Biology subjects

Gallagher, M.

Publications and source records attributed to Gallagher, M..

17 recordsLinked to original sources

bioRxiv2026

Vestibular Perturbation Disrupts Source and Reality Monitoring

The vestibular system has been implicated in several aspects of self-representation, including bodily self-location, yet its role in episodic source and reality monitoring remains unclear. Moreover, symptoms of depersonalisation and derealisation (DPDR) have been associated with both vestibular dysfunction and altered source and reality monitoring. We tested whether noisy galvanic vestibular stimulation (nGVS) modulates source and reality monitoring during a word-encoding paradigm and whether this increased symptoms of DPDR. Sixty young adults (N = 30 active nGVS, N = 30 sham) encoded words that varied by context (spoken vs. imagined), agentic source (self vs. other), and valence (positive vs. threat) before completing source/reality judgments. Active nGVS reduced overall accuracy relative to sham on both reality and source monitoring. Across conditions, self-referential items were remembered with greater sensitivity compared to other-referential items, and spoken items were recalled with greater sensitivity than imagined items. We additionally show an interaction effect whereby active nGVS reduced accuracy specifically for imagined and threat-valenced items. Trait DPDR did not moderate the effects of stimulation, although higher trait DPDR was associated with a more liberal reality-monitoring response criterion. Results indicate that transient vestibular perturbation via nGVS can impair source monitoring for internalised and threatening stimuli and impairs cognitive distinctions between internally and externally generated events in general, supporting a role for vestibular input in maintaining self-other and reality boundaries in episodic memory.

neuroscience↗

bioRxiv2025

Multimodal analysis defines GNG4 as a distinguishing feature of germinal center-positioned CD4 T follicular helper cells in humans

CD4 T follicular helper (Tfh) cells coordinate humoral immune responses within germinal centers (GC) of lymphoid tissue. Despite their critical roles in vaccination and autoimmunity, the gene expression programs that define functionally distinct human Tfh states-- and the molecular pathways engaged by Tfh positioned within the GC niche--remain incompletely understood. This gap has limited translational efforts to monitor or therapeutically target specific Tfh states for clinical benefit. Here, we delineate human CD4 T cell heterogeneity in tonsils and peripheral blood using trimodal single-cell sequencing and spectral flow cytometry to define epigenomic, transcriptional, and proteomic features of distinct Tfh states. Tfh with a GC-like phenotype exhibited markedly increased chromatin accessibility and both mRNA and protein expression of G protein subunit gamma 4 (GNG4). In tonsil, single-cell spatial transcriptomics defined GNG4 expression as a distinguishing feature of activated Tfh states within spatially demarcated GC compartments, with greater specificity than conventionally GC-associated features such as BCL6, TOX2, and S1PR2. In contrast, GNG4- Tfh primarily localized to nonGC regions and exhibited a resting, Th17-polarized phenotype. Together, these data highlight GNG4 as a central feature of activated, GC-positioned Tfh cell identity in humans. One Sentence SummaryGNG4 expression defines activated CD4 T follicular helper cells localized to the germinal center of human lymphoid tissue.

immunology↗

bioRxiv2025

Parallel circadian-like oscillations in LTP and excitation inhibition balance in mouse CA1 reverse direction after puberty

Long-term potentiation (LTP), the best-characterized form of Hebbian synaptic plasticity, is well known to be under strong circadian regulation. In mice and rats, both nocturnal species, most studies indicate that LTP in the hippocampal CA1 region is more robust when induced during the dark phase. Our examination of the underlying mechanisms at the CA3 to CA1 synapse provides evidence that the capacity to express LTP does not differ between the light and dark cycles of the 24-hour day. Instead, the magnitude of theta-burst stimulation-induced LTP (TBS-LTP) correlates with daily fluctuations in the ratio of synaptic excitation to inhibition (E/I ratio): both the E/I ratio and TBS-LTP are higher during the dark phase. Consistent with a causal relationship, blockade of inhibition abolishes the light-dark difference in TBS-LTP induction, likewise, pairing-induced LTP, which is less constrained by inhibitory recruitment, does not differ between cycles. Supporting this model, using the APP/PS1 model of AD we observed that neither the E/I ratio nor TBS-LTP change during the light cycle. Finally, we made the intriguing observation that these daily oscillations reverse direction after puberty in WT mice, shifting from being larger in the dark cycle of 2-month-old mice to being larger in the light cycle in 8-month-old mice. This developmental switch may reflect an age-dependent reorganization of circadian control over hippocampal plasticity.

