Pharmacological blockade of CRHR1 prevents early-onset puberty and enhanced anxiety-like behavior induced by early-life adversity in female Sprague Dawley rats

Pubertal development is regulated by hypothalamic neuroendocrine signaling and is sensitive to interactions between stress- and reproductive-related pathways. In particular, corticotropin-releasing hormone (CRH) signaling via corticotropin-releasing hormone receptor 1 (CRHR1) represents a key point of crosstalk between stress and pubertal maturation. Early-life adversity, such as the maternal separation (MS) model in rodents, has been shown to increase CRH expression and therefore has the potential to dysregulate CRHR1 signaling. We previously reported that MS-exposed female rats display early pubertal onset, with heightened anxiety-like behavior that was correlated with pubertal timing. The current study examined whether CRHR1 dysregulation mediates the effects of MS on both pubertal timing and anxiety-like behavior, as assessed by the acoustic startle response (ASR), in female rats. CRHR1 signaling was pharmacologically manipulated using the CRHR1 antagonist antalarmin during MS exposure. Pubertal development and ASR were assessed, as well as pre-pubertal hypothalamic CRHR1 expression. Protein quantification of pre-pubertal hypothalamic cell membrane and cytoplasmic fractions revealed that MS increases CRHR1 internalization in the arcuate nucleus and in the anterior hypothalamus following MS. As expected, MS significantly advanced pubertal timing; however, accelerated puberty was normalized by treatment with antalarmin during MS. Treatment with a high dose of antalarmin, however, delayed puberty in both MS and control animals. MS also increased ASR in adolescent females, which was prevented by antalarmin treatment during MS. Additionally, antalarmin decreased cFos activity in the basolateral amygdala (BLA) and bed nucleus of stria terminalis (BNST). Together, these findings support a potential model in which altered CRHR1 signaling during negative early environments disrupts HPA-HPG axis crosstalk, triggering early onset of puberty and increased anxiety-like behavior in female rats. Targeting CRHR1 signaling during sensitive developmental windows may provide a therapeutic avenue for mitigating these long-term impacts of early life stress.