Circuit mechanisms underlying cortical communications

National Institute Of Mental Health

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Abstract

To understand the principles of long-range connectivity in cortical communication, our efforts have focused on the following three projects during FY23. Functional connectivity of diverse long-range inputs to sensory cortex is aimed at achieving a mechanistic understanding of the functional connectivity of feedback / top-down projections to the primary sensory cortex. We have systematically examined the synaptic strength from different brain areas to diverse neuronal types in the primary somatosensory cortex (S1) and determined how the primary sensory cortex uses input-area-dependent, preferential recruitment of specific types of GABAergic interneurons to parse information from diverse feedback projections. Based on this framework, we investigate how cortical feedback projections to S1 are altered in a transgenic mouse line in which SynGAP1 (synaptic Ras GTPase-activating protein 1), one of the neurodevelopmental (NDD) high risk genes, is mutated in different types of GABAergic interneurons (INs). SynGAP1 encodes the synaptic Ras GTPase-activating protein 1 (SynGAP1), a crucial protein involved in the formation of postsynaptic densities and in the activity-dependent regulation of excitatory synaptic strength. SynGAP1 mutations in human patients are commonly found in individuals diagnosed with intellectual disability (ID), schizophrenia and autism spectrum disorder. While the importance of SynGAP1 in the excitatory neurons has been extensively studied, the role of SynGAP1 in cortical GABAergic neurons is largely unknown. We asked whether and how the disruptions of SynGAP1, one of NDD risk genes, in different GABAergic IN subtypes lead to the impairment of input-area-dependent corticocortical communication. We found multiple layers of abnormality in cortico-cortical interactions including glutamatergic synaptic transmission, oscillation in a local network, synchrony between relevant cortical areas, and sensory perception. The goal of the second project, development mechanism of cortical disinhibitory circuits is to address the developmental mechanism of synaptic specificity of cortical disinhibitory connections during early development. Disinhibition mediated by vasoactive intestinal polypeptide (VIP)-positive GABAergic interneurons (INs) is a robust circuit motif found in all cortical areas. VIP INs inhibit other types of cortical GABAergic INs, but its inhibition of dendrite-targeting somatostatin (SST)-positive INs is particularly strong, leading to the disinhibition of pyramidal neurons. This cortical disinhibitory circuit motif has been shown to play an important role in sensorimotor integration, selective attention, gain control, and circuit plasticity. However, the mechanisms by which this robust circuit motif emerges throughout the cortex during early development is largely unknown. Ongoing work investigates which factors are critical for the stability and plasticity of strong inhibitory connections from VIP INs to SST INs during early development. We found that VIP INs preferentially form synaptic connections to SST INs earlier than to other cell types, and that the emergence of this inhibitory-to-inhibitory connection is governed by activity of the presynaptic VIP INs. The spontaneous activity of VIP INs during early development permanently affects the top-down modulation of S1 during adulthood. The third project, the structural and functional organization of cortical subnetworks, is aimed at understanding the principles that govern the functional heterogeneity of principal neurons in sensory cortex. Neuronal connections within and across brain areas provide the scaffolding for neuronal function. While the connectivity of cortical neurons has been mapped at a macroscale level, linking connectivity rules with activity patterns at the level of single neurons remains challenging. We investigated anatomical wiring rules for the functional heterogeneity of cortical neurons using in vivo two-photon calcium imaging, neuropharmacology, single-cell based monosynaptic input tracing, and optogenetic tools. We characterized the neural representations of behavioral state in S1 during spontaneous movements in both single neurons and across neuronal populations. Representations were independent of sensory feedback, stable over time, and robust to pharmacologic inhibition of neuromodulatory, but not glutamatergic transmission. Analysis of brain-wide presynaptic networks of single neurons with distinct activity profiles during spontaneous movements revealed characteristic patterns of anatomical input. Despite the high degree of convergence from brain-wide inputs at the single-cell level, neurons more sensitive to behavioral state received a smaller proportion of inputs from motor cortical areas and a larger proportion of inputs from thalamic nuclei. Optogenetic inhibition of thalamic inputs suppressed behavioral state-related activity. Our study suggest that behavior state-encoding cortical neurons receive a characteristic brain-wide inputs, and that preconfigured networks constrain neuronal function.