Ventral Subiculum

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Anthony A. Grace - One of the best experts on this subject based on the ideXlab platform.

  • Psychogenic Stress Activates C-Fos in Nucleus Accumbens-Projecting Neurons of the Hippocampal Ventral Subiculum.
    The international journal of neuropsychopharmacology, 2017
    Co-Authors: Witold J Lipski, Sofia M. Dibble, Linda Rinaman, Anthony A. Grace
    Abstract:

    © The Author 2017. Background: The Ventral Subiculum is known to be activated by the presentation of novel stressors. It has been hypothesized that neuronal ensembles at the Ventral aspect of the hippocampal formation are involved in context-dependent processing and can guide the learning of appropriate action selections in response to threatening contexts. Artificial activation of the Ventral Subiculum can excite medium spiny neurons of the nucleus accumbens and can increase the excitability of mesolimbic dopamine neurons via a polysynaptic pathway through the basal ganglia. However, it remains unknown whether this circuit can be activated by aversive experience, and if so, whether Ventral Subiculum engages nucleus accumbens monosynaptically. Methods: To address this, the retrograde tracer fluorogold was used in rats to label neurons projecting to the caudomedial nucleus accumbens. One to 2 weeks later, the same rats were exposed to psychogenic stress (i.e., acute restraint in a novel test room) or served as nonhandled controls, followed by dual immunocytochemical localization of retrogradely transported tracer and nuclear Fos. Results: Compared with controls, rats exposed to psychogenic stress displayed more fluorogold-positive Ventral Subiculum neurons that were double-labeled for Fos. Conclusion: This study establishes that the direct pathway from Ventral Subiculum to the caudomedial nucleus accumbens is activated by stressful experience.

  • Dopamine System Dysregulation in Major Depressive Disorders.
    The international journal of neuropsychopharmacology, 2017
    Co-Authors: Pauline Belujon, Anthony A. Grace
    Abstract:

    Anhedonia is considered a core feature of major depressive disorder, and the dopamine system plays a pivotal role in the hedonic deficits described in this disorder. Dopaminergic activity is complex and under the regulation of multiple brain structures, including the Ventral Subiculum of the hippocampus and the basolateral amygdala. Whereas basic and clinical studies demonstrate deficits of the dopaminergic system in depression, the origin of these deficits likely lies in dysregulation of its regulatory afferent circuits. This review explores the current information regarding the afferent modulation of the dopaminergic system and its relevance to major depressive disorder, as well as some of the system-level effects of novel antidepressants such as agomelatine and ketamine.

  • Loss of parvalbumin in the hippocampus of MAM schizophrenia model rats is attenuated by peripubertal diazepam
    The international journal of neuropsychopharmacology, 2016
    Co-Authors: Anthony A. Grace
    Abstract:

    Background: Loss of parvalbumin interneurons in the hippocampus is a robust finding in schizophrenia brains. Rats exposed during embryonic day 17 to methylazoxymethanol acetate exhibit characteristics consistent with an animal model of schizophrenia, including decreased parvalbumin interneurons in the Ventral hippocampus. We reported previously that peripubertal administration of diazepam prevented the emergence of pathophysiology in adult methylazoxymethanol acetate rats. Methods: We used an unbiased stereological method to examine the impact of peripubertal diazepam treatment on parvalbumin interneuron number in the Ventral Subiculum, dentate gyrus of the hippocampus and the basolateral amygdala. Results: Methylazoxymethanol acetate rats with peripubertal diazepam showed significantly more parvalbumin interneurons (3355±173 in the Ventral Subiculum, 1211±76 in the dentate gyrus) than methylazoxymethanol acetate without diazepam (2375±109 and 824±54, respectively). No change was found in the basolateral amygdala. Conclusions: Peripubertal diazepam attenuated the decrease of parvalbumin in the Ventral hippocampus of methylazoxymethanol acetate rats.

