Biology subjects

McLaurin, J.

Publications and source records attributed to McLaurin, J..

9 recordsLinked to original sources

bioRxiv2026

Aberrant cortical reorganization and astrogliosis underlie memory deficit post-traumatic brain injury: a longitudinal multiscale multimodal study

Integrating high-dimensional neuroimaging data across spatial scales remains a fundamental bottleneck in quantitative neuroscience. Here, we apply emerging analytical techniques including functional connectome gradient mapping and 3D segmentation of whole-brain cellular resolution microscopy data in a mouse model of traumatic brain injury. At the macroscale, longitudinal functional MRI revealed a transition from frontal hyperconnectivity to hippocampal hypoconnectivity and unimodal-transmodal gradient contraction indicating network dedifferentiation. At the cellular scale, deep-learning based segmentation of whole-brain light-sheet fluorescence microscopy volumes quantified regional astrogliosis, neuronal hyperactivity, and single-axon loss undetected by standard diffusion MRI. Multiscale multimodal data integration not only identified quantitative biomarkers predictive of memory performance post-injury but also enabled validation of in vivo modalities against more sensitive ex vivo histology. This study demonstrates a framework for probing complex multi-network cognitive functions and neurological disorders of network dysfunction.

neuroscience↗

bioRxiv2025

Stable neuronal representations to repeated stimulation underlie cognitive resilience in Alzheimer's disease pathology

While Alzheimers Disease (AD) typically triggers cognitive decline, some individuals with significant AD pathology maintain normal cognition into late life. Understanding the neuronal underpinnings of such cognitive resilience would propel the development of interventions for delaying dementia. To this end, we used cognitive testing to identify a subset of cognitively resilient 13-month-old TgF344-AD rats (established AD) and their non-transgenic littermates, followed by Neuropixels recording from 8500 neurons during repeated somatosensory stimulation. Cognitively resilient TgF344-AD rats recruited fewer neurons yet displayed more stable neuronal representations during repeated stimulations in cortical excitatory and hippocampal inhibitory ensembles, with reduced excitatory spike burstiness during network activation and a distinct pattern of functional synaptic connectivity. These associations existed independently of amyloid and tau levels. For the first time, our study revealed neuronal population-level hallmarks of maintained cognition that may serve as a novel neurophysiological biomarker of cognitive resilience and a target for stabilizing cognition.

neuroscience↗

bioRxiv2025

Quantitative profiling of whole-brain connectomes at single-axon resolution using deep learning and high-resolution light sheet microscopy

Revealing how individual axons create a brain-wide connectome would be indispensable for understanding brain function and behavior, yet remains technically challenging. We introduce MAPL3, an end-to-end pipeline that integrates self-supervised learning with an innovative deep architecture to capture local and global brain-wide axonal projections. MAPL3 enables subject- and population-level quantitative laminar analysis, generalizes across experiments, and outperforms state-of-the-art methods. We showcase its ability to map the circuitry of the orbitofrontal cortex from single axons to whole-brain projectome.

neuroscience↗

bioRxiv2024

Unveiling the Structural Proteome of an Alzheimer's Disease Rat Brain Model

Studying native protein structures at near-atomic resolution in crowded environment presents a challenge. Consequently, understanding the structural intricacies of proteins within pathologically affected tissues often relies on mass spectrometry and proteomic analysis. In this study, we utilized electron cryomicroscopy (cryo-EM) and a specific method of analysis called Build and Retrieve (BaR) to investigate structural characteristics of protein complexes such as post-translational modification, active site occupancy, and arrested conformational state in Alzheimers Disease (AD) using brain lysate from a rat model (TgF344-AD) of the disease. Our findings reveal novel insights into the architecture of these complexes, which we corroborate through mass spectrometry analysis. Interestingly, it has been shown that the dysfunction of these protein complexes extends beyond AD, implicating them in cancer, as well as other neurodegenerative disorders such as Parkinsons disease, Huntingtons disease, and Schizophrenia. By elucidating the structural details of these complexes, our work not only enhances our understanding of disease pathology but also suggests new avenues for future approaches in therapeutic intervention.

biochemistry↗

bioRxiv2024

Obesity differentially effects the somatosensory cortex and striatum of TgF344-AD rats

