Cognitive symptoms are a clinically important component of many psychiatric disorders, affecting complex domains, like long-term memory, mediated by coordinated interaction of activity across brain-wide networks. Importantly, the specific neuronal dynamics and mechanisms underlying integrated network function are incompletely understood, even in health. The objective of this proposal is to understand how correlated neuronal dynamics in a clinically important memory-related network, the default mode network (DMN), contribute to memory processing using a mouse model. The central hypothesis is that correlated low- frequency activity across the DMN occurs in short periods of time associated with propagation of memory-related activity between network structures. The proposal probes DMN function by combining optogenetics with a novel optical technique, multifiber photometry (MFP), which directly measures neuronal dynamics simultaneously across DMN areas. My preliminary studies using MFP show slow correlated dynamics in excitatory neuron populations across DMN (but not a control area) in mouse. I can now directly probe the real- time network-wide neuronal activity and interactions associated with correlated DMN dynamics during memory.
Aim 1 will determine how reliably theta, 3-10Hz activity classically associated with memory, propagates through the DMN in its correlated state.
Aim 2 will examine DMN dynamics induced by memory (fear conditioning), and their relationship to recall (context recall).
Aim 3 will demonstrate DMN interactions during memory by optogenetically inhibiting individual areas during memory processing and measuring resulting network dynamics.
These aims represent the first in-depth dissection of neuronal dynamics across the DMN during memory. They utilize an innovative approach, leveraging novel and generalizable methods in a mouse model to generate fundamental insight into DMN function during long- term memory, with relevance to human neuroimaging findings and clinical symptoms. In the process, I will become proficient in all-optical approaches to probing distributed networks, analysis of network-wide activity, and integrated behavioral testing. I will work with an expert advisory committee (Dr. Deisseroth, Dr. Blair, Dr. Wiltgen, Dr. Etkin, Dr. O?Hara) with pioneering experience mentoring trainees in these methods. This training in cutting-edge systems neuroscience, will critically supplement my molecular and cellular neuroscience background, allowing me to launch a career as an independent investigator examining how distributed neural circuits integrate and regulate their function to generate cognition in health and disease.
Human studies have revealed the default mode network as a distinct, large-scale network prominently involved in cognition and psychiatric disease, however the application of these findings to clinical treatment is limited by our lack of knowledge about the neuronal basis and function of this network. This proposal uses cutting edge technologies in a mouse model to demonstrate the real-time, network-wide excitatory neuronal dynamics and interactions across the default mode network during memory processing. This work will significantly shape our understanding of default mode network function and its role in coordinating distributed neuronal activity for memory processing, leading to important insights for development of novel circuit-based treatment strategies for core cognitive symptoms of psychiatric disease such as memory impairment.