  • footshock induced responses in Ventral Subiculum neurons are mediated by locus coeruleus noradrenergic afferents
    European Neuropsychopharmacology, 2013
    Co-Authors: Witold J Lipski, Anthony A. Grace
    Abstract:

    Abstract The Ventral Subiculum (vSub) of the hippocampus is critically involved in mediating the forebrain's response to stress, particularly with regard to psychogenic stressors. Stress, in turn, is known to aggravate many psychiatric conditions including schizophrenia, depression, anxiety, and drug abuse. Pathological alterations in hippocampal function have been identified in all these disorders; thus, it is of interest to understand how stress affects this brain region. The vSub receives dense projections from the stress-related locus coeruleus (LC); however, it is not known what role this input plays in signaling stressful stimuli. In this study, the direct LC innervation of the vSub was investigated as a potential mediator of stress responses in this region. To examine responses to an acute stressor, the effect of footshock on single vSub neurons was tested in rats. Footshock inhibited 13%, and activated 48% of neurons in this region. Importantly, responses to footshock were correlated with LC stimulation-evoked responses in single neurons, and LC inactivation blocked these responses. Furthermore, prazosin, an alpha-1 antagonist, reversed footshock-evoked inhibition, revealing an underlying activation. Inactivation of the basolateral amygdala (BLA) did not block phasic footshock-evoked activation; however, it reduced tonic activity in the vSub. These results suggest that the LC NE system plays an important role in mediating stress responses in the vSub. Footshock evokes both inhibition and excitation in the vSub, by activating noradrenergic inputs from the LC. These responses may contribute to stress adaptation; while an imbalance of this system may lead to pathological stress responses in mental disorders.

  • Activation and Inhibition of Neurons in the Hippocampal Ventral Subiculum by Norepinephrine and Locus Coeruleus Stimulation
    Neuropsychopharmacology, 2013
    Co-Authors: Witold J Lipski, Anthony A. Grace
    Abstract:

    The Ventral Subiculum (vSub) has been implicated in a wide range of neurocognitive functions, including responses to fear, stress, and anxiety. The vSub receives dense noradrenergic (NE) inputs from the locus coeruleus (LC), and the LC-NE system is heavily implicated in attention and is known to be activated by stressors. However, the way in which the neurons in the vSub respond to activation of the LC-NE is not well understood. In this study, the direct LC innervation of the vSub was investigated. The effect of norepinephrine (NE) on single vSub neurons was examined using microiontophoresis combined with electrophysiological recordings in anesthetized rats, and this response compared with the effect of electrical stimulation of the LC. Iontophoretic NE inhibited all vSub neurons tested, whereas LC stimulation inhibited 16% and activated 38% of neurons. Inhibition was mediated primarily by alpha-2 receptors, whereas activation was mediated by beta-adrenergic receptors. Furthermore, this effect was not mediated via the LC-basolateral amygdala (BLA) pathway, because BLA inactivation did not block LC stimulation-evoked activation of the vSub. These results indicate that the LC-NE system is a potent modulator of vSub activity. Based on these findings, stress-induced activation of the LC-NE system is expected to evoke inhibition and activation in the vSub, both of which may contribute to stress adaptation, whereas an imbalance of this system may lead to pathological stress responses in mental disorders.

James P Herman - One of the best experts on this subject based on the ideXlab platform.

  • mifepristone decreases depression like behavior and modulates neuroendocrine and central hypothalamic pituitary adrenocortical axis responsiveness to stress
    Psychoneuroendocrinology, 2010
    Co-Authors: Aynara C Wulsin, James P Herman, Matia B Solomon
    Abstract:

    Summary Glucocorticoid dyshomeostasis is observed in a proportion of depressed individuals. As a result, glucocorticoid receptor (GR) antagonists are currently being tested as potential anti-depressants. The current study was designed to test the efficacy of mifepristone, a GR antagonist, in mitigating behavioral, neuroendocrine and central nervous system (CNS) responses to an acute stressor. Adult male rats were treated for 5 days with mifepristone (10 mg/kg) and then exposed to the forced swim test (FST). Treatment with mifepristone decreased immobility and increased swimming (but not climbing) behavior in the FST, consistent with anti-depressant action. In addition, mifepristone dampened the ACTH response to FST exposure. In the CNS, mifepristone increased c-Fos expression in all subdivisions of the medial prefrontal cortex (mPFC) and decreased neuronal activity in some subdivisions of the hippocampus including the CA2, CA3, and hilus region of the dentate gyrus in animals exposed to FST. In contrast, mifepristone increased neuronal activity in the Ventral Subiculum (output region of the hippocampus) and decreased c-Fos expression in the central amygdala (CeA) in animals exposed to FST. These data suggest that anti-depressant efficacy and perhaps HPA dampening properties of RU486 are related to alterations in key limbic circuits mediating CNS stress responses, resulting in enhanced stress inhibition (via the mPFC and Ventral Subiculum) as well as decreased stress excitation (central amygdala). Overall the data suggest that drugs targeting the glucocorticoid receptor may ameliorate stress dysfunction associated with depressive illness.

  • Regulation of forebrain GABAergic stress circuits following lesion of the Ventral Subiculum.
    Brain research, 2006
    Co-Authors: Nancy K. Mueller, C. Mark Dolgas, James P Herman
    Abstract:

    Ventral Subiculum (vSUB) lesions enhance corticosterone responses to psychogenic stressors via trans-synaptic influences on paraventricular nucleus (PVN) neurons. Synaptic relays likely occur in GABA-rich regions interconnecting the vSUB and PVN. The current study examines whether vSUB lesions compromise stress-induced c-fos induction and GABA biosynthetic capacity in putative limbic-hypothalamic stress relays. Male Sprague-Dawley rats received bilateral ibotenate or sham lesions of the vSUB. Animals were divided into two groups, with one group receiving exposure to novelty stress and the other left unstressed. Exposure to novelty stress increased c-fos mRNA expression in the PVN to a greater degree in vSUB lesion relative to shams, consistent with an inhibitory role for the vSUB in the HPA stress response. However, c-fos induction was not affected in other forebrain GABAergic stress pathways, such as the lateral septum, medial preoptic area or dorsomedial hypothalamus. vSUB lesions increased GAD65 or GAD67 mRNA levels in several efferent targets, including anterior and posterior subnuclei of the bed nucleus of the stria terminalis and lateral septum. Lesions did not effect stress-induced increases in GAD65 expression in principal output nuclei of the amygdala. The current data suggest that loss of vSUB innervations produces a compensatory increase in GAD expression in subcortical targets; however, this up-regulation is insufficient to block lesion-induced stress hyperresponsiveness, perhaps driven by amygdalar disinhibition of the PVN.

  • Role of the Ventral Subiculum in stress integration.
    Behavioural brain research, 2006
    Co-Authors: James P Herman, Nancy K. Mueller
    Abstract:

    The mammalian Subiculum plays a prominent role in inhibition of the hypothalamo-pituitary-adrenocortical (HPA) axis. Lesion and stimulation studies indicate that the hippocampus, acting via output neurons of the Ventral Subiculum, acts to attenuate stress-induced glucocorticoid release. Lesions of the Ventral Subiculum enhance glucocorticoid secretion following psychogenic, but not systemic stressors, indicating that the influence of this structure on the HPA system is stressor-specific. Anatomical analyses fail to demonstrate direct interactions of the Subiculum with principal stress-effector neurons in the paraventricular hypothalamus, consistent with a trans-synaptic mechanism of action. Accordingly, tracing data indicate that glutamatergic Ventral Subiculum neurons innervate GABAergic neurons in several paraventricular nucleus-projecting neurons in the hypothalamus and basal forebrain, suggesting that inhibition is mediated by glutamate-GABA relays. The Subiculum also innervates several limbic forebrain structures that in turn have bisynaptic projections to paraventricular neurons, such as the prefrontal cortex, amygdala and lateral septum, suggesting that the Subiculum may have a generalized up-stream influence on limbic stress integration. Finally, recent information suggests that the Subiculum may also be stress excitatory under some circumstances, and that there may be substantial strain or individual differences in the net contribution of the Subiculum, to stress integration. Overall, the present state of knowledge indicates that the role of the Subiculum in stress integration is complex, and likely involves interactions of stress-relevant subicular output with limbic-hypothalamic stress-integrative circuits.

