Biology subjects

Smith, Y.

Publications and source records attributed to Smith, Y..

12 recordsLinked to original sources

bioRxiv2026

Caudate nucleus aging and its association with brain disorders

The caudate nucleus supports cognition and goal-directed behavior, undergoes age-associated changes, and is implicated in substance use, psychiatric, and neurodegenerative disorders. However, how aging alters its diverse cell types and how such changes relate to diseases remains poorly understood. To address these questions, we assembled single nucleus transcriptomic atlases of the caudate tissue, comprising 963,842 nuclei from 178 human donors, including controls and individuals with alcohol use disorder (AUD) or opioid use disorder (OUD), and 83,699 nuclei from six healthy rhesus macaques. We also curated 3,139 bulk RNA-seq profiles from the caudate and other brain regions spanning controls and multiple diagnostic groups, as well as paired RNA and chromatin accessibility profiles from 257,524 caudate nuclei across 161 control and AUD donors. These datasets enabled comparisons across age, species, brain regions, and diagnostic groups. We found shared glial aging features in humans and macaques, whereas neuronal changes were more divergent. Inferred neuron-to-neuron communication declined with age, with greater declines in AUD. Both transcriptional and chromatin accessibility profiles showed nonlinear age-associated patterns, with pronounced changes in later adulthood. In donors with AUD, age-associated changes appeared earlier, with altered trajectories in lipid metabolism, mitochondrial function, and neuronal signaling. Across comparisons involving AUD, OUD, bipolar disorder, schizophrenia, and Alzheimer disease, mitochondrial function and fatty acid metabolism emerged as consensus features linking caudate aging to diseases, although the direction and extent of overlap varied by disorder and brain region. Together, these findings define cellular and regulatory features of primate caudate aging and reveal shared and context-dependent relationships between aging and brain disorders.

neuroscience↗

bioRxiv2026

GABAergic and glutamatergic synaptic networks and mitochondrial morphology in the thalamic ventral motor and centromedian nuclei of Rhesus Monkey: A comparative 3D Electron Microscopic Analysis between Control and Parkinsonian State

The ventral motor and the centromedian (CM) nuclei receive prominent GABAergic inputs from the basal ganglia, massive glutamatergic projections from motor cortices and significant GABAergic afferents from the reticular thalamic nucleus. There is strong evidence that disrupted processing of information through these connections may contribute to the pathophysiology of the basal ganglia-thalamocortical loop in Parkinson's disease (PD). To further assess potential ultrastructural changes in synaptic connectivity and mitochondrial integrity that may contribute to these network dysfunctions, we used a 3D electron microscopic approach to determine whether the pattern of synaptic innervation and morphological integrity of dendritic mitochondria are altered in the basal ganglia-receiving parvocellular ventral anterior nucleus (VApc) and CM neurons of MPTP-treated parkinsonian monkeys. Three main conclusions can be drawn from our findings: (1) Although the overall pattern of synaptic innervation of VApc and CM neurons is not altered in parkinsonian monkeys, the volume of putative corticothalamic terminals is significantly increased in both nuclei, (2) the prevalence of corticothalamic terminals in contact with distal dendrites is several orders of magnitude higher in VApc than CM in both control and parkinsonian monkeys, (3) the complexity and ultrastructural integrity of dendritic mitochondria is altered in CM, but not in the VApc, of parkinsonian monkeys. These findings lay the foundation for future studies of changes in cortical neuromodulation of VApc and CM neurons in parkinsonism and suggest that mitochondrial defects may contribute to the degeneration of CM neurons in PD.

neuroscience↗

bioRxiv2026

From unsupervised clustering to atlas-guided annotation in cohort-scale spatial omics with HiCAT

Pathologist-annotated tissue regions provide a fundamental reference for examining spatial omics data, yet such annotations are available for a limited number of samples due to the substantial manual effort required. Moreover, these annotations are derived from morphology within individual histology images, which can overlook molecularly defined regions and obscure intra-sample heterogeneity. To address these limitations, we present HiCAT, a machine-learning framework that automatically generates pathologist-informed region annotations and characterizes regional heterogeneity in spatial omics data. Across seven datasets, HiCAT consistently outperforms state-of-the-art methods, achieving a median relative improvement of 107% in accuracy. Beyond transferring pathologist annotations, HiCAT uncovers molecularly informed regional heterogeneity not captured by original annotations, including tumor subregions associated with clinical outcomes and brain subregions aligned with spatiotemporal disease progression. By generating consistent, highly granular, and biologically informative region annotations across large cohorts, HiCAT enables scalable downstream analysis and provides training labels for foundation models in spatial biology.

genomics↗

bioRxiv2026

Effects of Glutamate Delta 1 Receptor (GluD1) Deletion on the Ultrastructural Features of Corticostriatal and Thalamostriatal Synapses in Mice

The glutamate delta 1 receptor (GluD1) represents a unique subtype of ionotropic glutamate receptors that is strongly expressed in the mammalian striatum. Disruptions of the GRID1 gene, which encodes GluD1, have been associated with neuropsychiatric disorders, including schizophrenia and autism spectrum disorder; however, the role of GluD1 in the brain remains poorly understood. Previous studies in mice have demonstrated that the knockout of striatal GluD1 led to fear-conditioning deficits and depressive-like behaviors. Furthermore, these mice exhibited reduced excitatory input to the striatum due to a loss of thalamostriatal innervation, whereas corticostriatal innervation was unaffected. In this study, we examined whether changes in synapse morphology contribute to the observed functional deficits. We found that the ablation of GluD1 does not affect synaptic targeting patterns of corticostriatal and thalamostriatal terminals, using transmission electron microscopy. We further utilized three-dimensional reconstruction to obtain quantitative data on synapse ultrastructure and found no significant changes in corticostriatal and thalamostriatal synaptic components, including the presynaptic terminal volume, postsynaptic density area and morphology, and postsynaptic dendritic spine volume. These findings support a model in which GluD1 regulates input-specific circuit organization and synaptic connectivity rather than the structural morphology of individual synapses.

