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Sample records for stria terminalis induces

  1. Allopregnanolone induces state-dependent fear via the bed nucleus of the stria terminalis.

    PubMed

    Acca, Gillian M; Mathew, Abel S; Jin, Jingji; Maren, Stephen; Nagaya, Naomi

    2017-03-01

    Gonadal steroids and their metabolites have been shown to be important modulators of emotional behavior. Allopregnanolone (ALLO), for example, is a metabolite of progesterone that has been linked to anxiety-related disorders such as posttraumatic stress disorder. In rodents, it has been shown to reduce anxiety in a number of behavioral paradigms including Pavlovian fear conditioning. We have recently found that expression of conditioned contextual (but not auditory) freezing in rats can be suppressed by infusion of ALLO into the bed nucleus of the stria terminalis (BNST). To further explore the nature of this effect, we infused ALLO into the BNST of male rats prior to both conditioning and testing. We found that suppression of contextual fear occurred when the hormone was present during either conditioning or testing but not during both procedures, suggesting that ALLO acts in a state-dependent manner within the BNST. A shift in interoceptive context during testing for animals conditioned under ALLO provided further support for this mechanism of hormonal action on contextual fear. Interestingly, infusions of ALLO into the basolateral amygdala produced a state-independent suppression of both conditioned contextual and auditory freezing. Altogether, these results suggest that ALLO can influence the acquisition and expression of fear memories by both state-dependent and state-independent mechanisms. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Ethanol-induced anxiolysis and neuronal activation in the amygdala and bed nucleus of the stria terminalis

    PubMed Central

    Sharko, Amanda C.; Kaigler, Kris F.; Fadel, Jim R.; Wilson, Marlene A.

    2016-01-01

    High rates of comorbidity for anxiety and alcohol-use disorders suggest a causal relationship between these conditions. Previous work demonstrates basal anxiety levels in outbred Long-Evans rats correlate with differences in voluntary ethanol consumption and that amygdalar Neuropeptide Y (NPY) systems may play a role in this relationship. The present work explores the possibility that differences in sensitivity to ethanol’s anxiolytic effects contribute to differential ethanol self-administration in these animals and examines the potential role of central and peripheral NPY in mediating this relationship. Animals were first exposed to the elevated plus maze (EPM) to assess individual differences in anxiety-like behaviors and levels of circulating NPY and corticosterone (CORT). Rats were then tested for anxiety-like behavior in the light-dark box (LD box) following acute ethanol treatment (1 g/kg; intraperitoneally [i.p.]), and neuronal activation in the amygdala and bed nucleus of the stria terminalis (BNST) was assessed using Fos immunohistochemistry. EPM exposure increased plasma CORT levels without altering plasma NPY levels. Acute ethanol treatment significantly increased light-dark transitions and latency to re-enter the light arena, but no differences were seen between high- and low-anxiety groups and no correlations were found between anxiety-like behaviors in the EPM and LD box. Acute ethanol treatment significantly increased Fos immunoreactivity in the BNST and the central amygdala. Although NPY neurons were not significantly activated following ethanol exposure, in saline-treated animals lower levels of anxiety-like behavior in the LD box (more time in the light arena and more transitions) were correlated with higher NPY-positive cell density in the central amygdala. Our results suggest that activation of the CeA and BNST are involved in the behavioral expression of ethanol-induced anxiolysis, and that differences in basal anxiety state may be

  3. Ethanol-induced anxiolysis and neuronal activation in the amygdala and bed nucleus of the stria terminalis.

    PubMed

    Sharko, Amanda C; Kaigler, Kris F; Fadel, Jim R; Wilson, Marlene A

    2016-02-01

    High rates of comorbidity for anxiety and alcohol-use disorders suggest a causal relationship between these conditions. Previous work demonstrates basal anxiety levels in outbred Long-Evans rats correlate with differences in voluntary ethanol consumption and that amygdalar Neuropeptide Y (NPY) systems may play a role in this relationship. The present work explores the possibility that differences in sensitivity to ethanol's anxiolytic effects contribute to differential ethanol self-administration in these animals and examines the potential role of central and peripheral NPY in mediating this relationship. Animals were first exposed to the elevated plus maze (EPM) to assess individual differences in anxiety-like behaviors and levels of circulating NPY and corticosterone (CORT). Rats were then tested for anxiety-like behavior in the light-dark box (LD box) following acute ethanol treatment (1 g/kg; intraperitoneally [i.p.]), and neuronal activation in the amygdala and bed nucleus of the stria terminalis (BNST) was assessed using Fos immunohistochemistry. EPM exposure increased plasma CORT levels without altering plasma NPY levels. Acute ethanol treatment significantly increased light-dark transitions and latency to re-enter the light arena, but no differences were seen between high- and low-anxiety groups and no correlations were found between anxiety-like behaviors in the EPM and LD box. Acute ethanol treatment significantly increased Fos immunoreactivity in the BNST and the central amygdala. Although NPY neurons were not significantly activated following ethanol exposure, in saline-treated animals lower levels of anxiety-like behavior in the LD box (more time in the light arena and more transitions) were correlated with higher NPY-positive cell density in the central amygdala. Our results suggest that activation of the CeA and BNST are involved in the behavioral expression of ethanol-induced anxiolysis, and that differences in basal anxiety state may be correlated

  4. How does pain induce negative emotion? Role of the bed nucleus of the stria terminalis in pain-induced place aversion.

    PubMed

    Minami, M; Ide, S

    2015-01-01

    Pain consists of sensory-discriminative and negative-affective components. Neuronal mechanisms for the sensory component of pain have been investigated extensively. On the other hand, neuronal mechanisms for the affective component of pain remain to be investigated. Recent behavioral studies have revealed the brain regions and neuronal mechanisms involved in the affective component of pain. Glutamatergic transmission within the anterior cingulate cortex and basolateral amygdaloid nucleus plays a critical role in pain-induced aversion. Noradrenaline and corticotropin-releasing factor (CRF) within the ventral and dorsolateral parts of the bed nucleus of the stria terminalis (BNST), respectively, play important roles in paininduced aversion. Electrophysiological studies have revealed that both noradrenaline and CRF activate type II BNST neurons, which may inhibit the BNST output neurons. A recent histochemical study showed that most VTA-projecting BNST output neurons are GABAergic neurons, which preferentially make synaptic contact with VTA GABAergic neurons. Therefore, activation of VTA-projecting BNST output neurons should increase the neuronal excitability of VTA dopaminergic (DAergic) neurons through increased inhibitory input to VTA GABAergic neurons, which negatively regulate VTA DAergic neurons. Pain-induced release of noradrenaline and CRF within the BNST may activate type II BNST neurons, which could suppress VTA-projecting BNST output neurons, thereby attenuating the excitatory influence to the VTA DAergic neurons. Recent optogenetic studies suggest that the suppression of VTA DAergic neurons is sufficient to induce place aversion. Pain-induced place aversion may be due to the suppression of VTA DAergic neurons via the processing of nociceptive information within the BNST.

  5. Temporary inactivation of the anterior part of the bed nucleus of the stria terminalis blocks alarm pheromone-induced defensive behavior in rats

    PubMed Central

    Breitfeld, Tino; Bruning, Johann E. A.; Inagaki, Hideaki; Takeuchi, Yukari; Kiyokawa, Yasushi; Fendt, Markus

    2015-01-01

    Rats emit an alarm pheromone in threatening situations. Exposure of rats to this alarm pheromone induces defensive behaviors, such as head out behavior, and increases c-Fos expression in brain areas involved in the mediation of defensive behaviors. One of these brain areas is the anterior bed nucleus of the stria terminalis (aBNST). The goal of the present study was to investigate if pharmacological inactivation of the aBNST by local microinjections of the GABAA receptor-agonist muscimol modulates alarm pheromone-induced defensive behaviors. We first established the behavioral paradigm of alarm pheromone-induced defensive behaviors in Sprague-Dawley rats in our laboratory. In a second experiment, we inactivated the aBNST, then exposed rats to one of four different odors (neck odor, female urine, alarm pheromone, fox urine) and tested the effects of the aBNST inactivation on the behavior in response to these odors. Our data show that temporary inactivation of the aBNST blocked head out behavior in response to the alarm pheromone. This indicates that the aBNST plays an important role in the mediation of the alarm pheromone-induced defensive behavior in rats. PMID:26441496

  6. Orexin-A Induces Anxiety-like Behavior through Interactions with Glutamatergic Receptors in the Bed Nucleus of the Stria Terminalis of Rats

    PubMed Central

    Lungwitz, Elizabeth A.; Molosh, Andrei; Johnson, Philip L.; Harvey, Brian P.; Dirks, Rachel C.; Dietrich, Amy; Minick, Pamela; Shekhar, Anantha; Truitt, William A.

    2012-01-01

    The hypothalamic neuropeptide orexin (ORX) has been implicated in anxiety, and anxiety-like behaviors. The purpose of these studies was to determine the role of ORX, specifically orexin-A (ORX-A) in the bed nucleus of the stria terminalis (BNST) on anxiety-like behaviors in rats. Rats injected with ORX-A into the BNST displayed greater anxiety-like measures in the social interaction and elevated plus maze tests compared to vehicle treated controls. Such anxiety-like behaviors were not observed when the ORX-A injections were adjacent to the BNST, in the medial septum. The anxiety-inducing effects of direct infusions of ORX-A into the BNST may be a consequence of increased activation of BNST neurons. In BNST slice preparations using patch-clamp techniques, ORX-A induced membrane depolarization and generation of action potentials in a subset of BNST neurons. The anxiety-inducing effects of ORX-A in the BNST also appear to be dependent on NMDA-type glutamate receptor activity, as pre-injecting the NMDA antagonist AP5 into the BNST blocked anxiogenic effects of local ORX-A injections. Injections of AMPA-type receptor antagonists into the BNST prior to ORX-A resulted in only a partial attenuation of anxiety-like behaviors. PMID:22652097

  7. Effect of sex differences and gonadal hormones on kainic acid-induced neurodegeneration in the bed nucleus of the stria terminalis of the rat.

    PubMed

    Pereno, German Leandro; Balaszczuk, Verónica; Beltramino, Carlos Alberto

    2012-05-01

    Previously we have demonstrated that medial nucleus of the amygdala, which is part of medial extended amygdala, is damaged by status epilepticus induced by kainic acid (KA) and this neurodegeneration was prevents by estrogen replacement. The medial bed nucleus of stria terminalis (BSTM) also belong to medial extended amygdala and it is uncertain whether the gonadal hormones are protective or not against this neurotoxicity in the BSTM. Here we show that a single i.p. injection of KA (9 mg/kg) induces neurodegeneration in the subnuclei of the BSTM of rats with different degrees of intensity in males and females. A differential neuroprotective effect of the gonadal hormones was also observed. In diestrous rats, massive neuronal death similar to that in the ovariectomized females was detected. BSTM neurons of proestrous rats, like the ovariectomized treated with estrogen, were significantly less affected by the KA. Testosterone produced a mild neuroprotective action, but dihydrotestosterone did not protect. A similar pattern was observed in all male groups. This results show that estrogen protects BSTM neurons from KA neurotoxicity and androgens are partially neuroprotective; and probably this effect of androgens is due to conversion to estrogen. Copyright © 2010 Elsevier GmbH. All rights reserved.

  8. Suckling induces a daily rhythm in the preoptic area and lateral septum but not in the bed nucleus of the stria terminalis in lactating rabbit does.

    PubMed

    Meza, Enrique; Aguirre, Juan; Waliszewski, Stefan; Caba, Mario

    2015-01-01

    Maternal behavior in the rabbit is restricted to a brief nursing period every day. Previously, we demonstrated that this event induces daily rhythms of Period1 (PER1) protein, the product of the clock gene Per1, in oxytocinergic and dopaminergic populations in the hypothalamus of lactating rabbit does. This is significant for the periodic production and ejection of milk, but the activation of other areas of the brain has not been explored. Here, we hypothesised that daily suckling would induce a rhythm in the preoptic area, lateral septum, and bed nucleus of the stria terminalis, which are important areas for the expression of maternal behavior in mammals, including the rabbit. To this end, we analysed PER1 expression in those areas through a complete 24-h cycle at lactation day 7. Does were scheduled to nurse during either the day at 10:00 h [zeitgeber time (ZT)03] or the night at 02:00 h (ZT19). Non-pregnant, non-lactating females were used as controls. In contrast to control females, lactating does showed a clear, significant rhythm of PER1 that shifted in parallel with the timing of nursing in the preoptic area and lateral septum. We determined that the maximal expression of PER1 at 8 h after scheduled nursing decreased significantly at 24 and 48 h after the absence of suckling. This effect was more pronounced in the lateral septum than in the preoptic area. We conclude that daily suckling is a powerful stimulus inducing rhythmic activity in brain structures in the rabbit that appear to form part of a maternal entrainable circuit. © 2014 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

  9. Suckling induces a daily rhythm in the preoptic area and lateral septum but not in the bed nucleus of the stria terminalis in lactating rabbit does

    PubMed Central

    Meza, Enrique; Aguirre, Juan; Waliszewski, Stefan; Caba, Mario

    2014-01-01

    Maternal behavior in the rabbit is restricted to a brief nursing period every day. Previously we demonstrated that this event induces daily rhythms of PER1 protein, the product of the clock gene Per1, in oxytocinergic and dopaminergic populations in the hypothalamus of lactating rabbit does. This is significant for the periodic production and ejection of milk, but the activation of other areas of the brain has not been explored. Here we hypothesized that daily suckling will induce a rhythm in the preoptic area, lateral septum and bed nucleus of the stria terminalis, which are important areas for the expression of maternal behavior in mammals including the rabbit. To this end, we analyzed PER1 expression in those areas through a complete 24-h cycle at lactation day 7. Does were scheduled to nurse during either the day at 10:00 (ZT03) or the night at 02:00 (ZT19) h. Non-pregnant, non-lactating females were used as controls. In contrast to control females, lactating does show a clear, significant rhythm of PER1 that shifts in parallel to timing of nursing in the preoptic area and lateral septum. We determined that the maximal expression of PER1 at 8 h after scheduled nursing decreased significantly at 24 and 48 h after the absence of suckling. This effect was more pronounced in the lateral septum than in the preoptic area. We conclude that daily suckling is a powerful stimulus that induces rhythmic activity in brain structures in the rabbit that appear to be part of a maternal entrainable circuit. PMID:25370159

  10. Androgen Receptors in the Posterior Bed Nucleus of the Stria Terminalis Increase Neuropeptide Expression and the Stress-Induced Activation of the Paraventricular Nucleus of the Hypothalamus

    PubMed Central

    Bingham, Brenda; Myung, Clara; Innala, Leyla; Gray, Megan; Anonuevo, Adam; Viau, Victor

    2011-01-01

    The posterior bed nuclei of the stria terminalis (BST) are important neural substrate for relaying limbic influences to the paraventricular nucleus (PVN) of the hypothalamus to inhibit hypothalamic-pituitary-adrenal (HPA) axis responses to emotional stress. Androgen receptor-expressing cells within the posterior BST have been identified as projecting to the PVN region. To test a role for androgen receptors in the posterior BST to inhibit PVN motor neurons, we compared the effects of the non-aromatizable androgen dihydrotestosterone (DHT), the androgen receptor antagonist hydroxyflutamide (HF), or a combination of both drugs implanted unilaterally within the posterior BST. Rats bearing unilateral implants were analyzed for PVN Fos induction in response to acute-restraint stress and relative levels of corticotrophin-releasing hormone and arginine vasopressin (AVP) mRNA. Glutamic acid decarboxylase (GAD) 65 and GAD 67 mRNA were analyzed in the posterior BST to test a local involvement of GABA. There were no changes in GAD expression to support a GABA-related mechanism in the BST. For PVN neuropeptide expression and Fos responses, basic effects were lateralized to the sides of the PVN ipsilateral to the implants. However, opposite to our expectations of an inhibitory influence of androgen receptors in the posterior BST, PVN AVP mRNA and stress-induced Fos were augmented in response to DHT and attenuated in response to HF. These results suggest that a subset of androgen receptor-expressing cells within the posterior BST region may be responsible for increasing the biosynthetic capacity and stress-induced drive of PVN motor neurons. PMID:21412226

  11. Sex differences in stress-induced social withdrawal: role of brain derived neurotrophic factor in the bed nucleus of the stria terminalis

    PubMed Central

    Greenberg, Gian D.; Laman-Maharg, Abigail; Campi, Katharine L.; Voigt, Heather; Orr, Veronica N.; Schaal, Leslie; Trainor, Brian C.

    2014-01-01

    Depression and anxiety disorders are more common in women than men, and little is known about the neurobiological mechanisms that contribute to this disparity. Recent data suggest that stress-induced changes in neurotrophins have opposing effects on behavior by acting in different brain networks. Social defeat has been an important approach for understanding neurotrophin action, but low female aggression levels in rats and mice have limited the application of these methods primarily to males. We examined the effects of social defeat in monogamous California mice (Peromyscus californicus), a species in which both males and females defend territories. We demonstrate that defeat stress increases mature brain-derived neurotrophic factor (BDNF) protein but not mRNA in the bed nucleus of the stria terminalis (BNST) in females but not males. Changes in BDNF protein were limited to anterior subregions of the BNST, and there were no changes in the adjacent nucleus accumbens (NAc). The effects of defeat on social withdrawal behavior and BDNF were reversed by chronic, low doses of the antidepressant sertraline. However, higher doses of sertraline restored social withdrawal and elevated BDNF levels. Acute treatment with a low dose of sertraline failed to reverse the effects of defeat. Infusions of the selective tyrosine-related kinase B receptor (TrkB) antagonist ANA-12 into the anterior BNST specifically increased social interaction in stressed females but had no effect on behavior in females naïve to defeat. These results suggest that stress-induced increases in BDNF in the anterior BNST contribute to the exaggerated social withdrawal phenotype observed in females. PMID:24409132

  12. Stress-induced alterations in anxiety-like behavior and adaptations in plasticity in the bed nucleus of the stria terminalis.

    PubMed

    Conrad, Kelly L; Louderback, Katherine M; Gessner, Caitlin P; Winder, Danny G

    2011-08-03

    In vulnerable individuals, exposure to stressors can result in chronic disorders such as generalized anxiety disorder (GAD), major depressive disorder (MDD), and post-traumatic stress disorder (PTSD). The extended amygdala is critically implicated in mediating acute and chronic stress responsivity and anxiety-like behaviors. The bed nucleus of the stria terminalis (BNST), a subregion of the extended amygdala, serves as a relay of corticolimbic information to the paraventricular nucleus of the hypothalamus (PVN) to directly influence the stress response. To investigate the influence of the corticosteroid milieu and housing conditions on BNST function, adult C57Bl/6J were either acutely or chronically administered corticosterone (CORT, 25mg/kg in sesame oil) or vehicle (sesame oil) or were group housed or socially isolated for 1 day (acute) or 6-8 weeks (chronic). To ascertain whether these stressors could influence anxiety-like behavior, studies were performed using the novel open-field (NOF) and the elevated zero maze (EZM) tests. To investigate potential associated changes in plasticity, alterations in BNST function were assessed using ex vivo extracellular field potential recordings in the (dorsal-lateral) dlBNST and a high frequency stimulus protocol to induce long-term potentiation (LTP). Our results suggest that chronic CORT injections and chronic social isolation housing conditions lead to an increase in anxiety-like behavior on the EZM and NOF. Chronically stressed mice also displayed a parallel blunting of LTP in the dlBNST. Conversely, acute social isolation housing had no effect on anxiety-like behavior but still resulted in a blunting of LTP in the dlBNST. Collectively, our results suggest acute and chronic stressors can have a distinct profile on plasticity in the BNST that is not uniformly associated with an increase in anxiety-like behavior.

  13. Inputs to the ventrolateral bed nucleus of the stria terminalis

    PubMed Central

    Shin, Jung-Won; Geerling, Joel C.; Loewy, Arthur D.

    2009-01-01

    The ventrolateral bed nucleus of the stria terminalis (BSTvl) receives direct input from two specific subpopulations of neurons in the nucleus tractus solitarius (NTS). It is heavily innervated by aldosterone-sensitive NTS neurons, which are selectively activated by sodium depletion, and by the A2 noradrenergic neurons, which are activated by visceral, immune- and stress-related stimuli. Here, we used a retrograde neuronal tracer to identify other brain sites that innervate the BSTvl. Five general brain regions contained retrogradely labeled neurons: cerebral cortex (infralimbic and insular regions), rostral forebrain structures (subfornical organ, organum vasculosum of the lamina terminalis, taenia tecta, nucleus accumbens, lateral septum, endopiriform nucleus, dorsal BST, substantia innominata, and most prominently the amygdala – primarily its basomedial and central subnuclei), thalamus (central medial, intermediodorsal, reuniens, and most prominently the paraventricular thalamic nucleus), hypothalamus (medial preoptic area, perifornical, arcuate, dorsomedial, parasubthalamic, and posterior hypothalamic nuclei), and brainstem (periaqueductal gray matter, dorsal and central superior raphe nuclei, parabrachial nucleus, pre-locus coeruleus region, NTS, and A1 noradrenergic neurons in the caudal ventrolateral medulla). In the arcuate hypothalamic nucleus, some retrogradely-labeled neurons contained either agouti-related peptide or cocaine-amphetamine regulated transcript. Of the numerous retrogradely labeled neurons in the perifornical hypothalamic area, few contained melanin concentrating hormone or orexin. In the brainstem, many retrogradely labeled neurons were either serotoninergic or catecholaminergic. In summary, the BSTvl receives inputs from a variety of brain sites implicated in hunger, salt and water intake, stress, arousal, and reward. PMID:18853414

  14. Tissue plasminogen activator in the bed nucleus of stria terminalis regulates acoustic startle.

    PubMed

    Matys, T; Pawlak, R; Strickland, S

    2005-01-01

    The bed nucleus of stria terminalis is a basal forebrain region involved in regulation of hormonal and behavioral responses to stress. In this report we demonstrate that bed nucleus of stria terminalis has a high and localized expression of tissue plasminogen activator, a serine protease with neuromodulatory properties and implicated in neuronal plasticity. Tissue plasminogen activator activity in the bed nucleus of stria terminalis is transiently increased in response to acute restraint stress or i.c.v. administration of a major stress mediator, corticotropin-releasing factor. We show that tissue plasminogen activator is important in bed nucleus of stria terminalis function using two criteria: 1, Neuronal activation in this region as measured by c-fos induction is reduced in tissue plasminogen activator-deficient mice; and 2, a bed nucleus of stria terminalis-dependent behavior, potentiation of acoustic startle by corticotropin-releasing factor, is attenuated in tissue plasminogen activator-deficient mice. These studies identify a novel site of tissue plasminogen activator expression in the mouse brain and demonstrate a functional role for this protease in the bed nucleus of stria terminalis.

  15. Functional Heterogeneity in the Bed Nucleus of the Stria Terminalis

    PubMed Central

    Gungor, Nur Zeynep

    2016-01-01

    Early work stressed the differing involvement of the central amygdala (CeA) and bed nucleus of the stria terminalis (BNST) in the genesis of fear versus anxiety, respectively. In 2009, Walker, Miles, and Davis proposed a model of amygdala-BNST interactions to explain these functional differences. This model became extremely influential and now guides a new wave of studies on the role of BNST in humans. Here, we consider evidence for and against this model, in the process highlighting central principles of BNST organization. This analysis leads us to conclude that BNST's influence is not limited to the generation of anxiety-like responses to diffuse threats, but that it also shapes the impact of discrete threatening stimuli. It is likely that BNST-CeA interactions are involved in modulating responses to such threats. In addition, whereas current views emphasize the contributions of the anterolateral BNST region in anxiety, accumulating data indicate that the anteromedial and anteroventral regions also play a critical role. The presence of multiple functional subregions within the small volume of BNST raises significant technical obstacles for functional imaging studies in humans. PMID:27488624

  16. Neuronal Correlates of Fear Conditioning in the Bed Nucleus of the Stria Terminalis

    ERIC Educational Resources Information Center

    Haufler, Darrell; Nagy, Frank Z.; Pare, Denis

    2013-01-01

    Lesion and inactivation studies indicate that the central amygdala (CeA) participates in the expression of cued and contextual fear, whereas the bed nucleus of the stria terminalis (BNST) is only involved in the latter. The basis for this functional dissociation is unclear because CeA and BNST form similar connections with the amygdala and…

  17. Neuronal Correlates of Fear Conditioning in the Bed Nucleus of the Stria Terminalis

    ERIC Educational Resources Information Center

    Haufler, Darrell; Nagy, Frank Z.; Pare, Denis

    2013-01-01

    Lesion and inactivation studies indicate that the central amygdala (CeA) participates in the expression of cued and contextual fear, whereas the bed nucleus of the stria terminalis (BNST) is only involved in the latter. The basis for this functional dissociation is unclear because CeA and BNST form similar connections with the amygdala and…

  18. Extracellular-signal regulated kinase 1-dependent metabotropic glutamate receptor 5-induced long-term depression in the bed nucleus of the stria terminalis is disrupted by cocaine administration.

    PubMed

    Grueter, Brad A; Gosnell, Heather B; Olsen, Christopher M; Schramm-Sapyta, Nicole L; Nekrasova, Tanya; Landreth, Gary E; Winder, Danny G

    2006-03-22

    The bed nucleus of the stria terminalis (BNST) is a key component of the CNS stress and reward circuit. Synaptic plasticity in this region could in part underlie the persistent behavioral alterations in generalized anxiety and addiction. Group I metabotropic glutamate receptors (mGluRs) have been implicated in stress, addiction, and synaptic plasticity, but their roles in the BNST are unknown. We find that activation of group I mGluRs in the dorsal BNST induces depression of excitatory synaptic transmission through two distinct mechanisms. First, a combined activation of group I mGluRs (mGluR1 and mGluR5) induces a transient depression that is cannabinoid 1 receptor dependent. Second, as with endocannabinoid-independent group I mGluR long-term depression (LTD) in the adult hippocampus, we find that activation of mGluR5 induces an extracellular signal-regulated kinase (ERK)-dependent LTD. Surprisingly, our data demonstrate that this LTD requires the ERK1 rather than ERK2 isoform, establishing a key role for this isoform in the CNS. Finally, we find that this LTD is dramatically reduced after multiple exposures but not a single exposure to cocaine, suggesting a role for this form of plasticity in the actions of psychostimulants on anxiety and reward circuitries and their emergent control of animal behavior.

  19. Regulation of bed nucleus of the stria terminalis PACAP expression by stress and corticosterone.

    PubMed

    Lezak, Kimberly R; Roman, Carolyn W; Braas, Karen M; Schutz, Kristin C; Falls, William A; Schulkin, Jay; May, Victor; Hammack, Sayamwong E

    2014-11-01

    Single-nucleotide polymorphisms (SNPs) in the genes for pituitary adenylyl cyclase-activating peptide (PACAP) and the PAC1 receptor have been associated with stress-related psychiatric disorders. Although, from recent work, we have argued that stress-induced PACAP expression in the bed nucleus of the stria terminalis (BNST) may mediate stress-related psychopathology, it is unclear whether stress-induced increases in BNST PACAP expression require acute or repeated stressor exposure and whether increased BNST PACAP expression is related to stress-induced increases in circulating glucocorticoids. In the current work, we have used real-time quantitative polymerase chain reaction (qPCR) to assess transcript expression in brain punches from rats after stressor exposure paradigms or corticosterone injection. BNST PACAP and PAC1 receptor transcript expression was increased only after 7 days of repeated stressor exposure; no changes in transcript levels were observed 2 or 24 hours after a single-restraint session. Moreover, repeated corticosterone treatment for 7 days was not sufficient to reliably increase BNST PACAP transcript levels, suggesting that stress-induced elevations in corticosterone may not be the primary drivers of BNST PACAP expression. These results may help clarify the mechanisms and temporal processes that underlie BNST PACAP induction for intervention in stress-related anxiety disorders.

  20. Role of bed nucleus of the stria terminalis corticotrophin-releasing factor receptors in frustration stress-induced binge-like palatable food consumption in female rats with a history of food restriction.

    PubMed

    Micioni Di Bonaventura, Maria Vittoria; Ciccocioppo, Roberto; Romano, Adele; Bossert, Jennifer M; Rice, Kenner C; Ubaldi, Massimo; St Laurent, Robyn; Gaetani, Silvana; Massi, Maurizio; Shaham, Yavin; Cifani, Carlo

    2014-08-20

    We developed recently a binge-eating model in which female rats with a history of intermittent food restriction show binge-like palatable food consumption after 15 min exposure to the sight of the palatable food. This "frustration stress" manipulation also activates the hypothalamic-pituitary-adrenal stress axis. Here, we determined the role of the stress neurohormone corticotropin-releasing factor (CRF) in stress-induced binge eating in our model. We also assessed the role of CRF receptors in the bed nucleus of the stria terminalis (BNST), a brain region implicated in stress responses and stress-induced drug seeking, in stress-induced binge eating. We used four groups that were first exposed or not exposed to repeated intermittent cycles of regular chow food restriction during which they were also given intermittent access to high-caloric palatable food. On the test day, we either exposed or did not expose the rats to the sight of the palatable food for 15 min (frustration stress) before assessing food consumption for 2 h. We found that systemic injections of the CRF1 receptor antagonist R121919 (2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7 dipropylamino pyrazolo[1,5-a]pyrimidine) (10-20 mg/kg) and BNST (25-50 ng/side) or ventricular (1000 ng) injections of the nonselective CRF receptor antagonist D-Phe-CRF(12-41) decreased frustration stress-induced binge eating in rats with a history of food restriction. Frustration stress also increased Fos (a neuronal activity marker) expression in ventral and dorsal BNST. Results demonstrate a critical role of CRF receptors in BNST in stress-induced binge eating in our rat model. CRF1 receptor antagonists may represent a novel pharmacological treatment for bingeing-related eating disorders. Copyright © 2014 the authors 0270-6474/14/3411316-09$15.00/0.

  1. Role of Bed Nucleus of the Stria Terminalis Corticotrophin-Releasing Factor Receptors in Frustration Stress-Induced Binge-Like Palatable Food Consumption in Female Rats with a History of Food Restriction

    PubMed Central

    Micioni Di Bonaventura, Maria Vittoria; Ciccocioppo, Roberto; Romano, Adele; Bossert, Jennifer M.; Rice, Kenner C.; Ubaldi, Massimo; St. Laurent, Robyn; Gaetani, Silvana; Massi, Maurizio; Shaham, Yavin

    2014-01-01

    We developed recently a binge-eating model in which female rats with a history of intermittent food restriction show binge-like palatable food consumption after 15 min exposure to the sight of the palatable food. This “frustration stress” manipulation also activates the hypothalamic–pituitary–adrenal stress axis. Here, we determined the role of the stress neurohormone corticotropin-releasing factor (CRF) in stress-induced binge eating in our model. We also assessed the role of CRF receptors in the bed nucleus of the stria terminalis (BNST), a brain region implicated in stress responses and stress-induced drug seeking, in stress-induced binge eating. We used four groups that were first exposed or not exposed to repeated intermittent cycles of regular chow food restriction during which they were also given intermittent access to high-caloric palatable food. On the test day, we either exposed or did not expose the rats to the sight of the palatable food for 15 min (frustration stress) before assessing food consumption for 2 h. We found that systemic injections of the CRF1 receptor antagonist R121919 (2,5-dimethyl-3-(6-dimethyl-4-methylpyridin-3-yl)-7 dipropylamino pyrazolo[1,5-a]pyrimidine) (10–20 mg/kg) and BNST (25–50 ng/side) or ventricular (1000 ng) injections of the nonselective CRF receptor antagonist d-Phe-CRF(12–41) decreased frustration stress-induced binge eating in rats with a history of food restriction. Frustration stress also increased Fos (a neuronal activity marker) expression in ventral and dorsal BNST. Results demonstrate a critical role of CRF receptors in BNST in stress-induced binge eating in our rat model. CRF1 receptor antagonists may represent a novel pharmacological treatment for bingeing-related eating disorders. PMID:25143612

  2. Medullary norepinephrine neurons modulate local oxygen concentrations in the bed nucleus of the stria terminalis

    PubMed Central

    Bucher, Elizabeth S; Fox, Megan E; Kim, Laura; Kirkpatrick, Douglas C; Rodeberg, Nathan T; Belle, Anna M; Wightman, R  Mark

    2014-01-01

    Neurovascular coupling is understood to be the underlying mechanism of functional hyperemia, but the actions of the neurotransmitters involved are not well characterized. Here we investigate the local role of the neurotransmitter norepinephrine in the ventral bed nucleus of the stria terminalis (vBNST) of the anesthetized rat by measuring O2, which is delivered during functional hyperemia. Extracellular changes in norepinephrine and O2 were simultaneously monitored using fast-scan cyclic voltammetry. Introduction of norepinephrine by electrical stimulation of the ventral noradrenergic bundle or by iontophoretic ejection induced an initial increase in O2 levels followed by a brief dip below baseline. Supporting the role of a hyperemic response, the O2 increases were absent in a brain slice containing the vBNST. Administration of selective pharmacological agents demonstrated that both phases of this response involve β-adrenoceptor activation, where the delayed decrease in O2 is sensitive to both α- and β-receptor subtypes. Selective lesioning of the locus coeruleus with the neurotoxin DSP-4 confirmed that these responses are caused by the noradrenergic cells originating in the nucleus of the solitary tract and A1 cell groups. Overall, these results support that non-coerulean norepinephrine release can mediate activity-induced O2 influx in a deep brain region. PMID:24714037

  3. Adolescent nicotine alters dendritic morphology in the bed nucleus of the stria terminalis.

    PubMed

    Smith, Kelsey C; Ehlinger, Daniel G; Smith, Robert F

    2015-03-17

    Adolescent nicotine increases dendritic elaboration in several areas associated with the extended amygdala. It also increases anxiety-like behavior in adulthood. An unresolved question is whether adolescent nicotine alters dendritic structure in the bed nucleus of the stria terminalis (BNST), which may contribute to altered anxiety-like behavior. To investigate this possibility, adolescent male Sprague-Dawley rats were administered nicotine (0.5mg/kg/day) 3 days a week for 2 consecutive weeks, starting at postnatal day P (32). 17 days following the end of dosing, brains were processed for Golgi-Cox staining, and neurons were digitally reconstructed in three dimensions. Animals previously treated with nicotine exhibited an increase in the total number of branches and total length of dendrites on BNST neurons. Sholl analysis revealed an increase in the number of intersections with concentric spheres, increased amount of dendritic material within concentric spheres, and an increase of dendritic branching within concentric spheres occurring between 20 and 300 μm from the soma in dendrites. Collectively, our results show that adolescent nicotine alters dendritic structure (by triggering new branch growth), and, by inference, connectivity of the BNST, which may contribute to alterations in behavior induced by adolescent nicotine.

  4. Effects of clonidine injections into the bed nucleus of the stria terminalis on fear and anxiety behavior in rats.

    PubMed

    Schweimer, Judith; Fendt, Markus; Schnitzler, Hans-Ulrich

    2005-01-10

    Emotions such as fear and anxiety are mediated by a neural network containing nuclei like the amygdala, the bed nucleus of the stria terminalis and the periaqueductal gray. Noradrenaline is a neurotransmitter closely connected with the processing of stimuli eliciting these emotions. The bed nucleus of the stria terminalis contains the highest density of noradrenaline within the brain. In the present study, we investigated effects of injections of the noradrenergic alpha2-adrenoceptor agonist clonidine into the bed nucleus of the stria terminalis on learned and unlearned fear (anxiety) in rats on different animal models of fear and anxiety: acquisition and expression of fear-potentiated startle, sensitization of the acoustic startle response by foot shocks and light-enhanced startle. Clonidine injections disrupted acquisition and expression of fear-potentiated startle, as well as light-enhanced startle, whereas sensitization was not affected. These results indicate that noradrenaline within the bed nucleus of the stria terminalis mediates both fear and anxiety. We suggest that there is rather a neurochemical than a neuroanatomical dissociation between learned fear and anxiety as hypothesized by Walker and Davis (Walker, D.L. and M. Davis, 1997b, Double dissociation between the involvement of the bed nucleus of the stria terminalis and the central nucleus of the amygdala in startle increases produced by conditioned versus unconditioned fear, J. Neurosci. 17, 9375-9383.).

  5. Role of the bed nucleus of the stria terminalis versus the amygdala in fear, stress, and anxiety.

    PubMed

    Walker, David L; Toufexis, Donna J; Davis, Michael

    2003-02-28

    The bed nucleus of the stria terminalis is a limbic forebrain structure that receives heavy projections from, among other areas, the basolateral amygdala, and projects in turn to hypothalamic and brainstem target areas that mediate many of the autonomic and behavioral responses to aversive or threatening stimuli. Despite its strategic anatomical position, initial attempts to implicate the bed nucleus of the stria terminalis in conditioned fear were largely unsuccessful. Recent studies have shown, however, that the bed nucleus of the stria terminalis does participate in certain types of anxiety and stress responses. In this work, we review these findings and suggest from the emerging pattern of evidence that, although the bed nucleus of the stria terminalis may not be necessary for rapid-onset, short-duration behaviors which occur in response to specific threats, the bed nucleus of the stria terminalis may mediate slower-onset, longer-lasting responses that frequently accompany sustained threats, and that may persist even after threat termination.

  6. Exogenous corticosterone induces the expression of the clock protein, PERIOD2, in the oval nucleus of the bed nucleus of the stria terminalis and the central nucleus of the amygdala of adrenalectomized and intact rats.

    PubMed

    Segall, Lauren A; Amir, Shimon

    2010-10-01

    The cyclical expression of the clock protein PERIOD2 (PER2) in select regions of the limbic forebrain is contingent upon the rhythmic secretion of the adrenal glucocorticoid, corticosterone. Daily rhythmic PER2 expression in the oval nucleus of the bed nucleus of the stria terminalis (BNSTov) and the central nucleus of the amygdala (CEA) is abolished with the removal of the adrenal glands but restored with rhythmic hormone replacement via the drinking water at a time corresponding to the endogenous peak of circulating glucocorticoids. Here, we investigated the effects of serial or acute systemic injections of corticosterone on the expression of PER2 in the BNSTov and CEA of both adrenalectomized (ADX) and intact rats. We sought to determine whether there is a temporal window of corticosterone sensitivity by delivering the hormone at a time corresponding to trough levels of circulating glucocorticoids, at lights on. We found that daily morning injections of corticosterone induced PER2 expression in the BNSTov and CEA of ADX rats, with levels peaking 1 h after injection. In intact rats, daily morning injections significantly upregulated the expression of PER2 in the BNSTov and CEA 1 h after injection and dampened the evening peak, while a single injection abolished the rhythm of PER2 expression in the CEA but had no effect on PER2 in the BNSTov. Our findings suggest that despite the potential masking effect of signals from the light-entrained master clock, daytime chronic and acute corticosterone administration can alter the rhythmic expression of PER2 in the BNSTov and CEA, and that the response is region-specific and dependent on the duration of treatment.

  7. The bed nucleus of the stria terminalis regulates ethanol-seeking behavior in mice.

    PubMed

    Pina, Melanie M; Young, Emily A; Ryabinin, Andrey E; Cunningham, Christopher L

    2015-12-01

    Drug-associated stimuli are considered important factors in relapse to drug use. In the absence of drug, these cues can trigger drug craving and drive subsequent drug seeking. One structure that has been implicated in this process is the bed nucleus of the stria terminalis (BNST), a chief component of the extended amygdala. Previous studies have established a role for the BNST in cue-induced cocaine seeking. However, it is unclear if the BNST underlies cue-induced seeking of other abused drugs such as ethanol. In the present set of experiments, BNST involvement in ethanol-seeking behavior was assessed in male DBA/2J mice using the conditioned place preference procedure (CPP). The BNST was inhibited during CPP expression using electrolytic lesions (Experiment 1), co-infusion of GABAA and GABAB receptor agonists muscimol and baclofen (M+B; Experiment 2), and activation of inhibitory designer receptors exclusively activated by designer drugs (hM4Di-DREADD) with clozapine-N-oxide (CNO; Experiment 3). The magnitude of ethanol CPP was reduced significantly by each of these techniques. Notably, infusion of M+B (Exp. 2) abolished CPP altogether. Follow-up studies to Exp. 3 showed that ethanol cue-induced c-Fos immunoreactivity in the BNST was reduced by hM4Di activation (Experiment 4) and in the absence of hM4Di, CNO did not affect ethanol CPP (Experiment 5). Combined, these findings demonstrate that the BNST is involved in the modulation of cue-induced ethanol-seeking behavior. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. The Bed Nucleus of the Stria Terminalis Regulates Ethanol-Seeking Behavior in Mice

    PubMed Central

    Pina, Melanie M.; Young, Emily A.; Ryabinin, Andrey E.; Cunningham, Christopher L.

    2015-01-01

    Drug-associated stimuli are considered important factors in relapse to drug use. In the absence of drug, these cues can trigger drug craving and drive subsequent drug seeking. One structure that has been implicated in this process is the bed nucleus of the stria terminalis (BNST), a chief component of the extended amygdala. Previous studies have established a role for the BNST in cue-induced cocaine seeking. However, it is unclear if the BNST underlies cue-induced seeking of other abused drugs such as ethanol. In the present set of experiments, BNST involvement in ethanol-seeking behavior was assessed in male DBA/2J mice using the conditioned place preference procedure (CPP). The BNST was inhibited during CPP expression using electrolytic lesions (Experiment 1), co-infusion of GABAA and GABAB receptor agonists muscimol and baclofen (M+B; Experiment 2), and activation of inhibitory designer receptors exclusively activated by designer drugs (hM4Di-DREADD) with clozapine-N-oxide (CNO; Experiment 3). The magnitude of ethanol CPP was reduced significantly by each of these techniques. Notably, infusion of M+B (Exp. 2) abolished CPP altogether. Follow-up studies to Exp. 3 showed that ethanol cue-induced c-Fos immunoreactivity in the BNST was reduced by hM4Di activation (Experiment 4) and in the absence of hM4Di, CNO did not affect ethanol CPP (Experiment 5). Combined, these findings demonstrate that the BNST is involved in the modulation of cue-induced ethanol-seeking behavior. PMID:26302652

  9. Ethanol induced adaptations in 5-HT2c receptor signaling in the bed nucleus of stria terminalis: Implications for anxiety during ethanol withdrawal

    PubMed Central

    Marcinkiewcz, Catherine A.; Dorrier, Cayce E.; Lopez, Alberto J.; Kash, Thomas L.

    2015-01-01

    One of the hallmarks of alcohol dependence is the presence of a withdrawal syndrome during abstinence, which manifests as physical craving for alcohol accompanied by subjective feelings of anxiety. Using a model of chronic intermittent ethanol (CIE) vapor in mice, we investigated the role of serotonin2c signaling in the BNST as a neural substrate underlying ethanol-induced anxiety during withdrawal. Mice were subjected to a 5-day CIE regimen of 16 hours of ethanol vapor exposure followed by an 8 hour “withdrawal” period between exposures. After the 5th and final exposure, mice were withdrawn for 24 hours or 1 week before experiments began. Anxiety-like behavior was assessed in the social approach, light dark, and open field test with mice showing deficits in social, but not general anxiety-like behavior that was alleviated by pretreatment with the 5HT2c-R antagonist SB 242,084 (3 mg/kg, i.p.) 24 hours and 1 week post-CIE. Using immunohistochemistry and whole cell patch clamp electrophysiology, we also found that CIE increased FOS-IR and enhanced neuronal excitability in the ventral BNST (vBNST) 24 hrs into withdrawal in a 5HT2c-R dependent manner. This enhanced excitability persisted for 1 week post-CIE. We also found that mCPP, a 5HT2c/b agonist, induced a more robust depolarization in cells of the vBNST in CIE mice, confirming that 5HT2c-R signaling is upregulated in the vBNST following CIE. Taken together, these results suggest that CIE upregulates 5HT2c-R signaling in the vBNST, leading to increased excitability. This enhanced excitability of the vBNST may drive increased anxiety-like behavior during ethanol withdrawal. PMID:25229718

  10. Ethanol induced adaptations in 5-HT2c receptor signaling in the bed nucleus of the stria terminalis: implications for anxiety during ethanol withdrawal.

    PubMed

    Marcinkiewcz, Catherine A; Dorrier, Cayce E; Lopez, Alberto J; Kash, Thomas L

    2015-02-01

    One of the hallmarks of alcohol dependence is the presence of a withdrawal syndrome during abstinence, which manifests as physical craving for alcohol accompanied by subjective feelings of anxiety. Using a model of chronic intermittent ethanol (CIE) vapor in mice, we investigated the role of serotonin2c receptor (5HT2c-R) signaling in the BNST as a neural substrate underlying ethanol-induced anxiety during withdrawal. Mice were subjected to a 5-day CIE regimen of 16 h of ethanol vapor exposure followed by an 8 h "withdrawal" period between exposures. After the 5th and final exposure, mice were withdrawn for 24 h or 1 week before experiments began. Anxiety-like behavior was assessed in the social approach, light dark, and open field tests with mice showing deficits in social, but not general anxiety-like behavior that was alleviated by pretreatment with the 5HT2c-R antagonist SB 242,084 (3 mg/kg, i.p.) 24 h and 1 week post-CIE. Using immunohistochemistry and whole cell patch clamp electrophysiology, we also found that CIE increased FOS-IR and enhanced neuronal excitability in the ventral BNST (vBNST) 24 h into withdrawal in a 5HT2c-R dependent manner. This enhanced excitability persisted for 1 week post-CIE. We also found that mCPP, a 5HT2c/b agonist, induced a more robust depolarization in cells of the vBNST in CIE mice, confirming that 5HT2c-R signaling is upregulated in the vBNST following CIE. Taken together, these results suggest that CIE upregulates 5HT2c-R signaling in the vBNST, leading to increased excitability. This enhanced excitability of the vBNST may drive increased anxiety-like behavior during ethanol withdrawal. Published by Elsevier Ltd.

  11. ASIC1A in the bed nucleus of the stria terminalis mediates TMT-evoked freezing

    PubMed Central

    Taugher, Rebecca J.; Ghobbeh, Ali; Sowers, Levi P.; Fan, Rong; Wemmie, John A.

    2015-01-01

    Mice display an unconditioned freezing response to TMT, a predator odor isolated from fox feces. Here we found that in addition to freezing, TMT caused mice to decrease breathing rate, perhaps because of the aversive smell. Consistent with this possibility, olfactory bulb lesions attenuated this effect of TMT, as well as freezing. Interestingly, butyric acid, another foul odor, also caused mice to reduce breathing rate. However, unlike TMT, butyric acid did not induce freezing. Thus, although these aversive odors may affect breathing, the unpleasant smell and suppression of breathing by themselves are insufficient to cause freezing. Because the acid-sensing ion channel-1A (ASIC1A) has been previously implicated in TMT-evoked freezing, we tested whether Asic1a disruption also altered breathing. We found that TMT reduced breathing rate in both Asic1a+/+ and Asic1a−/− mice, suggesting that ASIC1A is not required for TMT to inhibit breathing and that the absence of TMT-evoked freezing in the Asic1a−/− mice is not due to an inability to detect TMT. These observations further indicate that ASIC1A must affect TMT freezing in another way. Because the bed nucleus of the stria terminalis (BNST) has been critically implicated in TMT-evoked freezing and robustly expresses ASIC1A, we tested whether ASIC1A in the BNST plays a role in TMT-evoked freezing. We disrupted ASIC1A in the BNST of Asic1aloxP/loxP mice by delivering Cre recombinase to the BNST with an adeno-associated virus (AAV) vector. We found that disrupting ASIC1A in the BNST reduced TMT-evoked freezing relative to control mice in which a virus expressing eGFP was injected. To test whether ASIC1A in the BNST was sufficient to increase TMT-evoked freezing, we used another AAV vector to express ASIC1A in the BNST of Asic1a−/− mice. We found region-restricted expression of ASIC1A in the BNST increased TMT-elicited freezing. Together, these data suggest that the BNST is a key site of ASIC1A action in TMT

  12. The Proinflammatory Cytokine Interleukin 18 Regulates Feeding by Acting on the Bed Nucleus of the Stria Terminalis.

    PubMed

    Francesconi, Walter; Sánchez-Alavez, Manuel; Berton, Fulvia; Alboni, Silvia; Benatti, Cristina; Mori, Simone; Nguyen, William; Zorrilla, Eric; Moroncini, Gianluca; Tascedda, Fabio; Conti, Bruno

    2016-05-04

    The proinflammatory cytokine IL-18 has central anorexigenic effects and was proposed to contribute to loss of appetite observed during sickness. Here we tested in the mouse the hypothesis that IL-18 can decrease food intake by acting on neurons of the bed nucleus of the stria terminalis (BST), a component of extended amygdala recently shown to influence feeding via its projections to the lateral hypothalamus (LH). We found that both subunits of the heterodimeric IL-18 receptor are highly expressed in the BST and that local injection of recombinant IL-18 (50 ng/ml) significantly reduced c-fos activation and food intake for at least 6 h. Electrophysiological experiments performed in BST brain slices demonstrated that IL-18 strongly reduces the excitatory input on BST neurons through a presynaptic mechanism. The effects of IL-18 are cell-specific and were observed in Type III but not in Type I/II neurons. Interestingly, IL-18-sensitve Type III neurons were recorded in the juxtacapsular BST, a region that contains BST-LH projecting neurons. Reducing the excitatory input on Type III GABAergic neurons, IL-18 can increase the firing of glutamatergic LH neurons through a disinhibitory mechanism. Imbalance between excitatory and inhibitory activity in the LH can induce changes in food intake. Effects of IL-18 were mediated by the IL-18R because they were absent in neurons from animals null for IL-18Rα (Il18ra(-/-)), which lack functional IL-18 receptors. In conclusion, our data show that IL-18 may inhibit feeding by inhibiting the activity of BST Type III GABAergic neurons. Loss of appetite during sickness is a common and often debilitating phenomenon. Although proinflammatory cytokines are recognized as mediators of these anorexigenic effects, their mechanism and sites of action remain poorly understood. Here we show that interleukin 18, an anorexigenic cytokine, can act on neurons of the bed nucleus of the stria terminalis to reduce food intake via the IL-18 receptor

  13. Desipramine and citalopram attenuate pretest swim-induced increases in prodynorphin immunoreactivity in the dorsal bed nucleus of the stria terminalis and the lateral division of the central nucleus of the amygdala in the forced swimming test.

    PubMed

    Chung, Sung; Kim, Hee Jeong; Kim, Hyun Ju; Choi, Sun Hye; Cho, Jin Hee; Cho, Yun Ha; Kim, Dong-Hoon; Shin, Kyung Ho

    2014-10-01

    Dynorphin in the nucleus accumbens shell plays an important role in antidepressant-like effect in the forced swimming test (FST), but it is unclear whether desipramine and citalopram treatments alter prodynorphin levels in other brain areas. To explore this possibility, we injected mice with desipramine and citalopram 0.5, 19, and 23 h after a 15-min pretest swim and observed changes in prodynorphin expression before the test swim, which was conducted 24 h after the pretest swim. The pretest swim increased prodynorphin immunoreactivity in the dorsal bed nucleus of the stria terminalis (dBNST) and lateral division of the central nucleus of the amygdala (CeL). This increase in prodynorphin immunoreactivity in the dBNST and CeL was blocked by desipramine and citalopram treatments. Similar changes in prodynorphin mRNA levels were observed in the dBNST and CeL, but these changes did not reach significance. To understand the underlying mechanism, we assessed changes in phosphorylated CREB at Ser(133) (pCREB) immunoreactivity in the dBNST and central nucleus of the amygdala (CeA). Treatment with citalopram but not desipramine after the pretest swim significantly increased pCREB immunoreactivity only in the dBNST. These results suggest that regulation of prodynorphin in the dBNST and CeL before the test swim may be involved in the antidepressant-like effect of desipramine and citalopram in the FST and suggest that changes in pCREB immunoreactivity in these areas may not play an important role in the regulation of prodynorphin in the dBNST and CeA.

  14. Resting State Connectivity of the Bed Nucleus of the Stria Terminalis at Ultra-high Field

    PubMed Central

    Torrisi, Salvatore; O'Connell, Katherine; Davis, Andrew; Reynolds, Richard; Balderston, Nick; Fudge, Julie; Grillon, Christian; Ernst, Monique

    2015-01-01

    The bed nucleus of the stria terminalis (BNST), a portion of the ‘extended amygdala’, is implicated in the pathophysiology of anxiety and addiction disorders. Its small size and connection to other small regions prevents standard imaging techniques from easily capturing it and its connectivity with confidence. Seed-based resting state functional connectivity is an established method for mapping functional connections across the brain from a region of interest. We therefore mapped the BNST resting state network with high spatial resolution using 7 Tesla fMRI, demonstrating the in vivo reproduction of many human BNST connections previously described only in animal research. We identify strong BNST functional connectivity in amygdala, hippocampus and thalamic subregions, caudate, periaqueductal gray, hypothalamus and cortical areas such as the medial PFC and precuneus. This work, which demonstrates the power of ultra-high field for mapping functional connections in the human, is an important step towards elucidating cortical and subcortical regions and subregions of the BNST network. PMID:26178381

  15. Anatomical and neurochemical definition of the nucleus of the stria terminalis in Japanese quail (Coturnix japonica).

    PubMed

    Aste, N; Balthazart, J; Absil, P; Grossmann, R; Mülhbauer, E; Viglietti-Panzica, C; Panzica, G C

    1998-06-29

    This study in birds provides anatomical, immunohistochemical, and hodological data on a prosencephalic region in which the nomenclature is still a matter of discussion. In quail, this region is located just dorsal to the anterior commissure and extends from the level of the medial part of the preoptic area at its most rostral end to the caudal aspects of the nucleus preopticus medialis. At this caudal level, it reaches its maximal elongation and extends from the ventral tip of the lateral ventricles to the dorsolateral aspects of the paraventricular nucleus. This area contains aromatase-immunoreactive cells and a sexually dimorphic population of small, vasotocinergic neurons. The Nissl staining of adjacent sections revealed the presence of a cluster of intensely stained cells outlining the same region delineated by the vasotocin-immunoreactive structures. Cytoarchitectonic, immunohistochemical, and in situ hybridization data support the notion that this area is similar and is probably homologous to the medial part of the nucleus of the stria terminalis of the mammalian brain. The present data provide a clear definition of this nucleus in quail: They show for the first time the presence of sexually dimorphic vasotocinergic neurons in this region of the quail brain and provide the first detailed description of this region in an avian species.

  16. Medullary Norepinephrine Projections Release Norepinephrine into the Contralateral Bed Nucleus of the Stria Terminalis

    PubMed Central

    2016-01-01

    Central norepinephrine signaling influences a wide range of behavioral and physiological processes, and the ventral bed nucleus of the stria terminalis (vBNST) receives some of the densest norepinephrine innervation in the brain. Previous work describes norepinephrine neurons as projecting primarily unilaterally; however, recent evidence for cross-hemispheric catecholamine signaling challenges this idea. Here, we use fast-scan cyclic voltammetry and retrograde tracing to characterize cross-hemispheric norepinephrine signaling in the vBNST. We delivered stimulations to noradrenergic pathways originating in the A1/A2 and locus coeruleus and found hemispherically equivalent norepinephrine release in the vBNST regardless of stimulated hemisphere. Unilateral retrograde tracing revealed that medullary, but not locus coeruleus norepinephrine neurons send cross-hemispheric projections to the vBNST. Further characterization with pharmacological lesions revealed that stimulations of the locus coeruleus and its axon bundles likely elicit vBNST norepinephrine release through indirect activation. These experiments are the first to demonstrate contralateral norepinephrine release and establish that medullary, but not coerulean neurons are responsible for norepinephrine release in the vBNST. PMID:27617735

  17. MORPHINE PRODUCES CIRCUIT-SPECIFIC NEUROPLASTICITY IN THE BED NUCLEUS OF THE STRIA TERMINALIS

    PubMed Central

    Dumont, É. C.; Rycroft, B. K.; Maiz, J.; Williams, J. T.

    2013-01-01

    The bed nucleus of the stria terminalis (BST) is a brain structure located at the interface of the cortex and the cerebrospinal trunk. The BST is a cluster of nuclei organized in a complex intrinsic network that receives inputs from cortical and subcortical sources, and that sends a widespread top-down projection. There is growing evidence that the BST is a key component in the neurobiological basis of substance abuse. In the present study, the regulation of excitatory inputs onto identified neurons in the BST was examined in rats treated chronically with morphine. Neurons projecting to the ventral tegmental area (VTA) were identified by retrograde transport of fluorescent microspheres and recorded in the whole-cell voltage clamp configuration in brain slices. Selective excitatory inputs to these neurons were electrically evoked with electrodes placed in the medial and lateral aspects of the dorsal BST. The chronic morphine treatment selectively increased AMPA-dependent excitatory postsynaptic currents in a subset of inputs activated by dorso-lateral stimulation in the BST. Inputs activated by medial stimulation were not affected by morphine. Likewise, the inputs to neurons that did not project to the VTA were not changed by morphine. Altogether, these results extend the understanding of neuronal circuits intrinsically sensitive to drugs of abuse within the BST. PMID:18343592

  18. Stress Modulation of Opposing Circuits in the Bed Nucleus of the Stria Terminalis

    PubMed Central

    Daniel, Sarah E; Rainnie, Donald G

    2016-01-01

    The anterior bed nucleus of the stria terminalis (BNST) has been recognized as a critical structure in regulating trait anxiety, contextual fear memory, and appetitive behavior, and is known to be sensitive to stress manipulations. As one of the most complex structures in the central nervous system, the intrinsic circuitry of the BNST is largely unknown; however, recent technological developments have allowed researchers to begin to untangle the internal connections of the nucleus. This research has revealed the possibility of two opposing circuits, one anxiolytic and one anxiogenic, within the BNST, the relative strength of which determines the behavioral outcome. The balance of these pathways is critical in maintaining a normal physiological and behavioral state; however, stress and drugs of abuse can differentially affect the opposing circuitry within the nucleus to shift the balance to a pathological state. In this review, we will examine how stress interacts with the neuromodulators, corticotropin-releasing factor, norepinephrine, dopamine, and serotonin to affect the circuitry of the BNST as well as how synaptic plasticity in the BNST is modulated by stress, resulting in long-lasting changes in the circuit and behavioral state. PMID:26096838

  19. Bed nucleus of the stria terminalis NMDA receptors and nitric oxide modulate contextual fear conditioning in rats.

    PubMed

    Hott, Sara C; Gomes, Felipe V; Uliana, Daniela L; Vale, Gabriel T; Tirapelli, Carlos R; Resstel, Leonardo B M

    2017-01-01

    The bed nucleus of the stria terminalis (BNST) modulates anxiety-like responses, including conditioned emotional responses. Evidence suggests that glutamatergic neurotransmission in the BNST plays a role in the modulation of defensive responses. However, little is known about the involvement of glutamate NMDA receptor activation within the BNST, and its resultant increase in nitric oxide (NO) levels, in the expression of contextual fear conditioning (CFC). We investigated whether the antagonism of NMDA receptors or the reduction of NO levels in the BNST would attenuate behavioral and autonomic responses (i.e. increase in arterial pressure and heart rate, and decrease in tail cutaneous temperature) of rats submitted to a CFC paradigm. Intra-BNST infusion of AP7, an NMDA receptor antagonist, attenuated both behavioral and autonomic changes induced by CFC. Similar results were observed with NPLA and c-PTIO, an nNOS inhibitor and an NO scavenger, respectively. A positive correlation between BNST NO levels and the time spent in freezing behavior was also observed for animals submitted to the CFC. These findings indicate that the expression of CFC involves a facilitation of BNST NMDA receptor-NO signaling. This article is part of the Special Issue entitled 'Ionotropic glutamate receptors'. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. The bed nucleus of the stria terminalis modulates learning after stress in masculinized but not cycling females.

    PubMed

    Bangasser, Debbie A; Shors, Tracey J

    2008-06-18

    Exposure to an acute stressful event enhances classical eyeblink conditioning in male rats, but severely impairs conditioning in female rats. Previous studies have demonstrated that the hippocampus and amygdala critically mediate this effect in both sexes. Thus, although stress affects learning in opposite ways, the structures involved are similar. Previously, we found that the bed nucleus of the stria terminalis (BNST) is also necessary for the enhanced learning after stress in male rats. Here we used BNST inactivation to determine whether the BNST, a sexually dimorphic brain region, is required in female rats for the impaired learning after stress. Interestingly, inactivation of the BNST did not prevent the stress-induced impairment of conditioning in females. Thus, unlike the hippocampus and amygdala, the BNST is critically involved in the modulation of learning by stress in males, but not in females. This exclusive involvement in males may be caused by the sex differences within the BNST. These sex differences result from early testosterone exposure, which masculinizes brain regions including the BNST. Previously, we reported that, like males, females with brains that are masculinized at birth learn better after stressful experience. Here we found that the enhanced learning after stress in masculinized females was prevented by BNST inactivation, just like in males. These data suggest that a masculinized BNST is required for the enhanced learning after a stressful experience. Importantly, together these studies indicate that males and females can engage different brain structures to modulate learning after a stressful experience.

  1. Neuregulin 1-ErbB4 signaling in the bed nucleus of the stria terminalis regulates anxiety-like behavior.

    PubMed

    Geng, Fei; Zhang, Jie; Wu, Jian-Lin; Zou, Wen-Jun; Liang, Zhi-Ping; Bi, Lin-Lin; Liu, Ji-Hong; Kong, Ying; Huang, Chu-Qiang; Li, Xiao-Wen; Yang, Jian-Ming; Gao, Tian-Ming

    2016-08-04

    The bed nucleus of the stria terminalis (BNST), a nucleus defined as part of the extended amygdala, is involved in the expression of anxiety disorders. However, the regulatory mechanisms of BNST inhibitory activity that is involved in anxiety are unknown. Here, we showed that blocking neuregulin 1 (NRG1)-ErbB4 signaling in the BNST of mice, by either neutralizing endogenous NRG1 with ecto-Erbb4 or antagonizing the ErbB4 receptor with its specific inhibitor, produced anxiogenic responses. Interestingly, application of exogenous NRG1 into the BNST induced no anxiolytic effects, suggesting saturating activity of endogenous NRG1. While infusion of the GABAA receptor antagonist bicuculline into the BNST also led to anxiety-related behaviors, it did not worsen the anxiogenic effects produced by blocking NRG1-ErbB4 signaling, suggesting possible involvement of GABAergic neurotransmission. Further, in vitro electrophysiological recordings showed that BNST NRG1-ErbB4 signaling regulated the presynaptic GABA release. Together, these results suggest that NRG1-ErbB4 signaling in the BNST may play an important role in regulating anxiety-like behaviors. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

  2. Neurogenetic and morphogenetic heterogeneity in the bed nucleus of the stria terminalis

    SciTech Connect

    Bayer, S.A.

    1987-11-01

    Neurogenesis and morphogenesis in the rat bed nucleus of the stria terminalis (strial bed nucleus) were examined with (/sup 3/H)thymidine autoradiography. For neurogenesis, the experimental animals were the offspring of pregnant females given an injection of (/sup 3/H)thymidine on 2 consecutive gestational days. Nine groups of embryos were exposed to (/sup 3/H)thymidine on E13-E14, E14-E15,... E21-E22, respectively. On P60, the percentage of labeled cells and the proportion of cells originating during 24-hour periods were quantified at six anteroposterior levels in the strial bed nucleus. On the basis of neurogenetic gradients, the strial bed nucleus was divided into anterior and posterior parts. The anterior strial bed nucleus shows a caudal (older) to rostral (younger) neurogenetic gradient. Cells in the vicinity of the anterior commissural decussation are generated mainly between E13 and E16, cells just posterior to the nucleus accumbens mainly between E15 and E17. Within each rostrocaudal level, neurons originate in combined dorsal to ventral and medial to lateral neurogenetic gradients so that the oldest cells are located ventromedially and the youngest cells dorsolaterally. The most caudal level has some small neurons adjacent to the internal capsule that originate between E17 and E20. In the posterior strial bed nucleus, neurons extend ventromedially into the posterior preoptic area. Cells are generated simultaneously along the rostrocaudal plane in a modified lateral (older) to medial (younger) neurogenetic gradient. Ventrolateral neurons originate mainly between E13 and E16, dorsolateral neurons mainly between E15 and E16, and medial neurons mainly between E15 and E17. The youngest neurons are clumped into a medial core area just ventral to the fornix.

  3. Medullary taste responses are modulated by the bed nucleus of the stria terminalis.

    PubMed

    Smith, David V; Ye, Mi-Kyung; Li, Cheng-Shu

    2005-06-01

    Previous studies have shown a modulatory influence of limbic forebrain areas, such as the central nucleus of the amygdala and lateral hypothalamus, on the activity of taste-responsive cells in the nucleus of the solitary tract (NST). The bed nucleus of the stria terminalis (BST), which receives gustatory afferent information, also sends descending axons to the NST. The present studies were designed to investigate the role of the BST in the modulation of NST gustatory activity. Extracellular action potentials were recorded from 101 taste-responsive cells in the NST of urethane-anesthetized hamsters and analyzed for a change in excitability following bilateral electrical stimulation of the BST. The response of NST taste cells to stimulation of the BST was predominately inhibitory. Orthodromic inhibitory responses were observed in 29 of 101 (28.7%) NST taste-responsive cells, with four cells inhibited bilaterally. An increase in excitability was observed in seven of the 101 (6.9%) NST taste cells. Of the 34 cells showing these responses, 25 were modulated by the ipsilateral BST and 15 by the contralateral; four were inhibited bilaterally and two inhibited ipsilaterally and excited contralaterally. The duration of inhibitory responses (mean = 177.9 ms) was significantly longer than that of excitatory responses (35.4 ms). Application of subthreshold electrical stimulation to the BST during taste trials inhibited or excited the taste responses of every BST-responsive NST cell tested with this protocol. NST neurons that were most responsive to sucrose, NaCl, citric acid or quinine hydrochloride were all affected by BST stimulation, although citric acid-best cells were significantly more often modulated and NaCl-best less often modulated than expected by chance. These results combine with excitatory and inhibitory modulation of NST neurons by the insular cortex, lateral hypothalamus and central nucleus of the amygdala to demonstrate extensive centrifugal modulation of

  4. Glutamatergic systems in the bed nucleus of the stria terminalis, effects on cardiovascular system.

    PubMed

    Hatam, Masoumeh; Nasimi, Ali

    2007-04-01

    The bed nucleus of the stria terminalis (BST) is a part of the limbic system. Two studies have shown that microinjection of L: -glutamate in the BST elicited cardiovascular depressive and bradycardic responses, but in one study, both pressor and depressor responses were observed in the chemical stimulation of BST by glutamate in the urethane-anesthetized rats. Also, the roles of glutamate receptor subtypes have not been investigated yet. The aim of this study was to find the effects of glutamate and its receptors on the blood pressure and heart rate in the BST of urethane-anesthetized rats. The drugs (50 nl) were microinjected into the BST of anaesthetized rats. The blood pressure and heart rate were recorded throughout each experiment. The average changes in the mean arterial pressure and heart rate at different intervals were compared both within each case group and between the case and the control groups, using repeated measures ANOVA. Microinjection of L: -glutamate (0.25 M) into the BST resulted in the decrease of the mean arterial pressure (-18.85 +/- 3.84 mmHg) and heart rate (-18 +/- 4 beats/min). Injection of AP5, antagonist of glutamate NMDA receptor (2.5 , 5 mM) and CNQX, antagonist of glutamate AMPA receptor (0.5, 1 mM) had no significant effect on the mean arterial pressure and heart rate. Either Ap5 or CNQX, when co-injected with glutamate, abolished the depressor and bradycardic effects of glutamate, suggesting that simultaneous activation of both glutamate receptors is necessary for the effect of glutamate system to emerge.

  5. The bed nucleus of the stria terminalis mediates inter-individual variations in anxiety and fear.

    PubMed

    Duvarci, Sevil; Bauer, Elizabeth P; Paré, Denis

    2009-08-19

    While learning to fear stimuli that predict danger promotes survival, the inability to inhibit fear to inappropriate cues leads to a pernicious cycle of avoidance behaviors. Previous studies have revealed large inter-individual variations in fear responding with clinically anxious humans exhibiting a tendency to generalize learned fear to safe stimuli or situations. To shed light on the origin of these inter-individual variations, we subjected rats to a differential auditory fear conditioning paradigm in which one conditioned auditory stimulus (CS+) was paired to footshocks whereas a second (CS-) was not. We compared the behavior of rats that received pretraining excitotoxic lesions of the bed nucleus of the stria terminalis (BNST) to that of sham rats. Sham rats exhibit a continuum of anxious/fearful behaviors. At one end of the continuum were rats that displayed a poor ability to discriminate between the CS+ and CS-, high contextual freezing, and an anxiety-like trait in the elevated plus maze (EPM). At the other end were rats that display less fear generalization to the CS-, lower freezing to context, and a nonanxious trait in the EPM. Although BNST-lesioned rats acquired similarly high levels of conditioned fear to the CS+, they froze less than sham rats to the CS-. In fact, BNST-lesioned rats behaved like sham rats with high discriminative abilities in that they exhibited low contextual fear and a nonanxious phenotype in the EPM. Overall, this suggests that inter-individual variations in fear generalization and anxiety phenotype are determined by BNST influences on the amygdala and/or its targets.

  6. Allopregnanolone in the bed nucleus of the stria terminalis modulates contextual fear in rats

    PubMed Central

    Nagaya, Naomi; Acca, Gillian M.; Maren, Stephen

    2015-01-01

    Trauma- and stress-related disorders are among the most common types of mental illness affecting the U.S. population. For many of these disorders, there is a striking sex difference in lifetime prevalence; for instance, women are twice as likely as men to be affected by posttraumatic stress disorder (PTSD). Gonadal steroids and their metabolites have been implicated in sex differences in fear and anxiety. One example, allopregnanolone (ALLO), is a neuroactive metabolite of progesterone that allosterically enhances GABAA receptor activity and has anxiolytic effects. Like other ovarian hormones, it not only occurs at different levels in males and females but also fluctuates over the female reproductive cycle. One brain structure that may be involved in neuroactive steroid regulation of fear and anxiety is the bed nucleus of the stria terminalis (BNST). To explore this question, we examined the consequences of augmenting or reducing ALLO activity in the BNST on the expression of Pavlovian fear conditioning in rats. In Experiment 1, intra-BNST infusions of ALLO in male rats suppressed freezing behavior (a fear response) to the conditioned context, but did not influence freezing to a discrete tone conditioned stimulus (CS). In Experiment 2, intra-BNST infusion of either finasteride (FIN), an inhibitor of ALLO synthesis, or 17-phenyl-(3α,5α)-androst-16-en-3-ol, an ALLO antagonist, in female rats enhanced contextual freezing; neither treatment affected freezing to the tone CS. These findings support a role for ALLO in modulating contextual fear via the BNST and suggest that sex differences in fear and anxiety could arise from differential steroid regulation of BNST function. The susceptibility of women to disorders such as PTSD may be linked to cyclic declines in neuroactive steroid activity within fear circuitry. PMID:26300750

  7. Allopregnanolone in the bed nucleus of the stria terminalis modulates contextual fear in rats.

    PubMed

    Nagaya, Naomi; Acca, Gillian M; Maren, Stephen

    2015-01-01

    Trauma- and stress-related disorders are among the most common types of mental illness affecting the U.S. population. For many of these disorders, there is a striking sex difference in lifetime prevalence; for instance, women are twice as likely as men to be affected by posttraumatic stress disorder (PTSD). Gonadal steroids and their metabolites have been implicated in sex differences in fear and anxiety. One example, allopregnanolone (ALLO), is a neuroactive metabolite of progesterone that allosterically enhances GABAA receptor activity and has anxiolytic effects. Like other ovarian hormones, it not only occurs at different levels in males and females but also fluctuates over the female reproductive cycle. One brain structure that may be involved in neuroactive steroid regulation of fear and anxiety is the bed nucleus of the stria terminalis (BNST). To explore this question, we examined the consequences of augmenting or reducing ALLO activity in the BNST on the expression of Pavlovian fear conditioning in rats. In Experiment 1, intra-BNST infusions of ALLO in male rats suppressed freezing behavior (a fear response) to the conditioned context, but did not influence freezing to a discrete tone conditioned stimulus (CS). In Experiment 2, intra-BNST infusion of either finasteride (FIN), an inhibitor of ALLO synthesis, or 17-phenyl-(3α,5α)-androst-16-en-3-ol, an ALLO antagonist, in female rats enhanced contextual freezing; neither treatment affected freezing to the tone CS. These findings support a role for ALLO in modulating contextual fear via the BNST and suggest that sex differences in fear and anxiety could arise from differential steroid regulation of BNST function. The susceptibility of women to disorders such as PTSD may be linked to cyclic declines in neuroactive steroid activity within fear circuitry.

  8. Nuclei-and condition-specific responses to pain in the bed nucleus of the stria terminalis

    PubMed Central

    Morano, Tania J.; Bailey, Nicole J.; Cahill, Catherine M.; Dumont, Éric C.

    2014-01-01

    The bed nucleus of the stria terminalis (BST) is a basal forebrain structure considered to be part of a cortico-striato-pallidal system that coordinates autonomic, neuroendocrine and behavioural physiological responses. Recent evidence suggests that the BST plays a role in the emotional aspect of pain. The objective of the present study was to further understand the neurophysiological bases underlying the involvement of the BST in the pain experience, in both acute and chronic pain conditions. Using c-Fos as an indicator of neuronal activation, the results demonstrated that a single toe-pinch in rats produced nuclei-and condition-specific neuronal responses within the anterior region of the BST (antBST). Specifically, acute noxious stimulation increased c-Fos in the dorsal medial (dAM) and fusiform (FU) nuclei. Chronic neuropathic pain induced by chronic constriction injury (CCI) of the sciatic nerve decreased the number of c-Fos positive cells following acute mechanical stimulation in the dAM and FU nuclei, and increased c-Fos immunoreactivity in the ventral medial (vAM) aspect of the BST. In addition, the results revealed a nuclei-specific sensitivity to the surgical procedure. Following noxious stimulation to animals that received a sham surgery, c-Fos immunoreactivity was blunted in the FU nucleus while it increased in the oval (OV) nucleus of the BST. Altogether, this study demonstrates that pain induces nuclei-and condition-specific neuronal activation in the BST revealing an intriguing supraspinal neurobiological substrate that may contribute to the physiology of acute nociception and the pathophysiology of chronic pain. PMID:18164529

  9. Role of the bed nucleus of the stria terminalis in aversive learning and memory.

    PubMed

    Goode, Travis D; Maren, Stephen

    2017-09-01

    Surviving threats in the environment requires brain circuits for detecting (or anticipating) danger and for coordinating appropriate defensive responses (e.g., increased cardiac output, stress hormone release, and freezing behavior). The bed nucleus of the stria terminalis (BNST) is a critical interface between the "affective forebrain"-including the amygdala, ventral hippocampus, and medial prefrontal cortex-and the hypothalamic and brainstem areas that have been implicated in neuroendocrine, autonomic, and behavioral responses to actual or anticipated threats. However, the precise contribution of the BNST to defensive behavior is unclear, both in terms of the antecedent stimuli that mobilize BNST activity and the consequent defensive reactions. For example, it is well known that the BNST is essential for contextual fear conditioning, but dispensable for fear conditioning to discrete conditioned stimuli (CSs), at least as indexed by freezing behavior. However, recent evidence suggests that there are circumstances in which contextual freezing may persist independent of the BNST. Furthermore, the BNST is involved in the reinstatement (or relapse) of conditioned freezing to extinguished discrete CSs. As such, there are critical gaps in understanding how the BNST contributes to fundamental processes involved in Pavlovian fear conditioning. Here, we attempt to provide an integrative account of BNST function in fear conditioning. We discuss distinctions between unconditioned stress and conditioned fear and the role of BNST circuits in organizing behaviors associated with these states. We propose that the BNST mediates conditioned defensive responses-not based on the modality or duration of the antecedent threat or the duration of the behavioral response to the threat-but rather as consequence the ability of an antecedent stimulus to predict when an aversive outcome will occur (i.e., its temporal predictability). We argue that the BNST is not uniquely mobilized by

  10. CRF receptor type 2 neurons in the posterior bed nucleus of the stria terminalis critically contribute to stress recovery.

    PubMed

    Henckens, M J A G; Printz, Y; Shamgar, U; Dine, J; Lebow, M; Drori, Y; Kuehne, C; Kolarz, A; Eder, M; Deussing, J M; Justice, N J; Yizhar, O; Chen, A

    2016-08-23

    The bed nucleus of the stria terminalis (BNST) is critical in mediating states of anxiety, and its dysfunction has been linked to stress-related mental disease. Although the anxiety-related role of distinct subregions of the anterior BNST was recently reported, little is known about the contribution of the posterior BNST (pBNST) to the behavioral and neuroendocrine responses to stress. Previously, we observed abnormal expression of corticotropin-releasing factor receptor type 2 (CRFR2) to be associated with post-traumatic stress disorder (PTSD)-like symptoms. Here, we found that CRFR2-expressing neurons within the pBNST send dense inhibitory projections to other stress-related brain regions (for example, the locus coeruleus, medial amygdala and paraventricular nucleus), implicating a prominent role of these neurons in orchestrating the neuroendocrine, autonomic and behavioral response to stressful situations. Local CRFR2 activation by urocortin 3 depolarized the cells, increased the neuronal input resistance and increased firing of action potentials, indicating an enhanced excitability. Furthermore, we showed that CRFR2-expressing neurons within the pBNST are critically involved in the modulation of the behavioral and neuroendocrine response to stress. Optogenetic activation of CRFR2 neurons in the pBNST decreased anxiety, attenuated the neuroendocrine stress response, ameliorated stress-induced anxiety and impaired the fear memory for the stressful event. Moreover, activation following trauma exposure reduced the susceptibility for PTSD-like symptoms. Optogenetic inhibition of pBNST CRFR2 neurons yielded opposite effects. These data indicate the relevance of pBNST activity for adaptive stress recovery.Molecular Psychiatry advance online publication, 23 August 2016; doi:10.1038/mp.2016.133.

  11. CGRP Antagonist Infused into the Bed Nucleus of the Stria Terminalis Impairs the Acquisition and Expression of Context but Not Discretely Cued Fear

    ERIC Educational Resources Information Center

    Sink, Kelly S.; Davis, Michael; Walker, David L.

    2013-01-01

    Calcitonin gene-related peptide (CGRP) infusions into the bed nucleus of the stria terminalis (BNST) evoke increases in startle amplitude and increases in anxiety-like behavior in the plus maze. Conversely, intra-BNST infusions of the CGRP antagonist CGRP[subscript 8-37] block unconditioned startle increases produced by fox odor. Here we evaluate…

  12. CGRP Antagonist Infused into the Bed Nucleus of the Stria Terminalis Impairs the Acquisition and Expression of Context but Not Discretely Cued Fear

    ERIC Educational Resources Information Center

    Sink, Kelly S.; Davis, Michael; Walker, David L.

    2013-01-01

    Calcitonin gene-related peptide (CGRP) infusions into the bed nucleus of the stria terminalis (BNST) evoke increases in startle amplitude and increases in anxiety-like behavior in the plus maze. Conversely, intra-BNST infusions of the CGRP antagonist CGRP[subscript 8-37] block unconditioned startle increases produced by fox odor. Here we evaluate…

  13. Cannabidiol injected into the bed nucleus of the stria terminalis modulates baroreflex activity through 5-HT1A receptors.

    PubMed

    Alves, Fernando H F; Crestani, Carlos C; Gomes, Felipe V; Guimarães, Francisco S; Correa, Fernando M A; Resstel, Leonardo B M

    2010-09-01

    Cannabidiol (CBD) is a non-psychotomimetic constituent of the Cannabis sativa plant that inhibits behavioral and cardiovascular responses to aversive situations, facilitating 5-HT1A-mediated neurotransmission. Previous results from our group suggest that the bed nucleus of the stria terminalis (BNST) may be involved in CBD's anti-aversive effects. To investigate whether the cardiovascular effects of the CBD could involve a direct drug effect on the BNST, we evaluated the effects of CBD microinjection into this structure on baroreflex activity. We also verified whether these effects were mediated by the activation of 5-HT(1A) receptors. Bilateral microinjection of CBD (60 nmol/100 nL) into the BNST increased the bradycardiac response to arterial pressure increases. However, no changes were observed in tachycardiac responses evoked by arterial pressure decreases. Pretreatment of the BNST with the selective 5-HT(1A) receptor antagonist WAY100635 (0.37 nmol/100 nL) prevented CBD effects on the baroreflex activity. Moreover, microinjection of the 5-HT(1A) receptor agonist 8-OH-DPAT (4 nmol/100 nL) caused effects that were similar to those observed after the microinjection of CBD, which were also blocked by pretreatment with WAY100635. In conclusion, the present studies show that the microinjection of CBD into the BNST has a facilitatory influence on the baroreflex response to blood pressure increases, acting through the activation of 5-HT1A receptors.

