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.
Highlights
The irritable bowel syndrome (IBS) is a common functional disease characterized by chronic abdominal pain and abnormality of bowel movement (Thompson et al, 1999; Farmer and Aziz, 2013), with a morbidity of approximately between 7 and 21% worldwide (Lovell and Ford, 2012; Vich Vila et al, 2018)
Our previous studies identified that corticotrophinreleasing factor (CRF) neurons in the paraventricular nucleus (PVN) and hypothalamic-pituitary-adrenal (HPA) axis were involved in the development of maternal separation (MS)-induced visceral hypersensitivity (Zhang et al, 2016; Tang et al, 2017)
The time point of each behavior experiments could not have resulted in the bias which might have occurred in mice undergoing all the behavior experiments
Summary
The irritable bowel syndrome (IBS) is a common functional disease characterized by chronic abdominal pain and abnormality of bowel movement (Thompson et al, 1999; Farmer and Aziz, 2013), with a morbidity of approximately between 7 and 21% worldwide (Lovell and Ford, 2012; Vich Vila et al, 2018). Our previous studies identified that corticotrophinreleasing factor (CRF) neurons in the paraventricular nucleus (PVN) and hypothalamic-pituitary-adrenal (HPA) axis were involved in the development of MS-induced visceral hypersensitivity (Zhang et al, 2016; Tang et al, 2017). The activation of PVN CRF neurons and HPA axis is regulated by a variety of mechanisms, such as glucocorticoid feedback (Kloet, 2013), excitatory activity of glutamate neurons (Gunn et al, 2013) and the inhibitory action of γ-aminobutyric acid (GABA) neurons (Cullinan et al, 2008). There is morphological evidence that the GABA synapses in medial parvocellular paraventricular hypothalamus (PVNmp) account for approximately half of all synapses (Decavel and Van den Pol, 1990), wherein PVNmp cells receive GABAergic inhibitory inputs mainly from the marginal structures, including the medial preoptic area, the bed nucleus of the stria terminalis (BNST), and the medial hypothalamic nucleus (Ulrich-Lai and Herman, 2009). The revelation of the upstream inhibitory nucleus projecting to PVN CRF neurons is of significance
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