Chronic intermittent heat exposure induces anxiety in female mice via TLR4 upregulation in paraventricular nucleus CRH neurons

Environmental stress has long been recognized as a pivotal contributor to the onset of anxiety. In this study, we reported that two weeks of chronic intermittent heat exposure (CIHE) induces anxiety only in female mice and is accompanied by a significant reduction in the responsiveness of corticotropin-releasing hormone (CRH) neurons located in the paraventricular nucleus (PVN). Moreover, toll-like receptor 4 (TLR4), which is expressed on CRH neurons, has been identified as a critical mediator of this process. Further research has demonstrated that the overexpression of TLR4 in CRH neurons in the PVN contributes to the development of anxiety in mice by disrupting synaptic signaling in supramammillary nucleus (SuMM) projections from CRH neurons. Oral ester β-hydroxybutyl (HBET) can effectively prevent anxiety induced by CIHE in mice. In summary, our research provides compelling evidence that TLR4 expressed on PVN CRH neurons plays a pivotal role in mediating anxiety-like behaviors in mice induced by CIHE and offers potential therapeutic strategies for addressing stress-related metabolic and psychiatric complications.