  14. NMDA-receptor-dependent plasticity in the bed nucleus of the stria terminalis triggers long-term anxiolysis

    PubMed Central

    Glangetas, Christelle; Massi, Léma; Fois, Giulia R.; Jalabert, Marion; Girard, Delphine; Diana, Marco; Yonehara, Keisuke; Roska, Botond; Xu, Chun; Lüthi, Andreas; Caille, Stéphanie; Georges, François

    2017-01-01

    Anxiety is controlled by multiple neuronal circuits that share robust and reciprocal connections with the bed nucleus of the stria terminalis (BNST), a key structure controlling negative emotional states. However, it remains unknown how the BNST integrates diverse inputs to modulate anxiety. In this study, we evaluated the contribution of infralimbic cortex (ILCx) and ventral subiculum/CA1 (vSUB/CA1) inputs in regulating BNST activity at the single-cell level. Using trans-synaptic tracing from single-electroporated neurons and in vivo recordings, we show that vSUB/CA1 stimulation promotes opposite forms of in vivo plasticity at the single-cell level in the anteromedial part of the BNST (amBNST). We find that an NMDA-receptor-dependent homosynaptic long-term potentiation is instrumental for anxiolysis. These findings suggest that the vSUB/CA1-driven LTP in the amBNST is involved in eliciting an appropriate response to anxiogenic context and dysfunction of this compensatory mechanism may underlie pathologic anxiety states. PMID:28218243

  15. Overshadowed by the amygdala: the bed nucleus of the stria terminalis emerges as key to psychiatric disorders

    PubMed Central

    Lebow, M A; Chen, A

    2016-01-01

    The bed nucleus of the stria terminalis (BNST) is a center of integration for limbic information and valence monitoring. The BNST, sometimes referred to as the extended amygdala, is located in the basal forebrain and is a sexually dimorphic structure made up of between 12 and 18 sub-nuclei. These sub-nuclei are rich with distinct neuronal subpopulations of receptors, neurotransmitters, transporters and proteins. The BNST is important in a range of behaviors such as: the stress response, extended duration fear states and social behavior, all crucial determinants of dysfunction in human psychiatric diseases. Most research on stress and psychiatric diseases has focused on the amygdala, which regulates immediate responses to fear. However, the BNST, and not the amygdala, is the center of the psychogenic circuit from the hippocampus to the paraventricular nucleus. This circuit is important in the stimulation of the hypothalamic–pituitary–adrenal axis. Thus, the BNST has been largely overlooked with respect to its possible dysregulation in mood and anxiety disorders, social dysfunction and psychological trauma, all of which have clear gender disparities. In this review, we will look in-depth at the anatomy and projections of the BNST, and provide an overview of the current literature on the relevance of BNST dysregulation in psychiatric diseases. PMID:26878891

  16. The bed nucleus of stria terminalis and the amygdala as targets of antenatal glucocorticoids: implications for fear and anxiety responses.

    PubMed

    Oliveira, Mário; Rodrigues, Ana-João; Leão, Pedro; Cardona, Diana; Pêgo, José Miguel; Sousa, Nuno

    2012-04-01

    Several human and experimental studies have shown that early life adverse events can shape physical and mental health in adulthood. Stress or elevated levels of glucocorticoids (GCs) during critical periods of development seem to contribute for the appearance of neurospyschiatric conditions such as anxiety and depression, albeit the underlying mechanisms remain to be fully elucidated. The aim of the present study was to determine the long-term effect of prenatal exposure to dexamethasone- DEX (synthetic GC widely used in clinics) in fear and anxious behavior and identify the neurochemical, morphological and molecular correlates. Prenatal exposure to DEX triggers a hyperanxious phenotype and altered fear behavior in adulthood. These behavioral traits were correlated with increased volume of the bed nucleus of the stria terminalis (BNST), particularly the anteromedial subdivision which presented increased dendritic length; in parallel, we found an increased expression of synapsin and NCAM in the BNST of these animals. Remarkably, DEX effects were opposite in the amygdala, as this region presented reduced volume due to significant dendritic atrophy. Albeit no differences were found in dopamine and its metabolite levels in the BNST, this neurotransmitter was substantially reduced in the amygdala, which also presented an up-regulation of dopamine receptor 2. Altogether, our results show that in utero DEX exposure can modulate anxiety and fear behavior in parallel with significant morphological, neurochemical and molecular changes; importantly, GCs seem to differentially affect distinct brain regions involved in this type of behaviors.

  17. Dopamine decreases NMDA currents in the oval bed nucleus of the stria terminalis of cocaine self-administering rats.

    PubMed

    Krawczyk, Michal; deBacker, Julian; Mason, Xenos; Jones, Andrea A; Dumont, Eric C

    2014-06-03

    Dopamine (DA) and N-methyl-D-aspartate receptors (NMDARs) contribute in the neural processes underlying drug-driven behaviors. DA is a potent modulator of NMDAR, but few studies have investigated the functional interaction between DA and NMDAR in the context of substance abuse. We combined the rat model of cocaine self-administration with brain slice electrophysiology to study DA modulation of NMDA currents in the oval bed nucleus of the stria terminalis (ovBNST), a dense DA terminal field involved in maintenance of cocaine self-administration amongst other drug related behaviors. Long-Evans rats self-administered intravenous cocaine (0.75 mg/kg/injection) on a progressive ratio (PR) schedule of reinforcement for 15 days and whole-cell patch-clamp recordings were done on the 16th day. DA reduced NMDA currents in brain-slices from cocaine self-administering rats, but not in those of drug-naïve and sucrose self-administering, or when cocaine exposure was passive (yoked), revealing a mechanism unique to voluntary cocaine intake. DA reduced NMDA currents by activating G-protein-coupled D1- and D2-like receptors that converged on phospholipase C and protein phosphatases. Accordingly, our study reveals a mechanism that may contribute to dysfunctional synaptic plasticity associated with drug-driven behaviors during acute withdrawal.

  18. Compensation in the neural circuitry of fear conditioning awakens learning circuits in the bed nuclei of the stria terminalis.

    PubMed

    Poulos, Andrew M; Ponnusamy, Ravikumar; Dong, Hong-Wei; Fanselow, Michael S

    2010-08-17

    The basolateral amygdala (BLA) is thought to be essential for fear learning. However, extensive training can overcome the loss of conditional fear evident following lesions and inactivation of the BLA. Such results suggest the existence of a primary BLA-dependent and a compensatory BLA-independent neural circuit. We tested the hypothesis that the bed nuclei of the stria terminalis (BST) provides this compensatory plasticity. Using extensive context-fear conditioning, we demonstrate that combined BLA and BST lesions prevented fear acquisition and expression. Additionally, protein synthesis in the BST was critical only for consolidation of BLA-independent but not BLA-dependent fear. Moreover, fear acquired after BLA lesions resulted in greater activation of BST regions that receive hippocampal efferents. These results suggest that the BST is capable of functioning as a compensatory site in the acquisition and consolidation of context-fear memories. Unlocking such neural compensation holds promise for understanding situations when brain damage impairs normal function or failure to regulate compensatory sites leads to anxiety disorders.

  19. Mechanisms of Neuroplasticity and Ethanol's Effects on Plasticity in the Striatum and Bed Nucleus of the Stria Terminalis.

    PubMed

    Lovinger, David M; Kash, Thomas L

    2015-01-01

    Long-lasting changes in synaptic function (i.e., synaptic plasticity) have long been thought to contribute to information storage in the nervous system. Although synaptic plasticity mainly has adaptive functions that allow the organism to function in complex environments, it is now clear that certain events or exposure to various substances can produce plasticity that has negative consequences for organisms. Exposure to drugs of abuse, in particular ethanol, is a life experience that can activate or alter synaptic plasticity, often resulting in increased drug seeking and taking and in many cases addiction.Two brain regions subject to alcohol's effects on synaptic plasticity are the striatum and bed nucleus of the stria terminalis (BNST), both of which have key roles in alcohol's actions and control of intake. The specific effects depend on both the brain region analyzed (e.g., specific subregions of the striatum and BNST) and the duration of ethanol exposure (i.e., acute vs. chronic). Plastic changes in synaptic transmission in these two brain regions following prolonged ethanol exposure are thought to contribute to excessive alcohol drinking and relapse to drinking. Understanding the mechanisms underlying this plasticity may lead to new therapies for treatment of these and other aspects of alcohol use disorder.

  20. Genetic cell targeting uncovers specific neuronal types and distinct subregions in the bed nucleus of the stria terminalis

    PubMed Central

    Nguyen, Amanda Q.; Cruz, Julie A.D. Dela; Sun, Yanjun; Holmes, Todd C.; Xu, Xiangmin

    2017-01-01

    The bed nucleus of the stria terminalis (BNST) plays an important role in fear, stress, and anxiety. It contains a collection of sub-nuclei delineated by gross cytoarchitecture features; however, there has yet to be a systematic examination of specific BNST neuronal types and their associated neurochemical makeup. The present study focuses on improved characterization of the anterior BNST based on differing molecular and chemical expression aided by mouse genetics. Specific Cre driver lines crossed with a fluorescent reporter line were used for genetic cell targeting and immunochemical staining. Using this new approach, we were able to robustly identify specific excitatory and inhibitory cell types in the BNST. The presence and distribution of excitatory neurons were firmly established; glutamatergic neurons in the anterior BNST accounted for about 14% and 31% of dorsal and ventral BNST cells, respectively. GABAergic neurons expressing different isoforms of glutamic acid decarboxylase were found to have differential sub-regional distributions. Almost no parvalbumin-expressing cells were found in the BNST, while somatostatin-expressing cells and calretinin-expressing cells account for modest proportions of BNST cells. In addition, vasoactive intestinal peptide-expressing axonal plexuses were prominent in the oval and juxtacapsular (jc) subregions. In addition, we discovered that corticotropin-releasing hormone (CRH) expressing cells contain GABAergic and glutamatergic subpopulations. Together, this study reveals new information on excitatory and inhibitory neurons in the BNST, which will facilitate genetic dissection and functional studies of BNST subregions. PMID:26718312

  1. Importance of CRF receptor-mediated mechanisms of the bed nucleus of the stria terminalis in the processing of anxiety and pain.

    PubMed

    Tran, Lee; Schulkin, Jay; Greenwood-Van Meerveld, Beverley

    2014-10-01

    Corticotropin-releasing factor (CRF)-mediated mechanisms in the bed nucleus of the stria terminalis (BNST) have a pivotal role in stress-induced anxiety and hyperalgesia. Although CRF is known to activate two receptor subtypes, CRF1 and CRF2, attempts to delineate the specific role of each subtype in modulating anxiety and nociception have been inconsistent. Here we test the hypothesis that CRF1 and CRF2 receptor activation in the anteriolateral BNST (BNSTAL) facilitates divergent mechanisms modulating comorbid anxiety and hyperalgesia. Microinfusions of the specific antagonists CP376395 and Astressin2B into the BNSTAL were used to investigate CRF1 and CRF2 receptor functions, respectively. We found that CRF1 and CRF2 receptors in the BNSTAL had opposing effects on exploratory behavior in the elevated plus-maze, somatic mechanical threshold, and the autonomic and endocrine response to stress. However, CRF1 or CRF2 receptor antagonism in the BNSTAL revealed complementary roles in facilitating the acoustic startle and visceromotor reflexes. Our results suggest that the net effect of CRF1 and CRF2 receptor activation in the BNSTAL is pathway-dependent and provides important insight into the CRF receptor-associated circuitry that likely underpins stress-induced pathologies.

  2. Metabotropic Glutamate Receptor Subtype 7 in the Bed Nucleus of the Stria Terminalis is Essential for Intermale Aggression

    PubMed Central

    Masugi-Tokita, Miwako; Flor, Peter J; Kawata, Mitsuhiro

    2016-01-01

    Metabotropic glutamate receptor subtype 7 (mGluR7) is a member of group III mGluRs, which localize to the presynaptic active zones of the mammalian central nervous system. Although histological, genetic, and electrophysiological studies ensure the importance of mGluR7, its roles in behavior and physiology remain largely unknown. Using a resident–intruder paradigm, we found a severe reduction in intermale aggressive behavior in mGluR7 knockout (KO) mice. We also found alterations in other social behaviors in male mGluR7 KO mice, including sexual behavior toward male intruders. Because olfaction is critical for rodent social behavior, including aggression, we performed an olfaction test, finding that mGluR7 KO mice failed to show interest in the smell of male urine. To clarify the olfactory deficit, we then exposed mice to urine and analyzed c-Fos-immunoreactivity, discovering a remarkable reduction in neural activity in the bed nucleus of the stria terminalis (BNST) of mGluR7 KO mice. Finally, intra-BNST administration of the mGluR7-selective antagonist 6-(4-methoxyphenyl)-5-methyl-3-pyridin-4-ylisoxazolo[4,5-c]pyridin-4(5H)-one (MMPIP) also reproduced the phenotype of mGluR7 KO mice, including reduced aggression and altered social interaction. Thus mGluR7 may work as an ‘enhancer of neural activity' in the BNST and is important for intermale aggression. Our findings demonstrate that mGluR7 is essential for social behavior and innate behavior. Our study on mGluR7 in the BNST will shed light on future therapies for emotional disorders in humans. PMID:26149357

  3. Whole-brain mapping of afferent projections to the bed nucleus of the stria terminalis in tree shrews.

    PubMed

    Ni, Rong-Jun; Luo, Peng-Hao; Shu, Yu-Mian; Chen, Ju-Tao; Zhou, Jiang-Ning

    2016-10-01

    The bed nucleus of the stria terminalis (BST) plays an important role in integrating and relaying input information to other brain regions in response to stress. The cytoarchitecture of the BST in tree shrews (Tupaia belangeri chinensis) has been comprehensively described in our previous publications. However, the inputs to the BST have not been described in previous reports. The aim of the present study was to investigate the sources of afferent projections to the BST throughout the brain of tree shrews using the retrograde tracer Fluoro-Gold (FG). The present results provide the first detailed whole-brain mapping of BST-projecting neurons in the tree shrew brain. The BST was densely innervated by the prefrontal cortex, entorhinal cortex, ventral subiculum, amygdala, ventral tegmental area, and parabrachial nucleus. Moreover, moderate projections to the BST originated from the medial preoptic area, supramammillary nucleus, paraventricular thalamic nucleus, pedunculopontine tegmental nucleus, dorsal raphe nucleus, locus coeruleus, and nucleus of the solitary tract. Afferent projections to the BST are identified in the ventral pallidum, nucleus of the diagonal band, ventral posteromedial thalamic nucleus, posterior complex of the thalamus, interfascicular nucleus, retrorubral field, rhabdoid nucleus, intermediate reticular nucleus, and parvicellular reticular nucleus. In addition, the different densities of BST-projecting neurons in various regions were analyzed in the tree shrew brains. In summary, whole-brain mapping of direct inputs to the BST is delineated in tree shrews. These brain circuits are implicated in the regulation of numerous physiological and behavioral processes including stress, reward, food intake, and arousal.

  4. Altered functional connectivity of the subthalamus and the bed nucleus of the stria terminalis in obsessive-compulsive disorder.

    PubMed

    Cano, M; Alonso, P; Martínez-Zalacaín, I; Subirà, M; Real, E; Segalàs, C; Pujol, J; Cardoner, N; Menchón, J M; Soriano-Mas, C

    2017-08-22

    The assessment of inter-regional functional connectivity (FC) has allowed for the description of the putative mechanism of action of treatments such as deep brain stimulation (DBS) of the nucleus accumbens in patients with obsessive-compulsive disorder (OCD). Nevertheless, the possible FC alterations of other clinically-effective DBS targets have not been explored. Here we evaluated the FC patterns of the subthalamic nucleus (STN) and the bed nucleus of the stria terminalis (BNST) in patients with OCD, as well as their association with symptom severity. Eighty-six patients with OCD and 104 healthy participants were recruited. A resting-state image was acquired for each participant and a seed-based analysis focused on our two regions of interest was performed using statistical parametric mapping software (SPM8). Between-group differences in FC patterns were assessed with two-sample t test models, while the association between symptom severity and FC patterns was assessed with multiple regression analyses. In comparison with controls, patients with OCD showed: (1) increased FC between the left STN and the right pre-motor cortex, (2) decreased FC between the right STN and the lenticular nuclei, and (3) increased FC between the left BNST and the right frontopolar cortex. Multiple regression analyses revealed a negative association between clinical severity and FC between the right STN and lenticular nucleus. This study provides a neurobiological framework to understand the mechanism of action of DBS on the STN and the BNST, which seems to involve brain circuits related with motor response inhibition and anxiety control, respectively.

  5. The response of neurons in the bed nucleus of the stria terminalis to serotonin: Implications for anxiety

    PubMed Central

    Hammack, Sayamwong E.; Guo, JiDong; Hazra, Rimi; Dabrowska, Joanna; Myers, Karyn M.; Rainnie, Donald G.

    2009-01-01

    Substantial evidence has suggested that the activity of the bed nucleus of the stria terminalis (BNST) mediates many forms of anxiety-like behavior in human and non-human animals. These data have led many investigators to suggest that abnormal processing within this nucleus may underlie anxiety disorders in humans, and effective anxiety treatments may restore normal BNST functioning. Currently some of the most effective treatments for anxiety disorders are drugs that modulate serotonin (5-HT) systems, and several decades of research have suggested that the activation of 5-HT can modulate anxiety-like behavior. Despite these facts, relatively few studies have examined how activity within the BNST is modulated by 5-HT. Here we review our own investigations using in vitro whole-cell patch-clamp electrophysiological methods on brain sections containing the BNST to determine the response of BNST neurons to exogenous 5-HT application. Our data suggest that the response of BNST neurons to 5-HT is complex, displaying both inhibitory and excitatory components, which are mediated by 5-HT1A, 5-HT2A, 5-HT2C and 5-HT7 receptors. Moreover, we have shown that the selective activation of the inhibitory response to 5-HT reduces anxiety-like behavior, and we describe data suggesting that the activation of the excitatory response to 5-HT may be anxiogenic. We propose that in the normal state, the function of 5-HT is to dampen activity within the BNST (and consequent anxiety-like behavior) during exposure to threatening stimuli; however, we suggest that changes in the balance of the function of BNST 5-HT receptor subtypes could alter the response of BNST neurons to favor excitation and produce a pathological state of increase anxiety. PMID:19467288

  6. Regulation of ventral tegmental area by bed nucleus of the stria terminalis is required for expression of cocaine preference

    PubMed Central

    Sartor, Gregory C.; Aston-Jones, Gary

    2012-01-01

    Lateral hypothalamic (LH) orexin neurons are essential for the expression of a cocaine place preference. However, afferents that regulate activity of these orexin neurons during reward behaviors are not completely understood. Using tract tracing combined with Fos staining, we examined LH afferents for Fos induction during cocaine preference in rats. We found that ventral bed nucleus of the stria terminalis (vBNST) was a major input to the LH orexin cell field that was significantly Fos-activated during cocaine conditioned place preference (CPP). Inactivation of vBNST with baclofen plus muscimol blocked expression of cocaine CPP. Surprisingly, such inactivation of vBNST also increased Fos induction in LH orexin neurons; as activity in these cells is normally associated with increased preference, this result indicates that a vBNST-orexin connection is unlikely to be responsible for CPP that is dependent on vBNST activity. Because previous studies have revealed that vBNST regulates dopamine cells in ventral tegmental area (VTA), known to be involved in CPP and other reward functions, we tested whether vBNST afferents to VTA are necessary for cocaine CPP. We found that disconnection of vBNST and VTA (using local microinjections of baclofen plus muscimol unilaterally into vBNST and contralateral VTA) significantly attenuated expression of cocaine preference. However, blocking ionotropic glutamatergic afferents to VTA from vBNST did not significantly reduce cocaine preference. These results indicate that a non-glutamatergic vBNST-VTA projection is involved in expression of cocaine preference. PMID:23039920

  7. Interactions of norepinephrine and galanin in the central amygdala and lateral bed nucleus of the stria terminalis modulate the behavioral response to acute stress.

    PubMed

    Morilak, David A; Cecchi, Marco; Khoshbouei, Habibeh

    2003-06-27

    Many aspects of drug abuse and addiction share neurobiological substrates with the modulatory processes underlying the response and adaptation to acute stress. In particular, the ascending noradrenergic system has been implicated in facilitating the response to stress, and in stress-induced reinstatement of drug seeking behavior. Thus, to better understand the link between stress and addictive behaviors, it would be informative to understand better the modulatory function of the ascending noradrenergic system, and its interaction with other neurotransmitters with which it is closely associated or co-localized, such as the neuropeptide galanin. In this paper, we review a series of studies investigating the functional interactions of norepinephrine and galanin in modulating the behavioral response to acute stress in two components of the extended amygdala, the central nucleus of the amygdala and the lateral bed nucleus of the stria terminalis. We showed that norepinephrine facilitates behavioral reactivity to stress on the elevated plus-maze and social interaction tests. However, when stress-induced activation of the noradrenergic system was enhanced by blocking inhibitory adrenergic autoreceptors, galanin release was recruited in the central amygdala, acting to attenuate the behavioral response to stress. By contrast, stress-induced galanin release in the lateral bed nucleus appeared to be independent of enhanced noradrenergic activation, and unlike the central amygdala, both galanin and norepinephrine facilitated behavioral stress reactivity in the bed nucleus. The different modes of interaction and differential region- and response-specificity of galanin and norepinephrine suggest that a complex neural circuit interconnecting these two regions is involved in the modulatory effects of norepinephrine and galanin on the behavioral response to stress. Such complexity may allow for flexibility and plasticity in stress adaptation, and may also contribute to behavioral

  8. PAC1 receptor antagonism in the bed nucleus of the stria terminalis (BNST) attenuates the endocrine and behavioral consequences of chronic stress

    PubMed Central

    Roman, Carolyn W.; Lezak, Kim R.; Hartsock, Matthew J.; Falls, William A.; Braas, Karen M.; Howard, Alan B.; Hammack, Sayamwong E.; May, Victor

    2015-01-01

    Summary Chronic or repeated stressor exposure can induce a number of maladaptive behavioral and physiological consequences and among limbic structures, the bed nucleus of the stria terminalis (BNST) has been implicated in the integration and interpretation of stress responses. Previous work has demonstrated that chronic variate stress (CVS) exposure in rodents increases BNST pituitary adenylate cyclase activating polypeptide (PACAP, Adcyap1) and PAC1 receptor (Adcyap1r1) transcript expression, and that acute BNST PACAP injections can stimulate anxiety-like behavior. Here we show that chronic stress increases PACAP expression selectively in the oval nucleus of the dorsolateral BNST in patterns distinct from those for corticotropin releasing hormone (CRH). Among receptor subtypes, BNST PACAP signaling through PAC1 receptors not only heightened anxiety responses as measured by different behavioral parameters but also induced anorexic-like behavior to mimic the consequences of stress. Conversely, chronic inhibition of BNST PACAP signaling by continuous infusion with the PAC1 receptor antagonist PACAP(6-38) during the week of CVS attenuated these stress-induced behavioral responses and changes in weight gain. BNST PACAP signaling stimulated the hypothalamic-pituitary-adrenal (HPA) axis and heightened corticosterone release; further, BNST PACAP(6-38) administration blocked corticosterone release in a sensitized stress model. In aggregate with recent associations of PACAP/PAC1 receptor dysregulation with altered stress responses including post-traumatic stress disorder, these data suggest that BNST PACAP/PAC1 receptor signaling mechanisms may coordinate the behavioral and endocrine consequences of stress. PMID:25001965

  9. Role of bed nucleus of the stria terminalis and amygdala AMPA receptors in the development and expression of context conditioning and sensitization of startle by prior shock

    PubMed Central

    Davis, Michael

    2013-01-01

    A core symptom of post-traumatic stress disorder is hyper-arousal—manifest in part by increases in the amplitude of the acoustic startle reflex. Gewirtz et al. (Prog Neuropsychopharmacol Biol Psychiatry 22:625–648, 1998) found that, in rats, persistent shock-induced startle increases were prevented by pre-test electrolytic lesions of the bed nucleus of the stria terminalis (BNST). We used reversible inactivation to determine if similar effects reflect actions on (a) BNST neurons themselves versus fibers-of-passage, (b) the development versus expression of such increases, and (c) associative fear versus non-associative sensitization. Twenty-four hours after the last of three shock sessions, startle was markedly enhanced when rats were tested in a non-shock context. These increases decayed over the course of several days. Decay was unaffected by context exposure, and elevated startle was restored when rats were tested for the first time in the original shock context. Thus, both associative and non-associative components could be measured under different conditions. Pre-test intra-BNST infusions of the AMPA receptor antagonist NBQX (3 μg/side) blocked the non-associative (as did infusions into the basolateral amygdala) but not the associative component, whereas pre-shock infusions disrupted both. NBQX did not affect baseline startle or shock reactivity. These results indicate that AMPA receptors in or very near to the BNST are critical for the expression and development of non-associative shock-induced startle sensitization, and also for context fear conditioning, but not context fear expression. More generally, they suggest that treatments targeting the BNST may be clinically useful for treating trauma-related hyper-arousal and perhaps for retarding its development. PMID:23934654

  10. Projections from Bed Nuclei of the Stria Terminalis, Anteromedial Area: Cerebral Hemisphere Integration of Neuroendocrine, Autonomic, and Behavioral Aspects of Energy Balance

    PubMed Central

    DONG, HONG-WEI; SWANSON, LARRY W.

    2008-01-01

    The anteromedial area of the bed nuclei of the stria terminalis (BSTam) is the relatively undifferentiated region of the anterior medial (anteromedial) group of the bed nuclei of the stria terminalis (BSTamg), which also includes the more distinct dorsomedial, magnocellular, and ventral nuclei. The overall pattern of axonal projections from the rat BSTam was analyzed with the PHAL anterograde pathway tracing method. Brain areas receiving relatively moderate to strong inputs from the BSTam fall into five general categories: neuroendocrine system (regions containing pools of magnocellular oxytocin neurons, and parvicellular corticotropin-releasing hormone, thyrotropin-releasing hormone, somatostatin, and dopamine neurons); central autonomic control network (central amygdalar nucleus, descending paraventricular nucleus, and ventrolateral periaqueductal gray); hypothalamic visceromotor pattern generator network (5 of 6 known components); behavior control column (descending paraventricular nucleus and associated arcuate nucleus; ventral tegmental area and associated nucleus accumbens and substantia innominata); and behavioral state control (supramammillary and tuberomammillary nuclei). The BSTam projects lightly to thalamocortical feedback loops (via the medial-midline-intralaminar thalamus). Its pattern of axonal projections, combined with its pattern of neural inputs (the most varied of all BST cell groups), suggest that the BSTam is part of a striatopallidal differentiation involved in coordinating neuroendocrine, autonomic, and behavioral or somatic responses associated with maintaining energy balance homeostasis. PMID:16304685

  11. Protracted withdrawal from alcohol and drugs of abuse impairs long-term potentiation of intrinsic excitability in the juxtacapsular bed nucleus of the stria terminalis

    PubMed Central

    Francesconi, Walter; Berton, Fulvia; Repunte-Canonigo, Vez; Hagihara, Kazuki; Thurbon, David; Lekic, Dusan; Specio, Sheila E.; Greenwell, Thomas N.; Chen, Scott A.; Rice, Kenner C.; Richardson, Heather N.; O’Dell, Laura E.; Zorrilla, Eric P.; Morales, Marisela; Koob, George F.; Sanna, Pietro Paolo

    2010-01-01

    The juxtacapsular BNST (jcBNST) is activated in response to basolateral amygdala (BLA) inputs through the stria terminalis and projects back to the anterior BLA and to the central nucleus of the amygdala (CeA). Here we show a form of long-term potentiation of the intrinsic excitability (LTP-IE) of jcBNST neurons in response to high-frequency stimulation (HFS) of the stria terminalis. This LTP-IE, which was characterized by a decrease in the firing threshold and increased temporal fidelity of firing, was impaired during protracted withdrawal from self-administration of alcohol, cocaine, and heroin. Such impairment was graded and was more pronounced in rats that self-administered amounts of the drugs sufficient to maintain dependence. Dysregulation of the CRF system has been implicated in manifestation of protracted withdrawal from dependent drug use. Administration of the selective corticotropin-releasing factor receptor 1 (CRF1) antagonist R121919, but not of the CRF2 antagonist astressin2-B (A2-B), normalized jcBNST LTP-IE in animals with a history of alcohol dependence; repeated, but not acute, administration of CRF itself produced a decreased jcBNST LTP-IE. Thus, changes in the integration properties of jcBNST neurons mediated by chronic activation of the CRF system may contribute to the persistent emotional dysregulation associated with protracted withdrawal. PMID:19403807

  12. Vasopressin and sympathetic systems mediate the cardiovascular effects of the GABAergic system in the bed nucleus of the stria terminalis.

    PubMed

    Hatam, Masoumeh; Kharazmi, Fatemeh; Nasimi, Ali

    2009-12-01

    The bed nucleus of the stria terminalis (BST) is an important part of the limbic system. It has been shown that chemical stimulation of the BST elicited cardiovascular depressive and bradycardic responses. It was also demonstrated that GABA is present in the BST, though its role in cardiovascular control is not yet understood. This study was performed to find the effects of GABA receptor subtypes in the BST on cardiovascular responses and to find the possible mechanisms that mediate these responses in urethane-anesthetized rats. Microinjection of muscimol (500 pmol/100 nl), a GABA(A) agonist, into the BST produced a weak unsignificant decrease in the mean arterial pressure (MAP) and heart rate (HR). Injection of bicuculline methiodide (BMI, 100 pmol/100 nl), a GABA(A) antagonist, caused a significant increase in the MAP (41.3+/-5.1 mmHg) as well as in the HR (33.2+/-5.6 beats/min). Injection of two doses (500 and 1000 pmol/100 nl) of phaclofen, a GABA(B) antagonist, produced no significant change in either MAP or HR. Administration (i.v.) of the muscarinic receptor blocker, homatropine methyl bromide had no effect on the magnitude of mean arterial pressure or heart rate responses to BMI. This suggests that the parasympathetic system is not involved in these responses. However, administration (i.v.) of the nicotinic receptor blocker, hexamethonium bromide had no effect on the magnitude of mean arterial pressure response but abolished heart rate response to BMI. This suggests that the sympathetic system is involved in the bradycardic effect of GABA. On the other hand, administration (i.v.) of a selective vasopressin V(1) receptor antagonist abolished the pressor effect of BMI, which indicates that the GABAergic system of the BST decreases the arterial pressure via tonic inhibition of vasopressin release. In summary, we demonstrated, for the first time, that GABA exerts its influence in the BST through the activation of GABA(A), but not GABA(B), receptors that, in

  13. Efferent projection from the bed nucleus of the stria terminalis suppresses activity of taste-responsive neurons in the hamster parabrachial nuclei.

    PubMed

    Li, Cheng-Shu; Cho, Young K

    2006-10-01

    Although the reciprocal projections between the bed nucleus of the stria terminalis (BNST) and the gustatory parabrachial nuclei (PbN) have been demonstrated neuroanatomically, there is no direct evidence showing that the projections from the PbN to the BNST carry taste information or that descending inputs from the BNST to the PbN modulate the activity of PbN gustatory neurons. A recent electrophysiological study has demonstrated that the BNST exerts modulatory influence on taste neurons in the nucleus of the solitary tract (NST), suggesting that the BNST may also modulate the activity of taste neurons in the PbN. In the present study, we recorded from 117 taste-responsive neurons in the PbN and examined their responsiveness to electrical stimulation of the BNST bilaterally. Thirteen neurons (11.1%) were antidromically invaded from the BNST, mostly from the ipsilateral side (12 cells), indicating that a subset of taste neurons in the PbN project their axons to the BNST. The BNST stimulation induced orthodromic responses on most of the PbN neurons: 115 out of 117 (98.3%), including all BNST projection units. This descending modulation on the PbN gustatory neurons was exclusively inhibitory. We also confirmed that activation of this efferent inhibitory projection from the BNST reduces taste responses of PbN neurons in all units tested. The BNST is part of the neural circuits that involve stress-associated feeding behavior. It is also known that brain stem gustatory nuclei, including the PbN, are associated with feeding behavior. Therefore, this neural substrate may be important in the stress-elicited alteration in ingestive behavior.

  14. Reversible Inactivation of the Bed Nucleus of the Stria Terminalis Prevents Reinstatement But Not Renewal of Extinguished Fear1,2,3

    PubMed Central

    Goode, Travis D.; Kim, Janice J.

    2015-01-01

    Abstract The extinction of conditioned fear is labile. For example, fear to an extinguished conditioned stimulus (CS) returns after presentation of an aversive stimulus (“reinstatement”) or a change in context (“renewal”). Substantial research implicates the bed nucleus of the stria terminalis (BNST) in the stress-induced relapse of extinguished behaviors, such as in instrumental drug seeking, but its role in the relapse of extinguished fear responses is not clear. Here, we explored the role of the BNST in both the reinstatement and renewal of fear, two forms of relapse that are differentially triggered by stress. In Experiment 1, rats received pairings of an auditory CS and footshock unconditioned stimulus (US) followed by an extinction procedure. After extinction, rats received an unsignaled US to reinstate fear to the extinguished CS. Twenty-four hours later, they were infused with either muscimol or vehicle into the BNST immediately prior to a CS retrieval test. In Experiment 2, rats were conditioned and extinguished in two distinct contexts. Twenty-four hours after extinction, the rats were infused with muscimol, NBQX, or vehicle immediately prior to a CS retrieval test in either the extinction context or a different (but familiar) context. In both experiments, freezing behavior served as the index of conditioned fear. The results revealed that BNST inactivation prevented reinstatement (Experiment 1), but not renewal (Experiment 2), of conditioned freezing to the extinguished CS. Hence, the BNST is critical for the reinstatement of extinguished fear in an aversive context, but not for the contextual retrieval processes that mediate fear renewal. PMID:26464990

  15. A Corticotropin Releasing Factor Pathway for Ethanol Regulation of the Ventral Tegmental Area in the Bed Nucleus of the Stria Terminalis

    PubMed Central

    Silberman, Yuval; Matthews, Robert T.; Winder, Danny G.

    2013-01-01

    A growing literature suggests that catecholamines and corticotropin releasing factor (CRF) interact in a serial manner to activate the bed nucleus of the stria terminalis (BNST) in order to drive stress- or cue-induced drug- and alcohol-seeking behaviors. Data suggests that these behaviors are driven in part by BNST projections to the ventral tegmental area (VTA). Together these findings suggest the existence of a CRF-signaling pathway within the BNST that is engaged by catecholamines and regulates the activity of BNST neurons projecting to the VTA. Here we test three aspects of this model: 1) whether catecholamines modify CRF neuron activity in the BNST, 2) whether CRF regulates excitatory drive onto VTA-projecting BNST neurons, and 3) whether this system is altered by ethanol exposure and withdrawal. A CRF neuron fluorescent reporter strategy was utilized to identify BNST CRF neurons for whole cell patch clamp analysis in acutely prepared slices. Using this approach, we found that both dopamine and isoproterenol significantly depolarized BNST CRF neurons. Furthermore, using a fluorescent microsphere based identification strategy; we found that CRF enhances the frequency of spontaneous EPSCs onto VTA-projecting BNST neurons in naïve mice. This action of CRF was occluded during acute withdrawal from chronic intermittent ethanol exposure. These findings suggest that dopamine and isoproterenol may enhance CRF release from local BNST sources, leading to enhancement of excitatory neurotransmission on VTA-projecting neurons, and that this pathway is engaged by patterns of alcohol exposure and withdrawal known to drive excessive alcohol intake. PMID:23325234

  16. High-resolution and cell-type-specific photostimulation mapping shows weak excitatory vs. strong inhibitory inputs in the bed nucleus of the stria terminalis

    PubMed Central

    Ikrar, Taruna; Sun, Yanjun; Santos, Rommel; Holmes, Todd C.; Francesconi, Walter; Berton, Fulvia

    2016-01-01

    The bed nucleus of the stria terminalis (BNST) is a key component of the extended amygdala and has been implicated in anxiety and addiction. As individual neurons function within neural circuits, it is important to understand local microcircuits and larger network connections of identified neuronal types and understand how maladaptive changes in the BNST neural networks are induced by stress and drug abuse. However, due to limitations of classic anatomical and physiological methods, the local circuit organization of synaptic inputs to specific BNST neuron types is not well understood. In this study, we report on the application of high-resolution and cell-type-specific photostimulation methodology developed in our laboratory to local circuit mapping in the BNST. Under calibrated experimental conditions, laser photostimulation via glutamate uncaging or channelrhodopsin-2 photoactivation evokes spiking of BNST neurons perisomatically, without activating spikes from axons of passage or distal dendrites. Whole cell recordings, combined with spatially restricted photostimulation of presynaptic neurons at many different locations over a large region, allow high-resolution mapping of presynaptic input sources to single recorded neurons in the BNST. We constructed maps of synaptic inputs impinging onto corticotrophin-releasing hormone-expressing (CRH+) BNST neurons in the dorsolateral BNST and found that the CRH+ neurons receive predominant local inhibitory synaptic connections with very weak excitatory connections. Through cell-type-specific optogenetic stimulation mapping, we generated maps of somatostatin-expressing neuron-specific inhibitory inputs to BNST neurons. Taken together, the photostimulation-based techniques offer us powerful tools for determining the functional organization of local circuits of specific BNST neuron types. PMID:27052587

  17. A corticotropin releasing factor pathway for ethanol regulation of the ventral tegmental area in the bed nucleus of the stria terminalis.

    PubMed

    Silberman, Yuval; Matthews, Robert T; Winder, Danny G

    2013-01-16

    A growing literature suggests that catecholamines and corticotropin-releasing factor (CRF) interact in a serial manner to activate the bed nucleus of the stria terminalis (BNST) to drive stress- or cue-induced drug- and alcohol-seeking behaviors. Data suggest that these behaviors are driven in part by BNST projections to the ventral tegmental area (VTA). Together, these findings suggest the existence of a CRF-signaling pathway within the BNST that is engaged by catecholamines and regulates the activity of BNST neurons projecting to the VTA. Here we test three aspects of this model to determine: (1) whether catecholamines modify CRF neuron activity in the BNST; (2) whether CRF regulates excitatory drive onto VTA-projecting BNST neurons; and (3) whether this system is altered by ethanol exposure and withdrawal. A CRF neuron fluorescent reporter strategy was used to identify BNST CRF neurons for whole-cell patch-clamp analysis in acutely prepared slices. Using this approach, we found that both dopamine and isoproterenol significantly depolarized BNST CRF neurons. Furthermore, using a fluorescent microsphere-based identification strategy we found that CRF enhances the frequency of spontaneous EPSCs onto VTA-projecting BNST neurons in naive mice. This action of CRF was occluded during acute withdrawal from chronic intermittent ethanol exposure. These findings suggest that dopamine and isoproterenol may enhance CRF release from local BNST sources, leading to enhancement of excitatory neurotransmission on VTA-projecting neurons, and that this pathway is engaged by patterns of alcohol exposure and withdrawal known to drive excessive alcohol intake.

  18. Sex chromosome complement determines sex differences in aromatase expression and regulation in the stria terminalis and anterior amygdala of the developing mouse brain.

    PubMed

    Cisternas, Carla D; Tome, Karina; Caeiro, Ximena E; Dadam, Florencia M; Garcia-Segura, Luis M; Cambiasso, María J

    2015-10-15

    Aromatase, which converts testosterone in estradiol, is involved in the generation of brain sex dimorphisms. Here we used the "four core genotypes" mouse model, in which the effect of gonadal sex and sex chromosome complement is dissociated, to determine if sex chromosomes influence the expression of brain aromatase. The brain of 16 days old XY mouse embryos showed higher aromatase expression in the stria terminalis and the anterior amygdaloid area than the brain of XX embryos, independent of gonadal sex. Furthermore, estradiol or dihydrotestosterone increased aromatase expression in cultures of anterior amygdala neurons derived from XX embryos, but not in those derived from XY embryos. This effect was also independent of gonadal sex. The expression of other steroidogenic molecules, estrogen receptor-α and androgen receptor was not influenced by sex chromosomes. In conclusion, sex chromosomes determine sex dimorphisms in aromatase expression and regulation in the developing mouse brain.

  19. Corticotropin-releasing factor type II (CRF-sub-2) receptors in the bed nucleus of the stria terminalis modulate conditioned defeat in Syrian hamsters (Mesocricetus auratus).

    PubMed

    Cooper, Matthew A; Huhman, Kim L

    2005-08-01

    In Syrian hamsters (Mesocricetus auratus), social defeat produces a subsequent increase in submissive and defensive behavior and a loss of normal territorial aggression, which the authors have called conditioned defeat. In this study, the authors investigated the effect of blocking corticotropin-releasing factor (CRF) Type I and Type II receptors on conditioned defeat. Intracerebroventricular infusion of the CRF-sub-2 receptor antagonist antisauvagine-30 prior to testing significantly reduced conditioned defeat compared with vehicle controls, whereas the CRF-sub-1 receptor antagonist CP-154,526 had no effect. Also, infusion of antisauvagine-30 into the bed nucleus of the stria terminalis (BNST) 15 min, but not immediately, prior to testing reduced conditioned defeat in a dose-dependent manner. The authors' results provide evidence that CRF-sub-2 receptors in the BNST, but not CRF-sub-1 receptors, are an important component in the neural circuitry regulating conditioned defeat.

  20. Maternally responsive neurons in the bed nucleus of the stria terminalis and medial preoptic area: putative circuits for regulating anxiety and reward

    PubMed Central

    McHenry, Jenna A.; Rubinow, David R.; Stuber, Garret D

    2016-01-01

    Postpartum neuropsychiatric disorders are a major source of morbidity and mortality and affect at least 10% of childbearing women. Affective dysregulation within this context has been identified in association with changes in reproductive steroids. Steroids promote maternal actions and modulate affect, but can also destabilize mood in some but not all women. Potential brain regions that mediate these effects include the medial preoptic area (mPOA) and ventral bed nucleus of the stria terminalis (vBNST). Herein, we review the regulation of neural activity in the mPOA/vBNST by environmental and hormonal concomitants in puerperal females. Such activity may influence maternal anxiety and motivation and have significant implications for postpartum affective disorders. Future directions for research are also explored, including physiological circuit-level approaches to gain insight into the functional connectivity of hormone-responsive maternal circuits that modulate affect. PMID:25910426

  1. Activation of corticotropin releasing factor-containing neurons in the rat central amygdala and bed nucleus of the stria terminalis following exposure to two different anxiogenic stressors.

    PubMed

    Butler, Ryan K; Oliver, Elisabeth M; Sharko, Amanda C; Parilla-Carrero, Jeffrey; Kaigler, Kris F; Fadel, Jim R; Wilson, Marlene A

    2016-05-01

    Rats exposed to the odor of a predator or to the elevated plus maze (EPM) express unique unconditioned fear behaviors. The extended amygdala has previously been demonstrated to mediate the response to both predator odor and the EPM. We seek to determine if divergent amygdalar microcircuits are associated with the different behavioral responses. The current experiments compared activation of corticotropin-releasing factor (CRF)-containing neuronal populations in the central amygdala and bed nucleus of the stria terminalis (BNST) of rats exposed to either the EPM (5 min) versus home cage controls, or predator (ferret) odor versus butyric acid, or no odor (30 min). Sections of the brains were prepared for dual-labeled immunohistochemistry and counts of c-Fos co-localized with CRF were made in the centrolateral and centromedial amygdala (CLA and CMA) as well as the dorsolateral (dl), dorsomedial (dm), and ventral (v) BNST. Ferret odor-exposed rats displayed an increase in duration and a decrease in latency of defensive burying versus control rats. Exposure to both predator stress and EPM induced neuronal activation in the BNST, but not the central amygdala, and similar levels of neuronal activation were seen in both the high and low anxiety groups in the BNST after EPM exposure. Dual-labeled immunohistochemistry showed a significant increase in the percentage of CRF/c-Fos co-localization in the vBNST of ferret odor-exposed rats compared to control and butyric acid-exposed groups as well as EPM-exposed rats compared to home cage controls. In addition, an increase in the percentage of CRF-containing neurons co-localized with c-Fos was observed in the dmBNST after EPM exposure. No changes in co-localization of CRF with c-Fos was observed with these treatments in either the CLA or CMA. These results suggest that predator odor and EPM exposure activates CRF neurons in the BNST to a much greater extent than CRF neurons of the central amygdala, and indicates unconditioned

  2. Activation of corticotropin releasing factor-containing neurons in the rat central amygdala and bed nucleus of the stria terminalis following exposure to two different anxiogenic stressors

    PubMed Central

    Butler, Ryan K.; Oliver, Elisabeth M.; Sharko, Amanda C.; Parilla-Carrero, Jeffrey; Kaigler, Kris F.; Fadel, Jim R.; Wilson, Marlene A.

    2016-01-01

    Rats exposed to the odor of a predator or to the elevated plus maze (EPM) express unique unconditioned fear behaviors. The extended amygdala has previously been demonstrated to mediate the response to both predator odor and the EPM. We seek to determine if divergent amygdalar microcircuits are associated with the different behavioral responses. The current experiments compared activation of corticotropin-releasing factor (CRF)-containing neuronal populations in the central amygdala and bed nucleus of the stria terminalis (BNST) of rats exposed to either the EPM (5 minutes) versus home cage controls, or predator ferret odor versus butyric acid, or no odor (30 minutes). Sections of the brains were prepared for dual-labeled immunohistochemistry and counts of c-Fos co-localized with CRF were made in the centrolateral and centromedial amygdala (CLA and CMA) as well as the dorsolateral (dl), dorsomedial (dm), and ventral (v) BNST. Ferret odor-exposed rats displayed an increase in duration and a decrease in latency of defensive burying versus control rats. Exposure to both predator stress and EPM induced neuronal activation in the BNST, but not the central amygdala, and similar levels of neuronal activation were seen in both the high and low anxiety groups in the BNST after EPM exposure. Dual-labeled immunohistochemistry showed a significant increase in the percentage of CRF/c-Fos co-localization in the vBNST of ferret odor-exposed rats compared to control and butyric acid-exposed groups as well as EPM-exposed rats compared to home cage controls. In addition, an increase in the percentage of CRF-containing neurons co-localized with c-Fos was observed in the dmBNST after EPM exposure. No changes in co-localization of CRF with c-Fos was observed with these treatments in either the CLA or CMA. These results suggest that predator odor and EPM exposure activates CRF neurons in the BNST to a much greater extent than CRF neurons of the central amygdala, and indicates

  3. Glucocorticoid rhythms control the rhythm of expression of the clock protein, Period2, in oval nucleus of the bed nucleus of the stria terminalis and central nucleus of the amygdala in rats.

    PubMed

    Segall, L A; Perrin, J S; Walker, C-D; Stewart, J; Amir, S

    2006-07-07

    We investigated the involvement of the adrenal glucocorticoid, corticosterone, in the control of the rhythmic expression of the circadian clock protein, Period2, in forebrain nuclei known to be sensitive to glucocorticoids, stressors and drugs of abuse, the oval nucleus of the bed nucleus of the stria terminalis and the central nucleus of the amygdala. We found previously that the daily rhythm of Period2 in these nuclei is uniquely dependent on the integrity of the adrenal glands (Amir S, Lamont EW, Robinson B, Stewart J (2004) A circadian rhythm in the expression of PERIOD2 protein reveals a novel SCN-controlled oscillator in the oval nucleus of the bed nucleus of the stria terminalis. J Neurosci 24:781-790; Lamont EW, Robinson B, Stewart J, Amir S (2005) The central and basolateral nuclei of the amygdala exhibit opposite diurnal rhythms of expression of the clock protein Period2. Proc Natl Acad Sci U S A 102:4180-4184). We now show that, in rats, in the absence of the adrenals, corticosterone replacement via the drinking water, which is associated with daily fluctuations in corticosterone levels, restores the rhythm of Period2 in the oval nucleus of the bed nucleus of the stria terminalis and central nucleus of the amygdala. Corticosterone replacement via constant-release pellets has no effect. These results underscore the importance of circadian glucocorticoid signaling in Period2 rhythms in the oval nucleus of the bed nucleus of the stria terminalis and central nucleus of the amygdala and suggest a novel mechanism whereby stressors, drugs of abuse, and other abnormal states that affect the patterns of circulating glucocorticoids can alter the functional output of these nuclei.

  4. Excitation of GABAergic Neurons in the Bed Nucleus of the Stria Terminalis Triggers Immediate Transition from Non-Rapid Eye Movement Sleep to Wakefulness in Mice.

    PubMed

    Kodani, Shota; Soya, Shingo; Sakurai, Takeshi

    2017-07-26

    Emotionally salient situations usually trigger arousal along with autonomic and neuroendocrine reactions. To determine whether the extended amygdala plays a role in sleep-wakefulness regulation, we examined the effects of optogenetic and pharmacogenetic excitation of GABAergic neurons in the bed nucleus of the stria terminalis (GABA(BNST) neurons). Acute optogenetic excitation of these cells during nonrapid eye movement (NREM) sleep resulted in an immediate state transition to wakefulness, whereas stimulation during REM sleep showed no effect on sleep-wakefulness states in male mice. An anterograde tracing study suggested GABA(BNST) neurons send axonal projections to several brain regions implicated in arousal, including the preoptic area, lateral hypothalamus, periaqueductal gray, deep mesencephalic nucleus, and parabrachial nucleus. A dual orexin receptor antagonist, DORA-22, did not affect the optogenetic transition from NREM sleep to wakefulness. Chemogenetic excitation of GABA(BNST) neurons evoked a sustained wakefulness state, but this arousal effect was markedly attenuated by DORA-22. These observations suggest that GABA(BNST) neurons play an important role in transition from NREM sleep to wakefulness without the function of orexin neurons, but prolonged excitation of these cells mobilizes the orexin system to sustain wakefulness.SIGNIFICANCE STATEMENT We examined the role of the bed nucleus of the stria terminalis (BNST) in the regulation of wakefulness. Optogenetic excitation of GABAergic neurons in the BNST (GABA(BNST) neurons) during nonrapid eye movement (NREM) sleep in mice resulted in immediate transition to a wakefulness state without function of orexins. Prolonged excitation of GABA(BNST) neurons by a chemogenetic method evoked a longer-lasting, sustained wakefulness state, which was abolished by preadministration of a dual orexin receptor antagonist, DORA-22. This study revealed a role of the BNST GABAergic system in sleep-wakefulness control

  5. Dissociation between amygdala and bed nucleus of the stria terminalis during threat anticipation in female post-traumatic stress disorder patients.

    PubMed

    Brinkmann, Leonie; Buff, Christine; Neumeister, Paula; Tupak, Sara V; Becker, Michael P I; Herrmann, Martin J; Straube, Thomas

    2017-04-01

    Feelings of uncontrollability and anxiety regarding possibly harmful events are key features of post-traumatic stress disorder (PTSD) symptomatology. Due to a lack of studies, the neural correlates of anticipatory anxiety in PTSD are still poorly understood. During functional magnetic resonance imaging, female PTSD patients with interpersonal violence trauma and healthy controls (HC) anticipated the temporally unpredictable presentation of aversive (human scream) or neutral sounds. Based on separate analysis models, we investigated phasic and sustained brain activations. PTSD patients reported increased anxiety during anticipation of aversive versus neutral sounds. Furthermore, we found both increased initial, phasic amygdala activation and increased sustained activation of the bed nucleus of the stria terminalis (BNST) during anticipation of aversive versus neutral sounds in PTSD patients in comparison to HC. PTSD patients as compared with HC also showed increased phasic responses in mid-cingulate cortex (MCC), posterior cingulate cortex (PCC), mid-insula and lateral prefrontal cortex (PFC) as well as increased sustained responses in MCC, PCC, anterior insula and lateral and medial PFC. Our results demonstrate a relationship between anticipatory anxiety in PTSD patients and hyperresponsiveness of brain regions that have previously been associated with PTSD symptomatology. Additionally, the dissociation between amygdala and BNST indicates distinct temporal and functional characteristics and suggests that phasic fear and sustained anxiety responses are enhanced during unpredictable anticipation of aversive stimuli in PTSD. Hum Brain Mapp 38:2190-2205, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  6. GABA and NMDA receptors in CRF neurons have opposing effects in fear acquisition and anxiety in central amygdala vs. bed nucleus of the stria terminalis.

    PubMed

    Gafford, Georgette M; Ressler, Kerry J

    2015-11-01

    This article is part of a Special Issue "SBN 2014". Beginning with Vale and Colleagues in 1981, corticotropin releasing factor (CRF) also called corticotropin releasing hormone (CRH) has repeatedly been identified as an important contributor to fear and anxiety behavior. These findings have proven useful to further our understanding of disorders that have significant fear-dysregulation, such as post-traumatic stress, as well as other stress- and anxiety-related disorders. Unfortunately, the data are not all in agreement. In particular the role of CRF in fear learning is controversial, with studies pointing to contradictory effects from CRF manipulation even within the same brain structure. Further, very few studies address the potentially promising role of CRF manipulation in fear extinction behavior. Here, we briefly review the role of CRF in anxiety, fear learning and extinction, focusing on recent cell-type and neurotransmitter-specific studies in the amygdala and bed nucleus of the stria terminalis (BNST) that may help to synthesize the available data on the role of CRF in fear and anxiety-related behaviors. Copyright © 2015. Published by Elsevier Inc.

  7. Involvement of the oxytocin system in the bed nucleus of the stria terminalis in the sex-specific regulation of social recognition

    PubMed Central

    Dumais, Kelly M.; Alonso, Andrea G.; Immormino, Marisa A.; Bredewold, Remco; Veenema, Alexa H.

    2015-01-01

    Sex differences in the oxytocin (OT) system in the brain may explain why OT often regulates social behaviors in sex-specific ways. However, a link between sex differences in the OT system and sex-specific regulation of social behavior has not been tested. Here, we determined whether sex differences in the OT receptor (OTR) or in OT release in the posterior bed nucleus of the stria terminalis (pBNST) mediates sex-specific regulation of social recognition in rats. We recently showed that, compared to female rats, male rats have a three-fold higher OTR binding density in the pBNST, a sexually dimorphic area implicated in the regulation of social behaviors. We now demonstrate that OTR antagonist (5 ng/0.5 μl/side) administration into the pBNST impairs social recognition in both sexes, while OT (100 pg/0.5 μl/side) administration into the pBNST prolongs the duration of social recognition in males only. These effects seem specific to social recognition, as neither treatment altered total social investigation time in either sex. Moreover, baseline OT release in the pBNST, as measured with in vivo microdialysis, did not differ between the sexes. However, males showed higher OT release in the pBNST during social recognition compared to females. These findings suggest a sex-specific role of the OT system in the pBNST in the regulation of social recognition. PMID:26630388

  8. Corticotropin releasing factor type-1 receptor antagonism in the dorsolateral bed nucleus of the stria terminalis disrupts contextually conditioned fear, but not unconditioned fear to a predator odor.

    PubMed

    Asok, Arun; Schulkin, Jay; Rosen, Jeffrey B

    2016-08-01

    The bed nucleus of the stria terminalis (BNST) plays a critical role in fear and anxiety. The BNST is important for contextual fear learning, but the mechanisms regulating this function remain unclear. One candidate mechanism is corticotropin-releasing-factor (CRF) acting at CRF type 1 receptors (CRFr1s). Yet, there has been little progress in elucidating if CRFr1s in the BNST are involved in different types of fear (conditioned and/or unconditioned). Therefore, the present study investigated the effect of antalarmin, a potent CRFr1 receptor antagonist, injected intracerebroventricularly (ICV) and into the dorsolateral BNST (LBNST) during single trial contextual fear conditioning or exposure to the predator odor 2,5-dihydro-2,4,5-trimethylthiazoline (TMT). Neither ICV nor LBNST antalarmin disrupted unconditioned freezing to TMT. In contrast, ICV and LBNST antalarmin disrupted the retention of contextual fear when tested 24h later. Neither ICV nor LBNST antalarmin affected baseline or post-shock freezing-indicating antalarmin does not interfere with the early phases of contextual fear acquisition. Antalarmin did not (1) permanently affect the ability to learn and express contextual fear, (2) change responsivity to footshocks, or (3) affect the ability to freeze. Our findings highlight an important role for CRFr1s within the LBNST during contextually conditioned fear, but not unconditioned predator odor fear. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Vasopressin and sympathetic system mediate the cardiovascular effects of the angiotensin II in the bed nucleus of the stria terminalis in rat.

    PubMed

    Nasimi, Ali; Kafami, Marzieh

    2016-07-01

    The bed nucleus of the stria terminalis (BST) is involved in cardiovascular regulation. The angiotensin II (Ang II) receptor (AT1), and angiotensinogen were found in the BST. In our previous study we found that microinjection of Ang II into the BST produced a pressor response. This study was performed to find the mechanisms mediating this response in anesthetized rats. Ang II was microinjected into the BST and the cardiovascular responses were re-tested after systemic injection of a blocker of autonomic or vasopressin V1 receptor. The ganglionic nicotinic receptor blocker, hexamethonium dichloride, attenuated the pressor response to Ang II, indicating that the cardiovascular sympathetic system is involved in the pressor effect of Ang II. A selective vasopressin V1 receptor antagonist greatly attenuated the pressor effect of Ang II, indicating that the Ang II increases the arterial pressure via stimulation of vasopressin release as well. In conclusion, in the BST, Ang II as a neurotransmitter increases blood pressure by exciting cardiovascular sympathetic system and directly or indirectly causing vasopressin to release into bloodstream by VPN. This is an interesting new finding that not only circulating Ang II but also brain Ang II makes vasopressin release. Copyright © 2016 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.

  10. Cardiovascular and single-unit responses to microinjection of angiotensin II into the bed nucleus of the stria terminalis in rat.

    PubMed

    Kafami, M; Nasimi, A

    2015-08-06

    The bed nucleus of the stria terminalis (BST) is part of the limbic system located in the rostral forebrain. BST is involved in behavioral, neuroendocrine and autonomic functions, including cardiovascular regulation. The angiotensin II (Ang II) receptor, AT1, was found in the BST, however its effects on the cardiovascular system and on single-unit responses have not been studied yet. In the present study, Ang II was microinjected into the BST of anesthetized rats and cardiovascular and single-unit responses were recorded simultaneously. Furthermore the responses were re-tested after the microinjection of a blocker of the AT1 receptor, losartan, into the BST. We found that microinjection of Ang II into the BST produced a pressor response of 11±1mmHg for a duration of 2-8min. Ang II had no consistent effect on heart rate. It also produced two types of single-unit responses in the BST, short excitatory and long inhibitory. Blockade of AT1 receptors abolished both the cardiovascular and single-unit responses, indicating that the responses were mediated through AT1 receptors. These findings imply that Ang II may be utilized as a neurotransmitter and may play a role in returning blood pressure toward normal during hypotension. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  11. In Vivo Voltammetric Monitoring of Norepinephrine Release in the Rat Ventral Bed Nucleus of the Stria Terminalis and Anteroventral Thalamic Nucleus

    PubMed Central

    Park, Jinwoo; Kile, Brian M.; Wightman, R. Mark

    2010-01-01

    The role and contribution of the dense noradrenergic innervation in the ventral bed nucleus of the stria terminalis (vBNST) and anteroventral thalamic nucleus (AV) to biological function and animal behaviors is poorly understood due to the small size of these nuclei. The aim of this study was to compare norepinephrine release and uptake in the vBNST with that in the AV of anesthetized rats. Measurements were made in vivo with fast-scan cyclic voltammetry following electrical stimulation of noradrenergic projection pathways, either the dorsal noradrenergic bundle (DNB) or the ventral noradrenergic bundle (VNB). The substance detected was identified as norepinephrine based upon voltammetric, anatomical, neurochemical, and pharmacological evidence. Fast-scan cyclic voltammetry enables the selective monitoring of local norepinephrine overflow in the vBNST evoked by the stimulation of either the DNB or VNB while norepinephrine in the AV was only evoked by DNB stimulation. The α2-adrenoceptor antagonist, yohimbine, and the norepinephrine uptake inhibitor, desipramine, increased norepinephrine overflow and slowed its disappearance in both regions. However, control of extracellular norepinephrine by both autoreceptors and uptake was greater in the AV. The greater control exerted by autoreceptors and uptake in the AV resulted in reduced extracellular concentration compared to the vBNST when large numbers of stimulation pulses were employed. The differences in noradrenergic transmission observed in the terminal fields of the vBNST and the AV may differentially regulate activity in these two regions that both contain high densities of norepinephrine terminals. PMID:20128849

  12. Emerging Role for Corticotropin Releasing Factor Signaling in the Bed Nucleus of the Stria Terminalis at the Intersection of Stress and Reward

    PubMed Central

    Silberman, Yuval; Winder, Danny G.

    2013-01-01

    Stress and anxiety play an important role in the development and maintenance of drug and alcohol addiction. The bed nucleus of the stria terminalis (BNST), a brain region involved in the production of long-term stress-related behaviors, plays an important role in animal models of relapse, such as reinstatement to previously extinguished drug-seeking behaviors. While a number of neurotransmitter systems have been suggested to play a role in these behaviors, recent evidence points to the neuropeptide corticotropin releasing factor (CRF) as being critically important in BNST-mediated reinstatement behaviors. Although numerous studies indicate that the BNST is a complex brain region with multiple afferent and efferent systems and a variety of cell types, there has only been limited work to determine how CRF modulates this complex neuronal system at the circuit level. Recent work from our lab and others have begun to unravel these BNST neurocircuits and explore their roles in CRF-related reinstatement behaviors. This review will examine the role of CRF signaling in drug addiction and reinstatement with an emphasis on critical neurocircuitry within the BNST that may offer new insights into treatments for addiction. PMID:23755023

  13. Projections from Bed Nuclei of the Stria Terminalis, Magnocellular Nucleus: Implications for Cerebral Hemisphere Regulation of Micturition, Defecation, and Penile Erection

    PubMed Central

    DONG, HONG-WEI; SWANSON, LARRY W.

    2008-01-01

    The basic structural organization of axonal projections from the small but distinct magnocellular and ventral nuclei (of the bed nuclei of the stria terminalis) were analyzed with the PHAL anterograde tract tracing method in adult male rats. The former's overall projection pattern is complex, with over 80 distinct terminal fields ipsilateral to injection sites. Innervated regions in the cerebral hemisphere and brainstem fall into 9 general functional categories: cerebral nuclei, behavior control column, orofacial motor-related, humorosensory/thirst-related, brainstem autonomic control network, neuroendocrine, hypothalamic visceromotor pattern generator network, thalamocortical feedback loops, and behavioral state control. The most novel findings indicate that the magnocellular nucleus projects to virtually all known major parts of the brain network that controls pelvic functions including micturition, defecation, and penile erection—as well as to brain networks controlling nutrient and body water homeostasis. This and other evidence suggests that the magnocellular nucleus is part of a cortico-striatopallidal differentiation modulating and coordinating pelvic functions with the maintenance of nutrient and body water homeostasis. Projections of the ventral nucleus are a subset of those generated by the magnocellular nucleus, with the obvious difference that the ventral nucleus does not project detectably to Barrington's nucleus, the subfornical organ, the median preoptic and parastrial nuclei, the neuroendocrine system, and midbrain orofacial motor-related regions. PMID:16304682

  14. Projections from Bed Nuclei of the Stria Terminalis, Dorsomedial Nucleus: Implications for Cerebral Hemisphere Integration of Neuroendocrine, Autonomic, and Drinking Responses

    PubMed Central

    DONG, HONG-WEI; SWANSON, LARRY W.

    2008-01-01

    The overall projection pattern of a tiny bed nuclei of the stria terminalis anteromedial group differentiation, the dorsomedial nucleus (BSTdm), was analyzed with the PHAL anterograde pathway-tracing method in rats. Many brain regions receive a relatively moderate to strong input from the BSTdm. They fall into 8 general categories: humeral sensory-related (subfornical organ and median preoptic nucleus—involved in initiating drinking behavior and salt appetite), neuroendocrine system (magnocellular: oxytocin, vasopressin; parvicellular: gonadotropin-releasing hormone, somatostatin, thyrotropin-releasing hormone, corticotropin-releasing hormone), central autonomic control network (central amygdalar nucleus, BST anterolateral group, descending paraventricular hypothalamic nucleus, retrochiasmatic area, ventrolateral periaqueductal gray, Barrington's nucleus), hypothalamic visceromotor pattern generator network (5 of 6 known components), behavior control column (ingestive: descending paraventricular nucleus; reproductive: lateral medial preoptic nucleus; defensive: anterior hypothalamic nucleus; foraging: ventral tegmental area, along with interconnected nucleus accumbens and substantia innominata), orofacial motor control (retrorubral area), thalamocortical feedback loops (paraventricular, central medial, intermediodorsal, and medial mediodorsal nuclei; nucleus reuniens), and behavioral state control (subparaventricular zone, ventrolateral preoptic nucleus, tuberomammillary nucleus, supramammillary nucleus, lateral habenula, and raphé nuclei). This pattern of axonal projections, and what little is known of its inputs, suggest that the BSTdm is part of a striatopallidal differentiation involved in coordinating the homeostatic and behavioral responses associated thirst and salt appetite, although clearly it may relate them to other functions as well. The BSTdm generates the densest known inputs directly to the neuroendocrine system from any part of the cerebral

  15. Emerging role for corticotropin releasing factor signaling in the bed nucleus of the stria terminalis at the intersection of stress and reward.

    PubMed

    Silberman, Yuval; Winder, Danny G

    2013-01-01

    Stress and anxiety play an important role in the development and maintenance of drug and alcohol addiction. The bed nucleus of the stria terminalis (BNST), a brain region involved in the production of long-term stress-related behaviors, plays an important role in animal models of relapse, such as reinstatement to previously extinguished drug-seeking behaviors. While a number of neurotransmitter systems have been suggested to play a role in these behaviors, recent evidence points to the neuropeptide corticotropin releasing factor (CRF) as being critically important in BNST-mediated reinstatement behaviors. Although numerous studies indicate that the BNST is a complex brain region with multiple afferent and efferent systems and a variety of cell types, there has only been limited work to determine how CRF modulates this complex neuronal system at the circuit level. Recent work from our lab and others have begun to unravel these BNST neurocircuits and explore their roles in CRF-related reinstatement behaviors. This review will examine the role of CRF signaling in drug addiction and reinstatement with an emphasis on critical neurocircuitry within the BNST that may offer new insights into treatments for addiction.

  16. CALCITONIN GENE-RELATED PEPTIDE IN THE BED NUCLEUS OF THE STRIA TERMINALIS PRODUCES AN ANXIETY-LIKE PATTERN OF BEHAVIOR AND INCREASES NEURAL ACTIVATION IN ANXIETY-RELATED STRUCTURES

    PubMed Central

    Sink, KS; Walker, DL; Yang, Y; Davis, M

    2011-01-01

    Calcitonin gene-related peptide (CGRP) evokes anxiety-like responses when infused into the lateral ventricle of rats. Because the bed nucleus of the stria terminalis (BNST) lies immediately adjacent to the lateral ventricle, is rich in CGRP receptors, and has itself been implicated in anxiety, we evaluated the hypothesis that these effects are attributable to stimulation of CGRP receptors within the BNST itself. Bilateral intra-BNST, but not dorsal, CGRP infusions (0, 200, 400, 800 ng/side) dose-dependently enhanced startle amplitude, and produced an anxiety-like response on the elevated plus maze. Intra-BNST infusion of the CGRP antagonist, αCGRP8-37, blocked the effect of CGRP on startle, and also blocked startle potentiation produced by exposure to trimethylthiazoline (TMT – a component of fox feces that induces anxiety-like behavior in rats). Intra-BNST, but not dorsal, CGRP infusions also increased c-Fos immunoreactivity in a number of anxiety-related brain areas (central nucleus of the amygdala, locus coeruleus, ventrolateral septal nucleus, paraventricular hypothalamic nucleus, lateral hypothalamus, lateral parabrachial nucleus, dorsal raphe nucleus, and nucleus accumbens shell), all of which receive direct projections from the BNST. Together, the results indicate that the activation of BNST CGRP receptors is both necessary and sufficient for some anxiety responses and that these effects may be mediated by activation of a wider network of BNST efferent structures. If so, inhibition of CGRP receptors may be a clinically useful strategy for anxiety reduction. PMID:21289190

  17. Noradrenergic alpha-2 receptor modulators in the ventral bed nucleus of the stria terminalis – effects on anxiety behavior in postpartum and virgin female rats

    PubMed Central

    Smith, Carl D.; Piasecki, Christopher C.; Weera, Marcus; Olszewicz, Joshua; Lonstein, Joseph S.

    2014-01-01

    Emotional hyper-reactivity can inhibit maternal responsiveness in female rats and other animals. Maternal behavior in postpartum rats is disrupted by increasing norepinephrine release in the ventral bed nucleus of the stria terminalis (BSTv) with the α2-autoreceptor antagonist, yohimbine, or the more selective α2-autoreceptor antagonist, idazoxan (Smith et al., 2012). Because high noradrenergic activity in the BSTv can also increase anxiety-related behaviors, increased anxiety may underlie the disrupted mothering of dams given yohimbine or idazoxan. To assess this possibility, anxiety-related behaviors in an elevated plus maze were assessed in postpartum rats after administration of yohimbine or idazoxan. It was further assessed if the α2-autoreceptor agonist clonidine (which decreases norepinephrine release) would, conversely, reduce dams’ anxiety. Groups of diestrous virgins were also examined. It was found that peripheral or intra-BSTv yohimbine did increase anxiety-related behavior in postpartum females. However, BSTv infusion of idazoxan did not reproduce yohimbine’s anxiogenic effects and anxiety was not reduced by peripheral or intra-BSTv clonidine. Because yohimbine is a weak 5HT1A receptor agonist, other groups of females received BSTv infusion of the 5HT1A receptor agonist 8OH-DPAT, but it did not alter their anxiety-related behavior. Lastly, levels of norepinephrine and serotonin in tissue punches from the BSTv did not differ between postpartum and diestrous rats, but serotonin turnover was lower in mothers. These results suggest that the impaired maternal behavior after BSTv infusion of yohimbine or idazoxan cannot both be readily explained by an increase in dams’ anxiety, and that BSTv α2-autoreceptor modulation alone has little influence anxiety-related behaviors in postpartum or diestrous rats. PMID:23796237

  18. Moxd1 Is a Marker for Sexual Dimorphism in the Medial Preoptic Area, Bed Nucleus of the Stria Terminalis and Medial Amygdala

    PubMed Central

    Tsuneoka, Yousuke; Tsukahara, Shinji; Yoshida, Sachine; Takase, Kenkichi; Oda, Satoko; Kuroda, Masaru; Funato, Hiromasa

    2017-01-01

    The brain shows various sex differences in its structures. Various mammalian species exhibit sex differences in the sexually dimorphic nucleus of the preoptic area (SDN-POA) and parts of the extended amygdala such as the principal nucleus of the bed nucleus of the stria terminalis (BNSTpr) and posterodorsal part of the medial amygdala (MePD). The SDN-POA and BNSTpr are male-biased sexually dimorphic nuclei, and characterized by the expression of calbindin D-28K (calbindin 1). However, calbindin-immunoreactive cells are not restricted to the SDN-POA, but widely distributed outside of the SDN-POA. To find genes that are more specific to sexually dimorphic nuclei, we selected candidate genes by searching the Allen brain atlas and examined the detailed expressions of the candidate genes using in situ hybridization. We found that the strong expression of monooxygenase DBH-like 1 (Moxd1) was restricted to the SDN-POA, BNSTpr and MePD. The numbers of Moxd1-positive cells in the SDN-POA, BNSTpr and MePD in male mice were larger than those in female mice. Most of the Moxd1-positive cells in the SDN-POA and BNSTpr expressed calbindin. Neonatal castration of male mice reduced the number of Moxd1-positive cells in the SDN-POA, whereas gonadectomy in adulthood did not change the expression of the Moxd1 gene in the SDN-POA in both sexes. These results suggest that the Moxd1 gene is a suitable marker for sexual dimorphic nuclei in the POA, BNST and amygdala, which enables us to manipulate sexually dimorphic neurons to examine their roles in sex-biased physiology and behaviors. PMID:28396628

  19. Acute Tryptophan Depletion Increases Translational Indices of Anxiety but not Fear: Serotonergic Modulation of the Bed Nucleus of the Stria Terminalis?

    PubMed Central

    Robinson, Oliver J; Overstreet, Cassie; Allen, Phillip S; Pine, Daniel S; Grillon, Christian

    2012-01-01

    Serotonin is strongly implicated in the mammalian stress response, but surprisingly little is known about its mode of action. Recent data suggest that serotonin can inhibit aversive responding in humans, but this remains underspecified. In particular, data in rodents suggest that global serotonin depletion may specifically increase long-duration bed nucleus of the stria terminalis (BNST)-mediated aversive responses (ie, anxiety), but not short-duration BNST-independent responses (ie, fear). Here, we extend these findings to humans. In a balanced, placebo-controlled crossover design, healthy volunteers (n=20) received a controlled diet with and without the serotonin precursor tryptophan (acute tryptophan depletion; ATD). Aversive states were indexed by translational acoustic startle measures. Fear and anxiety were operationally defined as the increase in startle reactivity during short- and long-duration threat periods evoked by predictable shock (fear-potentiated startle) and by the context in which the shocks were administered (anxiety-potentiated startle), respectively. ATD significantly increased long-duration anxiety-potentiated startle but had no effect on short-duration fear-potentiated startle. These results suggest that serotonin depletion in humans selectively increases anxiety but not fear. Current translational frameworks support the proposition that ATD thus disinhibits dorsal raphé-originating serotonergic control of corticotropin-releasing hormone-mediated excitation of the BNST. This generates a candidate neuropharmacological mechanism by which depleted serotonin may increase response to sustained threats, alongside clear implications for our understanding of the manifestation and treatment of mood and anxiety disorders. PMID:22491355

  20. Regional difference in sex steroid action on formation of morphological sex differences in the anteroventral periventricular nucleus and principal nucleus of the bed nucleus of the stria terminalis.

    PubMed

    Kanaya, Moeko; Tsuda, Mumeko C; Sagoshi, Shoko; Nagata, Kazuyo; Morimoto, Chihiro; Thu, Chaw Kyi Tha; Toda, Katsumi; Kato, Shigeaki; Ogawa, Sonoko; Tsukahara, Shinji

    2014-01-01

    Sex steroid action is critical to form sexually dimorphic nuclei, although it is not fully understood. We previously reported that masculinization of the principal nucleus of the bed nucleus of the stria terminalis (BNSTp), which is larger and has more neurons in males than in females, involves aromatized testosterone that acts via estrogen receptor-α (ERα), but not estrogen receptor-β (ERβ). Here, we examined sex steroid action on the formation of the anteroventral periventricular nucleus (AVPV) that is larger and has more neurons in females. Morphometrical analysis of transgenic mice lacking aromatase, ERα, or ERβ genes revealed that the volume and neuron number of the male AVPV were significantly increased by deletion of aromatase and ERα genes, but not the ERβ gene. We further examined the AVPV and BNSTp of androgen receptor knockout (ARKO) mice. The volume and neuron number of the male BNSTp were smaller in ARKO mice than those in wild-type mice, while no significant effect of ARKO was found on the AVPV and female BNSTp. We also examined aromatase, ERα, and AR mRNA levels in the AVPV and BNSTp of wild-type and ARKO mice on embryonic day (ED) 18 and postnatal day (PD) 4. AR mRNA in the BNSTp and AVPV of wild-type mice was not expressed on ED18 and emerged on PD4. In the AVPV, the aromatase mRNA level was higher on ED18, although the ERα mRNA level was higher on PD4 without any effect of AR gene deletion. Aromatase and ERα mRNA levels in the male BNSTp were significantly increased on PD4 by AR gene deletion. These results suggest that estradiol signaling via ERα during the perinatal period and testosterone signaling via AR during the postnatal period are required for masculinization of the BNSTp, whereas the former is sufficient to defeminize the AVPV.

  1. Common and distinct neural inputs to the medial central nucleus of the amygdala and anterior ventrolateral bed nucleus of stria terminalis in rats

    PubMed Central

    Bienkowski, Michael S.

    2013-01-01

    The central nucleus of the amygdala (CEA) and lateral bed nucleus of stria terminalis (BST) are highly interconnected limbic forebrain regions that share similar connectivity with other brain regions that coordinate behavioral and physiological responses to internal and environmental stressors. Their similar connectivity is frequently referred to when describing the CEA and lateral BST together as a unified “central extended amygdala”. However, the CEA and BST reportedly play distinct roles in behavioral and physiological responses associated with fear, anxiety, and social defeat, presumably due to differences in connectivity. To identify common and unique sources of input to the CEA and lateral BST, we performed dual retrograde tracing. Fluorogold and cholera toxin β were iontophoresed into the medial CEA (CEAm) and the anterior ventrolateral BST (BSTvl) of adult male rats. The anatomical distribution of tracer-labeled neurons was mapped throughout the brain. Regions with overlapping populations of CEAm- and BSTvl-projecting neurons were further examined for the presence of double-labeled neurons. Although most regions with input to the mCEA also projected to the BSTvl, and vice versa, cortical and sensory system-related regions projected more robustly to the CEAm, while motor system-related regions primarily innervated the BSTvl. The incidence of double-labeled neurons with collateralized axonal inputs to the CEAm and BSTvl was relatively small (~2 to 13%) and varied across regions, suggesting regional differences in the degree of coordinated CEAm and BSTvl input. The demonstrated similarities and differences in inputs to CEAm and BSTvl provide new anatomical insights into the functional organization of these limbic forebrain regions. PMID:22362201

  2. Targeting bed nucleus of the stria terminalis for severe obsessive-compulsive disorder: more unexpected lead placement in obsessive-compulsive disorder than in surgery for movement disorders.

    PubMed

    Nuttin, Bart; Gielen, Frans; van Kuyck, Kris; Wu, Hemmings; Luyten, Laura; Welkenhuysen, Marleen; Brionne, Thomas C; Gabriëls, Loes

    2013-01-01

    In preparation for a multicenter study, a protocol was written on how to perform surgical targeting of the bed nucleus of the stria terminalis, based on the lead implantation experience in patients with treatment-refractory obsessive-compulsive disorder (OCD) at the Universitaire Ziekenhuizen Leuven (UZ Leuven). When analyzing the postoperative images, we were struck by the fact that the difference between the postoperative position of the leads and the planned position seemed larger than expected. The precision of targeting in four patients with severe OCD who received bilateral model 3391 leads (Medtronic) was compared with the precision of targeting in the last seven patients who underwent surgery at UZ Leuven for movement disorders (four with Parkinson disease and three with essential tremor; all received bilateral leads). Because the leads implanted in six of the seven patients with movement disorders were model 3387 leads (Medtronic), targeting precision was also analyzed in four patients with OCD in whom model 3387 leads were implanted in the same target as the other patients with OCD. In the patients with OCD, every implanted lead deviated at least 1.3 mm from its intended position in at least one of three directions (lateral, anteroposterior, and depth), whereas in the patients with movement disorders, the maximal deviation of any of all implanted leads was 1.3 mm. The deviations in lead placement were comparable in patients with OCD who received a model 3387 implant and patients who received a model 3391 implant. In the patients with OCD, all leads were implanted more posteriorly than planned. The cause of the posterior deviation could not be determined with certainty. The most likely cause was an increased mechanical resistance of the brain tissue along the trajectory when following the targeting protocol compared with the trajectories classically used for subthalamic nucleus or ventral intermediate nucleus of the thalamus stimulation. Copyright © 2013

  3. Oxytocin receptor neurotransmission in the dorsolateral bed nucleus of the stria terminalis facilitates the acquisition of cued fear in the fear-potentiated startle paradigm in rats.

    PubMed

    Moaddab, Mahsa; Dabrowska, Joanna

    2017-07-15

    Oxytocin (OT) is a hypothalamic neuropeptide that modulates fear and anxiety-like behaviors. Dorsolateral bed nucleus of the stria terminalis (BNSTdl) plays a critical role in the regulation of fear and anxiety, and expresses high levels of OT receptor (OTR). However, the role of OTR neurotransmission within the BNSTdl in mediating these behaviors is unknown. Here, we used adult male Sprague-Dawley rats to investigate the role of OTR neurotransmission in the BNSTdl in the modulation of the acoustic startle response, as well as in the acquisition and consolidation of conditioned fear using fear potentiated startle (FPS) paradigm. Bilateral intra-BNSTdl administration of OT (100 ng) did not affect the acquisition of conditioned fear response. However, intra-BNSTdl administration of specific OTR antagonist (OTA), (d(CH2)5(1), Tyr(Me)(2), Thr(4), Orn(8), des-Gly-NH2(9))-vasotocin, (200 ng), prior to the fear conditioning session, impaired the acquisition of cued fear, without affecting a non-cued fear component of FPS. Neither OTA, nor OT affected baseline startle or shock reactivity during fear conditioning. Therefore, the observed impairment of cued fear after OTA infusion resulted from the specific effect on the formation of cued fear. In contrast to the acquisition, neither OTA nor OT affected the consolidation of FPS, when administered after the completion of fear conditioning session. Taken together, these results reveal the important role of OTR neurotransmission in the BNSTdl in the formation of conditioned fear to a discrete cue. This study also highlights the role of the BNSTdl in learning to discriminate between threatening and safe stimuli. Copyright © 2017 Elsevier Ltd. All rights reserved.

  4. Dissociation in control of physiological and behavioral responses to emotional stress by cholinergic neurotransmission in the bed nucleus of the stria terminalis in rats.

    PubMed

    Gouveia, Marianna K; Miguel, Tarciso T; Busnardo, Cristiane; Scopinho, América A; Corrêa, Fernando M A; Nunes-de-Souza, Ricardo L; Crestani, Carlos C

    2016-02-01

    The bed nucleus of the stria terminalis (BNST) is a forebrain structure implicated in physiological and behavioral responses to emotional stress. However, the local neurochemical mechanisms mediating the BNST control of stress responses are not fully known. Here, we investigated the involvement of BNST cholinergic neurotransmission, acting via muscarinic receptors, in cardiovascular (increase in blood pressure and heart rate and fall in tail skin temperature) and neuroendocrine (increase in plasma corticosterone) responses and behavioral consequences (anxiogenic-like effect in the elevated plus-maze) evoked by acute restraint stress in rats. Bilateral microinjection into the BNST of either the choline uptake inhibitor hemicholinium-3 (3 nmol/100 nl) or the muscarinic receptor antagonist methylatropine (3 nmol/100 nl) enhanced the heart rate increase and inhibited the anxiogenic-like effect observed in the elevated plus-maze evoked by restraint. However, neither hemicholinium-3 nor methylatropine affected the increase in blood pressure and plasma corticosterone levels and the fall in tail skin temperature. Facilitation of local cholinergic signaling by microinjection of the acetylcholinesterase inhibitor neostigmine (0.1 nmol/100 nl) into the BNST reduced restraint-evoked pressor and tachycardiac responses and the fall in tail cutaneous temperature, without affecting the increase in plasma corticosterone. All effects of neostigmine were completely abolished by local BNST pretreatment with methylatropine. These findings indicate an opposite role of BNST cholinergic neurotransmission, acting via local muscarinic receptor, in control of cardiovascular responses (inhibitory influence) and emotional consequences (facilitatory influence) evoked by restraint stress. Furthermore, present findings provide evidence that BNST control of neuroendocrine responses to stress is mediated by mechanisms others than local cholinergic signaling.