1Lifestyle choices leading to obesity, hypertension and diabetes in mid-life contribute directly to the risk of late-life Alzheimers disease (AD). However, in late-life or in late-stage AD conditions, obesity reduces the risk of AD and disease progression. To examine the mechanisms underlying this paradox, TgF344-AD rats were fed a varied high-carbohydrate, high-fat (HCHF) diet to induce obesity from nine months of age representing early stages of AD to twelve months of age in which rats exhibit the full spectrum of AD symptomology. We hypothesized regions primarily composed of gray matter, such as the somatosensory cortex (SSC), would be differentially affected compared to regions primarily composed of white matter, such as the striatum. We found increased myelin and oligodendrocytes in the somatosensory cortex of rats fed the HCHF diet with an absence of neuronal loss. We observed decreased inflammation in the somatosensory cortex despite increased AD pathology. Compared to the somatosensory cortex, the striatum had fewer changes. Overall, our results suggest that the interaction between diet and AD progression affects myelination in a brain region specific manner such that regions with a lower density of white matter are preferentially effected. Our results offer a possible mechanistic explanation for the obesity paradox.

neuroscience↗

bioRxiv2024

Obesity Facilitates Sex-Specific Improvement In Cognition And Neuronal Function In A Rat Model Of Alzheimer's Disease

Obesity reduces or increases the risk of developing Alzheimers disease (AD) depending on whether it is assessed in mid-life or late-life. There is currently no consensus on the relationship between obesity and AD or the mechanism or their interaction. Here, we aim to differentiate the cause-and-effect relationship between obesity and AD in a controlled rat model of AD. We induced obesity in 9-month-old TgF344-AD rats, that is pathology-load wise similar to early symptomatic phase of human AD. To more accurately model human obesity, we fed both TgF344-AD and non-transgenic littermates a varied high-carbohydrate-high-fat diet consisting of human food for 3 months. Obesity increased overall glucose metabolism and slowed cognitive decline in TgF344-AD rats, specifically executive function, without affecting non-transgenic rats. Pathological analyses of prefrontal cortex and hippocampus showed that obesity in TgF344-AD rats produced varied effects, with increased density of myelin and oligodendrocytes, lowered density and activation of microglia that we propose contributes to the cognitive improvement. However, obesity also decreased neuronal density, and promoted deposition of amyloid-beta plaques and tau inclusions. After 6 months on the high-carbohydrate-high-fat diet, detrimental effects on density of neurons, amyloid-beta plaques, and tau inclusions persisted while the beneficial effects on myelin, microglia, and cognitive functions remained albeit with a lower effect size. By examining the effect of sex, we found that both beneficial and detrimental effects of obesity were stronger in female TgF344-AD rats indicating that obesity during early symptomatic phase of AD is protective in females.

neuroscience↗

bioRxiv2024

NEUROG2 regulates a human-specific neurodevelopmental gene regulatory program

Unique hallmarks of human neocortical development include slower rates of neurogenesis and the establishment of an extracellular matrix-rich, outer-subventricular zone that supports basal neural progenitor cell expansion. How gene regulatory networks have evolved to support these human-specific neurodevelopmental features is poorly understood. Mining single cell data from cerebral organoids and human fetal cortices, we found that NEUROG2 expression is enriched in basal neural progenitor cells. To identify and purify NEUROG2-expressing cells and trace their short-term lineage, we engineered two NEUROG2-mCherry knock-in human embryonic stem cell lines to produce cerebral organoids. Transcriptomic profiling of mCherry-high organoid cells revealed elevated expression of PPP1R17, associated with a fast-evolving human-accelerated regulatory region, oligodendrocyte precursor cell and extracellular matrix-associated gene transcripts. Conversely, only neurogenic gene transcripts were enriched in mCherry-high cortical cells from Neurog2:mCherry knock-in mice. Finally, we show that Neurog2 is sufficient to induce Ppp1r17, which slows human neural progenitor cell division, and Col13a1, an extracellular matrix gene, in P19 cells. NEUROG2 thus regulates a human neurodevelopmental gene regulatory program implicated in supporting a pro-proliferative basal progenitor cell niche and tempering the neurogenic pace. SUMMARY STATEMENTTranscriptomic analyses of NEUROG2-mCherry knock-in human embryonic stem cell-derived cerebral organoids reveal a link between NEUROG2 and extracellular matrix remodeling during human cortical development.

