Circuit mechanisms underlying cortical communications

National Institute Of Mental Health

Investigators

Linked publications, trials & patents

Abstract

To understand the principles of long-range connectivity in cortical communication, our efforts have focused on the following four projects during FY22. 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 one of the neurodevelopmental (NDD) high risk genes is mutated in different types of GABAergic interneurons (INs). The goal of the second project, cortical development of inhibitory-to-inhibitory connections, is to address the developmental process of cortical inhibitory-to-inhibitory synaptic specificity 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. The third project, the structural organization of cortical subnetworks, is aimed at understanding the principles that govern the functional heterogeneity of principal neurons in sensory cortex. Neuronal activity in the superficial layer of the primary sensory cortex is highly heterogenous in relation to various aspects of the animal's behavior. We asked whether functionally heterogeneous subnetworks are constrained by specific long-range and local presynaptic ensembles. This study provides the circuit-based mechanism for the organization of cortical subnetworks. Using single cell-initiated, monosynaptic rabies virus tracing combined with calcium imaging, we found that behavior state-encoding (spontaneous movement) neurons show characteristic long-range and local presynaptic networks. Our results reveal connectivity rules that support functional heterogeneity of cortical principal cells. In the fourth project, we investigate the role of higher-order thalamic nucleus in sensory perception. Somatosensation is an active process. Despite that action and sensation are tightly integrated contingent on the animals goal during active sensation, the neuronal substrates and circuits that mediate such interaction remain poorly understood. Anatomical studies suggest that whisker-dependent sensorimotor integration takes place in multiple closed loops in the brain. The posteromedial (POm) thalamic nucleus, the higher-order thalamic nucleus in the rodent somatosensory system, is an anatomical hub broadly connected with multiple sensory and motor brain areas, yet it weakly responds to passive sensory stimulation and whisker movements. To understand the role of POm in sensory perception, we developed a self-initiated, two-alternative forced-choice task in freely moving animals during active sensing. Using optogenetic and chemogenetic manipulation, we show that POm thalamic nucleus plays a significant role in sensory perception and the projection from the primary somatosensory cortex to POm is critical for the contribution of POm in sensory perception during active sensing. Ongoing work investigates dynamic neuronal activity of POm cells during active sensing.