Biology subjects

Grossman, S.

Publications and source records attributed to Grossman, S..

10 recordsLinked to original sources

bioRxiv2026

Classification of image category based on spatially distributed, transient high-frequency events

Transient high-frequency activity (HFA) in local field potentials exhibits substantial variability across trials and behavioral states, yet its functional role in sensory representation remains poorly understood. Here, we tested whether transient HFA events carry stimulus-related information through their temporal, spectral, and phase-dependent properties. Using intracranial recordings from 21 human participants performing a visual localizer task, we extracted transient HFA events and quantified their features using information-theoretic and decoding analyses. Individual event features carried only modest information about stimulus identity, and response magnitude and morphology-related properties contributed minimally to decoding performance. Instead, decoding was dominated by temporal alignment and low-frequency phase. Critically, representing transient events as distributed low-frequency phase configurations across electrodes substantially improved cross-trial decoding performance, whereas disrupting distributed phase structure eliminated this decoding advantage. These findings indicate that stimulus-related structure in transient HFA does not primarily arise from isolated local event properties, but instead emerges through distributed, phase-dependent network dynamics. More broadly, the results provide a framework for understanding how transient high-frequency neural activity contributes to sensory representations across distributed cortical networks.

neuroscience↗

bioRxiv2025

The developing tendon and enthesis are hypoxic and rely on hypoxia-inducible factor 1a (Hif1a) during postnatal development

The tendon-bone enthesis is a specialized fibrocartilaginous tissue crucial for muscle-to-bone force transmission, yet its postnatal development is not fully understood. Emerging evidence suggests hypoxia plays a pivotal role in enthesis maturation akin to its function in skeletal growth plates, with Hypoxia Inducible Factor 1 alpha (HIF-1) acting as a key regulator of cellular adaptation (e.g., cell survival, extracellular matrix (ECM) deposition). Here, we investigated the spatial and temporal dynamics of hypoxia in the murine Achilles tendon enthesis and elucidated the role of Hif1a in enthesis cell survival and ECM formation using Scleraxis-lineage conditional knockout (ScxCre; Hif1a cKO) mice. We found that while neonatal tendons rapidly resolve hypoxia after birth, the enthesis maintains a hypoxic niche through postnatal day 5, mirroring a gradient observed in growth plates. Disruption of HIF-1 in enthesis-resident cells resulted in pronounced deficits in grip strength, abnormal tendon-bone attachment morphology, disrupted calcaneal architecture, impaired mineralization, and significant ECM disorganization. Histological analyses revealed persistent cell death and loss of the characteristic fibrocartilaginous gradient in cKO entheses, including dysregulated collagen alignment. In vitro, HIF-1-deficient tendon fibroblasts exhibited blunted transcriptional responses to hypoxia, altered metabolic gene expression, and changes in ECM deposition. Collectively, our findings illuminate hypoxia as a sustained niche in the postnatal enthesis, with HIF-1 critically required for cell survival, ECM organization, and enthesis structural integrity. This work advances our understanding of enthesis biology and provides insights relevant to tendon-bone attachment disorders and regenerative strategies.

developmental biology↗

bioRxiv2025

Neural replay is connected to latent cause inference and supports fast generalization

Dynamic environments require generalizing knowledge through two computational mechanisms: Inferring clusters of equivalent observations and propagating reward expectations within a cluster. While neural replay has been linked to both, past work has not studied these processes simultaneously, leaving their relative importance for replay unclear. We used fMRI and computational modeling to investigate latent cause inference and replay in 52 participants during a value-based task with shared rewards across bandits. Participants learned this structure and achieved one-shot generalization after reversals, consistent with a latent cause inference process. fMRI during predecision pauses revealed backwards replay of shared-reward bandits in the visual cortex and medial temporal lobe. Trial-wise fluctuations in visual replay strength and content were better explained by value updates than by structure learning. Conversely, abstract reward structure representations were localized specifically to the MTL. These results demonstrate that on-task replay serves reward propagation within learned latent structures to facilitate fast generalization.

neuroscience↗

bioRxiv2025

AMPK signaling is dysregulated in human tendinopathy and loss of AMPKα1 leads to cell, matrix and mechanical dysfunction in mouse Achilles tendon