developmental biology↗

bioRxiv2023

Enhanced prefrontal nicotinic signaling as evidence of active compensation in Alzheimer's disease models

BackgroundCognitive reserve allows for resilience to neuropathology, potentially through active compensation. Here, we examine ex vivo electrophysiological evidence for active compensation in Alzheimers disease (AD) focusing on the cholinergic innervation of layer 6 in prefrontal cortex. Cholinergic pathways are vulnerable to neuropathology in AD and its preclinical models, and their modulation of deep layer prefrontal cortex is essential for attention and executive function. MethodsWe functionally interrogate cholinergic modulation of prefrontal layer 6 pyramidal neurons in two preclinical models: a compound transgenic AD mouse that permits optogenetically-triggered release of endogenous acetylcholine and a transgenic AD rat that closely recapitulates the human trajectory of AD. We then tested the impact of therapeutic interventions to further amplify the compensated responses and preserve the typical kinetic profile of cholinergic signaling. ResultsIn two AD models, we find a potentially-compensatory upregulation of functional cholinergic responses above non-transgenic controls after onset of pathology. To identify the locus of this enhanced cholinergic signal, we dissect key pre- and post-synaptic components with pharmacological strategies. We identify a significant and selective increase in post-synaptic nicotinic receptor signalling on prefrontal cortical neurons. To probe the additional impact of therapeutic intervention on the adapted circuit, we test cholinergic and nicotinic-selective pro-cognitive treatments. The inhibition of acetylcholinesterase further enhances endogenous cholinergic responses but greatly distorts their kinetics. Positive allosteric modulation of nicotinic receptors, by contrast, enhances endogenous cholinergic responses and retains their rapid kinetics. ConclusionsWe demonstrate that functional nicotinic upregulation occurs within the prefrontal cortex in two AD models. Promisingly, this nicotinic signal can be further enhanced while preserving its rapid kinetic signature. Taken together, our work suggests compensatory mechanisms are active within the prefrontal cortex that can be harnessed by nicotinic receptor positive allosteric modulation, highlighting a new direction for cognitive treatment in AD neuropathology.

neuroscience↗

bioRxiv2022

Common genetic variants in CHRNA5 alter β-amyloid neuropathology and highlight chandelier cells in human aging and Alzheimer's disease

Changes in high-affinity nicotinic acetylcholine receptors are intricately connected to neuropathology in Alzheimers Disease (AD). Protective and cognitive-enhancing roles for the nicotinic 5 subunit have been identified, but this gene has not been closely examined in the context of human aging and dementia. Therefore, we investigate the nicotinic 5 gene CHRNA5 and the impact of relevant single nucleotide polymorphisms (SNPs) in prefrontal cortex from 922 individuals with matched genotypic and post-mortem RNA sequencing in the Religious Orders Study and Memory and Aging Project (ROS/MAP). We find that a genotype robustly linked to increased expression of CHRNA5 (rs1979905A2) predicts significantly reduced cortical {beta}-amyloid load. Intriguingly, co-expression analysis suggests CHRNA5 has a distinct cellular expression profile compared to other nicotinic receptor genes. Consistent with this prediction, single nucleus RNA sequencing from 22 individuals reveals CHRNA5 expression is disproportionately-elevated in chandelier neurons, a distinct subtype of inhibitory neuron known for its role in excitatory/inhibitory (E/I) balance. We show that chandelier neurons are enriched in amyloid-binding proteins compared to basket cells, the other major subtype of PVALB-positive interneurons. Consistent with the hypothesis that nicotinic receptors in chandelier cells normally protect against {beta}-amyloid, cell-type proportion analysis from 549 individuals reveals these neurons show amyloid-associated vulnerability only in individuals with impaired function/trafficking of nicotinic 5-containing receptors due to homozygosity of the missense CHRNA5 SNP (rs16969968A2). Taken together, these findings suggest that CHRNA5 and its nicotinic 5 subunit exert a neuroprotective role in aging and Alzheimers disease centered on chandelier interneurons.

neuroscience↗