Biology subjects

Chakraborty, P.

Publications and source records attributed to Chakraborty, P..

At least 19 recordsLinked to original sources

bioRxiv2026

Malignant and stromal partial EMT programmes and cetuximab outcome in head and neck cancer

Partial epithelial-to-mesenchymal transition (pEMT) was defined in single malignant cells of head and neck squamous cell carcinoma but is usually scored in bulk tumours. In three single-cell datasets, its laminin-332 and hemidesmosome genes were expressed by malignant cells (the malignant arm) and its fibrillar collagens and vimentin by fibroblasts (the stromal arm). In bulk tumours the stromal arm dominated co-expression, so standard pEMT scores mainly measure stroma. We recovered the malignant arm with a classifier trained on single cells and a 12-gene core. In 40 patients treated with platinum and cetuximab, both malignant measures were higher in those with long progression-free survival (area under the curve 0.78 and 0.82), and the stromal arm was not. The malignant arm was inseparable from the Basal subtype, whose score did as well or better in these patients (0.93) and in two xenograft panels. Bulk pEMT scores should be read by cell of origin.

cancer biology↗

bioRxiv2026

SpinForecast: chain-free probabilistic backbone assignment of intrinsically disordered proteins from NMR chemical shifts

Assigning peaks in NMR spectra to specific residues is an essential but time-consuming step in the study of intrinsically disordered proteins (IDPs). Conventional approaches rely on building chains of sequential connectivities between peaks, which are particularly prone to failure in disordered systems due to spectral overlap, missing peaks, and proline-rich sequences. Here we present SpinForecast, a tool that performs chain-free probabilistic backbone assignment of IDPs from chemical shifts alone, without requiring peaks to be linked into sequential chains. SpinForecast predicts residue-specific chemical shift distributions from a disorder-filtered subset of the Biomolecular Magnetic Resonance Data Bank (BMRB), incorporating nearest-neighbour residue effects and corrections for temperature and pH. Experimental chemical shifts are then assigned to residues by Bayes theorem, using residue-specific chemical shift distributions as likelihoods. We validate SpinForecast on three disordered proteins, IAPP (37 residues), NUPR1 (82 residues), and JPT2 (218 residues), achieving 100% confidence assignments for 74%, 57%, and 44% of in-distribution peaks, respectively, all with at least 99% accuracy. Where single assignments cannot be determined for these systems, the correct assignment was contained within the returned set of candidate assignments in greater than 97% of cases. SpinForecast is freely available at https://tools.bindresearch.org/bindbox/SpinForecast.

biophysics↗

bioRxiv2026

Kinase-specific phosphorylation of tau outside the amyloid core encodes fibril fold selection

Tauopathies are defined by the accumulation of filamentous tau assemblies that adopt disease-specific molecular conformations, or tau strains. Although tau is extensively hyperphosphorylated in Alzheimers disease, how phosphorylation patterns influence tau folding and strain selection remains unclear. Here, we show that site-specific phosphorylation of 0N3R tau by extracellular signal-regulated kinase 2 (ERK2), occurring predominantly within the proline-rich region and largely excluding the microtubule-binding domain, is sufficient to direct tau assembly into a structurally homogeneous fibril conformation. Residue-resolved NMR spectroscopy identifies a defined and quantifiable ERK2 phosphorylation pattern in the proline-rich region of tau. Cryo-electron microscopy at 3.0 [A] resolution reveals that ERK2-phosphorylated 3R tau assembles into filaments with an ordered cross-{beta} fold adopting an Alzheimers disease PHF fold, despite the absence of phospho-sites within the fibril core. These filaments exhibit robust seeding activity in tau biosensor cells. Together, these results demonstrate that kinase-specific phosphorylation outside the amyloid core can be sufficient to bias tau toward a defined fibril structure, establishing a direct mechanistic link between kinase specificity, post-translational modification, and tau strain formation.

molecular biology↗

bioRxiv2026

Dynamic Histone Lysine Methylation and Demethylation in Wood Frog (Rana sylvatica) Liver During Anoxia

