Plasticity and social neuromodulation of developing auditory cortical circuits - Project Summary/Abstract Postnatal development is a formative time for animals like humans and rodents that are born immature, dependent upon caretakers for survival and with brains that are still growing and changing. Many of these changes are subject to environmental influence, such that the characteristics of early-life surroundings can have potent and long-lasting effects on neural development. However, it has been challenging to study how the developing brain engages with its environment and changes with sensory experience. With newly developed methods for longitudinally tracking how neurons in the auditory cortex of young mice respond to sounds from the onset of hearing throughout development, this proposal seeks to overcome those challenges and gain novel insight into the postnatal plasticity of the auditory cortex. The long-term goal is to enhance our understanding of the neural and environmental factors that influence both healthy and disordered auditory system development. The K99 phase of this project will focus on how external auditory cues (Aim 1) and internal neuromodulators (acetylcholine, Aim 2) act upon excitatory and inhibitory neurons of the auditory cortex to shape their responses to sounds during a specific ‘critical period’ of postnatal auditory cortex development. Aim 1 will probe how distinct cell-types dynamically change their ‘tuning’ to different features of sounds over the course of the critical period. Aim 2 will utilize developmental imaging and additional training in in vitro electrophysiology and chemogenetics to reveal how cholinergic neuromodulation of cortical inhibitory circuitry changes during early development and affects critical period plasticity. Together, the K99 phase will test the overarching hypothesis that increased cholinergic neuromodulation of inhibition during development helps to dynamically change individual neurons’ sensory representations to reflect the sensory statistics of the early acoustic environment. The R00 will apply a similar combination of in vivo optical and in vitro electrophysiological approaches with functional manipulations to investigate the development of cholinergic (Aim 3) and oxytocin (Aim 4) neuromodulatory signaling in the developing auditory cortex and test if oxytocin plays a generalized or social-context-specific role in modulating critical period plasticity. Altogether these experiments will test the hypothesis that multiple neuromodulatory systems can regulate developmental plasticity by acting on developing inhibitory circuits, but that oxytocin neuromodulation particularly facilitates ‘social gating’ of experience-dependent plasticity. This project will involve advanced technical training (in in vivo optical methods, patch clamp electrophysiology, and computational approaches for analysis of large, multidimensional datasets) that can be optimally provided by the sponsor Dr. Robert Froemke’s laboratory and the host institution, the NYU School of Medicine, as well as an exceptional postdoc advisory committee that brings diverse expertise and experience. Finally, the sponsor and the broader institution have a proven track record in providing exemplary professional development training towards the candidate’s goal of obtaining a top faculty position and launching their own successful research program.
