caspase-3 and PARP protein levels in MCAO-operated animals injected with vehicle, whereas quercetin administration attenuated these increases in MCAO injury. This study reveals the neuroprotective effect of quercetin in an MCAO-induced animal model and demonstrates the regulation of caspase-3 and PARP expression by quercetin treatment. These results suggest that quercetin exerts a neuroprotective effect through preventing the MCAO-induced activation of apoptotic pathways affecting caspase-3 and PARP expression.

Assessing neurodevelopmental effects of arsenolipids in pre-differentiated human neurons.

PubMed

Witt, Barbara; Ebert, Franziska; Meyer, Sören; Francesconi, Kevin A; Schwerdtle, Tanja

2017-11-01

In the general population exposure to arsenic occurs mainly via diet. Highest arsenic concentrations are found in seafood, where arsenic is present predominantly in its organic forms including arsenolipids. Since recent studies have provided evidence that arsenolipids could reach the brain of an organism and exert toxicity in fully differentiated human neurons, this work aims to assess the neurodevelopmental toxicity of arsenolipids. Neurodevelopmental effects of three arsenic-containing hydrocarbons (AsHC), two arsenic-containing fatty acids (AsFA), arsenite and dimethylarsinic acid (DMA V ) were characterized in pre-differentiated human neurons. AsHCs and arsenite caused substantial cytotoxicity in a similar, low concentration range, whereas AsFAs and DMA V were less toxic. AsHCs were highly accessible for cells and exerted pronounced neurodevelopmental effects, with neurite outgrowth and the mitochondrial membrane potential being sensitive endpoints; arsenite did not substantially decrease those two endpoints. In fully differentiated neurons, arsenite and AsHCs caused neurite toxicity. These results indicate for a neurodevelopmental potential of AsHCs. Taken into account the possibility that AsHCs might easily reach the developing brain when exposed during early life, neurotoxicity and neurodevelopmental toxicity cannot be excluded. Further studies are needed in order to progress the urgently needed risk assessment. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Complementary interactions between command-like interneurons that function to activate and specify motor programs.

PubMed

Wu, Jin-Sheng; Wang, Nan; Siniscalchi, Michael J; Perkins, Matthew H; Zheng, Yu-Tong; Yu, Wei; Chen, Song-an; Jia, Ruo-nan; Gu, Jia-Wei; Qian, Yi-Qing; Ye, Yang; Vilim, Ferdinand S; Cropper, Elizabeth C; Weiss, Klaudiusz R; Jing, Jian

2014-05-07

Motor activity is often initiated by a population of command-like interneurons. Command-like interneurons that reliably drive programs have received the most attention, so little is known about how less reliable command-like interneurons may contribute to program generation. We study two electrically coupled interneurons, cerebral-buccal interneuron-2 (CBI-2) and CBI-11, which activate feeding motor programs in the mollusk Aplysia californica. Earlier work indicated that, in rested preparations, CBI-2, a powerful activator of programs, can trigger ingestive and egestive programs. CBI-2 reliably generated ingestive patterns only when it was repeatedly stimulated. The ability of CBI-2 to trigger motor activity has been attributed to the two program-promoting peptides it contains, FCAP and CP2. Here, we show that CBI-11 differs from CBI-2 in that it contains FCAP but not CP2. Furthermore, it is weak in its ability to drive programs. On its own, CBI-11 is therefore less effective as a program activator. When it is successful, however, CBI-11 is an effective specifier of motor activity; that is, it drives mostly ingestive programs. Importantly, we found that CBI-2 and CBI-11 complement each other's actions. First, prestimulation of CBI-2 enhanced the ability of CBI-11 to drive programs. This effect appears to be partly mediated by CP2. Second, coactivation of CBI-11 with CBI-2 makes CBI-2 programs immediately ingestive. This effect may be mediated by specific actions that CBI-11 exerts on pattern-generating interneurons. Therefore, different classes of command-like neurons in a motor network may make distinct, but potentially complementary, contributions as either activators or specifiers of motor activity.

Complementary Interactions between Command-Like Interneurons that Function to Activate and Specify Motor Programs

PubMed Central

Wu, Jin-Sheng; Wang, Nan; Siniscalchi, Michael J.; Perkins, Matthew H.; Zheng, Yu-Tong; Yu, Wei; Chen, Song-an; Jia, Ruo-nan; Gu, Jia-Wei; Qian, Yi-Qing; Ye, Yang; Vilim, Ferdinand S.; Cropper, Elizabeth C.; Weiss, Klaudiusz R.

2014-01-01

Motor activity is often initiated by a population of command-like interneurons. Command-like interneurons that reliably drive programs have received the most attention, so little is known about how less reliable command-like interneurons may contribute to program generation. We study two electrically coupled interneurons, cerebral-buccal interneuron-2 (CBI-2) and CBI-11, which activate feeding motor programs in the mollusk Aplysia californica. Earlier work indicated that, in rested preparations, CBI-2, a powerful activator of programs, can trigger ingestive and egestive programs. CBI-2 reliably generated ingestive patterns only when it was repeatedly stimulated. The ability of CBI-2 to trigger motor activity has been attributed to the two program-promoting peptides it contains, FCAP and CP2. Here, we show that CBI-11 differs from CBI-2 in that it contains FCAP but not CP2. Furthermore, it is weak in its ability to drive programs. On its own, CBI-11 is therefore less effective as a program activator. When it is successful, however, CBI-11 is an effective specifier of motor activity; that is, it drives mostly ingestive programs. Importantly, we found that CBI-2 and CBI-11 complement each other's actions. First, prestimulation of CBI-2 enhanced the ability of CBI-11 to drive programs. This effect appears to be partly mediated by CP2. Second, coactivation of CBI-11 with CBI-2 makes CBI-2 programs immediately ingestive. This effect may be mediated by specific actions that CBI-11 exerts on pattern-generating interneurons. Therefore, different classes of command-like neurons in a motor network may make distinct, but potentially complementary, contributions as either activators or specifiers of motor activity. PMID:24806677

3-hydroxymorphinan is neurotrophic to dopaminergic neurons and is also neuroprotective against LPS-induced neurotoxicity.

PubMed

Zhang, Wei; Qin, Liya; Wang, Tongguang; Wei, Sung-Jen; Gao, Hui-ming; Liu, Jie; Wilson, Belinda; Liu, Bin; Zhang, Wanqin; Kim, Hyoung-Chun; Hong, Jau-Shyong

2005-03-01

The purpose of this study was to develop a novel therapy for Parkinson's disease (PD). We recently reported that dextromethorphan (DM), an active ingredient in a variety of widely used anticough remedies, protected dopaminergic neurons in rat primary mesencephalic neuron-glia cultures against lipopolysaccharide (LPS)-mediated degeneration and provided potent protection for dopaminergic neurons in a MPTP mouse model. The underlying mechanism for the protective effect of DM was attributed to its anti-inflammatory activity through inhibition of microglia activation. In an effort to develop more potent compounds for the treatment of PD, we have screened a series of analogs of DM, and 3-hydroxymorphinan (3-HM) emerged as a promising candidate for this purpose. Our study using primary mesencephalic neuron-glia cultures showed that 3-HM provided more potent neuroprotection against LPS-induced dopaminergic neurotoxicity than its parent compound. The higher potency of 3-HM was attributed to its neurotrophic effect in addition to the anti-inflammatory effect shared by both DM and 3-HM. First, we showed that 3-HM exerted potent neuroprotective and neurotrophic effects on dopaminergic neurons in rat primary mesencephalic neuron-glia cultures treated with LPS. The neurotrophic effect of 3-HM was glia-dependent since 3-HM failed to show any protective effect in the neuron-enriched cultures. We subsequently demonstrated that it was the astroglia, not the microglia, that contributed to the neurotrophic effect of 3-HM. This conclusion was based on the reconstitution studies, in which we added different percentages of microglia (10-20%) or astroglia (40-50%) back to the neuron-enriched cultures and found that 3-HM was neurotrophic after the addition of astroglia, but not microglia. Furthermore, 3-HM-treated astroglia-derived conditioned media exerted a significant neurotrophic effect on dopaminergic neurons. It appeared likely that 3-HM caused the release of neurotrophic factor(s) from astroglia, which in turn was responsible for the neurotrophic effect. Second, the anti-inflammatory mechanism was also important for the neuroprotective activity of 3-HM because the more microglia were added back to the neuron-enriched cultures, the more significant neuroprotective effect was observed. The anti-inflammatory mechanism of 3-HM was attributed to its inhibition of LPS-induced production of an array of pro-inflammatory and neurotoxic factors, including nitric oxide (NO), tumor necrosis factor alpha (TNF-alpha), prostaglandin E2 (PGE2) and reactive oxygen species (ROS). In conclusion, this study showed that 3-HM exerted potent neuroprotection by acting on two different targets: a neurotrophic effect mediated by astroglia and an anti-inflammatory effect mediated by the inhibition of microglial activation. 3-HM thus possesses these two important features necessary for an effective neuroprotective agent. In view of the well-documented very low toxicity of DM and its analogs, this report may provide an important new direction for the development of therapeutic interventions for inflammation-related diseases such as PD.

Implications of the Babinet Principle for Casimir interactions

NASA Astrophysics Data System (ADS)

Maghrebi, Mohammad F.; Jaffe, Robert L.; Abravanel, Ronen

2011-09-01

We formulate the Babinet Principle (BP) as a relation between scattering amplitudes and combine it with multiple scattering techniques to derive new properties of electromagnetic Casimir forces. We show that the Casimir force exerted by a planar conductor or dielectric on a self-complementary perforated planar mirror is approximately half that on a uniform mirror independent of the distance between them. Also, the BP suggests that Casimir edge effects are generically anomalously small. Furthermore, the BP can be used to relate any planar object to its complementary geometry, a relation we use to estimate Casimir forces between two screens with apertures.

Otx genes in neurogenesis of mesencephalic dopaminergic neurons.

PubMed

Simeone, Antonio; Puelles, Eduardo; Omodei, Daniela; Acampora, Dario; Di Giovannantonio, Luca Giovanni; Di Salvio, Michela; Mancuso, Pietro; Tomasetti, Carmine

2011-08-01

Mesencephalic-diencephalic dopaminergic (mdDA) neurons play a relevant role in the control of movement, behavior, and cognition. Indeed loss and/or abnormal functioning of mdDA neurons are responsible for Parkinson's disease as well as for addictive and psychiatric disorders. In the last years a wealth of information has been provided on gene functions controlling identity, fate, and proliferation of mdDA progenitors. This review will focus on the role exerted by Otx genes in early decisions regulating sequential steps required for the neurogenesis of mesencephalic dopaminergic (mesDA) neurons. In this context, the regulatory network involving Otx functional interactions with signaling molecules and transcription factors required to promote or prevent the development of mesDA neurons will be analyzed in detail. Copyright © 2011 Wiley Periodicals, Inc.

Paracrine control of vascularization and neurogenesis by neurotrophins.

PubMed

Emanueli, Costanza; Schratzberger, Peter; Kirchmair, Rudolf; Madeddu, Paolo

2003-10-01

The neuronal system plays a fundamental role in the maturation of primitive embryonic vascular network by providing a paracrine template for blood vessel branching and arterial differentiation. Furthermore, postnatal vascular and neural regeneration cooperate in the healing of damaged tissue. Neurogenesis continues in adulthood although confined to specific brain regions. Following ischaemic insult, neural staminal cells contribute towards the healing process through the stimulation of neurogenesis and vasculogenesis. Evidence indicates that nerves and blood vessels exert a reciprocal control of their own growth by paracrine mechanisms. For instance, guidance factors, including vascular endothelial growth factor A (VEGF-A) and semaphorins, which share the ability of binding neuropilin receptors, play a pivotal role in the tridimensional growth pattern of arterial vessels and nerves. Animal models and clinical studies have demonstrated a role of VEGF-A in the pathogenesis of ischaemic and diabetic neuropathies. Further, supplementation with VEGF-A ameliorates neuronal recovery by exerting protective effects on nerves and stimulating reparative neovascularization. Human tissue kallikrein, a recently discovered angiogenic and arteriogenic factor, accelerates neuronal recovery by stimulating the growth of vasa nervorum. Conversely, the neurotrophin nerve growth factor, known to regulate neuronal survival and differentiation, is now regarded as a stimulator of angiogenesis and arteriogenesis. These results indicate that angiogenesis and neurogenesis are paracrinally regulated by growth factors released by endothelial cells and neurons. Supplementation of these growth factors, alone or in combination, could benefit the treatment of ischaemic diseases and neuropathies.

Loss of MeCP2 in Parvalbumin-and Somatostatin-Expressing Neurons in Mice Leads to Distinct Rett Syndrome-like Phenotypes.

PubMed

Ito-Ishida, Aya; Ure, Kerstin; Chen, Hongmei; Swann, John W; Zoghbi, Huda Y

2015-11-18

Inhibitory neurons are critical for proper brain function, and their dysfunction is implicated in several disorders, including autism, schizophrenia, and Rett syndrome. These neurons are heterogeneous, and it is unclear which subtypes contribute to specific neurological phenotypes. We deleted Mecp2, the mouse homolog of the gene that causes Rett syndrome, from the two most populous subtypes, parvalbumin-positive (PV+) and somatostatin-positive (SOM+) neurons. Loss of MeCP2 partially impairs the affected neuron, allowing us to assess the function of each subtype without profound disruption of neuronal circuitry. We found that mice lacking MeCP2 in either PV+ or SOM+ neurons have distinct, non-overlapping neurological features: mice lacking MeCP2 in PV+ neurons developed motor, sensory, memory, and social deficits, whereas those lacking MeCP2 in SOM+ neurons exhibited seizures and stereotypies. Our findings indicate that PV+ and SOM+ neurons contribute complementary aspects of the Rett phenotype and may have modular roles in regulating specific behaviors. Copyright © 2015 Elsevier Inc. All rights reserved.

Genetic inhibition of neurotransmission reveals role of glutamatergic input to dopamine neurons in high-effort behavior.

PubMed

Hutchison, M A; Gu, X; Adrover, M F; Lee, M R; Hnasko, T S; Alvarez, V A; Lu, W

2018-05-01

Midbrain dopamine neurons are crucial for many behavioral and cognitive functions. As the major excitatory input, glutamatergic afferents are important for control of the activity and plasticity of dopamine neurons. However, the role of glutamatergic input as a whole onto dopamine neurons remains unclear. Here we developed a mouse line in which glutamatergic inputs onto dopamine neurons are specifically impaired, and utilized this genetic model to directly test the role of glutamatergic inputs in dopamine-related functions. We found that while motor coordination and reward learning were largely unchanged, these animals showed prominent deficits in effort-related behavioral tasks. These results provide genetic evidence that glutamatergic transmission onto dopaminergic neurons underlies incentive motivation, a willingness to exert high levels of effort to obtain reinforcers, and have important implications for understanding the normal function of the midbrain dopamine system.

Low Dose Isoflurane Exerts Opposing Effects on Neuronal Network Excitability in Neocortex and Hippocampus

PubMed Central

Ranft, Andreas; von Meyer, Ludwig; Zieglgänsberger, Walter; Kochs, Eberhard; Dodt, Hans-Ulrich

2012-01-01

The anesthetic excitement phase occurring during induction of anesthesia with volatile anesthetics is a well-known phenomenon in clinical practice. However, the physiological mechanisms underlying anesthetic-induced excitation are still unclear. Here we provide evidence from in vitro experiments performed on rat brain slices that the general anesthetic isoflurane at a concentration of about 0.1 mM can enhance neuronal network excitability in the hippocampus, while simultaneously reducing it in the neocortex. In contrast, isoflurane tissue concentrations above 0.3 mM expectedly caused a pronounced reduction in both brain regions. Neuronal network excitability was assessed by combining simultaneous multisite stimulation via a multielectrode array with recording intrinsic optical signals as a measure of neuronal population activity. PMID:22723999

Optimizing promoters for recombinant adeno-associated virus-mediated gene expression in the peripheral and central nervous system using self-complementary vectors.

PubMed

Gray, Steven J; Foti, Stacey B; Schwartz, Joel W; Bachaboina, Lavanya; Taylor-Blake, Bonnie; Coleman, Jennifer; Ehlers, Michael D; Zylka, Mark J; McCown, Thomas J; Samulski, R Jude

2011-09-01

With the increased use of small self-complementary adeno-associated viral (AAV) vectors, the design of compact promoters becomes critical for packaging and expressing larger transgenes under ubiquitous or cell-specific control. In a comparative study of commonly used 800-bp cytomegalovirus (CMV) and chicken β-actin (CBA) promoters, we report significant differences in the patterns of cell-specific gene expression in the central and peripheral nervous systems. The CMV promoter provides high initial neural expression that diminishes over time. The CBA promoter displayed mostly ubiquitous and high neural expression, but substantially lower expression in motor neurons (MNs). We report the creation of a novel hybrid form of the CBA promoter (CBh) that provides robust long-term expression in all cells observed with CMV or CBA, including MNs. To develop a short neuronal promoter to package larger transgenes into AAV vectors, we also found that a 229-bp fragment of the mouse methyl-CpG-binding protein-2 (MeCP2) promoter was able to drive neuron-specific expression within the CNS. Thus the 800-bp CBh promoter provides strong, long-term, and ubiquitous CNS expression whereas the MeCP2 promoter allows an extra 570-bp packaging capacity, with low and mostly neuronal expression within the CNS, similar to the MeCP2 transcription factor.

Sonic hedgehog expression in corticofugal projection neurons directs cortical microcircuit formation.

PubMed

Harwell, Corey C; Parker, Philip R L; Gee, Steven M; Okada, Ami; McConnell, Susan K; Kreitzer, Anatol C; Kriegstein, Arnold R

2012-03-22

The precise connectivity of inputs and outputs is critical for cerebral cortex function; however, the cellular mechanisms that establish these connections are poorly understood. Here, we show that the secreted molecule Sonic Hedgehog (Shh) is involved in synapse formation of a specific cortical circuit. Shh is expressed in layer V corticofugal projection neurons and the Shh receptor, Brother of CDO (Boc), is expressed in local and callosal projection neurons of layer II/III that synapse onto the subcortical projection neurons. Layer V neurons of mice lacking functional Shh exhibit decreased synapses. Conversely, the loss of functional Boc leads to a reduction in the strength of synaptic connections onto layer Vb, but not layer II/III, pyramidal neurons. These results demonstrate that Shh is expressed in postsynaptic target cells while Boc is expressed in a complementary population of presynaptic input neurons, and they function to guide the formation of cortical microcircuitry. Copyright © 2012 Elsevier Inc. All rights reserved.

Autoimmunity as a Driving Force of Cognitive Evolution

PubMed Central

Nataf, Serge

2017-01-01

In the last decades, increasingly robust experimental approaches have formally demonstrated that autoimmunity is a physiological process involved in a large range of functions including cognition. On this basis, the recently enunciated “brain superautoantigens” theory proposes that autoimmunity has been a driving force of cognitive evolution. It is notably suggested that the immune and nervous systems have somehow co-evolved and exerted a mutual selection pressure benefiting to both systems. In this two-way process, the evolutionary-determined emergence of neurons expressing specific immunogenic antigens (brain superautoantigens) has exerted a selection pressure on immune genes shaping the T-cell repertoire. Such a selection pressure on immune genes has translated into the emergence of a finely tuned autoimmune T-cell repertoire that promotes cognition. In another hand, the evolutionary-determined emergence of brain-autoreactive T-cells has exerted a selection pressure on neural genes coding for brain superautoantigens. Such a selection pressure has translated into the emergence of a neural repertoire (defined here as the whole of neurons, synapses and non-neuronal cells involved in cognitive functions) expressing brain superautoantigens. Overall, the brain superautoantigens theory suggests that cognitive evolution might have been primarily driven by internal cues rather than external environmental conditions. Importantly, while providing a unique molecular connection between neural and T-cell repertoires under physiological conditions, brain superautoantigens may also constitute an Achilles heel responsible for the particular susceptibility of Homo sapiens to “neuroimmune co-pathologies” i.e., disorders affecting both neural and T-cell repertoires. These may notably include paraneoplastic syndromes, multiple sclerosis as well as autism, schizophrenia and neurodegenerative diseases. In the context of this theoretical frame, a specific emphasis is given here to the potential evolutionary role exerted by two families of genes, namely the MHC class II genes, involved in antigen presentation to T-cells, and the Foxp genes, which play crucial roles in language (Foxp2) and the regulation of autoimmunity (Foxp3). PMID:29123465

Gallium phosphide nanowires as a substrate for cultured neurons.

PubMed

Hällström, Waldemar; Mårtensson, Thomas; Prinz, Christelle; Gustavsson, Per; Montelius, Lars; Samuelson, Lars; Kanje, Martin

2007-10-01

Dissociated sensory neurons were cultured on epitaxial gallium phosphide (GaP) nanowires grown vertically from a gallium phosphide surface. Substrates covered by 2.5 microm long, 50 nm wide nanowires supported cell adhesion and axonal outgrowth. Cell survival was better on nanowire substrates than on planar control substrates. The cells interacted closely with the nanostructures, and cells penetrated by hundreds of wires were observed as well as wire bending due to forces exerted by the cells.

Oligodendrocyte-Neuron Interactions: Impact on Myelination and Brain Function.

PubMed

Shimizu, Takeshi; Osanai, Yasuyuki; Ikenaka, Kazuhiro

2018-01-01

In the past, glial cells were considered to be 'glue' cells whose primary role was thought to be merely filling gaps in neural circuits. However, a growing number of reports have indicated the role of glial cells in higher brain function through their interaction with neurons. Myelin was originally thought to be just a sheath structure surrounding neuronal axons, but recently it has been shown that myelin exerts effects on the conduction velocity of neuronal axons even after myelin formation. Therefore, the investigation of glial cell properties and the neuron-glial interactions is important for understanding higher brain function. Moreover, since there are many neurological disorders caused by glial abnormalities, further understanding of glial cell-related diseases and the development of effective therapeutic strategies are warranted. In this review, we focused on oligodendrocyte-neuron interactions, with particular attention on (1) axonal signals underlying oligodendrocyte differentiation and myelination, (2) neuronal activity-dependent myelination and (3) the effects of myelination on higher brain function.

Identification and Successful Negotiation of a Metabolic Checkpoint in Direct Neuronal Reprogramming.

PubMed

Gascón, Sergio; Murenu, Elisa; Masserdotti, Giacomo; Ortega, Felipe; Russo, Gianluca L; Petrik, David; Deshpande, Aditi; Heinrich, Christophe; Karow, Marisa; Robertson, Stephen P; Schroeder, Timm; Beckers, Johannes; Irmler, Martin; Berndt, Carsten; Angeli, José P Friedmann; Conrad, Marcus; Berninger, Benedikt; Götz, Magdalena

2016-03-03

Despite the widespread interest in direct neuronal reprogramming, the mechanisms underpinning fate conversion remain largely unknown. Our study revealed a critical time point after which cells either successfully convert into neurons or succumb to cell death. Co-transduction with Bcl-2 greatly improved negotiation of this critical point by faster neuronal differentiation. Surprisingly, mutants with reduced or no affinity for Bax demonstrated that Bcl-2 exerts this effect by an apoptosis-independent mechanism. Consistent with a caspase-independent role, ferroptosis inhibitors potently increased neuronal reprogramming by inhibiting lipid peroxidation occurring during fate conversion. Genome-wide expression analysis confirmed that treatments promoting neuronal reprogramming elicit an anti-oxidative stress response. Importantly, co-expression of Bcl-2 and anti-oxidative treatments leads to an unprecedented improvement in glial-to-neuron conversion after traumatic brain injury in vivo, underscoring the relevance of these pathways in cellular reprograming irrespective of cell type in vitro and in vivo. Copyright © 2016 Elsevier Inc. All rights reserved.

Potentiometric Dye Imaging for Pheochromocytoma and Cortical Neurons with a Novel Measurement System Using an Integrated Complementary Metal-Oxide-Semiconductor Imaging Device

NASA Astrophysics Data System (ADS)

Kobayashi, Takuma; Tagawa, Ayato; Noda, Toshihiko; Sasagawa, Kiyotaka; Tokuda, Takashi; Hatanaka, Yumiko; Tamura, Hideki; Ishikawa, Yasuyuki; Shiosaka, Sadao; Ohta, Jun

2010-11-01

The combination of optical imaging with voltage-sensitive dyes is a powerful tool for studying the spatiotemporal patterns of neural activity and understanding the neural networks of the brain. To visualize the potential status of multiple neurons simultaneously using a compact instrument with high density and a wide range, we present a novel measurement system using an implantable biomedical photonic LSI device with a red absorptive light filter for voltage-sensitive dye imaging (BpLSI-red). The BpLSI-red was developed for sensing fluorescence by the on-chip LSI, which was designed by using complementary metal-oxide-semiconductor (CMOS) technology. A micro-electro-mechanical system (MEMS) microfabrication technique was used to postprocess the CMOS sensor chip; light-emitting diodes (LEDs) were integrated for illumination and to enable long-term cell culture. Using the device, we succeeded in visualizing the membrane potential of 2000-3000 cells and the process of depolarization of pheochromocytoma cells (PC12 cells) and mouse cerebral cortical neurons in a primary culture with cellular resolution. Therefore, our measurement application enables the detection of multiple neural activities simultaneously.

A model for neurite growth and neuronal morphogenesis.

PubMed

Li, G H; Qin, C D

1996-02-01

A model is presented for tensile regulation of neuritic growth. It is proposed that the neurite tension can be determined by Hooke's law and determines the growth rate of neurites. The growth of a neurite is defined as the change in its unstretched length. Neuritic growth rate is assumed to increase in proportion to tension magnitude over a certain threshold [Dennerll et al., J. Cell Biol. 107: 665-674 (1988)]. The movement of branch nodes also contributes to the neuronal morphogenesis. It is supposed that the rate of a branch-node displacement is in proportion to the resultant neuritic tension exerted on this node. To deal with the growth-cone movement, it is further supposed that the environment exerts a traction force on the growth cone and the rate of growth-cone displacement is determined by the vector sum of the neuritic tension and the traction force. A group of differential equations are used to describe the model. The key point of the model is that the traction force and the neuritic tension are in opposition to generate a temporal contrast-enhancing mechanism. Results of a simulation study suggest that the model can explain some phenomena related to neuronal morphogenesis.

Acupuncture therapy for stroke patients.

PubMed

Li, Xin; Wang, Qiang

2013-01-01

Acupuncture is one of the most important parts of Traditional Chinese Medicine, has been used for more than 3000 years as prevention and treatment for various diseases in China as well as in adjacent regions, and is widely accepted in western countries in recent years. More and more clinical trials revealed that acupuncture shows positive effect in stroke, not only as a complementary and alternative medicine for poststroke rehabilitation but also as a preventive strategy which could induce cerebral ischemic tolerance, especially when combined with modern electrotherapy. Acupuncture has some unique characteristics, which include acupoint specificity and parameter-dependent effect. It also involves complicated mechanism to exert the beneficial effect on stroke. Series of clinical trials have shown that acupuncture primarily regulates the release of neurochemicals, hemorheology, cerebral microcirculation, metabolism, neuronal activity, and the function of specific brain region. Animal studies showed that the effects of acupuncture therapy on stroke were possibly via inhibition of postischemic inflammatory reaction, stimulation of neurogenesis and angiogenesis, and influence on neural plasticity. Mechanisms for its preconditioning effect include activity enhancement of antioxidant, regulation of the endocannabinoid system, and inhibition of apoptosis. Although being controversial, acupuncture is a promising preventive and treatment strategy for stroke, but further high-quality clinical trials would be needed to provide more confirmative evidence. © 2013 Elsevier Inc. All rights reserved.

Estrogenic agonist activity of ICI 182,780 (Faslodex) in hippocampal neurons: implications for basic science understanding of estrogen signaling and development of estrogen modulators with a dual therapeutic profile.

PubMed

Zhao, Liqin; O'Neill, Kathleen; Brinton, Roberta Diaz

2006-12-01

The present study sought to determine the characteristics of ICI 182,780 (Faslodex) action in rat primary hippocampal neurons. We first investigated the neuroprotective efficacy of ICI 182,780 against neurodegenerative insults associated with Alzheimer's disease and related disorders. Dose-response analyses revealed that ICI 182,780, in a concentration-dependent manner, significantly promoted neuron survival following exposure to either excitotoxic glutamate (200 muM)- or beta-amyloid(1-42) (1.5 muM)-induced neurodegeneration of hippocampal neurons. At a clinically relevant concentration of 50 ng/ml, ICI 182,780 exerted nearly maximal neuroprotection against both insults with efficacy comparable with that induced by the endogenous estrogen 17beta-estradiol. Thereafter, we investigated the impact of 50 ng/ml ICI 182,780 on mechanisms of 17beta-estradiol-inducible neuronal plasticity and neuroprotection. Results of these analyses demonstrated that ICI 182,780 directly induced a series of rapid intracellular Ca(2+) concentration ([Ca(2+)](i)) oscillations in a pattern comparable with that of 17beta-estradiol. In addition, ICI 182,780 exerted dual regulation of the glutamate-induced rise in [Ca(2+)](i) identical to that induced by 17beta-estradiol. Further analyses demonstrated that ICI 182,780 induced significant activation of extracellular signal-regulated kinase 1/2 and Akt (protein kinase B) and significantly increased expression of spinophilin and Bcl-2, with efficacy comparable with neurons treated with 17beta-estradiol. Taken together, results of these in vitro analyses of ICI 182,780 provide direct evidence of an estrogenic agonist profile of ICI 182,780 action in rat hippocampal neurons. Therapeutic development of neuroselective estrogen receptor modulators that mimic ICI 182,780 is discussed with respect to the potential of safe and efficacious alternatives to estrogen therapy for the prevention of postmenopausal cognitive decline and late-onset Alzheimer's disease.

GABA regulates synaptic integration of newly generated neurons in the adult brain

NASA Astrophysics Data System (ADS)

Ge, Shaoyu; Goh, Eyleen L. K.; Sailor, Kurt A.; Kitabatake, Yasuji; Ming, Guo-Li; Song, Hongjun

2006-02-01

Adult neurogenesis, the birth and integration of new neurons from adult neural stem cells, is a striking form of structural plasticity and highlights the regenerative capacity of the adult mammalian brain. Accumulating evidence suggests that neuronal activity regulates adult neurogenesis and that new neurons contribute to specific brain functions. The mechanism that regulates the integration of newly generated neurons into the pre-existing functional circuitry in the adult brain is unknown. Here we show that newborn granule cells in the dentate gyrus of the adult hippocampus are tonically activated by ambient GABA (γ-aminobutyric acid) before being sequentially innervated by GABA- and glutamate-mediated synaptic inputs. GABA, the major inhibitory neurotransmitter in the adult brain, initially exerts an excitatory action on newborn neurons owing to their high cytoplasmic chloride ion content. Conversion of GABA-induced depolarization (excitation) into hyperpolarization (inhibition) in newborn neurons leads to marked defects in their synapse formation and dendritic development in vivo. Our study identifies an essential role for GABA in the synaptic integration of newly generated neurons in the adult brain, and suggests an unexpected mechanism for activity-dependent regulation of adult neurogenesis, in which newborn neurons may sense neuronal network activity through tonic and phasic GABA activation.

Gene expression of Caenorhabditis elegans neurons carries information on their synaptic connectivity.

PubMed

Kaufman, Alon; Dror, Gideon; Meilijson, Isaac; Ruppin, Eytan

2006-12-08

The claim that genetic properties of neurons significantly influence their synaptic network structure is a common notion in neuroscience. The nematode Caenorhabditis elegans provides an exciting opportunity to approach this question in a large-scale quantitative manner. Its synaptic connectivity network has been identified, and, combined with cellular studies, we currently have characteristic connectivity and gene expression signatures for most of its neurons. By using two complementary analysis assays we show that the expression signature of a neuron carries significant information about its synaptic connectivity signature, and identify a list of putative genes predicting neural connectivity. The current study rigorously quantifies the relation between gene expression and synaptic connectivity signatures in the C. elegans nervous system and identifies subsets of neurons where this relation is highly marked. The results presented and the genes identified provide a promising starting point for further, more detailed computational and experimental investigations.

Gliotransmitters travel in time and space.

PubMed

Araque, Alfonso; Carmignoto, Giorgio; Haydon, Philip G; Oliet, Stéphane H R; Robitaille, Richard; Volterra, Andrea

2014-02-19

The identification of the presence of active signaling between astrocytes and neurons in a process termed gliotransmission has caused a paradigm shift in our thinking about brain function. However, we are still in the early days of the conceptualization of how astrocytes influence synapses, neurons, networks, and ultimately behavior. In this Perspective, our goal is to identify emerging principles governing gliotransmission and consider the specific properties of this process that endow the astrocyte with unique functions in brain signal integration. We develop and present hypotheses aimed at reconciling confounding reports and define open questions to provide a conceptual framework for future studies. We propose that astrocytes mainly signal through high-affinity slowly desensitizing receptors to modulate neurons and perform integration in spatiotemporal domains complementary to those of neurons. Copyright © 2014 Elsevier Inc. All rights reserved.

Osthole promotes neuronal differentiation and inhibits apoptosis via Wnt/β-catenin signaling in an Alzheimer's disease model.

PubMed

Yao, Yingjia; Gao, Zhong; Liang, Wenbo; Kong, Liang; Jiao, Yanan; Li, Shaoheng; Tao, Zhenyu; Yan, Yuhui; Yang, Jingxian

2015-12-15

Neurogenesis is the process by which neural stem cells (NSCs) proliferate and differentiate into neurons. This is diminished in several neurodegenerative disorders such as Alzheimer's disease (AD), which is characterized by the deposition of amyloid (A)β peptides and neuronal loss. Stimulating NSCs to replace lost neurons is therefore a promising approach for AD treatment. Our previous study demonstrated that osthole modulates NSC proliferation and differentiation, and may reduce Aβ protein expression in nerve cells. Here we investigated the mechanism underlying the effects of osthole on NSCs. We found that osthole enhances NSC proliferation and neuronal differentiation while suppressing apoptosis, effects that were exerted via activation of Wnt/β-catenin signaling. These results provide evidence that osthole can potentially be used as a therapeutic agent in the treatment of AD and other neurodegenerative disorders. Copyright © 2015 Elsevier Inc. All rights reserved.

Differential distribution of voltage-gated ion channels in cortical neurons: implications for epilepsy.

PubMed

Child, Nicholas D; Benarroch, Eduardo E

2014-03-18

Neurons contain different functional somatodendritic and axonal domains, each with a characteristic distribution of voltage-gated ion channels, synaptic inputs, and function. The dendritic tree of a cortical pyramidal neuron has 2 distinct domains, the basal and the apical dendrites, both containing dendritic spines; the different domains of the axon are the axonal initial segment (AIS), axon proper (which in myelinated axons includes the node of Ranvier, paranodes, juxtaparanodes, and internodes), and the axon terminals. In the cerebral cortex, the dendritic spines of the pyramidal neurons receive most of the excitatory synapses; distinct populations of γ-aminobutyric acid (GABA)ergic interneurons target specific cellular domains and thus exert different influences on pyramidal neurons. The multiple synaptic inputs reaching the somatodendritic region and generating excitatory postsynaptic potentials (EPSPs) and inhibitory postsynaptic potentials (IPSPs) sum and elicit changes in membrane potential at the AIS, the site of initiation of the action potential.

Neuropeptide transmission in brain circuits

PubMed Central

van den Pol, Anthony N.

2014-01-01

Neuropeptides are found in many mammalian CNS neurons where they play key roles in modulating neuronal activity. In contrast to amino acid transmitter release at the synapse, neuropeptide release is not restricted to the synaptic specialization, and after release, a neuropeptide may diffuse some distance to exert its action through a G-protein coupled receptor. Some neuropeptides such as hypocretin/orexin are synthesized only in single regions of the brain, and the neurons releasing these peptides probably have similar functional roles. Other peptides such as neuropeptide Y (NPY) are synthesized throughout the brain, and neurons that synthesize the peptide in one region have no anatomical or functional connection with NPY neurons in other brain regions. Here, I review converging data revealing a complex interaction between slow-acting neuromodulator peptides and fast-acting amino acid transmitters in the control of energy homeostasis, drug addiction, mood and motivation, sleep-wake states, and neuroendocrine regulation. PMID:23040809

Genome-Wide Search Reveals the Existence of a Limited Number of Thyroid Hormone Receptor Alpha Target Genes in Cerebellar Neurons

PubMed Central

Chatonnet, Fabrice; Guyot, Romain; Picou, Frédéric; Bondesson, Maria; Flamant, Frederic

2012-01-01

Thyroid hormone (T3) has a major influence on cerebellum post-natal development. The major phenotypic landmark of exposure to low levels of T3 during development (hypothyroidism) in the cerebellum is the retarded inward migration of the most numerous cell type, granular neurons. In order to identify the direct genetic regulation exerted by T3 on cerebellar neurons and their precursors, we used microarray RNA hybridization to perform a time course analysis of T3 induced gene expression in primary cultures of cerebellar neuronal cell. These experiments suggest that we identified a small set of genes which are directly regulated, both in vivo and in vitro, during cerebellum post-natal development. These modest changes suggest that T3 does not acts directly on granular neurons and mainly indirectly influences the cellular interactions taking place during development. PMID:22586439

Decoding sound level in the marmoset primary auditory cortex.

PubMed

Sun, Wensheng; Marongelli, Ellisha N; Watkins, Paul V; Barbour, Dennis L

2017-10-01

Neurons that respond favorably to a particular sound level have been observed throughout the central auditory system, becoming steadily more common at higher processing areas. One theory about the role of these level-tuned or nonmonotonic neurons is the level-invariant encoding of sounds. To investigate this theory, we simulated various subpopulations of neurons by drawing from real primary auditory cortex (A1) neuron responses and surveyed their performance in forming different sound level representations. Pure nonmonotonic subpopulations did not provide the best level-invariant decoding; instead, mixtures of monotonic and nonmonotonic neurons provided the most accurate decoding. For level-fidelity decoding, the inclusion of nonmonotonic neurons slightly improved or did not change decoding accuracy until they constituted a high proportion. These results indicate that nonmonotonic neurons fill an encoding role complementary to, rather than alternate to, monotonic neurons. NEW & NOTEWORTHY Neurons with nonmonotonic rate-level functions are unique to the central auditory system. These level-tuned neurons have been proposed to account for invariant sound perception across sound levels. Through systematic simulations based on real neuron responses, this study shows that neuron populations perform sound encoding optimally when containing both monotonic and nonmonotonic neurons. The results indicate that instead of working independently, nonmonotonic neurons complement the function of monotonic neurons in different sound-encoding contexts. Copyright © 2017 the American Physiological Society.

Direct Activation of Sleep-Promoting VLPO Neurons by Volatile Anesthetics Contributes to Anesthetic Hypnosis

PubMed Central

Moore, Jason T; Chen, Jingqiu; Han, Bo; Meng, Qing Cheng; Veasey, Sigrid C; Beck, Sheryl G; Kelz, Max B

2013-01-01

Summary Background Despite seventeen decades of continuous clinical use, the neuronal mechanisms through which volatile anesthetics act to produce unconsciousness remain obscure. One emerging possibility is that anesthetics exert their hypnotic effects by hijacking endogenous arousal circuits. A key sleep-promoting component of this circuitry is the ventrolateral preoptic nucleus (VLPO), a hypothalamic region containing both state-independent neurons and neurons that preferentially fire during natural sleep. Results Using c-Fos immunohistochemistry as a biomarker for antecedent neuronal activity, we show that isoflurane and halothane increase the number of active neurons in the VLPO, but only when mice are sedated or unconscious. Destroying VLPO neurons produces an acute resistance to isoflurane-induced hypnosis. Electrophysiological studies prove that the neurons depolarized by isoflurane belong to the subpopulation of VLPO neurons responsible for promoting natural sleep, while neighboring non-sleep-active VLPO neurons are unaffected by isoflurane. Finally, we show that this anesthetic-induced depolarization is not solely due to a presynaptic inhibition of wake-active neurons as previously hypothesized, but rather is due to a direct postsynaptic effect on VLPO neurons themselves arising from the closing of a background potassium conductance. Conclusions Cumulatively, this work demonstrates that anesthetics are capable of directly activating endogenous sleep-promoting networks and that such actions contribute to their hypnotic properties. PMID:23103189

Complementary Therapies for Significant Dysfunction from Tinnitus: Treatment Review and Potential for Integrative Medicine.

PubMed

Wolever, Ruth Q; Price, Rebecca; Hazelton, A Garrett; Dmitrieva, Natalia O; Bechard, Elizabeth M; Shaffer, Janet K; Tucci, Debara L

2015-01-01

Tinnitus is a prevalent and costly chronic condition; no universally effective treatment exists. Only 20% of patients who report tinnitus actually seek treatment, and when treated, most patients commonly receive sound-based and educational (SBE) therapy. Additional treatment options are necessary, however, for nonauditory aspects of tinnitus (e.g., anxiety, depression, and significant interference with daily life) and when SBE therapy is inefficacious or inappropriate. This paper provides a comprehensive review of (1) conventional tinnitus treatments and (2) promising complementary therapies that have demonstrated some benefit for severe dysfunction from tinnitus. While there has been no systematic study of the benefits of an Integrative Medicine approach for severe tinnitus, the current paper reviews emerging evidence suggesting that synergistic combinations of complementary therapies provided within a whole-person framework may augment SBE therapy and empower patients to exert control over their tinnitus symptoms without the use of medications, expensive devices, or extended programs.

Excitatory motor neurons are local oscillators for backward locomotion.

PubMed

Gao, Shangbang; Guan, Sihui Asuka; Fouad, Anthony D; Meng, Jun; Kawano, Taizo; Huang, Yung-Chi; Li, Yi; Alcaire, Salvador; Hung, Wesley; Lu, Yangning; Qi, Yingchuan Billy; Jin, Yishi; Alkema, Mark; Fang-Yen, Christopher; Zhen, Mei

2018-01-23

Cell- or network-driven oscillators underlie motor rhythmicity. The identity of C. elegans oscillators remains unknown. Through cell ablation, electrophysiology, and calcium imaging, we show: (1) forward and backward locomotion is driven by different oscillators; (2) the cholinergic and excitatory A-class motor neurons exhibit intrinsic and oscillatory activity that is sufficient to drive backward locomotion in the absence of premotor interneurons; (3) the UNC-2 P/Q/N high-voltage-activated calcium current underlies A motor neuron's oscillation; (4) descending premotor interneurons AVA, via an evolutionarily conserved, mixed gap junction and chemical synapse configuration, exert state-dependent inhibition and potentiation of A motor neuron's intrinsic activity to regulate backward locomotion. Thus, motor neurons themselves derive rhythms, which are dually regulated by the descending interneurons to control the reversal motor state. These and previous findings exemplify compression: essential circuit properties are conserved but executed by fewer numbers and layers of neurons in a small locomotor network. © 2017, Gao et al.

Interneuronal Transfer and Distal Action of Tetanus Toxin and Botulinum Neurotoxins A and D in Central Neurons.

PubMed

Bomba-Warczak, Ewa; Vevea, Jason D; Brittain, Joel M; Figueroa-Bernier, Annette; Tepp, William H; Johnson, Eric A; Yeh, Felix L; Chapman, Edwin R

2016-08-16

Recent reports suggest that botulinum neurotoxin (BoNT) A, which is widely used clinically to inhibit neurotransmission, can spread within networks of neurons to have distal effects, but this remains controversial. Moreover, it is not known whether other members of this toxin family are transferred between neurons. Here, we investigate the potential distal effects of BoNT/A, BoNT/D, and tetanus toxin (TeNT), using central neurons grown in microfluidic devices. Toxins acted upon the neurons that mediated initial entry, but all three toxins were also taken up, via an alternative pathway, into non-acidified organelles that mediated retrograde transport to the somato-dendritic compartment. Toxins were then released into the media, where they entered and exerted their effects upon upstream neurons. These findings directly demonstrate that these agents undergo transcytosis and interneuronal transfer in an active form, resulting in long-distance effects. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Agmatine Ameliorates High Glucose-Induced Neuronal Cell Senescence by Regulating the p21 and p53 Signaling.

PubMed

Song, Juhyun; Lee, Byeori; Kang, Somang; Oh, Yumi; Kim, Eosu; Kim, Chul-Hoon; Song, Ho-Taek; Lee, Jong Eun

2016-02-01

Neuronal senescence caused by diabetic neuropathy is considered a common complication of diabetes mellitus. Neuronal senescence leads to the secretion of pro-inflammatory cytokines, the production of reactive oxygen species, and the alteration of cellular homeostasis. Agmatine, which is biosynthesized by arginine decarboxylation, has been reported in previous in vitro to exert a protective effect against various stresses. In present study, agmatine attenuated the cell death and the expression of pro-inflammatory cytokines such as IL-6, TNF-alpha and CCL2 in high glucose in vitro conditions. Moreover, the senescence associated-β-galatosidase's activity in high glucose exposed neuronal cells was reduced by agmatine. Increased p21 and reduced p53 in high glucose conditioned cells were changed by agmatine. Ultimately, agmatine inhibits the neuronal cell senescence through the activation of p53 and the inhibition of p21. Here, we propose that agmatine may ameliorate neuronal cell senescence in hyperglycemia.

Neuronal Activity Promotes Glioma Growth through Neuroligin-3 Secretion.

PubMed

Venkatesh, Humsa S; Johung, Tessa B; Caretti, Viola; Noll, Alyssa; Tang, Yujie; Nagaraja, Surya; Gibson, Erin M; Mount, Christopher W; Polepalli, Jai; Mitra, Siddhartha S; Woo, Pamelyn J; Malenka, Robert C; Vogel, Hannes; Bredel, Markus; Mallick, Parag; Monje, Michelle

2015-05-07

Active neurons exert a mitogenic effect on normal neural precursor and oligodendroglial precursor cells, the putative cellular origins of high-grade glioma (HGG). By using optogenetic control of cortical neuronal activity in a patient-derived pediatric glioblastoma xenograft model, we demonstrate that active neurons similarly promote HGG proliferation and growth in vivo. Conditioned medium from optogenetically stimulated cortical slices promoted proliferation of pediatric and adult patient-derived HGG cultures, indicating secretion of activity-regulated mitogen(s). The synaptic protein neuroligin-3 (NLGN3) was identified as the leading candidate mitogen, and soluble NLGN3 was sufficient and necessary to promote robust HGG cell proliferation. NLGN3 induced PI3K-mTOR pathway activity and feedforward expression of NLGN3 in glioma cells. NLGN3 expression levels in human HGG negatively correlated with patient overall survival. These findings indicate the important role of active neurons in the brain tumor microenvironment and identify secreted NLGN3 as an unexpected mechanism promoting neuronal activity-regulated cancer growth. Copyright © 2015 Elsevier Inc. All rights reserved.

Diminished perisomatic GABAergic terminals on cortical neurons adjacent to amyloid plaques.

PubMed

Garcia-Marin, Virginia; Blazquez-Llorca, Lidia; Rodriguez, José-Rodrigo; Boluda, Susana; Muntane, Gerard; Ferrer, Isidro; Defelipe, Javier

2009-01-01

One of the main pathological hallmarks of Alzheimer's disease (AD) is the accumulation of plaques in the cerebral cortex, which may appear either in the neuropil or in direct association with neuronal somata. Since different axonal systems innervate the dendritic (mostly glutamatergic) and perisomatic (mostly GABAergic) regions of neurons, the accumulation of plaques in the neuropil or associated with the soma might produce different alterations to synaptic circuits. We have used a variety of conventional light, confocal and electron microscopy techniques to study their relationship with neuronal somata in the cerebral cortex from AD patients and APP/PS1 transgenic mice. The main finding was that the membrane surfaces of neurons (mainly pyramidal cells) in contact with plaques lack GABAergic perisomatic synapses. Since these perisomatic synapses are thought to exert a strong influence on the output of pyramidal cells, their loss may lead to the hyperactivity of the neurons in contact with plaques. These results suggest that plaques modify circuits in a more selective manner than previously thought.

Encoding of social signals in all three electrosensory pathways of Eigenmannia virescens.

PubMed

Stöckl, Anna; Sinz, Fabian; Benda, Jan; Grewe, Jan

2014-11-01

Extracting complementary features in parallel pathways is a widely used strategy for a robust representation of sensory signals. Weakly electric fish offer the rare opportunity to study complementary encoding of social signals in all of its electrosensory pathways. Electrosensory information is conveyed in three parallel pathways: two receptor types of the tuberous (active) system and one receptor type of the ampullary (passive) system. Modulations of the fish's own electric field are sensed by these receptors and used in navigation, prey detection, and communication. We studied the neuronal representation of electric communication signals (called chirps) in the ampullary and the two tuberous pathways of Eigenmannia virescens. We first characterized different kinds of chirps observed in behavioral experiments. Since Eigenmannia chirps simultaneously drive all three types of receptors, we studied their responses in in vivo electrophysiological recordings. Our results demonstrate that different electroreceptor types encode different aspects of the stimuli and each appears best suited to convey information about a certain chirp type. A decoding analysis of single neurons and small populations shows that this specialization leads to a complementary representation of information in the tuberous and ampullary receptors. This suggests that a potential readout mechanism should combine information provided by the parallel processing streams to improve chirp detectability. Copyright © 2014 the American Physiological Society.

Widespread transduction of astrocytes and neurons in the mouse central nervous system after systemic delivery of a self-complementary AAV-PHP.B vector.

PubMed

Rincon, Melvin Y; de Vin, Filip; Duqué, Sandra I; Fripont, Shelly; Castaldo, Stephanie A; Bouhuijzen-Wenger, Jessica; Holt, Matthew G

2018-04-01

Until recently, adeno-associated virus 9 (AAV9) was considered the AAV serotype most effective in crossing the blood-brain barrier (BBB) and transducing cells of the central nervous system (CNS), following systemic injection. However, a newly engineered capsid, AAV-PHP.B, is reported to cross the BBB at even higher efficiency. We investigated how much we could boost CNS transgene expression by using AAV-PHP.B carrying a self-complementary (sc) genome. To allow comparison, 6 weeks old C57BL/6 mice received intravenous injections of scAAV2/9-GFP or scAAV2/PHP.B-GFP at equivalent doses. Three weeks postinjection, transgene expression was assessed in brain and spinal cord. We consistently observed more widespread CNS transduction and higher levels of transgene expression when using the scAAV2/PHP.B-GFP vector. In particular, we observed an unprecedented level of astrocyte transduction in the cortex, when using a ubiquitous CBA promoter. In comparison, neuronal transduction was much lower than previously reported. However, strong neuronal expression (including spinal motor neurons) was observed when the human synapsin promoter was used. These findings constitute the first reported use of an AAV-PHP.B capsid, encapsulating a scAAV genome, for gene transfer in adult mice. Our results underscore the potential of this AAV construct as a platform for safer and more efficacious gene therapy vectors for the CNS.

Direct projections from hypothalamic orexin neurons to brainstem cardiac vagal neurons.

PubMed

Dergacheva, Olga; Yamanaka, Akihiro; Schwartz, Alan R; Polotsky, Vsevolod Y; Mendelowitz, David

2016-12-17

Orexin neurons are known to augment the sympathetic control of cardiovascular function, however the role of orexin neurons in parasympathetic cardiac regulation remains unclear. To test the hypothesis that orexin neurons contribute to parasympathetic control we selectively expressed channelrhodopsin-2 (ChR2) in orexin neurons in orexin-Cre transgenic rats and examined postsynaptic currents in cardiac vagal neurons (CVNs) in the dorsal motor nucleus of the vagus (DMV). Simultaneous photostimulation and recording in ChR2-expressing orexin neurons in the lateral hypothalamus resulted in reliable action potential firing as well as large whole-cell currents suggesting a strong expression of ChR2 and reliable optogenetic excitation. Photostimulation of ChR2-expressing fibers in the DMV elicited short-latency (ranging from 3.2ms to 8.5ms) postsynaptic currents in 16 out of 44 CVNs tested. These responses were heterogeneous and included excitatory glutamatergic (63%) and inhibitory GABAergic (37%) postsynaptic currents. The results from this study suggest different sub-population of orexin neurons may exert diverse influences on brainstem CVNs and therefore may play distinct functional roles in parasympathetic control of the heart. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Aortic Baroreceptors Display Higher Mechanosensitivity than Carotid Baroreceptors.

PubMed

Lau, Eva On-Chai; Lo, Chun-Yin; Yao, Yifei; Mak, Arthur Fuk-Tat; Jiang, Liwen; Huang, Yu; Yao, Xiaoqiang

2016-01-01

Arterial baroreceptors are mechanical sensors that detect blood pressure changes. It has long been suggested that the two arterial baroreceptors, aortic and carotid baroreceptors, have different pressure sensitivities. However, there is no consensus as to which of the arterial baroreceptors are more sensitive to changes in blood pressure. In the present study, we employed independent methods to compare the pressure sensitivity of the two arterial baroreceptors. Firstly, pressure-activated action potential firing was measured by whole-cell current clamp with a high-speed pressure clamp system in primary cultured baroreceptor neurons. The results show that aortic depressor neurons possessed a higher percentage of mechano-sensitive neurons. Furthermore, aortic baroreceptor neurons show a lower pressure threshold than that of carotid baroreceptor neurons. Secondly, uniaxial stretching of baroreceptor neurons, that mimics the forces exerted on blood vessels, elicited a larger increase in intracellular Ca(2+) rise in aortic baroreceptor neurons than in carotid baroreceptor neurons. Thirdly, the pressure-induced action potential firing in the aortic depressor nerve recorded in vivo was also higher. The present study therefore provides for a basic physiological understanding on the pressure sensitivity of the two baroreceptor neurons and suggests that aortic baroreceptors have a higher pressure sensitivity than carotid baroreceptors.

Species and Sex Differences in the Morphogenic Response of Primary Rodent Neurons to 3,3′-Dichlorobiphenyl (PCB 11)

PubMed Central

Sethi, Sunjay; Keil, Kimberly P.

2017-01-01

PCB 11 is an emerging global pollutant that we recently showed promotes axonal and dendritic growth in primary rat neuronal cell cultures. Here, we address the influence of sex and species on neuronal responses to PCB 11. Neuronal morphology was quantified in sex-specific primary hippocampal and cortical neuron-glia co-cultures derived from neonatal C57BL/6J mice and Sprague Dawley rats exposed for 48 h to vehicle (0.1% DMSO) or PCB 11 at concentrations ranging from 1 fM to 1 nM. Total axonal length was quantified in tau-1 immunoreactive neurons at day in vitro (DIV) 2; dendritic arborization was assessed by Sholl analysis at DIV 9 in neurons transfected with MAP2B-FusRed. In mouse cultures, PCB 11 enhanced dendritic arborization in female, but not male, hippocampal neurons and male, but not female, cortical neurons. In rat cultures, PCB 11 promoted dendritic arborization in male and female hippocampal and cortical neurons. PCB 11 also increased axonal growth in mouse and rat neurons of both sexes and neuronal cell types. These data demonstrate that PCB 11 exerts sex-specific effects on neuronal morphogenesis that vary depending on species, neurite type, and neuronal cell type. These findings have significant implications for risk assessment of this emerging developmental neurotoxicant. PMID:29295518

Species and Sex Differences in the Morphogenic Response of Primary Rodent Neurons to 3,3'-Dichlorobiphenyl (PCB 11).

PubMed

Sethi, Sunjay; Keil, Kimberly P; Lein, Pamela J

2017-12-23

PCB 11 is an emerging global pollutant that we recently showed promotes axonal and dendritic growth in primary rat neuronal cell cultures. Here, we address the influence of sex and species on neuronal responses to PCB 11. Neuronal morphology was quantified in sex-specific primary hippocampal and cortical neuron-glia co-cultures derived from neonatal C57BL/6J mice and Sprague Dawley rats exposed for 48 h to vehicle (0.1% DMSO) or PCB 11 at concentrations ranging from 1 fM to 1 nM. Total axonal length was quantified in tau-1 immunoreactive neurons at day in vitro (DIV) 2; dendritic arborization was assessed by Sholl analysis at DIV 9 in neurons transfected with MAP2B-FusRed. In mouse cultures, PCB 11 enhanced dendritic arborization in female, but not male, hippocampal neurons and male, but not female, cortical neurons. In rat cultures, PCB 11 promoted dendritic arborization in male and female hippocampal and cortical neurons. PCB 11 also increased axonal growth in mouse and rat neurons of both sexes and neuronal cell types. These data demonstrate that PCB 11 exerts sex-specific effects on neuronal morphogenesis that vary depending on species, neurite type, and neuronal cell type. These findings have significant implications for risk assessment of this emerging developmental neurotoxicant.

Role of AGC1/aralar in the metabolic synergies between neuron and glia.

PubMed

Contreras, Laura

2015-09-01

Brain energetic requirements are elevated due to the high cost of impulse transmission and information storage, and are met mainly by glucose oxidation. The energy needs are closely matched by metabolic regulation, which requires the close cooperation of neurons and astrocytes and involves highly regulated fluxes of metabolites between cells. The metabolism in each type of cell is determined in part by its proteomic profile, which has been regarded as complementary. This review will consider the cellular distribution of the mitochondrial aspartate-glutamate carrier, aralar/AGC1/SLC25A12, and its role in the synergic metabolism between neurons and astrocytes. Copyright © 2015 Elsevier Ltd. All rights reserved.

Loss of Balance between Striatal Feedforward Inhibition and Corticostriatal Excitation Leads to Tremor.

PubMed

Oran, Yael; Bar-Gad, Izhar

2018-02-14

Fast-spiking interneurons (FSIs) exert powerful inhibitory control over the striatum and are hypothesized to balance the massive excitatory cortical and thalamic input to this structure. We recorded neuronal activity in the dorsolateral striatum and globus pallidus (GP) concurrently with the detailed movement kinematics of freely behaving female rats before and after selective inhibition of FSI activity using IEM-1460 microinjections. The inhibition led to the appearance of episodic rest tremor in the body part that depended on the somatotopic location of the injection within the striatum. The tremor was accompanied by coherent oscillations in the local field potential (LFP). Individual neuron activity patterns became oscillatory and coherent in the tremor frequency. Striatal neurons, but not GP neurons, displayed additional temporal, nonoscillatory correlations. The subsequent reduction in the corticostriatal input following muscimol injection to the corresponding somatotopic location in the primary motor cortex led to disruption of the tremor and a reduction of the LFP oscillations and individual neuron's phase-locked activity. The breakdown of the normal balance of excitation and inhibition in the striatum has been shown previously to be related to different motor abnormalities. Our results further indicate that the balance between excitatory corticostriatal input and feedforward FSI inhibition is sufficient to break down the striatal decorrelation process and generate oscillations resulting in rest tremor typical of multiple basal ganglia disorders. SIGNIFICANCE STATEMENT Fast-spiking interneurons (FSIs) play a key role in normal striatal processing by exerting powerful inhibitory control over the network. FSI malfunctions have been associated with abnormal processing of information within the striatum that leads to multiple movement disorders. Here, we study the changes in neuronal activity and movement kinematics following selective inhibition of these neurons. The injections led to the appearance of episodic rest tremor, accompanied by coherent oscillations in neuronal activity, which was reversed following corticostriatal inhibition. These results suggest that the balance between corticostriatal excitation and feedforward FSI inhibition is crucial for maintaining the striatal decorrelation process, and that its breakdown leads to the formation of oscillations resulting in rest tremor typical of multiple basal ganglia disorders. Copyright © 2018 the authors 0270-6474/18/381699-12$15.00/0.

Pregnenolone sulphate enhances spatial orientation and object discrimination in adult male rats: evidence from a behavioural and electrophysiological study.

PubMed

Plescia, Fulvio; Sardo, Pierangelo; Rizzo, Valerio; Cacace, Silvana; Marino, Rosa Anna Maria; Brancato, Anna; Ferraro, Giuseppe; Carletti, Fabio; Cannizzaro, Carla

2014-01-01

Neurosteroids can alter neuronal excitability interacting with specific neurotransmitter receptors, thus affecting several functions such as cognition and emotionality. In this study we investigated, in adult male rats, the effects of the acute administration of pregnenolone-sulfate (PREGS) (10mg/kg, s.c.) on cognitive processes using the Can test, a non aversive spatial/visual task which allows the assessment of both spatial orientation-acquisition and object discrimination in a simple and in a complex version of the visual task. Electrophysiological recordings were also performed in vivo, after acute PREGS systemic administration in order to investigate on the neuronal activation in the hippocampus and the perirhinal cortex. Our results indicate that, PREGS induces an improvement in spatial orientation-acquisition and in object discrimination in the simple and in the complex visual task; the behavioural responses were also confirmed by electrophysiological recordings showing a potentiation in the neuronal activity of the hippocampus and the perirhinal cortex. In conclusion, this study demonstrates that PREGS systemic administration in rats exerts cognitive enhancing properties which involve both the acquisition and utilization of spatial information, and object discrimination memory, and also correlates the behavioural potentiation observed to an increase in the neuronal firing of discrete cerebral areas critical for spatial learning and object recognition. This provides further evidence in support of the role of PREGS in exerting a protective and enhancing role on human memory. Copyright © 2013. Published by Elsevier B.V.

The visual orientation memory of Drosophila requires Foraging (PKG) upstream of Ignorant (RSK2) in ring neurons of the central complex

PubMed Central

Kuntz, Sara; Poeck, Burkhard; Sokolowski, Marla B.; Strauss, Roland

2012-01-01

Orientation and navigation in a complex environment requires path planning and recall to exert goal-driven behavior. Walking Drosophila flies possess a visual orientation memory for attractive targets which is localized in the central complex of the adult brain. Here we show that this type of working memory requires the cGMP-dependent protein kinase encoded by the foraging gene in just one type of ellipsoid-body ring neurons. Moreover, genetic and epistatic interaction studies provide evidence that Foraging functions upstream of the Ignorant Ribosomal-S6 Kinase 2, thus revealing a novel neuronal signaling pathway necessary for this type of memory in Drosophila. PMID:22815538

Paradigms for pharmacological characterization of C. elegans synaptic transmission mutants.

PubMed

Locke, Cody; Berry, Kalen; Kautu, Bwarenaba; Lee, Kyle; Caldwell, Kim; Caldwell, Guy

2008-08-18

The nematode, Caenorhabditis elegans, has become an expedient model for studying neurotransmission. C. elegans is unique among animal models, as the anatomy and connectivity of its nervous system has been determined from electron micrographs and refined by pharmacological assays. In this video, we describe how two complementary neural stimulants, an acetylcholinesterase inhibitor, called aldicarb, and a gamma-aminobutyric acid (GABA) receptor antagonist, called pentylenetetrazole (PTZ), may be employed to specifically characterize signaling at C. elegans neuromuscular junctions (NMJs) and facilitate our understanding of antagonistic neural circuits. Of 302 C. elegans neurons, nineteen GABAergic D-type motor neurons innervate body wall muscles (BWMs), while four GABAergic neurons, called RMEs, innervate head muscles. Conversely, thirty-nine motor neurons express the excitatory neurotransmitter, acetylcholine (ACh), and antagonize GABA transmission at BWMs to coordinate locomotion. The antagonistic nature of GABAergic and cholinergic motor neurons at body wall NMJs was initially determined by laser ablation and later buttressed by aldicarb exposure. Acute aldicarb exposure results in a time-course or dose-responsive paralysis in wild-type worms. Yet, loss of excitatory ACh transmission confers resistance to aldicarb, as less ACh accumulates at worm NMJs, leading to less stimulation of BWMs. Resistance to aldicarb may be observed with ACh-specific or general synaptic function mutants. Consistent with antagonistic GABA and ACh transmission, loss of GABA transmission, or a failure to negatively regulate ACh release, confers hypersensitivity to aldicarb. Although aldicarb exposure has led to the isolation of numerous worm homologs of neurotransmission genes, aldicarb exposure alone cannot efficiently determine prevailing roles for genes and pathways in specific C. elegans motor neurons. For this purpose, we have introduced a complementary experimental approach, which uses PTZ. Neurotransmission mutants display clear phenotypes, distinct from aldicarb-induced paralysis, in response to PTZ. Wild-type worms, as well as mutants with specific inabilities to release or receive ACh, do not show apparent sensitivity to PTZ. However, GABA mutants, as well as general synaptic function mutants, display anterior convulsions in a time-course or dose-responsive manner. Mutants that cannot negatively regulate general neurotransmitter release and, thus, secrete excessive amounts of ACh onto BWMs, become paralyzed on PTZ. The PTZ-induced phenotypes of discrete mutant classes indicate that a complementary approach with aldicarb and PTZ exposure paradigms in C. elegans may accelerate our understanding of neurotransmission. Moreover, videos demonstrating how we perform pharmacological assays should establish consistent methods for C. elegans research.

Tramadol and propentofylline coadministration exerted synergistic effects on rat spinal nerve ligation-induced neuropathic pain.

PubMed

Zhang, Jin; Wu, Dan; Xie, Cheng; Wang, Huan; Wang, Wei; Zhang, Hui; Liu, Rui; Xu, Li-Xian; Mei, Xiao-Peng

2013-01-01

Neuropathic pain is an intractable clinical problem. Drug treatments such as tramadol have been reported to effectively decrease neuropathic pain by inhibiting the activity of nociceptive neurons. It has also been reported that modulating glial activation could also prevent or reverse neuropathic pain via the administration of a glial modulator or inhibitor, such as propentofylline. Thus far, there has been no clinical strategy incorporating both neuronal and glial participation for treating neuropathic pain. Therefore, the present research study was designed to assess whether coadministration of tramadol and propentofylline, as neuronal and glial activation inhibitors, respectively, would exert a synergistic effect on the reduction of rat spinal nerve ligation (SNL)-induced neuropathic pain. Rats underwent SNL surgery to induce neuropathic pain. Pain behavioral tests were conducted to ascertain the effect of drugs on SNL-induced mechanical allodynia with von-Frey hairs. Proinflammatory factor interleukin-1β (IL-1β) expression was also detected by Real-time RT-PCR. Intrathecal tramadol and propentofylline administered alone relieved SNL-induced mechanical allodynia in a dose-dependent manner. Tramadol and propentofylline coadministration exerted a more potent effect in a synergistic and dose dependent manner than the intrathecal administration of either drug alone. Real-time RT-PCR demonstrated IL-1β up-expression in the ipsilateral spinal dorsal horn after the lesion, which was significantly decreased by tramadol and propentofylline coadministration. Inhibiting proinflammatory factor IL-1β contributed to the synergistic effects of tramadol and propentofylline coadministration on rat peripheral nerve injury-induced neuropathic pain. Thus, our study provided a rationale for utilizing a novel strategy for treating neuropathic pain by blocking the proinflammatory factor related pathways in the central nervous system.

Tramadol and Propentofylline Coadministration Exerted Synergistic Effects on Rat Spinal Nerve Ligation-Induced Neuropathic Pain

PubMed Central

Wang, Huan; Wang, Wei; Zhang, Hui; Liu, Rui; Xu, Li-Xian; Mei, Xiao-Peng

2013-01-01

Neuropathic pain is an intractable clinical problem. Drug treatments such as tramadol have been reported to effectively decrease neuropathic pain by inhibiting the activity of nociceptive neurons. It has also been reported that modulating glial activation could also prevent or reverse neuropathic pain via the administration of a glial modulator or inhibitor, such as propentofylline. Thus far, there has been no clinical strategy incorporating both neuronal and glial participation for treating neuropathic pain. Therefore, the present research study was designed to assess whether coadministration of tramadol and propentofylline, as neuronal and glial activation inhibitors, respectively, would exert a synergistic effect on the reduction of rat spinal nerve ligation (SNL)-induced neuropathic pain. Rats underwent SNL surgery to induce neuropathic pain. Pain behavioral tests were conducted to ascertain the effect of drugs on SNL-induced mechanical allodynia with von-Frey hairs. Proinflammatory factor interleukin-1β (IL-1β) expression was also detected by Real-time RT-PCR. Intrathecal tramadol and propentofylline administered alone relieved SNL-induced mechanical allodynia in a dose-dependent manner. Tramadol and propentofylline coadministration exerted a more potent effect in a synergistic and dose dependent manner than the intrathecal administration of either drug alone. Real-time RT-PCR demonstrated IL-1β up-expression in the ipsilateral spinal dorsal horn after the lesion, which was significantly decreased by tramadol and propentofylline coadministration. Inhibiting proinflammatory factor IL-1β contributed to the synergistic effects of tramadol and propentofylline coadministration on rat peripheral nerve injury-induced neuropathic pain. Thus, our study provided a rationale for utilizing a novel strategy for treating neuropathic pain by blocking the proinflammatory factor related pathways in the central nervous system. PMID:24009718

Diet and cognition: interplay between cell metabolism and neuronal plasticity.

PubMed

Gomez-Pinilla, Fernando; Tyagi, Ethika

2013-11-01

To discuss studies in humans and animals revealing the ability of foods to benefit the brain: new information with regards to mechanisms of action and the treatment of neurological and psychiatric disorders. Dietary factors exert their effects on the brain by affecting molecular events related to the management of energy metabolism and synaptic plasticity. Energy metabolism influences neuronal function, neuronal signaling, and synaptic plasticity, ultimately affecting mental health. Epigenetic regulation of neuronal plasticity appears as an important mechanism by which foods can prolong their effects on long-term neuronal plasticity. The prime focus of the discussion is to emphasize the role of cell metabolism as a mediator for the action of foods on the brain. Oxidative stress promotes damage to phospholipids present in the plasma membrane such as the omega-3 fatty acid docosahexenoic acid, disrupting neuronal signaling. Thus, dietary docosahexenoic acid seems crucial for supporting plasma membrane function, interneuronal signaling, and cognition. The dual action of brain-derived neurotrophic factor in neuronal metabolism and synaptic plasticity is crucial for activating signaling cascades under the action of diet and other environmental factors, using mechanisms of epigenetic regulation.

Metabolic changes of cultured DRG neurons induced by adenosine using confocal microscopy imaging

NASA Astrophysics Data System (ADS)

Zheng, Liqin; Huang, Yimei; Chen, Jiangxu; Wang, Yuhua; Yang, Hongqin; Zhang, Yanding; Xie, Shusen

2012-12-01

Adenosine exerts multiple effects on pain transmission in the peripheral nervous system. This study was performed to use confocal microscopy to evaluate whether adenosine could affect dorsal root ganglia (DRG) neurons in vitro and test which adenosine receptor mediates the effect of adenosine on DRG neurons. After adding adenosine with different concentration, we compared the metabolic changes by the real time imaging of calcium and mitochondria membrane potential using confocal microscopy. The results showed that the effect of 500 μM adenosine on the metabolic changes of DRG neurons was more significant than others. Furthermore, four different adenosine receptor antagonists were used to study which receptor mediated the influences of adenosine on the cultured DRG neurons. All adenosine receptor antagonists especially A1 receptor antagonist (DPCPX) had effect on the Ca2+ and mitochondria membrane potential dynamics of DRG neurons. The above studies demonstrated that the effect of adenosine which may be involved in the signal transmission on the sensory neurons was dose-dependent, and all the four adenosine receptors especially the A1R may mediate the transmission.

Yin Yang 1 Is a Critical Repressor of Matrix Metalloproteinase-9 Expression in Brain Neurons*

PubMed Central

Rylski, Marcin; Amborska, Renata; Zybura, Katarzyna; Mioduszewska, Barbara; Michaluk, Piotr; Jaworski, Jacek; Kaczmarek, Leszek

2008-01-01

Membrane depolarization controls long lasting adaptive neuronal changes in brain physiology and pathology. Such responses are believed to be gene expression-dependent. Notably, however, only a couple of gene repressors active in nondepolarized neurons have been described. In this study, we show that in the unstimulated rat hippocampus in vivo, as well as in the nondepolarized brain neurons in primary culture, the transcriptional regulator Yin Yang 1 (YY1) is bound to the proximal Mmp-9 promoter and strongly represses Mmp-9 transcription. Furthermore, we demonstrate that monoubiquitinated and CtBP1 (C-terminal binding protein 1)-bound YY1 regulates Mmp-9 mRNA synthesis in rat brain neurons controlling its transcription apparently via HDAC3-dependent histone deacetylation. In conclusion, our data suggest that YY1 exerts, via epigenetic mechanisms, a control over neuronal expression of MMP-9. Because MMP-9 has recently been shown to play a pivotal role in physiological and pathological neuronal plasticity, YY1 may be implicated in these phenomena as well. PMID:18940814

Complementary theta resonance filtering by two spatially segregated mechanisms in CA1 hippocampal pyramidal neurons.

PubMed

Hu, Hua; Vervaeke, Koen; Graham, Lyle J; Storm, Johan F

2009-11-18

Synaptic input to a neuron may undergo various filtering steps, both locally and during transmission to the soma. Using simultaneous whole-cell recordings from soma and apical dendrites from rat CA1 hippocampal pyramidal cells, and biophysically detailed modeling, we found two complementary resonance (bandpass) filters of subthreshold voltage signals. Both filters favor signals in the theta (3-12 Hz) frequency range, but have opposite location, direction, and voltage dependencies: (1) dendritic H-resonance, caused by h/HCN-channels, filters signals propagating from soma to dendrite when the membrane potential is close to rest; and (2) somatic M-resonance, caused by M/Kv7/KCNQ and persistent Na(+) (NaP) channels, filters signals propagating from dendrite to soma when the membrane potential approaches spike threshold. Hippocampal pyramidal cells participate in theta network oscillations during behavior, and we suggest that that these dual, polarized theta resonance mechanisms may convey voltage-dependent tuning of theta-mediated neural coding in the entorhinal/hippocampal system during locomotion, spatial navigation, memory, and sleep.

Olfactory receptor neurons use gain control and complementary kinetics to encode intermittent odorant stimuli

PubMed Central

Gorur-Shandilya, Srinivas; Demir, Mahmut; Long, Junjiajia; Clark, Damon A; Emonet, Thierry

2017-01-01

Insects find food and mates by navigating odorant plumes that can be highly intermittent, with intensities and durations that vary rapidly over orders of magnitude. Much is known about olfactory responses to pulses and steps, but it remains unclear how olfactory receptor neurons (ORNs) detect the intensity and timing of natural stimuli, where the absence of scale in the signal makes detection a formidable olfactory task. By stimulating Drosophila ORNs in vivo with naturalistic and Gaussian stimuli, we show that ORNs adapt to stimulus mean and variance, and that adaptation and saturation contribute to naturalistic sensing. Mean-dependent gain control followed the Weber-Fechner relation and occurred primarily at odor transduction, while variance-dependent gain control occurred at both transduction and spiking. Transduction and spike generation possessed complementary kinetic properties, that together preserved the timing of odorant encounters in ORN spiking, regardless of intensity. Such scale-invariance could be critical during odor plume navigation. DOI: http://dx.doi.org/10.7554/eLife.27670.001 PMID:28653907

Glucose rapidly induces different forms of excitatory synaptic plasticity in hypothalamic POMC neurons.

PubMed

Hu, Jun; Jiang, Lin; Low, Malcolm J; Rui, Liangyou

2014-01-01

Hypothalamic POMC neurons are required for glucose and energy homeostasis. POMC neurons have a wide synaptic connection with neurons both within and outside the hypothalamus, and their activity is controlled by a balance between excitatory and inhibitory synaptic inputs. Brain glucose-sensing plays an essential role in the maintenance of normal body weight and metabolism; however, the effect of glucose on synaptic transmission in POMC neurons is largely unknown. Here we identified three types of POMC neurons (EPSC(+), EPSC(-), and EPSC(+/-)) based on their glucose-regulated spontaneous excitatory postsynaptic currents (sEPSCs), using whole-cell patch-clamp recordings. Lowering extracellular glucose decreased the frequency of sEPSCs in EPSC(+) neurons, but increased it in EPSC(-) neurons. Unlike EPSC(+) and EPSC(-) neurons, EPSC(+/-) neurons displayed a bi-phasic sEPSC response to glucoprivation. In the first phase of glucoprivation, both the frequency and the amplitude of sEPSCs decreased, whereas in the second phase, they increased progressively to the levels above the baseline values. Accordingly, lowering glucose exerted a bi-phasic effect on spontaneous action potentials in EPSC(+/-) neurons. Glucoprivation decreased firing rates in the first phase, but increased them in the second phase. These data indicate that glucose induces distinct excitatory synaptic plasticity in different subpopulations of POMC neurons. This synaptic remodeling is likely to regulate the sensitivity of the melanocortin system to neuronal and hormonal signals.

Finding and recognizing objects in natural scenes: complementary computations in the dorsal and ventral visual systems

PubMed Central

Rolls, Edmund T.; Webb, Tristan J.

2014-01-01

Searching for and recognizing objects in complex natural scenes is implemented by multiple saccades until the eyes reach within the reduced receptive field sizes of inferior temporal cortex (IT) neurons. We analyze and model how the dorsal and ventral visual streams both contribute to this. Saliency detection in the dorsal visual system including area LIP is modeled by graph-based visual saliency, and allows the eyes to fixate potential objects within several degrees. Visual information at the fixated location subtending approximately 9° corresponding to the receptive fields of IT neurons is then passed through a four layer hierarchical model of the ventral cortical visual system, VisNet. We show that VisNet can be trained using a synaptic modification rule with a short-term memory trace of recent neuronal activity to capture both the required view and translation invariances to allow in the model approximately 90% correct object recognition for 4 objects shown in any view across a range of 135° anywhere in a scene. The model was able to generalize correctly within the four trained views and the 25 trained translations. This approach analyses the principles by which complementary computations in the dorsal and ventral visual cortical streams enable objects to be located and recognized in complex natural scenes. PMID:25161619

Effects of an Environmentally-relevant Mixture of Pyrethroid Insecticides on Spontaneous Activity in Primary Cortical Networks on Microelectrode Arrays

EPA Science Inventory

Pyrethroid insecticides exert their insecticidal and toxicological effects primarily by disrupting voltage-gated sodium channel (VGSC) function, resulting in altered neuronal excitability. Numerous studies of individual pyrethroids have characterized effects on mammalian VGSC fun...

In utero exposure to dioxin causes neocortical dysgenesis through the actions of p27Kip1

PubMed Central

Mitsuhashi, Takayuki; Yonemoto, Junzo; Sone, Hideko; Kosuge, Yasuhiro; Kosaki, Kenjiro; Takahashi, Takao

2010-01-01

Dioxins have been reported to exert various adverse effects, including cell-cycle dysregulation in vitro and impairment of spatial learning and memory after in utero exposure in rodents. Furthermore, children born to mothers who are exposed to dioxin analogs polychlorinated dibenzofurans or polychlorinated biphenyls have developmental impairments in cognitive functions. Here, we show that in utero exposure to dioxins in mice alters differentiation patterns of neural progenitors and leads to decreased numbers of non-GABAergic neurons and thinner deep neocortical layers. This reduction in number of non-GABAergic neurons is assumed to be caused by accumulation of cyclin-dependent kinase inhibitor p27Kip1 in nuclei of neural progenitors. Lending support to this presumption, mice lacking p27Kip1 are not susceptible to in utero dioxin exposure. These results show that environmental pollutants may affect neocortical histogenesis through alterations of functions of specific gene(s)/protein(s) (in our case, dioxins), exerting adverse effects by altering functions of p27Kip1. PMID:20805476

Neuroprotective actions of the synthetic estrogen 17alpha-ethynylestradiol in the hippocampus.

PubMed

Picazo, Ofir; Becerril-Montes, Adriana; Huidobro-Perez, Delia; Garcia-Segura, Luis M

2010-07-01

17alpha-ethynylestradiol (EE2), a major constituent of many oral contraceptives, is similar in structure to 17beta-estradiol, which has neuroprotective properties in several animal models. This study explored the potential neuroprotective actions of EE2 against kainic and quinolinic acid toxicity in the hippocampus of adult ovariectomized Wistar rats. A decrease in the number of Nissl-stained neurons and the induction of vimentin immunoreactivity in astrocytes was observed in the hilus of the dentate gyrus of the hippocampus after the administration of either kainic acid or quinolinic acid. EE2 prevented the neuronal loss and the induction of vimentin immunoreactivity induced by kainic acid at low (1 microg/rat) and high (10-100 microg/rat) doses and exerted a protection against quinolinic acid toxicity at a low dose (1 microg/rat) only. These observations demonstrate that EE2 exerts neuroprotective actions against excitotoxic insults. This finding is relevant for the design of new neuroprotective estrogenic compounds.

4,4'-Diisothiocyanatostilbene-2,2'-disulfonic acid attenuates spontaneous recurrent seizures and vasogenic edema following lithium-pilocarpine induced status epilepticus.

PubMed

Yang, Tingting; Lin, Zhenzhou; Xie, Ling; Wang, Yao; Pan, Suyue

2017-07-13

Vasogenic edema induced by blood brain barrier disruption and neuronal loss play an important role in the epileptogenic process. 4,4'- diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) is a commonly used anion channel inhibitor that has been reported to exert an anticonvulsant effect in rat hippocampus in vitro. The present study aimed to investigate whether DIDS could prevent epileptogenic process in rat lithium-pilocarpine model of temporal lobe epilepsy. The tight junction proteins and serum extravasation were examined in the piriform cortex 3days after status epilepticus. The findings showed that status epilepticus induced vasogenic edema. Based on these findings, rats were intracerebroventricularly infused with saline and DIDS 1 week after surgery, DIDS reduced vasogenic edema and prevented neuronal loss following status epilepticus in the piriform cortex. Moreover, spontaneous recurrent seizures were recorded by continuous video monitoring. DIDS significantly reduced the frequency and duration of spontaneous recurrent seizures from day 28 to day 42 post status epilepticus. These findings demonstrated that DIDS attenuated vasogenic edema and neuronal apoptosis and might exert disease-modifying effect in animal model of temporal lobe epilepsy. These results explored a novel therapeutic strategy for treatment of epilepsy. Copyright © 2017 Elsevier B.V. All rights reserved.

Neuroprotective Effects of Citicoline in in Vitro Models of Retinal Neurodegeneration

PubMed Central

Matteucci, Andrea; Varano, Monica; Gaddini, Lucia; Mallozzi, Cinzia; Villa, Marika; Pricci, Flavia; Malchiodi-Albedi, Fiorella

2014-01-01

In recent years, citicoline has been the object of remarkable interest as a possible neuroprotectant. The aim of this study was to investigate if citicoline affected cell survival in primary retinal cultures and if it exerted neuroprotective activity in conditions modeling retinal neurodegeneration. Primary retinal cultures, obtained from rat embryos, were first treated with increasing concentrations of citicoline (up to 1000 μM) and analyzed in terms of apoptosis and caspase activation and characterized by immunocytochemistry to identify neuronal and glial cells. Subsequently, excitotoxic concentration of glutamate or High Glucose-containing cell culture medium (HG) was administered as well-known conditions modeling neurodegeneration. Glutamate or HG treatments were performed in the presence or not of citicoline. Neuronal degeneration was evaluated in terms of apoptosis and loss of synapses. The results showed that citicoline did not cause any damage to the retinal neuroglial population up to 1000 μM. At the concentration of 100 μM, it was able to counteract neuronal cell damage both in glutamate- and HG-treated retinal cultures by decreasing proapoptotic effects and contrasting synapse loss. These data confirm that citicoline can efficiently exert a neuroprotective activity. In addition, the results suggest that primary retinal cultures, under conditions inducing neurodegeneration, may represent a useful system to investigate citicoline neuroprotective mechanisms. PMID:24736780

Distemper virus encephalitis exerts detrimental effects on hippocampal neurogenesis.