Anoxia is a major stress for most vertebrates and frequently accompanies harsh winter conditions, particularly in species that spend much of the season frozen solid. North American freeze-tolerant wood frogs (Rana sylvatica) can survive several months without oxygen and endure whole-body freezing for up to eight months of the year, with [~]70% of total body water frozen as extracellular ice, yet revive when temperatures rise in spring. Survival depends on multiple adaptations, including tolerance of prolonged oxygen deprivation while frozen, when breathing and circulation are halted. A key strategy involves hepatic glycogen mobilization, producing large amounts of glucose that are distributed to tissues where it functions both as a cryoprotectant and as a substrate for anaerobic ATP production. The present study examines the role of histone lysine methylation and demethylation in regulating liver proteins under anoxic conditions. Relative protein expression of seven histone methyltransferases (ASH2L-S, ASH2L-L, RBBP5, SETD8, SMYD2, ESET, SETD1), six lysine demethylases (KDM1A, KDM3B, KDM4A, KDM4B, KDM5A, KDM5C), and eight histone marks (H3K4me1, H3K4me2, H3K9me3, H3K27me3, H3K36me3, H3K79me3, H4K20me1, H4K20me3) were evaluated in wood frog liver under control, 4-hour, and 24-hour anoxia exposures. The data indicate that histone lysine methylation and demethylation contribute significantly to transcriptional regulation under anoxia. Specifically, H3K4, H3K36, and H3K79 methylation were associated with transcriptional activation, whereas H3K9, H3K27, and H4K20 methylation correlated with transcriptional repression. These findings highlight the dynamic role of epigenetic regulation in supporting hypometabolism and stress adaptation in freeze-tolerant wood frogs.

molecular biology↗

bioRxiv2026

Bistability to Quad-stability: Emergence of Hybrid Phenotypes & Enhanced Spatio-temporal Plasticity in Presence of Host-Circuit Coupling

In the context of multistability-driven diseases, like cancer, spatio-temporal plasticity plays a significant role to achieve a spectrum of phenotypic variations. The interplay between gene regulatory networks and environmental factors, such as resource competition and spatial diffusion, plays a crucial role in determining cellular behaviour and phenotypic heterogeneity. Though reaction-diffusion frameworks have been widely applied in developmental biology, less attention has been paid to the simultaneous effects of resource competition and growth feedback on spatial organization. In this paper, we observed that a bistable genetic circuit under high resource competition due to growth feedback gives rise to multiple emergent phenotypes, as observed in cancer systems. Furthermore, we observed how spatial diffusion coupled with intrinsic nonlinearity can drive the emergence of distinct spatial dynamics over time. The observed spatiotemporal plasticity can also be driven by the comparative stability of the fixed points, diffusivity, and asymmetry of diffusion. Our findings highlight that growth-induced resource competition combined with diffusion can provide deeper insights into metastasis and cancer progression.

cancer biology↗

bioRxiv2026

Spatial pattern formation as a consequence of Protease Competition

Exploring the emergence of spatio-temporal patterns due to nonlinearities in gene expression is a relatively new development. In this work, we explore the effect of resource constraint on gene regulatory motif from both equilibrium and spatio-temporal standpoint, taking into consideration the degradation class of resource, protease. We have demonstrated that protease-tagged degradation can cause an emergent bistability to form in the system in a steady-state scenario. Instead of a graded linear response in protein synthesis, two Saddle-node bifurcations caused by protease competition provide a switch-like response with hysteresis, where two drastically differing protein concentrations can coexist. We next turn our attention to spatio-temporal analysis: we extend our study for a two-dimensional sheet of cells with diffusible protein molecules and report the stationary patterns.To investigate the reasons behind these non-homogeneous stationary patterns, we investigate the traveling wave solution and observe that a stationary pattern is formed by the traveling wave solution. Considering that proteases play a major role in the regulation and expression of genes in a variety of diseased scenarios, the repercussions of this spatial patterning caused by protease competition can be extensive in gene regulatory systems.