neuroscience↗

bioRxiv2025

Altered NPTX2 dynamics associated with impaired cognitive aging

Changes in synaptic integrity and neural activity homeostasis are hallmarks of brain aging and are closely tied to cognitive outcomes. Yet, defining their relationship across the continuum from normal aging to neurodegenerative disease has proven challenging. Recent research investigating the dynamic changes of neuronal pentraxin 2 (NPTX2, or Narp, neuronal activity-related pentraxin) in cerebrospinal fluid (CSF) of Alzheimers disease (AD) subjects supports its promise as a prognostic marker of disease progression, possibly as an expression of synaptic damage related to cognitive impairment. However, studies in human subjects are unable to clearly differentiate age-related and disease-related processes. Here we took advantage of a well-characterized rat model that displays substantial individual differences in hippocampal memory during aging, uncontaminated by slowly progressive, spontaneous neurodegenerative disease. Through this approach, we aimed to interrogate the underlying neural substrates that mediate aging as a uniquely permissive condition and the primary risk for neurodegeneration. We found that successful cognitive aging is associated with an elevation of NPTX2 levels above that found in young or cognitively impaired subjects. Pharmacological engagement of neural activity was sufficient to increase NPTX2 levels in all subjects, but cognitively-impaired aged subjects failed to recruit NPTX2 in response to a hippocampus-dependent memory task. Together the findings demonstrate that changes in NPTX2 are coupled to differential cognitive outcomes of aging, and that successful neurocognitive aging is associated with adaptive upregulation of NPTX2, not simply the persistence of youthful synaptic dynamics. Significance StatementAlthough aging is the most prominent risk factor for Alzheimer Disease (AD), the age-dependent processes that disrupt neurophysiological homeostasis leading to neurodegenerative disease remain poorly defined. Alterations in NPTX2, a synaptic protein biomarker for AD, may elucidate aging processes underlying pathological trajectories. We examined NPTX2 in an aging context and identified circuit specific alterations of NPTX2 that are coupled with distinct memory outcomes in aging in the absence of potential confounds of neurodegenerative disease. Greater NPTX2, associated with successful cognitive aging, may reflect coordinated molecular and circuit-level adaptations that sustain memory-relevant hippocampal activity. Development of targets and interventions that promote neuroadaptive network homeostasis, bending the trajectory of aging away from neurodegeneration, are a potentially valuable alternative to current therapeutic strategies.

neuroscience↗

bioRxiv2024

Pharmacological inhibition of Fms-like kinase 3 (FLT3) promotes neuronal maturation and suppresses seizure in a mouse model

Fms-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase predominantly expressed in blood and brain cells. While the FLT3 signaling pathway has been extensively studied in blood cell development and leukemia, its role in the brain remains largely unexplored. Through our groups previous high-throughput drug screening work unexpectedly found that several small molecule FLT3 inhibitors (FLT3i), including KW-2449 and Sunitinib, enhance expression of the gene encoding chloride transporter KCC2 in neurons. KCC2 is crucial for brain development and function, and its dysregulation is linked to many brain diseases. These findings suggest previously unrecognized roles of FLT3 signaling in brain health and disease that have yet to be systematically studied. In this study, we utilized a functional genomics approach to investigate the transcriptomic changes induced by pharmacological inhibition of the FLT3 pathway in brain cells, including cultured primary mouse neurons, a human stem cell-derived neuronal model of Rett syndrome (RTT), and human stem cell-derived microglia cultures. Our results show that treating human or mouse neurons with FLT3i drugs significantly upregulates genes crucial for brain development while downregulating genes linked to neuroinflammation. In contrast, FLT3i treatment of human microglia, which do not express FLT3, has no effect on their gene expression, highlighting the cell type-specific roles of FLT3 signaling in the brain. To further understand how FLT3 signaling regulates the expression of neuronal maturation genes such as KCC2, we conducted a curated CRISPR screen that identified a number of transcription factors involved in FLT3i-mediated KCC2 activation in neurons. The mRNA and protein levels of several neurodevelopmental disorder (NDD) risk genes are significantly upregulated in FLT3i-treated neurons, indicating potential therapeutic applications of FLT3i in rescuing underexpression and/or haploinsufficiency of disease-associated genes. In our in vivo studies, we evaluated the efficacy of the FLT3i drug KW-2449 in mice, demonstrating that it can effectively cross the blood-brain barrier, induce KCC2 protein expression for up to 24 hours after a single injection, and reduces seizure activity in a chemoconvulsant-induced mouse model of temporal lobe epilepsy. Collectively, our findings uncover previously unrecognized roles of neuron-specific FLT3 signaling in promoting neuronal maturation and reducing neuroinflammation. These results suggest that FLT3 kinase signaling regulates a transcriptional program vital for brain development and function, position it as a promising therapeutic target for NDD treatment.