PubMed

von Rüden, E-L; Avemary, J; Zellinger, C; Algermissen, D; Bock, P; Beineke, A; Baumgärtner, W; Stein, V M; Tipold, A; Potschka, H

2012-08-01

Despite knowledge about the impact of brain inflammation on hippocampal neurogenesis, data on the influence of virus encephalitis on dentate granule cell neurogenesis are so far limited. Canine distemper is considered an interesting model of virus encephalitis, which can be associated with a chronic progressing disease course and can cause symptomatic seizures. To determine the impact of canine distemper virus (CDV) infection on hippocampal neurogenesis, we compared post-mortem tissue from dogs with infection with and without seizures, from epileptic dogs with non-viral aetiology and from dogs without central nervous system diseases. The majority of animals with infection and with epilepsy of non-viral aetiology exhibited neuronal progenitor numbers below the age average in controls. Virus infection with and without seizures significantly decreased the mean number of neuronal progenitor cells by 43% and 76% as compared to age-matched controls. Ki-67 labelling demonstrated that hippocampal cell proliferation was neither affected by infection nor by epilepsy of non-viral aetiology. Analysis of CDV infection in cells expressing caspase-3, doublecortin or Ki-67 indicated that infection of neuronal progenitor cells is extremely rare and suggests that infection might damage non-differentiated progenitor cells, hamper neuronal differentiation and promote glial differentiation. A high inter-individual variance in the number of lectin-reactive microglial cells was evident in dogs with distemper infection. Statistical analyses did not reveal a correlation between the number of lectin-reactive microglia cells and neuronal progenitor cells. Our data demonstrate that virus encephalitis with and without seizures can exert detrimental effects on hippocampal neurogenesis, which might contribute to long-term consequences of the disease. The lack of a significant impact of distemper virus on Ki-67-labelled cells indicates that the infection affected neuronal differentiation and survival of newborn cells rather than hippocampal cell proliferation. © 2011 The Authors. Neuropathology and Applied Neurobiology © 2011 British Neuropathological Society.

Ultrastructure of spines and associated terminals on brainstem neurons controlling auditory input

PubMed Central

Brown, M. Christian; Lee, Daniel J.; Benson, Thane E.

2013-01-01

Spines are unique cellular appendages that isolate synaptic input to neurons and play a role in synaptic plasticity. Using the electron microscope, we studied spines and their associated synaptic terminals on three groups of brainstem neurons: tensor tympani motoneurons, stapedius motoneurons, and medial olivocochlear neurons, all of which exert reflexive control of processes in the auditory periphery. These spines are generally simple in shape; they are infrequent and found on the somata as well as the dendrites. Spines do not differ in volume among the three groups of neurons. In all cases, the spines are associated with a synaptic terminal that engulfs the spine rather than abuts its head. The positions of the synapses are variable, and some are found at a distance from the spine, suggesting that the isolation of synaptic input is of diminished importance for these spines. Each group of neurons receives three common types of synaptic terminals. The type of terminal associated with spines of the motoneurons contains pleomorphic vesicles, whereas the type associated with spines of olivocochlear neurons contains large round vesicles. Thus, spine-associated terminals in the motoneurons appear to be associated with inhibitory processes but in olivocochlear neurons they are associated with excitatory processes. PMID:23602963

Direct activation of sleep-promoting VLPO neurons by volatile anesthetics contributes to anesthetic hypnosis.

PubMed

Moore, Jason T; Chen, Jingqiu; Han, Bo; Meng, Qing Cheng; Veasey, Sigrid C; Beck, Sheryl G; Kelz, Max B

2012-11-06

Despite seventeen decades of continuous clinical use, the neuronal mechanisms through which volatile anesthetics act to produce unconsciousness remain obscure. One emerging possibility is that anesthetics exert their hypnotic effects by hijacking endogenous arousal circuits. A key sleep-promoting component of this circuitry is the ventrolateral preoptic nucleus (VLPO), a hypothalamic region containing both state-independent neurons and neurons that preferentially fire during natural sleep. Using c-Fos immunohistochemistry as a biomarker for antecedent neuronal activity, we show that isoflurane and halothane increase the number of active neurons in the VLPO, but only when mice are sedated or unconscious. Destroying VLPO neurons produces an acute resistance to isoflurane-induced hypnosis. Electrophysiological studies prove that the neurons depolarized by isoflurane belong to the subpopulation of VLPO neurons responsible for promoting natural sleep, whereas neighboring non-sleep-active VLPO neurons are unaffected by isoflurane. Finally, we show that this anesthetic-induced depolarization is not solely due to a presynaptic inhibition of wake-active neurons as previously hypothesized but rather is due to a direct postsynaptic effect on VLPO neurons themselves arising from the closing of a background potassium conductance. Cumulatively, this work demonstrates that anesthetics are capable of directly activating endogenous sleep-promoting networks and that such actions contribute to their hypnotic properties. Copyright © 2012 Elsevier Ltd. All rights reserved.

Dietary polyphenols exert neuroprotective effects by attenuating neuronal and astrocytic damage in cerebral ischemia

USDA-ARS?s Scientific Manuscript database

Polyphenols are natural substances with variable phenolic structures and are found in vegetables, fruits, grains, bark, roots, tea, and wine. There are over 8000 polyphenolic structures identified in plants, but edible plants contain only several hundred polyphenolic structures. Recent interest in...

A scalable neural chip with synaptic electronics using CMOS integrated memristors.

PubMed

Cruz-Albrecht, Jose M; Derosier, Timothy; Srinivasa, Narayan

2013-09-27

The design and simulation of a scalable neural chip with synaptic electronics using nanoscale memristors fully integrated with complementary metal-oxide-semiconductor (CMOS) is presented. The circuit consists of integrate-and-fire neurons and synapses with spike-timing dependent plasticity (STDP). The synaptic conductance values can be stored in memristors with eight levels, and the topology of connections between neurons is reconfigurable. The circuit has been designed using a 90 nm CMOS process with via connections to on-chip post-processed memristor arrays. The design has about 16 million CMOS transistors and 73 728 integrated memristors. We provide circuit level simulations of the entire chip performing neuronal and synaptic computations that result in biologically realistic functional behavior.

Motor neuron cell-nonautonomous rescue of spinal muscular atrophy phenotypes in mild and severe transgenic mouse models

PubMed Central

Liu, Ying Hsiu; Sahashi, Kentaro; Rigo, Frank; Bennett, C. Frank

2015-01-01

Survival of motor neuron (SMN) deficiency causes spinal muscular atrophy (SMA), but the pathogenesis mechanisms remain elusive. Restoring SMN in motor neurons only partially rescues SMA in mouse models, although it is thought to be therapeutically essential. Here, we address the relative importance of SMN restoration in the central nervous system (CNS) versus peripheral tissues in mouse models using a therapeutic splice-switching antisense oligonucleotide to restore SMN and a complementary decoy oligonucleotide to neutralize its effects in the CNS. Increasing SMN exclusively in peripheral tissues completely rescued necrosis in mild SMA mice and robustly extended survival in severe SMA mice, with significant improvements in vulnerable tissues and motor function. Our data demonstrate a critical role of peripheral pathology in the mortality of SMA mice and indicate that peripheral SMN restoration compensates for its deficiency in the CNS and preserves motor neurons. Thus, SMA is not a cell-autonomous defect of motor neurons in SMA mice. PMID:25583329

Estrogen receptors in neuropeptide Y neurons: at the crossroads of feeding and reproduction.

PubMed

Acosta-Martinez, Maricedes; Horton, Teresa; Levine, Jon E

2007-03-01

Hypothalamic neuropeptide Y (NPY) neurons function as physiological integrators in at least two different neuroendocrine systems - one governing feeding and the other controlling reproduction. Estrogen might modulate both systems by regulating NPY gene expression; it might reduce food intake by suppressing NPY expression, and evoke reproductive hormone surges by stimulating it. How can estrogen exert opposing effects in an ostensibly homogeneous NPY neuronal population? Recent work with immortalized NPY-producing cells suggests that the ratio of estrogen receptor alpha:estrogen receptor beta can determine the direction and temporal pattern of transcriptional responses to estrogen. Because this ratio might itself be physiologically regulated, these findings provide one explanation for multiple neuropeptidergic responses to a single steroid hormone.

Distinct Mechanisms Produce Functionally Complementary Actions of Neuropeptides that are Structurally Related but Derived from Different Precursors

PubMed Central

Vilim, F.S.; Sasaki, K.; Rybak, J.; Alexeeva, V.; Cropper, E.; Jing, J.; Orekhova, I.V.; Brezina, V.; Price, D.; Romanova, E.V.; Rubakhin, S.S.; Hatcher, N.; Sweedler, J.V.; Weiss, K.R.

2010-01-01

Many bioactive neuropeptides containing RFamide at their C-terminus have been described in both invertebrates and vertebrates. To obtain insight into the functional logic of RFamide signaling, we investigate it here in the feeding system of Aplysia. We focus on the expression, localization, and actions of two families of RFamide peptides, the FRFamides and FMRFamide, in the central neuronal circuitry and the peripheral musculature that generate the feeding movements. We describe the cloning of the FRFamide precursor protein and show that the FRFamides and FMRFamide are derived from different precursors. We map the expression of the FRFamide and FMRFamide precursors in the feeding circuitry using in-situ hybridization and immunostaining, and confirm proteolytic processing of the FRFamide precursor by mass spectrometry. We show that the two precursors are expressed in different populations of sensory neurons in the feeding system. In a representative feeding muscle, we demonstrate the presence of both FRFamides and FMRFamide and their release, probably from the processes of the sensory neurons in the muscle. Both centrally and in the periphery, the FRFamides and FMRFamide act in distinct ways, apparently through distinct mechanisms, that nevertheless, from an overall functional perspective, their actions are complementary. Together, the FRFamides and FMRFamide convert feeding motor programs from ingestive to egestive, and depress feeding muscle contractions. We conclude that these structurally related peptides, even though derived from different precursors, expressed in different neurons, and acting through different mechanisms, remain related to each other in the functional roles that they play in the system. PMID:20053896

First-spike latency in Hodgkin's three classes of neurons.

PubMed

Wang, Hengtong; Chen, Yueling; Chen, Yong

2013-07-07

We study the first-spike latency (FSL) in Hodgkin's three classes of neurons with the Morris-Lecar neuron model. It is found that all the three classes of neurons can encode an external stimulus into FSLs. With DC inputs, the FSLs of all of the neurons decrease with input intensity. With input current decreased to the threshold, class 1 neurons show an arbitrary long FSL whereas class 2 and 3 neurons exhibit the short-limit FSLs. When the input current is sinusoidal, the amplitude, frequency and initial phase can be encoded by all the three classes of neurons. The FSLs of all of the neurons decrease with the input amplitude and frequency. When the input frequency is too high, all of the neurons respond with infinite FSLs. When the initial phase increases, the FSL decreases and then jumps to a maximal value and finally decreases linearly. With changes in the input parameters, the FSLs of the class 1 and 2 neurons exhibit similar properties. However, the FSL of the class 3 neurons became slightly longer and only produces responses for a narrow range of initial phase if input frequencies are low. Moreover, our results also show that the FSL and firing rate responses are mutually independent processes and that neurons can encode an external stimulus into different FSLs and firing rates simultaneously. This finding is consistent with the current theory of dual or multiple complementary coding mechanisms. Copyright © 2013 Elsevier Ltd. All rights reserved.

Microfluidic measurement of effects of ACF7/MACF1 gene on the mechanics of primary cortical neurons

NASA Astrophysics Data System (ADS)

Lee, Donghee; Ka, Minhan; Kim, Woo-Yang; Ryu, Sangjin

2014-03-01

Actin filaments and microtubules play important roles in determining the mechanics of cells, and ACF7/MACF1 (Actin Crosslinking Family 7/Microtubule And Actin Crosslinking Factor 1) gene seems to be closely related to connections between actin filaments and microtubules. To identify such roles of the ACF7/MACF1 gene of primary cortical neurons, we isolated neuronal cells from the cerebral cortex of the embryonic mouse brain, which is important in memory, language and perception. We exerted viscous shear flow to normal neuronal cells and ACF7/MACF1 gene knockout neuronal cells using rectangular microfluidic channels. While changing viscous shear stress on the cells, we recorded changes in the morphology of the two cell types using video microscopy. Having analyzed the deformation of the cells, we could quantitatively correlate differences in the morphological change between the both normal and ACF7/MACF1 gene knockout neuronal cells to the applied shear force, which will contribute toward identifying cell mechanical roles of the ACF7/MACF1 gene.

BDNF - A key player in cardiovascular system.

PubMed

Pius-Sadowska, Ewa; Machaliński, Bogusław

2017-09-01

Neurotrophins (NTs) were first identified as target-derived survival factors for neurons of the central and peripheral nervous system (PNS). They are known to control neural cell fate, development and function. Independently of their neuronal properties, NTs exert unique cardiovascular activity. The heart is innervated by sensory, sympathetic and parasympathetic neurons, which require NTs during early development and in the establishment of mature properties, contributing to the maintenance of cardiovascular homeostasis. The identification of molecular mechanisms regulated by NTs and involved in the crosstalk between cardiac sympathetic nerves, cardiomyocytes, cardiac fibroblasts, and vascular cells, has a fundamental importance in both normal heart function and disease. The article aims to review the recent data on the effects of Brain-Derived Neurotrophic Factor (BDNF) on various cardiovascular neuronal and non-neuronal functions such as the modulation of synaptic properties of autonomic neurons, axonal outgrowth and sprouting, formation of the vascular and neural networks, smooth muscle migration, and control of endothelial cell survival and cardiomyocytes. Understanding these mechanisms may be crucial for developing novel therapeutic strategies, including stem cell-based therapies. Copyright © 2017 Elsevier Ltd. All rights reserved.

A Negative Allosteric Modulator for α5 Subunit-Containing GABA Receptors Exerts a Rapid and Persistent Antidepressant-Like Action without the Side Effects of the NMDA Receptor Antagonist Ketamine in Mice

PubMed Central

Nelson, Mackenzie E.; Krimmel, Samuel R.; Georgiou, Polymnia; Gould, Todd D.

2017-01-01

Abstract New antidepressant pharmacotherapies that provide rapid relief of depressive symptoms are needed. The NMDA receptor antagonist ketamine exerts rapid antidepressant actions in depressed patients but also side effects that complicate its clinical utility. Ketamine promotes excitatory synaptic strength, likely by producing high-frequency correlated activity in mood-relevant regions of the forebrain. Negative allosteric modulators of GABA-A receptors containing α5 subunits (α5 GABA-NAMs) should also promote high-frequency correlated electroencephalogram (EEG) activity and should therefore exert rapid antidepressant responses. Because α5 subunits display a restricted expression in the forebrain, we predicted that α5 GABA-NAMs would produce activation of principle neurons but exert fewer side effects than ketamine. We tested this hypothesis in male mice and observed that the α5 GABA-NAM MRK-016 exerted an antidepressant-like response in the forced swim test at 1 and 24 h after administration and an anti-anhedonic response after chronic stress in the female urine sniffing test (FUST). Like ketamine, MRK-016 produced a transient increase in EEG γ power, and both the increase in γ power and its antidepressant effects in the forced swim test were blocked by prior administration of the AMPA-type glutamate receptor antagonist 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX). Unlike ketamine, however, MRK-016 produced no impairment of rota-rod performance, no reduction of prepulse inhibition (PPI), no conditioned-place preference (CPP), and no change in locomotion. α5 GABA-NAMs, thus reproduce the rapid antidepressant-like actions of ketamine, perhaps via an AMPA receptor (AMPAR)-dependent increase in coherent neuronal activity, but display fewer potential negative side effects. These compounds thus demonstrate promise as clinically useful fast-acting antidepressants. PMID:28275719

Glucose Rapidly Induces Different Forms of Excitatory Synaptic Plasticity in Hypothalamic POMC Neurons

PubMed Central

Hu, Jun; Jiang, Lin; Low, Malcolm J.; Rui, Liangyou

2014-01-01

Hypothalamic POMC neurons are required for glucose and energy homeostasis. POMC neurons have a wide synaptic connection with neurons both within and outside the hypothalamus, and their activity is controlled by a balance between excitatory and inhibitory synaptic inputs. Brain glucose-sensing plays an essential role in the maintenance of normal body weight and metabolism; however, the effect of glucose on synaptic transmission in POMC neurons is largely unknown. Here we identified three types of POMC neurons (EPSC(+), EPSC(−), and EPSC(+/−)) based on their glucose-regulated spontaneous excitatory postsynaptic currents (sEPSCs), using whole-cell patch-clamp recordings. Lowering extracellular glucose decreased the frequency of sEPSCs in EPSC(+) neurons, but increased it in EPSC(−) neurons. Unlike EPSC(+) and EPSC(−) neurons, EPSC(+/−) neurons displayed a bi-phasic sEPSC response to glucoprivation. In the first phase of glucoprivation, both the frequency and the amplitude of sEPSCs decreased, whereas in the second phase, they increased progressively to the levels above the baseline values. Accordingly, lowering glucose exerted a bi-phasic effect on spontaneous action potentials in EPSC(+/−) neurons. Glucoprivation decreased firing rates in the first phase, but increased them in the second phase. These data indicate that glucose induces distinct excitatory synaptic plasticity in different subpopulations of POMC neurons. This synaptic remodeling is likely to regulate the sensitivity of the melanocortin system to neuronal and hormonal signals. PMID:25127258

Complementary and Alternative Medicine Strategies for Therapeutic Gut Microbiota Modulation in Inflammatory Bowel Disease and their Next-Generation Approaches.

PubMed

Basson, Abigail R; Lam, Minh; Cominelli, Fabio

2017-12-01

The human gut microbiome exerts a major impact on human health and disease, and therapeutic gut microbiota modulation is now a well-advocated strategy in the management of many diseases, including inflammatory bowel disease (IBD). Scientific and clinical evidence in support of complementary and alternative medicine, in targeting intestinal dysbiosis among patients with IBD, or other disorders, has increased dramatically over the past years. Delivery of "artificial" stool replacements for fecal microbiota transplantation (FMT) could provide an effective, safer alternative to that of human donor stool. Nevertheless, optimum timing of FMT administration in IBD remains unexplored, and future investigations are essential. Copyright © 2017 Elsevier Inc. All rights reserved.

Rational modulation of neuronal processing with applied electric fields.

PubMed

Bikson, Marom; Radman, Thomas; Datta, Abhishek

2006-01-01

Traditional approaches to electrical stimulation, using trains of supra-threshold pulses to trigger action potentials, may be replaced or augmented by using 'rational' sub-threshold stimulation protocols that incorporate knowledge of single neuron geometry, inhomogeneous tissue properties, and nervous system information coding. Sub-threshold stimulation, at intensities (well) below those sufficient to trigger action potentials, may none-the-less exert a profound effect on brain function through modulation of concomitant neuronal activity. For example, small DC fields may coherently polarize a network of neurons and thus modulate the simultaneous processing of afferent synaptic input as well as resulting changes in synaptic plasticity. Through 'activity-dependent plasticity', sub-threshold fields may allow specific targeting of pathological networks and are thus particularly suitable to overcome the poor anatomical focus of noninvasive (transcranial) electrical stimulation. Additional approaches to improve targeting in transcranial stimulation using novel electrode configurations are also introduced.

Protective effects of nicergoline against neuronal cell death induced by activated microglia and astrocytes.

PubMed

Mizuno, Tetsuya; Kuno, Reiko; Nitta, Atsumi; Nabeshima, Toshitaka; Zhang, Guiqin; Kawanokuchi, Jun; Wang, Jinyan; Jin, Shijie; Takeuchi, Hideyuki; Suzumura, Akio

2005-12-20

We examined the neuroprotective role of nicergoline in neuron-microglia or neuron-astrocytes co-cultures. Nicergoline, an ergoline derivative, significantly suppressed the neuronal cell death induced by co-culture with activated microglia or astrocytes stimulated with lipopolysaccharide (LPS) and interferon (IFN)-gamma. To elucidate the mechanism by which nicergoline exerts a neuroprotective effect, we examined the production of inflammatory mediators and neurotrophic factors in activated microglia and astrocytes following nicergoline treatment. In microglia stimulated with LPS and IFN-gamma, nicergoline suppressed the production of superoxide anions, interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha in a dose-dependent manner. In astrocytes, nicergoline also suppressed the production of proinflammatory cytokines and enhanced brain-derived neurotrophic factor (BDNF). Thus, nicergoline-mediated neuroprotection resulted primarily from the inhibition of inflammatory mediators and the upregulation of neurotrophic factors by glial cells.

Prenatal exposure to bisphenol A impacts midbrain dopamine neurons and hippocampal spine synapses in non-human primates

PubMed Central

Elsworth, John D.; Jentsch, J. David; VandeVoort, Catherine A.; Roth, Robert H.; Redmond, D. Eugene; Leranth, Csaba

2013-01-01

Prevalent use of bisphenol-A (BPA) in the manufacture of resins, plastics and paper products has led to frequent exposure of most people to this endocrine disruptor. Some rodent studies have suggested that BPA can exert detrimental effects on brain development. However as rodent models cannot be relied on to predict consequences of human exposure to BPA during development, it is important to investigate the effects of BPA on non-human primate brain development. Previous research suggests that BPA preferentially targets dopamine neurons in ventral mesencephalon and glutamatergic neurons in hippocampus, so the present work examined the susceptibility of these systems to low dose BPA exposure at the fetal and juvenile stages of development in non-human primates. Exposure of pregnant rhesus monkeys to relatively low levels of BPA during the final 2 months of gestation, induced abnormalities in fetal ventral mesencephalon and hippocampus. Specifically, light microscopy revealed a decrease in tyrosine hydroxylase-expressing (dopamine) neurons in the midbrain of BPA-exposed fetuses and electron microscopy identified a reduction in spine synapses in the CA1 region of hippocampus. In contrast, administration of BPA to juvenile vervet monkeys (14–18 months of age) was without effect on these indices, or on dopamine and serotonin concentrations in striatum and prefrontal cortex, or on performance of a cognitive task that tests working memory capacity. These data indicate that BPA exerts an age-dependent detrimental impact on primate brain development, at blood levels within the range measured in humans having only environmental contact with BPA. PMID:23337607

Long-Term Treatment with Losartan Attenuates Seizure Activity and Neuronal Damage Without Affecting Behavioral Changes in a Model of Co-morbid Hypertension and Epilepsy.

PubMed

Tchekalarova, Jana D; Ivanova, Natasha; Atanasova, Dimitrina; Pechlivanova, Daniela M; Lazarov, Nikolai; Kortenska, Lidia; Mitreva, Rumiana; Lozanov, Valentin; Stoynev, Alexander

2016-08-01

Over the last 10 years, accumulated experimental and clinical evidence has supported the idea that AT1 receptor subtype is involved in epilepsy. Recently, we have shown that the selective AT1 receptor antagonist losartan attenuates epileptogenesis and exerts neuroprotection in the CA1 area of the hippocampus in epileptic Wistar rats. This study aimed to verify the efficacy of long-term treatment with losartan (10 mg/kg) after kainate-induced status epilepticus (SE) on seizure activity, behavioral and biochemical changes, and neuronal damage in a model of co-morbid hypertension and epilepsy. Spontaneous seizures were video- and EEG-monitored in spontaneously hypertensive rats (SHRs) for a 16-week period after SE. The behavior was analyzed by open field, elevated plus maze, sugar preference test, and forced swim test. The levels of serotonin in the hippocampus and neuronal loss were estimated by HPLC and hematoxylin and eosin staining, respectively. The AT1 receptor antagonism delayed the onset of seizures and alleviated their frequency and duration during and after discontinuation of treatment. Losartan showed neuroprotection mostly in the CA3 area of the hippocampus and the septo-temporal hilus of the dentate gyrus in SHRs. However, the AT1 receptor antagonist did not exert a substantial influence on concomitant with epilepsy behavioral changes and decreased 5-HT levels in the hippocampus. Our results suggest that the antihypertensive therapy with an AT1 receptor blocker might be effective against seizure activity and neuronal damage in a co-morbid hypertension and epilepsy.

Exchanging the minimal cell binding fragments of tetanus neurotoxin in botulinum neurotoxin A and B impacts their toxicity at the neuromuscular junction and central neurons.

PubMed

Höltje, Markus; Schulze, Sebastian; Strotmeier, Jasmin; Mahrhold, Stefan; Richter, Karin; Binz, Thomas; Bigalke, Hans; Ahnert-Hilger, Gudrun; Rummel, Andreas

2013-12-01

The modular four domain structure of clostridial neurotoxins supports the idea to reassemble individual domains from tetanus and botulinum neurotoxins to generate novel molecules with altered pharmacological properties. To treat disorders of the central nervous system drug transporter molecules based on catalytically inactive clostridial neurotoxins circumventing the passage of the blood-brain-barrier are desired. Such molecules can be produced based on the highly effective botulinum neurotoxin serotype A incorporating the retrograde axonal sorting property of tetanus neurotoxin which is supposed to be encoded within its C-terminal cell binding domain HC. The corresponding exchange of the tetanus neurotoxin HC-fragment in botulinum neurotoxin A yielded the novel hybrid molecule AATT which displayed decreased potency at the neuromuscular junction like tetanus neurotoxin but exerted equal activity in cortical neurons compared to botulinum neurotoxin A wild-type. Minimizing the tetanus neurotoxin cell binding domain to its N- or C-terminal half drastically reduced the potencies of AATA and AAAT in cortical neurons indicating that the structural motif mediating sorting of tetanus neurotoxin is predominantly encoded within the entire HC-fragment. However, the reciprocal exchange resulted in TTAA which showed a similar potency as tetanus neurotoxin at the neuromuscular junction indicating that the tetanus neurotoxin portion prevents a high potency as observed for botulinum neurotoxins. In conclusion, clostridial neurotoxin based inactivated drug transporter for targeting central neurons should contain the cell binding domain of tetanus neurotoxin to exert its tropism for the central nervous system. Copyright © 2013 Elsevier Ltd. All rights reserved.

Targeting demyelination and virtual hypoxia with high-dose biotin as a treatment for progressive multiple sclerosis.

PubMed

Sedel, Frédéric; Bernard, Delphine; Mock, Donald M; Tourbah, Ayman

2016-11-01

Progressive multiple sclerosis (MS) is a severely disabling neurological condition, and an effective treatment is urgently needed. Recently, high-dose biotin has emerged as a promising therapy for affected individuals. Initial clinical data have shown that daily doses of biotin of up to 300 mg can improve objective measures of MS-related disability. In this article, we review the biology of biotin and explore the properties of this ubiquitous coenzyme that may explain the encouraging responses seen in patients with progressive MS. The gradual worsening of neurological disability in patients with progressive MS is caused by progressive axonal loss or damage. The triggers for axonal loss in MS likely include both inflammatory demyelination of the myelin sheath and primary neurodegeneration caused by a state of virtual hypoxia within the neuron. Accordingly, targeting both these pathological processes could be effective in the treatment of progressive MS. Biotin is an essential co-factor for five carboxylases involved in fatty acid synthesis and energy production. We hypothesize that high-dose biotin is exerting a therapeutic effect in patients with progressive MS through two different and complementary mechanisms: by promoting axonal remyelination by enhancing myelin production and by reducing axonal hypoxia through enhanced energy production. This article is part of the Special Issue entitled 'Oligodendrocytes in Health and Disease'. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Biological conservation law as an emerging functionality in dynamical neuronal networks.

PubMed

Podobnik, Boris; Jusup, Marko; Tiganj, Zoran; Wang, Wen-Xu; Buldú, Javier M; Stanley, H Eugene

2017-11-07

Scientists strive to understand how functionalities, such as conservation laws, emerge in complex systems. Living complex systems in particular create high-ordered functionalities by pairing up low-ordered complementary processes, e.g., one process to build and the other to correct. We propose a network mechanism that demonstrates how collective statistical laws can emerge at a macro (i.e., whole-network) level even when they do not exist at a unit (i.e., network-node) level. Drawing inspiration from neuroscience, we model a highly stylized dynamical neuronal network in which neurons fire either randomly or in response to the firing of neighboring neurons. A synapse connecting two neighboring neurons strengthens when both of these neurons are excited and weakens otherwise. We demonstrate that during this interplay between the synaptic and neuronal dynamics, when the network is near a critical point, both recurrent spontaneous and stimulated phase transitions enable the phase-dependent processes to replace each other and spontaneously generate a statistical conservation law-the conservation of synaptic strength. This conservation law is an emerging functionality selected by evolution and is thus a form of biological self-organized criticality in which the key dynamical modes are collective.

Biological conservation law as an emerging functionality in dynamical neuronal networks

PubMed Central

Podobnik, Boris; Tiganj, Zoran; Wang, Wen-Xu; Buldú, Javier M.

2017-01-01

Scientists strive to understand how functionalities, such as conservation laws, emerge in complex systems. Living complex systems in particular create high-ordered functionalities by pairing up low-ordered complementary processes, e.g., one process to build and the other to correct. We propose a network mechanism that demonstrates how collective statistical laws can emerge at a macro (i.e., whole-network) level even when they do not exist at a unit (i.e., network-node) level. Drawing inspiration from neuroscience, we model a highly stylized dynamical neuronal network in which neurons fire either randomly or in response to the firing of neighboring neurons. A synapse connecting two neighboring neurons strengthens when both of these neurons are excited and weakens otherwise. We demonstrate that during this interplay between the synaptic and neuronal dynamics, when the network is near a critical point, both recurrent spontaneous and stimulated phase transitions enable the phase-dependent processes to replace each other and spontaneously generate a statistical conservation law—the conservation of synaptic strength. This conservation law is an emerging functionality selected by evolution and is thus a form of biological self-organized criticality in which the key dynamical modes are collective. PMID:29078286

Allatostatin-A neurons inhibit feeding behavior in adult Drosophila.

PubMed

Hergarden, Anne Christina; Tayler, Timothy D; Anderson, David J

2012-03-06

How the brain translates changes in internal metabolic state or perceived food quality into alterations in feeding behavior remains poorly understood. Studies in Drosophila larvae have yielded information about neuropeptides and circuits that promote feeding, but a peptidergic neuron subset whose activation inhibits feeding in adult flies, without promoting metabolic changes that mimic the state of satiety, has not been identified. Using genetically based manipulations of neuronal activity, we show that activation of neurons (or neuroendocrine cells) expressing the neuropeptide allatostatin A (AstA) inhibits or limits several starvation-induced changes in feeding behavior in adult Drosophila, including increased food intake and enhanced behavioral responsiveness to sugar. Importantly, these effects on feeding behavior are observed in the absence of any measurable effects on metabolism or energy reserves, suggesting that AstA neuron activation is likely a consequence, not a cause, of metabolic changes that induce the state of satiety. These data suggest that activation of AstA-expressing neurons promotes food aversion and/or exerts an inhibitory influence on the motivation to feed and implicate these neurons and their associated circuitry in the mechanisms that translate the state of satiety into alterations in feeding behavior.

Allatostatin-A neurons inhibit feeding behavior in adult Drosophila

PubMed Central

Hergarden, Anne Christina; Tayler, Timothy D.; Anderson, David J.

2012-01-01

How the brain translates changes in internal metabolic state or perceived food quality into alterations in feeding behavior remains poorly understood. Studies in Drosophila larvae have yielded information about neuropeptides and circuits that promote feeding, but a peptidergic neuron subset whose activation inhibits feeding in adult flies, without promoting metabolic changes that mimic the state of satiety, has not been identified. Using genetically based manipulations of neuronal activity, we show that activation of neurons (or neuroendocrine cells) expressing the neuropeptide allatostatin A (AstA) inhibits or limits several starvation-induced changes in feeding behavior in adult Drosophila, including increased food intake and enhanced behavioral responsiveness to sugar. Importantly, these effects on feeding behavior are observed in the absence of any measurable effects on metabolism or energy reserves, suggesting that AstA neuron activation is likely a consequence, not a cause, of metabolic changes that induce the state of satiety. These data suggest that activation of AstA-expressing neurons promotes food aversion and/or exerts an inhibitory influence on the motivation to feed and implicate these neurons and their associated circuitry in the mechanisms that translate the state of satiety into alterations in feeding behavior. PMID:22345563

Correlation of fingertip shear force direction with somatosensory cortical activity in monkey

PubMed Central

Fortier-Poisson, Pascal; Langlais, Jean-Sébastien

2015-01-01

To examine the activity of somatosensory cortex (S1) neurons to self-generated shear forces on the index and thumb, two monkeys were trained to grasp a stationary metal tab with a key grip and exert forces without the fingers slipping in one of four orthogonal directions for 1 s. A majority (∼85%) of slowly adapting and rapidly adapting (RA) S1 neurons had activity modulated with shear force direction. The cells were recorded mainly in areas 1 and 2 of the S1, although some area 3b neurons also responded to shear direction or magnitude. The preferred shear vectors were distributed in every direction, with tuning arcs varying from 50° to 170°. Some RA neurons sensitive to dynamic shear force direction also responded to static shear force but within a narrower range, suggesting that the direction of the shear force may influence the adaptation rate. Other neurons were modulated with shear forces in diametrically opposite directions. The directional sensitivity of S1 cortical neurons is consistent with recordings from cutaneous afferents showing that shear direction, even without slip, is a powerful stimulus to S1 neurons. PMID:26467520

Diet and cognition: interplay between cell metabolism and neuronal plasticity

PubMed Central

Gomez-Pinilla, Fernando; Tyagi, Ethika

2014-01-01

Purpose of Study To discuss studies in humans and animals revealing the ability of foods to benefit the brain: new information with regards to mechanisms of action and the treatment of neurological and psychiatric disorders. Recent Findings Dietary factors exert their effects on the brain by affecting molecular events related to the management of energy metabolism and synaptic plasticity. Energy metabolism influences neuronal function, neuronal signaling, and synaptic plasticity, ultimately affecting mental health. Epigenetic regulation of neuronal plasticity appears as an important mechanism by which foods can prolong their effects on long term neuronal plasticity. Summary The prime focus of the discussion is to emphasize the role of cell metabolism as a mediator for the action of foods on the brain. Oxidative stress promotes damage to phospholipids present in the plasma membrane such as the omega-3 fatty acid DHA, disrupting neuronal signaling. Thus, dietary DHA seems crucial for supporting plasma membrane function, interneuronal signaling, and cognition. The dual action of brain-derived neurotrophic factor (BDNF) in neuronal metabolism and synaptic plasticity is crucial for activating signaling cascades under the action of diet and other environmental factors, using mechanisms of epigenetic regulation. PMID:24071781

Multifaceted effects of oligodendroglial exosomes on neurons: impact on neuronal firing rate, signal transduction and gene regulation.

PubMed

Fröhlich, Dominik; Kuo, Wen Ping; Frühbeis, Carsten; Sun, Jyh-Jang; Zehendner, Christoph M; Luhmann, Heiko J; Pinto, Sheena; Toedling, Joern; Trotter, Jacqueline; Krämer-Albers, Eva-Maria

2014-09-26

Exosomes are small membranous vesicles of endocytic origin that are released by almost every cell type. They exert versatile functions in intercellular communication important for many physiological and pathological processes. Recently, exosomes attracted interest with regard to their role in cell-cell communication in the nervous system. We have shown that exosomes released from oligodendrocytes upon stimulation with the neurotransmitter glutamate are internalized by neurons and enhance the neuronal stress tolerance. Here, we demonstrate that oligodendroglial exosomes also promote neuronal survival during oxygen-glucose deprivation, a model of cerebral ischaemia. We show the transfer from oligodendrocytes to neurons of superoxide dismutase and catalase, enzymes which are known to help cells to resist oxidative stress. Additionally, we identify various effects of oligodendroglial exosomes on neuronal physiology. Electrophysiological analysis using in vitro multi-electrode arrays revealed an increased firing rate of neurons exposed to oligodendroglial exosomes. Moreover, gene expression analysis and phosphorylation arrays uncovered differentially expressed genes and altered signal transduction pathways in neurons after exosome treatment. Our study thus provides new insight into the broad spectrum of action of oligodendroglial exosomes and their effects on neuronal physiology. The exchange of extracellular vesicles between neural cells may exhibit remarkable potential to impact brain performance. © 2014 The Author(s) Published by the Royal Society. All rights reserved.

Dopaminergic Neurons Controlling Anterior Pituitary Functions: Anatomy and Ontogenesis in Zebrafish.

PubMed

Fontaine, Romain; Affaticati, Pierre; Bureau, Charlotte; Colin, Ingrid; Demarque, Michaël; Dufour, Sylvie; Vernier, Philippe; Yamamoto, Kei; Pasqualini, Catherine

2015-08-01

Dopaminergic (DA) neurons located in the preoptico-hypothalamic region of the brain exert a major neuroendocrine control on reproduction, growth, and homeostasis by regulating the secretion of anterior pituitary (or adenohypophysis) hormones. Here, using a retrograde tract tracing experiment, we identified the neurons playing this role in the zebrafish. The DA cells projecting directly to the anterior pituitary are localized in the most anteroventral part of the preoptic area, and we named them preoptico-hypophyseal DA (POHDA) neurons. During development, these neurons do not appear before 72 hours postfertilization (hpf) and are the last dopaminergic cell group to differentiate. We found that the number of neurons in this cell population continues to increase throughout life proportionally to the growth of the fish. 5-Bromo-2'-deoxyuridine incorporation analysis suggested that this increase is due to continuous neurogenesis and not due to a phenotypic change in already-existing neurons. Finally, expression profiles of several genes (foxg1a, dlx2a, and nr4a2a/b) were different in the POHDA compared with the adjacent suprachiasmatic DA neurons, suggesting that POHDA neurons develop as a distinct DA cell population in the preoptic area. This study offers some insights into the regional identity of the preoptic area and provides the first bases for future functional genetic studies on the development of DA neurons controlling anterior pituitary functions.

Interleukin-10 Protection against Lipopolysaccharide-Induced Neuro-Inflammation and Neurotoxicity in Ventral Mesencephalic Cultures

PubMed Central

Zhu, Yan; Chen, Xiao; Liu, Zhan; Peng, Yu-Ping; Qiu, Yi-Hua

2015-01-01

Interleukin (IL)-10, an anti-inflammatory cytokine, is expressed in the brain and can inhibit microglial activation. Herein, we utilized lipopolysaccharide (LPS)-induced inflammatory Parkinson’s disease (PD) cell model to determine whether microglia and astrocytes are necessary targets for IL-10 neuroprotection. Primary ventral mesencephalic (VM) cultures with different composition of neurons, microglia and astrocytes were prepared. The cells were exposed to IL-10 (15, 50 or 150 ng/mL) 1 h prior to LPS (50 ng/mL) treatment. LPS induced dopaminergic and non-dopaminergic neuronal loss in VM cultures, VM neuron-enriched cultures, and neuron-microglia co-cultures, but not in neuron-astrocyte co-cultures. IL-10 reduced LPS-induced neuronal loss particularly in single VM neuron cultures. Pro-inflammatory mediators (TNF-α, IL-1β, inducible nitric oxide synthase and cyclooxygenase-2) were upregulated in both neuron-microglia and neuron-astrocyte co-cultures by LPS. In contrast, neurotrophic factors (brain-derived neurotrophic factor, insulin-like growth factor-1 or glial cell-derived neurotrophic factor) were downregulated in neuron-microglia co-cultures, but upregulated in neuron-astrocyte co-cultures by LPS. IL-10 reduced both the increase in production of the pro-inflammatory mediators and the decrease in production of the neurotrophic factors induced by LPS. These results suggest that astrocytes can balance LPS neurotoxicity by releasing more neurotrophic factors and that IL-10 exerts neuroprotective property by an extensive action including direct on neurons and indirect via inhibiting microglial activation. PMID:26729090

Interleukin-10 Protection against Lipopolysaccharide-Induced Neuro-Inflammation and Neurotoxicity in Ventral Mesencephalic Cultures.

PubMed

Zhu, Yan; Chen, Xiao; Liu, Zhan; Peng, Yu-Ping; Qiu, Yi-Hua

2015-12-28

Interleukin (IL)-10, an anti-inflammatory cytokine, is expressed in the brain and can inhibit microglial activation. Herein, we utilized lipopolysaccharide (LPS)-induced inflammatory Parkinson's disease (PD) cell model to determine whether microglia and astrocytes are necessary targets for IL-10 neuroprotection. Primary ventral mesencephalic (VM) cultures with different composition of neurons, microglia and astrocytes were prepared. The cells were exposed to IL-10 (15, 50 or 150 ng/mL) 1 h prior to LPS (50 ng/mL) treatment. LPS induced dopaminergic and non-dopaminergic neuronal loss in VM cultures, VM neuron-enriched cultures, and neuron-microglia co-cultures, but not in neuron-astrocyte co-cultures. IL-10 reduced LPS-induced neuronal loss particularly in single VM neuron cultures. Pro-inflammatory mediators (TNF-α, IL-1β, inducible nitric oxide synthase and cyclooxygenase-2) were upregulated in both neuron-microglia and neuron-astrocyte co-cultures by LPS. In contrast, neurotrophic factors (brain-derived neurotrophic factor, insulin-like growth factor-1 or glial cell-derived neurotrophic factor) were downregulated in neuron-microglia co-cultures, but upregulated in neuron-astrocyte co-cultures by LPS. IL-10 reduced both the increase in production of the pro-inflammatory mediators and the decrease in production of the neurotrophic factors induced by LPS. These results suggest that astrocytes can balance LPS neurotoxicity by releasing more neurotrophic factors and that IL-10 exerts neuroprotective property by an extensive action including direct on neurons and indirect via inhibiting microglial activation.

Microelectrode array-induced neuronal alignment directs neurite outgrowth: analysis using a fast Fourier transform (FFT).

PubMed

Radotić, Viktorija; Braeken, Dries; Kovačić, Damir

2017-12-01

Many studies have shown that the topography of the substrate on which neurons are cultured can promote neuronal adhesion and guide neurite outgrowth in the same direction as the underlying topography. To investigate this effect, isotropic substrate-complementary metal-oxide-semiconductor (CMOS) chips were used as one example of microelectrode arrays (MEAs) for directing neurite growth of spiral ganglion neurons. Neurons were isolated from 5 to 7-day-old rat pups, cultured 1 day in vitro (DIV) and 4 DIV, and then fixed with 4% paraformaldehyde. For analysis of neurite alignment and orientation, fast Fourier transformation (FFT) was used. Results revealed that on the micro-patterned surface of a CMOS chip, neurons orient their neurites along three directional axes at 30, 90, and 150° and that neurites aligned in straight lines between adjacent pillars and mostly followed a single direction while occasionally branching perpendicularly. We conclude that the CMOS substrate guides neurites towards electrodes by means of their structured pillar organization and can produce electrical stimulation of aligned neurons as well as monitoring their neural activities once neurites are in the vicinity of electrodes. These findings are of particular interest for neural tissue engineering with the ultimate goal of developing a new generation of MEA essential for improved electrical stimulation of auditory neurons.

Complementary functions of SK and Kv7/M potassium channels in excitability control and synaptic integration in rat hippocampal dentate granule cells

PubMed Central

Mateos-Aparicio, Pedro; Murphy, Ricardo; Storm, Johan F

2014-01-01

The dentate granule cells (DGCs) form the most numerous neuron population of the hippocampal memory system, and its gateway for cortical input. Yet, we have only limited knowledge of the intrinsic membrane properties that shape their responses. Since SK and Kv7/M potassium channels are key mechanisms of neuronal spiking and excitability control, afterhyperpolarizations (AHPs) and synaptic integration, we studied their functions in DGCs. The specific SK channel blockers apamin or scyllatoxin increased spike frequency (excitability), reduced early spike frequency adaptation, fully blocked the medium-duration AHP (mAHP) after a single spike or spike train, and increased postsynaptic EPSP summation after spiking, but had no effect on input resistance (Rinput) or spike threshold. In contrast, blockade of Kv7/M channels by XE991 increased Rinput, lowered the spike threshold, and increased excitability, postsynaptic EPSP summation, and EPSP–spike coupling, but only slightly reduced mAHP after spike trains (and not after single spikes). The SK and Kv7/M channel openers 1-EBIO and retigabine, respectively, had effects opposite to the blockers. Computational modelling reproduced many of these effects. We conclude that SK and Kv7/M channels have complementary roles in DGCs. These mechanisms may be important for the dentate network function, as CA3 neurons can be activated or inhibition recruited depending on DGC firing rate. PMID:24366266

Glucose-monitoring neurons in the mediodorsal prefrontal cortex.

PubMed

Nagy, Bernadett; Szabó, István; Papp, Szilárd; Takács, Gábor; Szalay, Csaba; Karádi, Zoltán

2012-03-20

The mediodorsal prefrontal cortex (mdPFC), a key structure of the limbic neural circuitry, plays important roles in the central regulation of feeding. As an integrant part of the forebrain dopamine (DA) system, it performs complex roles via interconnections with various brain areas where glucose-monitoring (GM) neurons have been identified. The main goal of the present experiments was to examine whether similar GM neurons exist in the mediodorsal prefrontal cortex. To search for such chemosensory cells here, and to estimate their involvement in the DA circuitry, extracellular single neuron activity of the mediodorsal prefrontal cortex of anesthetized Wistar and Sprague-Dawley rats was recorded by means of tungsten wire multibarreled glass microelectrodes during microelectrophoretic administration of d-glucose and DA. One fourth of the neurons tested changed in firing rate in response to glucose, thus, proved to be elements of the forebrain GM neural network. DA responsive neurons in the mdPFC were found to represent similar proportion of all cells; the glucose-excited units were shown to display excitatory whereas the glucose-inhibited neurons were demonstrated to exert mainly inhibitory responses to dopamine. The glucose-monitoring neurons of the mdPFC and their distinct DA sensitivity are suggested to be of particular significance in adaptive processes of the central feeding control. Copyright © 2012 Elsevier B.V. All rights reserved.

The rostral parvicellular reticular formation neurons mediate lingual nerve input to the rostral ventrolateral medulla.

PubMed

Ishizuka, Ken'Ichi; Satoh, Yoshihide

2012-08-16

In rats that had been anesthetized by urethane-chloralose, we investigated whether neurons in the rostral part of the parvicellular reticular formation (rRFp) mediate lingual nerve input to the rostral ventrolateral medulla (RVLM), which is involved in somato-visceral sensory integration and in controlling the cardiovascular system. We determined the effect of the lingual nerve stimulation on activity of the rRFp neurons that were activated antidromically by stimulation of the RVLM. Stimulation of the lingual trigeminal afferent gave rise to excitatory effects (10/26, 39%), inhibitory effects (6/26, 22%) and no effect (10/26, 39%) on the RVLM-projecting rRFp neurons. About two-thirds of RVLM-projecting rRFp neurons exhibited spontaneous activity; the remaining one-third did not. A half (13/26) of RVLM-projecting rRFp neurons exhibited a pulse-related activity, suggesting that they receive a variety of peripheral and CNS inputs involved in cardiovascular function. We conclude that the lingual trigeminal input exerts excitatory and/or inhibitory effects on a majority (61%) of the RVLM-projecting rRFp neurons, and their neuronal activity may be involved in the cardiovascular responses accompanied by the defense reaction. Copyright © 2012 Elsevier B.V. All rights reserved.

Neuropeptide Y and agouti-related peptide mediate complementary functions of hyperphagia and reduced energy expenditure in leptin receptor deficiency.

PubMed

Luo, Na; Marcelin, Genevieve; Liu, Shun Mei; Schwartz, Gary; Chua, Streamson

2011-03-01

Neuropeptide Y (NPY) and agouti-related peptide (AGRP) can produce hyperphagia, reduce energy expenditure, and promote triglyceride deposition in adipose depots. As these two neuropeptides are coexpressed within the hypothalamic arcuate nucleus and mediate a major portion of the obesity caused by leptin signaling deficiency, we sought to determine whether the two neuropeptides mediated identical or complementary actions. Because of separate neuropeptide receptors and signal transduction mechanisms, there is a possibility of distinct encoding systems for the feeding and energy expenditure aspects of leptin-regulated metabolism. We have genetically added NPY deficiency and/or AGRP deficiency to LEPR deficiency isolated to AGRP cells. Our results indicate that the obesity of LEPR deficiency in AGRP/NPY neurons can produce obesity with either AGRP or NPY alone with AGRP producing hyperphagia while NPY promotes reduced energy expenditure. The absence of both NPY and AGRP prevents the development of obesity attributable to isolated LEPR deficiency in AGRP/NPY neurons. Operant behavioral testing indicated that there were no alterations in the reward for a food pellet from the AGRP-specific LEPR deficiency.

Neuropeptide Y and Agouti-Related Peptide Mediate Complementary Functions of Hyperphagia and Reduced Energy Expenditure in Leptin Receptor Deficiency

PubMed Central

Luo, Na; Marcelin, Genevieve; Liu, Shun Mei; Schwartz, Gary

2011-01-01

Neuropeptide Y (NPY) and agouti-related peptide (AGRP) can produce hyperphagia, reduce energy expenditure, and promote triglyceride deposition in adipose depots. As these two neuropeptides are coexpressed within the hypothalamic arcuate nucleus and mediate a major portion of the obesity caused by leptin signaling deficiency, we sought to determine whether the two neuropeptides mediated identical or complementary actions. Because of separate neuropeptide receptors and signal transduction mechanisms, there is a possibility of distinct encoding systems for the feeding and energy expenditure aspects of leptin-regulated metabolism. We have genetically added NPY deficiency and/or AGRP deficiency to LEPR deficiency isolated to AGRP cells. Our results indicate that the obesity of LEPR deficiency in AGRP/NPY neurons can produce obesity with either AGRP or NPY alone with AGRP producing hyperphagia while NPY promotes reduced energy expenditure. The absence of both NPY and AGRP prevents the development of obesity attributable to isolated LEPR deficiency in AGRP/NPY neurons. Operant behavioral testing indicated that there were no alterations in the reward for a food pellet from the AGRP-specific LEPR deficiency. PMID:21285324

Significance of the Centrally Expressed TRP Channel "Painless" in "Drosophila" Courtship Memory

ERIC Educational Resources Information Center

Sakai, Takaomi; Sato, Shoma; Ishimoto, Hiroshi; Kitamoto, Toshihiro

2013-01-01

Considerable evidence has demonstrated that transient receptor potential (TRP) channels play vital roles in sensory neurons, mediating responses to various environmental stimuli. In contrast, relatively little is known about how TRP channels exert their effects in the central nervous system to control complex behaviors. This is also true for the…

Ethanol-Sensitive Pacemaker Neurons in the Mouse External Globus Pallidus

PubMed Central

Abrahao, Karina P; Chancey, Jessica H; Chan, C Savio; Lovinger, David M

2017-01-01

Although ethanol is one of the most widely used drugs, we still lack a full understanding of which neuronal subtypes are affected by this drug. Pacemaker neurons exert powerful control over brain circuit function, but little is known about ethanol effects on these types of neurons. Neurons in the external globus pallidus (GPe) generate pacemaker activity that controls basal ganglia, circuitry associated with habitual and compulsive drug use. We performed patch-clamp recordings from GPe neurons and found that bath application of ethanol dose-dependently decreased the firing rate of low-frequency GPe neurons, but did not alter the firing of high-frequency neurons. GABA or glutamate receptor antagonists did not block the ethanol effect. The GPe is comprised of a heterogeneous population of neurons. We used Lhx6-EGFP and Npas1-tdTm mice strains to identify low-frequency neurons. Lhx6 and Npas1 neurons exhibited decreased firing with ethanol, but only Npas1 neurons were sensitive to 10 mM ethanol. Large-conductance voltage and Ca2+-activated K+ (BK) channel have a key role in the ethanol effect on GPe neurons, as the application of BK channel inhibitors blocked the ethanol-induced firing decrease. Ethanol also increased BK channel open probability measured in single-channel recordings from Npas1-tdTm neurons. In addition, in vivo electrophysiological recordings from GPe showed that ethanol decreased the firing of a large subset of low-frequency neurons. These findings indicate how selectivity of ethanol effects on pacemaker neurons can occur, and enhance our understanding of the mechanisms contributing to acute ethanol effects on the basal ganglia. PMID:27827370

Neuron-derived IgG protects dopaminergic neurons from insult by 6-OHDA and activates microglia through the FcγR I and TLR4 pathways.

PubMed

Zhang, Jie; Niu, Na; Wang, Mingyu; McNutt, Michael A; Zhang, Donghong; Zhang, Baogang; Lu, Shijun; Liu, Yuqing; Liu, Zhihui

2013-08-01

Oxidative and immune attacks from the environment or microglia have been implicated in the loss of dopaminergic neurons of Parkinson's disease. The role of IgG which is an important immunologic molecule in the process of Parkinson's disease has been unclear. Evidence suggests that IgG can be produced by neurons in addition to its traditionally recognized source B lymphocytes, but its function in neurons is poorly understood. In this study, extensive expression of neuron-derived IgG was demonstrated in dopaminergic neurons of human and rat mesencephalon. With an in vitro Parkinson's disease model, we found that neuron-derived IgG can improve the survival and reduce apoptosis of dopaminergic neurons induced by 6-hydroxydopamine toxicity, and also depress the release of NO from microglia triggered by 6-hydroxydopamine. Expression of TNF-α and IL-10 in microglia was elevated to protective levels by neuron-derived IgG at a physiologic level via the FcγR I and TLR4 pathways and microglial activation could be attenuated by IgG blocking. All these data suggested that neuron-derived IgG may exert a self-protective function by activating microglia properly, and IgG may be involved in maintaining immunity homeostasis in the central nervous system and serve as an active factor under pathological conditions such as Parkinson's disease. Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.

Loss of Functional A-Type Potassium Channels in the Dendrites of CA1 Pyramidal Neurons from a Mouse Model of Fragile X Syndrome

PubMed Central

Routh, Brandy N.; Johnston, Daniel

2013-01-01

Despite the critical importance of voltage-gated ion channels in neurons, very little is known about their functional properties in Fragile X syndrome: the most common form of inherited cognitive impairment. Using three complementary approaches, we investigated the physiological role of A-type K+ currents (IKA) in hippocampal CA1 pyramidal neurons from fmr1-/y mice. Direct measurement of IKA using cell-attached patch-clamp recordings revealed that there was significantly less IKA in the dendrites of CA1 neurons from fmr1-/y mice. Interestingly, the midpoint of activation for A-type K+ channels was hyperpolarized for fmr1-/y neurons compared with wild-type, which might partially compensate for the lower current density. Because of the rapid time course for recovery from steady-state inactivation, the dendritic A-type K+ current in CA1 neurons from both wild-type and fmr1-/y mice is likely mediated by KV4 containing channels. The net effect of the differences in IKA was that back-propagating action potentials had larger amplitudes producing greater calcium influx in the distal dendrites of fmr1-/y neurons. Furthermore, CA1 pyramidal neurons from fmr1-/y mice had a lower threshold for LTP induction. These data suggest that loss of IKA in hippocampal neurons may contribute to dendritic pathophysiology in Fragile X syndrome. PMID:24336711

GLP2: an underestimated signal for improving glycaemic control and insulin sensitivity.

PubMed

Amato, Antonella; Baldassano, Sara; Mulè, Flavia

2016-05-01

Glucagon-like peptide 2 (GLP2) is a proglucagon-derived peptide produced by intestinal enteroendocrine L-cells and by a discrete population of neurons in the brainstem, which projects mainly to the hypothalamus. The main biological actions of GLP2 are related to the regulation of energy absorption and maintenance of mucosal morphology, function and integrity of the intestine; however, recent experimental data suggest that GLP2 exerts beneficial effects on glucose metabolism, especially in conditions related to increased uptake of energy, such as obesity, at least in the animal model. Indeed, mice lacking GLP2 receptor selectively in hypothalamic neurons that express proopiomelanocortin show impaired postprandial glucose tolerance and hepatic insulin resistance (by increased gluconeogenesis). Moreover, GLP2 acts as a beneficial factor for glucose metabolism in mice with high-fat diet-induced obesity. Thus, the aim of this review is to update and summarize current knowledge about the role of GLP2 in the control of glucose homeostasis and to discuss how this molecule could exert protective effects against the onset of related obesity type 2 diabetes. © 2016 Society for Endocrinology.

Structure-activity relationship of sulfated hetero/galactofucan polysaccharides on dopaminergic neuron.

PubMed

Wang, Jing; Liu, Huaide; Jin, Weihua; Zhang, Hong; Zhang, Quanbin

2016-01-01

Parkinson's disease (PD) is associated with progressive loss of dopaminergic neurons and more-widespread neuronal changes that cause complex symptoms. The aim of this study was to investigate the structure-activity relationship of sulfated hetero-polysaccharides (DF1) and sulfated galactofucan polysaccharides (DF2) on dopaminergic neuron in vivo and in vitro. Treatment with samples significantly ameliorated the depletion of both DA and TH-, Bcl-2- and Bax-positive neurons in MPTP-induced PD mice, DF1 showed the highest activity. The in vitro results found that DF1 and DF2 could reverse the decreased mitochondrial activity and the increased LDL release induced by MPP(+) (P<0.01 or P<0.001) which provides further evidence that DF1 and DF2 also exerts a direct protection against the neuronal injury caused by MPP(+). Furthermore, the administration of samples effectively decreased lipid peroxidation and increased the level/activities of GSH, GSH-PX, MDA and CAT in MPTP mice. Thus, the neuron protective effect may be mediated, in part, through antioxidant activity and the prevention of cell apoptosis. The chemical composition of DF1, DF2 and DF differed markedly, the DF1 fraction had the most complex chemical composition and showed the highest neuron protective activity. These results suggest that diverse monosaccharides and uronic acid might contribute to neuron protective activity. Copyright © 2015 Elsevier B.V. All rights reserved.

Gamma-hydroxybutyric acid (GHB) and the mesoaccumbens reward circuit: evidence for GABA(B) receptor-mediated effects.

PubMed

Pistis, M; Muntoni, A L; Pillolla, G; Perra, S; Cignarella, G; Melis, M; Gessa, G L

2005-01-01

Gamma-hydroxybutyric acid (GHB) is a short-chain fatty acid naturally occurring in the mammalian brain, which recently emerged as a major recreational drug of abuse. GHB has multiple neuronal mechanisms including activation of both the GABA(B) receptor, and a distinct GHB-specific receptor. This complex GHB-GABA(B) receptor interaction is probably responsible for the multifaceted pharmacological, behavioral and toxicological profile of GHB. Drugs of abuse exert remarkably similar effects upon reward-related circuits, in particular the mesolimbic dopaminergic system and the nucleus accumbens (NAc). We used single unit recordings in vivo from urethane-anesthetized rats to characterize the effects of GHB on evoked firing in NAc "shell" neurons and on spontaneous activity of antidromically identified dopamine (DA) cells located in the ventral tegmental area. GHB was studied in comparison with the GABA(B) receptor agonist baclofen and antagonist (2S)(+)-5,5-dimethyl-2-morpholineacetic acid (SCH50911). Additionally, we utilized a GHB analog, gamma-(p-methoxybenzil)-gamma-hydroxybutyric acid (NCS-435), devoid of GABA(B) binding properties, but with high affinity for specific GHB binding sites. In common with other drugs of abuse, GHB depressed firing in NAc neurons evoked by the stimulation of the basolateral amygdala. On DA neurons, GHB exerted heterogeneous effects, which were correlated to the baseline firing rate of the cells but led to a moderate stimulation of the DA system. All GHB actions were mediated by GABA(B) receptors, since they were blocked by SCH50911 and were not mimicked by NCS-435. Our study indicates that the electrophysiological profile of GHB is close to typical drugs of abuse: both inhibition of NAc neurons and moderate to strong stimulation of DA transmission are distinctive features of diverse classes of abused drugs. Moreover, it is concluded that addictive and rewarding properties of GHB do not necessarily involve a putative high affinity GHB receptor.

Roles of p62 in BDNF-dependent autophagy suppression and neuroprotection against mitochondrial dysfunction in rat cortical neurons.

PubMed

Wu, Chia-Lin; Chen, Chien-Hui; Hwang, Chi-Shin; Chen, Shang-Der; Hwang, Wei-Chao; Yang, Ding-I

2017-03-01

Previously, we have reported that pre-conditioning of primary rat cortical neurons with brain-derived neurotrophic factor (BDNF) may exert neuroprotective effects against 3-nitropropionic acid (3-NP), a mitochondrial complex II inhibitor. However, the underlying mechanisms, especially potential involvements of autophagy, remain elusive. In this work, we tested the hypothesis that BDNF may suppress 3-NP-induced autophagy to exert its neuroprotective effects by inducing the expression of p62/sequestosome-1 in primary cortical neurons. We found that 3-NP increased total level of microtubule-associated protein 1A/1B-light chain (LC)-3 as well as the LC3-II/LC3-I ratio, an index of autophagy, in primary cortical neurons. BDNF decreased LC3-II/LC3-I ratio and time-dependently induced expression of p62. Knockdown of p62 by siRNA restored LC3-II/LC3-I ratio and increased total LC3 levels associated with BDNF exposure; p62 knockdown also abolished BDNF-dependent neuroprotection against 3-NP. Upstream of p62, we found that BDNF triggered phosphorylation of mammalian target of rapamycin (mTOR) and its downstream mediator p70S6K; importantly, the mTOR inhibitor rapamycin reduced both BDNF-dependent p62 induction as well as 3-NP resistance. BDNF is known to induce c-Jun in cortical neurons. We found that c-Jun knockdown in part attenuated BDNF-mediated p62 induction, whereas p62 knockdown had no significant effects on c-Jun expression. In addition to suppressing p62 induction, rapamycin also partially suppressed BDNF-induced c-Jun expression, but c-Jun knockdown failed to affect mTOR activation. Together, our results suggested that BDNF inhibits 3-NP-induced autophagy via, at least in part, mTOR/c-Jun-dependent induction of p62 expression, together contributing to neuroprotection against mitochondrial inhibition. © 2016 International Society for Neurochemistry.

Implementation of an integrated op-amp based chaotic neuron model and observation of its chaotic dynamics

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

Jung, Jinwoo; Lee, Jewon; Song, Hanjung

2011-03-15

This paper presents a fully integrated circuit implementation of an operational amplifier (op-amp) based chaotic neuron model with a bipolar output function, experimental measurements, and analyses of its chaotic behavior. The proposed chaotic neuron model integrated circuit consists of several op-amps, sample and hold circuits, a nonlinear function block for chaotic signal generation, a clock generator, a nonlinear output function, etc. Based on the HSPICE (circuit program) simulation results, approximated empirical equations for analyses were formulated. Then, the chaotic dynamical responses such as bifurcation diagrams, time series, and Lyapunov exponent were calculated using these empirical equations. In addition, we performedmore » simulations about two chaotic neuron systems with four synapses to confirm neural network connections and got normal behavior of the chaotic neuron such as internal state bifurcation diagram according to the synaptic weight variation. The proposed circuit was fabricated using a 0.8-{mu}m single poly complementary metal-oxide semiconductor technology. Measurements of the fabricated single chaotic neuron with {+-}2.5 V power supplies and a 10 kHz sampling clock frequency were carried out and compared with the simulated results.« less

Selenoprotein T Exerts an Essential Oxidoreductase Activity That Protects Dopaminergic Neurons in Mouse Models of Parkinson's Disease

PubMed Central

Boukhzar, Loubna; Hamieh, Abdallah; Cartier, Dorthe; Tanguy, Yannick; Alsharif, Ifat; Castex, Matthieu; Arabo, Arnaud; Hajji, Sana El; Bonnet, Jean-Jacques; Errami, Mohammed; Falluel-Morel, Anthony; Chagraoui, Abdeslam; Lihrmann, Isabelle

2016-01-01

Abstract Aims: Oxidative stress is central to the pathogenesis of Parkinson's disease (PD), but the mechanisms involved in the control of this stress in dopaminergic cells are not fully understood. There is increasing evidence that selenoproteins play a central role in the control of redox homeostasis and cell defense, but the precise contribution of members of this family of proteins during the course of neurodegenerative diseases is still elusive. Results: We demonstrated first that selenoprotein T (SelT) whose gene disruption is lethal during embryogenesis, exerts a potent oxidoreductase activity. In the SH-SY5Y cell model of dopaminergic neurons, both silencing and overexpression of SelT affected oxidative stress and cell survival. Treatment with PD-inducing neurotoxins such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or rotenone triggered SelT expression in the nigrostriatal pathway of wild-type mice, but provoked rapid and severe parkinsonian-like motor defects in conditional brain SelT-deficient mice. This motor impairment was associated with marked oxidative stress and neurodegeneration and decreased tyrosine hydroxylase activity and dopamine levels in the nigrostriatal system. Finally, in PD patients, we report that SelT is tremendously increased in the caudate putamen tissue. Innovation: These results reveal the activity of a novel selenoprotein enzyme that protects dopaminergic neurons against oxidative stress and prevents early and severe movement impairment in animal models of PD. Conclusions: Our findings indicate that selenoproteins such as SelT play a crucial role in the protection of dopaminergic neurons against oxidative stress and cell death, providing insight into the molecular underpinnings of this stress in PD. Antioxid. Redox Signal. 24, 557–574. PMID:26866473

alpha-Amino-3-hydroxy-5-methyl-4-isoxazole propionate attenuates glutamate-induced caspase-3 cleavage via regulation of glycogen synthase kinase 3beta.

PubMed

Nishimoto, Takaaki; Kihara, Takeshi; Akaike, Akinori; Niidome, Tetsuhiro; Sugimoto, Hachiro

2008-04-01

Preconditioning of sublethal ischemia exhibits neuroprotection against subsequent ischemia-induced neuronal death. It has been indicated that glutamate, an excitatory amino acid, is involved in the pathogenesis of ischemia-induced neuronal death or neurodegeneration. To elucidate whether prestimulation of glutamate receptor could counter ischemia-induced neuronal death or neurodegeneration, we examined the effect of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), an ionotropic subtype of glutamate receptor, on excess glutamate-induced excitotoxicity using primary cortical neuronal cultures. We found that AMPA exerted a neuroprotective effect in a time- and concentration-dependent manner. A blocker of phosphatidylinositol-3 kinase (PI3K), LY294002 (10 microM), significantly attenuated AMPA-induced protection. In addition, Ser473 of Akt/PKB, a downstream target of PI3K, was phosphorylated by AMPA administration (10 microM). Glycogen synthase kinase 3beta (GSK3beta), which has been reported to be inactivated by Akt, was phosphorylated at Ser9 by AMPA. Ser9-phosphorylated GSK3beta or inactivated form would be a key molecule for neuroprotection, insofar as lithium chloride (100 microM) and SB216763 (10 microM), inhibitors of GSK3beta, also induced phosphorylation of GSK3beta at Ser9 and exerted neuroprotection, respectively. Glutamate (100 microM) increased cleaved caspase-3, an apoptosis-related cysteine protease, and caspase-3 inhibitor (Ac-DEVD-CHO; 1 microM) blocked glutamate-induced excitotoxicity in our culture. AMPA (10 microM, 24 hr) and SB216763 (10 microM) prominently decreased glutamate-induced caspase-3 cleavage. These findings suggest that AMPA activates PI3K-Akt and subsequently inhibits GSK3beta and that inactivated GSK3beta attenuates glutamate-induced caspase-3 cleavage and neurotoxicity.

Functional role of ambient GABA in refining neuronal circuits early in postnatal development

PubMed Central

Cellot, Giada; Cherubini, Enrico

2013-01-01

Early in development, γ-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the mature brain, depolarizes and excites targeted neurons by an outwardly directed flux of chloride, resulting from the peculiar balance between the cation-chloride importer NKCC1 and the extruder KCC2. The low expression of KCC2 at birth leads to accumulation of chloride inside the cell and to the equilibrium potential for chloride positive respect to the resting membrane potential. GABA exerts its action via synaptic and extrasynaptic GABAA receptors mediating phasic and tonic inhibition, respectively. Here, recent data on the contribution of “ambient” GABA to the refinement of neuronal circuits in the immature brain have been reviewed. In particular, we focus on the hippocampus, where, prior to the formation of conventional synapses, GABA released from growth cones and astrocytes in a calcium- and SNARE (soluble N-ethylmaleimide-sensitive-factor attachment protein receptor)-independent way, diffuses away to activate in a paracrine fashion extrasynaptic receptors localized on distal neurons. The transient increase in intracellular calcium following the depolarizing action of GABA leads to inhibition of DNA synthesis and cell proliferation. Tonic GABA exerts also a chemotropic action on cell migration. Later on, when synapses are formed, GABA spilled out from neighboring synapses, acting mainly on extrasynaptic α5, β2, β3, and γ containing GABAA receptor subunits, provides the membrane depolarization necessary for principal cells to reach the window where intrinsic bursts are generated. These are instrumental in triggering calcium transients associated with network-driven giant depolarizing potentials which act as coincident detector signals to enhance synaptic efficacy at emerging GABAergic and glutamatergic synapses. PMID:23964205

Amino acids as central synaptic transmitters or modulators in mammalian thermoregulation

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

Bligh, J.

1981-11-01

Of the amino acids that affect the activity of central neurons, aspartate and glutamate (which exert generally excitatory influences) and glycine, taurine, and ..gamma..-aminobutyric acid (GABA) (which generally exert inhibitory influences) are the strongest neurotransmitter candidates. As with other putative transmitter substances, their effects on body temperature when injected into the cerebral ventricles or the preoptic hypothalamus tend to vary within and between species. These effects are uninterpretable without accompanying information regarding effector activity changes and the influences of dose and ambient temperature. Observations necessary for analysis of apparent action have been made in studies of the effects of intracerebroventricularmore » injections of these amino acids into sheep. Aspartate and glutamate have similar excitatory effects on the pathway from cold sensors, whereas taurine and GABA exert inhibitory influences on the neural pathways that activate both heat production and heat loss effectors. Glycine appears to be without effect.« less

Self-referential forces are sufficient to explain different dendritic morphologies

PubMed Central

Memelli, Heraldo; Torben-Nielsen, Benjamin; Kozloski, James

2013-01-01

Dendritic morphology constrains brain activity, as it determines first which neuronal circuits are possible and second which dendritic computations can be performed over a neuron's inputs. It is known that a range of chemical cues can influence the final shape of dendrites during development. Here, we investigate the extent to which self-referential influences, cues generated by the neuron itself, might influence morphology. To this end, we developed a phenomenological model and algorithm to generate virtual morphologies, which are then compared to experimentally reconstructed morphologies. In the model, branching probability follows a Galton–Watson process, while the geometry is determined by “homotypic forces” exerting influence on the direction of random growth in a constrained space. We model three such homotypic forces, namely an inertial force based on membrane stiffness, a soma-oriented tropism, and a force of self-avoidance, as directional biases in the growth algorithm. With computer simulations we explored how each bias shapes neuronal morphologies. We show that based on these principles, we can generate realistic morphologies of several distinct neuronal types. We discuss the extent to which homotypic forces might influence real dendritic morphologies, and speculate about the influence of other environmental cues on neuronal shape and circuitry. PMID:23386828

Microtubule nucleation and organization in dendrites

PubMed Central

Delandre, Caroline; Amikura, Reiko; Moore, Adrian W.

2016-01-01

ABSTRACT Dendrite branching is an essential process for building complex nervous systems. It determines the number, distribution and integration of inputs into a neuron, and is regulated to create the diverse dendrite arbor branching patterns characteristic of different neuron types. The microtubule cytoskeleton is critical to provide structure and exert force during dendrite branching. It also supports the functional requirements of dendrites, reflected by differential microtubule architectural organization between neuron types, illustrated here for sensory neurons. Both anterograde and retrograde microtubule polymerization occur within growing dendrites, and recent studies indicate that branching is enhanced by anterograde microtubule polymerization events in nascent branches. The polarities of microtubule polymerization events are regulated by the position and orientation of microtubule nucleation events in the dendrite arbor. Golgi outposts are a primary microtubule nucleation center in dendrites and share common nucleation machinery with the centrosome. In addition, pre-existing dendrite microtubules may act as nucleation sites. We discuss how balancing the activities of distinct nucleation machineries within the growing dendrite can alter microtubule polymerization polarity and dendrite branching, and how regulating this balance can generate neuron type-specific morphologies. PMID:27097122

In vitro assay using engineered yeast vacuoles for neuronal SNARE-mediated membrane fusion

PubMed Central

Ko, Young-Joon; Lee, Miriam; Kang, KyeongJin; Song, Woo Keun; Jun, Youngsoo

2014-01-01

Intracellular membrane fusion requires not only SNARE proteins but also other regulatory proteins such as the Rab and Sec1/Munc18 (SM) family proteins. Although neuronal SNARE proteins alone can drive the fusion between synthetic liposomes, it remains unclear whether they are also sufficient to induce the fusion of biological membranes. Here, through the use of engineered yeast vacuoles bearing neuronal SNARE proteins, we show that neuronal SNAREs can induce membrane fusion between yeast vacuoles and that this fusion does not require the function of the Rab protein Ypt7p or the SM family protein Vps33p, both of which are essential for normal yeast vacuole fusion. Although excess vacuolar SNARE proteins were also shown to mediate Rab-bypass fusion, this fusion required homotypic fusion and vacuole protein sorting complex, which bears Vps33p and was accompanied by extensive membrane lysis. We also show that this neuronal SNARE-driven vacuole fusion can be stimulated by the neuronal SM protein Munc18 and blocked by botulinum neurotoxin serotype E, a well-known inhibitor of synaptic vesicle fusion. Taken together, our results suggest that neuronal SNARE proteins are sufficient to induce biological membrane fusion, and that this new assay can be used as a simple and complementary method for investigating synaptic vesicle fusion mechanisms. PMID:24821814

ApoER2 Controls Not Only Neuronal Migration in the Intermediate Zone But Also Termination of Migration in the Developing Cerebral Cortex.

PubMed

Hirota, Yuki; Kubo, Ken-Ichiro; Fujino, Takahiro; Yamamoto, Tokuo T; Nakajima, Kazunori

2018-01-01

Neuronal migration contributes to the establishment of mammalian brain. The extracellular protein Reelin sends signals to various downstream molecules by binding to its receptors, the apolipoprotein E receptor 2 (ApoER2) and very low-density lipoprotein receptor and exerts essential roles in the neuronal migration and formation of the layered neocortex. However, the cellular and molecular functions of Reelin signaling in the cortical development are not yet fully understood. Here, to gain insight into the role of Reelin signaling during cortical development, we examined the migratory behavior of Apoer2-deficient neurons in the developing brain. Stage-specific labeling of newborn neurons revealed that the neurons ectopically invaded the marginal zone (MZ) and that neuronal migration of both early- and late-born neurons was disrupted in the intermediate zone (IZ) in the Apoer2 KO mice. Rescue experiments showed that ApoER2 functions both in cell-autonomous and noncell-autonomous manners, that Rap1, integrin, and Akt are involved in the termination of migration beneath the MZ, and that Akt also controls neuronal migration in the IZ downstream of ApoER2. These data indicate that ApoER2 controls multiple processes in neuronal migration, including the early stage of radial migration and termination of migration beneath the MZ in the developing neocortex. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

BDNF heightens the sensitivity of motor neurons to excitotoxic insults through activation of TrkB

NASA Technical Reports Server (NTRS)

Hu, Peter; Kalb, Robert G.; Walton, K. D. (Principal Investigator)

2003-01-01

The survival promoting and neuroprotective actions of brain-derived neurotrophic factor (BDNF) are well known but under certain circumstances this growth factor can also exacerbate excitotoxic insults to neurons. Prior exploration of the receptor through which BDNF exerts this action on motor neurons deflects attention away from p75. Here we investigated the possibility that BDNF acts through the receptor tyrosine kinase, TrkB, to confer on motor neurons sensitivity to excitotoxic challenge. We blocked BDNF activation of TrkB using a dominant negative TrkB mutant or a TrkB function blocking antibody, and found that this protected motor neurons against excitotoxic insult in cultures of mixed spinal cord neurons. Addition of a function blocking antibody to BDNF to mixed spinal cord neuron cultures is also neuroprotective indicating that endogenously produced BDNF participates in vulnerability to excitotoxicity. We next examined the intracellular signaling cascades that are engaged upon TrkB activation. Previously we found that inhibition of the phosphatidylinositide-3'-kinase (PI3'K) pathway blocks BDNF-induced excitotoxic sensitivity. Here we show that expression of a constitutively active catalytic subunit of PI3'K, p110, confers excitotoxic sensitivity (ES) upon motor neurons not incubated with BDNF. Parallel studies with purified motor neurons confirm that these events are likely to be occuring specifically within motor neurons. The abrogation of BDNF's capacity to accentuate excitotoxic insults may make it a more attractive neuroprotective agent.

Astrocytes express specific variants of CaM KII delta and gamma, but not alpha and beta, that determine their cellular localizations.

PubMed

Vallano, M L; Beaman-Hall, C M; Mathur, A; Chen, Q

2000-04-01

Multiple isoforms of type II Ca(2+)-calmodulin-dependent kinase (CaM KII) are composed of two major neuron-specific subunits, designated alpha and beta, and two less well-characterized subunits that are also expressed in non-neuronal tissues, designated delta and gamma. Regulated expression of these 4 gene products, and several variants produced by alternative splicing, shows temporal and regional specificity and influences intracellular targeting. We used immunoblotting and RT-PCR to analyze subunit and variant expression and distribution in cultured cerebellar astrocytes and neurons, and whole cerebellar cortex from rodent brain. The data indicate that: (i) astrocytes express a single splice variant of delta, namely delta(2); (ii) like neurons, astrocytes express two forms of CaM KII gamma; gamma(B) and gamma(A); (iii) these CaM KII variants are enriched in the supernate fraction in astrocytes, and the particulate fraction in neurons; (iv) unlike neurons, astrocytes do not express detectable levels of alpha or beta subunits or their respective splice variants. The results indicate that neurons and astrocytes express distinct CaM KII subunits and variants that localize to distinct subcellular compartments and, by inference, exert distinct cellular functions. Copyright 2000 Wiley-Liss, Inc.

Low-Dose Ethanol Preconditioning Protects Against Oxygen-Glucose Deprivation/Reoxygenation-Induced Neuronal Injury By Activating Large Conductance, Ca2+-Activated K+ Channels In Vitro.

PubMed

Su, Fang; Guo, An-Chen; Li, Wei-Wei; Zhao, Yi-Long; Qu, Zheng-Yi; Wang, Yong-Jun; Wang, Qun; Zhu, Yu-Lan

2017-02-01

Increasing evidence suggests that low to moderate ethanol ingestion protects against the deleterious effects of subsequent ischemia/reperfusion; however, the underlying mechanism has not been elucidated. In the present study, we showed that expression of the neuronal large-conductance, Ca 2+ -activated K + channel (BK Ca ) α-subunit was upregulated in cultured neurons exposed to oxygen-glucose deprivation/reoxygenation (OGD/R) compared with controls. Preconditioning with low-dose ethanol (10 mmol/L) increased cell survival rate in neurons subjected to OGD/R, attenuated the OGD/R-induced elevation of cytosolic Ca 2+ levels, and reduced the number of apoptotic neurons. Western blots revealed that ethanol preconditioning upregulated expression of the anti-apoptotic protein Bcl-2 and downregulated the pro-apoptotic protein Bax. The protective effect of ethanol preconditioning was antagonized by a BK Ca channel inhibitor, paxilline. Inside-out patches in primary neurons also demonstrated the direct activation of the BK Ca channel by 10 mmol/L ethanol. The above results indicated that low-dose ethanol preconditioning exerts its neuroprotective effects by attenuating the elevation of cytosolic Ca 2+ and preventing neuronal apoptosis, and this is mediated by BK Ca channel activation.

Sulforaphane protects cortical neurons against 5-S-cysteinyl-dopamine-induced toxicity through the activation of ERK1/2, Nrf-2 and the upregulation of detoxification enzymes.

PubMed

Vauzour, David; Buonfiglio, Maria; Corona, Giulia; Chirafisi, Joselita; Vafeiadou, Katerina; Angeloni, Cristina; Hrelia, Silvana; Hrelia, Patrizia; Spencer, Jeremy P E

2010-04-01

The degeneration of dopaminergic neurons in the substantia nigra has been linked to the formation of the endogenous neurotoxin 5-S-cysteinyl-dopamine. Sulforaphane (SFN), an isothiocyanate derived from the corresponding precursor glucosinolate found in cruciferous vegetables has been observed to exert a range of biological activities in various cell populations. In this study, we show that SFN protects primary cortical neurons against 5-S-cysteinyl-dopamine induced neuronal injury. Pre-treatment of cortical neurons with SFN (0.01-1 microM) resulted in protection against 5-S-cysteinyl-dopamine-induced neurotoxicity, which peaked at 100 nM. This protection was observed to be mediated by the ability of SFN to modulate the extracellular signal-regulated kinase 1 and 2 and the activation of Kelch-like ECH-associated protein 1/NF-E2-related factor-2 leading to the increased expression and activity of glutathione-S-transferase (M1, M3 and M5), glutathione reductase, thioredoxin reductase and NAD(P)H oxidoreductase 1. These data suggest that SFN stimulates the NF-E2-related factor-2 pathway of antioxidant gene expression in neurons and may protect against neuronal injury relevant to the aetiology of Parkinson's disease.

Distribution of the P2X2 receptor and chemical coding in ileal enteric neurons of obese male mice (ob/ob)

PubMed Central

Mizuno, Márcia Sanae; Crisma, Amanda Rabello; Borelli, Primavera; Schäfer, Bárbara Tavares; Silveira, Mariana Póvoa; Castelucci, Patricia

2014-01-01

AIM: To investigate the colocalization, density and profile of neuronal areas of enteric neurons in the ileum of male obese mice. METHODS: The small intestinal samples of male mice in an obese group (OG) (C57BL/6J ob/ob) and a control group (CG) (+/+) were used. The tissues were analyzed using a double immunostaining technique for immunoreactivity (ir) of the P2X2 receptor, nitric oxide synthase (NOS), choline acetyl transferase (ChAT) and calretinin (Calr). Also, we investigated the density and profile of neuronal areas of the NOS-, ChAT- and Calr-ir neurons in the myenteric plexus. Myenteric neurons were labeled using an NADH-diaphorase histochemical staining method. RESULTS: The analysis demonstrated that the P2X2 receptor was expressed in the cytoplasm and in the nuclear and cytoplasmic membranes only in the CG. Neuronal density values (neuron/cm2) decreased 31% (CG: 6579 ± 837; OG: 4556 ± 407) and 16.5% (CG: 7796 ± 528; OG: 6513 ± 610) in the NOS-ir and calretinin-ir neurons in the OG, respectively (P < 0.05). Density of ChAT-ir (CG: 6200 ± 310; OG: 8125 ± 749) neurons significantly increased 31% in the OG (P < 0.05). Neuron size studies demonstrated that NOS, ChAT, and Calr-ir neurons did not differ significantly between the CG and OG groups. The examination of NADH-diaphorase-positive myenteric neurons revealed an overall similarity between the OG and CG. CONCLUSION: Obesity may exert its effects by promoting a decrease in P2X2 receptor expression and modifications in the density of the NOS-ir, ChAT-ir and CalR-ir myenteric neurons. PMID:25320527

Lack of Intrinsic GABAergic Connections in the Thalamic Reticular Nucleus of the Mouse.

PubMed

Hou, Guoqiang; Smith, Alison G; Zhang, Zhong-Wei

2016-07-06

It is generally thought that neurons in the thalamic reticular nucleus (TRN) form GABAergic synapses with other TRN neurons and that these interconnections are important for the function of the TRN. However, the existence of such intrinsic connections is controversial. We combine two complementary approaches to examine intrinsic GABAergic connections in the TRN of the mouse. We find that optogenetic stimulation of TRN neurons and their axons evokes GABAergic IPSCs in TRN neurons in mice younger than 2 weeks of age but fails to do so after that age. Blocking synaptic release from TRN neurons through conditional deletion of vesicular GABA transporter has no effect on spontaneous IPSCs recorded in TRN neurons aged 2 weeks or older while dramatically reducing GABAergic transmission in thalamic relay neurons. These results demonstrate that except for a short period after birth, the TRN of the mouse lacks intrinsic GABAergic connections. The thalamic reticular nucleus has a critical role in modulating information transfer from the thalamus to the cortex. It has been proposed that neurons in the thalamic reticular nucleus are interconnected through GABAergic synapses and that these connections serve important functions. Our results show that except for the first 2 weeks after birth, the thalamic reticular nucleus of the mouse lacks intrinsic GABAergic connections. Copyright © 2016 the authors 0270-6474/16/367246-07$15.00/0.

