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Targeting supramammillary circuits restores cognitive and noncognitive function in Alzheimer’s disease

ABSTRACT: Although progressive cognitive decline is the hallmark symptom in Alzheimer’s disease (AD) patients, patients often develop noncognitive neuropsychiatric symptoms, such as anxiety and depression. The neural circuit basis for these different AD symptoms is poorly understood. Therapeutic strategies effectively targeting both cognitive and noncognitive symptoms in AD are largely lacking. Here we identified molecularly and functionally distinct supramammillary (SuM) subpopulations projecting to dorsal dentate gyrus (dDG) or ventral dentate gyrus (vDG), which differentially involved in memory and mood regulation. Interestingly, dDG- and vDG-projecting SuM neurons in AD model mice exhibited aberrant activity during cognitive and affective behaviors, respectively. Optogenetic activation of SuM-dDG or SuM-vDG pathways selectively rescued memory impairment and anxiety/depression-like behavioral deficits in AD mice. Furthermore, cross-species comparison of AD mouse and human phosphoproteomes revealed that SuM stimulation reversed pathological phosphorylation of mouse-to-human conserved proteins related to broad AD deficits. Thus, targeting SuM circuits may be an effective strategy for treating both cognitive and non-cognitive symptoms in AD patients.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Ling Xie

LAB HEAD: Juan Song

PROVIDER: PXD055911 | Pride | 2025-09-25

REPOSITORIES: Pride

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			Action	DRS
	20210423_AD_s1_TMT8_p_500ng_1.raw	Raw
	20210423_AD_s1_TMT8_p_500ng_2.raw	Raw
	20210423_AD_s2_TMT10_p_500ng_1.raw	Raw
	20210423_AD_s2_TMT10_p_500ng_2.raw	Raw
	20210601_AD_TMTs1_p.raw	Raw

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Project description:Maternal 5-HT1A-receptor (R) is required for the timely development of the hippocampus and the establishment of emotional behaviors in Swiss-Webster (SW) mice. A partial and/or complete loss of maternal 5-HT1AR results in delayed ventral dentate granule cell (v-DGC) development and subsequent anxiety-like phenotype in the wild-type offspring by a non-genetic, presumably epigenetic mechanism. Here we tested v-DGCs for genome-wide DNA methylation changes elicited by the receptor deficient maternal environment. We identified a set of hypomethylated regions in the offspring of receptor deficient mothers. A significant fraction of these maternal-differentially methylated regions (m-DMRs) mapped to strong CpG islands, sequences that are typically not methylated or if methylated, resistant to environmental-induced changes. Many m-DMRs mapped to exons and some were associated with expression changes. Their hypomethylation was due to an arrest in de novo methylation and, to a lesser extent, to demethylation during postnatal life indicating that the perturbation in methylation coincides with the developmental delay in DGC maturation in the offspring of receptor deficient mothers. Inhibiting methylation in differentiating neurons impaired their maturation further suggesting a link between de novo methylation and neuronal differentiation. These data suggest that methylation at specific exonic CpG-islands may contribute to the mechanism through which maternal 5-HT1AR modulates hippocampal development and consecutively the level of anxiety in the SW offspring. Reduced 5-HT1AR-binding has been reported in individuals, particularly in association with anxiety/depression, including peri/postpartum depression. Therefore, maternal receptor deficit may contribute, via a non-genetic mechanism, to the high prevalence and heritability of anxiety disorders in human. Comparison of methylation patterns in ventral Dentate Gyrus cells of wild type mice versus 5HT1A receptor knockouts, as well as the effect of the maternal 5HT1A genotype

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Targeting supramammillary circuits restores cognitive and noncognitive function in Alzheimer’s disease

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