Enhancing dorsolateral striatum activity as a compensatory strategy improves spatial memory in a mouse model of Alzheimer’s disease

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive cognitive decline due to pathological changes primarily affecting hippocampus and cortex. Notably, some AD patients maintain cognitive function despite significant neuropathology, a phenomenon attributed to neural compensation, whereby less affected brain regions increase their activity to support cognitive processes. The dorsolateral striatum (DLS), a region relatively spared in early AD, represents a potential compensatory target. Although traditionally associated with procedural learning and habit formation, recent evidence indicates that the DLS can also contribute to declarative memory. Here, we investigated whether enhancing DLS activity could improve spatial memory deficits in a mouse model of AD. Six-month-old male APP23 mice showed spatial memory deficits in the Morris Water Maze (MWM), together with increased levels of APP, p-Tau, and GFAP in the hippocampus. We enhanced DLS activity during memory acquisition and early consolidation using chemogenetic activation (AAV2-hSyn-hM3D(Gq)-mCherry). Mice received clozapine-N-oxide (CNO, 3mg/kg, i.p.) or saline before the first and immediately after the final training session in a massed MWM protocol. Chemogenetic activation of the DLS significantly improved spatial memory 24 h after training in CNO-treated APP23 mice compared to saline-treated APP23 controls. These findings were confirmed using an optogenetic approach (AAVDJ-CaMKIIa-hChR2(C128S/D156A)-EYFP; 470nm, 1mW, 1ms pulse delivered before the first and after the final training session). We are currently investigating the effects of DLS activation in 3xTg AD mice. These results support the potential of targeting relatively preserved neural circuits as a compensatory strategy to counteract cognitive deficits in Alzheimer’s disease.