Hyperactive basolateral amygdala mediates comorbid anxiety in chronic rhinosinusitis

Anxiety disorder is a common but often overlooked comorbidity in patients with chronic rhinosinusitis (CRS). However, it remains unclear which specific brain regions are involved in CRS-related anxiety-like behaviors, as well as how neural-immune interactions contribute to the progression of comorbid anxiety in CRS. Anxiety symptoms in CRS patients were evaluated using the Hospital Anxiety and Depression Scale (HADS). A papain-induced CRS mouse model was established to examine anxiety-like behaviors and associated neural and immunological alterations. Behavioral assays were combined with immunohistochemistry, in vivo fiber photometry, electrophysiology, viral tracing, and chemogenetic manipulation to identify brain regions and circuits. Peripheral inflammation, sympathetic activity, blood-brain barrier (BBB) integrity and the effects of IL-33 neutralization on peripheral inflammation, anxiety-like behaviors, and neuronal excitability were also examined. Persistent anxiety was observed in CRS patients and mice, even after improvement of sinonasal inflammation. In CRS mice, anxiety-like behaviors were linked to selective hyperactivation of BLA CaMKIIα-positive neurons, with increased intrinsic excitability and excitatory synaptic input shifting the excitation-inhibition balance toward excitation. Chemogenetic inhibition of BLA neurons alleviated anxiety-like behaviors and reduced sympathetic nerve fiber density, norepinephrine release, and nasal eosinophilic inflammation, whereas activation produced the opposite effects. Functional analyses implicate a BLA-centered network involving the vHPC and premammillary nucleus (PMN) in regulating peripheral sympathetic and immune responses. Additionally, CRS mice exhibited impaired BBB integrity, and IL-33 neutralization mitigated peripheral inflammation, improved anxiety-like behaviors, and decreased BLA hyperexcitability. Dysregulated excitatory activity in the BLA underlies anxiety comorbidity in CRS. Our findings support the involvement of a BLA-centered functional network encompassing the vHPC and PMN in the regulation of sympathetic activity and peripheral inflammation.