Neuronal couplings between retinal ganglion cells inferred by efficient inverse statistical physics methods

PubMed Central

Cocco, Simona; Leibler, Stanislas; Monasson, Rémi

2009-01-01

Complexity of neural systems often makes impracticable explicit measurements of all interactions between their constituents. Inverse statistical physics approaches, which infer effective couplings between neurons from their spiking activity, have been so far hindered by their computational complexity. Here, we present 2 complementary, computationally efficient inverse algorithms based on the Ising and “leaky integrate-and-fire” models. We apply those algorithms to reanalyze multielectrode recordings in the salamander retina in darkness and under random visual stimulus. We find strong positive couplings between nearby ganglion cells common to both stimuli, whereas long-range couplings appear under random stimulus only. The uncertainty on the inferred couplings due to limitations in the recordings (duration, small area covered on the retina) is discussed. Our methods will allow real-time evaluation of couplings for large assemblies of neurons. PMID:19666487

Excitatory motor neurons are local oscillators for backward locomotion

PubMed Central

Guan, Sihui Asuka; Fouad, Anthony D; Meng, Jun; Kawano, Taizo; Huang, Yung-Chi; Li, Yi; Alcaire, Salvador; Hung, Wesley; Lu, Yangning; Qi, Yingchuan Billy; Jin, Yishi; Alkema, Mark; Fang-Yen, Christopher

2018-01-01

Cell- or network-driven oscillators underlie motor rhythmicity. The identity of C. elegans oscillators remains unknown. Through cell ablation, electrophysiology, and calcium imaging, we show: (1) forward and backward locomotion is driven by different oscillators; (2) the cholinergic and excitatory A-class motor neurons exhibit intrinsic and oscillatory activity that is sufficient to drive backward locomotion in the absence of premotor interneurons; (3) the UNC-2 P/Q/N high-voltage-activated calcium current underlies A motor neuron’s oscillation; (4) descending premotor interneurons AVA, via an evolutionarily conserved, mixed gap junction and chemical synapse configuration, exert state-dependent inhibition and potentiation of A motor neuron’s intrinsic activity to regulate backward locomotion. Thus, motor neurons themselves derive rhythms, which are dually regulated by the descending interneurons to control the reversal motor state. These and previous findings exemplify compression: essential circuit properties are conserved but executed by fewer numbers and layers of neurons in a small locomotor network. PMID:29360035

Area-specific temporal control of corticospinal motor neuron differentiation by COUP-TFI

PubMed Central

Tomassy, Giulio Srubek; De Leonibus, Elvira; Jabaudon, Denis; Lodato, Simona; Alfano, Christian; Mele, Andrea; Macklis, Jeffrey D.; Studer, Michèle

2010-01-01

Transcription factors with gradients of expression in neocortical progenitors give rise to distinct motor and sensory cortical areas by controlling the area-specific differentiation of distinct neuronal subtypes. However, the molecular mechanisms underlying this area-restricted control are still unclear. Here, we show that COUP-TFI controls the timing of birth and specification of corticospinal motor neurons (CSMN) in somatosensory cortex via repression of a CSMN differentiation program. Loss of COUP-TFI function causes an area-specific premature generation of neurons with cardinal features of CSMN, which project to subcerebral structures, including the spinal cord. Concurrently, genuine CSMN differentiate imprecisely and do not project beyond the pons, together resulting in impaired skilled motor function in adult mice with cortical COUP-TFI loss-of-function. Our findings indicate that COUP-TFI exerts critical areal and temporal control over the precise differentiation of CSMN during corticogenesis, thereby enabling the area-specific functional features of motor and sensory areas to arise. PMID:20133588

The Role of Rab Proteins in Neuronal Cells and in the Trafficking of Neurotrophin Receptors

PubMed Central

Bucci, Cecilia; Alifano, Pietro; Cogli, Laura

2014-01-01

Neurotrophins are a family of proteins that are important for neuronal development, neuronal survival and neuronal functions. Neurotrophins exert their role by binding to their receptors, the Trk family of receptor tyrosine kinases (TrkA, TrkB, and TrkC) and p75NTR, a member of the tumor necrosis factor (TNF) receptor superfamily. Binding of neurotrophins to receptors triggers a complex series of signal transduction events, which are able to induce neuronal differentiation but are also responsible for neuronal maintenance and neuronal functions. Rab proteins are small GTPases localized to the cytosolic surface of specific intracellular compartments and are involved in controlling vesicular transport. Rab proteins, acting as master regulators of the membrane trafficking network, play a central role in both trafficking and signaling pathways of neurotrophin receptors. Axonal transport represents the Achilles' heel of neurons, due to the long-range distance that molecules, organelles and, in particular, neurotrophin-receptor complexes have to cover. Indeed, alterations of axonal transport and, specifically, of axonal trafficking of neurotrophin receptors are responsible for several human neurodegenerative diseases, such as Huntington’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis and some forms of Charcot-Marie-Tooth disease. In this review, we will discuss the link between Rab proteins and neurotrophin receptor trafficking and their influence on downstream signaling pathways. PMID:25295627

Nicotine Modulates Multiple Regions in the Limbic Stress Network Regulating Activation of Hypophysiotrophic Neurons in Hypothalamic Paraventricular Nucleus

PubMed Central

Yu, Guoliang; Sharp, Burt M.

2012-01-01

Nicotine intake affects CNS responses to stressors. We reported that nicotine self-administration (SA) augmented the hypothalamo-pituitary-adrenal (HPA) stress response, in part due to altered neurotransmission and neuropeptide expression within hypothalamic paraventricular nucleus (PVN). Limbic-PVN interactions involving medial prefrontal cortex, amygdala, bed nucleus of the stria terminalis (BST) greatly impact the HPA stress response. Therefore, we investigated the effects of nicotine SA on stress-induced neuronal activation in limbic-PVN network, using c-Fos protein immunohistochemistry and retrograde tracing. Nicotine decreased stress-induced c-Fos in prelimbic cortex (PrL), anteroventral BST (avBST), and peri-PVN; but increased c-Fos induction in medial amygdala (MeA), locus coeruleus, and PVN. Fluoro-gold (FG) was injected into avBST or PVN, since GABAergic neurons in avBST projecting to PVN corticotrophin-releasing factor (CRF) neurons relay information from both PrL glutamatergic and MeA GABAergic neurons. The stress-induced c-Fos expression in retrograde-labeled FG+ neurons was decreased in PrL by nicotine, but increased in MeA, and also reduced in avBST. Therefore, within limbic-PVN network, nicotine SA exerts selective regional effects on neuronal activation by stress. These findings expand the mechanistic framework by demonstrating altered limbic-BST-PVN interactions underlying the disinhibition of PVN CRF neurons, an essential component of the amplified HPA response to stress by nicotine. PMID:22578217

Decoding brain state transitions in the pedunculopontine nucleus: cooperative phasic and tonic mechanisms

PubMed Central

Petzold, Anne; Valencia, Miguel; Pál, Balázs; Mena-Segovia, Juan

2015-01-01

Cholinergic neurons of the pedunculopontine nucleus (PPN) are most active during the waking state. Their activation is deemed to cause a switch in the global brain activity from sleep to wakefulness, while their sustained discharge may contribute to upholding the waking state and enhancing arousal. Similarly, non-cholinergic PPN neurons are responsive to brain state transitions and their activation may influence some of the same targets of cholinergic neurons, suggesting that they operate in coordination. Yet, it is not clear how the discharge of distinct classes of PPN neurons organize during brain states. Here, we monitored the in vivo network activity of PPN neurons in the anesthetized rat across two distinct levels of cortical dynamics and their transitions. We identified a highly structured configuration in PPN network activity during slow-wave activity that was replaced by decorrelated activity during the activated state (AS). During the transition, neurons were predominantly excited (phasically or tonically), but some were inhibited. Identified cholinergic neurons displayed phasic and short latency responses to sensory stimulation, whereas the majority of non-cholinergic showed tonic responses and remained at high discharge rates beyond the state transition. In vitro recordings demonstrate that cholinergic neurons exhibit fast adaptation that prevents them from discharging at high rates over prolonged time periods. Our data shows that PPN neurons have distinct but complementary roles during brain state transitions, where cholinergic neurons provide a fast and transient response to sensory events that drive state transitions, whereas non-cholinergic neurons maintain an elevated firing rate during global activation. PMID:26582977

Identification of Genes Enriched in GnRH Neurons by Translating Ribosome Affinity Purification and RNAseq in Mice.

PubMed

Burger, Laura L; Vanacker, Charlotte; Phumsatitpong, Chayarndorn; Wagenmaker, Elizabeth R; Wang, Luhong; Olson, David P; Moenter, Suzanne M

2018-04-01

Gonadotropin-releasing hormone (GnRH) neurons are a nexus of fertility regulation. We used translating ribosome affinity purification coupled with RNA sequencing to examine messenger RNAs of GnRH neurons in adult intact and gonadectomized (GDX) male and female mice. GnRH neuron ribosomes were tagged with green fluorescent protein (GFP) and GFP-labeled polysomes isolated by immunoprecipitation, producing one RNA fraction enhanced for GnRH neuron transcripts and one RNA fraction depleted. Complementary DNA libraries were created from each fraction and 50-base, paired-end sequencing done and differential expression (enhanced fraction/depleted fraction) determined with a threshold of >1.5- or <0.66-fold (false discovery rate P ≤ 0.05). A core of ∼840 genes was differentially expressed in GnRH neurons in all treatments, including enrichment for Gnrh1 (∼40-fold), and genes critical for GnRH neuron and/or gonadotrope development. In contrast, non-neuronal transcripts were not enriched or were de-enriched. Several epithelial markers were also enriched, consistent with the olfactory epithelial origins of GnRH neurons. Interestingly, many synaptic transmission pathways were de-enriched, in accordance with relatively low innervation of GnRH neurons. The most striking difference between intact and GDX mice of both sexes was a marked downregulation of genes associated with oxidative phosphorylation and upregulation of glucose transporters in GnRH neurons from GDX mice. This may suggest that GnRH neurons switch to an alternate fuel to increase adenosine triphosphate production in the absence of negative feedback when GnRH release is elevated. Knowledge of the GnRH neuron translatome and its regulation can guide functional studies and can be extended to disease states, such as polycystic ovary syndrome.

NeuronMetrics: Software for Semi-Automated Processing of Cultured-Neuron Images

PubMed Central

Narro, Martha L.; Yang, Fan; Kraft, Robert; Wenk, Carola; Efrat, Alon; Restifo, Linda L.

2007-01-01

Using primary cell culture to screen for changes in neuronal morphology requires specialized analysis software. We developed NeuronMetrics™ for semi-automated, quantitative analysis of two-dimensional (2D) images of fluorescently labeled cultured neurons. It skeletonizes the neuron image using two complementary image-processing techniques, capturing fine terminal neurites with high fidelity. An algorithm was devised to span wide gaps in the skeleton. NeuronMetrics uses a novel strategy based on geometric features called faces to extract a branch-number estimate from complex arbors with numerous neurite-to-neurite contacts, without creating a precise, contact-free representation of the neurite arbor. It estimates total neurite length, branch number, primary neurite number, territory (the area of the convex polygon bounding the skeleton and cell body), and Polarity Index (a measure of neuronal polarity). These parameters provide fundamental information about the size and shape of neurite arbors, which are critical factors for neuronal function. NeuronMetrics streamlines optional manual tasks such as removing noise, isolating the largest primary neurite, and correcting length for self-fasciculating neurites. Numeric data are output in a single text file, readily imported into other applications for further analysis. Written as modules for ImageJ, NeuronMetrics provides practical analysis tools that are easy to use and support batch processing. Depending on the need for manual intervention, processing time for a batch of ~60 2D images is 1.0–2.5 hours, from a folder of images to a table of numeric data. NeuronMetrics’ output accelerates the quantitative detection of mutations and chemical compounds that alter neurite morphology in vitro, and will contribute to the use of cultured neurons for drug discovery. PMID:17270152

NeuronMetrics: software for semi-automated processing of cultured neuron images.

PubMed

Narro, Martha L; Yang, Fan; Kraft, Robert; Wenk, Carola; Efrat, Alon; Restifo, Linda L

2007-03-23

Using primary cell culture to screen for changes in neuronal morphology requires specialized analysis software. We developed NeuronMetrics for semi-automated, quantitative analysis of two-dimensional (2D) images of fluorescently labeled cultured neurons. It skeletonizes the neuron image using two complementary image-processing techniques, capturing fine terminal neurites with high fidelity. An algorithm was devised to span wide gaps in the skeleton. NeuronMetrics uses a novel strategy based on geometric features called faces to extract a branch number estimate from complex arbors with numerous neurite-to-neurite contacts, without creating a precise, contact-free representation of the neurite arbor. It estimates total neurite length, branch number, primary neurite number, territory (the area of the convex polygon bounding the skeleton and cell body), and Polarity Index (a measure of neuronal polarity). These parameters provide fundamental information about the size and shape of neurite arbors, which are critical factors for neuronal function. NeuronMetrics streamlines optional manual tasks such as removing noise, isolating the largest primary neurite, and correcting length for self-fasciculating neurites. Numeric data are output in a single text file, readily imported into other applications for further analysis. Written as modules for ImageJ, NeuronMetrics provides practical analysis tools that are easy to use and support batch processing. Depending on the need for manual intervention, processing time for a batch of approximately 60 2D images is 1.0-2.5 h, from a folder of images to a table of numeric data. NeuronMetrics' output accelerates the quantitative detection of mutations and chemical compounds that alter neurite morphology in vitro, and will contribute to the use of cultured neurons for drug discovery.

Subliminal words durably affect neuronal activity.

PubMed

Gaillard, Raphaël; Cohen, Laurent; Adam, Claude; Clemenceau, Stéphane; Hasboun, Dominique; Baulac, Michel; Willer, Jean-Claude; Dehaene, Stanislas; Naccache, Lionel

2007-10-08

Unconscious mental representations elicited by subliminal stimuli are marked by their fleeting lifetimes, usually below 1 s. Can such evanescent subliminal stimuli, nevertheless, lead to long-lasting learning? To date, evidence suggesting a long-term influence of briefly perceived stimuli on behaviour or brain activity is scarce and questionable. In this study, we used intracranial recordings to provide the first direct demonstration that unconsciously perceived subliminal words could exert long-lasting effects on neuronal signals. When repeating subliminal words over long interstimulus intervals, we observed electrophysiological repetition effects. These unconscious repetition effects suggest that the single presentation of a masked word can durably affect neural architecture.

Disruption of communication between peripheral and central trigeminovascular neurons mediates the antimigraine action of 5HT1B/1D receptor agonists

PubMed Central

Levy, Dan; Jakubowski, Moshe; Burstein, Rami

2004-01-01

Triptans are 5HT1B/1D receptor agonists commonly prescribed for migraine headache. Although originally designed to constrict dilated intracranial blood vessels, the mechanism and site of action by which triptans abort the migraine pain remain unknown. We showed recently that sensitization of peripheral and central trigeminovascular neurons plays an important role in the pathophysiology of migraine pain. Here we examined whether the drug sumatriptan can prevent and/or suppress peripheral and central sensitization by using single-unit recording in our animal model of intracranial pain. We found that sumatriptan effectively prevented the induction of sensitization (i.e., increased spontaneous firing; increased neuronal sensitivity to intracranial mechanical stimuli) in central trigeminovascular neurons (recorded in the dorsal horn), but not in peripheral trigeminovascular neurons (recorded in the trigeminal ganglion). After sensitization was established in both types of neuron, sumatriptan effectively normalized intracranial mechanical sensitivity of central neurons, but failed to reverse such hypersensitivity in peripheral neurons. In both the peripheral and central neurons, the drug failed to attenuate the increased spontaneous activity established during sensitization. These results suggest that neither peripheral nor central trigeminovascular neurons are directly inhibited by sumatriptan. Rather, triptan action appears to be exerted through presynaptic 5HT1B/1D receptors in the dorsal horn to block synaptic transmission between axon terminals of the peripheral trigeminovascular neurons and cell bodies of their central counterparts. We therefore suggest that the analgesic action of triptan can be attained specifically in the absence, but not in the presence, of central sensitization. PMID:15016917

Disruption of communication between peripheral and central trigeminovascular neurons mediates the antimigraine action of 5HT 1B/1D receptor agonists.

PubMed

Levy, Dan; Jakubowski, Moshe; Burstein, Rami

2004-03-23

Triptans are 5HT(1B/1D) receptor agonists commonly prescribed for migraine headache. Although originally designed to constrict dilated intracranial blood vessels, the mechanism and site of action by which triptans abort the migraine pain remain unknown. We showed recently that sensitization of peripheral and central trigeminovascular neurons plays an important role in the pathophysiology of migraine pain. Here we examined whether the drug sumatriptan can prevent and/or suppress peripheral and central sensitization by using single-unit recording in our animal model of intracranial pain. We found that sumatriptan effectively prevented the induction of sensitization (i.e., increased spontaneous firing; increased neuronal sensitivity to intracranial mechanical stimuli) in central trigeminovascular neurons (recorded in the dorsal horn), but not in peripheral trigeminovascular neurons (recorded in the trigeminal ganglion). After sensitization was established in both types of neuron, sumatriptan effectively normalized intracranial mechanical sensitivity of central neurons, but failed to reverse such hypersensitivity in peripheral neurons. In both the peripheral and central neurons, the drug failed to attenuate the increased spontaneous activity established during sensitization. These results suggest that neither peripheral nor central trigeminovascular neurons are directly inhibited by sumatriptan. Rather, triptan action appears to be exerted through presynaptic 5HT(1B/1D) receptors in the dorsal horn to block synaptic transmission between axon terminals of the peripheral trigeminovascular neurons and cell bodies of their central counterparts. We therefore suggest that the analgesic action of triptan can be attained specifically in the absence, but not in the presence, of central sensitization.

Unfavorable effect of levetiracetam on cultured hippocampal neurons after hyperthermic injury.

PubMed

Sendrowski, Krzysztof; Sobaniec, Piotr; Poskrobko, Elżbieta; Rusak, Małgorzata; Sobaniec, Wojciech

2017-06-01

The aim of this study was to examine the viability of neurons and the putative neuroprotective effects of second-generation antiepileptic drug, levetiracetam (LEV), on cultured hippocampal neurons injured by hyperthermia. Primary cultures of rat's hippocampal neurons at 7day in vitro (DIV) were incubated in the presence or absence of LEV in varied concentrations under hyperthermic conditions. Cultures were heated in a temperature of 40°C for 24h or in a temperature of 41°C for 6h. Flow cytometry with Annexin V/PI staining as well as fluorescent microscopy assay were used for counting and establishing neurons as viable, necrotic or apoptotic. Additionally, the release of lactate dehydrogenase (LDH) to the culture medium, as a marker of cell death, was evaluated. Assessment was performed after 9DIV and 10 DIV. Incubation of hippocampal cultures in hyperthermic conditions resulted in statistically significant increase in the number of injured neurons when compared with non-heated control cultures. Intensity of neuronal destruction was dependent on temperature-value. When incubation temperature 40°C was used, over 80% of the population of neurons remained viable after 10 DIV. Under higher temperature 41°C, only less than 60% of neurons were viable after 10 DIV. Both apoptotic and necrotic pathways of neuronal death induced by hyperthermia were confirmed by Annexin V/PI staining. LEV showed no neuroprotective effects in the current model of hyperthermia in vitro. Moreover, drug, especially when used in higher concentrations, exerted unfavorable intensification of aponecrosis of cultured hippocampal neurons. Copyright © 2017. Published by Elsevier Urban & Partner Sp. z o.o.

Neurotensin enhances glutamatergic EPSCs in VTA neurons by acting on different neurotensin receptors.

PubMed

Bose, Poulomee; Rompré, Pierre-Paul; Warren, Richard A

2015-11-01

Neurotensin (NT) is an endogenous neuropeptide that modulates dopamine and glutamate neurotransmission in several limbic regions innervated by neurons located in the ventral tegmental area (VTA). While several studies showed that NT exerted a direct modulation on VTA dopamine neurons less is known about its role in the modulation of glutamatergic neurotransmission in this region. The present study was aimed at characterising the effects of NT on glutamate-mediated responses in different populations of VTA neurons. Using whole cell patch clamp recording technique in horizontal rat brain slices, we measured the amplitude of glutamatergic excitatory post-synaptic currents (EPSCs) evoked by electrical stimulation of VTA afferents before and after application of different concentrations of NT1-13 or its C-terminal fragment, NT8-13. Neurons were classified as either Ih(+) or Ih(-) based on the presence or absence of a hyperpolarisation activated cationic current (Ih). We found that NT1-13 and NT8-13 produced comparable concentration dependent increase in the amplitude of EPSCs in both Ih(+) and Ih(-) neurons. In Ih(+) neurons, the enhancement effect of NT8-13 was blocked by both antagonists, while in Ih(-) neurons it was blocked by the NTS1/NTS2 antagonist, SR142948A, but not the preferred NTS1 antagonist, SR48692. In as much as Ih(-) neurons are non-dopaminergic neurons and Ih(+) neurons represent both dopamine and non-dopamine neurons, we can conclude that NT enhances glutamatergic mediated responses in dopamine, and in a subset of non-dopamine, neurons by acting respectively on NTS1 and an NT receptor other than NTS1. Copyright © 2015 Elsevier Inc. All rights reserved.

Corticosterone affects the differentiation of a neuronal cerebral cortex-derived cell line through modulation of the nicotinic acetylcholine receptor.

PubMed

Baier, C J; Franco, D L; Gallegos, C E; Mongiat, L A; Dionisio, L; Bouzat, C; Caviedes, P; Barrantes, F J

2014-08-22

Chronic exposure to stress hormones has an impact on brain structures relevant to cognition. Nicotinic acetylcholine receptors (AChRs) are involved in numerous cognitive processes including learning and memory formation. In order to better understand the molecular mechanisms of chronic stress-triggered mental disease, the effect of corticosterone (CORT) on the biology of AChRs was studied in the neuronal cell line CNh. We found that chronic treatment with CORT reduced the expression levels of the α7-type neuronal AChR and, to a lesser extent, of α4-AChR. CORT also delayed the acquisition of the mature cell phenotype in CNh cells. Chronic nicotine treatment affected the differentiation of CNh cells and exerted a synergistic effect with CORT, suggesting that AChR could participate in signaling pathways that control the cell cycle. Overexpression of α7-AChR-GFP abolished the CORT effects on the cell cycle and the specific α7-AChR inhibitor, methyllycaconitine, mimicked the proliferative action exerted by CORT. Whole-cell voltage-clamp recordings showed a significant decrease in nicotine-evoked currents in CORT-treated cells. Taken together, these observations indicate that AChRs, and the α7-AChR in particular, could act as modulators of the differentiation of CNh cells and that CORT could impair the acquisition of a mature phenotype by affecting the function of this AChR subtype. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

Influence of respiratory motor neurone activity on human autonomic and haemodynamic rhythms

NASA Technical Reports Server (NTRS)

Gonschorek, A. S.; Lu, L. L.; Halliwill, J. R.; Beightol, L. A.; Taylor, J. A.; Painter, J. A.; Warzel, H.; Eckberg, D. L.

2001-01-01

Although humans hold great advantages over other species as subjects for biomedical research, they also bring major disadvantages. One is that among the many rhythmic physiological signals that can be recorded, there is no sure way to know which individual change precedes another, or which change represents cause and which represents effect. In an attempt to deal with the inherent complexity of research conducted in intact human subjects, we developed and used a structural equation model to analyse responses of healthy young men to pharmacological changes of arterial pressure and graded inspiratory resistance, before and after vagomimetic atropine. Our model yielded a good fit of the experimental data, with a system weighted R2 of 0.77, and suggested that our treatments exerted both direct and indirect influences on the variables we measured. Thus, infusions of nitroprusside and phenylephrine exerted all of their direct effects by lowering and raising arterial pressure; the changes of R-R intervals, respiratory sinus arrhythmia and arterial pressure fluctuations that these drugs provoked, were indirect consequences of arterial pressure changes. The only direct effect of increased inspiratory resistance was augmentation of arterial pressure fluctuations. These results may provide a new way to disentangle and understand responses of intact human subjects to experimental forcings. The principal new insight we derived from our modelling is that respiratory gating of vagal-cardiac motor neurone firing is nearly maximal at usual levels of arterial pressure and inspiratory motor neurone activity.

Retrograde monosynaptic tracing reveals the temporal evolution of inputs onto new neurons in the adult dentate gyrus and olfactory bulb

PubMed Central

Deshpande, Aditi; Bergami, Matteo; Ghanem, Alexander; Conzelmann, Karl-Klaus; Lepier, Alexandra; Götz, Magdalena; Berninger, Benedikt

2013-01-01

Identifying the connectome of adult-generated neurons is essential for understanding how the preexisting circuitry is refined by neurogenesis. Changes in the pattern of connectivity are likely to control the differentiation process of newly generated neurons and exert an important influence on their unique capacity to contribute to information processing. Using a monosynaptic rabies virus-based tracing technique, we studied the evolving presynaptic connectivity of adult-generated neurons in the dentate gyrus (DG) of the hippocampus and olfactory bulb (OB) during the first weeks of their life. In both neurogenic zones, adult-generated neurons first receive local connections from multiple types of GABAergic interneurons before long-range projections become established, such as those originating from cortical areas. Interestingly, despite fundamental similarities in the overall pattern of evolution of presynaptic connectivity, there were notable differences with regard to the development of cortical projections: although DG granule neuron input originating from the entorhinal cortex could be traced starting only from 3 to 5 wk on, newly generated neurons in the OB received input from the anterior olfactory nucleus and piriform cortex already by the second week. This early glutamatergic input onto newly generated interneurons in the OB was matched in time by the equally early innervations of DG granule neurons by glutamatergic mossy cells. The development of connectivity revealed by our study may suggest common principles for incorporating newly generated neurons into a preexisting circuit. PMID:23487772

From receptor balance to rational glucocorticoid therapy.

PubMed

de Kloet, E Ron

2014-08-01

Corticosteroids secreted as end product of the hypothalamic-pituitary-adrenal axis act like a double-edged sword in the brain. The hormones coordinate appraisal processes and decision making during the initial phase of a stressful experience and promote subsequently cognitive performance underlying the management of stress adaptation. This action exerted by the steroids on the initiation and termination of the stress response is mediated by 2 related receptor systems: mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs). The receptor types are unevenly distributed but colocalized in abundance in neurons of the limbic brain to enable these complementary hormone actions. This contribution starts from a historical perspective with the observation that phasic occupancy of GR during ultradian rhythmicity is needed to maintain responsiveness to corticosteroids. Then, during stress, initially MR activation enhances excitability of limbic networks that are engaged in appraisal and emotion regulation. Next, the rising hormone concentration occupies GR, resulting in reallocation of energy to limbic-cortical circuits with a role in behavioral adaptation and memory storage. Upon MR:GR imbalance, dysregulation of the hypothalamic-pituitary-adrenal axis occurs, which can enhance an individual's vulnerability. Imbalance is characteristic for chronic stress experience and depression but also occurs during exposure to synthetic glucocorticoids. Hence, glucocorticoid psychopathology may develop in susceptible individuals because of suppression of ultradian/circadian rhythmicity and depletion of endogenous corticosterone from brain MR. This knowledge generated from testing the balance hypothesis can be translated to a rational glucocorticoid therapy.

Adenosine inhibits activity of hypocretin/orexin neurons via A1 receptor in the lateral hypothalamus: a possible sleep-promoting effect

PubMed Central

Liu, Zhong-Wu; Gao, Xiao-Bing

2006-01-01

Neurons in the lateral hypothalamus (LH) that contain hypocretin/orexin have been established as important promoters of arousal. Deficiencies in the hypocretin/orexin system lead to narcolepsy. The inhibition of hypocretin/orexin neurons by sleep-promoting neurotransmitters has been suggested as one part of the sleep regulation machinery. Adenosine has been identified as a sleep promoter and its role in sleep regulation in the basal forebrain has been well documented. However, the effect of adenosine on arousal-promoting hypocretin/orexin neurons has not been addressed, despite recent evidence that immunocytochemical visualization of adenosine receptors was detected in these neurons. In this study, we examined the hypothesis that adenosine inhibits the activity of hypocretin/orexin neurons by using electrophysiological methods in brain slices from mice expressing green fluorescent protein in hypocretin/orexin neurons. We found that adenosine significantly attenuated the frequency of action potentials without a change in membrane potential in hypocretin/orexin neurons. The adenosine-mediated inhibition is due to depression of excitatory synaptic transmission to hypocretin/orexin neurons, since adenosine depresses the amplitude of evoked excitatory postsynaptic potential and the frequency of spontaneous and miniature excitatory postsynaptic currents in these neurons. At the cell body of the hypocretin/orexin neurons, adenosine inhibits voltage-dependent calcium currents without the induction of GIRK current. The inhibitory effect of adenosine is dose-dependent, pertussis toxin-sensitive and mediated via A1 receptors. In summary, our data suggest that in addition to its effect in the basal forebrain, adenosine exerts its sleep-promoting effect in the LH via inhibition of hypocretin/orexin neurons. PMID:17093123

Optogenetic identification of hypothalamic orexin neuron projections to paraventricular spinally projecting neurons.

PubMed

Dergacheva, Olga; Yamanaka, Akihiro; Schwartz, Alan R; Polotsky, Vsevolod Y; Mendelowitz, David

2017-04-01

Orexin neurons, and activation of orexin receptors, are generally thought to be sympathoexcitatory; however, the functional connectivity between orexin neurons and a likely sympathetic target, the hypothalamic spinally projecting neurons (SPNs) in the paraventricular nucleus of the hypothalamus (PVN) has not been established. To test the hypothesis that orexin neurons project directly to SPNs in the PVN, channelrhodopsin-2 (ChR2) was selectively expressed in orexin neurons to enable photoactivation of ChR2-expressing fibers while examining evoked postsynaptic currents in SPNs in rat hypothalamic slices. Selective photoactivation of orexin fibers elicited short-latency postsynaptic currents in all SPNs tested ( n = 34). These light-triggered responses were heterogeneous, with a majority being excitatory glutamatergic responses (59%) and a minority of inhibitory GABAergic (35%) and mixed glutamatergic and GABAergic currents (6%). Both glutamatergic and GABAergic responses were present in the presence of tetrodotoxin and 4-aminopyridine, suggesting a monosynaptic connection between orexin neurons and SPNs. In addition to generating postsynaptic responses, photostimulation facilitated action potential firing in SPNs (current clamp configuration). Glutamatergic, but not GABAergic, postsynaptic currents were diminished by application of the orexin receptor antagonist almorexant, indicating orexin release facilitates glutamatergic neurotransmission in this pathway. This work identifies a neuronal circuit by which orexin neurons likely exert sympathoexcitatory control of cardiovascular function. NEW & NOTEWORTHY This is the first study to establish, using innovative optogenetic approaches in a transgenic rat model, that there are robust heterogeneous projections from orexin neurons to paraventricular spinally projecting neurons, including excitatory glutamatergic and inhibitory GABAergic neurotransmission. Endogenous orexin release modulates glutamatergic, but not GABAergic, neurotransmission in these pathways. Copyright © 2017 the American Physiological Society.

Increased miR-124-3p in microglial exosomes following traumatic brain injury inhibits neuronal inflammation and contributes to neurite outgrowth via their transfer into neurons.

PubMed

Huang, Shan; Ge, Xintong; Yu, Jinwen; Han, Zhaoli; Yin, Zhenyu; Li, Ying; Chen, Fanglian; Wang, Haichen; Zhang, Jianning; Lei, Ping

2018-01-01

Neuronal inflammation is the characteristic pathologic change of acute neurologic impairment and chronic traumatic encephalopathy after traumatic brain injury (TBI). Inhibiting the excessive inflammatory response is essential for improving the neurologic outcome. To clarify the regulatory mechanism of microglial exosomes on neuronal inflammation in TBI, we focused on studying the impact of microglial exosomal miRNAs on injured neurons in this research. We used a repetitive (r)TBI mouse model and harvested the injured brain extracts from the acute to the chronic phase of TBI to treat cultured BV2 microglia in vitro The microglial exosomes were collected for miRNA microarray analysis, which showed that the expression level of miR-124-3p increased most apparently in the miRNAs. We found that miR-124-3p promoted the anti-inflamed M2 polarization in microglia, and microglial exosomal miR-124-3p inhibited neuronal inflammation in scratch-injured neurons. Further, the mammalian target of rapamycin (mTOR) signaling was implicated as being involved in the regulation of miR-124-3p by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses. Using the mTOR activator MHY1485 we confirmed that the inhibitory effect of exosomal miR-124-3p on neuronal inflammation was exerted by suppressing the activity of mTOR signaling. PDE4B was predicted to be the target gene of miR-124-3p by pathway analysis. We proved that it was directly targeted by miR-124-3p with a luciferase reporter assay. Using a PDE4B overexpressed lentivirus transfection system, we suggested that miR-124-3p suppressed the activity of mTOR signaling mainly through inhibiting the expression of PDE4B. In addition, exosomal miR-124-3p promoted neurite outgrowth after scratch injury, characterized by an increase on the number of neurite branches and total neurite length, and a decreased expression on RhoA and neurodegenerative proteins [Aβ-peptide and p-Tau]. It also improved the neurologic outcome and inhibited neuroinflammation in mice with rTBI. Taken together, increased miR-124-3p in microglial exosomes after TBI can inhibit neuronal inflammation and contribute to neurite outgrowth via their transfer into neurons. miR-124-3p exerted these effects by targeting PDE4B, thus inhibiting the activity of mTOR signaling. Therefore, miR-124-3p could be a promising therapeutic target for interventions of neuronal inflammation after TBI. miRNAs manipulated microglial exosomes may provide a novel therapy for TBI and other neurologic diseases.-Huang, S., Ge, X., Yu, J., Han, Z., Yin, Z., Li, Y., Chen, F., Wang, H., Zhang, J., Lei, P. Increased miR-124-3p in microglial exosomes following traumatic brain injury inhibits neuronal inflammation and contributes to neurite outgrowth via their transfer into neurons. © FASEB.

Modulation of extracellular ATP content of mast cells and DRG neurons by irradiation: studies on underlying mechanism of low-level-laser therapy.

PubMed

Wang, Lina; Hu, Lei; Grygorczyk, Ryszard; Shen, Xueyong; Schwarz, Wolfgang

2015-01-01

Low-level-laser therapy (LLLT) is an effective complementary treatment, especially for anti-inflammation and wound healing in which dermis or mucus mast cells (MCs) are involved. In periphery, MCs crosstalk with neurons via purinergic signals and participate in various physiological and pathophysiological processes. Whether extracellular ATP, an important purine in purinergic signaling, of MCs and neurons could be modulated by irradiation remains unknown. In this study, effects of red-laser irradiation on extracellular ATP content of MCs and dorsal root ganglia (DRG) neurons were investigated and underlying mechanisms were explored in vitro. Our results show that irradiation led to elevation of extracellular ATP level in the human mast cell line HMC-1 in a dose-dependent manner, which was accompanied by elevation of intracellular ATP content, an indicator for ATP synthesis, together with [Ca(2+)]i elevation, a trigger signal for exocytotic ATP release. In contrast to MCs, irradiation attenuated the extracellular ATP content of neurons, which could be abolished by ARL 67156, a nonspecific ecto-ATPases inhibitor. Our results suggest that irradiation potentiates extracellular ATP of MCs by promoting ATP synthesis and release and attenuates extracellular ATP of neurons by upregulating ecto-ATPase activity. The opposite responses of these two cell types indicate complex mechanisms underlying LLLT.

Selective inhibition of miR-92 in hippocampal neurons alters contextual fear memory.

PubMed

Vetere, Gisella; Barbato, Christian; Pezzola, Silvia; Frisone, Paola; Aceti, Massimiliano; Ciotti, MariaTeresa; Cogoni, Carlo; Ammassari-Teule, Martine; Ruberti, Francesca

2014-12-01

Post-transcriptional gene regulation mediated by microRNAs (miRNAs) is implicated in memory formation; however, the function of miR-92 in this regulation is uncharacterized. The present study shows that training mice in contextual fear conditioning produces a transient increase in miR-92 levels in the hippocampus and decreases several miR-92 gene targets, including: (i) the neuronal Cl(-) extruding K(+) Cl(-) co-transporter 2 (KCC2) protein; (ii) the cytoplasmic polyadenylation protein (CPEB3), an RNA-binding protein regulator of protein synthesis in neurons; and (iii) the transcription factor myocyte enhancer factor 2D (MEF2D), one of the MEF2 genes which negatively regulates memory-induced structural plasticity. Selective inhibition of endogenous miR-92 in CA1 hippocampal neurons, by a sponge lentiviral vector expressing multiple sequences imperfectly complementary to mature miR-92 under the control of the neuronal specific synapsin promoter, leads to up-regulation of KCC2, CPEB3 and MEF2D, impairs contextual fear conditioning, and prevents a memory-induced increase in the spine density. Taken together, the results indicate that neuronal-expressed miR-92 is an endogenous fine regulator of contextual fear memory in mice. © 2014 Wiley Periodicals, Inc.

Excitatory innervation of caudal hypoglossal nucleus from nucleus reticularis gigantocellularis in the rat.

PubMed

Yang, C C; Chan, J Y; Chan, S H

1995-03-01

We examined the possible innervation of the caudal hypoglossal nucleus by the nucleus reticularis gigantocellularis of the medulla oblongata, based on single-neuron recording and retrograde tracing experiments in Sprague-Dawley rats. Under pentobarbital sodium (50 mg/kg, i.p.) anesthesia, electrical stimulation of the caudal portion of the nucleus reticularis gigantocellularis with repetitive 0.5-ms rectangular pulses increased (46 of 51 neurons) the basal discharge frequency of spontaneously active cells, or evoked spike activity in silent, hypoglossal neurons located at the level of the obex. This excitatory effect was related to the intensity (25-100 microA) and/or frequency (0.5-20 Hz) of the stimulating pulses to the nucleus reticularis gigantocellularis. Perikaryal activation of neurons by microinjection of L-glutamate (0.5 nmol, 25 nl) into the caudal portion of the nucleus reticularis gigantocellularis similarly produced an excitatory action on eight of 14 hypoglossal neurons. Retrogradely labeled neurons were found bilaterally within the confines of the nucleus reticularis gigantocellularis following unilateral microinjection of wheatgerm agglutinin-conjugated horseradish peroxidase or Fast Blue into the corresponding hypoglossal recording sites. Furthermore, the distribution of labeled neurons in the nucleus reticularis gigantocellularis substantially overlapped with the loci of electrical or chemical stimulation. These complementary electrophysiological and neuroanatomical results support the conclusion that an excitatory link exists between the nucleus reticularis gigantocellularis and at least the caudal portion of the hypoglossal nucleus in the rat.

Neural plasticity explored by correlative two-photon and electron/SPIM microscopy

NASA Astrophysics Data System (ADS)

Allegra Mascaro, A. L.; Silvestri, L.; Costantini, I.; Sacconi, L.; Maco, B.; Knott, G. W.; Pavone, F. S.

2013-06-01

Plasticity of the central nervous system is a complex process which involves the remodeling of neuronal processes and synaptic contacts. However, a single imaging technique can reveal only a small part of this complex machinery. To obtain a more complete view, complementary approaches should be combined. Two-photon fluorescence microscopy, combined with multi-photon laser nanosurgery, allow following the real-time dynamics of single neuronal processes in the cerebral cortex of living mice. The structural rearrangement elicited by this highly confined paradigm of injury can be imaged in vivo first, and then the same neuron could be retrieved ex-vivo and characterized in terms of ultrastructural features of the damaged neuronal branch by means of electron microscopy. Afterwards, we describe a method to integrate data from in vivo two-photon fluorescence imaging and ex vivo light sheet microscopy, based on the use of major blood vessels as reference chart. We show how the apical dendritic arbor of a single cortical pyramidal neuron imaged in living mice can be found in the large-scale brain reconstruction obtained with light sheet microscopy. Starting from its apical portion, the whole pyramidal neuron can then be segmented and located in the correct cortical layer. With the correlative approach presented here, researchers will be able to place in a three-dimensional anatomic context the neurons whose dynamics have been observed with high detail in vivo.

Epigenetic mechanisms: critical contributors to long-term memory formation.

PubMed

Lubin, Farah D; Gupta, Swati; Parrish, R Ryley; Grissom, Nicola M; Davis, Robin L

2011-12-01

Recent advances in chromatin biology have identified a role for epigenetic mechanisms in the regulation of neuronal gene expression changes, a necessary process for proper synaptic plasticity and memory formation. Experimental evidence for dynamic chromatin remodeling influencing gene transcription in postmitotic neurons grew from initial reports describing posttranslational modifications of histones, including phosphorylation and acetylation occurring in various brain regions during memory consolidation. An accumulation of recent studies, however, has also highlighted the importance of other epigenetic modifications, such as DNA methylation and histone methylation, as playing a role in memory formation. This present review examines learning-induced gene transcription by chromatin remodeling underlying long-lasting changes in neurons, with direct implications for the study of epigenetic mechanisms in long-term memory formation and behavior. Furthermore, the study of epigenetic gene regulation, in conjunction with transcription factor activation, can provide complementary lines of evidence to further understanding transcriptional mechanisms subserving memory storage.

Reorganization of corticospinal output during motor learning

PubMed Central

Peters, Andrew J.; Lee, Jun; Hedrick, Nathan G.; O’Neil, Keelin; Komiyama, Takaki

2017-01-01

Motor learning is accompanied by widespread changes within the motor cortex, but it is unknown whether these changes are ultimately funneled through a stable corticospinal output channel or if the corticospinal output itself is plastic. We investigated the consistency of the relationship between corticospinal neuron activity and movement through in vivo two-photon calcium imaging in mice learning a lever-press task. Corticospinal neurons exhibited heterogeneous correlations with movement, with the majority of movement-modulated neurons decreasing activity during movement. Individual cells changed their activity across days which led to novel associations between corticospinal activity and movement. Unlike previous observations in layer 2/3, activity accompanying learned movements did not become more consistent with learning, and instead the activity of dissimilar movements became more decorrelated. These results indicate that the relationship between corticospinal activity and movement is dynamic, and the types of activity and plasticity are different from and possibly complementary to layer 2/3. PMID:28671694

A modeling framework for deriving the structural and functional architecture of a short-term memory microcircuit.

PubMed

Fisher, Dimitry; Olasagasti, Itsaso; Tank, David W; Aksay, Emre R F; Goldman, Mark S

2013-09-04

Although many studies have identified neural correlates of memory, relatively little is known about the circuit properties connecting single-neuron physiology to behavior. Here we developed a modeling framework to bridge this gap and identify circuit interactions capable of maintaining short-term memory. Unlike typical studies that construct a phenomenological model and test whether it reproduces select aspects of neuronal data, we directly fit the synaptic connectivity of an oculomotor memory circuit to a broad range of anatomical, electrophysiological, and behavioral data. Simultaneous fits to all data, combined with sensitivity analyses, revealed complementary roles of synaptic and neuronal recruitment thresholds in providing the nonlinear interactions required to generate the observed circuit behavior. This work provides a methodology for identifying the cellular and synaptic mechanisms underlying short-term memory and demonstrates how the anatomical structure of a circuit may belie its functional organization. Copyright © 2013 Elsevier Inc. All rights reserved.

Perinatal asphyxia exerts lifelong effects on neuronal responsiveness to stress in specific brain regions in the rat.

PubMed

Salchner, Peter; Engidawork, Ephrem; Hoeger, Harald; Lubec, Barbara; Singewald, Nicolas

2003-09-01

Perinatal asphyxia (PA) causes irreversible damage to the brain of newborns and can produce neurologic and behavioral changes later in life. To identify neuronal substrates underlying the effects of PA, we investigated whether and how neuronal responsiveness to an established stress challenge is affected. We used Fos expression as a marker of neuronal activation and examined the pattern of Fos expression in response to acute swim stress in 24-month-old rats exposed to a 20-minute PA insult. Swim stress produced a similar pattern of Fos expression in control and asphyxiated rats in 34 brain areas. Asphyxiated rats displayed a higher number of stress-induced Fos-positive cells in the nucleus of the solitary tract, parabrachial nucleus, periaqueductal gray, paraventricular hypothalamic nucleus, nucleus accumbens, caudate-putamen, and prelimbic cortex. No differences in the Fos response to stress were observed in other regions, including the locus ceruleus, amygdala, hippocampus, or septum. These data provide functional anatomic evidence that PA has lifelong effects on neuronal communication and leads to an abnormal, augmented neuronal responsiveness to stress in specific brain areas, particularly in the main telencephalic target regions of the mesencephalic dopamine projections, as well as in a functionally related set of brain regions associated with autonomic and neuroendocrine regulation.

Turmeric extract inhibits apoptosis of hippocampal neurons of trimethyltin-exposed rats.

PubMed

Yuliani, S; Widyarini, S; Mustofa; Partadiredja, G

2017-01-01

The aim of the present study was to reveal the possible antiapoptotic effect of turmeric (Curcuma longa Linn.) on the hippocampal neurons of rats exposed to trimethyltin (TMT). Oxidative damage in the hippocampus can induce the apoptosis of neurons associated with the pathogenesis of dementiaMETHODS. The ethanolic turmeric extract and a citicoline (as positive control) solution were administered to the TMT-exposed rats for 28 days. The body weights of rats were recorded once a week. The hippocampal weights and imumunohistochemical expression of caspase 3 proteins in the CA1 and CA2-CA3 regions of the hippocampi were examined at the end of the experiment. Immunohistochemical analysis showed that the injection of TMT increased the expression of caspase 3 in the CA1 and CA2-CA3 regions of hippocampus. TMT also decreased the body and hippocampal weights. Furthermore, the administration of 200 mg/kg bw dose of turmeric extract decreased the caspase 3 expression in the CA2-CA3 pyramidal neurons but not in the CA1 neurons. It also prevented the decrease of the body and hippocampal weights. We suggest that the 200 mg/kg bw dose of turmeric extract may exert antiapoptotic effect on the hippocampal neurons of the TMT-exposed rats (Tab. 1, Fig. 3, Ref. 49).

Posterior lateral hypothalamic axon terminals are in contact with trigeminal premotor neurons in the parvicellular reticular formation of the rat medulla oblongata.

PubMed

Notsu, Kazuki; Tsumori, Toshiko; Yokota, Shigefumi; Sekine, Joji; Yasui, Yukihiko

2008-12-09

This study was performed to understand the anatomical substrates of hypothalamic modulation of jaw movements. After cholera toxin B subunit (CTb) injection into the parvicellular reticular formation (RFp) of the rat medulla oblongata, where many trigeminal premotor neurons have been known to exist, numerous CTb-labeled neurons were found in the posterior lateral hypothalamus (PLH) bilaterally with a clear-cut ipsilateral dominance. After ipsilateral injections of biotinylated dextran amine (BDA) into the PLH and CTb into the motor trigeminal nucleus (Vm), the prominent distribution of BDA-labeled axon terminals around CTb-labeled neurons was found in the RFp region just ventral to the nucleus of the solitary tract and medial to the spinal trigeminal nucleus ipsilateral to the injection sites. Within the neuropil of the RFp, BDA-labeled axon terminals made an asymmetrical synaptic contact predominantly with dendrites and additionally with somata of the RFp neurons, some of which were labeled with CTb. It was further revealed that these BDA-labeled axon terminals were immunoreactive for vesicular glutamate transporter 2. The present data suggest that the PLH plays an important role in the control of jaw movements by exerting its glutamatergic excitatory action upon RFp neurons presynaptic to trigeminal motoneurons.

Enhancing excitability of dopamine neurons promotes motivational behaviour through increased action initiation.

PubMed

Boekhoudt, Linde; Wijbrans, Ellen C; Man, Jodie H K; Luijendijk, Mieneke C M; de Jong, Johannes W; van der Plasse, Geoffrey; Vanderschuren, Louk J M J; Adan, Roger A H

2018-01-01

Motivational deficits are a key symptom in multiple psychiatric disorders, including major depressive disorder, schizophrenia and addiction. A likely neural substrate for these motivational deficits is the brain dopamine (DA) system. In particular, DA signalling in the nucleus accumbens, which originates from DA neurons in the ventral tegmental area (VTA), has been identified as a crucial substrate for effort-related and activational aspects of motivation. Unravelling how VTA DA neuronal activity relates to motivational behaviours is required to understand how motivational deficits in psychiatry can be specifically targeted. In this study, we therefore used designer receptors exclusively activated by designer drugs (DREADD) in TH:Cre rats, in order to determine the effects of chemogenetic DA neuron activation on different aspects of motivational behaviour. We found that chemogenetic activation of DA neurons in the VTA, but not substantia nigra, significantly increased responding for sucrose under a progressive ratio schedule of reinforcement. More specifically, high effort exertion was characterized by increased initiations of reward-seeking actions. This effect was dependent on effort requirements and instrumental contingencies, but was not affected by sucrose pre-feeding. Together, these findings indicate that VTA DA neuronal activation drives motivational behaviour by facilitating action initiation. With this study, we show that enhancing excitability of VTA DA neurons is a viable strategy to improve motivational behaviour. Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.

Dissecting the role of Engrailed in adult dopaminergic neurons--Insights into Parkinson disease pathogenesis.

PubMed

Rekaik, Hocine; Blaudin de Thé, François-Xavier; Prochiantz, Alain; Fuchs, Julia; Joshi, Rajiv L

2015-12-21

The homeoprotein Engrailed (Engrailed-1/Engrailed-2, collectively En1/2) is not only a survival factor for mesencephalic dopaminergic (mDA) neurons during development, but continues to exert neuroprotective and physiological functions in adult mDA neurons. Loss of one En1 allele in the mouse leads to progressive demise of mDA neurons in the ventral midbrain starting from 6 weeks of age. These mice also develop Parkinson disease-like motor and non-motor symptoms. The characterization of En1 heterozygous mice have revealed striking parallels to central mechanisms of Parkinson disease pathogenesis, mainly related to mitochondrial dysfunction and retrograde degeneration. Thanks to the ability of homeoproteins to transduce cells, En1/2 proteins have also been used to protect mDA neurons in various experimental models of Parkinson disease. This neuroprotection is partly linked to the ability of En1/2 to regulate the translation of certain nuclear-encoded mitochondrial mRNAs for complex I subunits. Other transcription factors that govern mDA neuron development (e.g. Foxa1/2, Lmx1a/b, Nurr1, Otx2, Pitx3) also continue to function for the survival and maintenance of mDA neurons in the adult and act through partially overlapping but also diverse mechanisms. Copyright © 2015 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

Ketone bodies are protective against oxidative stress in neocortical neurons.

PubMed

Kim, Do Young; Davis, Laurie M; Sullivan, Patrick G; Maalouf, Marwan; Simeone, Timothy A; van Brederode, Johannes; Rho, Jong M

2007-06-01

Ketone bodies (KB) have been shown to prevent neurodegeneration in models of Parkinson's and Alzheimer's diseases, but the mechanisms underlying these effects remain unclear. One possibility is that KB may exert antioxidant activity. In the current study, we explored the effects of KB on rat neocortical neurons exposed to hydrogen peroxide (H(2)O(2)) or diamide - a thiol oxidant and activator of mitochondrial permeability transition (mPT). We found that: (i) KB completely blocked large inward currents induced by either H(2)O(2) or diamide; (ii) KB significantly decreased the number of propidium iodide-labeled cells in neocortical slices after exposure to H(2)O(2) or diamide; (iii) KB significantly decreased reactive oxygen species (ROS) levels in dissociated neurons and in isolated neocortical mitochondria; (iv) the electrophysiological effects of KB in neurons exposed to H(2)O(2) or diamide were mimicked by bongkrekic acid and cyclosporin A, known inhibitors of mPT, as well as by catalase and DL - dithiothreitol, known antioxidants; (v) diamide alone did not significantly alter basal ROS levels in neurons, supporting previous studies indicating that diamide-induced neuronal injury may be mediated by mPT opening; and (vi) KB significantly increased the threshold for calcium-induced mPT in isolated mitochondria. Taken together, our data suggest that KB may prevent mPT and oxidative injury in neocortical neurons, most likely by decreasing mitochondrial ROS production.

Neuroprotective Effect of Arctigenin via Upregulation of P-CREB in Mouse Primary Neurons and Human SH-SY5Y Neuroblastoma Cells

PubMed Central

Zhang, Nan; Wen, Qingping; Ren, Lu; Liang, Wenbo; Xia, Yang; Zhang, Xiaodan; Zhao, Dan; Sun, Dong; Hu, Yv; Hao, Haiguang; Yan, Yaping; Zhang, Guangxian; Yang, Jingxian; Kang, Tingguo

2013-01-01

Arctigenin (Arc) has been shown to act on scopolamine-induced memory deficit mice and to provide a neuroprotective effect on cultured cortical neurons from glutamate-induced neurodegeneration through mechanisms not completely defined. Here, we investigated the neuroprotective effect of Arc on H89-induced cell damage and its potential mechanisms in mouse cortical neurons and human SH-SY5Y neuroblastoma cells. We found that Arc prevented cell viability loss induced by H89 in human SH-SY5Y cells. Moreover, Arc reduced intracellular beta amyloid (Aβ) production induced by H89 in neurons and human SH-SY5Y cells, and Arc also inhibited the presenilin 1(PS1) protein level in neurons. In addition, neural apoptosis in both types of cells, inhibition of neurite outgrowth in human SH-SY5Y cells and reduction of synaptic marker synaptophysin (SYN) expression in neurons were also observed after H89 exposure. All these effects induced by H89 were markedly reversed by Arc treatment. Arc also significantly attenuated downregulation of the phosphorylation of CREB (p-CREB) induced by H89, which may contribute to the neuroprotective effects of Arc. These results demonstrated that Arc exerted the ability to protect neurons and SH-SY5Y cells against H89-induced cell injury via upregulation of p-CREB. PMID:24025424

Cholinergic Mesopontine Signals Govern Locomotion and Reward Through Dissociable Midbrain Pathways

PubMed Central

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

2016-01-01

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

Social Control of Hypothalamus-Mediated Male Aggression.

PubMed

Yang, Taehong; Yang, Cindy F; Chizari, M Delara; Maheswaranathan, Niru; Burke, Kenneth J; Borius, Maxim; Inoue, Sayaka; Chiang, Michael C; Bender, Kevin J; Ganguli, Surya; Shah, Nirao M

2017-08-16

How environmental and physiological signals interact to influence neural circuits underlying developmentally programmed social interactions such as male territorial aggression is poorly understood. We have tested the influence of sensory cues, social context, and sex hormones on progesterone receptor (PR)-expressing neurons in the ventromedial hypothalamus (VMH) that are critical for male territorial aggression. We find that these neurons can drive aggressive displays in solitary males independent of pheromonal input, gonadal hormones, opponents, or social context. By contrast, these neurons cannot elicit aggression in socially housed males that intrude in another male's territory unless their pheromone-sensing is disabled. This modulation of aggression cannot be accounted for by linear integration of environmental and physiological signals. Together, our studies suggest that fundamentally non-linear computations enable social context to exert a dominant influence on developmentally hard-wired hypothalamus-mediated male territorial aggression. Copyright © 2017 Elsevier Inc. All rights reserved.

Protection of dopaminergic neurons by electroconvulsive shock in an animal model of Parkinson's disease.

PubMed

Anastasia, Agustín; de Erausquin, Gabriel A; Wojnacki, José; Mascó, Daniel H

2007-11-01

Electroconvulsive shock (ECS) improves motor function in Parkinson's disease. In rats, ECS stimulates the expression of various factors some of which have been proposed to exert neuroprotective actions. We have investigated the effects of ECS on 6-hydroxydopamine (6-OHDA)-injected rats. Three weeks after a unilateral administration of 6-OHDA, 85-95% nigral dopaminergic neurons are lost. Chronic ECS prevented this cell loss, protect the nigrostriatal pathway (assessed by FloroGold retrograde labeling) and reduce motor impairment in 6-OHDA-treated animals. Injection of 6-OHDA caused loss of expression of glial cell-line derived neurotrophic factor (GDNF) in the substantia nigra. Chronic ECS completely prevented this loss of GDNF expression in 6-OHDA-treated animals. We also found that protected dopaminergic neurons co-express GDNF receptor proteins. These results strongly suggest that endogenous changes in GDNF expression may participate in the neuroprotective mechanism of ECS against 6-OHDA induced toxicity.

Potential role of monkey inferior parietal neurons coding action semantic equivalences as precursors of parts of speech.

PubMed

Yamazaki, Yumiko; Yokochi, Hiroko; Tanaka, Michio; Okanoya, Kazuo; Iriki, Atsushi

2010-01-01

The anterior portion of the inferior parietal cortex possesses comprehensive representations of actions embedded in behavioural contexts. Mirror neurons, which respond to both self-executed and observed actions, exist in this brain region in addition to those originally found in the premotor cortex. We found that parietal mirror neurons responded differentially to identical actions embedded in different contexts. Another type of parietal mirror neuron represents an inverse and complementary property of responding equally to dissimilar actions made by itself and others for an identical purpose. Here, we propose a hypothesis that these sets of inferior parietal neurons constitute a neural basis for encoding the semantic equivalence of various actions across different agents and contexts. The neurons have mirror neuron properties, and they encoded generalization of agents, differentiation of outcomes, and categorization of actions that led to common functions. By integrating the activities of these mirror neurons with various codings, we further suggest that in the ancestral primates' brains, these various representations of meaningful action led to the gradual establishment of equivalence relations among the different types of actions, by sharing common action semantics. Such differential codings of the components of actions might represent precursors to the parts of protolanguage, such as gestural communication, which are shared among various members of a society. Finally, we suggest that the inferior parietal cortex serves as an interface between this action semantics system and other higher semantic systems, through common structures of action representation that mimic language syntax.

Potential role of monkey inferior parietal neurons coding action semantic equivalences as precursors of parts of speech

PubMed Central

Yamazaki, Yumiko; Yokochi, Hiroko; Tanaka, Michio; Okanoya, Kazuo; Iriki, Atsushi

2010-01-01

The anterior portion of the inferior parietal cortex possesses comprehensive representations of actions embedded in behavioural contexts. Mirror neurons, which respond to both self-executed and observed actions, exist in this brain region in addition to those originally found in the premotor cortex. We found that parietal mirror neurons responded differentially to identical actions embedded in different contexts. Another type of parietal mirror neuron represents an inverse and complementary property of responding equally to dissimilar actions made by itself and others for an identical purpose. Here, we propose a hypothesis that these sets of inferior parietal neurons constitute a neural basis for encoding the semantic equivalence of various actions across different agents and contexts. The neurons have mirror neuron properties, and they encoded generalization of agents, differentiation of outcomes, and categorization of actions that led to common functions. By integrating the activities of these mirror neurons with various codings, we further suggest that in the ancestral primates' brains, these various representations of meaningful action led to the gradual establishment of equivalence relations among the different types of actions, by sharing common action semantics. Such differential codings of the components of actions might represent precursors to the parts of protolanguage, such as gestural communication, which are shared among various members of a society. Finally, we suggest that the inferior parietal cortex serves as an interface between this action semantics system and other higher semantic systems, through common structures of action representation that mimic language syntax. PMID:20119879

A serotonin and melanocortin circuit mediates D-fenfluramine anorexia.

PubMed

Xu, Yong; Jones, Juli E; Lauzon, Danielle A; Anderson, Jason G; Balthasar, Nina; Heisler, Lora K; Zinn, Andrew R; Lowell, Bradford B; Elmquist, Joel K

2010-11-03

D-Fenfluramine (D-Fen) increases serotonin (5-HT) content in the synaptic cleft and exerts anorexigenic effects in animals and humans. However, the neural circuits that mediate these effects are not fully identified. To address this issue, we assessed the efficacy of D-Fen-induced hypophagia in mouse models with manipulations of several genes in selective populations of neurons. Expectedly, we found that global deletion of 5-HT 2C receptors (5-HT(2C)Rs) significantly attenuated D-Fen-induced anorexia. These anorexigenic effects were restored in mice with 5-HT(2C)Rs expressed only in pro-opiomelanocortin (POMC) neurons. Further, we found that deletion of melanocortin 4 receptors (MC4Rs), a downstream target of POMC neurons, abolished anorexigenic effects of D-Fen. Reexpression of MC4Rs only in SIM1 neurons in the hypothalamic paraventricular nucleus and neurons in the amygdala was sufficient to restore the hypophagic property of D-Fen. Thus, our results identify a neurochemically defined neural circuit through which D-Fen influences appetite and thereby indicate that this 5-HT(2C)R/POMC-MC4R/SIM1 circuit may yield a more refined target to exploit for weight loss.

A Serotonin and Melanocortin Circuit Mediates d-Fenfluramine Anorexia

PubMed Central

Xu, Yong; Jones, Juli E.; Lauzon, Danielle A.; Anderson, Jason G.; Balthasar, Nina; Heisler, Lora K.; Zinn, Andrew R.; Lowell, Bradford B.; Elmquist, Joel K.

2012-01-01

d-Fenfluramine (d-Fen) increases serotonin (5-HT) content in the synaptic cleft and exerts anorexigenic effects in animals and humans. However, the neural circuits that mediate these effects are not fully identified. To address this issue, we assessed the efficacy of d-Fen-induced hypophagia in mouse models with manipulations of several genes in selective populations of neurons. Expectedly, we found that global deletion of 5-HT 2C receptors (5-HT2CRs) significantly attenuated d-Fen-induced anorexia. These anorexigenic effects were restored in mice with 5-HT2CRs expressed only in pro-opiomelanocortin (POMC) neurons. Further, we found that deletion of melanocortin 4 receptors (MC4Rs), a downstream target of POMC neurons, abolished anorexigenic effects of d-Fen. Reexpression of MC4Rs only in SIM1 neurons in the hypothalamic paraventricular nucleus and neurons in the amygdala was sufficient to restore the hypophagic property of d-Fen. Thus, our results identify a neurochemically defined neural circuit through which d-Fen influences appetite and thereby indicate that this 5-HT2CR/POMC-MC4R/SIM1 circuit may yield a more refined target to exploit for weight loss. PMID:21048120

Enhancement of synaptic transmission induced by BDNF in cultured cortical neurons

NASA Astrophysics Data System (ADS)

He, Jun; Gong, Hui; Zeng, Shaoqun; Li, Yanling; Luo, Qingming

2005-03-01

Brain-derived neurotrophic factor (BDNF), like other neurotrophins, has long-term effects on neuronal survival and differentiation; furthermore, BDNF has been reported to exert an acute potentiation of synaptic activity and are critically involved in long-term potentiation (LTP). We found that BDNF rapidly induced potentiation of synaptic activity and an increase in the intracellular Ca2+ concentration in cultured cortical neurons. Within minutes of BDNF application to cultured cortical neurons, spontaneous firing rate was dramatically increased as were the frequency and amplitude of excitatory spontaneous postsynaptic currents (EPSCs). Fura-2 recordings showed that BDNF acutely elicited an increase in intracellular calcium concentration ([Ca2+]c). This effect was partially dependent on [Ca2+]o; The BDNF-induced increase in [Ca2+]c can not be completely blocked by Ca2+-free solution. It was completely blocked by K252a and partially blocked by Cd2+ and TTX. The results demonstrate that BDNF can enhances synaptic transmission and that this effect is accompanied by a rise in [Ca2+]c that requires two route: the release of Ca2+ from intracellular calcium stores and influx of extracellular Ca2+ through voltage-dependent Ca2+ channels in cultured cortical neurons.

5-s-Cysteinyl-conjugates of catecholamines induce cell damage, extensive DNA base modification and increases in caspase-3 activity in neurons.

PubMed

Spencer, Jeremy P E; Whiteman, Matthew; Jenner, Peter; Halliwell, Barry

2002-04-01

A decrease in reduced glutathione levels in dopamine containing nigral cells in Parkinson's disease may result from the formation of cysteinyl-adducts of catecholamines, which in turn exert toxicity on nigral cells. We show that exposure of neurons (CSM 14.1) to 5-S-cysteinyl conjugates of dopamine, L-DOPA, DOPAC or DHMA causes neuronal damage, increases in oxidative DNA base modification and an elevation of caspase-3 activity in cells. Damage to neurons was apparent 12-48 h of post-exposure and there were increases in caspase-3 activity in neurons after 6 h. These changes were paralleled by large increases in pyrimidine and purine base oxidation products, such as 8-OH-guanine suggesting that 5-S-cysteinyl conjugates of catecholamines are capable of diffusing into cells and stimulating the formation of reactive oxygen species (ROS), which may then lead to a mechanism of cell damage involving caspase-3. Indeed, intracellular ROS were observed to rise sharply on exposure to the conjugates. These results suggest one mechanism by which oxidative stress may occur in the substantia nigra in Parkinson's disease.

Genistein inhibition of OGD-induced brain neuron death correlates with its modulation of apoptosis, voltage-gated potassium and sodium currents and glutamate signal pathway.

PubMed

Ma, Xue-Ling; Zhang, Feng; Wang, Yu-Xiang; He, Cong-Cong; Tian, Kun; Wang, Hong-Gang; An, Di; Heng, Bin; Liu, Yan-Qiang

2016-07-25

In the present study, we established an in vitro model of hypoxic-ischemia via exposing primary neurons of newborn rats to oxygen-glucose deprivation (OGD) and observing the effects of genistein, a soybean isoflavone, on hypoxic-ischemic neuron viability, apoptosis, voltage-activated potassium (Kv) and sodium (Nav) currents, and glutamate receptor subunits. The results indicated that OGD exposure reduced the viability and increased the apoptosis of brain neurons. Meanwhile, OGD exposure caused changes in the current-voltage curves and current amplitude values of voltage-activated potassium and sodium currents; OGD exposure also decreased GluR2 expression and increased NR2 expression. However, genistein at least partially reversed the effects caused by OGD. The results suggest that hypoxic-ischemia-caused neuronal apoptosis/death is related to an increase in K(+) efflux, a decrease in Na(+) influx, a down-regulation of GluR2, and an up-regulation of NR2. Genistein may exert some neuroprotective effects via the modulation of Kv and Nav currents and the glutamate signal pathway, mediated by GluR2 and NR2. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Residual effect of a 7-amino metabolite of clonazepam on GABAA receptor function in the nucleus reticularis thalami of the rat.

PubMed

Munakata, Mitsutoshi; Tsuchiya, Shigeru

2008-10-01

A considerable amount of 7-aminoclonazepam (ACZP), a major metabolite of clonazepam (CZP), is present in the brain during CZP treatment, yet the pharmacological properties of ACZP remain unknown. We investigated the effects of ACZP on the GABA(A) receptor-mediated currents (I(GABA)) in neurons from the nucleus reticularis thalami (NRT) of the rat, using a nystatin-perforated patch technique. Neurons in which CZP (10 nM) exerted prominent augmentation (>100% augmentation) of I(GABA), which comprised 32% of the neurons tested, were included for the analysis of ACZP. In these neurons, ACZP augmented I(GABA), which was blocked by 10 microM flumazenil, a benzodiazepine receptor (BZR) antagonist. The half-maximal effective concentration of ACZP was 124 nM, whereas that of CZP was 1.8 nM. The maximal enhancements induced by ACZP and CZP were 38% and 170%, respectively. In neurons from the ventrobasal complex of the thalamus, the effect of ACZP was negligible. Our results suggest that ACZP was a weak partial BZR agonist and that ACZP may competitively modify the effect of CZP, leading to clinical consequences for patients with high levels of ACZP.

Estradiol-Dependent Stimulation and Suppression of Gonadotropin-Releasing Hormone Neuron Firing Activity by Corticotropin-Releasing Hormone in Female Mice.

PubMed

Phumsatitpong, Chayarndorn; Moenter, Suzanne M

2018-01-01

Gonadotropin-releasing hormone (GnRH) neurons are the final central regulators of reproduction, integrating various inputs that modulate fertility. Stress typically inhibits reproduction but can be stimulatory; stress effects can also be modulated by steroid milieu. Corticotropin-releasing hormone (CRH) released during the stress response may suppress reproduction independent of downstream glucocorticoids. We hypothesized CRH suppresses fertility by decreasing GnRH neuron firing activity. To test this, mice were ovariectomized (OVX) and either implanted with an estradiol capsule (OVX+E) or not treated further to examine the influence of estradiol on GnRH neuron response to CRH. Targeted extracellular recordings were used to record firing activity from green fluorescent protein-identified GnRH neurons in brain slices before and during CRH treatment; recordings were done in the afternoon when estradiol has a positive feedback effect to increase GnRH neuron firing. In OVX mice, CRH did not affect the firing rate of GnRH neurons. In contrast, CRH exhibited dose-dependent stimulatory (30 nM) or inhibitory (100 nM) effects on GnRH neuron firing activity in OVX+E mice; both effects were reversible. The dose-dependent effects of CRH appear to result from activation of different receptor populations; a CRH receptor type-1 agonist increased firing activity in GnRH neurons, whereas a CRH receptor type-2 agonist decreased firing activity. CRH and specific agonists also differentially regulated short-term burst frequency and burst properties, including burst duration, spikes/burst, and/or intraburst interval. These results indicate that CRH alters GnRH neuron activity and that estradiol is required for CRH to exert both stimulatory and inhibitory effects on GnRH neurons. Copyright © 2018 Endocrine Society.

The neuroprotective role and mechanisms of TERT in neurons with oxygen-glucose deprivation.

PubMed

Li, J; Qu, Y; Chen, D; Zhang, L; Zhao, F; Luo, L; Pan, L; Hua, J; Mu, D

2013-11-12

Telomerase reverse transcriptase (TERT) is reported to protect neurons from apoptosis induced by various stresses including hypoxia-ischemia (HI). However, the mechanisms by which TERT exerts its anti-apoptotic role in neurons with HI injury remain unclear. In this study, we examined the protective role and explored the possible mechanisms of TERT in neurons with HI injury in vitro. Primary cultured neurons were exposed to oxygen and glucose deprivation (OGD) for 3h followed by reperfusion to mimic HI injury in vivo. Plasmids containing TERT antisense, sense nucleotides, or mock were transduced into neurons at 48h before OGD. Expression and distribution of TERT were measured by immunofluorescence labeling and western blot. The expression of cleaved caspase 3 (CC3), Bcl-2 and Bax were detected by western blot. Neuronal apoptosis was measured with terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL). The mitochondrial reactive oxygen species (ROS) were measured by MitoSOX Red staining. Fluorescent probe JC-1 was used to measure the mitochondrial membrane potential (ΔΨm). We found that TERT expression increased at 8h and peaked at 24h in neurons after OGD. CC3 expression and neuronal apoptosis were induced and peaked at 24h after OGD. TERT inhibition significantly increased CC3 expression and neuronal apoptosis after OGD treatment. Additionally, TERT inhibition decreased the expression ratio of Bcl-2/Bax, and enhanced ROS production and ΔΨm dissipation after OGD. These data suggest that TERT plays a neuroprotective role via anti-apoptosis in neurons after OGD. The underlying mechanisms may be associated with regulating Bcl-2/Bax expression ratio, attenuating ROS generation, and increasing mitochondrial membrane potential. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

Atrophy and neuron loss: effects of a protein-deficient diet on sympathetic neurons.

PubMed

Gomes, Silvio Pires; Nyengaard, Jens Randel; Misawa, Rúbia; Girotti, Priscila Azevedo; Castelucci, Patrìcia; Blazquez, Francisco Hernandez Javier; de Melo, Mariana Pereira; Ribeiro, Antonio Augusto Coppi

2009-12-01

Protein deficiency is one of the biggest public health problems in the world, accounting for about 30-40% of hospital admissions in developing countries. Nutritional deficiencies lead to alterations in the peripheral nervous system and in the digestive system. Most studies have focused on the effects of protein-deficient diets on the enteric neurons, but not on sympathetic ganglia, which supply extrinsic sympathetic input to the digestive system. Hence, in this study, we investigated whether a protein-restricted diet would affect the quantitative structure of rat coeliac ganglion neurons. Five male Wistar rats (undernourished group) were given a pre- and postnatal hypoproteinic diet receiving 5% casein, whereas the nourished group (n = 5) was fed with 20% casein (normoproteinic diet). Blood tests were carried out on the animals, e.g., glucose, leptin, and triglyceride plasma concentrations. The main structural findings in this study were that a protein-deficient diet (5% casein) caused coeliac ganglion (78%) and coeliac ganglion neurons (24%) to atrophy and led to neuron loss (63%). Therefore, the fall in the total number of coeliac ganglion neurons in protein-restricted rats contrasts strongly with no neuron losses previously described for the enteric neurons of animals subjected to similar protein-restriction diets. Discrepancies between our figures and the data for enteric neurons (using very similar protein-restriction protocols) may be attributable to the counting method used. In light of this, further systematic investigations comparing 2-D and 3-D quantitative methods are warranted to provide even more advanced data on the effects that a protein-deficient diet may exert on sympathetic neurons. (c) 2009 Wiley-Liss, Inc. Copyright 2009 Wiley-Liss, Inc.

Investigating local and long-range neuronal network dynamics by simultaneous optogenetics, reverse microdialysis and silicon probe recordings in vivo

PubMed Central

Taylor, Hannah; Schmiedt, Joscha T.; Çarçak, Nihan; Onat, Filiz; Di Giovanni, Giuseppe; Lambert, Régis; Leresche, Nathalie; Crunelli, Vincenzo; David, Francois

2014-01-01

Background The advent of optogenetics has given neuroscientists the opportunity to excite or inhibit neuronal population activity with high temporal resolution and cellular selectivity. Thus, when combined with recordings of neuronal ensemble activity in freely moving animals optogenetics can provide an unprecedented snapshot of the contribution of neuronal assemblies to (patho)physiological conditions in vivo. Still, the combination of optogenetic and silicone probe (or tetrode) recordings does not allow investigation of the role played by voltage- and transmitter-gated channels of the opsin-transfected neurons and/or other adjacent neurons in controlling neuronal activity. New method and results We demonstrate that optogenetics and silicone probe recordings can be combined with intracerebral reverse microdialysis for the long-term delivery of neuroactive drugs around the optic fiber and silicone probe. In particular, we show the effect of antagonists of T-type Ca2+ channels, hyperpolarization-activated cyclic nucleotide-gated channels and metabotropic glutamate receptors on silicone probe-recorded activity of the local opsin-transfected neurons in the ventrobasal thalamus, and demonstrate the changes that the block of these thalamic channels/receptors brings about in the network dynamics of distant somatotopic cortical neuronal ensembles. Comparison with existing methods This is the first demonstration of successfully combining optogenetics and neuronal ensemble recordings with reverse microdialysis. This combination of techniques overcomes some of the disadvantages that are associated with the use of intracerebral injection of a drug-containing solution at the site of laser activation. Conclusions The combination of reverse microdialysis, silicone probe recordings and optogenetics can unravel the short and long-term effects of specific transmitter- and voltage-gated channels on laser-modulated firing at the site of optogenetic stimulation and the actions that these manipulations exert on distant neuronal populations. PMID:25004203

Investigating local and long-range neuronal network dynamics by simultaneous optogenetics, reverse microdialysis and silicon probe recordings in vivo.

PubMed

Taylor, Hannah; Schmiedt, Joscha T; Carçak, Nihan; Onat, Filiz; Di Giovanni, Giuseppe; Lambert, Régis; Leresche, Nathalie; Crunelli, Vincenzo; David, Francois

2014-09-30

The advent of optogenetics has given neuroscientists the opportunity to excite or inhibit neuronal population activity with high temporal resolution and cellular selectivity. Thus, when combined with recordings of neuronal ensemble activity in freely moving animals optogenetics can provide an unprecedented snapshot of the contribution of neuronal assemblies to (patho)physiological conditions in vivo. Still, the combination of optogenetic and silicone probe (or tetrode) recordings does not allow investigation of the role played by voltage- and transmitter-gated channels of the opsin-transfected neurons and/or other adjacent neurons in controlling neuronal activity. We demonstrate that optogenetics and silicone probe recordings can be combined with intracerebral reverse microdialysis for the long-term delivery of neuroactive drugs around the optic fiber and silicone probe. In particular, we show the effect of antagonists of T-type Ca(2+) channels, hyperpolarization-activated cyclic nucleotide-gated channels and metabotropic glutamate receptors on silicone probe-recorded activity of the local opsin-transfected neurons in the ventrobasal thalamus, and demonstrate the changes that the block of these thalamic channels/receptors brings about in the network dynamics of distant somatotopic cortical neuronal ensembles. This is the first demonstration of successfully combining optogenetics and neuronal ensemble recordings with reverse microdialysis. This combination of techniques overcomes some of the disadvantages that are associated with the use of intracerebral injection of a drug-containing solution at the site of laser activation. The combination of reverse microdialysis, silicone probe recordings and optogenetics can unravel the short and long-term effects of specific transmitter- and voltage-gated channels on laser-modulated firing at the site of optogenetic stimulation and the actions that these manipulations exert on distant neuronal populations. Copyright © 2014. Published by Elsevier B.V.

The median preoptic nucleus reciprocally modulates activity of arousal-related and sleep-related neurons in the perifornical lateral hypothalamus.

PubMed

Suntsova, Natalia; Guzman-Marin, Ruben; Kumar, Sunil; Alam, Md Noor; Szymusiak, Ronald; McGinty, Dennis

2007-02-14

The perifornical-lateral hypothalamic area (PF/LH) contains neuronal groups playing an important role in control of waking and sleep. Among the brain regions that regulate behavioral states, one of the strongest sources of projections to the PF/LH is the median preoptic nucleus (MnPN) containing a sleep-active neuronal population. To evaluate the role of MnPN afferents in the control of PF/LH neuronal activity, we studied the responses of PF/LH cells to electrical stimulation or local chemical manipulation of the MnPN in freely moving rats. Single-pulse electrical stimulation evoked responses in 79% of recorded PF/LH neurons. No cells were activated antidromically. Direct and indirect transsynaptic effects depended on sleep-wake discharge pattern of PF/LH cells. The majority of arousal-related neurons, that is, cells discharging at maximal rates during active waking (AW) or during AW and rapid eye movement (REM) sleep, exhibited exclusively or initially inhibitory responses to stimulation. Sleep-related neurons, the cells with elevated discharge during non-REM and REM sleep or selectively active in REM sleep, exhibited exclusively or initially excitatory responses. Activation of the MnPN via microdialytic application of L-glutamate or bicuculline resulted in reduced discharge of arousal-related and in excitation of sleep-related PF/LH neurons. Deactivation of the MnPN with muscimol caused opposite effects. The results indicate that the MnPN contains subset(s) of neurons, which exert inhibitory control over arousal-related and excitatory control over sleep-related PF/LH neurons. We hypothesize that MnPN sleep-active neuronal group has both inhibitory and excitatory outputs that participate in the inhibitory control of arousal-promoting PF/LH mechanisms.

Feedforward and feedback inhibition in neostriatal GABAergic spiny neurons.

PubMed

Tepper, James M; Wilson, Charles J; Koós, Tibor

2008-08-01

There are two distinct inhibitory GABAergic circuits in the neostriatum. The feedforward circuit consists of a relatively small population of GABAergic interneurons that receives excitatory input from the neocortex and exerts monosynaptic inhibition onto striatal spiny projection neurons. The feedback circuit comprises the numerous spiny projection neurons and their interconnections via local axon collaterals. This network has long been assumed to provide the majority of striatal GABAergic inhibition and to sharpen and shape striatal output through lateral inhibition, producing increased activity in the most strongly excited spiny cells at the expense of their less strongly excited neighbors. Recent results, mostly from recording experiments of synaptically connected pairs of neurons, have revealed that the two GABAergic circuits differ markedly in terms of the total number of synapses made by each, the strength of the postsynaptic response detected at the soma, the extent of presynaptic convergence and divergence and the net effect of the activation of each circuit on the postsynaptic activity of the spiny neuron. These data have revealed that the feedforward inhibition is powerful and widespread, with spiking in a single interneuron being capable of significantly delaying or even blocking the generation of spikes in a large number of postsynaptic spiny neurons. In contrast, the postsynaptic effects of spiking in a single presynaptic spiny neuron on postsynaptic spiny neurons are weak when measured at the soma, and unable to significantly affect spike timing or generation. Further, reciprocity of synaptic connections between spiny neurons is only rarely observed. These results suggest that the bulk of the fast inhibition that has the strongest effects on spiny neuron spike timing comes from the feedforward interneuronal system whereas the axon collateral feedback system acts principally at the dendrites to control local excitability as well as the overall level of activity of the spiny neuron.

Involvement of Receptor-like Protein Tyrosine Phosphatase ζ/RPTPβ and Its Ligand Pleiotrophin/Heparin-binding Growth-associated Molecule (HB-GAM) in Neuronal Migration

PubMed Central

Maeda, Nobuaki; Noda, Masaharu

1998-01-01

Pleiotrophin/heparin-binding growth-associated molecule (HB-GAM) is a specific ligand of protein tyrosine phosphatase ζ (PTPζ)/receptor-like protein tyrosine phosphatase β (RPTPβ) expressed in the brain as a chondroitin sulfate proteoglycan. Pleiotrophin and PTPζ isoforms are localized along the radial glial fibers, a scaffold for neuronal migration, suggesting that these molecules are involved in migratory processes of neurons during brain development. In this study, we examined the roles of pleiotrophin-PTPζ interaction in the neuronal migration using cell migration assay systems with glass fibers and Boyden chambers. Pleiotrophin and poly-l-lysine coated on the substratums stimulated cell migration of cortical neurons, while laminin, fibronectin, and tenascin exerted almost no effect. Pleiotrophin-induced and poly-l-lysine–induced neuronal migrations showed significant differences in sensitivity to various molecules and reagents. Polyclonal antibodies against the extracellular domain of PTPζ, PTPζ-S, an extracellular secreted form of PTPζ, and sodium vanadate, a protein tyrosine phosphatase inhibitor, added into the culture medium strongly suppressed specifically the pleiotrophin-induced neuronal migration. Furthermore, chondroitin sulfate C but not chondroitin sulfate A inhibited pleiotrophin-induced neuronal migration, in good accordance with our previous findings that chondroitin sulfate constitutes a part of the pleiotrophin-binding site of PTPζ, and PTPζ-pleiotrophin binding is inhibited by chondroitin sulfate C but not by chondroitin sulfate A. Immunocytochemical analysis indicated that the transmembrane forms of PTPζ are expressed on the migrating neurons especially at the lamellipodia along the leading processes. These results suggest that PTPζ is involved in the neuronal migration as a neuronal receptor of pleiotrophin distributed along radial glial fibers. PMID:9660874

Augmentation of glycolytic metabolism by meclizine is indispensable for protection of dorsal root ganglion neurons from hypoxia-induced mitochondrial compromise.

PubMed

Zhuo, Ming; Gorgun, Murat F; Englander, Ella W

2016-10-01

To meet energy demands, dorsal root ganglion (DRG) neurons harbor high mitochondrial content, which renders them acutely vulnerable to disruptions of energy homeostasis. While neurons typically rely on mitochondrial energy production and have not been associated with metabolic plasticity, new studies reveal that meclizine, a drug, recently linked to modulations of energy metabolism, protects neurons from insults that disrupt energy homeostasis. We show that meclizine rapidly enhances glycolysis in DRG neurons and that glycolytic metabolism is indispensable for meclizine-exerted protection of DRG neurons from hypoxic stress. We report that supplementation of meclizine during hypoxic exposure prevents ATP depletion, preserves NADPH and glutathione stores, curbs reactive oxygen species (ROS) and attenuates mitochondrial clustering in DRG neurites. Using extracellular flux analyzer, we show that in cultured DRG neurons meclizine mitigates hypoxia-induced loss of mitochondrial respiratory capacity. Respiratory capacity is a measure of mitochondrial fitness and cell ability to meet fluctuating energy demands and therefore, a key determinant of cellular fate. While meclizine is an 'old' drug with long record of clinical use, its ability to modulate energy metabolism has been uncovered only recently. Our findings documenting neuroprotection by meclizine in a setting of hypoxic stress reveal previously unappreciated metabolic plasticity of DRG neurons as well as potential for pharmacological harnessing of the newly discovered metabolic plasticity for protection of peripheral nervous system under mitochondria compromising conditions. Copyright © 2016 Elsevier Inc. All rights reserved.

Endothelial nitric oxide synthase protects neurons against ischemic injury through regulation of brain-derived neurotrophic factor expression.

PubMed

Li, Shi-Ting; Pan, Jing; Hua, Xu-Ming; Liu, Hong; Shen, Sa; Liu, Jia-Fu; Li, Bin; Tao, Bang-Bao; Ge, Xiao-Li; Wang, Xu-Hui; Shi, Juan-Hong; Wang, Xiao-Qiang

2014-02-01

Several lines of evidence demonstrated that endothelial nitric oxide synthase (eNOS) confers protective effects during cerebral ischemia. In this study, we explored the underlying cellular and molecular mechanisms of neuroprotection by eNOS. A series of in vivo and in vitro ischemic models were employed to study the role of eNOS in maintaining neuronal survival and to identify the downstream factors. The current data showed that pretreatment with a specific eNOS inhibitor, L-N5-(1-iminoethyl) ornithine (L-NIO), aggravated the neuronal loss in the rat cerebral ischemic model, accompanied by reduction in brain-derived neurotrophic factor (BDNF) level, which was consistent with the findings in an oxygen-glucose deprivation model (OGD) with two neuronal cells: primary rat cortical neurons and human neuroblastoma SH-SY5Y cells. Furthermore, the extensive neuronal loss induced by L-NIO was totally abolished by exogenous BDNF in both in vitro and in vivo models. On the other hand, eNOS overexpression through an adenoviral vector exerted a prominent protective effect on the neuronal cells subject to OGD, and the protective effect was totally abrogated by a neutralizing anti-BDNF antibody. Collectively, our results indicate that the neuroprotection of neuron-derived eNOS against the cerebral ischemia was mediated through the regulation of BDNF secretion. In conclusion, our discovery provides a novel explanation for the neuroprotective effect of eNOS under pathological ischemic conditions such as stroke. © 2014 John Wiley & Sons Ltd.