  5. Contribution of amygdala to the pressor response elicited by microinjection of angiotensin II into the bed nucleus of the stria terminalis.

    PubMed

    Kafami, Marzieh; Nasimi, Ali

    2016-10-01

    The bed nucleus of the stria terminalis (BST) is part of the limbic system located in the rostral forebrain. BST is involved in behavioral, neuroendocrine and autonomic functions, including cardiovascular regulation. The amygdala, plays an important role in mediating the behavioral and physiological responses associated with fear and anxiety, including cardiovascular responses. In a previous study, we showed that microinjection of AngII into the BST produced a pressor and two types of single-unit responses in the BST, short excitatory and long inhibitory. This study was performed to find possible involvement of amygdala in cardiovascular responses elicited by microinjection of AngII into the BST, using blockade of the central nucleus of amygdala (CeA) and single unit recording from the CeA, while injecting AngII into the BST in anesthetized rat. Blockade of CeA attenuated the pressor response to microinjection of AngII into the BST. Eighty-six AngII microinjections were given into the BST and 198 single unit responses were recorded from CeA simultaneously, from which 89 showed a short duration excitatory response and 109 showed no responses. In conclusion, microinjection of AngII into the BST produces a short excitatory single unit response in the CeA, resulting in contribution of amygdala to the resulted pressor response. Taken together, our study and previous studies suggest a plausible hypothesis that these two nuclei perform their cardiovascular functions in cooperation with each other. Copyright © 2016. Published by Elsevier Inc.

  6. The role of the cholinergic system of the bed nucleus of the stria terminalis on the cardiovascular responses and the baroreflex modulation in rats.

    PubMed

    Nasimi, Ali; Hatam, Masoumeh

    2011-04-22

    The bed nucleus of the stria terminalis (BST) is a limbic structure involved in cardiovascular regulation and modulation of responses to stress. The BST contains high levels of muscarinic receptors. This study was performed to find the effects of cholinergic system of the BST on the cardiovascular regulation and the baroreflex modulation in rats. Drugs (50-100nl) were microinjected into the BST of 53 urethane anesthetized male rats. The mean arterial pressure and heart rate changes were measured. The baroreflex gain was evaluated by finding the slope of the reflex bradycardia in response to increases in mean arterial pressure due to phenylephrine injection (i.v.). We found that microinjection of acetylcholine (3 and 6nmol/50nl) into the BST increased mean arterial pressure and had no effect on heart rate. Local microinjection of homatropine abolished the effect of Ach on the cardiovascular responses indicating involvement of muscarinic receptors. Local injection of homatropine did not affect the reflexive bradycardia. Local injection of acetylcholine decreased the slope of the reflexive bradycardia indicating that Ach system of the BST inhibits the baroreflex. Acute ablation of the BST by cobalt chloride also significantly decreased the slope, indicating the excitatory action of the BST on the baroreflex parasympathetic component. In conclusion, we showed for the first time that microinjection of acetylcholine into the BST evokes a pressor response by activating the local muscarinic receptors. Release of Ach into the BST, probably during stress, inhibits the baroreflex, but with no stress, the BST facilitates the baroreflex. Copyright © 2011 Elsevier B.V. All rights reserved.

  7. mGluR8 Modulates Excitatory Transmission in the Bed Nucleus of the Stria Terminalis in a Stress-Dependent Manner

    PubMed Central

    Gosnell, Heather B; Silberman, Yuval; Grueter, Brad A; Duvoisin, Robert M; Raber, Jacob; Winder, Danny G

    2011-01-01

    Metabotropic glutamate receptors (mGluRs) are important modulators of excitatory transmission, and have been implicated in anxiety and stress-related behaviors. Previously, we showed that group III mGluR agonists could depress excitatory synaptic transmission in the bed nucleus of the stria terminalis (BNST), an integral component of the anxiety circuitry. Here, we provide converging evidence indicating that this effect is mediated primarily by mGluR8, is exerted presynaptically, and is modulated by noradrenergic signaling and stress. The effects of the group III mGluR agonist L-AP4 on excitatory transmission are not potentiated by the mGluR4-selective allosteric potentiator PHCCC, but are mimicked by the mGluR8-selective agonist DCPG. Consistent with these results, mGluR8-like immunoreactivity is seen in the BNST, and the actions of L-AP4 on excitatory transmission are absent in slices from mGluR8 knockout (KO) mice. Application of DCPG is associated with an increase in paired-pulse evoked glutamate synaptic currents, and a decrease in spontaneous glutamate synaptic current frequency, consistent with a primarily presynaptic action. mGluR8-mediated suppression of excitatory transmission is disrupted ex vivo by activation of α1 adrenergic receptors (α1 ARs). BNST mGluR8 function is also disrupted by both acute and chronic in vivo exposure to restraint stress, and in brain slices from α2A AR KO mice. These studies show that mGluR8 is an important regulator of excitatory transmission in the BNST, and suggest that this receptor is selectively disrupted by noradrenergic signaling and by both acute and chronic stress. PMID:21451497

  8. Chemosensory and hormone information are relayed directly between the medial amygdala, posterior bed nucleus of the stria terminalis, and medial preoptic area in male Syrian hamsters

    PubMed Central

    Been, Laura E.; Petrulis, Aras

    2011-01-01

    In many rodent species, including Syrian hamsters, the expression of appropriate social behavior depends critically on the perception and identification of conspecific odors. The behavioral response to these odors is mediated by a network of steroid-sensitive ventral forebrain nuclei including the medial amygdala (Me), posterior bed nucleus of the stria terminalis (BNST) and medial preoptic area (MPOA). Although it is well-known that Me, BNST, and MPOA are densely interconnected and each uniquely modulates odor-guided social behaviors, the degree to which conspecific odor information and steroid hormone cues are directly relayed between these nuclei is unknown. To answer this question, we injected the retrograde tracer, cholera toxin B (CTB), into the BNST or MPOA of male subjects and identified whether retrogradely-labeled cells in Me and BNST 1) expressed immediate early genes (IEGs) following exposure to male and/or female odors or 2) expressed androgen receptor (AR). Although few retrogradely-labeled cells co-localized with IEGs, a higher percentage of BNST- and MPOA-projecting cells in the posterior Me (MeP) expressed IEGs in response to female odors than to male odors. The percentage of retrogradely-labeled cells that expressed IEGs did not, however, differ between and female- and male- odor-exposed groups in the anterior Me (MeA), posterointermediate BNST (BNSTpi), or posteromedial BNST (BNSTpm). Many retrogradely-labeled cells co-localized with AR, and a higher percentage of retrogradely-labeled MeP and BNSTpm cells expressed AR than retrogradely-labeled MeA and BNSTpi cells, respectively. Together, these data demonstrate that Me, BNST, and MPOA interact as a functional circuit to process sex-specific odor cues and hormone information in male Syrian hamsters. PMID:21316366

  9. Involvement of the oxytocin system in the bed nucleus of the stria terminalis in the sex-specific regulation of social recognition.

    PubMed

    Dumais, Kelly M; Alonso, Andrea G; Immormino, Marisa A; Bredewold, Remco; Veenema, Alexa H

    2016-02-01

    Sex differences in the oxytocin (OT) system in the brain may explain why OT often regulates social behaviors in sex-specific ways. However, a link between sex differences in the OT system and sex-specific regulation of social behavior has not been tested. Here, we determined whether sex differences in the OT receptor (OTR) or in OT release in the posterior bed nucleus of the stria terminalis (pBNST) mediates sex-specific regulation of social recognition in rats. We recently showed that, compared to female rats, male rats have a three-fold higher OTR binding density in the pBNST, a sexually dimorphic area implicated in the regulation of social behaviors. We now demonstrate that OTR antagonist (5 ng/0.5 μl/side) administration into the pBNST impairs social recognition in both sexes, while OT (100 pg/0.5 μl/side) administration into the pBNST prolongs the duration of social recognition in males only. These effects seem specific to social recognition, as neither treatment altered total social investigation time in either sex. Moreover, baseline OT release in the pBNST, as measured with in vivo microdialysis, did not differ between the sexes. However, males showed higher OT release in the pBNST during social recognition compared to females. These findings suggest a sex-specific role of the OT system in the pBNST in the regulation of social recognition. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. Moxd1 Is a Marker for Sexual Dimorphism in the Medial Preoptic Area, Bed Nucleus of the Stria Terminalis and Medial Amygdala.

    PubMed

    Tsuneoka, Yousuke; Tsukahara, Shinji; Yoshida, Sachine; Takase, Kenkichi; Oda, Satoko; Kuroda, Masaru; Funato, Hiromasa

    2017-01-01

    The brain shows various sex differences in its structures. Various mammalian species exhibit sex differences in the sexually dimorphic nucleus of the preoptic area (SDN-POA) and parts of the extended amygdala such as the principal nucleus of the bed nucleus of the stria terminalis (BNSTpr) and posterodorsal part of the medial amygdala (MePD). The SDN-POA and BNSTpr are male-biased sexually dimorphic nuclei, and characterized by the expression of calbindin D-28K (calbindin 1). However, calbindin-immunoreactive cells are not restricted to the SDN-POA, but widely distributed outside of the SDN-POA. To find genes that are more specific to sexually dimorphic nuclei, we selected candidate genes by searching the Allen brain atlas and examined the detailed expressions of the candidate genes using in situ hybridization. We found that the strong expression of monooxygenase DBH-like 1 (Moxd1) was restricted to the SDN-POA, BNSTpr and MePD. The numbers of Moxd1-positive cells in the SDN-POA, BNSTpr and MePD in male mice were larger than those in female mice. Most of the Moxd1-positive cells in the SDN-POA and BNSTpr expressed calbindin. Neonatal castration of male mice reduced the number of Moxd1-positive cells in the SDN-POA, whereas gonadectomy in adulthood did not change the expression of the Moxd1 gene in the SDN-POA in both sexes. These results suggest that the Moxd1 gene is a suitable marker for sexual dimorphic nuclei in the POA, BNST and amygdala, which enables us to manipulate sexually dimorphic neurons to examine their roles in sex-biased physiology and behaviors.

  11. Aging and estradiol effects on gene expression in the medial preoptic area, bed nucleus of the stria terminalis, and posterodorsal medial amygdala of male rats.

    PubMed

    Nutsch, Victoria L; Bell, Margaret R; Will, Ryan G; Yin, Weiling; Wolfe, Andrew; Gillette, Ross; Dominguez, Juan M; Gore, Andrea C

    2017-02-15

    Studies on the role of hormones in male reproductive aging have traditionally focused on testosterone, but estradiol (E2) also plays important roles in the control of masculine physiology and behavior. Our goal was to examine the effects of E2 on the expression of genes selected for E2-sensitivity, involvement in behavioral neuroendocrine functions, and impairments with aging. Mature adult (MAT, 5 mo) and aged (AG, 18 mo) Sprague-Dawley male rats were castrated, implanted with either vehicle or E2 subcutaneous capsules, and euthanized one month later. Bilateral punches were taken from the bed nucleus of the stria terminalis (BnST), posterodorsal medial amygdala (MePD) and the preoptic area (POA). RNA was extracted, and expression of 48 genes analyzed by qPCR using Taqman low-density arrays. Results showed that effects of age and E2 were age- and region-specific. In the POA, 5 genes were increased with E2 compared to vehicle, and there were no age effects. By contrast the BnST showed primarily age-related changes, with 6 genes decreasing with age. The MePD had 5 genes that were higher in aged than mature males, and 17 genes with significant interactions between age and E2. Gene families identified in the MePD included nuclear hormone receptors, neurotransmitters and neuropeptides and their receptors. Ten serum hormones were assayed in these same males, with results revealing both age- and E2-effects, in several cases quite profound. These results support the idea that the male brain continues to be highly sensitive to estradiol even with aging, but the nature of the response can be substantially different in mature and aging animals. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  12. Regulation of the ventral tegmental area by the bed nucleus of the stria terminalis is required for expression of cocaine preference.

    PubMed

    Sartor, Gregory C; Aston-Jones, Gary

    2012-12-01

    Lateral hypothalamus (LH) orexin neurons are essential for the expression of a cocaine place preference. However, the afferents that regulate the activity of these orexin neurons during reward behaviors are not completely understood. Using tract tracing combined with Fos staining, we examined LH afferents for Fos induction during cocaine preference in rats. We found that the ventral bed nucleus of the stria terminalis (vBNST) was a major input to the LH orexin cell field that was significantly Fos-activated during cocaine conditioned place preference (CPP). Inactivation of the vBNST with baclofen plus muscimol blocked expression of cocaine CPP. Surprisingly, such inactivation of the vBNST also increased Fos induction in LH orexin neurons; as activity in these cells is normally associated with increased preference, this result indicates that a vBNST-orexin connection is unlikely to be responsible for CPP that is dependent on vBNST activity. Because previous studies have revealed that vBNST regulates dopamine cells in the ventral tegmental area (VTA), which is known to be involved in CPP and other reward functions, we tested whether vBNST afferents to the VTA are necessary for cocaine CPP. We found that disconnection of the vBNST and VTA (using local microinjections of baclofen plus muscimol unilaterally into the vBNST and contralateral VTA) significantly attenuated expression of cocaine preference. However, blocking ionotropic glutamatergic afferents to the VTA from the vBNST did not significantly reduce cocaine preference. These results indicate that a non-glutamatergic vBNST-VTA projection is involved in expression of cocaine preference. © 2012 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

  13. Regional Difference in Sex Steroid Action on Formation of Morphological Sex Differences in the Anteroventral Periventricular Nucleus and Principal Nucleus of the Bed Nucleus of the Stria Terminalis

    PubMed Central

    Kanaya, Moeko; Tsuda, Mumeko C.; Sagoshi, Shoko; Nagata, Kazuyo; Morimoto, Chihiro; Tha Thu, Chaw Kyi; Toda, Katsumi; Kato, Shigeaki; Ogawa, Sonoko; Tsukahara, Shinji

    2014-01-01

    Sex steroid action is critical to form sexually dimorphic nuclei, although it is not fully understood. We previously reported that masculinization of the principal nucleus of the bed nucleus of the stria terminalis (BNSTp), which is larger and has more neurons in males than in females, involves aromatized testosterone that acts via estrogen receptor-α (ERα), but not estrogen receptor-β (ERβ). Here, we examined sex steroid action on the formation of the anteroventral periventricular nucleus (AVPV) that is larger and has more neurons in females. Morphometrical analysis of transgenic mice lacking aromatase, ERα, or ERβ genes revealed that the volume and neuron number of the male AVPV were significantly increased by deletion of aromatase and ERα genes, but not the ERβ gene. We further examined the AVPV and BNSTp of androgen receptor knockout (ARKO) mice. The volume and neuron number of the male BNSTp were smaller in ARKO mice than those in wild-type mice, while no significant effect of ARKO was found on the AVPV and female BNSTp. We also examined aromatase, ERα, and AR mRNA levels in the AVPV and BNSTp of wild-type and ARKO mice on embryonic day (ED) 18 and postnatal day (PD) 4. AR mRNA in the BNSTp and AVPV of wild-type mice was not expressed on ED18 and emerged on PD4. In the AVPV, the aromatase mRNA level was higher on ED18, although the ERα mRNA level was higher on PD4 without any effect of AR gene deletion. Aromatase and ERα mRNA levels in the male BNSTp were significantly increased on PD4 by AR gene deletion. These results suggest that estradiol signaling via ERα during the perinatal period and testosterone signaling via AR during the postnatal period are required for masculinization of the BNSTp, whereas the former is sufficient to defeminize the AVPV. PMID:25398007

  14. Double dissociation between the involvement of the bed nucleus of the stria terminalis and the central nucleus of the amygdala in startle increases produced by conditioned versus unconditioned fear.

    PubMed

    Walker, D L; Davis, M

    1997-12-01

    The amplitude of the acoustic startle response is reliably enhanced when elicited in the presence of bright light (light-enhanced startle) or in the presence of cues previously paired with shock (fear-potentiated startle). Light-enhanced startle appears to reflect an unconditioned response to an anxiogenic stimulus, whereas fear-potentiated startle reflects a conditioned response to a fear-eliciting stimulus. We examine the involvement of the basolateral nucleus of the amygdala, the central nucleus of the amygdala, and the bed nucleus of the stria terminalis in both phenomena. Immediately before light-enhanced or fear-potentiated startle testing, rats received intracranial infusions of the AMPA receptor antagonist 2, 3-dihydroxy-6-nitro-7-sulphamoylbenzo(F)-quinoxaline (3 microg) or PBS. Infusions into the central nucleus of the amygdala blocked fear-potentiated but not light-enhanced startle, and infusions into the bed nucleus of the stria terminalis blocked light-enhanced but not fear-potentiated startle. Infusions into the basolateral amygdala disrupted both phenomena. These findings indicate that the neuroanatomical substrates of fear-potentiated and light-enhanced startle, and perhaps more generally of conditioned and unconditioned fear, may be anatomically dissociated.

  15. Early effects of gonadal steroids on the neuron number in the medial posterior region and the lateral division of the bed nucleus of the stria terminalis in the rat.

    PubMed

    Guillamón, A; Segovia, S; del Abril, A

    1988-12-01

    This work investigates the possible existence of sex differences in the number of neurons in the medial posterior region (BNSTMp) and the lateral division (BNSTL) of the bed nucleus of the stria terminalis in the rat. These two zones of the bed nucleus of the stria terminalis belong, respectively, to the vomeronasal system (VNS), and to the main olfactory system (MOS). In the BNSTMp, males showed a greater number of neurons than females. Early postnatal (Day 1 after birth) orchidectomy in males, and androgenization in females, eliminated and reversed these differences. In the BNSTL, sexual dimorphism was restricted to its anterior region (BNSTLa). Females showed there a greater number of neurons than males. Male orchidectomy on Day 1 after birth increased the number of neurons, while female androgenization produced the opposite effect. The results obtained in this study support the hypothesis that the VNS is sexodimorphic, and suggest that sex differences exist in MOS, and that these differences are controlled by gonadal steroids during the perinatal period.

  16. GluN2B-containing NMDA receptors blockade rescues bidirectional synaptic plasticity in the bed nucleus of the stria terminalis of cocaine self-administering rats.

    PubMed

    deBacker, Julian; Hawken, Emily R; Normandeau, Catherine P; Jones, Andrea A; Di Prospero, Cynthia; Mechefske, Elysia; Gardner Gregory, James; Hayton, Scott J; Dumont, Éric C

    2015-01-01

    Drugs of abuse have detrimental effects on homeostatic synaptic plasticity in the motivational brain network. Bidirectional plasticity at excitatory synapses helps keep neural circuits within a functional range to allow for behavioral flexibility. Therefore, impaired bidirectional plasticity of excitatory synapses may contribute to the behavioral hallmarks of addiction, yet this relationship remains unclear. Here we tracked excitatory synaptic strength in the oval bed nucleus of the stria terminalis (ovBNST) using whole-cell voltage-clamp recordings in brain slices from rats self-administering sucrose or cocaine. In the cocaine group, we measured both a persistent increase in AMPA to NMDA ratio (A:N) and slow decay time of NMDA currents throughout the self-administration period and after withdrawal from cocaine. In contrast, the sucrose group exhibited an early increase in A:N ratios (acquisition) that returned toward baseline values with continued self-administration (maintenance) and after withdrawal. The sucrose rats also displayed a decrease in NMDA current decay time with continued self-administration (maintenance), which normalized after withdrawal. Cocaine self-administering rats exhibited impairment in NMDA-dependent long-term depression (LTD) that could be rescued by GluN2B-containing NMDA receptor blockade. Sucrose self-administering rats demonstrated no impairment in NMDA-dependent LTD. During the maintenance period of self-administration, in vivo (daily intraperitoneally for 5 days) pharmacologic blockade of GluN2B-containing NMDA receptors did not reduce lever pressing for cocaine. However, in vivo GluN2B blockade did normalize A:N ratios in cocaine self-administrating rats, and dissociated the magnitude of ovBNST A:N ratios from drug-seeking behavior after protracted withdrawal. Altogether, our data demonstrate when and how bidirectional plasticity at ovBNST excitatory synapses becomes dysfunctional with cocaine self-administration and that NMDA

  17. Effects of blocking developmental cell death on sexually dimorphic calbindin cell groups in the preoptic area and bed nucleus of the stria terminalis.

    PubMed

    Gilmore, Richard F; Varnum, Megan M; Forger, Nancy G

    2012-02-15

    Calbindin-D28 has been used as a marker for the sexually dimorphic nucleus of the preoptic area (SDN-POA). Males have a distinct cluster of calbindin-immunoreactive (ir) cells in the medial preoptic area (CALB-SDN) that is reduced or absent in females. However, it is not clear whether the sex difference is due to the absolute number of calbindin-ir cells or to cell position (that is, spread), and the cellular mechanisms underlying the sex difference are not known. We examined the number of cells in the CALB-SDN and surrounding regions of C57Bl/6 mice and used mice lacking the pro-death gene, Bax, to test the hypothesis that observed sex differences are due to cell death. Experiment 1 compared the number of cells in the CALB-SDN and surrounding regions in adult males, females, and females injected with estradiol benzoate on the day of birth. In experiment 2, cell number in the CALB-SDN and adjacent regions were compared in wild-type and Bax knockout mice of both sexes. In addition, calbindin-ir cells were quantified within the principal nucleus of the bed nucleus of the stria terminalis (BNSTp), a nearby region that is larger in males due to Bax-dependent cell death. Males had more cells in the CALB-SDN as well as in surrounding regions than did females, and estradiol treatment of females at birth masculinized both measures. Bax deletion had no effect on cell number in the CALB-SDN or surrounding regions but increased calbindin-ir cell number in the BNSTp. The sex difference in the CALB-SDN of mice results from an estrogen-dependent difference in cell number with no evidence found for greater spread of cells in females. Blocking Bax-dependent cell death does not prevent sex differences in calbindin-ir cell number in the BNST or CALB-SDN but increases calbindin-ir cell number in the BNSTp of both sexes.

  18. Effects of blocking developmental cell death on sexually dimorphic calbindin cell groups in the preoptic area and bed nucleus of the stria terminalis

    PubMed Central

    2012-01-01

    Background Calbindin-D28 has been used as a marker for the sexually dimorphic nucleus of the preoptic area (SDN-POA). Males have a distinct cluster of calbindin-immunoreactive (ir) cells in the medial preoptic area (CALB-SDN) that is reduced or absent in females. However, it is not clear whether the sex difference is due to the absolute number of calbindin-ir cells or to cell position (that is, spread), and the cellular mechanisms underlying the sex difference are not known. We examined the number of cells in the CALB-SDN and surrounding regions of C57Bl/6 mice and used mice lacking the pro-death gene, Bax, to test the hypothesis that observed sex differences are due to cell death. Methods Experiment 1 compared the number of cells in the CALB-SDN and surrounding regions in adult males, females, and females injected with estradiol benzoate on the day of birth. In experiment 2, cell number in the CALB-SDN and adjacent regions were compared in wild-type and Bax knockout mice of both sexes. In addition, calbindin-ir cells were quantified within the principal nucleus of the bed nucleus of the stria terminalis (BNSTp), a nearby region that is larger in males due to Bax-dependent cell death. Results Males had more cells in the CALB-SDN as well as in surrounding regions than did females, and estradiol treatment of females at birth masculinized both measures. Bax deletion had no effect on cell number in the CALB-SDN or surrounding regions but increased calbindin-ir cell number in the BNSTp. Conclusions The sex difference in the CALB-SDN of mice results from an estrogen-dependent difference in cell number with no evidence found for greater spread of cells in females. Blocking Bax-dependent cell death does not prevent sex differences in calbindin-ir cell number in the BNST or CALB-SDN but increases calbindin-ir cell number in the BNSTp of both sexes. PMID:22336348

  19. The bed nucleus of the stria terminalis in the Syrian hamster (Mesocricetus auratus): absence of vasopressin expression in standard and wild-derived hamsters and galanin regulation by seasonal changes in circulating sex steroids.

    PubMed

    Bolborea, M; Ansel, L; Weinert, D; Steinlechner, S; Pévet, P; Klosen, P

    2010-02-03

    The bed nucleus of the stria terminalis (BNST) is a nucleus of the forebrain highly sensitive to sex steroids and containing vasopressin neurons implicated in several social- and reproduction-related behaviours such as scent-marking, aggression, pair bonding and parental behaviour. Sexually dimorphic vasopressin expression in BNST neurons has been reported in almost all rodents, with the notable exception of the Syrian hamster. In this species, vasopressin expression is completely absent in the BNST. Because almost all Syrian hamsters used in research are derived from a very small breeding stock captured in 1930, we compared commercially available Syrian hamsters with a recently captured, wild-derived breeding stock. We checked for vasopressin expression using in situ hybridization and immunohistochemistry. Vasopressin expression in BNST neurons was completely absent in both breeding stocks, confirming the absence of BNST vasopressin expression in Mesocricetus auratus and ruling out a breeding artefact. Because vasopressin expression in BNST neurons appears to be strictly dependent on circulating sex steroids, the absence of vasopressin expression in Syrian hamster BNST neurons might be due to an insensitivity of these neurons to sex steroids. BNST vasopressin neurons also express galanin. Although galanin expression in the BNST is not sexually dimorphic in the Syrian hamster, it appears to be regulated by sex steroids. In the Djungarian hamster, photoperiodically driven seasonal variations of circulating sex steroids result in a seasonal rhythm of galanin expression in BNST neurons. We analysed the sex steroid dependence of galanin expression in the Syrian hamster. Castration and short photoperiod-induced sexual quiescence both resulted in downregulation of galanin mRNA in cell bodies (BNST) and immunoreactivity in the fibres (lateral septum). Testosterone supplementation of short photoperiod-adapted animals was able to restore galanin expression. Thus Syrian

  20. Overexpression of corticotropin-releasing factor receptor type 2 in the bed nucleus of stria terminalis improves posttraumatic stress disorder-like symptoms in a model of incubation of fear.

    PubMed

    Elharrar, Einat; Warhaftig, Gal; Issler, Orna; Sztainberg, Yehezkel; Dikshtein, Yahav; Zahut, Roy; Redlus, Lior; Chen, Alon; Yadid, Gal

    2013-12-01

    Posttraumatic stress disorder (PTSD) is a severe, persistent psychiatric disorder in response to a traumatic event, causing intense anxiety and fear. These responses may increase over time upon conditioning with fear-associated cues, a phenomenon termed fear incubation. Corticotropin-releasing factor receptor type 1 (CRFR1) is involved in activation of the central stress response, while corticotropin-releasing factor receptor type 2 (CRFR2) has been suggested to mediate termination of this response. Corticotropin-releasing factor (CRF) receptors are found in stress-related regions, including the bed nucleus of stria terminalis (BNST), which is implicated in sustained fear. Fear-related behaviors were analyzed in rats exposed to predator-associated cues, a model of psychological trauma, over 10 weeks. Rats were classified as susceptible (PTSD-like) or resilient. Expression levels of CRF receptors were measured in the amygdala nuclei and BNST of the two groups. In addition, lentiviruses overexpressing CRFR2 were injected into the medial division, posterointermediate part of the BNST (BSTMPI) of susceptible and resilient rats and response to stress cues was measured. We found that exposure to stress and stress-associated cues induced a progressive increase in fear response of susceptible rats. The behavioral manifestations of these rats were correlated both with sustained elevation in CRFR1 expression and long-term downregulation in CRFR2 expression in the BSTMPI. Intra-BSTMPI injection of CRFR2 overexpressing lentiviruses attenuated behavioral impairments of susceptible rats. These results implicate the BNST CRF receptors in the mechanism of coping with stress. Our findings suggest increase of CRFR2 levels as a new approach for understanding stress-related atypical psychiatric syndromes such as PTSD. © 2013 Society of Biological Psychiatry.

  1. Excitotoxic lesions of the bed nucleus of the stria terminalis (BNST) attenuate the effects of repeated stress on weight gain: Evidence for the recruitment of BNST activity by repeated, but not acute, stress

    PubMed Central

    Roman, Carolyn; Lezak, Kimberly R.; Kocho-Schellenberg, Margaret; Garret, Mark; Braas, Karen; May, Victor; Hammack, Sayamwong E.

    2011-01-01

    Exposure to repeated stress can lead to diverse and widespread behavioral consequences, including reduction in food and water intake and subsequent diminution in weight gain. Many reports have suggested that repeated stress substantially alters the neurochemistry, morphology and physiology of neurons within the bed nucleus of the stria terminalis (BNST). Here we investigate the role of the BNST in mediating the reduced weight gain observed during repeated stress. Rats exposed to a one-week variate stress paradigm exhibited a reduction in weight gain over the course of the 7 day paradigm. Excitotoxic lesions to a subregion of the anterolateral BNST containing the oval nucleus had no effects early in the 7 day paradigm, but significantly attenuated the effects of repeated stress on weight gain by the last day of stress. These data suggest that at least two mechanisms mediate the effects of stress on body weight gain, and that when stressor exposure becomes repeated, the BNST is recruited, worsening the symptoms of stressor exposure. PMID:22101300

  2. Excitotoxic lesions of the bed nucleus of the stria terminalis (BNST) attenuate the effects of repeated stress on weight gain: evidence for the recruitment of BNST activity by repeated, but not acute, stress.

    PubMed

    Roman, Carolyn W; Lezak, Kimberly R; Kocho-Schellenberg, Margaret; Garret, Mark A; Braas, Karen; May, Victor; Hammack, Sayamwong E

    2012-02-01

    Exposure to repeated stress can lead to diverse and widespread behavioral consequences, including reduction in food and water intake and subsequent diminution in weight gain. Many reports have suggested that repeated stress substantially alters the neurochemistry, morphology and physiology of neurons within the bed nucleus of the stria terminalis (BNST). Here we investigate the role of the BNST in mediating the reduced weight gain observed during repeated stress. Rats exposed to a one-week variate stress paradigm exhibited a reduction in weight gain over the course of the 7-day paradigm. Excitotoxic lesions to a subregion of the anterolateral BNST containing the oval nucleus had no effects early in the 7-day paradigm, but significantly attenuated the effects of repeated stress on weight gain by the last day of stress. These data suggest that at least two mechanisms mediate the effects of stress on body weight gain, and that when stressor exposure becomes repeated, the BNST is recruited, worsening the symptoms of stressor exposure. Copyright © 2011 Elsevier B.V. All rights reserved.

  3. Antidepressants share the ability to increase catecholamine output in the bed nucleus of stria terminalis: a possible role in antidepressant therapy?

    PubMed

    Cadeddu, Roberto; Ibba, Marcello; Sadile, Adolfo; Carboni, Ezio

    2014-05-01

    Antidepressants include a relatively wide spectrum of drugs that increase the synaptic concentration of monoamines, mostly through neurotransmitter reuptake blockade. The bed nucleus of stria teminalis (BNST) is considered a relay station in mediating the activation of stress response but also in the acquisition and expression of emotions. BNST is richly innervated by monoamines and sends back projections to the nucleus of origin. We previously showed that the administration of selective blockers of norepinephrine transporter (NET) increases the extracellular concentration (output) of dopamine, suggesting that dopamine could be captured by NET in the BNST. The aim of this study, carried out by means of in vivo microdialysis, was to ascertain the acute effects that antidepressants with varying mechanisms of action have on dopamine and norepinephrine output in the BNST. We observed that all the antidepressants tested (5-20 mg/kg i.p.) increased the output of catecholamines, dose dependently. In particular, the maximum increases (as a percent of basal) for norepinephrine and dopamine respectively, were as follows: desipramine, 239 and 137; reboxetine, 185 and 128; imipramine, 512 and 359; citalopram, 95 and 122; fluoxetine, 122 and 68; bupropion, 255 and 164. These results suggest that catecholamine transmission in the BNST may be part of a common downstream pathway that is involved in the action mechanism of antidepressants. Consequently, it is hypothesized that a dysfunction of neuronal transmission in this brain area may have a role in the etiology of affective disorders.

  4. Noise-induced hearing loss: the effect of melanin in the stria vascularis.

    PubMed

    Bartels, S; Ito, S; Trune, D R; Nuttall, A L

    2001-04-01

    Conflicting investigations regarding the potential protective effect of melanin against noise-induced sensorineural hearing loss have suggested that eumelanin and pheomelanin may have differing effects within the stria vascularis. Three strains of C57BL/6J mice, (+/+, a/a) wild-types (dark coats/black eyes), (c2j/c2j, a/a), albinos (white coats/pink eyes), and (+/+, Ay/Ay) yellow mice (yellow coats/black eyes), were subjected to five consecutive days of broad band noise exposure at 112 dB(A) SPL for 3 h/day. Cochlear function was evaluated with auditory brainstem response audiometry to pure tones immediately pre-exposure, 5-6 h postexposure, and 14 days post-exposure. No significant difference in the degree of sensorineural hearing loss induced in the three strains of mice was identified. The eumelanin and pheomelanin content of each stria vascularis and amount of protein per stria for both mouse and guinea pig (2/NCR) were determined via high performance liquid chromatography. No pheomelanin was found in the stria of yellow mice, suggesting that coat color is not an accurate predictor of strial melanin content. The melanin content per mg of strial protein was higher in mice than in guinea pigs. A species-specific difference in melanin content does not explain the absence of a protective effect in mice.

  5. Lesions of the posterior bed nucleus of the stria terminalis eliminate opposite-sex odor preference and delay copulation in male Syrian hamsters: role of odor volatility and sexual experience

    PubMed Central

    Been, Laura E.; Petrulis, Aras

    2010-01-01

    In Syrian hamsters (Mesocricetus auratus), the expression of reproductive behavior requires the perception of social odors. The behavioral response to these odors is mediated by a network of ventral forebrain nuclei, including the posterior bed nucleus of the stria terminalis (pBNST). Previous studies have tested the role of pBNST in reproductive behavior, but the use of large, fiber-damaging lesions in these studies make it difficult to attribute post-lesion deficits to pBNST specifically. Thus, the current study used discrete, excitotoxic lesions of pBNST to test the role of pBNST in opposite-sex odor preference and copulatory behavior in both sexually-naïve and sexually-experienced males. Lesions of pBNST decreased sexually-naïve males’ investigation of volatile female odors, resulting in an elimination of opposite-sex odor preference. This elimination of preference was not due to a sensory deficit, as males with pBNST lesions were able to discriminate between odors. When, however, subjects were given sexual experience prior to pBNST lesions, their preference for volatile opposite-sex odors remained intact post-lesion. Similarly, when sexually-naïve or sexually-experienced subjects were allowed to contact the social odors during the preference test, lesions of pBNST decreased males’ investigation of female odors, but did not eliminate preference for opposite-sex odors, regardless of sexual experience. Finally, lesions of pBNST delayed the copulatory sequence in sexually-naïve, but not sexually-experienced, males such that they took longer to mount, intromit, ejaculate, and display long intromissions. Together, these results demonstrate that pBNST plays a unique and critical role in both appetitive and consummatory aspects of male reproductive behaviors. PMID:20597978

  6. DISTRIBUTION OF CATECHOLAMINERGIC AND PEPTIDERGIC CELLS IN THE GERBIL MEDIAL AMYGADALA, CAUDAL PREOPTIC AREA AND CAUDAL BED NUCLEI OF THE STRIA TERMINALIS WITH A FOCUS ON AREAS ACTIVATED AT EJACULATION

    PubMed Central

    Simmons, Danielle A.; Yahr, Pauline

    2010-01-01

    The posterodorsal preoptic nucleus (PdPN), lateral part of the posterodorsal medial amygdala (MeApd) and medial part of the medial preoptic nucleus (MPNm) are activated at ejaculation in male gerbils as assessed by Fos expression. We sought to immunocytochemically visualize substance P (SP), cholecystokinin (CCK), oxytocin, vasopressin and tyrosine hydroxylase (TH), a catecholaminergic marker, in the mating-activated cells, but the need for colchicine precluded behavioral testing. Instead, we detailed distributions of cells containing these molecules in the medial amygdala, caudal preoptic area and caudal bed nuclei of the stria terminalis (BST) and quantified their densities in the PdPN, MPNm and lateral MeApd for comparison to densities previously assessed for mating-activated efferents from these sites. TH cells were as dense in the PdPN and lateral MeApd as activated efferents to the anteroventral periventricular nucleus. In the lateral MeApd, TH cells were grouped where cells activated at ejaculation are clustered and where CCK cells form a ball. Lateral MeApd CCK cells and PdPN SP cells were as dense as activated efferents to the principal BST. Oxytocinergic PdPN cells and SP cells in the MPNm were as dense as mating-activated efferents to the lateral MeApd. If some oxytocin cells in the PdPN project to the neurohypophysis, as in rats, they could be a source of the oxytocin secreted at ejaculation. Since gerbils are monogamous and biparental, it was also interesting that, unlike monogamous prairie voles, they had few TH cells in the MeApd or dorsal BST, resembling promiscuous rats, hamsters and meadow voles. PMID:21087661

  7. Altered anxiety-like behavior and long-term potentiation in the bed nucleus of the stria terminalis in adult mice exposed to chronic social isolation, unpredictable stress, and ethanol beginning in adolescence.

    PubMed

    Conrad, Kelly L; Winder, Danny G

    2011-09-01

    Alcohol and chronic stress exposure, especially during adolescence, can lead to an increased risk in adulthood of developing alcohol use disorders. To date, however, no study has assessed the potential long-term effects of chronic intermittent and unpredictable ethanol (EtOH) exposure in mice chronically stressed beginning in adolescence on brain function and anxiety-like behaviors in adulthood. In particular, alterations in function of the bed nucleus of the stria terminalis (BNST), a brain region heavily implicated in anxiety-related behaviors and altered plasticity following EtOH exposure, may play a key role in the pathological responses to chronic stress and EtOH. In the present study, adolescent and adult C57Bl/6J mice were exposed to a regimen of chronic social isolation and unpredictable stressors and EtOH (or air [sham]; CSI-CUS-EtOH and CSI-CUS-Sham, respectively) for 8-10 weeks. In adulthood, mice were tested for altered anxiety-like behavior (elevated plus maze [EPM] and modified social interaction [SI] test). Following behavioral testing, mice were reexposed to CSI-CUS-EtOH (and CSI-CUS-Sham for controls) for an additional 3 days. Four to six hours following the final EtOH (or air) exposure, field potential recordings of the dorsal-lateral (dl)BNST were performed. Mice first exposed during adolescence to CSI-CUS-EtOH displayed lower levels of anxiety-like behavior on the EPM compared with mice first exposed to CSI-CUS-EtOH during adulthood and control mice only exposed to CSI-CUS-Sham, regardless of age of first exposure. However, mice first exposed to CSI-CUS-EtOH during adulthood displayed lower levels of anxiety-like behavior on the SI test compared with mice first exposed during adolescence and control CSI-CUS-Sham mice. CSI-CUS-EtOH exposure, regardless of age, produced blunted expression of long-term potentiation (LTP) in the dlBNST compared with CSI-CUS-Sham mice. This study demonstrates age-dependent effects of chronic unpredictable ethanol

  8. Roles for pituitary adenylate cyclase-activating peptide (PACAP) expression and signaling in the bed nucleus of the stria terminalis (BNST) in mediating the behavioral consequences of chronic stress.

    PubMed

    Hammack, Sayamwong E; Roman, Carolyn W; Lezak, Kimberly R; Kocho-Shellenberg, Margaret; Grimmig, Bethany; Falls, William A; Braas, Karen; May, Victor

    2010-11-01

    Anxiety disorders are frequently long-lasting and debilitating for more than 40 million American adults. Although stressor exposure plays an important role in the etiology of some anxiety disorders, the mechanisms by which exposure to stressful stimuli alters central circuits that mediate anxiety-like emotional behavior are still unknown. Substantial evidence has implicated regions of the central extended amygdala, including the bed nucleus of the stria terminalis (BNST) and the central nucleus of the amygdala as critical structures mediating fear- and anxiety-like behavior in both humans and animals. These areas organize coordinated fear- and anxiety-like behavioral responses as well as peripheral stress responding to threats via direct and indirect projections to the paraventricular nucleus of the hypothalamus and brainstem regions (Walker et al. Eur J Pharmacol 463:199-216, 2003, Prog Neuropsychopharmacol Biol Psychiatry 33(8):1291-1308, 2009; Ulrich-Lai and Herman Nat Rev Neurosci 10:397-409, 2009). In particular, the BNST has been argued to mediate these central and peripheral responses when the perceived threat is of long duration (Waddell et al. Behav Neurosci 120:324-336, 2006) and/or when the anxiety-like response is sustained (Walker and Davis Brain Struct Funct 213:29-42, 2008); hence, the BNST may mediate pathological anxiety-like states that result from exposure to chronic stress. Indeed, chronic stress paradigms result in enhanced BNST neuroplasticity that has been associated with pathological anxiety-like states (Vyas et al. Brain Res 965:290-294, 2003; Pego et al. Eur J Neurosci 27:1503-1516, 2008). Here we review evidence that suggests that pituitary adenylate cyclase-activating polypeptide (PACAP) and corticotropin-releasing hormone (CRH) work together to modulate BNST function and increase anxiety-like behavior. Moreover, we have shown that BNST PACAP as well as its cognate PAC1 receptor is substantially upregulated following chronic stress

  9. [Drinking behavior and c-fos expression induced by chemical or electrical stimulation of SFO in rat brain].

    PubMed

    Li, Xu-Ping; Jiang, Xing-Hong

    2002-08-01

    To compare the drinking behavior and c-fos expression induced by chemical or electrical stimulation of subfornical organ (SFO) in rat brain. L-glutamic acid microinjection and constant electrical current were used as chemical and electrical stimulation of SFO, respectively. The water intake over 1 h was recorded and Fos expression was examined immunohistochemically. A similar volume of water intake and Fos expression pattern were induced by both methods of stimulation of SFO. These include 11 forebrain areas (organum vasculosum of the lamina terminalis, median preoptic nucleus, hypothalamic paraventricular nucleus, supraoptic nucleus and lateral hypothalamic area, paraventricular nucleus, reunions nucleus and central medial nucleus of thalamus, bed nucleus of the stria terminalis, perifornical dorsal area and substantia innominata) and 4 areas of hindbrain (area postrema, nucleus solitary tract, lateral parabrachial nucleus and dorsal raphe nucleus). The drinking behavior and Fos expression in brain induced by SFO stimulation are the results of activation of the neuronal bodies in SFO.

  10. The Slowly Enlarging Ventriculus Terminalis

    PubMed Central

    Woodley-Cook, Joel; Konieczny, Magdalena; Spears, Julian

    2016-01-01

    Summary Background A cerebral spinal fluid (CSF) cavity within the conus medullaris has been described by the term ventriculus terminalis (VT) or the fifth ventricle. The finding of a VT on MRI imaging of the lumbar spine is often incidental but may be found in patients with low back pain or neuromuscular deficits. These lesions, when identified, are thought to regress or remain stable in terms of size, although some have been described to enlarge in the presence of post-traumatic meningeal hemorrhages or deformities of the vertebral canal. Case Report We describe a case of a slowly growing VT in a patient with progressing lower limb weakness without any history or imaging findings of trauma or spinal canal abnormalities. Conclusions We present an intriguing case of a slowly growing VT in a woman with progressive neurological symptoms. Surgical fenestration provided complete symptomatic relief and follow-up imaging two years after surgery demonstrated no evidence of recurrence. This, to our knowledge, is the first described case of a slowly enlarging VT independent of any other imaging findings. PMID:27867442

  11. Interaction of GABA and norepinephrine in the lateral division of the bed nucleus of the stria terminals in anesthetized rat, correlating single-unit and cardiovascular responses.

    PubMed

    Yeganeh, Fahimeh; Nasimi, Ali; Hatam, Masoumeh

    2017-07-25

    The bed nucleus of the stria terminalis (BST) consists of multiple anatomically distinct nuclei. The lateral division, which receives dense noradrenergic innervation, has been implicated in cardiovascular regulation and modulation of responses to stress. This study is performed to identify the cardiovascular and single-unit responses of the lateral BST to norepinephrine (NE), involved adrenoceptors, and possible interaction with GABAergic system of the BST in urethane-anesthetized rats. NE, adrenoreceptor antagonists, and GABAA antagonist were microinjected into the lateral division of BST, while arterial pressure (AP), heart rate (HR), and single-unit responses were simultaneously recorded. NE microinjected into the lateral division of BST produced depressor and bradycardic responses. The decrease in AP and HR to NE was blocked by prazosin, an α1-adrenoreceptor antagonist, but not by yohimbine, an α2 antagonist. Furthermore, injections of the GABAA receptor antagonist, bicuculline methiodide (BMI), into the lateral BST abolished the NE-induced depressor and bradycardic responses. We also observed single-unit responses consisting of excitatory and inhibitory responses correlated with cardiovascular function to the microinjection of NE. In conclusion, these data provide the first evidence that microinjection of NE in the lateral division of BST produces depressor and bradycardic responses in urethane-anesthetized rat. The depressor and bradycardiac response are mediated by local α1- but not α2-adrenoceptors. α1-AR activates the GABAergic system within the BST, which in turn produces depressor and bradycardic responses. Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.

  12. Evaluating the stria content in optical glasses

    NASA Astrophysics Data System (ADS)

    Doladugina, V. S.

    2004-12-01

    This paper discusses previously unpublished results of a large collaborative project carried out by Russian and German specialists on the study of the stria content of glasses with the purpose of estimating the possibility of creating a unified standard corresponding to world requirements. A comparison of the techniques existing in the USSR and the German Democratic Republic in 1981-82 in the form of GOST [State Standard] 3521-82 and TGL 21790 did not lead to a positive result, and it was impossible to create a unified document on the evaluation and monitoring of the stria content of uncolored optical glasses. The causes of the situation thus created are explained, and possible ways of solving this problem are considered.

  13. Adenine nucleotides of the stria vascularis.

    PubMed

    Thalmann, I; Marcus, N Y; Thalmann, R

    1979-01-01

    The levels of the adenine nucleotides ATP, ADP, and AMP in the stria vascularis were measured under normal conditions, and following various durations of ischemia. The concentrations of these compounds were used for the calculation of the adenylate energy charge, the energy status and the phosphorylation state of the stria. Following 10 min of ischemia the adenylate energy charge had decreased three fold, the energy status seven fold and the phosphorylation state 14 fold. To study the potential for recovery of strial function following various brief and prolonged ischemic intervals, a method for the perfusion of the ear via the anterior inferior cerebellar artery was developed. For various reasons it was found advantageous to use "artifical blood" as perfusate, relying upon fluorocarbons as oxygen carriers. The endolymphatic potential was used as electrical indicator of strial function. Recovery of the endolymphatic potential following brief periods of ischemia was paralleled by a corresponding increase of the ATP levels and a drastic decrease of the AMP levels of the stria vascularis. Preliminary results on the effects of substrate-free perfusion are presented.

  14. Freeze fracturing of the human stria vascularis.

    PubMed

    Bagger-Sjöbäck, D; Engström, B; Steinholtz, L; Hillerdal, M

    1987-01-01

    The stria vascularis is an important functional element in the mammalian cochlea. This special tissue is considered to be the source of the endocochlear potential and thus the driving force for the production of a receptor response to the auditory stimulus. In order to maintain its function, the stria vascularis needs to be separated from the endolymphatic space by a tight seal. This seal is comprised of tight junctions in the marginal cell layer. The junctional arrangement in the stria vascularis is described, utilizing the freeze-fracturing technique which allows the visualization of large expansions of plasma membrane. The marginal cells are generally separated by tight junctions of the moderately tight to tight type. In places, however, even so-called leaky junctions with only a few sealing strands are present. Whereas the intermediate cell layer seems to lack tight junctions, the basal cells are connected by extensive tight junctions more or less covering the entire cell. These junctions seem to form an extremely tight barrier against the spiral ligament. Gap junctions are also present in the tissue. Intermediate cells as well as the basal cells are coupled by gap junctions. In the basal cell layer, gap junctional elements may also be found inside the large tight junctions comprising so-called mixed junctions.

  15. [Morphological changes in the stria vascularis and hair cells after mastoid-vibration using a cutting bur].

    PubMed

    Miyasaka, H

    1999-11-01

    Severe sesorineural deafness develops occasionally after tympanoplasty. Since a vibration induced by the drill during surgery is thought to be one of the cause, we examined its effect on the inner ear in this study. Five guinea pigs aged about 1 month were used. The right ear of each animal was used as the control, and the left ear underwent stimulation with the drill induced vibration. The vibration was applied to the temporal bone for 60 seconds using a cutting bur. After the vibration, the stria vascularis and hair cells in the cochlea were examined. For the investigation of the permeability of the stria vascularis, horseradish peroxidase (HRP) was injected intravenously as a tracer, and the tissue was observed with a light and an electron microscopes. Three sections of the stria vascularis from each of the superior turn (the third turn) and the inferior turn (the basal turn) of bilateral cochleae were randomly prepared, and they were classified into Types I to IV according to the degree of HRP leakage. When a hair cell had even one vacuole inside, it was classified as a vacuole-positive cell. After stimulation with the drill-induced vibration, about 10% of the blood vessels of the stria vascularis showed severe leakage of HRP (Types III, IV). In the intermediate cells, partial degeneration of mitochondria was found. No significant difference in the permeability of the blood vessels was found between the turns. The route of leakage of HRP from blood vessels of the stria vascularis was neither the transport via pinocytotic vesicle nor passage through the intercellular space of endothelial cells. The leakage through a tubular-like structure in the endothelial cells was observed. Since no HRP was found in this tubular-like structure ordinarily, a channel might have been opened by injury due to the vibration. The leakage from the blood vessels of the stria vascularis in the control side could scarcely be observed. Many hair cells in the drill-stimulation side in

  16. Development of the nervus terminalis: origin and migration.

    PubMed

    Whitlock, Kathleen E

    2004-09-01

    The origin of the nervus terminalis is one of the least well understood developmental events involved in generating the cranial ganglia of the forebrain in vertebrate animals. This cranial nerve forms at the formidable interface of the anteriormost limits of migrating cranial neural crest cells, the terminal end of the neural tube and the differentiating olfactory and adenohypophyseal placodes. The complex cellular interactions that give rise to the various structures associated with the sensory placode (olfactory) and endocrine placode (adenohypophysis) surround and engulf this enigmatic cranial nerve. The tortured history of nervus terminalis development (see von Bartheld, this issue, pages 13-24) reflects the lack of consensus on the origin (or origins), as well as the experimental difficulties in uncovering the origin, of the nervus terminalis. Recent technical advances have allowed us to make headway in understanding the origin(s) of this nerve. The emergence of the externally fertilized zebrafish embryo as a model system for developmental biology and genetics has shed new light on this century-old problem. Coupled with new developmental models are techniques that allow us to trace lineage, visualize gene expression, and genetically ablate cells, adding to our experimental tools with which to follow up on studies provided by our scientific predecessors. Through these techniques, a picture is emerging in which the origin of at least a subset of the nervus terminalis cells lies in the cranial neural crest. In this review, the data surrounding this finding will be discussed in light of recent findings on neural crest and placode origins. Copyright 2004 Wiley-Liss, Inc.

  17. Intense pulsed light hair removal in a patient with congenital hypertrichosis terminalis.

    PubMed

    Attia, Abeer; El Noury, Amr; Abd Alhafez, Mamdouh

    2012-01-01

    We report a case of 1-year-old girl with congenital hypertrichosis terminalis treated using intense pulsed light for hair removal. Repeated sessions were performed every 3 weeks. Facial hair reduction was achieved after 12 sessions and body hair reduction after 15 sessions. Intense pulsed light resulted in 75% reduction of hair in congenital hypertrichosis terminalis.

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

    PubMed

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

    2010-09-01

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

  19. Organ of Corti and Stria Vascularis: Is there an Interdependence for Survival?

    PubMed Central

    Liu, Huizhan; Li, Yi; Chen, Lei; Zhang, Qian; Pan, Ning; Nichols, David H.; Zhang, Weiping J.; Fritzsch, Bernd

    2016-01-01

    Cochlear hair cells and the stria vascularis are critical for normal hearing. Hair cells transduce mechanical stimuli into electrical signals, whereas the stria is responsible for generating the endocochlear potential (EP), which is the driving force for hair cell mechanotransduction. We questioned whether hair cells and the stria interdepend for survival by using two mouse models. Atoh1 conditional knockout mice, which lose all hair cells within four weeks after birth, were used to determine whether the absence of hair cells would affect function and survival of stria. We showed that stria morphology and EP remained normal for long time despite a complete loss of all hair cells. We then used a mouse model that has an abnormal stria morphology and function due to mutation of the Mitf gene to determine whether hair cells are able to survive and transduce sound signals without a normal electrochemical environment in the endolymph. A strial defect, reflected by missing intermediate cells in the stria and by reduction of EP, led to systematic outer hair cell death from the base to the apex after postnatal day 18. However, an 18-mV EP was sufficient for outer hair cell survival. Surprisingly, inner hair cell survival was less vulnerable to reduction of the EP. Our studies show that normal function of the stria is essential for adult outer hair cell survival, while the survival and normal function of the stria vascularis do not depend on functional hair cells. PMID:28030585

  20. Seasonal changes of fructans in dimorphic roots of Ichthyothere terminalis (Spreng.) Blake (Asteraceae) growing in Cerrado.

    PubMed

    de Almeida, Lorrayne Veloso; Ferri, Pedro Henrique; Seraphin, José Carlos; de Moraes, Moemy Gomes

    2017-11-15

    Cerrado is a floristically rich savanna in Brazil, whose vegetation consists of a physiognomic mosaic, influenced by rainfall seasonality. In the dry season rainfall is substantially lower and reduces soil water supply, mainly for herbs and subshrubs. Climatic seasonal variations may well define phenological shifts and induce fluctuations of plant reserve pools. Some Cerrado native species have thickened underground organs that bear buds and store reserves, as adaptive features to enable plant survival following environmental stresses. Asteraceae species accumulate fructans in storage organs, which are not only reserve, but also protecting compounds against the effects of cold and drought. Ichthyothere terminalis is one Asteraceae species abundant in cerrado rupestre, with underground organs consisting of thickened orthogravitropic and diagravitropic roots. The objectives of this study were to analyze how abiotic environmental factors and plant phenology influence fructan dynamics in field grown plants, and verify if fructan metabolism differs in both root types for one year. I. terminalis accumulates inulin-type fructans in 10-40% of the dry mass in both root types. Fructan dynamics have similar patterns described for other Asteraceae species, exhibiting a proportional increase of polysaccharides with the senescence of the aerial organs. Multivariate analyzes showed that, as rainfall decreased, environmental factors had a stronger influence on metabolite levels than phenological shifts in both root types. Only slight differences were found in fructan dynamics between orthogravitropic and diagravitropic roots, suggesting they may have similar fructan metabolism regulation. However, these small differences may reflect distinct microclimatic conditions in both root types and also represent the influence of sink strength. Copyright © 2017 Elsevier B.V. All rights reserved.

  1. [Neuronal mechanisms underlying pain-induced negative emotions].

    PubMed

    Minami, Masabumi

    2012-11-01

    Pain consists of sensory-discriminative and negative emotional components. Although the neuronal basis of the sensory component of pain has been studied extensively, the neuronal mechanisms underlying the negative emotional component are not well understood. Recently, behavioral studies using a conditioned place paradigm have successfully elucidated the neuronal circuits and mechanisms underlying the negative emotional component of pain. Excitotoxic lesions of the anterior cingulate cortex (ACC), central amygdaloid nucleus, basolateral amygdaloid nucleus (BLA), or bed nucleus of the stria terminalis (BNST) suppress intraplantar formalin-induced aversive responses. Glutamatergic transmission within the ACC and BLA via N-methyl-D-asparate (NMDA) receptors has been shown to play a critical role in these aversive responses. In the BNST, especially its ventral part, noradrenergic transmission via β-adrenergic receptors has been shown to be important for pain-induced aversion. Because persistent pain is frequently associated with psychological and emotional dysfunctions, studies on the neuronal circuits and molecular mechanisms involved in the negative emotional component of pain may have considerable clinical importance in the treatment of chronic pain. Here, I have reviewed behavioral studies investigating the neuronal mechanisms underlying the negative emotional component of pain and have introduced our data showing the pivotal role of amygdala and BNST in pain-induced aversion.

  2. Distribution and Functional Expression of Kv4 Family α Subunits and Associated KChIP β Subunits in the Bed Nucleus of the Stria Terminalis

    PubMed Central

    Rainnie, Donald G.; Hazra, Rimi; Dabrowska, Joanna; Guo, Ji-Dong; Li, Chen Chen; Dewitt, Sarah; Muly, E. Chris

    2014-01-01

    Regulation of BNSTALG neuronal firing activity is tightly regulated by the opposing actions of the fast outward potassium current, IA, mediated by α subunits of the Kv4 family of ion channels, and the transient inward calcium current, IT. Together, these channels play a critical role in regulating the latency to action potential onset, duration, and frequency, as well as dendritic back-propagation and synaptic plasticity. Previously we have shown that Type I–III BNSTALG neurons express mRNA transcripts for each of the Kv4 α subunits. However, the biophysical properties of native IA channels are critically dependent on the formation of macromolecular complexes of Kv4 channels with a family of chaperone proteins, the potassium channel-interacting proteins (KChIP1–4). Here we used a multidisciplinary approach to investigate the expression and function of Kv4 channels and KChIPs in neurons of the rat BNSTALG. Using immunofluorescence we demonstrated the pattern of localization of Kv4.2, Kv4.3, and KChIP1–4 proteins in the BNSTALG. Moreover, our single-cell reverse-transcription polymerase chain reaction (scRT-PCR) studies revealed that mRNA transcripts for Kv4.2, Kv4.3, and all four KChIPs were differentially expressed in Type I–III BNSTALG neurons. Furthermore, immunoelectron microscopy revealed that Kv4.2 and Kv4.3 channels were primarily localized to the dendrites and spines of BNSTALG neurons, and are thus ideally situated to modulate synaptic transmission. Consistent with this observation, in vitro patch clamp recordings showed that reducing postsynaptic IA in these neurons lowered the threshold for long-term potentiation (LTP) induction. These results are discussed in relation to potential modulation of IA channels by chronic stress. PMID:24037673

  3. Subfrontal trans-lamina terminalis approach to a third ventricular craniopharyngioma.

    PubMed

    Choudhri, Omar; Chang, Steven D

    2016-01-01

    Craniopharyngiomas are benign, partly cystic epithelial tumors that can rarely occur in a retrochiasmatic location with involvement of the third ventricle. The lamina terminalis is an important neurosurgical corridor to these craniopharyngiomas in the anterior portion of the third ventricle. We present a video case of a large midline suprasellar and third ventricular craniopharyngioma in a 32-year-old male with visual disturbances. The tumor was approached with a subfrontal translamina terminalis exposure, and a gross-total resection of the tumor was achieved. This surgery involved working through a lamina terminalis fenestration around the optic nerve, optic chiasm, optic tracts, and the anterior communicating artery complex. This video illustrates the techniques employed in performing a transbasal anterior skull base approach to the third ventricle and demonstrates vivid surgical anatomy of neurovascular structures around the lamina terminalis. The video can be found here: https://youtu.be/fCYMgx8SnKs .

  4. When is a mass not a mass? An unusual presentation of prominent crista terminalis.

    PubMed

    Salim, Handi; Palit, Amitabh; Maher, Abdul

    2016-02-15

    This case report describes a patient in whom echocardiography showed borderline left ventricular hypertrophy and a mass adjacent to the right atrial wall. This naturally caused some concern as the differential diagnoses included that of a right atrial myxoma and further investigations were organised. A subsequent cardiac MRI revealed this thickening to be a prominent crista terminalis. The crista terminalis is a variant of normal anatomical structures within the right atrium, which mimics an atrial mass. 2016 BMJ Publishing Group Ltd.

  5. Ethanol-induced alterations of c-Fos immunoreactivity in specific limbic brain regions following ethanol discrimination training.

    PubMed

    Besheer, Joyce; Schroeder, Jason P; Stevenson, Rebekah A; Hodge, Clyde W

    2008-09-26

    The discriminative stimulus properties of ethanol are functionally regulated by ionotropic GABA(A) and NMDA receptors in specific limbic brain regions including the nucleus accumbens, amygdala, and hippocampus, as determined by microinjection studies. The purpose of the present work was to further investigate potential neural substrates of ethanol's discriminative stimulus effects by examining if ethanol discrimination learning produces changes in brain regional response to ethanol. To accomplish this goal, immunohistochemistry was used to assess the effects of ethanol (2 g/kg) on c-Fos immunoreactivity (Fos-IR). Comparisons in ethanol-induced Fos-IR were made between a group of rats that was trained to discriminate the stimulus properties of ethanol (2 g/kg, IG) from water (IG) and a drug/behavior-matched control group that did not receive differential reinforcement for lever selection, which precluded acquisition of discriminative stimulus control by ethanol. In some brain regions discrimination training had no effect on ethanol-induced Fos-IR changes (caudate putamen, bed nucleus of the stria terminalis, and CA1 region of the hippocampus). In contrast, discrimination training altered the pattern of ethanol-induced Fos-IR in the nucleus accumbens (core), medial septum, and the hippocampus (dentate and CA3). These results indicate that having behavior under the stimulus control of ethanol can change ethanol-induced Fos-IR in some brain regions. This suggests that learning about the subjective properties of ethanol produces adaptive changes in how the brain responds to acute ethanol exposure.

  6. Distinct neuronal activation patterns are associated with PCP-induced social withdrawal and its reversal by the endocannabinoid-enhancing drug URB597

    PubMed Central

    Matricon, Julien; Seillier, Alexandre; Giuffrida, Andrea

    2016-01-01

    The fatty acid amide hydrolase inhibitor, URB597, an endocannabinoid enhancing drug, reverses social withdrawal in the sub-chronic PCP rat model of schizophrenia, but reduces social interaction (SI) in controls. To identify the anatomical substrates associated with PCP-induced social withdrawal and the contrasting effects of URB597 on SI in PCP- versus saline-treated rats, we analyzed SI-induced c-Fos expression in 28 brain areas relevant to schizophrenia and/or social behavior following vehicle or URB597 administration. In saline-treated rats, SI was accompanied by changes in c-Fos expression in the infralimbic and orbitofrontal cortices, dorsomedial caudate putamen, ventrolateral nucleus of the septum, dorsolateral periaqueductal gray (dlPAG) and central amygdala. Except for the dlPAG, these changes were not observed in PCP-treated rats or in saline-treated rats receiving URB597. In the dorsomedial part of the bed nucleus of the stria terminalis (dmBNST), SI-induced c-Fos expression was observed only in PCP-treated rats. Interestingly, URB597 in PCP-treated rats restored a similar c-Fos expression pattern as observed in saline-treated rats: activation of the orbitofrontal cortex, inhibition of the central amygdala and suppression of activation of the dmBNST. These data suggest that orbitofrontal cortex, central amygdala and dmBNST play a critical role in the reversal of PCP-induced social withdrawal by URB597. PMID:27091613

  7. Altered responsiveness of BNST and amygdala neurons in trauma-induced anxiety

    PubMed Central

    Rodríguez-Sierra, O E; Goswami, S; Turesson, H K; Pare, D

    2016-01-01

    A highly conserved network of brain structures regulates the expression of fear and anxiety in mammals. Many of these structures display abnormal activity levels in post-traumatic stress disorder (PTSD). However, some of them, like the bed nucleus of the stria terminalis (BNST) and amygdala, are comprised of several small sub-regions or nuclei that cannot be resolved with human neuroimaging techniques. Therefore, we used a well-characterized rat model of PTSD to compare neuronal properties in resilient vs PTSD-like rats using patch recordings obtained from different BNST and amygdala regions in vitro. In this model, a persistent state of extreme anxiety is induced in a subset of susceptible rats following predatory threat. Previous animal studies have revealed that the central amygdala (CeA) and BNST are differentially involved in the genesis of fear and anxiety-like states, respectively. Consistent with these earlier findings, we found that between resilient and PTSD-like rats were marked differences in the synaptic responsiveness of neurons in different sectors of BNST and CeA, but whose polarity was region specific. In light of prior data about the role of these regions, our results suggest that control of fear/anxiety expression is altered in PTSD-like rats such that the influence of CeA is minimized whereas that of BNST is enhanced. A model of the amygdalo-BNST interactions supporting the PTSD-like state is proposed. PMID:27434491

  8. Oxytocin Reduces Cocaine Seeking and Reverses Chronic Cocaine-Induced Changes in Glutamate Receptor Function

    PubMed Central

    Zhou, Luyi; Sun, Wei-Lun; Young, Amy B.; Lee, Kunhee; McGinty, Jacqueline F.

    2015-01-01

    Background: Oxytocin, a neurohypophyseal neuropeptide, is a potential mediator and regulator of drug addiction. However, the cellular mechanisms of oxytocin in drug seeking remain unknown. Methods: In the present study, we used a self-administration/reinstatement model to study the effects of oxytocin on cocaine seeking and its potential interaction with glutamate function at the receptor level. Results: Systemic oxytocin dose-dependently reduced cocaine self-administration during various schedules of reinforcement, including fixed ratio 1, fixed ratio 5, and progressive ratio. Oxytocin also attenuated reinstatement to cocaine seeking induced by cocaine prime or conditioned cues. Western-blot analysis indicated that oxytocin increased phosphorylation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptor GluA1 subunit at the Ser 845 site with or without accompanying increases in phosphorylation of extracellular signal-regulated kinase, in several brain regions, including the prefrontal cortex, bed nucleus of the stria terminalis, amygdala, and dorsal hippocampus. Immunoprecipitation of oxytocin receptor and GluA1 subunit receptors further demonstrated a physical interaction between these 2 receptors, although the interaction was not influenced by chronic cocaine or oxytocin treatment. Oxytocin also attenuated sucrose seeking in a GluA1- or extracellular-signal-regulated kinase-independent manner. Conclusions: These findings suggest that oxytocin mediates cocaine seeking through interacting with glutamate receptor systems via second messenger cascades in mesocorticolimbic regions. PMID:25539504

  9. The hallucinogen d-lysergic acid diethylamide (d-LSD) induces the immediate-early gene c-Fos in rat forebrain.

    PubMed

    Frankel, Paul S; Cunningham, Kathryn A

    2002-12-27

    The hallucinogen d-lysergic acid diethylamide (d-LSD) evokes dramatic somatic and psychological effects. In order to analyze the neural activation induced by this unique psychoactive drug, we tested the hypothesis that expression of the immediate-early gene product c-Fos is induced in specific regions of the rat forebrain by a relatively low, behaviorally active, dose of d-LSD (0.16 mg/kg, i.p.); c-Fos protein expression was assessed at 30 min, and 1, 2 and 4 h following d-LSD injection. A time- and region-dependent expression of c-Fos was observed with a significant increase (P<0.05) in the number of c-Fos-positive cells detected in the anterior cingulate cortex at 1 h, the shell of the nucleus accumbens at 1 and 2 h, the bed nucleus of stria terminalis lateral at 2 h and the paraventricular hypothalamic nucleus at 1, 2 and 4 h following systemic d-LSD administration. These data demonstrate a unique pattern of c-Fos expression in the rat forebrain following a relatively low dose of d-LSD and suggest that activation of these forebrain regions contributes to the unique behavioral effects of d-LSD. Copyright 2002 Elsevier Science B.V.

  10. Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress

    PubMed Central

    Mantsch, John R; Baker, David A; Funk, Douglas; Lê, Anh D; Shaham, Yavin

    2016-01-01

    In human addicts, drug relapse and craving are often provoked by stress. Since 1995, this clinical scenario has been studied using a rat model of stress-induced reinstatement of drug seeking. Here, we first discuss the generality of stress-induced reinstatement to different drugs of abuse, different stressors, and different behavioral procedures. We also discuss neuropharmacological mechanisms, and brain areas and circuits controlling stress-induced reinstatement of drug seeking. We conclude by discussing results from translational human laboratory studies and clinical trials that were inspired by results from rat studies on stress-induced reinstatement. Our main conclusions are (1) The phenomenon of stress-induced reinstatement, first shown with an intermittent footshock stressor in rats trained to self-administer heroin, generalizes to other abused drugs, including cocaine, methamphetamine, nicotine, and alcohol, and is also observed in the conditioned place preference model in rats and mice. This phenomenon, however, is stressor specific and not all stressors induce reinstatement of drug seeking. (2) Neuropharmacological studies indicate the involvement of corticotropin-releasing factor (CRF), noradrenaline, dopamine, glutamate, kappa/dynorphin, and several other peptide and neurotransmitter systems in stress-induced reinstatement. Neuropharmacology and circuitry studies indicate the involvement of CRF and noradrenaline transmission in bed nucleus of stria terminalis and central amygdala, and dopamine, CRF, kappa/dynorphin, and glutamate transmission in other components of the mesocorticolimbic dopamine system (ventral tegmental area, medial prefrontal cortex, orbitofrontal cortex, and nucleus accumbens). (3) Translational human laboratory studies and a recent clinical trial study show the efficacy of alpha-2 adrenoceptor agonists in decreasing stress-induced drug craving and stress-induced initial heroin lapse. PMID:25976297

  11. Adolescent nicotine induces persisting changes in development of neural connectivity.

    PubMed

    Smith, Robert F; McDonald, Craig G; Bergstrom, Hadley C; Ehlinger, Daniel G; Brielmaier, Jennifer M

    2015-08-01

    Adolescent nicotine induces persisting changes in development of neural connectivity. A large number of brain changes occur during adolescence as the CNS matures. These changes suggest that the adolescent brain may still be susceptible to developmental alterations by substances which impact its growth. Here we review recent studies on adolescent nicotine which show that the adolescent brain is differentially sensitive to nicotine-induced alterations in dendritic elaboration, in several brain areas associated with processing reinforcement and emotion, specifically including nucleus accumbens, medial prefrontal cortex, basolateral amygdala, bed nucleus of the stria terminalis, and dentate gyrus. Both sensitivity to nicotine, and specific areas responding to nicotine, differ between adolescent and adult rats, and dendritic changes in response to adolescent nicotine persist into adulthood. Areas sensitive to, and not sensitive to, structural remodeling induced by adolescent nicotine suggest that the remodeling generally corresponds to the extended amygdala. Evidence suggests that dendritic remodeling is accompanied by persisting changes in synaptic connectivity. Modeling, electrophysiological, neurochemical, and behavioral data are consistent with the implication of our anatomical studies showing that adolescent nicotine induces persisting changes in neural connectivity. Emerging data thus suggest that early adolescence is a period when nicotine consumption, presumably mediated by nicotine-elicited changes in patterns of synaptic activity, can sculpt late brain development, with consequent effects on synaptic interconnection patterns and behavior regulation. Adolescent nicotine may induce a more addiction-prone phenotype, and the structures altered by nicotine also subserve some emotional and cognitive functions, which may also be altered. We suggest that dendritic elaboration and associated changes are mediated by activity-dependent synaptogenesis, acting in part

  12. Neurokinin-1 receptor antagonism attenuates neuronal activity triggered by stress-induced reinstatement of alcohol seeking

    PubMed Central

    Schank, J.R.; Nelson, B.S.; Damadzic, R.; Tapocik, J.D.; Yao, M.; King, C.E.; Rowe, K.E.; Cheng, K.; Rice, K.C.; Heilig, M.

    2015-01-01

    Substance P (SP) and its cognate neurokinin-1 receptor (NK1R) are involved in alcohol-related behaviors. We have previously reported that NK1R antagonism attenuates stress-induced reinstatement of alcohol seeking and suppresses escalated alcohol self-administration, but does not affect primary reinforcement or cue-induced reinstatement. Here, we administered an NK1R antagonist or vehicle prior to footshock-induced reinstatement of alcohol seeking, and mapped the resulting neuronal activation using Fos immunohistochemistry. As expected, vehicle treated animals exposed to footshock showed induction of Fos immunoreactivity in several regions of the brain stress circuitry, including the amygdala (AMG), nucleus accumbens (NAC), dorsal raphe nucleus (DR), prefrontal cortex (PFC), and bed nucleus of the stria terminalis (BNST). NK1R antagonism selectively suppressed the stress-induced increase in Fos in the DR and NAC shell. In the DR, Fos-induction by stress largely overlapped with tryptophan hydroxylase (TrpH), indicating activation of serotonergic neurons. Of NAC shell neurons activated during stress-induced reinstatement of alcohol seeking, about 30% co-expressed dynorphin (DYN), while 70% co-expressed enkephalin (ENK). Few (<1%) activated NAC shell neurons co-expressed choline acetyltransferase (ChAT), which labels the cholinergic interneurons of this region. Infusion of the NK1R antagonist L822429 into the NAC shell blocked stress-induced reinstatement of alcohol seeking. In contrast, L822429 infusion into the DR had no effect, suggesting that the influence of NK1R signaling on neuronal activity in the DR is indirect. Taken together, our results outline a potential pathway through which endogenous NK1R activation mediates stress-induced alcohol seeking. PMID:26188146

  13. Morphological observation of the stria vascularis in midkine and pleiotrophin knockout mice.

    PubMed

    Sone, Michihiko; Muramatsu, Hisako; Muramatsu, Takashi; Nakashima, Tsutomu

    2011-02-01

    Midkine and Pleiotrophin are low molecular weight basic proteins with closely related structures and serve as growth/differentiation factors. They have been reported to be expressed in the cochlea during the embryonic and perinatal periods. In the present study, we focused on the roles of midkine and pleiotrophin in the stria vascularis and investigated morphological changes using mice deficient in these genes. Midkine knockout, pleiotrophin knockout, and double knockout mice were used and compared to wild-type mice. Auditory brain stem responses (ABRs) and cochlear blood flows were measured in each type of mice. Pathological changes in the stria vascularis were examined by light microscopy, including immunohistochemical staining with anti-Kir4.1 antibody, and electron microscopy. Hearing thresholds examined by ABRs were significantly higher in midkine knockout and pleiotrophin knockout mice than in wild-type mice. Double knockout mice showed higher thresholds compared to midkine knockout and pleiotrophin knockout mice. Blood flow in the lateral walls did not significantly differ and light microscopy examination showed an almost normal appearance of the stria vascularis in these knockout mice. However, the expression of Kir4.1 was weak in the knockout mice and severe vacuolar degeneration was observed by electron microscopy in the intermediate cells of the double knockout mice. The present study demonstrates that midkine and pleiotrophin play some roles for the morphological maintenance of intermediate cell in the stria vascularis. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  14. The complete mitochondrial genome of the hybrid of Megalobrama terminalis (♀) × Megalobrama amblycephala (♂).

    PubMed

    Zhang, Weizhuo; Zhao, Yan; Guan, Ningnan; Nie, Chunhong; Zhang, Xiujie; Gao, Zexia

    2016-07-01

    In this study, the complete mitochondrial genome of the hybrid of Megalobrama terminalis (♀) × Megalobrama amblycephala (♂) was determined. The total length of the genome was 16,622 bp in accordance with the female parent, and the overall base composition was 31.13% A, 24.94% T, 27.72% C and 16.21% G, with a slight A + T bias. The genome contained 13 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes and 2 main non-coding regions (the control region and the origin of the light strand replication). The 99.48% sequence identity between the hybrid and its female parent, M. terminalis, confirmed the maternal inheritance pattern followed by the mitochondrial genome of the hybrid bream; however, it was interesting to find a total of 86 mutation sites in 12 genes or regions. The phylogenetic analysis indicated that the studied hybrid was relatively more close to M. terminalis, and the result was in agreement with their conventional taxonomic relationship. The genome information reported here may provide important information for further studies on the mitochondrial inheritance mechanisms in hybrids.

  15. Calretinin and FMRFamide immunoreactivity in the nervus terminalis of prenatal tree shrews (Tupaia belangeri).

    PubMed

    Malz, Cordula Renate; Kuhn, Hans-Jürg

    2002-04-30

    The distribution and development of FMRFamide- and calretinin-immunoreactive neurons were investigated in the nervus terminalis of prenatal tree shrews from gestation day 19 onwards. The first FMRFamide-immunoreactive cells were observed medially in the olfactory epithelium on gestation day 20. From gestation day 23 onwards, the migrating nervus terminalis ganglion cells showed FMRFamide calretinin immunoreactivity. The distribution pattern of FMRFamide- and calretinin-immunoreactive cells was similar along the migratory route and in the ganglion of the terminal nerve. However, most probably calretinin and FMRFamide were expressed in separate neuronal populations. For the first time in a mammal, FMRFamide and calretinin are reported to occur in the migrating perikarya and neuronal processes of the nervus terminalis during prenatal development. The results suggest (i) an early activation of the rostral FMRFamide-immunoreactive migratory stream comparable to that described for the GnRH-immunoreactive part of the terminal nerve in other mammals and possibly (ii) an involvement of calretinin in mechanisms of cell migration and outgrowth of neuronal processes in the terminal nerve during the studied period.

  16. Stria vascularis and cochlear hair cell changes in syphilis: A human temporal bone study.

    PubMed

    Hızlı, Ömer; Kaya, Serdar; Hızlı, Pelin; Paparella, Michael M; Cureoglu, Sebahattin

    2016-12-01

    To observe any changes in stria vascularis and cochlear hair cells in patients with syphilis. We examined 13 human temporal bone samples from 8 patients with syphilis (our syphilis group), as well as 12 histopathologically normal samples from 9 age-matched patients without syphilis (our control group). We compared, between the two groups, the mean area of the stria vascularis (measured with conventional light microscopy connected to a personal computer) and the mean percentage of cochlear hair cell loss (obtained from cytocochleograms). In our syphilis group, only 1 (7.7%) of the 13 samples had precipitate in the endolymphatic or perilymphatic spaces; 8 (61.5%) of the samples revealed the presence of endolymphatic hydrops (4 cochlear, 4 saccular). The mean area of the stria vascularis did not significantly differ, in any turn of the cochlea, between the 2 groups (P>0.1). However, we did find significant differences between the 2 groups in the mean percentage of outer hair cells in the apical turn (P<0.026) and in the mean percentage of inner hair cells in the basal (P=0.001), middle (P=0.004), and apical (P=0.018) turns. In 7 samples in our syphilis group, we observed either complete loss of the organ of Corti or a flattened organ of Corti without any cells in addition to the absence of both outer and inner hair cells. In this study, syphilis led either to complete loss of the organ of Corti or to significant loss of cochlear hair cells, in addition to cochleosaccular hydrops. But the area of the stria vascularis did not change. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  17. The neural background of hyper-emotional aggression induced by post-weaning social isolation.

    PubMed

    Toth, Mate; Tulogdi, Aron; Biro, Laszlo; Soros, Petra; Mikics, Eva; Haller, Jozsef

    2012-07-15

    Post-weaning social isolation in rats is believed to model symptoms of early social neglect-induced externalizing problems including aggression-related problems. We showed earlier that rats reared in social isolation were hyper-aroused during aggressive contacts, delivered substantially more attacks that were poorly signaled and were preferentially aimed at vulnerable body parts of opponents (head, throat and belly). Here we studied the neural background of this type of aggression by assessing the expression of the activation marker c-Fos in 22 brain areas of male Wistar rats submitted to resident-intruder conflicts. Post-weaning social isolation readily produced the behavioral alterations noticed earlier. Social isolation significantly increased the activation of brain areas that are known to directly or indirectly control inter-male aggression. Particularly, the medial and lateral orbitofrontal cortices, anterior cingulate cortex, bed nucleus of the stria terminalis, medial and basolateral amygdala, hypothalamic attack area, hypothalamic paraventricular nucleus and locus coeruleus showed increased activations. This contrasts our earlier findings obtained in rats with experimentally induced hypoarousal, where abnormal attack patterns were associated with over-activated central amygdala, lateral hypothalamus, and ventrolateral periaqueductal gray that are believed to control predatory attacks. We have observed no similar activation patterns in rats socially isolated from weaning. In summary, these findings suggest that despite some phenotypic similarities, the neuronal background of hypo and hyperarousal-associated abnormal forms of aggression are markedly different. While the neuronal activation patterns induced by normal rivalry and hypoarousal-driven aggression are qualitative different, hyperarousal-associated aggression appears to be an exaggerated form of rivalry aggression.

  18. Site specific effects of anosmia and cloacal gland anesthesia on Fos expression induced in male quail brain by sexual behavior

    PubMed Central

    Taziaux, Mélanie; Keller, Matthieu; Ball, Gregory F.; Balthazart, Jacques

    2008-01-01

    In rats, expression of the immediate early gene, c-fos observed in the brain following male copulatory behavior relates mostly to the detection of olfactory information originating from the female and to somatosensory feedback from the penis. However, quail, like most birds, are generally considered to have a relatively poorly developed sense of smell. Furthermore, quail have no intromittent organ (e.g., penis). It is therefore intriguing that expression of male copulatory behavior induces in quail and rats a similar pattern of c-fos expression in the medial preoptic area (mPOA), bed nucleus of the stria terminalis (BSTM) and parts of the amygdala. We analyzed here by immunocytochemistry Fos expression in the mPOA/BSTM/amygdala of male quail that had been allowed to copulate with a female during standardized tests. Before these tests, some of the males had either their nostrils plugged, or their cloacal area anesthetized, or both. A control group was not exposed to females. These manipulations did not affect frequencies of male sexual behavior and all birds exposed to a female copulated normally. In the mPOA, the increased Fos expression induced by copulation was not affected by the cloacal gland anesthesia but was markedly reduced in subjects deprived of olfactory input. Both manipulations affected copulation-induced Fos expression in the BSTM. No change in Fos expression was observed in the amygdala. Thus immediate early gene expression in the mPOA and BSTM of quail is modulated at least in part by olfactory cues and/or somatosensory stimuli originating from the cloacal gland. Future work should specify the nature of these stimuli and their function in the expression of avian male sexual behavior. PMID:18638505

  19. Nitric oxide synthase-cyclo-oxygenase pathways in organum vasculosum laminae terminalis: possible role in pyrogenic fever in rabbits.

    PubMed Central

    Lin, J. H.; Lin, M. T.

