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

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

PROVIDER: PRJNA1018259 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR26083300_1.fastq.gz	Fastqsanger.gz
	SRR26083300_2.fastq.gz	Fastqsanger.gz
	SRR26083301_1.fastq.gz	Fastqsanger.gz
	SRR26083301_2.fastq.gz	Fastqsanger.gz
	SRR26083302_1.fastq.gz	Fastqsanger.gz

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

Project description: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.

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Reduced adult neurogenesis and neuronal abnormalities in the hippocampus underlie cognitive deficiency following prenatal administration of the anti-epileptic drug valproic acid

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CBP is required for environmental enrichment-induced neurogenesis and cognitive enhancement.

Project description:The epigenetic changes of the chromatin represent an attractive molecular substrate for adaptation to the environment. We examined here the role of CBP, a histone acetyltransferase involved in mental retardation, in the genesis and maintenance of long-lasting systemic and behavioral adaptations to environmental enrichment (EE). Morphological and behavioral analyses demonstrated that EE ameliorates deficits associated to CBP-deficiency. However, CBP-deficient mice also showed a strong defect in environment-induced neurogenesis and impaired EE-enhanced spatial navigation and patter separation ability. These defects correlated with an attenuation of the transcriptional program induced in response to EE and with deficits in histone acetylation at the promoters of EE-regulated, neurogenesis-related genes. Additional experiments in CBP restricted and inducible knockout mice indicated that environment-induced adult neurogenesis is extrinsically regulated by CBP function in mature granule cells. Overall, our experiments demonstrate that the environment alters gene expression by impinging on activities involved in modifying the epigenome and identify CBP-dependent transcriptional neuroadaptation as an important mediator of EE-induced benefits, a finding with important implications for mental retardation therapeutics. To identify those genes whose expression was altered in the hippocampus of cbp heterozygous mice both under basal conditions and after 2 weeks of exposure to environmental enrichment, we performed a gene profiling analysis of hippocampal tissue using high-density oligonucleotide microarrays. We obtained quintuplicate (standard housing) and triplicate (environmental enrichment) samples containing total RNA from the hippocampi of four 3-month old females of either genotype (in total 32 cbp+/- mice and 32 wild type littermates were used in the experiment).

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