neuroscience↗

bioRxiv2024

Insights into Health Data Science Education: A Qualitative Content Analysis

BackgroundEarly career researchers in Health Data Science (HDS) struggle to effectively manage their learning process due to the novel and interdisciplinary nature of this field. To date, there is limited understanding about learning strategies in health data science. Therefore, we aim to uncover learning strategies that early career researchers employ to address their educational challenges, as well as shed light on their preferences regarding HDS teaching approach and course design. MethodIn this study, we conducted a qualitative content analysis through semistructured interviews with ten early career researchers, including individuals pursuing masters, PhD, and postdoctoral research programmes in HDS, across two higher education institutions in the United Kingdom. Interviews were carried out in person from June 2023 to August 2023. Data were analysed qualitatively using NVivo software. Descriptive statistics were employed for quantitative analysis. ResultsRegarding learning strategies, we identified ten main categories with 22 codes, including collaboration, information seeking, active learning, focus granularity, elaboration, organisation, order granularity, goal orientation, reviewing, and deep learning strategies. Regarding course design and teaching, we discovered four categories with 14 codes, including course materials, duration and complexity, online discussion, and teaching approaches. ConclusionsEarly career researchers used a range of learning strategies aligned with well-established learning theories, such as peer learning, information seeking, and active learning. It is also evident that learners in HDS favour interactive courses that provide them with hands-on experience and interactive discussion. The insights derived from our findings can enhance the quality of education in HDS.

scientific communication and education↗

bioRxiv2024

Providing Insights into Health Data Science Education through Artificial Intelligence

BackgroundHealth Data Science (HDS) is a novel interdisciplinary field that integrates biological, clinical, and computational sciences with the aim of analysing clinical and biological data through the utilisation of computational methods. Training healthcare specialists who are knowledgeable in both health and data sciences is highly required, important, and challenging. Therefore, it is essential to analyse students learning experiences through artificial intelligence techniques in order to provide both teachers and learners with insights about effective learning strategies and to improve existing HDS course designs. MethodsWe applied artificial intelligence methods to uncover learning tactics and strategies employed by students in an HDS massive open online course with over 3,000 students enrolled. We also used statistical tests to explore students engagement with different resources (such as reading materials and lecture videos) and their level of engagement with various HDS topics. ResultsWe found that students in HDS employed four learning tactics, such as actively connecting new information to their prior knowledge, taking assessments and practising programming to evaluate their understanding, collaborating with their classmates, and repeating information to memorise. Based on the employed tactics, we also found three types of learning strategies, including low engagement (Surface learners), moderate engagement (Strategic learners), and high engagement (Deep learners), which are in line with well-known educational theories. The results indicate that successful students allocate more time to practical topics, such as projects and discussions, make connections among concepts, and employ peer learning. ConclusionsWe applied artificial intelligence techniques to provide new insights into HDS education. Based on the findings, we provide pedagogical suggestions not only for course designers but also for teachers and learners that have the potential to improve the learning experience of HDS students.