    1996-01-01

    1. Fever was induced in rabbits by administration of Escherichia coli endotoxin (lipopolysaccharide; LPS; 0.001-10 micrograms) into the organum vasculosum laminae terminalis (OVLT). Deep body temperature was evaluated over a period of 7 h. 2. The LPS-induced febrile response was mimicked by intra-OVLT injection of the nitric oxide (NO) donors, S-nitroso-acetylpenicillamine (SNAP, 1-10 micrograms), sodium nitroprusside (SNP, 50 micrograms), or hydroxylamine (10 micrograms), the cyclic GMP analogue 8-bromo-cyclic GMP (8-Br-cyclic GMP, 10-100 micrograms), or prostaglandin E2 (PGE2, 0.2 micrograms). 3. Dexamethasone (Dex, a potent inhibitor of the transcription of inducible NO synthase, iNOS, 10 micrograms), anisomycin (a protein synthesis inhibitor, 100 micrograms), L-N5-(1-iminoethyl)ornithine (L-NIO; an irreversible NOS inhibitor, 10-200 micrograms), aminoguanidine (a specific iNOS inhibitor, 1000 micrograms), or NG-methyl-L-arginine acetate (L-NMMA, a NOS inhibitor, 100 micrograms) inhibited fever induced by LPS when injected into the OVLT 1 h before LPS injection. An intra-OVLT dose of 1000 micrograms of NG-nitro-L-arginine methyl ester (L-NAME, a potent inhibitor of constitutive NOS) did not exhibit antipyretic effects. 4. Methylene blue (an inhibitor of NOS and soluble guanylate cyclase, 1-10 micrograms), 6-(phenylamino)-5,8-quinolinedione (LY-83583; an inhibitor of soluble guanylate cyclase and NO release, 20 micrograms), or indomethacin (an inhibitor of cyclo-oxygenase, COX, 400 micrograms) inhibited fever induced by LPS when injected into the OVLT 1 h before LPS injection. Pretreatment with methylene blue or haemoglobin (a NO scavenger, 100 micrograms) attenuated the fever induced by intra-OVLT injection of SNAP. 5. The PGE2-induced fever was potentiated, rather then attenuated, by pretreatment with an intra-OVLT dose of animoguanidine (1000 micrograms), L-NMMA (100 micrograms) or L-NIO (200 micrograms). 6. These results suggest that iNOS-COX pathways in the

  20. Distinct neuronal activation patterns are associated with PCP-induced social withdrawal and its reversal by the endocannabinoid-enhancing drug URB597.

    PubMed

    Matricon, Julien; Seillier, Alexandre; Giuffrida, Andrea

    2016-09-01

    The fatty acid amide hydrolase inhibitor, URB597, an endocannabinoid enhancing drug, reverses social withdrawal in the sub-chronic PCP rat model of schizophrenia, but reduces social interaction (SI) in controls. To identify the anatomical substrates associated with PCP-induced social withdrawal and the contrasting effects of URB597 on SI in PCP- versus saline-treated rats, we analyzed SI-induced c-Fos expression in 28 brain areas relevant to schizophrenia and/or social behavior following vehicle or URB597 administration. In saline-treated rats, SI was accompanied by changes in c-Fos expression in the infralimbic and orbitofrontal cortices, dorsomedial caudate putamen, ventrolateral nucleus of the septum, dorsolateral periaqueductal gray (dlPAG) and central amygdala. Except for the dlPAG, these changes were not observed in PCP-treated rats or in saline-treated rats receiving URB597. In the dorsomedial part of the bed nucleus of the stria terminalis (dmBNST), SI-induced c-Fos expression was observed only in PCP-treated rats. Interestingly, URB597 in PCP-treated rats restored a similar c-Fos expression pattern as observed in saline-treated rats: activation of the orbitofrontal cortex, inhibition of the central amygdala and suppression of activation of the dmBNST. These data suggest that orbitofrontal cortex, central amygdala and dmBNST play a critical role in the reversal of PCP-induced social withdrawal by URB597. Copyright © 2016 Elsevier Ireland Ltd and Japan Neuroscience Society. All rights reserved.

  1. Ascending caudal medullary catecholamine pathways drive sickness-induced deficits in exploratory behavior: brain substrates for fatigue?

    PubMed

    Gaykema, Ronald P A; Goehler, Lisa E

    2011-03-01

    Immune challenges can lead to marked behavioral changes, including fatigue, reduced social interest, anorexia, and somnolence, but the precise neuronal mechanisms that underlie sickness behavior remain elusive. Part of the neurocircuitry influencing behavior associated with illness likely includes viscerosensory nuclei located in the caudal brainstem, based on findings that inactivation of the dorsal vagal complex (DVC) can prevent social withdrawal. These brainstem nuclei contribute multiple neuronal projections that target different components of autonomic and stress-related neurocircuitry. In particular, catecholaminergic neurons in the ventrolateral medulla (VLM) and DVC target the hypothalamus and drive neuroendocrine responses to immune challenge, but their particular role in sickness behavior is not known. To test whether this catecholamine pathway also mediates sickness behavior, we compared effects of DVC inactivation with targeted lesion of the catecholamine pathway on exploratory behavior, which provides an index of motivation and fatigue, and associated patterns of brain activation assessed by immunohistochemical detection of c-Fos protein. LPS treatment dramatically reduced exploratory behavior, and produced a pattern of increased c-Fos expression in brain regions associated with stress and autonomic adjustments paraventricular hypothalamus (PVN), bed nucleus of the stria terminalis (BST), central amygdala (CEA), whereas activation was reduced in regions involved in exploratory behavior (hippocampus, dorsal striatum, ventral tuberomammillary nucleus, and ventral tegmental area). Both DVC inactivation and catecholamine lesion prevented reductions in exploratory behavior and completely blocked the inhibitory LPS effects on c-Fos expression in the behavior-associated regions. In contrast, LPS-induced activation in the CEA and BST was inhibited by DVC inactivation but not by catecholamine lesion. The findings support the idea that parallel pathways from

  2. Addictive and non-addictive drugs induce distinct and specific patterns of ERK activation in mouse brain.

    PubMed

    Valjent, Emmanuel; Pagès, Christiane; Hervé, Denis; Girault, Jean-Antoine; Caboche, Jocelyne

    2004-04-01

    A major goal of research on addiction is to identify the molecular mechanisms of long-lasting behavioural alterations induced by drugs of abuse. Cocaine and delta-9-tetrahydrocannabinol (THC) activate extracellular signal-regulated kinase (ERK) in the striatum and blockade of the ERK pathway prevents establishment of conditioned place preference to these drugs. However, it is not known whether activation of ERK in the striatum is specific for these two drugs and/or this brain region. We studied the appearance of phospho-ERK immunoreactive neurons in CD-1 mouse brain following acute administration of drugs commonly abused by humans, cocaine, morphine, nicotine and THC, or of other psychoactive compounds including caffeine, scopolamine, antidepressants and antipsychotics. Each drug generated a distinct regional pattern of ERK activation. All drugs of abuse increased ERK phosphorylation in nucleus accumbens, lateral bed nucleus of the stria terminalis, central amygdala and deep layers of prefrontal cortex, through a dopamine D1 receptor-dependent mechanism. Although some non-addictive drugs moderately activated ERK in a few of these areas, they never induced this combined pattern of strong activation. Antidepressants and caffeine activated ERK in hippocampus and cerebral cortex. Typical antipsychotics mildly activated ERK in dorsal striatum and superficial prefrontal cortex, whereas clozapine had no effect in the striatum, but more widespread effects in cortex and amygdala. Our results outline a subset of structures in which ERK activation might specifically contribute to the long-term effects of drugs of abuse, and suggest mapping ERK activation in brain as a way to identify potential sites of action of psychoactive drugs.

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

    PubMed

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

    2008-10-01

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

  4. Ascending caudal medullary catecholamine pathways drive sickness-induced deficits in exploratory behavior: brain substrates for fatigue?

    PubMed Central

    Gaykema, Ronald P.A.; Goehler, Lisa E.

    2010-01-01

    Immune challenges can lead to marked behavioral changes, including fatigue, reduced social interest, anorexia, and somnolence, but the precise neuronal mechanisms that underlie sickness behavior remain elusive. Part of the neurocircuitry influencing behavior associated with illness likely includes viscerosensory nuclei located in the caudal brainstem, based on findings that inactivation of the dorsal vagal complex (DVC) can prevent social withdrawal. These brainstem nuclei contribute multiple neuronal projections that target different components of autonomic and stress-related neurocircuitry. In particular, catecholaminergic neurons in the ventrolateral medulla (VLM) and DVC target the hypothalamus and drive neuroendocrine responses to immune challenge, but their particular role in sickness behavior is not known. To test whether this catecholamine pathway also mediates sickness behavior, we compared effects of DVC inactivation with targeted lesion of the catecholamine pathway on exploratory behavior, which provides an index of motivation and fatigue, and associated patterns of brain activation assessed by immunohistochemical detection of c-Fos protein. LPS treatment dramatically reduced exploratory behavior, and produced a pattern of increased c-Fos expression in brain regions associated with stress and autonomic adjustments paraventricular hypothalamus (PVN), bed nucleus of the stria terminalis (BST), central amygdala (CEA), whereas activation was reduced in regions involved in exploratory behavior (hippocampus, dorsal striatum, ventral tuberomammillary nucleus, and ventral tegmental area). Both DVC inactivation and catecholamine lesion prevented reductions in exploratory behavior and completely blocked the inhibitory LPS effects on c-Fos expression in the behavior-associated regions. In contrast, LPS-induced activation in the CEA and BST was inhibited by DVC inactivation but not by catecholamine lesion. The findings support the idea that parallel pathways from

  5. CRF-R1 activation in the anterior-dorsal BNST induces maternal neglect in lactating rats via an HPA axis-independent central mechanism

    PubMed Central

    Klampfl, Stefanie M.; Brunton, Paula J.; Bayerl, Doris S.; Bosch, Oliver J.

    2016-01-01

    Adequate maternal behavior in rats requires minimal corticotropin-releasing factor receptor (CRF-R) activation in the medial-posterior bed nucleus of the stria terminalis (mpBNST). Based on the architectural heterogeneity of the BNST and its distinct inter-neural connectivity, we tested whether CRF-R manipulation in another functional part, the anterior-dorsal BNST (adBNST), differentially modulates maternal behavior. We demonstrate that in the adBNST, activation of CRF-R1 reduced arched back nursing (ABN) and nursing, whereas activation of CRF-R2 resulted in an initial reduction in nursing but significantly increased the incidence of ABN 5 h after the treatment. Following stressor exposure, which is detrimental to maternal care, ABN tended to be protected by CRF-R1 blockade. Maternal motivation, maternal aggression, and anxiety were unaffected by any manipulation. Furthermore, under basal and stress conditions, activation of adBNST CRF-R1 increased plasma ACTH and corticosterone concentrations, whereas stimulation of adBNST CRF-R2 increased basal plasma ACTH and corticosterone concentrations, but blocked the stress-induced increase in plasma corticosterone secretion. Moreover, both the CRF-R1 and -R2 antagonists prevented the stress-induced increase in plasma corticosterone secretion. Importantly, elevated levels of circulating corticosterone induced by intra-adBNST administration of CRF-R1 or -R2 agonist did not impact maternal care. Finally, Crf mRNA expression in the adBNST was increased during lactation; however, Crfr1 mRNA expression was similar between lactating and virgin rats. In conclusion, maternal care is impaired by adBNST CRF-R1 activation, and this appears to be the result of a central action, rather than an effect of elevated circulating levels of CORT. These data provide new insights into potential causes of disturbed maternal behavior postpartum. PMID:26630389

  6. Neural correlates underlying naloxone-induced amelioration of sexual behavior deterioration due to an alarm pheromone

    PubMed Central

    Kobayashi, Tatsuya; Kiyokawa, Yasushi; Takeuchi, Yukari; Mori, Yuji

    2015-01-01

    Sexual behavior is suppressed by various types of stressors. We previously demonstrated that an alarm pheromone released by stressed male Wistar rats is a stressor to other rats, increases the number of mounts needed for ejaculation, and decreases the hit rate (described as the number of intromissions/sum of the mounts and intromissions). This deterioration in sexual behavior was ameliorated by pretreatment with the opioid receptor antagonist naloxone. However, the neural mechanism underlying this remains to be elucidated. Here, we examined Fos expression in 31 brain regions of pheromone-exposed rats and naloxone-pretreated pheromone-exposed rats 60 min after 10 intromissions. As previously reported, the alarm pheromone increased the number of mounts and decreased the hit rate. In addition, Fos expression was increases in the anterior medial division (BNSTam), anterior lateral division (BNSTal) and posterior division (BNSTp) of the bed nucleus of the stria terminalis, parvocellular part of the paraventricular nucleus of the hypothalamus, arcuate nucleus, dorsolateral and ventrolateral periaqueductal gray, and nucleus paragigantocellularis (nPGi). Fos expression was decreased in the magnocellular part of the paraventricular nucleus of the hypothalamus. Pretreatment with naloxone blocked the pheromone-induced changes in Fos expression in the magnocellular part of the paraventricular nucleus of the hypothalamus, ventrolateral periaqueductal gray, and nPGi. Based on these results, we hypothesize that the alarm pheromone deteriorated sexual behavior by activating the ventrolateral periaqueductal gray-nucleus paragigantocellularis cluster and suppressing the magnocellular part of the paraventricular nucleus of the hypothalamus (PVN) via the opioidergic pathway. PMID:25755631

  7. Brain regions influenced by the lateral parabrachial nucleus in angiotensin II-induced water intake.

    PubMed

    Davern, P J; McKinley, M J

    2013-11-12

    This study examined which brain regions are influenced by an inhibitory lateral parabrachial nucleus (LPBN) mechanism that affects water intake. Controls and rats with bilateral LPBN lesions were administered angiotensin II (AngII) (0.5mg/kg subcutaneous - SC), drinking responses measured, and brains processed for Fos-immunohistochemistry. A separate group of LPBN-lesioned and non-lesioned animals were denied water for 90 min prior to perfusion to remove any confounding factor of water intake. LPBN-lesioned rats drank a cumulative volume of 9 mL compared with <4 mL by controls (p<0.01). Compared with sham-lesioned animals, Fos expression was attenuated in overdrinking LPBN-lesioned rats in the median preoptic nucleus (MnPO), paraventricular nucleus of the hypothalamus (PVN), supraoptic nucleus (SON) (p<0.001), bed nucleus of the stria terminalis and central nucleus of the amygdala (p<0.01). In LPBN-lesioned rats that did not drink, greater numbers of activated neurons were detected in the PVN (p<0.001), SON (p<0.01), MnPO, nucleus of the solitary tract (NTS) and area postrema (p<0.05) in response to SC AngII, compared with non-lesioned rats. These data suggest that the direct effects of LPBN lesions caused an increase in AngII-induced water intake and in rats that did not drink an increase in Fos expression, while indirect secondary effects of LPBN lesions caused a reduction in Fos expression possibly related to excessive ingestion of water. An inhibitory mechanism, likely related to arterial baroreceptor stimulation, relayed by neurons located in the LPBN influences the responses of the MnPO, PVN and SON to increases in peripheral AngII.

  8. Oxytocin reduces cocaine seeking and reverses chronic cocaine-induced changes in glutamate receptor function.

    PubMed

    Zhou, Luyi; Sun, Wei-Lun; Young, Amy B; Lee, Kunhee; McGinty, Jacqueline F; See, Ronald E

    2014-10-31

    Oxytocin, a neurohypophyseal neuropeptide, is a potential mediator and regulator of drug addiction. However, the cellular mechanisms of oxytocin in drug seeking remain unknown. In the present study, we used a self-administration/reinstatement model to study the effects of oxytocin on cocaine seeking and its potential interaction with glutamate function at the receptor level. Systemic oxytocin dose-dependently reduced cocaine self-administration during various schedules of reinforcement, including fixed ratio 1, fixed ratio 5, and progressive ratio. Oxytocin also attenuated reinstatement to cocaine seeking induced by cocaine prime or conditioned cues. Western-blot analysis indicated that oxytocin increased phosphorylation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptor GluA1 subunit at the Ser 845 site with or without accompanying increases in phosphorylation of extracellular signal-regulated kinase, in several brain regions, including the prefrontal cortex, bed nucleus of the stria terminalis, amygdala, and dorsal hippocampus. Immunoprecipitation of oxytocin receptor and GluA1 subunit receptors further demonstrated a physical interaction between these 2 receptors, although the interaction was not influenced by chronic cocaine or oxytocin treatment. Oxytocin also attenuated sucrose seeking in a GluA1- or extracellular-signal-regulated kinase-independent manner. These findings suggest that oxytocin mediates cocaine seeking through interacting with glutamate receptor systems via second messenger cascades in mesocorticolimbic regions. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  9. Changes in activity of the organon vasculosum laminae terminalis in the annual cycle in Rana temporaria.

    PubMed

    Krawczyk, S; Dziubek, K; Lach, H

    1978-01-01

    In 70 sexually mature male and femal Rana temporaria frogs captured in natural habitat, mean nuclear volumes for the cells of the pars ependymalis and pars parenchymalis of the organon vasculosum laminae terminalis (OVLT) were determined in seven characteristic stages in life. The mean nuclear volume for the cells of the pars ependymalis and pars parenchymalis of the OVLT showed distinct annual fluctuation. Maximum nuclear volume of the cells in both investigated parts of the OVLT were observed during the breeding period (Ist decade of April), and minimum volume of the nuclei of the pars ependymalis at the beginning of hibernation (IIIrd decade of October), and in the pars parenchymalis near the end of active life (Ist decade of September).

  10. Head anatomy of adult Sisyra terminalis (Insecta: Neuroptera: Sisyridae)--functional adaptations and phylogenetic implications.

    PubMed

    Randolf, Susanne; Zimmermann, Dominique; Aspöck, Ulrike

    2013-11-01

    The external and internal head anatomy of Sisyra terminalis is described in detail and compared with data from literature. A salivary pump consisting of a peculiar reservoir and a hitherto unknown muscle, M. ductus salivarii, is newly described for Neuroptera. The upward folded paraglossae form a secondary prolongation of the salivary system. These structures are discussed as functional adaptations for feeding on aphids and desiccated honeydew. In a phylogenetic analysis the basal position of the Sisyridae within Neuroptera is retrieved. The following new synapomorphies are postulated: (1) for Neuropterida, the presence of a M. submentomentalis and prepharyngeal ventral transverse muscles, and the absence of a M. submentopraementalis; (2) for Neuroptera and Sialidae, the presence of a mandibular gland; (3) for Neuroptera, the presence of four scapopedicellar muscles; (4) for Neuroptera exclusive Nevrorthidae and Sisyridae, the weakening of dorsal tentorial arms, the presence of a M. tentoriomandibularis medialis superior and the shifted origin of M. tentoriocardinalis.

  11. Ventral Lamina Terminalis Mediates Enhanced Cardiovascular Responses of RVLM Neurons During Increased Dietary Salt

    PubMed Central

    Adams, Julye M.; Bardgett, Megan E.; Stocker, Sean D.

    2009-01-01

    Increased dietary salt enhances sympathoexcitatory and sympathoinhibitory responses evoked from the rostral ventrolateral medulla (RVLM). The purpose of the present study was to determine whether neurons of the forebrain lamina terminalis (LT) mediated these changes in the RVLM. Male Sprague-Dawley rats with and without LT lesions were fed normal chow and given access to water or 0.9% NaCl for 14-15 days. Unilateral injection of L-glutamate into the RVLM produced significantly larger increases in renal sympathetic nerve activity (SNA) and arterial blood pressure (ABP) of sham rats ingesting 0.9% NaCl versus water. However, these differences were not observed between ventral LT-lesioned rats drinking 0.9% NaCl versus water. Similar findings were observed when angiotensin II or GABA were injected into the RVLM. Interestingly, a subset of animals drinking 0.9% but with damage restricted to the organum vasculosum of the lamina terminalis did not show enhanced responses to L-glutamate or GABA. In marked contrast, RVLM injection of L-glutamate or GABA produced exaggerated SNA and ABP responses in animals drinking 0.9% NaCl versus water after an acute ventral LT lesion or chronic lesion of the subfornical organ. Additional experiments demonstrate plasma sodium concentration and osmolality were increased at night in rats ingesting 0.9% NaCl. These findings suggest that neurons of the ventral LT mediate the ability of increased dietary salt to enhance the responsiveness of RVLM sympathetic neurons. PMID:19506102

  12. Effectiveness of Intraventricular Endoscopic Lamina Terminalis Fenestration in Comparison with Standard ETV: Systematic Review of Literature.

    PubMed

    Giussani, Carlo; Guida, Lelio; Trezza, Andrea; Sganzerla, Erik Pietro

    2017-07-01

    Endoscopic third ventriculostomy is a consolidated technique for the treatment of hydrocephalus. Despite its effectiveness and feasibility, several technical limitations about its use in certain situations have been described. Lamina terminalis-endoscopic third ventriculostomy (LT-ETV) has been proposed as an alternative technique. Authors systematically reviewed the literature in order to define the effectiveness and limits in comparison with standard ETV. This systematic review followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement. It has also been registered with the PROSPERO International Prospective Register of Systematic Reviews (CRD42016041596). MEDLINE, Web of Knowledge, and EMBASE were independently searched. Seven studies were found to be eligible. A case of ours was added to the series, totaling 41 patients (mean patient age ± SD was 21.6 ± 20.7 years). Endoscopic findings leading surgeons to perform LT-ETV were abnormal ventricular anatomy (24, 57%), inadequate/insufficient interpeduncular subarachnoid space (11, 26%), a combination of both (5, 12%), and intraoperatory, unsatisfactory third ventricle floor fenestration (2, 5%). Most common pathologies were neurocysticercosis (12, 28.57%), aqueductal stenosis (8, 19%), tuberculous meningitis (4, 9.52%), and medulloblastoma (3, 7.14%). A flexible endoscope was the most used device (36 procedures, 86%), while not determining a statistical relevant diminution of complications in comparison with a rigid endoscope (P = 1.0). An overall success rate of 69% was registered, increasing to 89% if just the first year of follow-up was considered. LT-ETV can be considered a successful technical option when standard ETV cannot be performed, although more complex cerebrovascular anatomy is involved. Therefore we suggest that lateral terminalis fenestration is a valid technical option in experienced hands. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Functional correlates of activity in neurons projecting from the lamina terminalis to the ventrolateral periaqueductal gray

    PubMed Central

    Uschakov, Aaron; McGinty, Dennis; Szymusiak, Ronald; McKinley, Michael J.

    2010-01-01

    The lamina terminalis (LT) consists of the organum vasculosum of the lamina terminalis (OVLT) the median preoptic nucleus (MnPO) and the subfornical organ (SFO). All subdivisions of the LT project to the ventrolateral periaqueductal gray (vlPAG). The LT and the vlPAG are implicated in several homeostatic and behavioral functions including body fluid homeostasis, thermoregulation and the regulation of sleep and waking. By combining visualization of c-Fos protein and retrograde neuroanatomical tracer we have examined the functional correlates of LT-vlPAG projection neurons. Rats were injected with retrograde tracer into the vlPAG and following a one week recovery period, they were subjected to either, hypertonic saline administration (0.5M NaCl, 1ml/100g-i.p.), 24hrs water deprivation, isoproterenol administration (increases circulating AngII; 50μg/kg-s.c.), heat exposure (39°C for 60 mins) or permitted 180 minutes spontaneous sleep. Retrogradely labelled neurons from the vlPAG and double labelled neurons were then identified and quantified throughout the LT. OVLT-vlPAG projection neurons were most responsive to hypertonic saline and water deprivation. SFO-vlPAG projection neurons were most active following isoproterenol administration and MnPO-vlPAG projection neurons displayed significantly more Fos immunostaining following water deprivation, heat exposure and sleep. These results support the existence of functional subdivisions of LT-vlPAG projecting neurons and indicate three patterns of activity that correspond to thermal and sleep wake regulation, osmotic or hormonal stimuli. PMID:20092577

  14. ATP-containing vesicles in stria vascular marginal cell cytoplasms in neonatal rat cochlea are lysosomes

    PubMed Central

    Liu, Jun; Liu, Wenjing; Yang, Jun

    2016-01-01

    We confirmed that ATP is released from cochlear marginal cells in the stria vascular but the cell organelle in which ATP stores was not identified until now. Thus, we studied the ATP-containing cell organelles and suggest that these are lysosomes. Primary cultures of marginal cells of Sprague-Dawley rats aged 1–3 days was established. Vesicles within marginal cells stained with markers were identified under confocal laser scanning microscope and transmission electron microscope (TEM). Then ATP release from marginal cells was measured after glycyl-L-phenylalanine-ß- naphthylamide (GPN) treatment using a bioluminescent assay. Quinacrine-stained granules within marginal cells were labeled with LysoTracker, a lysosome tracer, and lysosomal-associated membrane protein 1(LAMP1), but not labeled with the mitochondrial tracer MitoTracker. Furthermore, LysoTracker-labelled puncta showed accumulation of Mant-ATP, an ATP analog. Treatment with 200 μM GPN quenched fluorescently labeled puncta after incubation with LysoTracker or quinacrine, but not MitoTracker. Quinacrine-labeled organelles observed by TEM were lysosomes, and an average 27.7 percent increase in ATP luminescence was observed in marginal cells extracellular fluid after GPN treatment. ATP-containing vesicles in cochlear marginal cells of the stria vascular from neonatal rats are likely lysosomes. ATP release from marginal cells may be via Ca2+-dependent lysosomal exocytosis. PMID:26864824

  15. Prostaglandin E(2) fever mediated by inhibition of the GABAergic transmission in the region immediately adjacent to the organum vasculosum of the lamina terminalis.

    PubMed

    Osaka, Toshimasa

    2008-08-01

    Unilateral microinjection of prostaglandin (PG)E(2) into a region immediately adjacent to the organum vasculosum of the lamina terminalis (peri-OVLT) in the preoptic area elicited thermogenic, tachycardic, cutaneous vasoconstrictive, and hyperthermic responses simultaneously in urethane-chloralose-anesthetized rats. The magnitude of these responses increased dose-dependently over the range of 57 fmol-2.8 pmol, except for the vasoconstrictive response. Microinjection of a GABA(A) receptor antagonist, bicuculline methiodide or gabazine (5-20 pmol), into the PGE(2)-sensitive site in the peri-OVLT region also elicited responses similar to those induced by PGE(2). Although administration of a GABA(A) receptor agonist, muscimol (10 pmol), microinjected into the same site alone usually had no effect on the rate of whole-body O(2) consumption, heart rate or colon and skin temperatures, all PGE(2)-induced responses were blocked 10 min after the muscimol pretreatment and recovered at 50-90 min. Pretreatment with the vehicle, saline, had no effect on the PGE(2)-induced responses. These results suggest that spontaneous release of GABA and tonic activation of GABA(A) receptors in the peri-OVLT region prevent the elevation in the body core temperature under normal circumstances and that PGE(2)-induced febrile responses are mediated, at least in part, by inhibition of the GABAergic transmission in this area.

  16. Study of Fos, androgen receptor and testosterone expression in the sub-regions of medial amygdala, bed nucleus of stria terminalis and medial preoptic area in male Mandarin voles in response to chemosensory stimulation.

    PubMed

    He, Fengqin; Wu, Ruiyong; Yu, Peng

    2014-01-01

    In many rodent species, including mandarin voles (Microtus mandarinus), the behavioral response to odors is regulated by a network of steroid-sensitive ventral forebrain nuclei including the medial amygdala (Me), bed nucleus of the striaterminalis (BNST), and medial preoptic area (MPOA). Although it is well-known that Me, BNST, and MPOA are closely interconnected, function independently in regulating odor-guided social behaviors, little is known about how order information is processed in the sub-regions of Me, BNST, and MPOA. In order to answer this question, we let male mandarin voles expose to two different odors including female vaginal fluid (FVF) and male flank gland secretion (MFGS) and detect the expression of Fos, androgen receptor (AR) and testosterone (T) in the sub-regions of Me, BNST, and MPOA. We found that FVF stimulus caused increased Fos, AR and T expression in the posterior subdivision of the Me (MeP), the posterior medial subdivision of the BNST (BNSTpm), and the medial preoptic nucleus (MPN), while MFGS stimulus did not change Fos, AR and T expression neither in the MeP, BNSTpm, and MPN nor in the anterior subdivision of the Me (MeA), the posterointermediate subdivision of the BNST (BNSTpi), and the lateral subdivision of the MPOA (MPOAl). Serum testosterone levels were increased after 1h in males exposed to FVF. This study provides insight in understanding the relationship between female odor stimulation and Fos, AR and T expression in specific brain areas in males, and the regulatory role of testosterone in this biochemical process. Copyright © 2013 Elsevier B.V. All rights reserved.

  17. Region-Specific Onset of Handling-Induced Changes in Corticotropin-Releasing Factor and Glucocorticoid Receptor Expression

    PubMed Central

    Fenoglio, Kristina A.; Brunson, Kristen L.; Avishai-Eliner, Sarit; Chen, Yuncai; Baram, Tallie Z.

    2011-01-01

    Early-life experience including maternal care profoundly influences hormonal stress responses during adulthood. Daily handling on postnatal day (P) 2–9, eliciting augmented maternal care upon returning pups to their cage, permanently modifies the expression of the stress neuromodulators corticotropin-releasing factor (CRF) and glucocorticoid receptor (GR). We have previously demonstrated reduced hypothalamic CRF expression already at the end of the handling period, followed by enhanced hippocampal GR mRNA levels (by P45). However, the initial site(s) and time of onset of these enduring changes have remained unclear. Therefore, we used semiquantitative in situ hybridization to delineate the spatiotemporal evolution of CRF and GR expression throughout stress-regulatory brain regions in handled (compared with undisturbed) pups. Enhanced CRF mRNA expression was apparent in the amygdaloid central nucleus (ACe) of handled pups already by P6. By P9, the augmented CRF mRNA levels persisted in ACe, accompanied by increased peptide expression in the bed nucleus of the stria terminalis and reduced expression in the paraventricular nucleus. The earliest change in GR consisted of reduced expression in the ACe of handled pups on P9, a time point when hippocampal GR expression was not yet affected. Thus, altered gene expression in ACe, bed nucleus of the stria terminalis as well as paraventricular nucleus may contribute to the molecular cascade by which handling (and increased maternal care) influences the stress response long term. PMID:15044366

  18. Increased vasopressin expression in the BNST accompanies paternally induced territoriality in male and female California mouse offspring.

    PubMed

    Yohn, Christine N; Leithead, Amanda B; Becker, Elizabeth A

    2017-03-27

    While developmental consequences of parental investment on species-typical social behaviors has been extensively characterized in same-sex parent-offspring interactions, the impact of opposite-sex relationships is less clear. In the bi-parental California mouse (Peromyscus californicus), paternal retrieval behavior induces territorial aggression and the expression of arginine vasopressin (AVP) in adult male offspring. Although similar patterns of territorially emerge among females, the sexually dimorphic AVP system has not been considered since it is generally thought to regulate male-typical behavior. However, we recently demonstrated that male and female P. californicus offspring experience increases in plasma testosterone following paternal retrieval. Since AVP expression is androgen-dependent during development, we postulate that increases in AVP expression may accompany territoriality in female, as well as male offspring. To explore this aim, adult P. californicus offspring that received either high or low levels of paternal care (retrievals) during early development were tested for territoriality and immunohistochemical analysis of AVP within the bed nucleus of the stria terminalis (BNST), paraventricular nucleus (PVN), and supraoptic nucleus (SON). Consistent with previous studies, high care offspring were more aggressive than low care offspring. Moreover, high care offspring had significantly more AVP immunoreactive (AVP-ir) cells within the BNST than low care offspring. This pattern was observed within female as well as male offspring, suggesting an equally salient role for paternal care on female offspring physiology. Regardless of early social experience, sex differences in AVP persisted in the BNST, with males having greater expression than females.

  19. Mechanism generating endocochlear potential: role played by intermediate cells in stria vascularis.

    PubMed Central

    Takeuchi, S; Ando, M; Kakigi, A

    2000-01-01

    The endocochlear DC potential (EP) is generated by the stria vascularis, and essential for the normal function of hair cells. Intermediate cells are melanocytes in the stria vascularis. To examine the contribution of the membrane potential of intermediate cells (E(m)) to the EP, a comparison was made between the effects of K(+) channel blockers on the E(m) and those on the EP. The E(m) of dissociated guinea pig intermediate cells was measured in the zero-current clamp mode of the whole-cell patch clamp configuration. The E(m) changed by 55.1 mV per 10-fold changes in extracellular K(+) concentration. Ba(2+), Cs(+), and quinine depressed the E(m) in a dose-dependent manner, whereas tetraethylammonium at 30 mM and 4-aminopyridine at 10 mM had no effect. The reduction of the E(m) by Ba(2+) and Cs(+) was enhanced by lowering the extracellular K(+) concentration from 3.6 mM to 1.2 mM. To examine the effect of the K(+) channel blockers on the EP, the EP of guinea pigs was maintained by vascular perfusion, and K(+) channel blockers were administered to the artificial blood. Ba(2+), Cs(+) and quinine depressed the EP in a dose-dependent manner, whereas tetraethylammonium at 30 mM and 4-aminopyridine at 10 mM did not change the EP. A 10-fold increase in the K(+) concentration in the artificial blood caused a minor decrease in the EP of only 10.6 mV. The changes in the EP were similar to those seen in the E(m) obtained at the lower extracellular K(+) concentration of 1.2 mM. On the basis of these results, we propose that the EP is critically dependent on the voltage jump across the plasma membrane of intermediate cells, and that K(+) concentration in the intercellular space in the stria vascularis may be actively controlled at a concentration lower than the plasma level. PMID:11053131

  20. Corticotropin-Releasing Factor Modulation of Forebrain GABAergic Transmission has a Pivotal Role in the Expression of Anabolic Steroid-Induced Anxiety in the Female Mouse

    PubMed Central

    Oberlander, Joseph G; Henderson, Leslie P

    2012-01-01

    Increased anxiety is commonly observed in individuals who illicitly administer anabolic androgenic steroids (AAS). Behavioral effects of steroid abuse have become an increasing concern in adults and adolescents of both sexes. The dorsolateral bed nucleus of the stria terminalis (dlBnST) has a critical role in the expression of diffuse anxiety and is a key site of action for the anxiogenic neuromodulator, corticotropin releasing factor (CRF). Here we demonstrate that chronic, but not acute, exposure of female mice during adolescence to AAS augments anxiety-like behaviors; effects that were blocked by central infusion of the CRF receptor type 1 antagonist, antalarmin. AAS treatment selectively increased action potential (AP) firing in neurons of the central amygdala (CeA) that project to the dlBnST, increased the frequency of GABAA receptor-mediated spontaneous inhibitory postsynaptic currents (sIPSCs) in dlBnST target neurons, and decreased both c-FOS immunoreactivity (IR) and AP frequency in these postsynaptic cells. Acute application of antalarmin abrogated the enhancement of GABAergic inhibition induced by chronic AAS exposure whereas application of CRF to brain slices of naïve mice mimicked the actions of this treatment. These results, in concert with previous data demonstrating that chronic AAS treatment results in enhanced levels of CRF mRNA in the CeA and increased CRF-IR in the dlBnST neuropil, are consistent with a mechanism in which the enhanced anxiety elicited by chronic AAS exposure involves augmented inhibitory activity of CeA afferents to the dlBnST and CRF-dependent enhancement of GABAergic inhibition in this brain region. PMID:22298120

  1. Increased dietary sodium alters Fos expression in the lamina terminalis during intravenous angiotensin II infusion.

    PubMed

    Bealer, Steven L; Metcalf, Cameron S; Heyborne, Ryan

    2007-03-01

    These studies examined the effects of increased dietary sodium on expression of Fos, the protein product of c-fos, in forebrain structures in the rat following intravenous infusion with angiotensin II (AngII). Animals were provided with either tap water (Tap) or isotonic saline solution (Iso) as their sole drinking fluid for 3-5 weeks prior to testing. Rats were then implanted with catheters in a femoral artery and vein. The following day, the conscious, unrestrained animals received iv infusion of either isotonic saline (Veh), AngII, or phenylephrine (Phen) for 2 h. Blood pressure and heart rate were monitored continuously throughout the procedure. Brains were subsequently processed for evaluation of Fos-like immunoreactivity (Fos-Li IR) in the organum vasculosum of the lamina terminalis (OVLT), the subfornical organ (SFO), and the median preoptic nucleus (MnPO). Fos-Li IR was significantly increased in the SFO and OVLT of animals consuming both Tap and Iso following AngII, but not Phen, compared to Veh infusions. Furthermore, Fos-Li IR in the MnPO was increased following AngII infusion in rats consuming a high sodium diet, but not in animals drinking Tap. These data suggest that increased dietary sodium sensitizes the MnPO neurons to excitatory input from brain areas responding to circulating AngII.

  2. A case of transient hypothermia after trans-lamina terminalis and third ventricle clipping of an extremely high-position basilar tip aneurysm

    PubMed Central

    Ikawa, Fusao; Hamasaki, Osamu; Kurokawa, Yasuharu; Yonezawa, Ushio; Kurisu, Kaoru

    2015-01-01

    Reports on the trans-lamina terminalis and trans-third ventricular approach are rare. The risk associated with this approach is unknown. After an unsuccessful endovascular surgery, we performed direct surgical clipping via the third ventricle on a 78-year-old woman presenting with an extremely high-positioned, ruptured basilar tip aneurysm. She experienced transient hypothermia for 5 days, and it was considered that this was due to hypothalamic dysfunction. It is necessary to recognize that there is the potential for hypothermia after surgery via the lamina terminalis and third ventricle, even though the mechanisms of hypothalamic thermoregulation are still unclear. PMID:27489684

  3. FMRFamide-like immunoreactive nervus terminalis innervation to the pituitary in the catfish, Clarias batrachus (Linn.): demonstration by lesion and immunocytochemical techniques

    NASA Technical Reports Server (NTRS)

    Krishna, N. S.; Subhedar, N.; Schreibman, M. P.

    1992-01-01

    Certain thick FMRFamide-like immunoreactive fibers arising from the ganglion cells of nervus terminalis in the olfactory bulb of Clarias batrachus can be traced centripetally through the medial olfactory tract, telencephalon, lateral preoptic area, tuberal area, and hypothalamohypophysial tract to the pituitary. Following 6 days of bilateral olfactory tract transection, the immunoreactivity in the thick fibers, caudal to the lesion site, was partially eliminated, whereas after 10 and 14 days, it was totally abolished in the processes en route to the pituitary. The results indicate a direct innervation of the pituitary gland by the FMRFamide-like peptide containing fibers of the nervus terminalis.

  4. FMRFamide-like immunoreactive nervus terminalis innervation to the pituitary in the catfish, Clarias batrachus (Linn.): demonstration by lesion and immunocytochemical techniques

    NASA Technical Reports Server (NTRS)

    Krishna, N. S.; Subhedar, N.; Schreibman, M. P.

    1992-01-01

    Certain thick FMRFamide-like immunoreactive fibers arising from the ganglion cells of nervus terminalis in the olfactory bulb of Clarias batrachus can be traced centripetally through the medial olfactory tract, telencephalon, lateral preoptic area, tuberal area, and hypothalamohypophysial tract to the pituitary. Following 6 days of bilateral olfactory tract transection, the immunoreactivity in the thick fibers, caudal to the lesion site, was partially eliminated, whereas after 10 and 14 days, it was totally abolished in the processes en route to the pituitary. The results indicate a direct innervation of the pituitary gland by the FMRFamide-like peptide containing fibers of the nervus terminalis.

  5. Connexin30 deficiency causes instrastrial fluid–blood barrier disruption within the cochlear stria vascularis

    PubMed Central

    Cohen-Salmon, Martine; Regnault, Béatrice; Cayet, Nadège; Caille, Dorothée; Demuth, Karine; Hardelin, Jean-Pierre; Janel, Nathalie; Meda, Paolo; Petit, Christine

    2007-01-01

    The endocochlear potential (EP) is essential to hearing, because it provides approximately half of the driving force for the mechanoelectrical transduction current in auditory hair cells. The EP is produced by the stria vascularis (SV), a vascularized bilayer epithelium of the cochlea lateral wall. The absence of the gap junction protein connexin30 (Cx30) in Cx30−/− mice results in the SV failure to produce an EP, which mainly accounts for the severe congenital hearing impairment of these mice. Here, we show that the SV components of the EP electrogenic machinery and the epithelial barriers limiting the intrastrial fluid space, which are both necessary for the EP production, were preserved in Cx30−/− mice. In contrast, the endothelial barrier of the capillaries supplying the SV was disrupted before EP onset. This disruption is expected to result in an intrastrial electric shunt that is sufficient to account for the absence of the EP production. Immunofluorescence analysis of wild-type mice detected Cx30 in the basal and intermediate cells of the SV but not in the endothelial cells of the SV capillaries. Moreover, dye-coupling experiments showed that endothelial cells were not coupled to the SV basal, intermediate, and marginal cells. SV transcriptome analysis revealed a significant down-regulation of betaine homocysteine S-methyltransferase (Bhmt) in the Cx30−/− mice, which was restricted to the SV and resulted in a local increase in homocysteine, a known factor of endothelial dysfunction. Disruption of the SV endothelial barrier is a previously undescribed pathogenic process underlying hearing impairment. PMID:17400755

  6. Development of the stria vascularis and potassium regulation in the human fetal cochlea: Insights into hereditary sensorineural hearing loss

    PubMed Central

    de Groot, John C.M.J.; van Iperen, Liesbeth; Huisman, Margriet A.; Frijns, Johan H.M.

    2015-01-01

    ABSTRACT Sensorineural hearing loss (SNHL) is one of the most common congenital disorders in humans, afflicting one in every thousand newborns. The majority is of heritable origin and can be divided in syndromic and nonsyndromic forms. Knowledge of the expression profile of affected genes in the human fetal cochlea is limited, and as many of the gene mutations causing SNHL likely affect the stria vascularis or cochlear potassium homeostasis (both essential to hearing), a better insight into the embryological development of this organ is needed to understand SNHL etiologies. We present an investigation on the development of the stria vascularis in the human fetal cochlea between 9 and 18 weeks of gestation (W9–W18) and show the cochlear expression dynamics of key potassium‐regulating proteins. At W12, MITF+/SOX10+/KIT+ neural‐crest‐derived melanocytes migrated into the cochlea and penetrated the basement membrane of the lateral wall epithelium, developing into the intermediate cells of the stria vascularis. These melanocytes tightly integrated with Na+/K+‐ATPase‐positive marginal cells, which started to express KCNQ1 in their apical membrane at W16. At W18, KCNJ10 and gap junction proteins GJB2/CX26 and GJB6/CX30 were expressed in the cells in the outer sulcus, but not in the spiral ligament. Finally, we investigated GJA1/CX43 and GJE1/CX23 expression, and suggest that GJE1 presents a potential new SNHL associated locus. Our study helps to better understand human cochlear development, provides more insight into multiple forms of hereditary SNHL, and suggests that human hearing does not commence before the third trimester of pregnancy. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 75: 1219–1240, 2015 PMID:25663387

  7. The complete mitochondrial genome of the hybrid of Megalobrama amblycephala (♀) × Megalobrama terminalis (♂).

    PubMed

    Wan, Shiming; Zhong, Jia; Nie, Chunhong; Gao, Zexia; Zhang, Xiujie

    2016-11-01

    In this study, we determined the complete mitochondrial DNA sequence of the hybrid of Megalobrama amblycephala (♀) × Megalobrama terminalis (♂) for the first time. The complete mitochondrial genome of the hybrid bream was sequenced to be 16,623 bp in size in accordance with the female parent, M. amblycephala. The genome contained 13 protein-coding genes, 22 transfer RNA genes, 2 ribosomal RNA genes and 2 main non-coding regions (the control region and the origin of the light strand replication). Sequence alignment between the mitochondrial genomes of the hybrid and its female parent showed that a total of 23 mutation sites were found in 10 genes or regions, in particular, six sense mutations in four protein-coding genes (including COX1, ATP6, ND6 and Cytb). The genome information presented here may play an important role in further study on the genetic mechanisms of mitochondrial DNA in hybrids.

  8. A Switch in Keystone Seed-Dispersing Ant Genera between Two Elevations for a Myrmecochorous Plant, Acacia terminalis

    PubMed Central

    Thomson, Fiona J.; Auld, Tony D.; Ramp, Daniel; Kingsford, Richard T.

    2016-01-01

    The dispersal capacity of plant species that rely on animals to disperse their seeds (biotic dispersal) can alter with changes to the populations of their keystone dispersal vectors. Knowledge on how biotic dispersal systems vary across landscapes allows better understanding of factors driving plant persistence. Myrmecochory, seed dispersal by ants, is a common method of biotic dispersal for many plant species throughout the world. We tested if the seed dispersal system of Acacia terminalis (Fabaceae), a known myrmecochore, differed between two elevations in the Greater Blue Mountains World Heritage Area, in southeastern Australia. We compared ant assemblages, seed removal rates of ants and other vertebrates (bird and mammal) and the dominant seed-dispersing ant genera. At low elevations (c. 200 m a.s.l) seed removal was predominantly by ants, however, at high elevation sites (c. 700 m a.s.l) vertebrate seed dispersers or seed predators were present, removing over 60% of seeds from experimental depots when ants were excluded. We found a switch in the keystone seed-dispersing ant genera from Rhytidoponera at low elevations sites to Aphaenogaster at high elevation sites. This resulted in more seeds being removed faster at low elevation sites compared to high elevation sites, however long-term seed removal rates were equal between elevations. Differences in the keystone seed removalist, and the addition of an alternate dispersal vector or seed predator at high elevations, will result in different dispersal and establishment patterns for A. terminalis at different elevations. These differences in dispersal concur with other global studies that report myrmecochorous dispersal systems alter with elevation. PMID:27310262

  9. Phytophthora terminalis sp. nov. and Phytophthora occultans sp. nov., two invasive pathogens of ornamental plants in Europe.

    PubMed

    Man In 't Veld, Willem A; Rosendahl, Karin C H M; van Rijswick, Patricia C J; Meffert, Johan P; Westenberg, Marcel; van de Vossenberg, Bart T L H; Denton, Geoff; van Kuik, Fons A J

    2015-01-01

    In the past decade several Phytophthora strains were isolated from diseased Pachysandra terminalis plants suffering stem base and root rot, originating from the Netherlands and Belgium. All isolates were homothallic and had a felt-like colony pattern, produced semi-papillate sporangia, globose oogonia and had a maximum growth at ~ 27 C. Several additional Phytophthora strains were isolated from diseased Buxus sempervirens plants, originating from the Netherlands and Belgium, which had sustained stem base and root rot; similar strains also were isolated from Acer palmatum, Choisya ternata and Taxus in the United Kingdom. All isolates were homothallic and had a stellate colony pattern, produced larger semi-papillate sporangia and smaller globose oogonia than the isolates from Pa. terminalis and had a maximum growth temperature of ~ 30 C. Phylogenetic analyses of both species using the internal transcribed spacer region of the nuc rDNA (ITS), mt cytochrome oxidases subunit I gene (CoxI) and nuc translation elongation factor 1-α gene (TEF1α) revealed that all sequences of each species were identical at each locus and unique to that species, forming two distinct clusters in subclade 2a. Sequence analysis of partial β-tubulin genes showed that both taxa share an identical sequence that is identical to that of Ph. himalsilva, a species originating from Asia, suggesting a common Asian origin. Pathogenicity trials demonstrated disease symptoms on their respective hosts, and re-isolation and re-identification of the inoculated pathogens confirmed Koch's postulates. © 2015 by The Mycological Society of America.

  10. A Switch in Keystone Seed-Dispersing Ant Genera between Two Elevations for a Myrmecochorous Plant, Acacia terminalis.

    PubMed

    Thomson, Fiona J; Auld, Tony D; Ramp, Daniel; Kingsford, Richard T

    2016-01-01

    The dispersal capacity of plant species that rely on animals to disperse their seeds (biotic dispersal) can alter with changes to the populations of their keystone dispersal vectors. Knowledge on how biotic dispersal systems vary across landscapes allows better understanding of factors driving plant persistence. Myrmecochory, seed dispersal by ants, is a common method of biotic dispersal for many plant species throughout the world. We tested if the seed dispersal system of Acacia terminalis (Fabaceae), a known myrmecochore, differed between two elevations in the Greater Blue Mountains World Heritage Area, in southeastern Australia. We compared ant assemblages, seed removal rates of ants and other vertebrates (bird and mammal) and the dominant seed-dispersing ant genera. At low elevations (c. 200 m a.s.l) seed removal was predominantly by ants, however, at high elevation sites (c. 700 m a.s.l) vertebrate seed dispersers or seed predators were present, removing over 60% of seeds from experimental depots when ants were excluded. We found a switch in the keystone seed-dispersing ant genera from Rhytidoponera at low elevations sites to Aphaenogaster at high elevation sites. This resulted in more seeds being removed faster at low elevation sites compared to high elevation sites, however long-term seed removal rates were equal between elevations. Differences in the keystone seed removalist, and the addition of an alternate dispersal vector or seed predator at high elevations, will result in different dispersal and establishment patterns for A. terminalis at different elevations. These differences in dispersal concur with other global studies that report myrmecochorous dispersal systems alter with elevation.

  11. Patterns of Brain Activation and Meal Reduction Induced by Abdominal Surgery in Mice and Modulation by Rikkunshito.

    PubMed

    Wang, Lixin; Mogami, Sachiko; Yakabi, Seiichi; Karasawa, Hiroshi; Yamada, Chihiro; Yakabi, Koji; Hattori, Tomohisa; Taché, Yvette

    2015-01-01

    Abdominal surgery inhibits food intake and induces c-Fos expression in the hypothalamic and medullary nuclei in rats. Rikkunshito (RKT), a Kampo medicine improves anorexia. We assessed the alterations in meal microstructure and c-Fos expression in brain nuclei induced by abdominal surgery and the modulation by RKT in mice. RKT or vehicle was gavaged daily for 1 week. On day 8 mice had no access to food for 6-7 h and were treated twice with RKT or vehicle. Abdominal surgery (laparotomy-cecum palpation) was performed 1-2 h before the dark phase. The food intake and meal structures were monitored using an automated monitoring system for mice. Brain sections were processed for c-Fos immunoreactivity (ir) 2-h after abdominal surgery. Abdominal surgery significantly reduced bouts, meal frequency, size and duration, and time spent on meals, and increased inter-meal interval and satiety ratio resulting in 92-86% suppression of food intake at 2-24 h post-surgery compared with control group (no surgery). RKT significantly increased bouts, meal duration and the cumulative 12-h food intake by 11%. Abdominal surgery increased c-Fos in the prelimbic, cingulate and insular cortexes, and autonomic nuclei, such as the bed nucleus of the stria terminalis, central amygdala, hypothalamic supraoptic (SON), paraventricular and arcuate nuclei, Edinger-Westphal nucleus (E-W), lateral periaqueduct gray (PAG), lateral parabrachial nucleus, locus coeruleus, ventrolateral medulla and nucleus tractus solitarius (NTS). RKT induced a small increase in c-Fos-ir neurons in the SON and E-W of control mice, and in mice with surgery there was an increase in the lateral PAG and a decrease in the NTS. These findings indicate that abdominal surgery inhibits food intake by increasing both satiation (meal duration) and satiety (meal interval) and activates brain circuits involved in pain, feeding behavior and stress that may underlie the alterations of meal pattern and food intake inhibition. RKT improves

  12. Patterns of Brain Activation and Meal Reduction Induced by Abdominal Surgery in Mice and Modulation by Rikkunshito

    PubMed Central

    Wang, Lixin; Mogami, Sachiko; Yakabi, Seiichi; Karasawa, Hiroshi; Yamada, Chihiro; Yakabi, Koji; Hattori, Tomohisa; Taché, Yvette

    2015-01-01

    Abdominal surgery inhibits food intake and induces c-Fos expression in the hypothalamic and medullary nuclei in rats. Rikkunshito (RKT), a Kampo medicine improves anorexia. We assessed the alterations in meal microstructure and c-Fos expression in brain nuclei induced by abdominal surgery and the modulation by RKT in mice. RKT or vehicle was gavaged daily for 1 week. On day 8 mice had no access to food for 6–7 h and were treated twice with RKT or vehicle. Abdominal surgery (laparotomy-cecum palpation) was performed 1–2 h before the dark phase. The food intake and meal structures were monitored using an automated monitoring system for mice. Brain sections were processed for c-Fos immunoreactivity (ir) 2-h after abdominal surgery. Abdominal surgery significantly reduced bouts, meal frequency, size and duration, and time spent on meals, and increased inter-meal interval and satiety ratio resulting in 92–86% suppression of food intake at 2–24 h post-surgery compared with control group (no surgery). RKT significantly increased bouts, meal duration and the cumulative 12-h food intake by 11%. Abdominal surgery increased c-Fos in the prelimbic, cingulate and insular cortexes, and autonomic nuclei, such as the bed nucleus of the stria terminalis, central amygdala, hypothalamic supraoptic (SON), paraventricular and arcuate nuclei, Edinger-Westphal nucleus (E-W), lateral periaqueduct gray (PAG), lateral parabrachial nucleus, locus coeruleus, ventrolateral medulla and nucleus tractus solitarius (NTS). RKT induced a small increase in c-Fos-ir neurons in the SON and E-W of control mice, and in mice with surgery there was an increase in the lateral PAG and a decrease in the NTS. These findings indicate that abdominal surgery inhibits food intake by increasing both satiation (meal duration) and satiety (meal interval) and activates brain circuits involved in pain, feeding behavior and stress that may underlie the alterations of meal pattern and food intake inhibition. RKT

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

    PubMed

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

    2008-05-15

    The administration of low dose opioid antagonists has been explored as a potential means of detoxification in opiate dependence. Previous results from our laboratory have shown that concurrent administration of low dose naltrexone in the drinking water of rats implanted with subcutaneous morphine pellets attenuates behavioral and biochemical signs of withdrawal in brainstem noradrenergic nuclei. Noradrenergic projections originating from the nucleus tractus solitarius (NTS) and the locus coeruleus (LC) have previously been shown to be important neural substrates involved in the somatic expression of opiate withdrawal. The hypothesis that low dose naltrexone treatment attenuates noradrenergic hyperactivity typically associated with opiate withdrawal was examined in the present study by assessing norepinephrine tissue content and norepinephrine efflux using in vivo microdialysis coupled to high performance liquid chromatography (HPLC) with electrochemical detection (ED). The frontal cortex (FC), amygdala, bed nucleus of the stria terminalis (BNST) and cerebellum were analyzed for tissue content of norepinephrine following withdrawal in morphine dependent rats. Naltrexone-precipitated withdrawal elicited a significant decrease in tissue content of norepinephrine in the BNST and amygdala. This decrease was significantly attenuated in the BNST of rats that received low dose naltrexone pre-treatment compared to controls. No significant difference was observed in the other brain regions examined. In a separate group of rats, norepinephrine efflux was assessed with in vivo microdialysis in the BNST or the FC of morphine dependent rats or placebo treated rats subjected to naltrexone-precipitated withdrawal that received either naltrexone in their drinking water (5 mg/L) or unadulterated water. Following baseline dialysate collection, withdrawal was precipitated by injection of naltrexone and sample collection continued for an additional 4 h. At the end of the experiment

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

    PubMed Central

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

    2009-01-01

    The administration of low dose opioid antagonists has been explored as a potential means of detoxification in opiate dependence. Previous results from our laboratory have shown that concurrent administration of low dose naltrexone in the drinking water of rats implanted with subcutaneous morphine pellets attenuates behavioral and biochemical signs of withdrawal in brainstem noradrenergic nuclei. Noradrenergic projections originating from the nucleus tractus solitarius (NTS) and the locus coeruleus (LC) have previously been shown to be important neural substrates involved in the somatic expression of opiate withdrawal. The hypothesis that low dose naltrexone treatment attenuates noradrenergic hyperactivity typically associated with opiate withdrawal was examined in the present study by assessing norepinephrine tissue content and norepinephrine efflux using in vivo microdialysis coupled to high performance liquid chromatography (HPLC) with electrochemical detection (ED). The frontal cortex (FC), amygdala, bed nucleus of the stria terminalis (BNST) and cerebellum were analyzed for tissue content of norepinephrine following withdrawal in morphine dependent rats. Naltrexone precipitated withdrawal elicited a significant decrease in tissue content of norepinephrine in the BNST and amygdala. This decrease was significantly attenuated in the BNST of rats that received low dose naltrexone pretreatment compared to controls. No significant difference was observed in the other brain regions examined. In a separate group of rats, norepinephrine efflux was assessed with in vivo microdialysis in the BNST or the FC of morphine dependent rats or placebo treated rats subjected to naltrexone-precipitated withdrawal that received either naltrexone in their drinking water (5 mg/L) or unadulterated water. Following baseline dialysate collection, withdrawal was precipitated by injection of naltrexone and sample collection continued for an additional four hours. At the end of the

  15. Androgen receptors and estrogen receptors are colocalized in male rat hypothalamic and limbic neurons that express Fos immunoreactivity induced by mating.

    PubMed

    Gréco, B; Edwards, D A; Michael, R P; Clancy, A N

    1998-01-01

    Conversion of testosterone into estradiol is important for male rat sexual behavior, and both steroids probably contribute to mating. The distributions of neurons containing androgen receptors (AR) and estrogen receptors (ER) overlap, and many AR-immunoreactive (AR-ir) neurons express Fos immunoreactivity (Fos-ir) induced by mating. Because mating-induced Fos-ir in the male rat occurs mainly in AR-ir neurons, and because both steroids are important for mating, we hypothesized that (i) AR-ir and ER-ir are colocalized and that (ii) some of these neurons are activated during mating. We examined, in adjacent sections from the medial preoptic area (MPN) through the central tegmental field (CTF), the expression of ER-ir in: (i) AR-ir-containing neurons, and (ii) Fos-ir-expressive neurons. PG21 anti-AR, OA-11-824 anti-c-fos, H222 or 1D5 anti-ER primary antibodies were visualized, respectively, with cyanine-conjugated, fluorescein- or cyanine-conjugated, and fluorescein-conjugated secondary antibodies in male rats which were killed 1 h after ejaculating with a receptive female. In MPN, bed nucleus of the stria terminalis (BNST), and medial amygdala (MEA), 80-90% of ER-ir labeling occurred in AR-ir-positive neurons but only about 30% of AR-ir neurons were ER-ir-positive. No ER-ir was found in the CTF. This suggests the presence of three types of brain neurons sensitive to gonadal steroid hormones: neurons sensitive to androgens only, neurons sensitive to both androgens and estrogens, and neurons sensitive to estrogens only. About 50% of ER-ir labeling occurred in cells expressing mating-induced Fos-ir but only about 30% of Fos-ir neurons were ER-ir-positive. These findings suggest that, in the MPN, at least two different neuronal populations are activated during mating: the first contains AR-ir only and the second contains AR-ir and ER-ir. In the BNST and MEA, at least three hormonally sensitive populations are activated during mating: the two described above plus a third

  16. Regional Fos-expression induced by γ-hydroxybutyrate (GHB): comparison with γ-butyrolactone (GBL) and effects of co-administration of the GABAB antagonist SCH 50911 and putative GHB antagonist NCS-382.

    PubMed

    van Nieuwenhuijzen, P S; McGregor, I S; Chebib, M; Hunt, G E

    2014-09-26

    γ-Hydroxybutyrate (GHB) has a complex array of neural actions that include effects on its own high-affinity GHB receptor, the release of neuroactive steroids, and agonist actions at GABAA and GABAB receptors. We previously reported partial overlap in the c-Fos expression patterns produced by GHB and the GABAB agonist, baclofen in rats. The present study extends these earlier findings by examining the extent to which GHB Fos expression and behavioral sedation are prevented by (2S)-(+)-5,5-dimethyl-2-morpholineacetic acid (SCH 50911), a GABAB antagonist, and NCS-382, a putative antagonist at the high-affinity GHB receptor. We also compare Fos expression caused by GHB and its precursor γ-butyrolactone (GBL), which is a pro-drug for GHB but lacks the high sodium content of the parent GHB molecule. Both GHB (1,000 mg/kg) and GBL (600 mg/kg) induced rapid sedation in rats that lasted over 90 min and caused similar Fos expression patterns, albeit with GBL causing greater activation of the nucleus accumbens (core and shell) and dentate gyrus (granular layer). Pretreatment with SCH 50911 (100mg/kg) partly reversed the sedative effects of GHB and significantly reduced GHB-induced Fos expression in only four regions: the tenia tecta, lateral habenula, dorsal raphe and laterodorsal tegmental nucleus. NCS-382 (50mg/kg) had no effect on GHB-induced sedation or Fos expression. When given alone, both NCS-382 and SCH 50911 increased Fos expression in the bed nucleus of the stria terminalis, central amygdala, parasubthalamic nucleus and nucleus of the solitary tract. SCH 50911 alone affected the Islands of Calleja and the medial, central and paraventricular thalamic nuclei. Overall, this study shows a surprising lack of reversal of GHB-induced Fos expression by two relevant antagonists, both of which have marked intrinsic actions. This may reflect the limited doses tested but also suggests that GHB Fos expression reflects mechanisms independent of GHB and GABAB receptors.

  17. A candidate of organum vasculosum of the lamina terminalis with neuronal connections to neurosecretory preoptic nucleus in eels.

    PubMed

    Mukuda, Takao; Hamasaki, Sawako; Koyama, Yuka; Takei, Yoshio; Kaidoh, Toshiyuki; Inoué, Takao

    2013-09-01

    Systemic angiotensin II (Ang II) is a dipsogen in terrestrial vertebrates and seawater teleosts. In eels, Ang II acts on the area postrema, a sensory circumventricular organ (CVO) and elicits water intake but other sensory CVOs have not yet been found in the eel forebrain. To identify sensory CVOs in the forebrain, eels were peripherally injected with Evans blue, which immediately binds to albumin, or a rabbit IgG protein. Extravasation of these proteins, which cannot cross the blood–brain barrier (BBB), was observed in the brain parenchyma of the anteroventral preoptic recess (PR) walls. Fenestrated capillaries were observed in the parenchymal margin of the ventral wall of the PR, confirming a deficit of the BBB in the eel forebrain. Immunostaining for tyrosine hydroxylase (TH) and choline acetyltransferase (ChAT) detected neurons in the lateral region of the anterior parvocellular preoptic nucleus (PPa), which were strongly stained by BBB-impermeable N-hydroxysulfosuccinimide. In the periventricular region of the PPa, many neurons incorporated biotinylated dextran amine conjugated to fluorescein, a retrograde axonal tracer, injected into the magnocellular preoptic nucleus (PM), indicating neuronal connections from the PPa to the PM. The mammalian paraventricular and supraoptic nuclei, homologous to the teleost PM, receive principal neuronal projections from the organum vasculosum of the lamina terminalis (OVLT). These results strongly suggest that the periventricular subpopulation of the PPa, which is most likely to be a component of the OVLT, serves as a functional window of access for systemic signal molecules such as Ang II.

  18. Congenital generalized hypertrichosis terminalis: a proposed classification and a plea to avoid the ambiguous term "Ambras syndrome".

    PubMed

    Chen, WenChieh; Ring, Johannes; Happle, Rudolf

    2015-01-01

    Congenital generalized hypertrichosis terminalis (CGHT) is a heterogenous group of diseases with continuing excessive growth of terminal hair. "Ambras syndrome" was first coined by Baumeister in 1993 to describe a case of nonsyndromic CGHT which was erroneously analogized to the portrait paintings of Petrus Gonzales and his children, exhibited in Ambras Castle near Innsbruck, Austria. This family probably, a syndromic type with abnormal dentition, inherited as an autosomal dominant trait. CGHT associated with gingival hyperplasia is probably a particular entity typified by the historical cases of Julia Pastrana and her son. An X-linked type of CGHT has likewise been categorized as "Ambras syndrome". Moreover, some reports have mistakenly classified "Ambras syndrome" as an example of hypertrichosis lanuginosa. Potential gene loci identified so far may include 8q22, 17q24.2-q24.3 and Xq24-q27.1. The designation "Ambras syndrome" has thus been applied to various types of congenital hypertrichosis that differ to such degree that the name "Ambras" has no specific meaning, neither in the past nor in the future. Hence, this misleading term should now be jettisoned.

  19. Deafness in LIMP2-deficient mice due to early loss of the potassium channel KCNQ1/KCNE1 in marginal cells of the stria vascularis

    PubMed Central

    Knipper, Marlies; Claussen, Cathrin; Rüttiger, Lukas; Zimmermann, Ulrike; Lüllmann-Rauch, Renate; Eskelinen, Eeva-Liisa; Schröder, Jenny; Schwake, Michael; Saftig, Paul

    2006-01-01

    Our previous studies revealed a critical role of the lysosomal membrane protein LIMP2 in the regulation of membrane transport processes in the endocytic pathway. Here we show that LIMP2-deficient mice display a progressive high-frequency hearing loss and decreased otoacoustic emissions as early as 4 weeks of age. In temporal overlap to hearing impairment, fluorescence immunohistochemical studies revealed that the potassium channel KCNQ1 and its β-subunit KCNE1 were almost completely lost in the luminal part of marginal cells in the stria vascularis, affecting first higher and later also lower frequency processing cochlear turns. Concomitant with this, the expression of megalin, a multiligand endocytic receptor, was reduced in luminal surfaces of marginal cells within the stria vascularis. KCNQ1/KCNE1 and megalin were also lost in the dark cells of the vestibular system. Although LIMP2 is normally expressed in all cells of the stria vascularis, in the organ of Corti and cochlear neurons, the lack of LIMP2 preferentially caused a loss of KCNQ1/KCNE1 and megalin, and structural changes were only seen months later, indicating that these proteins are highly sensitive to disturbances in the lysosomal pathway. The spatio-temporal correlation of the loss of KCNQ1/KCNE1 surface expression and loss of hearing thresholds supports the notion that the decline of functional KCNQ1/KCNE1 is likely to be the primary cause of the hearing loss. Our findings suggest an important role for LIMP2 in the control of the localization and the level of apically expressed membrane proteins such as KCNQ1, KCNE1 and megalin in the stria vascularis. PMID:16901941

  20. Deafness in LIMP2-deficient mice due to early loss of the potassium channel KCNQ1/KCNE1 in marginal cells of the stria vascularis.

    PubMed

    Knipper, Marlies; Claussen, Cathrin; Rüttiger, Lukas; Zimmermann, Ulrike; Lüllmann-Rauch, Renate; Eskelinen, Eeva-Liisa; Schröder, Jenny; Schwake, Michael; Saftig, Paul

    2006-10-01

    Our previous studies revealed a critical role of the lysosomal membrane protein LIMP2 in the regulation of membrane transport processes in the endocytic pathway. Here we show that LIMP2-deficient mice display a progressive high-frequency hearing loss and decreased otoacoustic emissions as early as 4 weeks of age. In temporal overlap to hearing impairment, fluorescence immunohistochemical studies revealed that the potassium channel KCNQ1 and its beta-subunit KCNE1 were almost completely lost in the luminal part of marginal cells in the stria vascularis, affecting first higher and later also lower frequency processing cochlear turns. Concomitant with this, the expression of megalin, a multiligand endocytic receptor, was reduced in luminal surfaces of marginal cells within the stria vascularis. KCNQ1/KCNE1 and megalin were also lost in the dark cells of the vestibular system. Although LIMP2 is normally expressed in all cells of the stria vascularis, in the organ of Corti and cochlear neurons, the lack of LIMP2 preferentially caused a loss of KCNQ1/KCNE1 and megalin, and structural changes were only seen months later, indicating that these proteins are highly sensitive to disturbances in the lysosomal pathway. The spatio-temporal correlation of the loss of KCNQ1/KCNE1 surface expression and loss of hearing thresholds supports the notion that the decline of functional KCNQ1/KCNE1 is likely to be the primary cause of the hearing loss. Our findings suggest an important role for LIMP2 in the control of the localization and the level of apically expressed membrane proteins such as KCNQ1, KCNE1 and megalin in the stria vascularis.

  1. Ion transport mechanisms responsible for K+ secretion and the transepithelial voltage across marginal cells of stria vascularis in vitro.

    PubMed

    Wangemann, P; Liu, J; Marcus, D C

    1995-04-01

    It has long been accepted that marginal cells of stria vascularis are involved in the generation of the endocochlear potential and the secretion of K+. The present study was designed to provide evidence for this hypothesis and for a cell model proposed to explain K+ secretion and the generation of the endocochlear potential. Stria vascularis from the cochlea of the gerbil was isolated and mounted into a micro-Ussing chamber such that the apical and basolateral membrane of marginal cells could be perfused independently. In this preparation, the transepithelial voltage (Vt) and resistance (Rt) were measured across marginal cells and the resulting equivalent short circuit current (Isc) was calculated (Isc = Vt/Rt). Further, K+ secretion (JK+,probe) was measured with a K(+)-selective vibrating probe in the vicinity of the apical membrane. In the absence of extrinsic chemical driving forces, when both sides of the marginal cell epithelium were bathed with a perilymph-like solution, Vt was 8 mV (apical side positive), Rt was 10 ohm-cm2 and Isc was 850 microA/cm2 (N = 27). JK+,probe was outwardly directed from the apical membrane and reversibly inhibited by basolateral bumetanide, a blocker of the Na+/Cl-/K+ cotransporter. On the basolateral but not apical side, oubain and bumetanide each caused a decline of Vt and an increase of Rt suggesting the presence of the Na,K-ATPase and the Na+/Cl-/K+ cotransporter in the basolateral membrane. The responses to [Cl-] steps demonstrated a significant Cl- conductance in the basolateral membrane and a small Cl- conductance in the paracellular pathway or the apical membrane. The responses to [Na+] steps demonstrated no significant Na+ conductance in the basolateral membrane and a small Na+ or nonselective cation conductance in the apical membrane or paracellular pathway. The responses to [K+] steps demonstrated a large K+ conductance in the apical membrane. Apical application of 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS

  2. Effective G-protein coupling of Y2 receptors along axonal fiber tracts and its relevance for epilepsy.

    PubMed

    Dum, Elisabeth; Fürtinger, Sabine; Gasser, Elisabeth; Bukovac, Anneliese; Drexel, Meinrad; Tasan, Ramon; Sperk, Günther

    2017-02-01

    Neuropeptide Y (NPY)-Y2 receptors are G-protein coupled receptors and, upon activation, induce opening of potassium channels or closing of calcium channels. They are generally presynaptically located. Depending on the neuron in which they are expressed they mediate inhibition of release of NPY and of the neuron's classical transmitter GABA, glutamate or noradrenaline, respectively. Here we provide evidence that Y2 receptor binding is inhibited dose-dependently by GTPγS along Schaffer collaterals, the stria terminalis and the fimbria indicating that Y2 receptors are functionally coupled to G-proteins along these fiber tracts. Double immune fluorescence revealed coexistence of Y2-immunoreactivity with β-tubulin, a marker for axons in the stria terminalis, but not with synaptophysin labeling presynaptic terminals, supporting the localization of Y2 receptors along axonal tracts. After kainic acid-induced seizures in rats, GTPγS-induced inhibition of Y2 receptor binding is facilitated in the Schaffer collaterals but not in the stria terminalis. Our data indicate that Y2 receptors are not only located at nerve terminals but also along fiber tracts and are there functionally coupled to G-proteins.

  3. The Effect of Fenestration of Lamina Terminalis on the Vasospasm and Shunt-Dependent Hydrocephalus in Patients Following Subarachnoid Haemorrhage

    PubMed Central

    Hatefi, Masoud; Azhary, Shirzad; Naebaghaee, Hussein; Mohamadi, Hasan Reza

    2015-01-01

    Background and Aims: SAH (Sub Arachnoid Haemorrhage) is a life threatening that is associated with complications such as vasospasm and shunt-dependent hydrocephalus. The purpose of this study was to assess the effect of FLT (Fenestration of Lamina Terminalis) on the incidence of vasospasm and shunt-dependent hydrocephalus in ACoA (Anterior Communicating Artery) aneurismal in SAH. Materials and Methods: The data of 50 ruptured ACoA aneurism patients were selected during the year 2001-2009 admitted to Imam Hussein hospital, Tehran, IR. In a randomized double-blind trial patients assigned in two group {with fenestration (FLT, n=25), without fenestration (No FLT, n=25)}. All patients underwent craniotomy by a single neurosurgeon. Patient’s age, sex, Hunt-Hess grade, Fisher grade, vasospasm, presence of hydrocephalus and incidences of shunt-dependent hydrocephalus were compared between groups. Results: There were no significant differences among groups in relation to demographic characteristics, neurological scale scores (Hunt-Hess grade) and the severity of the SAH (Fisher grade) (p>0.05). The rate of hydrocephalus on admission, were 24% and 16% in FLT and no FLT group respectively (p>0.05). The shunt placement postoperatively in FLT and no FLT group were 16% and 12% respectively (p>0.05). The clinical vasospasm was 20% and 24% in FLT and no FLT group respectively (p>0.05). Conclusion: Despite FLT can be a safe method there were not significant differences of FLT on the incidence of vasospasm and shunt-dependent hydrocephalus. A systematic evaluation with multisurgeon, multicentre and with greater sample size to disclose reality is suggested. PMID:26393164

  4. Expression and Vesicular Localization of Mouse Trpml3 in Stria Vascularis, Hair Cells, and Vomeronasal and Olfactory Receptor Neurons

    PubMed Central

    Flores, Emma N.; García-Añoveros, Jaime

    2013-01-01

    TRPML3 is a member of the mucolipin branch of the transient receptor potential cation channel family. A dominant missense mutation in Trpml3 (also known as Mcoln3) causes deafness and vestibular impairment characterized by stereocilia disorganization, hair cell loss, and endocochlear potential reduction. Both marginal cells of the stria vascularis and hair cells express Trpml3 mRNA. Here we used in situ hybridization, quantitative RT-qPCR, and immunohistochemistry with several antisera raised against TRPML3 to determine the expression and subcellular distribution of TRPML3 in the inner ear as well as in other sensory organs. We also use Trpml3 knockout tissues to distinguish TRPML3-specific from nonspecific immunoreactivities. We find that TRPML3 localizes to vesicles of hair cells and strial marginal cells but not to stereociliary ankle links or pillar cells, which nonspecifically react with two antisera raised against TRPML3. Upon cochlear maturation, TRPML3 protein is redistributed to perinuclear vesicles of strial marginal cells and is augmented in inner hair cells vs. outer hair cells. Mouse somato-sensory neurons, retinal neurons, and taste receptor cells do not appear to express physiologically relevant levels of TRPML3. Finally, we found that vomeronasal and olfactory sensory receptor cells do express TRPML3 mRNA and protein, which localizes to vesicles in their somas and dendrites as well as at apical den dritic knobs. PMID:21344404

  5. The effect of fenestration of the lamina terminalis on the incidence of shunt-dependent hydrocephalus after aneurysmal subarachnoid hemorrhage (FISH)

    PubMed Central

    Tao, Chuanyuan; Fan, Chaofeng; Hu, Xin; Ma, Junpeng; Ma, Lu; Li, Hao; Liu, Yi; Sun, Hong; He, Min; You, Chao

    2016-01-01

    Abstract Background: Shunt-dependent hydrocephalus (SDH) is a well-known sequela following aneurysmal hemorrhage, adversely affecting the outcome after securing ruptured aneurysm. Fenestration of lamina terminalis (FLT) creates an anterior ventriculostomy, facilitates cerebrospinal fluid circulation and clot clearance in the basal cistern. However, controversy exists over whether microsurgical FLT during aneurysm repair can decrease the incidence of SDH. Aims: The study is designed to determine the efficacy of lamina terminalis fenestration on the reduction of SDH after aneurysm clipping. Methods/Design: A total of 288 patients who meet the inclusion criteria will be randomized into single aneurysm clipping or aneurysm clipping plus FLT in the Department of Neurosurgery, West China Hospital. Follow-up was performed 1, 3, 6, and 12 months after aneurysm clipping. The primary outcome is the incidence of SDH and the secondary outcomes include cerebral vasospasm, functional outcome evaluated by the modified Rankin Scale and Extended Glasgow Outcome Scale, and mortality. Discussion: The FISH trial is a large randomized, parallel controlled clinical trial to define the therapeutic value of FLT, the results of which will help to guide the surgical procedure and resolve the long-puzzled debate in the neurosurgical community. Conclusions: This protocol will determine the efficacy of FLT in the setting of aneurysmal subarachnoid hemorrhage. Trial registration identifier: http://www.chictr.org.cn/edit.aspx?pid=15691&htm=4 Chinese Clinical Trial Registry: ChiCTR-INR-16009249. PMID:28033279

  6. The effect of fenestration of the lamina terminalis on the incidence of shunt-dependent hydrocephalus after aneurysmal subarachnoid hemorrhage (FISH): Study protocol for a randomized controlled trial.

    PubMed

    Tao, Chuanyuan; Fan, Chaofeng; Hu, Xin; Ma, Junpeng; Ma, Lu; Li, Hao; Liu, Yi; Sun, Hong; He, Min; You, Chao

    2016-12-01

    Shunt-dependent hydrocephalus (SDH) is a well-known sequela following aneurysmal hemorrhage, adversely affecting the outcome after securing ruptured aneurysm. Fenestration of lamina terminalis (FLT) creates an anterior ventriculostomy, facilitates cerebrospinal fluid circulation and clot clearance in the basal cistern. However, controversy exists over whether microsurgical FLT during aneurysm repair can decrease the incidence of SDH. The study is designed to determine the efficacy of lamina terminalis fenestration on the reduction of SDH after aneurysm clipping. A total of 288 patients who meet the inclusion criteria will be randomized into single aneurysm clipping or aneurysm clipping plus FLT in the Department of Neurosurgery, West China Hospital. Follow-up was performed 1, 3, 6, and 12 months after aneurysm clipping. The primary outcome is the incidence of SDH and the secondary outcomes include cerebral vasospasm, functional outcome evaluated by the modified Rankin Scale and Extended Glasgow Outcome Scale, and mortality. The FISH trial is a large randomized, parallel controlled clinical trial to define the therapeutic value of FLT, the results of which will help to guide the surgical procedure and resolve the long-puzzled debate in the neurosurgical community. This protocol will determine the efficacy of FLT in the setting of aneurysmal subarachnoid hemorrhage. CHINESE CLINICAL TRIAL REGISTRY:: ChiCTR-INR-16009249.

  7. Studies on South-east Asian fireflies: Abscondita, a new genus with details of life history, flashing patterns and behaviour of Abs. chinensis (L.) and Abs. terminalis (Olivier) (Coleoptera: Lampyridae: Luciolinae).

    PubMed

    Ballantyne, Lesley; Fu, Xinhua; Lambkin, Christine; Jeng, Ming-Luen; Faust, Lynn; Wijekoon, M C D; Li, Daiqin; Zhu, Tengfui

    2013-01-01

    Abscondita, a new genus of fireflies from South-east Asia, is described from males and females of Abs. anceyi (Olivier 1883), Abs. cerata (Olivier 1911), Abs. chinensis (L. 1767), Abs. perplexa (Walker 1858), Abs. promelaena (Walker 1858) and Abs. terminalis (Olivier 1883), all transferred from Luciola Laporte. Both L. dubia Olivier 1903 and L. dejeani Gemminger 1870 are synonymised with Luciola perplexa (Walker), and L. aegrota Olivier 1891 and L. melaspis Bourgeois 1909 with L. promelaena Walker. Females are characterised by their bursa plates. Larvae are associated and described for Abs. anceyi (Olivier), Abs. chinensis (L.) and Abs. terminalis (Olivier). Taxonomic issues regarding the identification of species with very similar colouration of pale dorsum and black tipped elytra are addressed and in some cases resolved. A neotype for Luciola chinensis (L.) is erected and Luciola praeusta (Kiesenwetter 1874) is synonymised with L. chinensis (L.). Descriptions of life histories, biology and flashing patterns of populations of Abs. chinensis and Abs. terminalis from central China are included. A bs. terminalis is the first Asian firefly known to possess multiple flash trains where males are documented to display with repeating flash trains.

  8. Activation of organum vasculosum of lamina terminalis, median preoptic nucleus, and medial preoptic area in anticipation of nursing in rabbit pups.

    PubMed

    Moreno, María Luisa; Meza, Enrique; Morgado, Elvira; Juárez, Claudia; Ramos-Ligonio, Angel; Ortega, Arturo; Caba, Mario

    2013-12-01

    Rhythmic feeding in rabbit pups is a natural model to study food entrainment because, similar to rodents under a schedule of food restriction, these animals show food-anticipatory activity (FAA) prior to daily nursing. In rodents, several brain systems, including the orexinergic system, shift their activity to the restricted feeding schedule, and remain active when subjects are hungry. As the lamina terminalis and regions of the preoptic area participate in the control of behavioral arousal, it was hypothesized that these brain regions are also activated during FAA. Thus, the effects of daily milk ingestion on FOS protein expression in the organum vasculosum of lamina terminalis (OVLT), median preoptic nucleus (MnPO), and medial preoptic area (MPOA) were examined using immunohistochemistry before and after scheduled time of nursing in nursed and fasted subjects. Additionally, FOS expression was explored in orexin (ORX) cells in the lateral hypothalamic area and in the supraoptic nucleus (SON) because of their involvement in arousal and fluid ingestion, respectively. Pups were entrained by daily nursing, as indicated by a significant increase in locomotor behavior before scheduled time of nursing in both nursed and fasted subjects. FOS was significantly higher in the OVLT, MnPO, and MPOA at the time of nursing, and decreased 8 h later in nursed pups. In fasted subjects, this effect persisted in the OVLT, whereas in the MnPO and MPOA, values did not drop at 8 h later, but remained at the same level or higher than those at the time of scheduled nursing. In addition, FOS was significantly higher in ORX cells during FAA in nursed pups in comparison with 8 h later, but in fasted subjects it remained high during most fasting time points. Additionally, OVLT, SON, and ORX cells were activated 1.5 h after nursing. We conclude that the OVLT, MnPO, and MPOA, but not SON, may participate in FAA, as they show activation before suckling of periodic milk ingestion, and that

  9. De Novo 17q24.2-q24.3 microdeletion presenting with generalized hypertrichosis terminalis, gingival fibromatous hyperplasia, and distinctive facial features.

