CORTICOTROPIN RELEASING FACTOR IN THE MEDIAL SEPTUM AND ITS EFFECTS ON COGNITION

Abstract

Stress can disrupt a variety of cognitive processes, including learning and memory. Previous studies in rodents have demonstrated that central infusions of the stress-neuropeptide, corticotropin releasing factor (CRF), can disrupt mnemonic processes. However, where CRF is working within the brain to regulate cognition is largely underexplored. A candidate region for direct CRF regulation is the medial septum (MS), because this forebrain cholinergic nucleus is critical for spatial learning and CRF receptors are found on cholinergic neurons therein. We assessed whether administering CRF directly into the MS impaired spatial learning in male and female rats. We infused different doses of CRF or the vehicle, artificial cerebral spinal fluid, into the MS prior to testing on an object location task, which tests spatial learning, and a novel object recognition task, which does not test spatial learning. On the object location task, we found that, overall; CRF in the MS reduced time spent exploring the displaced object compared to the familiar object, suggesting that this manipulation impairs spatial reference learning. In addition, males were more sensitive to this effect than females, such that a low dose of CRF in the MS that had no effect in females disrupted object location learning in males. In the novel object recognition task, the CRF in the MS did not decrease preference for the novel object in either sex, suggesting that the effects of CRF in the MS are specific to spatial learning, which requires an intact hippocampus. Next, we assessed the receptor subtype involved by pretreating with a CRFR1 antagonist, prior to testing the effects of the high dose of CRF in the MS on spatial learning. We found that the CRFR1 antagonist recovered the spatial learning deficits similarly in both sexes. Lastly, we examined the influence of circulating ovarian hormones in regulating sensitivity of the MS to CRF by accessing estrous cycle stage, as well as, conducting ovariectomy and sham ovariectomy. We did not find an influence of ovarian hormones using any of these manipulations, suggesting that these hormones do not play a protective role against the impairing effects of CRF in the MS on spatial learning. Collectively, these studies reveal that CRF in the MS selectively impairs spatial learning, especially in males, highlighting an unexplored mechanism by which stress can regulate cognition. Clinically, these findings suggest that drugs which block the effects of CRF represent a viable therapeutic option to treat cognitive deficits that characterize certain stress-related psychiatric disorders.