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

Doctor of Philosophy, Case Western Reserve University, 2024, Neurosciences

Control of metabolic homeostasis is governed by the melanocortin system in the hypothalamus which includes the paraventricular nucleus of the hypothalamus (PVH). We previously identified that ErbB4 which is a risk gene for the development of obesity is expressed in the PVH yet the precise function of ErbB4 in the PVH remained unexplored. First, we characterized the function of ErbB4 in the PVH and its relationship to energy metabolism by specifically deleting ErbB4 in the PVH. Deletion of ErbB4 in the PVH increases mouse body weight and decreases energy expenditure in a food intake independent manner. Second, we identified that ErbB4 in the PVH is expressed in OXT neurons and deletion of ErbB4 in OXT cells decreases energy expenditure. Finally, we provide circuit level evidence that ErbB4-positive neurons of the PVH project to brainstem nuclei necessary for energy expenditure, the nucleus of the solitary tract (NTS).

Committee: Heather Broihier (Committee Chair); George Dubyak (Committee Member); Wen-Cheng Xiong (Advisor); Peng Zhang (Committee Member) Subjects: Neurobiology; Neurology; Neurosciences

Doctor of Philosophy, Case Western Reserve University, 2022, Neurosciences

Neurotrophic factors are released in the brain in response to neural activity. In so doing, they can modulate neuronal circuits. Yet how exactly neurotrophic factors impact networks of the brain and by what underlying mechanisms are just becoming understood. Neuregulin 1 (NRG1) is one such trophic factor that is released in the brain upon neuronal activity. NRG1 binds to and stimulates the receptor tyrosine kinase (RTK) ErbB4 that is expressed in inhibitory interneurons. Stimulation of ErbB4 kinase then increases Gamma-Aminobutyric Acid (GABA) neurotransmission in the cortex and HPC. Yet how ErbB4 kinase dynamically impacts the cortex, HPC, and relevant behaviors remains unknown. By developing a novel chemo-genetic animal model to specifically manipulate ErbB4 kinase, we identify two distinct network functions of the brain that ErbB4 kinase regulates, along with relevant behaviors involved in these network functions. First, we identify a novel behavioral function for the ventral HPC (vHPC) to prefrontal cortex (PFC) circuit. We find that the vHPC-PFC is highly synchronous during top-down attention. We next identify how ErbB4 plays a role in top-down attention, by regulating vHPC-PFC synchronicity. We further validate that ErbB4 kinase dynamically regulates GABAergic transmission via presynaptic xviii modulation. Lastly, we identify how ErbB4, via regulation of GABAergic transmission, controls vHPC-PFC synchrony through vHPC inputs to the PFC that lead PFC neurons to fire in phase. Together, we identify how ErbB4 kinase dynamically regulates the synchrony between two regions for top-down attention. Next, we examine how NRG1-ErbB4 kinase regulates a memory consolidation network event in the HPC called the sharp wave ripple (SW-R). Specifically, we find that NRG1-ErbB4 kinase dynamically regulate the occurrence of SW-Rs, especially during awake periods. Furthermore, we uncover that ErbB4 kinase regulates levels of neuronal firing, specifically pyramidal neurons (Py (open full item for complete abstract)

Committee: Lin Mei Dr. (Advisor); Ben Strowbridge Dr. (Committee Chair); Qian Sun Dr. (Committee Member); Dominique Durand Dr. (Committee Member); Heather Broihier Dr. (Committee Member) Subjects: Neurobiology; Neurosciences