synthetic biology↗

bioRxiv2026

A generalized scaling law to characterize coordinated brain activity

Complex ecological systems obey universal scaling laws such as Taylors law, which links population variance to the sample mean. Whether other complex systems with integrated and segregated functional networks--such as the human brain--follow analogous scaling laws, and how these laws behave under synchronized activity, remains unknown. Progress has been hindered because neural signals at all measurement scales contain both positive and negative values, whereas Taylors law was developed for non-negative ecological data. Here we introduce a generalized spatial scaling law that replaces the sample mean with the root-mean-square (RMS) of detrended activity, extending Taylor-like scaling to signed multivariate time series in neural and other complex systems. Within this framework, we quantify synchrony using a dedicated metric of functional coordination and show analytically, and via numerical simulations using multivariate Poisson, binomial, uniform and gamma distributions, that the scaling exponent is inversely related to synchrony. Applying this approach to human fMRI data from three large lifespan cohorts (N = 840, ages 18-88) reveals distinct age-related trajectories of the scaling exponent, with healthy aging characterized by a substantial synchrony-induced reduction in the exponent. The synchrony-scaling relationship remains stable during resting-state activity but progressively shifts during naturalistic tasks across the lifespan, and is particularly strong in limbic, subcortical, and cerebellar subnetworks, indicating preservation at subnetwork levels. Finally, individuals with ADHD exhibit disrupted synchrony-scaling coupling, highlighting the potential clinical and translational utility of this generalized scaling metric.

neuroscience↗

bioRxiv2026

Phosphorylation Protects Oncogenic RAS from LZTR1-Mediated Degradation

Oncogenic KRAS and NRAS mutations are common in hematologic malignancies, but how they signal is less well characterized than in carcinomas. To uncover novel RAS biology and potential therapeutic vulnerabilities, we employed a multi-omics screening approach in multiple myeloma to identify regulators of RAS activity. We report that the phosphatase PP1C dephosphorylates the conserved T148 residue on RAS, which in turn permits LZTR1-dependent proteasomal degradation. Notably, LZTR1 is ineffective against KRAS A146 gain-of-function mutations, which are adjacent to T148 and prevalent in hematologic cancers. Remarkably, we find that KRAS protein is four-fold less stable in hematologic versus carcinoma cells, offering a unique therapeutic opportunity targeting RAS protein stability mechanisms. The kinases PAK1 and PAK2 shield RAS from LZTR1-dependent degradation by phosphorylating T148, and targeting PAK1/2 activity improves RAS-directed therapy. Collectively, our findings reveal a novel regulatory circuit governing RAS stability that is preferentially active in blood cancers and potentially druggable.

cancer biology↗

bioRxiv2025

Scaling of the Bicoid morphogen gradient: the effect of state dependent diffusion

The mechanisms underlying the scaling of the Bicoid morphogen gradient in Drosophila with the embryo size is not clearly understood. We propose a model with a spatially varying diffusion coefficient along the anterior-posterior axis, that is proportional to the nearly periodic spatial distribution of the nucleo-cytoplasmic domains and alternating between regions of fast and slow diffusion. We postulate that for specific interpretation of the heterogeneous environment, where the space available for free diffusion within an energid is assumed to be proportional to the embryo size, a change in the embryo size can lead to a size-dependent scaling of the gradient lengthscale. We further study a two component model with slow and fast diffusing Bicoid, and identify this model to be equivalent to the heterogeneous diffusion model further postulating that the fast-state occupancy which is a measure of the fraction of time spent in the fast diffusing state, should also scale with the embryo size via the energid size. Finally, we incorporate nuclear shuttling into our model to understand the effect of shuttling on the gradient lengthscale and scaling with embryo size. We argue that for the particular case where the degradation within the nucleus is low, nuclear shuttling does not perturb the Bicoid gradient. Our study suggests that scaling of the gradient length scale is possible due to spatial heterogeneity and does not depend on nuclear trapping as suggested previously.

