Distribution of corticotropin-releasing factor receptor 1 in the developing mouse forebrain: A novel sex difference revealed in the rostral periventricular hypothalamus

Abstract

Corticotropin-releasing factor (CRF) signaling through CRF receptor 1 (CRFR1) regulates autonomic, endocrine and behavioral responses to stress and has been implicated in the pathophysiology of several disorders including anxiety, depression, and addiction. Using a validated CRFR1 reporter mouse line (bacterial artificial chromosome identified by green fluorescence protein (BAC GFP-CRFR1)), we investigated the distribution of CRFR1 in the developing mouse forebrain. Distribution of CRFR1 was investigated at postnatal days (P) 0, 4, and 21 in male and female mice. CRFR1 increased with age in several regions including the medial amygdala, arcuate nucleus, paraventricular hypothalamus, medial septum, CA1 hippocampal area, and the lateral habenula. Regions showing decreased CRFR1 expression with increased age include the intermediate portion of the periventricular hypothalamic nucleus, and CA3 hippocampal area. We report a sexually dimorphic expression of CRFR1 within the rostral portion of the anteroventral periventricular nucleus of the hypothalamus (AVPV/PeN), a region known to regulate ovulation, reproductive and maternal behaviors. Females had a greater number of CRFR1-GFP-ir cells at all time points in the AVPV/PeN and CRFR1-GFP-ir was nearly absent in males by P21. Overall, alterations in CRFR1-GFP-ir distribution based on age and sex may contribute to observed age- and sex-dependent differences in stress regulation.

Characterization and gonadal hormone regulation of a sexually dimorphic corticotropin‐releasing factor receptor 1 cell group

“…A two-way ANOVA revealed a significant sex difference in AVPV/ PeN CRFR1 cells (F(1,26) = 75.50, p ≤ 0.001) matching our previous The current study characterized a novel cluster of CRFR1-ir cells that previous work from our laboratory has shown to be sexually dimorphic from P0-P21 mice (Rosinger et al, 2017). Other AVPV/PeN cell phenotypes such as TH and KISS are known to be more abundant in female than male rodents (Poling & Kauffman, 2013;Scott et al, 2015;Semaan et al, 2010).…”

“…Specifically, CRF/CRFR1 signaling has been shown to facilitate dendrite and synapse formation in the developing olfactory bulb (Garcia et al, ). Notably, AVPV/PeN CRFR1 cell number also appears to decrease between P0 and P60 in both sexes, a decline we have previously reported (Rosinger et al, ). This decrease in CRFR1 cell number might reflect ongoing apoptosis in the AVPV during the postnatal period.…”

“…CRFR1‐immunoreactivity (−ir) is reported to be greater in female rats within the nucleus accumbens, olfactory tubercle, piriform cortex, anterior cingulate (Wealthington, Hamki, & Cooke, ). Furthermore, our laboratory recently discovered a dense cluster of CRFR1 expressing cells within the rostral anteroventral periventricular nucleus (AVPV/PeN) that is prominent in female mice but largely absent in males (Rosinger, Jacobskind, Park, Justice, & Zuloaga, ). This sex difference in CRFR1 is present by birth and persists through postnatal development.…”

Corticotropin-Releasing Factor Receptor 1 in the Anterior Cingulate Cortex Mediates Maternal Absence-Induced Attenuation of Transport Response in Mouse Pups

“…In primates and rodents, adult ACC neurons strongly express the CRF receptor CRFR1 ( Millan et al, 1986 ; Potter et al, 1994 ). It should be noted that the CRFR1 expression level changes dynamically along with postnatal development at many rodent brain areas ( Weathington et al, 2014 ; Zachary et al, 2017 ), as found in the ACC in this study ( Figures 4E – G ). Low expression of CRFR1 in the PVN has been confirmed throughout the development in the above studies as well as in our study.…”

Dysregulation of the Lateral Habenula in Major Depressive Disorder

“…Dysregulation of this system has been strongly linked with the development of affective disorders (Bangasser and Valentino, 2014). In contrast with the MHb which does not express CRF receptor 1 (CRFR1) positive cells in mice, LHb CRF expression increases over the course of development from P4 onward (Rosinger et al, 2017), highlighting an important distinction between the habenular nuclei. Restraint stress in male Sprague-Dawley rats activated CRF positive neurons in the PVN to a similar extent when the stress occurred in the light or dark cycle, as measured by measured by increased expression of the immediate early gene c-Fos.…”