Biology subjects

Sahay, A.

Publications and source records attributed to Sahay, A..

10 recordsLinked to original sources

bioRxiv2025

Neotenic expansion of adult-born dentate granule cells reconfigures GABAergic inhibition to enhance social memory consolidation

Adult-born dentate granule cells (abDGCs) contribute to hippocampal dentate gyrus (DG)-CA3/CA2 circuit functions in memory encoding, retrieval and consolidation. Heightened synaptic and structural plasticity of immature abDGCs is thought to govern their distinct contributions to circuit and network mechanisms of hippocampal-dependent memory operations. Protracted maturation or neoteny of abDGCs in higher mammals is hypothesized to offset decline in adult hippocampal neurogenesis by expanding the capacity for circuit and network plasticity underlying different memory operations. Here, we provide evidence for this hypothesis by genetically modelling the effective impact of neoteny of abDGCs on circuitry, network properties and social cognition in mice. We show that selective synchronous expansion of a single cohort of 4 weeks old immature, but not 8 weeks old mature abDGCs, increases functional recruitment of fast spiking parvalbumin expressing inhibitory interneurons (PV INs) in CA3/CA2, number of PV IN-CA3/CA2 synapses, and GABAergic inhibition of CA3/CA2. This transient increase in feed-forward inhibition in DG-CA2 decreased social memory interference and enhanced social memory consolidation. In vivo local field potential recordings revealed that the expansion of a single cohort of 4-week-old abDGCs increased baseline power, amplitude, and duration, as well as sensitivity to social investigation-dependent rate changes of sharp-wave ripples (SWRs) in CA1 and CA2, a neural substrate for memory consolidation. Inhibitory neuron-targeted chemogenetic manipulations implicate CA3/CA2 INs, including PV INs, as necessary and sufficient for social memory consolidation following neotenic expansion of the abDGC population and in wild-type mice, respectively. These studies suggest that neoteny of abDGCs may represent an evolutionary adaptation to support cognition by reconfiguring PV IN-CA3/CA2 circuitry and emergent network properties underlying memory consolidation.

neuroscience↗

bioRxiv2024

A dorsal hippocampus-prodynorphinergic dorsolateral septum-to-lateral hypothalamus circuit mediates contextual gating of feeding

Adaptive regulation of feeding depends on linkage of internal states and food outcomes with contextual cues. Human brain imaging has identified dysregulation of a hippocampal-lateral hypothalamic area (LHA) network in binge eating, but mechanistic instantiation of underlying cell-types and circuitry is lacking. Here, we identify an evolutionary conserved and discrete Prodynorphin (Pdyn)-expressing subpopulation of Somatostatin (Sst)-expressing inhibitory neurons in the dorsolateral septum (DLS) that receives primarily dorsal, but not ventral, hippocampal inputs. DLS(Pdyn) neurons inhibit LHA GABAergic neurons and confer context- and internal state-dependent calibration of feeding. Viral deletion of Pdyn in the DLS mimicked effects seen with optogenetic silencing of DLS Pdyn INs, suggesting a potential role for DYNORPHIN-KAPPA OPIOID RECEPTOR signaling in contextual regulation of food-seeking. Together, our findings illustrate how the dorsal hippocampus has evolved to recruit an ancient LHA feeding circuit module through Pdyn DLS inhibitory neurons to link contextual information with regulation of food consumption. HIGHLIGHTSO_LIDLS(Pdyn) neurons receive dense input from the dorsal but not ventral hippocampus C_LIO_LIDLS(Pdyn) neurons inhibit GABAergic neurons in the LHA C_LIO_LISilencing dorsal hippocampus-DLS(Pdyn)-LHA circuit nodes abolishes context-conditioned feeding C_LIO_LIPdyn in the DLS is necessary for context-conditioned feeding C_LI

neuroscience↗

bioRxiv2024

An aging-sensitive compensatory secretory phospholipase that confers neuroprotection and cognitive resilience

Breakdown of lipid homeostasis is thought to contribute to pathological aging, the largest risk factor for neurodegenerative disorders such as Alzheimers Disease (AD). Cognitive reserve theory posits a role for compensatory mechanisms in the aging brain in preserving neuronal circuit functions, staving off cognitive decline, and mitigating risk for AD. However, the identities of such mechanisms have remained elusive. A screen for hippocampal dentate granule cell (DGC) synapse loss-induced factors identified a secreted phospholipase, Pla2g2f, whose expression increases in DGCs during aging. Pla2g2f deletion in DGCs exacerbates aging-associated pathophysiological changes including synapse loss, inflammatory microglia, reactive astrogliosis, impaired neurogenesis, lipid dysregulation and hippocampal-dependent memory loss. Conversely, boosting Pla2g2f in DGCs during aging is sufficient to preserve synapses, reduce inflammatory microglia and reactive gliosis, prevent hippocampal-dependent memory impairment and modify trajectory of cognitive decline. Ex vivo, neuronal-PLA2G2F mediates intercellular signaling to decrease lipid droplet burden in microglia. Boosting Pla2g2f expression in DGCs of an aging-sensitive AD model reduces amyloid load and improves memory. Our findings implicate PLA2G2F as a compensatory neuroprotective factor that maintains lipid homeostasis to counteract aging-associated cognitive decline.

neuroscience↗

bioRxiv2024

Distinct mechanisms of non-autonomous UPRER mediated by GABAergic, glutamatergic, and octopaminergic neurons.