Tendinopathy is a debilitating tendon disorder affecting millions of people, characterized by pain, swelling, and diminished biomechanical properties. While the precise mechanisms underlying tendon homeostasis remain unclear, metabolic regulation plays a critical role. In this study, we combine transcriptomic analysis of human tendinopathic samples with a conditional mouse model in which Prkaa1 (encoding AMPK1) is selectively deleted in tendon progenitors to elucidate the role of AMPK signaling in tendon homeostasis. RNA sequencing of diseased human tendons revealed downregulation of key metabolic genes, including several involved in the mitochondrial electron transport chain and AMPK signaling pathways, alongside an increase in markers associated with senescence and a secretory inflammatory profile. In parallel, mice with loss of Prkaa1 function exhibited normal postnatal development; however, by one month of age, tendons demonstrated widespread transcriptional alterations related to cell cycle regulation and ECM organization. By three months, AMPK1-deficient tendons showed significant reductions in mechanical strength and increased expression of senescence markers p21 and p16, progressing to prominent ectopic calcification with age. In vitro studies further confirmed that tendon fibroblasts lacking AMPK1 have altered ECM substrate adhesion profiles. Importantly, voluntary exercise partially rescued these deficits by enhancing ECM organization and reducing senescence marker expression. Collectively, our findings demonstrate that AMPK1 is critical for maintaining energy balance, regulating ECM remodeling, and preventing premature cellular senescence in tendon. These insights highlight AMPK signaling as a promising therapeutic target and underscore the beneficial role of exercise in mitigating tendinopathic changes.

pathology↗

bioRxiv2024

Functional Changes to Achilles Tendon and Enthesis in a Mouse Model of an Adolescent Masculine Gender-Affirming Hormone Treatment

Many transgender youth seek gender affirming care, such as puberty suppression, to prolong decision-making and to align their physical sex characteristics with their gender identity. During peripubertal growth, connective tissues such as tendon rapidly adapt to applied mechanical loads (e.g., exercise) yet if and how tendon adaptation is influenced by sex and gender affirming hormone therapy during growth remains unknown. The goal of this study was to understand the how pubertal suppression influences the structural and functional properties of the Achilles tendon using an established mouse model of transmasculine gender affirming hormone therapy. C57BL/6N female-born mice were assigned to experimental groups to mimic gender-affirming hormone therapy in human adolescents, and treatment was initiated prior to the onset of puberty (at postnatal day 26, P26). Experimental groups included controls and mice serially treated with gonadotropin release hormone analogue (GnRHa), delayed Testosterone (T), or GnRHa followed by T. We found that puberty suppression using GnRHa, with and without T, improved the overall tendon load capacity in female-born mice. Treatment with T resulted in an increase in the maximum load that tendon can withstand before failure. Additionally, we found that GnRHa, but not T, treatment resulted in a significant increase in cell density at the Achilles enthesis. NEW & NOTEWORTHYThese findings demonstrate that puberty suppression or testosterone does not negatively influence tendon structural or functional properties in a mouse model of transmasculine gender affirming care. In all treatment groups, the ability of the tendon to withstand load was significantly increased. Puberty suppression with GnRHa significantly increased enthesis cell density, suggesting an extended growth phase. These findings elucidate the effects of gender affirming care on the structural and functional properties of the tendon and enthesis.

physiology↗

bioRxiv2018

Where does time go when you blink?

Retinal input is frequently lost due to eye blinks, yet humans rarely notice these gaps in visual input. While previous studies focused on the psychophysical and neural correlates of diminished awareness to blinks, the impact of blinks on the perceived time of concurrent events is unknown. Here, we investigated whether the subjective sense of time is altered by spontaneous eye blinks, and how this link may inform mechanisms of time perception. We found that participants significantly underestimated the duration of a visual stimulus when a blink occurred during the stimulus. Importantly, this effect was not present when durations of an auditory stimulus were judged. These results point to a link between spontaneous blinks, previously demonstrated to induce suppression of activity in early visual cortex, and a compression of subjective time. The findings suggest that ongoing encoding within modality-specific sensory cortices, independent of conscious awareness, inform the subjective sense of time.

neuroscience↗

bioRxiv2018

Face-selective units in human ventral temporal cortex reactivate during free recall

