An Activity‐Dependent NEPAS–PTX3 Axis Links Neurovascular and Myelin Deficits to Cognitive Impairment

ABSTRACT Acquired cognitive impairments occur in diverse neurological and psychiatric conditions, yet the mechanisms linking neural circuit activity to neurovascular function remain poorly understood. Using a mouse model of nicotine withdrawal (WD), we identified an activity‐dependent NEPAS–pentraxin‐3 (PTX3) axis in mPFC neurons that couples circuit hypoactivity to cognitive deficits. In this model, NEPAS expression is significantly upregulated in mPFC neurons, accompanied by reduced myelin formation. Neuronal activity in mPFC and PVA is suppressed and chemogenetic activation of the PVA–mPFC neural circuit downregulates NEPAS. Elevated neuronal NEPAS suppresses the secretion of PTX3, thereby impairing angiogenesis. Conversely, knockdown of neuronal NEPAS restores PTX3 expression and angiogenesis, alleviates myelin formation deficits, and improves cognitive memory following nicotine WD. Notably, activation of the PVA–mPFC neural circuit produces similar therapeutic effects. Human transcriptomic data reveal a consistently elevated HIF‐3α expression in ex‐smokers versus controls. Our findings demonstrate that the NEPAS–PTX3 axis in mPFC neurons links neural circuit hypoactivity to neurovascular and myelin deficits, providing a mechanistic framework for acquired cognitive impairment. This pathway represents a potential target for neuromodulation‐based therapies in prefrontal circuit dysfunction associated cognitive disorders.