The capacity to deal with stress declines during the aging process, and preservation of cellular stress responses is critical to healthy aging. The unfolded protein response of the endoplasmic reticulum (UPRER) is one such conserved mechanism, which is critical for the maintenance of several major functions of the ER during stress, including protein folding and lipid metabolism. Hyperactivation of the UPRER by overexpression of the major transcription factor, xbp-1s, solely in neurons drives lifespan extension as neurons send a neurotransmitter-based signal to other tissue to activate UPRER in a non-autonomous fashion. Previous work identified serotonergic, dopaminergic, and tyraminergic neurons in this signaling paradigm. To further expand our understanding of the neural circuitry that underlies the non-autonomous signaling of ER stress, we activated UPRER solely in glutamatergic, octopaminergic, and GABAergic neurons in C. elegans and paired whole-body transcriptomic analysis with functional assays. We found that UPRER-induced signals from glutamatergic neurons increased expression of canonical protein homeostasis pathways and octopaminergic neurons promoted pathogen response pathways; while minor, statistically significant changes were observed in lipid metabolism-related genes with GABAergic UPRER activation. These findings provide further evidence for the distinct role neuronal subtypes play in driving the diverse response to ER stress.

cell biology↗

bioRxiv2024

Single-Cell multiomics reveals ENL mutation perturbs kidney developmental trajectory by rewiring gene regulatory landscape

Cell differentiation during organogenesis relies on precise epigenetic and transcriptional control. Disruptions to this regulation can result in developmental abnormalities and malignancies, yet the underlying mechanisms are not well understood. Wilms tumors, a type of embryonal tumor closely linked to disrupted organogenesis, harbor mutations in epigenetic regulators in 30-50% of cases. However, the role of these regulators in kidney development and pathogenesis remains unexplored. By integrating mouse modeling, histological characterizations, and single-cell transcriptomics and chromatin accessibility profiling, we show that a Wilms tumor-associated mutation in the chromatin reader protein ENL disrupts kidney development trajectory by rewiring the gene regulatory landscape. Specifically, the mutant ENL promotes the commitment of nephron progenitors while simultaneously restricting their differentiation by dysregulating key transcription factor regulons, particularly the HOX clusters. It also induces the emergence of abnormal progenitor cells that lose their chromatin identity associated with kidney specification. Furthermore, the mutant ENL might modulate stroma-nephron interactions via paracrine Wnt signaling. These multifaceted effects caused by the mutation result in severe developmental defects in the kidney and early postnatal mortality in mice. Notably, transient inhibition of the histone acetylation binding activity of mutant ENL with a small molecule displaces transcriptional condensates formed by mutant ENL from target genes, abolishes its gene activation function, and restores developmental defects in mice. This work provides new insights into how mutations in epigenetic regulators can alter the gene regulatory landscape to disrupt kidney developmental programs at single-cell resolution in vivo. It also offers a proof-of-concept for the use of epigenetics-targeted agents to rectify developmental defects.

cancer biology↗

bioRxiv2023

An inhibitory circuit-based enhancer of Dyrk1a function reverses Dyrk1a-associated impairment insocial recognition

Heterozygous mutations in the Dual specificity tyrosine-phosphorylation-regulated kinase 1a Dyrk1a gene define a syndromic form of Autism Spectrum Disorder. The synaptic and circuit mechanisms mediating Dyrk1a functions in social cognition are unclear. Here, we identify a social experience-sensitive mechanism in hippocampal mossy fiber-parvalbumin interneuron (PV IN) synapses by which Dyrk1a recruits feedforward inhibition of CA3 and CA2 to promote social recognition. We employ genetic epistasis logic to identify a cytoskeletal protein, Ablim3, as a synaptic substrate of Dyrk1a. We demonstrate that Ablim3 downregulation in dentate granule cells of adult hemizygous Dyrk1a mice is sufficient to restore PV IN mediated inhibition of CA3 and CA2 and social recognition. Acute chemogenetic activation of PV INs in CA3/CA2 of adult hemizygous Dyrk1a mice also rescued social recognition. Together, these findings illustrate how targeting Dyrk1a synaptic and circuit substrates as "enhancers of Dyrk1a function" harbors potential to reverse Dyrk1a haploinsufficiency-associated circuit and cognition impairments. HighlightsDyrk1a in mossy fibers recruits PV IN mediated feed-forward inhibition of CA3 and CA2 Dyrk1a-Ablim3 signaling in mossy fiber-PV IN synapses promotes inhibition of CA3 and CA2 Downregulating Ablim3 restores PV IN excitability, CA3/CA2 inhibition and social recognition in Dyrk1a+/- mice Chemogenetic activation of PV INs in CA3/CA2 rescues social recognition in Dyrk1a+/- mice