Nicotine modulates multiple regions in the limbic stress network regulating activation of hypophysiotrophic neurons in hypothalamic paraventricular nucleus.

PubMed

Yu, Guoliang; Sharp, Burt M

2012-08-01

Nicotine intake affects CNS responses to stressors. We reported that nicotine self-administration (SA) augmented the hypothalamo-pituitary-adrenal (HPA) stress response, in part because of the altered neurotransmission and neuropeptide expression within hypothalamic paraventricular nucleus (PVN). Limbic-PVN interactions involving medial prefrontal cortex, amygdala, and bed nucleus of the stria terminalis (BST) greatly impact the HPA stress response. Therefore, we investigated the effects of nicotine SA on stress-induced neuronal activation in limbic-PVN network, using c-Fos protein immunohistochemistry and retrograde tracing. Nicotine decreased stress-induced c-Fos in prelimbic cortex (PrL), anteroventral BST (avBST), and peri-PVN, but increased c-Fos induction in medial amygdala (MeA), locus coeruleus, and PVN. Fluoro-gold (FG) was injected into avBST or PVN, as GABAergic neurons in avBST projecting to PVN corticotrophin-releasing factor neurons relay information from both PrL glutamatergic and MeA GABAergic neurons. The stress-induced c-Fos expression in retrograde-labeled FG+ neurons was decreased in PrL by nicotine, but increased in MeA, and also reduced in avBST. Therefore, within limbic-PVN network, nicotine SA exerts selective regional effects on neuronal activation by stress. These findings expand the mechanistic framework by demonstrating altered limbic-BST-PVN interactions underlying the disinhibition of PVN corticotrophin-releasing factor neurons, an essential component of the amplified HPA response to stress by nicotine. © 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.

ΔN-Bcl-xL, a therapeutic target for neuroprotection

PubMed Central

Park, Han-A; Jonas, Elizabeth A.

2017-01-01

The B-cell lymphoma-extra large (Bcl-xL) is a mitochondrial anti-apoptotic protein that plays a role in neuroprotection. However, during excitotoxic stimulation, Bcl-xL undergoes caspase-dependent cleavage and produces a fragmented form, ΔN-Bcl-xL. Accumulation of ΔN-Bcl-xL is associated with mitochondrial dysfunction and neuronal death. Therefore, strategies to inhibit the activity or formation of ΔN-Bcl-xL protect the brain against excitotoxic injuries. Our team found that the pharmacological inhibitor ABT-737 exerts dose dependent effects in primary neurons. When primary hippocampal neurons were treated with 1 μM ABT-737, glutamate-mediated mitochondrial damage and neuronal death were exacerbated, whereas 10 nM ABT-737, a 100-fold lower concentration, protected mitochondrial function and enhanced neuronal viability against glutamate toxicity. In addition, we suggested acute vs. prolonged formation of ΔN-Bcl-xL may have different effects on mitochondrial or neuronal functions. Unlike acute production of ΔN-Bcl-xL by glutamate, overexpression of ΔN-Bcl-xL did not cause drastic changes in neuronal viability. We predicted that neurons undergo adaptation and may activate altered metabolism to compensate for ΔN-Bcl-xL-mediated mitochondrial dysfunction. Although the detailed mechanism of ABT-mediated neurotoxicity neuroprotection is still unclear, our study shows that the mitochondrial membrane protein ΔN-Bcl-xL is a central target for interventions. PMID:29239317

Antioxidants prevent ethanol-associated apoptosis in fetal rhombencephalic neurons.

PubMed

Antonio, Angeline M; Druse, Mary J

2008-04-14

It is well known that ethanol damages the developing nervous system by augmenting apoptosis. Previously, this laboratory reported that ethanol augments apoptosis in fetal rhombencephalic neurons, and that the increased apoptosis is associated with reduced activity of the phosphatidylinositol 3-kinase pathway and downstream expression of pro-survival genes. Other laboratories have shown that another mechanism by which ethanol induces apoptosis in developing neurons is through the generation of reactive oxygen species (ROS) and the associated oxidative stress. The present study used an in vitro model to investigate the potential neuroprotective effects of several antioxidants against ethanol-associated apoptosis in fetal rhombencephalic neurons. The investigated antioxidants included three phenolics: (-)-epigallocatechin-3-gallate (EGCG), a flavanoid polyphenol found in green tea; curcumin, found in tumeric; and resveratrol (3,5,4'-trihydroxystilbene), a component of red wine. Additional antioxidants, including melatonin, a naturally occurring indole, and alpha-lipoic acid, a naturally occurring dithiol, were also investigated. These studies demonstrated that a 24-hour treatment of fetal rhombencephalic neurons with 75 mM ethanol caused a 3-fold increase in the percentage of apoptotic neurons. However, co-treatment of these cultures with any of the five different antioxidants prevented ethanol-associated apoptosis. Antioxidant treatment did not alter the extent of apoptosis in control neurons, i.e., those cultured in the absence of ethanol. These studies showed that several classes of antioxidants can exert neuroprotection against ethanol-associated apoptosis in fetal rhombencephalic neurons.

The Slow Dynamics of Intracellular Sodium Concentration Increase the Time Window of Neuronal Integration: A Simulation Study

PubMed Central

Zylbertal, Asaph; Yarom, Yosef; Wagner, Shlomo

2017-01-01

Changes in intracellular Na+ concentration ([Na+]i) are rarely taken into account when neuronal activity is examined. As opposed to Ca2+, [Na+]i dynamics are strongly affected by longitudinal diffusion, and therefore they are governed by the morphological structure of the neurons, in addition to the localization of influx and efflux mechanisms. Here, we examined [Na+]i dynamics and their effects on neuronal computation in three multi-compartmental neuronal models, representing three distinct cell types: accessory olfactory bulb (AOB) mitral cells, cortical layer V pyramidal cells, and cerebellar Purkinje cells. We added [Na+]i as a state variable to these models, and allowed it to modulate the Na+ Nernst potential, the Na+-K+ pump current, and the Na+-Ca2+ exchanger rate. Our results indicate that in most cases [Na+]i dynamics are significantly slower than [Ca2+]i dynamics, and thus may exert a prolonged influence on neuronal computation in a neuronal type specific manner. We show that [Na+]i dynamics affect neuronal activity via three main processes: reduction of EPSP amplitude in repeatedly active synapses due to reduction of the Na+ Nernst potential; activity-dependent hyperpolarization due to increased activity of the Na+-K+ pump; specific tagging of active synapses by extended Ca2+ elevation, intensified by concurrent back-propagating action potentials or complex spikes. Thus, we conclude that [Na+]i dynamics should be considered whenever synaptic plasticity, extensive synaptic input, or bursting activity are examined. PMID:28970791

Pharmacological modulation of the voltage-gated neuronal Kv7/KCNQ/M-channel alters the intrinsic excitability and synaptic responses of pyramidal neurons in rat prefrontal cortex slices.

PubMed

Peng, Hui; Bian, Xi-Ling; Ma, Fu-Cui; Wang, Ke-Wei

2017-09-01

The prefrontal cortex (PFC) critical for higher cognition is implicated in neuropsychiatric diseases, such as Alzheimer's disease, depression and schizophrenia. The voltage-activated Kv7/KCNQ/M-channel or M-current modulates the neuronal excitability that defines the fundamental mechanism of brain function. However, whether M-current functions to regulate the excitability of PFC neurons remains elusive. In this study, we recorded the native M-current from PFC layer V pyramidal neurons in rat brain slices and showed that it modulated the intrinsic excitability and synaptic responses of PFC pyramidal neurons. Application of a specific M-channel blocker XE991 (40 μmol/L) or opener retigabine (10 μmol/L) resulted in inhibition or activation of M-current, respectively. In the current-clamp recordings, inhibition of M-current was evidenced by the increased average spike frequency and the reduced first inter-spike interval (ISI), spike onset latency and fast afterhyperpolarization (fAHP), whereas activation of M-current caused opposite responses. Furthermore, inhibition of M-current significantly increased the amplitude of excitatory postsynaptic potentials (EPSPs) and depolarized the resting membrane potential (RMP) without affecting the miniature EPSC (mEPSC) frequency. These data demonstrate that voltage-gated neuronal Kv7/KCNQ/M-current modulates the excitability and synaptic transmission of PFC neurons, suggesting that pharmacological modulation of M-current in the PFC may exert beneficial effects on cognitive deficits implicated in the pathophysiology of neuropsychiatric disorders.

Synthesis and pharmacology of alkanediguanidinium compounds that block the neuronal nicotinic acetylcholine receptor.

PubMed

Villarroya, M; Gandía, L; López, M G; García, A G; Cueto, S; García-Navio, J L; Alvarez-Builla, J

1996-08-01

Taking as models the polyamine toxin fraction FTX from the funnel-web spider venom, and the guanidinium moiety of guanethidine, a series of azaalkane-1, omega-diguanidinium salts were obtained. Some of them blocked ion fluxes through the neuronal nicotinic receptors for acetylcholine (nAChR). The blockade was exerted at submicromolar concentrations, suggesting a highly selective interaction with the nAChR. In fact, the active compounds on the nAChR ion channel did not recognize the voltage-dependent Na+ or Ca2+ channels of bovine adrenal chromaffin cells. Therefore, these compounds may be useful tools to clarify the functions of nAChR receptors in the central and peripheral nervous systems.

Neuroprotective Properties of Endocannabinoids N-Arachidonoyl Dopamine and N-Docosahexaenoyl Dopamine Examined in Neuronal Precursors Derived from Human Pluripotent Stem Cells.

PubMed

Novosadova, E V; Arsenyeva, E L; Manuilova, E S; Khaspekov, L G; Bobrov, M Yu; Bezuglov, V V; Illarioshkin, S N; Grivennikov, I A

2017-11-01

Neuroprotective properties of endocannabinoids N-arachidonoyl dopamine (NADA) and N-docosahexaenoyl dopamine (DHDA) were examined in neuronal precursor cells differentiated from human induced pluripotent stem cells and subjected to oxidative stress. Both compounds exerted neuroprotective activity, which was enhanced by elevating the concentration of the endocannabinoids within the 0.1-10 µM range. However, both agents at 10 µM concentration showed a marked toxic effect resulting in death of ~30% of the cells. Finally, antagonists of cannabinoid receptors as well as the receptor of the TRPV1 endovanilloid system did not hamper the neuroprotective effects of these endocannabinoids.

A simple method for characterizing passive and active neuronal properties: application to striatal neurons.

PubMed

Lepora, Nathan F; Blomeley, Craig P; Hoyland, Darren; Bracci, Enrico; Overton, Paul G; Gurney, Kevin

2011-11-01

The study of active and passive neuronal dynamics usually relies on a sophisticated array of electrophysiological, staining and pharmacological techniques. We describe here a simple complementary method that recovers many findings of these more complex methods but relies only on a basic patch-clamp recording approach. Somatic short and long current pulses were applied in vitro to striatal medium spiny (MS) and fast spiking (FS) neurons from juvenile rats. The passive dynamics were quantified by fitting two-compartment models to the short current pulse data. Lumped conductances for the active dynamics were then found by compensating this fitted passive dynamics within the current-voltage relationship from the long current pulse data. These estimated passive and active properties were consistent with previous more complex estimations of the neuron properties, supporting the approach. Relationships within the MS and FS neuron types were also evident, including a graduation of MS neuron properties consistent with recent findings about D1 and D2 dopamine receptor expression. Application of the method to simulated neuron data supported the hypothesis that it gives reasonable estimates of membrane properties and gross morphology. Therefore detailed information about the biophysics can be gained from this simple approach, which is useful for both classification of neuron type and biophysical modelling. Furthermore, because these methods rely upon no manipulations to the cell other than patch clamping, they are ideally suited to in vivo electrophysiology. © 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

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

PubMed

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

1990-01-01

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

Calretinin immunoreactivity in the claustrum of the rat

PubMed Central

Druga, Rastislav; Salaj, Martin; Barinka, Filip; Edelstein, Lawrence; Kubová, Hana

2015-01-01

The claustrum is a telencephalic structure which consists of dorsal segment adjoining the insular cortex and a ventral segment termed also endopiriform nucleus (END). The dorsal segment (claustrum) is divided into a dorsal and ventral zone, while the END is parcellated into dorsal, ventral and intermediate END. The claustrum and the END consist of glutamatergic projection neurons and GABAergic local interneurons coexpressing calcium binding proteins. Among neurons expressing calcium binding proteins the calretinin (CR)-immunoreactive interneurons exert specific functions in neuronal circuits, including disinhibition of excitatory neurons. Previous anatomical data indicate extensive and reciprocally organized claustral projections with cerebral cortex. We asked if the distribution of cells immunoreactive for CR delineates anatomical or functional subdivisions in the claustrum and in the END. Both segments of the claustrum and all subdivisions of the END contained CR immunoreactive neurons with varying distribution. The ventral zone of the claustrum exhibited weak labeling with isolated cell bodies and thin fibers and is devoid of immunoreactive puncta. Within the medial margin of the intermediate END we noted a group of strongly positive neurons. Cells immunoreactive for CR in all subdivisions of the claustrum and END were bipolar, multipolar and oval with smooth, beaded aspiny dendrites. Small number of CR-immunoreactive neurons displayed thin dendrites which enter to adjoining structures. Penetration of dendrites was reciprocal. These results show an inhomogenity over the claustrum and the END in distribution and types of CR immunoreactive neurons. The distribution of the CR-immunoreactive neurons respects the anatomical but not functional zones of the claustral complex. PMID:25653596

Methamphetamine induces heme oxygenase-1 expression in cortical neurons and glia to prevent its toxicity

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

Huang, Y.-N.; Wu, C.-H.; Department of Biology and Anatomy, National Defense Medical Center, Taipei, Taiwan 114

2009-11-01

The impairment of cognitive and motor functions in humans and animals caused by methamphetamine (METH) administration underscores the importance of METH toxicity in cortical neurons. The heme oxygenase-1 (HO-1) exerts a cytoprotective effect against various neuronal injures; however, it remains unclear whether HO-1 is involved in METH-induced toxicity. We used primary cortical neuron/glia cocultures to explore the role of HO-1 in METH-induced toxicity. Exposure of cultured cells to various concentrations of METH (0.1, 0.5, 1, 3, 5, and 10 mM) led to cytotoxicity in a concentration-dependent manner. A METH concentration of 5 mM, which caused 50% of neuronal death andmore » glial activation, was chosen for subsequent experiments. RT-PCR and Western blot analysis revealed that METH significantly induced HO-1 mRNA and protein expression, both preceded cell death. Double and triple immunofluorescence staining further identified HO-1-positive cells as activated astrocytes, microglia, and viable neurons, but not dying neurons. Inhibition of the p38 mitogen-activated protein kinase pathway significantly blocked HO-1 induction by METH and aggravated METH neurotoxicity. Inhibition of HO activity using tin protoporphyrine IX significantly reduced HO activity and exacerbated METH neurotoxicity. However, prior induction of HO-1 using cobalt protoporphyrine IX partially protected neurons from METH toxicity. Taken together, our results suggest that induction of HO-1 by METH via the p38 signaling pathway may be protective, albeit insufficient to completely protect cortical neurons from METH toxicity.« less

Area 18 of the cat: the first step in processing visual movement information.

PubMed

Orban, G A

1977-01-01

In cats, responses of area 18 neurons to different moving patterns were measured. The influence of three movement parameters--direction, angular velocity, and amplitude of movement--were tested. The results indicate that in area 18 no ideal movement detector exists, but that simple and complex cells each perform complementary operations of primary visual areas, i.e. analysis and detection of movement.

Expression of ESR1 in Glutamatergic and GABAergic Neurons Is Essential for Normal Puberty Onset, Estrogen Feedback, and Fertility in Female Mice.

PubMed

Cheong, Rachel Y; Czieselsky, Katja; Porteous, Robert; Herbison, Allan E

2015-10-28

Circulating estradiol exerts a profound influence on the activity of the gonadotropin-releasing hormone (GnRH) neuronal network controlling fertility. Using genetic strategies enabling neuron-specific deletion of estrogen receptor α (Esr1), we examine here whether estradiol-modulated GABA and glutamate transmission are critical for the functioning of the GnRH neuron network in the female mouse. Using Vgat- and Vglut2-ires-Cre knock-in mice and ESR1 immunohistochemistry, we demonstrate that subpopulations of GABA and glutamate neurons throughout the limbic forebrain express ESR1, with ESR1-GABAergic neurons being more widespread and numerous than ESR1-glutamatergic neurons. We crossed Vgat- and Vglut2-ires-Cre mice with an Esr1(lox/lox) line to generate animals with GABA-neuron-specific or glutamate-neuron-specific deletion of Esr1. Vgat-ires-Cre;Esr1(lox/lox) mice were infertile, with abnormal estrous cycles, and exhibited a complete failure of the estrogen positive feedback mechanism responsible for the preovulatory GnRH surge. However, puberty onset and estrogen negative feedback were normal. Vglut2-ires-Cre;Esr1(lox/lox) mice were also infertile but displayed a wider range of deficits, including advanced puberty onset, abnormal negative feedback, and abolished positive feedback. Whereas <25% of preoptic kisspeptin neurons expressed Cre in Vgat- and Vglut2-ires-Cre lines, ∼70% of arcuate kisspeptin neurons were targeted in Vglut2-ires-Cre;Esr1(lox/lox) mice, possibly contributing to their advanced puberty phenotype. These observations show that, unexpectedly, ESR1-GABA neurons are only essential for the positive feedback mechanism. In contrast, we reveal the key importance of ESR1 in glutamatergic neurons for multiple estrogen feedback loops within the GnRH neuronal network required for fertility in the female mouse. Copyright © 2015 the authors 0270-6474/15/3514533-11$15.00/0.

Single neuronal recordings using surface micromachined polysilicon microelectrodes.

PubMed

Muthuswamy, Jit; Okandan, Murat; Jackson, Nathan

2005-03-15

Bulk micromachining techniques of silicon have been used successfully in the past several years to microfabricate microelectrodes for monitoring single neurons in acute and chronic experiments. In this study we report for the first time a novel surface micromachining technique to microfabricate a very thin polysilicon microelectrode that can be used for monitoring single-unit activity in the central nervous system. The microelectrodes are 3 mm long and 50 microm x 3.75 microm in cross-section. Excellent signal to noise ratios in the order of 25-35 dB were obtained while recording neuronal action potentials. The microelectrodes successfully penetrated the brains after a microincision of the dura mater. Chronic implantation of the microprobe for up to 33 days produced only minor gliosis. Since the polysilicon shank acts as a conductor, additional processing steps involved in laying conductor lines on silicon substrates are avoided. Further, surface micromachining allows for fabricating extremely thin microelectrodes which could result in decreased inflammatory responses. We conclude that the polysilicon microelectrode reported here could be a complementary approach to bulk-micromachined silicon microelectrodes for chronic monitoring of single neurons in the central nervous system.

From point process observations to collective neural dynamics: Nonlinear Hawkes process GLMs, low-dimensional dynamics and coarse graining

PubMed Central

Truccolo, Wilson

2017-01-01

This review presents a perspective on capturing collective dynamics in recorded neuronal ensembles based on multivariate point process models, inference of low-dimensional dynamics and coarse graining of spatiotemporal measurements. A general probabilistic framework for continuous time point processes reviewed, with an emphasis on multivariate nonlinear Hawkes processes with exogenous inputs. A point process generalized linear model (PP-GLM) framework for the estimation of discrete time multivariate nonlinear Hawkes processes is described. The approach is illustrated with the modeling of collective dynamics in neocortical neuronal ensembles recorded in human and non-human primates, and prediction of single-neuron spiking. A complementary approach to capture collective dynamics based on low-dimensional dynamics (“order parameters”) inferred via latent state-space models with point process observations is presented. The approach is illustrated by inferring and decoding low-dimensional dynamics in primate motor cortex during naturalistic reach and grasp movements. Finally, we briefly review hypothesis tests based on conditional inference and spatiotemporal coarse graining for assessing collective dynamics in recorded neuronal ensembles. PMID:28336305

From point process observations to collective neural dynamics: Nonlinear Hawkes process GLMs, low-dimensional dynamics and coarse graining.

PubMed

Truccolo, Wilson

2016-11-01

This review presents a perspective on capturing collective dynamics in recorded neuronal ensembles based on multivariate point process models, inference of low-dimensional dynamics and coarse graining of spatiotemporal measurements. A general probabilistic framework for continuous time point processes reviewed, with an emphasis on multivariate nonlinear Hawkes processes with exogenous inputs. A point process generalized linear model (PP-GLM) framework for the estimation of discrete time multivariate nonlinear Hawkes processes is described. The approach is illustrated with the modeling of collective dynamics in neocortical neuronal ensembles recorded in human and non-human primates, and prediction of single-neuron spiking. A complementary approach to capture collective dynamics based on low-dimensional dynamics ("order parameters") inferred via latent state-space models with point process observations is presented. The approach is illustrated by inferring and decoding low-dimensional dynamics in primate motor cortex during naturalistic reach and grasp movements. Finally, we briefly review hypothesis tests based on conditional inference and spatiotemporal coarse graining for assessing collective dynamics in recorded neuronal ensembles. Published by Elsevier Ltd.

Cux1 and Cux2 regulate dendritic branching, spine morphology and synapses of the upper layer neurons of the cortex

PubMed Central

Cubelos, Beatriz; Sebastián-Serrano, Alvaro; Beccari, Leonardo; Calcagnotto, Maria Elisa; Cisneros, Elsa; Kim, Seonhee; Dopazo, Ana; Alvarez-Dolado, Manuel; Redondo, Juan Miguel; Bovolenta, Paola; Walsh, Christopher A.; Nieto, Marta

2010-01-01

Summary Dendrite branching and spine formation determines the function of morphologically distinct and specialized neuronal subclasses. However, little is known about the programs instructing specific branching patterns in vertebrate neurons and whether such programs influence dendritic spines and synapses. Using knockout and knockdown studies combined with morphological, molecular and electrophysiological analysis we show that the homeobox Cux1 and Cux2 are intrinsic and complementary regulators of dendrite branching, spine development and synapse formation in layer II–III neurons of the cerebral cortex. Cux genes control the number and maturation of dendritic spines partly through direct regulation of the expression of Xlr3b and Xlr4b, chromatin remodeling genes previously implicated in cognitive defects. Accordingly, abnormal dendrites and synapses in Cux2−/− mice correlate with reduced synaptic function and defects in working memory. These demonstrate critical roles of Cux in dendritogenesis and highlight novel subclass-specific mechanisms of synapse regulation that contribute to the establishment of cognitive circuits. PMID:20510857

Ventromedial medulla inhibitory neuron inactivation induces REM sleep without atonia and REM sleep behavior disorder.

PubMed

Valencia Garcia, Sara; Brischoux, Frédéric; Clément, Olivier; Libourel, Paul-Antoine; Arthaud, Sébastien; Lazarus, Michael; Luppi, Pierre-Hervé; Fort, Patrice

2018-02-05

Despite decades of research, there is a persistent debate regarding the localization of GABA/glycine neurons responsible for hyperpolarizing somatic motoneurons during paradoxical (or REM) sleep (PS), resulting in the loss of muscle tone during this sleep state. Combining complementary neuroanatomical approaches in rats, we first show that these inhibitory neurons are localized within the ventromedial medulla (vmM) rather than within the spinal cord. We then demonstrate their functional role in PS expression through local injections of adeno-associated virus carrying specific short-hairpin RNA in order to chronically impair inhibitory neurotransmission from vmM. After such selective genetic inactivation, rats display PS without atonia associated with abnormal and violent motor activity, concomitant with a small reduction of daily PS quantity. These symptoms closely mimic human REM sleep behavior disorder (RBD), a prodromal parasomnia of synucleinopathies. Our findings demonstrate the crucial role of GABA/glycine inhibitory vmM neurons in muscle atonia during PS and highlight a candidate brain region that can be susceptible to α-synuclein-dependent degeneration in RBD patients.

Cholinergic Signaling Exerts Protective Effects in Models of Sympathetic Hyperactivity-Induced Cardiac Dysfunction

PubMed Central

Gavioli, Mariana; Lara, Aline; Almeida, Pedro W. M.; Lima, Augusto Martins; Damasceno, Denis D.; Rocha-Resende, Cibele; Ladeira, Marina; Resende, Rodrigo R.; Martinelli, Patricia M.; Melo, Marcos Barrouin; Brum, Patricia C.; Fontes, Marco Antonio Peliky; Souza Santos, Robson A.; Prado, Marco A. M.; Guatimosim, Silvia

2014-01-01

Cholinergic control of the heart is exerted by two distinct branches; the autonomic component represented by the parasympathetic nervous system, and the recently described non-neuronal cardiomyocyte cholinergic machinery. Previous evidence has shown that reduced cholinergic function leads to deleterious effects on the myocardium. Yet, whether conditions of increased cholinergic signaling can offset the pathological remodeling induced by sympathetic hyperactivity, and its consequences for these two cholinergic axes are unknown. Here, we investigated two models of sympathetic hyperactivity: i) the chronic beta-adrenergic receptor stimulation evoked by isoproterenol (ISO), and ii) the α2A/α2C-adrenergic receptor knockout (KO) mice that lack pre-synaptic adrenergic receptors. In both models, cholinergic signaling was increased by administration of the cholinesterase inhibitor, pyridostigmine. First, we observed that isoproterenol produces an autonomic imbalance characterized by increased sympathetic and reduced parasympathetic tone. Under this condition transcripts for cholinergic proteins were upregulated in ventricular myocytes, indicating that non-neuronal cholinergic machinery is activated during adrenergic overdrive. Pyridostigmine treatment prevented the effects of ISO on autonomic function and on the ventricular cholinergic machinery, and inhibited cardiac remodeling. α2A/α2C-KO mice presented reduced ventricular contraction when compared to wild-type mice, and this dysfunction was also reversed by cholinesterase inhibition. Thus, the cardiac parasympathetic system and non-neuronal cardiomyocyte cholinergic machinery are modulated in opposite directions under conditions of increased sympathetic drive or ACh availability. Moreover, our data support the idea that pyridostigmine by restoring ACh availability is beneficial in heart disease. PMID:24992197

Ultrasonic modulation of neural circuit activity.

PubMed

Tyler, William J; Lani, Shane W; Hwang, Grace M

2018-06-01

Ultrasound (US) is recognized for its use in medical imaging as a diagnostic tool. As an acoustic energy source, US has become increasingly appreciated over the past decade for its ability to non-invasively modulate cellular activity including neuronal activity. Data obtained from a host of experimental models has shown that low-intensity US can reversibly modulate the physiological activity of neurons in peripheral nerves, spinal cord, and intact brain circuits. Experimental evidence indicates that acoustic pressures exerted by US act, in part, on mechanosensitive ion channels to modulate activity. While the precise mechanisms of action enabling US to both stimulate and suppress neuronal activity remain to be clarified, there are several advantages conferred by the physics of US that make it an appealing option for neuromodulation. For example, it can be focused with millimeter spatial resolutions through skull bone to deep-brain regions. By increasing our engineering capability to leverage such physical advantages while growing our understanding of how US affects neuronal function, the development of a new generation of non-invasive neurotechnology can be developed using ultrasonic methods. Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.

Mechanistic studies of the toxicity of zinc gluconate in the olfactory neuronal cell line Odora

PubMed Central

Hsieh, Heidi; Vignesh, Kavitha Subramanian; Deepe, George S.; Choubey, Divaker; Shertzer, Howard G.; Genter, Mary Beth

2016-01-01

Zinc is both an essential and potentially toxic metal. It is widely believed that oral zinc supplementation can reduce the effects of the common cold; however, there is strong clinical evidence that intranasal (IN) zinc gluconate (ZG) gel treatment for this purpose causes anosmia, or the loss of the sense of smell, in humans. Using the rat olfactory neuron cell line, Odora, we investigated the molecular mechanism by which zinc exposure exerts its toxic effects on olfactory neurons. Following treatment of Odora cells with 100 and 200 μM ZG for 0-24 h, RNA-seq and in silico analyses revealed up-regulation of pathways associated with zinc metal response, oxidative stress, and ATP production. We observed that Odora cells recovered from zinc-induced oxidative stress, but ATP depletion persisted with longer exposure to ZG. ZG exposure increased levels of NLRP3 and IL-1β protein levels in a time-dependent manner, suggesting that zinc exposure may cause an inflammasome-mediated cell death, pyroptosis, in olfactory neurons. PMID:27179668

Mechanistic studies of the toxicity of zinc gluconate in the olfactory neuronal cell line Odora.

PubMed

Hsieh, Heidi; Vignesh, Kavitha Subramanian; Deepe, George S; Choubey, Divaker; Shertzer, Howard G; Genter, Mary Beth

2016-09-01

Zinc is both an essential and potentially toxic metal. It is widely believed that oral zinc supplementation can reduce the effects of the common cold; however, there is strong clinical evidence that intranasal (IN) zinc gluconate (ZG) gel treatment for this purpose causes anosmia, or the loss of the sense of smell, in humans. Using the rat olfactory neuron cell line, Odora, we investigated the molecular mechanism by which zinc exposure exerts its toxic effects on olfactory neurons. Following treatment of Odora cells with 100 and 200μM ZG for 0-24h, RNA-seq and in silico analyses revealed up-regulation of pathways associated with zinc metal response, oxidative stress, and ATP production. We observed that Odora cells recovered from zinc-induced oxidative stress, but ATP depletion persisted with longer exposure to ZG. ZG exposure increased levels of NLRP3 and IL-1β protein levels in a time-dependent manner, suggesting that zinc exposure may cause an inflammasome-mediated cell death, pyroptosis, in olfactory neurons. Copyright © 2016 Elsevier Ltd. All rights reserved.

Enriched environment protects the nigrostriatal dopaminergic system and induces astroglial reaction in the 6-OHDA rat model of Parkinson's disease.

PubMed

Anastasía, Agustín; Torre, Luciana; de Erausquin, Gabriel A; Mascó, Daniel H

2009-05-01

Enriched environment (EE) is neuroprotective in several animal models of neurodegeneration. It stimulates the expression of trophic factors and modifies the astrocyte cell population which has been said to exert neuroprotective effects. We have investigated the effects of EE on 6-hydroxydopamine (6-OHDA)-induced neuronal death after unilateral administration to the medial forebrain bundle, which reaches 85-95% of dopaminergic neurons in the substantia nigra after 3 weeks. Continuous exposure to EE 3 weeks before and after 6-OHDA injection prevents neuronal death (assessed by tyrosine hydroxylase staining), protects the nigrostriatal pathway (assessed by Fluorogold retrograde labeling) and reduces motor impairment. Four days after 6-OHDA injection, EE was associated with a marked increase in glial fibrillary acidic protein staining and prevented neuronal death (assessed by Fluoro Jade-B) but not partial loss of tyrosine hydroxylase staining in the anterior substantia nigra. These results robustly demonstrate that EE preserves the entire nigrostriatal system against 6-OHDA-induced toxicity, and suggests that an early post-lesion astrocytic reaction may participate in the neuroprotective mechanism.

Modification of ubiquitin-C-terminal hydrolase-L1 by cyclopentenone prostaglandins exacerbates hypoxic injury

PubMed Central

Liu, Hao; Li, Wenjin; Ahmad, Muzamil; Miller, Tricia M.; Rose, Marie E.; Poloyac, Samuel M.; Uechi, Guy; Balasubramani, Manimalha; Hickey, Robert W.; Graham, Steven H.

2010-01-01

Cyclopentenone prostaglandins (CyPGs), such as 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), are active prostaglandin metabolites exerting a variety of biological effects that may be important in the pathogenesis of neurological diseases. Ubiquitin-C-terminal hydrolase L1 (UCH-L1) is a brain specific deubiquitinating enzyme whose aberrant function has been linked to neurodegenerative disorders. We report that [15d-PGJ2] detected by quadrapole mass spectrometry (MS) increases in rat brain after temporary focal ischemia, and that treatment with 15d-PGJ2 induces accumulation of ubiquitinated proteins and exacerbates cell death in normoxic and hypoxic primary neurons. 15d-PGJ2 covalently modifies UCH-L1 and inhibits its hydrolase activity. Pharmacologic inhibition of UCH-L1 exacerbates hypoxic neuronal death while transduction with a TAT-UCH-L1 fusion protein protects neurons from hypoxia. These studies indicate UCH-L1 function is important in hypoxic neuronal death and excessive production of CyPGs after stroke may exacerbate ischemic injury by modification and inhibition of UCH-L1. PMID:20933087

The Visual Orientation Memory of "Drosophila" Requires Foraging (PKG) Upstream of Ignorant (RSK2) in Ring Neurons of the Central Complex

ERIC Educational Resources Information Center

Kuntz, Sara; Poeck, Burkhard; Sokolowski, Marla B.; Strauss, Roland

2012-01-01

Orientation and navigation in a complex environment requires path planning and recall to exert goal-driven behavior. Walking "Drosophila" flies possess a visual orientation memory for attractive targets which is localized in the central complex of the adult brain. Here we show that this type of working memory requires the cGMP-dependent protein…

Dual embedded agency: physicians implement integrative medicine in health-care organizations.

PubMed

Keshet, Yael

2013-11-01

The paradox of embedded agency addresses the question of how embedded agents are able to conceive of new ideas and practices and then implement them in institutionalized organizations if social structures exert so powerful an influence on behavior, and agents operate within a framework of institutional constraints. This article proposes that dual embedded agency may provide an explanation of the paradox. The article draws from an ethnographic study that examined the ways in which dual-trained physicians, namely medical doctors trained also in some modality of complementary and alternative medicine, integrate complementary and alternative medicine into the biomedical fortress of mainstream health-care organizations. Participant observations were conducted during the years 2006-2011. The observed physicians were found to be embedded in two diverse medical cultures and to have a hybrid professional identity that comprised two sets of health-care values. Seeking to introduce new ideas and practices associated with complementary and alternative medicine to medical institutions, they maneuvered among the constraints of institutional structures while using these very structures, in an isomorphic mode of action, as a platform for launching complementary and alternative medicine practices and values. They drew on the complementary and alternative medicine philosophical principle of interconnectedness and interdependency of seemingly polar opposites or contrary forces and acted to achieve change by means of nonadversarial strategies. By addressing the structure-agency dichotomy, this study contributes to the literature on change in institutionalized health-care organizations. It likewise contributes both theoretically and empirically to the study of integrative medicine and to the further development of this relatively new area of inquiry within the sociology of medicine.

Coordination of distinct but interacting rhythmic motor programs by a modulatory projection neuron using different co-transmitters in different ganglia

PubMed Central

Kwiatkowski, Molly A.; Gabranski, Emily R.; Huber, Kristen E.; Chapline, M. Christine; Christie, Andrew E.; Dickinson, Patsy S.

2013-01-01

SUMMARY While many neurons are known to contain multiple neurotransmitters, the specific roles played by each co-transmitter within a neuron are often poorly understood. Here, we investigated the roles of the co-transmitters of the pyloric suppressor (PS) neurons, which are located in the stomatogastric nervous system (STNS) of the lobster Homarus americanus. The PS neurons are known to contain histamine; using RT-PCR, we identified a second co-transmitter as the FMRFamide-like peptide crustacean myosuppressin (Crust-MS). The modulatory effects of Crust-MS application on the gastric mill and pyloric patterns, generated in the stomatogastric ganglion (STG), closely resembled those recorded following extracellular PS neuron stimulation. To determine whether histamine plays a role in mediating the effects of the PS neurons in the STG, we bath-applied histamine receptor antagonists to the ganglion. In the presence of the antagonists, the histamine response was blocked, but Crust-MS application and PS stimulation continued to modulate the gastric and pyloric patterns, suggesting that PS effects in the STG are mediated largely by Crust-MS. PS neuron stimulation also excited the oesophageal rhythm, produced in the commissural ganglia (CoGs) of the STNS. Application of histamine, but not Crust-MS, to the CoGs mimicked this effect. Histamine receptor antagonists blocked the ability of both histamine and PS stimulation to excite the oesophageal rhythm, providing strong evidence that the PS neurons use histamine in the CoGs to exert their effects. Overall, our data suggest that the PS neurons differentially utilize their co-transmitters in spatially distinct locations to coordinate the activity of three independent networks. PMID:23393282

Coordination of distinct but interacting rhythmic motor programs by a modulatory projection neuron using different co-transmitters in different ganglia.

PubMed

Kwiatkowski, Molly A; Gabranski, Emily R; Huber, Kristen E; Chapline, M Christine; Christie, Andrew E; Dickinson, Patsy S

2013-05-15

While many neurons are known to contain multiple neurotransmitters, the specific roles played by each co-transmitter within a neuron are often poorly understood. Here, we investigated the roles of the co-transmitters of the pyloric suppressor (PS) neurons, which are located in the stomatogastric nervous system (STNS) of the lobster Homarus americanus. The PS neurons are known to contain histamine; using RT-PCR, we identified a second co-transmitter as the FMRFamide-like peptide crustacean myosuppressin (Crust-MS). The modulatory effects of Crust-MS application on the gastric mill and pyloric patterns, generated in the stomatogastric ganglion (STG), closely resembled those recorded following extracellular PS neuron stimulation. To determine whether histamine plays a role in mediating the effects of the PS neurons in the STG, we bath-applied histamine receptor antagonists to the ganglion. In the presence of the antagonists, the histamine response was blocked, but Crust-MS application and PS stimulation continued to modulate the gastric and pyloric patterns, suggesting that PS effects in the STG are mediated largely by Crust-MS. PS neuron stimulation also excited the oesophageal rhythm, produced in the commissural ganglia (CoGs) of the STNS. Application of histamine, but not Crust-MS, to the CoGs mimicked this effect. Histamine receptor antagonists blocked the ability of both histamine and PS stimulation to excite the oesophageal rhythm, providing strong evidence that the PS neurons use histamine in the CoGs to exert their effects. Overall, our data suggest that the PS neurons differentially utilize their co-transmitters in spatially distinct locations to coordinate the activity of three independent networks.

A computational relationship between thalamic sensory neural responses and contrast perception.

PubMed

Jiang, Yaoguang; Purushothaman, Gopathy; Casagrande, Vivien A

2015-01-01

Uncovering the relationship between sensory neural responses and perceptual decisions remains a fundamental problem in neuroscience. Decades of experimental and modeling work in the sensory cortex have demonstrated that a perceptual decision pool is usually composed of tens to hundreds of neurons, the responses of which are significantly correlated not only with each other, but also with the behavioral choices of an animal. Few studies, however, have measured neural activity in the sensory thalamus of awake, behaving animals. Therefore, it remains unclear how many thalamic neurons are recruited and how the information from these neurons is pooled at subsequent cortical stages to form a perceptual decision. In a previous study we measured neural activity in the macaque lateral geniculate nucleus (LGN) during a two alternative forced choice (2AFC) contrast detection task, and found that single LGN neurons were significantly correlated with the monkeys' behavioral choices, despite their relatively poor contrast sensitivity and a lack of overall interneuronal correlations. We have now computationally tested a number of specific hypotheses relating these measured LGN neural responses to the contrast detection behavior of the animals. We modeled the perceptual decisions with different numbers of neurons and using a variety of pooling/readout strategies, and found that the most successful model consisted of about 50-200 LGN neurons, with individual neurons weighted differentially according to their signal-to-noise ratios (quantified as d-primes). These results supported the hypothesis that in contrast detection the perceptual decision pool consists of multiple thalamic neurons, and that the response fluctuations in these neurons can influence contrast perception, with the more sensitive thalamic neurons likely to exert a greater influence.

Study of the protective effects of nootropic agents against neuronal damage induced by amyloid-beta (fragment 25-35) in cultured hippocampal neurons.

PubMed

Sendrowski, Krzysztof; Sobaniec, Wojciech; Stasiak-Barmuta, Anna; Sobaniec, Piotr; Popko, Janusz

2015-04-01

Alzheimer's disease (AD) is a common neurodegenerative disorder, in which progressive neuron loss, mainly in the hippocampus, is observed. The critical events in the pathogenesis of AD are associated with accumulation of β-amyloid (Aβ) peptides in the brain. Deposits of Aβ initiate a neurotoxic "cascade" leading to apoptotic death of neurons. Aim of this study was to assess a putative neuroprotective effects of two nootropic drugs: piracetam (PIR) and levetiracetam (LEV) on Aβ-injured hippocampal neurons in culture. Primary cultures of rat's hippocampal neurons at 7 day in vitro were exposed to Aβ(25-35) in the presence or absence of nootropics in varied concentrations. Flow cytometry with Annexin V/PI staining was used for counting and establishing neurons as viable, necrotic or apoptotic. Additionally, release of lactate dehydrogenase (LDH) to the culture medium, as a marker of cell death, was evaluated. Aβ(25-35) caused concentration-dependent death of about one third number of hippocampal neurons, mainly through an apoptotic pathway. In drugs-containing cultures, number of neurons injured with 20 μM Aβ(25-35) was about one-third lesser for PIR and almost two-fold lesser for LEV. When 40 μM Aβ(25-35) was used, only LEV exerted beneficial neuroprotective action, while PIR was ineffective. Our results suggest the protective potential of both studied nootropics against Aβ-induced death of cultured hippocampal neurons with more powerful neuroprotective effects of LEV. Copyright © 2014 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Rescue of hyperexcitability in hippocampal CA1 neurons from Mecp2 (-/y) mouse through surface potential neutralization

PubMed Central

Mironov, Sergej L.

2018-01-01

Hyperventilation is a known feature of Rett syndrome (RTT). However, how hyperventilation is related to other RTT symptoms such as hyperexcitability is unknown. Intense breathing during hyperventilation induces hypocapnia and culminates in respiratory alkalosis. Alkalinization of extracellular milieu can trigger epilepsy in patients who already have neuronal hyperexcitability. By combining patch-clamp electrophysiology and quantitative glutamate imaging, we compared excitability of CA1 neurons of WT and Mecp2 (-/y) mice, and analyzed the biophysical properties of subthreshold membrane channels. The results show that Mecp2 (-/y) CA1 neurons are hyperexcitable in normal pH (7.4) and are increasingly vulnerable to alkaline extracellular pH (8.4), during which their excitability increased further. Under normal pH conditions, an abnormal negative shift in the voltage-dependencies of HCN (hyperpolarization-activated cyclic nucleotide-gated) and calcium channels in the CA1 neurons of Mecp2 (-/y) mice was observed. Alkaline pH also enhanced excitability in wild-type (WT) CA1 neurons through modulation of the voltage dependencies of HCN- and calcium channels. Additionally alkaline pH augmented spontaneous glutamate release and burst firing in WT CA1 neurons. Conversely, acidic pH (6.4) and 8 mM Mg2+ exerted the opposite effect, and diminished hyperexcitability in Mecp2 (-/y) CA1 neurons. We propose that the observed effects of pH and Mg2+ are mediated by changes in the neuronal membrane surface potential, which consecutively modulates the gating of HCN and calcium channels. The results provide insight to pivotal cellular mechanisms that can regulate neuronal excitability and help to devise treatment strategies for hyperexcitability induced symptoms of Rett syndrome. PMID:29621262

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

PubMed

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

2017-07-01

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

Human neural stem cells improve cognition and promote synaptic growth in two complementary transgenic models of Alzheimer's disease and neuronal loss.

PubMed

Ager, Rahasson R; Davis, Joy L; Agazaryan, Andy; Benavente, Francisca; Poon, Wayne W; LaFerla, Frank M; Blurton-Jones, Mathew

2015-07-01

Alzheimer's disease (AD) is the most prevalent age-related neurodegenerative disorder, affecting over 35 million people worldwide. Pathologically, AD is characterized by the progressive accumulation of β-amyloid (Aβ) plaques and neurofibrillary tangles within the brain. Together, these pathologies lead to marked neuronal and synaptic loss and corresponding impairments in cognition. Current treatments, and recent clinical trials, have failed to modify the clinical course of AD; thus, the development of novel and innovative therapies is urgently needed. Over the last decade, the potential use of stem cells to treat cognitive impairment has received growing attention. Specifically, neural stem cell transplantation as a treatment for AD offers a novel approach with tremendous therapeutic potential. We previously reported that intrahippocampal transplantation of murine neural stem cells (mNSCs) can enhance synaptogenesis and improve cognition in 3xTg-AD mice and the CaM/Tet-DT(A) model of hippocampal neuronal loss. These promising findings prompted us to examine a human neural stem cell population, HuCNS-SC, which has already been clinically tested for other neurodegenerative disorders. In this study, we provide the first evidence that transplantation of research grade HuCNS-SCs can improve cognition in two complementary models of neurodegeneration. We also demonstrate that HuCNS-SC cells can migrate and differentiate into immature neurons and glia and significantly increase synaptic and growth-associated markers in both 3xTg-AD and CaM/Tet-DTA mice. Interestingly, improvements in aged 3xTg-AD mice were not associated with altered Aβ or tau pathology. Rather, our findings suggest that human NSC transplantation improves cognition by enhancing endogenous synaptogenesis. Taken together, our data provide the first preclinical evidence that human NSC transplantation could be a safe and effective therapeutic approach for treating AD. © 2014 The Authors. Hippocampus Published by Wiley Periodicals, Inc.

The Relevance of AgRP Neuron-Derived GABA Inputs to POMC Neurons Differs for Spontaneous and Evoked Release

PubMed Central

2017-01-01

Hypothalamic agouti-related peptide (AgRP) neurons potently stimulate food intake, whereas proopiomelanocortin (POMC) neurons inhibit feeding. Whether AgRP neurons exert their orexigenic actions, at least in part, by inhibiting anorexigenic POMC neurons remains unclear. Here, the connectivity between GABA-releasing AgRP neurons and POMC neurons was examined in brain slices from male and female mice. GABA-mediated spontaneous IPSCs (sIPSCs) in POMC neurons were unaffected by disturbing GABA release from AgRP neurons either by cell type-specific deletion of the vesicular GABA transporter or by expression of botulinum toxin in AgRP neurons to prevent vesicle-associated membrane protein 2-dependent vesicle fusion. Additionally, there was no difference in the ability of μ-opioid receptor (MOR) agonists to inhibit sIPSCs in POMC neurons when MORs were deleted from AgRP neurons, and activation of the inhibitory designer receptor hM4Di on AgRP neurons did not affect sIPSCs recorded from POMC neurons. These approaches collectively indicate that AgRP neurons do not significantly contribute to the strong spontaneous GABA input to POMC neurons. Despite these observations, optogenetic stimulation of AgRP neurons reliably produced evoked IPSCs in POMC neurons, leading to the inhibition of POMC neuron firing. Thus, AgRP neurons can potently affect POMC neuron function without contributing a significant source of spontaneous GABA input to POMC neurons. Together, these results indicate that the relevance of GABAergic inputs from AgRP to POMC neurons is state dependent and highlight the need to consider different types of transmitter release in circuit mapping and physiologic regulation. SIGNIFICANCE STATEMENT Agouti-related peptide (AgRP) neurons play an important role in driving food intake, while proopiomelanocortin (POMC) neurons inhibit feeding. Despite the importance of these two well characterized neuron types in maintaining metabolic homeostasis, communication between these cells remains poorly understood. To provide clarity to this circuit, we made electrophysiological recordings from mouse brain slices and found that AgRP neurons do not contribute spontaneously released GABA onto POMC neurons, although when activated with channelrhodopsin AgRP neurons inhibit POMC neurons through GABA-mediated transmission. These findings indicate that the relevance of AgRP to POMC neuron GABA connectivity depends on the state of AgRP neuron activity and suggest that different types of transmitter release should be considered when circuit mapping. PMID:28667175

The Relevance of AgRP Neuron-Derived GABA Inputs to POMC Neurons Differs for Spontaneous and Evoked Release.

PubMed

Rau, Andrew R; Hentges, Shane T

2017-08-02

Hypothalamic agouti-related peptide (AgRP) neurons potently stimulate food intake, whereas proopiomelanocortin (POMC) neurons inhibit feeding. Whether AgRP neurons exert their orexigenic actions, at least in part, by inhibiting anorexigenic POMC neurons remains unclear. Here, the connectivity between GABA-releasing AgRP neurons and POMC neurons was examined in brain slices from male and female mice. GABA-mediated spontaneous IPSCs (sIPSCs) in POMC neurons were unaffected by disturbing GABA release from AgRP neurons either by cell type-specific deletion of the vesicular GABA transporter or by expression of botulinum toxin in AgRP neurons to prevent vesicle-associated membrane protein 2-dependent vesicle fusion. Additionally, there was no difference in the ability of μ-opioid receptor (MOR) agonists to inhibit sIPSCs in POMC neurons when MORs were deleted from AgRP neurons, and activation of the inhibitory designer receptor hM4Di on AgRP neurons did not affect sIPSCs recorded from POMC neurons. These approaches collectively indicate that AgRP neurons do not significantly contribute to the strong spontaneous GABA input to POMC neurons. Despite these observations, optogenetic stimulation of AgRP neurons reliably produced evoked IPSCs in POMC neurons, leading to the inhibition of POMC neuron firing. Thus, AgRP neurons can potently affect POMC neuron function without contributing a significant source of spontaneous GABA input to POMC neurons. Together, these results indicate that the relevance of GABAergic inputs from AgRP to POMC neurons is state dependent and highlight the need to consider different types of transmitter release in circuit mapping and physiologic regulation. SIGNIFICANCE STATEMENT Agouti-related peptide (AgRP) neurons play an important role in driving food intake, while proopiomelanocortin (POMC) neurons inhibit feeding. Despite the importance of these two well characterized neuron types in maintaining metabolic homeostasis, communication between these cells remains poorly understood. To provide clarity to this circuit, we made electrophysiological recordings from mouse brain slices and found that AgRP neurons do not contribute spontaneously released GABA onto POMC neurons, although when activated with channelrhodopsin AgRP neurons inhibit POMC neurons through GABA-mediated transmission. These findings indicate that the relevance of AgRP to POMC neuron GABA connectivity depends on the state of AgRP neuron activity and suggest that different types of transmitter release should be considered when circuit mapping. Copyright © 2017 the authors 0270-6474/17/377362-11$15.00/0.

Ghrelin decreases firing activity of gonadotropin-releasing hormone (GnRH) neurons in an estrous cycle and endocannabinoid signaling dependent manner.

PubMed

Farkas, Imre; Vastagh, Csaba; Sárvári, Miklós; Liposits, Zsolt

2013-01-01

The orexigenic peptide, ghrelin is known to influence function of GnRH neurons, however, the direct effects of the hormone upon these neurons have not been explored, yet. The present study was undertaken to reveal expression of growth hormone secretagogue receptor (GHS-R) in GnRH neurons and elucidate the mechanisms of ghrelin actions upon them. Ca(2+)-imaging revealed a ghrelin-triggered increase of the Ca(2+)-content in GT1-7 neurons kept in a steroid-free medium, which was abolished by GHS-R-antagonist JMV2959 (10 µM) suggesting direct action of ghrelin. Estradiol (1nM) eliminated the ghrelin-evoked rise of Ca(2+)-content, indicating the estradiol dependency of the process. Expression of GHS-R mRNA was then confirmed in GnRH-GFP neurons of transgenic mice by single cell RT-PCR. Firing rate and burst frequency of GnRH-GFP neurons were lower in metestrous than proestrous mice. Ghrelin (40 nM-4 μM) administration resulted in a decreased firing rate and burst frequency of GnRH neurons in metestrous, but not in proestrous mice. Ghrelin also decreased the firing rate of GnRH neurons in males. The ghrelin-evoked alterations of the firing parameters were prevented by JMV2959, supporting the receptor-specific actions of ghrelin on GnRH neurons. In metestrous mice, ghrelin decreased the frequency of GABAergic mPSCs in GnRH neurons. Effects of ghrelin were abolished by the cannabinoid receptor type-1 (CB1) antagonist AM251 (1µM) and the intracellularly applied DAG-lipase inhibitor THL (10 µM), indicating the involvement of retrograde endocannabinoid signaling. These findings demonstrate that ghrelin exerts direct regulatory effects on GnRH neurons via GHS-R, and modulates the firing of GnRH neurons in an ovarian-cycle and endocannabinoid dependent manner.

The physiological basis of complementary and alternative medicines for polycystic ovary syndrome.

PubMed

Raja-Khan, Nazia; Stener-Victorin, Elisabet; Wu, XiaoKe; Legro, Richard S

2011-07-01

Polycystic ovary syndrome (PCOS) is a common endocrine disorder that is characterized by chronic hyperandrogenic anovulation leading to symptoms of hirsutism, acne, irregular menses, and infertility. Multiple metabolic and cardiovascular risk factors are associated with PCOS, including insulin resistance, obesity, type 2 diabetes, hypertension, inflammation, and subclinical atherosclerosis. However, current treatments for PCOS are only moderately effective at controlling symptoms and preventing complications. This article describes how the physiological effects of major complementary and alternative medicine (CAM) treatments could reduce the severity of PCOS and its complications. Acupuncture reduces hyperandrogenism and improves menstrual frequency in PCOS. Acupuncture's clinical effects are mediated via activation of somatic afferent nerves innervating the skin and muscle, which, via modulation of the activity in the somatic and autonomic nervous system, may modulate endocrine and metabolic functions in PCOS. Chinese herbal medicines and dietary supplements may also exert beneficial physiological effects in PCOS, but there is minimal evidence that these CAM treatments are safe and effective. Mindfulness has not been investigated in PCOS, but it has been shown to reduce psychological distress and exert positive effects on the central and autonomic nervous systems, hypothalamic-pituitary-adrenal axis, and immune system, leading to reductions in blood pressure, glucose, and inflammation. In conclusion, CAM treatments may have beneficial endocrine, cardiometabolic, and reproductive effects in PCOS. However, most studies of CAM treatments for PCOS are small, nonrandomized, or uncontrolled. Future well-designed studies are needed to further evaluate the safety, effectiveness, and mechanisms of CAM treatments for PCOS.

Anterior cingulate synapses in prefrontal areas 10 and 46 suggest differential influence in cognitive control

PubMed Central

Medalla, M.; Barbas, H.

2011-01-01

Dorsolateral prefrontal areas 46 and 10 are involved in distinct aspects of cognition. Area 46 has a key role in working memory tasks, and frontopolar area 10 is recruited in complex multi-task operations. Both areas are innervated by the anterior cingulate cortex (ACC) a region associated with emotions and memory, but is also important for attentional control through unknown synaptic mechanisms. Here we found that in rhesus monkeys (Macaca mulatta) most axon terminals labeled from tracers injected in ACC area 32 innervated spines of presumed excitatory neurons, but about 20–30% formed mostly large synapses with dendritic shafts of presumed inhibitory neurons in the upper layers (I–IIIa) of dorsolateral areas 10, 46, and 9. Moreover, area 32 terminals targeted preferentially calbindin and, to a lesser extent, calretinin neurons, which are thought to be inhibitory neurons that modulate the gain of task-relevant activity during working memory tasks. Area 46 was distinguished as recipient of more (by ~40%) area 32 synapses on putative inhibitory neurons. Area 10 stood apart as recipient of significantly larger (by ~40% in volume) area 32 terminals on spines of putative excitatory neurons. These synaptic specializations suggest that area 32 has complementary roles, potentially enhancing inhibition in area 46 and strengthening excitation in area 10, which may help direct attention to new tasks while temporarily holding in memory another task. PMID:21123554

Enhancing Perception of Contaminated Food through Acid-Mediated Modulation of Taste Neuron Responses

PubMed Central

Chen, Yan; Amrein, Hubert

2015-01-01

SUMMARY Background Natural foods not only contain nutrients, but also non-nutritious and potentially harmful chemicals. Thus, animals need to evaluate food content in order to make adequate feeding decisions. Results Here, we investigate the effects of acids on the taste neuron responses and on taste behavior of desirable, nutritious sugars and sugar/bitter compound mixtures in Drosophila melanogaster. Using Ca2+ imaging, we show that acids neither activate sweet nor bitter taste neurons in tarsal taste sensilla. However, they suppress responses to bitter compounds in bitter-sensing neurons. Moreover, acids reverse suppression of bitter compounds exerted on sweet-sensing neurons. Consistent with these observations, behavioral analyses show that bitter compound-mediated inhibition on feeding behavior is alleviated by acids. To investigate the cellular mechanism by which acids modulate these effects, we silenced bitter sensing gustatory neurons. Surprisingly, this intervention had little effect on acid-mediated de-repression of sweet neuron or feeding responses to either sugar/bitter compound mixtures, or sugar/bitter compound/acid mixtures, suggesting two independent pathways by which bitter compounds are sensed. Conclusions Our investigations reveal that acids, when presented in dietary relevant concentrations, enhance the perception of sugar/bitter compound mixtures. Drosophila’s natural food sources - fruits and cohabitating yeast - are rich in sugars and acids, but are rapidly colonized by microorganisms, such as fungi, protozoan parasites and bacteria, many of which produce bitter compounds. We propose that acids present in most fruits counteract the inhibitory effects of these bitter compounds during feeding. PMID:25131671

The V1a and V1b, but not V2, vasopressin receptor genes are expressed in the supraoptic nucleus of the rat hypothalamus, and the transcripts are essentially colocalized in the vasopressinergic magnocellular neurons.

PubMed

Hurbin, A; Boissin-Agasse, L; Orcel, H; Rabié, A; Joux, N; Desarménien, M G; Richard, P; Moos, F C

1998-11-01

We have identified and visualized the vasopressin (VP) receptors expressed by hypothalamic magnocellular neurons in supraoptic and paraventricular nuclei. To do this, we used RT-PCR on total RNA extracts from supraoptic nuclei or on single freshly dissociated supraoptic neurons, and in situ hybridization on frontal sections of hypothalamus of Wistar rats. The RT-PCR on supraoptic RNA extracts revealed that mainly V1a, but also V1b, subtypes of VP receptors are expressed from birth to adulthood. No V2 receptor messenger RNA (mRNA) was detected. Furthermore, the single-cell RT-nested PCR indicated that the V1a receptor mRNA is present in vasopressinergic magnocellular neurons. In light of these results, in situ hybridization was performed to visualize the V1a and V1b receptor mRNAs in supraoptic and paraventricular nuclei. Simultaneously, we coupled this approach to: 1) in situ hybridization detection of oxytocin or VP mRNAs; or 2) immunocytochemistry to detect the neuropeptides. This provided a way of identifying the neurons expressing perceptible amounts of V1a or V1b receptor mRNAs as vasopressinergic neurons. Here, we suggest that the autocontrol exerted specifically by VP on vasopressinergic neurons is mediated through, at least, V1a and V1b subtype receptors.

Screening with an NMNAT2-MSD platform identifies small molecules that modulate NMNAT2 levels in cortical neurons.

PubMed

Ali, Yousuf O; Bradley, Gillian; Lu, Hui-Chen

2017-03-07

Nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) is a key neuronal maintenance factor and provides potent neuroprotection in numerous preclinical models of neurological disorders. NMNAT2 is significantly reduced in Alzheimer's, Huntington's, Parkinson's diseases. Here we developed a Meso Scale Discovery (MSD)-based screening platform to quantify endogenous NMNAT2 in cortical neurons. The high sensitivity and large dynamic range of this NMNAT2-MSD platform allowed us to screen the Sigma LOPAC library consisting of 1280 compounds. This library had a 2.89% hit rate, with 24 NMNAT2 positive and 13 negative modulators identified. Western analysis was conducted to validate and determine the dose-dependency of identified modulators. Caffeine, one identified NMNAT2 positive-modulator, when systemically administered restored NMNAT2 expression in rTg4510 tauopathy mice to normal levels. We confirmed in a cell culture model that four selected positive-modulators exerted NMNAT2-specific neuroprotection against vincristine-induced cell death while four selected NMNAT2 negative modulators reduced neuronal viability in an NMNAT2-dependent manner. Many of the identified NMNAT2 positive modulators are predicted to increase cAMP concentration, suggesting that neuronal NMNAT2 levels are tightly regulated by cAMP signaling. Taken together, our findings indicate that the NMNAT2-MSD platform provides a sensitive phenotypic screen to detect NMNAT2 in neurons.

Screening with an NMNAT2-MSD platform identifies small molecules that modulate NMNAT2 levels in cortical neurons

PubMed Central

Ali, Yousuf O.; Bradley, Gillian; Lu, Hui-Chen

2017-01-01

Nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) is a key neuronal maintenance factor and provides potent neuroprotection in numerous preclinical models of neurological disorders. NMNAT2 is significantly reduced in Alzheimer’s, Huntington’s, Parkinson’s diseases. Here we developed a Meso Scale Discovery (MSD)-based screening platform to quantify endogenous NMNAT2 in cortical neurons. The high sensitivity and large dynamic range of this NMNAT2-MSD platform allowed us to screen the Sigma LOPAC library consisting of 1280 compounds. This library had a 2.89% hit rate, with 24 NMNAT2 positive and 13 negative modulators identified. Western analysis was conducted to validate and determine the dose-dependency of identified modulators. Caffeine, one identified NMNAT2 positive-modulator, when systemically administered restored NMNAT2 expression in rTg4510 tauopathy mice to normal levels. We confirmed in a cell culture model that four selected positive-modulators exerted NMNAT2-specific neuroprotection against vincristine-induced cell death while four selected NMNAT2 negative modulators reduced neuronal viability in an NMNAT2-dependent manner. Many of the identified NMNAT2 positive modulators are predicted to increase cAMP concentration, suggesting that neuronal NMNAT2 levels are tightly regulated by cAMP signaling. Taken together, our findings indicate that the NMNAT2-MSD platform provides a sensitive phenotypic screen to detect NMNAT2 in neurons. PMID:28266613

Phenytoin attenuates the hyper-exciting neurotransmission in cultured embryonic cortical neurons.

PubMed

Chou, Ming-Yi; Lee, Chun-Yao; Liou, Horng-Huei; Pan, Chien-Yuan

2014-08-01

Phenytoin is an effective anti-epileptic drug that inhibits Na(+) channel activities; however, how phenytoin modulates synaptic transmission to soothe epileptic symptoms is not clear. To characterize the effects of phenytoin regulation on neurotransmission, we studied the electrophysical properties of cultured embryonic cortical neurons. Phenytoin inhibited the inward Na(+) current in a dose-dependent manner with an IC50 of 16.8 μM, and at 100 μM, the inhibitory effect of phenytoin on the Na(+) current was proportional to the frequency applied. In cultured neurons, phenytoin significantly decreased the action potential firing rate and the peak potential. To study the effect of phenytoin in neurotransmission, we measured the Ca(2+) responses from stimulated target neurons and their neighboring neurons. Phenytoin significantly suppressed the Ca(2+) responses evoked by strong stimulations in the target and neighboring neurons, and exerted a decreased inhibitory effect under moderate stimulation. Picrotoxin, a GABAA receptor antagonist, enhanced the recorded spontaneous excitatory postsynaptic current activities. After picrotoxin-induced enhancement, phenytoin had a more pronounced effect on the suppression of the spontaneous hyper-exciting excitatory postsynaptic current (>100 pA), but it only mildly inhibited the general excitatory postsynaptic current. Our results demonstrate that phenytoin suppresses the efficacy of neurotransmission especially for the high-frequency stimulation by reducing the Na(+) channel activity and can potentially alleviate epileptiform activity. Copyright © 2014 Elsevier Ltd. All rights reserved.

IGF-I: A Key Growth Factor that Regulates Neurogenesis and Synaptogenesis from Embryonic to Adult Stages of the Brain

PubMed Central

Nieto-Estévez, Vanesa; Defterali, Çağla; Vicario-Abejón, Carlos

2016-01-01

The generation of neurons in the adult mammalian brain requires the activation of quiescent neural stem cells (NSCs). This activation and the sequential steps of neuron formation from NSCs are regulated by a number of stimuli, which include growth factors. Insulin-like growth factor-I (IGF-I) exert pleiotropic effects, regulating multiple cellular processes depending on their concentration, cell type, and the developmental stage of the animal. Although IGF-I expression is relatively high in the embryonic brain its levels drop sharply in the adult brain except in neurogenic regions, i.e., the hippocampus (HP) and the subventricular zone-olfactory bulb (SVZ-OB). By contrast, the expression of IGF-IR remains relatively high in the brain irrespective of the age of the animal. Evidence indicates that IGF-I influences NSC proliferation and differentiation into neurons and glia as well as neuronal maturation including synapse formation. Furthermore, recent studies have shown that IGF-I not only promote adult neurogenesis by regulating NSC number and differentiation but also by influencing neuronal positioning and migration as described during SVZ-OB neurogenesis. In this article we will revise and discuss the actions reported for IGF-I signaling in a variety of in vitro and in vivo models, focusing on the maintenance and proliferation of NSCs/progenitors, neurogenesis, and neuron integration in synaptic circuits. PMID:26941597

Bax regulates neuronal Ca2+ homeostasis.

PubMed

D'Orsi, Beatrice; Kilbride, Seán M; Chen, Gang; Perez Alvarez, Sergio; Bonner, Helena P; Pfeiffer, Shona; Plesnila, Nikolaus; Engel, Tobias; Henshall, David C; Düssmann, Heiko; Prehn, Jochen H M

2015-01-28

Excessive Ca(2+) entry during glutamate receptor overactivation ("excitotoxicity") induces acute or delayed neuronal death. We report here that deficiency in bax exerted broad neuroprotection against excitotoxic injury and oxygen/glucose deprivation in mouse neocortical neuron cultures and reduced infarct size, necrotic injury, and cerebral edema formation after middle cerebral artery occlusion in mice. Neuronal Ca(2+) and mitochondrial membrane potential (Δψm) analysis during excitotoxic injury revealed that bax-deficient neurons showed significantly reduced Ca(2+) transients during the NMDA excitation period and did not exhibit the deregulation of Δψm that was observed in their wild-type (WT) counterparts. Reintroduction of bax or a bax mutant incapable of proapoptotic oligomerization equally restored neuronal Ca(2+) dynamics during NMDA excitation, suggesting that Bax controlled Ca(2+) signaling independently of its role in apoptosis execution. Quantitative confocal imaging of intracellular ATP or mitochondrial Ca(2+) levels using FRET-based sensors indicated that the effects of bax deficiency on Ca(2+) handling were not due to enhanced cellular bioenergetics or increased Ca(2+) uptake into mitochondria. We also observed that mitochondria isolated from WT or bax-deficient cells similarly underwent Ca(2+)-induced permeability transition. However, when Ca(2+) uptake into the sarco/endoplasmic reticulum was blocked with the Ca(2+)-ATPase inhibitor thapsigargin, bax-deficient neurons showed strongly elevated cytosolic Ca(2+) levels during NMDA excitation, suggesting that the ability of Bax to support dynamic ER Ca(2+) handling is critical for cell death signaling during periods of neuronal overexcitation. Copyright © 2015 the authors 0270-6474/15/351706-17$15.00/0.

Nitric Oxide Exerts Basal and Insulin-Dependent Anorexigenic Actions in POMC Hypothalamic Neurons

PubMed Central

Wellhauser, Leigh; Chalmers, Jennifer A.

2016-01-01

The arcuate nucleus of the hypothalamus represents a key center for the control of appetite and feeding through the regulation of 2 key neuronal populations, notably agouti-related peptide/neuropeptide Y and proopimelanocortin (POMC)/cocaine- and amphetamine-regulated transcript neurons. Altered regulation of these neuronal networks, in particular the dysfunction of POMC neurons upon high-fat consumption, is a major pathogenic mechanism involved in the development of obesity and type 2 diabetes mellitus. Efforts are underway to preserve the integrity or enhance the functionality of POMC neurons in order to prevent or treat these metabolic diseases. Here, we report for the first time that the nitric oxide (NO−) donor, sodium nitroprusside (SNP) mediates anorexigenic actions in both hypothalamic tissue and hypothalamic-derived cell models by mediating the up-regulation of POMC levels. SNP increased POMC mRNA in a dose-dependent manner and enhanced α-melanocortin-secreting hormone production and secretion in mHypoA-POMC/GFP-2 cells. SNP also enhanced insulin-driven POMC expression likely by inhibiting the deacetylase activity of sirtuin 1. Furthermore, SNP enhanced insulin-dependent POMC expression, likely by reducing the transcriptional repression of Foxo1 on the POMC gene. Prolonged SNP exposure prevented the development of insulin resistance. Taken together, the NO− donor SNP enhances the anorexigenic potential of POMC neurons by promoting its transcriptional expression independent and in cooperation with insulin. Thus, increasing cellular NO− levels represents a hormone-independent method of promoting anorexigenic output from the existing POMC neuronal populations and may be advantageous in the fight against these prevalent disorders. PMID:26930171

Methamphetamine Inhibits the Glucose Uptake by Human Neurons and Astrocytes: Stabilization by Acetyl-L-Carnitine

PubMed Central

Szlachetka, Adam M.; Haorah, James

2011-01-01

Methamphetamine (METH), an addictive psycho-stimulant drug exerts euphoric effects on users and abusers. It is also known to cause cognitive impairment and neurotoxicity. Here, we hypothesized that METH exposure impairs the glucose uptake and metabolism in human neurons and astrocytes. Deprivation of glucose is expected to cause neurotoxicity and neuronal degeneration due to depletion of energy. We found that METH exposure inhibited the glucose uptake by neurons and astrocytes, in which neurons were more sensitive to METH than astrocytes in primary culture. Adaptability of these cells to fatty acid oxidation as an alternative source of energy during glucose limitation appeared to regulate this differential sensitivity. Decrease in neuronal glucose uptake by METH was associated with reduction of glucose transporter protein-3 (GLUT3). Surprisingly, METH exposure showed biphasic effects on astrocytic glucose uptake, in which 20 µM increased the uptake while 200 µM inhibited glucose uptake. Dual effects of METH on glucose uptake were paralleled to changes in the expression of astrocytic glucose transporter protein-1 (GLUT1). The adaptive nature of astrocyte to mitochondrial β-oxidation of fatty acid appeared to contribute the survival of astrocytes during METH-induced glucose deprivation. This differential adaptive nature of neurons and astrocytes also governed the differential sensitivity to the toxicity of METH in these brain cells. The effect of acetyl-L-carnitine for enhanced production of ATP from fatty oxidation in glucose-free culture condition validated the adaptive nature of neurons and astrocytes. These findings suggest that deprivation of glucose-derived energy may contribute to neurotoxicity of METH abusers. PMID:21556365

BNN27, a 17-Spiroepoxy Steroid Derivative, Interacts With and Activates p75 Neurotrophin Receptor, Rescuing Cerebellar Granule Neurons from Apoptosis.

PubMed

Pediaditakis, Iosif; Kourgiantaki, Alexandra; Prousis, Kyriakos C; Potamitis, Constantinos; Xanthopoulos, Kleanthis P; Zervou, Maria; Calogeropoulou, Theodora; Charalampopoulos, Ioannis; Gravanis, Achille

2016-01-01

Neurotrophin receptors mediate a plethora of signals affecting neuronal survival. The p75 pan-neurotrophin receptor controls neuronal cell fate after its selective activation by immature and mature isoforms of all neurotrophins. It also exerts pleiotropic effects interacting with a variety of ligands in different neuronal or non-neuronal cells. In the present study, we explored the biophysical and functional interactions of a blood-brain-barrier (BBB) permeable, C17-spiroepoxy steroid derivative, BNN27, with p75 NTR receptor. BNN27 was recently shown to bind to NGF high-affinity receptor, TrkA. We now tested the p75 NTR -mediated effects of BNN27 in mouse Cerebellar Granule Neurons (CGNs), expressing p75 NTR , but not TrkA receptors. Our findings show that BNN27 physically interacts with p75 NTR receptors in specific amino-residues of its extracellular domain, inducing the recruitment of p75 NTR receptor to its effector protein RIP2 and the simultaneous release of RhoGDI in primary neuronal cells. Activation of the p75 NTR receptor by BNN27 reverses serum deprivation-induced apoptosis of CGNs resulting in the decrease of the phosphorylation of pro-apoptotic JNK kinase and of the cleavage of Caspase-3, effects completely abolished in CGNs, isolated from p75 NTR null mice. In conclusion, BNN27 represents a lead molecule for the development of novel p75 NTR ligands, controlling specific p75 NTR -mediated signaling of neuronal cell fate, with potential applications in therapeutics of neurodegenerative diseases and brain trauma.

BNN27, a 17-Spiroepoxy Steroid Derivative, Interacts With and Activates p75 Neurotrophin Receptor, Rescuing Cerebellar Granule Neurons from Apoptosis

PubMed Central

Pediaditakis, Iosif; Kourgiantaki, Alexandra; Prousis, Kyriakos C.; Potamitis, Constantinos; Xanthopoulos, Kleanthis P.; Zervou, Maria; Calogeropoulou, Theodora; Charalampopoulos, Ioannis; Gravanis, Achille

2016-01-01

Neurotrophin receptors mediate a plethora of signals affecting neuronal survival. The p75 pan-neurotrophin receptor controls neuronal cell fate after its selective activation by immature and mature isoforms of all neurotrophins. It also exerts pleiotropic effects interacting with a variety of ligands in different neuronal or non-neuronal cells. In the present study, we explored the biophysical and functional interactions of a blood-brain-barrier (BBB) permeable, C17-spiroepoxy steroid derivative, BNN27, with p75NTR receptor. BNN27 was recently shown to bind to NGF high-affinity receptor, TrkA. We now tested the p75NTR-mediated effects of BNN27 in mouse Cerebellar Granule Neurons (CGNs), expressing p75NTR, but not TrkA receptors. Our findings show that BNN27 physically interacts with p75NTR receptors in specific amino-residues of its extracellular domain, inducing the recruitment of p75NTR receptor to its effector protein RIP2 and the simultaneous release of RhoGDI in primary neuronal cells. Activation of the p75NTR receptor by BNN27 reverses serum deprivation-induced apoptosis of CGNs resulting in the decrease of the phosphorylation of pro-apoptotic JNK kinase and of the cleavage of Caspase-3, effects completely abolished in CGNs, isolated from p75NTR null mice. In conclusion, BNN27 represents a lead molecule for the development of novel p75NTR ligands, controlling specific p75NTR-mediated signaling of neuronal cell fate, with potential applications in therapeutics of neurodegenerative diseases and brain trauma. PMID:28082899

Dispensable, Redundant, Complementary, and Cooperative Roles of Dopamine, Octopamine, and Serotonin in Drosophila melanogaster

PubMed Central

Chen, Audrey; Ng, Fanny; Lebestky, Tim; Grygoruk, Anna; Djapri, Christine; Lawal, Hakeem O.; Zaveri, Harshul A.; Mehanzel, Filmon; Najibi, Rod; Seidman, Gabriel; Murphy, Niall P.; Kelly, Rachel L.; Ackerson, Larry C.; Maidment, Nigel T.; Jackson, F. Rob; Krantz, David E.

2013-01-01

To investigate the regulation of Drosophila melanogaster behavior by biogenic amines, we have exploited the broad requirement of the vesicular monoamine transporter (VMAT) for the vesicular storage and exocytotic release of all monoamine neurotransmitters. We used the Drosophila VMAT (dVMAT) null mutant to globally ablate exocytotic amine release and then restored DVMAT activity in either individual or multiple aminergic systems, using transgenic rescue techniques. We find that larval survival, larval locomotion, and female fertility rely predominantly on octopaminergic circuits with little apparent input from the vesicular release of serotonin or dopamine. In contrast, male courtship and fertility can be rescued by expressing DVMAT in octopaminergic or dopaminergic neurons, suggesting potentially redundant circuits. Rescue of major aspects of adult locomotion and startle behavior required octopamine, but a complementary role was observed for serotonin. Interestingly, adult circadian behavior could not be rescued by expression of DVMAT in a single subtype of aminergic neurons, but required at least two systems, suggesting the possibility of unexpected cooperative interactions. Further experiments using this model will help determine how multiple aminergic systems may contribute to the regulation of other behaviors. Our data also highlight potential differences between behaviors regulated by standard exocytotic release and those regulated by other mechanisms. PMID:23086220

Differential expression of VGLUT1 or VGLUT2 in the trigeminothalamic or trigeminocerebellar projection neurons in the rat.

PubMed

Ge, Shun-Nan; Li, Zhi-Hong; Tang, Jun; Ma, Yunfei; Hioki, Hiroyuki; Zhang, Ting; Lu, Ya-Cheng; Zhang, Fu-Xing; Mizuno, Noboru; Kaneko, Takeshi; Liu, Ying-Ying; Lung, Mandy Siu Yu; Gao, Guo-Dong; Li, Jin-Lian

2014-01-01

The vesicular glutamate transporters, VGLUT1 and VGLUT2, reportedly display complementary distribution in the rat brain. However, co-expression of them in single neurons has been reported in some brain areas. We previously found co-expression of VGLUT1 and VGLUT2 mRNAs in a number of single neurons in the principal sensory trigeminal nucleus (Vp) of the adult rat; the majority of these neurons sent their axons to the thalamic regions around the posteromedial ventral nucleus (VPM) and the posterior nuclei (Po). It is well known that trigeminothalamic (T-T) projection fibers arise not only from the Vp but also from the spinal trigeminal nucleus (Vsp), and that trigeminocerebellar (T-C) projection fibers take their origins from both of the Vp and Vsp. Thus, in the present study, we examined the expression of VGLUT1 and VGLUT2 in Vp and Vsp neurons that sent their axons to the VPM/Po regions or the cortical regions of the cerebellum. For this purpose, we combined fluorescence in situ hybridization (FISH) histochemistry with retrograde tract-tracing; immunofluorescence histochemistry was also combined with anterograde tract-tracing. The results indicate that glutamatergic Vsp neurons sending their axons to the cerebellar cortical regions mainly express VGLUT1, whereas glutamatergic Vsp neurons sending their axons to the thalamic regions express VGLUT2. The present data, in combination with those of our previous study, indicate that glutamatergic Vp neurons projecting to the cerebellar cortical regions express mainly VGLUT1, whereas the majority of glutamatergic Vp neurons projecting to the thalamus co-express VGLUT1 and VGLUT2.

Opposing Effects of Acute versus Chronic Blockade of Frontal Cortex Somatostatin-Positive Inhibitory Neurons on Behavioral Emotionality in Mice

PubMed Central

Soumier, Amelie; Sibille, Etienne

2014-01-01

Reduced expression of somatostatin (SST) is reported across chronic brain conditions including major depression and normal aging. SST is a signaling neuropeptide and marker of gamma-amino butyric acid (GABA) neurons, which specifically inhibit pyramidal neuron dendrites. Studies in auditory cortex suggest that chronic reduction in dendritic inhibition induces compensatory homeostatic adaptations that oppose the effects of acute inhibition. Whether such mechanisms occur in frontal cortex (FC) and affect behavioral outcome is not known. Here, we used two complementary viral vector strategies to examine the effects of acute vs chronic inhibition of SST-positive neurons on behavioral emotionality in adult mice. SST-IRES-Cre mice were injected in FC (prelimbic/precingulate) with CRE-dependent adeno-associated viral (AAV) vector encoding the engineered Gi/o-coupled human muscarinic M4 designer receptor exclusively activated by a designer drug (DREADD-hM4Di) or a control reporter (AAV-DIO-mCherry) for acute or chronic cellular inhibition. A separate cohort was injected with CRE-dependent AAV vectors expressing diphtheria toxin (DTA) to selectively ablate FC SST neurons. Mice were assessed for anxiety- and depressive-like behaviors (defined as emotionality). Results indicate that acute inhibition of FC SST neurons increased behavioral emotionality, whereas chronic inhibition decreased behavioral emotionality. Furthermore, ablation of FC SST neurons also decreased behavioral emotionality under baseline condition and after chronic stress. Together, our results reveal opposite effects of acute and chronic inhibition of FC SST neurons on behavioral emotionality and suggest the recruitment of homeostatic plasticity mechanisms that have implications for understanding the neurobiology of chronic brain conditions affecting dendritic-targeting inhibitory neurons. PMID:24690741

Opposing effects of acute versus chronic blockade of frontal cortex somatostatin-positive inhibitory neurons on behavioral emotionality in mice.

PubMed

Soumier, Amelie; Sibille, Etienne

2014-08-01

Reduced expression of somatostatin (SST) is reported across chronic brain conditions including major depression and normal aging. SST is a signaling neuropeptide and marker of gamma-amino butyric acid (GABA) neurons, which specifically inhibit pyramidal neuron dendrites. Studies in auditory cortex suggest that chronic reduction in dendritic inhibition induces compensatory homeostatic adaptations that oppose the effects of acute inhibition. Whether such mechanisms occur in frontal cortex (FC) and affect behavioral outcome is not known. Here, we used two complementary viral vector strategies to examine the effects of acute vs chronic inhibition of SST-positive neurons on behavioral emotionality in adult mice. SST-IRES-Cre mice were injected in FC (prelimbic/precingulate) with CRE-dependent adeno-associated viral (AAV) vector encoding the engineered Gi/o-coupled human muscarinic M4 designer receptor exclusively activated by a designer drug (DREADD-hM4Di) or a control reporter (AAV-DIO-mCherry) for acute or chronic cellular inhibition. A separate cohort was injected with CRE-dependent AAV vectors expressing diphtheria toxin (DTA) to selectively ablate FC SST neurons. Mice were assessed for anxiety- and depressive-like behaviors (defined as emotionality). Results indicate that acute inhibition of FC SST neurons increased behavioral emotionality, whereas chronic inhibition decreased behavioral emotionality. Furthermore, ablation of FC SST neurons also decreased behavioral emotionality under baseline condition and after chronic stress. Together, our results reveal opposite effects of acute and chronic inhibition of FC SST neurons on behavioral emotionality and suggest the recruitment of homeostatic plasticity mechanisms that have implications for understanding the neurobiology of chronic brain conditions affecting dendritic-targeting inhibitory neurons.

The role of GluN2A and GluN2B NMDA receptor subunits in AgRP and POMC neurons on body weight and glucose homeostasis.

PubMed

Üner, Aykut; Gonçalves, Gabriel H M; Li, Wenjing; Porceban, Matheus; Caron, Nicole; Schönke, Milena; Delpire, Eric; Sakimura, Kenji; Bjørbæk, Christian

2015-10-01

Hypothalamic agouti-related peptide (AgRP) and pro-opiomelanocortin (POMC) expressing neurons play critical roles in control of energy balance. Glutamatergic input via n-methyl-d-aspartate receptors (NMDARs) is pivotal for regulation of neuronal activity and is required in AgRP neurons for normal body weight homeostasis. NMDARs typically consist of the obligatory GluN1 subunit and different GluN2 subunits, the latter exerting crucial differential effects on channel activity and neuronal function. Currently, the role of specific GluN2 subunits in AgRP and POMC neurons on whole body energy and glucose balance is unknown. We used the cre-lox system to genetically delete GluN2A or GluN2B only from AgRP or POMC neurons in mice. Mice were then subjected to metabolic analyses and assessment of AgRP and POMC neuronal function through morphological studies. We show that loss of GluN2B from AgRP neurons reduces body weight, fat mass, and food intake, whereas GluN2B in POMC neurons is not required for normal energy balance control. GluN2A subunits in either AgRP or POMC neurons are not required for regulation of body weight. Deletion of GluN2B reduces the number of AgRP neurons and decreases their dendritic length. In addition, loss of GluN2B in AgRP neurons of the morbidly obese and severely diabetic leptin-deficient Lep (ob/ob) mice does not affect body weight and food intake but, remarkably, leads to full correction of hyperglycemia. Lep (ob/ob) mice lacking GluN2B in AgRP neurons are also more sensitive to leptin's anti-obesity actions. GluN2B-containing NMDA receptors in AgRP neurons play a critical role in central control of body weight homeostasis and blood glucose balance via mechanisms that likely involve regulation of AgRP neuronal survival and structure, and modulation of hypothalamic leptin action.

Pharmacological Effects of Active Components of Chinese Herbal Medicine in the Treatment of Alzheimer's Disease: A Review.

