Synaptic and cellular mechanisms of neuronal synchronization

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Project Summary/Abstract Neuronal activity must be precisely coordinated to provide an accurate representation of our environment, a feature exemplified by the electrical patterns measured in the brain during spatial navigation and memory retrieval. While the activity of individual neurons is tuned to specific features such as physical location or speed, simultaneous observations at the network level reveals electrical oscillations reflecting the coordinated activity of thousands of neurons. Therefore, a central goal of neuroscience is to understand how network activity emerges from the interactions between individual neurons. The neuronal architecture is relatively well-conserved across multiple brain regions: a population of highly heterogenous inhibitory interneurons (INs) with dense connectivity control a large population of excitatory neurons. Thus, the mechanisms controlling INs themselves are poised to have a dramatic impact on network activity. Previous studies support the existence of small populations of INs that selectively synapse onto other INs. These relatively sparse INs operate disinhibitory networks that could have a profound impact on network activity. Here, I investigate how coordinated activity emerges from neuronal interactions by investigating how disinhibition controls hippocampal circuits. In Aim 1, I will dissect a disinhibitory circuits controlling parvalbumin-expressing (PV) INs, a class of neurons controlling the firing of pyramidal cells. My preliminary results show that an overlooked class of INs known as backprojecting (BP) INs hierarchically control PV-INs. I devised an intersectional genetic strategy to specifically access BP-INs and establish their role in the network. Under Aim 2, I will explore how disinhibition maintains temporal neuronal sequences, a hallmark feature of coordinated neuronal activity during network oscillations. I will focus on when and how BP-INs are recruited during network oscillations and on the downstream effects of their activity by working in vitro. Under Aim 3, I will reconstruct the impact of disinhibitory neurons on hippocampal network dynamics. I will determine the necessity and the sufficiency of BP-INs in controlling hippocampal network oscillations at different phases. Overall, this research will shed light on the physiological functions of disinhibition, a well-conserved, but generally understudied circuit feature. During the K99 phase of the award, I will benefit from the mentorship of Drs. Tsien and Buzsáki at New York University Grossman School of Medicine to obtain additional training in system neuroscience. The training plan proposed will equip me with the necessary research and professional skills to start an independent career at the intersection between cellular and system neuroscience in the R00 phase. This work is further motivated by observations that dysregulation in neuronal coordination can lead to neurological disorders such as autism spectrum disorders and epilepsies. In the long term, studying how inhibitory neurons and disinhibition control neuronal network activity will provide a better understanding of these pathological conditions.