    PubMed

    Afifi, Hanan H; Fukai, Ryoko; Miyake, Noriko; Gamal El Din, Amina A; Eid, Maha M; Eid, Ola M; Thomas, Manal M; El-Badry, Tarek H; Tosson, Angie M S; Abdel-Salam, Ghada M H; Matsumoto, Naomichi

    2015-10-01

    Generalized hypertrichosis is a feature of several genetic disorders, and the nosology of these entities is still provisional. Recent studies have implicated chromosome 17q24.2-q24.3 microdeletion and the reciprocal microduplication in a very rare form of congenital generalized hypertrichosis terminalis (CGHT) with or without gingival hyperplasia. Here, we report on a 5-year-old Egyptian girl born to consanguineous parents. The girl presented with CGHT and gingival hyperplasia for whom we performed detailed clinical, pathological, and molecular studies. The girl had coarse facies characterized by bilateral epicanthic folds, thick and abundant eyelashes, a broad nose, full cheeks, and lips that constituted the distinctive facial features for this syndrome. Biopsy of the gingiva showed epithelial marked acanthosis and hyperkeratosis with hyperplastic thick collagen bundles and dense fibrosis in the underlying tissues. Array analysis indicated a 17q24.2-q24.3 chromosomal microdeletion. We validated this microdeletion by real-time quantitative PCR and confirmed a perfect co-segregation of the disease phenotype within the family. In summary, this study indicates that 17q24.2-q24.3 microdeletion caused CGHT with gingival hyperplasia and distinctive facies, which should be differentiated from the autosomal recessive type that lacks the distinctive facies.

  10. Identification of the CART neuropeptide circuitry processing TMT-induced predator stress.

    PubMed

    Sharma, Anju; Rale, Abhishek; Utturwar, Kaweri; Ghose, Aurnab; Subhedar, Nishikant

    2014-12-01

    Abundance of cocaine- and amphetamine-regulated transcript (CART) neuropeptide in the limbic areas like the olfactory system, central nucleus of amygdala (CeA), ventral bed nucleus of stria terminalis (vBNST) and the hypothalamus suggests involvement of the peptide in emotive processing. We examined the role of CART in mediating fear, a strong emotion with profound survival value. Rats, exposed to 2,4,5-trimethyl-3-thiazoline (TMT), a predator related cue extracted from fox feces, showed significant increase in freezing, escape and risk assessment behavior, whereas grooming was reduced. Neuronal activity was up-regulated in the CeA and vBNST in terms of increased immunoreactivity in CART elements and c-Fos expression. Increased expression of both the markers was also seen in some discrete magnocellular as well as parvicellular subdivisions of the paraventricular nucleus (PVN). However, CART containing mitral cells in the main or accessory olfactory bulb did not respond. CART antibody was stereotaxically injected bilaterally into the CeA to locally immunoneutralize endogenous CART. On exposure to TMT, these rats showed reduced freezing, risk assessment and escape behavior while grooming was restored to normal value. We suggest that the CART signaling in the CeA and vBNST, but not in the olfactory system, might be an important component of the innate fear processing, and expression of stereotypic behavior, while CART in the PVN subdivisions might mediate the neuroendocrine response to predator stress. Copyright © 2014 Elsevier Ltd. All rights reserved.

  11. Differential effects of unilateral lesions in the medial amygdala on spontaneous and induced ovulation.

    PubMed

    Sanchez, M A; Dominguez, R

    1995-01-01

    The possible existence of asymmetry in the control of ovulation by the medial amygdala was explored. Unilateral lesions of the medial amygdala were performed on each day of the estrous cycle. The estral index diminished in almost all animals with a lesion in the right side of medial amygdala. Lesions of the right medial amygdala, when performed on diestrus-1, resulted in a significant decrease in the number of rats ovulating compared to controls (4/8 vs. 8/8, p < 0.05). In ovulating animals a significant reduction in the number of ova shed by the left ovary was found (2.2 +/- 0.8 vs. 6.3 +/- 0.8, p < 0.05). Lesions of the stria terminalis performed on diestrus-1 did not affect ovulation. In a second experiment, administration of GnRH did not restore ovulation in rats with lesions of the right medial amygdala. However, sequential injections of PMSG-hCG did result in ovulation by all members of a group of lesioned animals. In this last condition a significant decrease in the number of ova shed by the right ovary was found compared to animals in the lesion-only condition (1.5 +/- 0.5 vs. 6.0 +/- 1.5, p < 0.05). These data suggest that control of ovulation by the medial amygdala is asymmetric and varies during the estrous cycle.

  12. [Deafness, induced by sodium ethacrynate in guinea pigs, alleviated by microwave treatment].

    PubMed

    Chen, X M; Din, D L; Luo, D F; Huangfu, M S; Jin, X M

    1992-01-01

    Microwave is used to treat temporal hearing loss caused by intravenous injection of the ethacrynic acid in guinea pigs. The recovery of hearing is much faster in the treated groups than in the control group. The article proposes possible mechanism of the effects against the ethacrynic acid induced deafness and assume that the result of this research can provide an experimental basis for treatment of some perceptive deafness due to ischemia of stria vascularis of the cochlea.

  13. Differential co-localization with choline acetyltransferase in nervus terminalis suggests functional differences for GnRH isoforms in bonnethead sharks (Sphyrna tiburo)

    PubMed Central

    Moeller, John F.; Meredith, Michael

    2010-01-01

    The nervus terminalis (NT) is a vertebrate cranial nerve whose function in adults is unknown. In bonnethead sharks the nerve is anatomically independent of the olfactory system, with two major cell populations within one or more ganglia along its exposed length. Most cells are immunoreactive for either gonadotropin-releasing hormone (GnRH) or RFamide-like peptides. To define further the cell populations and connectivity, we used double-label immuno-cytochemistry with antisera to different isoforms of GnRH and to choline acetyltransferase (ChAT). The labeling patterns of two GnRH antisera revealed different populations of GnRH immunoreactive (ir) cell-profiles in the NT ganglion. One antiserum labeled a large group of cells and fibers, which likely contain mammalian GnRH (GnRH-I) as described in previous studies, and which were ChAT immunoreactive. The other antiserum labeled large club-like structures, which were anuclear, and a sparse number of fibers, but with no clear labeling of cell bodies in the ganglion. These club structures were choline acetyltrasferase (ChAT) negative, and preabsorption control tests suggest they may contain chicken-GnRH-II (GnRH-II) or dogfish GnRH. The second major NT ganglion cell-type was immunoreactive for RF-amides, which regulate GnRH release in other vertebrates, and may provide an intraganglionic influence on GnRH release. The immunocytochemical and anatomical differences between the two GnRH immunoreactive profile types indicate possible functional differences for these isoforms in the NT. The club-like structures may be sites of GnRH release into the general circulation since these structures were observed near blood vessels and resembled structures seen in the median eminence of rats. PMID:20950589

  14. Copy-number mutations on chromosome 17q24.2-q24.3 in congenital generalized hypertrichosis terminalis with or without gingival hyperplasia.

    PubMed

    Sun, Miao; Li, Ning; Dong, Wu; Chen, Zugen; Liu, Qing; Xu, Yiming; He, Guang; Shi, Yongyong; Li, Xin; Hao, Jiajie; Luo, Yang; Shang, Dandan; Lv, Dan; Ma, Fen; Zhang, Dai; Hua, Rui; Lu, Chaoxia; Wen, Yaran; Cao, Lihua; Irvine, Alan D; McLean, W H Irwin; Dong, Qi; Wang, Ming-Rong; Yu, Jun; He, Lin; Lo, Wilson H Y; Zhang, Xue

    2009-06-01

    Congenital generalized hypertrichosis terminalis (CGHT) is a rare condition characterized by universal excessive growth of pigmented terminal hairs and often accompanied with gingival hyperplasia. In the present study, we describe three Han Chinese families with autosomal-dominant CGHT and a sporadic case with extreme CGHT and gingival hyperplasia. We first did a genome-wide linkage scan in a large four-generation family. Our parametric multipoint linkage analysis revealed a genetic locus for CGHT on chromosome 17q24.2-q24.3. Further two-point linkage and haplotyping with microsatellite markers from the same chromosome region confirmed the genetic mapping and showed in all the families a microdeletion within the critical region that was present in all affected individuals but not in unaffected family members. We then carried out copy-number analysis with the Affymetrix Genome-Wide Human SNP Array 6.0 and detected genomic microdeletions of different sizes and with different breakpoints in the three families. We validated these microdeletions by real-time quantitative PCR and confirmed their perfect cosegregation with the disease phenotype in the three families. In the sporadic case, however, we found a de novo microduplication. Two-color interphase FISH analysis demonstrated that the duplication was inverted. These copy-number variations (CNVs) shared a common genomic region in which CNV is not reported in the public database and was not detected in our 434 unrelated Han Chinese normal controls. Thus, pathogenic copy-number mutations on 17q24.2-q24.3 are responsible for CGHT with or without gingival hyperplasia. Our work identifies CGHT as a genomic disorder.

  15. Crystal structure of 6-SST/6-SFT from Pachysandra terminalis, a plant fructan biosynthesizing enzyme in complex with its acceptor substrate 6-kestose.

    PubMed

    Lammens, Willem; Le Roy, Katrien; Yuan, Shuguang; Vergauwen, Rudy; Rabijns, Anja; Van Laere, André; Strelkov, Sergei V; Van den Ende, Wim

    2012-04-01

    Fructans play important roles as reserve carbohydrates and stress protectants in plants, and additionally serve as prebiotics with emerging antioxidant properties. Various fructan types are synthesized by an array of plant fructosyltransferases belonging to family 32 of the glycoside hydrolases (GH32), clustering together with GH68 in Clan-J. Here, the 3D structure of a plant fructosyltransferase from a native source, the Pachysandra terminalis 6-SST/6-SFT (Pt6-SST/6-SFT), is reported. In addition to its 1-SST (1-kestose-forming) and hydrolytic side activities, the enzyme uses sucrose to create graminan- and levan-type fructans, which are probably associated with cold tolerance in this species. Furthermore, a Pt6-SST/6-SFT complex with 6-kestose was generated, representing a genuine acceptor binding modus at the +1, +2 and +3 subsites in the active site. The enzyme shows a unique configuration in the vicinity of its active site, including a unique D/Q couple located at the +1 subsite that plays a dual role in donor and acceptor substrate binding. Furthermore, it shows a unique orientation of some hydrophobic residues, probably contributing to its specific functionality. A model is presented showing formation of a β(2-6) fructosyl linkage on 6-kestose to create 6,6-nystose, a mechanism that differs from the creation of a β(2-1) fructosyl linkage on sucrose to produce 1-kestose. The structures shed light on the evolution of plant fructosyltransferases from their vacuolar invertase ancestors, and contribute to further understanding of the complex structure-function relationships within plant GH32 members. © 2011 The Authors. The Plant Journal © 2011 Blackwell Publishing Ltd.

  16. Detection of catecholamine and luteinizing hormone-releasing hormone (LH-RH) containing nerve endings in the median eminence and the organon vasculosum laminae terminalis by fluorescence histochemistry and immunohistochemistry on the same microscopic sections.

    PubMed

    Ibata, Y; Watanabe, K; Kinoshita, H; Kubo, S; Sano, Y; Sin, S; Hashimura, E; Imagawa, K

    1979-02-01

    Distribution of catecholamine (CA) and LH-RH nerve endings in the median eminence (ME) and the organon vasculosum laminae terminalis (OVLT) of the rat was investigated by application of fluorescence histochemistry and immunohistochemistry on the same sections of the tissue. In the ME, those two kinds of endings coexisted in the lateral portion of the middle part of ME, and in the wall of tuberoinfundibular sulcus, where they might be considered to have functional correlation. In the OVLT they were also distributed in fairly near distance, but they were not so closely associated as observed in the ME.

  17. Combined effects of dietary fructooligosaccharide and Bacillus licheniformis on innate immunity, antioxidant capability and disease resistance of triangular bream (Megalobrama terminalis).

    PubMed

    Zhang, Chun-Nuan; Li, Xiang-Fei; Xu, Wei-Na; Jiang, Guang-Zhen; Lu, Kang-Le; Wang, Li-Na; Liu, Wen-Bin

    2013-11-01

    This study was conducted to investigate the effects of fructooligosaccharide (FOS) and Bacillus licheniformis (B. licheniformis) and their interaction on innate immunity, antioxidant capability and disease resistance of triangular bream Megalobrama terminalis (average initial weight 30.5 ± 0.5 g). Nine experimental diets were formulated to contain three FOS levels (0, 0.3% and 0.6%) and three B. licheniformis levels (0, 1 × 10(7), 5 × 10(7) CFU g(-1)) according to a 3 × 3 factorial design. At the end of the 8-week feeding trial, fish were challenged by Aeromonas hydrophila (A. hydrophila) and survival rate was recorded for the next 7 days. The results showed that leucocyte counts, alternative complement activity as well as total serum protein and globulin contents all increased significantly (P < 0.05) as dietary B. licheniformis levels increased from 0 to 1 × 10(7) CFU g(-1), while little difference (P > 0.05) was observed in these parameters in terms of dietary FOS levels. Both plasma alkaline phosphatase and phenoloxidase activities were significantly (P < 0.05) affected only by dietary FOS levels with the highest values observed in fish fed 0.6 and 0.3% FOS, respectively. Both immunoglobulin M content and liver superoxide dismutase (SOD) activity were significantly affected (P > 0.05) by both FOS and B. licheniformis. Liver catalase, glutathione peroxidase as well as plasma SOD activities of fish fed 1 × 10(7) CFU g(-1)B. licheniformis were all significantly (P < 0.05) higher than that of the other groups, whereas the opposite was true for malondialdehyde content. After A. hydrophila challenge, survival rate was not affected (P > 0.05) by either FOS levels or B. licheniformis contents, whereas a significant (P < 0.05) interaction between these two substances was observed with the highest value observed in fish fed 0.3% FOS and 1 × 10(7) CFU g(-1)B. licheniformis. The results of this study indicated that dietary FOS and B. licheniformis could

  18. Brief pup exposure induces Fos expression in the lateral habenula and serotonergic caudal dorsal raphe nucleus of paternally experienced male California mice (Peromyscus californicus).

    PubMed

    de Jong, T R; Measor, K R; Chauke, M; Harris, B N; Saltzman, W

    2010-09-01

    Fathers play a substantial role in infant care in a small but significant number of mammalian species, including humans. However, the neural circuitry controlling paternal behavior is much less understood than its female counterpart. In order to characterize brain areas activated by paternal care, male California mice were separated from their female mate and litter for 3 h and then exposed to a pup or a control object (a glass pebble with the approximate size and oblong shape of a newborn pup) for 10 min. All males receiving a pup showed a strong paternal response towards it, whereas males receiving a pebble interacted with it only occasionally. Despite the clear behavioral differences, exposure to a pup did not increase Fos-like immunoreactivity (Fos-LIR) compared to a pebble in brain areas previously found to be associated with parental care, including the medial preoptic nucleus and medial bed nucleus of the stria terminalis. Pup exposure did, however, significantly increase Fos-LIR in the lateral habenula (LHb) and in predominantly serotonergic neurons in the caudal dorsal raphe nucleus (DRC), as compared to pebble exposure. Both the LHb and DRC are known to be involved in the behavioral responses to strong emotional stimuli; therefore, these areas might play a role in controlling parental behavior in male California mice.

  19. Unbiased Stereological Estimation of the Spiral Ligament and Stria Vascularis Volumes in Aging and Ménière’s Disease Using Archival Human Temporal Bones

    PubMed Central

    Ishiyama, Gail; Tokita, Joshua; Lopez, Ivan; Tang, Yong

    2006-01-01

    The present study applies the unbiased stereological technique—Cavalieri principle to measure the volumes of the stria vascularis (SV) and the spiral ligament (SL) using postmortem archival human temporal bones from normal young and older subjects and subjects with Ménière’s disease. Normative data was obtained from subjects without ages ranging from 15 to 84 years old who had no history of audiovestibular disease (N = 25). For comparison purposes, the normative specimens were divided into three groups: group 1 (n = 8) had ages ranging from 15 to 38 years old, average age = 23.9; group 2 (n = 8) had ages ranging from 51 to 59 years old, average age = 55.1; group 3 (n = 9) had ages ranging from 64 to 84 years old, average age = 74.3. The average SV volume of group 3 (0.479 mm3) was significantly lower than that of group 1 (0.705 mm3) (p < 0.0005) and was significantly lower than that of group 2 (0.603 mm3) (p = 0.01). The average SL volume of group 3 (8.42 mm3) was significantly lower than that of group 1 (9.54 mm3) (p<0.05), but was not significantly lower than that of group 2 (8.58 mm3). Five subjects with Ménière’s disease, confirmed by histopathological examination (ages ranging from 63 to 91 years old, average age = 73.4), were studied. The average SV volume in Ménière’s subjects (0.378 mm3) was significantly lower than age-matched controls (p<0.05). The average SL volume in Ménière’s subjects (7.01 mm3) was also significantly lower than age-matched controls (p<0.05). The SV and SL volumes were unaffected by gender. The present study demonstrates for the first time the use of the unbiased stereological technique—Cavalieri principle—as a reliable and efficient method to obtain volumetric estimates of the SV and the SL by using archival human temporal bone specimens. PMID:17160359

  20. Unexpected presence of graminan- and levan-type fructans in the evergreen frost-hardy eudicot Pachysandra terminalis (Buxaceae): purification, cloning, and functional analysis of a 6-SST/6-SFT enzyme.

    PubMed

    Van den Ende, Wim; Coopman, Marlies; Clerens, Stefan; Vergauwen, Rudy; Le Roy, Katrien; Lammens, Willem; Van Laere, André

    2011-01-01

    About 15% of flowering plants accumulate fructans. Inulin-type fructans with β(2,1) fructosyl linkages typically accumulate in the core eudicot families (e.g. Asteraceae), while levan-type fructans with β(2,6) linkages and branched, graminan-type fructans with mixed linkages predominate in monocot families. Here, we describe the unexpected finding that graminan- and levan-type fructans, as typically occurring in wheat (Triticum aestivum) and barley (Hordeum vulgare), also accumulate in Pachysandra terminalis, an evergreen, frost-hardy basal eudicot species. Part of the complex graminan- and levan-type fructans as accumulating in vivo can be produced in vitro by a sucrose:fructan 6-fructosyltransferase (6-SFT) enzyme with inherent sucrose:sucrose 1-fructosyltransferase (1-SST) and fructan 6-exohydrolase side activities. This enzyme produces a series of cereal-like graminan- and levan-type fructans from sucrose as a single substrate. The 6-SST/6-SFT enzyme was fully purified by classic column chromatography. In-gel trypsin digestion led to reverse transcription-polymerase chain reaction-based cDNA cloning. The functionality of the 6-SST/6-SFT cDNA was demonstrated after heterologous expression in Pichia pastoris. Both the recombinant and native enzymes showed rather similar substrate specificity characteristics, including peculiar temperature-dependent inherent 1-SST and fructan 6-exohydrolase side activities. The finding that cereal-type fructans accumulate in a basal eudicot species further confirms the polyphyletic origin of fructan biosynthesis in nature. Our data suggest that the fructan syndrome in P. terminalis can be considered as a recent evolutionary event. Putative connections between abiotic stress and fructans are discussed.

  1. Unexpected Presence of Graminan- and Levan-Type Fructans in the Evergreen Frost-Hardy Eudicot Pachysandra terminalis (Buxaceae): Purification, Cloning, and Functional Analysis of a 6-SST/6-SFT Enzyme1[W

    PubMed Central

    Van den Ende, Wim; Coopman, Marlies; Clerens, Stefan; Vergauwen, Rudy; Le Roy, Katrien; Lammens, Willem; Van Laere, André

    2011-01-01

    About 15% of flowering plants accumulate fructans. Inulin-type fructans with β(2,1) fructosyl linkages typically accumulate in the core eudicot families (e.g. Asteraceae), while levan-type fructans with β(2,6) linkages and branched, graminan-type fructans with mixed linkages predominate in monocot families. Here, we describe the unexpected finding that graminan- and levan-type fructans, as typically occurring in wheat (Triticum aestivum) and barley (Hordeum vulgare), also accumulate in Pachysandra terminalis, an evergreen, frost-hardy basal eudicot species. Part of the complex graminan- and levan-type fructans as accumulating in vivo can be produced in vitro by a sucrose:fructan 6-fructosyltransferase (6-SFT) enzyme with inherent sucrose:sucrose 1-fructosyltransferase (1-SST) and fructan 6-exohydrolase side activities. This enzyme produces a series of cereal-like graminan- and levan-type fructans from sucrose as a single substrate. The 6-SST/6-SFT enzyme was fully purified by classic column chromatography. In-gel trypsin digestion led to reverse transcription-polymerase chain reaction-based cDNA cloning. The functionality of the 6-SST/6-SFT cDNA was demonstrated after heterologous expression in Pichia pastoris. Both the recombinant and native enzymes showed rather similar substrate specificity characteristics, including peculiar temperature-dependent inherent 1-SST and fructan 6-exohydrolase side activities. The finding that cereal-type fructans accumulate in a basal eudicot species further confirms the polyphyletic origin of fructan biosynthesis in nature. Our data suggest that the fructan syndrome in P. terminalis can be considered as a recent evolutionary event. Putative connections between abiotic stress and fructans are discussed. PMID:21037113

  2. Amygdala afferents from the mediobasal hypothalamus: an electrophysiological and neuroanatomical study in the rat.

    PubMed

    Renaud, L P; Hopkins, D A

    1977-02-01

    Electrophysiological techniques and the retrograde transport of horseradish peroxidase (HRP) were used to determine the efferent projections from the caudal mediobasal hypothalamus to the amygdala. In pentobarbital anesthetized rats, the activity of 1780 mediobasal hypothalamic neurons was examined for response to stimulation sites in the amygdala and stria terminalis. Evidence of orthodromic activation from both stimulation sties was commonly observed. Sixty-five cells mostly located in the ventromedial nucleus displayed antidromic invasion from the basolateral, basomedial or cortical amygdala over a latency range of 5-34 msec (mean 15.3 +/- 6.7 msec S.D.). Three of 440 tested cells displayed antidromic activation from stimulation on the stria terminalis. Amygdala evoked antidromic responses were still present after lesions of the stria terminalis. May ipsilateral ventromedial hypothalamic neurons and a few cells in the ipsilateral arcuate nucelus and periventricular region and contralateral ventromedial nucleus displayed retrograde transport of HRP after an infection into the amygdala. Lesions of the stria terminalis had little effect on the numbers of HRP labeled neurons. Relatively more neurons were labeled retrogradely after medial injections than after lateral injections in the amygdala. Data from both electrophysiological and anatomical techniques therefore indicate that certain mediobasal hypothalamic neurons, particularly those located in the ipsilateral ventromedial nucleus, project to the amygdala probably via a route other than the stria terminalis. Thus there is substantial evidence in the rat for reciprocal connections between the amygdala and the hypothalamic ventromedial nucleus.

  3. Glycine receptor α3 and α2 subunits mediate tonic and exogenous agonist-induced currents in forebrain.

    PubMed

    McCracken, Lindsay M; Lowes, Daniel C; Salling, Michael C; Carreau-Vollmer, Cyndel; Odean, Naomi N; Blednov, Yuri A; Betz, Heinrich; Harris, R Adron; Harrison, Neil L

    2017-08-22

    Neuronal inhibition can occur via synaptic mechanisms or through tonic activation of extrasynaptic receptors. In spinal cord, glycine mediates synaptic inhibition through the activation of heteromeric glycine receptors (GlyRs) composed primarily of α1 and β subunits. Inhibitory GlyRs are also found throughout the brain, where GlyR α2 and α3 subunit expression exceeds that of α1, particularly in forebrain structures, and coassembly of these α subunits with the β subunit appears to occur to a lesser extent than in spinal cord. Here, we analyzed GlyR currents in several regions of the adolescent mouse forebrain (striatum, prefrontal cortex, hippocampus, amygdala, and bed nucleus of the stria terminalis). Our results show ubiquitous expression of GlyRs that mediate large-amplitude currents in response to exogenously applied glycine in these forebrain structures. Additionally, tonic inward currents were also detected, but only in the striatum, hippocampus, and prefrontal cortex (PFC). These tonic currents were sensitive to both strychnine and picrotoxin, indicating that they are mediated by extrasynaptic homomeric GlyRs. Recordings from mice deficient in the GlyR α3 subunit (Glra3(-/-)) revealed a lack of tonic GlyR currents in the striatum and the PFC. In Glra2(-/Y) animals, GlyR tonic currents were preserved; however, the amplitudes of current responses to exogenous glycine were significantly reduced. We conclude that functional α2 and α3 GlyRs are present in various regions of the forebrain and that α3 GlyRs specifically participate in tonic inhibition in the striatum and PFC. Our findings suggest roles for glycine in regulating neuronal excitability in the forebrain.

  4. Amygdalar vocalization pathways in the squirrel monkey.

    PubMed

    Jürgens, U

    1982-06-10

    In 22 squirrel monkeys (Saimiri sciureus) vocalization-eliciting electrodes were implanted into the amygdala and along the trajectory of the stria terminalis. Then, lesions were placed in the stria terminalis, its bed nucleus, the ventral amygdalofugal pathway and several di- and mesencephalic structures in order to find out the pathways along which the amygdala exerts its vocalization-controlling influence. It was found that different call types are controlled by different pathways. Purring and chattering calls, which express a self-confident, challenging attitude and an attempt to recruit fellow-combatants in intra-specific mobbing, respectively, are controlled via the stria terminalis; alarm peep and groaning calls, in contrast, which indicate flight motivation and resentment, respectively, are triggered via the ventral amygdalofugal fibre bundle. Both pathways traverse the dorsolateral and dorsomedial hypothalamus, respectively, and unite in the periaqueductal grey of the midbrain.

  5. Alcohol consumption increases locomotion in an open field and induces Fos-immunoreactivity in reward and approach/withdrawal-related neurocircuitries.

    PubMed

    Wscieklica, Tatiana; de Barros Viana, Milena; Le Sueur Maluf, Luciana; Pouza, Kathlein Cristiny Peres; Spadari, Regina Célia; Céspedes, Isabel Cristina

    2016-02-01

    Drug addiction is a chronically relapsing disorder characterized by compulsion to seek and take the drug, loss of control in limiting intake and, eventually, the emergence of a negative emotional state when access to the drug is prevented. Both dopamine and corticotropin-releasing factor (CRF)-mediated systems seem to play important roles in the modulation of alcohol abuse and dependence. The present study investigated the effects of alcohol consumption on anxiety and locomotor parameters and on the activation of dopamine and CRF-innervated brain regions. Male Wistar rats were given a choice of two bottles for 31 days, one containing water and the other a solution of saccharin + alcohol. Control animals only received water and a solution of 0.2% saccharin. On the 31st day, animals were tested in the elevated plus-maze and open field, and euthanized immediately after the behavioral tests. An independent group of animals was treated with ethanol and used to measure blood ethanol concentration. Results showed that alcohol intake did not alter behavioral measurements in the plus-maze, but increased the number of crossings in the open field, an index of locomotor activity. Additionally, alcohol intake increased Fos-immunoreactivity (Fos-ir) in the prefrontal cortex, in the shell region of the nucleus accumbens, in the medial and central amygdala, in the bed nucleus of the stria terminalis, in the septal region, and in the paraventricular and dorsomedial hypothalamus, structures that have been linked to reward and to approach/withdrawal behavior. These observations might be relevant to a better understanding of the behavioral and physiological alterations that follow alcohol consumption.

  6. A non-peptide oxytocin receptor agonist, WAY-267,464, alleviates novelty-induced hypophagia in mice: insights into changes in c-Fos immunoreactivity.

    PubMed

    Olszewski, Pawel K; Ulrich, Christine; Ling, Nicholas; Allen, Kerry; Levine, Allen S

    2014-09-01

    Anxiety caused by the novelty of food or of the environment where the food is presented leads to suppression of consumption (hyponeophagia) reflected by an increased latency to begin feeding and decreased food intake. Studies suggest that some anxiolytics, mainly benzodiazepines and SSRIs, resolve hyponeophagia. Though the neurohormone oxytocin (OT) affects both anxiety responsiveness and feeding-related homeostasis, the link between OT and hyponeophagia has not been established. The current experiments examined the effect of OT receptor stimulation on hyponeophagia in mice and associated changes in brain activity. We found that the OT receptor agonist, WAY-267,464, at 10 and 30 mg/kg b. wt. IP, reduced the latency to approach food and increased the amount of food eaten in hyponeophagia tests differing in animals' motivation to eat (hunger, reward) and the anxiogenic context of environmental novelty (illumination and type of the cage). This effect was abolished by the pretreatment with the OT receptor antagonist, L-368,899, at 10mg/kg b. wt. The antagonist also suppressed social transmission of preference for novel food. Mice subjected to novelty conditions causing hypophagia showed significant changes in c-Fos immunoreactivity in the hippocampus, lateral septum, cingulate and piriform cortex and in the bed nucleus of the stria terminalis, lateral division, posterolateral part (STLP). The pretreatment with WAY-267,464 restored c-Fos levels in the STLP to values detected in control animals subjected to non-anxiogenic conditions. We conclude that OT plays a role in shaping the magnitude of the novelty stress-provoked hypophagia and the activity of the relevant neural networks. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Effect of desipramine and citalopram treatment on forced swimming test-induced changes in cocaine- and amphetamine-regulated transcript (CART) immunoreactivity in mice.

    PubMed

    Chung, Sung; Kim, Hee Jeong; Kim, Hyun Ju; Choi, Sun Hye; Kim, Jin Wook; Kim, Jeong Min; Shin, Kyung Ho

    2014-05-01

    Recent study demonstrates antidepressant-like effect of cocaine- and amphetamine-regulated transcript (CART) in the forced swimming test (FST), but less is known about whether antidepressant treatments alter levels of CART immunoreactivity (CART-IR) in the FST. To explore this possibility, we assessed the treatment effects of desipramine and citalopram, which inhibit the reuptake of norepinephrine and serotonin into the presynaptic terminals, respectively, on changes in levels of CART-IR before and after the test swim in mouse brain. Levels of CART-IR in the nucleus accumbens shell (AcbSh), dorsal bed nucleus of the stria terminalis (dBNST), and hypothalamic paraventricular nucleus (PVN) were significantly increased before the test swim by desipramine and citalopram treatments. This increase in CART-IR in the AcbSh, dBNST, and PVN before the test swim remained elevated by desipramine treatment after the test swim, but this increase in these brain areas returned to near control levels after test swim by citalopram treatment. Citalopram, but not desipramine, treatment increased levels of CART-IR in the central nucleus of the amygdala (CeA) and the locus ceruleus (LC) before the test swim, and this increase was returned to control levels after the test swim in the CeA, but not in the LC. These results suggest common and distinct regulation of CART by desipramine and citalopram treatments in the FST and raise the possibility that CART in the AcbSh, dBNST, and CeA may be involved in antidepressant-like effect in the FST.

  8. Involvement of calpain-I and microRNA34 in kanamycin-induced apoptosis of inner ear cells.

    PubMed

    Yu, Li; Tang, Hao; Jiang, Xiao Hua; Tsang, Lai Ling; Chung, Yiu Wa; Chan, Hsiao Chang

    2010-12-01

    Inner ear cells, including hair cells, spiral ganglion cells, stria vascularis cells and supporting cells on the basilar membrane, play a major role in transducing hearing signals and regulating inner ear homoeostasis. However, their functions are often damaged by antibiotic-induced ototoxicity. Apoptosis is probably involved in inner ear cell injury following aminoglycoside treatment. Calpain, a calcium-dependent protease, is essential for mediating and promoting cell death. We have therefore investigated the involvement of calpain in the molecular mechanism underlying ototoxicity induced by the antibiotic kanamycin in mice. Kanamycin (750 mg/kg) mainly induced cell death of cochlear cells, including stria vascularis cells, supporting cells and spiral ganglion cells, but not hair cells within the organ of Corti. Cell death due to apoptosis occurred in a time-dependent manner with concomitant up-regulation of calpain expression. Furthermore, the expression levels of two microRNAs, mir34a and mir34c, were altered in a dose-dependent manner in cochlear cells. These novel findings demonstrated the involvement of both calpain and microRNAs in antibiotic-induced ototoxicity.

  9. An in vitro mouse model of congenital cytomegalovirus-induced pathogenesis of the inner ear cochlea.

    PubMed

    Melnick, Michael; Jaskoll, Tina

    2013-02-01

    Congenital human cytomegalovirus (CMV) infection is the leading nongenetic etiology of sensorineural hearing loss (SNHL) at birth and prelingual SNHL not expressed at birth. The paucity of temporal bone autopsy specimens from infants with congenital CMV infection has hindered the critical correlation of histopathology with pathogenesis. Here, we present an in vitro embryonic mouse model of CMV-infected cochleas that mimics the human sites of viral infection and associated pathology. There is a striking dysplasia/hyperplasia in mouse CMV-infected cochlear epithelium and mesenchyme, including organ of Corti hair and supporting cells and stria vascularis. This is concomitant with significant dysregulation of p19, p21, p27, and Pcna gene expression, as well as proliferating cell nuclear antigen (PCNA) protein expression. Other pathologies similar to those arising from known deafness gene mutations include downregulation of KCNQ1 protein expression in the stria vascularis, as well as hypoplastic and dysmorphic melanocytes. Thus, this model provides a relevant and reliable platform within which the detailed cell and molecular biology of CMV-induced deafness may be studied.

  10. An In Vitro Mouse Model of Congenital Cytomegalovirus-induced Pathogenesis of the Inner Ear Cochlea

    PubMed Central

    Melnick, Michael; Jaskoll, Tina

    2015-01-01

    Congenital human cytomegalovirus (CMV) infection is the leading nongenetic etiology of sensorineural hearing loss (SNHL) at birth and prelingual SNHL not expressed at birth. The paucity of temporal bone autopsy specimens from infants with congenital CMV infection has hindered the critical correlation of histopathology with pathogenesis. Here, we present an in vitro embryonic mouse model of CMV-infected cochleas that mimics the human sites of viral infection and associated pathology. There is a striking dysplasia/hyperplasia in mouse CMV-infected cochlear epithelium and mesenchyme, including organ of Corti hair and supporting cells and stria vascularis. This is concomitant with significant dysregulation of p19, p21, p27, and Pcna gene expression, as well as proliferating cell nuclear antigen (PCNA) protein expression. Other pathologies similar to those arising from known deafness gene mutations include downregulation of KCNQ1 protein expression in the stria vascularis, as well as hypoplastic and dysmorphic melanocytes. Thus, this model provides a relevant and reliable platform within which the detailed cell and molecular biology of CMV-induced deafness may be studied. PMID:23281115

  11. Reinforcing concomitants of electrically elicited vocalizations.

    PubMed

    Jürgens, U

    1976-09-24

    In 38 squirrel monkeys 251 vocalization-producing electrode positions were tested for their positive and negative reinforcing properties. Two groups of vocalization-producing brain areas could be distinguished: One group in which the electrically elicited vocalization was independent of the accompanying reinforcement effect, and a second group in which vocalization and reinforcement effect were correlated. The first group included the anterior cingulate gyrus, the adjacent supplementary motor area, gyrus rectus, ventromedial edge of the capsula interna, caudal periaqueductal gray and adjacent parabrachial region. The second group consited of the caudatum, septum, substantia innominata, amygdala, inferior thalamic peduncle, stria terminalis, midline thalamus, ventral and periventricular hypothalamus, substantia nigra, rostral periaqueductal gray, dorsolateral midbrain tegmentum and lateral medulla. It is hypothesized that the first group contains predominantly or exclusively "primary" vocalization substrates; the second group is thought to be composed mainly of structures whose stimulation yields vocalization secondarily due to stimulus induced motivational changes.

  12. Enduring attenuation of norepinephrine synaptic availability and augmentation of the pharmacological and behavioral effects of desipramine by repeated immobilization stress.

    PubMed

    Gonzáles, Marco A; Miranda, Ana Pamela; Orrego, Horacio; Silva, Rodolfo; Forray, María Inés

    2017-02-20

    Here we provide evidence that repeated immobilization stress (RIS) in rats induces a persistent increase in noradrenergic activity in the anterior aspects of the anterolateral bed nucleus of the stria terminalis (alBNST). This increase in noradrenergic activity results from both enhanced synthesis and reuptake of norepinephrine (NE). It leads to a decrease in the synaptic availability of NE, which elicits an augmented noradrenergic response to the inhibitors of NE reuptake (NRIs), such as desipramine (DMI), an antidepressant. The enduring depression-like behavior and the augmentation of the climbing behavior seen in repeatedly stressed rats following subchronic administration of DMI in the forced swimming test (FST) might be explained by a dysregulation of noradrenergic transmission observed in alBNST. Taken together, we propose that dysregulation of noradrenergic transmission such as the one described in the present work may represent a mechanism underlying major depressive disorders (MDD) with melancholic features in humans.

  13. A retracting wire knife for cutting fiber bundles and making sheet lesions of brain tissue.

    PubMed

    Shibata, M; Russell, I S

    1979-07-01

    A retracting knife which has two cutting wires for the transection of fiber bundles is described. The knife holds the fiber bundles of the stria terminalis between the two cutting wires and transects them by a shearing movement as the wires close. In addition, the feasability of such a knife producing a sheet lesion around the n. caudatus is also described.

  14. Sex-Specific Effects of Stress on Oxytocin Neurons Correspond With Responses to Intranasal Oxytocin.

    PubMed

    Steinman, Michael Q; Duque-Wilckens, Natalia; Greenberg, Gian D; Hao, Rebecca; Campi, Katharine L; Laredo, Sarah A; Laman-Maharg, Abigail; Manning, Claire E; Doig, Ian E; Lopez, Eduardo M; Walch, Keenan; Bales, Karen L; Trainor, Brian C

    2016-09-01

    Oxytocin (OT) is considered to be a stress-buffering hormone, dampening the physiologic effects of stress. However, OT can also be anxiogenic. We examined acute and long-lasting effects of social defeat on OT neurons in male and female California mice. We used immunohistochemistry for OT and c-fos cells to examine OT neuron activity immediately after defeat (n = 6-9) and 2 weeks (n = 6-9) and 10 weeks (n = 4-5) later. We quantified Oxt messenger RNA with quantitative polymerase chain reaction (n = 5-9). Intranasal OT was administered to naïve and stressed mice tested in social interaction and resident-intruder tests (n = 8-14). Acute exposure to a third episode of defeat increased OT/c-fos colocalizations in the paraventricular nucleus of both sexes. In the medioventral bed nucleus of the stria terminalis, defeat increased Oxt messenger RNA, total OT neurons, and OT/c-fos colocalizations in female mice but not male mice. Intranasal OT failed to reverse stress-induced social withdrawal in female mice and reduced social interaction behavior in female mice naïve to defeat. In contrast, intranasal OT increased social interaction in stressed male mice and reduced freezing in the resident-intruder test. Social defeat induces long-lasting increases in OT production and OT/c-fos cells in the medioventral bed nucleus of the stria terminalis of female mice but not male mice. Intranasal OT largely reversed the effects of stress on behavior in male mice, but effects were mixed in female mice. These results suggest that changes in OT-sensitive networks contribute to sex differences in behavioral responses to stress. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

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

    PubMed Central

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

    2016-01-01

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

  16. Involvement of prolactin-releasing peptide in the activation of oxytocin neurones in response to food intake.

    PubMed

    Yamashita, M; Takayanagi, Y; Yoshida, M; Nishimori, K; Kusama, M; Onaka, T

    2013-05-01

    Food intake activates neurones expressing prolactin-releasing peptide (PrRP) in the medulla oblongata and oxytocin neurones in the hypothalamus. Both PrRP and oxytocin have been shown to have an anorexic action. In the present study, we investigated whether the activation of oxytocin neurones following food intake is mediated by PrRP. We first examined the expression of PrRP receptors (also known as GPR10) in rats. Immunoreactivity of PrRP receptors was observed in oxytocin neurones and in vasopressin neurones in the paraventricular and supraoptic nuclei of the hypothalamus and in the bed nucleus of the stria terminalis. Application of PrRP to isolated supraoptic nuclei facilitated the release of oxytocin and vasopressin. In mice, re-feeding increased the expression of Fos protein in oxytocin neurones of the hypothalamus and bed nucleus of the stria terminalis. The increased expression of Fos protein in oxytocin neurones following re-feeding or i.p. administration of cholecystokinin octapeptide (CCK), a peripheral satiety factor, was impaired in PrRP-deficient mice. CCK-induced oxytocin increase in plasma was also impaired in PrRP-deficient mice. Furthermore, oxytocin receptor-deficient mice showed an increased meal size, as reported in PrRP-deficient mice and in CCKA receptor-deficient mice. These findings suggest that PrRP mediates, at least in part, the activation of oxytocin neurones in response to food intake, and that the CCK-PrRP-oxytocin pathway plays an important role in the control of the termination of each meal. © 2013 British Society for Neuroendocrinology.

  17. Involvement of Prolactin-Releasing Peptide in the Activation of Oxytocin Neurones in Response to Food Intake

    PubMed Central

    Yamashita, M; Takayanagi, Y; Yoshida, M; Nishimori, K; Kusama, M; Onaka, T

    2013-01-01

    Food intake activates neurones expressing prolactin-releasing peptide (PrRP) in the medulla oblongata and oxytocin neurones in the hypothalamus. Both PrRP and oxytocin have been shown to have an anorexic action. In the present study, we investigated whether the activation of oxytocin neurones following food intake is mediated by PrRP. We first examined the expression of PrRP receptors (also known as GPR10) in rats. Immunoreactivity of PrRP receptors was observed in oxytocin neurones and in vasopressin neurones in the paraventricular and supraoptic nuclei of the hypothalamus and in the bed nucleus of the stria terminalis. Application of PrRP to isolated supraoptic nuclei facilitated the release of oxytocin and vasopressin. In mice, re-feeding increased the expression of Fos protein in oxytocin neurones of the hypothalamus and bed nucleus of the stria terminalis. The increased expression of Fos protein in oxytocin neurones following re-feeding or i.p. administration of cholecystokinin octapeptide (CCK), a peripheral satiety factor, was impaired in PrRP-deficient mice. CCK-induced oxytocin increase in plasma was also impaired in PrRP-deficient mice. Furthermore, oxytocin receptor-deficient mice showed an increased meal size, as reported in PrRP-deficient mice and in CCKA receptor-deficient mice. These findings suggest that PrRP mediates, at least in part, the activation of oxytocin neurones in response to food intake, and that the CCK–PrRP–oxytocin pathway plays an important role in the control of the termination of each meal. PMID:23363338

  18. Protective role of misoprostol against cisplatin-induced ototoxicity.

    PubMed

    Doğan, Murat; Polat, Halil; Yaşar, Mehmet; Kaya, Altan; Bayram, Ali; Şenel, Fatma; Özcan, İbrahim

    2016-11-01

    Cis-diammineedichloroplatinum (cisplatin) is a chemotherapeutic agent that is widely used in the treatment of many cancers. Nephrotoxicity, ototoxicity and neurotoxicity are dose-limiting adverse effects for cisplatin. The cellular and molecular mechanisms underlying cisplatin-induced ototoxicity aren't fully understood. It has been proposed that cisplatin primarily cause damage at the cochlea, outer hair cells in particular, leading to excessive production of free oxygen radicals in the organ of Corti, stria vascularis, spiral ligament, and spiral ganglionic cells. The cytotoxicity is associated with the generation of reactive oxygen species (ROS); thus, there is an increasing interest on antioxidants with an effort to discover the established protection against cisplatin-induced ototoxicity over time. Misoprostol (MP) has gained considerable interest as a reactive oxygen species scavenger in recent years. To best of our knowledge, there is no study about protective effect of MP, a prostaglandin E1 (PGE1) analogue, on cisplatin-induced ototoxicity. In our study, we show that protective effects of misoprostol on cisplatin-induced ototoxcity on rats.

  19. Calpain mediated cisplatin-induced ototoxicity in mice

    PubMed Central

    Chang, Liang; Wang, Aimei

    2013-01-01

    Ototoxic drug-induced apoptosis of inner ear cells has been shown to be associated with calpain expression. Cisplatin has severe ototoxicity, and can induce cochlear cell apoptosis. This study assumed that cisplatin activated calpain expression in apoptotic cochlear cells. A mouse model of cisplatin-induced ototoxicity was established by intraperitoneal injection with cisplatin (2.5, 3.5, 4.5, 5.5 mg/kg). Immunofluorescence staining, image analysis and western blotting were used to detect the expression of calpain 1 and calpain 2 in the mouse cochlea. At the same time, the auditory brainstem response was measured to observe the change in hearing. Results revealed that after intraperitoneal injection with cisplatin for 5 days, the auditory brainstem response threshold shifts increased in mice. Calpain 1 and calpain 2 expression significantly increased in outer hair cells, the spiral ganglion and stria vascularis. Calpain 2 protein expression markedly increased with an increased dose of cisplatin. Results suggested that calpain 1 and calpain 2 mediated cisplatin-induced ototoxicity in BALB/c mice. During this process, calpain 2 plays a leading role. PMID:25206508

  20. Endolymphatic perfusion with EGTA-acetoxymethyl ester inhibits asphyxia- and furosemide-induced decrease in endocochlear potential in guinea pigs.

    PubMed

    Mineharu, Akihito; Mori, Yoshiaki; Nimura, Yoshitsugu; Takamaki, Atsuko; Araki, Michitoshi; Yamaji, Junko; Yoshida, Ryotaro; Takenaka, Hiroshi; Kubota, Takahiro

    2005-02-01

    We examined the effect of the Ca(2+) concentration in the endolymph ([Ca](e)) or in the endolymphatic surface cells ([Ca](i)) on the endocochlear potential (EP) by using an endolymphatic or perilymphatic perfusion technique, respectively. (i) A large increase in [Ca](e) up to approximately 10(-3) M with a fall in the EP was induced by transient asphyxia ( approximately 2 min) or by the intravenous administration of furosemide (60 mg/kg), and a significant correlation was obtained between the EP and p[Ca](e) (= -log [Ca](e), r = 0.998). (ii) Perfusion of the endolymph with 10 mM EGTA for 5 min neither produced any significant change in the EP nor altered the asphyxia-induced change in EP (DeltaEP(asp)), suggesting that neither [Ca](e) nor the Ca(2+) concentration gradient across the stria vascularis contributed directly to the generation of the EP in the condition of low [Ca](e). In contrast, endolymphatic perfusion with high Ca(2+) (more than 10 mM) produced a decrease in EP and a significant correlation was obtained between the EP and the Ca(2+) concentration of perfusion solution (r = 0.982), suggesting that Ca(2+) permeability may exist across the stria vascularis. (iii) The administration of a Ca(2+) chelator, EGTA-acetoxymethyl ester (AM, 0.3 mM), to the endolymph, which produced a gradual increase in EP, suppressed significantly, by 60-80%, DeltaEP(asp) or furosemide-induced changes in EP. In contrast, perilymphatic administration of 0.5 mM EGTA-AM caused no significant suppression of the DeltaEP(asp). These findings suggest that [Ca](i) plays an important role in generating/maintaining a large positive EP.

  1. The paracrine effect of mesenchymal human stem cells restored hearing in β-tubulin induced autoimmune sensorineural hearing loss.

    PubMed

    Yoo, T J; Du, Xiaoping; Zhou, Bin

    2015-12-01

    The aim of this study was to examine the activities of hASCs (Human Adipose tissue Derived Stem Cells) on experimental autoimmune hearing loss (EAHL) and how human stem cells regenerated mouse cochlea cells. We have restored hearing in 19 years old white female with autoimmune hearing loss with autologous adipose tissue derived stem cells and we wish to understand the mechanism of restoration of hearing in animal model. BALB/c mice underwent to develop EAHL; mice with EAHL were given hASCs intraperitoneally once a week for 6 consecutive weeks. ABR were examined over time. The helper type 1 autoreactive responses and T-reg cells were examined. H&E staining or immunostaining with APC conjugated anti-HLA-ABC antibody were conducted. The organ of Corti, stria vascularis, spira ligament and spiral ganglion in stem cell group are normal. In control group, without receiving stem cells, the organ of Corti is replaced by a single layer of cells, atrophy of stria vascularis. Systemic infusion of hASCs significantly improved hearing function and protected hair cells in established EAHL. The hASCs decreased the proliferation of antigen specific Th1/Th17 cells and induced the production of anti-inflammatory cytokine interleukin10 in splenocytes. They also induced the generation of antigen specific CD4(+)CD25(+)Foxp3(+)T-reg cells. The experiment showed the restoration is due to the paracrine activities of human stem cells, since there are newly regenerated mice spiral ganglion cells, not human mesenchymal stem cells derived tissue given by intraperitoneally. Copyright © 2015. Published by Elsevier B.V.

  2. Neural activity associated with monitoring the oscillating threat value of a tarantula.

    PubMed

    Mobbs, Dean; Yu, Rongjun; Rowe, James B; Eich, Hannah; FeldmanHall, Oriel; Dalgleish, Tim

    2010-11-23

    Phylogenetic threats such as spiders evoke our deepest primitive fears. When close or looming, such threats engage evolutionarily conserved monitoring systems and defense reactions that promote self-preservation. With the use of a modified behavioral approach task within functional MRI, we show that, as a tarantula was placed closer to a subject's foot, increased experiences of fear coincided with augmented activity in a cascade of fear-related brain networks including the periaqueductal gray, amygdala, and bed nucleus of the stria terminalis. Activity in the amygdala was also associated with underprediction of the tarantula's threat value and, in addition to the bed nucleus of the stria terminalis, with monitoring the tarantula's threat value as indexed by its direction of movement. Conversely, the orbitofrontal cortex was engaged as the tarantula grew more distant, suggesting that this region emits safety signals or expels fear. Our findings fractionate the neurobiological mechanisms associated with basic fear and potentially illuminate the perturbed reactions that characterize clinical phobias.

  3. Inhibitors of Histone Deacetylases Attenuate Noise-Induced Hearing Loss.

    PubMed

    Chen, Jun; Hill, Kayla; Sha, Su-Hua

    2016-08-01

    Loss of auditory sensory hair cells is the major pathological feature of noise-induced hearing loss (NIHL). Currently, no established clinical therapies for prevention or amelioration of NIHL are available. The absence of treatments is due to our lack of a comprehensive understanding of the molecular mechanisms underlying noise-induced damage. Our previous study indicates that epigenetic modification of histones alters hair cell survival. In this study, we investigated the effect of noise exposure on histone H3 lysine 9 acetylation (H3K9ac) in the inner ear of adult CBA/J mice and determined if inhibition of histone deacetylases by systemic administration of suberoylanilide hydroxamic acid (SAHA) could attenuate NIHL. Our results showed that H3K9ac was decreased in the nuclei of outer hair cells (OHCs) and marginal cells of the stria vascularis in the basal region after exposure to a traumatic noise paradigm known to induce permanent threshold shifts (PTS). Consistent with these results, levels of histone deacetylases 1, 2, and 3 (HDAC1, HDAC2 and HDAC3) were increased predominately in the nuclei of cochlear cells. Silencing of HDAC1, HDAC2, or HDAC3 with siRNA reduced the expression of the target HDAC in OHCs, but did not attenuate noise-induced PTS, whereas treatment with the pan-HDAC inhibitor SAHA, also named vorinostat, reduced OHC loss, and attenuated PTS. These findings suggest that histone acetylation is involved in the pathogenesis of noise-induced OHC death and hearing loss. Pharmacological targeting of histone deacetylases may afford a strategy for protection against NIHL.

  4. Cadmium and naphthalene-induced hyperglycemia in the fiddler crab, Uca pugilator: Differential modes of action on the neutroendocrine system

    SciTech Connect

    Reddy, P.S.; Katyayani, R.V.; Fingerman, M.

    1996-03-01

    Hyperglycemia is a typical response of aquatic organisms to heavy metals. In crustaceans, the medulla terminalis X-organ-sinus gland neuroendocrine complex in the eyestalk is the source of the crustacean hyperglycemic hormone (CHH). The role of CHH in pollutant-induced b1ood glucose changes has only recently begun to be studied. Reddy provided evidence that CHH mediates cadmium-induced hyperglycemia in the red swamp crayfish, Procambarus clarkii. In a study of another hormonally-regulated function, color changes, cadmium exposure resulted in pigment in the melanophores of the fiddler crab, Uca pugilator, becoming less dispersed than in unexposed crabs. Earlier studies showed that, like cadmium, both a PCB, Aroclor 1242, and naphthalene induced black pigment aggregation in Uca poor. In general, when crabs are exposed to a pollutant, hydrocarbon or cadmium, they aggregate the pigment in their melanophores, but apparently by different mechanisms. Hydrocarbons appear to inhibit release of black pigment-dispersing hormone (BDPH), whereas cadmium appears to inhibit its synthesis. These apparent different modes of action of cadmium and naphthalene on the color change mechanism led us to compare the impact of these pollutants on the hormonal regulation of blood glucose in Uca pugilator. The present study was performed to determine (1) whether cadmium and naphthalene induce hyperglycemia in Uca pugilator, (2) whether CH has a role, if naphthalene and cadmium do induce hyperglycemia, and (3) the effects, if any, of cadmium and naphthalene on CHH activity in the eyestalk neuroendocrine complex.

  5. Blockade of prostaglandin E2-induced thermogenesis by unilateral microinjection of GABAA receptor antagonist into the preoptic area.

    PubMed

    Osaka, Toshimasa

    2008-09-16

    Previous studies have demonstrated that pretreatment of rats with a GABA(A) receptor antagonist microinjected bilaterally into the preoptic area (POA) blocked cold- or lipopolysaccharide-induced thermogenesis. Here, the involvement of GABA(A) receptors in prostaglandin (PG)E2-induced fever was examined. Thermogenic, tachycardic, vasoconstrictive, and hyperthermic responses were elicited by the unilateral microinjection of 0.57-1.1 pmol PGE2 into the region adjacent to the organum vasculosum of the lamina terminalis in urethane-chloralose-anesthetized rats. All these responses were blocked 10 min after pretreatment of the rats with a GABA(A) receptor antagonist, bicuculline methiodide or gabazine (50-500 pmol), microinjected unilaterally into the POA; and recovery occurred at approximately 70 min. Though the antagonist treatment alone had no effect on the O2 consumption rate or colonic temperature, it did elicit a bradycardic response. Pretreatment with the vehicle, saline, had no effect on the PGE2-induced responses. However, the blocking action of bicuculline/gabazine was efficacious when the agent was administered unilaterally, but not necessarily bilaterally, into the POA either contralateral or ipsilateral to the PGE2 injection site. These results suggest that the PGE2-induced responses are not simply mediated by the GABAergic transmission from the PGE2-sensitive site to the thermoefferent structure in the POA, although a tonic inhibitory input to POA neurons has a permissive role for the full expression of PGE2-induced fever.

  6. Projections from the anteroventral part of the medial amygdaloid nucleus in the rat.

    PubMed

    Novaes, Leonardo S; Shammah-Lagnado, Sara J

    2011-11-03

    The medial amygdaloid nucleus (Me) integrates pheromonal and olfactory information with gonadal hormone cues, being implicated in social behaviors. It is divided cytoarchitectonically in an anterodorsal, anteroventral (MeAV), posterodorsal and posteroventral part, whose projections are well characterized, except for those of the tiny MeAV. Here, MeAV efferents were examined in the rat with the anterograde Phaseolus vulgaris leucoagglutinin (PHA-L) and retrograde Fluoro-Gold (FG) tracers and compared with those of other Me parts. The present PHA-L observations show that the MeAV projects profusely to itself, but its projections to other Me parts are modest. In conjunction with FG experiments, they suggest that the MeAV innervates robustly a restricted set of structures it shares with the anterodorsal and/or posteroventral Me. Its major targets are the core of the ventromedial hypothalamic nucleus (especially the dorsomedial and central parts), reached mainly via the stria terminalis, and the amygdalostriatal transition area. In addition, the MeAV innervates substantially the lateral and posterior basomedial amygdaloid nuclei and the intraamygdaloid bed nucleus of the stria terminalis. In contrast to other Me parts, it provides only modest inputs to the main and accessory olfactory systems, medial bed nucleus of the stria terminalis and reproductive hypothalamic nuclei. This anatomical framework suggests that the MeAV may play a role in orienting responses to chemosensory cues and defensive behaviors elicited by the odor of predators.

  7. Treatment Outcome-Related White Matter Differences in Veterans with Posttraumatic Stress Disorder

    PubMed Central

    Kennis, Mitzy; van Rooij, Sanne J H; Tromp, Do P M; Fox, Andrew S; Rademaker, Arthur R; Kahn, René S; Kalin, Ned H; Geuze, Elbert

    2015-01-01

    Posttraumatic stress disorder (PTSD) is a debilitating disorder that has been associated with brain abnormalities, including white matter alterations. However, little is known about the effect of treatment on these brain alterations. To investigate the course of white matter alterations in PTSD, we used a longitudinal design investigating treatment effects on white matter integrity using diffusion tensor imaging (DTI). Diffusion tensor and magnetization transfer images were obtained pre- and posttreatment from veterans with (n=39) and without PTSD (n=22). After treatment, 16 PTSD patients were remitted, and 23 had persistent PTSD based on PTSD diagnosis. The dorsal and hippocampal cingulum bundle, stria terminalis, and fornix were investigated as regions of interest. Exploratory whole-brain analyses were also performed. Groups were compared with repeated-measures ANOVA for fractional anisotropy (FA), and magnetization transfer ratio. Persistently symptomatic PTSD patients had increasing FA of the dorsal cingulum over time, and at reassessment these FA values were higher than both combat controls and the remitted PTSD group. Group-by-time interactions for FA were found in the hippocampal cingulum, fornix, and stria terminalis, posterior corona radiata, and superior longitudinal fasciculus. Our results indicate that higher FA of the dorsal cingulum bundle may be an acquired feature of persistent PTSD that develops over time. Furthermore, treatment might have differential effects on the hippocampal cingulum, fornix, stria terminalis, posterior corona radiata, and superior longitudinal fasciculus in remitted vs persistent PTSD patients. This study contributes to a better understanding of the neural underpinnings of PTSD treatment outcome. PMID:25837284

  8. Neuropeptide Y Input to the Rat Basolateral Amygdala Complex and Modulation by Conditioned Fear

    PubMed Central

    Leitermann, Randy J.; Rostkowski, Amanda B.; Urban, Janice H.

    2016-01-01

    Within the basolateral amygdaloid complex (BLA), Neuropeptide Y (NPY) buffers against protracted anxiety and fear. While the importance of NPY's actions in the BLA is well-documented, little is known about the source(s) of NPY fibers to this region. These current studies identified sources of NPY projections to the BLA using a combination of anatomical and neurochemical approaches. NPY innervation of the BLA was assessed in rats by examining the degree of NPY co-expression within interneurons or catecholaminergic fibers using somatostatin and tyrosine hydroxylase (TH) or dopamine β-hydroxylase (DβH), respectively. Numerous NPY+/somatostatin+ and NPY+/somatostatin- fibers were observed suggesting at least two populations of NPY fibers within the BLA. No co-localization was noted between NPY and TH or DβH immunoreactivities. Additionally, Fluorogold retrograde tracing with immunohistochemistry was used to identify the precise origin of NPY projections to the BLA. FG+/NPY+ cells were identified within the amygdalostriatal transition area (AStr), stria terminalis and scattered throughout the bed nucleus of the stria terminalis (BNST). The subpopulation of NPY neurons in the AStr also co-expressed somatostatin. Subjecting animals to a conditioned fear paradigm increased NPY gene expression within the AStr, whereas no changes were observed within the BLA or stria terminalis. Overall, these studies identified limbic regions associated with stress circuits providing NPY input to the BLA and demonstrated a unique NPY projection from the AStr may participate in the regulation of conditioned fear. PMID:26779765

  9. Hydrogen Inhalation Protects against Ototoxicity Induced by Intravenous Cisplatin in the Guinea Pig.

    PubMed

    Fransson, Anette E; Kisiel, Marta; Pirttilä, Kristian; Pettersson, Curt; Videhult Pierre, Pernilla; Laurell, Göran F E

    2017-01-01

    Introduction: Permanent hearing loss and tinnitus as side-effects from treatment with the anticancer drug cisplatin is a clinical problem. Ototoxicity may be reduced by co-administration of an otoprotective agent, but the results in humans have so far been modest. Aim: The present preclinical in vivo study aimed to explore the protective efficacy of hydrogen (H2) inhalation on ototoxicity induced by intravenous cisplatin. Materials and Methods: Albino guinea pigs were divided into four groups. The Cispt (n = 11) and Cispt+H2 (n = 11) groups were given intravenous cisplatin (8 mg/kg b.w., injection rate 0.2 ml/min). Immediately after, the Cispt+H2 group also received gaseous H2 (2% in air, 60 min). The H2 group (n = 5) received only H2 and the Control group (n = 7) received neither cisplatin nor H2. Ototoxicity was assessed by measuring frequency specific ABR thresholds before and 96 h after treatment, loss of inner (IHCs) and outer (OHCs) hair cells, and by performing densitometry-based immunohistochemistry analysis of cochlear synaptophysin, organic transporter 2 (OCT2), and copper transporter 1 (CTR1) at 12 and 7 mm from the round window. By utilizing metabolomics analysis of perilymph the change of metabolites in the perilymph was assessed. Results: Cisplatin induced electrophysiological threshold shifts, hair cell loss, and reduced synaptophysin immunoreactivity in the synapse area around the IHCs and OHCs. H2 inhalation mitigated all these effects. Cisplatin also reduced the OCT2 intensity in the inner and outer pillar cells and in the stria vascularis as well as the CTR1 intensity in the synapse area around the IHCs, the Deiters' cells, and the stria vascularis. H2 prevented the majority of these effects. Conclusion: H2 inhalation can reduce cisplatin-induced ototoxicity on functional, cellular, and subcellular levels. It is proposed that synaptopathy may serve as a marker for cisplatin ototoxicity. The effect of H2 on the antineoplastic activity of cisplatin

  10. Observation of permeability of blood-labyrinth barrier during cytomegalovirus-induced hearing loss.

    PubMed

    Li, Xuanyi; Shi, Xi; Qiao, Yuehua; Xu, Kailin; Zeng, Lingyu; Wang, Caiji; Xu, Zhou; Niu, Haichen

    2014-07-01

    Congenital cytomegalovirus (CMV) infection is the most common infectious cause of sensorineural hearing loss in children. This study aims to investigate the pathogenesis CMV-induced hearing loss from the view of integrity of blood-labyrinth-barrier (BLB). Newborn BALB/c mice were randomly divided into three groups (n=22, respectively): CMV group, control group and normal group. The CMV group and control group were intracerebrally injected with equal volume (15 μl) of murine CMV (MCMV; 10(4)IU/0.1 ml) and PBS, respectively, and normal group did not receive any treatment. After three weeks, auditory-evoked brainstem response was assessed, and permeability of BLB was evaluated by Evans blue method. Means between groups were compared using t-test. We observed that mice injected with MCMV had a hearing loss and it was connected with the permeability changes of BLB. Besides, using hematoxylin-eosin staining, we noticed hyperaemia in stria vascularis and spiral ligament and bleeding in scala vestibule and scala tympani in CMV group. All these data indicated the possible association between CMV-induced hearing loss and BLB dysfunction with the characteristics of inflammation. Our data provide a possible path to investigate the mechanism of CMV-induced hearing damage. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  11. Maternal Gestational Hypertension-Induced Sensitization of Angiotensin II Hypertension Is Reversed by Renal Denervation or Angiotensin-Converting Enzyme Inhibition in Rat Offspring.

    PubMed

    Xue, Baojian; Yin, Haifeng; Guo, Fang; Beltz, Terry G; Thunhorst, Robert L; Johnson, Alan Kim

    2017-04-01

    Numerous findings demonstrate that there is a strong association between maternal health during pregnancy and cardiovascular disease in adult offspring. The purpose of the present study was to test whether maternal gestational hypertension modulates brain renin-angiotensin-aldosterone system (RAAS) and proinflammatory cytokines that sensitizes angiotensin II-elicited hypertensive response in adult offspring. In addition, the role of renal nerves and the RAAS in the sensitization process was investigated. Reverse transcription polymerase chain reaction analyses of structures of the lamina terminalis and paraventricular nucleus indicated upregulation of mRNA expression of several RAAS components and proinflammatory cytokines in 10-week-old male offspring of hypertensive dams. Most of these increases were significantly inhibited by either renal denervation performed at 8 weeks of age or treatment with an angiotensin-converting enzyme inhibitor, captopril, in drinking water starting at weaning. When tested beginning at 10 weeks of age, a pressor dose of angiotensin II resulted in enhanced upregulation of mRNA expression of RAAS components and proinflammatory cytokines in the lamina terminalis and paraventricular nucleus and an augmented pressor response in male offspring of hypertensive dams. The augmented blood pressure change and most of the increases in gene expression in the offspring were abolished by either renal denervation or captopril. The results suggest that maternal hypertension during pregnancy enhances pressor responses to angiotensin II through overactivity of renal nerves and the RAAS in male offspring and that upregulation of the brain RAAS and proinflammatory cytokines in these offspring may contribute to maternal gestational hypertension-induced sensitization of the hypertensive response to angiotensin II. © 2017 American Heart Association, Inc.

  12. Neurotoxicity of ecstasy (MDMA): an overview.

    PubMed

    Sarkar, Sumit; Schmued, Larry

    2010-08-01

    "Ecstasy" (MDMA) is a powerful hallucinogenic drug which has raised concern worldwide because of its high abuse liability. A plethora of studies have demonstrated that MDMA has the potential to induce neurotoxicity both in human and laboratory animals. Although research on MDMA has been carried out by many different laboratories, the mechanism underlying MDMA induced toxicity has not been fully elucidated. MDMA has the ability to reduce serotonin levels in terminals of axons in the cortex of rats and mice. Recently we have shown that it also has the potential to produce degenerate neurons in discrete areas of the brain such as insular and parietal cortex, thalamus, tenia tecta and bed nucleus of stria terminalis (BST). Acute effects of MDMA can result in a constellation of changes including arrthymias, hypertension, hyperthermia, serotonin (5-HT) syndrome, liver problems, seizures and also long lasting neurocognitive impairments including mood disturbances. In human MDMA abusers, there is evidence for reduction of serotonergic biochemical markers. Several factors may contribute to the MDMA-induced neurotoxicity, especially hyperthermia. Other factors potentially influencing MDMA toxicity include monoamine oxidase metabolism of dopamine and serotonin, nitric oxide generation, glutamate excitotoxicity, serotonin 2A receptor agonism and the formation of MDMA neurotoxic metabolites. In this review we will cover the following topics: pharmacological mechanisms, metabolic pathways and acute effects in laboratory animals, as well as in humans, with special attention on the mechanism and pathology of MDMA induced neurotoxicity.

  13. Effects of ozone (O3) therapy on cisplatin-induced ototoxicity in rats.

    PubMed

    Koçak, Hasan Emre; Taşkın, Ümit; Aydın, Salih; Oktay, Mehmet Faruk; Altınay, Serdar; Çelik, Duygu Sultan; Yücebaş, Kadir; Altaş, Bengül

    2016-12-01

    The aim of this study is to investigate the effect of rectal ozone and intratympanic ozone therapy on cisplatin-induced ototoxicity in rats. Eighteen female Wistar albino rats were included in our study. External auditory canal and tympanic membrane examinations were normal in all rats. The rats were randomly divided into three groups. Initially, all the rats were tested with distortion product otoacoustic emissions (DPOAE), and emissions were measured normally. All rats were injected with 5-mg/kg/day cisplatin for 3 days intraperitoneally. Ototoxicy had developed in all rats, as confirmed with DPOAE after 1 week. Rectal and intratympanic ozone therapy group was Group 1. No treatment was administered for the rats in Group 2 as the control group. The rats in Group 3 were treated with rectal ozone. All the rats were tested with DPOAE under general anesthesia, and all were sacrificed for pathological examination 1 week after ozone administration. Their cochleas were removed. The outer hair cell damage and stria vascularis damage were examined. In the statistical analysis conducted, a statistically significant difference between Group 1 and Group 2 was observed in all frequencies according to the DPOAE test. In addition, between Group 2 and Group 3, a statistically significant difference was observed in the DPOAE test. However, a statistically significant difference was not observed between Group 1 and Group 3 according to the DPOAE test. According to histopathological scoring, the outer hair cell damage score was statistically significantly high in Group 2 compared with Group 1. In addition, the outer hair cell damage score was also statistically significantly high in Group 2 compared with Group 3. Outer hair cell damage scores were low in Group 1 and Group 3, but there was no statistically significant difference between these groups. There was no statistically significant difference between the groups in terms of stria vascularis damage score examinations

  14. Functional and topographic concordance of right atrial neural structures inducing sinus tachycardia.

    PubMed

    Eickholt, Christian; Mischke, Karl; Schimpf, Thomas; Knackstedt, Christian; Scherer, Kira; Pauza, Danius; Marx, Nikolaus; Shin, Dong-In; Kelm, Malte; Meyer, Christian

    2013-01-01

    Cardiorespiratory autonomic control is in tight interaction with an intracardiac neural network modulating sinus node function. To gain novel mechanistical insights and to investigate possible novel targets concerning the treatment of inadequate sinus tachycardia, we aimed to characterize functionally and topographically the right atrial neural network modulating sinus node function. In 16 sheep 3-dimensional electro-anatomical mapping of the right atrium was performed. In five animals additionally magnetically steered remote navigation was used. Selective stimulation of nerve fibers was conducted by applying high frequency (200 Hz) electrical impulses within the atrial refractory period. Histological analysis of whole heart preparations by acetylcholinesterase staining was performed and compared to the acquired neuroanatomical mapping.We found that neural stimulation in the cranial part of the right atrium, within a perimeter around the sinus node area, elicited predominantly shortening of the sinus cycle length of -20.3 ± 10.1 % (n = 80, P < 0.05). Along the course of the crista terminalis atrial premature beats (n = 117) and atrial fibrillation (n = 123) could be induced. Catheter stability was excellent during remote catheter navigation. Histological work-up (n = 4) was in accord with the distribution of neurostimulation sites. Ganglions were mainly innervated by the dorsal right-atrial subplexus, with substantial additional input from the ventral right atrial subplexus. In conclusion, our findings suggest a functional and topographic concordance of right atrial neural structures inducing sinus tachycardia. This might open up new avenues in the treatment of heart rate related disorders.

  15. Role of the copper transporter, CTR1, in platinum-induced ototoxicity.

    PubMed

    More, Swati S; Akil, Omar; Ianculescu, Alexandra G; Geier, Ethan G; Lustig, Lawrence R; Giacomini, Kathleen M

    2010-07-14

    The goal of this study was to determine the role of an influx copper transporter, CTR1, in the ototoxicity induced by cisplatin, a potent anticancer platinum analog used in the treatment of a variety of solid tumors. As determined through reverse transcriptase-PCR (RT-PCR), quantitative RT-PCR, Western blot, and immunohistochemistry, mouse CTR1 (Ctr1) was found to be abundantly expressed and highly localized at the primary sites of cisplatin toxicity in the inner ear, mainly outer hair cells (OHCs), inner hair cells, stria vascularis, spiral ganglia, and surrounding nerves in the mouse cochlea. A CTR1 substrate, copper sulfate, decreased the uptake and cytotoxicity of cisplatin in HEI-OC1, a cell line that expresses many molecular markers reminiscent of OHCs. Small interfering RNA-mediated knockdown of Ctr1 in this cell line caused a corresponding decrease in cisplatin uptake. In mice, intratympanic administration of copper sulfate 30 min before intraperitoneal administration of cisplatin was found to prevent hearing loss at click stimulus and 8, 16, and 32 kHz frequencies. To date, the utility of cisplatin remains severely limited because of its ototoxic effects. The studies described in this report suggest that cisplatin-induced ototoxicity and cochlear uptake can be modulated by administration of a CTR1 inhibitor, copper sulfate. The possibility of local administration of CTR1 inhibitors during cisplatin therapy as a means of otoprotection is thereby raised.

  16. Role of the copper transporter, CTR1, in platinum-induced ototoxicity

    PubMed Central

    More, Swati S.; Akil, Omar; Ianculescu, Alexandra G.; Geier, Ethan G.; Lustig, Lawrence R.; Giacomini, Kathleen M.

    2010-01-01

    The goal of this study was to determine the role of an influx copper transporter, CTR1, in the ototoxicity induced by cisplatin, a potent anticancer platinum analog used in the treatment of a variety of solid tumors. As determined through RT-PCR, quantitative RT-PCR (qPCR), Western blot and immunohistochemistry, mouse CTR1 (Ctr1) was found to be abundantly expressed and highly localized at the primary sites of cisplatin toxicity in the inner ear; mainly outer hair cells (OHC), inner hair cells (IHC), stria vascularis (SV), spiral ganglia (SG) and surrounding nerves in the mouse cochlea. A CTR1 substrate, copper sulfate, decreased the uptake and cytotoxicity of cisplatin in HEI-OC1, a cell line that expresses many molecular markers reminiscent of OHCs. siRNA-mediated knockdown of Ctr1 in this cell line caused a corresponding decrease in cisplatin uptake. In mice, intratympanic administration of copper sulfate 30 min before intraperitoneal administration of cisplatin was found to prevent hearing loss at click stimulus and 8, 16 and 32 kHz frequencies. To date, the utility of cisplatin remains severely limited due to its ototoxic effects. The studies described in this report suggest that cisplatin induced ototoxicity and cochlear uptake can be modulated by administration of a CTR1 inhibitor, copper sulfate. The possibility of local administration of CTR1 inhibitors during cisplatin therapy as a means of otoprotection is thereby raised. PMID:20631178

  17. The mGlu5 receptor antagonist MPEP activates specific stress-related brain regions and lacks neurotoxic effects of the NMDA receptor antagonist MK-801: significance for the use as anxiolytic/antidepressant drug.

    PubMed

    Inta, Dragos; Filipovic, Dragana; Lima-Ojeda, Juan M; Dormann, Christof; Pfeiffer, Natascha; Gasparini, Fabrizio; Gass, Peter

    2012-04-01

    Glutamatergic agents have been conceptualized as powerful, fast-acting alternatives to monoaminergic-based antidepressants. NMDA receptor antagonists such as ketamine or MK-801 are therapeutically effective, but their clinical use is hampered by psychotomimetic effects, accompanied by neurotoxicity in the retrosplenial and cingulate cortex. Antagonists of metabotropic mGlu5 receptors like MPEP elicit both robust antidepressant and anxiolytic effects; however, the underlying mechanisms are yet unknown. mGlu5 receptors closely interact with NMDA receptors, but whether MPEP induces neurotoxicity similar to NMDA receptor antagonists has not been elucidated. We show here using c-Fos brain mapping that MPEP administration results in a restricted activation of distinct stress-related brain areas, including the bed nucleus of stria terminalis (BNST), central nucleus of the amygdala, and paraventricular nucleus of the hypothalamus (PVNH), in a pattern similar to that induced by classical antidepressants and anxiolytics. Unlike the NMDA antagonist MK-801, MPEP does not injure the adult retrosplenial cortex, in which it fails to induce heat shock protein 70 (Hsp70). Moreover, MPEP does not elicit to the same extent as MK-801 apoptosis in cortical areas at perinatal stages, as revealed by caspase 3 expression. These data identify new cellular targets for the anxiolytic and antidepressant effect of MPEP, indicating also in addition that in contrast to MK-801, it lacks the cortical neurotoxicity associated with psychotomimetic side-effects. Copyright © 2012 Elsevier Ltd. All rights reserved.

  18. Effects of repeated tianeptine treatment on CRF mRNA expression in non-stressed and chronic mild stress-exposed rats.

    PubMed

    Kim, Sung-Jin; Park, Sang-Ha; Choi, Song-Hyen; Moon, Bo-Hyun; Lee, Kuem-Ju; Kang, Seung Woo; Lee, Min-Soo; Choi, Sang-Hyun; Chun, Boe-Gwun; Shin, Kyung-Ho

    2006-06-01

    Accumulating evidence suggests that dysregulation of corticotropin-releasing factor (CRF) may play a role in depression and that this dysregulation may be corrected by antidepressant drug treatment. Here, we examined whether chronic mild stress (CMS) alters CRF mRNA levels in stress-related brain areas including the bed nucleus of the stria terminalis (BNST) and the central nucleus of amygdala (CeA), and whether repeated tianeptine treatment can attenuate CMS-induced changes in CRF mRNA levels. Male rats were exposed to CMS for 19 days, and control animals were subjected to brief handling. Both groups were injected daily with tianeptine or saline. CMS significantly increased CRF mRNA levels in the dorsal BNST (dBNST), but not in other areas. Repeated tianeptine treatment prevented the CMS-induced increase in CRF mRNA levels in the dBNST, and reduced CRF mRNA levels in dBNST in non-stressed controls. Moreover, repeated tianeptine treatment significantly decreased CRF mRNA levels in the ventral BNST and CeA of non-stressed controls as well as CMS-exposed rats. These results show that CMS induces a rather selective increase of CRF mRNA in the dBNST. In addition, these results suggest that repeated tianeptine treatment diminishes the basal activity of CRF neurons and reduces their sensitivity to stress.

  19. The protective role of tetramethylpyrazine against cisplatin-induced ototoxicity.

    PubMed

    Bayram, Ali; Kaya, Altan; Akay, Ebru; Hıra, İbrahim; Özcan, İbrahim

    2017-03-01

    The aim of the present study was to investigate the protective effect of tetramethylpyrazine (TMP) on cisplatin-induced ototoxicity in rats. Forty healthy, female, 24-week-old, Sprague-Dawley rats (n = 40) were randomly assigned to four groups as follows: group one (n = 10) received intraperitoneal (i.p.) physiological saline at daily doses of 3 mg/kg for seven days; group two (n = 10) received a single dose of i.p. 15 mg/kg cisplatin; group three (n = 10) received i.p. 140 mg/kg TMP daily for seven days plus a single dose of i.p. 15 mg/kg cisplatin on the fourth day; group four (n = 10) received i.p. 140 mg/kg TMP daily for seven days. Auditory brainstem response (ABR) and distortion product otoacoustic emission (DPOAE) measurements were obtained from the animals (40 rats, 80 ears) under general anesthesia before and after drug administration. The temporal bulla of animals were bilaterally removed for immunohistopathological examination. In group two, DPOAE and ABR values were significantly deteriorated after drug administration, whereas there was no statistically significant difference between the pre- and posttreatment DPOAE and ABR values for all frequencies for groups one, three and four. The mean scores for external ciliated cells (ECCs), stria vascularis (SV) and spiral ganglion (SG) injuries in hematoxylin and eosin (H&E) staining, and also caspase-3 immunoreactivity were significantly higher in group two than in the other groups. In the present study, the protective effect of TMP on cisplatin ototoxicity was demonstrated through studies of electrophysiology and immunohistopathology. Co-administration of TMP may have potential protective effects against cisplatin-induced ototoxicity. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Analysis of behavioral constraints and the neuroanatomy of fear to the predator odor trimethylthiazoline: a model for animal phobias.

    PubMed

    Rosen, Jeffrey B; Pagani, Jerome H; Rolla, Katherine L G; Davis, Cameron

    2008-09-01

    Specific phobias, including animal phobias, are the most common anxiety disorders, and have a strong innate and genetic component. Research on the neurobiology and environmental constraints of innate fear of predators in rodents may be useful in elucidating mechanisms of animal phobias in humans. The present article reviews research on innate fear in rats to trimethylthiazoline (TMT), an odor originally isolated from fox feces. TMT induces unconditioned freezing and other defensive responses that are regulated by the dose of TMT and the shape of the testing environment. Contextual conditioning induced by TMT occurs, but is constrained by the environment. Lesion studies indicate the amygdala circuitry subserving fear conditioning is not necessary for unconditioned fear to TMT. Additionally, a medial hypothalamic defensive circuit also appears not necessary for unconditioned freezing to TMT, whereas circuits that include the medial nucleus of the amygdala and the bed nucleus of the stria terminalis are essential. The importance of these findings of innate predator odor fear in rodents to animal phobias in humans is discussed.

  1. Role of nitric oxide in brain regions related to defensive reactions.

    PubMed

    Guimarães, F S; Beijamini, V; Moreira, F A; Aguiar, D C; de Lucca, A C B

    2005-01-01

    Nitric oxide synthase (NOS) positive neurons are located in most brain areas related to defensive reactions, including the dorsolateral periaqueductal grey (dlPAG). NOS inhibitors injected into this structure induce anxiolytic-like responses whereas NO donors promote flight reactions. Intra-dlPAG administration of carboxy-PTIO, a NO scavenger, or ODQ, a soluble guanylate cyclase inhibitor, produced anxiolytic-like effects on rats exposed to the elevated plus-maze (EPM). A double-staining experiment using NADPHd histochemistry and c-Fos immunohistochemistry in rats exposed to a cat or to the EPM showed increased activation of NO producing neurons in the dlPAG, paraventricular and lateral nuclei of hypothalamus and dorsal raphe nucleus. Cat exposure also increased activation of NOS neurons in the medial amygdala, dorsal pre-mammillary nucleus and bed nucleus of stria terminalis. Local infusion into the dlPAG of a glutamate NMDA-receptor antagonist (AP7) or a benzodiazepine agonist (midazolam) completely prevented the flight reactions induced by intra-dlPAG administration of SIN-1, a NO donor. The responses were also inhibited by the 5-HT2A/C agonist DOI but not by a 5-HT1A agonist. These results suggest a modulatory role for NO on brain areas related to defensive reactions, probably by interacting with glutamate, serotonin and/or GABA-mediated neurotransmission.

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

    PubMed

    Jürgens, U; Lu, C L

    1993-06-01

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

  3. Subcortical BOLD responses during visual sexual stimulation vary as a function of implicit porn associations in women

    PubMed Central

    de Jong, Peter J.; Georgiadis, Janniko R.

    2014-01-01

    Lifetime experiences shape people’s attitudes toward sexual stimuli. Visual sexual stimulation (VSS), for instance, may be perceived as pleasurable by some, but as disgusting or ambiguous by others. VSS depicting explicit penile–vaginal penetration (PEN) is relevant in this respect, because the act of penetration is a core sexual activity. In this study, 20 women without sexual complaints participated. We used functional magnetic resonance imaging and a single-target implicit association task to investigate how brain responses to PEN were modulated by the initial associations in memory (PEN-‘hot’ vs PEN-disgust) with such hardcore pornographic stimuli. Many brain areas responded to PEN in the same way they responded to disgust stimuli, and PEN-induced brain activity was prone to modulation by subjective disgust ratings toward PEN stimuli. The relative implicit PEN-disgust (relative to PEN-‘hot’) associations exclusively modulated PEN-induced brain responses: comparatively negative (PEN-disgust) implicit associations with pornography predicted the strongest PEN-related responses in the basal forebrain (including nucleus accumbens and bed nucleus of stria terminalis), midbrain and amygdala. Since these areas are often implicated in visual sexual processing, the present findings should be taken as a warning: apparently their involvement may also indicate a negative or ambivalent attitude toward sexual stimuli. PMID:23051899

  4. Subcortical BOLD responses during visual sexual stimulation vary as a function of implicit porn associations in women.

