An imbalance of excitation and inhibition in the prefrontal cortex (PFC) is implicated in neuropsychiatric disorders such as schizophrenia, autism, and epilepsy. In addition to shaping the electrical activity of principal excitatory neuron, synaptic inhibition also regulates neuronal biochemical processes, such as calcium signaling to impact synaptic plasticity. However, the precise cellular and sub-cellular mechanisms underlying GABAergic actions are not well understood. Using a combination of optogenetics and two-photon microscopy techniques, the goal of the proposed work is to investigate the impact of synaptic inhibition mediated by distinct GABAergic interneurons on dendritic calcium signaling and synaptic plasticity in the PFC. Results from this work will provide new understanding of the dynamic interplay between excitation and inhibition underlying healthy brain circuit function and suggest future directions of research for cellular mechanisms of neuropsychiatric disease. Work in this proposal will be conducted at Yale University, an institution with a long-standing history f well-established research programs in the field of Mental Health. The countless number of academic departments and interdepartmental programs provides a rich intellectual resource. Specifically, the proposed research will be performed in the Higley laboratory, which has two multi-photon microscope setups capable of both imaging and electrophysiological experiments. In addition, there is lab space for development of my own research program such as a dedicated surgical bay for viral injections. Moreover, a state-of-the-art microscopy core is available for advanced cellular imaging capabilities and employs specially trained imaging experts who act as additional sources of technical knowledge. In terms of career development, the Department of Neurobiology sponsors numerous seminars and journal clubs to cultivate intellectual and scientific interactions among faculty, postdocs and students. My long-term career goal is to advance our understanding of how transient and long-lasting modifications in excitatory synaptic strength are regulated. While it is known that inhibition can serve as a negative regulator of plasticity, the precise mechanisms by which it does so are unclear. From this mentored training, I will obtain knowledge and expertise in the use of optical methods in cortical circuits to study excitatory and inhibitory synaptic integration and plasticity. I am confident that with the guidance of Dr. Higley and Dr. McCormick, who are experts in the field of synapse physiology and are meticulous in their approach to science, I will be better equipped for a successful independent research career examining inhibitory regulation of excitatory transmission and plasticity using a multi-disciplinary approach.
Neurons communicate with each other through connections known as synapses, which can either be excitatory or inhibitory. The manner with which synaptic excitation and inhibition interact determines the magnitude and timing of neuronal output. Our research goal is to understand how different inhibitory cells can regulate excitatory responses to contribute to overall neural activity underlying brain function in both health and disease.
|Amatrudo, Joseph M; Olson, Jeremy P; Lur, G et al. (2014) Wavelength-selective one- and two-photon uncaging of GABA. ACS Chem Neurosci 5:64-70|