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 reduc-tion 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 cogni-tive relevance of cross-hemispheric (CH) communication remain poorly understood. Here, we show that nov-elty 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 be-tween 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 high-lighting its impairment in mouse models of neurodegeneration.

Automated summary

A reduction in white matter and correlated activity is observed in neurodegenerative diseases, but the underlying mechanisms and cognitive relevance are unclear. This study reveals a novel circuit connecting the two cerebral hemispheres in the visual cortex, which plays a role in novelty discrimination behavior. Impairment of this circuit is observed in mouse models of neurodegeneration.