    PubMed

    Borg, Charmaine; de Jong, Peter J; Georgiadis, Janniko R

    2014-02-01

    Lifetime experiences shape people's attitudes toward sexual stimuli. Visual sexual stimulation (VSS), for instance, may be perceived as pleasurable by some, but as disgusting or ambiguous by others. VSS depicting explicit penile-vaginal penetration (PEN) is relevant in this respect, because the act of penetration is a core sexual activity. In this study, 20 women without sexual complaints participated. We used functional magnetic resonance imaging and a single-target implicit association task to investigate how brain responses to PEN were modulated by the initial associations in memory (PEN-'hot' vs PEN-disgust) with such hardcore pornographic stimuli. Many brain areas responded to PEN in the same way they responded to disgust stimuli, and PEN-induced brain activity was prone to modulation by subjective disgust ratings toward PEN stimuli. The relative implicit PEN-disgust (relative to PEN-'hot') associations exclusively modulated PEN-induced brain responses: comparatively negative (PEN-disgust) implicit associations with pornography predicted the strongest PEN-related responses in the basal forebrain (including nucleus accumbens and bed nucleus of stria terminalis), midbrain and amygdala. Since these areas are often implicated in visual sexual processing, the present findings should be taken as a warning: apparently their involvement may also indicate a negative or ambivalent attitude toward sexual stimuli.

  5. Hypothalamic Orexin-A Neurons Are Involved in the Response of the Brain Stress System to Morphine Withdrawal

    PubMed Central

    Laorden, M. Luisa; Ferenczi, Szilamér; Pintér-Kübler, Bernadett; González-Martín, Laura L.; Lasheras, M. Carmen; Kovács, Krisztina J.; Milanés, M. Victoria; Núñez, Cristina

    2012-01-01

    Both the hypothalamus-pituitary-adrenal (HPA) axis and the extrahypothalamic brain stress system are key elements of the neural circuitry that regulates the negative states during abstinence from chronic drug exposure. Orexins have recently been hypothesized to modulate the extended amygdala and to contribute to the negative emotional state associated with dependence. This study examined the impact of chronic morphine and withdrawal on the lateral hypothalamic (LH) orexin A (OXA) gene expression and activity as well as OXA involvement in the brain stress response to morphine abstinence. Male Wistar rats received chronic morphine followed by naloxone to precipitate withdrawal. The selective OX1R antagonist SB334867 was used to examine whether orexins' activity is related to somatic symptoms of opiate withdrawal and alterations in HPA axis and extended amygdala in rats dependent on morphine. OXA mRNA was induced in the hypothalamus during morphine withdrawal, which was accompanied by activation of OXA neurons in the LH. Importantly, SB334867 attenuated the somatic symptoms of withdrawal, and reduced morphine withdrawal-induced c-Fos expression in the nucleus accumbens (NAc) shell, bed nucleus of stria terminalis, central amygdala and hypothalamic paraventricular nucleus, but did not modify the HPA axis activity. These results highlight a critical role of OXA signalling, via OX1R, in activation of brain stress system to morphine withdrawal and suggest that all orexinergic subpopulations in the lateral hypothalamic area contribute in this response. PMID:22590628

  6. Mesolimbic neuropeptide W coordinates stress responses under novel environments.

    PubMed

    Motoike, Toshiyuki; Long, Jeffrey M; Tanaka, Hirokazu; Sinton, Christopher M; Skach, Amber; Williams, S Clay; Hammer, Robert E; Sakurai, Takeshi; Yanagisawa, Masashi

    2016-05-24

    Neuropeptide B (NPB) and neuropeptide W (NPW) are endogenous neuropeptide ligands for the G protein-coupled receptors NPBWR1 and NPBWR2. Here we report that the majority of NPW neurons in the mesolimbic region possess tyrosine hydroxylase immunoreactivity, indicating that a small subset of dopaminergic neurons coexpress NPW. These NPW-containing neurons densely and exclusively innervate two limbic system nuclei in adult mouse brain: the lateral bed nucleus of the stria terminalis and the lateral part of the central amygdala nucleus (CeAL). In the CeAL of wild-type mice, restraint stress resulted in an inhibition of cellular activity, but this stress-induced inhibition was attenuated in the CeAL neurons of NPW(-/-) mice. Moreover, the response of NPW(-/-) mice to either formalin-induced pain stimuli or a live rat (i.e., a potential predator) was abnormal only when they were placed in a novel environment: The mice failed to show the normal species-specific self-protective and aversive reactions. In contrast, the behavior of NPW(-/-) mice in a habituated environment was indistinguishable from that of wild-type mice. These results indicate that the NPW/NPBWR1 system could play a critical role in the gating of stressful stimuli during exposure to novel environments.

  7. Mesolimbic neuropeptide W coordinates stress responses under novel environments

    PubMed Central

    Motoike, Toshiyuki; Long, Jeffrey M.; Tanaka, Hirokazu; Sinton, Christopher M.; Skach, Amber; Williams, S. Clay; Hammer, Robert E.; Sakurai, Takeshi; Yanagisawa, Masashi

    2016-01-01

    Neuropeptide B (NPB) and neuropeptide W (NPW) are endogenous neuropeptide ligands for the G protein-coupled receptors NPBWR1 and NPBWR2. Here we report that the majority of NPW neurons in the mesolimbic region possess tyrosine hydroxylase immunoreactivity, indicating that a small subset of dopaminergic neurons coexpress NPW. These NPW-containing neurons densely and exclusively innervate two limbic system nuclei in adult mouse brain: the lateral bed nucleus of the stria terminalis and the lateral part of the central amygdala nucleus (CeAL). In the CeAL of wild-type mice, restraint stress resulted in an inhibition of cellular activity, but this stress-induced inhibition was attenuated in the CeAL neurons of NPW−/− mice. Moreover, the response of NPW−/− mice to either formalin-induced pain stimuli or a live rat (i.e., a potential predator) was abnormal only when they were placed in a novel environment: The mice failed to show the normal species-specific self-protective and aversive reactions. In contrast, the behavior of NPW−/− mice in a habituated environment was indistinguishable from that of wild-type mice. These results indicate that the NPW/NPBWR1 system could play a critical role in the gating of stressful stimuli during exposure to novel environments. PMID:27140610

  8. Water deprivation-induced sodium appetite: humoral and cardiovascular mediators and immediate early genes.

    PubMed

    De Luca, Laurival A; Xu, Zhice; Schoorlemmer, Guus H M; Thunhorst, Robert L; Beltz, Terry G; Menani, José V; Johnson, Alan Kim

    2002-02-01

    Adult rats deprived of water for 24-30 h were allowed to rehydrate by ingesting only water for 1-2 h. Rats were then given access to both water and 1.8% NaCl. This procedure induced a sodium appetite defined by the operational criteria of a significant increase in 1.8% NaCl intake (3.8 +/- 0.8 ml/2 h; n = 6). Expression of Fos (as assessed by immunohistochemistry) was increased in the organum vasculosum of the lamina terminalis (OVLT), median preoptic nucleus (MnPO), subfornical organ (SFO), and supraoptic nucleus (SON) after water deprivation. After rehydration with water but before consumption of 1.8% NaCl, Fos expression in the SON disappeared and was partially reduced in the OVLT and MnPO. However, Fos expression did not change in the SFO. Water deprivation also 1) increased plasma renin activity (PRA), osmolality, and plasma Na+; 2) decreased blood volume; and 3) reduced total body Na+; but 4) did not alter arterial blood pressure. Rehydration with water alone caused only plasma osmolality and plasma Na+ concentration to revert to euhydrated levels. The changes in Fos expression and PRA are consistent with a proposed role for ANG II in the control of the sodium appetite produced by water deprivation followed by rehydration with only water.

  9. Water deprivation-induced sodium appetite: humoral and cardiovascular mediators and immediate early genes

    NASA Technical Reports Server (NTRS)

    De Luca, Laurival A Jr; Xu, Zhice; Schoorlemmer, Guus H M.; Thunhorst, Robert L.; Beltz, Terry G.; Menani, Jose V.; Johnson, Alan Kim

    2002-01-01

    Adult rats deprived of water for 24-30 h were allowed to rehydrate by ingesting only water for 1-2 h. Rats were then given access to both water and 1.8% NaCl. This procedure induced a sodium appetite defined by the operational criteria of a significant increase in 1.8% NaCl intake (3.8 +/- 0.8 ml/2 h; n = 6). Expression of Fos (as assessed by immunohistochemistry) was increased in the organum vasculosum of the lamina terminalis (OVLT), median preoptic nucleus (MnPO), subfornical organ (SFO), and supraoptic nucleus (SON) after water deprivation. After rehydration with water but before consumption of 1.8% NaCl, Fos expression in the SON disappeared and was partially reduced in the OVLT and MnPO. However, Fos expression did not change in the SFO. Water deprivation also 1) increased plasma renin activity (PRA), osmolality, and plasma Na+; 2) decreased blood volume; and 3) reduced total body Na+; but 4) did not alter arterial blood pressure. Rehydration with water alone caused only plasma osmolality and plasma Na+ concentration to revert to euhydrated levels. The changes in Fos expression and PRA are consistent with a proposed role for ANG II in the control of the sodium appetite produced by water deprivation followed by rehydration with only water.

  10. Water deprivation-induced sodium appetite: humoral and cardiovascular mediators and immediate early genes

    NASA Technical Reports Server (NTRS)

    De Luca, Laurival A Jr; Xu, Zhice; Schoorlemmer, Guus H M.; Thunhorst, Robert L.; Beltz, Terry G.; Menani, Jose V.; Johnson, Alan Kim

    2002-01-01

    Adult rats deprived of water for 24-30 h were allowed to rehydrate by ingesting only water for 1-2 h. Rats were then given access to both water and 1.8% NaCl. This procedure induced a sodium appetite defined by the operational criteria of a significant increase in 1.8% NaCl intake (3.8 +/- 0.8 ml/2 h; n = 6). Expression of Fos (as assessed by immunohistochemistry) was increased in the organum vasculosum of the lamina terminalis (OVLT), median preoptic nucleus (MnPO), subfornical organ (SFO), and supraoptic nucleus (SON) after water deprivation. After rehydration with water but before consumption of 1.8% NaCl, Fos expression in the SON disappeared and was partially reduced in the OVLT and MnPO. However, Fos expression did not change in the SFO. Water deprivation also 1) increased plasma renin activity (PRA), osmolality, and plasma Na+; 2) decreased blood volume; and 3) reduced total body Na+; but 4) did not alter arterial blood pressure. Rehydration with water alone caused only plasma osmolality and plasma Na+ concentration to revert to euhydrated levels. The changes in Fos expression and PRA are consistent with a proposed role for ANG II in the control of the sodium appetite produced by water deprivation followed by rehydration with only water.

  11. Origin and pharmacological response of atrial tachyarrhythmias induced by activation of mediastinal nerves in canines.

    PubMed

    Armour, J Andrew; Richer, Louis-Philippe; Pagé, Pierre; Vinet, Alain; Kus, Teresa; Vermeulen, Michel; Nadeau, Réginald; Cardinal, René

    2005-03-31

    We sought to determine the sites of origin of atrial tachyarrhythmias induced by activating mediastinal nerves, as well as the response of such arrhythmias to autonomic modulation. Under general anaesthesia, atrioventricular block was induced after thoracotomy in 19 canines. Brief trains of 5 electrical stimuli were delivered to right-sided mediastinal nerves during the atrial refractory period. Unipolar electrograms were recorded from 191 right and left atrial epicardial sites under several conditions, i.e. (i) with intact nervous systems and following (ii) acute decentralization of the intrathoracic nervous system or administration of (iii) atropine, (iv) timolol, (v) hexamethonium. Concomitant right atrial endocardial mapping was performed in 7 of these dogs. Mediastinal nerve stimulation consistently initiated bradycardia followed by atrial tachyarrhythmias. In the initial tachyarrhythmia beats, early epicardial breakthroughs were identified in the right atrial free wall (28/50 episodes) or Bachmann bundle region (22/50), which corresponded to endocardial sites of origin associated with the right atrial subsidiary pacemaker complex, i.e. the crista terminalis and dorsal locations including the right atrial aspect of the interatrial septum. Neuronally induced responses were eliminated by atropine, modified by timolol and unaffected by acute neuronal decentralization. After hexamethonium, responses to extra-pericardial but not intra-pericardial nerve stimulation were eliminated. It is concluded that concomitant activation of cholinergic and adrenergic efferent intrinsic cardiac neurons induced by right-sided efferent neuronal stimulation initiates atrial tachyarrhythmias that originate from foci anatomically related to the right atrial pacemaker complex and tissues underlying major atrial ganglionated plexuses.

  12. Bilateral Renal Denervation Ameliorates Isoproterenol-Induced Heart Failure through Downregulation of the Brain Renin-Angiotensin System and Inflammation in Rat

    PubMed Central

    Li, Jian-Dong; Cheng, Ai-Yuan; Huo, Yan-Li; Fan, Jie; Zhang, Yu-Ping; Fang, Zhi-Qin; Sun, Hong-Sheng; Peng, Wei; Zhang, Jin-Shun

    2016-01-01

    Heart failure (HF) is characterized by cardiac dysfunction along with autonomic unbalance that is associated with increased renin-angiotensin system (RAS) activity and elevated levels of proinflammatory cytokines (PICs). Renal denervation (RD) has been shown to improve cardiac function in HF, but the protective mechanisms remain unclear. The present study tested the hypothesis that RD ameliorates isoproterenol- (ISO-) induced HF through regulation of brain RAS and PICs. Chronic ISO infusion resulted in remarked decrease in blood pressure (BP) and increase in heart rate and cardiac dysfunction, which was accompanied by increased BP variability and decreased baroreflex sensitivity and HR variability. Most of these adverse effects of ISO on cardiac and autonomic function were reversed by RD. Furthermore, ISO upregulated mRNA and protein expressions of several components of the RAS and PICs in the lamina terminalis and hypothalamic paraventricular nucleus, two forebrain nuclei involved in cardiovascular regulations. RD significantly inhibited the upregulation of these genes. Either intracerebroventricular AT1-R antagonist, irbesartan, or TNF-α inhibitor, etanercept, mimicked the beneficial actions of RD in the ISO-induced HF. The results suggest that the RD restores autonomic balance and ameliorates ISO-induced HF and that the downregulated RAS and PICs in the brain contribute to these beneficial effects of RD. PMID:27746855

  13. Microbial Neuraminidase Induces a Moderate and Transient Myelin Vacuolation Independent of Complement System Activation.

    PubMed

    Granados-Durán, Pablo; López-Ávalos, María Dolores; Cifuentes, Manuel; Pérez-Martín, Margarita; Fernández-Arjona, María Del Mar; Hughes, Timothy R; Johnson, Krista; Morgan, B Paul; Fernández-Llebrez, Pedro; Grondona, Jesús M

    2017-01-01

    Some central nervous system pathogens express neuraminidase (NA) on their surfaces. In the rat brain, a single intracerebroventricular (ICV) injection of NA induces myelin vacuolation in axonal tracts. Here, we explore the nature, the time course, and the role of the complement system in this damage. The spatiotemporal analysis of myelin vacuolation was performed by optical and electron microscopy. Myelin basic protein-positive area and oligodendrocyte transcription factor (Olig2)-positive cells were quantified in the damaged bundles. Neuronal death in the affected axonal tracts was assessed by Fluoro-Jade B and anti-caspase-3 staining. To evaluate the role of the complement, membrane attack complex (MAC) deposition on damaged bundles was analyzed using anti-C5b9. Rats ICV injected with the anaphylatoxin C5a were studied for myelin damage. In addition, NA-induced vacuolation was studied in rats with different degrees of complement inhibition: normal rats treated with anti-C5-blocking antibody and C6-deficient rats. The stria medullaris, the optic chiasm, and the fimbria were the most consistently damaged axonal tracts. Vacuolation peaked 7 days after NA injection and reverted by day 15. Olig2+ cell number in the damaged tracts was unaltered, and neurodegeneration associated with myelin alterations was not detected. MAC was absent on damaged axonal tracts, as revealed by C5b9 immunostaining. Rats ICV injected with the anaphylatoxin C5a displayed no myelin injury. When the complement system was experimentally or constitutively inhibited, NA-induced myelin vacuolation was similar to that observed in normal rats. Microbial NA induces a moderate and transient myelin vacuolation that is not caused either by neuroinflammation or complement system activation.

  14. Reward deficiency and anti-reward in pain chronification.

    PubMed

    Borsook, D; Linnman, C; Faria, V; Strassman, A M; Becerra, L; Elman, I

    2016-09-01

    Converging lines of evidence suggest that the pathophysiology of pain is mediated to a substantial degree via allostatic neuroadaptations in reward- and stress-related brain circuits. Thus, reward deficiency (RD) represents a within-system neuroadaptation to pain-induced protracted activation of the reward circuits that leads to depletion-like hypodopaminergia, clinically manifested anhedonia, and diminished motivation for natural reinforcers. Anti-reward (AR) conversely pertains to a between-systems neuroadaptation involving over-recruitment of key limbic structures (e.g., the central and basolateral amygdala nuclei, the bed nucleus of the stria terminalis, the lateral tegmental noradrenergic nuclei of the brain stem, the hippocampus and the habenula) responsible for massive outpouring of stressogenic neurochemicals (e.g., norepinephrine, corticotropin releasing factor, vasopressin, hypocretin, and substance P) giving rise to such negative affective states as anxiety, fear and depression. We propose here the Combined Reward deficiency and Anti-reward Model (CReAM), in which biopsychosocial variables modulating brain reward, motivation and stress functions can interact in a 'downward spiral' fashion to exacerbate the intensity, chronicity and comorbidities of chronic pain syndromes (i.e., pain chronification). Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  15. AgRP Neurons Control Systemic Insulin Sensitivity via Myostatin Expression in Brown Adipose Tissue.

    PubMed

    Steculorum, Sophie M; Ruud, Johan; Karakasilioti, Ismene; Backes, Heiko; Engström Ruud, Linda; Timper, Katharina; Hess, Martin E; Tsaousidou, Eva; Mauer, Jan; Vogt, Merly C; Paeger, Lars; Bremser, Stephan; Klein, Andreas C; Morgan, Donald A; Frommolt, Peter; Brinkkötter, Paul T; Hammerschmidt, Philipp; Benzing, Thomas; Rahmouni, Kamal; Wunderlich, F Thomas; Kloppenburg, Peter; Brüning, Jens C

    2016-03-24

    Activation of Agouti-related peptide (AgRP) neurons potently promotes feeding, and chronically altering their activity also affects peripheral glucose homeostasis. We demonstrate that acute activation of AgRP neurons causes insulin resistance through impairment of insulin-stimulated glucose uptake into brown adipose tissue (BAT). AgRP neuron activation acutely reprograms gene expression in BAT toward a myogenic signature, including increased expression of myostatin. Interference with myostatin activity improves insulin sensitivity that was impaired by AgRP neurons activation. Optogenetic circuitry mapping reveals that feeding and insulin sensitivity are controlled by both distinct and overlapping projections. Stimulation of AgRP → LHA projections impairs insulin sensitivity and promotes feeding while activation of AgRP → anterior bed nucleus of the stria terminalis (aBNST)vl projections, distinct from AgRP → aBNSTdm projections controlling feeding, mediate the effect of AgRP neuron activation on BAT-myostatin expression and insulin sensitivity. Collectively, our results suggest that AgRP neurons in mice induce not only eating, but also insulin resistance by stimulating expression of muscle-related genes in BAT, revealing a mechanism by which these neurons rapidly coordinate hunger states with glucose homeostasis.

  16. Revisiting the neural role of estrogen receptor beta in male sexual behavior by conditional mutagenesis.

    PubMed

    Naulé, Lydie; Marie-Luce, Clarisse; Parmentier, Caroline; Martini, Mariangela; Albac, Christelle; Trouillet, Anne-Charlotte; Keller, Matthieu; Hardin-Pouzet, Hélène; Mhaouty-Kodja, Sakina

    2016-04-01

    Estradiol derived from neural aromatization of gonadal testosterone plays a key role in the perinatal organization of the neural circuitry underlying male sexual behavior. The aim of this study was to investigate the contribution of neural estrogen receptor (ER) β in estradiol-induced effects without interfering with its peripheral functions. For this purpose, male mice lacking ERβ in the nervous system were generated. Analyses of males in two consecutive tests with a time interval of two weeks showed an effect of experience, but not of genotype, on the latencies to the first mount, intromission, pelvic thrusting and ejaculation. Similarly, there was an effect of experience, but not of genotype, on the number of thrusts and mating length. Neural ERβ deletion had no effect on the ability of males to adopt a lordosis posture in response to male mounts, after castration and priming with estradiol and progesterone. Indeed, only low percentages of both genotypes exhibited a low lordosis quotient. It also did not affect their olfactory preference. Quantification of tyrosine hydroxylase- and kisspeptin-immunoreactive neurons in the preoptic area showed unaffected sexual dimorphism of both populations in mutants. By contrast, the number of androgen receptor- and ERα-immunoreactive cells was significantly increased in the bed nucleus of stria terminalis of mutant males. These data show that neural ERβ does not play a crucial role in the organization and activation of the neural circuitry underlying male sexual behavior. These discrepancies with the phenotype of global ERβ knockout models are discussed.

  17. Serotonin engages an anxiety and fear-promoting circuit in the extended amygdala

    PubMed Central

    D’Agostino, Giuseppe; Halladay, Lindsay R.; Hardaway, J. Andrew; DiBerto, Jeffrey F.; Navarro, Montserrat; Burnham, Nathan; Cristiano, Claudia; Dorrier, Cayce E.; Tipton, Gregory J.; Ramakrishnan, Charu; Kozicz, Tamas; Deisseroth, Karl; Thiele, Todd E.; McElligott, Zoe A.; Holmes, Andrew; Heisler, Lora K.; Kash, Thomas L.

    2016-01-01

    Summary paragraph Serotonin (5-hydroxytryptamine; 5-HT) is a neurotransmitter that has an essential role in the regulation of emotion. The precise circuits through which aversive states are orchestrated by 5-HT, however, have not yet been defined. Here we show that 5-HT from the dorsal raphe nucleus (5-HTDRN) enhances fear and anxiety and activates a subpopulation of corticotropin-releasing factor (CRF) neurons in the bed nucleus of the stria terminalis (CRFBNST). Specifically, 5-HTDRN projections to the BNST, via actions at 5-HT2C receptors (5-HT2CRs), engage a CRFBNST inhibitory microcircuit that silences anxiolytic BNST outputs to the ventral tegmental area (VTA) and lateral hypothalamus (LH). Further, we demonstrate that this CRFBNST inhibitory circuit underlies aversive behavior following acute exposure to selective serotonin reuptake inhibitors (SSRIs). This early aversive effect is mediated via the corticotrophin releasing factor type 1 receptor (CRF1R) given that CRF1R antagonism is sufficient to prevent acute SSRI-induced enhancements in aversive learning. These results reveal an essential 5-HTDRN→CRFBNST circuit governing fear and anxiety and provide a potential mechanistic explanation for the clinical observation of early adverse events to SSRI treatment in some patients with anxiety disorders1,2. PMID:27556938

  18. Physical interaction is not necessary for the induction of housing-type social buffering of conditioned hyperthermia in male rats.

    PubMed

    Kiyokawa, Yasushi; Kodama, Yuka; Takeuchi, Yukari; Mori, Yuji

    2013-11-01

    In social animals, housing with conspecific animals after a stressful event attenuates the subsequent adverse outcomes due to the event, and this has been called housing-type social buffering. We have previously found that housing-type social buffering attenuates the enhancement of hyperthermia and Fos expression in the paraventricular nucleus of the hypothalamus that occurs in response to an aversive conditioned stimulus in male rats. Here, we analyzed the role of physical interactions during social housing in the induction of housing-type social buffering. When a fear-conditioned subject was alone after the conditioning and then exposed to the conditioned stimulus, it showed behavioral, autonomic, and neural stress responses. However, social housing, during which physical interactions were prevented by wire mesh, attenuated these autonomic and neural stress responses, as has been seen in previous studies. These results suggested that physical interaction was not necessary for the induction of housing-type social buffering. With this social cohabitation model, we then found that social cohabitation increased Fos expression in the posterior complex of the anterior olfactory nucleus of the fear-conditioned subject. Social cohabitation also increased Fos expression in 11 brain regions, including the prefrontal cortex, the nucleus accumbens, the bed nucleus of the stria terminalis, and the medial, lateral, basal, and cortical amygdala. These results provide information about the neural mechanisms that induce housing-type social buffering.

  19. Serotonin engages an anxiety and fear-promoting circuit in the extended amygdala.

    PubMed

    Marcinkiewcz, Catherine A; Mazzone, Christopher M; D'Agostino, Giuseppe; Halladay, Lindsay R; Hardaway, J Andrew; DiBerto, Jeffrey F; Navarro, Montserrat; Burnham, Nathan; Cristiano, Claudia; Dorrier, Cayce E; Tipton, Gregory J; Ramakrishnan, Charu; Kozicz, Tamas; Deisseroth, Karl; Thiele, Todd E; McElligott, Zoe A; Holmes, Andrew; Heisler, Lora K; Kash, Thomas L

    2016-09-01

    Serotonin (also known as 5-hydroxytryptamine (5-HT)) is a neurotransmitter that has an essential role in the regulation of emotion. However, the precise circuits have not yet been defined through which aversive states are orchestrated by 5-HT. Here we show that 5-HT from the dorsal raphe nucleus (5-HT(DRN)) enhances fear and anxiety and activates a subpopulation of corticotropin-releasing factor (CRF) neurons in the bed nucleus of the stria terminalis (CRF(BNST)) in mice. Specifically, 5-HT(DRN) projections to the BNST, via actions at 5-HT2C receptors (5-HT2CRs), engage a CRF(BNST) inhibitory microcircuit that silences anxiolytic BNST outputs to the ventral tegmental area and lateral hypothalamus. Furthermore, we demonstrate that this CRF(BNST) inhibitory circuit underlies aversive behaviour following acute exposure to selective serotonin reuptake inhibitors (SSRIs). This early aversive effect is mediated via the corticotrophin-releasing factor type 1 receptor (CRF1R, also known as CRHR1), given that CRF1R antagonism is sufficient to prevent acute SSRI-induced enhancements in aversive learning. These results reveal an essential 5-HT(DRN)→CRF(BNST) circuit governing fear and anxiety, and provide a potential mechanistic explanation for the clinical observation of early adverse events to SSRI treatment in some patients with anxiety disorders.

  20. Amphetamine treatment affects the extra-hypothalamic vasopressinergic system in a sex- and nucleus-dependent manner.

    PubMed

    Ahumada, C; Bahamondes, C; Cerda, C A; Silva, R A; Cruz, G; Moya, P R; Sotomayor-Zárate, R; Renard, G M

    2017-04-01

    The lateral septum (LS), a brain structure implicated in addictive behaviours, regulates the activation of dopaminergic neurones in the ventral tegmental area. Vasopressinergic projections from the extended amygdala to the LS, which are sexually dimorphic, could be responsible for the vulnerability to addiction in a sex-dependent manner. The present study aimed to investigate the modulatory effects of amphetamine (AMPH) on the expression of vasopressin (AVP) in the vasopressinergic extra-hypothalamic system in sensitised male and female rats. Adult male and female Sprague-Dawley rats underwent an AMPH-locomotor sensitisation protocol. Acute AMPH increased AVP mRNA expression in the medial amygdala (MeA), whereas AMPH-induced sensitisation increased AVP mRNA expression in the bed nucleus of the stria terminalis (BNST) only in females. Interestingly, the increase in AVP expression in BNST was higher in oestrus females compared to dioestrus females and acute AMPH resulted in a decrease in AVP levels in the LS, only in males. Thus, there are complex and region-specific interactions between AMPH and the extra-hypothalamic vasopressinergic system in the brain, underlying possible alterations in different behaviours caused by acute and chronic AMPH exposure. © 2017 British Society for Neuroendocrinology.

  1. Social defeat stress potentiates thermal sensitivity in operant models of pain processing

    PubMed Central

    Marcinkiewcz, Catherine A.; Green, Megan K.; Devine, Darragh P.; Duarte, Peter; Vierck, Charles J.; Yezierski, Robert P.

    2013-01-01

    Higher-order processing of nociceptive input is distributed in corticolimbic regions of the brain, including the anterior cingulate, parieto-insular and prefrontal cortices, as well as subcortical structures such as the bed nucleus of stria terminalis and amygdala. In addition to their role in pain processing, these regions encode or modulate emotional, motivational and sensory responses to stress. Thus, pain and stress pathways in the brain intersect at cortical and subcortical forebrain structures. Accordingly, previous work has shown that acute restraint stress in female rats induces heat hyperalgesia in a forebrain-dependent operant test of thermal escape. In the present study, we investigated the effects of social defeat stress in male rats on the operant escape task, as well as in a test of nociceptive thermal preference. After establishing baseline behaviors in these tests, separate groups of rats were socially defeated by dominant “resident” male rats. They were tested for thermal preference after 5 successive social defeat sessions. Escape from cold, heat and a neutral warm temperature also was evaluated after social defeat. Defeated rats exhibited a significant increase in cold preference after social defeat compared to the baseline. In the escape task, the rats exhibited increased escape from warm and nociceptive cold and heat temperatures. Thus, chronic social stress produces hyperalgesia for both hot and cold stimuli in male rats, suggesting a mutually facilitatory cross-regulation between central pathways regulating stress and pain. PMID:19059227

  2. Orexin administration to mice that underwent chronic stress produces bimodal effects on emotion-related behaviors.

    PubMed

    Chung, Hye-Seung; Kim, Jae-Gon; Kim, Jae-Won; Kim, Hyung-Wook; Yoon, Bong-June

    2014-11-01

    Orexin plays diverse roles in regulating behaviors, such as sleep and wake, reward processing, arousal, and stress and anxiety. The orexin system may accomplish these multiple tasks through its complex innervations throughout the brain. The emerging evidence indicates a role of orexin in emotional behaviors; however, most of the previous studies have investigated the function of orexin in naïve animals. Here, we examined a functional role of orexin in mice that had been exposed to repeated stress. Chronic social defeat stress produced differential social interaction behaviors in mice (susceptible versus resilient) and these two groups of mice displayed different levels of prepro-orexin in the hypothalamus. Exogenously added orexin A to the brain induced an antidepressant-like effect in only the susceptible mice but not in the resilient mice. In contrast, orexin A and orexin B infused together produced an anxiogenic effect in only the resilient mice and not in the susceptible mice. Furthermore, we found that the antidepressant-like effect of orexin A is mediated by the bed nucleus of the stria terminalis (BNST) after exposure to chronic restraint stress. These findings reveal a bimodal effect of the orexin system in regulating emotional behavior that depends on stress susceptibility.

  3. Functional identification of a neurocircuit regulating blood glucose

    PubMed Central

    Meek, Thomas H.; Nelson, Jarrell T.; Matsen, Miles E.; Dorfman, Mauricio D.; Guyenet, Stephan J.; Damian, Vincent; Allison, Margaret B.; Scarlett, Jarrad M.; Nguyen, Hong T.; Thaler, Joshua P.; Olson, David P.; Myers, Martin G.; Schwartz, Michael W.; Morton, Gregory J.

    2016-01-01

    Previous studies implicate the hypothalamic ventromedial nucleus (VMN) in glycemic control. Here, we report that selective inhibition of the subset of VMN neurons that express the transcription factor steroidogenic-factor 1 (VMNSF1 neurons) blocks recovery from insulin-induced hypoglycemia whereas, conversely, activation of VMNSF1 neurons causes diabetes-range hyperglycemia. Moreover, this hyperglycemic response is reproduced by selective activation of VMNSF1 fibers projecting to the anterior bed nucleus of the stria terminalis (aBNST), but not to other brain areas innervated by VMNSF1 neurons. We also report that neurons in the lateral parabrachial nucleus (LPBN), a brain area that is also implicated in the response to hypoglycemia, make synaptic connections with the specific subset of glucoregulatory VMNSF1 neurons that project to the aBNST. These results collectively establish a physiological role in glucose homeostasis for VMNSF1 neurons and suggest that these neurons are part of an ascending glucoregulatory LPBN→VMNSF1→aBNST neurocircuit. PMID:27001850

  4. Dopamine D2 receptors gate generalization of conditioned threat responses through mTORC1 signaling in the extended amygdala

    PubMed Central

    De Bundel, Dimitri; Zussy, Charleine; Espallergues, Julie; Gerfen, Charles R; Girault, Jean-Antoine; Valjent, Emmanuel

    2016-01-01

    Overgeneralization of conditioned threat responses is a robust clinical marker of anxiety disorders. In overgeneralization, responses that are appropriate to threat-predicting cues are evoked by perceptually similar safety-predicting cues. Inappropriate learning of conditioned threat responses may thus form an etiological basis for anxiety disorders. The role of dopamine (DA) in memory encoding is well established. Indeed by signaling salience and valence, DA is thought to facilitate discriminative learning between stimuli representing safety or threat. However, the neuroanatomical and biochemical substrates through which DA modulates overgeneralization of threat responses remain poorly understood. Here we report that the modulation of DA D2 receptor (D2R) signaling bidirectionally regulates the consolidation of fear responses. While the blockade of D2R induces generalized fear responses, its stimulation facilitates discriminative learning between stimuli representing safety or threat. Moreover, we show that controlled fear generalization requires the coordinated activation of D2R in the bed nucleus of the stria terminalis (BNST) and the central amygdala (CEA). Finally, we identify the mTORC1 cascade activation as an important molecular event by which D2R mediates its effects. These data reveal that D2R signaling in the extended amygdala constitutes an important checkpoint through which DA participates in the control of threat processing and the emergence of overgeneralized fear responses. PMID:26782052

  5. CART neuropeptide modulates the extended amygdalar CeA-vBNST circuit to gate expression of innate fear.

    PubMed

    Rale, Abhishek; Shendye, Ninad; Bodas, Devika S; Subhedar, Nishikant; Ghose, Aurnab

    2017-11-01

    Innate fear is critical for the survival of animals and is under tight homeostatic control. Deregulation of innate fear processing is thought to underlie pathological phenotypes including, phobias and panic disorders. Although central processing of conditioned fear has been extensively studied, the circuitry and regulatory mechanisms subserving innate fear remain relatively poorly defined. In this study, we identify cocaine- and amphetamine-regulated transcript (CART) neuropeptide signaling in the central amygdala (CeA) - ventral bed nucleus of stria terminalis (vBNST) axis as a key modulator of innate fear expression. 2,4,5-trimethyl-3-thiazoline (TMT), a component of fox faeces, induces a freezing response whose intensity is regulated by the extent of CART-signaling in the CeA neurons. Abrogation of CART activity in the CeA attenuates the freezing response and reduces activation of vBNST neurons. Conversely, ectopically elevated CART signaling in the CeA potentiates the fear response concomitant with enhanced vBNST activation. We show that local levels of CART signaling modulate the activation of CeA neurons by NMDA receptor-mediated glutamatergic inputs, in turn, regulating activity in the vBNST. This study identifies the extended amygdalar CeA-vBNST circuit as a CART modulated axis encoding innate fear. CART signaling regulates the glutamatergic excitatory drive in the CeA-vBNST circuit, in turn, gating the expression of the freezing response to TMT. Copyright © 2017 Elsevier Ltd. All rights reserved.

  6. Quantitative autoradiography of /sup 3/H-nomifensine binding sites in rat brain

    SciTech Connect

    Scatton, B.; Dubois, A.; Dubocovich, M.L.; Zahniser, N.R.; Fage, D.

    1985-03-04

    The distribution of /sup 3/H-nomifensine binding sites in the rat brain has been studied by quantitative autoradiography. The binding of /sup 3/H-nomifensine to caudate putamen sections was saturable, specific, of a highly affinity (Kd = 56 nM) and sodium-dependent. The dopamine uptake inhibitors benztropine, nomifensine, cocaine, bupropion and amfonelic acid were the most potent competitors of /sup 3/H-nomifensine binding to striatal sections. The highest levels of (benztropine-displaceable) /sup 3/H-nomifensine binding sites were found in the caudate-putamen, the olfactory tubercle and the nucleus accumbens. 6-Hydroxy-dopamine-induced lesion of the ascending dopaminergic bundle resulted in a marked decrease in the /sup 3/H-ligand binding in these areas. Moderately high concentrations of the /sup 3/H-ligand were observed in the bed nucleus of the stria terminalis, the anteroventral thalamic nucleus, the cingulate cortex, the lateral septum, the hippocampus, the amygdala, the zona incerta and some hypothalamic nuclei. There were low levels of binding sites in the habenula, the dorsolateral geniculate body, the substantia nigra, the ventral tegmental area and the periaqueductal gray matter. These autoradiographic data are consistent with the hypothesis that /sup 3/H-nomifensine binds primarily to the presynaptic uptake site for dopamine but also labels the norepinephrine uptake site. 33 references, 2 figures, 1 table.

  7. Pro-arrhythmogenic effects of atrial fibrillation-induced electrical remodelling: insights from the three-dimensional virtual human atria.

    PubMed

    Colman, Michael A; Aslanidi, Oleg V; Kharche, Sanjay; Boyett, Mark R; Garratt, Clifford; Hancox, Jules C; Zhang, Henggui

    2013-09-01

    Chronic atrial fibrillation (AF) is associated with structural and electrical remodelling in the atria, which are associated with a high recurrence of AF. Through biophysically detailed computer modelling, this study investigated mechanisms by which AF-induced electrical remodelling promotes and perpetuates AF. A family of Courtemanche-Ramirez-Nattel variant models of human atrial cell action potentials (APs), taking into account of intrinsic atrial electrophysiological properties, was modified to incorporate various experimental data sets on AF-induced changes of major ionic channel currents (ICaL, IKur, Ito, IK1, IKs, INaCa) and on intracellular Ca(2+) handling. The single cell models for control and AF-remodelled conditions were incorporated into multicellular three-dimensional (3D) atrial tissue models. Effects of the AF-induced electrical remodelling were quantified as the changes of AP profile, AP duration (APD) and its dispersion across the atria, and the vulnerability of atrial tissue to the initiation of re-entry. The dynamic behaviour of re-entrant excitation waves in the 3D models was characterised. In our simulations, AF-induced electrical remodelling abbreviated atrial APD non-uniformly across the atria; this resulted in relatively short APDs co-existing with marked regional differences in the APD at junctions of the crista terminalis/pectinate muscle, pulmonary veins/left atrium. As a result, the measured tissue vulnerability to re-entry initiation at these tissue junctions was increased. The AF-induced electrical remodelling also stabilized and accelerated re-entrant excitation waves, leading to rapid and sustained re-entry. Under the AF-remodelled condition, re-entrant scroll waves in the 3D model degenerated into persistent and erratic wavelets, leading to fibrillation. In conclusion, realistic 3D atrial tissue models indicate that AF-induced electrical remodelling produces regionally heterogeneous and shortened APD; these respectively facilitate

  8. Chemotherapy-induced anorexia is accompanied by activation of brain pathways signaling dehydration.

    PubMed

    Sinno, Maria Hamze; Coquerel, Quentin; Boukhettala, Nabile; Coëffier, Moïse; Gallas, Syrine; Terashi, Mutsumi; Ibrahim, Ayman; Breuillé, Denis; Déchelotte, Pierre; Fetissov, Sergueï O

    2010-12-02

    Cancer chemotherapy is accompanied by anorexia and mucositis. To clarify the mechanisms of chemotherapy-induced anorexia, we studied the expression of c-fos and appetite-regulating neuropeptidergic and inflammatory mediators in the hypothalamus of rats treated with methotrexate (MTX). Sprague-Dawley rats received MTX (2.5mg/kg, subcutaneously) on three consecutive days and were compared with ad libitum- and pair-fed control rats five days after the first injection. MTX administration inhibited food and water intake and induced lean and fat mass losses. MTX also induced mucositis and diarrhea without changes in plasma osmolality. Pair-fed rats lost a similar amount of body weight but had no mucositis or diarrhea. Increased number of c-fos positive hypothalamic vasopressin neurosecretory neurons as well as numerous c-fos positive cells in the subfornical organ and in the organum vasculosum of the lamina terminalis were found in MTX-treated as compared to control or pair-fed rats. In both MTX and pair-fed rats, a decrease of hypothalamic proopiomelanocortin mRNA expression and low plasma levels of interleukin-1β (IL-1β) were found reflecting probably the energy deficit. No significant changes of IL-1β mRNA expression and intensity of microglial staining in the hypothalamus were found in MTX-treated rats. The pattern of c-fos expression in the hypothalamus during MTX treatment is similar to that seen with systemic dehydration, which is known to cause anorexia. No evidence of inflammatory origin of anorexia was found, suggesting that chemotherapy accompanied by mucositis and diarrhea may cause anorexia associated with systemic dehydration. Copyright © 2010 Elsevier Inc. All rights reserved.

  9. Connectivity between the superior colliculus and the amygdala in humans and macaque monkeys: virtual dissection with probabilistic DTI tractography

    PubMed Central

    Koller, Kristin; Bultitude, Janet H.; Mullins, Paul; Ward, Robert; Mitchell, Anna S.; Bell, Andrew H.

    2015-01-01

    It has been suggested that some cortically blind patients can process the emotional valence of visual stimuli via a fast, subcortical pathway from the superior colliculus (SC) that reaches the amygdala via the pulvinar. We provide in vivo evidence for connectivity between the SC and the amygdala via the pulvinar in both humans and rhesus macaques. Probabilistic diffusion tensor imaging tractography revealed a streamlined path that passes dorsolaterally through the pulvinar before arcing rostrally to traverse above the temporal horn of the lateral ventricle and connect to the lateral amygdala. To obviate artifactual connectivity with crossing fibers of the stria terminalis, the stria was also dissected. The putative streamline between the SC and amygdala traverses above the temporal horn dorsal to the stria terminalis and is positioned medial to it in humans and lateral to it in monkeys. The topography of the streamline was examined in relation to lesion anatomy in five patients who had previously participated in behavioral experiments studying the processing of emotionally valenced visual stimuli. The pulvinar lesion interrupted the streamline in two patients who had exhibited contralesional processing deficits and spared the streamline in three patients who had no deficit. Although not definitive, this evidence supports the existence of a subcortical pathway linking the SC with the amygdala in primates. It also provides a necessary bridge between behavioral data obtained in future studies of neurological patients, and any forthcoming evidence from more invasive techniques, such as anatomical tracing studies and electrophysiological investigations only possible in nonhuman species. PMID:26224780

  10. Murine CMV-Induced Hearing Loss Is Associated with Inner Ear Inflammation and Loss of Spiral Ganglia Neurons

    PubMed Central

    Golemac, Mijo; Pugel, Ester Pernjak; Jonjic, Stipan; Britt, William J.

    2015-01-01

    Congenital human cytomegalovirus (HCMV) occurs in 0.5–1% of live births and approximately 10% of infected infants develop hearing loss. The mechanism(s) of hearing loss remain unknown. We developed a murine model of CMV induced hearing loss in which murine cytomegalovirus (MCMV) infection of newborn mice leads to hematogenous spread of virus to the inner ear, induction of inflammatory responses, and hearing loss. Characteristics of the hearing loss described in infants with congenital HCMV infection were observed including, delayed onset, progressive hearing loss, and unilateral hearing loss in this model and, these characteristics were viral inoculum dependent. Viral antigens were present in the inner ear as were CD3+ mononuclear cells in the spiral ganglion and stria vascularis. Spiral ganglion neuron density was decreased after infection, thus providing a mechanism for hearing loss. The lack of significant inner ear histopathology and persistence of inflammation in cochlea of mice with hearing loss raised the possibility that inflammation was a major component of the mechanism(s) of hearing loss in MCMV infected mice. PMID:25875183

  11. Mitochondrial DNA common deletion increases susceptibility to noise-induced hearing loss in a mimetic aging rat model.

    PubMed

    Yu, Jintao; Wang, Yanjun; Liu, Peng; Li, Qingyu; Sun, Yu; Kong, Weijia

    2014-10-24

    Noise-induced hearing loss (NIHL) is an important occupational health hazard. However, susceptibility to NIHL remains poorly understood. The present study was designed to investigate whether mitochondrial DNA common deletion (CD) increases the susceptibility of individuals to NIHL. A mimetic aging rat model harboring increased CD in the inner ear was established by chronic d-galactose administration, and the synergic effect of CD and noise on hearing sensitivity was assessed. We determined that although developed the same magnitude of temporary threshold shifts and hair cell loss, the d-galactose treated rats with increased CD in the inner ear exhibited a longer hearing recovery process and experienced higher permanent hearing threshold shifts at high frequencies than the saline-treated control rats. Greater supporting cell damage and stria vascularis ultrastructural changes were observed in d-galactose treated rats three weeks after recovery. The results suggested that the elevated CD in the inner ear could increase an individual's susceptibility to NIHL, which likely through a reduction in the self-repairing capability within the cochlea after acoustic injury.

  12. Murine CMV-induced hearing loss is associated with inner ear inflammation and loss of spiral ganglia neurons.

    PubMed

    Bradford, Russell D; Yoo, Young-Gun; Golemac, Mijo; Pugel, Ester Pernjak; Jonjic, Stipan; Britt, William J

    2015-04-01

    Congenital human cytomegalovirus (HCMV) occurs in 0.5-1% of live births and approximately 10% of infected infants develop hearing loss. The mechanism(s) of hearing loss remain unknown. We developed a murine model of CMV induced hearing loss in which murine cytomegalovirus (MCMV) infection of newborn mice leads to hematogenous spread of virus to the inner ear, induction of inflammatory responses, and hearing loss. Characteristics of the hearing loss described in infants with congenital HCMV infection were observed including, delayed onset, progressive hearing loss, and unilateral hearing loss in this model and, these characteristics were viral inoculum dependent. Viral antigens were present in the inner ear as were CD(3+) mononuclear cells in the spiral ganglion and stria vascularis. Spiral ganglion neuron density was decreased after infection, thus providing a mechanism for hearing loss. The lack of significant inner ear histopathology and persistence of inflammation in cochlea of mice with hearing loss raised the possibility that inflammation was a major component of the mechanism(s) of hearing loss in MCMV infected mice.

  13. Ethanol-seeking behavior is expressed directly through an extended amygdala to midbrain neural circuit.

    PubMed

    Pina, Melanie M; Cunningham, Christopher L

    2017-01-01

    Abstinent alcohol-dependent individuals experience an enduring sensitivity to cue-induced craving and relapse to drinking. There is considerable evidence indicating that structures within the midbrain and extended amygdala are involved in this process. Individually, the ventral tegmental area (VTA) and the bed nucleus of the stria terminalis (BNST) have been shown to modulate cue-induced ethanol-seeking behavior. It is hypothesized that cue-induced seeking is communicated through a direct projection from the BNST to VTA. In the current experiments, an intersectional viral strategy was used in DBA/2J mice to selectively target and inhibit BNST projections to the VTA during a test of ethanol conditioned place preference (CPP). Inhibitory designer receptors exclusively activated by designer drugs (hM4Di DREADDs) were expressed in VTA-projecting BNST (BNST-VTA) cells by infusing a retrograde herpes-simplex virus encoding cre recombinase (HSV-Cre) into VTA and a cre-inducible adeno-associated virus encoding hM4Di (AAV-DIO-hM4Di) into BNST. Before testing the expression of preference, clozapine-N-oxide (CNO) was peripherally administered to activate hM4Di receptors and selectively inhibit these cells. Ethanol CPP expression was blocked by CNO-mediated inhibition of BNST-VTA cells. A follow-up study revealed this effect was specific to CNO activation of hM4Di as saline- and CNO-treated mice infused with a control vector (HSV-GFP) in place of HSV-Cre showed significant CPP. These findings establish a role for a direct BNST input to VTA in cue-induced ethanol-seeking behavior.

  14. Estrogen regulation of the brain renin-angiotensin system in protection against angiotensin II-induced sensitization of hypertension.

    PubMed

    Xue, Baojian; Zhang, Zhongming; Beltz, Terry G; Guo, Fang; Hay, Meredith; Johnson, Alan Kim

    2014-07-15

    This study investigated sex differences in the sensitization of angiotensin (ANG) II-induced hypertension and the role of central estrogen and ANG-(1-7) in this process. Male and female rats were implanted for telemetered blood pressure (BP) recording. A subcutaneous subpressor dose of ANG II was given alone or concurrently with intracerebroventricular estrogen, ANG-(1-7), an ANG-(1-7) receptor antagonist A-779 or vehicle for 1 wk (induction). After a 1-wk rest (delay), a pressor dose of ANG II was given for 2 wk (expression). In males and ovariectomized females, subpressor ANG II had no sustained effect on BP during induction, but produced an enhanced hypertensive response to the subsequent pressor dose of ANG II during expression. Central administration of estrogen or ANG-(1-7) during induction blocked ANG II-induced sensitization. In intact females, subpressor ANG II treatment produced a decrease in BP during induction and delay, and subsequent pressor ANG II treatment given during expression produced only a slight but significant increase in BP. However, central blockade of ANG-(1-7) by intracerebroventricular infusion of A-779 during induction restored the decreased BP observed in females during induction and enhanced the pressor response to the ANG II treatment during expression. RT-PCR analyses indicated that estrogen given during induction upregulated mRNA expression of the renin-angiotensin system (RAS) antihypertensive components, whereas both central estrogen and ANG-(1-7) downregulated mRNA expression of RAS hypertensive components in the lamina terminalis. The results indicate that females are protected from ANG II-induced sensitization through central estrogen and its regulation of brain RAS.

  15. Central endogenous angiotensin-(1-7) protects against aldosterone/NaCl-induced hypertension in female rats.

    PubMed

    Xue, Baojian; Zhang, Zhongming; Johnson, Ralph F; Guo, Fang; Hay, Meredith; Johnson, Alan Kim

    2013-09-01

    In comparison to male rodents, females are protected against angiotensin (ANG) II- and aldosterone (Aldo)-induced hypertension. However, the mechanisms underlying this protective effect are not well understood. ANG-(1-7) is formed from ANG II by angiotensin-converting enzyme 2 (ACE2) and has an antihypertensive effect in the central nervous system (CNS). The present study tested the hypothesis that central ANG-(1-7) plays an important protective role in attenuating the development of Aldo/NaCl-hypertension in female rats. Systemic infusion of Aldo into intact female rats with 1% NaCl as their sole drinking fluid resulted in a slight increase in blood pressure (BP). Intracerebroventricular (icv) infusion of A-779, an ANG-(1-7) receptor (Mas-R) antagonist, significantly augmented the pressor effects of Aldo/NaCl. In contrast, systemic Aldo/NaCl induced a significant increase in BP in ovariectomized (OVX) female rats, and central infusion of ANG-(1-7) significantly attenuated this Aldo/NaCl pressor effect. The inhibitory effect of ANG-(1-7) on the Aldo/NaCl pressor effect was abolished by concurrent infusion of A-779. RT-PCR analyses showed that there was a corresponding change in mRNA expression of several renin-angiotensin system components, estrogen receptors and an NADPH oxidase subunit in the lamina terminalis. Taken together these results suggest that female sex hormones regulate an antihypertensive axis of the brain renin-angiotensin system involving ACE2/ANG-(1-7)/Mas-R that plays an important counterregulatory role in protecting against the development of Aldo/NaCl-induced hypertension.

  16. Central Renin-Angiotensin System Activation and Inflammation Induced by High-Fat Diet Sensitize Angiotensin II-Elicited Hypertension.

    PubMed

    Xue, Baojian; Thunhorst, Robert L; Yu, Yang; Guo, Fang; Beltz, Terry G; Felder, Robert B; Johnson, Alan Kim

    2016-01-01

    Obesity has been shown to promote renin-angiotensin system activity and inflammation in the brain and to be accompanied by increased sympathetic activity and blood pressure. Our previous studies demonstrated that administration of a subpressor dose of angiotensin (Ang) II sensitizes subsequent Ang II-elicited hypertension. The present study tested whether high-fat diet (HFD) feeding also sensitizes the Ang II-elicited hypertensive response and whether HFD-induced sensitization is mediated by an increase in renin-angiotensin system activity and inflammatory mechanisms in the brain. HFD did not increase baseline blood pressure, but enhanced the hypertensive response to Ang II compared with a normal-fat diet. The sensitization produced by the HFD was abolished by concomitant central infusions of either a tumor necrosis factor-α synthesis inhibitor, pentoxifylline, an Ang II type 1 receptor blocker, irbesartan, or an inhibitor of microglial activation, minocycline. Furthermore, central pretreatment with tumor necrosis factor-α mimicked the sensitizing action of a central subpressor dose of Ang II, whereas central pentoxifylline or minocycline abolished this Ang II-induced sensitization. Real-time quantitative reverse transcription-polymerase chain reaction analysis of lamina terminalis tissue indicated that HFD feeding, central tumor necrosis factor-α, or a central subpressor dose of Ang II upregulated mRNA expression of several components of the renin-angiotensin system and proinflammatory cytokines, whereas inhibition of Ang II type 1 receptor and of inflammation reversed these changes. The results suggest that HFD-induced sensitization of Ang II-elicited hypertension is mediated by upregulation of the brain renin-angiotensin system and of central proinflammatory cytokines. © 2015 American Heart Association, Inc.

  17. Genetic knockdown of estrogen receptor-alpha in the subfornical organ augments ANG II-induced hypertension in female mice

    PubMed Central

    Zhang, Zhongming; Beltz, Terry G.; Guo, Fang; Hay, Meredith; Johnson, Alan Kim

    2014-01-01

    The present study tested the hypotheses that 1) ERα in the brain plays a key role in the estrogen-protective effects against ANG II-induced hypertension, and 2) that the subfornical organ (SFO) is a key site where ERα mediates these protective actions. In this study, a “floxed” ERα transgenic mouse line (ERαflox) was used to create models in which ERα was knocked down in the brain or just in the SFO. Female mice with ERα ablated in the nervous system (Nestin-ERα− mice) showed greater increases in blood pressure (BP) in response to ANG II. Furthermore, females with ERα knockdown specifically in the SFO [SFO adenovirus-Cre (Ad-Cre) injected ERαflox mice] also showed an enhanced pressor response to ANG II. Immunohistochemical (IHC), RT-PCR, and Western blot analyses revealed a marked reduction in the expression of ERα in nervous tissues and, in particular, in the SFO. These changes were not present in peripheral tissues in Nestin-ERα− mice or Ad-Cre-injected ERαflox mice. mRNA expression of components of the renin-angiotensin system in the lamina terminalis were upregulated in Nestin-ERα− mice. Moreover, ganglionic blockade on day 7 after ANG II infusions resulted in a greater reduction of BP in Nestin-ERα− mice or SFO Ad-Cre-injected mice, suggesting that knockdown of ERα in the nervous system or the SFO alone augments central ANG II-induced increase in sympathetic tone. The results indicate that interfering with the action of estrogen on SFO ERα is sufficient to abolish the protective effects of estrogen against ANG II-induced hypertension. PMID:25552661

  18. Genetic knockdown of estrogen receptor-alpha in the subfornical organ augments ANG II-induced hypertension in female mice.

    PubMed

    Xue, Baojian; Zhang, Zhongming; Beltz, Terry G; Guo, Fang; Hay, Meredith; Johnson, Alan Kim

    2015-03-15

    The present study tested the hypotheses that 1) ERα in the brain plays a key role in the estrogen-protective effects against ANG II-induced hypertension, and 2) that the subfornical organ (SFO) is a key site where ERα mediates these protective actions. In this study, a "floxed" ERα transgenic mouse line (ERα(flox)) was used to create models in which ERα was knocked down in the brain or just in the SFO. Female mice with ERα ablated in the nervous system (Nestin-ERα(-) mice) showed greater increases in blood pressure (BP) in response to ANG II. Furthermore, females with ERα knockdown specifically in the SFO [SFO adenovirus-Cre (Ad-Cre) injected ERα(flox) mice] also showed an enhanced pressor response to ANG II. Immunohistochemical (IHC), RT-PCR, and Western blot analyses revealed a marked reduction in the expression of ERα in nervous tissues and, in particular, in the SFO. These changes were not present in peripheral tissues in Nestin-ERα(-) mice or Ad-Cre-injected ERα(flox) mice. mRNA expression of components of the renin-angiotensin system in the lamina terminalis were upregulated in Nestin-ERα(-) mice. Moreover, ganglionic blockade on day 7 after ANG II infusions resulted in a greater reduction of BP in Nestin-ERα(-) mice or SFO Ad-Cre-injected mice, suggesting that knockdown of ERα in the nervous system or the SFO alone augments central ANG II-induced increase in sympathetic tone. The results indicate that interfering with the action of estrogen on SFO ERα is sufficient to abolish the protective effects of estrogen against ANG II-induced hypertension. Copyright © 2015 the American Physiological Society.

  19. Estrogen regulation of the brain renin-angiotensin system in protection against angiotensin II-induced sensitization of hypertension

    PubMed Central

    Zhang, Zhongming; Beltz, Terry G.; Guo, Fang; Hay, Meredith; Johnson, Alan Kim

    2014-01-01

    This study investigated sex differences in the sensitization of angiotensin (ANG) II-induced hypertension and the role of central estrogen and ANG-(1–7) in this process. Male and female rats were implanted for telemetered blood pressure (BP) recording. A subcutaneous subpressor dose of ANG II was given alone or concurrently with intracerebroventricular estrogen, ANG-(1–7), an ANG-(1–7) receptor antagonist A-779 or vehicle for 1 wk (induction). After a 1-wk rest (delay), a pressor dose of ANG II was given for 2 wk (expression). In males and ovariectomized females, subpressor ANG II had no sustained effect on BP during induction, but produced an enhanced hypertensive response to the subsequent pressor dose of ANG II during expression. Central administration of estrogen or ANG-(1–7) during induction blocked ANG II-induced sensitization. In intact females, subpressor ANG II treatment produced a decrease in BP during induction and delay, and subsequent pressor ANG II treatment given during expression produced only a slight but significant increase in BP. However, central blockade of ANG-(1–7) by intracerebroventricular infusion of A-779 during induction restored the decreased BP observed in females during induction and enhanced the pressor response to the ANG II treatment during expression. RT-PCR analyses indicated that estrogen given during induction upregulated mRNA expression of the renin-angiotensin system (RAS) antihypertensive components, whereas both central estrogen and ANG-(1–7) downregulated mRNA expression of RAS hypertensive components in the lamina terminalis. The results indicate that females are protected from ANG II-induced sensitization through central estrogen and its regulation of brain RAS. PMID:24858844

  20. Central renin-angiotensin system activation and inflammation induced by high fat diet sensitize angiotensin II-elicited hypertension

    PubMed Central

    Xue, Baojian; Thunhorst, Robert L.; Yu, Yang; Guo, Fang; Beltz, Terry G.; Felder, Robert B.; Johnson, Alan Kim

    2016-01-01

    Obesity has been shown to promote renin-angiotensin system (RAS) activity and inflammation in the brain and to be accompanied by increased sympathetic activity and blood pressure (BP). Our previous studies demonstrated that administration of a subpressor dose of angiotensin (Ang) II sensitizes subsequent Ang II-elicited hypertension. The present study tested whether high fat diet (HFD) feeding also sensitizes the Ang II-elicited hypertensive response and whether HFD-induced sensitization is mediated by an increase in RAS activity and inflammatory mechanisms in the brain. HFD did not increase baseline BP, but enhanced the hypertensive response to Ang II compared to a normal fat diet. The sensitization produced by the HFD was abolished by concomitant central infusions of either a tumor necrosis factor α (TNF-α) synthesis inhibitor, pentoxifylline, an Ang II type 1 receptor (AT1-R) blocker, irbesartan or an inhibitor of microglial activation, minocycline. Furthermore, central pretreatment with TNF-α mimicked the sensitizing action of a central subpressor dose of Ang II, whereas central pentoxifylline or minocycline abolished this Ang II-induced sensitization. RT-PCR analysis of lamina terminalis tissue indicated that HFD feeding, central TNF-α or a central subpressor dose of Ang II upregulated mRNA expression of several components of the RAS and proinflammatory cytokines, whereas inhibition of AT1-R and of inflammation reversed these changes. The results suggest that HFD-induced sensitization of Ang II-elicited hypertension is mediated by upregulation of the brain RAS and of central proinflammatory cytokines. PMID:26573717

  1. Catecholamine distribution in feline hypothalamus.

    PubMed

    Cheung, Y; Sladek, J R

    1975-12-01

    Catecholamine distribution was examined in cat hypothalamus using the histochemical fluorescence technique of Falck and Hillarp. The heaviest accumulations of catecholamine-containing varicosities were seen within the: anterior periventricular nucleus; dorsal hypothalamic area; bed nucleus of the inferior thalamic peduncle; doral component of the paraventricular nucleus; dorsomedial nucleus; infundibular nucleus; bed nucleus of the stria terminalis-medial division; and supraoptic nucelus. Catecholaminergic perikarya were observed within periventricular, dorsal, and caudal hypothalamic areas as well as within the supramamillary nucleus and caudal diencephalon. Catecholamine distribution in cat hypothalamus possesses both similarities and dissimilarities in relation to distributions reported in other mammals.

  2. Localization and characterization of (/sup 3/H)desmethylimipramine binding sites in rat brain by quantitative autoradiography

    SciTech Connect

    Biegon, A.; Rainbow, T.C.

    1983-05-01

    The high affinity binding sites for the antidepressant desmethlyimipramine (DMI) have been localized in rat brain by quantitative autoradiography. There are high concentrations of binding sites in the locus ceruleus, the anterior ventral thalamus, the ventral portion of the bed nucleus of the stria terminalis, the paraventricular and the dorsomedial nuclei of the hypothalamus. The distribution of DMI binding sites is in striking accord with the distribution of norepinephrine terminals. Pretreatment of rats with the neurotoxin 6-hydroxydopamine, which causes a selective degeneration of catecholamine terminals, results in 60 to 90% decrease in DMI binding. These data support the idea that high affinity binding sites for DMI are located on presynaptic noradrenergic terminals.

  3. Glutamate and the aggression neural circuit in adolescent anabolic steroid-treated Syrian hamsters (Mesocricetus auratus).

    PubMed

    Carrillo, Maria; Ricci, Lesley A; Melloni, Richard H

    2011-10-01

    Adolescent exposure to anabolic androgenic steroids (AAS) alters the development and activity of the glutamate neural system in the latero-anterior hypothalamus (LAH) in hamsters (Mesocricetus auratus); that is, an important neural component of the adolescent AAS-induced aggressive response. In this article, we used retrograde tracing to investigate glutamate-specific alterations in the connections between the LAH and several other nuclei implicated in adolescent AAS-induced aggression. Briefly, hamsters were treated with AAS or sesame-oil control during adolescence and then microinjected with retrograde tracer into the medial amygdala (MeA), lateral septum (LS), or bed nucleus of the stria terminalis (BNST). Brains were then processed for vesicular glutamate transporter 2 (VGLUT2) and examined for AAS-induced changes in the number VGLUT2 cells containing retrograde tracer (VGLUT2/tracer) within the LAH. It is interesting to note that while aggressive AAS-treated hamsters injected retrograde tracer into the MeA showed a significant reduction in the number of VGLUT2/tracer cells in the LAH, aggressive AAS-treated hamsters injected tracer into the BNST showed a significant increase in the number of VGLUT2/tracer cells in the LAH when compared with controls. Last, AAS hamsters injected with tracer into the LS had a comparable number of LAH-VGLUT2/tracer cells to controls. The current results indicate that glutamate likely functions as the major aggression output system from the LAH and that adolescent AAS treatment significantly alters the neural circuitry modulating aggression. Moreover, increases in the number of glutamate projections from the LAH to the BNST in AAS hamsters identify the BNST as an area particularly important for the regulation of AAS-induced aggression.

  4. Estradiol selectively reduces central neural activation induced by hypertonic NaCl infusion in ovariectomized rats.

    PubMed

    Jones, Alexis B; Bass, Eryn E; Fan, Liming; Curtis, Kathleen S

    2012-09-10

    We recently reported that the latency to begin drinking water during slow, intravenous infusion of a concentrated NaCl solution was shorter in estradiol-treated ovariectomized rats compared to oil vehicle-treated rats, despite comparably elevated plasma osmolality. To test the hypothesis that the decreased latency to begin drinking is attributable to enhanced detection of increased plasma osmolality by osmoreceptors located in the CNS, the present study used immunocytochemical methods to label fos, a marker of neural activation. Increased plasma osmolality did not activate the subfornical organ (SFO), organum vasculosum of the lamina terminalis (OVLT), or the nucleus of the solitary tract (NTS) in either oil vehicle-treated rats or estradiol-treated rats. In contrast, hyperosmolality increased fos labeling in the area postrema (AP), the paraventricular nucleus of the hypothalamus (PVN) and the rostral ventrolateral medulla (RVLM) in both groups; however, the increase was blunted in estradiol-treated rats. These results suggest that estradiol has selective effects on the sensitivity of a population of osmo-/Na(+)-receptors located in the AP, which, in turn, alters activity in other central areas associated with responses to increased osmolality. In conjunction with previous reports that hyperosmolality increases blood pressure and that elevated blood pressure inhibits drinking, the current findings of reduced activation in AP, PVN, and RVLM-areas involved in sympathetic nerve activity-raise the possibility that estradiol blunts HS-induced blood pressure changes. Thus, estradiol may eliminate or reduce the initial inhibition of water intake that occurs during increased osmolality, and facilitate a more rapid behavioral response, as we observed in our recent study.

  5. Stressor and glucocorticoid-dependent induction of the immediate early gene kruppel-like factor 9: implications for neural development and plasticity.

    PubMed

    Bonett, Ronald M; Hu, Fang; Bagamasbad, Pia; Denver, Robert J

    2009-04-01

    Krüppel-like factor 9 (KLF9) is a thyroid hormone-induced, immediate early gene implicated in neural development in vertebrates. We analyzed stressor and glucocorticoid (GC)-dependent regulation of KLF9 expression in the brain of the frog Xenopus laevis, and investigated a possible role for KLF9 in neuronal differentiation. Exposure to shaking/confinement stressor increased plasma corticosterone (CORT) concentration, and KLF9 immunoreactivity in several brain regions, which included the medial amygdala and bed nucleus of the stria terminalis, anterior preoptic area (homologous to the mammalian paraventricular nucleus), and optic tectum (homologous to the mammalian superior colliculus). The stressor-induced KLF9 mRNA expression in the brain was blocked by pretreatment with the GC receptor antagonist RU486, or mimicked by injection of CORT. Treatment with CORT also caused a rapid and dose-dependent increase in KLF9 mRNA in X. laevis XTC-2 cells that was resistant to inhibition of protein synthesis. The action of CORT on KLF9 expression in XTC-2 cells was blocked by RU486, but not by the mineralocorticoid receptor antagonist spironolactone. To test for functional consequences of up-regulation of KLF9, we introduced a KLF9 expression plasmid into living tadpole brain by electroporation-mediated gene transfer. Forced expression of KLF9 in tadpole brain caused an increase in Golgi-stained cells, reflective of neuronal differentiation/maturation. Our results support that KLF9 is a direct, GC receptor target gene that is induced by stress, and functions as an intermediary in the actions of GCs on brain gene expression and neuronal structure.

  6. Regulatory interactions of stress and reward on rat forebrain opioidergic and GABAergic circuitry.

    PubMed

    Christiansen, A M; Herman, J P; Ulrich-Lai, Y M

    2011-03-01

    Palatable food intake reduces stress responses, suggesting that individuals may consume such ?comfort? food as self-medication for stress relief. The mechanism by which palatable foods provide stress relief is not known, but likely lies at the intersection of forebrain reward and stress regulatory circuits. Forebrain opioidergic and gamma-aminobutyric acid ergic signaling is critical for both reward and stress regulation, suggesting that these systems are prime candidates for mediating stress relief by palatable foods. Thus, the present study (1) determines how palatable ?comfort? food alters stress-induced changes in the mRNA expression of inhibitory neurotransmitters in reward and stress neurocircuitry and (2) identifies candidate brain regions that may underlie comfort food-mediated stress reduction. We used a model of palatable ?snacking? in combination with a model of chronic variable stress followed by in situ hybridization to determine forebrain levels of pro-opioid and glutamic acid decarboxylase (GAD) mRNA. The data identify regions within the extended amygdala, striatum, and hypothalamus as potential regions for mediating hypothalamic-pituitary-adrenal axis buffering following palatable snacking. Specifically, palatable snacking alone decreased pro-enkephalin-A (ENK) mRNA expression in the anterior bed nucleus of the stria terminalis (BST) and the nucleus accumbens, and decreased GAD65 mRNA in the posterior BST. Chronic stress alone increased ENK mRNA in the hypothalamus, nucleus accumbens, amygdala, and hippocampus; increased dynorphin mRNA in the nucleus accumbens; increased GAD65 mRNA in the anterior hypothalamus and BST; and decreased GAD65 mRNA in the dorsal hypothalamus. Importantly, palatable food intake prevented stress-induced gene expression changes in subregions of the hypothalamus, BST, and nucleus accumbens. Overall, these data suggest that complex interactions exist between brain reward and stress pathways and that palatable snacking can

  7. Inhibition of the central extended amygdala by loud noise and restraint stress

    PubMed Central

    Day, Heidi E. W.; Nebel, Scott; Sasse, Sarah; Campeau, Serge

    2008-01-01

    It is well established that the central nucleus of the amygdala (CEA) is involved in responses to stress, fear and anxiety. Many studies have used c-fos expression to map the brain's response to processive stress, but curiously the CEA generally is not highly activated. We have previously shown that exposure to a novel vs. home environment reduces amphetamine-induced activation of the lateral CEA (CEAl) and the oval nucleus of the bed nucleus of the stria terminalis (BSTov). This is consistent with the idea that processive stress inhibits neurons in these nuclei. We have tested this hypothesis by exposing rats to noise, at a range of intensities from non-stressful to stressful, or to restraint conditions, immediately after a remote injection of amphetamine, 2 mg/kg i.p., or interleukin-1β (IL-1β) 0.5 μg/kg i.p. (used to obtain a level of c-fos mRNA against which to measure inhibition). In keeping with our hypothesis, amphetamine- or IL-1β-induced c-fos and zif-268 mRNA were significantly decreased in the CEAl and BSTov under conditions of loud noise or restraint stress compared with control conditions. This inhibition does not require a stress-induced rise in corticosterone because data were similar in animals that had been adrenalectomized with a low-dose corticosterone replacement. As both the CEAl and BSTov are highly γ-aminobutyric acid (GABA) -ergic and project to the medial CEA (CEAm), their inhibition potentially causes an increased input to the CEAm. As the CEAm is a major output nucleus of the amygdala, this could have important consequences within the neural circuitry controlling responses to processive stress. PMID:15673443

  8. Increasing adult hippocampal neurogenesis in mice after exposure to unpredictable chronic mild stress may counteract some of the effects of stress.

    PubMed

    Culig, Luka; Surget, Alexandre; Bourdey, Marlene; Khemissi, Wahid; Le Guisquet, Anne-Marie; Vogel, Elise; Sahay, Amar; Hen, René; Belzung, Catherine

    2017-09-07

    Major depression is hypothesized to be associated with dysregulations of the hypothalamic-pituitary-adrenal (HPA) axis and impairments in adult hippocampal neurogenesis. Adult-born hippocampal neurons are required for several effects of antidepressants and increasing the rate of adult hippocampal neurogenesis (AHN) before exposure to chronic corticosterone is sufficient to protect against its harmful effects on behavior. However, it is an open question if increasing AHN after the onset of chronic stress exposure would be able to rescue behavioral deficits and which mechanisms might be involved in recovery. We investigated this question by using a 10-week unpredictable chronic mild stress (UCMS) model on a transgenic mouse line (iBax mice), in which the pro-apoptotic gene Bax can be inducibly ablated in neural stem cells following Tamoxifen injection, therefore enhancing the survival of newborn neurons in the adult brain. We did not observe any effect of our treatment in non-stress conditions, but we did find that increasing AHN after 2 weeks of UCMS is sufficient to counteract the effects of UCMS on certain behaviors (splash test and changes in coat state) and endocrine levels and thus to display some antidepressant-like effects. We observed that increasing AHN lowered the elevated basal corticosterone levels in mice exposed to UCMS. This was accompanied by a tamoxifen-induced reversal of the lack of stress-induced decrease in neuronal activation in the anteromedial division of the bed nucleus of the stria terminalis (BSTMA) after intrahippocampal dexamethasone infusion, pointing to a possible mechanism through which adult-born neurons might have exerted their effects. Our results contribute to the neurogenesis hypothesis of depression by suggesting that increasing AHN may be beneficial not just before, but also after exposure to stress by counteracting several of its effects, in part through regulating the HPA axis. Copyright © 2017 Elsevier Ltd. All rights

  9. Neuroanatomical Circuitry Mediating the Sensory Impact of Nicotine in the Central Nervous System

    PubMed Central

    Dehkordi, Ozra; Rose, Jed E.; Asadi, Sadegh; Manaye, Kebreten F.; Millis, Richard M.; Jayam-Trouth, Annapurni

    2014-01-01

    Direct actions of nicotine in the CNS appear to be essential for its reinforcing properties. However, activation of nicotinic acetylcholine receptors (nAChRs) on afferent sensory nerve fibers are important components of addiction to, and withdrawal from, cigarette smoking. The present study was to identify the neuroanatomical substrates activated by the peripheral actions of nicotine and to determine whether these sites overlap brain structures stimulated by direct actions of nicotine. Mouse brains were examined by immunohistochemistry for c-Fos protein after intraperitoneal injection of either nicotine (NIC, 30 and 40 µg/kg) and/or nicotine pyrrolidine methiodide (NIC-PM, 20 and 30 µg/kg). NIC-PM induced c-Fos immunoreactivity (IR) at multiple brain sites. In the brainstem, c-Fos IR was detected in locus coeruleus, laterodorsal tegmental nucleus and pedunculotegmental nucleus. In the midbrain, c-Fos IR was observed in areas overlapping the ventral tegmental area (VTA) which includes paranigral nucleus, parainterfascicular nucleus, parabrachial pigmental area and rostral VTA. Other structures of the nicotine brain-reward circuitry activated by NIC-PM included hypothalamus, paraventricular thalamic nucleus, lateral habenular nucleus, hippocampus, amygdala, accumbens nucleus, piriform cortex, angular insular cortex, anterior olfactory nucleus, lateral septal nucleus, bed nucleus of stria terminalis, cingulate and medial prefrontal cortex, olfactory tubercle, medial and lateral orbital cortex. Nicotine, acting through central and peripheral nAChRs, produced c-Fos IR in areas that overlapped NIC-PM induced c-Fos expressing sites. These neuroanatomical data are the first to demonstrate that the CNS structures which are the direct targets of nicotine are also anatomical substrates for the peripheral sensory impact of nicotine. PMID:25223294

  10. Evidence for the involvement of neuropeptide Y in the antidepressant effect of imipramine in type 2 diabetes.

    PubMed

    Nakhate, Kartik T; Yedke, Sadanand U; Bharne, Ashish P; Subhedar, Nishikant K; Kokare, Dadasaheb M

    2016-09-01

    Depression is a major comorbidity factor of diabetes and the outcome of one disorder influences the other. Our aim is to scrutinize the link between the two, if any. Since neuropeptide Y (NPY) system plays an important role in regulating central glucose sensing mechanisms, and also depression-related behavior, we test the involvement of NPY in the modulation of depression in type 2 diabetic mice. The mice were fed on high-fat diet and administered with low dose of streptozotocin to induce type 2 diabetes. These animals showed augmented plasma glucose and increased immobility time in tail suspension test (TST) suggesting induction of diabetes and depression. Intracerebroventricular (icv) treatment with NPY or NPY Y1 receptor agonist [Leu(31), Pro(34)]-NPY and intraperitoneal treatment with imipramine decreased immobility time. However, opposite effect was produced by NPY Y1 receptor antagonist BIBP3226 (icv). Moreover, reduced immobility time by imipramine was potentiated by NPY and [Leu(31), Pro(34)]-NPY, but attenuated by BIBP3226. Immunohistochemical analysis of the different nuclei of the extended amygdala, the region primarily involved in affective disorders, was undertaken. A significant reduction in NPY immunoreactivity in the central nucleus of amygdala, nucleus accumbens shell and lateral division of bed nucleus of stria terminalis of the diabetic mice was noticed; the response was ameliorated in imipramine treated animals. The results suggest that decreased NPY expression in the extended amygdala might be causally linked with the depression induced following type 2 diabetes and that the antidepressant action of imipramine in diabetic mice might be mediated by NPY-NPY Y1 receptor system. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Orexin 1 receptors are a novel target to modulate panic responses and the panic brain network.

    PubMed

    Johnson, Philip L; Samuels, Brian C; Fitz, Stephanie D; Federici, Lauren M; Hammes, Nathan; Early, Maureen C; Truitt, William; Lowry, Christopher A; Shekhar, Anantha

    2012-12-05

    Although the hypothalamic orexin system is known to regulate appetitive behaviors and promote wakefulness and arousal (Sakurai, 2007 [56]), this system may also be important in adaptive and pathological anxiety/stress responses (Suzuki et al., 2005 [4]). In a recent study, we demonstrated that CSF orexin levels were significantly higher in patients experiencing panic attacks compared to non-panicking depressed subjects (Johnson et al., 2010 [9]). Furthermore, genetically silencing orexin synthesis or blocking orexin 1 receptors attenuated lactate-induced panic in an animal model of panic disorder. Therefore, in the present study, we tested if orexin (ORX) modulates panic responses and brain pathways activated by two different panicogenic drugs. We conducted a series of pharmacological, behavioral, physiological and immunohistochemical experiments to study the modulation by the orexinergic inputs of anxiety behaviors, autonomic responses, and activation of brain pathways elicited by systemic injections of anxiogenic/panicogenic drugs in rats. We show that systemic injections of two different anxiogenic/panicogenic drugs (FG-7142, an inverse agonist at the benzodiazepine site of the GABA(A) receptor, and caffeine, a nonselective competitive adenosine receptor antagonist) increased c-Fos induction in a specific subset of orexin neurons located in the dorsomedial/perifornical (DMH/PeF) but not the lateral hypothalamus. Pretreating rats with an orexin 1 receptor antagonist attenuated the FG-7142-induced anxiety-like behaviors, increased heart rate, and neuronal activation in key panic pathways, including subregions of the central nucleus of the amygdala, bed nucleus of the stria terminalis, periaqueductal gray and in the rostroventrolateral medulla. Overall, the data here suggest that the ORX neurons in the DMH/PeF region are critical to eliciting coordinated panic responses and that ORX1 receptor antagonists constitute a potential novel treatment strategy for panic and

  12. Central nervous action of interleukin-1 mediates activation of limbic structures and behavioural depression in response to peripheral administration of bacterial lipopolysaccharide.

    PubMed

    Konsman, J P; Veeneman, J; Combe, C; Poole, S; Luheshi, G N; Dantzer, R

    2008-12-01

    Although receptors for the pro-inflammatory cytokine interleukin-1 have long been known to be expressed in the brain, their role in fever and behavioural depression observed during the acute phase response (APR) to tissue infection remains unclear. This may in part be due to the fact that interleukin-1 in the brain is bioactive only several hours after peripheral administration of bacterial lipopolysaccharide (LPS). To study the role of cerebral interleukin-1 action in temperature and behavioural changes, and activation of brain structures during the APR, interleukin-1 receptor antagonist (IL-1ra; 100 microg) was infused into the lateral brain ventricle 4 h after intraperitoneal (i.p.) LPS injection (250 microg/kg) in rats. I.p. LPS administration induced interleukin-1beta (IL-1beta) production in systemic circulation as well as in brain circumventricular organs and the choroid plexus. Intracerebroventricular (i.c.v.) infusion of IL-1ra 4 h after i.p. LPS injection attenuated the reduction in social interaction, a cardinal sign of behavioural depression during sickness, and c-Fos expression in the amygdala and bed nucleus of the stria terminalis. However, LPS-induced fever, rises in plasma corticosterone, body weight loss and c-Fos expression in the hypothalamus and caudal brainstem were not altered by i.c.v. infusion of IL-1ra. These findings, together with our previous observations showing that i.c.v. infused IL-1ra diffuses throughout perivascular spaces, where macrophages express interleukin-1 receptors, can be interpreted to suggest that circulating or locally produced brain IL-1beta acts on these cells to bring about behavioural depression and activation of limbic structures during the APR after peripheral LPS administration.

  13. Brain structures involved in the sexual behaviour of Ile de France rams with different sexual preferences and levels of sexual activity.

    PubMed

    Borja, Fernando; Fabre-Nys, Claude

    2012-01-15

    Using Fos, as a marker, we analysed the brain structures of rams, with different libidos or sexual preferences that had been activated by contact with males or females. Ile de France rams aged from 1.5 to 7 years were used. Fos immunoreactivity (Fos IR) was analysed in rams with high (HL) or low libido (LL) after 90 min of direct contact with females (HL DirF n=7 or LL DirF n=7) or in rams of high libido having indirect contact through a fence, with females (HL IndF n=6) or males (HL IndM n=5) and finally, in males who preferred other males as partners by indirect contact through a fence with males (MO IndM n=4). Direct or indirect contact with a preferred sexual partner (LL DirF, HL Dir F, HL IndF, MO IndM) induced the appearance of Fos-IR cells in several diencephalic and cortical structures. Conversely, indirect contact with males did not induce Fos-IR in males interested in females (HL IndM). In the medial preoptic area (MPOA), the paraventricular nucleus and the medial bed nucleus of the stria terminalis the cell density of Fos IR cells was higher in HL Dir F than in LL DirF suggesting involvement in sexual motivation whereas only the MPOA seemed involved the consummatory component of sexual behaviour (Fos IR density HL DirF>HL IndF). The enthorinal cortex was the only structure specifically activated by males attracted to other males (Fos IR density MO IndM>HL IndM) whereas Fos IR density did not differ between the HL IndF and HL IndM groups. Copyright © 2011 Elsevier B.V. All rights reserved.