  • Stressor-Selective Role of the Ventral Subiculum in Regulation of Neuroendocrine Stress Responses
    Endocrinology, 2004
    Co-Authors: Nancy K. Mueller, C. Mark Dolgas, James P Herman
    Abstract:

    The Ventral Subiculum (vSUB) confers inhibitory effects of the hippocampus on hypothalamo-pituitary-adrenocortical (HPA) axis responses to novelty and restraint. The current study was designed to evaluate the role of the vSUB in regulating HPA axis responses to stressors of diverse modalities. Male Sprague Dawley rats received bilateral ibotenic acid or saline injections into the region of the vSUB. Corticosterone secretion was assessed after exposure to hypoxia and elevated plus maze, with the two stress exposures occurring 5 d apart. Peak corticosterone responses to hypoxia were reduced in vSUB-lesion animals, indicating an attenuation of HPA axis responsiveness. A subsequent study revealed that hyporesponsivity to hypoxia was evident in chamber-naive as well as chamber-adapted animals, verifying that this effect was independent of previous experience in the testing environment. In contrast, the effects of vSUB lesions on corticosterone responses to the elevated plus maze exposure were substantially mor...

  • Role of GABA and Glutamate Circuitry in Hypothalamo‐Pituitary‐Adrenocortical Stress Integration
    Annals of the New York Academy of Sciences, 2004
    Co-Authors: James P Herman, Nancy K. Mueller, Helmer F. Figueiredo
    Abstract:

    GABA and glutamate play a major role in central integration of hypothalamo-pituitary-adrenocortical (HPA) stress responses. Recent work in our group has focused on mechanisms whereby GABAergic and glutamatergic circuits interact with parvocellular paraventricular nucleus (PVN) neurons controlling the HPA axis. GABAergic neurons in the bed nucleus of the stria terminalis, preoptic area, and hypothalamus can directly inhibit PVN outflow and thereby reduce ACTH secretion. In contrast, glutamate activates the HPA axis, presumably by way of hypothalamic and brainstem projections to the PVN. These inhibitory and excitatory PVN-projecting neurons are controlled by descending information from limbic forebrain structures, including glutamatergic neurons of the Ventral Subiculum, prefrontal cortex, and GABAergic cells from the amygdala and perhaps septum. Lesion studies indicate that the Ventral Subiculum and prefrontal cortex are involved in inhibition of HPA axis responses to psychogenic stimuli, whereas the amygdala is positioned to enhance hormone secretion by way of GABA-GABA disinhibitory connections. Thus, it seems the psychogenic responses to stress are gated by discrete sets of GABAergic neurons in the basal forebrain and hypothalamus. As such, these neurons are positioned to summate limbic inputs into net inhibitory tone on the PVN and may thus play a major role in HPA dysfunction seen in affective disease states and aging.

Kathryn A. Cunningham - One of the best experts on this subject based on the ideXlab platform.

Anthony G. Phillips - One of the best experts on this subject based on the ideXlab platform.

  • Activation of the Ventral Subiculum reinvigorates behavior after failure to achieve a goal: Implications for dopaminergic modulation of motivational processes.
    Behavioural brain research, 2018
    Co-Authors: David Lindenbach, Jeremy K. Seamans, Anthony G. Phillips
    Abstract:

    Abstract Previous studies confirm that brief electrical stimulation of glutamatergic afferents from the Ventral Subiculum (vSub) can significantly enhance dopamine release in the Ventral striatum for an extended duration (>20 min). However, the functional significance of this effect on motivated behavior remains to be specified. Here we tested the hypothesis that brief electrical stimulation of the Ventral Subiculum (20 Hz for 10 s) might increase effort expenditure for food rewards. Motivation was assessed by a progressive ratio lever pressing task, which requires continuous escalation of the numbers of lever presses to receive each subsequent sucrose pellet, eventually resulting in the failure to achieve the required ratio for a food reward. vSub stimulation at the start of a session did not affect the rate or total number of lever presses prior to reaching the “break point”. In contrast, stimulation of the vSub with identical parameters on a post break point trial resulted in a significant increase in total responses. These findings demonstrate that activation of the vSub with parameters that modulate dopamine efflux in the nucleus accumbens can re-activate goal-directed behavior after failure to achieve a goal. Our data highlight a possible role for the vSub in the pathophysiology and potential treatment of motivational processes linked to psychiatric disease.

  • Dopamine and Glutamate Interaction Mediates Reinstatement of Drug-Seeking Behavior by Stimulation of the Ventral Subiculum
    The international journal of neuropsychopharmacology, 2014
    Co-Authors: Pornnarin Taepavarapruk, Kelly A. Butts, Anthony G. Phillips
    Abstract:

    Background: Drug addiction is a chronic brain disease characterized by recurrent episodes of relapse to drug-seeking/-taking behaviors. The Ventral Subiculum, the primary output of the hippocampus, plays a critical role in mediating drug-seeking behavior. Methods: A d-amphetamine intravenous self-administration rat model was employed along with focal electrical stimulation of the Ventral Subiculum (20 Hz/200 pulses) to examine its role in reinstatement of drug-seeking behavior. Dopamine efflux in the nucleus accumbens was measured by in vivo microdialysis and subsequent HPLC-ED analyses. Pharmacological antagonism of dopamine and ionotropic glutamate receptors locally within the nucleus accumbens was employed to assess the role of glutamate and dopamine in reinstatement of drug-seeking behavior induced by stimulation of the Ventral Subiculum. Results: Here, we demonstrate that reinstatement of drug-seeking behavior following extinction of d-amphetamine selfadministration by rats was induced by electrical stimulation in the Ventral Subiculum but not the cortex. This reinstatement was accompanied by a significant increase in dopamine efflux in the nucleus accumbens and was disrupted by microinfusion of a dopamine D1 or D2 antagonist into the nucleus accumbens. Inhibition of N-methyl-D-aspartate or non- N-methyl-Daspartate receptors had no effect on the reinstatement induced by Ventral Subiculum stimulation, whereas co-infusion of D1 and N-methyl-D-aspartate antagonists at formerly ineffective doses prevented drug-seeking behavior. Conclusions: These data support the hypothesis that dopamine/glutamate interactions within the Ventral striatum related to memory processes are involved in relapse to addictive behavior.

  • Neurochemical correlates of relapse to d-amphetamine self-administration by rats induced by stimulation of the Ventral Subiculum.
    Psychopharmacology, 2003
    Co-Authors: Pornnarin Taepavarapruk, Anthony G. Phillips
    Abstract:

    Rationale and objectives Previous studies show that electrical stimulation of the Ventral Subiculum (vSub) can reinstate drug-seeking behavior in rats following extinction. This study examined whether vSub stimulation could also evoke reinitiation of d-amphetamine (d-AMPH) self-administration during voluntary abstinence following a prolonged bout of drug intake. Dynamic changes in extracellular levels of dopamine (DA) and metabolites in the nucleus accumbens (NAc) during 48-h unlimited access to d-AMPH by rats were monitored. Neurochemical correlates of relapse to d-AMPH administration induced by vSub stimulation or by experimenter administered d-AMPH infusions were also examined during voluntary abstinence in separate experiments.

