Cognitive processes, including working memory, are thought to manifest out of orchestrated communication across expansive brain networks. The prefrontal cortex (PFC) functions as a critical hub in these networks, wherein task-relevant information is dynamically gated and integrated to guide activity in distal brain regions and support contextually tuned behavior. PFC dysfunction is central to many theories of schizophrenia pathogenesis and correlates with cognitive deficits of the disorder. Modern research further supports that schizophrenia and its cognitive symptoms stem from broad patterns of aberrant neural synchrony and long-range circuit disconnectivity. However, the neural computations that give rise to normal and disordered cognition, and the micro- and macro-circuits of neurons that subserve these computations, are largely unknown. The Integrative Neuroscience Section has two principal goals: (1) to probe the neural circuit basis of normal cognition; and (2) to characterize the neural circuit and cognitive dysfunction in mouse models of genetic susceptibility to schizophrenia and related disorders. In this inaugural fiscal year of the Integrative Neuroscience Section, we have made important technical and experimental progress towards a multifaceted and rigorous exploration of these goals. Over the last year, we have recruited several exceptional postbaccalaureate and postdoctoral lab members with complementary training and expertise. We have established a laboratory that facilitates high-fidelity electrical recordings from multiple brain regions in freely behaving mice that will form the basis of our assessment of neural circuit computations and interactions. We have optimized procedures for electrode construction and implantation, constructed automated behavioral apparatuses capable of assessing an array of cognitive processes (e.g. spatial working memory), and established efficient pipelines for histological assessment of experimental brain tissue and electrophysiological data analysis. We have implemented optogenetic tools to manipulate the function of neurons and their projections during electrophysiological recordings in freely behaving mice. We are making progress on establishing other modern tools of circuit neuroscience including in vivo photometry and miniature microscope imaging of discrete cell and circuit functions during behavior. We are applying these and other tools to experimentally address our section aims. One series of experiments is targetted at probing the causal role of neural synchrony in prefrontal, hippocampal and thalamic circuits in normal cognitive function. We know from prior work of the Gordon Lab and others that discrete neural projections between these structures are necessary for frequency-specific inter-regional synchrony and normal working memory performance. We are now using optogenetics to either promote or disrupt specific oscillations in real time to modulate working memory performance. We are also positioning ourselves to leverage neuronal plasticity mechanisms to bias brain circuits towards more or less behaviorally relevant neural synchrony, and testing the ramifications of this plasticity on cognitive function. We are also expanding our efforts to probe the neural circuit basis of disease-relevant cognitive dysfunction, with a focus on using models harboring genetic variants that confer significant risk for developing psychiatric illness. The 22q11.2 microdeletion is one such variant, conferring 20-30 fold increased risk of developing schizophrenia, and associating with profound cognitive deficits comparable to those seen in the disorder. We are engaged in a more in-depth analysis of the circuit deficits and pharmacological treatment responsivity of mouse models of the 22q11.2 microdeletion and other genetic variants. We are also aimed towards applying the causal manipulations we establish to have positive effects on behaviorally relevant neural synchrony and cognitive function in wildtype mice in those with disease-relevant genetic variants.