  14. Sex differences in sensitivity to the depressive-like effects of the kappa opioid receptor agonist U-50488 in rats.

    PubMed

    Russell, Shayla E; Rachlin, Anna B; Smith, Karen L; Muschamp, John; Berry, Loren; Zhao, Zhiyang; Chartoff, Elena H

    2014-08-01

    Dynorphin, an endogenous ligand at kappa opioid receptors (KORs), produces depressive-like effects and contributes to addictive behavior in male nonhuman primates and rodents. Although comorbidity of depression and addiction is greater in women than men, the role of KORs in female motivated behavior is unknown. In adult Sprague-Dawley rats, we used intracranial self-stimulation to measure effects of the KOR agonist (±)-trans-U-50488 methanesulfonate salt (U-50488) (.0-10.0 mg/kg) on brain stimulation reward in gonadally intact and castrated males and in females at estrous cycle stages associated with low and high estrogen levels. Pharmacokinetic studies of U-50488 in plasma and brain were conducted. Immunohistochemistry was used to identify sex-dependent expression of U-50488-induced c-Fos in brain. U-50488 dose-dependently increased the frequency of stimulation (threshold) required to maintain intracranial self-stimulation responding in male and female rats, a depressive-like effect. However, females were significantly less sensitive than males to the threshold-increasing effects of U-50488, independent of estrous cycle stage in females or gonadectomy in males. Although initial plasma concentrations of U-50488 were higher in females, there were no sex differences in brain concentrations. Sex differences in U-50488-induced c-Fos activation were observed in corticotropin releasing factor-containing neurons of the paraventricular nucleus of the hypothalamus and primarily in non-corticotropin releasing factor-containing neurons of the bed nucleus of the stria terminalis. These data suggest that the role of KORs in motivated behavior of rats is sex-dependent, which has important ramifications for the study and treatment of mood-related disorders, including depression and drug addiction in people. Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  15. Orexin 1 receptors are a novel target to modulate panic responses and the panic brain network

    PubMed Central

    Johnson, Philip L.; Samuels, Brian C.; Fitz, Stephanie D.; Federici, Lauren M.; Hammes, Nathan; Early, Maureen C.; Truitt, William; Lowry, Christopher A.; Shekhar, Anantha

    2012-01-01

    Background Although the hypothalamic orexin system is known to regulate appetitive behaviors and promote wakefulness and arousal (Sakurai, 2007), this system may also be important in adaptive and pathological anxiety/stress responses (Suzuki et al., 2005). In a recent study, we demonstrated that CSF orexin levels were significantly higher in patients experiencing panic attacks compared to non-panicking depressed subjects (Johnson et al., 2010). Furthermore, genetically silencing orexin synthesis or blocking orexin 1 receptors attenuated lactate-induced panic in an animal model of panic disorder. Therefore, in the present study, we tested if orexin (ORX) modulates the panic responses and brain pathways activated by two different panicogenic drugs. Methods We conducted a series of pharmacological, behavioral, physiological and immunohistochemical experiments to study the modulation by the orexinergic inputs of anxiety behaviors, autonomic responses, and activation of brain pathways elicited by systemic injections of anxiogenic/panicogenic drugs in rats. Results We show that systemic injections of two different anxiogenic/panicogenic drugs (FG-7142, an inverse agonist at the benzodiazepine site of the GABAA receptor, and caffeine, a nonselective competitive adenosine receptor antagonist) increased c-Fos induction in a specific subset of orexin neurons located in the dorsomedial/ perifornical (DMH/PeF) but not the lateral hypothalamus. Pre-treating rats with an orexin 1 receptor antagonist attenuated the FG-7142-induced anxiety-like behaviors, increased heart rate, and neuronal activation in key panic pathways, including subregions of the central nucleus of the amygdala, bed nucleus of the stria terminalis, periaqueductal gray and in the rostroventrolateral medulla. Conclusion Overall, the data here suggest that the ORX neurons in the DMH/PeF region are critical to eliciting a coordinated panic responses and that ORX1 receptor antagonists constitute a potential novel

  16. Hypothalamic vasopressin systems are more sensitive to the long term effects of social defeat in males versus females

    PubMed Central

    Steinman, M.Q.; Laredo, S.A.; Lopez, E.M.; Manning, C.E.; Hao, R.C.; Doig, I.E.; Campi, K.L.; Flowers, A.E.; Knight, J.K.; Trainor, B.C.

    2014-01-01

    Vasopressin signaling has important effects on the regulation of social behaviors and stress responses, and is considered a promising pathway to target for new therapeutics of stress-induced psychiatric disorders. Although there is evidence for sex differences in the behavioral effects of arginine vasopressin (AVP), few data have directly compared the effects of stress on endogenous AVP signaling in males and females. We used California mice (Peromyscus californicus) to study the short and long term effects of social defeat stress on AVP immunoreactive cells in the paraventricular nucleus (PVN) and the posteromedial bed nucleus of the stria terminalis (BNSTmp). Acute exposure to defeat increased AVP/c-fos cells in the PVN and SON of both males and females. In contrast, there were sex differences in the long term effects of defeat. Males but not females exposed to defeat had less avp mRNA in the PVN, and in two experiments defeat reduced the number of AVP positive cells in the caudal PVN of males but not females. Interestingly, during relatively benign social encounters with a target mouse, there was a rapid decrease in AVP percent staining (including cell bodies and fibers) in the PVN of males but not females. Defeat reduced AVP percent staining in males, but did not block the socially induced decrease in percent staining. When mice were tested in resident-intruder tests, males exposed to defeat males were no less aggressive than control males whereas aggression was abolished in females. However, bouts of aggression were positively correlated with the number of AVP neurons in the BNSTmp of control males but not stressed males, suggesting that different mechanisms mediate aggression in control and stressed males. These data show that while acute AVP responses to defeat are similar in males and females, the long term effects of defeat on AVP are stronger in males. PMID:25306217

  17. Differential effects of cocaine on extracellular signal-regulated kinase phosphorylation in nuclei of the extended amygdala and prefrontal cortex of psychogenetically selected Roman high- and low-avoidance rats.

    PubMed

    Giorgi, Osvaldo; Corda, Maria G; Sabariego, Marta; Giugliano, Valentina; Piludu, Maria A; Rosas, Michela; Acquas, Elio

    2015-05-01

    Roman high (RHA)- and low (RLA)-avoidance rats are selectively bred for rapid vs. poor acquisition of active avoidance, respectively, and differ markedly in emotional reactivity, coping style, and behavioral and neurochemical responses to morphine and psychostimulants. Accordingly, acute cocaine induces more robust increments in locomotion and dopamine output in the nucleus accumbens shell (AcbSh) of RHA than of RLA rats. Cocaine induces short- and long-term neuronal plasticity via activation of the extracellular signal-regulated kinase (ERK) pathway. This study compares the effects of acute cocaine on ERK phosphorylation (pERK) in limbic brain areas of Roman rats. In RHA but not RLA rats, cocaine (5 mg/kg) increased pERK in the infralimbic prefrontal cortex and AcbSh, two areas involved in its acute effects, but did not modify pERK in the prelimbic prefrontal cortex and Acb core, which mediate the chronic effects of cocaine. Moreover, cocaine failed to affect pERK immunolabeling in the bed nucleus of stria terminalis pars lateralis and central amygdala of either line but increased it in the basolateral amygdala of RLA rats. These results extend to pERK expression previous findings on the greater sensitivity to acute cocaine of RHA vs. RLA rats and confirm the notion that genetic factors influence the differential responses of the Roman lines to addictive drugs. Moreover, they support the view that the Roman lines are a useful tool to investigate the molecular underpinnings of individual vulnerability to drug addiction. © 2014 Wiley Periodicals, Inc.

  18. Inducements revisited.

    PubMed

    Wilkinson, Martin; Moore, Andrew

    1999-04-01

    The paper defends the permissibility of paying inducements to research subjects against objections not covered in an earlier paper in Bioethics. The objections are that inducements would cause inequity, crowd out research, and undesirably commercialize the researcher-subject relationship. The paper shows how these objections presuppose implausible factual and/or normative claims. The final position reached is a qualified defence of freedom of contract which not only supports the permissibility of inducements but also offers guidance to ethics committees in dealing with practical problems that might arise if inducements are offered.

  19. Changes in central sodium and not osmolarity or lactate induce panic-like responses in a model of panic disorder.

    PubMed

    Molosh, Andre I; Johnson, Philip L; Fitz, Stephanie D; Dimicco, Joseph A; Herman, James P; Shekhar, Anantha

    2010-05-01

    Panic disorder is a severe anxiety disorder characterized by recurrent panic attacks that can be consistently provoked with intravenous (i.v.) infusions of hypertonic (0.5 M) sodium lactate (NaLac), yet the mechanism/CNS site by which this stimulus triggers panic attacks is unclear. Chronic inhibition of GABAergic synthesis in the dorsomedial hypothalamus/perifornical region (DMH/PeF) of rats induces a vulnerability to panic-like responses after i.v. infusion of 0.5 M NaLac, providing an animal model of panic disorder. Using this panic model, we previously showed that inhibiting the anterior third ventricle region (A3Vr; containing the organum vasculosum lamina terminalis, the median preoptic nucleus, and anteroventral periventricular nucleus) attenuates cardiorespiratory and behavioral responses elicited by i.v. infusions of NaLac. In this study, we show that i.v. infusions of 0.5 M NaLac or sodium chloride, but not iso-osmolar D-mannitol, increased 'anxiety' (decreased social interaction) behaviors, heart rate, and blood pressure responses. Using whole-cell patch-clamp preparations, we also show that bath applications of NaLac (positive control), but not lactic acid (lactate stimulus) or D-mannitol (osmolar stimulus), increases the firing rates of neurons in the A3Vr, which are retrogradely labeled from the DMH/PeF and which are most likely glutamatergic based on a separate study using retrograde tracing from the DMH/PeF in combination with in situ hybridization for vesicular glutamate transporter 2. These data show that hypertonic sodium, but not hyper-osmolarity or changes in lactate, is the key stimulus that provokes panic attacks in panic disorder, and is consistent with human studies.

  20. Changes in Central Sodium and not Osmolarity or Lactate Induce Panic-Like Responses in a Model of Panic Disorder

    PubMed Central

    Molosh, Andre I; Johnson, Philip L; Fitz, Stephanie D; DiMicco, Joseph A; Herman, James P; Shekhar, Anantha

    2010-01-01

    Panic disorder is a severe anxiety disorder characterized by recurrent panic attacks that can be consistently provoked with intravenous (i.v.) infusions of hypertonic (0.5 M) sodium lactate (NaLac), yet the mechanism/CNS site by which this stimulus triggers panic attacks is unclear. Chronic inhibition of GABAergic synthesis in the dorsomedial hypothalamus/perifornical region (DMH/PeF) of rats induces a vulnerability to panic-like responses after i.v. infusion of 0.5 M NaLac, providing an animal model of panic disorder. Using this panic model, we previously showed that inhibiting the anterior third ventricle region (A3Vr; containing the organum vasculosum lamina terminalis, the median preoptic nucleus, and anteroventral periventricular nucleus) attenuates cardiorespiratory and behavioral responses elicited by i.v. infusions of NaLac. In this study, we show that i.v. infusions of 0.5 M NaLac or sodium chloride, but not iso-osmolar -mannitol, increased ‘anxiety' (decreased social interaction) behaviors, heart rate, and blood pressure responses. Using whole-cell patch-clamp preparations, we also show that bath applications of NaLac (positive control), but not lactic acid (lactate stimulus) or -mannitol (osmolar stimulus), increases the firing rates of neurons in the A3Vr, which are retrogradely labeled from the DMH/PeF and which are most likely glutamatergic based on a separate study using retrograde tracing from the DMH/PeF in combination with in situ hybridization for vesicular glutamate transporter 2. These data show that hypertonic sodium, but not hyper-osmolarity or changes in lactate, is the key stimulus that provokes panic attacks in panic disorder, and is consistent with human studies. PMID:20130534

  1. Expression and dexamethasone-induced nuclear translocation of glucocorticoid and mineralocorticoid receptors in guinea pig cochlear cells.

    PubMed

    Kil, Sung-Hee; Kalinec, Federico

    2013-05-01

    Glucocorticoids (GC) are powerful anti-inflammatory agents frequently used to protect the auditory organ against damage associated with a variety of conditions, including noise exposure and ototoxic drugs as well as bacterial and viral infections. In addition to glucocorticoid receptors (GC-R), natural and synthetic GC are known to bind mineralocorticoid receptors (MC-R) with great affinity. We used light and laser scanning confocal microscopy to investigate the expression of GC-R and MC-R in different cell populations of the guinea pig cochlea, and their translocation to different cell compartments after treatment with the synthetic GC dexamethasone. We found expression of both types of receptors in the cytoplasm and nucleus of sensory inner and outer hair cells as well as pillar, Hensen and Deiters cells in the organ of Corti, inner and outer sulcus cells, spiral ganglion neurons and several types of spiral ligament and spiral limbus cells; stria vascularis cells expressed mostly MC-R whereas fibrocytes type IV were positive for GC-R only. GC-R and MC-R were also localized at or near the plasma membrane of pillar cells and outer hair cells, whereas GC-R were found at or near the plasma membrane of Hensen cells only. We investigated the relative levels of receptor expression in the cytoplasm and the nucleus of Hensen cells treated with dexamethasone, and found they varied in a way suggestive of dose-induced translocation. These results suggest that the oto-protective effects of GC could be associated with the concerted activation of genomic and non-genomic, GC-R and MC-R mediated signaling pathways in different regions of the cochlea. Copyright © 2013 Elsevier B.V. All rights reserved.

  2. Segregated pathways to the vomeronasal amygdala: differential projections from the anterior and posterior divisions of the accessory olfactory bulb.

    PubMed

    Mohedano-Moriano, Alicia; Pro-Sistiaga, Palma; Ubeda-Bañón, Isabel; Crespo, Carlos; Insausti, Ricardo; Martinez-Marcos, Alino

    2007-04-01

    Apically and basally located receptor neurons in the vomeronasal sensory epithelium express G(i2 alpha)- and G(o alpha)-proteins, V1R and V2R vomeronasal receptors, project to the anterior and posterior accessory olfactory bulb and respond to different stimuli, respectively. The extent to which secondary projections from the two portions of the accessory olfactory bulb are convergent in the vomeronasal amygdala is controversial. This issue is addressed by using anterograde and retrograde tract-tracing methods in rats including electron microscopy. Injections of dextran-amines, Fluoro Gold, cholera toxin-B subunit and Fast Blue were delivered to the anterior and posterior accessory olfactory bulb, bed nucleus of the stria terminalis, dorsal anterior amygdala and bed nucleus of the accessory olfactory tract/anteroventral medial amygdaloid nucleus. We have demonstrated that, apart from common vomeronasal-recipient areas, only the anterior accessory olfactory bulb projects to the bed nucleus of the stria terminalis, medial division, posteromedial part, and only the posterior accessory olfactory bulb projects to the dorsal anterior amygdala and deep cell layers of the bed nucleus of the accessory olfactory tract and the anteroventral medial amygdaloid nucleus. These results provide evidence that, excluding areas of convergence, the V1R and V2R vomeronasal pathways project to specific areas of the amygdala. These two vomeronasal subsystems are therefore anatomically and functionally separated in the telencephalon.

  3. Afferent and efferent projections of the anterior cortical amygdaloid nucleus in the mouse.

    PubMed

    Cádiz-Moretti, Bernardita; Abellán-Álvaro, María; Pardo-Bellver, Cecília; Martínez-García, Fernando; Lanuza, Enrique

    2017-09-01

    The anterior cortical amygdaloid nucleus (ACo) is a chemosensory area of the cortical amygdala that receives afferent projections from both the main and accessory olfactory bulbs. The role of this structure is unknown, partially due to a lack of knowledge of its connectivity. In this work, we describe the pattern of afferent and efferent projections of the ACo by using fluorogold and biotinylated dextranamines as retrograde and anterograde tracers, respectively. The results show that the ACo is reciprocally connected with the olfactory system and basal forebrain, as well as with the chemosensory and basomedial amygdala. In addition, it receives dense projections from the midline and posterior intralaminar thalamus, and moderate projections from the posterior bed nucleus of the stria terminalis, mesocortical structures and the hippocampal formation. Remarkably, the ACo projects moderately to the central nuclei of the amygdala and anterior bed nucleus of the stria terminalis, and densely to the lateral hypothalamus. Finally, minor connections are present with some midbrain and brainstem structures. The afferent projections of the ACo indicate that this nucleus might play a role in emotional learning involving chemosensory stimuli, such as olfactory fear conditioning. The efferent projections confirm this view and, given its direct output to the medial part of the central amygdala and the hypothalamic 'aggression area', suggest that the ACo can initiate defensive and aggressive responses elicited by olfactory or, to a lesser extent, vomeronasal stimuli. © 2017 Wiley Periodicals, Inc.

  4. Callous-unemotional traits drive reduced white-matter integrity in youths with conduct problems.

    PubMed

    Breeden, A L; Cardinale, E M; Lozier, L M; VanMeter, J W; Marsh, A A

    2015-10-01

    Callous-unemotional (CU) traits represent a significant risk factor for severe and persistent conduct problems in children and adolescents. Extensive neuroimaging research links CU traits to structural and functional abnormalities in the amygdala and ventromedial prefrontal cortex. In addition, adults with psychopathy (a disorder for which CU traits are a developmental precursor) exhibit reduced integrity in uncinate fasciculus, a white-matter (WM) tract that connects prefrontal and temporal regions. However, research in adolescents has not yet yielded similarly consistent findings. We simultaneously modeled CU traits and externalizing behaviors as continuous traits, while controlling for age and IQ, in order to identify the unique relationship of each variable with WM microstructural integrity, assessed using diffusion tensor imaging. We used tract-based spatial statistics to evaluate fractional anisotropy, an index of WM integrity, in uncinate fasciculus and stria terminalis in 47 youths aged 10-17 years, of whom 26 exhibited conduct problems and varying levels of CU traits. Whereas both CU traits and externalizing behaviors were negatively correlated with WM integrity in bilateral uncinate fasciculus and stria terminalis/fornix, simultaneously modeling both variables revealed that these effects were driven by CU traits; the severity of externalizing behavior was not related to WM integrity after controlling for CU traits. These results indicate that WM abnormalities similar to those observed in adult populations with psychopathy may emerge in late childhood or early adolescence, and may be critical to understanding the social and affective deficits observed in this population.

  5. Distribution of the inositol 1,4,5-trisphosphate receptor, P400, in adult rat brain.

    PubMed

    Rodrigo, J; Suburo, A M; Bentura, M L; Fernández, T; Nakade, S; Mikoshiba, K; Martínez-Murillo, R; Polak, J M

    1993-11-15

    The distribution of the inositol 1,4,5-trisphosphate receptor protein, P400, was investigated in adult rat brain by immunocytochemistry with the monoclonal antibody 4C11 raised against mouse cerebellar inositol 1,4,5-trisphosphate receptor protein. Immunoreactive neuronal cell bodies were detected in the cerebral cortex, the claustrum, the endopiriform nucleus, the corpus callosum, the anterior olfactory nuclei, the olfactory tubercle, the nucleus accumbens, the lateral septum, the bed nucleus of the stria terminalis, the hippocampal formation, the dentate gyrus, the caudate-putamen, the fundus striatum, the amygdaloid complex, the thalamus, the caudolateral part of the hypothalamus, the supramammillary nuclei, the substantia nigra, the pedunculopontine tegmental nucleus, the ventrotegmental area, the Purkinje cells in the cerebellum, the dorsal cochlear nucleus, the subnucleus oralis and caudalis of trigeminal nerve, and the dorsal horn of the spinal cord. Immunoreactive fibres were found in the medial forebrain bundle, the globus pallidus, the stria terminalis, the pyramidal tract, the spinal tract of trigeminal nerve, and the ventral horn of spinal cord. Nerve fibres forming a dense plexus ending in terminal-like boutons were detected in relation to nonimmunoreactive neurons of the dentate, interpositus, and fastigial nuclei of the cerebellum and around neurons of the vestibular nuclei. This receptor protein binds a specific second messenger, inositol 1,4,5-trisphosphate, which produces a mobilization of intracellular Ca2+ and a modulation of transmitter release.

  6. Neural activity associated with monitoring the oscillating threat value of a tarantula

    PubMed Central

    Mobbs, Dean; Yu, Rongjun; Rowe, James B.; Eich, Hannah; FeldmanHall, Oriel; Dalgleish, Tim

    2010-01-01

    Phylogenetic threats such as spiders evoke our deepest primitive fears. When close or looming, such threats engage evolutionarily conserved monitoring systems and defense reactions that promote self-preservation. With the use of a modified behavioral approach task within functional MRI, we show that, as a tarantula was placed closer to a subject's foot, increased experiences of fear coincided with augmented activity in a cascade of fear-related brain networks including the periaqueductal gray, amygdala, and bed nucleus of the stria terminalis. Activity in the amygdala was also associated with underprediction of the tarantula's threat value and, in addition to the bed nucleus of the stria terminalis, with monitoring the tarantula's threat value as indexed by its direction of movement. Conversely, the orbitofrontal cortex was engaged as the tarantula grew more distant, suggesting that this region emits safety signals or expels fear. Our findings fractionate the neurobiological mechanisms associated with basic fear and potentially illuminate the perturbed reactions that characterize clinical phobias. PMID:21059963

  7. Callous-unemotional traits drive reduced white-matter integrity in youths with conduct problems

    PubMed Central

    Breeden, A. L.; Cardinale, E. M.; Lozier, L. M.; VanMeter, J. W.; Marsh, A. A.

    2016-01-01

    Background Callous-unemotional (CU) traits represent a significant risk factor for severe and persistent conduct problems in children and adolescents. Extensive neuroimaging research links CU traits to structural and functional abnormalities in the amygdala and ventromedial prefrontal cortex. In addition, adults with psychopathy (a disorder for which CU traits are a developmental precursor) exhibit reduced integrity in uncinate fasciculus, a white-matter (WM) tract that connects prefrontal and temporal regions. However, research in adolescents has not yet yielded similarly consistent findings. Method We simultaneously modeled CU traits and externalizing behaviors as continuous traits, while controlling for age and IQ, in order to identify the unique relationship of each variable with WM microstructural integrity, assessed using diffusion tensor imaging. We used tract-based spatial statistics to evaluate fractional anisotropy, an index of WM integrity, in uncinate fasciculus and stria terminalis in 47 youths aged 10–17 years, of whom 26 exhibited conduct problems and varying levels of CU traits. Results Whereas both CU traits and externalizing behaviors were negatively correlated with WM integrity in bilateral uncinate fasciculus and stria terminalis/fornix, simultaneously modeling both variables revealed that these effects were driven by CU traits; the severity of externalizing behavior was not related to WM integrity after controlling for CU traits. Conclusions These results indicate that WM abnormalities similar to those observed in adult populations with psychopathy may emerge in late childhood or early adolescence, and may be critical to understanding the social and affective deficits observed in this population. PMID:26087816

  8. Distribution of sup 125 I-neurotensin binding sites in human forebrain: Comparison with the localization of acetylcholinesterase

    SciTech Connect

    Szigethy, E.; Quirion, R.; Beaudet, A. )

    1990-07-22

    The distribution of 125I-neurotensin binding sites was compared with that of acetylcholinesterase reactivity in the human basal forebrain by using combined light microscopic radioautography/histochemistry. High 125I-neurotensin binding densities were observed in the bed nucleus of the stria terminalis, islands of Calleja, claustrum, olfactory tubercle, and central nucleus of the amygdala; lower levels were seen in the caudate, putamen, medial septum, diagonal band nucleus, and nucleus basalis of Meynert. Adjacent sections processed for cholinesterase histochemistry demonstrated a regional overlap between the distribution of labeled neurotensin binding sites and that of intense acetylcholinesterase staining in all of the above regions, except in the bed nucleus of the stria terminalis, claustrum, and central amygdaloid nucleus, where dense 125I-neurotensin labeling was detected over areas containing only weak to moderate cholinesterase staining. At higher magnification, 125I-neurotensin-labeled binding sites in the islands of Calleja, supraoptic nucleus of the hypothalamus, medial septum, diagonal band nucleus, and nucleus basalis of Meynert were selectively associated with neuronal perikarya found to be cholinesterase-positive in adjacent sections. Moderate 125I-neurotensin binding was also apparent over the cholinesterase-reactive neuropil of these latter three regions. These data suggest that neurotensin (NT) may directly influence the activity of magnocellular cholinergic neurons in the human basal forebrain, and may be involved in the physiopathology of dementing disorders such as Alzheimer's disease, in which these neurons have been shown to be affected.

  9. Connections of the corticomedial amygdala in the golden hamster. II. Efferents of the ''olfactory amygdala''

    SciTech Connect

    Kevetter, G.A.; Winans, S.S.

    1981-03-20

    The anterior cortical (C1) and posterolateral cortical (C2) nuclei of the amygdala are designated the ''olfactory amygdala'' because they each receive direct projections from the main olfactory bulb. The efferents of these nuclei were traced after stereotaxic placement of 1-5 muCi tritiated proline in the corticomedial amygdala of the male golden hamsters. Following survival times of 12, 24, or 48 hours, 20 micron frozen sections of the brains were processed for light microscopic autoradiography. Efferents from C2 terminate in layers II and III of the olfactory tubercle and in layer Ib of pars ventralis and pars medialis of the anterior olfactory nucleus. Fibers from this nucleus also project to layers I and II of the infralimbic cortex and to the molecular layer of the agranular insular cortex. More posteriorly, fibers from C2 terminate in layer I of the dorsolateral entorhinal cortex, and in the endopiriform nucleus. From C1, efferent fibers travel in the stria terminalis and terminate in the precommissural bed nucleus of the stria terminalis and in the mediobasal hypothalamus. Efferents from C1 also innervate the molecular layer of C2, the amygdalo-hippocampal area, and the adjacent piriform cortex. Neurons in both C1 and C2 project to the molecular layer of the medial amygdaloid nucleus and the posteromedial cortical nucleus of the amygdala, the plexiform layer of the ventral subiculum, and the molecular layer of the lateral entorhinal cortex.

  10. Distribution of vasopressin, oxytocin and vasoactive intestinal polypeptide in the hypothalamus and extrahypothalamic regions of tree shrews.

    PubMed

    Ni, R-J; Shu, Y-M; Wang, J; Yin, J-C; Xu, L; Zhou, J-N

    2014-04-18

    Vasopressin (VP), oxytocin (OXT) and vasoactive intestinal polypeptide (VIP) in the brain modulate physiological and behavioral processes in many vertebrates. Day-active tree shrews, the closest relatives of primates, live singly or in pairs in territories that they defend vigorously against intruding conspecifics. However, anatomy concerning peptidergic neuron distribution in the tree shrew brain is less clear. Here, we examined the distribution of VP, OXT and VIP immunoreactivity in the hypothalamus and extrahypothalamic regions of tree shrews (Tupaia belangeri chinensis) using the immunohistochemical techniques. Most of VP and OXT immunoreactive (-ir) neurons were found in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus. In addition, VP-ir or OXT-ir neurons were scattered in the preoptic area, anterior hypothalamic areas, dorsomedial hypothalamic nucleus, stria terminalis, bed nucleus of the stria terminalis and medial amygdala. Interestingly, a high density of VP-ir fibers within the ventral lateral septum was observed in males but not in females. Both VP-ir and VIP-ir neurons were found in different subdivisions of the suprachiasmatic nucleus (SCN) with partial overlap. VIP-ir cells and fibers were also scattered in the cerebral cortex, anterior olfactory nucleus, amygdala and dentate gyrus of the hippocampus. These findings provide a comprehensive description of VIP and a detailed mapping of VP and OXT in the hypothalamus and extrahypothalamic regions of tree shrews, which is an anatomical basis for the participation of these neuropeptides in the regulation of circadian behavior and social behavior.

  11. Distribution of vasotocin- and vasoactive intestinal peptide-like immunoreactivity in the brain of blue tit (Cyanistes coeruleus)

    PubMed Central

    Montagnese, Catherine M.; Székely, Tamás; Csillag, András; Zachar, Gergely

    2015-01-01

    Blue tits (Cyanistes coeruleus) are songbirds, used as model animals in numerous studies covering a wide field of research. Nevertheless, the distribution of neuropeptides in the brain of this avian species remains largely unknown. Here we present some of the first results on distribution of Vasotocine (AVT) and Vasoactive intestinal peptide (VIP) in the brain of males and females of this songbird species, using immunohistochemistry mapping. The bulk of AVT-like cells are found in the hypothalamic supraoptic, paraventricular and suprachiasmatic nuclei, bed nucleus of the stria terminalis, and along the lateral forebrain bundle. Most AVT-like fibers course toward the median eminence, some reaching the arcopallium, and lateral septum. Further terminal fields occur in the dorsal thalamus, ventral tegmental area and pretectal area. Most VIP-like cells are in the lateral septal organ and arcuate nucleus. VIP-like fibers are distributed extensively in the hypothalamus, preoptic area, lateral septum, diagonal band of Broca. They are also found in the bed nucleus of the stria terminalis, amygdaloid nucleus of taenia, robust nucleus of the arcopallium, caudo-ventral hyperpallium, nucleus accumbens and the brainstem. Taken together, these results suggest that both AVT and VIP immunoreactive structures show similar distribution to other avian species, emphasizing evolutionary conservatism in the history of vertebrates. The current study may enable future investigation into the localization of AVT and VIP, in relation to behavioral and ecological traits in the brain of tit species. PMID:26236200

  12. Lipopolysaccharide-Induced Middle Ear Inflammation Disrupts the cochlear Intra-Strial Fluid–Blood Barrier through Down-Regulation of Tight Junction Proteins

    PubMed Central

    Zhang, Jinhui; Chen, Songlin; Hou, Zhiqiang; Cai, Jing; Dong, Mingmin; Shi, Xiaorui

    2015-01-01

    Middle ear infection (or inflammation) is the most common pathological condition that causes fluid to accumulate in the middle ear, disrupting cochlear homeostasis. Lipopolysaccharide, a product of bacteriolysis, activates macrophages and causes release of inflammatory cytokines. Many studies have shown that lipopolysaccharides cause functional and structural changes in the inner ear similar to that of inflammation. However, it is specifically not known how lipopolysaccharides affect the blood-labyrinth barrier in the stria vascularis (intra-strial fluid–blood barrier), nor what the underlying mechanisms are. In this study, we used a cell culture-based in vitro model and animal-based in vivo model, combined with immunohistochemistry and a vascular leakage assay, to investigate lipopolysaccharide effects on the integrity of the mouse intra-strial fluid–blood barrier. Our results show lipopolysaccharide-induced local infection significantly affects intra-strial fluid–blood barrier component cells. Pericytes and perivascular-resident macrophage-like melanocytes are particularly affected, and the morphological and functional changes in these cells are accompanied by substantial changes in barrier integrity. Significant vascular leakage is found in the lipopolysaccharide treated-animals. Consistent with the findings from the in vivo animal model, the permeability of the endothelial cell monolayer to FITC-albumin was significantly higher in the lipopolysaccharide-treated monolayer than in an untreated endothelial cell monolayer. Further study has shown the lipopolysaccharide-induced inflammation to have a major effect on the expression of tight junctions in the blood barrier. Lipopolysaccharide was also shown to cause high frequency hearing loss, corroborated by previous reports from other laboratories. Our findings show lipopolysaccharide-evoked middle ear infection disrupts inner ear fluid balance, and its particular effects on the intra-strial fluid

  13. Lipopolysaccharide-induced middle ear inflammation disrupts the cochlear intra-strial fluid-blood barrier through down-regulation of tight junction proteins.

    PubMed

    Zhang, Jinhui; Chen, Songlin; Hou, Zhiqiang; Cai, Jing; Dong, Mingmin; Shi, Xiaorui

    2015-01-01

    Middle ear infection (or inflammation) is the most common pathological condition that causes fluid to accumulate in the middle ear, disrupting cochlear homeostasis. Lipopolysaccharide, a product of bacteriolysis, activates macrophages and causes release of inflammatory cytokines. Many studies have shown that lipopolysaccharides cause functional and structural changes in the inner ear similar to that of inflammation. However, it is specifically not known how lipopolysaccharides affect the blood-labyrinth barrier in the stria vascularis (intra-strial fluid-blood barrier), nor what the underlying mechanisms are. In this study, we used a cell culture-based in vitro model and animal-based in vivo model, combined with immunohistochemistry and a vascular leakage assay, to investigate lipopolysaccharide effects on the integrity of the mouse intra-strial fluid-blood barrier. Our results show lipopolysaccharide-induced local infection significantly affects intra-strial fluid-blood barrier component cells. Pericytes and perivascular-resident macrophage-like melanocytes are particularly affected, and the morphological and functional changes in these cells are accompanied by substantial changes in barrier integrity. Significant vascular leakage is found in the lipopolysaccharide treated-animals. Consistent with the findings from the in vivo animal model, the permeability of the endothelial cell monolayer to FITC-albumin was significantly higher in the lipopolysaccharide-treated monolayer than in an untreated endothelial cell monolayer. Further study has shown the lipopolysaccharide-induced inflammation to have a major effect on the expression of tight junctions in the blood barrier. Lipopolysaccharide was also shown to cause high frequency hearing loss, corroborated by previous reports from other laboratories. Our findings show lipopolysaccharide-evoked middle ear infection disrupts inner ear fluid balance, and its particular effects on the intra-strial fluid-blood barrier

  14. Functional cross-talk between the hypothalamic-pituitary-gonadal and -adrenal axes.

    PubMed

    Viau, V

    2002-06-01

    Under normal conditions, the adrenal glucocorticoids, the endproduct of the hypothalamic-pituitary-adrenal (HPA) axis, provide a frontline of defence against threats to homeostasis (i.e. stress). On the other hand, chronic HPA drive and glucocorticoid hypersecretion have been implicated in the pathogenesis of several forms of systemic, neurodegenerative and affective disorders. The HPA axis is subject to gonadal influence, indicated by sex differences in basal and stress HPA function and neuropathologies associated with HPA dysfunction. Functional cross-talk between the gonadal and adrenal axes is due in large part to the interactive effects of sex steroids and glucocorticoids, explaining perhaps why several disease states linked to stress are sex-dependent. Realizing the interactive nature by which the hypothalamic-pituitary-gonadal and HPA systems operate, however, has made it difficult to model how these hormones act in the brain. Manipulation of one endocrine system is not without effects on the other. Simultaneous manipulation and assessment of both endocrine systems can overcome this problem. This dual approach in the male rat reveals that testosterone can act and interact on different aspects of basal and stress HPA function. Basal adrenocorticotropic hormone (ACTH) release is regulated by testosterone-dependent effects on arginine vasopressin synthesis, and corticosterone-dependent effects on corticotropin-releasing hormone (CRH) synthesis in the paraventricular nucleus (PVN) of the hypothalamus. In contrast, testosterone and corticosterone interact on stress-induced ACTH release and drive to the PVN motor neurones. Candidate structures mediating this interaction include several testosterone-sensitive afferents to the HPA axis, including the medial preoptic area, central and medial amygdala and bed nuclei of the stria terminalis. All of these relay homeostatic information and integrate reproductive and social behaviour. Because these modalities are affected

  15. Immediate and lasting effects of chronic daily methamphetamine exposure on activation of cells in hypothalamic-pituitary-adrenal axis-associated brain regions.

    PubMed

    Zuloaga, Damian G; Johnson, Lance A; Weber, Sydney; Raber, Jacob

    2016-02-01

    Chronic methamphetamine (MA) abuse leads to dependence and symptoms of withdrawal after use has ceased. Negative mood states associated with withdrawal, as well as drug reinstatement, have been linked to drug-induced disruption of the hypothalamic-pituitary-adrenal (HPA) axis. However, effects of chronic MA exposure or acute MA exposure following withdrawal on neural activation patterns within brain regions that regulate the HPA axis are unknown. In this study, neural activation patterns were assessed by quantification of c-Fos protein in mice exposed to different regimens of MA administration. (Experiment 1) Adult male mice were treated with MA (5 mg/kg) or saline once or once daily for 10 days. (Experiment 2) Mice were treated with MA or saline once daily for 10 days and following a 10-day withdrawal period were re-administered a final dose of MA or saline. c-Fos was quantified in brains after the final injection. (Experiment 1) Compared to exposure to a single dose of MA (5 mg/kg), chronic MA exposure decreased the number of c-Fos expressing cells in the paraventricular hypothalamus, dorsomedial hypothalamus, central amygdala, basolateral amygdala, bed nucleus of the stria terminalis (BNST), and CA3 hippocampal region. (Experiment 2) Compared to mice receiving their first dose of MA, mice chronically treated with MA, withdrawn, and re-administered MA, showed decreased c-Fos expressing cells within the central and basolateral amygdala, BNST, and CA3. HPA axis-associated amygdala, extended amygdala, and hippocampal regions endure lasting effects following chronic MA exposure and therefore may be linked to stress-related withdrawal symptoms.

  16. Potential contributions of efferents from medial prefrontal cortex to neural activation following sexual behavior in the male rat.

    PubMed

    Balfour, M E; Brown, J L; Yu, L; Coolen, L M

    2006-01-01

    The limbic system plays an important role in the regulation of sexual motivation and reward. At the core of this system is an interconnected mesocorticolimbic circuit, comprised of the ventral tegmental area, nucleus accumbens and medial prefrontal cortex. Previously, our laboratory showed that sexual behavior causes neural activation in the ventral tegmental area of male rats. The main goal of this study is to identify afferent inputs to ventral tegmental area neurons that may contribute to their activation during sexual behavior. Hence, the anterograde tracer biotinylated dextran amine was injected into subregions of the rat medial prefrontal cortex, which is known to project to the ventral tegmental area. Visualization of biotinylated dextran amine-labeled axons was combined with immunostaining for sex-induced Fos expression. Quantitative analysis showed that the majority of sex-activated ventral tegmental area neurons receive putative contacts from the infralimbic and prelimbic--but not the anterior cingulate--subregions of the medial prefrontal cortex. Thus, inputs from infralimbic area and prelimbic are in an anatomical position to provide a major source of input during sexual behavior. A second goal of this study was to determine if the medial prefrontal cortex projects to sex-activated neurons in other brain regions important for sexual behavior and motivation. Infralimbic area and prelimbic area sent projections to nucleus accumbens, medial preoptic area, principal nucleus of the bed nucleus of the stria terminalis, basolateral amygdala, and parvocellular subparafasicular thalamic nucleus. Thus, the infralimbic and prelimbic subregions of the medial prefrontal cortex may also influence sexual behavior and motivation via brain regions other than the ventral tegmental area.

  17. Paternal stress exposure alters sperm microRNA content and reprograms offspring HPA stress axis regulation

    PubMed Central

    Rodgers, Ali B.; Morgan, Christopher P.; Bronson, Stefanie L.; Revello, Sonia; Bale, Tracy L.

    2013-01-01

    Neuropsychiatric disease frequently presents with an underlying hypo- or hyper- reactivity of the HPA stress axis, suggesting an exceptional vulnerability of this circuitry to external perturbations. Parental lifetime exposures to environmental challenges are associated with increased offspring neuropsychiatric disease risk, and likely contribute to stress dysregulation. While maternal influences have been extensively examined, much less is known regarding the specific role of paternal factors. To investigate the potential mechanisms by which paternal stress may contribute to offspring hypothalamic-pituitary-adrenal (HPA) axis dysregulation, we exposed mice to six weeks of chronic stress prior to breeding. As epidemiological studies support variation in paternal germ cell susceptibility to reprogramming across the lifespan, male stress exposure occurred either throughout puberty or in adulthood. Remarkably, offspring of sires from both paternal stress groups displayed significantly reduced HPA axis stress responsivity. Gene set enrichment analyses in offspring stress regulating brain regions, the paraventricular nucleus (PVN) and the bed nucleus of stria terminalis (BNST), revealed global pattern changes in transcription suggestive of epigenetic reprogramming and consistent with altered offspring stress responsivity, including increased expression of glucocorticoid-responsive genes in the PVN. In examining potential epigenetic mechanisms of germ cell transmission, we found robust changes in sperm miRNA (miR) content, where nine specific miRs were significantly increased in both paternal stress groups. Overall, these results demonstrate that paternal experience across the lifespan can induce germ cell epigenetic reprogramming and impact offspring HPA stress axis regulation, and may therefore offer novel insight into factors influencing neuropsychiatric disease risk. PMID:23699511

  18. Dynamic changes in oxytocin receptor expression and activation at parturition in the rat brain.

    PubMed

    Meddle, Simone L; Bishop, Valerie R; Gkoumassi, Effimia; van Leeuwen, Fred W; Douglas, Alison J

    2007-10-01

    Oxytocin plays a pivotal role in rat parturition, acting within the brain to facilitate its own release in the supraoptic nucleus (SON) and paraventricular nucleus, and to stimulate maternal behavior. We investigated oxytocin receptor (OTR) expression and activation perinatally. Using a (35)S-labeled riboprobe complementary to OTR mRNA, OTR expression was quantified in proestrus virgin, 21- and 22-day pregnant, parturient (90 min. from pup 1 birth), and postpartum (4-12 h from parturition) rats. Peak OTR mRNA expression was observed at parturition in the SON, brainstem regions, medial preoptic area (mPOA), bed nucleus of the stria terminalis (BnST), and olfactory bulbs, but there was no change in the paraventricular nucleus and lateral septum. OTR mRNA expression was increased on the day of expected parturition in the SON and brainstem, suggesting that oxytocin controls the pathway mediating input from uterine signals. Likewise, OTR mRNA expression was increased in the mPOA and BnST during labor/birth. In the olfactory bulbs and medial amygdala, parturition induced increased OTR mRNA expression compared with pre-parturition, reflecting their immediate response to new stimuli at birth. Postpartum OTR expression in all brain regions returned to levels observed in virgin rats. Parturition significantly increased the number of double-immunolabeled cells for Fos and OTR within the SON, brainstem, BnST, and mPOA regions compared with virgin rats. Thus, there are dynamic region-dependent changes in OTR-expressing cells at parturition. This altered OTR distribution pattern in the brain perinatally reflects the crucial role oxytocin plays in orchestrating both birth and maternal behavior.

  19. Limbic brain activation for maternal acoustic perception and responding is different in mothers and virgin female mice.

    PubMed

    Geissler, Diana B; Sabine Schmidt, H; Ehret, Günter

    2013-01-01

    Mothers are primed to become maternal through hormonal changes during pregnancy and delivery of young, virgin females need experience with young for performing maternally. The activation of brain areas controlling maternal behavior can be studied by stimulus-induced expression of the immediate-early gene Fos and immunocytochemical labeling of the FOS protein in activated cells. With this technique we identified areas of the mouse limbic system stimulated by acoustically adequate or inadequate models of pup ultrasounds that, if perceived as adequate, direct the search for lost pups (phonotaxis). Behavioral observations and neural activation data suggest that adequate (50 kHz long tones) and inadequate ultrasound models (50 kHz short or 20 kHz long tones) are differently processed in limbic areas of mothers and virgin females with 1 or 5 days of pup-caring experience depending on the news value and the recognition of the stimuli: High numbers of FOS-positive cells in the medial preoptic area, lateral septum, and bed nucleus of the stria terminalis (mothers and virgins) relate to the salience (news value) of the perceived sounds; contextual stress may be reflected by high activation in parts of the amygdala and the ventromedial hypothalamus (virgins); high activation in the piriform cortex suggests associative learning of adequate sounds and in the entorhinal cortex remembering associations of adequate sounds with pups (virgins). Thus brain areas were differently activated in animals with maternal emotions, however different responses to pup cues depending on how they got primed to behave maternally and on how they evaluated the stimulation context. Copyright © 2012 Elsevier Ltd. All rights reserved.

  20. Progressive neuronal activation accompanies epileptogenesis caused by hippocampal glutamine synthetase inhibition.

    PubMed

    Albright, Benjamin; Dhaher, Roni; Wang, Helen; Harb, Roa; Lee, Tih-Shih W; Zaveri, Hitten; Eid, Tore

    2017-02-01

    Loss of glutamine synthetase (GS) in hippocampal astrocytes has been implicated in the causation of human mesial temporal lobe epilepsy (MTLE). However, the mechanism by which the deficiency in GS leads to epilepsy is incompletely understood. Here we ask how hippocampal GS inhibition affects seizure phenotype and neuronal activation during epilepsy development (epileptogenesis). Epileptogenesis was induced by infusing the irreversible GS blocker methionine sulfoximine (MSO) unilaterally into the hippocampal formation of rats. We then used continuous video-intracranial electroencephalogram (EEG) monitoring and c-Fos immunohistochemistry to determine the type of seizures and spatial distribution of neuronal activation early (1-5days postinfusion) and late (16-43days postinfusion) in epileptogenesis. Early in epileptogenesis, seizures were preferentially mild (stage 1-2), activating neurons in the entorhinal-hippocampal area, the basolateral amygdala, the piriform cortex, the midline thalamus, and the anterior olfactory area. Late in epileptogenesis, the seizures were generally more severe (stages 4-5) with neuronal activation extending to the neocortex, the bed nucleus of the stria terminalis, the mediodorsal thalamu\\s, and the central nucleus of the amygdala. Our findings demonstrate that inhibition of GS focally in the hippocampal formation triggers a process of epileptogenesis characterized by gradual worsening of seizure severity and involvement of progressively larger neuronal populations over a period of several weeks. Knowledge about the underlying mechanism of epileptogenesis is important because such knowledge may result in more specific and efficacious treatments of MTLE by moving away from large and poorly specific surgical resections to highly targeted surgical or pharmacological interventions of the epileptogenic process.

  1. Effects of chronic ethanol exposure on neuronal function in the prefrontal cortex and extended amygdala.

    PubMed

    Pleil, Kristen E; Lowery-Gionta, Emily G; Crowley, Nicole A; Li, Chia; Marcinkiewcz, Catherine A; Rose, Jamie H; McCall, Nora M; Maldonado-Devincci, Antoniette M; Morrow, A Leslie; Jones, Sara R; Kash, Thomas L

    2015-12-01

    Chronic alcohol consumption and withdrawal leads to anxiety, escalated alcohol drinking behavior, and alcohol dependence. Alterations in the function of key structures within the cortico-limbic neural circuit have been implicated in underlying the negative behavioral consequences of chronic alcohol exposure in both humans and rodents. Here, we used chronic intermittent ethanol vapor exposure (CIE) in male C57BL/6J mice to evaluate the effects of chronic alcohol exposure and withdrawal on anxiety-like behavior and basal synaptic function and neuronal excitability in prefrontal cortical and extended amygdala brain regions. Forty-eight hours after four cycles of CIE, mice were either assayed in the marble burying test (MBT) or their brains were harvested and whole-cell electrophysiological recordings were performed in the prelimbic and infralimbic medial prefrontal cortex (PLC and ILC), the lateral and medial central nucleus of the amygdala (lCeA and mCeA), and the dorsal and ventral bed nucleus of the stria terminalis (dBNST and vBNST). Ethanol-exposed mice displayed increased anxiety in the MBT compared to air-exposed controls, and alterations in neuronal function were observed in all brain structures examined, including several distinct differences between subregions within each structure. Chronic ethanol exposure induced hyperexcitability of the ILC, as well as a shift toward excitation in synaptic drive and hyperexcitability of vBNST neurons; in contrast, there was a net inhibition of the CeA. This study reveals extensive effects of chronic ethanol exposure on the basal function of cortico-limbic brain regions, suggests that there may be complex interactions between these regions in the regulation of ethanol-dependent alterations in anxiety state, and highlights the need for future examination of projection-specific effects of ethanol in cortico-limbic circuitry.

  2. Developmental changes in the acute ethanol sensitivity of glutamatergic and GABAergic transmission in the BNST.

    PubMed

    Wills, T A; Kash, T L; Winder, D G

    2013-11-01

    Glutamatergic and GABAergic transmission undergo significant changes during adolescence. Receptors for both of these transmitters (NMDAR, and GABAA) are known to be key targets for the acute effects of ethanol in adults. The current study set out to investigate the acute effects of ethanol on both NMDAR-mediated excitatory transmission and GABAergic inhibitory transmission within the bed nucleus of the stria terminalis (BNST) across age. The BNST is an area of the brain implicated in the negative reinforcing properties associated with alcohol dependence, and the BNST plays a critical role in stress-induced relapse. Therefore, assessing the developmental regulation of ethanol sensitivity in this key brain region is important to understanding the progression of ethanol dependence. To do this, whole-cell recordings of isolated NMDAR-evoked excitatory postsynaptic currents (eEPSCs) or evoked GABAergic inhibitory postsynaptic currents (eIPSCs) were performed on BNST neurons in slices from 4- or 8-week-old male C57BL/6J mice. Ethanol (50 mm) produced greater inhibition of NMDAR-eEPSCs in adolescent mice than in adult mice. This enhanced sensitivity in adolescence was not a result of shifts in function of the GluN2B subunit of the NMDAR, measured by Ro25-6981 inhibition and decay kinetics measured across age. Adolescent mice also exhibited greater ethanol sensitivity of GABAergic transmission, as ethanol (50 mm) enhanced eIPSCs in the BNST of adolescent but not adult mice. Collectively, this work illustrates that a moderate dose of ethanol produces greater inhibition of transmission in the BNST (through greater excitatory inhibition and enhancement of inhibitory transmission) in adolescents compared to adults. Given the role of the BNST in alcohol dependence, these developmental changes in acute ethanol sensitivity could accelerate neuroadaptations that result from chronic ethanol use during the critical period of adolescence.

  3. Oxytocin modulates unconditioned fear response in lactating dams: an fMRI study

    PubMed Central

    Febo, Marcelo; Shields, Jessica; Ferris, Craig F.; King, Jean A.

    2009-01-01

    Oxytocinergic neurotransmission during lactation contributes to reduction of anxiety levels and fear. However, our knowledge of where oxytocin acts in the brain to achieve this effect, particularly to an unconditioned fear stimulus, is incomplete. We used blood oxygenation level dependent (BOLD) fMRI to test whether central administration of oxytocin 45–60 minutes before fMRI scanning alters maternal brain activation in response to a predator scent (TMT, trimethylthiazoline). Comparison behavioral experiments that examined maternal responses to this unconditioned fear -inducing odor were carried out in a separate cohort of lactating rats given similar treatments. Behavioral experiments confirmed the effectiveness of oxytocin at reducing freezing behavior as compared to vehicle controls. Our fMRI findings indicate that oxytocin modulated both positive and negative BOLD responses across several olfactory and forebrain nuclei. Significantly greater percent increases in BOLD signal in response to TMT were observed in the anterior cingulate, bed nucleus of stria terminalis and perirhinal area of oxytocin pretreated rats. These animals also showed significantly larger percent decreases in BOLD in mammillary bodies, secondary motor cortex, gustatory cortex, prelimbic prefrontal cortex, orbital cortex, and the anterior olfactory nucleus. The observed pattern of brain activity suggests that oxytocin enhances neural processing in emotion and cognition driven brain areas such as the cingulate cortex, while dramatically reducing activity in areas also controlling autonomic, visceromotor and skeletomotor responses. The present data contribute to the growing literature suggesting the oxytocin modulate the integration of emotional and cognitive information through myriad brain regions to facilitate decreases in anxiety (even to an unconditioned stimulus) while potentially promoting pair-bonding, social memory and parental care. PMID:19766607

  4. From here to paternity: neural correlates of the onset of paternal behavior in California mice (Peromyscus californicus).

    PubMed

    de Jong, Trynke R; Chauke, Miyetani; Harris, Breanna N; Saltzman, Wendy

    2009-08-01

    In a minority of mammalian species, including humans, fathers play a significant role in infant care. Compared to maternal behavior, the neural and hormonal bases of paternal care are poorly understood. We analyzed behavioral, neuronal and neuropeptide responses towards unfamiliar pups in biparental California mice, comparing males housed with another male ("virgin males") or with a female before ("paired males") or after ("new fathers") the birth of their first litter. New fathers approached pups more rapidly and spent more time engaging in paternal behavior than virgin males. In each cage housing two virgin males, one was spontaneously paternal and one was not. New fathers and paired males spent more time sniffing and touching a wire mesh ball containing a newborn pup than virgin males. Only new fathers showed significantly increased Fos-like immunoreactivity in the medial preoptic nucleus (MPO) following exposure to a pup-containing ball, as compared to an empty ball. Moreover, Fos-LIR in the bed nucleus of the stria terminalis (STMV and STMPM) and caudal dorsal raphe nucleus (DRC) was increased in new fathers, independent of test condition. No differences were found among the groups in Fos-LIR in oxytocinergic or vasopressinergic neurons. These results suggest that sexual and paternal experiences facilitate paternal behavior, but other cues play a role as well. Paternal experience increases Fos-LIR induced by distal pup cues in the MPO, but not in oxytocin and vasopressin neurons. Fatherhood also appears to alter neurotransmission in the BNST and DRC, regions implicated in emotionality and stress-responsiveness.

  5. Nicotine evoked improvement in learning and memory is mediated through NPY Y1 receptors in rat model of Alzheimer's disease.

    PubMed

    Rangani, Ritesh J; Upadhya, Manoj A; Nakhate, Kartik T; Kokare, Dadasaheb M; Subhedar, Nishikant K

    2012-02-01

    We investigated the role of endogenous neuropeptide Y (NPY) system in nicotine-mediated improvement of learning and memory in rat model of Alzheimer's disease (AD). Intracerebroventricular (icv) colchicine treatment induced AD-like condition in rats and showed increased escape latency (decreased learning), and amnesic condition in probe test in Morris water maze. In these rats, nicotine (0.5mg/kg, intraperitoneal), NPY (100 ng/rat, icv) or NPY Y1 receptor agonist [Leu(31), Pro(34)]-NPY (0.04 ng/rat, icv) decreased escape latency by 54.76%, 55.81% and 44.18%, respectively, on day 4 of the acquisition. On the other hand, selective NPY Y1 receptor antagonist, BIBP3226 (icv) produced opposite effect (44.18%). In the probe test conducted at 24h time point, nicotine, NPY or [Leu(31), Pro(34)]-NPY increased the time spent by 72.72%, 44.11% and 26.47%, respectively; while BIBP3226 caused reduction (8.82%). It seems that while NPY or [Leu(31), Pro(34)]-NPY potentiated, BIBP3226 attenuated the learning and memory enhancing effects of nicotine. Brains of colchicine treated rats showed significant reduction in NPY-immunoreactivity in the nucleus accumbens shell (cells 62.23% and fibers 50%), bed nucleus of stria terminalis (fibers 71.58%), central nucleus of amygdala (cells 74.33%), arcuate nucleus (cells 70.97% and fibers 69.65%) and dentate gyrus (cells 58.54%). However, in these rats nicotine treatment for 4 days restored NPY-immunoreactivity to the control level. We suggest that NPY, perhaps acting via NPY Y1 receptors, might interact with the endogenous cholinergic system and play a role in improving the learning and memory processes in the rats with AD-like condition.

  6. Somatostatin receptor subtype 4 activation is involved in anxiety and depression-like behavior in mouse models.

    PubMed

    Scheich, Bálint; Gaszner, Balázs; Kormos, Viktória; László, Kristóf; Ádori, Csaba; Borbély, Éva; Hajna, Zsófia; Tékus, Valéria; Bölcskei, Kata; Ábrahám, István; Pintér, Erika; Szolcsányi, János; Helyes, Zsuzsanna

    2016-02-01

    Somatostatin regulates stress-related behavior and its expression is altered in mood disorders. However, little is known about the underlying mechanisms, especially about the importance of its receptors (sst1-sst5) in anxiety and depression-like behavior. Here we analyzed the potential role of sst4 receptor in these processes, since sst4 is present in stress-related brain regions, but there are no data about its functional relevance. Genetic deletion of sst4 (Sstr4(-/-)) and its pharmacological activation with the newly developed selective non-peptide agonist J-2156 were used. Anxiety was examined in the elevated plus maze (EPM) and depression-like behavior in the forced swim (FST) and tail suspension tests (TST). Neuronal activation during the TST was monitored by Fos immunohistochemistry, receptor expression was identified by sst4(LacZ) immunostaining in several brain regions. Sstr4(-/-) mice showed increased anxiety in the EPM and enhanced depression-like behavior in the FST. J-2156 (100 μg/kg i.p.) exhibited anxiolytic effect in the EPM and decreased immobility in the TST. J-2156 alone did not influence Fos immunoreactivity in intact mice, but significantly increased the stress-induced Fos response in the dorsal raphe nucleus, central projecting Edinger-Westphal nucleus, periaqueductal gray matter, the magnocellular, but not the parvocellular part of the hypothalamic paraventricular nucleus, lateral septum, bed nucleus of the stria terminalis and the amygdala. Notably, sst4(LacZ) immunoreactivity occurred in the central and basolateral amygdala. Together, these studies reveal that sst4 mediates anxiolytic and antidepressant-like effects by enhancing the stress-responsiveness of several brain regions with special emphasis on the amygdala. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

    PubMed Central

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

    2011-01-01

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

  8. Local oxytocin expression and oxytocin receptor binding in the male rat brain is associated with aggressiveness.

    PubMed

    Calcagnoli, Federica; de Boer, Sietse F; Beiderbeck, Daniela I; Althaus, Monika; Koolhaas, Jaap M; Neumann, Inga D

    2014-03-15

    We recently demonstrated in male wild-type Groningen rats that enhancing brain oxytocin (OXT) levels acutely produces marked pro-social explorative and anti-aggressive effects. Moreover, these pharmacologically-induced changes are moderated by the individual's aggressive phenotype, suggesting an inverse relationship between aggressiveness and tonic endogenous OXT signaling properties. Aim of the present study was to verify the hypothesis that variations in OXT expression and/or OXT receptor (OXTR) binding in selected brain regions are associated with different levels or forms of aggression. To this end, male resident wild-type Groningen rats that repeatedly contested and dominated intruder conspecifics were categorized as being low aggressive, highly aggressive or excessively aggressive. Their brains were subsequently collected and quantified for OXT mRNA expression and OXTR binding levels. Our results showed that OXT mRNA expression in the hypothalamic paraventricular nucleus (PVN), but not in the supraoptic nucleus (SON), negatively correlates with the level of offensiveness. In particular, the excessively aggressive group showed a significantly lower OXT mRNA expression in the PVN as compared to both low and highly aggressive groups. Further, the excessively aggressive animals showed the highest OXTR binding in the central amygdala (CeA) and bed nucleus of the stria terminalis (BNST). These findings demonstrate that male rats with excessively high levels and abnormal forms of aggressive behavior have diminished OXT transcription and enhanced OXTR binding capacities in specific nodes of the social behavioral brain circuitry. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. Modulation of nucleus accumbens connectivity by alcohol drinking and naltrexone in alcohol-preferring rats: A manganese-enhanced magnetic resonance imaging study.

    PubMed

    Dudek, Mateusz; Canals, Santiago; Sommer, Wolfgang H; Hyytiä, Petri

    2016-03-01

    The nonselective opioid receptor antagonist naltrexone is now used for the treatment of alcoholism, yet naltrexone's central mechanism of action remains poorly understood. One line of evidence suggests that opioid antagonists regulate alcohol drinking through interaction with the mesolimbic dopamine system. Hence, our goal here was to examine the role of the nucleus accumbens connectivity in alcohol reinforcement and naltrexone's actions using manganese-enhanced magnetic resonance imaging (MEMRI). Following long-term free-choice drinking of alcohol and water, AA (Alko Alcohol) rats received injections of MnCl2 into the nucleus accumbens for activity-dependent tracing of accumbal connections. Immediately after the accumbal injections, rats were imaged using MEMRI, and then allowed to drink either alcohol or water for the next 24h. Naltrexone was administered prior to the active dark period, and the second MEMRI was performed 24h after the first scan. Comparison of signal intensity at 1 and 24h after accumbal MnCl2 injections revealed an ipsilateral continuum through the ventral pallidum, bed nucleus of the stria terminalis, globus pallidus, and lateral hypothalamus to the substantia nigra and ventral tegmental area. Activation was also seen in the rostral part of the insular cortex and regions of the prefrontal cortex. Alcohol drinking resulted in enhanced activation of these connections, whereas naltrexone suppressed alcohol-induced activity. These data support the involvement of the accumbal connections in alcohol reinforcement and mediation of naltrexone's suppressive effects on alcohol drinking through their deactivation. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

  10. Blockade of 5-Ht3 receptors in the septal area increases Fos expression in selected brain areas.

    PubMed

    Urzedo-Rodrigues, Lilia S; Ferreira, Hilda S; Santana, Rejane Conceição; Luz, Carla Patrícia; Perrone, Camila F; Fregoneze, Josmara B

    2014-04-01

    Serotonin is widely distributed throughout the brain and is involved in a multiplicity of visceral, cognitive and behavioral responses. It has been previously shown that injections of different doses of ondansetron, a 5-HT3 receptor antagonist, into the medial septum/vertical limb of the diagonal band complex (MS/vDB) induce a hypertensive response in rats. On the other hand, administration of m-CPBG, a 5-HT3 agonist, into the MS/vDB inhibits the increase of blood pressure during restraint stress. However, it is unclear which neuronal circuitry is involved in these responses. The present study investigated Fos immunoreactive nuclei (Fos-IR) in different brain areas following the blockade of 5-HT3 receptors located in the MS/vDB in sham and in sinoaortic denervated (SAD) rats. Ondansetron injection into the MS/vDB increases Fos-IR in different brain areas including the limbic system (central amygdala and ventral part of the bed nucleus of the stria terminalis), hypothalamus (medial parvocellular parts of the paraventricular nucleus, anterodorsal preoptic area, dorsomedial hypothalamic nucleus), mesencephalon (ventrolateral periaqueductal gray region) and rhombencephalon (lateral parabrachial nucleus) in sham rats. Barodenervation results in higher Fos expression at the parvocellular and magnocellular part of the paraventricular nucleus, the lateral parabrachial nucleus, the central nucleus of amygdala, the locus coeruleus, the medial part of the nucleus of the solitary tract, the rostral ventrolateral medulla and the caudal ventrolateral medulla following 5-HT3receptor blockade in the MS/vDB. Based on the present results and previous data showing a hypertensive response to ondansetron injected into the MS/vDB, it is reasonable to suggest that 5-HT3receptors in the MS/vDB exert an inhibitory drive that may oscillate as a functional regulatory part of the complex central neuronal network participating in the control of blood pressure.

  11. The underestimated role of olfaction in avian reproduction ?

    PubMed Central

    Balthazart, Jacques; Taziaux, Mélanie

    2009-01-01

    Until the second half of the 20th century, it was broadly accepted that most birds are microsmatic if not anosmic and unable to detect and use olfactory information. Exceptions were eventually conceded for species like procellariiforms, vultures or kiwis that detect their food at least in part based on olfactory signals. During the past 20–30 years, many publications have appeared indicating that this view is definitely erroneous. We briefly review here anatomical, electrophysiological and behavioral data demonstrating that birds in general possess a functional olfactory system and are able to use olfactory information in a variety of ethological contexts, including reproduction. Recent work also indicates that brain activation induced by sexual interactions with a female is significantly affected by olfactory deprivation in Japanese quail. Brain activation was measured via immunocytochemical detection of the protein product of the immediate early gene c-fos. Changes observed concerned two brain areas that play a key role in the control of male sexual behavior, the medial preoptic nucleus and the bed nucleus of the stria terminalis therefore suggesting a potential role of olfaction in the control of reproduction. The widespread idea that birds are anosmic or microsmatic is thus not supported by the available experimental data and presumably originates in our anthropomorphic view that leads us to think that birds do not smell because they have a rigid beak and nostrils and do not obviously sniff. Experimental analysis of this phenomenon is thus warranted and should lead to a significant change in our understanding of avian biology. PMID:18804490

  12. Olfactory systems and neural circuits that modulate predator odor fear

    PubMed Central

    Takahashi, Lorey K.

    2014-01-01

    When prey animals detect the odor of a predator a constellation of fear-related autonomic, endocrine, and behavioral responses rapidly occur to facilitate survival. How olfactory sensory systems process predator odor and channel that information to specific brain circuits is a fundamental issue that is not clearly understood. However, research in the last 15 years has begun to identify some of the essential features of the sensory detection systems and brain structures that underlie predator odor fear. For instance, the main (MOS) and accessory olfactory systems (AOS) detect predator odors and different types of predator odors are sensed by specific receptors located in either the MOS or AOS. However, complex predator chemosignals may be processed by both the MOS and AOS, which complicate our understanding of the specific neural circuits connected directly and indirectly from the MOS and AOS to activate the physiological and behavioral components of unconditioned and conditioned fear. Studies indicate that brain structures including the dorsal periaqueductal gray (DPAG), paraventricular nucleus (PVN) of the hypothalamus, and the medial amygdala (MeA) appear to be broadly involved in predator odor induced autonomic activity and hypothalamic-pituitary-adrenal (HPA) stress hormone secretion. The MeA also plays a key role in predator odor unconditioned fear behavior and retrieval of contextual fear memory associated with prior predator odor experiences. Other neural structures including the bed nucleus of the stria terminalis and the ventral hippocampus (VHC) appear prominently involved in predator odor fear behavior. The basolateral amygdala (BLA), medial hypothalamic nuclei, and medial prefrontal cortex (mPFC) are also activated by some but not all predator odors. Future research that characterizes how distinct predator odors are uniquely processed in olfactory systems and neural circuits will provide significant insights into the differences of how diverse predator

  13. Dopaminergic Regulation of Mate Competition Aggression and Aromatase-Fos Colocalization in Vasotocin Neurons

    PubMed Central

    Kabelik, David; Kelly, Aubrey M.; Goodson, James L.

    2009-01-01

    Summary Recent experiments demonstrate that aggressive competition for potential mates involves different neural mechanisms than does territorial, resident-intruder aggression. However, despite the obvious importance of mate competition aggression, we know little about its regulation. Immediate early gene experiments show that in contrast to territorial aggression, mate competition in finches is accompanied by the activation of neural populations associated with affiliation and motivation, including vasotocin (VT) neurons in the medial bed nucleus of the stria terminalis (BSTm) and midbrain dopamine (DA) neurons that project to the BSTm. Although VT is known to facilitate mate competition aggression, the role of DA has not previously been examined. We now show that in male zebra finches (Taeniopygia guttata), mate competition aggression is inhibited by the D2 agonist quinpirole, though not the D1 agonist SKF-38393 or the D4 agonist PD168077. The D3 agonist 7-OH-DPAT also inhibited aggression, but only following high dose treatment that may affect aggression via non-specific binding to D2 receptors. Central VT infusion failed to restore D2 agonist-inhibited aggression in a subsequent experiment, demonstrating that D2 does not suppress aggression by inhibiting VT release from BSTm neurons. In a final experiment, we detected D2 agonist-induced increases in immunofluorescent colocalization of the product of the immediate early gene c-fos and the steroid-converting enzyme aromatase (ARO) within VT neurons of the BSTm. Thus, although VT and DA appear to influence mate competition aggression independently, BSTm VT neurons are clearly influenced by the activation of D2 receptors, which may modify future behaviors. PMID:19540858

  14. Conditioned Fear Inhibits c-fos mRNA Expression in the Central Extended Amygdala

    PubMed Central

    Day, Heidi E.W.; Kryskow, Elisa M.; Nyhuis, Tara J.; Herlihy, Lauren; Campeau, Serge

    2008-01-01

    We have shown previously that unconditioned stressors inhibit neurons of the lateral/capsular division of the central nucleus of the amygdala (CEAl/c) and oval division of the bed nucleus of the stria terminalis (BSTov), which form part of the central extended amygdala. The current study investigated whether conditioned fear inhibits c-fos mRNA expression in these regions. Male rats were trained either to associate a visual stimulus (light) with footshock or were exposed to the light alone. After training, animals were replaced in the apparatus, and 2 hours later injected remotely, via a catheter, with amphetamine (2 mg/kg i.p.), to induce c-fos mRNA and allow inhibition of expression to be measured. The rats were then presented with 15 visual stimuli over a 30 minute period. As expected, fear conditioned animals that were not injected with amphetamine, had extremely low levels of c-fos mRNA in the central extended amygdala. In contrast, animals that were trained with the light alone (no fear conditioning) and were injected with amphetamine had high levels of c-fos mRNA in the CEAl/c and BSTov. Animals that underwent fear-conditioning, and were re-exposed to the conditioned stimulus after amphetamine injection had significantly reduced levels of c-fos mRNA in both the BSTov and CEAl/c, compared to the non-conditioned animals. These data suggest that conditioned fear can inhibit neurons of the central extended amygdala. Because these neurons are GABAergic, and project to the medial CEA (an amygdaloid output region), this may be a novel mechanism whereby conditioned fear potentiates amygdaloid output. PMID:18634767

  15. Relationships between rapid changes in local aromatase activity and estradiol concentrations in male and female quail brain.

    PubMed

    Dickens, M J; de Bournonville, C; Balthazart, J; Cornil, C A

    2014-02-01

    Estradiol-17β (E2) synthesized in the brain plays a critical role in the activation of sexual behavior in many vertebrate species. Because E2 concentrations depend on aromatization of testosterone, changes in aromatase enzymatic activity (AA) are often utilized as a proxy to describe E2 concentrations. Utilizing two types of stimuli (sexual interactions and acute restraint stress) that have been demonstrated to reliably alter AA within minutes in opposite directions (sexual interactions=decrease, stress=increase), we tested in Japanese quail whether rapid changes in AA are paralleled by changes in E2 concentrations in discrete brain areas. In males, E2 in the pooled medial preoptic nucleus/medial portion of the bed nucleus of the stria terminalis (POM/BST) positively correlated with AA following sexual interactions. However, following acute stress, E2 decreased significantly (approximately 2-fold) in the male POM/BST despite a significant increase in AA. In females, AA positively correlated with E2 in both the POM/BST and mediobasal hypothalamus supporting a role for local, as opposed to ovarian, production regulating brain E2 concentrations. In addition, correlations of individual E2 in POM/BST and measurements of female sexual behavior suggested a role for local E2 synthesis in female receptivity. These data demonstrate that local E2 in the male brain changes in response to stimuli on a time course suggestive of potential non-genomic effects on brain and behavior. Overall, this study highlights the complex mechanisms regulating local E2 concentrations including rapid stimulus-driven changes in production and stress-induced changes in catabolism. Copyright © 2013 Elsevier Inc. All rights reserved.

  16. Beyond the Classic VTA: Extended Amygdala Projections to DA-Striatal Paths in the Primate.

    PubMed

    Fudge, Julie L; Kelly, Emily A; Pal, Ria; Bedont, Joseph L; Park, Lydia; Ho, Brian

    2017-03-22

    The central extended amygdala (CEA) has been conceptualized as a 'macrosystem' that regulates various stress-induced behaviors. Consistent with this, the CEA highly expresses corticotropin-releasing factor (CRF), an important modulator of stress responses. Stress alters goal-directed responses associated with striatal paths, including maladaptive responses such as drug seeking, social withdrawal, and compulsive behavior. CEA inputs to the midbrain dopamine (DA) system are positioned to influence striatal functions through mesolimbic DA-striatal pathways. However, the structure of this amygdala-CEA-DA neuron path to the striatum has been poorly characterized in primates. In primates, we combined neuronal tracer injections into various arms of the circuit through specific DA subpopulations to assess: (1) whether the circuit connecting amygdala, CEA, and DA cells follows CEA intrinsic organization, or a more direct topography involving bed nucleus vs central nucleus divisions; (2) CRF content of the CEA-DA path; and (3) striatal subregions specifically involved in CEA-DA-striatal loops. We found that the amygdala-CEA-DA path follows macrostructural subdivisions, with the majority of input/outputs converging in the medial central nucleus, the sublenticular extended amygdala, and the posterior lateral bed nucleus of the stria terminalis. The proportion of CRF+ outputs is >50%, and mainly targets the A10 parabrachial pigmented nucleus (PBP) and A8 (retrorubal field, RRF) neuronal subpopulations, with additional inputs to the dorsal A9 neurons. CRF-enriched CEA-DA projections are positioned to influence outputs to the 'limbic-associative' striatum, which is distinct from striatal regions targeted by DA cells lacking CEA input. We conclude that the concept of the CEA is supported on connectional grounds, and that CEA termination over the PBP and RRF neuronal populations can influence striatal circuits involved in associative learning.Neuropsychopharmacology advance online

  17. Nucleus Paragigantocellularis Afferents in Male and Female Rats: Organization, Gonadal Steroid Sensitivity, and Activation During Sexual Behavior

    PubMed Central

    Normandin, Joseph J.; Murphy, Anne Z.

    2010-01-01

    The central regulation of genital reflexes is poorly understood. The brainstem nucleus paragigantocellularis (nPGi) of rats is a well-established source of tonic inhibition of genital reflexes. However the organization, gonadal steroid sensitivity, and activity of nPGi afferents during sex have not been fully characterized in male and female rats. To delineate the anatomical and physiological organization of nPGi afferents, the retrograde tracer Fluorogold (FG) was injected into the nPGi of sexually experienced male and female rats. Animals engaged in sexual behavior one hour before sacrifice. Cells containing FG, estrogen receptor alpha (ERα), androgen receptor (AR), and the immediate-early gene product Fos were identified immunocytochemically. Retrograde labeling from the nPGi was prominent in the bed nucleus of the stria terminalis, paraventricular nucleus, posterior hypothalamus, precommissural nucleus, deep mesencephalic nucleus, and periaqueductal gray (PAG) of both sexes. Sex differences were observed in the caudal medial preoptic area (MPO), with significantly more FG+ cells observed in males and in the PAG and inferior colliculus where significantly more FG+ cells were observed in females. The majority of regions that contained FG+ cells also contained ERα or AR, indicating sensitivity to gonadal steroids. The proportions of FG+ cells that co-localized with sex-induced Fos was high in the PVN of both sexes, high in the MPO of males, but low in the PAG of both sexes despite the large number of PAG-nPGi output neurons and Fos+ cells in both sexes. The characterization of these afferents will lead to a further understanding of the neural regulation of genital reflexes. PMID:18393295

  18. Region-dependent dynamics of cAMP response element-binding protein phosphorylation in the basal ganglia

    PubMed Central

    Liu, Fu-Chin; Graybiel, Ann M.

    1998-01-01

    The cAMP response element-binding protein (CREB) is an activity-dependent transcription factor that is involved in neural plasticity. The kinetics of CREB phosphorylation have been suggested to be important for gene activation, with sustained phosphorylation being associated with downstream gene expression. If so, the duration of CREB phosphorylation might serve as an indicator for time-sensitive plastic changes in neurons. To screen for regions potentially involved in dopamine-mediated plasticity in the basal ganglia, we used organotypic slice cultures to study the patterns of dopamine- and calcium-mediated CREB phosphorylation in the major subdivisions of the striatum. Different durations of CREB phosphorylation were evoked in the dorsal and ventral striatum by activation of dopamine D1-class receptors. The same D1 stimulus elicited (i) transient phosphorylation (≤15 min) in the matrix of the dorsal striatum; (ii) sustained phosphorylation (≤2 hr) in limbic-related structures including striosomes, the nucleus accumbens, the fundus striati, and the bed nucleus of the stria terminalis; and (iii) prolonged phosphorylation (up to 4 hr or more) in cellular islands in the olfactory tubercle. Elevation of Ca2+ influx by stimulation of L-type Ca2+ channels, NMDA, or KCl induced strong CREB phosphorylation in the dorsal striatum but not in the olfactory tubercle. These findings differentiate the response of CREB to dopamine and calcium signals in different striatal regions and suggest that dopamine-mediated CREB phosphorylation is persistent in limbic-related regions of the neonatal basal ganglia. The downstream effects activated by persistent CREB phosphorylation may include time-sensitive neuroplasticity modulated by dopamine. PMID:9539803

  19. Forebrain patterns of c-Fos and FosB induction during cancer-associated anorexia-cachexia in rat.

    PubMed

    Konsman, Jan Pieter; Blomqvist, Anders

    2005-05-01

    Forebrain structures are necessary for the initiation of food intake and its coupling to energy expenditure. The cancer-related anorexia-cachexia syndrome is typified by a prolonged increase in metabolic rate resulting in body weight loss which, paradoxically, is accompanied by reduced food intake. The aim of the present work was to study the forebrain expression of Fos proteins as activation markers and thus to identify potential neurobiological mechanisms favouring catabolic processes or modulating food intake in rats suffering from cancer-related anorexia-cachexia. Neurons in forebrain structures showing most pronounced induction of Fos proteins were further identified neurochemically. To provoke anorexia-cachexia, cultured Morris hepatoma 7777 cells were injected subcutaneously in Buffalo rats. This resulted in a slowly growing tumour inducing approximately 7% body weight loss and a 20% reduction in food intake when the tumour represented 1-2% of body mass. Anorexia-cachexia in these animals was found to be accompanied by Fos induction in several hypothalamic nuclei including the paraventricular and ventromedial hypothalamus, in the parastrial nucleus, the amygdala, the bed nucleus of the stria terminalis, ventral striatal structures and the piriform and somatosensory cortices. Neurochemical identification revealed that the vast majority of FosB-positive neurons in the nucleus accumbens, ventral caudate-putamen and other ventral striatal structures contained prodynorphin or proenkephalin mRNA. These findings indicate that forebrain structures that are part of neuronal networks modulating catabolic pathways and food ingestion are activated during tumour-associated anorexia-cachexia and may contribute to the lack of compensatory eating in response to weight loss characterizing this syndrome.

  20. Brain regions associated with the reversal of cocaine conditioned place preference by environmental enrichment.

    PubMed

    Chauvet, C; Lardeux, V; Jaber, M; Solinas, M

    2011-06-16

    In addition to the known preventive effects of environmental enrichment (EE) on drug addiction, we have recently shown that EE can also have "curative" effects and eliminate addiction-related behaviors in mice and rats. In the present study, using Fos immunohistochemistry, we investigated brain regions involved in the elimination of cocaine conditioned place preference (CPP) produced by a 30-day exposure to EE. A first group of mice was conditioned to cocaine in the CPP apparatus, a second group that served as control received cocaine in a cage different from the CPP apparatus and a third control group received only saline injections. At the end of conditioning, we kept mice abstinent in the animal facility, housing them in standard environments (SE) or EE for 30 days and then we tested them for expression of CPP. SE, but not EE mice, conditioned to cocaine showed long-lasting preferences for the cocaine-paired compartment. Expression of CPP was paralleled by significant increases in the expression of Fos in the anterior cingulate cortex, the lateral caudate putamen, the shell of the nucleus accumbens, the dentate gyrus of the hippocampus, the basolateral and central nuclei of amygdala, the bed nucleus of the stria terminalis, and the ventral tegmental area. In contrast, EE mice showed levels of expression of FOS similar to control groups. These results demonstrate that EE can eliminate context-induced cocaine seeking and that this effect appears associated with a general reduction in the activation of several brain regions implicated in relapse. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

  1. Corticosteroid-dependent plasticity mediates compulsive alcohol drinking in rats

    PubMed Central

    Vendruscolo, Leandro F.; Barbier, Estelle; Schlosburg, Joel E.; Misra, Kaushik K.; Whitfield, Timothy W.; Logrip, Marian L.; Rivier, Catherine; Repunte-Canonigo, Vez; Zorrilla, Eric P.; Sanna, Pietro P.; Heilig, Markus; Koob, George F.

    2012-01-01

    Alcoholism is characterized by a compulsion to seek and ingest alcohol, loss of control over intake, and the emergence of a negative emotional state during abstinence. We hypothesized that sustained activation of neuroendocrine stress systems (e.g., corticosteroid release via the hypothalamic-pituitary-adrenal [HPA] axis) by alcohol intoxication and withdrawal and consequent alterations in glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) activation drive compulsive alcohol drinking. Our results showed that rats exposed to alcohol vapor to the point of dependence displayed increased alcohol intake, compulsive drinking measured by progressive-ratio responding, and persistent alcohol consumption despite punishment, assessed by adding quinine to the alcohol solution, compared with control rats that were not exposed to alcohol vapor. No group differences were observed in the self-administration of saccharin-sweetened water. Acute alcohol withdrawal was accompanied by downregulated GR mRNA in various stress/reward-related brain regions (i.e., prefrontal cortex, nucleus accumbens [NAc], and bed nucleus of the stria terminalis [BNST]), whereas protracted alcohol abstinence was accompanied by upregulated GR mRNA in the NAc core, ventral BNST, and central nucleus of the amygdala. No significant alterations in MR mRNA levels were found. Chronic GR antagonism with mifepristone (RU38486) prevented the escalation of alcohol intake and compulsive responding induced by chronic, intermittent alcohol vapor exposure. Chronic treatment with mifepristone also blocked escalated alcohol drinking and compulsive responding during protracted abstinence. Thus, the GR system appears to be involved in the development of alcohol dependence and may represent a potential pharmacological target for the treatment of alcoholism. PMID:22649234

  2. Brain activation by an olfactory stimulus paired with juvenile play in female rats.

    PubMed

    Paredes-Ramos, P; McCarthy, M M; Bowers, J M; Miquel, M; Manzo, J; Coria-Avila, G A

    2014-06-22

    We have previously shown that reward experienced during social play at juvenile age can be paired with artificial odors, and later in adulthood facilitate olfactory conditioned partner preferences (PP) in female rats. Herein, we examined the expression of FOS immunoreactivity (FOS-IR) following exposure to the odor paired with juvenile play (CS+). Starting at day P31 females received daily 30-min periods of social play with lemon-scented (paired group) or unscented females (unpaired group). At day P42, they were tested for play-PP with two juvenile males, one bearing the CS+ (lemon) and one bearing a novel odor (almond). Females were ovariectomized, hormone-primed and at day P55 tested for sexual-PP between two adult stud males scented with lemon or almond. In both tests, females from the paired group displayed conditioned PP (play or sexual) toward males bearing the CS+. In the present experiments females were exposed at day P59 to the CS+ during 60 min and their brains processed for FOS-IR. One group of female rats (Play+Sex) underwent play-PP and sexual-PP, whereas a second group of females (Play-only) underwent exclusively play-PP but not sexual-PP. Results showed that in the Play-only experiment exposure to the CS+ induced more FOS-IR in the medial prefrontal cortex, orbitofrontal cortex, dorsal striatum, and ventral tegmental area as compared to females from the unpaired group. In the Play+Sex experiment, more FOS-IR was observed in the piriform cortex, dorsal striatum, lateral septum, nucleus accumbens shell, bed nucleus of the stria terminalis and medial amygdala as compared to females from the unpaired group. Taken together, these results indicate mesocorticolimbic brain areas direct the expectation and/or choice of conditioned partners in female rats. In addition, transferring the meaning of play to sex preference requires different brain areas.

