Functional Implications of Sex Differences in Hippocampal Endocannabinoid Signaling

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Endocannabinoids (eCBs) are neuromodulators that affect behavioral phenomena such as cognition, learning, memory, eating and sex. eCBs are involved in emotional processing and are heavily implicated in regulating stress and anxiety. There is growing evidence supporting sex differences in the eCB system, whereby females possess lower levels of the CB1 receptor in several cortical structures compared to males. In previous studies, we demonstrated that exposure to chronic mild stress 1) differentially altered CB1 receptor levels in the hippocampus of male and female rats and 2) increased GABAergic CB1 function in males. This suggests that sex differences in the eCB system may underlie sex differences in response to stress and etiologies of stress-related disorders. For example, there is a 2:1 incidence rate of women diagnosed with stress-related disorders such as Major Depressive Disorder and Post-Traumatic-Stress-Disorder than men. Importantly, this disparity in mental disorders is not apparent until adolescence, when maturation of corticolimbic circuitry is critical for development of appropriate emotional processing and adaptive responses to stress. However, there is currently a dearth of data regarding the functional (neural plasticity and behavioral) significance of eCB sex differences. These omissions preclude a complete understanding of both normal eCB function and its role in the etiology and pathophysiology of neurobehavioral disorders. Our published data show a robust sex difference of CB1 function at hippocampal dendritic GABAergic synapses whereby female CB1 displays a higher sensitivity to exogenous activation compared to males. Exploring the mechanisms underlying this difference, we observe a mixture of constitutive CB1 activity, tonic eCB production and estrogen-mediated eCB production at adolescent female dendritic synapses. This is consistent with the literature on perisomatic eCB signaling in females. Importantly, these effects are not reported in similar studies of eCB signaling in males. We hypothesize that these sex differences across the somatodendritic axis in adolescent hippocampal pyramidal cells A) translate into functional differences in eCB-mediated synaptic plasticity and B) underlie sex differences in emotional learning and behavior. Synaptic plasticity experiments involving extracellular field and whole-cell patch clamp recordings will be performed in CA1 dendritic and perisomatic layers, respectively from adolescent male and female animals. Emotional behavior will be assessed using a hippocampal-dependent contextual fear conditioning. These investigations will provide further elucidation of eCB neural and behavioral function in both sexes. The results may provide insight into the mechanisms of sex differences in emotional processing and may have implications for understanding the pathophysiology of sex-biased neurobehavioral disorders.