Properties of face-responsive individual neurons in the human ventral temporal cortex (VTC) have yet to be studied, and their role in conscious perception remains unknown. To explore this, we implanted microelectrodes into the VTCs of eight human subjects undergoing invasive epilepsy monitoring. Most (26 of 33) category-selective units showed specificity for face stimuli, with a range of response profiles. Different face exemplars evoked consistent and discriminable responses in the population of units sampled. During a free recall task, face-selective units selectively reactivated in the absence of visual stimulation during the 2-second window prior to face recall events. Furthermore, the identity of the recalled face could be predicted by comparing activity preceding recall events to activity evoked by visual stimulation.

neuroscience↗

bioRxiv2018

Widespread suppression of high-order visual cortex during blinks and external predictable visual interruptions

Spontaneous eye blinks generate frequent potent interruptions to the retinal input and yet go unnoticed. As such, they provide an attractive approach to the study of the neural correlates of visual awareness. Here, we tested the potential role of predictability in generating blink-related effects using fMRI. While participants attentively watched still images of faces and houses, we monitored naturally occurring spontaneous blinks and introduced three kinds of matched visual interruptions: cued voluntary blinks, self-initiated (and hence, predictable) external darkenings, and physically similar but unpredictable external darkenings. These events impact was inspected using fMRI across the visual hierarchy. In early visual cortex, both spontaneous and voluntary blinks, as well as predictable and unpredictable external darkenings, led to largely similar positive responses in peripheral representations. In mid- and high-level visual cortex, all predictable conditions (spontaneous blinks, voluntary blinks, and self-initiated external darkenings) were associated with signal decreases. In contrast, unpredictable darkenings were associated with signal increases. These findings suggest that general-purpose prediction-related mechanisms are involved in producing a small but widespread suppression of mid- and high-order visual regions during blinks. Such suppression may down-regulate responses to predictable transients in the human visual hierarchy.

neuroscience↗

bioRxiv2018

Deep Convolutional modeling of human face selective columns reveals their role in pictorial face representation

Despite the massive accumulation of systems neuroscience findings, their functional meaning remains tentative, largely due to the absence of realistically performing models. The discovery that deep convolutional networks achieve human performance in realistic tasks offers fresh opportunities for such modeling. Here we show that the face-space topography of face-selective columns recorded intra-cranially in 32 patients significantly matches that of a DCNN having human-level face recognition capabilities. Three modeling aspects converge in pointing to a role of human face areas in pictorial rather than person identification: First, the match was confined to intermediate layers of the DCNN. Second, identity preserving image manipulations abolished the brain to DCNN correlation. Third, DCNN neurons matching face-column tuning displayed view-point selective receptive fields. Our results point to a \"convergent evolution\" of pattern similarities in biological and artificial face perception. They demonstrate DCNNs as a powerful modeling approach for deciphering the function of human cortical networks.

neuroscience↗

bioRxiv2017

Detecting genome-wide directional effects of transcription factor binding on polygenic disease risk

Biological interpretation of GWAS data frequently involves analyzing unsigned genomic annotations comprising SNPs involved in a biological process and assessing enrichment for disease signal. However, it is often possible to generate signed annotations quantifying whether each SNP allele promotes or hinders a biological process, e.g., binding of a transcription factor (TF). Directional effects of such annotations on disease risk enable stronger statements about causal mechanisms of disease than enrichments of corresponding unsigned annotations. Here we introduce a new method, signed LD profile regression, for detecting such directional effects using GWAS summary statistics, and we apply the method using 382 signed annotations reflecting predicted TF binding. We show via theory and simulations that our method is well-powered and is well-calibrated even when TF binding sites co-localize with other enriched regulatory elements, which can confound unsigned enrichment methods. We further validate our method by showing that it recovers known transcriptional regulators when applied to molecular QTL in blood. We then apply our method to eQTL in 48 GTEx tissues, identifying 651 distinct TF-tissue expression associations at per-tissue FDR < 5%, including 30 associations with robust evidence of tissue specificity. Finally, we apply our method to 46 diseases and complex traits (average N = 289,617) and identify 77 annotation-trait associations at per-trait FDR < 5% representing 12 independent TF-trait associations, and we conduct gene-set enrichment analyses to characterize the underlying transcriptional programs. Our results implicate new causal disease genes (including causal genes at known GWAS loci), and in some cases suggest a detailed mechanism for a causal genes effect on disease. Our method provides a new way to leverage functional data to draw inferences about disease etiology.

genetics↗