developmental biology↗

bioRxiv2025

Phase separation as a tunable regulator of canonical gene regulatory motifs

Gene regulatory networks govern essential cellular processes such as signal transduction, metabolism, and cell fate control. Within these networks, canonical motifs such as genetic toggle switches and repressilators serve as building blocks that generate bistable and oscillatory behaviors. An open question is how cells regulate the dynamical behavior of such motifs, both in natural contexts and in synthetic systems. Recent studies highlight phase separation of transcription factors (TFs) and nucleic acids as a key organizing principle of intracellular biochemistry. In this work, we explore how phase separation of TFs influences the dynamics of toggle switch and repressilator using mean-field theory and stochastic simulations. Our mean-field analysis reveals that phase separation reshapes motif dynamics by altering fixed-point stability and basin geometry in toggle switch, and by altering oscillatory cycles in repressilator. A key finding for both motifs is that when multiple TFs undergo phase separation, the one with the lowest saturation concentration for phase separation dominates system dynamics. Interestingly, stochastic simulations show that the impact of phase separation on fluctuations (or noise) in the abundance of transcription factors within network motifs is architecture-dependent and sharply contrasts with its buffering effect on noise in the expression of isolated genes. Overall, our results show that biomolecular phase separation acts as a physical principle for tuning stability and noise in gene regulatory networks, providing new insights into cellular decision-making.

biophysics↗

bioRxiv2025

Spatially-resolved Photoproximity Profiling of MYC Identifies a MYC-BAF Liability in Cancer Cells

The c-MYC transcription factor is aberrantly expressed in most human cancers to enhance expression of proliferative gene programs. Owing to its pseudo-ordered structure and reliance on extensive and dynamic protein-protein interactions in distinct transcriptional regulatory complexes, defining context-specific MYC interactors has remained challenging. Therefore, mapping MYC-centered complex topologies in disease relevant models could identify components critical for its function which may serve as therapeutic targets in MYC-driven cancers. Here, we present a matched pair of photoproximity probes coupled with quantitative proteomics which enable context-dependent mapping of protein complex topology inside cells. We applied this spatially resolved, intracellular photoproximity (siPROX) profiling workflow to map MYC interactomes across temporal, spatial and disease-relevant contexts. Basal and inhibitor-treated profiles confirmed interactions with a wide range of known chromatin-associated transcriptional regulatory factors that define the extended MYC transcriptional bubble in live cells. Time-resolved mapping of inhibitor treated cells identified dynamic remodeling of numerous transcriptional regulatory factors and identified several BAF complex members (e.g., PBRM1 and SMARCC1)1 that persist in the presence of bromodomain inhibition. Furthermore, spatial MYC topology maps in small cell lung cancer cells confirmed the presence of BAF complex members under conditions where MYC induced target gene expression, altered cell morphology and enhanced proliferation. Lastly, loss of BAF function via inhibition of SMARCA2/4 ATPase activity resulted in rapid loss of chromatin-bound and nuclear MYC levels, downregulation of MYC-dependent transcripts and MYC-specific cell growth in several cancer cell models. Together, these data highlight the potential for siPROX to identify spatially resolved, dynamic TF interactors and highlight MYC-proximal BAF interactions as a targetable liability to regulate MYC-dependent transcription and proliferation.

cancer biology↗

bioRxiv2025

Molecular Dynamics-Guided Design and Chemoproteomic Profiling of Covalent Kinase Activity Probes

Covalent small molecule activity probes can be powerful tools to interrogate protein function in native cellular environments. The design of family-wide activity probes requires an understanding of the molecular sources of general targeting potential and specificity to enable broad targeting of protein family members. Here, we developed and applied a multifaceted docking and molecular dynamics (MD) simulation pipeline to design and test cell-permeable covalent kinase activity probes from a set of hinge-binding pharmacophores. This computationally-guided approach yielded a new cell-active probe, K60P, which targets around 114 kinases across distinct kinase classes in live cells. Chemoproteomic profiling of this probe and a clinical candidate sharing the same indazole core, KW-2449, identified kinase and non-kinase target profiles that differ from recombinant protein assay profiles, underscoring the utility of native kinase profiling in situ. Biochemical studies with a model target kinase, ABL1, confirmed covalent labeling of the active site lysine across several kinase probes with distinct kinetics, as well as covalent labeling of key tyrosines in trans between ABL1 monomers. Finally, focused proteomics, kinetic modeling, and molecular dynamics simulations revealed that K60P, as well as the comparator probe XO44, preferentially engage with target kinases in their active, DFG-in conformations, which is driven by increasing population of reaction-ready small molecule conformation. These results together establish a computational and kinetic modeling framework for designing covalent activity probes and highlight the balance of target selectivity and kinetic efficiency as a key factor in determining their proteome-wide reactivity. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=155 SRC="FIGDIR/small/683178v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@1ea3e5forg.highwire.dtl.DTLVardef@1a4e999org.highwire.dtl.DTLVardef@1e468c3org.highwire.dtl.DTLVardef@99e04e_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2025