neuroscience↗

bioRxiv2022

Cell non-autonomous control of autophagy and metabolism by glial cells

Glia are the protectors of the nervous system, providing neurons with support and protection from cytotoxic insults. We previously discovered that four astrocyte-like glia can regulate organismal proteostasis and longevity in C. elegans. Expression of the UPRER transcription factor, XBP-1s, in these glia increases stress resistance, longevity, and activates the UPRER in intestinal cells via neuropeptides. Autophagy, a key regulator of metabolism and aging, has been described as a cell autonomous process. Surprisingly, we find that glial XBP-1s enhances proteostasis and longevity by cell non-autonomously reprogramming organismal lipid metabolism and activating autophagy. Glial XBP-1s regulates the activation of another transcription factor, HLH-30/TFEB, in the intestine. HLH-30 activates intestinal autophagy, increases intestinal lipid catabolism, and upregulates a robust transcriptional program. Our study reveals a novel role for glia in regulating peripheral lipid metabolism, autophagy, and organellar health through peripheral activation of HLH-30 and autophagy.

neuroscience↗

bioRxiv2021

Transcriptional regulation of neural stem cell expansion in adult hippocampus

Experience governs neurogenesis from radial-glial neural stem cells (RGLs) in the adult hippocampus to support memory. Transcription factors in RGLs integrate physiological signals to dictate self-renewal division mode. Whereas asymmetric RGL divisions drive neurogenesis during favorable conditions, symmetric divisions prevent premature neurogenesis while amplifying RGLs to anticipate future neurogenic demands. The identities of transcription factors regulating RGL symmetric self-renewal, unlike those that regulate RGL asymmetric self-renewal, are not known. Here, we show that the transcription factor Kruppel-like factor 9 (Klf9) is elevated in quiescent RGLs and inducible, deletion of Klf9 promotes RGL activation state. Clonal analysis and longitudinal intravital 2-photon imaging directly demonstrate that Klf9 functions as a brake on RGL symmetric self-renewal. In vivo translational profiling of RGLs lacking Klf9 generated a blueprint of RGL symmetric self-renewal for stem cell community. Together, these observations identify Klf9 as a transcriptional regulator of neural stem cell expansion in the adult hippocampus.

neuroscience↗

bioRxiv2021

A dentate gyrus-CA3 inhibitory circuit promotes evolution of hippocampal-cortical ensembles during memory consolidation

Memories encoded in the dentate gyrus (DG) - CA3 circuit of the hippocampus are routed from CA1 to anterior cingulate cortex (ACC) for consolidation. Although CA1 parvalbumin inhibitory neurons (PV INs) orchestrate hippocampal-cortical communication, we know less about CA3 PV INs or DG - CA3 principal neuron - IN circuit mechanisms that contribute to evolution of hippocampal-cortical ensembles during memory consolidation. Using viral genetics to selectively mimic and boost an endogenous learning-dependent circuit mechanism, DG cell recruitment of CA3 PV INs and feed-forward inhibition (FFI) in CA3, in combination with longitudinal in vivo calcium imaging, we demonstrate that FFI facilitates formation and maintenance of context-associated neuronal ensembles in CA1. Increasing FFI in DG - CA3 promoted context specificity of neuronal ensembles in ACC over time and enhanced long-term contextual fear memory. In vivo LFP recordings in mice with increased FFI in DG - CA3 identified enhanced CA1 sharp-wave ripple - ACC spindle coupling as a potential network mechanism facilitating memory consolidation. Our findings illuminate how FFI in DG - CA3 dictates evolution of ensemble properties in CA1 and ACC during memory consolidation and suggest a teacher-like function for hippocampal CA1 in stabilization and re-organization of cortical representations.

neuroscience↗

bioRxiv2019

Variational Autoencoder Modular Bayesian Networks (VAMBN) for Simulation of Heterogeneous Clinical Study Data

In the area of Big Data one of the major obstacles for the progress of biomedical research is the existence of data \"silos\", because legal and ethical constraints often do not allow for sharing sensitive patient data from clinical studies across institutions. While federated machine learning now allows for building models from scattered data, there is still the need to investigate, mine and understand clinical data that cannot be accessed directly. Simulation of sufficiently realistic virtual patients could be a way to fill this gap.\n\nIn this work we propose a new machine learning approach (VAMBN) to learn a generative model of longitudinal clinical study data. VAMBN considers typical key aspects of such data, namely limited sample size coupled with comparable many variables of different numerical scales and statistical properties, and many missing values. We show that with VAMBN we can simulate virtual patients in a sufficiently realistic manner while making theoretical guarantees on data privacy. In addition, VAMBN allows for simulating counterfactual scenarios. Hence, VAMBN could facilitate data sharing as well as design of clinical trials.

bioinformatics↗