Biology subjects

Tolias, K. F.

Publications and source records attributed to Tolias, K. F..

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

Primary cortical neurons form calcium-phosphate sheets with a bone-precursor-like ultrastructure

Calcium-phosphate (CaP) is a ubiquitous inorganic compound that plays an important structural role in healthy bone and teeth formation, but its pathologic buildup can occur in dyshomeostatic calcium disorders like Alzheimers disease and Leigh syndrome. The nexus of pathologic extracellular CaP in the nervous system is not well understood, but prior evidence suggests mitochondria could be a source. We have observed mitochondria-sized sheet-like CaP aggregates within functional wild type cortical neuron cultures at 1 and 20 DIV. Neurons were extracted from embryonic day 18 (E18) rat embryos following standard protocols to study neuronal structure and function. We have used a combination of cryo-ET, cryo-CLEM, and LDSAED to demonstrate that these aggregates are octacalcium phosphate-like, are associated with mitochondria, and that at least a portion are extruded via migrasomes. Visually similar aggregates were previously observed in Huntingtons disease model neurons, but in that study they were not observed in WT controls. These findings show that this CaP aggregation process occurs routinely in WT neurons and may reveal an important link for how mitochondria may participate in calcification, highlighting them as potential therapeutic targets in neurological disorders characterized by pathological calcification, such as Alzheimers disease.

neuroscience↗

bioRxiv2021

Tiam1-mediated synaptic plasticity drives comorbid depressive symptoms in chronic pain

Hyperactivity in the anterior cingulate cortex (ACC) drives comorbid depressive symptoms in chronic pain, but the cause of ACC hyperactivity is currently unclear. Ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, induces rapid and sustained antidepressant-like effects in chronic pain-induced depression in both patients and animal models. However, the mechanisms underlying ketamines sustained antidepressant effects remain elusive. Here, we show that Tiam1, a Rac1-specific guanine nucleotide exchange factor (GEF) that was previously identified as a critical mediator of NMDAR-dependent dendritic spine development, is activated in the ACC in chronic pain mice displaying depressive-like behaviors. Conditional deletion of Tiam1 from postnatal forebrain excitatory neurons, specific deletion of Tiam1 from ACC neurons, or pharmacological inhibition of the Tiam1-Rac1 signaling pathway prevents chronic pain-induced depressive-like behaviors in mice. Biochemical, morphological, and electrophysiological assays reveal that Tiam1 orchestrates synaptic structural and functional remodeling in ACC neurons via actin cytoskeleton reorganization and synaptic NMDAR stabilization. This Tiam1-coordinated synaptic plasticity underpins ACC hyperactivity and drives chronic pain-induced depressive-like behaviors. Ketamine induces sustained antidepressant effects in chronic pain by blocking Tiam1-mediated synaptic structural and functional plasticity in ACC neurons. Our results reveal Tiam1 as a key factor in the pathophysiology of chronic pain-induced depression and in the sustained antidepressant effects of ketamine in ACC neurons. These findings highlight Tiam1 as a potential therapeutic target for the treatment of comorbid depressive symptoms in chronic pain.

neuroscience↗