Role of Intracortical Mechanisms Vs. Bottom-Up Influences in Developmental Desynchronization of Cortical Network Activity - ABSTRACT Studying how cortical circuits mature is critical to understanding neurodevelopmental conditions as proper wiring of these circuits is important for perception and cognition. Initially, spontaneous neuronal activity in the developing neocortex is characterized by intermittent, brief bursts of synchronous network events that interrupt much longer periods of no activity. Network activity then undergoes a transition from network-wide synchronous events to the asynchronous, sparse neuronal firing seen in adults. This desynchronization of network activity is a robust phenomenon that is conserved across many species, including in humans; in mice, it occurs during the second postnatal week. Because sparse firing is conducive to greater computational coding power, desynchronization is a crucial step in neurodevelopment. However, the mechanisms driving cortical desynchronization are unknown. Understanding these mechanisms would provide insight into the maturation of neural circuits and, critically, into the origin of neurodevelopmental conditions (NDCs), such as autism, epilepsy, and intellectual disability. Indeed, cortical network synchrony during development is persistently elevated in some mouse models of NDCs, suggesting that the trajectory of desynchronization is different in those NDCs. There are two principal mechanisms that could underlie cortical desynchronization: 1) intracortical mechanisms, and 2) bottom-up mechanisms. Intracortical mechanisms, such as an increase in inhibition or a decrease in intrinsic neuronal excitability, could shift the network away from the runaway excitation needed to generate synchronous events. Alternatively, bottom-up mechanisms could directly drive cortical desynchronization via changes in the activity of upstream brain regions like the thalamus. This proposal will compare the primary somatosensory cortex (S1), which receives dense bottom-up input from the periphery via thalamic relay nuclei, to the secondary motor cortex (M2), a nearby cortical region that receives little direct input from the periphery, to elucidate the contributions of intracortical vs. bottom-up mechanisms. Specific aim 1 will test whether inhibition drives cortical desynchronization in S1 and in M2 by utilizing in vivo longitudinal 2-photon calcium imaging from postnatal days (P) 9 to 14 to assess how the trajectory of desynchronization changes when local inhibitory interneurons are chronically inhibited with chemogenetics during the desynchronization window. Specific aim 2 will determine the role of bottom-up mechanisms by testing whether disrupting synchronous thalamic activity can alter the trajectory of cortical desynchronization in S1 and in M2. Specific aim 3 will characterize the specific genetic changes occurring in S1 vs. M2 during desynchronization using single-nucleus RNA sequencing. Together, these aims will provide insight into how cortical circuits mature. Crucially, this proposal will investigate different regions of cortex—with vastly different inputs—to disambiguate the contribution of intracortical vs. bottom-up mechanisms in driving cortical desynchronization.