PubMed

Wang, Zhi-Yong; Liu, Jian-Gang; Li, Hao; Yang, Hui-Ming

2016-01-01

Alzheimer's disease (AD), the most common neurodegenerative disorder associated with dementia, not only severely decreases the quality of life for its victims, but also brings a heavy economic burden to the family and society. Unfortunately, few chemical drugs designed for clinical applications have reached the expected preventive or therapeutic effect so far, and combined with their significant side-effects, there is therefore an urgent need for new strategies to be developed for AD treatment. Traditional Chinese Medicine has accumulated many experiences in the treatment of dementia during thousands of years of practice; modern pharmacological studies have confirmed the therapeutic effects of many active components derived from Chinese herbal medicines (CHM). Ginsenoside Rg1, extracted from Radix Ginseng, exerts a [Formula: see text]-secretase inhibitor effect so as to decrease A[Formula: see text] aggregation. It can also inhibit the apoptosis of neuron cells. Tanshinone IIA, extracted from Radix Salviae miltiorrhizae, and baicalin, extracted from Radix Scutellariae[Formula: see text] can inhibit the oxidative stress injury in neuronal cells. Icariin, extracted from Epimedium brevicornum, can decrease A[Formula: see text] levels and the hyperphosphorylation of tau protein, and can also inhibit oxidative stress and apoptosis. Huperzine A, extracted from Huperzia serrata, exerts a cholinesterase inhibitor effect. Evodiamine, extracted from Fructus Evodiae, and curcumin, extracted from Rhizoma Curcumae Longae, exert anti-inflammatory actions. Curcumin can act on A[Formula: see text] and tau too. Due to the advantages of multi-target effects and fewer side effects, Chinese medicine is more appropriate for long-term use. In this present review, the pharmacological effects of commonly used active components derived from Chinese herbal medicines in the treatment of AD are discussed.

Neuronal synchrony and the relation between the blood-oxygen-level dependent response and the local field potential

PubMed Central

Nguyen, Mai; Winawer, Jonathan

2017-01-01

The most widespread measures of human brain activity are the blood-oxygen-level dependent (BOLD) signal and surface field potential. Prior studies report a variety of relationships between these signals. To develop an understanding of how to interpret these signals and the relationship between them, we developed a model of (a) neuronal population responses and (b) transformations from neuronal responses into the functional magnetic resonance imaging (fMRI) BOLD signal and electrocorticographic (ECoG) field potential. Rather than seeking a transformation between the two measures directly, this approach interprets each measure with respect to the underlying neuronal population responses. This model accounts for the relationship between BOLD and ECoG data from human visual cortex in V1, V2, and V3, with the model predictions and data matching in three ways: across stimuli, the BOLD amplitude and ECoG broadband power were positively correlated, the BOLD amplitude and alpha power (8–13 Hz) were negatively correlated, and the BOLD amplitude and narrowband gamma power (30–80 Hz) were uncorrelated. The two measures provide complementary information about human brain activity, and we infer that features of the field potential that are uncorrelated with BOLD arise largely from changes in synchrony, rather than level, of neuronal activity. PMID:28742093

Multivariable harmonic balance analysis of the neuronal oscillator for leech swimming.

PubMed

Chen, Zhiyong; Zheng, Min; Friesen, W Otto; Iwasaki, Tetsuya

2008-12-01

Biological systems, and particularly neuronal circuits, embody a very high level of complexity. Mathematical modeling is therefore essential for understanding how large sets of neurons with complex multiple interconnections work as a functional system. With the increase in computing power, it is now possible to numerically integrate a model with many variables to simulate behavior. However, such analysis can be time-consuming and may not reveal the mechanisms underlying the observed phenomena. An alternative, complementary approach is mathematical analysis, which can demonstrate direct and explicit relationships between a property of interest and system parameters. This paper introduces a mathematical tool for analyzing neuronal oscillator circuits based on multivariable harmonic balance (MHB). The tool is applied to a model of the central pattern generator (CPG) for leech swimming, which comprises a chain of weakly coupled segmental oscillators. The results demonstrate the effectiveness of the MHB method and provide analytical explanations for some CPG properties. In particular, the intersegmental phase lag is estimated to be the sum of a nominal value and a perturbation, where the former depends on the structure and span of the neuronal connections and the latter is roughly proportional to the period gradient, communication delay, and the reciprocal of the intersegmental coupling strength.

Crosstalks between kisspeptin neurons and somatostatin neurons are not photoperiod dependent in the ewe hypothalamus.

PubMed

Dufourny, Laurence; Lomet, Didier

2017-12-01

Seasonal reproduction is under the control of gonadal steroid feedback, itself synchronized by day-length or photoperiod. As steroid action on GnRH neurons is mostly indirect and therefore exerted through interneurons, we looked for neuroanatomical interactions between kisspeptin (KP) neurons and somatostatin (SOM) neurons, two populations targeted by sex steroids, in three diencephalic areas involved in the central control of ovulation and/or sexual behavior: the arcuate nucleus (ARC), the preoptic area (POA) and the ventrolateral part of the ventromedial hypothalamus (VMHvl). KP is the most potent secretagogue of GnRH secretion while SOM has been shown to centrally inhibit LH pulsatile release. Notably, hypothalamic contents of these two neuropeptides vary with photoperiod in specific seasonal species. Our hypothesis is that SOM inhibits KP neuron activity and therefore indirectly modulate GnRH release and that this effect may be seasonally regulated. We used sections from ovariectomized estradiol-replaced ewes killed after photoperiodic treatment mimicking breeding or anestrus season. We performed triple immunofluorescent labeling to simultaneously detect KP, SOM and synapsin, a marker for synaptic vesicles. Sections from the POA and from the mediobasal hypothalamus were examined using a confocal microscope. Randomly selected KP or SOM neurons were observed in the POA and ARC. SOM neurons were also observed in the VMHvl. In both the ARC and POA, nearly all KP neurons presented numerous SOM contacts. SOM neurons presented KP terminals more frequently in the ARC than in the POA and VMHvl. Quantitative analysis failed to demonstrate major seasonal variations of KP and SOM interactions. Our data suggest a possible inhibitory action of SOM on all KP neurons in both photoperiodic statuses. On the other hand, the physiological significance of KP modulation of SOM neuron activity and vice versa remain to be determined. Copyright © 2017 Elsevier Inc. All rights reserved.

THE MYSTERIOUS MOTIVATIONAL FUNCTIONS OF MESOLIMBIC DOPAMINE

PubMed Central

Salamone, John D.; Correa, Mercè

2012-01-01

Summary Nucleus accumbens dopamine is known to play a role in motivational processes, and dysfunctions of mesolimbic dopamine may contribute to motivational symptoms of depression and other disorders, as well as features of substance abuse. Although it has become traditional to label dopamine neurons as “reward” neurons, this is an over-generalization, and it is important to distinguish between aspects of motivation that are differentially affected by dopaminergic manipulations. For example, accumbens dopamine does not mediate primary food motivation or appetite, but is involved in appetitive and aversive motivational processes including behavioral activation, exertion of effort, approach behavior, sustained task engagement, Pavlovian processes and instrumental learning. In this review, we discuss the complex roles of dopamine in behavioral functions related to motivation. PMID:23141060

Effects of harmane (1-methyl-beta-carboline) on neurons in the nucleus accumbens of the rat.

PubMed

Ergene, E; Schoener, E P

1993-04-01

Harmane, a beta-carboline alkaloid reported to exert locomotor and psychoactive effects, is found in certain plants and also has been shown to exist in the mammalian brain as an endogenous substance. In this study, the effects of locally perfused harmane were examined on spontaneous neuronal activity in the nucleus accumbens of urethane-anesthetized rats. Extracellular single-unit recording, coupled with push-pull perfusion, enabled the discrimination of specific, dose-related effects of harmane across a wide concentration range. At lower concentrations (10(-9)-10(-11) M), excitation prevailed, while at higher concentrations (10(-8)-10(-6) M) depression was most pronounced. These findings suggest a neuromodulatory role for harmane in the forebrain reward system.

Bimodal control of stimulated food intake by the endocannabinoid system.

PubMed

Bellocchio, Luigi; Lafenêtre, Pauline; Cannich, Astrid; Cota, Daniela; Puente, Nagore; Grandes, Pedro; Chaouloff, Francis; Piazza, Pier Vincenzo; Marsicano, Giovanni

2010-03-01

Activation of cannabinoid type-1 receptors (CB(1)) is universally recognized as a powerful endogenous orexigenic signal, but the detailed underlying neuronal mechanisms are not fully understood. Using combined genetic and pharmacological approaches in mice, we found that ventral striatal CB(1) receptors exerted a hypophagic action through inhibition of GABAergic transmission. Conversely, brain CB(1) receptors modulating excitatory transmission mediated the well-known orexigenic effects of cannabinoids.

Double-Edge Sword of Sustained ROCK Activation in Prion Diseases through Neuritogenesis Defects and Prion Accumulation

PubMed Central

Alleaume-Butaux, Aurélie; Nicot, Simon; Pietri, Mathéa; Baudry, Anne; Dakowski, Caroline; Tixador, Philippe; Ardila-Osorio, Hector; Haeberlé, Anne-Marie; Bailly, Yannick; Peyrin, Jean-Michel; Launay, Jean-Marie; Kellermann, Odile; Schneider, Benoit

2015-01-01

In prion diseases, synapse dysfunction, axon retraction and loss of neuronal polarity precede neuronal death. The mechanisms driving such polarization defects, however, remain unclear. Here, we examined the contribution of RhoA-associated coiled-coil containing kinases (ROCK), key players in neuritogenesis, to prion diseases. We found that overactivation of ROCK signaling occurred in neuronal stem cells infected by pathogenic prions (PrPSc) and impaired the sprouting of neurites. In reconstructed networks of mature neurons, PrPSc-induced ROCK overactivation provoked synapse disconnection and dendrite/axon degeneration. This overactivation of ROCK also disturbed overall neurotransmitter-associated functions. Importantly, we demonstrated that beyond its impact on neuronal polarity ROCK overactivity favored the production of PrPSc through a ROCK-dependent control of 3-phosphoinositide-dependent kinase 1 (PDK1) activity. In non-infectious conditions, ROCK and PDK1 associated within a complex and ROCK phosphorylated PDK1, conferring basal activity to PDK1. In prion-infected neurons, exacerbated ROCK activity increased the pool of PDK1 molecules physically interacting with and phosphorylated by ROCK. ROCK-induced PDK1 overstimulation then canceled the neuroprotective α-cleavage of normal cellular prion protein PrPC by TACE α-secretase, which physiologically precludes PrPSc production. In prion-infected cells, inhibition of ROCK rescued neurite sprouting, preserved neuronal architecture, restored neuronal functions and reduced the amount of PrPSc. In mice challenged with prions, inhibition of ROCK also lowered brain PrPSc accumulation, reduced motor impairment and extended survival. We conclude that ROCK overactivation exerts a double detrimental effect in prion diseases by altering neuronal polarity and triggering PrPSc accumulation. Eventually ROCK emerges as therapeutic target to combat prion diseases. PMID:26241960

Th17 Cells Induce Dopaminergic Neuronal Death via LFA-1/ICAM-1 Interaction in a Mouse Model of Parkinson's Disease.

PubMed

Liu, Zhan; Huang, Yan; Cao, Bei-Bei; Qiu, Yi-Hua; Peng, Yu-Ping

2017-12-01

T helper (Th)17 cells, a subset of CD4 + T lymphocytes, have strong pro-inflammatory property and appear to be essential in the pathogenesis of many inflammatory diseases. However, the involvement of Th17 cells in Parkinson's disease (PD) that is characterized by a progressive degeneration of dopaminergic (DAergic) neurons in the nigrostriatal system is unclear. Here, we aimed to demonstrate that Th17 cells infiltrate into the brain parenchyma and induce neuroinflammation and DAergic neuronal death in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)- or 1-methyl-4-phenylpyridinium (MPP + )-induced PD models. Blood-brain barrier (BBB) disruption in the substantia nigra (SN) was assessed by the signal of FITC-labeled albumin that was injected into blood circulation via the ascending aorta. Live cell imaging system was used to observe a direct contact of Th17 cells with neurons by staining these cells using the two adhesion molecules, leukocyte function-associated antigen (LFA)-1 and intercellular adhesion molecule (ICAM)-1, respectively. Th17 cells invaded into the SN where BBB was disrupted in MPTP-induced PD mice. Th17 cells exacerbated DAergic neuronal loss and pro-inflammatory/neurotrophic factor disorders in MPP + -treated ventral mesencephalic (VM) cell cultures. A direct contact of LFA-1-stained Th17 cells with ICAM-1-stained VM neurons was dynamically captured. Either blocking LFA-1 in Th17 cells or blocking ICAM-1 in VM neurons with neutralizing antibodies abolished Th17-induced DAergic neuronal death. These results establish that Th17 cells infiltrate into the brain parenchyma of PD mice through lesioned BBB and exert neurotoxic property by promoting glial activation and importantly by a direct damage to neurons depending on LFA-1/ICAM-1 interaction.

Calcimimetic R568 inhibits tetrodotoxin-sensitive colonic electrolyte secretion and reduces c-fos expression in myenteric neurons.

PubMed

Sun, Xiangrong; Tang, Lieqi; Winesett, Steven; Chang, Wenhan; Cheng, Sam Xianjun

2018-02-01

Calcium-sensing receptor (CaSR) is expressed on neurons of both submucosal and myenteric plexuses of the enteric nervous system (ENS) and the CaSR agonist R568 inhibited Cl - secretion in intestine. The purpose of this study was to localize the primary site of action of R568 in the ENS and to explore how CaSR regulates secretion through the ENS. Two preparations of rat proximal and distal colon were used. The full-thickness preparation contained both the submucosal and myenteric plexuses, whereas for the "stripped" preparation the myenteric plexus with the muscle layers was removed. Both preparations were mounted onto Ussing chambers and Cl - secretory responses were compared by measuring changes in short circuit current (I sc ). Two tissue-specific CaSR knockouts (i.e., neuron-specific vs. enterocyte-specific) were generated to compare the effect of R568 on expression of c-fos protein in myenteric neurons by immunocytochemistry. In full-thickness colons, tetrodotoxin (TTX) inhibited I sc , both in proximal and distal colons. A nearly identical inhibition was produced by R568. However, in stripped preparations, while the effect of TTX on I sc largely remained, the effect of R568 was nearly completely eliminated. In keeping with this, R568 reduced c-fos protein expression only in myenteric neurons of wild type mice and mutant mice that contained CaSR in neurons (i.e., villin Cre/Casr flox/flox mice), but not in myenteric neurons of nestin Cre/Casr flox/flox mice in which neuronal cell CaSR was eliminated. These results indicate that R568 exerts its anti-secretory effects predominantly via CaSR-mediated inhibition of neuronal activity in the myenteric plexus. Published by Elsevier Inc.

EGFR mediates astragaloside IV-induced Nrf2 activation to protect cortical neurons against in vitro ischemia/reperfusion damages

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

Gu, Da-min; Lu, Pei-Hua, E-mail: lphty1_1@163.com; Zhang, Ke

In this study, we tested the potential role of astragaloside IV (AS-IV) against oxygen and glucose deprivation/re-oxygenation (OGD/R)-induced damages in murine cortical neurons, and studied the associated signaling mechanisms. AS-IV exerted significant neuroprotective effects against OGD/R by reducing reactive oxygen species (ROS) accumulation, thereby attenuating oxidative stress and neuronal cell death. We found that AS-IV treatment in cortical neurons resulted in NF-E2-related factor 2 (Nrf2) signaling activation, evidenced by Nrf2 Ser-40 phosphorylation, and its nuclear localization, as well as transcription of antioxidant-responsive element (ARE)-regulated genes: heme oxygenase-1 (HO-1), NAD(P)H:quinone oxidoreductase 1 (NQO-1) and sulphiredoxin 1 (SRXN-1). Knockdown of Nrf2 throughmore » lentiviral shRNAs prevented AS-IV-induced ARE genes transcription, and abolished its anti-oxidant and neuroprotective activities. Further, we discovered that AS-IV stimulated heparin-binding-epidermal growth factor (HB-EGF) release to trans-activate epidermal growth factor receptor (EGFR) in cortical neurons. Blockage or silencing EGFR prevented Nrf2 activation by AS-IV, thus inhibiting AS-IV-mediated anti-oxidant and neuroprotective activities against OGD/R. In summary, AS-IV protects cortical neurons against OGD/R damages through activating of EGFR-Nrf2 signaling. - Highlights: • Pre-treatment of astragaloside IV (AS-IV) protects murine cortical neurons from OGD/R. • AS-IV activates Nrf2-ARE signaling in murine cortical neurons. • Nrf2 is required for AS-IV-mediated anti-oxidant and neuroprotective activities. • AS-IV stimulates HB-EGF release to trans-activate EGFR in murine cortical neurons. • EGFR mediates AS-IV-induced Nrf2 activation and neuroprotection against OGD/R.« less

The Glutamatergic Neurons in the Spinal Cord of the Sea Lamprey: An In Situ Hybridization and Immunohistochemical Study

PubMed Central

Fernández-López, Blanca; Villar-Cerviño, Verona; Valle-Maroto, Silvia M.; Barreiro-Iglesias, Antón; Anadón, Ramón; Rodicio, María Celina

2012-01-01

Glutamate is the main excitatory neurotransmitter involved in spinal cord circuits in vertebrates, but in most groups the distribution of glutamatergic spinal neurons is still unknown. Lampreys have been extensively used as a model to investigate the neuronal circuits underlying locomotion. Glutamatergic circuits have been characterized on the basis of the excitatory responses elicited in postsynaptic neurons. However, the presence of glutamatergic neurochemical markers in spinal neurons has not been investigated. In this study, we report for the first time the expression of a vesicular glutamate transporter (VGLUT) in the spinal cord of the sea lamprey. We also study the distribution of glutamate in perikarya and fibers. The largest glutamatergic neurons found were the dorsal cells and caudal giant cells. Two additional VGLUT-positive gray matter populations, one dorsomedial consisting of small cells and another one lateral consisting of small and large cells were observed. Some cerebrospinal fluid-contacting cells also expressed VGLUT. In the white matter, some edge cells and some cells associated with giant axons (Müller and Mauthner axons) and the dorsolateral funiculus expressed VGLUT. Large lateral cells and the cells associated with reticulospinal axons are in a key position to receive descending inputs involved in the control of locomotion. We also compared the distribution of glutamate immunoreactivity with that of γ-aminobutyric acid (GABA) and glycine. Colocalization of glutamate and GABA or glycine was observed in some small spinal cells. These results confirm the glutamatergic nature of various neuronal populations, and reveal new small-celled glutamatergic populations, predicting that some glutamatergic neurons would exert complex actions on postsynaptic neurons. PMID:23110124

[Study of neuron-protective effect and mechanism of neuregulin1β against cerebral ischemia reperfusion-induced injury in rats].

PubMed

Ji, Y Q; Zhang, R; Teng, L; Li, H Y; Guo, Y L

2017-07-18

Objective: Thecurrent study is to explore the neuron-protective mechanism of neuregulin1β (NRG1β) in a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R) through inhibiting the c-Jun phosphorylation. Methods: After 24 h of MCAO/R (referring to Longa's method), neurobehavioral function was measured by modified neurological severity score (mNSS) test; the cerebral infarction volume was detected by triphenyltetrazolium chloride (TTC) staining; the blood brain barrier (BBB) permeability was measured by Evans Blue (EB); the neuron morphology of brain tissue was observed by Nissl stain; the ultra-structures of the neurons were observed by transmission electron microscopy (TEM); the apoptotic neurons were counted by in situ cell death detection kit colocalized with NeuN; the expressions of phospho-c-Jun was determined by immunofluorescent labeling and Western blot analysis. Results: Compared with the sham-operation rats, the rats receiving MCAO/R showed increased mNSS (9.7±1.2), cerebral infarction volume (41.4±3.0)%, permeability of BBB, deformation of neurons, ischemia-induced apoptosis (0.63±0.04), and enhanced expression of phospho-c-Jun protein (0.90±0.07) (all P <0.05). Our data indicated that NRG1β attenuated neurologic deficits (6.4±0.9), decreased the cerebral infarction volume (10.4±0.5), reduced EB extravasation (1.55±0.13) and the deformation of neurons, protected the ultra-structure of neurons, blocked ischemia-induced apoptosis (0.23±0.02), through down-regulated phospho-c-Jun expression (0.40±0.03) in MCAO/R rats ( P <0.05). Conclusion: NRG1β exerts neuron-protective effects against ischemia reperfusion-induced injury in rats through inhibiting the c-Jun phosphorylation.

Ferulic acid prevents cerebral ischemic injury-induced reduction of hippocalcin expression.

PubMed

Koh, Phil-Ok

2013-07-01

Intracellular calcium overload is a critical pathophysiological factor in ischemic injury. Hippocalcin is a neuronal calcium sensor protein that buffers intracellular calcium levels and protects cells from apoptotic stimuli. Ferulic acid exerts a neuroprotective effect in cerebral ischemia through its anti-oxidant and anti-inflammation activity. This study investigated whether ferulic acid contributes to hippocalcin expression during cerebral ischemia and glutamate exposure-induced neuronal cell death. Rats were immediately treated with vehicle or ferulic acid (100 mg/kg, i.v.) after middle cerebral artery occlusion (MCAO). Brain tissues were collected 24 h after MCAO and followed by assessment of cerebral infarct. Ferulic acid reduced MCAO-induced infarct regions. A proteomics approach elucidated a decrease in hippocalcin in MCAO-operated animals, ferulic acid attenuates the injury-induced decrease in hippocalcin expression. Reverse transcription-polymerase chain reaction and Western blot analyses confirmed that ferulic acid prevents the injury-induced decrease in hippocalcin. In cultured HT22 hippocampal cells, glutamate exposure increased the intracellular Ca(2+) levels, whereas ferulic acid attenuated this increase. Moreover, ferulic acid attenuated the glutamate toxicity-induced decrease in hippocalcin expression. These findings can suggest the possibility that ferulic acid exerts a neuroprotective effect through modulating hippocalcine expression and regulating intracellular calcium levels. Copyright © 2013 Wiley Periodicals, Inc.

L-type voltage-dependent calcium channel is involved in the snake venom group IA secretory phospholipase A2-induced neuronal apoptosis.

PubMed

Yagami, Tatsurou; Yamamoto, Yasuhiro; Kohma, Hiromi; Nakamura, Tsutomu; Takasu, Nobuo; Okamura, Noboru

2013-03-01

Snake venom group IA secretory phospholipase A2 (sPLA2-IA) is known as a neurotoxin. Snake venom sPLA2s are neurotoxic in vivo and in vitro, causing synergistic neurotoxicity to cortical cultures when applied with toxic concentrations of glutamate. However, it has not yet been cleared sufficiently how sPLA2-IA exerts neurotoxicity. Here, we found sPLA2-IA induced neuronal cell death in a concentration-dependent manner. This death was a delayed response requiring a latent time for 6h. sPLA2-IA-induced neuronal cell death was accompanied with apoptotic blebbing, condensed chromatin, and fragmented DNA, exhibiting apoptotic features. NMDA receptor blockers suppressed the neurotoxicity of sPLA2-IA, but an AMPA receptor blocker did not. Interestingly, L-type voltage-dependent Ca(2+) channel (L-VDCC) blocker significantly protected neurons from the sPLA2-IA-induced apoptosis. On the other hand, neither N-VDCC blockers nor P/Q-VDCC blocker did. In conclusion, we demonstrated that sPLA2-IA induced neuronal cell death via apoptosis. Furthermore, the present study suggests that not only NMDA receptor but also L-VDCC contributed to the neurotoxicity of snake venom sPLA2-IA. Copyright © 2013 Elsevier Inc. All rights reserved.

Glucagon-like Peptide-1 receptor signaling in the lateral parabrachial nucleus contributes to the control of food intake and motivation to feed.

PubMed

Alhadeff, Amber L; Baird, John-Paul; Swick, Jennifer C; Hayes, Matthew R; Grill, Harvey J

2014-08-01

Central glucagon-like peptide-1 receptor (GLP-1R) activation reduces food intake and the motivation to work for food, but the neurons and circuits mediating these effects are not fully understood. Although lateral parabrachial nucleus (lPBN) neurons are implicated in the control of food intake and reward, the specific role of GLP-1R-expressing lPBN neurons is unexplored. Here, neuroanatomical tracing, immunohistochemical, and behavioral/pharmacological techniques are used to test the hypothesis that lPBN neurons contribute to the anorexic effect of central GLP-1R activation. Results indicate that GLP-1-producing neurons in the nucleus tractus solitarius project monosynaptically to the lPBN, providing a potential endogenous mechanism by which lPBN GLP-1R signaling may exert effects on food intake control. Pharmacological activation of GLP-1R in the lPBN reduced food intake, and conversely, antagonism of GLP-1R in the lPBN increased food intake. In addition, lPBN GLP-1R activation reduced the motivation to work for food under a progressive ratio schedule of reinforcement. Taken together, these data establish the lPBN as a novel site of action for GLP-1R-mediated control of food intake and reward.

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

PubMed

Brené, S; Lindefors, N; Persson, H

1992-06-01

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

GABAergic ventrolateral pre-optic nucleus neurons are involved in the mediation of the anesthetic hypnosis induced by propofol

PubMed Central

Yuan, Jie; Luo, Zhuxin; Zhang, Yu; Zhang, Yi; Wang, Yuan; Cao, Song; Fu, Bao; Yang, Hao; Zhang, Lin; Zhou, Wenjing; Yu, Tian

2017-01-01

Intravenous anesthetics have been used clinically to induce unconsciousness for seventeen decades, however the mechanism of anesthetic-induced unconsciousness remains to be fully elucidated. It has previously been demonstrated that anesthetics exert sedative effects by acting on endogenous sleep-arousal circuits. However, few studies focus on the ventrolateral pre-optic (VLPO) to locus coeruleus (LC) sleep-arousal pathway. The present study aimed to investigate if VLPO is involved in unconsciousness induced by propofol. The present study additionally investigated if the inhibitory effect of propofol on LC neurons was mediated by activating VLPO neurons. Microinjection, target lesion and extracellular single-unit recordings were used to study the role of the VLPO-LC pathway in propofol anesthesia. The results demonstrated that GABAA agonist (THIP) or GABAA antagonist (gabazine) microinjections into VLPO altered the time of loss of righting reflex and the time of recovery of righting reflex. Furthermore, propofol suppressed the spontaneous firing activity of LC noradrenergic neurons. There was no significant difference observed in firing activity between VLPO sham lesion and VLPO lesion rats. The findings indicate that VLPO neurons are important in propofol-induced unconsciousness, however are unlikely to contribute to the inhibitory effect of propofol on LC spontaneous firing activity. PMID:28765955

Functional regeneration of the ex-vivo reconstructed mesocorticolimbic dopaminergic system.

PubMed

Dossi, Elena; Heine, Claudia; Servettini, Ilenio; Gullo, Francesca; Sygnecka, Katja; Franke, Heike; Illes, Peter; Wanke, Enzo

2013-12-01

CNS reparative-medicine therapeutic strategies need answers on the putative recapitulation of the basic rules leading to mammalian CNS development. To achieve this aim, we focus on the regeneration of functional connections in the mesocorticolimbic dopaminergic system. We used organotypic slice cocultures of ventral tegmental area/substantia nigra (VTA/SN) and prefrontal cortex (PFC) on a multielectrode array (MEA) platform to record spikes and local field potentials. The spontaneously growing synaptically based bidirectional bursting activity was followed from 2 to 28 days in vitro (DIV). A statistical analysis of excitatory and inhibitory neurons properties of the physiological firing activity demonstrated a remarkable, exponentially increasing maturation with a time constant of about 5-7 DIV. Immunohistochemistry demonstrated that the ratio of excitatory/inhibitory neurons (3:1) was in line with the functional results obtained. Exemplary pharmacology suggested that GABAA receptors were able to exert phasic and tonic inhibition typical of an adulthood network. Moreover, dopamine D2 receptor inactivation was equally inhibitory both on the spontaneous neuronal activity recorded by MEA and on patch-clamp electrophysiology in PFC pyramidal neurons. These results demonstrate that axon growth cones reach synaptic targets up to full functionality and that organotypic cocultures of the VTA/SN-PFC perfectly model their newly born dopaminergic, glutamatergic and GABAergic neuronal circuitries.

Accumulation of misfolded SOD1 in dorsal root ganglion degenerating proprioceptive sensory neurons of transgenic mice with amyotrophic lateral sclerosis.

PubMed

Sábado, Javier; Casanovas, Anna; Tarabal, Olga; Hereu, Marta; Piedrafita, Lídia; Calderó, Jordi; Esquerda, Josep E

2014-01-01

Amyotrophic lateral sclerosis (ALS) is an adult-onset progressive neurodegenerative disease affecting upper and lower motoneurons (MNs). Although the motor phenotype is a hallmark for ALS, there is increasing evidence that systems other than the efferent MN system can be involved. Mutations of superoxide dismutase 1 (SOD1) gene cause a proportion of familial forms of this disease. Misfolding and aggregation of mutant SOD1 exert neurotoxicity in a noncell autonomous manner, as evidenced in studies using transgenic mouse models. Here, we used the SOD1(G93A) mouse model for ALS to detect, by means of conformational-specific anti-SOD1 antibodies, whether misfolded SOD1-mediated neurotoxicity extended to neuronal types other than MNs. We report that large dorsal root ganglion (DRG) proprioceptive neurons accumulate misfolded SOD1 and suffer a degenerative process involving the inflammatory recruitment of macrophagic cells. Degenerating sensory axons were also detected in association with activated microglial cells in the spinal cord dorsal horn of diseased animals. As large proprioceptive DRG neurons project monosynaptically to ventral horn MNs, we hypothesise that a prion-like mechanism may be responsible for the transsynaptic propagation of SOD1 misfolding from ventral horn MNs to DRG sensory neurons.

Intelligent complementary sliding-mode control for LUSMS-based X-Y-theta motion control stage.

PubMed

Lin, Faa-Jeng; Chen, Syuan-Yi; Shyu, Kuo-Kai; Liu, Yen-Hung

2010-07-01

An intelligent complementary sliding-mode control (ICSMC) system using a recurrent wavelet-based Elman neural network (RWENN) estimator is proposed in this study to control the mover position of a linear ultrasonic motors (LUSMs)-based X-Y-theta motion control stage for the tracking of various contours. By the addition of a complementary generalized error transformation, the complementary sliding-mode control (CSMC) can efficiently reduce the guaranteed ultimate bound of the tracking error by half compared with the slidingmode control (SMC) while using the saturation function. To estimate a lumped uncertainty on-line and replace the hitting control of the CSMC directly, the RWENN estimator is adopted in the proposed ICSMC system. In the RWENN, each hidden neuron employs a different wavelet function as an activation function to improve both the convergent precision and the convergent time compared with the conventional Elman neural network (ENN). The estimation laws of the RWENN are derived using the Lyapunov stability theorem to train the network parameters on-line. A robust compensator is also proposed to confront the uncertainties including approximation error, optimal parameter vectors, and higher-order terms in Taylor series. Finally, some experimental results of various contours tracking show that the tracking performance of the ICSMC system is significantly improved compared with the SMC and CSMC systems.

The Role of Inhibition in a Computational Model of an Auditory Cortical Neuron during the Encoding of Temporal Information

PubMed Central

Bendor, Daniel

2015-01-01

In auditory cortex, temporal information within a sound is represented by two complementary neural codes: a temporal representation based on stimulus-locked firing and a rate representation, where discharge rate co-varies with the timing between acoustic events but lacks a stimulus-synchronized response. Using a computational neuronal model, we find that stimulus-locked responses are generated when sound-evoked excitation is combined with strong, delayed inhibition. In contrast to this, a non-synchronized rate representation is generated when the net excitation evoked by the sound is weak, which occurs when excitation is coincident and balanced with inhibition. Using single-unit recordings from awake marmosets (Callithrix jacchus), we validate several model predictions, including differences in the temporal fidelity, discharge rates and temporal dynamics of stimulus-evoked responses between neurons with rate and temporal representations. Together these data suggest that feedforward inhibition provides a parsimonious explanation of the neural coding dichotomy observed in auditory cortex. PMID:25879843

Exploring the brain on multiple scales with correlative two-photon and light sheet microscopy

NASA Astrophysics Data System (ADS)

Silvestri, Ludovico; Allegra Mascaro, Anna Letizia; Costantini, Irene; Sacconi, Leonardo; Pavone, Francesco S.

2014-02-01

One of the unique features of the brain is that its activity cannot be framed in a single spatio-temporal scale, but rather spans many orders of magnitude both in space and time. A single imaging technique can reveal only a small part of this complex machinery. To obtain a more comprehensive view of brain functionality, complementary approaches should be combined into a correlative framework. Here, we describe a method to integrate data from in vivo two-photon fluorescence imaging and ex vivo light sheet microscopy, taking advantage of blood vessels as reference chart. We show how the apical dendritic arbor of a single cortical pyramidal neuron imaged in living thy1-GFP-M mice can be found in the large-scale brain reconstruction obtained with light sheet microscopy. Starting from the apical portion, the whole pyramidal neuron can then be segmented. The correlative approach presented here allows contextualizing within a three-dimensional anatomic framework the neurons whose dynamics have been observed with high detail in vivo.

Complementary mechanisms create direction selectivity in the fly

PubMed Central

Haag, Juergen; Arenz, Alexander; Serbe, Etienne; Gabbiani, Fabrizio; Borst, Alexander

2016-01-01

How neurons become sensitive to the direction of visual motion represents a classic example of neural computation. Two alternative mechanisms have been discussed in the literature so far: preferred direction enhancement, by which responses are amplified when stimuli move along the preferred direction of the cell, and null direction suppression, where one signal inhibits the response to the subsequent one when stimuli move along the opposite, i.e. null direction. Along the processing chain in the Drosophila optic lobe, directional responses first appear in T4 and T5 cells. Visually stimulating sequences of individual columns in the optic lobe with a telescope while recording from single T4 neurons, we find both mechanisms at work implemented in different sub-regions of the receptive field. This finding explains the high degree of directional selectivity found already in the fly’s primary motion-sensing neurons and marks an important step in our understanding of elementary motion detection. DOI: http://dx.doi.org/10.7554/eLife.17421.001 PMID:27502554

Effects of Cannabidiol and Hypothermia on Short-Term Brain Damage in New-Born Piglets after Acute Hypoxia-Ischemia

PubMed Central

Lafuente, Hector; Pazos, Maria R.; Alvarez, Antonia; Mohammed, Nagat; Santos, Martín; Arizti, Maialen; Alvarez, Francisco J.; Martinez-Orgado, Jose A.

2016-01-01

Hypothermia is a standard treatment for neonatal encephalopathy, but nearly 50% of treated infants have adverse outcomes. Pharmacological therapies can act through complementary mechanisms with hypothermia improving neuroprotection. Cannabidiol could be a good candidate. Our aim was to test whether immediate treatment with cannabidiol and hypothermia act through complementary brain pathways in hypoxic-ischemic newborn piglets. Hypoxic-ischemic animals were randomly divided into four groups receiving 30 min after the insult: (1) normothermia and vehicle administration; (2) normothermia and cannabidiol administration; (3) hypothermia and vehicle administration; and (4) hypothermia and cannabidiol administration. Six hours after treatment, brains were processed to quantify the number of damaged neurons by Nissl staining. Proton nuclear magnetic resonance spectra were obtained and analyzed for lactate, N-acetyl-aspartate and glutamate. Metabolite ratios were calculated to assess neuronal damage (lactate/N-acetyl-aspartate) and excitotoxicity (glutamate/Nacetyl-aspartate). Western blot studies were performed to quantify protein nitrosylation (oxidative stress), content of caspase-3 (apoptosis) and TNFα (inflammation). Individually, the hypothermia and the cannabidiol treatments reduced the glutamate/Nacetyl-aspartate ratio, as well as TNFα and oxidized protein levels in newborn piglets subjected to hypoxic-ischemic insult. Also, both therapies reduced the number of necrotic neurons and prevented an increase in lactate/N-acetyl-aspartate ratio. The combined effect of hypothermia and cannabidiol on excitotoxicity, inflammation and oxidative stress, and on cell damage, was greater than either hypothermia or cannabidiol alone. The present study demonstrated that cannabidiol and hypothermia act complementarily and show additive effects on the main factors leading to hypoxic-ischemic brain damage if applied shortly after the insult. PMID:27462203

CDKL5 ensures excitatory synapse stability by reinforcing NGL-1-PSD95 interaction in the postsynaptic compartment and is impaired in patient iPSC-derived neurons.

PubMed

Ricciardi, Sara; Ungaro, Federica; Hambrock, Melanie; Rademacher, Nils; Stefanelli, Gilda; Brambilla, Dario; Sessa, Alessandro; Magagnotti, Cinzia; Bachi, Angela; Giarda, Elisa; Verpelli, Chiara; Kilstrup-Nielsen, Charlotte; Sala, Carlo; Kalscheuer, Vera M; Broccoli, Vania

2012-09-01

Mutations of the cyclin-dependent kinase-like 5 (CDKL5) and netrin-G1 (NTNG1) genes cause a severe neurodevelopmental disorder with clinical features that are closely related to Rett syndrome, including intellectual disability, early-onset intractable epilepsy and autism. We report here that CDKL5 is localized at excitatory synapses and contributes to correct dendritic spine structure and synapse activity. To exert this role, CDKL5 binds and phosphorylates the cell adhesion molecule NGL-1. This phosphorylation event ensures a stable association between NGL-1 and PSD95. Accordingly, phospho-mutant NGL-1 is unable to induce synaptic contacts whereas its phospho-mimetic form binds PSD95 more efficiently and partially rescues the CDKL5-specific spine defects. Interestingly, similarly to rodent neurons, iPSC-derived neurons from patients with CDKL5 mutations exhibit aberrant dendritic spines, thus suggesting a common function of CDKL5 in mice and humans.

Cortistatin is induced in brain tissue and exerts neuroprotection in a rat model of bacterial meningoencephalitis.

PubMed

Chiu, Chien-Tsai; Wen, Li-Li; Pao, Hsin-Ping; Wang, Jia-Yi

2011-11-15

There are fewer reports of brain infection by Klebsiella pneumoniae than there are in other organs, but an increase incidence and morbidity has been noted. We have previously developed a rat model of K. pneumoniae meningoencephalitis. Cortistatin (CST) is a recently discovered neuropeptide with endocrine activities in humans. In this study, we found that brain infection by K. pneumoniae increased endogenous prepro-CST messenger RNA expression, which occurred earlier than did leukocyte infiltration in vivo and also occurred in cultured neuron-glia. Postinfection treatment with CST (either intracerebroventricularly or intraperitoneally), but not somatostatin, reduced leukocyte recruitment and clinical illness as revealed by fever and clinical score in vivo. Postinfection increases of proinflammatory cytokine messenger RNA levels were attenuated by CST in neuron-glia cultures, further confirming a direct effect on neuroinflammation. Administration of CST resulted in less postinfection neuronal loss in vitro, suggesting a direct neuroprotective effect and potential as an adjuvant for treating bacterial meningoencephalitis.

Regulation of lipid metabolism by energy availability: a role for the central nervous system.

PubMed

Nogueiras, R; López, M; Diéguez, C

2010-03-01

The central nervous system (CNS) is crucial in the regulation of energy homeostasis. Many neuroanatomical studies have shown that the white adipose tissue (WAT) is innervated by the sympathetic nervous system, which plays a critical role in adipocyte lipid metabolism. Therefore, there are currently numerous reports indicating that signals from the CNS control the amount of fat by modulating the storage or oxidation of fatty acids. Importantly, some CNS pathways regulate adipocyte metabolism independently of food intake, suggesting that some signals possess alternative mechanisms to regulate energy homeostasis. In this review, we mainly focus on how neuronal circuits within the hypothalamus, such as leptin- ghrelin-and resistin-responsive neurons, as well as melanocortins, neuropeptide Y, and the cannabinoid system exert their actions on lipid metabolism in peripheral tissues such as WAT, liver or muscle. Dissecting the complicated interactions between peripheral signals and neuronal circuits regulating lipid metabolism might open new avenues for the development of new therapies preventing and treating obesity and its associated cardiometabolic sequelae.

Krebs Cycle Intermediates Protective against Oxidative Stress by Modulating the Level of Reactive Oxygen Species in Neuronal HT22 Cells.

PubMed

Sawa, Kenta; Uematsu, Takumi; Korenaga, Yusuke; Hirasawa, Ryuya; Kikuchi, Masatoshi; Murata, Kyohei; Zhang, Jian; Gai, Xiaoqing; Sakamoto, Kazuichi; Koyama, Tomoyuki; Satoh, Takumi

2017-03-16

Krebs cycle intermediates (KCIs) are reported to function as energy substrates in mitochondria and to exert antioxidants effects on the brain. The present study was designed to identify which KCIs are effective neuroprotective compounds against oxidative stress in neuronal cells. Here we found that pyruvate, oxaloacetate, and α-ketoglutarate, but not lactate, citrate, iso-citrate, succinate, fumarate, or malate, protected HT22 cells against hydrogen peroxide-mediated toxicity. These three intermediates reduced the production of hydrogen peroxide-activated reactive oxygen species, measured in terms of 2',7'-dichlorofluorescein diacetate fluorescence. In contrast, none of the KCIs-used at 1 mM-protected against cell death induced by high concentrations of glutamate-another type of oxidative stress-induced neuronal cell death. Because these protective KCIs did not have any toxic effects (at least up to 10 mM), they have potential use for therapeutic intervention against chronic neurodegenerative diseases.

Progesterone Inhibition of Neuronal Calcium Signaling Underlies Aspects of Progesterone-Mediated Neuroprotection

PubMed Central

Luoma, Jessie I; Stern, Christopher M; Mermelstein, Paul G.

2011-01-01

Progesterone is being utilized as a therapeutic means to ameliorate neuron loss and cognitive dysfunction following traumatic brain injury Although there have been numerous attempts to determine the means by which progesterone exerts neuroprotective effects, studies describing the underlying molecular mechanisms are lacking What has become clear, however, is the notion that progesterone can thwart several physiological processes that are detrimental to neuron function and survival, including inflammation, edema, demyelination and excitotoxicity One clue regarding the means by which progesterone has restorative value comes from the notion that these aforementioned biological processes all share the common theme of eliciting pronounced increases in intracellular calcium. Thus, we propose the hypothesis that progesterone regulation of calcium signaling underlies its ability to mitigate these cellular insults, ultimately leading to neuroprotection. Further, we describe recent findings that indicate neuroprotection is achieved via progesterone block of voltage-gated calcium channels, although additional outcomes may arise from blockade of various other ion channels and neurotransmitter receptors. PMID:22101209

Asymmetric temporal integration of layer 4 and layer 2/3 inputs in visual cortex.

PubMed

Hang, Giao B; Dan, Yang

2011-01-01

Neocortical neurons in vivo receive concurrent synaptic inputs from multiple sources, including feedforward, horizontal, and feedback pathways. Layer 2/3 of the visual cortex receives feedforward input from layer 4 and horizontal input from layer 2/3. Firing of the pyramidal neurons, which carries the output to higher cortical areas, depends critically on the interaction of these pathways. Here we examined synaptic integration of inputs from layer 4 and layer 2/3 in rat visual cortical slices. We found that the integration is sublinear and temporally asymmetric, with larger responses if layer 2/3 input preceded layer 4 input. The sublinearity depended on inhibition, and the asymmetry was largely attributable to the difference between the two inhibitory inputs. Interestingly, the asymmetric integration was specific to pyramidal neurons, and it strongly affected their spiking output. Thus via cortical inhibition, the temporal order of activation of layer 2/3 and layer 4 pathways can exert powerful control of cortical output during visual processing.

α-Adrenoceptor blockade modifies neurally induced atrial arrhythmias

PubMed Central

Richer, Louis-Philippe; Vinet, Alain; Kus, Teresa; Cardinal, René; Ardell, Jeffrey L.; Armour, John Andrew

2008-01-01

Our objective was to determine whether neuronally induced atrial arrhythmias can be modified by α-adrenergic receptor blockade. In 30 anesthetized dogs, trains of five electrical stimuli (1 mA; 1 ms) were delivered immediately after the P wave of the ECG to mediastinal nerves associated with the superior vena cava. Regional atrial electrical events were monitored with 191 atrial unipolar electrodes. Mediastinal nerve sites were identified that reproducibly initiated atrial arrhythmias. These sites were then restimulated following 1 h (time control, n = 6), or the intravenous administration of naftopidil (α1-adrenergic blocker: 0.2 mg/kg, n = 6), yohimbine (α2-adrenergic blocker: 1 mg/kg, n = 6) or both (n = 8). A ganglionic blocker (hexamethonium: 1 mg/kg) was tested in four dogs. Stimulation of mediastinal nerves sites consistently elicited atrial tachyarrhythmias. Repeat stimulation after 1 h in the time-control group exerted a 19% decrease of the sites still able to induce atrial tachyarrhythmias. Hexamethonium inactivated 78% of the previously active sites. Combined α-adrenoceptor blockade inactivated 72% of the previously active sites. Bradycardia responses induced by mediastinal nerve stimulation were blunted by hexamethonium, but not by α1,2-adrenergic blockade. Naftopidil or yohimbine alone eliminated atrial arrhythmia induction from 31% and 34% of the sites (similar to time control). We conclude that heterogeneous activation of the intrinsic cardiac nervous system results in atrial arrhythmias that involve intrinsic cardiac neuronal α-adrenoceptors. In contrast to the global suppression exerted by hexamethonium, we conclude that α-adrenoceptor blockade targets intrinsic cardiac local circuit neurons involved in arrhythmia formation and not the flow-through efferent projections of the cardiac nervous system. PMID:18716036

Alpha-adrenoceptor blockade modifies neurally induced atrial arrhythmias.

PubMed

Richer, Louis-Philippe; Vinet, Alain; Kus, Teresa; Cardinal, René; Ardell, Jeffrey L; Armour, John Andrew

2008-10-01

Our objective was to determine whether neuronally induced atrial arrhythmias can be modified by alpha-adrenergic receptor blockade. In 30 anesthetized dogs, trains of five electrical stimuli (1 mA; 1 ms) were delivered immediately after the P wave of the ECG to mediastinal nerves associated with the superior vena cava. Regional atrial electrical events were monitored with 191 atrial unipolar electrodes. Mediastinal nerve sites were identified that reproducibly initiated atrial arrhythmias. These sites were then restimulated following 1 h (time control, n = 6), or the intravenous administration of naftopidil (alpha(1)-adrenergic blocker: 0.2 mg/kg, n = 6), yohimbine (alpha(2)-adrenergic blocker: 1 mg/kg, n = 6) or both (n = 8). A ganglionic blocker (hexamethonium: 1 mg/kg) was tested in four dogs. Stimulation of mediastinal nerves sites consistently elicited atrial tachyarrhythmias. Repeat stimulation after 1 h in the time-control group exerted a 19% decrease of the sites still able to induce atrial tachyarrhythmias. Hexamethonium inactivated 78% of the previously active sites. Combined alpha-adrenoceptor blockade inactivated 72% of the previously active sites. Bradycardia responses induced by mediastinal nerve stimulation were blunted by hexamethonium, but not by alpha(1,2)-adrenergic blockade. Naftopidil or yohimbine alone eliminated atrial arrhythmia induction from 31% and 34% of the sites (similar to time control). We conclude that heterogeneous activation of the intrinsic cardiac nervous system results in atrial arrhythmias that involve intrinsic cardiac neuronal alpha-adrenoceptors. In contrast to the global suppression exerted by hexamethonium, we conclude that alpha-adrenoceptor blockade targets intrinsic cardiac local circuit neurons involved in arrhythmia formation and not the flow-through efferent projections of the cardiac nervous system.

Prospects for cannabinoid therapies in basal ganglia disorders.

PubMed

Fernández-Ruiz, Javier; Moreno-Martet, Miguel; Rodríguez-Cueto, Carmen; Palomo-Garo, Cristina; Gómez-Cañas, María; Valdeolivas, Sara; Guaza, Carmen; Romero, Julián; Guzmán, Manuel; Mechoulam, Raphael; Ramos, José A

2011-08-01

Cannabinoids are promising medicines to slow down disease progression in neurodegenerative disorders including Parkinson's disease (PD) and Huntington's disease (HD), two of the most important disorders affecting the basal ganglia. Two pharmacological profiles have been proposed for cannabinoids being effective in these disorders. On the one hand, cannabinoids like Δ(9) -tetrahydrocannabinol or cannabidiol protect nigral or striatal neurons in experimental models of both disorders, in which oxidative injury is a prominent cytotoxic mechanism. This effect could be exerted, at least in part, through mechanisms independent of CB(1) and CB(2) receptors and involving the control of endogenous antioxidant defences. On the other hand, the activation of CB(2) receptors leads to a slower progression of neurodegeneration in both disorders. This effect would be exerted by limiting the toxicity of microglial cells for neurons and, in particular, by reducing the generation of proinflammatory factors. It is important to mention that CB(2) receptors have been identified in the healthy brain, mainly in glial elements and, to a lesser extent, in certain subpopulations of neurons, and that they are dramatically up-regulated in response to damaging stimuli, which supports the idea that the cannabinoid system behaves as an endogenous neuroprotective system. This CB(2) receptor up-regulation has been found in many neurodegenerative disorders including HD and PD, which supports the beneficial effects found for CB(2) receptor agonists in both disorders. In conclusion, the evidence reported so far supports that those cannabinoids having antioxidant properties and/or capability to activate CB(2) receptors may represent promising therapeutic agents in HD and PD, thus deserving a prompt clinical evaluation. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Nogo-receptor 1 antagonization in combination with neurotrophin-4/5 is not superior to single factor treatment in promoting survival and morphological complexity of cultured dopaminergic neurons.

PubMed

Seiler, Stefanie; Di Santo, Stefano; Sahli, Sebastian; Andereggen, Lukas; Widmer, Hans Rudolf

2017-08-01

Cell transplantation using ventral mesencephalic tissue is an experimental approach to treat Parkinson's disease. This approach is limited by poor survival of the transplants and the high number of dopaminergic neurons needed for grafting. Increasing the yield of dopaminergic neurons in donor tissue is of great importance. We have previously shown that antagonization of the Nogo-receptor 1 by NEP1-40 promoted survival of cultured dopaminergic neurons and exposure to neurotrophin-4/5 increased dopaminergic cell densities in organotypic midbrain cultures. We investigated whether a combination of both treatments offers a novel tool to further improve dopaminergic neuron survival. Rat embryonic ventral mesencephalic neurons grown as organotypic free-floating roller tube or primary dissociated cultures were exposed to neurotrophin-4/5 and NEP1-40. The combined and single factor treatment resulted in significantly higher numbers of tyrosine hydroxylase positive neurons compared to controls. Significantly stronger tyrosine hydroxylase signal intensity was detected by Western blotting in the combination-treated cultures compared to controls but not compared to single factor treatments. Neurotrophin-4/5 and the combined treatment showed significantly higher signals for the neuronal marker microtubule-associated protein 2 in Western blots compared to control while no effects were observed for the astroglial marker glial fibrillary acidic protein between groups, suggesting that neurotrophin-4/5 targets mainly neuronal cells. Finally, NEP1-40 and the combined treatment significantly augmented tyrosine hydroxylase positive neurite length. Summarizing, our findings substantiate that antagonization of the Nogo-receptor 1 promotes dopaminergic neurons but does not further increase the yield of dopaminergic neurons and their morphological complexity when combined with neurotrophin-4/5 hinting to the idea that these treatments might exert their effects by activating common downstream pathways. Copyright © 2017 Elsevier B.V. All rights reserved.

LAT region factors mediating differential neuronal tropism of HSV-1 and HSV-2 do not act in trans.

PubMed

Bertke, Andrea S; Apakupakul, Kathleen; Ma, AyeAye; Imai, Yumi; Gussow, Anne M; Wang, Kening; Cohen, Jeffrey I; Bloom, David C; Margolis, Todd P

2012-01-01

After HSV infection, some trigeminal ganglion neurons support productive cycle gene expression, while in other neurons the virus establishes a latent infection. We previously demonstrated that HSV-1 and HSV-2 preferentially establish latent infection in A5+ and KH10+ sensory neurons, respectively, and that exchanging the latency-associated transcript (LAT) between HSV-1 and HSV-2 also exchanges the neuronal preference. Since many viral genes besides the LAT are functionally interchangeable between HSV-1 and HSV-2, we co-infected HSV-1 and HSV-2, both in vivo and in vitro, to determine if trans-acting viral factors regulate whether HSV infection follows a productive or latent pattern of gene expression in sensory neurons. The pattern of HSV-1 and HSV-2 latent infection in trigeminal neurons was no different following co-infection than with either virus alone, consistent with the hypothesis that a trans-acting viral factor is not responsible for the different patterns of latent infection of HSV-1 and HSV-2 in A5+ and KH10+ neurons. Since exchanging the LAT regions between the viruses also exchanges neuronal preferences, we infected transgenic mice that constitutively express 2.8 kb of the LAT region with the heterologous viral serotype. Endogenous expression of LAT did not alter the pattern of latent infection after inoculation with the heterologous serotype virus, demonstrating that the LAT region does not act in trans to direct preferential establishment of latency of HSV-1 and HSV-2. Using HSV1-RFP and HSV2-GFP in adult trigeminal ganglion neurons in vitro, we determined that HSV-1 and HSV-2 do not exert trans-acting effects during acute infection to regulate neuron specificity. Although some neurons were productively infected with both HSV-1 and HSV-2, no A5+ or KH10+ neurons were productively infected with both viruses. Thus, trans-acting viral factors do not regulate preferential permissiveness of A5+ and KH10+ neurons for productive HSV infection and preferential establishment of latent infection.

LAT Region Factors Mediating Differential Neuronal Tropism of HSV-1 and HSV-2 Do Not Act in Trans

PubMed Central

Bertke, Andrea S.; Apakupakul, Kathleen; Ma, AyeAye; Imai, Yumi; Gussow, Anne M.; Wang, Kening; Cohen, Jeffrey I.; Bloom, David C.; Margolis, Todd P.

2012-01-01

After HSV infection, some trigeminal ganglion neurons support productive cycle gene expression, while in other neurons the virus establishes a latent infection. We previously demonstrated that HSV-1 and HSV-2 preferentially establish latent infection in A5+ and KH10+ sensory neurons, respectively, and that exchanging the latency-associated transcript (LAT) between HSV-1 and HSV-2 also exchanges the neuronal preference. Since many viral genes besides the LAT are functionally interchangeable between HSV-1 and HSV-2, we co-infected HSV-1 and HSV-2, both in vivo and in vitro, to determine if trans-acting viral factors regulate whether HSV infection follows a productive or latent pattern of gene expression in sensory neurons. The pattern of HSV-1 and HSV-2 latent infection in trigeminal neurons was no different following co-infection than with either virus alone, consistent with the hypothesis that a trans-acting viral factor is not responsible for the different patterns of latent infection of HSV-1 and HSV-2 in A5+ and KH10+ neurons. Since exchanging the LAT regions between the viruses also exchanges neuronal preferences, we infected transgenic mice that constitutively express 2.8 kb of the LAT region with the heterologous viral serotype. Endogenous expression of LAT did not alter the pattern of latent infection after inoculation with the heterologous serotype virus, demonstrating that the LAT region does not act in trans to direct preferential establishment of latency of HSV-1 and HSV-2. Using HSV1-RFP and HSV2-GFP in adult trigeminal ganglion neurons in vitro, we determined that HSV-1 and HSV-2 do not exert trans-acting effects during acute infection to regulate neuron specificity. Although some neurons were productively infected with both HSV-1 and HSV-2, no A5+ or KH10+ neurons were productively infected with both viruses. Thus, trans-acting viral factors do not regulate preferential permissiveness of A5+ and KH10+ neurons for productive HSV infection and preferential establishment of latent infection. PMID:23300908

Diacylglycerol levels modulate the cellular distribution of the nicotinic acetylcholine receptor.

PubMed

Kamerbeek, Constanza B; Mateos, Melina V; Vallés, Ana S; Pediconi, María F; Barrantes, Francisco J; Borroni, Virginia

2016-05-01

Diacylglycerol (DAG), a second messenger involved in different cell signaling cascades, activates protein kinase C (PKC) and D (PKD), among other kinases. The present work analyzes the effects resulting from the alteration of DAG levels on neuronal and muscle nicotinic acetylcholine receptor (AChR) distribution. We employ CHO-K1/A5 cells, expressing adult muscle-type AChR in a stable manner, and hippocampal neurons, which endogenously express various subtypes of neuronal AChR. CHO-K1/A5 cells treated with dioctanoylglycerol (DOG) for different periods showed augmented AChR cell surface levels at short incubation times (30min-4h) whereas at longer times (18h) the AChR was shifted to intracellular compartments. Similarly, in cultured hippocampal neurons surface AChR levels increased as a result of DOG incubation for 4h. Inhibition of endogenous DAG catabolism produced changes in AChR distribution similar to those induced by DOG treatment. Specific enzyme inhibitors and Western blot assays revealed that DAGs exert their effect on AChR distribution through the modulation of the activity of classical PKC (cPKC), novel PKC (nPKC) and PKD activity. Copyright © 2016 Elsevier Ltd. All rights reserved.

[The effect of niflumic acid on gamma aminobutyric acid activated current in DRG neurons].

PubMed

Li, Li; Li, Jing; Ma, Ke-Tao; Cheng, Hong-Ju; Zhao, Lei; Wang, Yang; Si, Jun-Qiang

2013-01-01

To explore the modulatory effect of niflumic acid (NFA) on gamma aminobutyric acid (GABA)-activated currents of dorsal root ganglion (DRG) neurons in rat. The whole-cell patch-clamp technique was used to record the NFA- and GABA-activated currents in neurons freshly dissociated from rat DRG neurons. Application of NFA(0.1 - 100 micromol/L) could induce concentration-dependent outward currents in some cells (21/48,43.75%), and GABA (0.1 - 100 micromol/L) could induce concentration-dependent inward currents in some cells(150/159,94.32%). NFA-(100 micromol/L) and GABA-(100 micromol/L) activated currents were (0.27 +/- 0.06) nA (n = 12) and (1.29 +/- 0.72) nA (n = 53) respectively. However, pre-application of NFA (0.1 - 100 micromol/L) could inhibit the GABA-activated inward current which was identified to be GABAA receptor-mediated current. The inhibitory effects of NFA were concentration-dependent. NFA could not alter the EC50 (about 30 micromol/L) and inverse potential (about -10 mV) of GABA-activated current (P > 0.05). Pre-application of NFA exerts a more strong inhibitory effect on the peak value of GABA-activated current.

Melatonin-mediated β-catenin activation protects neuron cells against prion protein-induced neurotoxicity.

PubMed

Jeong, Jae-Kyo; Lee, Ju-Hee; Moon, Ji-Hong; Lee, You-Jin; Park, Sang-Youel

2014-11-01

Activation of β-catenin in neurons regulates mitochondrial function and protects against protein misfolding disorders, including Alzheimer's disease and Huntington's disease. Melatonin, a natural secretory product of the pineal gland, exerts neuroprotective effects through the activation of β-catenin. In this study, melatonin increased β-catenin protein expression and activation in human neuroblastoma cell lines SH-SY5Y cells. Melatonin also inhibited PrP (106-126)-induced neurotoxicity and the inhibition attenuated by treatment of β-catenin inhibitor ICG-001. Activation of β-catenin blocked PrP (106-126)-mediated downregulation of anti-apoptotic protein survivin and Bcl-2. Reduction of mitochondrial membrane potential, translocation of Bax, and cytochrome c release which induced by PrP (106-126) treatment were inhibited by β-catenin activation, which contributed to prevented PrP (106-126)-induced neuronal cell death. In conclusion, β-catenin activation by melatonin prevented PrP (106-126)-induced neuronal cell death through regulating anti-apoptotic proteins and mitochondrial pathways. These results also suggest the therapeutic value of Wnt/β-catenin signaling in prion-related disorders as influenced by melatonin. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Sodium cyanate-induced opening of calcium-activated potassium currents in hippocampal neuron-derived H19-7 cells.

PubMed

Huang, Chin-Wei; Huang, Chao-Ching; Huang, Mei-Han; Wu, Sheng-Nan; Hsieh, Yi-Jung

2005-03-29

We investigated the chemical toxic agent sodium cyanate (NaOCN) on the large conductance calcium-activated potassium channels (BK(Ca)) on hippocampal neuron-derived H19-7 cells. The whole-cell and cell-attach configuration of patch-clamp technique were applied to investigate the BK(Ca) currents in H19-7 cells in the presence of NaOCN (0.3 mM). NaOCN activated BK(Ca) channels on H19-7 cells. The single-channel conductance of BK(Ca) channels was 138+/-7pS. The presence of NaOCN (0.3 mM) caused an obvious increase in open probability of BK(Ca) channels. NaOCN did not exert effect on the slope of the activation curve and stimulated the activity of BK(Ca) channels in a voltage-dependent fashion in H19-7 cells. The presence of paxilline or EGTA significantly reduced the BK(Ca) amplitude, in comparison with the presence of NaOCN. These findings suggest that during NaOCN exposure, the activation of BK(Ca) channels in neurons could be one of the ionic mechanisms underlying the decreased neuronal excitability and neurological disorders.

Melatonin Protects SH-SY5Y Neuronal Cells Against Methamphetamine-Induced Endoplasmic Reticulum Stress and Apoptotic Cell Death.

PubMed

Wongprayoon, Pawaris; Govitrapong, Piyarat

2017-01-01

Methamphetamine (METH), a psychostimulant with highly neurotoxic effects, has been known to induce neuronal apoptosis in part through an endoplasmic reticulum (ER) stress pathway. Melatonin is an endogenous antioxidant compound that exerts protective effects against several neurodegenerative conditions, including METH-induced neurotoxicity, via various mechanisms. However, the role of melatonin in ER stress is still relatively unclear. In the present study, we investigated ER stress and neuronal apoptosis following METH treatment and the role of melatonin in METH-mediated ER stress-induced cell death in the SH-SY5Y neuroblastoma cell line. We found that METH caused the overexpression of ER stress-related genes, including C/EBP homologous protein and spliced X-box binding protein 1, in dose- and time-dependent manners. Moreover, METH time-dependently activated caspase-12 and -3, leading to cellular apoptosis. Furthermore, we demonstrated that pretreatment with melatonin attenuated the overexpression of ER stress-related genes and the cleavages of caspase-12 and -3 caused by METH exposure. Flow cytometry revealed that METH-mediated neuronal apoptosis was also prevented by melatonin. These findings suggest the protective effects of melatonin against ER stress and apoptosis caused by METH and other harmful agents.

Brain metabolism in health, aging, and neurodegeneration.

PubMed

Camandola, Simonetta; Mattson, Mark P

2017-06-01

Brain cells normally respond adaptively to bioenergetic challenges resulting from ongoing activity in neuronal circuits, and from environmental energetic stressors such as food deprivation and physical exertion. At the cellular level, such adaptive responses include the "strengthening" of existing synapses, the formation of new synapses, and the production of new neurons from stem cells. At the molecular level, bioenergetic challenges result in the activation of transcription factors that induce the expression of proteins that bolster the resistance of neurons to the kinds of metabolic, oxidative, excitotoxic, and proteotoxic stresses involved in the pathogenesis of brain disorders including stroke, and Alzheimer's and Parkinson's diseases. Emerging findings suggest that lifestyles that include intermittent bioenergetic challenges, most notably exercise and dietary energy restriction, can increase the likelihood that the brain will function optimally and in the absence of disease throughout life. Here, we provide an overview of cellular and molecular mechanisms that regulate brain energy metabolism, how such mechanisms are altered during aging and in neurodegenerative disorders, and the potential applications to brain health and disease of interventions that engage pathways involved in neuronal adaptations to metabolic stress. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

Phyto and endocannabinoids exert complex actions on calcium and zinc signaling in mouse cortical neurons.

PubMed

Bouron, Alexandre

2018-06-01

Live-cell imaging experiments were performed with the fluorescent Ca 2+ and Zn 2+ probes Fluo-4 and FluoZin-3 on cultured cortical neurons dissociated from embryonic mice to investigate the effects of the cannabinoids anandamide (AEA), cannabidiol (CBD), and N-arachidonoyl glycine (NAGly) on neuronal store-operated Ca 2+ entry (SOCE). When tested individually AEA, CBD or NAGly inhibited SOCE. CBD and NAGly also released Ca 2+ from the endoplasmic reticulum. Furthermore, NAGly mobilized Zn 2+ from a store distinct from the endoplasmic reticulum and mitochondria, and up-regulated the thapsigargin-evoked Ca 2+ release. All these effects developed in a cannabinoid receptor CB1/2 independent manner via an intracellular pathway sensitive to the GPR55 antagonist ML193. Evidence is presented that cannabinoids influence Ca 2+ and Zn 2+ signaling in central nervous system neurons. The lipid sensing receptor GPR55 seems to be a central actor governing these responses. In addition, the alteration of the cytosolic Zn 2+ levels produced by NAGly provides support for the existence of a connection between endocannabinoids and Zn 2+ signaling in the brain. Copyright © 2018 Elsevier Inc. All rights reserved.

C-peptide and Central Nervous System Complications in Diabetes

PubMed Central

Li, Zhen-guo

2004-01-01

Substantial evidence collected from clinical data and experimental studies has indicated that CNS is not spared from diabetes complications. Impairments in CNS function are well documented in both type 1 and type 2 diabetic patients as well as in various animal models of diabetes, in terms of alterations in cognition, neuropsychology, neurobehavior, electrophysiology, structure, neurochemistry and apoptotic activities. These data suggest that primary diabetic encephalopathy exists as a definable diabetic complication. The mechanisms underlying this CNS complication are not clear. Experimental studies have suggested that neuronal apoptosis may play an important role in neuronal loss and impaired cognitive function. In diabetes multiple factors are responsible for neuronal apoptosis, such as a perturbed IGF system, hyperglycemia and the aging process itself. Recent data suggest that insulin/C-peptide deficiency may exert an eminent role. Administration of C-peptide partially corrects the perturbed IGF system in the brain and prevents neuronal apoptosis in hippocampus of type 1 diabetes. In neuroblastoma SH-SY5Y cells C-peptide provides a dose-dependent stimulation on cell proliferation and an anti-apoptotic effect as well. These studies provide a basis for administration of C-peptide as a potentially effective therapy for type 1 diabetes. PMID:15198373

Elimination of GRK2 from cholinergic neurons reduces behavioral sensitivity to muscarinic receptor activation.

PubMed

Daigle, Tanya L; Caron, Marc G

2012-08-15

Although G-protein-coupled receptor kinase 2 (GRK2) is the most widely studied member of a family of kinases that has been shown to exert powerful influences on a variety of G-protein-coupled receptors, its role in the brain remains largely unknown. Here we report the localization of GRK2 in the mouse brain and generate novel conditional knock-out (KO) mice to assess the physiological importance of this kinase in cholinergic neurons. Mice with the selective deletion of GRK2 in this cell population (ChAT(IRES-cre)Grk2(f/f) KO mice) exhibit reduced behavioral responsiveness to challenge with oxotremorine-M (Oxo-M), a nonselective muscarinic acetylcholine receptor agonist. Specifically, Oxo-M-induced hypothermia, hypolocomotion, and salivation were markedly reduced in these animals, while analgesic responses were unaltered. In contrast, we found that GRK2 deficiency in cholinergic neurons does not alter cocaine-induced psychomotor activation, behavioral sensitization, or conditioned place preference. These results demonstrate that the elimination of GRK2 in cholinergic neurons reduces sensitivity to select muscarinic-mediated behaviors, while dopaminergic effects remain intact and further suggests that GRK2 may selectively impair muscarinic acetylcholine receptor-mediated function in vivo.

Differential dynamics of spatial attention, position, and color coding within the parietofrontal network.

PubMed

Astrand, Elaine; Ibos, Guilhem; Duhamel, Jean-René; Ben Hamed, Suliann

2015-02-18

Despite an ever growing knowledge on how parietal and prefrontal neurons encode low-level spatial and color information or higher-level information, such as spatial attention, an understanding of how these cortical regions process neuronal information at the population level is still missing. A simple assumption would be that the function and temporal response profiles of these neuronal populations match that of its constituting individual cells. However, several recent studies suggest that this is not necessarily the case and that the single-cell approach overlooks dynamic changes in how information is distributed over the neuronal population. Here, we use a time-resolved population pattern analysis to explore how spatial position, spatial attention and color information are differentially encoded and maintained in the macaque monkey prefrontal (frontal eye fields) and parietal cortex (lateral intraparietal area). Overall, our work brings about three novel observations. First, we show that parietal and prefrontal populations operate in two distinct population regimens for the encoding of sensory and cognitive information: a stationary mode and a dynamic mode. Second, we show that the temporal dynamics of a heterogeneous neuronal population brings about complementary information to that of its functional subpopulations. Thus, both need to be investigated in parallel. Last, we show that identifying the neuronal configuration in which a neuronal population encodes given information can serve to reveal this same information in a different context. All together, this work challenges common views on neural coding in the parietofrontal network. Copyright © 2015 the authors 0270-6474/15/353174-16$15.00/0.

Specific serine-proline phosphorylation and glycogen synthase kinase 3β-directed subcellular targeting of stathmin 3/Sclip in neurons.

PubMed

Devaux, Sara; Poulain, Fabienne E; Devignot, Véronique; Lachkar, Sylvie; Irinopoulou, Theano; Sobel, André

2012-06-22

During nervous system development, neuronal growth, migration, and functional morphogenesis rely on the appropriate control of the subcellular cytoskeleton including microtubule dynamics. Stathmin family proteins play major roles during the various stages of neuronal differentiation, including axonal growth and branching, or dendritic development. We have shown previously that stathmins 2 (SCG10) and 3 (SCLIP) fulfill distinct, independent and complementary regulatory roles in axonal morphogenesis. Although the two proteins have been proposed to display the four conserved phosphorylation sites originally identified in stathmin 1, we show here that they possess distinct phosphorylation sites within their specific proline-rich domains (PRDs) that are differentially regulated by phosphorylation by proline-directed kinases involved in the control of neuronal differentiation. ERK2 or CDK5 phosphorylate the two proteins but with different site specificities. We also show for the first time that, unlike stathmin 2, stathmin 3 is a substrate for glycogen synthase kinase (GSK) 3β both in vitro and in vivo. Interestingly, stathmin 3 phosphorylated at its GSK-3β target site displays a specific subcellular localization at neuritic tips and within the actin-rich peripheral zone of the growth cone of differentiating hippocampal neurons in culture. Finally, pharmacological inhibition of GSK-3β induces a redistribution of stathmin 3, but not stathmin 2, from the periphery toward the Golgi region of neurons. Stathmin proteins can thus be either regulated locally or locally targeted by specific phosphorylation, each phosphoprotein of the stathmin family fulfilling distinct and specific roles in the control of neuronal differentiation.

Towards circuit optogenetics.

PubMed

Chen, I-Wen; Papagiakoumou, Eirini; Emiliani, Valentina

2018-06-01

Optogenetics neuronal targeting combined with single-photon wide-field illumination has already proved its enormous potential in neuroscience, enabling the optical control of entire neuronal networks and disentangling their role in the control of specific behaviors. However, establishing how a single or a sub-set of neurons controls a specific behavior, or how functionally identical neurons are connected in a particular task, or yet how behaviors can be modified in real-time by the complex wiring diagram of neuronal connections requires more sophisticated approaches enabling to drive neuronal circuits activity with single-cell precision and millisecond temporal resolution. This has motivated on one side the development of flexible optical methods for two-photon (2P) optogenetic activation using either, or a hybrid of two approaches: scanning and parallel illumination. On the other side, it has stimulated the engineering of new opsins with modified spectral characteristics, channel kinetics and spatial distribution of expression, offering the necessary flexibility of choosing the appropriate opsin for each application. The need for optical manipulation of multiple targets with millisecond temporal resolution has imposed three-dimension (3D) parallel holographic illumination as the technique of choice for optical control of neuronal circuits organized in 3D. Today 3D parallel illumination exists in several complementary variants, each with a different degree of simplicity, light uniformity, temporal precision and axial resolution. In parallel, the possibility to reach hundreds of targets in 3D volumes has prompted the development of low-repetition rate amplified laser sources enabling high peak power, while keeping low average power for stimulating each cell. All together those progresses open the way for a precise optical manipulation of neuronal circuits with unprecedented precision and flexibility. Copyright © 2018 Elsevier Ltd. All rights reserved.

Coexpression of VGLUT1 and VGLUT2 in trigeminothalamic projection neurons in the principal sensory trigeminal nucleus of the rat.

PubMed

Ge, Shun-Nan; Ma, Yun-Fei; Hioki, Hiroyuki; Wei, Yan-Yan; Kaneko, Takeshi; Mizuno, Noboru; Gao, Guo-Dong; Li, Jin-Lian

2010-08-01

VGLUT1 and VGLUT2 have been reported to show complementary distributions in most brain regions and have been assumed to define distinct functional elements. In the present study, we first investigated the expression of VGLUT1 and VGLUT2 in the trigeminal sensory nuclear complex of the rat by dual-fluorescence in situ hybridization. Although VGLUT1 and/or VGLUT2 mRNA signals were detected in all the nuclei, colocalization was found only in the principal sensory trigeminal nucleus (Vp). About 64% of glutamatergic Vp neurons coexpressed VGLUT1 and VGLUT2, and the others expressed either VGLUT1 or VGLUT2, indicating that Vp neurons might be divided into three groups. We then injected retrograde tracer into the thalamic regions, including the posteromedial ventral nucleus (VPM) and posterior nuclei (Po), and observed that the majority of both VGLUT1- and VGLUT2-expressing Vp neurons were retrogradely labeled with the tracer. We further performed anterograde labeling of Vp neurons and observed immunoreactivies for anterograde tracer, VGLUT1, and VGLUT2 in the VPM and Po. Most anterogradely labeled axon terminals showed immunoreactivities for both VGLUT1 and VGLUT2 in the VPM and made asymmetric synapses with dendritic profiles of VPM neurons. On the other hand, in the Po, only a few axon terminals were labeled with anterograde tracer, and they were positive only for VGLUT2. The results indicated that Vp neurons expressing VGLUT1 and VGLUT2 project to the VPM, but not to the Po, although the functional differences of three distinct populations of Vp neurons, VGLUT1-, VGLUT2-, and VGLUT1/VGLUT2-expressing ones, remain unsettled. (c) 2010 Wiley-Liss, Inc.

Amyloid-beta aggregates cause alterations of astrocytic metabolic phenotype: impact on neuronal viability.

PubMed

Allaman, Igor; Gavillet, Mathilde; Bélanger, Mireille; Laroche, Thierry; Viertl, David; Lashuel, Hilal A; Magistretti, Pierre J

2010-03-03

Amyloid-beta (Abeta) peptides play a key role in the pathogenesis of Alzheimer's disease and exert various toxic effects on neurons; however, relatively little is known about their influence on glial cells. Astrocytes play a pivotal role in brain homeostasis, contributing to the regulation of local energy metabolism and oxidative stress defense, two aspects of importance for neuronal viability and function. In the present study, we explored the effects of Abeta peptides on glucose metabolism in cultured astrocytes. Following Abeta(25-35) exposure, we observed an increase in glucose uptake and its various metabolic fates, i.e., glycolysis (coupled to lactate release), tricarboxylic acid cycle, pentose phosphate pathway, and incorporation into glycogen. Abeta increased hydrogen peroxide production as well as glutathione release into the extracellular space without affecting intracellular glutathione content. A causal link between the effects of Abeta on glucose metabolism and its aggregation and internalization into astrocytes through binding to members of the class A scavenger receptor family could be demonstrated. Using astrocyte-neuron cocultures, we observed that the overall modifications of astrocyte metabolism induced by Abeta impair neuronal viability. The effects of the Abeta(25-35) fragment were reproduced by Abeta(1-42) but not by Abeta(1-40). Finally, the phosphoinositide 3-kinase (PI3-kinase) pathway appears to be crucial in these events since both the changes in glucose utilization and the decrease in neuronal viability are prevented by LY294002, a PI3-kinase inhibitor. This set of observations indicates that Abeta aggregation and internalization into astrocytes profoundly alter their metabolic phenotype with deleterious consequences for neuronal viability.

Manganese Nanoparticle Activates Mitochondrial Dependent Apoptotic Signaling and Autophagy in Dopaminergic Neuronal Cells

PubMed Central

Ngwa, Hilary Afeseh; Kanthasamy, Arthi; Gu, Yan; Fang, Ning; Anantharam, Vellareddy; Kanthasamy, Anumantha G.

2011-01-01

The production of man-made nanoparticles for various modern applications has increased exponentially in recent years, but the potential health effects of most nanoparticles are not well characterized. Unfortunately, in vitro nanoparticle toxicity studies are extremely limited by yet unresolved problems relating to dosimetry. In the present study, we systematically characterized manganese (Mn) nanoparticle sizes and examined the nanoparticle-induced oxidative signaling in dopaminergic neuronal cells. Differential interference contrast (DIC) microscopy and transmission electron microscopy (TEM) studies revealed that Mn nanoparticles range in size from single nanoparticles (~25 nM) to larger agglomerates when in treatment media. Manganese nanoparticles were effectively internalized in N27 dopaminergic neuronal cells, and they induced a time-dependent upregulation of the transporter protein transferrin. Exposure to 25–400 µg/mL Mn nanoparticles induced cell death in a time- and dose-dependent manner. Mn nanoparticles also significantly increased ROS, accompanied by a caspase-mediated proteolytic cleavage of proapoptotic protein kinase Cδ (PKCδ), as well as activation loop phosphorylation. Blocking Mn nanoparticle-induced ROS failed to protect against the neurotoxic effects, suggesting the involvement of other pathways. Further mechanistic studies revealed changes in Beclin1 and LC3, indicating that Mn nanoparticles induce autophagy. Primary mesencephalic neuron exposure to Mn nanoparticles induced loss of TH positive dopaminergic neurons and neuronal processes. Collectively, our results suggest that Mn nanoparticles effectively enter dopaminergic neuronal cells and exert neurotoxic effects by activating an apoptotic signaling pathway and autophagy, emphasizing the need for assessing possible health risks associated with an increased use of Mn nanoparticles in modern applications. PMID:21856324

Enhancing perception of contaminated food through acid-mediated modulation of taste neuron responses.

PubMed

Chen, Yan; Amrein, Hubert

2014-09-08

Natural foods contain not only nutrients, but also nonnutritious and potentially harmful chemicals. Thus, animals need to evaluate food content in order to make adequate feeding decisions. Here, we investigate the effects of acids on the taste neuron responses and on taste behavior of desirable, nutritious sugars and sugar/bitter compound mixtures in Drosophila melanogaster. Using Ca2+ imaging, we show that acids activate neither sweet nor bitter taste neurons in tarsal taste sensilla. However, they suppress responses to bitter compounds in bitter-sensing neurons. Moreover, acids reverse suppression of bitter compounds exerted on sweet-sensing neurons. Consistent with these observations, behavioral analyses show that bitter-compound-mediated inhibition on feeding behavior is alleviated by acids. To investigate the cellular mechanism by which acids modulate these effects, we silenced bitter-sensing gustatory neurons. Surprisingly, this intervention had little effect on acid-mediated derepression of sweet neuron or feeding responses to either sugar/bitter compound mixtures or sugar/bitter compound/acid mixtures, suggesting that there are two independent pathways by which bitter compounds are sensed. Our investigations reveal that acids, when presented in dietary relevant concentrations, enhance the perception of sugar/bitter compound mixtures. Drosophila's natural food sources-fruits and cohabitating yeast-are rich in sugars and acids but are rapidly colonized by microorganisms, such as fungi, protozoan parasites, and bacteria, many of which produce bitter compounds. We propose that the acids present in most fruits counteract the inhibitory effects of these bitter compounds during feeding. Copyright © 2014 Elsevier Ltd. All rights reserved.

Not GABA but glycine mediates segmental, propriospinal, and bulbospinal postsynaptic inhibition in adult mouse spinal forelimb motor neurons.

PubMed

Jiang, Juan; Alstermark, Bror

2015-02-04

The general view is that both glycine (Eccles, 1964) and GABA (Curtis and Felix, 1971) evoke postsynaptic inhibition in spinal motor neurons. In newborn or juvenile animals, there are conflicting results showing postsynaptic inhibition in motor neurons by corelease of GABA and glycine (Jonas et al., 1998) or by glycine alone (Bhumbra et al., 2012). To resolve the relative contributions of GABA and glycine to postsynaptic inhibition, we performed in vivo intracellular recordings from forelimb motor neurons in adult mice. Postsynaptic potentials evoked from segmental, propriospinal, and bulbospinal systems in motor neurons were compared across four different conditions: control, after gabazine, gabazine followed by strychnine, and strychnine alone. No significant differences were observed in the proportion of IPSPs and EPSPs between control and gabazine conditions. In contrast, EPSPs but not IPSPs were recorded after adding strychnine with gabazine or administering strychnine alone, suggesting an exclusive role for glycine in postsynaptic inhibition. To test whether the injected (intraperitoneal) dose of gabazine blocked GABAergic inhibitory transmission, we evoked GABAA receptor-mediated monosynaptic IPSPs in deep cerebellar nuclei neurons by stimulation of Purkinje cell fibers. No monosynaptic IPSPs could be recorded in the presence of gabazine, showing the efficacy of gabazine treatment. Our results demonstrate that, in the intact adult mouse, the postsynaptic inhibitory effects in spinal motor neurons exerted by three different systems, intrasegmental and intersegmental as well as supraspinal, are exclusively glycinergic. These findings emphasize the importance of glycinergic postsynaptic inhibition in motor neurons and challenge the view that GABA also contributes. Copyright © 2015 the authors 0270-6474/15/351991-08$15.00/0.

BDNF promotes the growth of human neurons through crosstalk with the Wnt/β-catenin signaling pathway via GSK-3β.

PubMed

Yang, Jin-Wei; Ru, Jin; Ma, Wei; Gao, Yan; Liang, Zhang; Liu, Jia; Guo, Jian-Hui; Li, Li-Yan

2015-12-01

Brain-derived neurotrophic factor (BDNF) plays an important role in neuronal growth; however, the downstream regulatory mechanisms remain unclear. In this study, we investigated whether BDNF exerts its neurotrophic effects through the Wnt/β-catenin signaling pathway in human embryonic spinal cord neurons in vitro. We found that neuronal growth (soma size and average neurite length) was increased by transfection with a BDNF overexpression plasmid. Western blotting and real-time quantitative PCR showed that expression of the BDNF pathway components TrkB, PI3K, Akt and PLC-γ was increased by BDNF overexpression. Furthermore, the Wnt signaling factors Wnt, Frizzled and Dsh and the downstream target β-catenin were upregulated, whereas GSK-3β was downregulated. In contrast, when BDNF signaling was downregulated with BDNF siRNA, the growth of neurons was decreased. Furthermore, BDNF signaling factors, Wnt pathway components and β-catenin were all downregulated, whereas GSK-3β was upregulated. This suggests that BDNF affects the growth of neurons in vitro through crosstalk with Wnt signaling, and that GSK-3β may be a critical factor linking these two pathways. To evaluate this possibility, we treated neurons with 6-bromoindirubin-3'-oxime (BIO), a small molecule GSK-3β inhibitor. BIO reduced the effects of BDNF upregulation/downregulation on soma size and average neurite length, and suppressed the impact of BDNF modulation on the Wnt signaling pathway. Taken together, our findings suggest that BDNF promotes the growth of neurons in vitro through crosstalk with the Wnt/β-catenin signaling pathway, and that this interaction may be mediated by GSK-3β. Copyright © 2015 Elsevier Ltd. All rights reserved.

