Thalamocortical networks consist of two parallel circuits that involve distinct thalamic and cortical neurons and have distinct nuclear, areal, and laminar distribution. A more specialized ‘core’ system consists of excitatory thalamic neurons that focally target the middle cortical layers, as classically described for sensory systems. A more diffuse ‘matrix’ system consists of excitatory thalamic neurons that broadly target the upper layers of multiple areas, integrating information across cortices. Growing evidence suggests differential involvement of core and matrix systems in the vital processes of sleep, attentional modulation and states of vigilance, multimodal integration, cognition, emotion, and action, and in the disruption of these processes in schizophrenia. However, little is known about the organization of these networks in the human brain and the distinct mechanisms of disruption of core vs matrix systems in schizophrenia and associated sleep disorders. Our overarching hypothesis is that core and matrix thalamocortical circuits vary in parallel with the systematic variation of cortical laminar structure and exhibit graded connection patterns, function, and dysfunction, such that the most plastic thalamocortical circuits allow functional flexibility but are also more vulnerable to disruption in psychiatric diseases, and prominently in schizophrenia. Based on this, we will test the hypotheses that core and matrix pathways differ in density, structure, termination pattern, and interactions with cortical inhibitory interneurons in prefrontal cortices and exhibit distinct pathophysiology in schizophrenia, with matrix circuits primarily affected along with their preferential innervation of limbic medial and orbital prefrontal areas, whereas core circuits will mostly affect lateral prefrontal cortices. The goal of the proposed studies is to investigate the unknown circuit interactions between core and matrix thalamocortical systems in humans, then compare and cross-validate these findings in rhesus macaques, using archival postmortem tissue and identical approaches, so we can then reliably study their pathophysiology in schizophrenia. We will use high-resolution microscopy to label and image pathways at multiple scales, from system to synapse in the brains of both species and will additionally use tract- tracing in monkeys and neurochemical labeling to cross-validate circuit interactions. We will study the density, caliber, and myelination of axons in core vs matrix pathways and estimate the g-ratio, which is directly associated with the speed of conduction, and thus reflects axonal function and integrity. Then we will use the novel quantitative circuit data to computationally model core and matrix thalamocortical network dynamics and disruptions in schizophrenia and associated sleep disorders. Our proposed studies are predicated on primate specializations that likely underlie normal and pathologic function through thalamus and cortex in primates, including humans. The proposed studies will yield novel data on the as-yet unknown neurochemical and synaptic organization and interactions of core and matrix circuits in primates, which critically affect the dynamics of sensory, affective, and goal directed processes, and are disrupted heterogeneously in schizophrenia.

Project Narrative Thalamocortical communications underlie processes of perception, attention, memory, emotions, and the sleep- wake cycle, and are disrupted in schizophrenia, but the underlying mechanisms of pathology are unknown. The goals of the proposed research project are to test the hypotheses that focal “core” and more widespread “matrix” thalamocortical pathways are differentially affected in schizophrenia, through mechanisms that involve distinct changes in their structure, physiology, and laminar interactions with cortical inhibitory neurons in medial, orbital, and lateral prefrontal cortices. Findings will help us model typical and abnormal brain function and provide the foundation to understand heterogeneous disruption of these networks in sleep disorders, attention deficits, and cognitive and affective impairments in schizophrenia, with important implications for the design of targeted therapeutic interventions.