Right-Lateralized Maladaptive Topological Reorganization in Hyperthyroidism

Hyperthyroidism (HT) has been associated with cognitive impairments, but the structural connectomic and molecular mechanisms underlying these deficits remain poorly understood. In this study, we investigated large-scale brain network reorganization using structural connectivity derived from diffusion MRI in patients with 30 hyperthyroidism and 28 matched control participants. Subject level connectomes were analyzed to characterize network topology, with a specific focus on hub architecture, nodal alterations, and hemispheric reorganization. To probe molecular underpinnings, we integrated normative neurotransmitter receptor and transporter density maps with network metrics, assessing their correspondence to observed connectomic disruptions. Individuals with hyperthyroidism exhibited increased structural connectivity, particularly in mid- and long-range connections, alongside disrupted network topology. These changes were characterized by reduced modularity, increased characteristic path length and hub reorganization, most prominently in subcortical and right-hemisphere regions. Importantly, network alterations were functionally relevant, as metrics showed significant associations with clinical and cognitive variables, including FT4 levels, BMI, and perceptuomotor performance in the hyperthyroid group. Spatial neuromolecular correspondence analyses further revealed that DAT, 5-HT2A, and NET were closely aligned with topological changes. Moreover, neurotransmitter-weighted within-module degree z-scores moderately predicted TSH levels in HT. Our findings demonstrate that hyperthyroidism is associated with an increase in redundant, spatially extended white matter connections and a marked right-lateralized asymmetry in network organization. Furthermore, serotonergic (5-HT1a) and dopaminergic (DAT) systems consistently contributed to the modulation of intra-modular hubness, suggesting their role in maladaptive structural reorganization that may underlie perceptuomotor dysfunction in hyperthyroidism.

neuroscience↗

bioRxiv2025

ARP2/3 complex mediates the neuropathology of PTEN-deficient human neural cells downstream of mTORC1 and mTORC2 hyperactivation

Mutations in the phosphatase and tensin homolog (PTEN) gene are linked to severe neurodevelopmental disorders. Loss of PTEN causes hyperactivation of both mechanistic target of rapamycin (mTOR) complexes, mTORC1 and mTORC2. Recent studies have shown that this dual hyperactivation is required for the neuropathology observed in PTEN-deficient human stem cell-derived neural cells. However, the molecular effectors that integrate these synergistic signals remain unknown. Here, we identify the actin-regulating ARP2/3 complex as a critical point of convergence downstream of mTORC1 and mTORC2. We show that concurrent hyperactivation of both complexes drives increased filamentous actin and elevated levels of the ARP2/3 complex subunits in PTEN-deficient human neural precursors and neurons. Pharmacological or genetic inhibition of ARP2/3 is sufficient to rescue multiple disease-relevant phenotypes, including neural precursor hyperproliferation, neuronal hypertrophy, and electrical hyperactivity, without affecting the upstream mTORC1 or mTORC2 hyperactivation. Together, these findings reveal the PTEN-mTOR-ARP2/3 signaling axis as a core mechanism of neuropathology and highlight ARP2/3 inhibition as a potential therapeutic strategy for PTEN-related neurodevelopmental disorders.

neuroscience↗

bioRxiv2025

Local homeostasis preserves global neural dynamics compensating for structural loss during human lifespan aging

