Biology subjects

Dooling, S. W.

Publications and source records attributed to Dooling, S. W..

3 recordsLinked to original sources

bioRxiv2026

Infant gut microbiomes contribute to metabolic states that impact brain function

Alterations in the gut microbiome are associated with neurodevelopmental disorders, but causal mechanisms and therapeutic strategies remain undefined. Here, we demonstrate that human infant microbiomes isolated during the first six months of life drive behavioral impairments in mice and that microbiota-based interventions restore mice to normal behavior. Early-life microbiomes from twelve infants who later exhibited cognitive deficits at 2 years old (low-scoring) transferred adverse metabolic, brain, and behavioral phenotypes to mice, in contrast to microbiomes from twenty-three cognitively typical or high-scoring infants. Deficits in mice were rescued by fecal microbiota transplant from high-scoring infants or a rationally designed consortium that promoted amino acid levels. We confirmed lower fecal amino acid concentrations in low-scoring infants and replicated the association between early-life microbiome composition and cognitive outcomes in a second geographically independent infant cohort. Altogether, we discovered an early-life microbiome-mediated metabolic state causally linked to cognitive deficits and amenable to microbial intervention.

microbiology↗

bioRxiv2025

Harnessing the Evolution of Proteostasis Networks to Reverse Cognitive Dysfunction

The integrated stress response (ISR) is a highly conserved network essential for maintaining cellular homeostasis and cognitive function. Here, we investigated how persistent ISR activation impacts cognitive performance, primarily focusing on a PPP1R15BR658C genetic variant associated with intellectual disability. By generating a novel mouse model that mimics this human condition, we revealed that this variant destabilizes the PPP1R15B*PP1 phosphatase complex, resulting in chronic ISR activation, impaired protein synthesis, and deficits in long-term memory. Importantly, we found that the cognitive and synaptic deficits in Ppp1r15bR658C mice are directly due to ISR activation. Leveraging insights from evolutionary biology, we characterized DP71L, a viral orthologue of PPP1R15B, through detailed molecular and structural analyses, uncovering its mechanism of action as a potent pan-ISR inhibitor. Remarkably, we found that DP71L not only buffers cognitive decline associated with a wide array of conditions--including Down syndrome, Alzheimers disease and aging--but also enhances long-term synaptic plasticity and memory in healthy mice. These findings highlight the promise of utilizing evolutionary insight to inform innovative therapeutic strategies.

neuroscience↗

bioRxiv2025

Mapping the ISR Landscape in Cognitive Disorders via single-cell multi-omics

Persistent activation of the integrated stress response (ISR) is a major driver of cognitive decline in both neurodevelopmental and neurodegenerative disorders. Using a new mouse model (Ppp1r15bR658C mice) that mimics the persistent ISR activation and cognitive decline observed in humans, we generated the first single-cell ISR atlas of the brain. By integrating single-cell RNA-seq and single-cell ATAC-seq with proteomics, we discovered that distinct brain cell types respond differently to persistent ISR activation and elicit cell-type-specific ISR programs. Interestingly, chromatin accessibility analyses revealed that the ISR downstream factor ATF4 is a key ISR effector in GABAergic neurons, while AP-1 (JUNB) is implicated in glutamatergic neurons. More importantly, selective deletion of ATF4 in GABAergic neurons--but not in glutamatergic neurons--impacts ISR-mediated cognitive decline in Ppp1r15bR658C mice, demonstrating that different neuronal subtypes rely on unique ISR downstream effectors to regulate mnemonic processes. Furthermore, we defined a comprehensive molecular signature of persistent ISR activation, which we showed could serve as a biomarker for cognitive dysfunction across neurodevelopmental, neurodegenerative disorders and normal aging. This multi-omic framework provides a key platform for exploring and validating new scientific hypotheses, significantly advancing our understanding of ISR-related brain disorders.

neuroscience↗