Disinhibition of PVN-projecting GABAergic neurons in AV region in BNST participates in visceral hypersensitivity in rats

Song, Yu; Meng, Qingxiang; Wu, Ke; Hua, Rong; Song, Zhijing; Song, Ying; Qin, Xia; Cao, Jun‐Li; Zhang, Yongmei

doi:10.1016/j.psyneuen.2020.104690

Cited by 23 publications

(23 citation statements)

References 45 publications

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“…Paradoxically, photoexcitation of PVN-innervating, ChR2-expressing GABAergic terminals from BNST-AV did enhance the visceral pain threshold and decrease the spontaneous discharge frequency of CRF neurons in PVN in MS mice, as well as the hM3Dq-expressing GABA terminals by chemogenetics ( Figure 6). These findings are compatible with the hypothesis that dysfunction of GABAergic BNST AV -PVN circuit might participate in the visceral hypersensitivity induced by neonatal colorectal distension in SD rats (Song et al, 2020).…”

Section: Discussionsupporting

confidence: 91%

“…Post hoc Bonferroni multiple comparisons showed that the firing frequency of CRF neurons was significantly increased compared with other three groups. In our previous study (Song et al, 2020), GABA has been reportedly implicated in the pathogenesis of visceral hypersensitivity, and we referred to the PVN administration of exogenous GABA (0.3mM, 0.2µL). The visceral hypersensitivity was altered after GABA treatment in NMS mice ( Figure 2F).…”

Section: Involvement Of Activation Of Crf Neurons In Pvn In the Ms-inmentioning

confidence: 99%

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BNSTAVGABA-PVNCRF Circuit Regulates Visceral Hypersensitivity Induced by Maternal Separation in Vgat-Cre Mice

et al. 2021

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Visceral hypersensitivity as a common clinical manifestation of irritable bowel syndrome (IBS) may contribute to the development of chronic visceral pain. Our prior studies authenticated that the activation of the corticotropin-releasing factor (CRF) neurons in paraventricular nucleus (PVN) contributed to visceral hypersensitivity in mice, but puzzles still remain with respect to the underlying hyperactivation of corticotropin-releasing factor neurons. Herein, we employed maternal separation (MS) to establish mouse model of visceral hypersensitivity. The neuronal circuits associated with nociceptive hypersensitivity involved paraventricular nucleus CRF neurons by means of techniques such as behavioral test, pharmacology, molecular biology, retrograde neuronal circuit tracers, electrophysiology, chemogenetics and optogenetics. MS could predispose the elevated firing frequency of CRF neurons in PVN in murine adulthood, which could be annulled via the injection of exogenous GABA (0.3mM, 0.2µl) into PVN. The PVN-projecting GABAergic neurons were mainly distributed in the anterior ventral (AV) region in the bed nucleus of stria terminalis (BNST), wherein the excitability of these GABAergic neurons was reduced. Casp3 virus was utilized to induce apoptosis of GABA neurons in BNST-AV region, resulting in the activation of CRF neurons in PVN and visceral hyperalgesia. In parallel, chemogenetic and optogenetic approaches to activate GABAergic BNSTAV-PVN circuit in MS mice abated the spontaneous firing frequency of PVN CRF neurons and prevented the development of visceral hypersensitivity. A priori, PVNCRF-projecting GABAergic neurons in BNST-AV region participated in the occurrence of visceral hypersensitivity induced by MS. Our research may provide a new insight into the neural circuit mechanism of chronic visceral pain.

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Section: Discussionsupporting

confidence: 91%

Section: Involvement Of Activation Of Crf Neurons In Pvn In the Ms-inmentioning

confidence: 99%

BNSTAVGABA-PVNCRF Circuit Regulates Visceral Hypersensitivity Induced by Maternal Separation in Vgat-Cre Mice

et al. 2021

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“…Visceral sensitivity was assessed by AWR and visceral pain threshold [ 7 , 41 ]. Mice were displaced in transparent plastic boxes (10 cm × 10 cm × 5 cm) on an elevated plexiglass platform, allowed for habituation for 15-20 min.…”

Section: Methodsmentioning

confidence: 99%

Predisposition of Neonatal Maternal Separation to Visceral Hypersensitivity via Downregulation of Small-Conductance Calcium-Activated Potassium Channel Subtype 2 (SK2) in Mice

