Glutamatergic and GABAergic anteroventral BNST projections to PVN CRH neurons regulate maternal separation-induced visceral pain

Early-life stress (ELS) is thought to cause the development of visceral pain disorders. While some individuals are vulnerable to visceral pain, others are resilient, but the intrinsic circuit and molecular mechanisms involved remain largely unclear. Herein, we demonstrate that inbred mice subjected to maternal separation (MS) could be separated into susceptible and resilient subpopulations by visceral hypersensitivity evaluation. Through a combination of chemogenetics, optogenetics, fiber photometry, molecular and electrophysiological approaches, we discovered that susceptible mice presented activation of glutamatergic projections or inhibition of GABAergic projections from the anteroventral bed nucleus of the stria terminalis (avBNST) to paraventricular nucleus (PVN) corticotropin-releasing hormone (CRH) neurons. However, resilience develops as a behavioral adaptation partially due to restoration of PVN SK2 channel expression and function. Our findings suggest that PVN CRH neurons are dually regulated by functionally opposing avBNST neurons and that this circuit may be the basis for neurobiological vulnerability to visceral pain.