Sexual Dimorphism in the Striatum Underlying Pathophysiological Consequences of Striatal Abnormalities

摘要

ABSTRACT Sexual dimorphism in the prevalence and presentation in neuropsychiatric disease is common, but the mechanisms underlying this dimorphism remain unclear. Neurodevelopmental diseases such as autism and Tourette’s syndrome (TS) are diagnosed at a 3 to 5 times more often in males than females, suggesting an underlying dimorphism in brain circuitry and/or in pathophysiology. The basal ganglia circuitry, and in particular pathology of interneurons in the striatum, is implicated in many neuropsychiatric disorders, including autism and TS. We have previously described a system in which we depleted specific interneurons in the striatum, including cholinergic interneurons (CINs) and fast spiking interneurons (FSIs), in the mouse striatum. We made the startling observation that ablation of striatal interneurons produces dysregulated activity in the basal ganglia network and a range of behavioral effects – loss of social preference, anxiety-like behavior, and repetitive motor pathology – but only in male mice, not in females. This parallels the sexual dimorphism seen in patients with autism and TS. This mouse striatal interneuron depletion system provides a unique opportunity to probe the mechanistic underpinnings of sexual dimorphism in basal ganglia function and pathology, and to delineate mechanisms that may contribute to dimorphism in human neuropsychiatric disease. To this end, we propose three Specific Aims. Our first Aim examines sexual dimorphism in healthy adult striatal circuitry, characterizing interneuron number, morphology, connectivity, and synaptic protein density through immunohistochemistry and biochemical methods. Our second Aim will examine sex- specific gene expression differences through RNA-seq bioinformatic analysis of striatal tissue and RNAscope analysis of specific neuronal subtypes. Our third Aim seeks to characterize the female-specific mechanism(s) that buffer the development of striatal circuit dysregulation and behavioral abnormalities following depletion of striatal CINs and FSIs in female mice. Here, we will test specific candidate mechanisms, grounded in our own and others’ pilot investigations. We hypothesize that baseline sexual dimorphism in striatal physiology and function underlies the sexual dimorphism in pathological circuity activity and behavioral changes following striatal interneuron depletion. An understanding of this innate dimorphism in mice may ultimately provide insight into the differential incidence and symptomology in males and females of human neuropsychiatric conditions characterized by basal ganglia dysfunction.