Corticotropin-releasing factor neurons in the bed nucleus of the stria terminalis exhibit sex-specific pain encoding in mice

Abstract

The bed nucleus of the stria terminalis (BNST) plays an emerging role in pain regulation. Pharmacological studies have found that inhibiting corticotropin-releasing factor (CRF) signaling in the BNST can selectively mitigate the sensory and affective-motivational components of pain. However, mechanistic insight on the source of CRF that drives BNST responses to these harmful experiences remains unknown. In the present study, we used a series of genetic approaches to show that CRF in the BNST is engaged in the processing and modulation of pain. We conducted cell-type specific in vivo calcium imaging in CRF-Cre mice and found robust and synchronized recruitment of BNSTCRF neurons during acute exposures to noxious heat. Distinct patterns of recruitment were observed by sex, as the magnitude and timing of heat responsive activity in BNSTCRF neurons differed for male and female mice. We then used a viral approach in Floxed-CRF mice to selectively reduce CRF expression in the BNST and found it decreased nociceptive sensitivity for both sexes and increased paw attending for females. Together, these findings reveal that CRF in the BNST influences multiple facets of the pain experience to impact the sex-specific expression of pain-related behaviors.

Disentangling the effects of Corticotrophin Releasing Factor and GABA release from the ventral bed nucleus of the stria terminalis on ethanol self-administration in mice

“…For the functional validation of this construct, each of these viruses were mixed in a 4:1 ratio with AAV8-Ef1a-double floxed-hChR2(H134R)-mCherry-WPRE-HGHpA (Addgene; Watertown, MA, USA) and injected with 300 nL per side. To selectively knock down CRF expression in the ventral BNST (26), CRH-flox mice were injected with either AAV8-hSyn-GFP or AAV8-hSyn-Cre-GFP (UNC Vector Core).…”

Distinct Encoding of Reward and Aversion by Peptidergic BNST Inputs to the VTA

“…Previous calcium imaging experiments in BNST-Crh neurons demonstrated that these cells respond to painful stimuli (Yu et al, 2021) and restraint stress (Luchsinger et al, 2021). In response to an acute noxious stimulus BNST-Crh neurons responded with approximately equal numbers having increased or decreased calcium signals (Yu et al, 2021).…”

Corticotropin Releasing Factor in the Bed Nucleus of the Stria Terminalis modulates the behavioral consequences of unpredictable threat

“…To determine the role of CRF in BNST neurons in Part fear, we used a viral approach to genetically knockdown CRF in the BNST 40 . To do this, we injected an AAV encoding cre recombinase or GFP bilaterally into the BNST of CRF lox/lox mice 40 three weeks prior to behavior testing (Figure 3A-C).…”