Longitudinal brain-wide recordings reveal early neurophysiological alterations in memory-impaired mice

Abstract

Scopolamine, a muscarinic receptor antagonist, is widely utilized to pharmacologically model Alzheimer’s disease (AD) due to its ability to mimic cholinergic deficits and induce memory impairments. Despite its common use in investigating behavioral and cognitive impairments in memory deficit animal models, the longitudinal brain-wide electrophysiological alterations associated with scopolamine administration remain largely unexplored. This study integrated electrophysiological and behavioral analyses to investigate scopolamine-induced cognitive deficits in mice. Using a 16-channel intracranial electroencephalography (iEEG) array, we tracked brain-wide oscillatory changes and functional connectivity over 6 weeks during memory task-related and task-free activities. The mouse’s pre-attentive sensory memory was assessed by auditory evoked potentials (AEPs) within the passive oddball mismatch negativity (MMN) paradigm, and the mouse’s spatial working memory was further evaluated using a Y-maze spontaneous alternation task. The auditory MMN responses indicated significant sensory discrimination impairments from Week 2 onward, and spontaneous theta oscillations demonstrated widespread disruptions by Week 3. Concurrently, scopolamine degraded the animal’s Y-maze successful alternation rates. The decline in alternation performance was correlated with the observed electrophysiological alterations, revealing the progressive impact of scopolamine on cognitive and neural functions. Furthermore, this study identified early electrophysiological biomarkers of brain functional network changes associated with memory impairments, in which functional connectivity abnormalities were observed from the first week of scopolamine administration, suggesting they have diagnostic potential in preclinical AD research. By bridging behavioral outcomes with brain-wide iEEG metrics, this work emphasizes the translational relevance of scopolamine models for understanding AD-like pathology and evaluating therapeutic interventions.