Biology subjects

Modi, H.

Publications and source records attributed to Modi, H..

7 recordsLinked to original sources

bioRxiv2026

From topography to connectome: Towards an integrated understanding of the resting brain

As the field expands from early research into the human connectome, there has been a fast expansion in the number of analytical approaches to study resting state functional MRI (rsfMRI) data. With increasing focus on individual differences, topographical brain maps of spatial organization have emerged in addition to traditional functional connectomes. Here, we developed a deep-learning model to embed maps of network topography and faithfully translate to individualized connectomes. Results confirmed the validity of the surface vision transformer based on reconstruction accuracy (0.73{+/-}0.09) and accurate topography-to-connectome translation (0.43{+/-}0.08). Importantly, translated connectomes retained identifiability and brain-cognition associations. These findings establish a direct mapping from spatial topography to connectomes that can be used to integrate scientific insights across rsfMRI sub-fields. This is an important step towards broadening our conceptualization of the connectome and supporting a broader integration of findings to inform a complete understanding of the human connectome. TeaserTranslating from spatial maps of brain organization to region-to-region connectomes retains shared individual differences.

bioinformatics↗

bioRxiv2025

Profiles of Aging Based on Cognition, Affect, and Brain Reserve

The aging paradox describes improvements in emotional wellbeing as a function of aging, despite declines in cognition. Conversely, late life depression has been associated with increased cognitive decline in aging. We sought to understand these seemingly contradictory patterns of cognitive and mental health in older age. Building on cognitive reserve, affective reserve, and brain reserve models of aging, we developed three alternative algorithmic approaches to group N=22,686 participants from the UK Biobank into different profiles of aging. Our results revealed that aging profiles identified using our data-driven brain reserve model, which incorporated measures of cognition, neuroticism, and brain volume, achieved the highest validation results. Importantly, only two of the four aging profiles were characterized by the aging paradox (i.e., improved emotionality and decreased cognition with age). We identified one profile characterized by particularly low levels of neuroticism and relative resilience to cognitive decline. Another profile benefited from relatively preserved brain volumes, potentially driven by younger ages and/or higher socioeconomic status. Conversely, we identified two profiles with poorer health characteristics, including one profile with elevated cardiovascular risk. Taken together, these findings enrich our understanding of the emotion paradox and highlight the value of taking a nuanced and stratified approach when studying aging. In the future, aging profiles could be used to target preventative strategies to address modifiable risk factors and improve lifespan and healthspan.

neuroscience↗

bioRxiv2025

Loss of brain insulin production impairs learning and memory in female mice

Diabetes is characterized by dysfunctional insulin release and action, and it is a risk factor for Alzheimers disease, the most common form of dementia. Alterations in brain insulin signalling and metabolism have been linked with Alzheimers disease. The ancestral insulin gene, Ins2, is transcribed locally within the brain. Here we demonstrate that hippocampal Ins2 mRNA is higher in females than males, and modulated by diet. To specifically determine how locally-produced insulin influences hippocampal function, we used mice with germline Ins2 knockout (Ins2-/-) and the normal complement of wildtype Ins1 alleles. Compensation from the Ins1 gene ensured normal glucose tolerance, normal insulin sensitivity, normal fasting insulin, and normal body weight under these conditions. Using the Morris water maze, we found that visuo-spatial learning and memory performance of female Ins2-/- mice was significantly impaired relative to wild-type mice, whereas the performance of male Ins2-/- and wild-type mice did not differ. We profiled isolated hippocampi from female Ins2-/- and littermate control mice using RNA sequencing to provide an unbiased analysis of gene expression differences that underlie these behavioural changes. Cyclin D1 (Ccnd1) was significantly reduced in Ins2-/- mice, prompting us to examine adult neurogenesis using exogenous mitotic marker EdU and the immature neuronal marker doublecortin (DCX). Our data demonstrate female-specific roles for brain-derived Ins2 on learning and memory function in mice. Research in contextO_ST_ABSWhat is already known about this subject?C_ST_ABSO_LIAlzheimers disease and type 2 diabetes share common risk factors and metabolic dysfunction. C_LIO_LIInsulin and insulin signalling are known to have positive effects on neuronal health and cognition. C_LIO_LILocal insulin production has been reported in the brain, including the hippocampus, which plays critical roles in learning and memory, as well as Alzheimers pathophysiology. C_LI What is the key question?O_LIWhat are the consequences of deleting the Ins2 gene, which selectively prevents local brain insulin production, on learning and memory in mice? C_LI What are the new findings?O_LIHippocampal insulin production via the Ins2 gene is sexually dimorphic and modulated by diet. C_LIO_LIKnocking out brain insulin production in Ins2-/- mice does not have significant effects on glucose homeostasis in these diet and housing conditions. C_LIO_LIKnocking out brain insulin production in Ins2-/- mice results in learning and memory impairments in female but not male mice. C_LI How might this impact on clinical practice in the foreseeable future?O_LIThese pre-clinical observations demonstrate a causal role for insulin in learning and memory, but will require additional human studies before they can impact clinical practice. C_LI

physiology↗

bioRxiv2025

The neuroimaging correlates of depression established across six large-scale datasets