scientific communication and education↗

bioRxiv2023

The precision of signals encoding active self-movement

Everyday actions like moving the head, walking around and reaching out to grasp objects are typically self-controlled. This presents a problem when studying the signals encoding such actions because active self-movement is difficult to experimentally control. Available techniques demand repeatable trials, but each action is unique, making it difficult to measure fundamental properties like psychophysical thresholds. Here, we present a novel paradigm that can be used to recover both precision and bias of self-movement signals with minimal constraint on the participant. The paradigm takes care of a hidden source of external noise not previously accounted for in techniques that link display motion to self-movement in real time (e.g. virtual reality). We use head rotations as an example of self-movement, and show that the precision of the signals encoding head movement depends on whether they are being used to judge visual motion or auditory motion. We find perceived motion is slowed during head movement in both cases, indicating that the non-image signals encoding active head rotation (motor commands, proprioception and vestibular cues) are biased to lower speeds and/or displacements. In a second experiment, we trained participants to rotate their heads at different rates and found that the precision of the head rotation signal rises proportionally with head speed (Webers Law). We discuss the findings in terms of the different motion cues used by vision and hearing, and the implications they have for Bayesian models of motion perception. NEW AND NOTEWORTHYWe present a psychophysical technique for measuring the precision of signals encoding active self-movements. Using head movements, we show that: (1) precision declines when active head rotation is combined with auditory as opposed to visual motion; (2) precision rises with head speed (Webers Law); (3) perceived speed is lower during head movement. The findings may reflect the steps needed to convert different cues into common currencies, and challenge standard Bayesian models of motion perception.

neuroscience↗

bioRxiv2022

The lateral habenula mediates the association of a conditioned stimulus with the absence of an appetitive unconditioned stimulus

The lateral habenula (LHb) has been implicated in conditioned inhibition. Here, the modulating effects of LHb activity on the association of a conditioned stimulus (CS) with the nonoccurrence of an unconditioned stimulus (US) were assessed in vivo using chemogenetic methods. Animals initially received explicitly unpaired CS light and US food presentations. Animals subjected to a retardation-of-acquisition task subsequently underwent light and food pairings, whereas those subjected to a summation task underwent compound light-tone and food pairings. The inhibitory light strength was assessed based on retardation of the acquisition of food-cup conditioned responses (CRs) in light-food pairings and comparisons of food-cup CRs to each stimulus in a CS-alone test following compound training. Neurotoxic LHb lesions and chemogenetic LHb inhibition throughout unpaired training attenuated the inhibitory light strength. Furthermore, chemogenetic LHb activation accelerated the decline in CR induced by repeated light-alone presentations following light-food pairings. Therefore, the LHb critically contributes to conditioned inhibition.

neuroscience↗

bioRxiv2021

Proximal CA3 is the primary locus of age-related pattern separation deficits in rats

Age-related deficits in pattern separation have been postulated to bias the output of hippocampal memory processing toward pattern completion, which can cause deficits in accurate memory retrieval. While the CA3 region of the hippocampus is often conceptualized as a homogeneous network involved in pattern completion, growing evidence demonstrates a functional gradient in CA3 along the transverse axis, as pattern-separated outputs (dominant in the more proximal CA3) transition to pattern-completed outputs (dominant in the more distal CA3). We examined the neural representations along the CA3 transverse axis in young (Y), aged memory-unimpaired (AU), and aged memory-impaired (AI) rats when different changes were made to the environment. Functional heterogeneity in CA3 was observed in Y and AU rats when the environmental similarity was high (altered cues or altered environment shapes in the same room), with more orthogonalized representations in proximal CA3 than in distal CA3. In contrast, AI rats showed reduced orthogonalization in proximal CA3 but showed normal (i.e., generalized) representations in distal CA3, with little evidence of a functional gradient. Under experimental conditions when the environmental similarity was low (different rooms), representations in proximal and distal CA3 remapped in all rats, showing that CA3 of AI rats is able to encode distinctive representations for inputs with greater dissimilarity. These experiments support the hypotheses that the aged-related bias towards hippocampal pattern completion is due to the loss in AI rats of the normal transition from pattern separation to pattern completion along the CA3 transverse axis.

