Doctor of Philosophy, Case Western Reserve University, 2025, Neurosciences

Layer 1 (L1) of the medial prefrontal cortex (mPFC) integrates long-range inputs and exerts pivotal control over deeper cortical layers, yet the specific roles of its GABAergic interneurons (L1INs) remain incompletely understood. Here, I combined morphological, electrophysiological, and behavioral approaches to elucidate the heterogeneity and function of mPFC L1INs in mice. Biocytin labeling identified three distinct morphological subtypes: neurogliaform cells (NGCs), elongated neurogliaform cells (eNGCs), and single-bouquet cell-like (SBC-like) cells, with divergent firing patterns. NGCs and eNGCs were predominantly late-spiking (LS) neurons, whereas SBC-like cells displayed non-late-spiking (NLS) firing more commonly. These L1INs formed interconnected electrical and chemical networks and exerted broad inhibitory effects on both pyramidal neurons and interneurons, highlighting their capacity to modulate deeper-layer neuronal activity. Functionally, in vivo calcium imaging during the tail suspension test (TST) revealed that L1INs displayed distinct calcium dynamics associated with active (escape/struggle) and inactive (immobility) behavioral states. Chronic restraint stress (CRS) induced behavioral despair and significantly altered L1IN activity: the fraction of L1INs active during immobility doubled (from 22.8% to 43.0%), while those active during escape/struggle decreased (from 50.6% to 32.9%). Subsequent circuit mapping indicated that following CRS, L1INs received enhanced excitatory input from the horizontal limb of the diagonal band (HDB) and diminished input from the ventromedial thalamus (vmTH). Moreover, optogenetic activation of HDB-to-mPFC L1 projections induced behavioral despair during the TST and triggered neuregulin-1 (NRG1) release from HDB terminals. This release shifted the firing pattern of mPFC ErbB4+ L1INs from LS to NLS, mirroring CRS effects. Notably, CRISPR/Cas9-mediated knockout of NRG1 in the HDB rescued the behavioral deficits, highlighting (open full item for complete abstract)

Committee: Wen-Cheng Xiong (Advisor); Lin Mei (Advisor); Peng Zhang (Committee Member); Hillel Chiel (Committee Member); Qian Sun (Committee Chair) Subjects: Neurosciences