Dataset Information

Neuroadaptations of presynaptic and postsynaptic GABA_B receptor function in the paraventricular nucleus in response to chronic unpredictable stress.

ABSTRACT:

Background and purpose

Chronic stress impairs GABA_A (GABA type A) receptor-mediated inhibition in the hypothalamic paraventricular nucleus (PVN). It is not clear whether GABA_B receptor function is also altered. We hypothesize that chronic stress alters GABA_B receptor function in PVN corticotrophin-releasing hormone (CRH) neurons to control hypothalamus-pituitary-adrenal axis activity.

Experimental approach

Whole-cell patch clamp recordings were made of PVN-CRH neurons expressing eGFP driven by CRH promoter in brain slices from unstressed rats and rats exposed to chronic unpredictable mild stress (CUMS).

Key results

CUMS elevated the basal circulating corticosterone levels and increased the basal firing activity of PVN-CRH neurons. Microinjection of GABA_B receptor agonist baclofen into the PVN suppressed the increased corticosterone levels in CUMS rats compared with unstressed rats. CUMS blunted the baclofen-induced inhibition on PVN-CRH neurons and outward currents in these neurons. Furthermore, CUMS reduced expression of GABA_B1 (GABA_B R1) protein in the PVN. Blocking NMDA receptors with AP5 restored the reduced baclofen-induced currents in CUMS rats but had no effect on GABA_B1 expression. Furthermore, CUMS treatment augmented the baclofen-induced decrease in the frequency of glutamatergic excitatory postsynaptic currents (EPSCs) and GABAergic inhibitor postsynaptic currents in PVN-CRH neurons. The GABA_B receptor antagonist CGP55845 increased the firing activity of PVN-CRH neurons only in CUMS-treated rats and not in unstressed rats.

Conclusions and implications

These findings suggest that chronic stress impairs postsynaptic GABA_B receptor function but augments presynaptic GABA_B receptor function in controlling glutamatergic and GABAergic synaptic inputs in PVN-CRH neurons.

SUBMITTER: Gao Y

PROVIDER: S-EPMC5554316 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Publications

Neuroadaptations of presynaptic and postsynaptic GABA<sub>B</sub> receptor function in the paraventricular nucleus in response to chronic unpredictable stress.

Gao Yonggang Y Zhou Jing-Jing JJ Zhu Yun Y Wang Li L Kosten Therese A TA Zhang Xiangjian X Li De-Pei DP

British journal of pharmacology 20170801 17

<h4>Background and purpose</h4>Chronic stress impairs GABA<sub>A</sub> (GABA type A) receptor-mediated inhibition in the hypothalamic paraventricular nucleus (PVN). It is not clear whether GABA<sub>B</sub> receptor function is also altered. We hypothesize that chronic stress alters GABA<sub>B</sub> receptor function in PVN corticotrophin-releasing hormone (CRH) neurons to control hypothalamus-pituitary-adrenal axis activity.<h4>Experimental approach</h4>Whole-cell patch clamp recordings were mad ...[more]

PMID: 28635080

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Project description:Chronic stress and depression impart increased risk for adverse cardiovascular events. Autonomic dysregulation, particularly sympathoexcitation, has long been associated with poor cardiovascular outcomes. Vasopressin (AVP) receptors with the paraventricular nucleus (PVN), known as an integrating locus for hemodynamic and autonomic function, have been implicated in behavior and stress. The present studies were designed to test the hypothesis that knockdown of vasopressin V1aR within the PVN in male Sprague Dawley rats subjected to chronic mild unpredictable stress (CMS) would result in lower resting hemodynamics and renal sympathetic nerve activity (RSNA) and mitigate the responses to acute stressors. Male rats underwent CMS for 4 weeks; controls were housed in standard caging. Twenty days into the paradigm, the PVN was injected with either small interfering RNA (siRNA) directed against V1aR or scrambled RNA (scrRNA). Arterial pressure, heart rate and RSNA were ascertained by telemetry with the animals in their home cages. Pretreatment with siRNA to V1aR prevented the increase in arterial pressure to PVN microinjection with exogenous AVP. Basal mean arterial pressure (MAP) was significantly higher in scrRNA-treated but not in siRNA-treated CMS rats vs control rats. Paradoxically, basal RSNA was approximately two-fold higher in siRNA-treated CMS rats. Acute emotional stress delivered as 15-sec air-jet resulted in greater peak and duration of the MAP and RSNA responses in scrRNA-treated CMS rats vs control; siRNA treatment inhibited the responses. The 15-sec exposure to ammonia to test the nasopharyngeal reflex, whose circuitry does not include the PVN, produced similar increases in arterial pressure, heart rate, and RSNA in controls and both groups of CMS rats. Thus, CMS increases arterial pressure and predisposes to greater hemodynamic and RSNA responses to acute emotional stress. The higher basal RSNA in siRNA-treated rats may be due to functional and/or anatomical neuroplasticity occurring during more protracted inhibition of V1aR PVN signaling. Vasopressinergic signaling via V1aR in PVN modulates the cardiovascular and sympathetic responses to both the chronic and acute stress.

Dataset Information

Neuroadaptations of presynaptic and postsynaptic GABA_B receptor function in the paraventricular nucleus in response to chronic unpredictable stress.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

Neuroadaptations of presynaptic and postsynaptic GABA<sub>B</sub> receptor function in the paraventricular nucleus in response to chronic unpredictable stress.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

Neuroadaptations of presynaptic and postsynaptic GABAB receptor function in the paraventricular nucleus in response to chronic unpredictable stress.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

Neuroadaptations of presynaptic and postsynaptic GABA<sub>B</sub> receptor function in the paraventricular nucleus in response to chronic unpredictable stress.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Neuroadaptations of presynaptic and postsynaptic GABA_B receptor function in the paraventricular nucleus in response to chronic unpredictable stress.