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Full text release has been delayed at the author's request until May 16, 2027

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Heterogeneity and Functional Roles of Layer 1 Interneurons in the Mouse Medial Prefrontal Cortex

Shen, Chen
http://orcid.org/0000-0001-5809-7632
http://rave.ohiolink.edu/etdc/view?acc_num=case1744238758897784

Abstract Details

2025, Doctor of Philosophy, Case Western Reserve University, 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 a crucial role for NRG1/ErbB4 signaling in behavioral motivation. Together, these findings elucidate the morphological and functional heterogeneity of mPFC L1INs and uncover a stress-sensitive HDB-to-mPFC L1 circuit, implicating NRG1/ErbB4 signaling in the regulation of L1IN dynamics and behavioral motivation.
Wen-Cheng Xiong (Advisor)
Lin Mei (Advisor)
Peng Zhang (Committee Member)
Hillel Chiel (Committee Member)
Qian Sun (Committee Chair)
238 p.
Neurosciences
Layer 1 interneurons; major depressive disorder; medial prefrontal cortex; HDB; neuron-derived neurotrophic factor (NDNF); neuregulin-1 (NRG1); ErbB4; calcium imaging

Recommended Citations

Citations

  • Shen, C. (2025). Heterogeneity and Functional Roles of Layer 1 Interneurons in the Mouse Medial Prefrontal Cortex [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1744238758897784

    APA Style (7th edition)

  • Shen, Chen. Heterogeneity and Functional Roles of Layer 1 Interneurons in the Mouse Medial Prefrontal Cortex. 2025. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1744238758897784.

    MLA Style (8th edition)

  • Shen, Chen. "Heterogeneity and Functional Roles of Layer 1 Interneurons in the Mouse Medial Prefrontal Cortex." Doctoral dissertation, Case Western Reserve University, 2025. http://rave.ohiolink.edu/etdc/view?acc_num=case1744238758897784

    Chicago Manual of Style (17th edition)

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© 2025, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.
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