Aging brain undergoes a structural decline over lifespan accompanied by changes in neurotransmitter levels, leading to altered functional markers. Past studies have reported human resting state brain display a remarkable preservation of coordination among neural assemblies stemming from an underlying neuro-computational principles along aging trajectories, however, the true nature of which remains unknown. Here, we identify the computational mechanisms with which neurotransmitters, such as altered GABA and glutamate concentrations, can preserve functional integration across lifespan aging, despite structural decline. We employ multiscale, biophysically grounded modeling, constrained by the empirically derived anatomical connectome of the human brain, where the neurotransmitter concentrations can be free parameters that are algorithmically adjusted to maintain regional homeostasis and optimal working point. The two estimated neurotransmitters can maintain critical firing rates in the brain region and mimic age-associated functional connectivity patterns, consistent with empirical observations. We identified invariant GABA and reduced glutamate as the principle computational mechanism that can explain the topological variation of functional connectivity along lifespan, validated using graph-theoretic metrics. The results are subsequently replicated on three distinct datasets. Thus, the study offers an operational framework that integrates brain network dynamics at macroscopic and molecular scales, to gain insight into age-associated neural disorders.

neuroscience↗

bioRxiv2025

Gut transit and gut microbiome changes occur prior to the onset of motor impairment in a mouse model of Machado-Joseph disease

We previously identified microbial shifts prior to the onset of motor and neurological symptoms within a mouse model of the fatal neurodegenerative disease Machado-Joseph disease (MJD). Here, we aimed to explore possible mechanisms contributing to these changes within the microbiome-gut-brain axis, and whether it preceded or followed central neurodegeneration. Here, we report that pre-symptomatic male MJD mice present with significantly different microbiome communities as early as 5-weeks-old. Furthermore, we show that male MJD mice have faster total gut transit times by 9-weeks-old, prior to signs of impaired motor function by 11-weeks-old. To elucidate whether these microbial and colonic functional changes are due to the presence of pathological and morphological changes in the gut, we quantified the formation of ataxin-3 protein aggregates within the gut and examined morphological changes within the gut of pre- and early symptomatic MJD mice relative to proteinopathy in the brain. Interestingly, we observed ataxin-3 aggregates within the brains of pre-symptomatic MJD mice, with significantly more aggregates present in MJD than WT mice from 7-weeks-of-age, an earlier timepoint than previously reported, coinciding with changes within the microbiome. However, we observed no ataxin-3 protein aggregates and no changes in enteric neuron populations or morphology within the gut. Analysis of endocrine factors involved in gut motility and inflammatory markers within the small intestine of 13-week-old males revealed increased expression of genes encoding cholecystokinin (Cck), ghrelin (Ghrl), heme oxygenase (Ho1), interleukin-1 beta (Il1b), and decreased inducible nitric oxide synthase (Nos2). Together, we demonstrate for the first time that colonic dysfunction occurs after gut microbiome changes, but prior to the onset of motor impairments in male MJD mice. Our work suggests that whilst proteinopathy or morphological changes within the gut may not be involved in these changes, inflammation and related endocrine changes could have a role in the interplay between the gut and brain during MJD development, warranting further investigation.

neuroscience↗

bioRxiv2025

Alpha-1 Antitrypsin Overexpressing Mesenchymal Stem/Stromal Cells Reverses Type 1 Diabetes via Promoting Treg Function and CD8+ T cell exhaustion

Mesenchymal stem/stromal cell (MSC) therapy holds great promise as both a therapeutic option and as a biofactory, as cells produce therapeutic proteins to augment their efficacy in disease treatment. This study investigates the therapeutic effects and the mechanistic insights of alpha-1 antitrypsin overexpressing MSCs (AAT-MSCs) in diabetes prevention and treatment. A single infusion of AAT-MSCs not only delayed diabetes onset but reversed new-onset type 1 diabetes (T1D) in the nonobese diabetic (NOD) mice. Using single-cell RNA sequencing, flow cytometry, and functional analyses, we characterized the impact of AAT-MSCs on immune cells, particularly CD4+ and CD8+ T cells, in pancreatic lymph nodes (PLNs) and islets of NOD mice. AAT-MSCs enhanced the immunosuppressive function and the communication of regulatory T cells (Tregs) with other immune cells while reducing the numbers of T helper 1 (Th1) cells and CD8+ cytotoxic T cells. In vitro experiments further confirmed the capacity of AAT-MSCs to promote the proliferation of Tregs, which consequently fostered an exhausted phenotype in CD8+ T cells, thereby facilitating {beta} cell survival and potentially aiding in diabetes remission. Thus, our findings underscore the significant protective effects of AAT-MSCs, delineate their novel mechanistic insight on recipient immune cells, and provide evidence for the clinical application of AAT-MSCs in treating T1D.

