The developing cortex exhibits complex patterns of spontaneous activity (SA) that is essential for proper development of neural circuits. Before the onset of vision, the majority of SA in the visual system is generated in the retina and propagates up the neuraxis to the cortex. These waves of SA drive glia-mediated synaptic pruning to promote circuit refinement. However, little is known at cellular resolution about the contribution of different cell classes (i.e. excitatory vs. inhibitory neurons (IN)) to the dynamics of wave propagation in visual cortex (VC), or the role of specific cell types in the emergence of central features of visual processing that are already established by eye-opening (EO), such as retinotopy, orientation-selectivity (OS) and direction- selectivity (DS). Furthermore, it is unknown how SA propagation is affected by environmental factors such as maternal immune activation (MIA). MIA is a major risk factor for cognitive impairment in offspring and causes a range of deficits in neurological function such as dysfunction of cortical INs. INs are particularly vulnerable to MIA since they do not finish migrating and sorting into their specific cortical layers until P7, yet little is known about how they become functionally integrated into circuits in the developing cortex. Balanced integration of excitatory and INs during cortical development is essential for proper flow of visual signals and modulating neuronal circuit function, with disruptions in E/I balance associated with many neurodevelopmental disorders such as autism, epilepsy, and amblyopia. The primary goal of my proposal is to establish the properties and role of different cell classes, including glia and subtypes of INs, in the development of SA in VC, and determine the role and mechanism of different types of MIA on SA before EO and emergence of cortical neuron receptive field properties after EO. These investigations will significantly enhance our understanding of neuroimmune interactions and expand my training in experimental and analytical techniques as I prepare for an independent investigator position. My proposal consists of three specific aims: 1) Determine the cortical cell types involved in retinal wave-driven activity and their role in emergence of OS and DS at EO, 2) Determine the role of MIA in shaping SA in the developing cortex, 3) Determine the role and mechanism of glial signaling, IL-17, IL-6, TNF, and IL-4 in development of structural and functional cortical architecture under MIA and normal conditions. During the K99 phase, under the guidance of Dr. Michael Crair and the support of my co-mentor Dr. Carla Rothlin, I will become proficient in several techniques, including in vivo 2- photon and widefield calcium imaging, computational methods for data analysis and visualization, and immune system regulation. During the R00 phase and beyond, my goal is to combine an array of techniques (such as specific immune system manipulations in utero, genome editing using CRISPR/Cas9, large-scale monitoring of SA before EO) to study interactions between various forms of MIA and early development of the visual system, and how these interactions underlie visual perception in both normal and pathological states.
Patterned spontaneous activity and GABAergic interneurons play critical roles in the normal development and maintenance of neocortical circuits. This proposal will determine how different modes of maternal immune activation (MIA) contribute to dysfunction of spontaneous activity and distinct genetically targeted interneuron populations in mouse models of MIA. We expect our findings to provide novel insights into the cellular underpinnings of MIA-induced cortical dysfunction associated with neurodevelopmental disorders such as autism and provide new avenues for therapeutic intervention.
