Cross-Hemispheric Circuit Dysfunction Impairs Novelty Discrimination in Alzheimer's Disease Mice

SUMMARYA clinical hallmark of Alzheimer’s disease is significant reductions 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 communication remain poorly studied. Here, we show that novelty discrimination behavior activated cross-hemispheric neurons and enhanced homotopic synchronized gamma oscillations in the visual cortex. Cross-hemispheric neurons provide excitatory drive required for synchronous gamma oscillations between hemispheres and unilateral inhibition of the cross-hemispheric circuit is sufficient to impair behavior. In the 5XFAD mouse model of Alzheimer’s disease, cross-hemispheric communication is compromised and novelty discrimination is impaired; a deficit rescued by gamma sensory stimulation. These data establish a causal link between a cross-hemispheric circuit and behavior and highlight its impairment in Alzheimer’s disease mice.