Stress is a physiological response to negative life experiences or environmental changes that could take a toll on mental health and increase the risk of developing psychiatric disorders. Cognitive impairments are a core feature of a multitude of psychiatric disorders linked to stress. Specifically, deficits in hippocampal-dependent memory are commonly observed in stress-related psychopathologies (Kim and Kim, 2023; Luine et al., 1994).

The prevalence of stress-related psychiatric disorders differs between men and women. Clinically, women are at an elevated risk of suffering from anxiety-related disorders, post-traumatic stress disorder (PTSD), and major depressive disorder, while men are more likely to suffer from substance use disorders and an earlier onset for schizophrenia (Bangasser and Valentino, 2014). This sex difference in the clinical population may be due to biological differences in how the brain responds to stress and stress hormones.

The stress response is triggered by a neuropeptide, corticotropin-releasing factor (CRF), that is released from the hypothalamus-pituitary-adrenal (HPA) axis, causing physiological, behavioral, and cognitive changes via activation of CRF receptors at the level of the pituitary and centrally in brain regions the mediate cognition (Hupalo et al., 2019). CRF-overexpressing transgenic mice exhibited impairments in spatial memory (Heinrichs et al., 1996). Moreover, studies from our group and others found attentional impairments in rats that received acute central infusions of CRF (Cole et al., 2016; Van't Veer et al., 2012).

CRF exerts neuromodulatory effects of stress on cognition via interactions with various neurotransmitter systems. The septohippocampal pathway has long been implicated in learning and memory and its involvement in mnemonic function and more recently has been a target for stress research. The medial septum (MS) is rich in CRF1 receptors and is therefore well positioned to have a direct impact of CRF release (Van Pett et al., 2000). Previously, we found that micro-infusions of a high dose of CRF into the MS impaired performance of both male and female rats in the Object-Location Memory task (Wiersielis et al., 2019). However, male rats were more sensitive than females to the memory-impairing effects of a low dose of intraseptal CRF, and the female resistance to these detriments was not due to circulating ovarian hormones. The mechanisms underlying the association between CRF-mediated modulation of MS neurons and sex-dependent changes in hippocampal-dependent memory are unclear.

The septohippocampal projections from the MS cholinergic neurons to the hippocampus are known to modulate the activity in hippocampal networks. In the present study, we utilized an in vivo biosensor-based electrochemistry approach to examine the impact of MS infusions of a low and a high dose CRF on hippocampal cholinergic signaling in male and female rats. We hypothesized that intrseptal CRF infusions would produce dose- and sex-dependent alterations in the dynamics of acetylcholine (ACh) release in the dorsal hippocampus.