Estrogen modulation of the lateral habenula and its ability to inhibit midbrain dopamine neurons

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Project Summary Several neurological and mental health disorders, including addiction, depression, chronic pain, and Parkinson’s disease, have notable sex differences in their prevalence, severity, or symptom presentation, which can be further amplified when co-morbidity is considered. Consequently, sex is an important variable to consider when developing potential treatment. Amongst the symptoms common to such disorders are changes in motivated behavior resulting from abnormal motivation, processing of salient environmental cues, and reward learning. Altered function of midbrain dopamine (DA) neurons are central to the changes in motivated behavior associated with these symptoms and, in addition, DA neuronal activity is modulated by circulating gonadal hormones. The lateral habenula (LHb) is also a significant regulator of DA cell firing and has been implicated in these same disorders. Despite this, little work has investigated the role of sex and gonadal hormones on LHb function. Our preliminary data have shown clear sex differences in LHb function, with the LHb having less inhibitory control over DA cells in female rats and with the LHb displaying a more regular firing pattern in female rats. Based on these novel and exciting findings, as well as previous literature, we hypothesize that gonadal hormones modulate both LHb activity and its ability to regulate midbrain neuronal activity. To determine the role circulating gonadal hormones play in LHb-induced inhibition of midbrain DA neurons (Specific Aim 1) we will compare female rats (intact, ovariectomized, or ovariectomized with estrogen replacement) and male rats (intact, castrated, or castrated with testosterone replacement) using an in vivo electrophysiological approach. We predict that the inhibitory effect of LHb stimulation on DA firing will become stronger in female rats following gonadectomy, negating the previously observed sex difference. We further predict that the phenotypical sex difference will be reinstated in female rats by estradiol replacement. To determine the role circulating gonadal hormones play in LHb firing rate and pattern (Specific Aim 2) we will compare a separate cohort of rats with the same group designations using an ex vivo electrophysiological approach. We predict that whole-cell patch-clamp recorded LHb neurons will fire in a less regular pattern and have increased susceptibility to hyperpolarization-induced burst firing in female rats following gonadectomy compared to their intact counterparts. We further predict that the phenotypical firing patterns will be reinstated in female rats with estradiol replacement. There is a gap in our knowledge regarding the interaction of the LHb and gonadal hormones; the proposed experiments are intended to begin to fill that gap. These experiments have the potential to provide a brain circuit-based mechanism of differing symptomatology by sex in several neurological and mental health disorders, leading to more precision in treatment development.