  • Neurochemical correlates of relapse to d-amphetamine self-administration by rats induced by stimulation of the Ventral Subiculum.
    Psychopharmacology, 2003
    Co-Authors: Pornnarin Taepavarapruk, Anthony G. Phillips
    Abstract:

    Previous studies show that electrical stimulation of the Ventral Subiculum (vSub) can reinstate drug-seeking behavior in rats following extinction. This study examined whether vSub stimulation could also evoke reinitiation of d-amphetamine (d-AMPH) self-administration during voluntary abstinence following a prolonged bout of drug intake. Dynamic changes in extracellular levels of dopamine (DA) and metabolites in the nucleus accumbens (NAc) during 48-h unlimited access to d-AMPH by rats were monitored. Neurochemical correlates of relapse to d-AMPH administration induced by vSub stimulation or by experimenter administered d-AMPH infusions were also examined during voluntary abstinence in separate experiments. In vivo microdialysis using high-pressure liquid chromatography with electrochemical detector (HPLC-EC) was used to monitor changes in DA and metabolite efflux in the NAc during a continuous access-abstinence-relapse cycle of d-AMPH self-administration in a 48-h test. The initial pattern of drug intake was associated with significant increases in DA efflux in the NAc. During the abstinence phase, DA efflux was near pre-session baseline values. Electrical stimulation at the vSub after 2 h of abstinence immediately induced a significant increase in DA efflux and reinstatement of drug self-administration behavior. Evoked DA release and responses on drug-paired lever induced by vSub stimulation were significantly greater than those induced by experimenter-administered d-AMPH. Relapse to drug-taking behavior can be triggered by activation of the subicular glutamatergic pathway to the NAc. This study also confirmed that during abstinence the neurochemical response of the mesolimbic DA system to d-AMPH is attenuated and this can be reversed by vSub stimulation.

  • Hyperlocomotion and increased dopamine efflux in the rat nucleus accumbens evoked by electrical stimulation of the Ventral Subiculum: role of ionotropic glutamate and dopamine D1 receptors.
    Psychopharmacology, 2000
    Co-Authors: Pornnarin Taepavarapruk, Stan B. Floresco, Anthony G. Phillips
    Abstract:

    Rationale and objectives: The role of glutamatergic afferents from the hippocampus in the modulation of dopamine (DA) efflux in the nucleus accumbens (NAcc) and concomitant increases in locomotor activity was examined following brief high-frequency electrical stimulation of the Ventral Subiculum (vSub). Reverse dialysis of ionotropic glutamate receptor (iGluR) antagonists into the NAcc identified the relative contributions of N-methyl-d-aspartate (NMDA) and non-NMDA glutamate receptors in the modulation of DA efflux, whereas microinjection of these compounds or selective DA D1 or D2 receptor antagonists were used to analyze the roles of glutamatergic and DA receptors in the stimulation-induced hyperlocomotion. Methods and results: Electrical stimulation of the vSub at 20 Hz (10 s, 300 µA) induced a significant increase in (1) DA levels in the NAcc (≈30% from pre-stimulation DA levels) and (2) locomotor activity (≈400%). The evoked DA release was completely blocked by reverse dialysis of a selective non-NMDA antagonist DNQX (10 µM and 100 µM), whereas only a high dose of the NMDA antagonist AP-V (100 µM) was effective. The increased motor activity, however, was only slightly attenuated by reverse dialysis of these drugs. Bilateral intra-NAcc injection of DNQX (1 µg/0.5 µl) blocked the increased motor activity induced by vSub stimulation relative to saline treatment. In contrast, bilateral intra-NAcc injection of AP-V (1 µg/ 0.5 µl) alone caused a significant increase in locomotor activity. The increased motor activity induced by vSub stimulation appears to be mediated through the DA D1 receptor, as systemic administration of the D1 antagonist SCH 23390 (0.25 mg/kg and 1 mg/kg), but not the D2 antagonist sulpiride (2 mg/kg and 10 mg/kg) blocked these effects. Conclusions: These data indicate an important role for hippocampal glutamatergic afferents in modulating the release of DA through iGluR on DA-receptive neurons in the NAcc and possibly on output neurons to the Ventral tegmental area, which subsequently elicits a prolonged increase in locomotor behavior. The role of this circuit in mediating context-dependent behavioral sensitization to repeated administration of psychostimulants is discussed.

Harshini Neelakantan - One of the best experts on this subject based on the ideXlab platform.

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