Chronic stress alters neurotransmitter co-expression and disrupts context discrimination in a sex-dependent manner

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.