Alterations in a cross-hemispheric circuit associates with novelty discrimination deficits in mouse models of neurodegeneration

A major pathological hallmark of neurodegenerative diseases, including Alzheimer’s, is a significant reduction in the white matter connecting the two cerebral hemispheres, as well as in the correlated activity between anatomically corresponding bilateral brain areas. However, the underlying circuit mechanisms and the cognitive relevance of cross-hemispheric (CH) communication remain poorly understood. Here, we show that novelty discrimination behavior activates CH neurons and enhances homotopic synchronized neural oscillations in the visual cortex. CH neurons provide excitatory drive required for synchronous neural oscillations between hemispheres, and unilateral inhibition of the CH circuit is sufficient to impair synchronous oscillations and novelty discrimination behavior. In the 5XFAD and Tau P301S mouse models, CH communication is altered, and novelty discrimination is impaired. These data reveal a hitherto uncharacterized CH circuit in the visual cortex, establishing a causal link between this circuit and novelty discrimination behavior and highlighting its impairment in mouse models of neurodegeneration. [Display omitted] •Novelty discrimination enhances neuronal activity in cross-hemispheric circuits•The visual cortex comprises a functional bidirectional CH circuit•CH neurons are indispensable for homotopic neural oscillations•CH communication is altered in 5XFAD and Tau P301S mice Adaikkan et al. discuss how a functional circuit comprised of cross-hemispheric neurons in the homotopic visual cortex is required for novelty discrimination and how alterations in this circuit lead to impaired discrimination-dependent tasks in mouse models of neurodegeneration.