Neuroimaging data offers noninvasive insights into the structural and functional organization of the brain and is therefore commonly used to study the neuroimaging correlates of depression. To date, a substantial body of literature has suggested reduced size of subcortical regions and abnormal functional connectivity in frontal and default mode networks linked to depression. However, recent meta analyses have failed to identify significant converging correlates of depression across the literature such that a conclusive mapping of the neuroimaging correlates of depression remains elusive. Here we leveraged 23,417 participants across six datasets to comprehensively establish the neuroimaging correlates of depression. We found reductions in gray matter volume/ cortical surface area associated with depression in the frontal cortex, anterior cingulate, and insula, confirming prior studies showing the importance of prefrontal and default mode regions in depression. Our findings demonstrate multiple surprising results, including a lack of depression correlates in subcortical brain regions, significant depression correlates in somatomotor and visual regions, and limited functional connectivity findings. Overall, these results shed new light on key brain regions involved in the pathophysiology of depression, updating our understanding of the neuroimaging correlates of depression. We anticipate that these insights will inform further research into the role of sensorimotor and visual regions in depression and into the impact of heterogeneity on functional connectivity correlates of depression.

neuroscience↗

bioRxiv2023

Systematic Identification of Post-Transcriptional Regulatory Modules

In our cells, a limited number of RNA binding proteins (RBPs) are responsible for all aspects of RNA metabolism across the entire transcriptome. To accomplish this, RBPs form regulatory units that act on specific target regulons. However, the landscape of RBP combinatorial interactions remains poorly explored. Here, we performed a systematic annotation of RBP combinatorial interactions via multimodal data integration. We built a large-scale map of RBP protein neighborhoods by generating in vivo proximity-dependent biotinylation datasets of 50 human RBPs. In parallel, we used CRISPR interference with single-cell readout to capture transcriptomic changes upon RBP knockdowns. By combining these physical and functional interaction readouts, along with the atlas of RBP mRNA targets from eCLIP assays, we generated an integrated map of functional RBP interactions. We then used this map to match RBPs to their context-specific functions and validated the predicted functions biochemically for four RBPs. This study highlights the previously underappreciated scale of the inter-RBP interactions, be it genetic or physical, and is a first step towards a more comprehensive understanding of post-transcriptional regulatory processes and their underlying molecular grammar.

systems biology↗

bioRxiv2020

Beta-cell specific insulin resistance promotes glucose-stimulated insulin hypersecretion

Abstract Insulin receptor (Insr) protein can be found at higher levels in pancreatic {beta}-cells than in most other tissues, but the consequences of {beta}-cell insulin resistance remain enigmatic. Ins1cre allele was used to delete Insr specifically in {beta}-cells of both female and male mice. Experimental mice were compared to Ins1cre-containing littermate controls at multiple ages and on multiple diets. RNA-seq of purified recombined {beta}-cells revealed transcriptomic consequences of Insr loss, which differed between female and male mice. Action potential and calcium oscillation frequencies were increased in Insr knockout {beta}- cells from female, but not male mice, whereas only male {beta}InsrKO mice had reduced ATP-coupled oxygen consumption rate and reduced expression of genes involved in ATP synthesis. Female {beta}InsrKO and {beta}InsrHET mice exhibited elevated insulin release in perifusion experiments, during hyperglycemic clamps, and following i.p. glucose challenge. Deletion of Insr did not alter {beta}-cell area up to 9 months of age, nor did it impair hyperglycemia-induced proliferation. Based on our data, we adapted a mathematical model to include {beta}-cell insulin resistance, which predicted that {beta}-cell Insr knockout would improve glucose tolerance depending on the degree of whole-body insulin resistance. Indeed, glucose tolerance was significantly improved in female {beta}InsrKO and {beta}InsrHET mice when compared to controls at 9, 21 and 39 weeks, and also in insulin-sensitive 4-week old males. We did not observe improved glucose tolerance in older male mice or in high fat diet-fed mice, corroborating the prediction that global insulin resistance obscures the effects of {beta}-cell specific insulin resistance. The propensity for hyperinsulinemia was associated with mildly reduced fasting glucose and increased body weight. We further validated our main in vivo findings using the Ins1-CreERT transgenic line and found that male mice had improved glucose tolerance 4 weeks after tamoxifen-mediated Insr deletion. Collectively, our data show that loss of {beta}-cell Insr contributes to glucose-induced hyperinsulinemia, thereby improving glucose homeostasis in otherwise insulin sensitive dietary and age contexts.

physiology↗

bioRxiv2019

Ins2 gene bursting activity defines a mature beta-cell state

Transcriptional and functional cellular specialization has been described for insulin-secreting {beta}-cells of the endocrine pancreas. However, it is not clear whether {beta}-cell heterogeneity is stable or reflects dynamic cellular states. We investigated the temporal kinetics of endogenous insulin gene activity using live cell imaging, with complementary experiments employing FACS and single cell RNA sequencing, in {beta}-cells from Ins2GFP knock-in mice. In vivo staining and FACS analysis of islets from Ins2GFP mice confirmed that at a given moment, ~25% of {beta}-cells exhibited significantly higher activity at the conserved insulin gene Ins2. Live cell imaging captured Ins2 gene activity dynamics in single {beta}-cells over days. Autocorrelation analysis revealed a subset of cells with oscillating behavior, with mean oscillation periods of 17 hours. Increased glucose concentrations stimulated more cells to oscillate and resulted in higher average Ins2 gene activity per cell. Single cell RNA sequencing showed that Ins2(GFP)HIGH {beta}-cells were enriched for markers of {beta}-cell maturity. Ins2(GFP)HIGH {beta}-cells were also significantly less viable at all glucose concentrations and in the context of ER stress. Collectively, our results demonstrate that the heterogeneity of insulin production, observed in mouse and human {beta}-cells, can be accounted for by dynamic states of insulin gene activity. BlurbPreviously reported pancreatic {beta}-cell heterogeneity reflects {beta}-cell state transitions.

cell biology↗