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

Abstract

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.

Enriched environment alleviates adolescent visceral pain, anxiety- and depression-like behaviors induced by neonatal maternal separation

“…However, the impact of different environments qualities on adolescent behavior and their mechanisms remains poorly underexplored. There is growing evidence that early life stress may permanently damage the developing brain, adversely affect behavior in adulthood, and increase the risk of chronic pain and psychopathology (17)(18)(19)(20)(21)(22)(23). However, little is known about the effects on puberty.…”

“…Early life stress was closely associated with the development of chronic pain and psychiatric disorders (17)(18)(19)(20)(21)(22)(23). Besides, early life stress can affect neuroinflammation, and neuroinflammation plays a role in chronic pain and psychiatric pathology (24)(25)(26).…”

Maternal Separation Induced Visceral Hypersensitivity Evaluated via Novel and Small Size Distention Balloon in Post-weaning Mice

“…The underlying mechanism of MS-induced visceral hypersensitivity has been widely studied in adult rats and mice (Tang et al, 2017;Fan et al, 2020;Chen et al, 2021;Huang et al, 2021). It was reported that sensitization of corticotropin-releasing factor (CRF) neurons in the hypothalamic paraventricular nucleus (PVN) plays an important role in the pathogenesis of visceral pain (Zhang et al, 2016).…”

“…Colorectal distention (CRD) is a widely used method for assessing visceral hypersensitivity (Larsson et al, 2003;Christianson and Gebhart, 2007;Annahazi et al, 2009;Huang et al, 2021). However, CRD for evaluation of visceral sensitivity has not been reported in post-weaning mice.…”

The Effect of Chronic Psychological Stress on Lower Urinary Tract Function: An Animal Model Perspective

“…), and stimulate adrenocorticotropic hormone secretion from the pituitary ( Kalantaridou et al, 2010 ). CRF could mediate general responses to stress and other responses such as visceral hyperalgesia ( Elman and Borsook, 2016 ; Chess-Williams et al, 2021 ; Huang et al, 2021 ). Other stress response-relevant brain regions include the prefrontal cortex, amygdala, and hippocampus ( Kalantaridou et al, 2010 ).…”