Gao

Hua

et al. 2020

Neural Plasticity

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Background. Visceral hypersensitivity is a common occurrence of gastrointestinal diseases such as irritable bowel syndrome (IBS), wherein early-life stress (ELS) may have a high predisposition to the development of visceral hypersensitivity in adulthood, with the specific underlying mechanism still elusive. Herein, we assessed the potential effect of small-conductance calcium-activated potassium channel subtype 2 (SK2) in the spinal dorsal horn (DH) on the pathogenesis of visceral hypersensitivity induced by maternal separation (MS) in mice. Methods. Neonatal mice were subjected to the MS paradigm, an established ELS model. In adulthood, the visceral pain threshold and the abdominal withdrawal reflex (AWR) were measured with an inflatable balloon. The elevated plus maze, open field test, sucrose preference test, and forced swim test were employed to evaluate the anxiety- and depression-like behaviors. The expression levels of SK2 in the spinal DH were determined by immunofluorescence and western blotting. The mRNA of SK2 and membrane palmitoylated protein 2 (MPP2) were determined by quantitative real-time polymerase chain reaction (qRT-PCR). Electrophysiology was applied to evaluate the neuronal firing rates and SK2 channel-mediated afterhyperpolarization current (IAHP). The interaction between MPP2 and SK2 was validated by coimmunoprecipitation. Results. In contrast to the naïve mice, ethological findings in MS mice revealed lowered visceral pain threshold, more evident anxiety- and depression-like behaviors, and downregulated expression of membrane SK2 protein and MPP2 protein. Moreover, electrophysiological results indicated increased neuronal firing rates and decreased IAHP in the spinal DH neurons. Nonetheless, intrathecal injection of the SK2 channel activator 1-ethyl-2-benzimidazolinone (1-EBIO) in MS mice could reverse the electrophysiological alterations and elevate the visceral pain threshold. In the naïve mice, administration of the SK2 channel blocker apamin abated IAHP and elevated spontaneous neuronal firing rates in the spinal DH neurons, reducing the visceral pain threshold. Finally, disruption of the MPP2 expression by small interfering RNA (siRNA) could amplify visceral hypersensitivity in naïve mice. Conclusions. ELS-induced visceral pain and visceral hypersensitivity are associated with the underfunction of SK2 channels in the spinal DH.

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“…One potential mechanism through which the PVT may influence HPA axis activity differentially in homotypic and heterotypic stress paradigms is through its glutamatergic (vGlut2-positive) projection to the BNST (Myers et al, 2014), a key limbic target of the PVT primarily consisting of GABAergic projection and interneurons. BNST GABA neurons project to the parvocellular region of the paraventricular nucleus of the hypothalamus (PVN) and can directly inhibit CRF neurons (Dong et al, 2001;Bienkowski and Rinaman, 2011;Crestani et al, 2013;Colmers and Bains, 2018;Song et al, 2020). Therefore, the PVT may be able to provide indirect inhibitory control on the HPA axis via the BNST.…”

Section: Circuit-specific Tuning Of the Pvtmentioning

confidence: 99%

Influences of Stress and Sex on the Paraventricular Thalamus: Implications for Motivated Behavior

Rowson

Pleil

2021

Front. Behav. Neurosci.

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The paraventricular nucleus of the thalamus (PVT) is a critical neural hub for the regulation of a variety of motivated behaviors, integrating stress and reward information from environmental stimuli to guide discrete behaviors via several limbic projections. Neurons in the PVT are activated by acute and chronic stressors, however several roles of the PVT in behavior modulation emerge only following repeated stress exposure, pointing to a role for hypothalamic pituitary adrenal (HPA) axis modulation of PVT function. Further, there may be a reciprocal relationship between the PVT and HPA axis in which chronic stress-induced recruitment of the PVT elicits an additional role for the PVT to regulate motivated behavior by modulating HPA physiology and thus the neuroendocrine response to stress itself. This complex interaction may make the PVT and its role in influencing motivated behavior particularly susceptible to chronic stress-induced plasticity in the PVT, especially in females who display increased susceptibility to stress-induced maladaptive behaviors associated with neuropsychiatric diseases. Though literature is describing the sex-specific effects of acute and chronic stress exposure on HPA axis activation and motivated behaviors, the impact of sex on the role of the PVT in modulating the behavioral and neuroendocrine response to stress is less well established. Here, we review what is currently known regarding the acute and chronic stress-induced activation and behavioral role of the PVT in male and female rodents. We further explore stress hormone and neuropeptide signaling mechanisms by which the HPA axis and PVT interact and discuss the implications for sex-dependent effects of chronic stress on the PVT’s role in motivated behaviors.

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Disinhibition of PVN-projecting GABAergic neurons in AV region in BNST participates in visceral hypersensitivity in rats

Cited by 23 publications

References 45 publications

BNSTAVGABA-PVNCRF Circuit Regulates Visceral Hypersensitivity Induced by Maternal Separation in Vgat-Cre Mice

BNSTAVGABA-PVNCRF Circuit Regulates Visceral Hypersensitivity Induced by Maternal Separation in Vgat-Cre Mice

Predisposition of Neonatal Maternal Separation to Visceral Hypersensitivity via Downregulation of Small-Conductance Calcium-Activated Potassium Channel Subtype 2 (SK2) in Mice

Influences of Stress and Sex on the Paraventricular Thalamus: Implications for Motivated Behavior

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