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<p>The lateral habenula (LHb) is a critical hub for stress-related behaviors, yet the sources of its corticotropin-releasing factor (CRF) inputs remain poorly defined. Using high-resolution imaging, RNAscope, and viral tracing, we identified a novel, intrinsic population of CRF-expressing LHb neurons (LHb<sup>CRF</sup>). These neurons are primarily VGLUT2 + , though a rostral subpopulation co-expresses GAD2. While chemogenetic activation of LHb<sup>CRF</sup> neurons did not impact place preference or anxiety-like behaviors, it selectively biased defensive strategies toward passive action-locking during the Visual Looming Shadow Test (VLST). Notably, this activation prolonged escape latencies in males and post-escape shelter stays in females. Electrophysiological and optogenetic characterization revealed significant sexual dimorphism: male LHb<sup>CRF</sup> neurons are more numerous and intrinsically excitable, whereas female LHb<sup>CRF</sup> neurons exhibit stronger local excitatory connectivity. These findings establish LHb<sup>CRF</sup> neurons as a sexually dimorphic circuit component that could modulate sex-specific defensive strategies under threat via divergent cellular and synaptic mechanisms between the sexes.</p>

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Neuroanatomical and behavioral characterization of corticotropin-releasing factor-expressing lateral Habenula neurons in mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月16日

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  • William J. Flerlage,
  • Shawn C. Gouty,
  • Emily H. Thomas,
  • Sarah C. Simmons,
  • Mumeko C. Tsuda,
  • Oana L. Rujan,
  • Regina C. Armstrong,
  • Catherine M. Davis,
  • Laxmi Iyer,
  • Emily Petrus,
  • Brian M. Cox,
  • T. John Wu,
  • Fereshteh S. Nugent

摘要

The lateral habenula (LHb) is a critical hub for stress-related behaviors, yet the sources of its corticotropin-releasing factor (CRF) inputs remain poorly defined. Using high-resolution imaging, RNAscope, and viral tracing, we identified a novel, intrinsic population of CRF-expressing LHb neurons (LHbCRF). These neurons are primarily VGLUT2 + , though a rostral subpopulation co-expresses GAD2. While chemogenetic activation of LHbCRF neurons did not impact place preference or anxiety-like behaviors, it selectively biased defensive strategies toward passive action-locking during the Visual Looming Shadow Test (VLST). Notably, this activation prolonged escape latencies in males and post-escape shelter stays in females. Electrophysiological and optogenetic characterization revealed significant sexual dimorphism: male LHbCRF neurons are more numerous and intrinsically excitable, whereas female LHbCRF neurons exhibit stronger local excitatory connectivity. These findings establish LHbCRF neurons as a sexually dimorphic circuit component that could modulate sex-specific defensive strategies under threat via divergent cellular and synaptic mechanisms between the sexes.