animal behavior and cognition↗

bioRxiv2020

Age-related Changes in Memory for Object and Position-In-Context

There has been considerable focus on investigating age-related memory changes in cognitively healthy older adults, in the absence of neurodegenerative disorders. Previous studies have reported age-related domain-specific changes in older adults, showing increased difficulty encoding and processing object information but minimal to no impairment in processing spatial information compared to younger adults. However, few of these studies have examined age-related changes in the encoding of concurrently presented object and spatial stimuli, specifically the integration of both spatial and non-spatial (object) information. To more closely resemble real-life memory encoding and the integration of both spatial and non-spatial information, the current study developed a new experimental paradigm with novel environments that allowed for the placement of different objects in different positions within the environment. The current findings show that older adults have decreased performance in recognizing changes of the object position within the spatial context but no significant differences in recognizing changes in the identity of the object within the spatial context compared to younger adults. These findings suggest there may be potential age-related differences in the mechanisms underlying the representations of complex environments and furthermore, the integration of spatial and non-spatial information may be differentially processed relative to independent and isolated representations of object and spatial information.

neuroscience↗

bioRxiv2020

Heterogeneity of age-related neural hyperactivity along the CA3 transverse axis

Age-related memory deficits are correlated with neural hyperactivity in the CA1 and CA3 regions of the hippocampus. Abnormal CA3 hyperactivity in aged rats has been proposed to contribute to an imbalance between the normal tradeoff between pattern separation and pattern completion, resulting in overly rigid representations. Recent evidence of functional heterogeneity along the CA3 transverse axis suggests that proximal CA3 supports pattern separation while distal CA3 supports pattern completion. It is not known whether age-related CA3 hyperactivity is uniformly represented along the CA3 transverse axis. We examined the firing rates of CA3 neurons from male young and aged Long-Evans rats along the CA3 transverse axis. Consistent with prior studies, young CA3 cells showed an increasing gradient in mean firing rate from proximal to distal CA3. However, aged CA3 cells showed an opposite trend, with a decreasing gradient from proximal to distal CA3. Thus, CA3 cells in aged rats were hyperactive in proximal CA3, but possibly hypoactive in distal CA3, compared to young rats. We suggest that, in combination with altered inputs from the entorhinal cortex and dentate gyrus, the proximal CA3 region of aged rats may switch from its normal function that reflects the pattern separation output of the DG and instead performs a computation that reflects an abnormal bias toward pattern completion. In parallel, distal CA3 of aged rats may create weaker attractor basins that promote bistable representations under certain conditions.

neuroscience↗

bioRxiv2020

AFTERHYPERPOLARIZATION AMPLITUDE IN CA1 PYRAMIDAL CELLS OF AGED LONG-EVANS RATS CHARACTERIZED FOR INDIVIDUAL DIFFERENCES

Altered neural excitability is considered a prominent contributing factor to cognitive decline during aging. A clear example is the excess neural activity observed in several temporal lobe structures of cognitively impaired older individuals in rodents and humans. At a cellular level, aging-related changes in mechanisms regulating intrinsic excitability have been well examined in pyramidal cells of the CA1 hippocampal subfield. Studies in the inbred Fisher 344 rat strain document an age-related increase in the slow afterhyperpolarization (AHP) that normally occurs after a burst of action potentials, and serves to reduce subsequent firing. We evaluated the status of the AHP in the outbred Long-Evans rat, a well-established model for studing individual differences in neurocognitive aging. In contrast to the findings reported in the Fisher 344 rats, in the Long-Evan rats we detected a selective reduction in AHP in cognitively impaired aged individuals. We discuss plausible scenarios to account for these differences and also discuss possible implications of these differences.

neuroscience↗

bioRxiv2020

Decreased investigatory head scanning during exploration in learning-impaired, aged rats

