PROJECT SUMMARY The incredible ability of the cerebral cortex to perform sophisticated computation, integration, and cognition relies on the intricate building of its complex neuronal architecture. The cerebral cortex primarily consists of densely packed excitatory neurons that are embellished with a small set of local inhibitory interneurons. Despite the small number, cortical interneurons have astonishing diversity in their transcriptome, morphology, electrophysiological property, and connectivity. A long-standing question is to understand how and why the diversity among cortical interneurons is generated and needed. The goal of the proposal is to understand how the subtypes of cortical interneurons adapt to the molecular identity of the excitatory neurons to which they pair to form specialized local microcircuits. The central hypothesis of this proposal is that distinct subtypes of cortical interneurons partner with different types of excitatory neurons. In other words, the composition and molecular identity of excitatory neurons in different cortical regions govern the distribution and composition of cortical interneuron subtypes. The specific aims will approach this hypothesis from two different angles. Using somatostatin-expressing cortical interneurons as an example, In Aim 1 I use mouse genetic tools to target different transcriptomic subtypes of deep-layer somatostatin interneurons to investigate their laminar distribution, morphology, and stereotyped local microcircuitry. I will use both anatomical and functional measures to demonstrate the selective connectivity towards different pyramidal neuron subtypes. In Aim 2, I utilize mutant mice in which the molecular identities of a subset of excitatory neurons are altered. Using single-cell RNA sequencing of cortical interneurons, in combination with in situ hybridization against marker genes for different somatostatin interneurons, I will investigate the effects of altering excitatory neuron identity on the composition and identity of local interneurons. Finally, in Aim 2 I test whether pyramidal neurons govern the survival of interneuron subtypes or guide interneurons to specific subtypes through extrinsic cues. Substantial preliminary results are presented in the research plan supporting the significance and feasibility of this proposal. The long-term objective of this work is to identify the molecular mechanisms underlying the lock-and-key mechanisms between subtypes of excitatory neurons and interneurons. This fellowship will support the next stage of training in my path towards becoming an independent neuroscientist. I aim to integrate the molecular neuroscience experimental techniques acquired during this training period to my previous electrophysiological technical background, which will enable me to answer scientific questions with multiple approaches. My long-term career goal is to conduct basic scientific research that will advance our understanding of the wiring and function of t...