Stress contributes to neuropsychiatric disorders by altering brain circuits and neurotransmitter signaling, often in a sex-dependent manner. The specifics of these stress-induced changes and their role in the development and perseverance of conditions like depression are largely unknown. We examined how context discrimination and neurotransmitter co-expression in the medial septum (MS) changes in response to unpredictable chronic mild stress (uCMS). Female mice subjected to uCMS showed significant context discrimination impairments compared to female controls, while male mice showed no differences in context discrimination as a result of uCMS. We conducted immunolabeling in the MS and found that in females, uCMS reduced the number of cholinergic (ChAT+) neurons while increasing the percent of neurons co-expressing ChAT & GAD67 (marker for GABAergic neurons). These changes suggest a link between chronic stress, neurotransmitter phenotype plasticity in the MS, and hippocampal dysfunction. These differences were observed in the absence of changes to apoptosis and overall neuron number and were specific to female mice; no significant changes to MS neurotransmitter expression was observed in males. Our future work will focus on further dissecting the specific molecular mechanisms behind these changes.

Acute stress exposure can elicit analgesic responses in multiple pain models. Research indicates that dopaminergic pathways in the hippocampus contribute to the analgesic responses elicited by forced swim stress, considered a combination of physical and psychological stress. Since psychological and physical stresses can trigger different brain pathways and areas, this study has examined how dopaminergic receptors in the CA1 region of the hippocampus affect the pain relief induced by restraint stress (RS), generally considered a psychological stress, in an acute pain model. Ninety-six Wistar rats underwent stereotaxic surgery, during which a cannula was unilaterally implanted in the CA1 region of the hippocampus. Five minutes prior to exposure to RS, D1- and D2-like dopamine receptor antagonists (SCH23390 and sulpiride, respectively) or their respective carriers, saline and DMSO, were administered in different doses (0.25, 1, and 4 µg/0.5 µl per rat) into the CA1 area. The analgesic effects of RS were examined with and without dopaminergic receptor antagonists using the tail-flick test. This study's findings indicated that the administration of SCH23390 and sulpiride into the CA1 area of the hippocampus at the maximal doses (4 µg/0.5 µl; P < 0.001) markedly diminished the analgesic benefits of RS in the acute pain paradigm. The magnitude of estimated ED50s in the effect of these antagonists on reducing the RS-induced analgesia was 1.64 µg for SCH23390 and 2.79 µg for sulpiride, suggesting that both dopamine D1-like and D2-like receptors in the CA1 region of the hippocampus likely contribute to the analgesic effects of RS in the rats.