Surgical Protocol for a Large, Resealable Cranial Window Enabling Longitudinal, Multi-Modal Electrophysiology...

The default mode network (DMN) is a central, large-scale brain network implicated in a range of cognitive functions and neuropsychiatric disorders, such as major depressive disorder (MDD). Studying the DMN's complex dynamics in animal models provides invaluable insights into its function in both healthy and pathological states. However, performing stable, long-term, large-scale electrophysiological recordings from the multiple deep and distributed nodes of the DMN in awake, behaving mice remains a significant challenge. Here, a novel two-phase surgical protocol is presented to create a large (4 mm × 7.6 mm), durable, and resealable cranial window in mice. The procedure is designed to preserve the integrity of the dura mater, which is paramount for long-term brain health and recording stability. This window enables simultaneous, repeated, longitudinal recordings from over 1,000 electrodes by combining surface-level micro-electrocorticography (µECoG) with two high-density intracranial electrode probes, providing unprecedented access to the DMN. This technique provides a robust platform for multi-modal, multi-scale interrogation of network-wide electrophysiological dynamics over several weeks, opening new avenues for investigating the neuroplastic changes underlying the pathophysiology of brain disorders and for evaluating the chronic effects of novel therapeutics.