Major depressive disorder (MDD) is a debilitating chronic illness that is two times more prevalent in women than in men. The mechanisms associated with the increased female susceptibility to depression remain poorly characterized. Aberrant neuronal oscillatory activity within the putative depression network is an emerging mechanism underlying MDD. However, innate sex differences in network activity and its contribution to depression vulnerability have not been well described. In this review, current evidence of sex differences in neuronal oscillatory activity, including the influence of sex hormones and female cycling, will first be described followed by evidence of disrupted neuronal circuit function in MDD and the effects of antidepressant treatment. Lastly, current knowledge of sex differences in MDD-associated aberrant circuit function and oscillatory activity will be highlighted, with an emphasis on the role of sex steroids and female cycling. Collectively, it is clear that there are significant gaps in the literature regarding innate and pathologically associated sex differences in network activity and that the elucidation of these differences is invaluable to our understanding of sex-specific vulnerabilities and therapies for MDD.

Background: Major depressive disorder is a chronic illness with a higher incidence in women. Dysregulated neural oscillatory activity is an emerging mechanism thought to underlie major depressive disorder, but whether sex differences in these rhythms contribute to the development of symptoms is unknown. Methods: We exposed male and female rats to chronic unpredictable stress and characterized them as stress-resilient or stress-susceptible based on behavioural output in the forced swim test and the sucrose preference test. To identify sex-specific neural oscillatory patterns associated with stress response, we recorded local field potentials from the prefrontal cortex, cingulate cortex, nucleus accumbens and dorsal hippocampus throughout stress exposure. Results: At baseline, female stress-resilient rats innately exhibited higher theta coherence in hippocampal connections compared with stress-susceptible female rats. Following stress exposure, additional oscillatory changes manifested: stress-resilient females were characterized by increased dorsal hippocampal theta power and cortical gamma power, and stress-resilient males were characterized by a widespread increase in high gamma coherence. In stress-susceptible animals, we observed a pattern of increased delta and reduced theta power; the changes were restricted to the cingulate cortex and dorsal hippocampus in males but occurred globally in females. Finally, stress exposure was accompanied by the time-dependent recruitment of specific neural pathways, which culminated in system-wide changes that temporally coincided with the onset of depression-like behaviour. Limitations: We could not establish causality between the electrophysiological changes and behaviours with the methodology we employed. Conclusion: Sex-specific neurophysiological patterns can function as early markers for stress vulnerability and the onset of depression-like behaviours in rats.

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Major Depressive Disorder (MDD) is a chronic illness with higher incidence in women.Dysregulated neural oscillatory activity is an emerging mechanism underlying MDD, however whether sex differences in these rhythms contribute to the development of MDD symptoms is unknown. Using the chronic unpredictable stress model, we found that stress-resilient and susceptible animals exhibited sex-specific oscillatory markers in the prefrontal cortex, cingulate cortex, nucleus accumbens and hippocampus. Resilient females were predominantly characterized by increased hippocampal theta power and coherence, while resilient males exhibited increased system-wide gamma coherence. In susceptible animals, the females displayed a widespread increase in delta and reduced theta power, however males showed few within-sex differences that could delineate stress susceptibility from resilience. Finally, stress responses were mediated by the temporal recruitment of specific neural pathways, culminating in system-wide changes that correlated with the expression of depression-like behaviours. These findings show that neurophysiological responses can serve as predictive markers of behaviours linked to depression in a sex-specific manner.3 MainAbout 10% of the world population suffers from major depressive disorder (MDD), with the prevalence being two times greater in women than in men 1,2 . Chronic stress is an established risk factor for the development of MDD 3 , with clinical and preclinical studies showing females have greater behavioural sensitivity to chronic stress exposure 4-7 . This suggests that sexdifferences exist within the stress response neural circuitry linked to the development of depression symptoms 8 . Despite the known predominance of depression in women, the majority of clinical and preclinical studies that have examined the influence of stress on depression have not employed sex as a factor. Thus, the mechanisms that contribute to increased female vulnerability to depression remain poorly understood.The dysregulation of circuit function within the putative depression network has been linked to depression symptoms and antidepressant responsiveness, with many studies focusing on low frequency changes 9 . Electroencephalography (EEG) studies most commonly report frontal and parietal alpha asymmetries as potential endophenotypes of MDD 10-13 , as these patterns have been found to distinguish currently symptomatic and remitted patients from individuals with no history of depression 11,12,14,15 . Alterations in midline theta activity in MDD are also commonly reported although results are not consistent, with some studies showing increased 16, 17 , decreased 18-21 or no change 22,23 in midline theta. A relationship between midline theta and antidepressant treatment response also exists but with the same discrepancies in findings 17, 20,[24][25][26] . Gamma band deficits are also implicated as a potential marker of MDD [27][28][29] and therapeutic antidepressant efficacy 30-32 , with increased gamma associated with the remission ...