Dysregulation of the Lateral Habenula in Major Depressive Disorder

Severe behavioural deficits in psychiatric diseases such as autism and schizophrenia have been hypothesized to arise from elevations in the cellular balance of excitation and inhibition (E/I balance) within neural microcircuitry. This hypothesis could unify diverse streams of pathophysiological and genetic evidence, but has not been susceptible to direct testing. Here we design and use several novel optogenetic tools to causally investigate the cellular E/I balance hypothesis in freely moving mammals, and explore the associated circuit physiology. Elevation, but not reduction, of cellular E/I balance within the mouse medial prefrontal cortex was found to elicit a profound impairment in cellular information processing, associated with specific behavioural impairments and increased high-frequency power in the 30-80 Hz range, which have both been observed in clinical conditions in humans. Consistent with the E/I balance hypothesis, compensatory elevation of inhibitory cell excitability partially rescued social deficits caused by E/I balance elevation. These results provide support for the elevated cellular E/I balance hypothesis of severe neuropsychiatric disease-related symptoms.

Depression is the leading cause of disease-related disability among women in the world today. Depression is much more common among women than men, with female/male risk ratios roughly 2:1. Recent epidemiological research is reviewed. Implications are suggested for needed future research. The higher prevalence of depression among women than men is due to higher risk of first onset, not to differential persistence or recurrence. Although the gender difference first emerges in puberty, other experiences related to changes in sex hormones (pregnancy, menopause, use of oral contraceptives, and use of hormone replacement therapy) do not significantly influence major depression. These observations suggest that the key to understanding the higher rates of depression among women than men lies in an investigation of the joint effects of biological vulnerabilities and environmental provoking experiences. Advancing understanding of female depression will require future epidemiologic research to focus on first onsets and to follow incident cohorts of young people through the pubertal transition into young adulthood with fine-grained measures of both sex hormones and gender-related environmental experiences. Experimental interventions aimed at primary prevention by jointly manipulating putative biological and environmental risk factors will likely be needed to adjudicate between contending causal hypotheses regarding the separate and joint effects of interrelated risk factors.