Interneurons differentially regulate discrete pathways from ventral hippocampus

项目总结/文摘

Project Summary/Abstract The current application is for an Administrative Supplement for Continuity of Biomedical and Behavioral Research Among First-Time Recipients of NIH Research Project Grant Awards. Hippocampal microcircuits are comprised of excitatory pyramidal cells, which integrate information and innervate downstream brain regions, and inhibitory interneurons, which function locally to regulate pyramidal cell activity and synchronicity. In the ventral hippocampus (vHipp), microcircuit dysfunction has been associated with a variety of neurological disorders, including neurodegenerative diseases, neurodevelopmental disorders, and psychiatric illnesses. Previous work has demonstrated that vHipp pyramidal cells differentially regulate schizophrenia-like behaviors depending on their downstream target. Similarly, unique classes of inhibitory interneurons (namely parvalbumin (PV)-positive and somatostatin (SST)-positive) also differently regulate schizophrenia-like behaviors. Therefore, the overarching hypothesis of the current proposal is that PV- and SST-positive interneurons differentially regulate the function of vHipp pyramidal cells depending on their projection target. During the K99 phase of the award, enhanced GFP recombination across synaptic partners (eGRASP) and electron microscopy were used to demonstrate that PV- and SST-positive interneurons differentially innervate vHipp pyramidal cells depending on their target (i.e. the NAc or mPFC). Specifically, PV-positive interneurons form a similar number of synapses on pyramidal cells that project to both the NAc and mPFC. SST-positive cells, however, form significantly fewer synapses on pyramidal cells that project to the mPFC. Further, fiber photometry, in vivo electrophysiology, and optogenetics were used to test the functional regulation of NAc vs mPFC projecting pyramidal cells by PV- and SST-positive interneurons in the vHipp. We found that PV-positive interneurons regulate the function of pyramidal cells that project to either the NAc or the mPFC while SST-positive interneurons only regulate the function of NAc-projecting pyramidal cells. These findings are in line with previously collected behavioral data demonstrating that SST-positive interneuron transplants have little impact on behaviors associated with the vHipp-mPFC pathway. During the R00 phase of the award, we have begun to test the hypothesis that microcircuit anatomy and function are altered by chronic stress, a predisposing factor for many neurological disorders, using eGRASP and fiber photometry. In line with the goals of the BRAIN Initiative, the results will provide insight into basic principles of neural circuit function and may lead to new strategies for the treatment and prevention of devastating neurological disorders. The Administrative Supplement will ensure that progress is made as the PI undergoes treatment for breast cancer.