Nicotinic modulation of deep layer somatostatin interneurons for visual critical period plasticity - Project Summary: The cortical plasticity during the juvenile critical period is the key impedance of recovery from neurodevelopmental disorders and brain trauma in later life. Neuromodulatory systems are abundant in the cortex and well-positioned to orchestrate experience-dependent plasticity. However, the increasingly recognized complexity of neuromodulatory circuits as well as the diversity of neuron subtypes pose a challenge to identify a specific neuromodulatory system and their cortical target to induce plasticity. The goal of this study is to identify novel molecular and circuit targets for inducing neuromodulatory changes that mediate plasticity during juvenile critical period. In our recent study, we found that only a deep cortical layer subpopulation of somatostatin- expressing interneurons with a low-threshold-spiking characteristic selectively expresses the α2 subunit containing nACh receptor (nAChRa2) and robustly responds to nicotinic ACh signaling during critical period. Using ocular dominance (OD) plasticity, a prevailing V1 critical period plasticity model, we found that enhancing nAChR signaling in this deep layer SST interneuron rapidly induced robust OD plasticity during critical period after just two days of monocular deprivation, and prolonged OD plasticity into adulthood. This study will test the hypothesis that, among various possible combinations of neuromodulatory systems and their cortical targets, nicotinic ACh modulation and deep layer SST interneurons in V1 expressing nAChRa2 are a novel combination of neuromodulatory circuit elements for inducing rapid local circuit modulation to restore juvenile-like visual cortex plasticity during critical period. We will test this hypothesis by taking full advantage of the recently developed genetically-engineered mouse lines to achieve subpopulation and cortical-layer-specific circuit-selective manipulation and measurement of gene expression or neural activity, beyond conventional cell-type level analyses, in combination with in vivo extracellular and in vitro slice electrophysiology with optogenetics, and chemogenetics. Aim1 will examine the contribution of nAChR signaling in deep layer SST interneurons on triggering OD plasticity during critical period. We will then dissect the contribution of LTS-SST to PV inhibitory circuit (Aim2) and to VIP inhibitory circuit (Aim3) to trigger OD plasticity.