  3. Sex-Dependent Effects of Prenatal Stress on Social Memory in Rats: A Role for Differential Expression of Central Vasopressin-1a Receptors.

    PubMed

    Grundwald, N J; Benítez, D P; Brunton, P J

    2016-04-01

    Prenatal stress (PNS) affects a number of traits in the offspring, including stress axis regulation, emotionality and cognition; however, much less is known about the effects of PNS on social memory and the underlying central mechanisms. In the present study, we investigated social preference, social memory under basal and stress conditions and olfactory memory for social and nonsocial odours in the adult offspring of dams exposed to social stress during late pregnancy. Given the key roles that the central oxytocin and vasopressin systems play in facilitating social memory, we further investigated the effects of PNS on the central expression of mRNA for oxytocin (Oxtr) and vasopressin-1a (Avpr1a) receptors. PNS did not affect social preference in either sex; however, social memory was impaired under basal conditions in PNS females but not PNS males. Accordingly, Avpr1a mRNA expression in the lateral septum and bed nucleus of stria terminalis (BNST) was unaltered in males but was significantly lower in PNS females compared to controls. No differences in Oxtr mRNA expression were detected between control and PNS offspring in either sex in any of the brain regions examined. Social memory deficits in PNS females persisted when social odours were used; however, this does not appear to be a result of impaired olfaction because memory for nonsocial odours was similar in control and PNS females. Under acute stress conditions, deficits in social memory were observed in both male and female control offspring; however, PNS males were unaffected. Moreover, acute stress facilitated social memory in PNS females and this was associated with an up-regulation of Avpr1a mRNA in the lateral septum and BNST. Our data support a role for altered signalling via central Avpr1a in PNS-induced sex-dependent changes in social memory and may have implications for understanding the aetiology of neurodevelopmental disorders characterised by social behaviour deficits in humans.

  4. The long-term effects of stress and kappa opioid receptor activation on conditioned place aversion in male and female California mice.

    PubMed

    Laman-Maharg, Abigail R; Copeland, Tiffany; Sanchez, Evelyn Ordoñes; Campi, Katharine L; Trainor, Brian C

    2017-08-14

    Psychosocial stress leads to the activation of kappa opioid receptors (KORs), which induce dysphoria and facilitate depression-like behaviors. However, less is known about the long-term effects of stress and KORs in females. We examined the long-term effects of social defeat stress on the aversive properties of KOR activation in male and female California mice (Peromyscus californicus) using a conditioned place aversion paradigm. Female California mice naïve to social defeat, formed a place aversion following treatment with 2.5mg/kg of the KOR agonist U50,488, but females exposed to defeat did not form a place aversion to this dose. This supports the finding by others that social defeat weakens the aversive properties of KOR agonists. In contrast, both control and stressed males formed an aversion to 10mg/kg of U50,488. We also examined EGR1 immunoreactivity, an indirect marker of neuronal activity, in the nucleus accumbens (NAc) and found that stress and treatment with 10mg/kg of U50,488 increased EGR1 immunoreactivity in the NAc core in females but reduced activation in males. The effects of stress and U50,488 on EGR1 were specific to the NAc, as we found no differences in the bed nucleus of the stria terminalis. In summary, our data indicate important sex differences in the long-term effects of stress and indicate the need for further study of the molecular mechanisms mediating the behavioral effects of KOR in both males and females. Copyright © 2017 Elsevier B.V. All rights reserved.

  5. The effects of perinatal testosterone exposure on the DNA methylome of the mouse brain are late-emerging.

    PubMed

    Ghahramani, Negar M; Ngun, Tuck C; Chen, Pao-Yang; Tian, Yuan; Krishnan, Sangitha; Muir, Stephanie; Rubbi, Liudmilla; Arnold, Arthur P; de Vries, Geert J; Forger, Nancy G; Pellegrini, Matteo; Vilain, Eric

    2014-01-01

    The biological basis for sex differences in brain function and disease susceptibility is poorly understood. Examining the role of gonadal hormones in brain sexual differentiation may provide important information about sex differences in neural health and development. Permanent masculinization of brain structure, function, and disease is induced by testosterone prenatally in males, but the possible mediation of these effects by long-term changes in the epigenome is poorly understood. We investigated the organizational effects of testosterone on the DNA methylome and transcriptome in two sexually dimorphic forebrain regions-the bed nucleus of the stria terminalis/preoptic area and the striatum. To study the contribution of testosterone to both the establishment and persistence of sex differences in DNA methylation, we performed genome-wide surveys in male, female, and female mice given testosterone on the day of birth. Methylation was assessed during the perinatal window for testosterone's organizational effects and in adulthood. The short-term effect of testosterone exposure was relatively modest. However, in adult animals the number of genes whose methylation was altered had increased by 20-fold. Furthermore, we found that in adulthood, methylation at a substantial number of sexually dimorphic CpG sites was masculinized in response to neonatal testosterone exposure. Consistent with this, testosterone's effect on gene expression in the striatum was more apparent in adulthood. Taken together, our data imply that the organizational effects of testosterone on the brain methylome and transcriptome are dramatic and late-emerging. Our findings offer important insights into the long-term molecular effects of early-life hormonal exposure.

  6. A role for the extended amygdala in the fear-enhancing effects of acute selective serotonin reuptake inhibitor treatment

    PubMed Central

    Ravinder, S; Burghardt, N S; Brodsky, R; Bauer, E P; Chattarji, S

    2013-01-01

    Selective serotonin reuptake inhibitors (SSRIs) are reported to exacerbate symptoms of anxiety when treatment is initiated. These clinical findings have been extended to animal models wherein SSRIs also potentiate anxiety and fear learning, which depend on the amygdala. Yet, little is known about the role of specific amygdalar circuits in these acute effects of SSRIs. Here, we first confirmed that a single injection of fluoxetine 1 h before auditory fear conditioning potentiated fear memory in rats. To probe the neural substrates underlying this enhancement, we analyzed the expression patterns of the immediate early gene, Arc (activity-regulated cytoskeleton-associated protein). Consistent with previous reports, fear conditioning induced Arc protein expression in the lateral and basal amygdala. However, this was not enhanced further by pre-treatment with fluoxetine. Instead, fluoxetine significantly enhanced expression of Arc in the central amygdala (CeA) and the bed nucleus of the stria terminalis (BNST). Next, we tested whether direct targeted infusions of fluoxetine into the CeA, or BNST, leads to the same fear-potentiating effect. Strikingly, direct infusion of fluoxetine into the BNST, but not the CeA, was sufficient to enhance fear memory. Moreover, this behavioral effect was also accompanied by robust Arc expression in the CeA, similar to the systemic injection. Our results identify a novel role for the BNST in the acute fear-enhancing effects of SSRIs. These findings highlight the need to look beyond the traditional focus on input nuclei of the amygdala and add to accumulating evidence implicating these microcircuits in gating fear and anxiety. PMID:23321806

  7. Effects of chronic ethanol exposure on neuronal function in the prefrontal cortex and extended amygdala

    PubMed Central

    Pleil, Kristen E.; Lowery-Gionta, Emily G.; Crowley, Nicole A.; Li, Chia; Marcinkiewcz, Catherine A.; Rose, Jamie H.; McCall, Nora M.; Maldonado-Devincci, Antoniette M.; Morrow, A. Leslie; Jones, Sara R.; Kash, Thomas L.

    2016-01-01

    Chronic alcohol consumption and withdrawal leads to anxiety, escalated alcohol drinking behavior, and alcohol dependence. Alterations in the function of key structures within the cortico-limbic neural circuit have been implicated in underlying the negative behavioral consequences of chronic alcohol exposure in both humans and rodents. Here, we used chronic intermittent ethanol vapor exposure (CIE) in male C57BL/6J mice to evaluate the effects of chronic alcohol exposure and withdrawal on anxiety-like behavior and basal synaptic function and neuronal excitability in prefrontal cortical and extended amygdala brain regions. Forty-eight hours after four cycles of CIE, mice were either assayed in the marble burying test (MBT) or their brains were harvested and whole-cell electrophysiological recordings were performed in the prelimbic and infralimbic medial prefrontal cortex (PLC and ILC), the lateral and medial central nucleus of the amygdala (lCeA and mCeA), and the dorsal and ventral bed nucleus of the stria terminalis (dBNST and vBNST). Ethanol-exposed mice displayed increased anxiety in the MBT compared to air-exposed controls, and alterations in neuronal function were observed in all brain structures examined, including several distinct differences between subregions within each structure. Chronic ethanol exposure induced hyperexcitability of the ILC, as well as a shift toward excitation in synaptic drive and hyperexcitability of vBNST neurons; in contrast, there was a net inhibition of the CeA. This study reveals extensive effects of chronic ethanol exposure on the basal function of cortico-limbic brain regions, suggests that there may be complex interactions between these regions in the regulation of ethanol-dependent alterations in anxiety state, and highlights the need for future examination of projection-specific effects of ethanol in cortico-limbic circuitry. PMID:26188147

  8. [Induced acne].

    PubMed

    Humbert, Philippe

    2002-04-15

    Induced acne belongs to the clinical forms of acne. Some dermatoses present with acne-like patterns. They can be induced or perpetuated by non physiological factors. Among these factors, medicines must always be considered, taken either topically (dermocorticoids, sulfur, anti-acneic topics) or generally (androgens, oral corticoids, ACTH, anti-epileptics, anti-depressive drugs, anti-tuberculosis medications). Halogens (iodine, bromine) found in inhaled or orally taken pharmaceutical products, or associated with occupational contact, can also induce acne. Acne of exogenous origin has been described in some specific occupations, and are induced by exposure to chlorine, industrial oils, tar. Sun exposure, PUVA therapy and ionizing radiation are potentially acneigenous. Finally acne caused by cosmetics includes acne cosmetica, brilliantine and oily creams acne and detergent acne.

  9. Sex Difference in Susceptibility and Resistance to Noise-Induced Hearing Loss in Chinchillas

    DTIC Science & Technology

    2000-10-01

    guinea pig and its effect on the acute cochlear toxicity of ethacrynic acid . Biochem. Pharmacol. 37:3743-3747. Lee, K.S., Kim, H.K., Moon, H.S., Hong...Harpur, E.S.. Geseher, A., 1988. Gluta- thione depletion in the guinea pig and its effect on the acute cochlear toxicity of ethacrynic acid . Biochem...potentials and enzyme activities after ethacrynic acid injection are secondary to stria vascularis ischemia. Assoc. Res. Otolaryngol. Abstr

  10. Inducing labor

    MedlinePlus

    ... inducing labor is to "break the bag of waters" or rupture the membranes. Your health care provider will do a pelvic exam and will guide a small plastic probe with a hook on the end through your cervix to create a hole in the membrane. This does not hurt you ...

  11. Inducing autophagy

    PubMed Central

    Harder, Lea M; Bunkenborg, Jakob; Andersen, Jens S

    2014-01-01

    Autophagy is a lysosomal-mediated catabolic process, which through degradation of different cytoplasmic components aids in maintaining cellular homeostasis and survival during exposure to extra- or intracellular stresses. Ammonia is a potential toxic and stress-inducing byproduct of glutamine catabolism, which has recently been found to induce autophagy in an MTOR independent way and support cancer cell survival. In this study, quantitative phosphoproteomics was applied to investigate the initial signaling events linking ammonia to the induction of autophagy. The MTOR inhibitor rapamycin was used as a reference treatment to emphasize the differences between an MTOR-dependent and -independent autophagy-induction. By this means 5901 phosphosites were identified of which 626 were treatment-specific regulated and 175 were coregulated. Investigation of the ammonia-specific regulated sites supported that MTOR activity was not affected, but indicated increased MAPK3 activity, regulation of proteins involved in Rho signal transduction, and a novel phosphorylation motif, serine-proline-threonine (SPT), which could be linked to cytoskeleton-associated proteins. MAPK3 could not be identified as the primary driver of ammonia-induced autophagy but instead the data suggested an upregulation of AMPK and the unfolded protein response (UPR), which might link ammonia to autophagy induction. Support of UPR induction was further obtained from the finding of increased protein levels of the ER stress markers DDIT3/CHOP and HSPA5 during ammonia treatment. The large-scale data set presented here comprises extensive high-quality quantitative information on phosphoprotein regulation in response to 2 very different autophagy inducers and should therefore be considered a general resource for the community. PMID:24300666

  12. Protective role of intratympanic nigella sativa oil against gentamicin induced hearing loss.

    PubMed

    Edizer, Deniz Tuna; Yigit, Ozgur; Cinar, Zehra; Gul, Mehmet; Kara, Eyyup; Yigitcan, Birgul; Hayır, Duygu; Atas, Ahmet

    2017-06-01

    Aminoglycosides, used to combat with life-threatening infections, have a substantial risk of hearing loss. Nigella sativa is an annual herbaceous plant and used for treatment of many diseases for ages. We aimed to investigate the protective role of intratympanic nigella sativa oil against gentamicin induced hearing loss in an animal model. Twenty eight guinea pigs were randomly divided into four groups: i-control, ii- Intratympanic nigella sativa oil (IT-NSO), iii- Intraperitoneal gentamicin (IP-G) and iv- Intraperitoneal gentamicin and intratympanic nigella sativa oil (IP-G + IT-NSO). Preoperative and postoperative hearing thresholds were determined with auditory brainstem response with click and 8 kHz tone-burst stimuli. Histological analysis of the cochlea specimens were performed under light microscope. Semiquantitative grading of the histological findings was carried out and compared between the groups. Highest posttreatment hearing thresholds were detected in IP-G group. Posttreatment mean hearing threshold of the IP-G group with click stimulus was significantly higher than the IP-G + IT-NSO group (p = 0.004). whereas the difference was not significant with 8 kHz tone-burst stimulus (p = 0.137). Both IP-G and IP-G + IT-NSO groups had significantly higher hearing thresholds compared to control and IT-NSO groups (p > 0.05). Histological examination of the control and IT-NSO groups demonstrated normal appearance of cochlear nerve, stria vascularis and organ of Corti. IP-G group showed the most severe histological alterations including hydropic and vacuolar degenerations, hair cell damage and deformation of the basilar mambrane. Histological evidence of damage was significantly reduced in IP-G + IT-NSO group compared to IP-G group. Addition of intratympanic NSO to systemic gentamicin was demonstrated to have beneficial effects in hearing thresholds which was supported by histological findings. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Exercise-Induced Bronchoconstriction

    MedlinePlus

    ... Conditions & Treatments ▸ Conditions Dictionary ▸ Exercise-Induced Bronchoconstriction Share | Exercise-Induced Bronchoconstriction (EIB) « Back to A to Z Listing Exercise-Induced Bronchoconstriction, (EIB), often known as exercise-induced ...

  14. Evaluation of the protective effects of hesperetin against cisplatin-induced ototoxicity in a rat animal model.

    PubMed

    Kara, Medine; Türkön, Hakan; Karaca, Turan; Güçlü, Oğuz; Uysal, Sema; Türkyılmaz, Mehmet; Demirtaş, Selim; Dereköy, Fevzi Sefa

    2016-06-01

    We aimed to investigate the effects of hesperetin as a flavanon both histopathologically and immunohistochemically on cochlear apoptosis in a rat model of cisplatin-induced ototoxicity (CIO). The evaluation of the effects of hesperetin on cisplatin-induced hearing loss was performed using distortion product otoacoustic emission (DPOAE). Twenty-eight wistar albino rats were used in the current study. The rats were randomly divided into four groups with seven rats in each group. Group C was exposed to a single dose of cisplatin (12mg/kg) by intraperitoneal injection. Group CH received intraperitoneally cisplatin (12mg/kg) and hesperetin (20mg/kg). Group H was exposed to hesperetin (20mg/kg) intraperitoneally. The sham group (group S) received normal saline (6cc) intraperitoneally. The measurements of DPOAE and signal-noise ratios (SNR) were performed before the treatment and again on the first and 6 days after administration of the drugs. Rats were sacrificed and cochleae were dissected 10 days after drug administration. The cochlear tissue was assessed in all groups by histopathologic, immunohistochemical and TUNEL assay. In addition, serum oxidative stress markers and antioxidant parameters were analyzed. There was a significant difference between the basal value and the sixth day at frequencies 8.4, 9.6 and 9.96 for group C. We also found a significant difference between the first and sixth day at frequencies 7.2, 8.4, 9.6 and 9.96. On the 6th day, there were significant differences between C and S groups at all frequencies except 2.4. We showed a significant difference between C and H groups at frequencies 4.8, 6.0, 8.4, 9.6 and 9.96. There was also a significant difference between C and CH groups at frequencies 2.4, and 3.6. We found lower levels of oxidants and higher levels of antioxidants in CH group as compared to C group. C group had a significantly greater number of TUNEL-positive cells than did S, H and CH groups. The number of TUNEL-positive cells in CH

  15. Ion channels in basolateral membrane of marginal cells dissociated from gerbil stria vascularis.

    PubMed

    Takeuchi, S; Ando, M; Kozakura, K; Saito, H; Irimajiri, A

    1995-03-01

    The basolateral membrane of isolated strial marginal cells has been probed for conductive pathways by the patch-clamp technique. Two types of voltage-insensitive channels were identified in both cell-attached and excised patches. Of these, frequently (69% of excised patches) observed was a Ca(2+)-activated nonselective cation channel having a unit conductance of 24.9 +/- 0.5 pS (N = 16). Other characteristics of this type in excised patches include: 1) linear I-V relations with 150 mM K+ (pipette)/150 mM Na+ (bath), 2) a permeability sequence of NH4+ > Na+ = K+ = Rb+ > Li+, 3) a flickering block by quinine or quinidine (both 1 mM), and 4) a dose dependent block of its activity by ADP or ATP (IC50,ATP/IC50,ADP = 20-35), both from the cytosolic side. Channels with similar characteristics were found in the apical membrane of the same cell; however, the basolateral channels were 2-4 times more densely distributed than the apical counterparts. Also frequently (57%) detected was a Cl- channel of 80.0 +/- 0.5 pS (N = 6), whose activity was Ca2+ independent. Additionally, this Cl- channel had: 1) linear I-V relations with symmetric Cl-, 2) a permeability sequence of Cl- > Br- > I- > or = NO3- > or = gluconate-, and 3) a complete and reversible block by 1 mM diphenylamine-2-carboxylate. In contrast to the apical Cl- channels, the basolateral ones had a much higher density (57% vs. < 1%) as well as a higher unit conductance (80 pS vs. 50 pS) than the apical counterpart. The relative abundance of these two types as the major conductive pathways for Na+, K+, and Cl- in the basolateral region must be taken into account when addressing the role of strial marginal cells in generating the positive endocochlear potential. The Cl- channel may facilitate Cl- distribution across the basolateral membrane.

  16. Negative Energy Balance Blocks Neural and Behavioral Responses to Acute Stress by “Silencing” Central Glucagon-Like Peptide 1 Signaling in Rats

    PubMed Central

    Maniscalco, James W.; Zheng, Huiyuan; Gordon, Patrick J.

    2015-01-01

    Previous reports indicate that caloric restriction attenuates anxiety and other behavioral responses to acute stress, and blunts the ability of stress to increase anterior pituitary release of adrenocorticotropic hormone. Since hindbrain glucagon-like peptide-1 (GLP-1) neurons and noradrenergic prolactin-releasing peptide (PrRP) neurons participate in behavioral and endocrine stress responses, and are sensitive to the metabolic state, we examined whether overnight food deprivation blunts stress-induced recruitment of these neurons and their downstream hypothalamic and limbic forebrain targets. A single overnight fast reduced anxiety-like behavior assessed in the elevated-plus maze and acoustic startle test, including marked attenuation of light-enhanced startle. Acute stress [i.e., 30 min restraint (RES) or 5 min elevated platform exposure] robustly activated c-Fos in GLP-1 and PrRP neurons in fed rats, but not in fasted rats. Fasting also significantly blunted the ability of acute stress to activate c-Fos expression within the anterior ventrolateral bed nucleus of the stria terminalis (vlBST). Acute RES stress suppressed dark-onset food intake in rats that were fed ad libitum, whereas central infusion of a GLP-1 receptor antagonist blocked RES-induced hypophagia, and reduced the ability of RES to activate PrRP and anterior vlBST neurons in ad libitum-fed rats. Thus, an overnight fast “silences” GLP-1 and PrRP neurons, and reduces both anxiety-like and hypophagic responses to acute stress. The partial mimicking of these fasting-induced effects in ad libitum-fed rats after GLP-1 receptor antagonism suggests a potential mechanism by which short-term negative energy balance attenuates neuroendocrine and behavioral responses to acute stress. SIGNIFICANCE STATEMENT The results from this study reveal a potential central mechanism for the “metabolic tuning” of stress responsiveness. A single overnight fast, which markedly reduces anxiety-like behavior in rats

  17. Topographical Fos induction within the ventral midbrain and projection sites following self-stimulation of the posterior mesencephalon.

    PubMed

    Marcangione, C; Rompré, P-P

    2008-07-17

    Rats will readily perform an operant response to self-administer electrical stimulation to the posterior mesencephalon (PM). Previous results show that axons that support self-stimulation travel between the PM and the ventral tegmental area (VTA) and that their activation increases firing of VTA neurons. The present work sought to extend these findings by describing the distribution of ventral midbrain neurons affected by PM self-stimulation. In Experiment 1, ventral midbrain Fos-immunoreactivity (IR) was assessed in three groups of rats implanted with a monopolar electrode; two groups were trained to self-administer stimulation, but only one was allowed to self-stimulate on the test day, whereas the third was never trained or tested. Self-stimulation induced prominent Fos-IR that was differentially distributed within the VTA and substantia nigra (SN). Control rats showed only sparse labeling. In Experiment 2, ventral midbrain Fos-IR was assessed with three additional groups trained to self-administer PM stimulation and tested as follows: Group-1 was allowed to self-stimulate, Group-2 received stimulation at parameters that failed to support self-stimulation (deemed non-rewarding) "yoked" to the rate of responding of Group-1, and Group-3 received no stimulation. PM self-stimulation induced Fos-IR throughout the rostral-caudal VTA and within the SN reticulata. Non-rewarding stimulation induced sparse Fos-IR, comparable to no stimulation. Fos-IR specific to PM self-stimulation was also observed within the bed nucleus of the stria terminalis (BNST) and nucleus accumbens (NAS)-shell, but not within NAS-core, caudate putamen, medial prefrontal or orbital cortices. These findings are consistent with evidence that reward or positive reinforcement can be triggered by chemical and electrical stimulation over a large rostral-caudal extent of the VTA. They suggest that among ventral midbrain projection sites, the BNST and NAS-shell constitute important components of the

  18. Exercise-Induced Asthma

    MedlinePlus

    ... Your 1- to 2-Year-Old Exercise-Induced Asthma KidsHealth > For Parents > Exercise-Induced Asthma Print A ... previous continue Tips for Kids With Exercise-Induced Asthma For the most part, kids with exercise-induced ...

  19. Lateral Hypothalamic Control of the Ventral Tegmental Area: Reward Evaluation and the Driving of Motivated Behavior.

    PubMed

    Tyree, Susan M; de Lecea, Luis

    2017-01-01

    The lateral hypothalamus (LH) plays an important role in many motivated behaviors, sleep-wake states, food intake, drug-seeking, energy balance, etc. It is also home to a heterogeneous population of neurons that express and co-express multiple neuropeptides including hypocretin (Hcrt), melanin-concentrating hormone (MCH), cocaine- and amphetamine-regulated transcript (CART) and neurotensin (NT). These neurons project widely throughout the brain to areas such as the locus coeruleus, the bed nucleus of the stria terminalis, the amygdala and the ventral tegmental area (VTA). Lateral hypothalamic projections to the VTA are believed to be important for driving behavior due to the involvement of dopaminergic reward circuitry. The purpose of this article is to review current knowledge regarding the lateral hypothalamic connections to the VTA and the role they play in driving these behaviors.

  20. Cognitive Deficits Correlate with White Matter Deterioration in Spinocerebellar Ataxia Type 2.

    PubMed

    Hernandez-Castillo, Carlos R; Vaca-Palomares, Israel; Galvez, Víctor; Campos-Romo, Aurelio; Diaz, Rosalinda; Fernandez-Ruiz, Juan

    2016-04-01

    The aim of this study was to explore the relationship between cognitive and white matter deterioration in a group of participants with spinocerebellar ataxia type 2 (SCA2). Fourteen genetically confirmed participants with SCA2 and 14 aged-matched controls participated in the study. Diffusion tensor imaging tract-based spatial statistics were performed to analyze structural white matter integrity. Significant group differences in the mean diffusivity were correlated with SCA2 cognitive deficits. Our analysis revealed higher mean diffusivity in the SCA2 group in cerebellar white matter, medial lemniscus, and middle cerebellar peduncle, among other regions. Cognitive scores correlated with white matter mean diffusivity in the parahippocampal area, inferior frontal and supramarginal gyri and the stria terminalis. Our findings show significant correlations between white matter microstructural damage in key areas affected in SCA2 and cognitive deficits. These findings result in a more comprehensive understanding of the effect of the neurodegenerative process in people with SCA2.

  1. Autoradiographic visualization of CNS receptors for vasoactive intestinal peptide

    SciTech Connect

    Shaffer, M.M.; Moody, T.W.

    1986-03-01

    Receptors for VIP were characterized in the rat CNS. /sup 125/I-VIP bound with high affinity to rat brain slices. Binding was time dependent and specific. Pharmacology studies indicated that specific /sup 125/I-VIP binding was inhibited with high affinity by VIP and low affinity by secretin and PHI. Using in vitro autoradiographic techniques high grain densities were present in the dentate gyrus, pineal gland, supraoptic and suprachiasmatic nuclei, superficial gray layer of the superior colliculus and the area postrema. Moderate grain densities were present in the olfactory bulb and tubercle, cerebral cortex, nucleus accumbens, caudate putamen, interstitial nucleus of the stria terminalis, paraventricular thalamic nucleus, medial amygdaloid nucleus, subiculum and the medial geniculate nucleus. Grains were absent in the corpus callosum and controls treated with 1 microM unlabeled VIP. The discrete regional distribution of VIP receptors suggest that it may function as an important modulator of neural activity in the CNS.

  2. Evidence for coordinated functional activity within the extended amygdala of non-human and human primates

    PubMed Central

    Oler, Jonathan A.; Birn, Rasmus M.; Patriat, Rémi; Fox, Andrew S.; Shelton, Steven E.; Burghy, Cory A.; Stodola, Diane E.; Essex, Marilyn J.; Davidson, Richard J.; Kalin, Ned H.

    2012-01-01

    Neuroanatomists posit that the central nucleus of the amygdala (Ce) and bed nucleus of the stria terminalis (BST) comprise two major nodes of a macrostructural forebrain entity termed the extended amygdala. The extended amygdala is thought to play a critical role in adaptive motivational behavior and is implicated in the pathophysiology of maladaptive fear and anxiety. Resting functional connectivity of the Ce was examined in 107 young anesthetized rhesus monkeys and 105 young humans using standard resting-state functional magnetic resonance imaging (fMRI) methods to assess temporal correlations across the brain. The data expand the neuroanatomical concept of the extended amygdala by finding, in both species, highly significant functional coupling between the Ce and the BST. These results support the use of in vivo functional imaging methods in nonhuman and human primates to probe the functional anatomy of major brain networks such as the extended amygdala. PMID:22465841

  3. Pituitary adenylate cyclase activating polypeptide in stress-related disorders: data convergence from animal and human studies.

    PubMed

    Hammack, Sayamwong E; May, Victor

    2015-08-01

    The maladaptive expression and function of several stress-associated hormones have been implicated in pathological stress and anxiety-related disorders. Among these, recent evidence has suggested that pituitary adenylate cyclase activating polypeptide (PACAP) has critical roles in central neurocircuits mediating stress-related emotional behaviors. We describe the PACAPergic systems, the data implicating PACAP in stress biology, and how altered PACAP expression and signaling may result in psychopathologies. We include our work implicating PACAP signaling within the bed nucleus of the stria terminalis in mediating the consequences of stressor exposure and relatedly, describe more recent studies suggesting that PACAP in the central nucleus of the amygdala may impact the emotional aspects of chronic pain states. In aggregate, these results are consistent with data suggesting that PACAP dysregulation is associated with posttraumatic stress disorder in humans. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

  4. Receptors for GRP/bombesin-like peptides in the rat forebrain

    SciTech Connect

    Wolf, S.S.; Moody, T.W.

    1985-01-01

    Binding sites in the rat forebrain were characterized using ( SVI-Tyr4)bombesin as a receptor probe. Pharmacology experiments indicate that gastrin releasing peptide (GRP) and the GRP fragments GRP as well as Ac-GRP inhibited radiolabeled (Tyr4)bombesin binding with high affinity. Biochemistry experiments indicated that heat, N-ethyl maleimide or trypsin greatly reduced radiolabeled (Tyr4)bombesin binding. Also, autoradiographic studies indicated that highest grain densities were present in the stria terminalis, periventricular and suprachiasmatic nucleus of the hypothalamus, dorsomedial and rhomboid thalamus, dentate gyrus, hippocampus and medial amygdaloid nucleus. The data suggest that CNS protein receptors, which are discretely distributed in the rat forebrain, may mediate the action of endogenous GRP/bombesin-like peptides.

  5. Pituitary adenylate cyclase activating polypeptide in stress-related disorders: data convergence from animal and human studies

    PubMed Central

    May, Victor

    2014-01-01

    The maladaptive expression and function of several stress-associated hormones have been implicated in pathological stress- and anxiety-related disorders. Among these, recent evidence has suggested that pituitary adenylate cyclase activating polypeptide (PACAP) has critical roles in central neurocircuits mediating stress-related emotional behaviors. We describe the PACAPergic systems, the data implicating PACAP in stress biology and how altered PACAP expression and signaling may result in psychopathologies. We include our work implicating PACAP signaling within the bed nucleus of the stria terminalis (BNST) in mediating the consequences of stressor exposure and relatedly, describe more recent studies suggesting that PACAP in the central nucleus of the amygdala (CeA) may impact the emotional aspects of chronic pain states. In aggregate, these results are consistent with data suggesting that PACAP dysregulation is associated with post-traumatic stress disorder (PTSD) in humans. PMID:25636177

  6. AgRP Neural Circuits Mediate Adaptive Behaviors in the Starved State

    PubMed Central

    Padilla, Stephanie L.; Qiu, Jian; Soden, Marta E.; Sanz, Elisenda; Nestor, Casey C; Barker, Forrest D.; Quintana, Albert; Zweifel, Larry S.; Rønnekleiv, Oline K.; Kelly, Martin J.; Palmiter, Richard D.

    2016-01-01

    In the face of starvation animals will engage in high-risk behaviors that would normally be considered maladaptive. Starving rodents for example will forage in areas that are more susceptible to predators and will also modulate aggressive behavior within a territory of limited or depleted nutrients. The neural basis of these adaptive behaviors likely involves circuits that link innate feeding, aggression, and fear. Hypothalamic AgRP neurons are critically important for driving feeding and project axons to brain regions implicated in aggression and fear. Using circuit-mapping techniques, we define a disynaptic network originating from a subset of AgRP neurons that project to the medial nucleus of the amygdala and then to the principle bed nucleus of the stria terminalis, which plays a role in suppressing territorial aggression and reducing contextual fear. We propose that AgRP neurons serve as a master switch capable of coordinating behavioral decisions relative to internal state and environmental cues. PMID:27019015

  7. Early Life Manipulations of the Nonapeptide System Alter Pair Maintenance Behaviors and Neural Activity in Adult Male Zebra Finches

    PubMed Central

    Baran, Nicole M.; Tomaszycki, Michelle L.; Adkins-Regan, Elizabeth

    2016-01-01

    Adult zebra finches (T. guttata) form socially monogamous pair bonds characterized by proximity, vocal communication, and contact behaviors. In this experiment, we tested whether manipulations of the nonapeptide hormone arginine vasotocin (AVT, avian homolog of vasopressin) and the V1a receptor (V1aR) early in life altered species-typical pairing behavior in adult zebra finches of both sexes. Although there was no effect of treatment on the tendency to pair in either sex, males in different treatments exhibited profoundly different profiles of pair maintenance behavior. Following a brief separation, AVT-treated males were highly affiliative with their female partner but sang very little compared to Controls. In contrast, males treated with a V1aR antagonist sang significantly less than Controls, but did not differ in affiliation. These effects on behavior in males were also reflected in changes in the expression of V1aR and immediate early gene activity in three brain regions known to be involved in pairing behavior in birds: the medial amygdala, medial bed nucleus of the stria terminalis, and the lateral septum. AVT males had higher V1aR expression in the medial amygdala than both Control and antagonist-treated males and immediate early gene activity of V1aR neurons in the medial amygdala was positively correlated with affiliation. Antagonist treated males showed decreased activity in the medial amygdala. In addition, there was a negative correlation between the activity of V1aR cells in the medial bed nucleus of the stria terminalis and singing. Treatment also affected the expression of V1aR and activity in the lateral septum, but this was not correlated with any behaviors measured. These results provide evidence that AVT and V1aR play developmental roles in specific pair maintenance behaviors and the neural substrate underlying these behaviors in a bird. PMID:27065824

  8. Efferent connections of the "olfactostriatum": a specialized vomeronasal structure within the basal ganglia of snakes.

    PubMed

    Martinez-Marcos, Alino; Ubeda-Bañon, Isabel; Lanuza, Enrique; Halpern, Mimi

    2005-05-01

    The olfactostriatum is a portion of the basal ganglia of snakes that receives substantial vomeronasal afferents through projections from the nucleus sphericus. In a preceding article, the olfactostriatum of garter snakes (Thamnophis sirtalis) was characterized on the basis of chemoarchitecture (distribution of serotonin, neuropeptide Y and tyrosine hydroxylase) and pattern of afferent connections [Martinez-Marcos, A., Ubeda-Banon, I., Lanuza, E., Halpern, M., 2005. Chemoarchitecture and afferent connections of the "olfactostriatum": a specialized vomeronasal structure within the basal ganglia of snakes. J. Chem. Neuroanat. 29, 49-69]. In the present study, its efferent connections have been investigated. The olfactostriatum projects to the main and accessory olfactory bulbs, lateral cortex, septal complex, ventral pallidum, external, ventral anterior and dorsolateral amygdalae, bed nucleus of the stria terminalis, preoptic area, lateral posterior hypothalamic nucleus, ventral tegmental area, substantia nigra and raphe nuclei. Tracer injections in the nucleus accumbens proper, a structure closely associated with the olfactostriatum, result in a similar pattern of efferent connections with the exception of those reaching the main and accessory olfactory bulbs, lateral cortex, external, ventral anterior and dorsolateral amygdalae and bed nucleus of the stria terminalis. These data, therefore, help to characterize the olfactostriatum, an apparently specialized area of the nucleus accumbens. Double labeling experiments after tracer injections in the nucleus sphericus and the lateral posterior hypothalamic nucleus demonstrate a pathway between these two structures through the olfactostriatum. Injections in the olfactostriatum and in the medial amygdala show parallel projections to the lateral posterior hypothalamic nucleus. Since this hypothalamic nucleus has been previously described as projecting to the hypoglossal nucleus, both, the medial amygdala and the

  9. Convergence of olfactory and vomeronasal projections in the rat basal telencephalon.

    PubMed

    Pro-Sistiaga, Palma; Mohedano-Moriano, Alicia; Ubeda-Bañon, Isabel; Del Mar Arroyo-Jimenez, Maria; Marcos, Pilar; Artacho-Pérula, Emilio; Crespo, Carlos; Insausti, Ricardo; Martinez-Marcos, Alino

    2007-10-01

    Olfactory and vomeronasal projections have been traditionally viewed as terminating in contiguous non-overlapping areas of the basal telencephalon. Original reports, however, described areas such as the anterior medial amygdala where both chemosensory afferents appeared to overlap. We addressed this issue by injecting dextran amines in the main or accessory olfactory bulbs of rats and the results were analyzed with light and electron microscopes. Simultaneous injections of different fluorescent dextran amines in the main and accessory olfactory bulbs were performed and the results were analyzed using confocal microscopy. Similar experiments with dextran amines in the olfactory bulbs plus FluoroGold in the bed nucleus of the stria terminalis indicate that neurons projecting through the stria terminalis could be integrating olfactory and vomeronasal inputs. Retrograde tracing experiments using FluoroGold or dextran amines confirm that areas of the rostral basal telencephalon receive inputs from both the main and accessory olfactory bulbs. While both inputs clearly converge in areas classically considered olfactory-recipient (nucleus of the lateral olfactory tract, anterior cortical amygdaloid nucleus, and cortex-amygdala transition zone) or vomeronasal-recipient (ventral anterior amygdala, bed nucleus of the accessory olfactory tract, and anteroventral medial amygdaloid nucleus), segregation is virtually complete at posterior levels such as the posteromedial and posterolateral cortical amygdalae. This provides evidence that areas so far considered receiving a single chemosensory modality are likely sites for convergent direct olfactory and vomeronasal inputs. Therefore, areas of the basal telencephalon should be reclassified as olfactory, vomeronasal, or mixed chemosensory structures, which could facilitate understanding of olfactory-vomeronasal interactions in functional studies.

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

    PubMed

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

    2009-06-05

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

  11. A novel model for neuroendocrine toxicology: neurobehavioral effects of BPA exposure in a prosocial species, the prairie vole (Microtus ochrogaster).

    PubMed

    Sullivan, Alana W; Beach, Elsworth C; Stetzik, Lucas A; Perry, Amy; D'Addezio, Alyssa S; Cushing, Bruce S; Patisaul, Heather B

    2014-10-01

    Impacts on brain and behavior have been reported in laboratory rodents after developmental exposure to bisphenol A (BPA), raising concerns about possible human effects. Epidemiological data suggest links between prenatal BPA exposure and altered affective behaviors in children, but potential mechanisms are unclear. Disruption of mesolimbic oxytocin (OT)/vasopressin (AVP) pathways have been proposed, but supporting evidence is minimal. To address these data gaps, we employed a novel animal model for neuroendocrine toxicology: the prairie vole (Microtus ochrogaster), which are more prosocial than lab rats or mice. Male and female prairie vole pups were orally exposed to 5-μg/kg body weight (bw)/d, 50-μg/kg bw/d, or 50-mg/kg bw/d BPA or vehicle over postnatal days 8-14. Subjects were tested as juveniles in open field and novel social tests and for partner preference as adults. Brains were then collected and assessed for immunoreactive (ir) tyrosine hydroxylase (TH) (a dopamine marker) neurons in the principal bed nucleus of the stria terminalis (pBNST) and TH-ir, OT-ir, and AVP-ir neurons in the paraventricular nucleus of the hypothalamus (PVN). Female open field activity indicated hyperactivity at the lowest dose and anxiety at the highest dose. Effects on social interactions were also observed, and partner preference formation was mildly inhibited at all dose levels. BPA masculinized principal bed nucleus of the stria terminalis TH-ir neuron numbers in females. Additionally, 50-mg/kg bw BPA-exposed females had more AVP-ir neurons in the anterior PVN and fewer OT-ir neurons in the posterior PVN. At the 2 lowest doses, BPA eliminated sex differences in PVN TH-ir neuron numbers and reversed this sex difference at the highest dose. Minimal behavioral effects were observed in BPA-exposed males. These data support the hypothesis that BPA alters affective behaviors, potentially via disruption of OT/AVP pathways.

  12. Distribution of secretoneurin-like immunoreactivity in comparison with substance P- and enkephalin-like immunoreactivities in various human forebrain regions.

    PubMed

    Marksteiner, J; Saria, A; Kirchmair, R; Pycha, R; Benesch, H; Fischer-Colbrie, R; Haring, C; Maier, H; Ransmayr, G

    1993-12-01

    The distribution of secretoneurin-like immunoreactivity, a peptide derived from secretogranin II, was studied by means of immunocytochemistry and compared to the pattern of staining for substance P- and enkephalin-like immunoreactivities in the human basal forebrain, with special reference to the basal ganglia. Secretoneurin-like immunoreactivity was characterized by gel filtration and reversed-phase high pressure liquid chromatography analysis. Chromatographic analysis revealed a single peak for secretoneurin-like immunoreactivity. No secretoneurin-immunopositive forms of high molecular weight were found. Secretoneurin-like immunoreactivity appeared mainly in dot- and fibre-like structures. In addition, a band-like terminal staining (woolly fibres) that has been shown by others for substance P- and enkephalin-like immunoreactivities, was also observed for secretoneurin-like immunoreactivity. Medium-sized cells were found arranged in clusters or singly within the caudate and putamen. In the basal ganglia, a high density of secretoneurin-like immunoreactivity was found in the internal segment of the globus pallidus, the ventral pallidum and in the pars reticulata of the substantia nigra. In these areas the immunostaining appeared mainly as woolly fibres. The bed nucleus of the stria terminalis and medial amygdala displayed a high density of fine beaded secretoneurin-like immunoreactive fibres, sometimes forming pericellular contacts. The nucelus basalis of Meynert was highly innervated by secretoneurin-like immunoreactive fibres, mainly in the form of woolly fibres. In general, a large overlap was found between secretoneurin- and substance P-like immunoreactivity in all examined areas of the basal ganglia. In the bed nucelus of the stria terminalis and medial amygdala secretoneurin-like immunoreactivity was distributed very similarly to enkephalin-like immunoreactivity. These data provide evidence that in different subsets of neurons and neuronal pathways

  13. Neuronal architecture in the rat central nucleus of the amygdala: a cytological, hodological, and immunocytochemical study.

    PubMed

    Cassell, M D; Gray, T S; Kiss, J Z

    1986-04-22

    The organization of neurons in the rat central nucleus of the amygdala (CNA) has been examined by using Nissl stain and immunocytochemical and retrograde tracing techniques. Four main subdivisions were identified on the basis of quantitative analyses of Nissl-stained material: medial (CM), lateral (CL), lateral capsular (CLC), and ventral (CV). An intermediate subdivision (CI), previously described by McDonald ('82), was apparent only in animals that had HRP-WGA injected into the bed nucleus of the stria terminalis. Large populations of neurotensin-, corticotropin-releasing factor (CRF)-, and enkephalin-immunoreactive neurons were present within the lateral divisions (mainly CL), although they were also seen within CM. Somatostatin-immunoreactive neurons were distributed mainly within CL and CM. Within CL, neurotensin- and enkephalin-immunoreactive neurons were more numerous laterally whereas CRF- and somatostatin-immunoreactive neurons were more numerous medially. Substance P-immunoreactive neurons were almost exclusively confined to CM. Only a few cholecystokinin- and vasoactive-polypeptide-immunoreactive neurons were seen in the CNA, and they were observed within CL, CV, and CM. The majority of neurons projecting to the dorsal medulla, hypothalamus, and ventral tegmental area were located within CM, although a significant number of cells were also seen within CL. Efferent projections to the bed nucleus of the stria terminalis were found to arise from neurons located within all subdivisions of the CNA. Thus, the distributional patterns of peptidergic and efferent neurons were not confined to individual cytoarchitectonically- defined subdivisions of the CNA. Rather, the results suggest overlapping medial to the lateral trends. Comparisons with the results of previous studies indicate that peptidergic and afferent terminal distribution patterns are more restricted to individual cytoarchitectonically defined subregions of the CNA. These observations suggest that the

  14. Distribution of secretagogin-containing neurons in the basal forebrain of mice, with special reference to the cholinergic corticopetal system.

    PubMed

    Gyengesi, Erika; Andrews, Zane B; Paxinos, George; Zaborszky, Laszlo

    2013-05-01

    Cholinergic and GABAergic corticopetal neurons in the basal forebrain play important roles in cortical activation, sensory processing, and attention. Cholinergic neurons are intermingled with peptidergic, and various calcium binding protein-containing cells, however, the functional role of these neurons is not well understood. In this study we examined the expression pattern of secretagogin (Scgn), a newly described calcium-binding protein, in neurons of the basal forebrain. We also assessed some of the corticopetal projections of Scgn neurons and their co-localization with choline acetyltransferase (ChAT), neuropeptide-Y, and other calcium-binding proteins (i.e., calbindin, calretinin, and parvalbumin). Scgn is expressed in cell bodies of the medial and lateral septum, vertical and horizontal diagonal band nuclei, and of the extension of the amygdala but it is almost absent in the ventral pallidum. Scgn is co-localized with ChAT in neurons of the bed nucleus of the stria terminalis, extension of the amygdala, and interstitial nucleus of the posterior limb of the anterior commissure. Scgn was co-localized with calretinin in the accumbens nucleus, medial division of the bed nucleus of stria terminalis, the extension of the amygdala, and interstitial nucleus of the posterior limb of the anterior commissure. We have not found co-expression of Scgn with parvalbumin, calbindin, or neuropeptide-Y. Retrograde tracing studies using Fluoro Gold in combination with Scgn-specific immunohistochemistry revealed that Scgn neurons situated in the nucleus of the horizontal limb of the diagonal band project to retrosplenial and cingulate cortical areas.

  15. Lesions in the medial posterior region of the BST impair sexual behavior in sexually experienced and inexperienced male rats.

    PubMed

    Claro, F; Segovia, S; Guilamón, A; Del Abril, A

    1995-01-01

    Previous studies have showed that lesions in the bed nucleus of the stria terminalis of experienced male rats impair some parameters of sexual behavior. The aim of this study was to examine the contribution of the medial posterior region of the bed nucleus of the stria terminalis (BSTMP), a sexually dimorphic region of this nucleus that pertains to the vomeronasal system, to the modulation of sexual behavior of the male rat. Small electrolytic bilateral lesions in the BSTMP were made in male heterosexual experienced and inexperienced rats. Sham lesioned animals were also tested as a control of the effects of the general surgical procedures. Behavioral tests were then performed to obtain standard measures of masculine sexual behavior. Our results indicate that the sexually experienced male rats with lesioned BSTMPs showed increases in the number of mounts and the number of intromissions and, consequently, in ejaculation latency. In contrast, the sexually naive male rats showed increases in first mount and intromission latencies and in ejaculation latency, but the latter occurred due to increases in the interintromission intervals. This group also showed low correlations between olfactory investigation of the anogenital area of the female and initiation and maintenance of copulatory behavior. The results suggest that sexual experience obtained in the very artificial conditions of laboratory tests could supply some of the cues provided by the BSTMP in the process of sensorial integration, which we hypothesize modulates the initiation and pacing of copulation. However, sexual experience does not apparently supply any other kinds of cues provided or processed in the BSTMP that are involved in modulating the elicitation of intromissions and ejaculations.

  16. Ethanol Administration Produces Divergent Changes in GABAergic Neuroactive Steroid Immunohistochemistry in the Rat Brain

    PubMed Central

    Cook, Jason B.; Dumitru, Ana Maria G.; O’Buckley, Todd K.; Morrow, A. Leslie

    2014-01-01

    Background The 5α-reduced pregnane neuroactive steroid (3α,5α)-3-hydroxypregnan-20-one (3α,5α-THP or allopregnanolone) is a potent positive modulator of GABAA receptors capable of modulating neuronal activity. In rats, systemic ethanol administration increases cerebral cortical and hippocampal levels of 3α,5α-THP, but the effects of ethanol on 3α,5α-THP levels in other brain regions are unknown. There is a large body of evidence suggesting that 3α,5α-THP enhances ethanol sensitivity, contributes to some behavioral effects of ethanol, and modulates ethanol reinforcement and motivation to drink. In the present study, we used immunohistochemistry (IHC) to determine ethanol-induced changes in cellular 3α,5α-THP expression in brain regions associated with ethanol actions and responses. Methods Male Wistar rats were administered ethanol (2g/kg) or saline intraperitoneally and after 60 minutes transcardially perfused. IHC was performed on free floating sections (3–4 sections/animal/brain region) using an affinity purified anti-3α,5α-THP primary antibody and immunoreactivity was visualized with 3,3′-diaminobenzidine. Results Ethanol significantly increased 3α,5α-THP immunoreactivity by 24±6% in the medial prefrontal cortex, 32±12% in the hippocampal CA1 pyramidal cell layer, 52±5% in the polymorph cell layer of the dentate gyrus, 44±15% in the bed nucleus of the stria terminalis, and by 36±6% in the paraventricular nucleus of the hypothalamus. In contrast, ethanol administration significantly reduced 3α,5α-THP immunoreactivity by 25±5% in the nucleus accumbens “shore” and 21±3% in the central nucleus of the amygdala. No changes were observed in the ventral tegmental area, dorsomedial striatum, granule cell layer of the dentate gyrus, or the lateral and basolateral amygdala. Conclusions The results suggest acute ethanol (2g/kg) produces divergent, brain region specific, effects on cellular 3α,5α-THP levels. Regional differences in the

  17. Overexpression of Forebrain CRH During Early Life Increases Trauma Susceptibility in Adulthood

    PubMed Central

    Toth, Mate; Flandreau, Elizabeth I; Deslauriers, Jessica; Geyer, Mark A; Mansuy, Isabelle M; Merlo Pich, Emilio; Risbrough, Victoria B

    2016-01-01

    Although early-life stress is a significant risk factor for developing anxiety disorders, including posttraumatic stress disorder (PTSD), the underlying mechanisms are unclear. Corticotropin releasing hormone (CRH) is disrupted in individuals with PTSD and early-life stress and hence may mediate the effects of early-life stress on PTSD risk. We hypothesized that CRH hyper-signaling in the forebrain during early development is sufficient to increase response to trauma in adulthood. To test this hypothesis, we induced transient, forebrain-specific, CRH overexpression during early-life (pre-puberty, CRHOEdev) in double-mutant mice (Camk2a-rtta2 × tetO-Crh) and tested their behavioral and gene expression responses to the predator stress model of PTSD in adulthood. In one cohort of CRHOEdev exposed and unexposed mice, avoidance and arousal behaviors were examined 7–15 days after exposure to predator stress. In another cohort, gene expression changes in Crhr1, Crhr2, and Fkbp51 in forebrain of CRHOEdev exposed and unexposed mice were examined 7 days after predator stress. CRHOEdev induced robust increases in startle reactivity and reductions in startle inhibition independently of predator stress in both male and female mice. Avoidance behaviors after predator stress were highly dependent on sex and CRHOEdev exposure. Whereas stressed females exhibited robust avoidance responses that were not altered by CRHOEdev, males developed significant avoidance only when exposed to both CRHOEdev and stress. Quantitative real-time-PCR analysis indicated that CRHOEdev unexposed males exhibit significant changes in Crhr2 expression in the amygdala and bed nucleus stria terminalis in response to stress, whereas males exposed to CRHOEdev did not. Similar to CRHOEdev males, females exhibited no significant Crhr2 gene expression changes in response to stress. Cortical Fkbp51 expression was also significantly reduced by stress and CRHOEdev exposure in males, but not in females. These

  18. Anatomical and functional implications of corticotrophin-releasing hormone neurones in a septal nucleus of the avian brain: an emphasis on glial-neuronal interaction via V1a receptors in vitro.

    PubMed

    Nagarajan, G; Jurkevich, A; Kang, S W; Kuenzel, W J

    2017-07-01

    Previously, we showed that corticotrophin-releasing hormone immunoreactive (CRH-IR) neurones in a septal structure are associated with stress and the hypothalamic-pituitary-adrenal axis in birds. In the present study, we focused upon CRH-IR neurones located within the septal structure called the nucleus of the hippocampal commissure (NHpC). Immunocytochemical and gene expression analyses were used to identify the anatomical and functional characteristics of cells within the NHpC. A comparative morphometry analysis showed that CRH-IR neurones in the NHpC were significantly larger than CRH-IR parvocellular neurones in the paraventricular nucleus of the hypothalamus (PVN) and lateral bed nucleus of the stria terminalis. Furthermore, these large neurones in the NHpC usually have more than two processes, showing characteristics of multipolar neurones. Utilisation of an organotypic slice culture method enabled testing of how CRH-IR neurones could be regulated within the NHpC. Similar to the PVN, CRH mRNA levels in the NHpC were increased following forskolin treatment. However, dexamethasone decreased forskolin-induced CRH gene expression only in the PVN and not in the NHpC, indicating differential inhibitory mechanisms in the PVN and the NHpC of the avian brain. Moreover, immunocytochemical evidence also showed that CRH-IR neurones reside in the NHpC along with the vasotocinergic system, comprising arginine vasotocin (AVT) nerve terminals and immunoreactive vasotocin V1a receptors (V1aR) in glia. Hence, we hypothesised that AVT acts as a neuromodulator within the NHpC to modulate activity of CRH neurones via glial V1aR. Gene expression analysis of cultured slices revealed that AVT treatment increased CRH mRNA levels, whereas a combination of AVT and a V1aR antagonist treatment decreased CRH mRNA expression. Furthermore, an attempt to identify an intercellular mechanism in glial-neuronal communication in the NHpC revealed that brain-derived neurotrophic factor (BDNF) and

  19. Chemical-Induced Vitiligo.

    PubMed

    Harris, John E

    2017-04-01

    Chemical-induced depigmentation of the skin has been recognized for more than 75 years, first as an occupational hazard but then extending to those using household commercial products as common as hair dyes. Since their discovery, these chemicals have been used therapeutically in patients with severe vitiligo to depigment their remaining skin and improve their appearance. Because chemical-induced depigmentation is clinically and histologically indistinguishable from nonchemically induced vitiligo, and because these chemicals appear to induce melanocyte autoimmunity, this phenomenon should be known as "chemical-induced vitiligo," rather than less accurate terms that have been previously used. Copyright © 2016 Elsevier Inc. All rights reserved.

  20. Cavitation-resistant inducer

    DOEpatents

    Dunn, Charlton; Subbaraman, Maria R.

    1989-01-01

    An improvement in an inducer for a pump wherein the inducer includes a hub, a plurality of radially extending substantially helical blades and a wall member extending about and encompassing an outer periphery of the blades. The improvement comprises forming adjacent pairs of blades and the hub to provide a substantially rectangular cross-sectional flow area which cross-sectional flow area decreases from the inlet end of the inducer to a discharge end of the inducer, resulting in increased inducer efficiency improved suction performance, reduced susceptibility to cavitation, reduced susceptibility to hub separation and reduced fabrication costs.

  1. Cavitation-resistant inducer

    DOEpatents

    Dunn, C.; Subbaraman, M.R.

    1989-06-13

    An improvement in an inducer for a pump is disclosed wherein the inducer includes a hub, a plurality of radially extending substantially helical blades and a wall member extending about and encompassing an outer periphery of the blades. The improvement comprises forming adjacent pairs of blades and the hub to provide a substantially rectangular cross-sectional flow area which cross-sectional flow area decreases from the inlet end of the inducer to a discharge end of the inducer, resulting in increased inducer efficiency improved suction performance, reduced susceptibility to cavitation, reduced susceptibility to hub separation and reduced fabrication costs. 11 figs.

  2. Flow-induced vibration

    SciTech Connect

    Blevins, R.D.

    1990-01-01

    This book reports on dimensional analysis; ideal fluid models; vortex-induced vibration; galloping and flutter; instability of tube and cylinder arrays; vibrations induced by oscillating flow; vibration induced by turbulence and sound; damping of structures; sound induced by vortex shedding; vibrations of a pipe containing a fluid flow; indices. It covers the analysis of the vibrations of structures exposed to fluid flows; explores applications for offshore platforms and piping; wind-induced vibration of buildings, bridges, and towers; and acoustic and mechanical vibration of heat exchangers, power lines, and process ducting.

  3. The extended amygdala and salt appetite

    NASA Technical Reports Server (NTRS)

    Johnson, A. K.; de Olmos, J.; Pastuskovas, C. V.; Zardetto-Smith, A. M.; Vivas, L.

    1999-01-01

    Both chemo- and mechanosensitive receptors are involved in detecting changes in the signals that reflect the status of body fluids and of blood pressure. These receptors are located in the systemic circulatory system and in the sensory circumventricular organs of the brain. Under conditions of body fluid deficit or of marked changes in fluid distribution, multiple inputs derived from these humoral and neural receptors converge on key areas of the brain where the information is integrated. The result of this central processing is the mobilization of homeostatic behaviors (thirst and salt appetite), hormone release, autonomic changes, and cardiovascular adjustments. This review discusses the current understanding of the nature and role of the central and systemic receptors involved in the facilitation and inhibition of thirst and salt appetite and on particular components of the central neural network that receive and process input derived from fluid- and cardiovascular-related sensory systems. Special attention is paid to the structures of the lamina terminalis, the area postrema, the lateral parabrachial nucleus, and their association with the central nucleus of the amygdala and the bed nucleus of the stria terminalis in controlling the behaviors that participate in maintaining body fluid and cardiovascular homeostasis.

  4. The extended amygdala and salt appetite

    NASA Technical Reports Server (NTRS)

    Johnson, A. K.; de Olmos, J.; Pastuskovas, C. V.; Zardetto-Smith, A. M.; Vivas, L.

    1999-01-01

    Both chemo- and mechanosensitive receptors are involved in detecting changes in the signals that reflect the status of body fluids and of blood pressure. These receptors are located in the systemic circulatory system and in the sensory circumventricular organs of the brain. Under conditions of body fluid deficit or of marked changes in fluid distribution, multiple inputs derived from these humoral and neural receptors converge on key areas of the brain where the information is integrated. The result of this central processing is the mobilization of homeostatic behaviors (thirst and salt appetite), hormone release, autonomic changes, and cardiovascular adjustments. This review discusses the current understanding of the nature and role of the central and systemic receptors involved in the facilitation and inhibition of thirst and salt appetite and on particular components of the central neural network that receive and process input derived from fluid- and cardiovascular-related sensory systems. Special attention is paid to the structures of the lamina terminalis, the area postrema, the lateral parabrachial nucleus, and their association with the central nucleus of the amygdala and the bed nucleus of the stria terminalis in controlling the behaviors that participate in maintaining body fluid and cardiovascular homeostasis.

  5. Fiber Tracts of the Medial and Inferior Surfaces of the Cerebrum.

    PubMed

    Baydin, Serhat; Gungor, Abuzer; Tanriover, Necmettin; Baran, Oguz; Middlebrooks, Erik H; Rhoton, Albert L

    2017-02-01

    Fiber dissection studies of the cerebrum have focused on the lateral surface. No comparable detailed studies have been done on the medial and inferior surfaces. The object of this study was to examine the fiber tracts, cortical, and subcortical structures of the medial and inferior aspects of the brain important in planning operative approaches along the interhemispheric fissure, parafalcine area, and basal surfaces of the cerebrum. Twenty formalin-fixed human hemispheres (10 brains) were examined by fiber dissection technique under ×6-×40 magnifications. The superior longitudinal fasciculus I, cingulum, inferior longitudinal fasciculus, uncinate fasciculus, optic radiations, tapetum, and callosal fibers were dissected step by step from medial to lateral, exposing the nucleus accumbens, subthalamic nucleus, red nucleus, and central midline structures (fornix, stria medullaris, and stria terminalis). Finally, the central core structures were dissected from medial to lateral. Understanding the fiber network underlying the medial and inferior aspects of the brain is important in surgical planning for approaches along the interhemispheric fissure, parafalcine area, and basal surfaces of the cerebrum. Copyright © 2016. Published by Elsevier Inc.

  6. Progesterone receptor in the forebrain of female gray short-tailed opossums: effects of exposure to male stimuli.

    PubMed

    Vitazka, Maria E; Cárdenas, Horacio; Cruz, Yolanda; Fadem, Barbara H; Norfolk, Jennifer R; Harder, John D

    2009-01-01

    Progesterone receptor immunoreactivity (PRir) in brain areas involved in reproductive behavior in eutherian species was examined for the first time in a female marsupial, the gray short-tailed opossum (Monodelphis domestica, hereinafter, opossum). PRir in nuclei of neurons, measured as area covered by stained nuclei, was seen in the arcuate nucleus (Arc); anteroventral periventricular nucleus (AVPv); bed nucleus of the stria terminalis (BST); medial preoptic area (MPOA), and ventromedial hypothalamus (VMH), but not in control areas adjacent to the hypothalamus or cortex. Female opossums are induced into cytological, urogenital sinus (UGS), estrus by male pheromones and into behavioral estrus, i.e., receptivity, by pairing with a male, and both estradiol (E) and progesterone (P) are involved in induction of receptivity in intact and ovariectomized females. PRir in the AVPv, MPOA, and VMH was very low in females that had never been exposed to males or their scent marks, i.e., naïve anestrous (NVA) females, and either previous or current exposure to males or their scent marks was associated with elevated PRir. PRir was significantly higher in the AVPv and MPOA of anestrous females with previous but no current exposure to males and their scent marks, i.e., experienced anestrous (EXPA) females, than in NVA females, but PRir was significantly lower in the MPOA and VMH of EXPA females than in females that were behaviorally receptive and had recently copulated, i.e., behavioral receptive estrous (BRE) females. PRir was higher in the VMH of both UGS estrous (UGSE) and BRE females compared to that in EXPA animals, but PRir did not differ between UGSE and BRE females in any of the 3 brain areas examined, including the MPOA These results provide evidence that pheromonal induction of estrus and sexual receptivity in opossums is associated with elevation of PRir in the VMH and MPOA and that prior exposure to males or their pheromones, even in the absence of current male stimuli

  7. Fos Expression in Rat Brain During Depletion-Induced Thirst and Salt Appetite

    NASA Technical Reports Server (NTRS)

    Thunhorst, R. L.; Xu, Z.; Cicha, M. Z.; Zardetto-Smith, A. M.; Johnson, A. K.

    1998-01-01

    The expression of Fos protein (Fos immunoreactivity, Fos-ir) was mapped in the brain of rats subjected to an angiotensin-dependent model of thirst and salt appetite. The physiological state associated with water and sodium ingestion was produced by the concurrent subcutaneous administration of the diuretic furosemide (10 mg/kg) and a low dose of the angiotensin-converting enzyme (ACE) inhibitor captopril (5 mg/kg; Furo/Cap treatment). The animals were killed 2 h posttreatment, and the brains were processed for Fos-ir to assess neural activation. Furo/Cap treatment significantly increased Fos-ir density above baseline levels both in structures of the lamina terminalis and hypothalamus known to mediate the actions of ANG 2 and in hindbrain regions associated with blood volume and pressure regulation. Furo/Cap treatment also typically increased Fos-ir density in these structures above levels observed after administration of furosemide or captopril separately. Fos-ir was reduced to a greater extent in forebrain than in hindbrain areas by a dose of captopril (100 mg/kg sc) known to block the actions of ACE in the brain. The present work provides further evidence that areas of lamina terminalis subserve angiotensin-dependent thirst and salt appetite.

  8. Flumazenil-induced ballism.

    PubMed

    Kim, Joong-Seok; Ko, Seok-Bum; Choi, Yeong-Bin; Lee, Kwang-Soo

    2003-04-01

    Flumazenil, an imidazobenzodiazepine, is the first benzodiazepine antagonist and is being used to reverse the adverse pharmacological effects of benzodiazepine. There have been a few reports on the central nevous system side effects with its use. We report a patient with generalized ballism following administration of flumazenil. The mechanism through which flumazenil induced this symptom is unknown. It is conceivable that flumazenil may antagonize the GABA-benzodiazepine receptor complex and induce dopamine hypersensitivity, thus induce dyskinesic symptoms.

  9. Flumazenil-induced ballism.

    PubMed Central

    Kim, Joong-Seok; Ko, Seok-Bum; Choi, Yeong-Bin; Lee, Kwang-Soo

    2003-01-01

    Flumazenil, an imidazobenzodiazepine, is the first benzodiazepine antagonist and is being used to reverse the adverse pharmacological effects of benzodiazepine. There have been a few reports on the central nevous system side effects with its use. We report a patient with generalized ballism following administration of flumazenil. The mechanism through which flumazenil induced this symptom is unknown. It is conceivable that flumazenil may antagonize the GABA-benzodiazepine receptor complex and induce dopamine hypersensitivity, thus induce dyskinesic symptoms. PMID:12692435

  10. Drug-induced nephropathies.

    PubMed

    Paueksakon, Paisit; Fogo, Agnes B

    2017-01-01

    Drugs are associated frequently with the development of various types of acute and chronic kidney diseases. Nephrotoxicity is associated most commonly with injury in the tubulointerstitial compartment manifested as either acute tubular injury or acute interstitial nephritis. A growing number of reports has also highlighted the potential for drug-induced glomerular disease, including direct cellular injury and immune-mediated injury. Recognition of drug-induced nephropathies and rapid discontinuation of the offending agents are critical to maximizing the likelihood of renal function recovery. This review will focus on the pathology and pathogenesis of drug-induced acute interstitial nephritis and drug-induced glomerular diseases.

  11. Stress-induced flowering

    PubMed Central

    Wada, Kaede C

    2010-01-01

    Many plant species can be induced to flower by responding to stress factors. The short-day plants Pharbitis nil and Perilla frutescens var. crispa flower under long days in response to the stress of poor nutrition or low-intensity light. Grafting experiments using two varieties of P. nil revealed that a transmissible flowering stimulus is involved in stress-induced flowering. The P. nil and P. frutescens plants that were induced to flower by stress reached anthesis, fruited and produced seeds. These seeds germinated, and the progeny of the stressed plants developed normally. Phenylalanine ammonialyase inhibitors inhibited this stress-induced flowering, and the inhibition was overcome by salicylic acid (SA), suggesting that there is an involvement of SA in stress-induced flowering. PnFT2, a P. nil ortholog of the flowering gene FLOWERING LOCUS T (FT) of Arabidopsis thaliana, was expressed when the P. nil plants were induced to flower under poor-nutrition stress conditions, but expression of PnFT1, another ortholog of FT, was not induced, suggesting that PnFT2 is involved in stress-induced flowering. PMID:20505356

  12. Teacher-Induced Errors.

    ERIC Educational Resources Information Center

    Richmond, Kent C.

    Students of English as a second language (ESL) often come to the classroom with little or no experience in writing in any language and with inaccurate assumptions about writing. Rather than correct these assumptions, teachers often seem to unwittingly reinforce them, actually inducing errors into their students' work. Teacher-induced errors occur…

  13. Mania Induced by Opipramol

    PubMed Central

    Firoz, Kazhungil; Khaleel, Asfia; Rajmohan, V; Kumar, Manoj; Raghuram, TM

    2015-01-01

    Antidepressants have propensity to induce manic switch in patients with bipolar disorder. Opipramol is an atypical anxiolytic and antidepressant drug which predominantly acts on sigma receptors. Although structurally resembles tricyclic antidepressant imipramine it does not have inhibitory action on the reuptake of norepinephrine/serotonin and hence it is not presumed to cause manic switch in bipolar depression. Here, we describe a case of mania induced by opipramol, in a patient with bipolar affective disorder who was treated for moderate depressive episode with lithium and opipramol and we discuss neurochemical hypothesis of opipramol-induced mania. PMID:25722522

  14. Exercise-induced anaphylaxis.

    PubMed

    Feldweg, Anna M

    2015-05-01

    Exercise-induced anaphylaxis is an uncommon disorder in which anaphylaxis occurs in response to physical exertion. Food-dependent exercise-induced anaphylaxis is a disorder with similar symptoms, although symptoms develop only if exercise takes place within a few hours of eating and, in most cases, only if a specific food is eaten. Management includes education about safe conditions for exercise, the importance of ceasing exercise immediately if symptoms develop, appropriate use of epinephrine, and, for patients with food-dependent exercise-induced anaphylaxis, avoidance of the culprit food for at least 4 hours before exercise. Copyright © 2015 Elsevier Inc. All rights reserved.

  15. Space Station Induced Monitoring

    NASA Technical Reports Server (NTRS)

    Spann, James F. (Editor); Torr, Marsha R. (Editor)

    1988-01-01

    This report contains the results of a conference convened May 10-11, 1988, to review plans for monitoring the Space Station induced environment, to recommend primary components of an induced environment monitoring package, and to make recommendations pertaining to suggested modifications of the Space Station External Contamination Control Requirements Document JSC 30426. The contents of this report are divided as Follows: Monitoring Induced Environment - Space Station Work Packages Requirements, Neutral Environment, Photon Emission Environment, Particulate Environment, Surface Deposition/Contamination; and Contamination Control Requirements.

  16. Exercise-induced asthma

    MedlinePlus

    ... medlineplus.gov/ency/patientinstructions/000036.htm Exercise-induced asthma To use the sharing features on this page, ... such as running, basketball, or soccer. Use Your Asthma Medicine Before you Exercise Take your short-acting, ...

  17. Trauma-induced coagulopathy.

    PubMed

    Katrancha, Elizabeth D; Gonzalez, Luis S

    2014-08-01

    Coagulopathy is the inability of blood to coagulate normally; in trauma patients, it is a multifactorial and complex process. Seriously injured trauma patients experience coagulopathies during the acute injury phase. Risk factors for trauma-induced coagulopathy include hypothermia, metabolic acidosis, hypoperfusion, hemodilution, and fluid replacement. In addition to the coagulopathy induced by trauma, many patients may also be taking medications that interfere with hemostasis. Therefore, medication-induced coagulopathy also is a concern. Traditional laboratory-based methods of assessing coagulation are being supported or even replaced by point-of-care tests. The evidence-based management of trauma-induced coagulopathy should address hypothermia, fluid resuscitation, blood components administration, and, if needed, medications to reverse identified coagulation disorders. ©2014 American Association of Critical-Care Nurses.

  18. Vitiligo, drug induced (image)

    MedlinePlus

    ... this person's face have resulted from drug-induced vitiligo. Loss of melanin, the primary skin pigment, occasionally ... is the case with this individual. The typical vitiligo lesion is flat and depigmented, but maintains the ...

  19. Drug-induced catatonia.

    PubMed

    Duggal, Harpreet S; Singh, Ira

    2005-09-01

    Catatonia is a heterogeneous syndrome that varies in etiology, presentation, course and sequelae. Initially conceptualized as a subtype of schizophrenia, catatonia is now recognized to occur not only with other psychiatric conditions but also with medical conditions and drug-induced and toxic states. While drug-induced catatonia is now a recognized entity, most studies club it with catatonia due to general medical conditions or organic catatonia, thus precluding any meaningful interpretation of such cases. The literature on drug-induced catatonia mostly draws from scattered case reports. This article attempts to review the available literature in this realm and integrate the information in an attempt to explore the epidemiology, etiology, mechanism and treatment of drug-induced catatonia.

  20. Glucocorticoid-induced osteonecrosis.

    PubMed

    Weinstein, Robert S

    2012-04-01

    Awareness of the need for prevention of glucocorticoid-induced fractures is growing, but glucocorticoid administration is often overlooked as the most common cause of nontraumatic osteonecrosis. Glucocorticoid-induced osteonecrosis develops in 9-40% of patients receiving long-term therapy although it may also occur with short-term exposure to high doses, after intra-articular injection, and without glucocorticoid-induced osteoporosis. The name, osteonecrosis, is misleading because the primary histopathological lesion is osteocyte apoptosis. Apoptotic osteocytes persist because they are anatomically unavailable for phagocytosis and, with glucocorticoid excess, decreased bone remodeling retards their replacement. Glucocorticoid-induced osteocyte apoptosis, a cumulative and unrepairable defect, uniquely disrupts the mechanosensory function of the osteocyte-lacunar-canalicular system and thus starts the inexorable sequence of events leading to collapse of the femoral head. Current evidence indicates that bisphosphonates may rapidly reduce pain, increase ambulation, and delay joint collapse in patients with osteonecrosis.

  1. Statin induced myotoxicity.

    PubMed

    Sathasivam, Sivakumar

    2012-06-01

    Statins are an effective treatment for the prevention of cardiovascular diseases and used extensively worldwide. However, myotoxicity induced by statins is a common adverse event and a major barrier to maximising cardiovascular risk reduction. The clinical spectrum of statin induced myotoxicity includes asymptomatic rise in creatine kinase concentration, myalgia, myositis and rhabdomyolysis. In certain cases, the cessation of statin therapy does not result in the resolution of muscular symptoms or the normalization of creatine kinase, raising the possibility of necrotizing autoimmune myopathy. There is increasing understanding and recognition of the pathophysiology and risk factors of statin induced myotoxicity. Careful history and physical examination in conjunction with selected investigations such as creatine kinase measurement, electromyography and muscle biopsy in appropriate clinical scenario help diagnose the condition. The management of statin induced myotoxicity involves statin cessation, the use of alternative lipid lowering agents or treatment regimes, and in the case of necrotizing autoimmune myopathy, immunosuppression.

  2. Electromagnetically induced phase grating.

    PubMed

    de Araujo, Luís E E

    2010-04-01

    I propose an electromagnetically induced phase grating based on the giant Kerr nonlinearity of an atomic medium under electromagnetically induced transparency. The atomic phase grating behaves similarly to an ideal sinusoidal phase grating, and it is capable of producing a pi phase excursion across a weak probe beam along with high transmissivity. The grating is created with arbitrarily weak fields, and diffraction efficiencies as high as 30% are predicted.

  3. Ethionamide-induced Pellagra.

    PubMed

    Gupta, Yashashree; Shah, Ira

    2015-08-01

    Pellagra is a disorder characterized by dermatitis, diarrhea, dementia and eventually death, resulting from a deficiency of niacin or its precursor tryptophan. Ethionamide (a second-line antituberculosis agent)-induced pellagra is rarely encountered in clinical practice. Prompt diagnosis and treatment with nicotinamide can prevent life-threatening complications. To date, only three cases have been reported. We report a 13-year-old girl presenting with ethionamide-induced pellagra that resolved after the administration of niacin.

  4. Levodopa-induced myoclonus.

    PubMed

    Klawans, H L; Goetz, C; Bergen, D

    1975-05-01

    Twelve parkinsonian patients on long-term levodopa therapy developed intermittent, myoclonic body jerks. The movements consisted of single unilateral or bilateral abrupt jerks of the extremities and occurred most frequently during sleep. Although directly related to daily dosage of levodopa, the myoclonus was specifically blocked by the serotonin antagonist, methysergide. Levodopa-induced myoclonus may be related to intermittent increases of activity of serotonin in the brain and results from levodopa-induced dysregulation of serotonin activity.

  5. Lorazepam-induced diplopia.

    PubMed

    Lucca, Jisha M; Ramesh, Madhan; Parthasarathi, Gurumurthy; Ram, Dushad

    2014-01-01

    Diplopia - seeing double - is a symptom with many potential causes, both neurological and ophthalmological. Benzodiazepine induced ocular side-effects are rarely reported. Lorazepam is one of the commonly used benzodiazepine in psychiatric practice. Visual problems associated with administration of lorazepam are rarely reported and the frequency of occurrence is not established. We report a rare case of lorazepam-induced diplopia in a newly diagnosed case of obsessive compulsive disorder.

  6. Paroxetine-induced galactorrhea.

    PubMed

    Gulati, Prannay; Chavan, B S; Das, Subhash

    2014-10-01

    Drug-induced galactorrhea has been reported with agents such as antidopaminergic antiemetics, antipsychotics, etc., with few case reports of galactorrhea with selective serotonin reuptake inhibitors, including paroxetine, being reported in last few decades. Prolactin levels have been found to be either raised or normal in these cases. We here report a case of paroxetine induced galactorrhea in a 48-year-old female patient of obsessive compulsive disorder, having hyperprolactinemic and euprolactinemic galactorrhea at different time with a pituitary incidentaloma.

  7. Paroxetine-induced galactorrhea

    PubMed Central

    Gulati, Prannay; Chavan, B. S.; Das, Subhash

    2014-01-01

    Drug-induced galactorrhea has been reported with agents such as antidopaminergic antiemetics, antipsychotics, etc., with few case reports of galactorrhea with selective serotonin reuptake inhibitors, including paroxetine, being reported in last few decades. Prolactin levels have been found to be either raised or normal in these cases. We here report a case of paroxetine induced galactorrhea in a 48-year-old female patient of obsessive compulsive disorder, having hyperprolactinemic and euprolactinemic galactorrhea at different time with a pituitary incidentaloma. PMID:25568484

  8. Induced polarization response of microbial induced sulfideprecipitation

    SciTech Connect

    Ntarlagiannis, Dimitrios; Williams, Kenneth Hurst; Slater, Lee; Hubbard, Susan

    2004-06-04

    A laboratory scale experiment was conducted to examine the use of induced polarization and electrical conductivity to monitor microbial induced sulfide precipitation under anaerobic conditions in sand filled columns. Three columns were fabricated; one for electrical measurements, one for geochemical sampling and a third non-inoculated column was used as a control. A continual upward flow of nutrients and metals in solution was established in each column. Desulfovibrio vulgaris microbes were injected into the middle of the geochemical and electrical columns. Iron and zinc sulfides precipitated along a microbial action front as a result of sulfate reduction due by Desulfovibrio vulgaris. The precipitation front initially developed near the microbial injection location, and subsequently migrated towards the nutrient inlet, as a result of chemotaxis by Desulfovibrio vulgaris. Sampling during and subsequent to the experiment revealed spatiotemporal changes in the biogeochemical measurements associated with microbial sulfate reduction. Conductivity measurements were insensitive to all biogeochemical changes occurred within the column. Changes in the IP response (of up to 14 mrad)were observed to coincide in place and in time with the active microbe respiration/sulfide precipitation front as determined from geochemical sampling. The IP response is correlated with the lactate concentration gradient, an indirect measurement of microbial metabolism, suggesting the potential of IP as a method for monitoring microbial respiration/activity. Post experimental destructive sample analysis and SEM imaging verified the geochemical results and supported our hypothesis that microbe induced sulfide precipitation is directly detectable using electrical methods. Although the processes not fully understood, the IP response appears to be sensitive to this anaerobic microbial precipitation, suggesting a possible novel application for the IP method.

  9. Radiation-Induced Bioradicals

    NASA Astrophysics Data System (ADS)

    Mondelaers, Win; Lahorte, Philippe

    This chapter is part one of a review in which the production and application of radiation-induced bioradicals is discussed. Bioradicals play a pivotal role in the complex chain of processes starting with the absorption of radiation in biological materials and ending with the radiation-induced biological after-effects. The general aspects of the four consecutive stages (physical, physicochemical, chemical and biological) are discussed from an interdisciplinary point of view. The close relationship between radiation dose and track structure, induced DNA damage and cell survival or killing is treated in detail. The repair mechanisms that cells employ, to insure DNA stability following irradiation, are described. Because of their great biomedical importance tumour suppressor genes involved in radiation-induced DNA repair and in checkpoint activation will be treated briefly, together with the molecular genetics of radiosensitivity. Part two of this review will deal with modern theoretical methods and experimental instrumentation for quantitative studies in this research field. Also an extensive overview of the applications of radiation-induced bioradicals will be given. A comprehensive list of references allows further exploration of this research field, characterised in the last decade by a substantial advance, both in fundamental knowledge and in range of applications.

  10. Chemotherapy-induced alopecia.

    PubMed

    Trüeb, Ralph M

    2010-12-01

    Few dermatologic conditions carry as much emotional distress as chemotherapy-induced hair loss. Forty-seven percent of female patients consider hair loss the most traumatic aspect of chemotherapy, and 8% would decline chemotherapy because of fear of hair loss. A number of agents have been evaluated on the basis of the current understanding of the underlying pathobiology. Among the agents that have been evaluated, topical minoxidil was able to reduce the severity or shorten the duration but could not prevent hair loss. The major approach to minimize chemotherapy-induced hair loss is by scalp cooling, although most published data on scalp cooling are of poor quality. Because chemotherapy-induced toxicity has been associated with nutritional status, nutritional assessment and support might confer beneficial effects. Several experimental approaches to the development of pharmacological agents are under evaluation including: anti-oxidants, cytokines and growth factors, cell cycle and proliferation modifiers, and inhibitors of apoptosis. At present, no approved pharmacologic treatment of chemotherapy-induced hair loss exists. The incidence and severity of the condition are variable and related to the particular chemotherapeutic protocol. Fortunately, chemotherapy-induced hair loss is mostly reversible, and appropriate hair and scalp care and temporarily wearing a wig may be the most effective coping strategy.

  11. Drug-induced mania.

    PubMed

    Peet, M; Peters, S

    1995-02-01

    Mania can occur by chance association during drug treatment, particularly in patients predisposed to mood disorder. Single case reports are unreliable, and evidence must be sought from large series of treated patients, particularly those with a matched control group. Drugs with a definite propensity to cause manic symptoms include levodopa, corticosteroids and anabolic-androgenic steroids. Antidepressants of the tricyclic and monoamine oxidase inhibitor classes can induce mania in patients with pre-existing bipolar affective disorder. Drugs which are probably capable of inducing mania, but for which the evidence is less scientifically secure, include other dopaminergic anti-Parkinsonian drugs, thyroxine, iproniazid and isoniazid, sympathomimetic drugs, chloroquine, baclofen, alprazolam, captopril, amphetamine and phencyclidine. Other drugs may induce mania rarely and idiosyncratically. Management involves discontinuation or dosage reduction of the suspected drug, if this is medically possible, and treatment of manic symptoms with antipsychotic drugs or lithium.

  12. Radiation-induced gliomas

    PubMed Central

    Prasad, Gautam; Haas-Kogan, Daphne A.

    2013-01-01

    Radiation-induced gliomas represent a relatively rare but well-characterized entity in the neuro-oncologic literature. Extensive retrospective cohort data in pediatric populations after therapeutic intracranial radiation show a clearly increased risk in glioma incidence that is both patient age- and radiation dose/volume-dependent. Data in adults are more limited but show heightened risk in certain groups exposed to radiation. In both populations, there is no evidence linking increased risk associated with routine exposure to diagnostic radiation. At the molecular level, recent studies have found distinct genetic differences between radiation-induced gliomas and their spontaneously-occurring counterparts. Clinically, there is understandable reluctance on the part of clinician