Molecular and Circuit Mechanisms of Neurexin1-Mediated Goal-Directed Dysfunction

点击翻译按钮获取中文摘要

Project Summary Synaptic adhesion molecules (SAMs) are implicated in the formation, specification and maintenance of neuronal connections. Pathway analyses of mutations associated with neuropsychiatric disease implicate synaptic dysfunction as a pathophysiological mechanism, making SAMs important candidates for deeper functional exploration. Studies in humans suggest that Neurexin1α (Nrxn1α), a presynaptically-localized organizer of synaptic architecture, is a partially penetrant genetic risk factor for multiple neuropsychiatric diseases displaying altered goal-directed processing. We demonstrate that Nrxn1α mutants exhibit robust changes in how rewards shape future choices, and may provide a neural circuit framework for understanding inflexible and perseverative actions associated with many neuropsychiatric disorders. This proposal therefore employs genetic, viral, electrophysiological and behavioral approaches in mice to explore how Nrxn1α mutations lead to neural circuit changes capable of altering reward processing. Nrxn1α is widely expressed in brain, but exhibits peak levels throughout cortex and thalamus, sites whose extensive projections to striatum regulate reward processing. Using retrograde-transported viruses or region-specific Cre transgenic mice, together with our Nrxn1α conditional allele, we will ablate Nrxn1α from cortex, thalamus or projection neurons targeting specific striatal compartments. Mice will be tested in our goal-directed tasks to reveal neural circuits wherein Nrxn1α dysfunction precipitates reward abnormalities. To elucidate how these circuits are physiologically altered in Nrxn1α mutants, we will electrophysiologically probe the synaptic strength of cortical and thalamic inputs to the DMS. Preliminary results suggest enhancements in basal excitatory synaptic drive onto both DMS spiny neuron subtypes. Using optogenetic-mediated afferent recruitment and field-normalized synaptic efficacy measures, we will determine input-specific synaptic strength changes in Nrxn1α mutants. Furthermore, we will employ sparse infections of a fused channelrhodopsin-Cre virus into our Nrxn1α conditionals together with acute slice electrophysiology to permit selective recruitment of Nrxn1α-null terminals, thereby gaining mechanistic insight into the cell-autonomous anatomical and synaptic abnormalities caused by Nrxn1α loss-of-function. The mere presence of circuit-specific physiological changes in Nrxn1α mutants does not functionally implicate them in goal-directed dysfunction. To prove this, and broaden our analyses of Nrxn1α disruption to a circuit level, we will use viral-based techniques for activity modulation to see whether mimicking Nrxn1α-associated physiological changes in wildtype mice can produce mutant-like GDB performance or whether counteracting these physiological alterations in mutant mice can suppress the mutant behavioral phenotype. Together, the proposed work investigates how goal-directed neural systems are altered by the synaptic and circuit changes accompanying Nrxn1α perturbation, and may provide a foundation for understanding common circuit changes in reward processing - a key step for circuit-specific intervention.