Circuit mechanisms underlying cortical communications

National Institute Of Mental Health

Investigators

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Abstract

Summary During FY25, our research has focused on three complementary projects to understand cortical circuit function and development: 1. Role of SynGAP1 in Cerebellum-Dependent Associative Learning Our earlier work investigated how information from diverse brain regions converges on the primary somatosensory cortex (wS1). We showed that long-range projections from different cortical areas selectively recruit subtypes of GABAergic interneurons (INs), and that each subset of INs shapes local microcircuit activity in distinct ways. Building on this, we examined how neurodevelopmental disorder risk genes in GABAergic neurons influence cortico-cortical communication. We focused on SynGAP1, a postsynaptic density protein essential for regulating excitatory synaptic strength. Mutations in SynGAP1 are strongly associated with intellectual disability, schizophrenia, and autism spectrum disorder. While its role in excitatory neurons has been widely studied, its function in cortical GABAergic neurons remains poorly understood. We asked whether disrupting SynGAP1 in specific GABAergic IN subtypes impairs input-area-dependent corticocortical communication. Our results revealed multiple abnormalities, including altered glutamatergic transmission, disrupted local oscillations, impaired interareal synchrony, and deficits in sensory perception. To connect these circuit-level disruptions to behavior, we next investigated SynGAP1 in cerebellar circuits, which provide a well-defined anatomical and functional model for associative learning. Using in situ analysis, we confirmed strong SynGAP1 expression in Purkinje cells. Conditional deletion of SynGAP1 in cerebellar neurons led to abnormal associative learning. Going forward, we plan to record activity from cerebellar neurons during learning tasks to dissect how SynGAP1 regulates input specificity, synaptic plasticity, and learning behavior. By linking SynGAP1-dependent circuit mechanisms to associative learning, this study provides insight into how postsynaptic signaling supports normal cognitive flexibility. At the same time, it helps explain how SynGAP1 mutations contribute to disrupted network communication and learning deficits observed in neurodevelopmental disorders. 2. Developmental Emergence of Behavioral State-Dependent Cortical Neurons In our previous study, we examined how long-range and local presynaptic networks of behavioral state-dependent neurons in wS1 are anatomically organized, and how these networks support the activity of these neurons. That work established a foundation for understanding the circuit basis of behavioral state sensitivity in the adult brain. Building on those findings, the current project asks when and how such functional properties first emerge during development. While cortical neuron heterogeneity is well studied in adults, much less is known about the developmental emergence of behavioral state-dependent properties, or how genetic and experiential factors shape them. Sensory selectivity has been the most extensively studied developmental property, particularly during the critical period when spontaneous cortical activity becomes desynchronized and sensory input from vision, hearing, and whisking begins to dominate. In contrast, how and when neurons become sensitive to behavioral states remains poorly understood. To address this, we are conducting longitudinal calcium imaging in wS1, tracking the same pyramidal neurons from early postnatal development through adulthood. These recordings are paired with behavioral monitoring of spontaneous movements and sensory stimulation, allowing us to directly relate movement patterns to neuronal activity. Our preliminary results indicate that movement-sensitive activity emerges as early as postnatal days 11-12, just before the critical period for active sensing. The ongoing work now aims to determine whether early patterns of neuronal activity can predict functional properties in adulthood, and to uncover the mechanisms that instruct the formation of behavioral state-sensitive subnetworks in wS1. By identifying how and when behavioral state-dependent cortical circuits develop, this study may provide insights into mechanisms that contribute to altered sensory and state-dependent cortical processing in neurodevelopmental disorders. 3. Role of Behavioral State-Dependent Neurons in Local Cortical Processing In primary sensory cortex, neurons that respond similarly to sensory inputs tend to form strong reciprocal connections. However, many cortical neurons are also strongly modulated by behavioral states such as movement. Indeed, spontaneous movement accounts for a large fraction of variance in cortical activity, even in primary sensory cortices. Yet, how movement-sensitive neurons shape local circuit dynamics during sensory processing remains poorly understood. Previous work from our lab revealed that connectivity rules at the level of individual neurons help explain how behavioral state-related activity arises in wS1. Using two-photon calcium imaging, neuropharmacology, single-cell-based monosynaptic input tracing, and optogenetics, we showed that behavioral state-dependent activity patterns are stable over time, minimally influenced by neuromodulation, and primarily driven by glutamatergic inputs. Importantly, the long-range inputs to these neurons diverged: state-sensitive neurons received fewer motor cortical inputs but a greater proportion of thalamic inputs. Optogenetic suppression of thalamic inputs reduced behavioral state-dependent activity, highlighting distinct long-range glutamatergic connectivity as a substrate for preconfigured network dynamics linked to behavioral state. Building on this, we examined how movement-sensitive neurons contribute to local processing in wS1. We combined two-photon calcium imaging with all-optical optogenetics, recording from L2/3 excitatory neurons while selectively activating movement-sensitive or sensory-responsive populations using a spatial light modulator. We used a GCaMP6s mouse line with AAV delivery of a soma-targeted, red-shifted opsin. Our results show that movement-sensitive neurons form distinct subnetworks within wS1. Together, this line of work suggests that distinct long-range glutamatergic inputs establish the functional selectivity of behavioral state-sensitive neurons, and that these neurons in turn form subnetworks that shape local cortical dynamics. This provides a framework for understanding how global brain states interact with local computations to support adaptive sensory processing across different behavioral contexts.