cell biology↗

bioRxiv2025

Feeding-fasting cycle of obesogenic food determines glucocorticoid neuromodulation of cortico-hippocampal activities sustaining long-term memory

BackgroundHighly caloric food consumed around the clock perturbs the metabolism and cognitive functioning. We hypothesized that obesogenic food could alter neuronal representations of memory depending on the feeding-fasting cycle. MethodsWe tracked memory performance, dendritic spine dynamics and neuronal representations of memory in C57Bl6J mice fed obesogenic food ad libitum from peri-adolescence. We aimed to correct energy rich diet-induced plasticity deficits and cognitive impairment with time-restricted feeding in males and females. We further used chemogenetics, pharmacology and knock-in mice to investigate functional correlates underlying diet-induced neurocognitive impairments. ResultsWe find that changes in the feeding-fasting cycle reverted the effects of ad libitum obesogenic food on memory impairment in both sexes (n=55, p=0.003). Concurrently, it also corrected the increased dendritic spine maintenance and neuroactivity in hippocampus and the decreased spine maintenance and activity in parietal cortex (n=48, p<0.005). Bi-directional effects in cortex and hippocampus mediated by glucocorticoid signalling are causal to behavioural changes (n=91, p=0.0008), and scaling hippocampal with cortical activities restored memory in mice fed obesogenic food (n=44, p=0.02). ConclusionThese results indicate that meal scheduling is a promising approach to confront glucocorticoid signalling bias and memory deficits caused by obesogenic food. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWhat and when we eat contributes to our health. This is particularly worrisome for kids and adolescents because of the lifelong effects that unrestricted snacking on highly caloric food could cause on brain maturation. A variety of school policies and nutritional programs have emerged to prevent poor nutritional habits. But obesity is on the rise and a major cause of neurological disabilities difficult to detect and treat. Human studies are limited by the size and duration of sampling with low resolution metrics to prove causality between nutritional habits and cognitive health trajectory. Animal studies showed that all-day snacking on highly caloric food disrupts innate biological rhythms that influence hormonal secretions, neuronal structure and function in brain regions that encode, store and retrieve memories. It isnt known if, like adipocytes and hepatocytes, the brain in obesity can develop glucocorticoid resistance -a state that would prevent the robust but complex effects of this hormone on memory- to the point that researchers still question whether glucocorticoids are a cause or solution to obesity related-brain comorbidities. Added value of this studyLongitudinal sampling of several metrics at multiple timepoints in mice fed highly caloric food since peri-adolescence up to adulthood showed that the trajectory of obesity-related brain comorbidities is corrected when reinstating the feeding/fasting cycle, albeit consuming highly caloric food. Glucocorticoid resistance -manifesting as receptor phosphorylation deficits impeding coincidence detection between glucocorticoid and neuronal activities -was reversible when reinstating the feeding/fasting cycle, albeit consuming highly caloric food. Studies in receptor mutant mice lacking a phosphorylation site-independent of glucocorticoids showed it is required to reinstate neuroplasticity to changes of feeding/fasting cycle, albeit consuming highly caloric food. Fos-trapping experiments showed less engagement of pyramidal neurons in the cortex when activity-dependent phosphorylation of glucocorticoid receptor was low, and more in the hippocampus of mice fed obesogenic diet, which reinstating the feeding/fasting cycle reverted, albeit consuming highly caloric food. Finally, chemogenetic experiments confirmed the requirement for the co-engagement of cortical and hippocampal pyramidal neurons to fully remember, despite poor nutritional habits. Implications of all the available evidenceThe cortico-hippocampal activities necessary for remembering are uncoupled by obesogenic food consumed ad libitum but not on meal scheduling, extending neuroimaging correlation studies in obese adolescents. Poor nutritional habits cause glucocorticoid resistance in the brain as previously suggested, with altered neuronal representation of memory that meal scheduling corrected. This result should transform school policies and familial nutritional habits to promote cognitive health. Future research will develop allosteric ligands targeting phosphorylation motifs in the glucocorticoid receptor as more specific alternative to orthosteric ligands for the treatment of obesity-related brain comorbidities.

neuroscience↗