Biology subjects

Rai, H.

Publications and source records attributed to Rai, H..

3 recordsLinked to original sources

bioRxiv2026

Input-and cell-type-specific developmental alterations to thalamic synapses in a Dravet syndrome mouse model

Dravet syndrome is an epileptic encephalopathy most often caused by loss-of-function mutations in the SCN1A gene, leading to haploinsufficiency of the voltage-gated sodium channel NaV1.1. Seizures begin during infancy and generally wane throughout childhood, but behavioral symptoms, such as intellectual disability, motor impairments, and autistic features, remain through adulthood. Seizures primarily stem from inhibitory neuron hypo-excitability in the cortex, hippocampus, and thalamus, but circuit abnormalities underlying persistent behavioral symptoms are poorly understood. Prior work showed synapse dysfunction in thalamocortical neurons in four-week-old DS mice. To understand when synaptic deficits develop and whether they could contribute to persistent thalamic dysfunction, we investigated synapse function in the ventral posterolateral (VPL) and ventral posteromedial (VPM) thalamus prior to seizure onset (P13-P17), after the period of highest seizure burden (P28-P32), and in adulthood (P58-P63). Recordings of VPL and VPM synaptic activity showed excitatory input to the VPL was significantly reduced after seizure onset and this reduction persisted through adulthood, while VPM excitatory input was unaffected. We further showed a selective reduction in the function and number of excitatory sensory synapses in the VPL, with no change to cortical synapses. VPL and VPM neurons both showed inhibitory synapse dysfunction at four weeks, which persisted into adult DS mice only in VPL neurons. These results revealed persistent input- and cell-type-specific alterations to thalamic synapses that develop after seizure onset and are maintained into adulthood, suggesting that synaptic deficits could contribute to ongoing circuit dysfunction in DS.

neuroscience↗

bioRxiv2025

Stress-Induced Alteration of Small Extracellular Vesicles Drives Amyloid-Beta Sequestration and Exacerbates Alzheimer's Disease Pathogenesis

While small extracellular vesicles (sEVs) are implicated in amyloid-beta (A{beta}) trafficking, the mechanisms governing their interaction with A{beta} aggregates and plaque formation remain unresolved. Here, we report a paradigm-shifting discovery: sEVs undergo dynamic structural remodelling in response to stress, enabling selective binding to A{beta} aggregates-a phenomenon absent under normal physiological conditions. Using multimodal stressors, including mechanical (ultrasonication/agitation), physical (hyperthermia), and biological (oxidative damage), we demonstrate that stress-modified sEVs exhibit high-affinity binding to small A{beta} aggregates (SA) through scaffold reorganization, as validated by super-resolution microscopy and quantitative colocalization assays. Crucially, these remodelled sEVs act as potent carriers, enhancing SA internalization by neuronal cells in vitro. Strikingly, in post-mortem Alzheimers disease (AD) brains and APP-PS1 transgenic mice, sEVs were spatially enriched at amyloid plaque margins, suggesting a direct role in A{beta} sequestration and plaque expansion. Consistent with clinical relevance, sEVs isolated from AD patients exhibited an intrinsic SA-binding capacity, recapitulating stress-induced interactions observed experimentally. Our findings reveal that stress-primed sEVs function as pathological chaperones, binding to and internalizing A{beta} aggregates, thereby accelerating plaque nucleation and disease progression. This study provides the first evidence of stress-mediated sEV plasticity as a critical driver of A{beta} pathology, redefining therapeutic strategies targeting extracellular vesicle biology in neurodegenerative disorders. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=95 SRC="FIGDIR/small/655679v2_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@107c76borg.highwire.dtl.DTLVardef@1b56848org.highwire.dtl.DTLVardef@d18636org.highwire.dtl.DTLVardef@1c26db4_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Dissociable patterns of dopamine dynamics and causal contributions to stimulus-response behaviors across striatal subregions.

Rationale: Midbrain dopamine (DA) neurons project principally towards the striatum, serving as key regulators of movement, motivation, and cognition. Different striatal dopaminergic (DA) pathways may regulate different aspects of cognition. Objectives: We investigated how different striatal DA pathways contribute to a known function of the striatum, visuomotor conditional learning. Methods: Using fiber photometry, we recorded DA transients in these regions as mice learned the touchscreen Visuo-Motor Conditional Learning task. Results: DA transients in all regions dynamically tracked task events, but differed in the timing of peak responses and ramp-like activity preceding a choice, indicating region-specific temporal dynamics across learning. Manipulations of reward probability revealed DA transients in all regions during reward delivery and omission that are consistent with an interpretation in terms of reward prediction error. Thus, DA dynamics in all regions could indicate involvement in visuomotor conditional learning. Therefore, to determine whether nigrostriatal or mesolimbic DA is necessary for learning, we chemogenetically inhibited DA striatal afferents, revealing that only DLS-projecting nigrostriatal DA, and not NAc-projecting mesolimbic striatal DA, was necessary for learning the task. Conclusion: These findings demonstrate functional heterogeneity of aspects of striatal DA signaling, and selective causal roles in the learning of visuomotor conditional learning.

animal behavior and cognition↗