Connections between EM2-containing terminals and GABA/μ-opioid receptor co-expressing neurons in the rat spinal trigeminal caudal nucleus

PubMed Central

Li, Meng-Ying; Wu, Zhen-Yu; Lu, Ya-Cheng; Yin, Jun-Bin; Wang, Jian; Zhang, Ting; Dong, Yu-Lin; Wang, Feng

2014-01-01

Endomorphin-2 (EM2) demonstrates a potent antinociceptive effect via the μ-opioid receptor (MOR). To provide morphological evidence for the pain control effect of EM2, the synaptic connections between EM2-immunoreactive (IR) axonal terminals and γ-amino butyric acid (GABA)/MOR co-expressing neurons in lamina II of the spinal trigeminal caudal nucleus (Vc) were investigated in the rat. Dense EM2-, MOR- and GABA-IR fibers and terminals were mainly observed in lamina II of the Vc. Within lamina II, GABA- and MOR-neuronal cell bodies were also encountered. The results of immunofluorescent histochemical triple-staining showed that approximately 14.2 or 18.9% of GABA-IR or MOR-IR neurons also showed MOR- or GABA-immunopositive staining in lamina II; approximately 45.2 and 36.1% of the GABA-IR and MOR-IR neurons, respectively, expressed FOS protein in their nuclei induced by injecting formalin into the left lower lip of the mouth. Most of the GABA/MOR, GABA/FOS, and MOR/FOS double-labeled neurons made close contacts with EM2-IR fibers and terminals. Immuno-electron microscopy confirmed that the EM2-IR terminals formed synapses with GABA-IR or MOR-IR dendritic processes and neuronal cell bodies in lamina II of the Vc. These results suggest that EM2 might participate in pain transmission and modulation by binding to MOR-IR and GABAergic inhibitory interneuron in lamina II of the Vc to exert inhibitory effect on the excitatory interneuron in lamina II and projection neurons in laminae I and III. PMID:25386121

Hypocretin-2 (orexin-B) modulation of superficial dorsal horn activity in rat

PubMed Central

Grudt, Timothy J; van den Pol, Anthony N; Perl, Edward R

2002-01-01

The hypothalamic peptides hypocretin-1 (orexin A) and hypocretin-2 (Hcrt-2; orexin B) are important in modulating behaviours demanding arousal, including sleep and appetite. Fibres containing hypocretin project from the hypothalamus to the superficial dorsal horn (SDH) of the spinal cord (laminae I and II); however, the effects produced by hypocretins on SDH neurones are unknown. To study the action of Hcrt-2 on individual SDH neurones, tight-seal, whole-cell recordings were made with biocytin-filled electrodes from rat lumbar spinal cord slices. In 19 of 63 neurones, Hcrt-2 (30 nm to 1 μm) evoked an inward (excitatory) current accompanied by an increase in baseline noise. The inward current and noise were unaffected by TTX but were blocked by the P2X purinergic receptor antagonist suramin (300–500 μm). Hcrt-2 (30 nm to 1 μm) increased the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in the majority of neurones. The sIPSC increase was blocked by strychnine (1 μm) and by TTX (1 μm), suggesting that the increased sIPSC frequency was glycine and action potential dependent. Hcrt-2 increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in a few neurones but had no effect on dorsal root-evoked EPSCs in these or in other neurones. Neurones located in outer lamina II, particularly radial and vertical cells, were most likely to respond to Hcrt-2. We conclude that Hcrt-2 has excitatory effects on certain SDH neurones, some of which exert inhibitory influences on other cells of the region, consistent with the perspective that hypocretin has a role in orchestrating reactions related to arousal, including nociception, pain and temperature sense. PMID:11790816

Cell-Autonomous Regulation of Dendritic Spine Density by PirB.

PubMed

Vidal, George S; Djurisic, Maja; Brown, Kiana; Sapp, Richard W; Shatz, Carla J

2016-01-01

Synapse density on cortical pyramidal neurons is modulated by experience. This process is highest during developmental critical periods, when mechanisms of synaptic plasticity are fully engaged. In mouse visual cortex, the critical period for ocular dominance (OD) plasticity coincides with the developmental pruning of synapses. At this time, mice lacking paired Ig-like receptor B (PirB) have excess numbers of dendritic spines on L5 neurons; these spines persist and are thought to underlie the juvenile-like OD plasticity observed in adulthood. Here we examine whether PirB is required specifically in excitatory neurons to exert its effect on dendritic spine and synapse density during the critical period. In mice with a conditional allele of PirB (PirB fl/fl ), PirB was deleted only from L2/3 cortical pyramidal neurons in vivo by timed in utero electroporation of Cre recombinase. Sparse mosaic expression of Cre produced neurons lacking PirB in a sea of wild-type neurons and glia. These neurons had significantly elevated dendritic spine density, as well as increased frequency of miniature EPSCs, suggesting that they receive a greater number of synaptic inputs relative to Cre - neighbors. The effect of cell-specific PirB deletion on dendritic spine density was not accompanied by changes in dendritic branching complexity or axonal bouton density. Together, results imply a neuron-specific, cell-autonomous action of PirB on synaptic density in L2/3 pyramidal cells of visual cortex. Moreover, they are consistent with the idea that PirB functions normally to corepress spine density and synaptic plasticity, thereby maintaining headroom for cells to encode ongoing experience-dependent structural change throughout life.

Altered expression of IGF-I system in neurons of the inflamed spinal cord during acute experimental autoimmune encephalomyelitis.

PubMed

Parvaneh Tafreshi, Azita; Talebi, Farideh; Ghorbani, Samira; Bernard, Claude; Noorbakhsh, Farshid

2017-10-01

There is growing evidence that the impaired IGF-I system contributes to neurodegeneration. In this study, we examined the spinal cords of the EAE, the animal model of multiple sclerosis, to see if the expression of the IGF-I system is altered. To induce EAE, C57/BL6 mice were immunized with the Hooke lab MOG kit, sacrificed at the peak of the disease and their spinal cords were examined for the immunoreactivities (ir) of the IGF-I, IGF binding protein-1 (IGFBP-1) and glycogen synthase kinase 3β (GSK3β), as one major downstream molecule in the IGF-I signaling. Although neurons in the non EAE spinal cords did not show the IGF-I immunoreactivity, they were numerously positive for the IGFBP-1. In the inflamed EAE spinal cord however, the patterns of expressions were reversed, that is, a significant increased number of IGF-I expressing neurons versus a reduced number of IGFBP-1 positive neurons. Moreover, while nearly all IGF-I-ir neurons expressed GSK3β, some expressed it more intensely. Considering our previous finding where we showed a significant reduced number of the inactive (phosphorylated) but not that of the total GSK3β expressing neurons in the EAE spinal cord, it is conceivable that the intense total GSK3β expression in the IGF-I-ir neurons belongs to the active form of GSK3β known to exert neuroinflammatory effects. We therefore suggest that the altered expression of the IGF-I system including GSK3β in spinal cord neurons might involve in pathophysiological events during the EAE. © 2017 Wiley Periodicals, Inc.

The Neuroprotective Effect of Klotho is Mediated via Regulation of Members of the Redox System*

PubMed Central

Zeldich, Ella; Chen, Ci-Di; Colvin, Teresa A.; Bove-Fenderson, Erin A.; Liang, Jennifer; Tucker Zhou, Tracey B.; Harris, David A.; Abraham, Carmela R.

2014-01-01

Generation of reactive oxygen species (ROS), leading to oxidative damage and neuronal cell death, plays an important role in the pathogenesis of neurodegenerative disorders, including Alzheimer disease. The present study aimed to examine the mechanism by which the anti-aging protein Klotho exerts neuroprotective effects against neuronal damage associated with neurodegeneration and oxidative stress. Pretreatment of rat primary hippocampal neurons and mouse hippocampal neuronal cell line HT22 with recombinant Klotho protected these cells from glutamate and oligomeric amyloid β (oAβ)-induced cytotoxicity. In addition, primary hippocampal neurons obtained from Klotho-overexpressing mouse embryos were more resistant to both cytotoxic insults, glutamate and oAβ, compared with neurons from wild-type littermates. An antioxidative stress array analysis of neurons treated with Klotho revealed that Klotho significantly enhances the expression of the thioredoxin/peroxiredoxin (Trx/Prx) system with the greatest effect on the induction of Prx-2, an antioxidant enzyme, whose increase was confirmed at the mRNA and protein levels. Klotho-induced phosphorylation of the PI3K/Akt pathway, a pathway important in apoptosis and longevity, was associated with sustained inhibitory phosphorylation of the transcription factor forkhead box O3a (FoxO3a) and was essential for the induction of Prx-2. Down-regulation of Prx-2 expression using a lentivirus harboring shRNA almost completely abolished the ability of Klotho to rescue neurons from glutamate-induced death and significantly, but not completely, inhibited cell death mediated by oAβ, suggesting that Prx-2 is a key modulator of neuroprotection. Thus, our results demonstrate, for the first time, the neuroprotective role of Klotho and reveal a novel mechanism underlying this effect. PMID:25037225

Fluoxetine protects against IL-1β-induced neuronal apoptosis via downregulation of p53.

PubMed

Shan, Han; Bian, Yaqi; Shu, Zhaoma; Zhang, Linxia; Zhu, Jialei; Ding, Jianhua; Lu, Ming; Xiao, Ming; Hu, Gang

2016-08-01

Fluoxetine, a selective serotonin reuptake inhibitor, exerts neuroprotective effects in a variety of neurological diseases including stroke, but the underlying mechanism remains obscure. In the present study, we addressed the molecular events in fluoxetine against ischemia/reperfusion-induced acute neuronal injury and inflammation-induced neuronal apoptosis. We showed that treatment of fluoxetine (40 mg/kg, i.p.) with twice injections at 1 h and 12 h after transient middle cerebral artery occlusion (tMCAO) respectively alleviated neurological deficits and neuronal apoptosis in a mouse ischemic stroke model, accompanied by inhibiting interleukin-1β (IL-1β), Bax and p53 expression and upregulating anti-apoptotic protein Bcl-2 level. We next mimicked neuroinflammation in ischemic stroke with IL-1β in primary cultured cortical neurons and found that pretreatment with fluoxetine (1 μM) prevented IL-1β-induced neuronal apoptosis and upregulation of p53 expression. Furthermore, we demonstrated that p53 overexpression in N2a cell line abolished the anti-apoptotic effect of fluoxetine, indicating that p53 downregulation is required for the protective role of fluoxetine in IL-1β-induced neuronal apoptosis. Fluoxetine downregulating p53 expression could be mimicked by SB203580, a specific inhibitor of p38, but blocked by anisomycin, a p38 activator. Collectively, our findings have revealed that fluoxetine protects against IL-1β-induced neuronal apoptosis via p38-p53 dependent pathway, which give us an insight into the potential of fluoxetine in terms of opening up novel therapeutic avenues for neurological diseases including stroke. Copyright © 2016 Elsevier Ltd. All rights reserved.

A Single Bolus of Docosahexaenoic Acid Promotes Neuroplastic Changes in the Innervation of Spinal Cord Interneurons and Motor Neurons and Improves Functional Recovery after Spinal Cord Injury.

PubMed

Liu, Zhuo-Hao; Yip, Ping K; Adams, Louise; Davies, Meirion; Lee, Jae Won; Michael, Gregory J; Priestley, John V; Michael-Titus, Adina T

2015-09-16

Docosahexaenoic acid (DHA) is an ω-3 polyunsaturated fatty acid that is essential in brain development and has structural and signaling roles. Acute DHA administration is neuroprotective and promotes functional recovery in animal models of adult spinal cord injury (SCI). However, the mechanisms underlying this recovery have not been fully characterized. Here we investigated the effects of an acute intravenous bolus of DHA delivered after SCI and characterized DHA-induced neuroplasticity within the adult injured spinal cord. We found robust sprouting of uninjured corticospinal and serotonergic fibers in a rat cervical hemisection SCI model. A mouse pyramidotomy model was used to confirm that this robust sprouting was not species or injury model specific. Furthermore, we demonstrated that corticospinal fibers sprouting to the denervated side of the cord following pyramidotomy contact V2a interneurons. We also demonstrated increased serotonin fibers and synaptophysin in direct contact with motor neurons. DHA also increased synaptophysin in rat cortical cell cultures. A reduction in phosphatase and tensin homolog (PTEN) has been shown to be involved in axonal regeneration and synaptic plasticity. We showed that DHA significantly upregulates miR-21 and downregulates PTEN in corticospinal neurons. Downregulation of PTEN and upregulation of phosphorylated AKT by DHA were also seen in primary cortical neuron cultures and were accompanied by increased neurite outgrowth. In summary, acute DHA induces anatomical and synaptic plasticity in adult injured spinal cord. This study shows that DHA has therapeutic potential in cervical SCI and provides evidence that DHA could exert its beneficial effects in SCI via enhancement of neuroplasticity. In this study, we show that an acute intravenous injection of docosahexaenoic acid (DHA) 30 min after spinal cord injury induces neuroplasticity. We found robust sprouting of uninjured corticospinal and serotonergic fibers in a rat hemisection spinal cord injury model. A mouse pyramidotomy model was used to confirm that the robust sprouting involved V2a interneurons. We show that DHA significantly upregulates miR-21 and phosphorylated AKT, and downregulates phosphatase and tensin homolog (PTEN), which is involved in suppressing anatomical plasticity, in corticospinal neurons and in primary cortical neuron cultures. We conclude that acute DHA can induce anatomical and synaptic plasticity. This provides direct evidence that DHA could exert its beneficial effects in spinal cord injury via neuroplasticity enhancement. Copyright © 2015 the authors 0270-6474/15/3512734-20$15.00/0.

snoU6 and 5S RNAs are not reliable miRNA reference genes in neuronal differentiation.

PubMed

Lim, Q E; Zhou, L; Ho, Y K; Wan, G; Too, H P

2011-12-29

Accurate profiling of microRNAs (miRNAs) is an essential step for understanding the functional significance of these small RNAs in both physiological and pathological processes. Quantitative real-time PCR (qPCR) has gained acceptance as a robust and reliable transcriptomic method to profile subtle changes in miRNA levels and requires reference genes for accurate normalization of gene expression. 5S and snoU6 RNAs are commonly used as reference genes in microRNA quantification. It is currently unknown if these small RNAs are stably expressed during neuronal differentiation. Panels of miRNAs have been suggested as alternative reference genes to 5S and snoU6 in various physiological contexts. To test the hypothesis that miRNAs may serve as stable references during neuronal differentiation, the expressions of eight miRNAs, 5S and snoU6 RNAs in five differentiating neuronal cell types were analyzed using qPCR. The stabilities of the expressions were evaluated using two complementary statistical approaches (geNorm and Normfinder). Expressions of 5S and snoU6 RNAs were stable under some but not all conditions of neuronal differentiation and thus are not suitable reference genes. In contrast, a combination of three miRNAs (miR-103, miR-106b and miR-26b) allowed accurate expression normalization across different models of neuronal differentiation. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

Temporal properties of responses to sound in the ventral nucleus of the lateral lemniscus.

PubMed

Recio-Spinoso, Alberto; Joris, Philip X

2014-02-01

Besides the rapid fluctuations in pressure that constitute the "fine structure" of a sound stimulus, slower fluctuations in the sound's envelope represent an important temporal feature. At various stages in the auditory system, neurons exhibit tuning to envelope frequency and have been described as modulation filters. We examine such tuning in the ventral nucleus of the lateral lemniscus (VNLL) of the pentobarbital-anesthetized cat. The VNLL is a large but poorly accessible auditory structure that provides a massive inhibitory input to the inferior colliculus. We test whether envelope filtering effectively applies to the envelope spectrum when multiple envelope components are simultaneously present. We find two broad classes of response with often complementary properties. The firing rate of onset neurons is tuned to a band of modulation frequencies, over which they also synchronize strongly to the envelope waveform. Although most sustained neurons show little firing rate dependence on modulation frequency, some of them are weakly tuned. The latter neurons are usually band-pass or low-pass tuned in synchronization, and a reverse-correlation approach demonstrates that their modulation tuning is preserved to nonperiodic, noisy envelope modulations of a tonal carrier. Modulation tuning to this type of stimulus is weaker for onset neurons. In response to broadband noise, sustained and onset neurons tend to filter out envelope components over a frequency range consistent with their modulation tuning to periodically modulated tones. The results support a role for VNLL in providing temporal reference signals to the auditory midbrain.

Force-related neuronal activity in two regions of the primate ventral premotor cortex.

PubMed

Hepp-Reymond, M C; Hüsler, E J; Maier, M A; Ql, H X

1994-05-01

Neuronal activity was recorded in the ventral premotor cortex of one monkey (Macaca fascicularis) trained to exert finely graded forces with thumb and index finger on a force sensor in a visuomotor step-tracking paradigm. Trials with two or three consecutive ramp-and-hold force steps were presented randomly. Most neurons displayed similar discharge patterns in the two- and three-step trials and were assigned to one of the following classes: phasic, phasic-tonic, tonic, decreasing, and mixed. For more than 50% of the neurons with tonic activity, positive or negative correlations between firing rate and force were statistically significant. The indices of force sensitivity were on average higher for the two-step than for the three-step trials, indicating that the correlations yielded linearity over only a limited force range. The force-related cells were located in two regions of the ventral premotor cortex. One group was ying rostrally within the inferior limb of the arcuate sulcus, from which microstimulation elicited movements of fingers and hand. In the other more caudal region, adjacent to the finger region of primary motor cortex, microstimulation was rarely effective, but all neurons had clear peripheral receptive fields on finger and hand. The data indicate that two populations of neurons, located in the ventral premotor cortex, are related to movement execution. Effective microstimulation also suggests that one of the populations has fairly direct access to the spinal motor apparatus.

Extrasynaptic Glycine Receptors of Rodent Dorsal Raphe Serotonergic Neurons: A Sensitive Target for Ethanol

PubMed Central

Maguire, Edward P; Mitchell, Elizabeth A; Greig, Scott J; Corteen, Nicole; Balfour, David J K; Swinny, Jerome D; Lambert, Jeremy J; Belelli, Delia

2014-01-01

Alcohol abuse is a significant medical and social problem. Several neurotransmitter systems are implicated in ethanol's actions, with certain receptors and ion channels emerging as putative targets. The dorsal raphe (DR) nucleus is associated with the behavioral actions of alcohol, but ethanol actions on these neurons are not well understood. Here, using immunohistochemistry and electrophysiology we characterize DR inhibitory transmission and its sensitivity to ethanol. DR neurons exhibit inhibitory ‘phasic' post-synaptic currents mediated primarily by synaptic GABAA receptors (GABAAR) and, to a lesser extent, by synaptic glycine receptors (GlyR). In addition to such phasic transmission mediated by the vesicular release of neurotransmitter, the activity of certain neurons may be governed by a ‘tonic' conductance resulting from ambient GABA activating extrasynaptic GABAARs. However, for DR neurons extrasynaptic GABAARs exert only a limited influence. By contrast, we report that unusually the GlyR antagonist strychnine reveals a large tonic conductance mediated by extrasynaptic GlyRs, which dominates DR inhibition. In agreement, for DR neurons strychnine increases their input resistance, induces membrane depolarization, and consequently augments their excitability. Importantly, this glycinergic conductance is greatly enhanced in a strychnine-sensitive fashion, by behaviorally relevant ethanol concentrations, by drugs used for the treatment of alcohol withdrawal, and by taurine, an ingredient of certain ‘energy drinks' often imbibed with ethanol. These findings identify extrasynaptic GlyRs as critical regulators of DR excitability and a novel molecular target for ethanol. PMID:24264816

Property of Regenerating Serotonin Fibers in the Hippocampus of Human Migration Disorders Model

NASA Astrophysics Data System (ADS)

Ueda, Shuichi; Ehara, Ayuka; Ohmomo, Hideki

Individual mood and mental conditions exert a great influence on one's own kansei. Abnormality or dysfunction of the 5-HT neuron system in the developing and/or adult brain is closely associated with their conditions. Thus, the 5-HT neuron system may play an important role in the neuronal mechanisms underlying kansei. Interestingly, previous studies have shown that heterotopic clusters in the hippocampus (hippocampal heterotopia), deriving from neocortical neurons, after prenatally treated with methylazoxymethanol acetate in rat (MAM rat), exhibit abundant 5-HT innervation. After neonatal intracisternal 5, 7-dihydroxytryptamine (DHT) injection, these 5-HT fibers degenerate and disappear throughout the forebrain, and then regenerating 5-HT fibers densely innervate in the hippocampal heterotopia. The 5-HT fiber system in the hippocampal heterotopia of MAM rat provides useful experimental models for study the plasticity of human migration disorder. In the present study, to evaluate the properties of regenerating 5-HT fibers in the hippocampal heterotopia of MAM rats, we examined the origin of these projections by combined retrograde transport and immunohistochemical methods. Prenatal exposure to MAM resulted in the formation of hippocampal heterotopia in the dorsal hippocampus. Regenerating 5-HT fibers formed a dense innervation within the hippocampal heterotopia after neonatal DHT injection. These projections appeared to arise mainly from 5-HT neurons in the median raphe nucleus, with a small portion from 5-HT neurons in the dorsal raphe nucleus. These findings suggest a specific profile of regenerating 5-HT fibers, providing the new insights for serotonergic plasticity.

Hydroxysafflor Yellow A Attenuates Neuron Damage by Suppressing the Lipopolysaccharide-Induced TLR4 Pathway in Activated Microglial Cells.

PubMed

Lv, Yanni; Qian, Yisong; Ou-Yang, Aijun; Fu, Longsheng

2016-11-01

Microglia activation initiates a neurological deficit cascade that contributes to substantial neuronal damage and impairment following ischemia stroke. Toll-like receptor 4 (TLR4) has been demonstrated to play a critical role in this cascade. In the current study, we tested the hypothesis that hydroxysafflor yellow A (HSYA), an active ingredient extracted from Flos Carthami tinctorii, alleviated inflammatory damage, and mediated neurotrophic effects in neurons by inducing the TLR4 pathway in microglia. A non-contact Transwell co-culture system comprised microglia and neurons was treated with HSYA followed by a 1 mg/mL lipopolysaccharide (LPS) stimulation. The microglia were activated prior to neuronal apoptosis, which were induced by increasing TLR4 expression in the activated microglia. However, HSYA suppressed TLR4 expression in the activated microglia, resulting in less neuronal damage at the early stage of LPS stimulation. Western blot analysis and immunofluorescence indicated that dose-dependently HSYA down-regulated TLR4-induced downstream effectors myeloid differentiation factor 88 (MyD88), nuclear factor kappa b (NF-κB), and the mitogen-activated protein kinases (MAPK)-regulated proteins c-Jun NH2-terminal protein kinase (JNK), protein kinase (ERK) 1/2 (ERK1/2), p38 MAPK (p38), as well as the LPS-induced inflammatory cytokine release. However, HSYA up-regulated brain-derived neurotrophic factor (BDNF) expression. Our data suggest that HSYA could exert neurotrophic and anti-inflammatory functions in response to LPS stimulation by inhibiting TLR4 pathway-mediated signaling.

Spatial distribution of neurons innervated by chandelier cells.

PubMed

Blazquez-Llorca, Lidia; Woodruff, Alan; Inan, Melis; Anderson, Stewart A; Yuste, Rafael; DeFelipe, Javier; Merchan-Perez, Angel

2015-09-01

Chandelier (or axo-axonic) cells are a distinct group of GABAergic interneurons that innervate the axon initial segments of pyramidal cells and are thus thought to have an important role in controlling the activity of cortical circuits. To examine the circuit connectivity of chandelier cells (ChCs), we made use of a genetic targeting strategy to label neocortical ChCs in upper layers of juvenile mouse neocortex. We filled individual ChCs with biocytin in living brain slices and reconstructed their axonal arbors from serial semi-thin sections. We also reconstructed the cell somata of pyramidal neurons that were located inside the ChC axonal trees and determined the percentage of pyramidal neurons whose axon initial segments were innervated by ChC terminals. We found that the total percentage of pyramidal neurons that were innervated by a single labeled ChC was 18-22 %. Sholl analysis showed that this percentage peaked at 22-35 % for distances between 30 and 60 µm from the ChC soma, decreasing to lower percentages with increasing distances. We also studied the three-dimensional spatial distribution of the innervated neurons inside the ChC axonal arbor using spatial statistical analysis tools. We found that innervated pyramidal neurons are not distributed at random, but show a clustered distribution, with pockets where almost all cells are innervated and other regions within the ChC axonal tree that receive little or no innervation. Thus, individual ChCs may exert a strong, widespread influence on their local pyramidal neighbors in a spatially heterogeneous fashion.

Acute stress promotes post-injury brain regeneration in fish.

PubMed

Sinyakov, Michael S; Haimovich, Amihai; Avtalion, Ramy R

2017-12-01

The central nervous system and the immune system, the two major players in homeostasis, operate in the ongoing bidirectional interaction. Stress is the third player that exerts strong effect on these two 'supersystems'; yet, its impact is studied much less. In this work employing carp model, we studied the influence of preliminary stress on neural and immune networks involved in post-injury brain regeneration. The relevant in vivo models of air-exposure stress and precisely directed cerebellum injury have been developed. Neuronal regeneration was evaluated by using specific tracers of cell proliferation and differentiation. Involvement of immune networks was accessed by monitoring the expression of selected T cells markers. Contrast difference between acute and chronic stress manifested in the fact that chronically stressed fish did not survive the brain injury. Neuronal regeneration appeared as a biphasic process whereas involvement of immune system proceeded as a monophasic route. In stressed fish, immune response was fast and accompanied or even preceded neuronal regeneration. In unstressed subjects, immune response took place on the second phase of neuronal regeneration. These findings imply an intrinsic regulatory impact of acute stress on neuronal and immune factors involved in post-injury brain regeneration. Stress activates both neuronal and immune defense mechanisms and thus contributes to faster regeneration. In this context, paradoxically, acute preliminary stress might be considered a distinct asset in speeding up the following post-injury brain regeneration. Copyright © 2017 Elsevier B.V. All rights reserved.

Rotigotine, a dopamine receptor agonist, increased BDNF protein levels in the rat cortex and hippocampus.

PubMed

Adachi, Naoki; Yoshimura, Aya; Chiba, Shuichi; Ogawa, Shintaro; Kunugi, Hiroshi

2018-01-01

Brain-derived neurotrophic factor (BDNF) critically controls the fate and function of the neuronal network and has received much attention as a target of many brain diseases. Dopaminergic system dysfunction has also been implicated in a variety of neuropsychiatric diseases. Rotigotine, a non-ergot dopamine receptor agonist, is used in the treatment of Parkinson's disease and restless legs syndrome. To investigate the effects of rotigotine on neuronal functions both in vivo and in vitro, rats and primary cortical neurons were administered rotigotine, and the mRNA and protein expression levels of BDNF, its receptor TrkB and downstream signaling molecules, and synaptic proteins were determined. We found that BDNF protein was increased in the cortex and hippocampus of rats after 7days of rotigotine treatment. In contrast, BDNF mRNAs were reduced 6h after rotigotine treatment in cultured neurons presumably through the transient suppression of neuronal activity. We identified differential expression of D1, D2, and D3 receptors in the rat brain and cultured neurons. The observed increase in the expression of BDNF protein in the cortex and hippocampus after subchronic administration of rotigotine suggests that it may exert its medical effect in part through improving BDNF function in the brain. In addition, our results highlight the complex relationships between rotigotine and BDNF expression, which depend on the brain region, time course, and dose of the drug. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

PrP(C) signalling in neurons: from basics to clinical challenges.

PubMed

Hirsch, Théo Z; Hernandez-Rapp, Julia; Martin-Lannerée, Séverine; Launay, Jean-Marie; Mouillet-Richard, Sophie

2014-09-01

The cellular prion protein PrP(C) was identified over twenty-five years ago as the normal counterpart of the scrapie prion protein PrP(Sc), itself the main if not the sole component of the infectious agent at the root of Transmissible Spongiform Encephalopathies (TSEs). PrP(C) is a ubiquitous cell surface protein, abundantly expressed in neurons, which constitute the targets of PrP(Sc)-mediated toxicity. Converging evidence have highlighted that neuronal, GPI-anchored PrP(C) is absolutely required for prion-induced neuropathogenesis, which warrants investigating into the normal function exerted by PrP(C) in a neuronal context. It is now well-established that PrP(C) can serve as a cell signalling molecule, able to mobilize transduction cascades in response to interactions with partners. This function endows PrP(C) with the capacity to participate in multiple neuronal processes, ranging from survival to synaptic plasticity. A diverse array of data have allowed to shed light on how this function is corrupted by PrP(Sc). Recently, amyloid Aβ oligomers, whose accumulation is associated with Alzheimer's disease (AD), were shown to similarly instigate toxic events by deviating PrP(C)-mediated signalling. Here, we provide an overview of the various signal transduction cascades ascribed to PrP(C) in neurons, summarize how their subversion by PrP(Sc) or Aβ oligomers contributes to TSE or AD neuropathogenesis and discuss the ensuing clinical implications. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

The Role of MAC1 in Diesel Exhaust Particle-induced Microglial Activation and Loss of Dopaminergic Neuron Function

PubMed Central

Levesque, Shannon; Taetzsch, Thomas; Lull, Melinda E.; Johnson, Jo Anne; McGraw, Constance; Block, Michelle L.

2013-01-01

Increasing reports support that air pollution causes neuroinflammation and is linked to central nervous system (CNS) disease/damage. Diesel exhaust particles (DEP) are a major component of urban air pollution, which has been linked to microglial activation and Parkinson’s disease-like pathology. To begin to address how DEP may exert CNS effects, microglia and neuron-glia cultures were treated with either nanometer-sized DEP (<0.22 µM; 50µg/mL), ultrafine carbon black (ufCB, 50µg/ml), or DEP extracts (eDEP; from 50 µg/ml DEP) and the effect of microglial activation and dopaminergic (DA) neuron function was assessed. All three treatments showed enhanced amoeboid microglia morphology, increased H2O2 production, and decreased DA uptake. Mechanistic inquiry revealed that the scavenger receptor inhibitor fucoidan blocked DEP internalization in microglia, but failed to alter DEP-induced H2O2 production in microglia. However, pretreatment with the MAC1/CD11b inhibitor antibody blocked microglial H2O2 production in response to DEP. MAC1−/− mesencephalic neuron-glia cultures were protected from DEP-induced loss of DA neuron function, as measured by DA uptake. These findings support that DEP may activate microglia through multiple mechanisms, where scavenger receptors regulate internalization of DEP and the MAC1 receptor is mandatory for both DEP-induced microglial H2O2 production and loss of DA neuron function. PMID:23470120

"Placebo effect is probably what we refer to as patient healing power": A qualitative pilot study examining how Norwegian complementary therapists reflect on their practice.

PubMed

Stub, Trine; Foss, Nina; Liodden, Ingrid

2017-05-12

Complementary therapists spend considerable time with their patients, especially in the first consultation. The communication between patients and their therapists is important for raising consciousness and activation of the patient's self-healing power. Thus, the aims in this study were to delineate what complementary therapists regard as essential in patient consultations, their view of the healing process, and how the therapists understand the placebo effect and its position in the healing process. Semi-structured individual interviews (n = 4), focus group interview (n = 1) and participant observation were conducted among four different complementary therapists in a Norwegian community. The text data was transcribed verbatim and the analysis of the material was conducted according to conventional and direct content analysis. Some codes were predefined and others were defined during the analysis. The pilot study showed that the implemented methods seems feasible and fit well with the aims of this study. Complementary therapists (chiropractor, naprapath (musculoskeletal therapist), acupuncturist and acupuncturist/homeopath) representing four different complementary modalities participated. A combination of the conversation and examination during the first consultation formed the basis for the therapist's choice of treatment. A successful consultation was characterized by a fruitful relationship between the therapist and the patient. Moreover, the therapist needs to be humble and show the patient respect. Patients' positive beliefs and expectations about the treatment play a significant role in the healing process. The more hope the therapist can bring about, the more easily the patient can start believing that it is possible to get well. This was a pilot study. Therefore the findings should be appreciated as limited and preliminary. Therapists' and patients' mutual understanding and treatment goals were essential for a successful consultation. The therapists emphasized their professional skills and therapeutic competence as important when building fruitful relationships with their patients. Exerting authority and making the patient feel confident were essential factors for a successful healing process. The complementary therapists understood the placebo effect as the patient's self-healing power, resulting from establishing trust and belief in the treatment process.

Regulation of tyrosine hydroxylase gene expression during differentiation of neuroblastoma cells.

PubMed

Summerhill, E M; Wood, K; Fishman, M C

1987-07-01

Differentiation of N1E-115 neuroblastoma cells into neuron-like cells, with extension of neurites and acquisition of excitable membranes, can be induced by dimethyl sulfoxide (DMSO). We have found this differentiation to be accompanied by an increase in tyrosine hydroxylase (TH) mRNA, an increase disproportionate to changes in mRNAs for other measured, non-neuron-specific genes. The mRNA increases slowly over several days and falls gradually after removal of DMSO. Nuclear run-on studies suggest that a change in the rate of transcription cannot explain the increase in steady-state mRNA levels. TH mRNA half-life does, however, increase. This suggests that regulation is exerted in this case not at the level of transcription but rather at that of mRNA stability.

α-Synuclein in Parkinson's Disease

PubMed Central

Stefanis, Leonidas

2012-01-01

α-Synuclein is a presynaptic neuronal protein that is linked genetically and neuropathologically to Parkinson's disease (PD). α-Synuclein may contribute to PD pathogenesis in a number of ways, but it is generally thought that its aberrant soluble oligomeric conformations, termed protofibrils, are the toxic species that mediate disruption of cellular homeostasis and neuronal death, through effects on various intracellular targets, including synaptic function. Furthermore, secreted α-synuclein may exert deleterious effects on neighboring cells, including seeding of aggregation, thus possibly contributing to disease propagation. Although the extent to which α-synuclein is involved in all cases of PD is not clear, targeting the toxic functions conferred by this protein when it is dysregulated may lead to novel therapeutic strategies not only in PD, but also in other neurodegenerative conditions, termed synucleinopathies. PMID:22355802

Impact of methamphetamine on dopamine neurons in primates is dependent on age: implications for development of Parkinson's disease

PubMed Central

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

2011-01-01

Methamphetamine is a CNS stimulant with limited therapeutic indications, but is widely abused. Short-term exposure to higher doses, or long-term exposure to lower doses, of methamphetamine induces lasting damage to nigrostriatal dopamine neurons in man and animals. Strong evidence indicates that the mechanism for this detrimental effect on dopamine neurons involves oxidative stress exerted by reactive oxygen species. This study investigates the relative susceptibility of dopamine neurons in mid-gestation, young, and adult (not aged) monkeys to 4 treatments with methamphetamine over 2 days. Primate dopamine neurons undergo natural cell death at mid-gestation, and we hypothesized that during this event they are particularly vulnerable to oxidative stress. The results indicated that at mid-gestation and in adults, dopamine neurons were susceptible to methamphetamine-induced damage, as indicated by loss of striatal TH immunoreactivity and dopamine concentration. However, dopamine neurons in young animals appeared totally resistant to the treatment, despite this group having higher brain levels of methamphetamine 3 hours after administration than the adults. As a possible explanation for the protection, striatal GDNF levels were elevated in young animals 1-week after treatment, but not in adults following methamphetamine treatment. Implications of these primate studies are: 1) the susceptibility of dopamine neurons at mid-gestation to methamphetamine warns against the risk of exposing pregnant women to the drug or oxidative stressors, and supports the hypothesis of Parkinson's disease being associated with oxidative stress during development, 2) elucidation of the mechanism of resistance of dopamine neurons in the young animals to methamphetamine-induced oxidative stress may provide targets for slowing or preventing age- or disease-related loss of adult nigrostriatal DA neurons, and 3) the increased striatal production of GDNF in young animals, but not in adults, in response to methamphetamine, suggests the possibility of an age-related change in the neurotrophic capacity of the striatal dopamine system. PMID:21640165

A MSFD complementary approach for the assessment of pressures, knowledge and data gaps in Southern European Seas: The PERSEUS experience.

PubMed

Crise, A; Kaberi, H; Ruiz, J; Zatsepin, A; Arashkevich, E; Giani, M; Karageorgis, A P; Prieto, L; Pantazi, M; Gonzalez-Fernandez, D; Ribera d'Alcalà, M; Tornero, V; Vassilopoulou, V; Durrieu de Madron, X; Guieu, C; Puig, P; Zenetos, A; Andral, B; Angel, D; Altukhov, D; Ayata, S D; Aktan, Y; Balcıoğlu, E; Benedetti, F; Bouchoucha, M; Buia, M-C; Cadiou, J-F; Canals, M; Chakroun, M; Christou, E; Christidis, M G; Civitarese, G; Coatu, V; Corsini-Foka, M; Cozzi, S; Deidun, A; Dell'Aquila, A; Dogrammatzi, A; Dumitrache, C; Edelist, D; Ettahiri, O; Fonda-Umani, S; Gana, S; Galgani, F; Gasparini, S; Giannakourou, A; Gomoiu, M-T; Gubanova, A; Gücü, A-C; Gürses, Ö; Hanke, G; Hatzianestis, I; Herut, B; Hone, R; Huertas, E; Irisson, J-O; İşinibilir, M; Jimenez, J A; Kalogirou, S; Kapiris, K; Karamfilov, V; Kavadas, S; Keskin, Ç; Kideyş, A E; Kocak, M; Kondylatos, G; Kontogiannis, C; Kosyan, R; Koubbi, P; Kušpilić, G; La Ferla, R; Langone, L; Laroche, S; Lazar, L; Lefkaditou, E; Lemeshko, I E; Machias, A; Malej, A; Mazzocchi, M-G; Medinets, V; Mihalopoulos, N; Miserocchi, S; Moncheva, S; Mukhanov, V; Oaie, G; Oros, A; Öztürk, A A; Öztürk, B; Panayotova, M; Prospathopoulos, A; Radu, G; Raykov, V; Reglero, P; Reygondeau, G; Rougeron, N; Salihoglu, B; Sanchez-Vidal, A; Sannino, G; Santinelli, C; Secrieru, D; Shapiro, G; Simboura, N; Shiganova, T; Sprovieri, M; Stefanova, K; Streftaris, N; Tirelli, V; Tom, M; Topaloğlu, B; Topçu, N E; Tsagarakis, K; Tsangaris, C; Tserpes, G; Tuğrul, S; Uysal, Z; Vasile, D; Violaki, K; Xu, J; Yüksek, A; Papathanassiou, E

2015-06-15

PERSEUS project aims to identify the most relevant pressures exerted on the ecosystems of the Southern European Seas (SES), highlighting knowledge and data gaps that endanger the achievement of SES Good Environmental Status (GES) as mandated by the Marine Strategy Framework Directive (MSFD). A complementary approach has been adopted, by a meta-analysis of existing literature on pressure/impact/knowledge gaps summarized in tables related to the MSFD descriptors, discriminating open waters from coastal areas. A comparative assessment of the Initial Assessments (IAs) for five SES countries has been also independently performed. The comparison between meta-analysis results and IAs shows similarities for coastal areas only. Major knowledge gaps have been detected for the biodiversity, marine food web, marine litter and underwater noise descriptors. The meta-analysis also allowed the identification of additional research themes targeting research topics that are requested to the achievement of GES. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Multiple-Color Optical Activation, Silencing, and Desynchronization of Neural Activity, with Single-Spike Temporal Resolution

PubMed Central

Han, Xue; Boyden, Edward S.

2007-01-01

The quest to determine how precise neural activity patterns mediate computation, behavior, and pathology would be greatly aided by a set of tools for reliably activating and inactivating genetically targeted neurons, in a temporally precise and rapidly reversible fashion. Having earlier adapted a light-activated cation channel, channelrhodopsin-2 (ChR2), for allowing neurons to be stimulated by blue light, we searched for a complementary tool that would enable optical neuronal inhibition, driven by light of a second color. Here we report that targeting the codon-optimized form of the light-driven chloride pump halorhodopsin from the archaebacterium Natronomas pharaonis (hereafter abbreviated Halo) to genetically-specified neurons enables them to be silenced reliably, and reversibly, by millisecond-timescale pulses of yellow light. We show that trains of yellow and blue light pulses can drive high-fidelity sequences of hyperpolarizations and depolarizations in neurons simultaneously expressing yellow light-driven Halo and blue light-driven ChR2, allowing for the first time manipulations of neural synchrony without perturbation of other parameters such as spiking rates. The Halo/ChR2 system thus constitutes a powerful toolbox for multichannel photoinhibition and photostimulation of virally or transgenically targeted neural circuits without need for exogenous chemicals, enabling systematic analysis and engineering of the brain, and quantitative bioengineering of excitable cells. PMID:17375185

A temporary local energy pool coupled to neuronal activity: fluctuations of extracellular lactate levels in rat brain monitored with rapid-response enzyme-based sensor.

PubMed

Hu, Y; Wilson, G S

1997-10-01

A successfully developed enzyme-based lactate microsensor with rapid response time allows the direct and continuous in vivo measurement of lactic acid concentration with high temporal resolution in brain extracellular fluid. The fluctuations coupled to neuronal activity in extracellular lactate concentration were explored in the dentate gyrus of the hippocampus of the rat brain after electrical stimulation of the perforant pathway. Extracellular glucose and oxygen levels were also detected simultaneously by coimplantation of a fast-response glucose sensor and an oxygen electrode, to provide novel information of trafficking of energy substances in real time related to local neuronal activity. The results first give a comprehensive picture of complementary energy supply and use of lactate and glucose in the intact brain tissue. In response to acute neuronal activation, the brain tissue shifts immediately to significant energy supply by lactate. A local temporary fuel "reservoir" is established behind the blood-brain barrier, evidenced by increased extracellular lactate concentration. The pool can be depleted rapidly, up to 28% in 10-12 s, by massive, acute neuronal use after stimulation and can be replenished in approximately 20 s. Glutamate-stimulated astrocytic glycolysis and the increase of regional blood flow may regulate the lactate concentration of the pool in different time scales to maintain local energy homeostasis.

Texture-dependent motion signals in primate middle temporal area

PubMed Central

Gharaei, Saba; Tailby, Chris; Solomon, Selina S; Solomon, Samuel G

2013-01-01

Neurons in the middle temporal (MT) area of primate cortex provide an important stage in the analysis of visual motion. For simple stimuli such as bars and plaids some neurons in area MT – pattern cells – seem to signal motion independent of contour orientation, but many neurons – component cells – do not. Why area MT supports both types of receptive field is unclear. To address this we made extracellular recordings from single units in area MT of anaesthetised marmoset monkeys and examined responses to two-dimensional images with a large range of orientations and spatial frequencies. Component and pattern cell response remained distinct during presentation of these complex spatial textures. Direction tuning curves were sharpest in component cells when a texture contained a narrow range of orientations, but were similar across all neurons for textures containing all orientations. Response magnitude of pattern cells, but not component cells, increased with the spatial bandwidth of the texture. In addition, response variability in all neurons was reduced when the stimulus was rich in spatial texture. Fisher information analysis showed that component cells provide more informative responses than pattern cells when a texture contains a narrow range of orientations, but pattern cells had more informative responses for broadband textures. Component cells and pattern cells may therefore coexist because they provide complementary and parallel motion signals. PMID:24000175

Safety of the Transcranial Focal Electrical Stimulation via Tripolar Concentric Ring Electrodes for Hippocampal CA3 Subregion Neurons in Rats

PubMed Central

2017-01-01

Epilepsy is a neurological disorder that affects approximately one percent of the world population. Noninvasive electrical brain stimulation via tripolar concentric ring electrodes has been proposed as an alternative/complementary therapy for seizure control. Previous results suggest its efficacy attenuating acute seizures in penicillin, pilocarpine-induced status epilepticus, and pentylenetetrazole-induced rat seizure models and its safety for the rat scalp, cortical integrity, and memory formation. In this study, neuronal counting was used to assess possible tissue damage in rats (n = 36) due to the single dose or five doses (given every 24 hours) of stimulation on hippocampal CA3 subregion neurons 24 hours, one week, and one month after the last stimulation dose. Full factorial analysis of variance showed no statistically significant difference in the number of neurons between control and stimulation-treated animals (p = 0.71). Moreover, it showed no statistically significant differences due to the number of stimulation doses (p = 0.71) nor due to the delay after the last stimulation dose (p = 0.96). Obtained results suggest that stimulation at current parameters (50 mA, 200 μs, 300 Hz, biphasic, charge-balanced pulses for 2 minutes) does not induce neuronal damage in the hippocampal CA3 subregion of the brain. PMID:29065603

Safety of the Transcranial Focal Electrical Stimulation via Tripolar Concentric Ring Electrodes for Hippocampal CA3 Subregion Neurons in Rats.

PubMed

Mucio-Ramírez, Samuel; Makeyev, Oleksandr

2017-01-01

Epilepsy is a neurological disorder that affects approximately one percent of the world population. Noninvasive electrical brain stimulation via tripolar concentric ring electrodes has been proposed as an alternative/complementary therapy for seizure control. Previous results suggest its efficacy attenuating acute seizures in penicillin, pilocarpine-induced status epilepticus, and pentylenetetrazole-induced rat seizure models and its safety for the rat scalp, cortical integrity, and memory formation. In this study, neuronal counting was used to assess possible tissue damage in rats ( n = 36) due to the single dose or five doses (given every 24 hours) of stimulation on hippocampal CA3 subregion neurons 24 hours, one week, and one month after the last stimulation dose. Full factorial analysis of variance showed no statistically significant difference in the number of neurons between control and stimulation-treated animals ( p  = 0.71). Moreover, it showed no statistically significant differences due to the number of stimulation doses ( p  = 0.71) nor due to the delay after the last stimulation dose ( p  = 0.96). Obtained results suggest that stimulation at current parameters (50 mA, 200  μ s, 300 Hz, biphasic, charge-balanced pulses for 2 minutes) does not induce neuronal damage in the hippocampal CA3 subregion of the brain.

Beta-phenylethylamine inhibits K+ currents in neocortical neurons of the rat: a possible mechanism of beta-phenylethylamine-induced seizures.

PubMed

Kitamura, Taro; Munakata, Mitsutoshi; Haginoya, Kazuhiro; Tsuchiya, Shigeru; Iinuma, Kazuie

2008-08-01

beta-Phenylethylamine (beta-PEA), an endogenous amine synthesized in the brain, serves as a neuromodulator and is involved in the pathophysiology of various neurological disorders such as depression, schizophrenia, and attention-deficit hyperactivity disorder. beta-PEA fully exerts the physiological effects within the nanomolar concentration range via the trace amine receptors, but beta-PEA also causes convulsions at much higher concentrations via an as yet unknown mechanism. To investigate the electrophysiological mechanism by which beta-PEA induces convulsions, we examined the effect of beta-PEA on ionic currents passing through the cell membrane of dissociated rat cerebral cortical neurons, using a patch-clamp technique. The external application of beta-PEA suppressed ionic currents which continuously flowed when the membrane potential was held at -25 mV. The suppression was in a concentration-dependent manner and a half-maximal effective concentration was 540 muM. These currents suppressed by beta-PEA consisted of two K(+) currents: a time- and voltage-dependent K(+) current (M-current) and a leakage K(+) current. The suppression of the M-current reduces the efficacy of the current in limiting excessive neuronal firing, and the suppression of the leakage K(+) current can cause membrane depolarization and thus promote neuronal excitation. Reducing both of these currents in concert may produce neuronal seizing activity, which could conceivably underlie the convulsions induced by high-dose beta-PEA.

Microglial activation and the nitric oxide/cGMP/PKG pathway underlie enhanced neuronal vulnerability to mitochondrial dysfunction in experimental multiple sclerosis.

PubMed

Mancini, Andrea; Tantucci, Michela; Mazzocchetti, Petra; de Iure, Antonio; Durante, Valentina; Macchioni, Lara; Giampà, Carmela; Alvino, Alessandra; Gaetani, Lorenzo; Costa, Cinzia; Tozzi, Alessandro; Calabresi, Paolo; Di Filippo, Massimiliano

2018-05-01

During multiple sclerosis (MS), a close link has been demonstrated to occur between inflammation and neuro-axonal degeneration, leading to the hypothesis that immune mechanisms may promote neurodegeneration, leading to irreversible disease progression. Energy deficits and inflammation-driven mitochondrial dysfunction seem to be involved in this process. In this work we investigated, by the use of striatal electrophysiological field-potential recordings, if the inflammatory process associated with experimental autoimmune encephalomyelitis (EAE) is able to influence neuronal vulnerability to the blockade of mitochondrial complex IV, a crucial component for mitochondrial activity responsible of about 90% of total cellular oxygen consumption. We showed that during the acute relapsing phase of EAE, neuronal susceptibility to mitochondrial complex IV inhibition is markedly enhanced. This detrimental effect was counteracted by the pharmacological inhibition of microglia, of nitric oxide (NO) synthesis and its intracellular pathway (involving soluble guanylyl cyclase, sGC, and protein kinase G, PKG). The obtained results suggest that mitochondrial complex IV exerts an important role in maintaining neuronal energetic homeostasis during EAE. The pathological processes associated with experimental MS, and in particular the activation of microglia and of the NO pathway, lead to an increased neuronal vulnerability to mitochondrial complex IV inhibition, representing promising pharmacological targets. Copyright © 2018 Elsevier Inc. All rights reserved.

Caspase-1 Deficiency Alleviates Dopaminergic Neuronal Death via Inhibiting Caspase-7/AIF Pathway in MPTP/p Mouse Model of Parkinson's Disease.

PubMed

Qiao, Chen; Zhang, Lin-Xia; Sun, Xi-Yang; Ding, Jian-Hua; Lu, Ming; Hu, Gang

2017-08-01

Caspase family has been recognized to be involved in dopaminergic (DA) neuronal death and to exert an unfavorable role in Parkinson's disease (PD) pathology. Our previous study has revealed that caspase-1, as an important component of NLRP3 inflammasome, induces microglia-mediated neuroinflammation in the pathogenesis of PD. However, the role of caspase-1 in DA neuronal degeneration in the onset of PD remains unclear. Here, we showed that caspase-1 knockout ameliorated DA neuronal loss and dyskinesia in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine/probenecid (MPTP/p)-induced PD model mice. We further found that caspase-1 knockout decreased MPTP/p-induced caspase-7 cleavage, subsequently inhibited nuclear translocation of poly (ADP-ribose) polymerase 1 (PARP1), and reduced the release of apoptosis-inducing factor (AIF). Consistently, we demonstrated that caspase-1 inhibitor suppressed caspase-7/PARP1/AIF-mediated apoptosis pathway by 1-methyl-4-phenylpyridinium ion (MPP + ) stimulation in SH-SY5Y cells. Caspase-7 overexpression reduced the protective effects of caspase-1 inhibitor on SH-SY5Y cell apoptosis. Collectively, our results have revealed that caspase-1 regulates DA neuronal death in the pathogenesis of PD in mice via caspase-7/PARP1/AIF pathway. These findings will shed new insight into the potential of caspase-1 as a target for PD therapy.

Decoding the language of epigenetics during neural development is key for understanding development as well as developmental neurotoxicity.

PubMed

Yeo, Michele; Patisaul, Heather; Liedtke, Wolfgang

2013-11-01

Neural development is a delicate process that can be disrupted by pollution that exerts detrimental impact on neural signaling. This commentary highlights recent discoveries in the arena of research at the interface of environmental toxicology and developmental neuroscience relating to toxicity mechanisms of bisphenol A (BPA), a ubiquitous chemical used in manufacturing of plastics and epoxy resins that is known to bind to and interfere with estrogen receptors, estrogen-receptor-related receptors and other receptors for gonadal steroids. It was recently observed that BPA disrupts the perinatal chloride shift, a key neurodevelopmental mechanism that brings down neuronal chloride from ~100 mM to ~20 mM within weeks. The chloride shift happens in all central nervous systems of vertebrates around parturition. High neuronal chloride supports neuron precursors' migrations, low neuronal chloride is the prerequisite for inhibitory action of neurotransmitters GABA and glycine, and thus an absolute requisite for normal functioning of the mature CNS. One critical contributor to the neuronal chloride shift is the concomitant upregulation of expression of the chloride-extruding transporter molecule, KCC2. We highlight recent findings including our discovery that BPA disrupts the chloride shift in a sex-specific manner by recruiting epigenetics mechanisms. These could be relevant for childhood neuropsychiatric disorders as well as for liability to develop chronic neuropsychiatric diseases later in life.

Developmental study of vitamin C distribution in children's brainstems by immunohistochemistry.

PubMed

Coveñas, R; González-Fuentes, J; Rivas-Infante, E; Lagartos-Donate, M J; Mangas, A; Geffard, M; Arroyo-Jiménez, M M; Cebada-Sánchez, S; Insausti, R; Marcos, P

2015-09-01

Vitamin C (Vit C) is an important antioxidant, exerts powerful neuroprotective brain effects and plays a role in neuronal development and maturation. Vit C is present in brain tissue at higher concentrations than in other organs, but its detailed distribution in brain is unknown. Immunohistochemical detection of this vitamin has been performed by using a highly specific antibody against Vit C. The aim of the present work was to analyze the distribution of Vit C in children's brainstems during postnatal development, comparing two groups of ages: younger and older than one year of life. In general, the same areas showing neurons with Vit C in young cases are also immunostained at older ages. The distribution of neurons containing Vit C was broader in the brainstems of older children, suggesting that brainstem neurons maintain or even increase their ability to retain Vit C along the life span. Immunohistochemical labeling revealed only cell bodies containing this vitamin, and no immunoreactive fibers were observed. The distribution pattern of Vit C in children's brainstems suggests a possible role of Vit C in brain homeostatic regulation. In addition, the constant presence of Vit C in neurons of locus coeruleus supports the important role of Vit C in noradrenaline synthesis, which seemed to be maintained along postnatal development. Copyright © 2015 Elsevier GmbH. All rights reserved.

Oleuropein isolated from Fraxinus rhynchophylla inhibits glutamate-induced neuronal cell death by attenuating mitochondrial dysfunction.

PubMed

Kim, Mi Hye; Min, Ju-Sik; Lee, Joon Yeop; Chae, Unbin; Yang, Eun-Ju; Song, Kyung-Sik; Lee, Hyun-Shik; Lee, Hong Jun; Lee, Sang-Rae; Lee, Dong-Seok

2017-04-27

Glutamate-induced neurotoxicity is related to excessive oxidative stress accumulation and results in the increase of neuronal cell death. In addition, glutamate has been reported to lead to neurodegenerative diseases, including Parkinson's and Alzheimer's diseases.It is well known that Fraxinus rhynchophylla contains a significant level of oleuropein (Ole), which exerts various pharmacological effects. However, the mechanism of neuroprotective effects of Ole is still poorly defined. In this study, we aimed to investigate whether Ole prevents glutamate-induced toxicity in HT-22 hippocampal neuronal cells. The exposure of the glutamate treatment caused neuronal cell death through an alteration of Bax/Bcl-2 expression and translocation of mitochondrial apoptosis-inducing factor (AIF) to the cytoplasm of HT-22 cells. In addition, glutamate induced an increase in dephosphorylation of dynamin-related protein 1 (Drp1), mitochondrial fragmentation, and mitochondrial dysfunction. The pretreatment of Ole decreased Bax expression, increased Bcl-2 expression, and inhibited the translocation of mitochondrial AIF to the cytoplasm. Furthermore, Ole amended a glutamate-induced mitochondrial dynamic imbalance and reduced the number of cells with fragmented mitochondria, regulating the phosphorylation of Drp1 at amino acid residue serine 637. In conclusion, our results show that Ole has a preventive effect against glutamate-induced toxicity in HT-22 hippocampal neuronal cells. Therefore, these data imply that Ole may be an efficient approach for the treatment of neurodegenerative diseases.

AgRP Neurons Can Increase Food Intake during Conditions of Appetite Suppression and Inhibit Anorexigenic Parabrachial Neurons.

PubMed

Essner, Rachel A; Smith, Alison G; Jamnik, Adam A; Ryba, Anna R; Trutner, Zoe D; Carter, Matthew E

2017-09-06

To maintain energy homeostasis, orexigenic (appetite-inducing) and anorexigenic (appetite suppressing) brain systems functionally interact to regulate food intake. Within the hypothalamus, neurons that express agouti-related protein (AgRP) sense orexigenic factors and orchestrate an increase in food-seeking behavior. In contrast, calcitonin gene-related peptide (CGRP)-expressing neurons in the parabrachial nucleus (PBN) suppress feeding. PBN CGRP neurons become active in response to anorexigenic hormones released following a meal, including amylin, secreted by the pancreas, and cholecystokinin (CCK), secreted by the small intestine. Additionally, exogenous compounds, such as lithium chloride (LiCl), a salt that creates gastric discomfort, and lipopolysaccharide (LPS), a bacterial cell wall component that induces inflammation, exert appetite-suppressing effects and activate PBN CGRP neurons. The effects of increasing the homeostatic drive to eat on feeding behavior during appetite suppressing conditions are unknown. Here, we show in mice that food deprivation or optogenetic activation of AgRP neurons induces feeding to overcome the appetite suppressing effects of amylin, CCK, and LiCl, but not LPS. AgRP neuron photostimulation can also increase feeding during chemogenetic-mediated stimulation of PBN CGRP neurons. AgRP neuron stimulation reduces Fos expression in PBN CGRP neurons across all conditions. Finally, stimulation of projections from AgRP neurons to the PBN increases feeding following administration of amylin, CCK, and LiCl, but not LPS. These results demonstrate that AgRP neurons are sufficient to increase feeding during noninflammatory-based appetite suppression and to decrease activity in anorexigenic PBN CGRP neurons, thereby increasing food intake during homeostatic need. SIGNIFICANCE STATEMENT The motivation to eat depends on the relative balance of activity in distinct brain regions that induce or suppress appetite. An abnormal amount of activity in neurons that induce appetite can cause obesity, whereas an abnormal amount of activity in neurons that suppress appetite can cause malnutrition and a severe reduction in body weight. The purpose of this study was to determine whether a population of neurons known to induce appetite ("AgRP neurons") could induce food intake to overcome appetite-suppression following administration of various appetite-suppressing compounds. We found that stimulating AgRP neurons could overcome various forms of appetite suppression and decrease neural activity in a separate population of appetite-suppressing neurons, providing new insights into how the brain regulates food intake. Copyright © 2017 the authors 0270-6474/17/378678-10$15.00/0.

Alpha Lipoamide Ameliorates Motor Deficits and Mitochondrial Dynamics in the Parkinson's Disease Model Induced by 6-Hydroxydopamine.

PubMed

Zhou, Bo; Wen, Min; Lin, Xin; Chen, Yun-Hua; Gou, Yun; Li, Yong; Zhang, Yi; Li, Hong-Wei; Tang, Lei

2018-05-01

The precise mechanisms underlying neuronal injury in Parkinson's disease (PD) are not yet fully elucidated; however, evidence from the in vitro and in vivo PD models suggest that mitochondrial dysfunction may play a major role in PD pathogenesis. Alpha lipoamide, a neutral amide derivative of the lipoic acid, is a better cofactor for mitochondrial dehydrogenase with a stronger protective effect on mitochondria than lipoic acid. Identification of these protective effects of alpha lipoamide on mitochondria, together with the evidence that mitochondrial dysfunction plays a critical role in PD, we speculate that alpha lipoamide may exert a protective effect in PD by regulating the mitochondrial function. The present study investigated the neuroprotective effects of alpha lipoamide in an animal model of PD induced by 6-hydroxydopamine (6-OHDA). The results demonstrated that alpha lipoamide could significantly antagonize the 6-OHDA-induced behavioral damages; restore ATP levels in the midbrain; and also improve the fragmentation, vacuolization, and morphology of the mitochondria. The results of Western blot indicated that alpha lipoamide significantly restored the number of dopaminergic neurons in midbrain and substantially recovered the balance between mitochondrial fission, fusion, and transport. In conclusion, the results demonstrated that alpha lipoamide might exert a significant neuroprotective effect in the animal model of PD by regulation of the dynamic properties of mitochondria.

Enhanced susceptibility of Prnp-deficient mice to kainate-induced seizures, neuronal apoptosis, and death: Role of AMPA/kainate receptors.

PubMed

Rangel, Alejandra; Burgaya, Ferran; Gavín, Rosalina; Soriano, Eduardo; Aguzzi, Adriano; Del Río, José A

2007-09-01

Normal physiologic functions of the cellular prion protein (PrPc) are still elusive. This GPI-anchored protein exerts many functions, including roles in neuron proliferation, neuroprotection or redox homeostasis. There are, however, conflicting data concerning its role in synaptic transmission. Although several studies report that PrPc participates in NMDA-mediated neurotransmission, parallel studies describe normal behavior of PrPc-mutant mice. Abnormal axon connections have been described in the dentate gyrus of the hippocampi of PrPc-deficient mice similar to those observed in epilepsy. A study indicates increased susceptibility to kainate (KA) in these mutant mice. We extend the observation of these studies by means of several histologic and biochemical analyses of KA-treated mice. PrPc-deficient mice showed increased sensitivity to KA-induced seizures in vivo and in vitro in organotypic slices. In addition, we show that this sensitivity is cell-specific because interference experiments to abolish PrPc expression increased susceptibility to KA in PrPc-expressing cells. We indicate a correlation of susceptibility to KA in cells lacking PrPc with the differential expression of GluR6 and GluR7 KA receptor subunits using real-time RT-PCR methods. These results indicate that PrPc exerts a neuroprotective role against KA-induced neurotoxicity, probably by regulating the expression of KA receptor subunits. (c) 2007 Wiley-Liss, Inc.

Contribution of Intrinsic Lactate to Maintenance of Seizure Activity in Neocortical Slices from Patients with Temporal Lobe Epilepsy and in Rat Entorhinal Cortex.

PubMed

Angamo, Eskedar Ayele; ul Haq, Rizwan; Rösner, Jörg; Gabriel, Siegrun; Gerevich, Zoltán; Heinemann, Uwe; Kovács, Richard

2017-08-23

Neuronal lactate uptake supports energy metabolism associated with synaptic signaling and recovery of extracellular ion gradients following neuronal activation. Altered expression of the monocarboxylate transporters (MCT) in temporal lobe epilepsy (TLE) hampers lactate removal into the bloodstream. The resulting increase in parenchymal lactate levels might exert both, anti- and pro-ictogen effects, by causing acidosis and by supplementing energy metabolism, respectively. Hence, we assessed the contribution of lactate to the maintenance of transmembrane potassium gradients, synaptic signaling and pathological network activity in chronic epileptic human tissue. Stimulus induced and spontaneous field potentials and extracellular potassium concentration changes (∆[K⁺] O ) were recorded in parallel with tissue pO₂ and pH in slices from TLE patients while blocking MCTs by α-cyano-4-hydroxycinnamic acid (4-CIN) or d-lactate. Intrinsic lactate contributed to the oxidative energy metabolism in chronic epileptic tissue as revealed by the changes in pO₂ following blockade of lactate uptake. However, unlike the results in rat hippocampus, ∆[K⁺] O recovery kinetics and field potential amplitude did not depend on the presence of lactate. Remarkably, inhibition of lactate uptake exerted pH-independent anti-seizure effects both in healthy rat and chronic epileptic tissue and this effect was partly mediated via adenosine 1 receptor activation following decreased oxidative metabolism.

Contribution of Intrinsic Lactate to Maintenance of Seizure Activity in Neocortical Slices from Patients with Temporal Lobe Epilepsy and in Rat Entorhinal Cortex

PubMed Central

Angamo, Eskedar Ayele; Haq, Rizwan ul; Rösner, Jörg; Gabriel, Siegrun; Gerevich, Zoltán; Heinemann, Uwe

2017-01-01

Neuronal lactate uptake supports energy metabolism associated with synaptic signaling and recovery of extracellular ion gradients following neuronal activation. Altered expression of the monocarboxylate transporters (MCT) in temporal lobe epilepsy (TLE) hampers lactate removal into the bloodstream. The resulting increase in parenchymal lactate levels might exert both, anti- and pro-ictogen effects, by causing acidosis and by supplementing energy metabolism, respectively. Hence, we assessed the contribution of lactate to the maintenance of transmembrane potassium gradients, synaptic signaling and pathological network activity in chronic epileptic human tissue. Stimulus induced and spontaneous field potentials and extracellular potassium concentration changes (∆[K+]O) were recorded in parallel with tissue pO2 and pH in slices from TLE patients while blocking MCTs by α-cyano-4-hydroxycinnamic acid (4-CIN) or d-lactate. Intrinsic lactate contributed to the oxidative energy metabolism in chronic epileptic tissue as revealed by the changes in pO2 following blockade of lactate uptake. However, unlike the results in rat hippocampus, ∆[K+]O recovery kinetics and field potential amplitude did not depend on the presence of lactate. Remarkably, inhibition of lactate uptake exerted pH-independent anti-seizure effects both in healthy rat and chronic epileptic tissue and this effect was partly mediated via adenosine 1 receptor activation following decreased oxidative metabolism. PMID:28832554

A Significant Role of the Truncated Ghrelin Receptor GHS-R1b in Ghrelin-induced Signaling in Neurons.

PubMed

Navarro, Gemma; Aguinaga, David; Angelats, Edgar; Medrano, Mireia; Moreno, Estefanía; Mallol, Josefa; Cortés, Antonio; Canela, Enric I; Casadó, Vicent; McCormick, Peter J; Lluís, Carme; Ferré, Sergi

2016-06-17

The truncated non-signaling ghrelin receptor growth hormone secretagogue R1b (GHS-R1b) has been suggested to simply exert a dominant negative role in the trafficking and signaling of the full and functional ghrelin receptor GHS-R1a. Here we reveal a more complex modulatory role of GHS-R1b. Differential co-expression of GHS-R1a and GHS-R1b, both in HEK-293T cells and in striatal and hippocampal neurons in culture, demonstrates that GHS-R1b acts as a dual modulator of GHS-R1a function: low relative GHS-R1b expression potentiates and high relative GHS-R1b expression inhibits GHS-R1a function by facilitating GHS-R1a trafficking to the plasma membrane and by exerting a negative allosteric effect on GHS-R1a signaling, respectively. We found a preferential Gi/o coupling of the GHS-R1a-GHS-R1b complex in HEK-293T cells and, unexpectedly, a preferential Gs/olf coupling in both striatal and hippocampal neurons in culture. A dopamine D1 receptor (D1R) antagonist blocked ghrelin-induced cAMP accumulation in striatal but not hippocampal neurons, indicating the involvement of D1R in the striatal GHS-R1a-Gs/olf coupling. Experiments in HEK-293T cells demonstrated that D1R co-expression promotes a switch in GHS-R1a-G protein coupling from Gi/o to Gs/olf, but only upon co-expression of GHS-R1b. Furthermore, resonance energy transfer experiments showed that D1R interacts with GHS-R1a, but only in the presence of GHS-R1b. Therefore, GHS-R1b not only determines the efficacy of ghrelin-induced GHS-R1a-mediated signaling but also determines the ability of GHS-R1a to form oligomeric complexes with other receptors, promoting profound qualitative changes in ghrelin-induced signaling. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

A Significant Role of the Truncated Ghrelin Receptor GHS-R1b in Ghrelin-induced Signaling in Neurons*

PubMed Central

Navarro, Gemma; Aguinaga, David; Angelats, Edgar; Medrano, Mireia; Moreno, Estefanía; Mallol, Josefa; Cortés, Antonio; Canela, Enric I.; Casadó, Vicent; McCormick, Peter J.; Lluís, Carme; Ferré, Sergi

2016-01-01

The truncated non-signaling ghrelin receptor growth hormone secretagogue R1b (GHS-R1b) has been suggested to simply exert a dominant negative role in the trafficking and signaling of the full and functional ghrelin receptor GHS-R1a. Here we reveal a more complex modulatory role of GHS-R1b. Differential co-expression of GHS-R1a and GHS-R1b, both in HEK-293T cells and in striatal and hippocampal neurons in culture, demonstrates that GHS-R1b acts as a dual modulator of GHS-R1a function: low relative GHS-R1b expression potentiates and high relative GHS-R1b expression inhibits GHS-R1a function by facilitating GHS-R1a trafficking to the plasma membrane and by exerting a negative allosteric effect on GHS-R1a signaling, respectively. We found a preferential Gi/o coupling of the GHS-R1a-GHS-R1b complex in HEK-293T cells and, unexpectedly, a preferential Gs/olf coupling in both striatal and hippocampal neurons in culture. A dopamine D1 receptor (D1R) antagonist blocked ghrelin-induced cAMP accumulation in striatal but not hippocampal neurons, indicating the involvement of D1R in the striatal GHS-R1a-Gs/olf coupling. Experiments in HEK-293T cells demonstrated that D1R co-expression promotes a switch in GHS-R1a-G protein coupling from Gi/o to Gs/olf, but only upon co-expression of GHS-R1b. Furthermore, resonance energy transfer experiments showed that D1R interacts with GHS-R1a, but only in the presence of GHS-R1b. Therefore, GHS-R1b not only determines the efficacy of ghrelin-induced GHS-R1a-mediated signaling but also determines the ability of GHS-R1a to form oligomeric complexes with other receptors, promoting profound qualitative changes in ghrelin-induced signaling. PMID:27129257

Bok Is Not Pro-Apoptotic But Suppresses Poly ADP-Ribose Polymerase-Dependent Cell Death Pathways and Protects against Excitotoxic and Seizure-Induced Neuronal Injury.

PubMed

D'Orsi, Beatrice; Engel, Tobias; Pfeiffer, Shona; Nandi, Saheli; Kaufmann, Thomas; Henshall, David C; Prehn, Jochen H M

2016-04-20

Bok (Bcl-2-related ovarian killer) is a Bcl-2 family member that, because of its predicted structural homology to Bax and Bak, has been proposed to be a pro-apoptotic protein. In this study, we demonstrate that Bok is highly expressed in neurons of the mouse brain but that bok was not required for staurosporine-, proteasome inhibition-, or excitotoxicity-induced apoptosis of cultured cortical neurons. On the contrary, we found that bok-deficient neurons were more sensitive to oxygen/glucose deprivation-induced injury in vitro and seizure-induced neuronal injury in vivo Deletion of bok also increased staurosporine-, excitotoxicity-, and oxygen/glucose deprivation-induced cell death in bax-deficient neurons. Single-cell imaging demonstrated that bok-deficient neurons failed to maintain their neuronal Ca(2+)homeostasis in response to an excitotoxic stimulus; this was accompanied by a prolonged deregulation of mitochondrial bioenergetics.bok deficiency led to a specific reduction in neuronal Mcl-1 protein levels, and deregulation of both mitochondrial bioenergetics and Ca(2+)homeostasis was rescued by Mcl-1 overexpression. Detailed analysis of cell death pathways demonstrated the activation of poly ADP-ribose polymerase-dependent cell death in bok-deficient neurons. Collectively, our data demonstrate that Bok acts as a neuroprotective factor rather than a pro-death effector during Ca(2+)- and seizure-induced neuronal injury in vitro and in vivo Bcl-2 proteins are essential regulators of the mitochondrial apoptosis pathway. The Bcl-2 protein Bok is highly expressed in the CNS. Because of its sequence similarity to Bax and Bak, Bok has long been considered part of the pro-apoptotic Bax-like subfamily, but no studies have yet been performed in neurons to test this hypothesis. Our study provides important new insights into the functional role of Bok during neuronal apoptosis and specifically in the setting of Ca(2+)- and seizure-mediated neuronal injury. We show that Bok controls neuronal Ca(2+)homeostasis and bioenergetics and, contrary to previous assumptions, exerts neuroprotective activities in vitro and in vivo Our results demonstrate that Bok cannot be placed unambiguously into the Bax-like Bcl-2 subfamily of pro-apoptotic proteins. Copyright © 2016 the authors 0270-6474/16/364564-15$15.00/0.

Hypothalamic Tuberomammillary Nucleus Neurons: Electrophysiological Diversity and Essential Role in Arousal Stability.

PubMed

Fujita, Akie; Bonnavion, Patricia; Wilson, Miryam H; Mickelsen, Laura E; Bloit, Julien; de Lecea, Luis; Jackson, Alexander C

2017-09-27

Histaminergic (HA) neurons, found in the posterior hypothalamic tuberomammillary nucleus (TMN), extend fibers throughout the brain and exert modulatory influence over numerous physiological systems. Multiple lines of evidence suggest that the activity of HA neurons is important in the regulation of vigilance despite the lack of direct, causal evidence demonstrating its requirement for the maintenance of arousal during wakefulness. Given the strong correlation between HA neuron excitability and behavioral arousal, we investigated both the electrophysiological diversity of HA neurons in brain slices and the effect of their acute silencing in vivo in male mice. For this purpose, we first validated a transgenic mouse line expressing cre recombinase in histidine decarboxylase-expressing neurons ( Hdc -Cre) followed by a systematic census of the membrane properties of both HA and non-HA neurons in the ventral TMN (TMNv) region. Through unsupervised hierarchical cluster analysis, we found electrophysiological diversity both between TMNv HA and non-HA neurons, and among HA neurons. To directly determine the impact of acute cessation of HA neuron activity on sleep-wake states in awake and behaving mice, we examined the effects of optogenetic silencing of TMNv HA neurons in vivo We found that acute silencing of HA neurons during wakefulness promotes slow-wave sleep, but not rapid eye movement sleep, during a period of low sleep pressure. Together, these data suggest that the tonic firing of HA neurons is necessary for the maintenance of wakefulness, and their silencing not only impairs arousal but is sufficient to rapidly and selectively induce slow-wave sleep. SIGNIFICANCE STATEMENT The function of monoaminergic systems and circuits that regulate sleep and wakefulness is often disrupted as part of the pathophysiology of many neuropsychiatric disorders. One such circuit is the posterior hypothalamic histamine (HA) system, implicated in supporting wakefulness and higher brain function, but has been difficult to selectively manipulate owing to cellular heterogeneity in this region. Here we use a transgenic mouse to interrogate both the characteristic firing properties of HA neurons and their specific role in maintaining wakefulness. Our results demonstrate that the acute, cell type-specific silencing of HA neurons during wakefulness is sufficient to not only impair arousal but to rapidly and selectively induce slow-wave sleep. This work furthers our understanding of HA-mediated mechanisms that regulate behavioral arousal. Copyright © 2017 the authors 0270-6474/17/379575-19$15.00/0.

Hypothalamic Tuberomammillary Nucleus Neurons: Electrophysiological Diversity and Essential Role in Arousal Stability

PubMed Central

Fujita, Akie; Mickelsen, Laura E.; Bloit, Julien

2017-01-01

Histaminergic (HA) neurons, found in the posterior hypothalamic tuberomammillary nucleus (TMN), extend fibers throughout the brain and exert modulatory influence over numerous physiological systems. Multiple lines of evidence suggest that the activity of HA neurons is important in the regulation of vigilance despite the lack of direct, causal evidence demonstrating its requirement for the maintenance of arousal during wakefulness. Given the strong correlation between HA neuron excitability and behavioral arousal, we investigated both the electrophysiological diversity of HA neurons in brain slices and the effect of their acute silencing in vivo in male mice. For this purpose, we first validated a transgenic mouse line expressing cre recombinase in histidine decarboxylase-expressing neurons (Hdc-Cre) followed by a systematic census of the membrane properties of both HA and non-HA neurons in the ventral TMN (TMNv) region. Through unsupervised hierarchical cluster analysis, we found electrophysiological diversity both between TMNv HA and non-HA neurons, and among HA neurons. To directly determine the impact of acute cessation of HA neuron activity on sleep–wake states in awake and behaving mice, we examined the effects of optogenetic silencing of TMNv HA neurons in vivo. We found that acute silencing of HA neurons during wakefulness promotes slow-wave sleep, but not rapid eye movement sleep, during a period of low sleep pressure. Together, these data suggest that the tonic firing of HA neurons is necessary for the maintenance of wakefulness, and their silencing not only impairs arousal but is sufficient to rapidly and selectively induce slow-wave sleep. SIGNIFICANCE STATEMENT The function of monoaminergic systems and circuits that regulate sleep and wakefulness is often disrupted as part of the pathophysiology of many neuropsychiatric disorders. One such circuit is the posterior hypothalamic histamine (HA) system, implicated in supporting wakefulness and higher brain function, but has been difficult to selectively manipulate owing to cellular heterogeneity in this region. Here we use a transgenic mouse to interrogate both the characteristic firing properties of HA neurons and their specific role in maintaining wakefulness. Our results demonstrate that the acute, cell type-specific silencing of HA neurons during wakefulness is sufficient to not only impair arousal but to rapidly and selectively induce slow-wave sleep. This work furthers our understanding of HA-mediated mechanisms that regulate behavioral arousal. PMID:28874450

A quantitative examination of the role of cargo-exerted forces in axonal transport

PubMed Central

Mitchell, Cassie S.; Lee, Robert H.

2009-01-01

Axonal transport, via molecular motors kinesin and dynein, is a critical process in supplying the necessary constituents to maintain normal neuronal function. In this study, we predict the role of cooperativity by motors of the same polarity across the entire spectrum of physiological axonal transport. That is, we examined how the number of motors, either kinesin or dynein, working together to move a cargo, results in the experimentally determined velocity profiles seen in fast and slow anterograde and retrograde transport. We quantified the physiological forces exerted on a motor by a cargo as a function of cargo size, transport velocity, and transport type. Our results show that the force exerted by our base case neurofilament (DNF=10nm, LNF=1.6μm) is ~1.25pN at 600nm/s; additionally, the force exerted by our base case organelle (DOrg=1μm) at 1,000nm/s is ~5.7pN. Our results indicate that while a single motor can independently carry an average cargo, cooperativity is required to produce the experimental velocity profiles for fast transport. However, no cooperativity is required to produce the slow transport velocity profiles; thus, a single dynein or kinesin can carry the average neurofilament retrogradely or anterogradely, respectively. The potential role cooperativity may play in the hypothesized mechanisms of motoneuron transport diseases such as Amyotrophic Lateral Sclerosis (ALS) is discussed. PMID:19150364

Dynamics of Cell Area and Force during Spreading

PubMed Central

Brill-Karniely, Yifat; Nisenholz, Noam; Rajendran, Kavitha; Dang, Quynh; Krishnan, Ramaswamy; Zemel, Assaf

2014-01-01

Experiments on human pulmonary artery endothelial cells are presented to show that cell area and the force exerted on a substrate increase simultaneously, but with different rates during spreading; rapid-force increase systematically occurred several minutes past initial spreading. We examine this theoretically and present three complementary mechanisms that may accompany the development of lamellar stress during spreading and underlie the observed behavior. These include: 1), the dynamics of cytoskeleton assembly at the cell basis; 2), the strengthening of acto-myosin forces in response to the generated lamellar stresses; and 3), the passive strain-stiffening of the cytoskeleton. PMID:25517168

14,15-EET promotes mitochondrial biogenesis and protects cortical neurons against oxygen/glucose deprivation-induced apoptosis

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

Wang, Lai; Chen, Man; Yuan, Lin

2014-07-18

Highlights: • 14,15-EET inhibits OGD-induced apoptosis in cortical neurons. • Mitochondrial biogenesis of cortical neurons is promoted by 14,15-EET. • 14,15-EET preserves mitochondrial function of cortical neurons under OGD. • CREB mediates effect of 14,15-EET on mitochondrial biogenesis and function. - Abstract: 14,15-Epoxyeicosatrienoic acid (14,15-EET), a metabolite of arachidonic acid, is enriched in the brain cortex and exerts protective effect against neuronal apoptosis induced by ischemia/reperfusion. Although apoptosis has been well recognized to be closely associated with mitochondrial biogenesis and function, it is still unclear whether the neuroprotective effect of 14,15-EET is mediated by promotion of mitochondrial biogenesis and functionmore » in cortical neurons under the condition of oxygen–glucose deprivation (OGD). In this study, we found that 14,15-EET improved cell viability and inhibited apoptosis of cortical neurons. 14,15-EET significantly increased the mitochondrial mass and the ratio of mitochondrial DNA to nuclear DNA. Key makers of mitochondrial biogenesis, peroxisome proliferator activator receptor gamma-coactivator 1 alpha (PGC-1α), nuclear respiratory factor 1 (NRF-1) and mitochondrial transcription factor A (TFAM), were elevated at both mRNA and protein levels in the cortical neurons treated with 14,15-EET. Moreover, 14,15-EET markedly attenuated the decline of mitochondrial membrane potential, reduced ROS, while increased ATP synthesis. Knockdown of cAMP-response element binding protein (CREB) by siRNA blunted the up-regulation of PGC-1α and NRF-1 stimulated by 14,15-EET, and consequently abolished the neuroprotective effect of 14,15-EET. Our results indicate that 14,15-EET protects neurons from OGD-induced apoptosis by promoting mitochondrial biogenesis and function through CREB mediated activation of PGC-1α and NRF-1.« less

Calpains are downstream effectors of bax-dependent excitotoxic apoptosis.

PubMed

D'Orsi, Beatrice; Bonner, Helena; Tuffy, Liam P; Düssmann, Heiko; Woods, Ina; Courtney, Michael J; Ward, Manus W; Prehn, Jochen H M

2012-02-01

Excitotoxicity resulting from excessive Ca(2+) influx through glutamate receptors contributes to neuronal injury after stroke, trauma, and seizures. Increased cytosolic Ca(2+) levels activate a family of calcium-dependent proteases with papain-like activity, the calpains. Here we investigated the role of calpain activation during NMDA-induced excitotoxic injury in embryonic (E16-E18) murine cortical neurons that (1) underwent excitotoxic necrosis, characterized by immediate deregulation of Ca(2+) homeostasis, a persistent depolarization of mitochondrial membrane potential (Δψ(m)), and insensitivity to bax-gene deletion, (2) underwent excitotoxic apoptosis, characterized by recovery of NMDA-induced cytosolic Ca(2+) increases, sensitivity to bax gene deletion, and delayed Δψ(m) depolarization and Ca(2+) deregulation, or (3) that were tolerant to excitotoxic injury. Interestingly, treatment with the calpain inhibitor calpeptin, overexpression of the endogenous calpain inhibitor calpastatin, or gene silencing of calpain protected neurons against excitotoxic apoptosis but did not influence excitotoxic necrosis. Calpeptin failed to exert a protective effect in bax-deficient neurons but protected bid-deficient neurons similarly to wild-type cells. To identify when calpains became activated during excitotoxic apoptosis, we monitored calpain activation dynamics by time-lapse fluorescence microscopy using a calpain-sensitive Förster resonance energy transfer probe. We observed a delayed calpain activation that occurred downstream of mitochondrial engagement and directly preceded neuronal death. In contrast, we could not detect significant calpain activity during excitotoxic necrosis or in neurons that were tolerant to excitotoxic injury. Oxygen/glucose deprivation-induced injury in organotypic hippocampal slice cultures confirmed that calpains were specifically activated during bax-dependent apoptosis and in this setting function as downstream cell-death executioners.

Valproic Acid Arrests Proliferation but Promotes Neuronal Differentiation of Adult Spinal NSPCs from SCI Rats.

PubMed

Chu, Weihua; Yuan, Jichao; Huang, Lei; Xiang, Xin; Zhu, Haitao; Chen, Fei; Chen, Yanyan; Lin, Jiangkai; Feng, Hua

2015-07-01

Although the adult spinal cord contains a population of multipotent neural stem/precursor cells (NSPCs) exhibiting the potential to replace neurons, endogenous neurogenesis is very limited after spinal cord injury (SCI) because the activated NSPCs primarily differentiate into astrocytes rather than neurons. Valproic acid (VPA), a histone deacetylase inhibitor, exerts multiple pharmacological effects including fate regulation of stem cells. In this study, we cultured adult spinal NSPCs from chronic compressive SCI rats and treated with VPA. In spite of inhibiting the proliferation and arresting in the G0/G1 phase of NSPCs, VPA markedly promoted neuronal differentiation (β-tubulin III(+) cells) as well as decreased astrocytic differentiation (GFAP(+) cells). Cell cycle regulator p21(Cip/WAF1) and proneural genes Ngn2 and NeuroD1 were increased in the two processes respectively. In vivo, to minimize the possible inhibitory effects of VPA to the proliferation of NSPCs as well as avoid other neuroprotections of VPA in acute phase of SCI, we carried out a delayed intraperitoneal injection of VPA (150 mg/kg/12 h) to SCI rats from day 15 to day 22 after injury. Both of the newborn neuron marker doublecortin and the mature neuron marker neuron-specific nuclear protein were significantly enhanced after VPA treatment in the epicenter and adjacent segments of the injured spinal cord. Although the impaired corticospinal tracks had not significantly improved, Basso-Beattie-Bresnahan scores in VPA treatment group were better than control. Our study provide the first evidence that administration of VPA enhances the neurogenic potential of NSPCs after SCI and reveal the therapeutic value of delayed treatment of VPA to SCI.

Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) Signaling and Cell Death in the Immature Central Nervous System after Hypoxia-Ischemia and Inflammation*

PubMed Central

Kichev, Anton; Rousset, Catherine I.; Baburamani, Ana A.; Levison, Steven W.; Wood, Teresa L.; Gressens, Pierre; Thornton, Claire; Hagberg, Henrik

2014-01-01

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the TNF family. The interaction of TRAIL with death receptor 4 (DR4) and DR5 can trigger apoptotic cell death. The aim of this study was to investigate the role of TRAIL signaling in neonatal hypoxia-ischemia (HI). Using a neonatal mouse model of HI, mRNA, and protein expression of TRAIL, DR5 and the TRAIL decoy receptors osteoprotegerin (OPG), mDcTRAILR1, and mDcTRAILR2 were determined. In vitro, mRNA expression of these genes was measured in primary neurons and oligodendrocyte progenitor cells (OPCs) after inflammatory cytokine (TNF-α/IFN-γ) treatment and/or oxygen and glucose deprivation (OGD). The toxicity of these various paradigms was also measured. The expression of TRAIL, DR5, OPG, and mDcTRAILR2 was significantly increased after HI. In vitro, inflammatory cytokines and OGD treatment significantly induced mRNAs for TRAIL, DR5, OPG, and mDcTRAILR2 in primary neurons and of TRAIL and OPG in OPCs. TRAIL protein was expressed primarily in microglia and astroglia, whereas DR5 co-localized with neurons and OPCs in vivo. OGD enhanced TNF-α/IFN-γ toxicity in both neuronal and OPC cultures. Recombinant TRAIL exerted toxicity alone or in combination with OGD and TNF-α/IFN-γ in primary neurons but not in OPC cultures. The marked increases in the expression of TRAIL and its receptors after cytokine exposure and OGD in primary neurons and OPCs were similar to those found in our animal model of neonatal HI. The toxicity of TRAIL in primary neurons suggests that TRAIL signaling participates in neonatal brain injury after inflammation and HI. PMID:24509861

Mercaptoacetate and fatty acids exert direct and antagonistic effects on nodose neurons via GPR40 fatty acid receptors.

PubMed

Darling, Rebecca A; Zhao, Huan; Kinch, Dallas; Li, Ai-Jun; Simasko, Steven M; Ritter, Sue

2014-07-01

β-mercaptoacetate (MA) is a drug known to block mitochondrial oxidation of medium- and long-chain fatty acids (FAs) and to stimulate feeding. Because MA-induced feeding is vagally dependent, it has been assumed that the feeding response is mediated by MA's antimetabolic action at a peripheral, vagally innervated site. However, MA's site of action has not yet been identified. Therefore, we used fluorescent calcium measurements in isolated neurons from rat nodose ganglia to determine whether MA has direct effects on vagal sensory neurons. We found that MA alone did not alter cytosolic calcium concentrations in nodose neurons. However, MA (60 μM to 6 mM) significantly decreased calcium responses to both linoleic acid (LA; 10 μM) and caprylic acid (C8; 10 μM) in all neurons responsive to LA and C8. GW9508 (40 μM), an agonist of the FA receptor, G protein-coupled receptor 40 (GPR40), also increased calcium levels almost exclusively in FA-responsive neurons. MA significantly inhibited this response to GW9508. MA did not inhibit calcium responses to serotonin, high K(+), or capsaicin, which do not utilize GPRs, or to CCK, which acts on a different GPR. GPR40 was detected in nodose ganglia by RT-PCR. Results suggest that FAs directly activate vagal sensory neurons via GPR40 and that MA antagonizes this effect. Thus, we propose that MA's nonmetabolic actions on GPR40 membrane receptors, expressed by multiple peripheral tissues in addition to the vagus nerve, may contribute to or mediate MA-induced stimulation of feeding. Copyright © 2014 the American Physiological Society.

Attention Increases Spike Count Correlations between Visual Cortical Areas.

PubMed

Ruff, Douglas A; Cohen, Marlene R

2016-07-13

Visual attention, which improves perception of attended locations or objects, has long been known to affect many aspects of the responses of neuronal populations in visual cortex. There are two nonmutually exclusive hypotheses concerning the neuronal mechanisms that underlie these perceptual improvements. The first hypothesis, that attention improves the information encoded by a population of neurons in a particular cortical area, has considerable physiological support. The second hypothesis is that attention improves perception by selectively communicating relevant visual information. This idea has been tested primarily by measuring interactions between neurons on very short timescales, which are mathematically nearly independent of neuronal interactions on longer timescales. We tested the hypothesis that attention changes the way visual information is communicated between cortical areas on longer timescales by recording simultaneously from neurons in primary visual cortex (V1) and the middle temporal area (MT) in rhesus monkeys. We used two independent and complementary approaches. Our correlative experiment showed that attention increases the trial-to-trial response variability that is shared between the two areas. In our causal experiment, we electrically microstimulated V1 and found that attention increased the effect of stimulation on MT responses. Together, our results suggest that attention affects both the way visual stimuli are encoded within a cortical area and the extent to which visual information is communicated between areas on behaviorally relevant timescales. Visual attention dramatically improves the perception of attended stimuli. Attention has long been thought to act by selecting relevant visual information for further processing. It has been hypothesized that this selection is accomplished by increasing communication between neurons that encode attended information in different cortical areas. We recorded simultaneously from neurons in primary visual cortex and the middle temporal area while rhesus monkeys performed an attention task. We found that attention increased shared variability between neurons in the two areas and that attention increased the effect of microstimulation in V1 on the firing rates of MT neurons. Our results provide support for the hypothesis that attention increases communication between neurons in different brain areas on behaviorally relevant timescales. Copyright © 2016 the authors 0270-6474/16/367523-12$15.00/0.

Attention Increases Spike Count Correlations between Visual Cortical Areas

PubMed Central

Cohen, Marlene R.

2016-01-01

Visual attention, which improves perception of attended locations or objects, has long been known to affect many aspects of the responses of neuronal populations in visual cortex. There are two nonmutually exclusive hypotheses concerning the neuronal mechanisms that underlie these perceptual improvements. The first hypothesis, that attention improves the information encoded by a population of neurons in a particular cortical area, has considerable physiological support. The second hypothesis is that attention improves perception by selectively communicating relevant visual information. This idea has been tested primarily by measuring interactions between neurons on very short timescales, which are mathematically nearly independent of neuronal interactions on longer timescales. We tested the hypothesis that attention changes the way visual information is communicated between cortical areas on longer timescales by recording simultaneously from neurons in primary visual cortex (V1) and the middle temporal area (MT) in rhesus monkeys. We used two independent and complementary approaches. Our correlative experiment showed that attention increases the trial-to-trial response variability that is shared between the two areas. In our causal experiment, we electrically microstimulated V1 and found that attention increased the effect of stimulation on MT responses. Together, our results suggest that attention affects both the way visual stimuli are encoded within a cortical area and the extent to which visual information is communicated between areas on behaviorally relevant timescales. SIGNIFICANCE STATEMENT Visual attention dramatically improves the perception of attended stimuli. Attention has long been thought to act by selecting relevant visual information for further processing. It has been hypothesized that this selection is accomplished by increasing communication between neurons that encode attended information in different cortical areas. We recorded simultaneously from neurons in primary visual cortex and the middle temporal area while rhesus monkeys performed an attention task. We found that attention increased shared variability between neurons in the two areas and that attention increased the effect of microstimulation in V1 on the firing rates of MT neurons. Our results provide support for the hypothesis that attention increases communication between neurons in different brain areas on behaviorally relevant timescales. PMID:27413161

In situ monitoring of myenteric neuron activity using acetylcholinesterase-modified AlGaN/GaN solution-gate field-effect transistors.

PubMed

Müntze, Gesche Mareike; Pouokam, Ervice; Steidle, Julia; Schäfer, Wladimir; Sasse, Alexander; Röth, Kai; Diener, Martin; Eickhoff, Martin

2016-03-15

The response characteristics of acetylcholinesterase-modified AlGaN/GaN solution-gate field-effect transistors (AcFETs) are quantitatively analyzed by means of a kinetic model. The characterization shows that the covalent enzyme immobilization process yields reproducible AcFET characteristics with a Michaelis constant KM of (122 ± 4) μM for the immobilized enzyme layer. The increase of KM by a factor of 2.4 during the first four measurement cycles is attributed to partial denaturation of the enzyme. The AcFETs were used to record the release of acetylcholine (ACh) by neuronal tissue cultivated on the gate area upon stimulation by rising the extracellular K(+) concentration. The neuronal tissue constituted of isolated myenteric neurons from four to 12 days old Wistar rats, or sections from the muscularis propria containing the myenteric plexus from adult rats. For both cases the AcFET response was demonstrated to be related to the activity of the immobilized acetylcholinesterase using the reversible acetylcholinesterase blocker donepezil. A concentration response curve of this blocking agent revealed a half maximal inhibitory concentration of 40 nM which is comparable to values measured by complementary in vitro methods. Copyright © 2015 Elsevier B.V. All rights reserved.

Combining NT3-overexpressing MSCs and PLGA microcarriers for brain tissue engineering: A potential tool for treatment of Parkinson's disease.

PubMed

Moradian, Hanieh; Keshvari, Hamid; Fasehee, Hamidreza; Dinarvand, Rassoul; Faghihi, Shahab

2017-07-01

Parkinson's disease (PD) is a progressive neurodegenerative disorder that characterized by destruction of substantia nigrostriatal pathway due to the loss of dopaminergic (DA) neurons. Regardless of substantial efforts for treatment of PD in recent years, an effective therapeutic strategy is still missing. In a multidisciplinary approach, bone marrow derived mesenchymal stem cells (BMSCs) are genetically engineered to overexpress neurotrophin-3 (nt-3 gene) that protect central nervous system tissues and stimulates neuronal-like differentiation of BMSCs. Poly(lactic-co-glycolic acid) (PLGA) microcarriers are designed as an injectable scaffold and synthesized via double emulsion method. The surface of PLGA microcarriers are functionalized by collagen as a bioadhesive agent for improved cell attachment. The results demonstrate effective overexpression of NT-3. The expression of tyrosine hydroxylase (TH) in transfected BMSCs reveal that NT-3 promotes the intracellular signaling pathway of DA neuron differentiation. It is also shown that transfected BMSCs are successfully attached to the surface of microcarriers. The presence of dopamine in peripheral media of cell/microcarrier complex reveals that BMSCs are successfully differentiated into dopaminergic neuron. Our approach that sustains presence of growth factor can be suggested as a novel complementary therapeutic strategy for treatment of Parkinson disease. Copyright © 2017 Elsevier B.V. All rights reserved.

Statistical analysis and data mining of digital reconstructions of dendritic morphologies.

PubMed

Polavaram, Sridevi; Gillette, Todd A; Parekh, Ruchi; Ascoli, Giorgio A

2014-01-01

Neuronal morphology is diverse among animal species, developmental stages, brain regions, and cell types. The geometry of individual neurons also varies substantially even within the same cell class. Moreover, specific histological, imaging, and reconstruction methodologies can differentially affect morphometric measures. The quantitative characterization of neuronal arbors is necessary for in-depth understanding of the structure-function relationship in nervous systems. The large collection of community-contributed digitally reconstructed neurons available at NeuroMorpho.Org constitutes a "big data" research opportunity for neuroscience discovery beyond the approaches typically pursued in single laboratories. To illustrate these potential and related challenges, we present a database-wide statistical analysis of dendritic arbors enabling the quantification of major morphological similarities and differences across broadly adopted metadata categories. Furthermore, we adopt a complementary unsupervised approach based on clustering and dimensionality reduction to identify the main morphological parameters leading to the most statistically informative structural classification. We find that specific combinations of measures related to branching density, overall size, tortuosity, bifurcation angles, arbor flatness, and topological asymmetry can capture anatomically and functionally relevant features of dendritic trees. The reported results only represent a small fraction of the relationships available for data exploration and hypothesis testing enabled by sharing of digital morphological reconstructions.

An ultra-low-voltage electronic implementation of inertial neuron model with nonmonotonous Liao's activation function.

PubMed

Kant, Nasir Ali; Dar, Mohamad Rafiq; Khanday, Farooq Ahmad

2015-01-01

The output of every neuron in neural network is specified by the employed activation function (AF) and therefore forms the heart of neural networks. As far as the design of artificial neural networks (ANNs) is concerned, hardware approach is preferred over software one because it promises the full utilization of the application potential of ANNs. Therefore, besides some arithmetic blocks, designing AF in hardware is the most important for designing ANN. While attempting to design the AF in hardware, the designs should be compatible with the modern Very Large Scale Integration (VLSI) design techniques. In this regard, the implemented designs should: only be in Metal Oxide Semiconductor (MOS) technology in order to be compatible with the digital designs, provide electronic tunability feature, and be able to operate at ultra-low voltage. Companding is one of the promising circuit design techniques for achieving these goals. In this paper, 0.5 V design of Liao's AF using sinh-domain technique is introduced. Furthermore, the function is tested by implementing inertial neuron model. The performance of the AF and inertial neuron model have been evaluated through simulation results, using the PSPICE software with the MOS transistor models provided by the 0.18-μm Taiwan Semiconductor Manufacturer Complementary Metal Oxide Semiconductor (TSM CMOS) process.

Phosphorylation mechanisms in dopamine transporter regulation.

PubMed

Foster, James D; Vaughan, Roxanne A

2017-10-01

The dopamine transporter (DAT) is a plasma membrane phosphoprotein that actively translocates extracellular dopamine (DA) into presynaptic neurons. The transporter is the primary mechanism for control of DA levels and subsequent neurotransmission, and is the target for abused and therapeutic drugs that exert their effects by suppressing reuptake. The transport capacity of DAT is acutely regulated by signaling systems and drug exposure, providing neurons the ability to fine-tune DA clearance in response to specific conditions. Kinase pathways play major roles in these mechanisms, and this review summarizes the current status of DAT phosphorylation characteristics and the evidence linking transporter phosphorylation to control of reuptake and other functions. Greater understanding of these processes may aid in elucidation of their possible contributions to DA disease states and suggest specific phosphorylation sites as targets for therapeutic manipulation of reuptake. Copyright © 2016. Published by Elsevier B.V.

Mmp1 processing of the PDF neuropeptide regulates circadian structural plasticity of pacemaker neurons.

PubMed

Depetris-Chauvin, Ana; Fernández-Gamba, Agata; Gorostiza, E Axel; Herrero, Anastasia; Castaño, Eduardo M; Ceriani, M Fernanda

2014-10-01

In the Drosophila brain, the neuropeptide PIGMENT DISPERSING FACTOR (PDF) is expressed in the small and large Lateral ventral neurons (LNvs) and regulates circadian locomotor behavior. Interestingly, PDF immunoreactivity at the dorsal terminals changes across the day as synaptic contacts do as a result of a remarkable remodeling of sLNv projections. Despite the relevance of this phenomenon to circuit plasticity and behavior, the underlying mechanisms remain poorly understood. In this work we provide evidence that PDF along with matrix metalloproteinases (Mmp1 and 2) are key in the control of circadian structural remodeling. Adult-specific downregulation of PDF levels per se hampers circadian axonal remodeling, as it does altering Mmp1 or Mmp2 levels within PDF neurons post-developmentally. However, only Mmp1 affects PDF immunoreactivity at the dorsal terminals and exerts a clear effect on overt behavior. In vitro analysis demonstrated that PDF is hydrolyzed by Mmp1, thereby suggesting that Mmp1 could directly terminate its biological activity. These data demonstrate that Mmp1 modulates PDF processing, which leads to daily structural remodeling and circadian behavior.

Mmp1 Processing of the PDF Neuropeptide Regulates Circadian Structural Plasticity of Pacemaker Neurons

PubMed Central

Depetris-Chauvin, Ana; Fernández-Gamba, Ágata; Gorostiza, E. Axel; Herrero, Anastasia; Castaño, Eduardo M.; Ceriani, M. Fernanda

2014-01-01

In the Drosophila brain, the neuropeptide PIGMENT DISPERSING FACTOR (PDF) is expressed in the small and large Lateral ventral neurons (LNvs) and regulates circadian locomotor behavior. Interestingly, PDF immunoreactivity at the dorsal terminals changes across the day as synaptic contacts do as a result of a remarkable remodeling of sLNv projections. Despite the relevance of this phenomenon to circuit plasticity and behavior, the underlying mechanisms remain poorly understood. In this work we provide evidence that PDF along with matrix metalloproteinases (Mmp1 and 2) are key in the control of circadian structural remodeling. Adult-specific downregulation of PDF levels per se hampers circadian axonal remodeling, as it does altering Mmp1 or Mmp2 levels within PDF neurons post-developmentally. However, only Mmp1 affects PDF immunoreactivity at the dorsal terminals and exerts a clear effect on overt behavior. In vitro analysis demonstrated that PDF is hydrolyzed by Mmp1, thereby suggesting that Mmp1 could directly terminate its biological activity. These data demonstrate that Mmp1 modulates PDF processing, which leads to daily structural remodeling and circadian behavior. PMID:25356918

Histamine Induces Alzheimer's Disease-Like Blood Brain Barrier Breach and Local Cellular Responses in Mouse Brain Organotypic Cultures

PubMed Central

Sedeyn, Jonathan C.; Wu, Hao; Hobbs, Reilly D.; Levin, Eli C.; Nagele, Robert G.; Venkataraman, Venkat

2015-01-01

Among the top ten causes of death in the United States, Alzheimer's disease (AD) is the only one that cannot be cured, prevented, or even slowed down at present. Significant efforts have been exerted in generating model systems to delineate the mechanism as well as establishing platforms for drug screening. In this study, a promising candidate model utilizing primary mouse brain organotypic (MBO) cultures is reported. For the first time, we have demonstrated that the MBO cultures exhibit increased blood brain barrier (BBB) permeability as shown by IgG leakage into the brain parenchyma, astrocyte activation as evidenced by increased expression of glial fibrillary acidic protein (GFAP), and neuronal damage-response as suggested by increased vimentin-positive neurons occur upon histamine treatment. Identical responses—a breakdown of the BBB, astrocyte activation, and neuronal expression of vimentin—were then demonstrated in brains from AD patients compared to age-matched controls, consistent with other reports. Thus, the histamine-treated MBO culture system may provide a valuable tool in combating AD. PMID:26697497

N-linked glycosylation of SV2 is required for binding and uptake of botulinum neurotoxin A.

PubMed

Yao, Guorui; Zhang, Sicai; Mahrhold, Stefan; Lam, Kwok-Ho; Stern, Daniel; Bagramyan, Karine; Perry, Kay; Kalkum, Markus; Rummel, Andreas; Dong, Min; Jin, Rongsheng

2016-07-01

Botulinum neurotoxin serotype A1 (BoNT/A1), a licensed drug widely used for medical and cosmetic applications, exerts its action by invading motoneurons. Here we report a 2.0-Å-resolution crystal structure of the BoNT/A1 receptor-binding domain in complex with its neuronal receptor, glycosylated human SV2C. We found that the neuronal tropism of BoNT/A1 requires recognition of both the peptide moiety and an N-linked glycan on SV2. This N-glycan-which is conserved in all SV2 isoforms across vertebrates-is essential for BoNT/A1 binding to neurons and for its potent neurotoxicity. The glycan-binding interface on SV2 is targeted by a human BoNT/A1-neutralizing antibody currently licensed as an antibotulism drug. Our studies reveal a new paradigm of host-pathogen interactions, in which pathogens exploit conserved host post-translational modifications, thereby achieving highly specific receptor binding while also tolerating genetic changes across multiple isoforms of receptors.

N-linked glycosylation of SV2 is required for binding and uptake of botulinum neurotoxin A

PubMed Central

Yao, Guorui; Zhang, Sicai; Mahrhold, Stefan; Lam, Kwok-ho; Stern, Daniel; Bagramyan, Karine; Perry, Kay; Kalkum, Markus; Rummel, Andreas; Dong, Min; Jin, Rongsheng

2016-01-01

Botulinum neurotoxin serotype A1 (BoNT/A1) is one of the most dangerous potential bioterrorism agents, and exerts its action by invading motoneurons. It is also a licensed drug widely used for medical and cosmetic applications. Here we report a 2.0 Å resolution crystal structure of BoNT/A1 receptor-binding domain in complex with its neuronal receptor, the glycosylated human SV2C. We find that the neuronal tropism of BoNT/A1 requires recognition of both the peptide moiety and an N-linked glycan on SV2. This N-glycan—conserved in all SV2 isoforms across vertebrates—is essential for BoNT/A1 binding to neurons and its potent neurotoxicity. The glycan-binding interface on SV2 is targeted by a human BoNT/A1-neutralizing antibody currently licensed as an anti-botulism drug. Our studies reveal a new paradigm of host-pathogen interactions, in which pathogens exploit conserved host post-translational modifications to achieve highly specific receptor binding while also tolerating genetic changes across multiple isoforms of receptors. PMID:27294781

Corticalization of motor control in humans is a consequence of brain scaling in primate evolution.

PubMed

Herculano-Houzel, Suzana; Kaas, Jon H; de Oliveira-Souza, Ricardo

2016-02-15

Control over spinal and brainstem somatomotor neurons is exerted by two sets of descending fibers, corticospinal/pyramidal and extrapyramidal. Although in nonhuman primates the effect of bilateral pyramidal lesions is mostly limited to an impairment of the independent use of digits in skilled manual actions, similar injuries in humans result in the locked-in syndrome, a state of mutism and quadriplegia in which communication can be established only by residual vertical eye movements. This behavioral contrast makes humans appear to be outliers compared with other primates because of our almost total dependence on the corticospinal/pyramidal system for the effectuation of movement. Here we propose, instead, that an increasing preponderance of the corticospinal/pyramidal system over motor control is an expected consequence of increasing brain size in primates because of the faster scaling of the number of neurons in the primary motor cortex over the brainstem and spinal cord motor neuron pools, explaining the apparent uniqueness of the corticalization of motor control in humans. © 2015 Wiley Periodicals, Inc.

Dysregulated expression of neuregulin-1 by cortical pyramidal neurons disrupts synaptic plasticity.

PubMed

Agarwal, Amit; Zhang, Mingyue; Trembak-Duff, Irina; Unterbarnscheidt, Tilmann; Radyushkin, Konstantin; Dibaj, Payam; Martins de Souza, Daniel; Boretius, Susann; Brzózka, Magdalena M; Steffens, Heinz; Berning, Sebastian; Teng, Zenghui; Gummert, Maike N; Tantra, Martesa; Guest, Peter C; Willig, Katrin I; Frahm, Jens; Hell, Stefan W; Bahn, Sabine; Rossner, Moritz J; Nave, Klaus-Armin; Ehrenreich, Hannelore; Zhang, Weiqi; Schwab, Markus H

2014-08-21

Neuregulin-1 (NRG1) gene variants are associated with increased genetic risk for schizophrenia. It is unclear whether risk haplotypes cause elevated or decreased expression of NRG1 in the brains of schizophrenia patients, given that both findings have been reported from autopsy studies. To study NRG1 functions in vivo, we generated mouse mutants with reduced and elevated NRG1 levels and analyzed the impact on cortical functions. Loss of NRG1 from cortical projection neurons resulted in increased inhibitory neurotransmission, reduced synaptic plasticity, and hypoactivity. Neuronal overexpression of cysteine-rich domain (CRD)-NRG1, the major brain isoform, caused unbalanced excitatory-inhibitory neurotransmission, reduced synaptic plasticity, abnormal spine growth, altered steady-state levels of synaptic plasticity-related proteins, and impaired sensorimotor gating. We conclude that an "optimal" level of NRG1 signaling balances excitatory and inhibitory neurotransmission in the cortex. Our data provide a potential pathomechanism for impaired synaptic plasticity and suggest that human NRG1 risk haplotypes exert a gain-of-function effect. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Neurite sprouting and synapse deterioration in the aging Caenorhabditis elegans nervous system.

PubMed

Toth, Marton Lorant; Melentijevic, Ilija; Shah, Leena; Bhatia, Aatish; Lu, Kevin; Talwar, Amish; Naji, Haaris; Ibanez-Ventoso, Carolina; Ghose, Piya; Jevince, Angela; Xue, Jian; Herndon, Laura A; Bhanot, Gyan; Rongo, Chris; Hall, David H; Driscoll, Monica

2012-06-27

Caenorhabditis elegans is a powerful model for analysis of the conserved mechanisms that modulate healthy aging. In the aging nematode nervous system, neuronal death and/or detectable loss of processes are not readily apparent, but because dendrite restructuring and loss of synaptic integrity are hypothesized to contribute to human brain decline and dysfunction, we combined fluorescence microscopy and electron microscopy (EM) to screen at high resolution for nervous system changes. We report two major components of morphological change in the aging C. elegans nervous system: (1) accumulation of novel outgrowths from specific neurons, and (2) physical decline in synaptic integrity. Novel outgrowth phenotypes, including branching from the main dendrite or new growth from somata, appear at a high frequency in some aging neurons, but not all. Mitochondria are often associated with age-associated branch sites. Lowered insulin signaling confers some maintenance of ALM and PLM neuron structural integrity into old age, and both DAF-16/FOXO and heat shock factor transcription factor HSF-1 exert neuroprotective functions. hsf-1 can act cell autonomously in this capacity. EM evaluation in synapse-rich regions reveals a striking decline in synaptic vesicle numbers and a diminution of presynaptic density size. Interestingly, old animals that maintain locomotory prowess exhibit less synaptic decline than same-age decrepit animals, suggesting that synaptic integrity correlates with locomotory healthspan. Our data reveal similarities between the aging C. elegans nervous system and mammalian brain, suggesting conserved neuronal responses to age. Dissection of neuronal aging mechanisms in C. elegans may thus influence the development of brain healthspan-extending therapies.

14,15-EET promotes mitochondrial biogenesis and protects cortical neurons against oxygen/glucose deprivation-induced apoptosis.

PubMed

Wang, Lai; Chen, Man; Yuan, Lin; Xiang, Yuting; Zheng, Ruimao; Zhu, Shigong

2014-07-18

14,15-Epoxyeicosatrienoic acid (14,15-EET), a metabolite of arachidonic acid, is enriched in the brain cortex and exerts protective effect against neuronal apoptosis induced by ischemia/reperfusion. Although apoptosis has been well recognized to be closely associated with mitochondrial biogenesis and function, it is still unclear whether the neuroprotective effect of 14,15-EET is mediated by promotion of mitochondrial biogenesis and function in cortical neurons under the condition of oxygen-glucose deprivation (OGD). In this study, we found that 14,15-EET improved cell viability and inhibited apoptosis of cortical neurons. 14,15-EET significantly increased the mitochondrial mass and the ratio of mitochondrial DNA to nuclear DNA. Key makers of mitochondrial biogenesis, peroxisome proliferator activator receptor gamma-coactivator 1 alpha (PGC-1α), nuclear respiratory factor 1 (NRF-1) and mitochondrial transcription factor A (TFAM), were elevated at both mRNA and protein levels in the cortical neurons treated with 14,15-EET. Moreover, 14,15-EET markedly attenuated the decline of mitochondrial membrane potential, reduced ROS, while increased ATP synthesis. Knockdown of cAMP-response element binding protein (CREB) by siRNA blunted the up-regulation of PGC-1α and NRF-1 stimulated by 14,15-EET, and consequently abolished the neuroprotective effect of 14,15-EET. Our results indicate that 14,15-EET protects neurons from OGD-induced apoptosis by promoting mitochondrial biogenesis and function through CREB mediated activation of PGC-1α and NRF-1. Copyright © 2014 Elsevier Inc. All rights reserved.

Streptozotocin alters glucose transport, connexin expression and endoplasmic reticulum functions in neurons and astrocytes.

PubMed

Biswas, Joyshree; Gupta, Sonam; Verma, Dinesh Kumar; Singh, Sarika

2017-07-25

The study was undertaken to explore the cell-specific streptozotocin (STZ)-induced mechanistic alterations. STZ-induced rodent model is a well-established experimental model of Alzheimer's disease (AD) and in our previous studies we have established it as an in vitro screening model of AD by employing N2A neuronal cells. Therefore, STZ was selected in the present study to understand the STZ-induced cell-specific alterations by utilizing neuronal N2A and astrocytes C6 cells. Both neuronal and astrocyte cells were treated with STZ at 10, 50, 100 and 1000μM concentrations for 48h. STZ exposure caused significant decline in cellular viability and augmented cytotoxicity of cells involving astrocytes activation. STZ treatment also disrupted the energy metabolism by altered glucose uptake and its transport in both cells as reflected with decreased expression of glucose transporters (GLUT) 1/3. The consequent decrease in ATP level and decreased mitochondrial membrane potential was also observed in both the cells. STZ caused increased intracellular calcium which could cause the initiation of endoplasmic reticulum (ER) stress. Significant upregulation of ER stress-related markers were observed in both cells after STZ treatment. The cellular communication of astrocytes and neurons was altered as reflected by increased expression of connexin 43 along with DNA fragmentation. STZ-induced apoptotic death was evaluated by elevated expression of caspase-3 and PI/Hoechst staining of cells. In conclusion, study showed that STZ exert alike biochemical alterations, ER stress and cellular apoptosis in both neuronal and astrocyte cells. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

Muscular contraction stimulates posterior hypothalamic neurons.

PubMed

Waldrop, T G; Stremel, R W

1989-02-01

Recent studies have suggested that the subthalamic locomotor region (STLR) of the posterior hypothalamus is involved in modulating cardiorespiratory responses to feedback from contracting muscles. The purpose of this study was to determine whether neurons in this hypothalamic region alter their discharge frequency during contraction of hindlimb muscles. Stainless steel electrodes were used to record single-unit activity of STLR neurons during static and rhythmic contractions of hindlimb muscles in anesthetized cats. Recordings were also made from neurons in areas outside but surrounding the subthalamic locomotor region. Contraction of the triceps surae muscles was induced by stimulation of the peripheral cut ends of the L7 and S1 ventral roots. Both static and rhythmic contractions of the triceps surae evoked an increase in the discharge rate of the majority of the STLR cells studied. Two types of excitatory responses were observed: 1) abrupt increases in discharge frequency at the onset of muscular contraction and 2) a delayed more gradual increase in firing. Most of the cells that responded to muscular contraction could be activated by mechanical probing of the triceps surae muscles. However, the changes in discharge frequency were unrelated to changes in arterial pressure occurring during muscular contraction. Most of the neurons located outside the STLR were slightly inhibited by or did not respond to muscular contraction. Thus input from contracting muscles exerts predominantly an excitatory effect on neurons in the posterior hypothalamus. These results are consistent with other studies which have concluded that this hypothalamic site is involved in influencing the cardiorespiratory responses to muscular contraction.

Neurite Sprouting and Synapse Deterioration in the Aging C. elegans Nervous System

PubMed Central

Toth, Marton; Melentijevic, Ilija; Shah, Leena; Bhatia, Aatish; Lu, Kevin; Talwar, Amish; Naji, Haaris; Ibanez-Ventoso, Carolina; Ghose, Piya; Jevince, Angela; Xue, Jian; Herndon, Laura A.; Bhanot, Gyan; Rongo, Chris; Hall, David H

2012-01-01

C. elegans is a powerful model for analysis of the conserved mechanisms that modulate healthy aging. In the aging nematode nervous system, neuronal death and/or detectable loss of processes are not readily apparent, but because dendrite restructuring and loss of synaptic integrity are hypothesized to contribute to human brain decline and dysfunction, we combined fluorescence microscopy and electron microscopy (EM) to screen at high resolution for nervous system changes. We report two major components of morphological change in the aging C. elegans nervous system: 1) accumulation of novel outgrowths from specific neurons, and 2) physical decline in synaptic integrity. Novel outgrowth phenotypes, including branching from the main dendrite or new growth from somata, appear at a high frequency in some aging neurons, but not all. Mitochondria are often associated with age-associated branch sites. Lowered insulin signaling confers some maintenance of ALM and PLM neuron structural integrity into old age, and both DAF-16/FOXO and heat shock factor transcription factor HSF-1 exert neuroprotective functions. hsf-1 can act cell autonomously in this capacity. EM evaluation in synapse-rich regions reveals a striking decline in synaptic vesicle numbers and a dimunition of presynaptic density size. Interestingly, old animals that maintain locomotory prowess exhibit less synaptic decline than same-age decrepit animals, suggesting that synaptic integrity correlates with locomotory healthspan. Our data reveal similarities between the aging C. elegans nervous system and mammalian brain, suggesting conserved neuronal responses to age. Dissection of neuronal aging mechanisms in C. elegans may thus influence the development of brain healthspan-extending therapies. PMID:22745480

Histone deacetylase inhibitors prevent p53-dependent and p53-independent Bax-mediated neuronal apoptosis through two distinct mechanisms.

PubMed

Uo, Takuma; Veenstra, Timothy D; Morrison, Richard S

2009-03-04

Pharmacological manipulation of protein acetylation levels by histone deacetylase (HDAC) inhibitors represents a novel therapeutic strategy to treat neurodegeneration as well as cancer. However, the molecular mechanisms that determine how HDAC inhibition exerts a protective effect in neurons as opposed to a cytotoxic action in tumor cells has not been elucidated. We addressed this issue in cultured postnatal mouse cortical neurons whose p53-dependent and p53-independent intrinsic apoptotic programs require the proapoptotic multidomain protein, Bax. Despite promoting nuclear p53 accumulation, Class I/II HDAC inhibitors (HDACIs) protected neurons from p53-dependent cell death induced by camptothecin, etoposide, heterologous p53 expression or the MDM2 inhibitor, nutlin-3a. HDACIs suppressed p53-dependent PUMA expression, a critical signaling intermediate linking p53 to Bax activation, thus preventing postmitochondrial events including cleavage of caspase-9 and caspase-3. In human SH-SY5Y neuroblastoma cells, however, HDACIs were not able to prevent p53-dependent cell death. Moreover, HDACIs also prevented caspase-3 cleavage in postnatal cortical neurons treated with staurosporine, 3-nitropropionic acid and a Bcl-2 inhibitor, all of which require the presence of Bax but not p53 to promote apoptosis. Although these three toxic agents displayed a requirement for Bax, they did not promote PUMA induction. These results demonstrate that HDACIs block Bax-dependent cell death by two distinct mechanisms to prevent neuronal apoptosis, thus identifying for the first time a defined molecular target for their neuroprotective actions.

Histone Deacetylase Inhibitors Prevent p53-dependent and Independent Bax-Mediated Neuronal Apoptosis Through Two Distinct Mechanisms

PubMed Central

Uo, Takuma; Veenstra, Timothy D.; Morrison, Richard S.

2009-01-01

Pharmacological manipulation of protein acetylation levels by histone deacetylase (HDAC) inhibitors represents a novel therapeutic strategy to treat neurodegeneration as well as cancer. However, the molecular mechanisms that determine how HDAC inhibition exerts a protective effect in neurons as opposed to a cytotoxic action in tumor cells has not been elucidated. We addressed this issue in cultured postnatal mouse cortical neurons whose p53-dependent and —independent intrinsic apoptotic programs require the pro-apoptotic multidomain protein, Bax. Despite promoting nuclear p53 accumulation, Class I/II HDAC inhibitors (HDACIs) protected neurons from p53-dependent cell death induced by camptothecin, etoposide, heterologous p53 expression or the MDM2 inhibitor, nutlin-3a. HDACIs suppressed p53-dependent PUMA expression, a critical signaling intermediate linking p53 to Bax activation, thus preventing post-mitochondrial events including cleavage of caspase-9 and -3. In human SH-SY5Y neuroblastoma cells, however, HDACIs were not able to prevent p53-dependent cell death. Moreover, HDACIs also prevented caspase-3 cleavage in postnatal cortical neurons treated with staurosporine, 3-nitropropionic acid and a Bcl-2 inhibitor, all of which require the presence of Bax but not p53 to promote apoptosis. Although these three toxic agents displayed a requirement for Bax, they did not promote PUMA induction. These results demonstrate that HDACIs block Bax-dependent cell death by two distinct mechanisms to prevent neuronal apoptosis, thus identifying for the first time a defined molecular target for their neuroprotective actions. PMID:19261878

The role of MAC1 in diesel exhaust particle-induced microglial activation and loss of dopaminergic neuron function.

PubMed

Levesque, Shannon; Taetzsch, Thomas; Lull, Melinda E; Johnson, Jo Anne; McGraw, Constance; Block, Michelle L

2013-06-01

Increasing reports support that air pollution causes neuroinflammation and is linked to central nervous system (CNS) disease/damage. Diesel exhaust particles (DEP) are a major component of urban air pollution, which has been linked to microglial activation and Parkinson's disease-like pathology. To begin to address how DEP may exert CNS effects, microglia and neuron-glia cultures were treated with either nanometer-sized DEP (< 0.22 μM; 50 μg/mL), ultrafine carbon black (ufCB, 50 μg/mL), or DEP extracts (eDEP; from 50 μg/mL DEP), and the effect of microglial activation and dopaminergic (DA) neuron function was assessed. All three treatments showed enhanced ameboid microglia morphology, increased H2 O2 production, and decreased DA uptake. Mechanistic inquiry revealed that the scavenger receptor inhibitor fucoidan blocked DEP internalization in microglia, but failed to alter DEP-induced H2 O2 production in microglia. However, pre-treatment with the MAC1/CD11b inhibitor antibody blocked microglial H2 O2 production in response to DEP. MAC1(-/-) mesencephalic neuron-glia cultures were protected from DEP-induced loss of DA neuron function, as measured by DA uptake. These findings support that DEP may activate microglia through multiple mechanisms, where scavenger receptors regulate internalization of DEP and the MAC1 receptor is mandatory for both DEP-induced microglial H2 O2 production and loss of DA neuron function. © 2013 International Society for Neurochemistry.

On-demand activation of the endocannabinoid system in the control of neuronal excitability and epileptiform seizures.

PubMed

Lutz, Beat

2004-11-01

Neurons intensively exchange information among each other using both inhibitory and excitatory neurotransmitters. However, if the balance of excitation and inhibition is perturbed, the intensity of excitatory transmission may exceed a certain threshold and epileptic seizures can occur. As the occurrence of epilepsy in the human population is about 1%, the search for therapeutic targets to alleviate seizures is warranted. Extracts of Cannabis sativa have a long history in the treatment of various neurological diseases, including epilepsy. However, cannabinoids have been reported to exert both pro- and anti-convulsive activities. The recent progress in understanding the endogenous cannabinoid system has allowed new insights into these opposing effects of cannabinoids. When excessive neuronal activity occurs, endocannabinoids are generated on demand and activate cannabinoid type 1 (CB1) receptors. Using mice lacking CB1 receptors in principal forebrain neurons in a model of epileptiform seizures, it was shown that CB1 receptors expressed on excitatory glutamatergic neurons mediate the anti-convulsive activity of endocannabinoids. Systemic activation of CB1 receptors by exogenous cannabinoids, however, are anti- or pro-convulsive, depending on the seizure model used. The pro-convulsive activity of exogenous cannabinoids might be explained by the notion that CB1 receptors expressed on inhibitory GABAergic neurons are also activated, leading to a decreased release of GABA, and to a concomitant increase in seizure susceptibility. The concept that the endogenous cannabinoid system is activated on demand suggests that a promising strategy to alleviate seizure frequency is the enhancement of endocannabinoid levels by inhibiting the cellular uptake and the degradation of these endogenous compounds.

The Kv7/KCNQ channel blocker XE991 protects nigral dopaminergic neurons in the 6-hydroxydopamine rat model of Parkinson's disease.

PubMed

Liu, Haixia; Jia, Lu; Chen, Xiaoyan; Shi, Limin; Xie, Junxia

2018-03-01

The excitability of dopaminergic neurons in the substantia nigra pars compacta (SNc) that supply the striatum with dopamine (DA) determines the function of the nigrostriatal system for motor coordination. We previously showed that 4-pyridinylmethyl-9(10H)-anthracenone (XE991), a specific blocker of Kv7/KCNQ channels, enhanced the excitability of nigral DA neurons and resulted in attenuation of haloperidol-induced catalepsy in a Parkinson's disease (PD) rat model. However, whether XE991 exhibits neuroprotective effects towards DA neuron degeneration remains unknown. The aim of this study was to investigate the effects of Kv7/KCNQ channel blocker, XE991, on 6-hydroxydopamine (6-OHDA)-induced nigral DA neuron degeneration and motor dysfunction. Using immunofluorescence staining and western blotting, we showed that intracerebroventricular administration of XE991 prevented the 6-OHDA-induced decrease in tyrosine hydroxylase (TH)-positive neurons and TH protein expression in the SNc. High-performance liquid chromatography with electrochemical detection (HPLC-ECD) also revealed that XE991 partly restored the levels of DA and its metabolites in the striatum. Moreover, XE991 decreased apomorphine (APO)-induced contralateral rotations, enhanced balance and coordination, and attenuated muscle rigidity in 6-OHDA-treated rats. Importantly, all neuroprotective effects by XE991 were abolished by co-application of Kv7/KCNQ channel opener retigabine and XE991. Thus, Kv7/KCNQ channel inhibition by XE991 can exert neuroprotective effects against 6-OHDA-induced degeneration of the nigrostriatal DA system and motor dysfunction. Copyright © 2017. Published by Elsevier Inc.

Leptin induces proliferation of neuronal progenitors and neuroprotection in a mouse model of Alzheimer's disease.

PubMed

Pérez-González, Rocío; Antequera, Desiree; Vargas, Teo; Spuch, Carlos; Bolós, Marta; Carro, Eva

2011-01-01

Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with senile amyloid-β (Aβ) plaques, neuronal death, and cognitive decline. Neurogenesis in the adult hippocampus, which is notably affected by progressive neurodegeneration and Aβ pathology, is implicated in learning and memory regulation. Human postmortem brains of AD patients and AβPP/PS1 double transgenic mice show increased neurodegeneration. Leptin, an adipose-derived hormone, promotes neurogenesis in the adult hippocampus, but the way in which this process occurs in the AD brain is still unknown. Thus, we sought to determine if leptin stimulated the proliferation of neuronal precursors in AβPP/PS1 mice. We estimated the number proliferating hippocampal cells after intracerebroventricular administration of a lentiviral vector encoding leptin. After 3 months of treatment with leptin we observed an increase in the number of BrdU-positive cells in the subgranular zone of the dentate gyrus, as shown by morphometric analysis. This increase resulted mainly from an increased proliferation of neuronal precursors. Additionally, leptin led to an attenuation of Aβ-induced neurodegeneration, as revealed by Fluoro-Jade staining. Our results suggest that in AβPP/PS1 mice, leptin exerts changes resembling acute neurotrophic and neuroprotective effects. These effects could serve as the basis for the design of future treatment strategies in AD.

Intrinsic and Extrinsic Neuromodulation of Olfactory Processing.

PubMed

Lizbinski, Kristyn M; Dacks, Andrew M

2017-01-01

Neuromodulation is a ubiquitous feature of neural systems, allowing flexible, context specific control over network dynamics. Neuromodulation was first described in invertebrate motor systems and early work established a basic dichotomy for neuromodulation as having either an intrinsic origin (i.e., neurons that participate in network coding) or an extrinsic origin (i.e., neurons from independent networks). In this conceptual dichotomy, intrinsic sources of neuromodulation provide a "memory" by adjusting network dynamics based upon previous and ongoing activation of the network itself, while extrinsic neuromodulators provide the context of ongoing activity of other neural networks. Although this dichotomy has been thoroughly considered in motor systems, it has received far less attention in sensory systems. In this review, we discuss intrinsic and extrinsic modulation in the context of olfactory processing in invertebrate and vertebrate model systems. We begin by discussing presynaptic modulation of olfactory sensory neurons by local interneurons (LNs) as a mechanism for gain control based on ongoing network activation. We then discuss the cell-class specific effects of serotonergic centrifugal neurons on olfactory processing. Finally, we briefly discuss the integration of intrinsic and extrinsic neuromodulation (metamodulation) as an effective mechanism for exerting global control over olfactory network dynamics. The heterogeneous nature of neuromodulation is a recurring theme throughout this review as the effects of both intrinsic and extrinsic modulation are generally non-uniform.

Depression of neuronal excitability and epileptic activities by group II metabotropic glutamate receptors in the medial entorhinal cortex.

PubMed

Zhang, Haopeng; Cilz, Nicholas I; Yang, Chuanxiu; Hu, Binqi; Dong, Hailong; Lei, Saobo

2015-11-01

Whereas the ionotropic glutamate receptors are the major mediator in glutamatergic transmission, the metabotropic glutamate receptors (mGluRs) usually play a modulatory role. Whereas the entorhinal cortex (EC) is an essential structure involved in the generation and propagation of epilepsy, the roles and mechanisms of mGluRs in epilepsy in the EC have not been determined. Here, we studied the effects of activation of group II metabotropic glutamate receptors (mGluRs II) on epileptiform activity induced by picrotoxin or deprivation of extracellular Mg2+ and neuronal excitability in the medial EC. We found that activation of mGluRs II by application of the selective agonist, LY354740, exerted robust inhibition on epileptiform activity. LY354740 hyperpolarized entorhinal neurons via activation of a K+ conductance and inhibition of a Na+ -permeable channel. LY354740-induced hyperpolarization was G protein-dependent, but independent of adenylyl cyclase and protein kinase A. However, the function of Gβγ was involved in mGluRs II-mediated depression of both neuronal excitability and epileptiform activity. Our results provide a novel cellular mechanism to explain the antiepileptic effects of mGluRs II in the treatment of epilepsy. © 2015 Wiley Periodicals, Inc.

Competition model for aperiodic stochastic resonance in a Fitzhugh-Nagumo model of cardiac sensory neurons.

PubMed

Kember, G C; Fenton, G A; Armour, J A; Kalyaniwalla, N

2001-04-01

Regional cardiac control depends upon feedback of the status of the heart from afferent neurons responding to chemical and mechanical stimuli as transduced by an array of sensory neurites. Emerging experimental evidence shows that neural control in the heart may be partially exerted using subthreshold inputs that are amplified by noisy mechanical fluctuations. This amplification is known as aperiodic stochastic resonance (ASR). Neural control in the noisy, subthreshold regime is difficult to see since there is a near absence of any correlation between input and the output, the latter being the average firing (spiking) rate of the neuron. This lack of correlation is unresolved by traditional energy models of ASR since these models are unsuitable for identifying "cause and effect" between such inputs and outputs. In this paper, the "competition between averages" model is used to determine what portion of a noisy, subthreshold input is responsible, on average, for the output of sensory neurons as represented by the Fitzhugh-Nagumo equations. A physiologically relevant conclusion of this analysis is that a nearly constant amount of input is responsible for a spike, on average, and this amount is approximately independent of the firing rate. Hence, correlation measures are generally reduced as the firing rate is lowered even though neural control under this model is actually unaffected.

Tau Deficiency Down-Regulated Transcription Factor Orthodenticle Homeobox 2 Expression in the Dopaminergic Neurons in Ventral Tegmental Area and Caused No Obvious Motor Deficits in Mice

PubMed Central

Tang, Xiaolu; Jiao, Luyan; Zheng, Meige; Yan, Yan; Nie, Qi; Wu, Ting; Wan, Xiaomei; Zhang, Guofeng; Li, Yonglin; Wu, Song; Jiang, Bin; Cai, Huaibin; Xu, Pingyi; Duan, Jinhai; Lin, Xian

2018-01-01

Tau protein participates in microtubule stabilization, axonal transport, and protein trafficking. Loss of normal tau function will exert a negative effect. However, current knowledge on the impact of tau deficiency on the motor behavior and related neurobiological changes is controversial. In this study, we examined motor functions and analyzed several proteins implicated in the maintenance of midbrain dopaminergic (DA) neurons (mDANs) function of adult and aged tau+/+, tau+/−, tau−/− mice. We found tau deficiency could not induce significant motor disorders. However, we discovered lower expression levels of transcription factors Orthodenticle homeobox 2 (OTX2) of mDANs in older aged mice. Compared with age-matched tau+/+ mice, there were 54.1% lower (p = 0.0192) OTX2 protein (OTX2-fluorescence intensity) in VTA DA neurons of tau+/−mice and 43.6% lower (p = 0.0249) OTX2 protein in VTA DA neurons of tau−/−mice at 18 months old. Combined with the relevant reports, our results suggested that tau deficiency alone might not be enough to mimic the pathology of Parkinson’s disease. However, OTX2 down-regulation indicates that mDANs of tau-deficient mice will be more sensitive to toxic damage from MPTP. PMID:29337233

Direct inhibition of retinoic acid catabolism by fluoxetine.

PubMed

Hellmann-Regen, Julian; Uhlemann, Ria; Regen, Francesca; Heuser, Isabella; Otte, Christian; Endres, Matthias; Gertz, Karen; Kronenberg, Golo

2015-09-01

Recent evidence from animal and human studies suggests neuroprotective effects of the SSRI fluoxetine, e.g., in the aftermath of stroke. The underlying molecular mechanisms remain to be fully defined. Because of its effects on the cytochrome P450 system (CYP450), we hypothesized that neuroprotection by fluoxetine is related to altered metabolism of retinoic acid (RA), whose CYP450-mediated degradation in brain tissue constitutes an important step in the regulation of its site-specific auto- and paracrine actions. Using traditional pharmacological in vitro assays, the effects of fluoxetine on RA degradation were probed in crude synaptosomes from rat brain and human-derived SH-SY5Y cells, and in cultures of neuron-like SH-SY5Y cells. Furthermore, retinoid-dependent effects of fluoxetine on neuronal survival following glutamate exposure were investigated in rat primary neurons cells using specific retinoid receptor antagonists. Experiments revealed dose-dependent inhibition of synaptosomal RA degradation by fluoxetine along with dose-dependent increases in RA levels in cell cultures. Furthermore, fluoxetine's neuroprotective effects against glutamate excitotoxicity in rat primary neurons were demonstrated to partially depend on RA signaling. Taken together, these findings demonstrate for the first time that the potent, pleiotropic antidepressant fluoxetine directly interacts with RA homeostasis in brain tissue, thereby exerting its neuroprotective effects.

Arctigenin reduces neuronal responses in the somatosensory cortex via the inhibition of non-NMDA glutamate receptors.

PubMed

Borbély, Sándor; Jócsák, Gergely; Moldován, Kinga; Sedlák, Éva; Preininger, Éva; Boldizsár, Imre; Tóth, Attila; Atlason, Palmi T; Molnár, Elek; Világi, Ildikó

2016-07-01

Lignans are biologically active phenolic compounds related to lignin, produced in different plants. Arctigenin, a dibenzylbutyrolactone-type lignan, has been used as a neuroprotective agent for the treatment of encephalitis. Previous studies of cultured rat cerebral cortical neurones raised the possibility that arctigenin inhibits kainate-induced excitotoxicity. The aims of the present study were: 1) to analyse the effect of arctigenin on normal synaptic activity in ex vivo brain slices, 2) to determine its receptor binding properties and test the effect of arctigenin on AMPA/kainate receptor activation and 3) to establish its effects on neuronal activity in vivo. Arctigenin inhibited glutamatergic transmission and reduced the evoked field responses. The inhibitory effect of arctigenin on the evoked field responses proved to be substantially dose dependent. Our results indicate that arctigenin exerts its effects under physiological conditions and not only on hyper-excited neurons. Furthermore, arctigenin can cross the blood-brain barrier and in the brain it interacts with kainate sensitive ionotropic glutamate receptors. These results indicate that arctigenin is a potentially useful new pharmacological tool for the inhibition of glutamate-evoked responses in the central nervous system in vivo. Copyright © 2016 Elsevier Ltd. All rights reserved.

Structure and inhibition analysis of the mouse SAD-B C-terminal fragment.

PubMed

Ma, Hui; Wu, Jing-Xiang; Wang, Jue; Wang, Zhi-Xin; Wu, Jia-Wei

2016-10-01

The SAD (synapses of amphids defective) kinases, including SAD-A and SAD-B, play important roles in the regulation of neuronal development, cell cycle, and energy metabolism. Our recent study of mouse SAD-A identified a unique autoinhibitory sequence (AIS), which binds at the junction of the kinase domain (KD) and the ubiquitin-associated (UBA) domain and exerts autoregulation in cooperation with UBA. Here, we report the crystal structure of the mouse SAD-B C-terminal fragment including the AIS and the kinase-associated domain 1 (KA1) at 2.8 Å resolution. The KA1 domain is structurally conserved, while the isolated AIS sequence is highly flexible and solvent-accessible. Our biochemical studies indicated that the SAD-B AIS exerts the same autoinhibitory role as that in SAD-A. We believe that the flexible isolated AIS sequence is readily available for interaction with KD-UBA and thus inhibits SAD-B activity.

The CRF Family of Neuropeptides and their Receptors - Mediators of the Central Stress Response

PubMed Central

Dedic, Nina; Chen, Alon; Deussing, Jan M.

2018-01-01

Background: Dysregulated stress neurocircuits, caused by genetic and/or environmental changes, underlie the development of many neuropsychiatric disorders. Corticotropin-releasing factor (CRF) is the major physiological activator of the hypothalamic-pituitary-adrenal (HPA) axis and conse-quently a primary regulator of the mammalian stress response. Together with its three family members, urocortins (UCNs) 1, 2, and 3, CRF integrates the neuroendocrine, autonomic, metabolic and behavioral responses to stress by activating its cognate receptors CRFR1 and CRFR2. Objective: Here we review the past and current state of the CRF/CRFR field, ranging from pharmacologi-cal studies to genetic mouse models and virus-mediated manipulations. Results: Although it is well established that CRF/CRFR1 signaling mediates aversive responses, includ-ing anxiety and depression-like behaviors, a number of recent studies have challenged this viewpoint by revealing anxiolytic and appetitive properties of specific CRF/CRFR1 circuits. In contrast, the UCN/CRFR2 system is less well understood and may possibly also exert divergent functions on physiol-ogy and behavior depending on the brain region, underlying circuit, and/or experienced stress conditions. Conclusion: A plethora of available genetic tools, including conventional and conditional mouse mutants targeting CRF system components, has greatly advanced our understanding about the endogenous mecha-nisms underlying HPA system regulation and CRF/UCN-related neuronal circuits involved in stress-related behaviors. Yet, the detailed pathways and molecular mechanisms by which the CRF/UCN-system translates negative or positive stimuli into the final, integrated biological response are not completely un-derstood. The utilization of future complementary methodologies, such as cell-type specific Cre-driver lines, viral and optogenetic tools will help to further dissect the function of genetically defined CRF/UCN neurocircuits in the context of adaptive and maladaptive stress responses. PMID:28260504

Mirtazapine exerts an anxiolytic-like effect through activation of the median raphe nucleus-dorsal hippocampal 5-HT pathway in contextual fear conditioning in rats.

PubMed

An, Yan; Chen, Chong; Inoue, Takeshi; Nakagawa, Shin; Kitaichi, Yuji; Wang, Ce; Izumi, Takeshi; Kusumi, Ichiro

2016-10-03

The functional role of serotonergic projections from the median raphe nucleus (MRN) to the dorsal hippocampus (DH) in anxiety remains understood poorly. The purpose of the present research was to examine the functional role of this pathway, using the contextual fear conditioning (CFC) model of anxiety. We show that intra-MRN microinjection of mirtazapine, a noradrenergic and specific serotonergic antidepressant, reduced freezing in CFC without affecting general motor activity dose-dependently, suggesting an anxiolytic-like effect. In addition, intra-MRN microinjection of mirtazapine dose-dependently increased extracellular concentrations of serotonin (5-HT) but not dopamine in the DH. Importantly, intra-DH pre-microinjection of WAY-100635, a 5-HT1A antagonist, significantly attenuated the effect of mirtazapine on freezing. These results, for the first time, suggest that activation of the MRN-DH 5-HT1A pathway exerts an anxiolytic-like effect in CFC. This is consistent with the literature that the hippocampus is essential for retrieval of contextual memory and that 5-HT1A receptor activation in the hippocampus primarily exerts an inhibitory effect on the neuronal activity. Copyright © 2016 Elsevier Inc. All rights reserved.

Biphasic effects of substance P on respiratory activity and respiration-related neurones in ventrolateral medulla in the neonatal rat brainstem in vitro.

PubMed

Shvarev, Y N; Lagercrantz, H; Yamamoto, Y

2002-01-01

The effects of substance P (SP) on respiratory activity in the brainstem-spinal cord preparation from neonatal rats (0-4 days old) were investigated. The respiratory activity was recorded from C4 ventral roots and intracellularly from three types of respiration-related neurones, i.e. pre-inspiratory (or biphasic E), three subtypes of inspiratory; expiratory and tonic neurones in the ventrolateral medulla (VLM). After the onset of SP bath application (10 nM-1 microM) a dose-dependent decline of burst rate (by 48%) occurred, followed by a weaker dose-dependent increase (by 17.5%) in burst rate. The biphasic effect of SP on inspiratory burst rate was associated with sustained membrane depolarization (in a range of 0.5-13 mV) of respiration-related and tonic neurones. There were no significant changes in membrane resistance in any type of neurones when SP was applied alone or when synaptic transmission was blocked with tetrodotoxin (TTX). The initial depolarization was associated with an increase in inspiratory drive potential (by 25%) as well as in bursting time (by 65%) and membrane excitability in inspiratory and pre-inspiratory neurones, which corresponded to the decrease in burst rate (C4 activity). The spiking frequency of expiratory and tonic neurones was also increased (by 36 and 48%). This activation was followed by restoration of the synaptic drive potential and bursting time in inspiratory and to a less extent in pre-inspiratory neurones, which corresponded to the increase in burst rate. The discharge frequency of expiratory and tonic neurones also decreased to control values. This phase followed the peak membrane depolarization. At the peak depolarization, SP reduced the amplitude of the action potential by 4-8% in all types of neurones. Our results suggest that SP exerts a general excitatory effect on respiration-related neurones and synaptic coupling within the respiratory network in the VLM. The transient changes in neuronal activity in the VLM may underlie the biphasic effect of SP in the brainstem respiration activity recorded in C4 roots. However, the biphasic effect of SP on inspiratory burst rate seems to be also defined by the balance in activity of other SP-sensitive systems and neurones in the respiratory network in the brainstem and spinal cord, which can modify the activity of medullary respiratory rhythm generator.

Autonomic control of the eye

PubMed Central

McDougal, David H.; Gamlin, Paul D.

2016-01-01

The autonomic nervous system influences numerous ocular functions. It does this by way of parasympathetic innervation from postganglionic fibers that originate from neurons in the ciliary and pterygopalatine ganglia, and by way of sympathetic innervation from postganglionic fibers that originate from neurons in the superior cervical ganglion. Ciliary ganglion neurons project to the ciliary body and the sphincter pupillae muscle of the iris to control ocular accommodation and pupil constriction, respectively. Superior cervical ganglion neurons project to the dilator pupillae muscle of the iris to control pupil dilation. Ocular blood flow is controlled both via direct autonomic influences on the vasculature of the optic nerve, choroid, ciliary body, and iris, as well as via indirect influences on retinal blood flow. In mammals, this vasculature is innervated by vasodilatory fibers from the pterygopalatine ganglion, and by vasoconstrictive fibers from the superior cervical ganglion. Intraocular pressure is regulated primarily through the balance of aqueous humor formation and outflow. Autonomic regulation of ciliary body blood vessels and the ciliary epithelium is an important determinant of aqueous humor formation; autonomic regulation of the trabecular meshwork and episcleral blood vessels is an important determinant of aqueous humor outflow. These tissues are all innervated by fibers from the pterygopalatine and superior cervical ganglia. In addition to these classical autonomic pathways, trigeminal sensory fibers exert local, intrinsic influences on many of these regions of the eye, as well as on some neurons within the ciliary and pterygopalatine ganglia. PMID:25589275

Rac1 and Rac3 have opposing functions in cell adhesion and differentiation of neuronal cells.

PubMed

Hajdo-Milasinović, Amra; Ellenbroek, Saskia I J; van Es, Saskia; van der Vaart, Babet; Collard, John G

2007-02-15

Rac1 and Rac3 are highly homologous members of the Rho small GTPase family. Rac1 is ubiquitously expressed and regulates cell adhesion, migration and differentiation in various cell types. Rac3 is primarily expressed in brain and may therefore have a specific function in neuronal cells. We found that depletion of Rac1 by short interference RNA leads to decreased cell-matrix adhesions and cell rounding in neuronal N1E-115 cells. By contrast, depletion of Rac3 induces stronger cell adhesions and dramatically increases the outgrowth of neurite-like protrusions, suggesting opposite functions for Rac1 and Rac3 in neuronal cells. Consistent with this, overexpression of Rac1 induces cell spreading, whereas overexpression of Rac3 results in a contractile round morphology. Rac1 is mainly found at the plasma membrane, whereas Rac3 is predominantly localized in the perinuclear region. Residues 185-187, present in the variable polybasic rich region at the carboxyl terminus are responsible for the difference in phenotype induced by Rac1 and Rac3 as well as for their different intracellular localization. The Rac1-opposing function of Rac3 is not mediated by or dependent on components of the RhoA signaling pathway. It rather seems that Rac3 exerts its function through negatively affecting integrin-mediated cell-matrix adhesions. Together, our data reveal that Rac3 opposes Rac1 in the regulation of cell adhesion and differentiation of neuronal cells.

Effects of nucleosides on glia - neuron interactions open up new vistas in the development of more effective antiepileptic drugs.

PubMed

Kovacs, Zsolt; Kardos, Julianna; Kekesi, Katalin A; Juhasz, Gabor; Lakatos, Renata; Heja, Laszlo

2015-01-01

One-third of epileptic patients are drug refractory due to the limited efficacy of antiepileptic therapy. Thus, there is an immense need to find more effective, safer and well-tolerated antiepileptic drugs. A great deal of results suggests that adenosine (Ado), guanosine (Guo), inosine (Ino) or uridine (Urd) are endogenous antiepileptogenic modulators. Furthermore, nucleosides and their derivatives may be safe and effective potential drugs in the treatment of epilepsy. Conversely, nucleosidergic modulatory system implying nucleoside levels, metabolism, receptors and transporters may also be involved in seizure pathomechanisms. Application of Ado receptor agonists as well as antagonists, elevation of nucleoside levels (e.g., by nucleoside metabolism inhibitors, and Adoreleasing implants) or utilization of non-Ado nucleosides may also turn to be useful approaches to decrease epileptic activity. However, all drugs exerting their effects on the nucleosidergic modulatory system may affect the fine regulation of glia-neuron interactions that are intimately governed by various nucleosidergic processes. Perturbation of the complex, bidirectional communication between neurons and astrocytes through these nucleosidergic modulatory mechanisms may lead to pathological changes in the central nervous system (CNS) and therefore may cause significant side effects. Thus, a deeper understanding of the nucleosidergic modulatory control over glia-neuron interactions is essential in order to develop more effective and safe nucleoside-based antiepileptic drugs. In this review article we focus on the role of Ado and Urd in glia-neuron interactions, placing emphasis on their implications for the treatment of epilepsy.

Plasticity of vagal brainstem circuits in the control of gastrointestinal function

PubMed Central

Browning, Kirsteen N; Travagli, R. Alberto

2010-01-01

The afferent vagus transmits sensory information from the gastrointestinal (GI) tract and other viscera to the brainstem via a glutamatergic synapse at the level of the nucleus of the solitary tract (NTS). Second order NTS neurons integrate this sensory information with inputs from other CNS regions that regulate autonomic functions and homeostasis. Glutamatergic and GABAergic neurons are responsible for conveying the integrated response to other nuclei, including the adjacent dorsal motor nucleus of the vagus (DMV). The preganglionic neurons in the DMV are the source of the parasympathetic motor response back to the GI tract. The glutamatergic synapse between the NTS and DMV is unlikely to be tonically active in regulating gastric motility and tone although almost all neurotransmitters tested so far modulate transmission at this synapse. In contrast, the tonic inhibitory GABAergic input from the NTS to the DMV appears to be critical in setting the tone of gastric motility and, under basal conditions, is unaffected by many neurotransmitters or neurohormones. This review is based, in part, on a presentation by Dr Browning at the 2009 ISAN meeting in Sydney, Australia and discusses how neurohormones and macronutrients modulate glutamatergic transmission to NTS neurons and GABAergic transmission to DMV neurons in relation to sensory information that is received from the GI tract. These neurohormones and macronutrients appear to exert efficient “on-demand” control of the motor output from the DMV in response to ever-changing demands required to maintain homeostasis. PMID:21147043

Decreased neuronal CD200 expression in IL-4-deficient mice results in increased neuroinflammation in response to lipopolysaccharide.

PubMed

Lyons, Anthony; McQuillan, Keith; Deighan, Brian F; O'Reilly, Julie-Ann; Downer, Eric J; Murphy, Aine C; Watson, Melanie; Piazza, Alessia; O'Connell, Florence; Griffin, Rebecca; Mills, Kingston H G; Lynch, Marina A

2009-10-01

Maintenance of the balance between pro- and anti-inflammatory cytokines in the brain, which is affected by the activation state of microglia, is important for maintenance of neuronal function. Evidence has suggested that IL-4 plays an important neuromodulatory role and has the ability to decrease lipopolysaccharide-induced microglial activation and the production of IL-1beta. We have also demonstrated that CD200-CD200R interaction is involved in immune homeostasis in the brain. Here, we investigated the anti-inflammatory role of IL-4 and, using in vitro and in vivo analysis, established that the effect of lipopolysaccharide was more profound in IL-4(-/-), compared with wildtype, mice. Intraperitoneal injection of lipopolysaccharide exerted a greater inhibitory effect on exploratory behaviour in IL-4(-/-), compared with wildtype, mice and this was associated with evidence of microglial activation. We demonstrate that the increase in microglial activation is inversely related to CD200 expression. Furthermore, CD200 was decreased in neurons prepared from IL-4(-/-) mice, whereas stimulation with IL-4 enhanced CD200 expression. Importantly, neurons prepared from wildtype, but not from IL-4(-/-), mice attenuated the lipopolysaccharide-induced increase in pro-inflammatory cytokine production by glia. These findings suggest that the neuromodulatory effect of IL-4, and in particular its capacity to maintain microglia in a quiescent state, may result from its ability to upregulate CD200 expression on neurons.

E-p-Methoxycinnamic acid protects cultured neuronal cells against neurotoxicity induced by glutamate

PubMed Central

Kim, So Ra; Sung, Sang Hyun; Jang, Young Pyo; Markelonis, George J; Oh, Tae H; Kim, Young Choong

2002-01-01

We previously reported that four new phenylpropanoid glycosides and six known cinnamate derivatives isolated from roots of Scrophularia buergeriana Miquel (Scrophulariaceae) protected cultured cortical neurons from neurotoxicity induced by glutamate. Here, we have investigated the structure-activity relationships in the phenylpropanoids using our primary culture system. The α,β-unsaturated ester moiety and the para-methoxy group in the phenylpropanoids appeared to play a vital role in neuroprotective activity. This suggested that E-p-methoxycinnamic acid (E-p-MCA) might be a crucial component for their neuroprotective activity within the phenylpropanoid compounds. E-p-MCA significantly attenuated glutamate-induced neurotoxicity when added prior to an excitotoxic glutamate challenge. The neuroprotective activity of E-p-MCA appeared to be more effective in protecting neurons against neurotoxicity induced by NMDA than from that induced by kainic acid. E-p-MCA inhibited the binding of [propyl-2,3-3H]-CGP39653 and [2-3H]-glycine to their respective binding sites on rat cortical membranes. However, even high concentrations of E-p-MCA failed to inhibit completely [propyl-2,3-3H]-CGP39653 and [2-3H]-glycine binding. Indeed, E-p-MCA diminished the calcium influx that routinely accompanies glutamate-induced neurotoxicity, and inhibited the subsequent overproduction of nitric oxide and cellular peroxide in glutamate-injured neurons. Thus, our results suggest that E-p-MCA exerts significant protective effects against neurodegeneration induced by glutamate in primary cultures of cortical neurons by an action suggestive of partial glutamatergic antagonism. PMID:11877337

Tau Deletion Prevents Stress-Induced Dendritic Atrophy in Prefrontal Cortex: Role of Synaptic Mitochondria.

PubMed

Lopes, Sofia; Teplytska, Larysa; Vaz-Silva, Joao; Dioli, Chrysoula; Trindade, Rita; Morais, Monica; Webhofer, Christian; Maccarrone, Giuseppina; Almeida, Osborne F X; Turck, Christoph W; Sousa, Nuno; Sotiropoulos, Ioannis; Filiou, Michaela D

2017-04-01

Tau protein in dendrites and synapses has been recently implicated in synaptic degeneration and neuronal malfunction. Chronic stress, a well-known inducer of neuronal/synaptic atrophy, triggers hyperphosphorylation of Tau protein and cognitive deficits. However, the cause-effect relationship between these events remains to be established. To test the involvement of Tau in stress-induced impairments of cognition, we investigated the impact of stress on cognitive behavior, neuronal structure, and the synaptic proteome in the prefrontal cortex (PFC) of Tau knock-out (Tau-KO) and wild-type (WT) mice. Whereas exposure to chronic stress resulted in atrophy of apical dendrites and spine loss in PFC neurons as well as significant impairments in working memory in WT mice, such changes were absent in Tau-KO animals. Quantitative proteomic analysis of PFC synaptosomal fractions, combined with transmission electron microscopy analysis, suggested a prominent role for mitochondria in the regulation of the effects of stress. Specifically, chronically stressed animals exhibit Tau-dependent alterations in the levels of proteins involved in mitochondrial transport and oxidative phosphorylation as well as in the synaptic localization of mitochondria in PFC. These findings provide evidence for a causal role of Tau in mediating stress-elicited neuronal atrophy and cognitive impairment and indicate that Tau may exert its effects through synaptic mitochondria. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Pre- and postsynaptic type-1 cannabinoid receptors control the alterations of glutamate transmission in experimental autoimmune encephalomyelitis.

PubMed

Musella, Alessandra; Sepman, Helena; Mandolesi, Georgia; Gentile, Antonietta; Fresegna, Diego; Haji, Nabila; Conrad, Andrea; Lutz, Beat; Maccarrone, Mauro; Centonze, Diego

2014-04-01

Type-1 cannabinoid receptors (CB1R) are important regulators of the neurodegenerative damage in multiple sclerosis (MS) and in experimental autoimmune encephalomyelitis (EAE). In GABAergic striatal neurons, CB1R stimulation exerts protective effects by limiting inflammation-induced potentiation of glutamate-mediated spontaneous excitatory postsynaptic currents (sEPSCs). Here we show that CB1R located on GABAergic or on glutamatergic neurons are differentially involved in the pre- and postsynaptic alterations of sEPSCs caused by EAE in the striatum. After induction of EAE, mice selectively lacking CB1R on GABAergic neurons (GABA-CB1R-KO) showed exacerbated alterations of sEPSC duration in GABAergic medium spiny neurons (MSN). On the other hand, EAE-induced alterations of corticostriatal sEPSC frequency were exacerbated only in mice lacking CB1R on glutamatergic neurons (Glu-CB1R-KO), indicating that this subset of receptors controls the effects of inflammation on glutamate release. While EAE severity was enhanced in whole CB1R-KO mice, GABA-CB1R-KO and Glu-CB1R-KO mice had similar motor deficits as the respective wild-type (WT) counterparts. Our results provide further evidence that CB1R are involved in EAE pathophysiology, and suggest that both pre- and postsynaptic alterations of glutamate transmission are important to drive excitotoxic neurodegeneration typical of this disorder. Copyright © 2014 Elsevier Ltd. All rights reserved.

Nuclear respiratory factor 2 regulates the expression of the same NMDA receptor subunit genes as NRF-1: both factors act by a concurrent and parallel mechanism to couple energy metabolism and synaptic transmission.

PubMed

Priya, Anusha; Johar, Kaid; Wong-Riley, Margaret T T

2013-01-01

Neuronal activity and energy metabolism are tightly coupled processes. Previously, we found that nuclear respiratory factor 1 (NRF-1) transcriptionally co-regulates energy metabolism and neuronal activity by regulating all 13 subunits of the critical energy generating enzyme, cytochrome c oxidase (COX), as well as N-methyl-d-aspartate (NMDA) receptor subunits 1 and 2B, GluN1 (Grin1) and GluN2B (Grin2b). We also found that another transcription factor, nuclear respiratory factor 2 (NRF-2 or GA-binding protein) regulates all subunits of COX as well. The goal of the present study was to test our hypothesis that NRF-2 also regulates specific subunits of NMDA receptors, and that it functions with NRF-1 via one of three mechanisms: complementary, concurrent and parallel, or a combination of complementary and concurrent/parallel. By means of multiple approaches, including in silico analysis, electrophoretic mobility shift and supershift assays, in vivo chromatin immunoprecipitation of mouse neuroblastoma cells and rat visual cortical tissue, promoter mutations, real-time quantitative PCR, and western blot analysis, NRF-2 was found to functionally regulate Grin1 and Grin2b genes, but not any other NMDA subunit genes. Grin1 and Grin2b transcripts were up-regulated by depolarizing KCl, but silencing of NRF-2 prevented this up-regulation. On the other hand, over-expression of NRF-2 rescued the down-regulation of these subunits by the impulse blocker TTX. NRF-2 binding sites on Grin1 and Grin2b are conserved among species. Our data indicate that NRF-2 and NRF-1 operate in a concurrent and parallel manner in mediating the tight coupling between energy metabolism and neuronal activity at the molecular level. Copyright © 2012 Elsevier B.V. All rights reserved.

Adrenoceptor-Mediated Post- and Pre-Synaptic Regulations of the Reticulospinal Neurons in Rat Caudal Pontine Reticular Nucleus.

PubMed

Yang, Nian; Qiao, Qi-Cheng; Liu, Yu-Hui; Zhang, Ji-Qiang; Hu, Zhi-An; Zhang, Jun

2016-12-01

The central noradrenergic system participates in diverse nervous functions. Nevertheless, our knowledge of the action of adrenoceptors in motor regulation is still lacking. Intriguingly, reticulospinal neurons in the caudal pontine reticular nucleus (PnC) receive fairly dense noradrenergic innervation and play an important role in motor control. Here, after demonstrating the expression of α1- and α2-adrenoceptors in the PnC, we found that noradrenaline elicited a post-synaptic effect (inward or outward whole-cell current at -70 mV holding) on PnC reticulospinal neurons. The α1- and α2-adrenoceptors were co-expressed in individual PnC reticulospinal neurons to mediate an inward and an outward current component at -70 mV holding, respectively, which, when superposed, produced the overall post-synaptic effects of noradrenaline (NA). More importantly, the activation of post-synaptic α1- or α2-adrenoceptors indeed exerted opposing modulations (excitation vs. inhibition) on the firing activities of individual PnC reticulospinal neurons. Furthermore, the activation and inhibition of the Na + -permeable non-selective cationic conductance (NSCC) were demonstrated to be coupled to α1- and α2-adrenoceptors, respectively. Additionally, the activation of α2-adrenoceptors activated K + conductance. Pre-synaptically, the α2-adrenoceptors were expressed to attenuate the miniature excitatory postsynaptic current (mEPSC) in PnC reticulospinal neurons, but not to affect the miniature inhibitory postsynaptic current (mIPSC). Consistently, the evoked EPSC in PnC reticulospinal neurons was suppressed after the activation of pre-synaptic α2-adrenoceptors. Thus, the excitatory input and post-synaptic dynamics of PnC reticulospinal neurons are indeed intricately modulated by the activation of α1- and α2-adrenoceptors, through which motor control may be regulated in an adaptive manner by the central noradrenergic system.

The Multifaceted Effects of Agmatine on Functional Recovery after Spinal Cord Injury through Modulations of BMP-2/4/7 Expressions in Neurons and Glial Cells

PubMed Central

Park, Yu Mi; Lee, Won Taek; Bokara, Kiran Kumar; Seo, Su Kyoung; Park, Seung Hwa; Kim, Jae Hwan; Yenari, Midori A.; Park, Kyung Ah; Lee, Jong Eun

2013-01-01

Presently, few treatments for spinal cord injury (SCI) are available and none have facilitated neural regeneration and/or significant functional improvement. Agmatine (Agm), a guanidinium compound formed from decarboxylation of L-arginine by arginine decarboxylase, is a neurotransmitter/neuromodulator and been reported to exert neuroprotective effects in central nervous system injury models including SCI. The purpose of this study was to demonstrate the multifaceted effects of Agm on functional recovery and remyelinating events following SCI. Compression SCI in mice was produced by placing a 15 g/mm2 weight for 1 min at thoracic vertebra (Th) 9 segment. Mice that received an intraperitoneal (i.p.) injection of Agm (100 mg/kg/day) within 1 hour after SCI until 35 days showed improvement in locomotor recovery and bladder function. Emphasis was made on the analysis of remyelination events, neuronal cell preservation and ablation of glial scar area following SCI. Agm treatment significantly inhibited the demyelination events, neuronal loss and glial scar around the lesion site. In light of recent findings that expressions of bone morphogenetic proteins (BMPs) are modulated in the neuronal and glial cell population after SCI, we hypothesized whether Agm could modulate BMP- 2/4/7 expressions in neurons, astrocytes, oligodendrocytes and play key role in promoting the neuronal and glial cell survival in the injured spinal cord. The results from computer assisted stereological toolbox analysis (CAST) demonstrate that Agm treatment dramatically increased BMP- 2/7 expressions in neurons and oligodendrocytes. On the other hand, BMP- 4 expressions were significantly decreased in astrocytes and oligodendrocytes around the lesion site. Together, our results reveal that Agm treatment improved neurological and histological outcomes, induced oligodendrogenesis, protected neurons, and decreased glial scar formation through modulating the BMP- 2/4/7 expressions following SCI. PMID:23349763

Neuroprotective and antioxidant activities of bamboo salt soy sauce against H2O2-induced oxidative stress in rat cortical neurons.

PubMed

Jeong, Jong Hee; Noh, Min-Young; Choi, Jae-Hyeok; Lee, Haiwon; Kim, Seung Hyun

2016-04-01

Bamboo salt (BS) and soy sauce (SS) are traditional foods in Asia, which contain antioxidants that have cytoprotective effects on the body. The majority of SS products contain high levels of common salt, consumption of which has been associated with numerous detrimental effects on the body. However, BS may be considered a healthier substitute to common salt. The present study hypothesized that SS made from BS, known as bamboo salt soy sauce (BSSS), may possess enhanced cytoprotective properties; this was evaluated using a hydrogen peroxide (H 2 O 2 )-induced neuronal cell death rat model. Rat neuronal cells were pretreated with various concentrations (0.001, 0.01, 0.1, 1 and 10%) of BSSS, traditional soy sauce (TRSS) and brewed soy sauce (BRSS), and were subsequently exposed to H 2 O 2 (100 µM). The viability of neuronal cells, and the occurrence of DNA fragmentation, was subsequently examined. Pretreatment of neuronal cells with TRSS and BRSS reduced cell viability in a concentration-dependent manner, whereas neuronal cells pretreated with BSSS exhibited increased cell viability, as compared with non-treated neuronal cells. Furthermore, neuronal cells pretreated with 0.01% BSSS exhibited the greatest increase in viability. Exposure of neuronal cells to H 2 O 2 significantly increased the levels of reactive oxygen species (ROS), B-cell lymphoma 2-associated X protein, poly (ADP-ribose), cleaved poly (ADP-ribose) polymerase, cytochrome c , apoptosis-inducing factor, cleaved caspase-9 and cleaved caspase-3, in all cases. Pretreatment of neuronal cells with BSSS significantly reduced the levels of ROS generated by H 2 O 2 , and increased the levels of phosphorylated AKT and phosphorylated glycogen synthase kinase-3β. Furthermore, the observed effects of BSSS could be blocked by administration of 10 µM LY294002, a phosphatidylinositol 3-kinase inhibitor. The results of the present study suggested that BSSS may exert positive neuroprotective effects against H 2 O 2 -induced cell death by reducing oxidative stress, enhancing survival signaling, and inhibiting death signals.

Live Imaging of Kv7.2/7.3 Cell Surface Dynamics at the Axon Initial Segment: High Steady-State Stability and Calpain-Dependent Excitotoxic Downregulation Revealed.

PubMed

Benned-Jensen, Tau; Christensen, Rasmus Kordt; Denti, Federico; Perrier, Jean-Francois; Rasmussen, Hanne Borger; Olesen, Søren-Peter

2016-02-17

The voltage-gated K(+) channels Kv7.2 and Kv7.3 are located at the axon initial segment (AIS) and exert strong control over action potential generation. Therefore, changes in their localization or cell surface numbers are likely to influence neuronal signaling. However, nothing is known about the cell surface dynamics of Kv7.2/7.3 at steady state or during short-term neuronal stimulation. This is primarily attributable to their membrane topology, which hampers extracellular epitope tagging. Here we circumvent this limitation by fusing an extra phluorin-tagged helix to the N terminus of human Kv7.3. This seven transmembrane chimera, named super ecliptic phluorin (SEP)-TAC-7.3, functions and traffics as a wild-type (WT) channel. We expressed SEP-TAC-7.3 in dissociated rat hippocampal neurons to examine the lateral mobility, surface numbers, and localization of AIS Kv7.2/7.3 heteromers using live imaging. We discovered that they are extraordinarily stable and exhibit a very low surface mobility both during steady state and neuronal stimulation. In the latter case, we also found that neither localization nor cell surface numbers were changed. However, at high glutamate loads, we observed a rapid irreversible endocytosis of Kv7.2/7.3, which required the activation of NR2B-containing NMDA receptors, Ca(2+) influx, and calpain activation. This excitotoxic mechanism may be specific to ankyrin G-bound AIS proteins because Nav1.2 channels, but not AIS GABAA receptors, were also endocytosed. In conclusion, we have, for the first time, characterized the cell surface dynamics of a full-length Kv7 channel using a novel chimeric strategy. This approach is likely also applicable to other Kv channels and thus of value for the additional characterization of this ion channel subfamily. The voltage-gated K(+) channels Kv7.2 and Kv7.3 exert strong control over action potential generation, but little is known about their cell surface dynamics. Using a novel phluorin-based approach, we here show that these channels are highly stable at steady state and different types of neuronal stimulation. However, at high glutamate loads, they undergo a rapid calpain-dependent endocytosis that likely represents an early response during excitotoxic states. Copyright © 2016 the authors 0270-6474/16/362261-06$15.00/0.

GYY4137, an H2S Slow-Releasing Donor, Prevents Nitrative Stress and α-Synuclein Nitration in an MPTP Mouse Model of Parkinson's Disease.

PubMed

Hou, Xiaoou; Yuan, Yuqing; Sheng, Yulan; Yuan, Baoshi; Wang, Yali; Zheng, Jiyue; Liu, Chun-Feng; Zhang, Xiaohu; Hu, Li-Fang

2017-01-01

The neuromodulator hydrogen sulfide (H 2 S) was shown to exert neuroprotection in different models of Parkinson's disease (PD) via its anti-inflammatory and anti-apoptotic properties. In this study, we evaluated the effect of an H 2 S slow-releasing compound GYY4137 (GYY) on a mouse PD model induced by acute injection with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). GYY was intraperitoneally (i.p.) injected once daily into male C57BL/6J mice 3 days before and 2 weeks after MPTP (14 mg/kg, four times at 2-h intervals, i.p.) administration. Saline was given as a control. Behavioral tests (rotarod, balance beam, and grid walking) showed that 50 mg/kg GYY significantly ameliorated MPTP-caused motor impairments. At lower doses (12.5 and 25 mg/kg) GYY exhibited a less obvious effect. Consistent with this, immunohistochemistry and western blot analysis demonstrated that 50 mg/kg GYY attenuated the loss of tyrosine hydroxylase (TH) positive neurons in the substantia nigra and the decrease of TH expression in the striatum of MPTP-treated mice. Moreover, at this regimen GYY relieved the nitrative stress, as indicated by the decreases in nitric oxide (NO) generation and neuronal NO synthase (nNOS) upregulation elicited by MPTP in the striatum. The suppression of GYY on nNOS expression was verified in vitro , and the results further revealed that Akt activation may participate in the inhibition by GYY on nNOS upregulation. More important, GYY reduced the nitrated modification of α-synuclein, a PD-related protein, in MPTP-induced mice. Overall, our findings suggest that GYY attenuated dopaminergic neuron degeneration and reduced α-synuclein nitration in the midbrain, thus exerting neuroprotection in MPTP-induced mouse model of PD.

Cytotoxic Effects of Ochratoxin A in Neuro-2a Cells: Role of Oxidative Stress Evidenced by N-acetylcysteine.

