Multisensory gamma stimulation enhances adult neurogenesis and improves cognitive function in male mice with Down Syndrome

Multisensory Gamma Stimulation (MGS) has previously been linked with improved cognitive performance in mouse models and patients with Alzheimer´s Disease (AD). In this study, we aimed to investigate the effects of chronic exposure to MGS in Ts65Dn mice, a mouse model of Down Syndrome (DS). For three weeks, mice were exposed daily to one hour of multisensory audiovisual stimulation or, as a control, one hour of ambient light and sound. Mice receiving MGS showed improved object recognition and spatial working memory. To gain mechanistic insight into how MGS improves cognitive function in Ts65Dn mice, we conducted single-nuclei RNA-seq (snRNA-seq) of hippocampal samples from control and treated mice. We found upregulation of genes related to synaptic organization and downregulation of genes related to aging and AD. Moreover, we detected upregulation of neurogenesis-related genes in the dentate gyrus. We validated these observations by demonstrating increased adult neurogenesis following MGS treatment. A potential mechanism underlying this MGS-mediated increase in adult neurogenesis is increased mitochondrial fusion. Together, our data indicate that MGS can ameliorate cognitive impairment in DS mice through modulation of conserved gene regulatory signatures and enhanced neurogenesis in hippocampal regions. These findings suggest that multisensory 40 Hz stimulation may have potential as a therapeutic approach to boost cognitive performance in individuals with Down Syndrome. Overall design: We exposed one group of Ts65Dn mice (ST group) to one hour of 40 Hz auditory and visual stimulation per day, while a parallel control group of Ts65Dn mice (NS group) was exposed to ambient light and sound. After three weeks of treatment period, hippocampal nuclei were subjected to single nuclei RNAseq using 10x Genomics.