Biology subjects

Mistry, P.

Publications and source records attributed to Mistry, P..

3 recordsLinked to original sources

bioRxiv2026

Whole-brain modeling of dynamic causal circuits in human cognition using amortized variational inference

Understanding dynamic mechanisms underlying cognition remains a major challenge in human neuroscience. Here, we develop, validate, and apply Multivariate Dynamical Systems Identification with Amortized Variational Inference (MDSI-AVI), a novel computational framework designed to address critical challenges in capturing asymmetric, context-dependent, whole-brain directed interactions while accounting for regional hemodynamic response variability in fMRI data. MDSI-AVI leverages simulation-based inference through forward and reverse variational inference to address the limitations of conventional variational methods in high-dimensional settings. By averaging over uncertainty in hemodynamic response parameters using forward simulation, MDSI-AVI provides well-calibrated posteriors of directed connectivity that scale efficiently to networks with hundreds of nodes. Applied to Human Connectome Project data (N=728), MDSI-AVI reveals new insights into working memory mechanisms, identifying the dorsal anterior insula as a critical hub influencing activity at the whole-brain level. We demonstrate task-dependent modulation of causal influences, where the salience network drives frontoparietal network activity, which differentially influences the default mode and sensorimotor networks depending on working memory load. These whole-brain causal interactions distinguish task conditions with high accuracy and predict working memory performance. Our framework demonstrates reproducible results across whole-brain parcellations, establishing MDSI-AVI as a robust tool for advancing our understanding of circuit dynamics in cognition and disease.

neuroscience↗

bioRxiv2022

Intrinsic reward-like dopamine and acetylcholine dynamics in striatum

External rewards like food and money are potent modifiers of behavior1,2. Pioneering studies established that these salient sensory stimuli briefly interrupt the tonic cell-autonomous discharge of neurons that produce the neuromodulators dopamine (DA) and acetylcholine (ACh): midbrain DA neurons (DANs) fire a burst of action potentials that broadly elevates DA levels in striatum3-5 at the same time as striatal cholinergic interneurons (CINs) produce a characteristic pause in firing6-8. These phasic responses are thought to create unique, temporally-limited conditions that motivate action and promote learning9-14. However, the dynamics of DA and ACh outside explicitly-rewarded situations remain poorly understood. Here we show that extracellular levels of DA and ACh fluctuate spontaneously in the striatum of mice and maintain the same temporal relationship as that evoked by reward. We show that this neuromodulatory coordination does not arise from direct interactions between DA and ACh within striatum. Periodic fluctuations in ACh are instead controlled by glutamatergic afferents, which act to locally synchronize spiking of striatal cholinergic interneurons. Together, our findings reveal that striatal neuromodulatory dynamics are autonomously organized by distributed extra-striatal afferents across behavioral contexts. The dominance of intrinsic reward-like rhythms in DA and ACh offers novel insights for explaining how reward-associated neural dynamics emerge and how the brain motivates action and promotes learning from within.

neuroscience↗

bioRxiv2022

Neuroinflammation in neuronopathic Gaucher disease: Role of microglia and NK cells

BackgroundNeuronopathic Gaucher Disease (nGD) is a rare neurodegenerative disorder caused by biallelic mutations in Gba, and buildup of glycosphingolipids in lysosomes. Neuronal injury and cell death are prominent pathological features, however the role of Gba in individual cell types and involvement of microglia, blood derived macrophages and immune infiltrates in nGD pathology remains enigmatic. MethodsHere, using single cell resolution of mouse nGD brains, we found induction of neuroinflammation pathways involving microglia, NK cells, astrocytes, and neurons. ResultsTargeted rescue of Gba in microglia and in neurons, respectively in Gba deficient, nGD mice reversed the buildup of glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph), concomitant with amelioration of neuroinflammation, reduced level of serum neurofilament light chain (Nf-L) and improved survival. The levels of bioactive lipid, GlcSph was strongly correlated with serum Nf-L and ApoE in nGD mouse models as well as GD patients. Gba rescue in microglia/macrophage compartment prolonged survival, that was further enhanced upon treatment with brain permeant inhibitor of glucosylceramide synthase, effects mediated via improved glycosphingolipid homeostasis and reversal of neuroinflammation involving activation of microglia, brain macrophages and NK cells. ConclusionsTogether, our study delineates individual cellular effects of Gba deficiency in nGD brains, highlighting the central role of neuroinflammation driven by microglia activation and the role of brain permeant small molecule glucosylceramide inhibitor in reversing complex multidimensional pathophysiology of nGD. Our findings advance disease biology whilst identifying compelling biomarkers of nGD to improve patient management, enrich clinical trials and illuminate therapeutic targets. FundingResearch grant from Sanofi Genzyme; other support includes R01NS110354.Yale Liver Center P30DK034989, pilot project grant.

immunology↗