PubMed

Bhat, Pratiksha V; Pandareesh; Khanum, Farhath; Tamatam, Anand

2016-01-01

Ochratoxin-A (OTA), is toxic secondary metabolite and is found to be a source of vast range of toxic effects like hepatotoxicity, nephrotoxicity. However, the information available currently regarding neurotoxic effects exerted by OTA is scanty. Hence, the present study was aimed to evaluate the neurotoxic effects of OTA and the possible mechanisms of toxicity as well as the role of cytotoxic oxidative stress on neuronal (Neuro-2a) cell line was evaluated in vitro. Results of the MTT and LDH assay showed that, OTA induced dose-dependent cell death in Neuro-2a cells and EC50 value was determined as 500 nM. OTA induced high levels of reactive oxygen species (ROS) and elevated levels of malondialdehyde, also loss of mitochondrial membrane potential was observed in a dose depended manner. Effects of OTA on ROS induced chromosomal DNA damage was assessed by Comet assay and plasmid DNA damage assay in which increase in DNA damage was observed in Neuro-2a cells by increasing the OTA concentration. Further western blotting analysis of OTA treated Neuro-2a cells indicated elevated expression levels of c-Jun, JNK3 and cleaved caspase-3 leading to apoptotic cell death. Other hand realtime-Q-PCR analysis clearly indicates the suppressed expression of neuronal biomarker genes including AChE, BDNF, TH and NOS2. Further N-acetylcysteine (NAC) pretreatment to Neuro-2a cells followed by OTA treatment clearly evidenced that, the significant reversal of toxic effects exerted by OTA on Neuro-2a cells. In the present study, results illustrate that ROS a principle event in oxidative stress was elevated by OTA toxicity in Neuro-2a cells. However, further in vivo, animal studies are in need to conclude the present study reports and the use of NAC as a remedy for OTA induced neuronal stress.

Prospects for cannabinoid therapies in basal ganglia disorders

PubMed Central

Fernández-Ruiz, Javier; Moreno-Martet, Miguel; Rodríguez-Cueto, Carmen; Palomo-Garo, Cristina; Gómez-Cañas, María; Valdeolivas, Sara; Guaza, Carmen; Romero, Julián; Guzmán, Manuel; Mechoulam, Raphael; Ramos, José A

2011-01-01

Cannabinoids are promising medicines to slow down disease progression in neurodegenerative disorders including Parkinson's disease (PD) and Huntington's disease (HD), two of the most important disorders affecting the basal ganglia. Two pharmacological profiles have been proposed for cannabinoids being effective in these disorders. On the one hand, cannabinoids like Δ9-tetrahydrocannabinol or cannabidiol protect nigral or striatal neurons in experimental models of both disorders, in which oxidative injury is a prominent cytotoxic mechanism. This effect could be exerted, at least in part, through mechanisms independent of CB1 and CB2 receptors and involving the control of endogenous antioxidant defences. On the other hand, the activation of CB2 receptors leads to a slower progression of neurodegeneration in both disorders. This effect would be exerted by limiting the toxicity of microglial cells for neurons and, in particular, by reducing the generation of proinflammatory factors. It is important to mention that CB2 receptors have been identified in the healthy brain, mainly in glial elements and, to a lesser extent, in certain subpopulations of neurons, and that they are dramatically up-regulated in response to damaging stimuli, which supports the idea that the cannabinoid system behaves as an endogenous neuroprotective system. This CB2 receptor up-regulation has been found in many neurodegenerative disorders including HD and PD, which supports the beneficial effects found for CB2 receptor agonists in both disorders. In conclusion, the evidence reported so far supports that those cannabinoids having antioxidant properties and/or capability to activate CB2 receptors may represent promising therapeutic agents in HD and PD, thus deserving a prompt clinical evaluation. LINKED ARTICLES This article is part of a themed issue on Cannabinoids in Biology and Medicine. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.163.issue-7 PMID:21545415

Neuroprotective potential of high-dose biotin.

PubMed

McCarty, Mark F; DiNicolantonio, James J

2017-11-01

A recent controlled trial has established that high-dose biotin supplementation - 100 mg, three times daily - has a stabilizing effect on progression of multiple sclerosis (MS). Although this effect has been attributed to an optimization of biotin's essential cofactor role in the brain, a case can be made that direct stimulation of soluble guanylate cyclase (sGC) by pharmacological concentrations of biotin plays a key role in this regard. The utility of high-dose biotin in MS might reflect an anti-inflammatory effect of cGMP on the cerebral microvasculature, as well on oligodendrocyte differentiation and on Schwann cell production of neurotrophic factors thought to have potential for managing MS. But biotin's ability to boost cGMP synthesis in the brain may have broader neuroprotective potential. In many types of neurons and neural cells, cGMP exerts neurotrophic-mimetic effects - entailing activation of the PI3K-Akt and Ras-ERK pathways - that promote neuron survival and plasticity. Hippocampal long term potentiation requires nitric oxide synthesis, which in turn promotes an activating phosphorylation of CREB via a pathway involving cGMP and protein kinase G (PKG). In Alzheimer's disease (AD), amyloid beta suppresses this mechanism by inhibiting sGC activity; agents which exert a countervailing effect by boosting cGMP levels tend to restore effective long-term potentiation in rodent models of AD. Moreover, NO/cGMP suppresses amyloid beta production within the brain by inhibiting expression of amyloid precursor protein and BACE1. In conjunction with cGMP's ability to oppose neuron apoptosis, these effects suggest that high-dose biotin might have potential for the prevention and management of AD. cGMP also promotes neurogenesis, and may lessen stroke risk by impeding atherogenesis and hypertrophic remodeling in the cerebral vasculature. The neuroprotective potential of high-dose biotin likely could be boosted by concurrent administration of brain-permeable phosphodiesterase-5 inhibitors. Copyright © 2017 Elsevier Ltd. All rights reserved.

Matrine attenuates focal cerebral ischemic injury by improving antioxidant activity and inhibiting apoptosis in mice

PubMed Central

ZHAO, PENG; ZHOU, RU; ZHU, XIAO-YUN; HAO, YIN-JU; LI, NAN; WANG, JIE; NIU, YANG; SUN, TAO; LI, YU-XIANG; YU, JIAN-QIANG

2015-01-01

Matrine, an active constituent of the Chinese herb, Sophora flavescens Ait., and it is known for its antioxidant, anti-inflammatory and antitumor activities. It has been demonstrated that matrine exerts protective effects against heart failure by decreasing the expression of caspase-3 and Bax, and increasing Bcl-2 levels. In this study, we aimed to determine whether these protective effects of matrine can be applied to cerebral ischemia. Following 7 successive days of treatment with matrine (7.5, 15 and 30 mg/kg) and nimodipine (1 mg/kg) by intraperitoneal injection, male Institute of Cancer Research (ICR) mice were subjected to middle cerebral artery occlusion (MCAO). Following reperfusion, the neurobehavioral score and brain infarct volume were estimated, and morphological changes were analyzed by hematoxylin and eosin (H&E) staining and electron microscopy. The percentage of apoptotic neurons was determined by flow cytometry. The levels of oxidative stress were assessed by measuring the levels of malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT), and the total antioxidant capacity (T-AOC). Western blot analysis and immunofluorescence staining were used to examine the expression of the apoptosis-related proteins, caspase-3, Bax and Bcl-2. Our results revealed that pre-treatment with matrine significantly decreased the infarct volume and improved the neurological scores. Matrine also reduced the percentage of apoptotic neurons and relieved neuronal morphological damage. Furthermore, matrine markedly decreased the MDA levels, and increased SOD, GSH-Px and CAT activity, and T-AOC. Western blot analysis and immunofluorescence staining revealed a marked decrease in caspase-3 expression and an increase in the Bcl-2/Bax ratio in the group pre-treated with matrine (30 mg/kg) as compared with the vehicle-treated group. The findings of the present study demonstrate that matrine exerts neuroprotective effects against cerebral ischemic injury and that these effects are associated with its antioxidant and anti-apoptotic properties. PMID:26135032

Tailor-made purified human platelet lysate concentrated in neurotrophins for treatment of Parkinson's disease.

PubMed

Chou, Ming-Li; Wu, Joe-Wei; Gouel, Flore; Jonneaux, Aurélie; Timmerman, Kelly; Renn, Ting-Yi; Laloux, Charlotte; Chang, Hung-Ming; Lin, Liang-Tzung; Devedjian, Jean-Christophe; Devos, David; Burnouf, Thierry

2017-10-01

Human platelet lysates (PLs), which contain multiple neurotrophins, have been proposed for treating neurodegenerative disorders, including Parkinson's disease (PD). However, current PLs suspended in plasma have high protein content and contain fibrinogen/fibrin and, following activation, also proteolytic and thrombogenic enzymes. Upon brain administration, such PLs may saturate the cerebrospinal fluid and exert neurotoxicity. We assessed whether purified PLs, concentrated in neurotrophins, protected dopaminergic neurons in PD models. Platelet concentrates were collected by apheresis and centrifuged to eliminate plasma and recover the platelets. Platelets were lysed by freeze-thaw cycles, and the 10-fold concentrated platelet pellet lysates (PPLs) were heat-treated (at 56 °C for 30 min). The heat-treated PPLs were low in total proteins, depleted in both plasma and platelet fibrinogen, and devoid of thrombogenic and proteolytic activities. They exerted very high neuroprotective activity when non-oncogenic, Lund human mesencephalic (LUHMES) cells that had differentiated into dopaminergic neurons were exposed to the MPP + neurotoxin. Heat treatment improved the neuroprotection and inactivated the neurotoxic blood-borne hepatitis C virus. PPL did not induce inflammation in BV2 microglial cells and inhibited COX-2 expression upon lipopolysaccharide exposure. Intranasal administration in mice revealed (a) diffusion of neurotrophins in the striatum and cortex, and (b) MPTP intoxication neuroprotection in the substantia nigra and striatum and the absence of neuroinflammation. These dedicated heat-treated PPLs can be a safe and valuable candidate for a therapeutic strategy for PD. Copyright © 2017 Elsevier Ltd. All rights reserved.

Effects of calcium (Ca(2+)) extrusion mechanisms on electrophysiological properties in a hypoglossal motoneuron: insight from a mathematical model.

PubMed

Horn, Kyle G; Solomon, Irene C

2014-01-01

Spike-frequency dynamics and spike shape can provide insight into the types of ion channels present in any given neuron and give a sense for the precise response any neuron may have to a given input stimulus. Motoneuron firing frequency over time is especially important due to its direct effect on motor output. Of particular interest is intracellular Ca(2+), which exerts a powerful influence on both firing properties over time and spike shape. In order to better understand the cellular mechanisms for the regulation of intracellular Ca(2+) and their effect on spiking behavior, we have modified a computational model of an HM to include a variety of Ca(2+) handling processes. For the current study, a series of HM models that include Ca(2+) pumps, Na(+)/Ca(2+) exchangers, and a generic exponential decay of excess Ca(2+) were generated. Simulations from these models indicate that although each extrusion mechanism exerts a similar effect on voltage, the firing properties change distinctly with the inclusion of additional Ca(2+)-related mechanisms: BK channels, Ca(2+) buffering, and diffusion of [Ca(2+)]i modeled via a linear diffusion partial differential equation. While an exponential decay of Ca(2+) seems to adequately capture short-term changes in firing frequency seen in biological data, internal diffusion of Ca(2+) appears to be necessary for capturing longer term frequency changes. © 2014 Elsevier B.V. All rights reserved.

Live-cell imaging of neurofilament transport in cultured neurons.

PubMed

Uchida, Atsuko; Monsma, Paula C; Fenn, J Daniel; Brown, Anthony

2016-01-01

Neurofilaments, which are the intermediate filaments of nerve cells, are space-filling cytoskeletal polymers that contribute to the growth of axonal caliber. In addition to their structural role, neurofilaments are cargos of axonal transport that move along microtubule tracks in a rapid, intermittent, and bidirectional manner. Though they measure just 10nm in diameter, which is well below the diffraction limit of optical microscopes, these polymers can reach 100 μm or more in length and are often packed densely, just tens of nanometers apart. These properties of neurofilaments present unique challenges for studies on their movement. In this article, we describe several live-cell fluorescence imaging strategies that we have developed to image neurofilament transport in axons of cultured neurons on short and long timescales. Together, these methods form a powerful set of complementary tools with which to study the axonal transport of these unique intracellular cargos. Copyright © 2016 Elsevier Inc. All rights reserved.

Keratinocytes mediate innocuous and noxious touch via ATP-P2X4 signaling

PubMed Central

Moehring, Francie; Cowie, Ashley M; Menzel, Anthony D; Weyer, Andy D; Grzybowski, Michael; Arzua, Thiago; Geurts, Aron M; Palygin, Oleg

2018-01-01

The first point of our body’s contact with tactile stimuli (innocuous and noxious) is the epidermis, the outermost layer of skin that is largely composed of keratinocytes. Here, we sought to define the role that keratinocytes play in touch sensation in vivo and ex vivo. We show that optogenetic inhibition of keratinocytes decreases behavioral and cellular mechanosensitivity. These processes are inherently mediated by ATP signaling, as demonstrated by complementary cutaneous ATP release and degradation experiments. Specific deletion of P2X4 receptors in sensory neurons markedly decreases behavioral and primary afferent mechanical sensitivity, thus positioning keratinocyte-released ATP to sensory neuron P2X4 signaling as a critical component of baseline mammalian tactile sensation. These experiments lay a vital foundation for subsequent studies into the dysfunctional signaling that occurs in cutaneous pain and itch disorders, and ultimately, the development of novel topical therapeutics for these conditions. PMID:29336303

A regulatory network to segregate the identity of neuronal subtypes.

PubMed

Lee, Seunghee; Lee, Bora; Joshi, Kaumudi; Pfaff, Samuel L; Lee, Jae W; Lee, Soo-Kyung

2008-06-01

Spinal motor neurons (MNs) and V2 interneurons (V2-INs) are specified by two related LIM-complexes, MN-hexamer and V2-tetramer, respectively. Here we show how multiple parallel and complementary feedback loops are integrated to assign these two cell fates accurately. While MN-hexamer response elements (REs) are specific to MN-hexamer, V2-tetramer-REs can bind both LIM-complexes. In embryonic MNs, however, two factors cooperatively suppress the aberrant activation of V2-tetramer-REs. First, LMO4 blocks V2-tetramer assembly. Second, MN-hexamer induces a repressor, Hb9, which binds V2-tetramer-REs and suppresses their activation. V2-INs use a similar approach; V2-tetramer induces a repressor, Chx10, which binds MN-hexamer-REs and blocks their activation. Thus, our study uncovers a regulatory network to segregate related cell fates, which involves reciprocal feedforward gene regulatory loops.

Transcranial direct-current stimulation as treatment in epilepsy.

PubMed

Gschwind, Markus; Seeck, Margitta

2016-12-01

Neuromodulation (NM) is a complementary therapy for patients with drug-resistant epilepsy. Vagal nerve stimulation and deep brain stimulation of the anterior thalamus are established techniques and have shown their efficacy in lowering seizure frequency, but they are invasive and rarely render patients seizure-free. Non-invasive NM techniques are therefore increasingly investigated in a clinical context. Areas covered: Current knowledge about transcranial direct-current stimulation (tDCS) and other non-invasive NM in patients with epilepsy, based on the available animal and clinical studies from PubMed search. Expert commentary: tDCS modulates neuronal membrane potentials, and consequently alters cortical excitability. Cathodal stimulation leads to cortical inhibition, which is of particular importance in epilepsy treatment. The antiepileptic efficacy is promising but still lacks systematic studies. The beneficial effect, seen in ~20%, outlasts the duration of stimulation, indicating neuronal plasticity and is therefore of great interest to obtain long-term effects.

Plasticity within non-cerebellar pathways rapidly shapes motor performance in vivo

PubMed Central

Mitchell, Diana E.; Della Santina, Charles C.; Cullen, Kathleen E.

2016-01-01

Although cerebellar mechanisms are vital to maintain accuracy during complex movements and to calibrate simple reflexes, recent in vitro studies have called into question the widely held view that synaptic changes within cerebellar pathways exclusively guide alterations in motor performance. Here we investigate the vestibulo-ocular reflex (VOR) circuitry by applying temporally precise activation of vestibular afferents in awake-behaving monkeys to link plasticity at different neural sites with changes in motor performance. Behaviourally relevant activation patterns produce rapid attenuation of direct pathway VOR neurons, but not their nerve input. Changes in the strength of this pathway are sufficient to induce a lasting decrease in the evoked VOR. In addition, indirect brainstem pathways display complementary nearly instantaneous changes, contributing to compensating for the reduced sensitivity of primary VOR neurons. Taken together, our data provide evidence that multiple sites of plasticity within VOR pathways can rapidly shape motor performance in vivo. PMID:27157829

Plasticity within non-cerebellar pathways rapidly shapes motor performance in vivo.

PubMed

Mitchell, Diana E; Della Santina, Charles C; Cullen, Kathleen E

2016-05-09

Although cerebellar mechanisms are vital to maintain accuracy during complex movements and to calibrate simple reflexes, recent in vitro studies have called into question the widely held view that synaptic changes within cerebellar pathways exclusively guide alterations in motor performance. Here we investigate the vestibulo-ocular reflex (VOR) circuitry by applying temporally precise activation of vestibular afferents in awake-behaving monkeys to link plasticity at different neural sites with changes in motor performance. Behaviourally relevant activation patterns produce rapid attenuation of direct pathway VOR neurons, but not their nerve input. Changes in the strength of this pathway are sufficient to induce a lasting decrease in the evoked VOR. In addition, indirect brainstem pathways display complementary nearly instantaneous changes, contributing to compensating for the reduced sensitivity of primary VOR neurons. Taken together, our data provide evidence that multiple sites of plasticity within VOR pathways can rapidly shape motor performance in vivo.

Dynamics of cell area and force during spreading.

PubMed

Brill-Karniely, Yifat; Nisenholz, Noam; Rajendran, Kavitha; Dang, Quynh; Krishnan, Ramaswamy; Zemel, Assaf

2014-12-16

Experiments on human pulmonary artery endothelial cells are presented to show that cell area and the force exerted on a substrate increase simultaneously, but with different rates during spreading; rapid-force increase systematically occurred several minutes past initial spreading. We examine this theoretically and present three complementary mechanisms that may accompany the development of lamellar stress during spreading and underlie the observed behavior. These include: 1), the dynamics of cytoskeleton assembly at the cell basis; 2), the strengthening of acto-myosin forces in response to the generated lamellar stresses; and 3), the passive strain-stiffening of the cytoskeleton. Copyright © 2014 Biophysical Society. Published by Elsevier Inc. All rights reserved.

Complementary activities of TPX2 and chTOG constitute an efficient importin-regulated microtubule nucleation module

PubMed Central

Roostalu, Johanna; Cade, Nicholas I.; Surrey, Thomas

2016-01-01

Spindle assembly and function require precise control of microtubule nucleation and dynamics. The chromatin-driven spindle assembly pathway exerts such control locally in the vicinity of chromosomes. One of the key targets of this pathway is TPX2. The molecular mechanism of how TPX2 stimulates microtubule nucleation is not understood. Using microscopy-based dynamic in vitro reconstitution assays with purified proteins, we find that human TPX2 directly stabilises growing microtubule ends and stimulates microtubule nucleation by stabilising early microtubule nucleation intermediates. Human microtubule polymerase chTOG (XMAP215/Msps/Stu2p/Dis1/Alp14 homolog) only weakly promotes nucleation, but acts synergistically with TPX2. Hence, a combination of distinct and complementary activities is sufficient for efficient microtubule formation in vitro. Importins control the efficiency of the microtubule nucleation by selectively blocking TPX2’s interaction with microtubule nucleation intermediates. This in vitro reconstitution reveals the molecular mechanism of regulated microtubule formation by a minimal nucleation module essential for chromatin-dependent microtubule nucleation in cells. PMID:26414402

Complementary activities of TPX2 and chTOG constitute an efficient importin-regulated microtubule nucleation module.

PubMed

Roostalu, Johanna; Cade, Nicholas I; Surrey, Thomas

2015-11-01

Spindle assembly and function require precise control of microtubule nucleation and dynamics. The chromatin-driven spindle assembly pathway exerts such control locally in the vicinity of chromosomes. One of the key targets of this pathway is TPX2. The molecular mechanism of how TPX2 stimulates microtubule nucleation is not understood. Using microscopy-based dynamic in vitro reconstitution assays with purified proteins, we find that human TPX2 directly stabilizes growing microtubule ends and stimulates microtubule nucleation by stabilizing early microtubule nucleation intermediates. Human microtubule polymerase chTOG (XMAP215/Msps/Stu2p/Dis1/Alp14 homologue) only weakly promotes nucleation, but acts synergistically with TPX2. Hence, a combination of distinct and complementary activities is sufficient for efficient microtubule formation in vitro. Importins control the efficiency of the microtubule nucleation by selectively blocking the interaction of TPX2 with microtubule nucleation intermediates. This in vitro reconstitution reveals the molecular mechanism of regulated microtubule formation by a minimal nucleation module essential for chromatin-dependent microtubule nucleation in cells.

Osthole inhibits histamine-dependent itch via modulating TRPV1 activity.

PubMed

Yang, Niu-Niu; Shi, Hao; Yu, Guang; Wang, Chang-Ming; Zhu, Chan; Yang, Yan; Yuan, Xiao-Lin; Tang, Min; Wang, Zhong-Li; Gegen, Tana; He, Qian; Tang, Kehua; Lan, Lei; Wu, Guan-Yi; Tang, Zong-Xiang

2016-05-10

Osthole, an active coumarin isolated from Cnidium monnieri (L.) Cusson, has long been used in China as an antipruritic herbal medicine; however, the antipruitic mechanism of osthole is unknown. We studied the molecular mechanism of osthole in histamine-dependent itch by behavioral test, Ca(2+) imaging, and electrophysiological experiments. First, osthole clearly remitted the scratching behaviors of mice induced with histamine, HTMT, and VUF8430. Second, in cultured dorsal root ganglion (DRG) neurons, osthole showed a dose-dependent inhibitory effect to histamine. On the same neurons, osthole also decreased the response to capsaicin and histamine. In further tests, the capsaicin-induced inward currents were inhibited by osthole. These results revealed that osthole inhibited histamine-dependent itch by modulating TRPV1 activity. This study will be helpful in understanding how osthole exerts anti-pruritus effects and suggests that osthole may be a useful treatment medicine for histamine-dependent itch.

Osthole inhibits histamine-dependent itch via modulating TRPV1 activity

PubMed Central

Yang, Niu-Niu; Shi, Hao; Yu, Guang; Wang, Chang-Ming; Zhu, Chan; Yang, Yan; Yuan, Xiao-Lin; Tang, Min; Wang, Zhong-li; Gegen, Tana; He, Qian; Tang, Kehua; Lan, Lei; Wu, Guan-Yi; Tang, Zong-Xiang

2016-01-01

Osthole, an active coumarin isolated from Cnidium monnieri (L.) Cusson, has long been used in China as an antipruritic herbal medicine; however, the antipruitic mechanism of osthole is unknown. We studied the molecular mechanism of osthole in histamine-dependent itch by behavioral test, Ca2+ imaging, and electrophysiological experiments. First, osthole clearly remitted the scratching behaviors of mice induced with histamine, HTMT, and VUF8430. Second, in cultured dorsal root ganglion (DRG) neurons, osthole showed a dose-dependent inhibitory effect to histamine. On the same neurons, osthole also decreased the response to capsaicin and histamine. In further tests, the capsaicin-induced inward currents were inhibited by osthole. These results revealed that osthole inhibited histamine-dependent itch by modulating TRPV1 activity. This study will be helpful in understanding how osthole exerts anti-pruritus effects and suggests that osthole may be a useful treatment medicine for histamine-dependent itch. PMID:27160770

Central and peripheral clocks are coupled by a neuropeptide pathway in Drosophila

PubMed Central

Selcho, Mareike; Millán, Carola; Palacios-Muñoz, Angelina; Ruf, Franziska; Ubillo, Lilian; Chen, Jiangtian; Bergmann, Gregor; Ito, Chihiro; Silva, Valeria; Wegener, Christian; Ewer, John

2017-01-01

Animal circadian clocks consist of central and peripheral pacemakers, which are coordinated to produce daily rhythms in physiology and behaviour. Despite its importance for optimal performance and health, the mechanism of clock coordination is poorly understood. Here we dissect the pathway through which the circadian clock of Drosophila imposes daily rhythmicity to the pattern of adult emergence. Rhythmicity depends on the coupling between the brain clock and a peripheral clock in the prothoracic gland (PG), which produces the steroid hormone, ecdysone. Time information from the central clock is transmitted via the neuropeptide, sNPF, to non-clock neurons that produce the neuropeptide, PTTH. These secretory neurons then forward time information to the PG clock. We also show that the central clock exerts a dominant role on the peripheral clock. This use of two coupled clocks could serve as a paradigm to understand how daily steroid hormone rhythms are generated in animals. PMID:28555616

Tianma Gouteng Yin, a Traditional Chinese Medicine decoction, exerts neuroprotective effects in animal and cellular models of Parkinson’s disease

PubMed Central

Liu, Liang-Feng; Song, Ju-Xian; Lu, Jia-Hong; Huang, Ying-Yu; Zeng, Yu; Chen, Lei-Lei; Durairajan, Siva Sundara Kumar; Han, Quan-Bin; Li, Min

2015-01-01

Tianma Gouteng Yin (TGY) is a traditional Chinese medicine (TCM) decoction widely used to treat symptoms associated with typical Parkinson’s disease (PD). In this study, the neuroprotective effects of water extract of TGY were tested on rotenone-intoxicated and human α-synuclein transgenic Drosophila PD models. In addition, the neuroprotective effect of TGY was also evaluated in the human dopaminergic neuroblastoma SH-SY5Y cell line treated with rotenone and the rotenone intoxicated hemi-parkinsonian rats. In rotenone-induced PD models, TGY improved survival rate, alleviated impaired locomotor function of Drosophila, mitigated the loss of dopaminergic neurons in hemi-parkinsonian rats and alleviated apoptotic cell death in SH-SY5Y cells; in α-synuclein transgenic Drosophila, TGY reduced the level of α-synuclein and prevented degeneration of dopaminergic neurons. Conclusively, TGY is neuroprotective in PD models both in vivo and in vitro. PMID:26578166

Pauses in cholinergic interneuron firing exert an inhibitory control on striatal output in vivo

PubMed Central

Zucca, Stefano; Zucca, Aya; Nakano, Takashi; Aoki, Sho

2018-01-01

The cholinergic interneurons (CINs) of the striatum are crucial for normal motor and behavioral functions of the basal ganglia. Striatal CINs exhibit tonic firing punctuated by distinct pauses. Pauses occur in response to motivationally significant events, but their function is unknown. Here we investigated the effects of pauses in CIN firing on spiny projection neurons (SPNs) – the output neurons of the striatum – using in vivo whole cell and juxtacellular recordings in mice. We found that optogenetically-induced pauses in CIN firing inhibited subthreshold membrane potential activity and decreased firing of SPNs. During pauses, SPN membrane potential fluctuations became more hyperpolarized and UP state durations became shorter. In addition, short-term plasticity of corticostriatal inputs was decreased during pauses. Our results indicate that, in vivo, the net effect of the pause in CIN firing on SPNs activity is inhibition and provide a novel mechanism for cholinergic control of striatal output. PMID:29578407

A brain-liver circuit regulates glucose homeostasis.

PubMed

Pocai, Alessandro; Obici, Silvana; Schwartz, Gary J; Rossetti, Luciano

2005-01-01

Increased glucose production (GP) is the major determinant of fasting hyperglycemia in diabetes mellitus. Previous studies suggested that lipid metabolism within specific hypothalamic nuclei is a biochemical sensor for nutrient availability that exerts negative feedback on GP. Here we show that central inhibition of fat oxidation leads to selective activation of brainstem neurons within the nucleus of the solitary tract and the dorsal motor nucleus of the vagus and markedly decreases liver gluconeogenesis, expression of gluconeogenic enzymes, and GP. These effects require central activation of ATP-dependent potassium channels (K(ATP)) and descending fibers within the hepatic branch of the vagus nerve. Thus, hypothalamic lipid sensing potently modulates glucose metabolism via neural circuitry that requires the activation of K(ATP) and selective brainstem neurons and intact vagal input to the liver. This crosstalk between brain and liver couples central nutrient sensing to peripheral nutrient production and its disruption may lead to hyperglycemia.

Neurons in the Primate Medial Basal Forebrain Signal Combined Information about Reward Uncertainty, Value, and Punishment Anticipation

PubMed Central

Leopold, David A.; Hikosaka, Okihide

2015-01-01

It has been suggested that the basal forebrain (BF) exerts strong influences on the formation of memory and behavior. However, what information is used for the memory-behavior formation is unclear. We found that a population of neurons in the medial BF (medial septum and diagonal band of Broca) of macaque monkeys encodes a unique combination of information: reward uncertainty, expected reward value, anticipation of punishment, and unexpected reward and punishment. The results were obtained while the monkeys were expecting (often with uncertainty) a rewarding or punishing outcome during a Pavlovian procedure, or unexpectedly received an outcome outside the procedure. In vivo anterograde tracing using manganese-enhanced MRI suggested that the major recipient of these signals is the intermediate hippocampal formation. Based on these findings, we hypothesize that the medial BF identifies various contexts and outcomes that are critical for memory processing in the hippocampal formation. PMID:25972172

The Effects of Locus Coeruleus and Norepinephrine in Methamphetamine Toxicity

PubMed Central

Ferrucci, Michela; Giorgi, Filippo S; Bartalucci, Alessia; Busceti, Carla L; Fornai, Francesco

2013-01-01

The activity of locus coeruleus (LC) neurons has been extensively investigated in a variety of behavioural states. In fact this norepinephrine (NE)-containing nucleus modulates many physiological and pathological conditions including the sleep-waking cycle, movement disorders, mood alterations, convulsive seizures, and the effects of drugs such as psychostimulants and opioids. This review focuses on the modulation exerted by central NE pathways on the behavioural and neurotoxic effects produced by the psychostimulant methamphetamine, essentially the modulation of the activity of mesencephalic dopamine (DA) neurons. In fact, although NE in itself mediates some behavioural effects induced by methamphetamine, NE modulation of DA release is pivotal for methamphetamine-induced behavioural states and neurotoxicity. These interactions are discussed on the basis of the state of the art of the functional neuroanatomy of central NE- and DA systems. Emphasis is given to those brain sites possessing a remarkable overlapping of both neurotransmitters. PMID:23814540

The prefrontal cortex: a target for antipsychotic drugs.

PubMed

Artigas, F

2010-01-01

At therapeutic doses, classical antipsychotic drugs occupy a large proportion of subcortical dopamine D2 receptors, whereas atypical antipsychotics preferentially occupy cortical 5-HT(2) receptors. However, the exact cellular and network basis of their therapeutic action is not fully understood. To review the mechanism of action of antipsychotic drugs with a particular emphasis on their action in the prefrontal cortex (PFC). The PFC controls a large number of higher brain functions altered in schizophrenia. Histological studies indicate the presence of a large proportion of PFC neurons expressing monoaminergic receptors sensitive to the action of atypical- and to a lesser extentclassical antipsychotic drugs. Functional studies also indicate that both drug families act at PFC level. Atypical antipsychotic drugs likely exert their therapeutic activity by a preferential action on PFC neurons, thus modulating the PFC output to basal ganglia circuits. Classical antipsychotics also interact with these PFC targets in addition to blocking massively striatal D2 receptors.

The use of mesenchymal stem cells (MSCs) for amyotrophic lateral sclerosis (ALS) therapy - a perspective on cell biological mechanisms.

PubMed

Tang, Bor Luen

2017-10-26

Recent clinical trials of mesenchymal stem cells (MSCs) transplantation have demonstrated procedural safety and clinical proof of principle with a modest indication of benefit in patients with amyotrophic lateral sclerosis (ALS). While replacement therapy remained unrealistic, the clinical efficacy of this therapeutic option could be potentially enhanced if we could better decipher the mechanisms underlying some of the beneficial effects of transplanted cells, and work toward augmenting or combining these in a strategic manner. Novel ways whereby MSCs could act in modifying disease progression should also be explored. In this review, I discuss the known, emerging and postulated mechanisms of action underlying effects that transplanted MSCs may exert to promote motor neuron survival and/or to encourage regeneration in ALS. I shall also speculate on how transplanted cells may alter the diseased environment so as to minimize non-neuron cell autonomous damages by immune cells and astrocytes.

Region-specific role of growth differentiation factor-5 in the establishment of sympathetic innervation.

PubMed

O'Keeffe, Gerard W; Gutierrez, Humberto; Howard, Laura; Laurie, Christopher W; Osorio, Catarina; Gavaldà, Núria; Wyatt, Sean L; Davies, Alun M

2016-02-15

Nerve growth factor (NGF) is the prototypical target-derived neurotrophic factor required for sympathetic neuron survival and for the growth and ramification of sympathetic axons within most but not all sympathetic targets. This implies the operation of additional target-derived factors for regulating terminal sympathetic axon growth and branching. Here report that growth differentiation factor 5 (GDF5), a widely expressed member of the transforming growth factor beta (TGFβ) superfamily required for limb development, promoted axon growth from mouse superior cervical ganglion (SCG) neurons independently of NGF and enhanced axon growth in combination with NGF. GDF5 had no effect on neuronal survival and influenced axon growth during a narrow window of postnatal development when sympathetic axons are ramifying extensively in their targets in vivo. SCG neurons expressed all receptors capable of participating in GDF5 signaling at this stage of development. Using compartment cultures, we demonstrated that GDF5 exerted its growth promoting effect by acting directly on axons and by initiating retrograde canonical Smad signalling to the nucleus. GDF5 is synthesized in sympathetic targets, and examination of several anatomically circumscribed tissues in Gdf5 null mice revealed regional deficits in sympathetic innervation. There was a marked, highly significant reduction in the sympathetic innervation density of the iris, a smaller though significant reduction in the trachea, but no reduction in the submandibular salivary gland. There was no reduction in the number of neurons in the SCG. These findings show that GDF5 is a novel target-derived factor that promotes sympathetic axon growth and branching and makes a distinctive regional contribution to the establishment of sympathetic innervation, but unlike NGF, plays no role in regulating sympathetic neuron survival.

Sexual differentiation of the brain: a model for drug-induced alterations of the reproductive system

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

Gorski, R.A.

1986-12-01

The process of the sexual differentiation of the brain represents a valuable model system for the study of the chemical modification of the mammalian brain. Although there are numerous functional and structural sex differences in the adult brain, these are imposed on an essentially feminine or bipotential brain by testicular hormones during a critical phase of perinatal development in the rat. It is suggested that a relatively marked structural sex difference in the rat brain, the sexually dimorphic nucleus of the preoptic area (SDN-POA), is a morphological signature of the permanent or organizational action of estradiol derived from the aromatizationmore » of testicular testosterone. The SDN-POA of the male rat is severalfold larger in volume and is composed of more neurons than that of the female. The observation that the mitotic formation of the neurons of the SDN-POA is specifically prolonged has enabled us to identify the time course and pathway of neuronal migration into the nucleus. Study of the development of the SDN-POA suggests that estradiol in the male increases the number of neurons which survive a phase of neuronal death by exerting a neurite growth promoting action and/or a direct neuronotrophic action. Finally, although it is clear that gonadal hormones have dramatic permanent effects on the brain during perinatal development, even after puberty and in adulthood gonadal steroids can alter neuronal structure and, perhaps as a corollary to this, have permanent effects on reproductive function. Although the brain may be most sensitive to gonadal hormones or exogenous chemical factors during perinatal development, such as sensitivity does not appear limited to this period.« less

Hypoxia Silences Retrotrapezoid Nucleus Respiratory Chemoreceptors via Alkalosis

PubMed Central

Basting, Tyler M.; Burke, Peter G.R.; Kanbar, Roy; Viar, Kenneth E.; Stornetta, Daniel S.; Stornetta, Ruth L.

2015-01-01

In conscious mammals, hypoxia or hypercapnia stimulates breathing while theoretically exerting opposite effects on central respiratory chemoreceptors (CRCs). We tested this theory by examining how hypoxia and hypercapnia change the activity of the retrotrapezoid nucleus (RTN), a putative CRC and chemoreflex integrator. Archaerhodopsin-(Arch)-transduced RTN neurons were reversibly silenced by light in anesthetized rats. We bilaterally transduced RTN and nearby C1 neurons with Arch (PRSx8-ArchT-EYFP-LVV) and measured the cardiorespiratory consequences of Arch activation (10 s) in conscious rats during normoxia, hypoxia, or hyperoxia. RTN photoinhibition reduced breathing equally during non-REM sleep and quiet wake. Compared with normoxia, the breathing frequency reduction (ΔfR) was larger in hyperoxia (65% FiO2), smaller in 15% FiO2, and absent in 12% FiO2. Tidal volume changes (ΔVT) followed the same trend. The effect of hypoxia on ΔfR was not arousal-dependent but was reversed by reacidifying the blood (acetazolamide; 3% FiCO2). ΔfR was highly correlated with arterial pH up to arterial pH (pHa) 7.5 with no frequency inhibition occurring above pHa 7.53. Blood pressure was minimally reduced suggesting that C1 neurons were very modestly inhibited. In conclusion, RTN neurons regulate eupneic breathing about equally during both sleep and wake. RTN neurons are the first putative CRCs demonstrably silenced by hypocapnic hypoxia in conscious mammals. RTN neurons are silent above pHa 7.5 and increasingly active below this value. During hyperoxia, RTN activation maintains breathing despite the inactivity of the carotid bodies. Finally, during hypocapnic hypoxia, carotid body stimulation increases breathing frequency via pathways that bypass RTN. PMID:25589748

Effects of Vinpocetine on mitochondrial function and neuroprotection in primary cortical neurons.

PubMed

Tárnok, K; Kiss, E; Luiten, P G M; Nyakas, C; Tihanyi, K; Schlett, K; Eisel, U L M

2008-12-01

Vinpocetine (ethyl apovincaminate), a synthetic derivative of the Vinca minor alkaloid vincamine, is widely used for the treatment of cerebrovascular-related diseases. One of the proposed mechanisms underlying its action is to protect against the cytotoxic effects of glutamate overexposure. Glutamate excitotoxicity leads to the disregulation of mitochondrial function and neuronal metabolism. As Vinpocetine has a binding affinity to the peripheral-type benzodiazepine receptor (PBR) involved in the mitochondrial transition pore complex, we investigated whether neuroprotection can be at least partially due to Vinpocetine's effects on PBRs. Neuroprotective effects of PK11195 and Ro5-4864, two drugs with selective and high affinity to PBR, were compared to Vinpocetine in glutamate excitotoxicity assays on primary cortical neuronal cultures. Vinpocetine exerted a neuroprotective action in a 1-50microM concentration range while PK11195 and Ro5-4864 were only slightly neuroprotective, especially in high (>25microM) concentrations. Combined pretreatment of neuronal cultures with Vinpocetine and PK11195 or Ro5-4864 showed increased neuroprotection in a dose-dependent manner, indicating that the different drugs may have different targets. To test this hypothesis, mitochondrial membrane potential (MMP) of cultured neurons was measured by flow cytometry. 25microM Vinpocetine reduced the decrease of mitochondrial inner membrane potential induced by glutamate exposure, but Ro5-4864 in itself was found to be more potent to block glutamate-evoked changes in MMP. Combination of Ro5-4864 and Vinpocetine treatment was found to be even more effective. In summary, the present results indicate that the neuroprotective action of vinpocetine in culture can not be explained by its effect on neuronal PBRs alone and that additional drug targets are involved.

Hippocampal Ghrelin-positive neurons directly project to arcuate hypothalamic and medial amygdaloid nuclei. Could they modulate food-intake?

PubMed

Russo, Cristina; Russo, Antonella; Pellitteri, Rosalia; Stanzani, Stefania

2017-07-13

Feeding is a process controlled by a complex of associations between external and internal stimuli. The processes that involve learning and memory seem to exert a strong control over appetite and food intake, which is modulated by a gastrointestinal hormone, Ghrelin (Ghre). Recent studies claim that Ghre is involved in cognitive and neurobiological mechanisms that underlie the conditioning of eating behaviors. The expression of Ghre increases in anticipation of food intake based on learned behaviors. The hippocampal Ghre-containing neurons neurologically influence the orexigenic hypothalamus and consequently the learned feeding behavior. The CA1 field of Ammon's horn of the hippocampus (H-CA1) constitutes the most important neural substrate to control both appetitive and ingestive behavior. It also innervates amygdala regions that in turn innervate the hypothalamus. A recent study also implies that Ghre effects on cue-potentiated feeding behavior occur, at the least, via indirect action on the amygdala. In the present study, we investigate the neural substrates through which endogenous Ghre communicates conditioned appetite and feeding behavior within the CNS. We show the existence of a neural Ghre dependent pathway whereby peripherally-derived Ghre activates H-CA1 neurons, which in turn activate Ghre-expressing hypothalamic and amygdaloid neurons to stimulate appetite and feeding behavior. To highlight this pathway, we use two fluorescent retrograde tracers (Fluoro Gold and Dil) and immunohistochemical detection of Ghre expression in the hippocampus. Triple fluorescent-labeling has determined the presence of H-CA1 Ghre-containing collateralized neurons that project to the hypothalamus and amygdala monosynaptically. We hypothesize that H-Ghre-containing neurons in H-CA1 modulate food-intake behavior through direct pathways to the arcuate hypothalamic nucleus and medial amygdaloid nucleus. Copyright © 2017 Elsevier B.V. All rights reserved.

The impact of two mild stressors on the nerve growth factor (NGF) immunoreactivity in the amygdala in aged rats compared to adult ones.

PubMed

Badowska-Szalewska, Ewa; Ludkiewicz, Beata; Krawczyk, Rafał; Moryś, Janusz

2016-04-01

Nerve growth factor (NGF) seems to play an important role in the ageing limbic system in response to stress. This study aimed to explore the influence of acute and chronic exposure to high-light open field (HL-OF) or forced swim (FS) stressors on the density of NGF immunoreactive (ir) neurons in the amygdala central (CeA), medial (MeA), lateral (LA) and basolateral (BLA) nuclei in adult (postnatal day 90; P90) and aged (P720) rats. In comparison with non-stressed rats, neither acute nor chronic HL-OF produced significant changes in the density of NGF-ir neurons of studied nuclei in P90 and P720 rats. However, not acute but chronic FS was the factor inducing an increase in the density of NGF-ir neurons in the CeA of both age groups and in the LA of P720 rats. Despite the lack of change in the density of NGF-ir neurons between P90 and P720 non-stressed rats, there were significant age-related changes in NGF-ir cells in FS and/or HL-OF stressed rats in all the tested nuclei, with the exception of the LA. It may be concluded that as far as the influence on NGF-ir cells in amygdaloid nuclei is concerned, HL-OF did not constitute an aggravating factor for rats in the ontogenetic periods studied. Moreover, upregulation of NGF-ir neurons predominantly in CeA after chronic FS seems to be neuroprotective. Age-dependent changes in the density of NGF-ir neurons in stressed rats are probably caused by ageing processes and they may point to dysregulation of excitatory control exerted by the amygdala. Copyright © 2015 Elsevier Ltd. All rights reserved.

PEA and luteolin synergistically reduce mast cell-mediated toxicity and elicit neuroprotection in cell-based models of brain ischemia.

PubMed

Parrella, Edoardo; Porrini, Vanessa; Iorio, Rosa; Benarese, Marina; Lanzillotta, Annamaria; Mota, Mariana; Fusco, Mariella; Tonin, Paolo; Spano, PierFranco; Pizzi, Marina

2016-10-01

The combination of palmitoylethanolamide (PEA), an endogenous fatty acid amide belonging to the family of the N-acylethanolamines, and the flavonoid luteolin has been found to exert neuroprotective activities in a variety of mouse models of neurological disorders, including brain ischemia. Indirect findings suggest that the two molecules can reduce the activation of mastocytes in brain ischemia, thus modulating crucial cells that trigger the inflammatory cascade. Though, no evidence exists about a direct effect of PEA and luteolin on mast cells in experimental models of brain ischemia, either used separately or in combination. In order to fill this gap, we developed a novel cell-based model of severe brain ischemia consisting of primary mouse cortical neurons and cloned mast cells derived from mouse fetal liver (MC/9 cells) subjected to oxygen and glucose deprivation (OGD). OGD exposure promoted both mast cell degranulation and the release of lactate dehydrogenase (LDH) in a time-dependent fashion. MC/9 cells exacerbated neuronal damage in neuron-mast cells co-cultures exposed to OGD. Likewise, the conditioned medium derived from OGD-exposed MC/9 cells induced significant neurotoxicity in control primary neurons. PEA and luteolin pre-treatment synergistically prevented the OGD-induced degranulation of mast cells and reduced the neurotoxic potential of MC/9 cells conditioned medium. Finally, the association of the two drugs promoted a direct synergistic neuroprotection even in pure cortical neurons exposed to OGD. In summary, our results indicate that mast cells release neurotoxic factors upon OGD-induced activation. The association PEA-luteolin actively reduces mast cell-mediated neurotoxicity as well as pure neurons susceptibility to OGD. Copyright © 2016 Elsevier B.V. All rights reserved.

Effects of nateglinide and repaglinide administered intracerebroventricularly on the CA3 hippocampal neuronal cell death and hyperglycemia induced by kainic acid in mice.

PubMed

Kim, Chea-Ha; Park, Soo-Hyun; Sim, Yun-Beom; Kim, Sung-Su; Kim, Su-Jin; Lim, Su-Min; Jung, Jun-Sub; Suh, Hong-Won

2014-05-01

Meglitinides (nateglinide and repaglinide) are widely used oral drugs for the treatment of type II diabetes mellitus. In the present study, the effects of meglinitides administered supraspinally on kainic acid (KA)-induced hippocampal neuronal cell death and hyperglycemia were studied in ICR mice. Mice were pretreated intracerebroventricularly (i.c.v.) with 30 μg of nateglinide and repaglinide for 10 min and then, mice were administered i.c.v. with KA (0.1 μg). The neuronal cell death in the CA3 region in the hippocampus was assessed 24h after KA administration and the blood glucose level was measured 30, 60, and 120 min after KA administration. We found that i.c.v. pretreatment with repaglinide attenuated the KA-induced neuronal cell death in CA3 region of the hippocampus and hyperglycemia. However, nateglinide pretreated i.c.v. did not affect the KA-induced neuronal cell death and hyperglycemia. In addition, KA administered i.c.v. caused an elevation of plasma corticosterone level and a reduction of the plasma insulin level. Furthermore, i.c.v. pretreatment with repaglinide attenuated KA-induced up-regulation of plasma corticosterone level. Furthermore, i.c.v. administration of repaglinide alone increased plasma insulin level and repaglinide pretreated i.c.v. caused a reversal of KA-induced hypoinsulinemic effect. Our results suggest that supraspinally administered repaglinide, but not nateglinide, exerts a protective effect against the KA-induced neuronal cells death in CA3 region of the hippocampus. The neuroprotective effect of repaglinide appears to be mediated by lowering the blood glucose level induced by KA. Copyright © 2014 Elsevier Inc. All rights reserved.

Convergent phosphomodulation of the major neuronal dendritic potassium channel Kv4.2 by pituitary adenylate cyclase-activating polypeptide.

PubMed

Gupte, Raeesa P; Kadunganattil, Suraj; Shepherd, Andrew J; Merrill, Ronald; Planer, William; Bruchas, Michael R; Strack, Stefan; Mohapatra, Durga P

2016-02-01

The endogenous neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is secreted by both neuronal and non-neuronal cells in the brain and spinal cord, in response to pathological conditions such as stroke, seizures, chronic inflammatory and neuropathic pain. PACAP has been shown to exert various neuromodulatory and neuroprotective effects. However, direct influence of PACAP on the function of intrinsically excitable ion channels that are critical to both hyperexcitation as well as cell death, remain largely unexplored. The major dendritic K(+) channel Kv4.2 is a critical regulator of neuronal excitability, back-propagating action potentials in the dendrites, and modulation of synaptic inputs. We identified, cloned and characterized the downstream signaling originating from the activation of three PACAP receptor (PAC1) isoforms that are expressed in rodent hippocampal neurons that also exhibit abundant expression of Kv4.2 protein. Activation of PAC1 by PACAP leads to phosphorylation of Kv4.2 and downregulation of channel currents, which can be attenuated by inhibition of either PKA or ERK1/2 activity. Mechanistically, this dynamic downregulation of Kv4.2 function is a consequence of reduction in the density of surface channels, without any influence on the voltage-dependence of channel activation. Interestingly, PKA-induced effects on Kv4.2 were mediated by ERK1/2 phosphorylation of the channel at two critical residues, but not by direct channel phosphorylation by PKA, suggesting a convergent phosphomodulatory signaling cascade. Altogether, our findings suggest a novel GPCR-channel signaling crosstalk between PACAP/PAC1 and Kv4.2 channel in a manner that could lead to neuronal hyperexcitability. Copyright © 2015 Elsevier Ltd. All rights reserved.

Identification of Novel Small Molecule Activators of Nuclear Factor-κB With Neuroprotective Action Via High-Throughput Screening

PubMed Central

Manuvakhova, Marina S.; Johnson, Guyla G.; White, Misti C.; Ananthan, Subramaniam; Sosa, Melinda; Maddox, Clinton; McKellip, Sara; Rasmussen, Lynn; Wennerberg, Krister; Hobrath, Judith V.; White, E. Lucile; Maddry, Joseph A.; Grimaldi, Maurizio

2012-01-01

Neuronal noncytokine-dependent p50/p65 nuclear factor-κB (the primary NF-κB complex in the brain) activation has been shown to exert neuroprotective actions. Thus neuronal activation of NF-κB could represent a viable neuroprotective target. We have developed a cell-based assay able to detect NF-κB expression enhancement, and through its use we have identified small molecules able to up-regulate NF-κB expression and hence trigger its activation in neurons. We have successfully screened approximately 300,000 compounds and identified 1,647 active compounds. Cluster analysis of the structures within the hit population yielded 14 enriched chemical scaffolds. One high-potency and chemically attractive representative of each of these 14 scaffolds and four singleton structures were selected for follow-up. The experiments described here highlighted that seven compounds caused noncanonical long-lasting NF-κB activation in primary astrocytes. Molecular NF-κB docking experiments indicate that compounds could be modulating NF-κB-induced NF-κB expression via enhancement of NF-κB binding to its own promoter. Prototype compounds increased p65 expression in neurons and caused its nuclear translocation without affecting the inhibitor of NF-κB (I-κB). One of the prototypical compounds caused a large reduction of glutamate-induced neuronal death. In conclusion, we have provided evidence that we can use small molecules to activate p65 NF-κB expression in neurons in a cytokine receptor-independent manner, which results in both long-lasting p65 NF-κB translocation/activation and decreased glutamate neurotoxicity. PMID:21046675

Neurotrophic actions of dopamine on the development of a serotonergic feeding circuit in Drosophila melanogaster

PubMed Central

2012-01-01

Background In the fruit fly, Drosophila melanogaster, serotonin functions both as a neurotransmitter to regulate larval feeding, and in the development of the stomatogastric feeding circuit. There is an inverse relationship between neuronal serotonin levels during late embryogenesis and the complexity of the serotonergic fibers projecting from the larval brain to the foregut, which correlate with perturbations in feeding, the functional output of the circuit. Dopamine does not modulate larval feeding, and dopaminergic fibers do not innervate the larval foregut. Since dopamine can function in central nervous system development, separate from its role as a neurotransmitter, the role of neuronal dopamine was assessed on the development, and mature function, of the 5-HT larval feeding circuit. Results Both decreased and increased neuronal dopamine levels in late embryogenesis during development of this circuit result in depressed levels of larval feeding. Perturbations in neuronal dopamine during this developmental period also result in greater branch complexity of the serotonergic fibers innervating the gut, as well as increased size and number of the serotonin-containing vesicles along the neurite length. This neurotrophic action for dopamine is modulated by the D2 dopamine receptor expressed during late embryogenesis in central 5-HT neurons. Animals carrying transgenic RNAi constructs to knock down both dopamine and serotonin synthesis in the central nervous system display normal feeding and fiber architecture. However, disparate levels of neuronal dopamine and serotonin during development of the circuit result in abnormal gut fiber architecture and feeding behavior. Conclusions These results suggest that dopamine can exert a direct trophic influence on the development of a specific neural circuit, and that dopamine and serotonin may interact with each other to generate the neural architecture necessary for normal function of the circuit. PMID:22413901

12-Deoxyphorbols Promote Adult Neurogenesis by Inducing Neural Progenitor Cell Proliferation via PKC Activation

PubMed Central

Geribaldi-Doldán, Noelia; Flores-Giubi, Eugenia; Murillo-Carretero, Maribel; García-Bernal, Francisco; Carrasco, Manuel; Macías-Sánchez, Antonio J.; Domínguez-Riscart, Jesús; Verástegui, Cristina; Hernández-Galán, Rosario

2016-01-01

Background: Neuropsychiatric and neurological disorders frequently occur after brain insults associated with neuronal loss. Strategies aimed to facilitate neuronal renewal by promoting neurogenesis constitute a promising therapeutic option to treat neuronal death-associated disorders. In the adult brain, generation of new neurons occurs physiologically throughout the entire life controlled by extracellular molecules coupled to intracellular signaling cascades. Proteins participating in these cascades within neurogenic regions constitute potential pharmacological targets to promote neuronal regeneration of injured areas of the central nervous system. Methodology: We have performed in vitro and in vivo approaches to determine neural progenitor cell proliferation to understand whether activation of kinases of the protein kinase C family facilitates neurogenesis in the adult brain. Results: We have demonstrated that protein kinase C activation by phorbol-12-myristate-13-acetate induces neural progenitor cell proliferation in vitro. We also show that the nontumorogenic protein kinase C activator prostratin exerts a proliferative effect on neural progenitor cells in vitro. This effect can be reverted by addition of the protein kinase C inhibitor G06850, demonstrating that the effect of prostratin is mediated by protein kinase C activation. Additionally, we show that prostratin treatment in vivo induces proliferation of neural progenitor cells within the dentate gyrus of the hippocampus and the subventricular zone. Finally, we describe a library of diterpenes with a 12-deoxyphorbol structure similar to that of prostratin that induces a stronger effect than prostratin on neural progenitor cell proliferation both in vitro and in vivo. Conclusions: This work suggests that protein kinase C activation is a promising strategy to expand the endogenous neural progenitor cell population to promote neurogenesis and highlights the potential of 12-deoxyphorbols as pharmaceutical agents to facilitate neuronal renewal. PMID:26224011

12-Deoxyphorbols Promote Adult Neurogenesis by Inducing Neural Progenitor Cell Proliferation via PKC Activation.

PubMed

Geribaldi-Doldán, Noelia; Flores-Giubi, Eugenia; Murillo-Carretero, Maribel; García-Bernal, Francisco; Carrasco, Manuel; Macías-Sánchez, Antonio J; Domínguez-Riscart, Jesús; Verástegui, Cristina; Hernández-Galán, Rosario; Castro, Carmen

2015-07-29

Neuropsychiatric and neurological disorders frequently occur after brain insults associated with neuronal loss. Strategies aimed to facilitate neuronal renewal by promoting neurogenesis constitute a promising therapeutic option to treat neuronal death-associated disorders. In the adult brain, generation of new neurons occurs physiologically throughout the entire life controlled by extracellular molecules coupled to intracellular signaling cascades. Proteins participating in these cascades within neurogenic regions constitute potential pharmacological targets to promote neuronal regeneration of injured areas of the central nervous system. We have performed in vitro and in vivo approaches to determine neural progenitor cell proliferation to understand whether activation of kinases of the protein kinase C family facilitates neurogenesis in the adult brain. We have demonstrated that protein kinase C activation by phorbol-12-myristate-13-acetate induces neural progenitor cell proliferation in vitro. We also show that the nontumorogenic protein kinase C activator prostratin exerts a proliferative effect on neural progenitor cells in vitro. This effect can be reverted by addition of the protein kinase C inhibitor G06850, demonstrating that the effect of prostratin is mediated by protein kinase C activation. Additionally, we show that prostratin treatment in vivo induces proliferation of neural progenitor cells within the dentate gyrus of the hippocampus and the subventricular zone. Finally, we describe a library of diterpenes with a 12-deoxyphorbol structure similar to that of prostratin that induces a stronger effect than prostratin on neural progenitor cell proliferation both in vitro and in vivo. This work suggests that protein kinase C activation is a promising strategy to expand the endogenous neural progenitor cell population to promote neurogenesis and highlights the potential of 12-deoxyphorbols as pharmaceutical agents to facilitate neuronal renewal. © The Author 2015. Published by Oxford University Press on behalf of CINP.

Regulation Of Hypothalamic Signaling By Tuberoinfundibular Peptide Of 39 Residues Is Critical For The Response To Cold: A Novel Peptidergic Mechanism Of Thermoregulation

PubMed Central

Dimitrov, Eugene L.; Kim, Yoon Yi; Usdin, Ted B.

2012-01-01

Euthermia is critical for mammalian homeostasis. Circuits within the preoptic hypothalamus regulate temperature, with fine control exerted via descending GABAergic inhibition of presympathetic motor neurons that control brown adipose tissue (BAT) thermogenesis and cutaneous vascular tone. The thermoregulatory role of hypothalamic excitatory neurons is less clear. Here we report peptidergic regulation of preoptic glutamatergic neurons that contributes to temperature regulation. Tuberoinfundibular peptide of 39 residues (TIP39) is a ligand for the parathyroid hormone 2 receptor (PTH2R). Both peptide and receptor are abundant in the preoptic hypothalamus. Based on PTH2R and vesicular glutamate transporter 2 (VGlut2) immunolabeling in animals with retrograde tracer injection, PTH2R containing glutamatergic fibers are presynaptic to neurons projecting from the median preoptic nucleus (MnPO) to the dorsomedial hypothalamus. Transneuronal retrograde pathway tracing with pseudorabies virus revealed connectivity between MnPO VGlut2 and PTH2R neurons and BAT. MnPO injection of TIP39 increased body temperature by 2° C for several hours. Mice lacking TIP39 signaling, either because of PTH2R null mutation or brain delivery of a PTH2R antagonist had impaired heat production upon cold exposure, but no change in basal temperature and no impairment in response to a hot environment. Thus, TIP39 appears to act on PTH2Rs present on MnPO glutamatergic terminals to regulate their activation of projection neurons and subsequent sympathetic BAT activation. This excitatory mechanism of heat production appears to be activated on demand, during cold exposure, and parallels the tonic inhibitory GABAergic control of body temperature. PMID:22159128

Hypoxia silences retrotrapezoid nucleus respiratory chemoreceptors via alkalosis.

PubMed

Basting, Tyler M; Burke, Peter G R; Kanbar, Roy; Viar, Kenneth E; Stornetta, Daniel S; Stornetta, Ruth L; Guyenet, Patrice G

2015-01-14

In conscious mammals, hypoxia or hypercapnia stimulates breathing while theoretically exerting opposite effects on central respiratory chemoreceptors (CRCs). We tested this theory by examining how hypoxia and hypercapnia change the activity of the retrotrapezoid nucleus (RTN), a putative CRC and chemoreflex integrator. Archaerhodopsin-(Arch)-transduced RTN neurons were reversibly silenced by light in anesthetized rats. We bilaterally transduced RTN and nearby C1 neurons with Arch (PRSx8-ArchT-EYFP-LVV) and measured the cardiorespiratory consequences of Arch activation (10 s) in conscious rats during normoxia, hypoxia, or hyperoxia. RTN photoinhibition reduced breathing equally during non-REM sleep and quiet wake. Compared with normoxia, the breathing frequency reduction (Δf(R)) was larger in hyperoxia (65% FiO2), smaller in 15% FiO2, and absent in 12% FiO2. Tidal volume changes (ΔV(T)) followed the same trend. The effect of hypoxia on Δf(R) was not arousal-dependent but was reversed by reacidifying the blood (acetazolamide; 3% FiCO2). Δf(R) was highly correlated with arterial pH up to arterial pH (pHa) 7.5 with no frequency inhibition occurring above pHa 7.53. Blood pressure was minimally reduced suggesting that C1 neurons were very modestly inhibited. In conclusion, RTN neurons regulate eupneic breathing about equally during both sleep and wake. RTN neurons are the first putative CRCs demonstrably silenced by hypocapnic hypoxia in conscious mammals. RTN neurons are silent above pHa 7.5 and increasingly active below this value. During hyperoxia, RTN activation maintains breathing despite the inactivity of the carotid bodies. Finally, during hypocapnic hypoxia, carotid body stimulation increases breathing frequency via pathways that bypass RTN. Copyright © 2015 the authors 0270-6474/15/350527-17$15.00/0.

Effects of an environmentally-relevant mixture of pyrethroid insecticides on spontaneous activity in primary cortical networks on microelectrode arrays.

PubMed

Johnstone, Andrew F M; Strickland, Jenna D; Crofton, Kevin M; Gennings, Chris; Shafer, Timothy J

2017-05-01

Pyrethroid insecticides exert their insecticidal and toxicological effects primarily by disrupting voltage-gated sodium channel (VGSC) function, resulting in altered neuronal excitability. Numerous studies of individual pyrethroids have characterized effects on mammalian VGSC function and neuronal excitability, yet studies examining effects of complex pyrethroid mixtures in mammalian neurons, especially in environmentally relevant mixture ratios, are limited. In the present study, concentration-response functions were characterized for five pyrethroids (permethrin, deltamethrin, cypermethrin, β-cyfluthrin and esfenvalerate) in an in vitro preparation containing cortical neurons and glia. As a metric of neuronal network activity, spontaneous mean network firing rates (MFR) were measured using microelectorde arrays (MEAs). In addition, the effect of a complex and exposure relevant mixture of the five pyrethroids (containing 52% permethrin, 28.8% cypermethrin, 12.9% β-cyfluthrin, 3.4% deltamethrin and 2.7% esfenvalerate) was also measured. Data were modeled to determine whether effects of the pyrethroid mixture were predicted by dose-addition. At concentrations up to 10μM, all compounds except permethrin reduced MFR. Deltamethrin and β-cyfluthrin were the most potent and reduced MFR by as much as 60 and 50%, respectively, while cypermethrin and esfenvalerate were of approximately equal potency and reduced MFR by only ∼20% at the highest concentration. Permethrin caused small (∼24% maximum), concentration-dependent increases in MFR. Effects of the environmentally relevant mixture did not depart from the prediction of dose-addition. These data demonstrate that an environmentally relevant mixture caused dose-additive effects on spontaneous neuronal network activity in vitro, and is consistent with other in vitro and in vivo assessments of pyrethroid mixtures. Published by Elsevier B.V.

Ventral pallidal projections to mediodorsal thalamus and ventral tegmental area play distinct roles in outcome-specific Pavlovian-instrumental transfer.

PubMed

Leung, Beatrice K; Balleine, Bernard W

2015-03-25

Outcome-specific Pavlovian-instrumental transfer (PIT) demonstrates the way that reward-related cues influence choice between instrumental actions. The nucleus accumbens shell (NAc-S) contributes critically to this effect, particularly through its output to the rostral medial ventral pallidum (VP-m). Using rats, we investigated in two experiments the role in the PIT effect of the two major outputs of this VP-m region innervated by the NAc-S, the mediodorsal thalamus (MD) and the ventral tegmental area (VTA). First, two retrograde tracers were injected into the MD and VTA to compare the neuronal activity of the two populations of projection neurons in the VP-m during PIT relative to controls. Second, the functional role of the connection between the VP-m and the MD or VTA was assessed using asymmetrical pharmacological manipulations before a PIT test. It was found that, whereas neurons in the VP-m projecting to the MD showed significantly more neuronal activation during PIT than those projecting to the VTA, neuronal activation of these latter neurons correlated with the size of the PIT effect. Disconnection of the two pathways during PIT also revealed different deficits in performance: disrupting the VP-m to MD pathway removed the response biasing effects of reward-related cues, whereas disrupting the VP-m to VTA pathway preserved the response bias but altered the overall rate of responding. The current results therefore suggest that the VP-m exerts distinct effects on the VTA and MD and that these latter structures mediate the motivational and cognitive components of specific PIT, respectively. Copyright © 2015 the authors 0270-6474/15/354953-12$15.00/0.

Turtle Functions Downstream of Cut in Differentially Regulating Class Specific Dendrite Morphogenesis in Drosophila

PubMed Central

Sulkowski, Mikolaj J.; Iyer, Srividya Chandramouli; Kurosawa, Mathieu S.; Iyer, Eswar Prasad R.; Cox, Daniel N.

2011-01-01

Background Dendritic morphology largely determines patterns of synaptic connectivity and electrochemical properties of a neuron. Neurons display a myriad diversity of dendritic geometries which serve as a basis for functional classification. Several types of molecules have recently been identified which regulate dendrite morphology by acting at the levels of transcriptional regulation, direct interactions with the cytoskeleton and organelles, and cell surface interactions. Although there has been substantial progress in understanding the molecular mechanisms of dendrite morphogenesis, the specification of class-specific dendritic arbors remains largely unexplained. Furthermore, the presence of numerous regulators suggests that they must work in concert. However, presently, few genetic pathways regulating dendrite development have been defined. Methodology/Principal Findings The Drosophila gene turtle belongs to an evolutionarily conserved class of immunoglobulin superfamily members found in the nervous systems of diverse organisms. We demonstrate that Turtle is differentially expressed in Drosophila da neurons. Moreover, MARCM analyses reveal Turtle acts cell autonomously to exert class specific effects on dendritic growth and/or branching in da neuron subclasses. Using transgenic overexpression of different Turtle isoforms, we find context-dependent, isoform-specific effects on mediating dendritic branching in class II, III and IV da neurons. Finally, we demonstrate via chromatin immunoprecipitation, qPCR, and immunohistochemistry analyses that Turtle expression is positively regulated by the Cut homeodomain transcription factor and via genetic interaction studies that Turtle is downstream effector of Cut-mediated regulation of da neuron dendrite morphology. Conclusions/Significance Our findings reveal that Turtle proteins differentially regulate the acquisition of class-specific dendrite morphologies. In addition, we have established a transcriptional regulatory interaction between Cut and Turtle, representing a novel pathway for mediating class specific dendrite development. PMID:21811639

Cholecystokinin and tyrosine hydroxylase messenger RNAs in neurons of rat mesencephalon: peptide/monoamine coexistence studies using in situ hybridization combined with immunocytochemistry.

PubMed

Seroogy, K; Schalling, M; Brené, S; Dagerlind, A; Chai, S Y; Hökfelt, T; Persson, H; Brownstein, M; Huan, R; Dixon, J

1989-01-01

The cellular localization of neurons expressing cholecystokinin (CCK) and tyrosine hydroxylase (TH) mRNAs was analysed in rat ventral mesencephalon using in situ hybridization techniques with both complementary DNA and synthetic oligonucleotide probes. Cell bodies distributed throughout the substantia nigra, ventral tegmental area, interfascicular nucleus, midline raphe nuclei, and central and ventral periaqueductal grey matter were found to contain CCK mRNA or TH mRNA as indicated by high densities of grains overlying the perikarya. The in situ hybridization technique was combined with immunocytochemistry on the same tissue section to localize the peptide or enzyme within its respective mRNA-containing somata. In addition, the presence of TH immunoreactivity was demonstrated within cell bodies labeled for CCK mRNA and immunostaining for CCK was detected within TH mRNA-containing neurons. In the medial geniculate nucleus a strong labeling for CCKmRNA was observed, in spite of the fact that so far no CCK-like immunoreactivity has been demonstrated in perikarya in this nucleus. The specificity of the probes was verified by RNA blot hybridization. These results confirm recent double-labeling immunocytochemical studies and further characterize the coexistence of CCK and TH at the level of their mRNAs as well as their post-translational products in a large population of mesencephalic dopamine neurons known to project to forebrain areas.

Assessing sensory versus optogenetic network activation by combining (o)fMRI with optical Ca2+ recordings.

PubMed

Schmid, Florian; Wachsmuth, Lydia; Schwalm, Miriam; Prouvot, Pierre-Hugues; Jubal, Eduardo Rosales; Fois, Consuelo; Pramanik, Gautam; Zimmer, Claus; Faber, Cornelius; Stroh, Albrecht

2016-11-01

Encoding of sensory inputs in the cortex is characterized by sparse neuronal network activation. Optogenetic stimulation has previously been combined with fMRI (ofMRI) to probe functional networks. However, for a quantitative optogenetic probing of sensory-driven sparse network activation, the level of similarity between sensory and optogenetic network activation needs to be explored. Here, we complement ofMRI with optic fiber-based population Ca 2+ recordings for a region-specific readout of neuronal spiking activity in rat brain. Comparing Ca 2+ responses to the blood oxygenation level-dependent signal upon sensory stimulation with increasing frequencies showed adaptation of Ca 2+ transients contrasted by an increase of blood oxygenation level-dependent responses, indicating that the optical recordings convey complementary information on neuronal network activity to the corresponding hemodynamic response. To study the similarity of optogenetic and sensory activation, we quantified the density of cells expressing channelrhodopsin-2 and modeled light propagation in the tissue. We estimated the effectively illuminated volume and numbers of optogenetically stimulated neurons, being indicative of sparse activation. At the functional level, upon either sensory or optogenetic stimulation we detected single-peak short-latency primary Ca 2+ responses with similar amplitudes and found that blood oxygenation level-dependent responses showed similar time courses. These data suggest that ofMRI can serve as a representative model for functional brain mapping. © The Author(s) 2015.

Optimal and Local Connectivity Between Neuron and Synapse Array in the Quantum Dot/Silicon Brain

NASA Technical Reports Server (NTRS)

Duong, Tuan A.; Assad, Christopher; Thakoor, Anikumar P.

2010-01-01

This innovation is used to connect between synapse and neuron arrays using nanowire in quantum dot and metal in CMOS (complementary metal oxide semiconductor) technology to enable the density of a brain-like connection in hardware. The hardware implementation combines three technologies: 1. Quantum dot and nanowire-based compact synaptic cell (50x50 sq nm) with inherently low parasitic capacitance (hence, low dynamic power approx.l0(exp -11) watts/synapse), 2. Neuron and learning circuits implemented in 50-nm CMOS technology, to be integrated with quantum dot and nanowire synapse, and 3. 3D stacking approach to achieve the overall numbers of high density O(10(exp 12)) synapses and O(10(exp 8)) neurons in the overall system. In a 1-sq cm of quantum dot layer sitting on a 50-nm CMOS layer, innovators were able to pack a 10(exp 6)-neuron and 10(exp 10)-synapse array; however, the constraint for the connection scheme is that each neuron will receive a non-identical 10(exp 4)-synapse set, including itself, via its efficacy of the connection. This is not a fully connected system where the 100x100 synapse array only has a 100-input data bus and 100-output data bus. Due to the data bus sharing, it poses a great challenge to have a complete connected system, and its constraint within the quantum dot and silicon wafer layer. For an effective connection scheme, there are three conditions to be met: 1. Local connection. 2. The nanowire should be connected locally, not globally from which it helps to maximize the data flow by sharing the same wire space location. 3. Each synapse can have an alternate summation line if needed (this option is doable based on the simple mask creation). The 10(exp 3)x10(exp 3)-neuron array was partitioned into a 10-block, 10(exp 2)x10(exp 3)-neuron array. This building block can be completely mapped within itself (10,000 synapses to a neuron).

Why does brain metabolism not favor burning of fatty acids to provide energy? - Reflections on disadvantages of the use of free fatty acids as fuel for brain

PubMed Central

Schönfeld, Peter; Reiser, Georg

2013-01-01

It is puzzling that hydrogen-rich fatty acids are used only poorly as fuel in the brain. The long-standing belief that a slow passage of fatty acids across the blood–brain barrier might be the reason. However, this has been corrected by experimental results. Otherwise, accumulated nonesterified fatty acids or their activated derivatives could exert detrimental activities on mitochondria, which might trigger the mitochondrial route of apoptosis. Here, we draw attention to three particular problems: (1) ATP generation linked to β-oxidation of fatty acids demands more oxygen than glucose, thereby enhancing the risk for neurons to become hypoxic; (2) β-oxidation of fatty acids generates superoxide, which, taken together with the poor anti-oxidative defense in neurons, causes severe oxidative stress; (3) the rate of ATP generation based on adipose tissue-derived fatty acids is slower than that using blood glucose as fuel. Thus, in periods of extended continuous and rapid neuronal firing, fatty acid oxidation cannot guarantee rapid ATP generation in neurons. We conjecture that the disadvantages connected with using fatty acids as fuel have created evolutionary pressure on lowering the expression of the β-oxidation enzyme equipment in brain mitochondria to avoid extensive fatty acid oxidation and to favor glucose oxidation in brain. PMID:23921897

Peribronchial innervation of the rat lung.

PubMed

Artico, Marco; Bosco, Sandro; Bronzetti, Elena; Felici, Laura M; Pelusi, Giuseppe; Lo Vasco, Vincenza Rita; Vitale, Marco

2004-10-01

Mammalian peribronchial tissue is supplied by several peptide-containing nerve fibers. Although it is well established that different neuropeptides exert significant effects on bronchial and vascular tone in the lungs, the role played by some neuromediators on the general regulation, differentiation and release of locally active substances is still controversial. We studied the innervation of rat peribronchial tissue by immunohistochemical techniques. The immunoperoxidase method with nickel amplification was applied to detect the distribution of nerve fibers using antibodies against the general neuronal marker PGP 9.5 (neuron-specific cytoplasmic protein), while the cholinacetyltransferase immunoreactivity was studied by immunohistochemistry. A slight immunoreactivity for NT receptors is observed in lung bronchial epithelium. There is increasing evidence that NTs may act with a paracrine mechanism regulating functional activity of neuronal and non-neuronal structures. A specific immunoreactivity for NTs and NT receptors was also demonstrated within different layers of large, medium and small sized intrapulmonary arteries and veins, according to a recent study of our group. Moreover our data describe the expression of NTs and NT receptors in lymphoid aggregates of the lung (BALT) in which both lymphocytes and macrophages express TrkA receptor and synthesize NTs. Our results show the presence of an extensive network of innervation in the rat peribronchial tissue, confirming a morphological basis for a possible neural modulation of the respiratory mucosa and the physiological/pathophysiological mechanisms of the lung.

Korean red ginseng extract exhibits neuroprotective effects through inhibition of apoptotic cell death.

PubMed

Kim, Sunyoung; Lee, Youngmoon; Cho, Jungsook

2014-01-01

Red ginseng has long been used as a traditional medicine in many East Asian countries including Korea. It is known to exhibit various pharmacological effects, including anti-oxidant, anti-cancer, anti-stress and anti-diabetes activities. To further explore its actions, the present study evaluated effects of Korean red ginseng (KRG) extract on neuronal injury induced by various types of insults using primary cultured rat cortical cells. KRG extract inhibited neuronal damage and generation of intracellular reactive oxygen species (ROS) induced by excitatory amino acids, such as glutamate and N-methyl-D-aspartate (NMDA), or by Aβ(25-35). To elucidate possible mechanism(s) by which KRG extract exerts neuroprotective action, its effects on apoptosis and apoptosis-related signaling molecules in neurons were assessed. KRG extract markedly increased phosphorylation of Bad at Ser 112 and inhibited Bax expression and caspase 3 activity. It also inhibited DNA fragmentation induced by NMDA or Aβ(25-35). These results indicate that KRG extract protects cultured neurons from excitotoxicity and Aβ(25-35)-induced toxicity through inhibition of ROS generation and apoptotic cell death. In addition, KRG extract inhibited β-secretase activity, implying that it may reduce Aβ peptide formation. Taken together, these findings suggest that KRG extract may be beneficial for the prevention and/or treatment of neurodegenerative disorders including Alzheimer's disease.

Involvement of ERK in NMDA receptor-independent cortical neurotoxicity of hydrogen sulfide

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

Kurokawa, Yuko; Sekiguchi, Fumiko; Kubo, Satoko

2011-11-04

Highlights: Black-Right-Pointing-Pointer Hydrogen sulfide causes NMDA receptor-independent neurotoxicity in mouse fetal cortical neurons. Black-Right-Pointing-Pointer Activation of ERK mediates the toxicity of hydrogen sulfide. Black-Right-Pointing-Pointer Apoptotic mechanisms are involved in the hydrogen-induced cell death. -- Abstract: Hydrogen sulfide (H{sub 2}S), a gasotransmitter, exerts both neurotoxicity and neuroprotection, and targets multiple molecules including NMDA receptors, T-type calcium channels and NO synthase (NOS) that might affect neuronal viability. Here, we determined and characterized effects of NaHS, an H{sub 2}S donor, on cell viability in the primary cultures of mouse fetal cortical neurons. NaHS caused neuronal death, as assessed by LDH release and trypanmore » blue staining, but did not significantly reduce the glutamate toxicity. The neurotoxicity of NaHS was resistant to inhibitors of NMDA receptors, T-type calcium channels and NOS, and was blocked by inhibitors of MEK, but not JNK, p38 MAP kinase, PKC and Src. NaHS caused prompt phosphorylation of ERK and upregulation of Bad, followed by translocation of Bax to mitochondria and release of mitochondrial cytochrome c, leading to the nuclear condensation/fragmentation. These effects of NaHS were suppressed by the MEK inhibitor. Our data suggest that the NMDA receptor-independent neurotoxicity of H{sub 2}S involves activation of the MEK/ERK pathway and some apoptotic mechanisms.« less

Free-Radical Scavenger Edaravone Treatment Confers Neuroprotection Against Traumatic Brain Injury in Rats

PubMed Central

Wang, Guo-Hua; Li, Yong-Cai; Li, Xia; Shi, Hong; Gao, Yan-Qin; Vosler, Peter S.

2011-01-01

Abstract Traumatic brain injury (TBI) is one of the leading causes of neurological disability in young adults. Edaravone, a novel synthetic small-molecule free-radical scavenger, has been shown to have a neuroprotective effect in both animal models of cerebral ischemia and stroke patients; however, the underlying mechanism is poorly understood. In this report, we investigated the potential mechanisms of edaravone treatment in a rat model of TBI. TBI was induced in the right cerebral cortex of male adult rats using Feeney's weight-drop method. Edaravone (0.75, 1.5, or 3 mg/kg) or vehicle (normal saline) was intravenously administered at 2 and 12 h after TBI. Edaravone treatment significantly decreased hippocampal CA3 neuron loss, reduced oxidative stress, and decreased neuronal programmed cell death compared to vehicle treatment. The protective effects of edaravone treatment were also related to the pathology of TBI on non-neuronal cells, as edaravone decreased astrocyte and glial activation. Lastly, edaravone treatment significantly reduced the presence of inflammatory cytokines, cerebral edema, blood–brain barrier (BBB) permeability, and, importantly, neurological deficits following TBI. Our results suggest that edaravone exerts a neuroprotective effect in the rat model of TBI. The likely mechanism is via inhibiting oxidative stress, leading to a decreased inflammatory response and glial activation, and thereby reducing neuronal death and improving neurological function. PMID:21732763

AP-1 proteins in the adult brain: facts and fiction about effectors of neuroprotection and neurodegeneration.

PubMed

Herdegen, T; Waetzig, V

2001-04-30

Jun and Fos proteins are induced and activated following most physiological and pathophysiological stimuli in the brain. Only few data allow conclusions about distinct functions of AP-1 proteins in neurodegeneration and neuroregeneration, and these functions mainly refer to c-Jun and its activation by JNKs. Apoptotic functions of activated c-Jun affect hippocampal, nigral and primary cultured neurons following excitotoxic stimulation and destruction of the neuron-target-axis including withdrawal of trophic molecules. The inhibition of JNKs might exert neuroprotection by subsequent omission of c-Jun activation. Besides endogenous neuronal functions, the c-Jun/AP-1 proteins can damage the nervous system by upregulation of harmful programs in non-neuronal cells (e.g. microglia) with release of neurodegenerative molecules. In contrast, the differentiation with neurite extension and maturation of neural cells in vitro indicate physiological and potentially neuroprotective functions of c-Jun and JNKs including sensoring for alterations in the cytoskeleton. This review summarizes the multiple molecular interfunctions which are involved in the shift from the physiological role to degenerative effects of the Jun/JNK-axis such as cell type-specific expression and intracellular localization of scaffold proteins and upstream activators, antagonistic phosphatases, interaction with other kinase systems, or the activation of transcription factors competing for binding to JNK proteins and AP-1 DNA elements.

Intrinsic and Extrinsic Neuromodulation of Olfactory Processing

PubMed Central

Lizbinski, Kristyn M.; Dacks, Andrew M.

2018-01-01

Neuromodulation is a ubiquitous feature of neural systems, allowing flexible, context specific control over network dynamics. Neuromodulation was first described in invertebrate motor systems and early work established a basic dichotomy for neuromodulation as having either an intrinsic origin (i.e., neurons that participate in network coding) or an extrinsic origin (i.e., neurons from independent networks). In this conceptual dichotomy, intrinsic sources of neuromodulation provide a “memory” by adjusting network dynamics based upon previous and ongoing activation of the network itself, while extrinsic neuromodulators provide the context of ongoing activity of other neural networks. Although this dichotomy has been thoroughly considered in motor systems, it has received far less attention in sensory systems. In this review, we discuss intrinsic and extrinsic modulation in the context of olfactory processing in invertebrate and vertebrate model systems. We begin by discussing presynaptic modulation of olfactory sensory neurons by local interneurons (LNs) as a mechanism for gain control based on ongoing network activation. We then discuss the cell-class specific effects of serotonergic centrifugal neurons on olfactory processing. Finally, we briefly discuss the integration of intrinsic and extrinsic neuromodulation (metamodulation) as an effective mechanism for exerting global control over olfactory network dynamics. The heterogeneous nature of neuromodulation is a recurring theme throughout this review as the effects of both intrinsic and extrinsic modulation are generally non-uniform. PMID:29375314

Nerve growth factor in the adult brain of a teleostean model for aging research: Nothobranchius furzeri.

PubMed

D'Angelo, L; Castaldo, L; Cellerino, A; de Girolamo, P; Lucini, C

2014-07-01

Nerve growth factor (NGF) acts on central nervous system neurons, regulating naturally occurring cell death, synaptic connectivity, fiber guidance and dendritic morphology. The dynamically regulated production of NGF beginning in development, extends throughout adult life and aging, exerting numerous roles through a surprising variety of neurons and glial cells. This study analyzes the localization of NGF in the brain of the teleost fish Nothobranchius furzeri, an emerging model for aging research due to its short lifespan. Immunochemical and immunohistochemical experiments were performed by employing an antibody mapping at the N-terminus of the mature chain human origin NGF. Western blot analysis revealed an intense and well defined band of 20 kDa, which corresponds to proNGF of N. furzeri. Immunohistochemistry revealed NGF immunoreactivity (IR) diffused throughout all regions of telencephalon, diencephalon, mesencephalon and rhomboencephalon. It was detected in neurons and in glial cells, the latter mostly lining the mesencephalic and rhomboencephalic ventricles. Particularly in neurons, NGF IR was localized in perikarya and, to a less extent, in fibers. The widespread distribution of proNGF suggests that it might modulate numerous physiological functions in the adult brain of N. furzeri. The present survey constitutes a baseline study to enhance the understanding of the mechanisms underlying the role of NGF during aging processes. Copyright © 2014 Elsevier GmbH. All rights reserved.

Why does brain metabolism not favor burning of fatty acids to provide energy? Reflections on disadvantages of the use of free fatty acids as fuel for brain.

PubMed

Schönfeld, Peter; Reiser, Georg

2013-10-01

It is puzzling that hydrogen-rich fatty acids are used only poorly as fuel in the brain. The long-standing belief that a slow passage of fatty acids across the blood-brain barrier might be the reason. However, this has been corrected by experimental results. Otherwise, accumulated nonesterified fatty acids or their activated derivatives could exert detrimental activities on mitochondria, which might trigger the mitochondrial route of apoptosis. Here, we draw attention to three particular problems: (1) ATP generation linked to β-oxidation of fatty acids demands more oxygen than glucose, thereby enhancing the risk for neurons to become hypoxic; (2) β-oxidation of fatty acids generates superoxide, which, taken together with the poor anti-oxidative defense in neurons, causes severe oxidative stress; (3) the rate of ATP generation based on adipose tissue-derived fatty acids is slower than that using blood glucose as fuel. Thus, in periods of extended continuous and rapid neuronal firing, fatty acid oxidation cannot guarantee rapid ATP generation in neurons. We conjecture that the disadvantages connected with using fatty acids as fuel have created evolutionary pressure on lowering the expression of the β-oxidation enzyme equipment in brain mitochondria to avoid extensive fatty acid oxidation and to favor glucose oxidation in brain.