"Head scanning" is an investigatory behavior that has been linked to spatial exploration and the one-trial formation or strengthening of place cells in the hippocampus. Previous studies have demonstrated that a subset of aged rats with normal spatial learning performance show head scanning rates during a novel, local-global cue-mismatch manipulation that are similar to those of young rats. However, these aged rats demonstrated different patterns of expression of neural activity markers in brain regions associated with spatial learning, perhaps suggesting neural mechanisms that compensate for age-related brain changes. These prior studies did not investigate the head scanning properties of aged rats that had spatial learning impairments. The present study analyzed head scanning behavior in young, aged-unimpaired, and aged-impaired Long Evans rats. Aged-impaired rats performed the head scan behavior at a lower rate than the young rats. These results suggest that decreased attention to spatial landmarks may be a contributing factor to the spatial learning deficits shown by the aged-impaired rats.

animal behavior and cognition↗

bioRxiv2019

An optimized protocol for iDISCO+ rat brain clearing, imaging, and analysis

The advent of whole brain clearing and imaging methods extends the breadth and depth at which brain-wide neural populations and structures can be studied. However, these methods have yet to be applied to larger brains, such as the brains of the common laboratory rat, despite the importance of these models in behavioral neuroscience research. Here we introduce AdipoClear+, an optimized immunolabeling and clearing methodology for application to adult rat brain hemispheres, and validate its application through the testing of common antibodies and electrode tract visualization. In order to extend the accessibility of this methodology for general use, we have developed an open source platform for the registration of rat brain volumes to standard brain atlases for high throughput analysis.

neuroscience↗

bioRxiv2019

Reduced Cognitive Performance in Aged Rats Correlates with Increased Excitation/Inhibition Ratio in the Dentate Gyrus in Response to Lateral Entorhinal Input

Aging often impairs cognitive functions associated with the medial temporal lobe (MTL). Anatomical studies identified the layer II pyramidal cells of the lateral entorhinal cortex (LEC) as one of the most vulnerable elements within the MTL. These cells provide a major excitatory input to the dentate gyrus hippocampal subfield by synapsing onto granule cells and onto local inhibitory interneurons, and a fraction of these contacts are lost in aged individuals with impaired learning. Using optogenetics we evaluated the functional status of the remaining inputs in an outbred rat model of aging that distinguishes between learning impaired and learning unimpaired individuals. We found that aging affects the pre- and postsynaptic strength of the LEC inputs onto granule cells. However, the magnitude these changes was similar in impaired and un-impaired rats. In contrast, the recruitment of inhibition by LEC activation was selectively reduced in the aged impaired subjects. These findings are consistent with the notion that the preservation of an adequate balance of excitation and inhibition is crucial for maintain proficient memory performance during aging.

neuroscience↗

bioRxiv2017

A dementia-associated risk variant near TMEM106B alters chromatin architecture and gene expression

Neurodegenerative diseases pose an extraordinary threat to the worlds aging population, yet no disease-modifying therapies are available. While genome-wide association studies (GWAS) have identified hundreds of novel risk loci for neurodegeneration, the mechanisms by which these loci influence disease risk are largely unknown. Indeed, of the many thousands of SNP-trait associations identified by GWAS over the past ~10 years, very few are understood mechanistically. Here, we investigate the association of common genetic variants at the 7p21 locus with risk for the neurodegenerative disease frontotemporal lobar degeneration. We show that variants associated with disease risk correlate with increased brain expression of the 7p21 gene TMEM106B, and no other genes. Furthermore, incremental increases in TMEM106B levels result in incremental increases in lysosomal phenotypes and cell toxicity. We then combine fine-mapping, bioinformatics, and bench-based approaches to functionally characterize all candidate causal variants at this locus. This approach identified a noncoding variant, rs1990620, which differentially recruits CTCF, influencing CTCF-mediated long-range chromatin looping interactions between multiple cis-regulatory elements, including the TMEM106B promoter. Our findings thus provide an in-depth analysis of the 7p21 locus linked by GWAS to frontotemporal lobar degeneration, nominating a causal variant and a causal mechanism for allele-specific expression and disease association at this locus. Finally, we show that genetic variants associated with risk for neurodegenerative diseases beyond frontotemporal lobar degeneration are enriched in brain CTCF-binding sites genome-wide, implicating CTCF-mediated gene regulation in risk for neurodegeneration more generally.

genetics↗