neuroscience↗

bioRxiv2026

Tumor Suppression across the Human miRNome Associates with Guanine-Rich Precursor Terminal Loops

MicroRNAs (miRNAs) play essential regulatory roles in controlling cell growth, proliferation, and differentiation in cancer. While functional studies have identified numerous oncogenic (oncomiRs) and tumor suppressor (TS) miRNAs, the structural features that differentiate these groups remain poorly understood. Here, we performed a comprehensive sequence analysis of 955 human pre-miRNA terminal loops (TLs), focusing on enrichment of single guanine (G) and GG dinucleotides. A quantitative G enrichment score was used to define 42 G-rich TL miRNAs and 17 G-free TL miRNAs as controls. Functional roles of these miRNAs were curated from 757 publications. The results show that G-rich TL miRNAs consistently display higher TS/oncomiR ratios than G-free TL miRNAs across most cancer types, with a significant enrichment observed in lung cancer (p = 0.023). Focusing on miR-139, a TS miRNA with a G-rich TL, integrative analysis of publicly available transcriptomic and proteomic data revealed its consistent downregulation across all stages of lung adenocarcinoma (LUAD), accompanied by reciprocal overexpression of its validated oncogenic target, CCNB1. These findings highlight the biological relevance of G-rich TL structures in miRNA-mediated tumor suppression in lung cancer, suggesting their consideration in future therapeutic strategies aimed at restoring vulnerable TS miRNAs.

molecular biology↗

bioRxiv2024

Regulator of G Protein Signaling 14 protein expression profile in the adult mouse brain

Regulator of G protein signaling 14 (RGS14) is a multifunctional signaling protein that serves as a natural suppressor of synaptic plasticity in the mouse brain. Our previous studies showed that RGS14 is highly expressed in postsynaptic dendrites and spines of pyramidal neurons in hippocampal area CA2 of the developing mouse brain. However, our more recent work with adult rhesus macaque brain shows that RGS14 is found in multiple neuron populations throughout hippocampal area CA1 and CA2, caudate nucleus, putamen, globus pallidus, substantia nigra, and amygdala in the adult rhesus monkey brain. In the mouse brain, we also have observed RGS14 protein in discrete limbic regions linked to reward behavior and addiction, including the central amygdala and the nucleus accumbens, but a comprehensive mapping of RGS14 protein expression in the adult mouse brain is lacking. Here, we report that RGS14 is more broadly expressed in mouse brain than previously known. Intense RGS14 staining is observed in specific neuron populations of the hippocampal formation, amygdala, septum, bed nucleus of stria terminalis and ventral striatum/nucleus accumbens. RGS14 is also observed in axon fiber tracts including the dorsal fornix, fimbria, stria terminalis, and the ventrohippocampal commissure. Moderate RGS14 staining is observed in various other adjacent regions not previously reported. These findings show that RGS14 is expressed in brain regions that govern aspects of core cognitive functions such as sensory perception, emotion, memory, motivation, and execution of actions, and suggests that RGS14 may serve to suppress plasticity and filter inputs in these brain regions to set the overall tone on experience-to-action processes.

neuroscience↗

bioRxiv2024

Decreased cellular excitability of pyramidal tract neurons in primary motor cortex leads to paradoxically increased network activity in simulated parkinsonian motor cortex

Primary motor cortex (M1) layer 5B pyramidal tract (PT5B) neurons develop intrinsic pathology in rodent and primate Parkinsons disease (PD) models. We used computer simulation to predict how decreased PT5B neuron excitability, identified with current injection in vitro, would change activity patterns of the M1 network. Using NEURON/NetPyNE, we implemented computer simulations of PT5B neurons based on control and 6-OHDA-treated mouse slice data. Parkinsonian PT5B neurons, in an otherwise unmodified simulated M1 network, produced major changes in LFP oscillatory power: an order of magnitude increase in beta band power around 15 Hz in the rest state. This demonstrated that relatively small changes in PT5B neuron excitability would alter oscillatory patterns of activity throughout the M1 circuit, increasing beta band power, a signature of PD pathophysiology. Dysfunction in PT5B neurons, the final-common-pathway to brainstem and spinal cord, provides a new target to treat PD motor symptoms.

neuroscience↗

bioRxiv2023

Structural Plasticity of GABAergic Pallidothalamic Terminals in MPTP-treated Parkinsonian Monkeys: A 3D Electron Microscopic Analysis

The globus pallidus pars interna (GPi) is a major source of GABAergic inhibition upon the motor thalamus. GPi neurons are endowed with properties that allow them to fire at a high rate and maintain a tonic inhibitory influence upon thalamocortical neurons. In parkinsonism, the firing rate of GPi neurons is further increased and their firing pattern switches from a tonic to a bursty mode, two pathophysiological changes associated with increased GABAergic pallidothalamic activity. At the thalamic level, GPi terminals display ultrastructural features (large diameter, multiple synapses, large number of mitochondria) that allow them to maintain tonic synaptic inhibition at high firing rate upon thalamocortical neurons in the parvocellular ventral anterior nucleus (VApc) and the centromedian nucleus (CM), the two main GPi-recipient motor thalamic nuclei in nonhuman primates. To determine if changes of GPi neurons activity are associated with neuroplastic reorganization of GPi terminals and their synapses, we used a Single Block Facing/Scanning Electron Microscopy (SBF/SEM), high resolution 3D electron microscopic approach to compare the morphometry of GPi terminals between 2 control and 2 MPTP-treated parkinsonian monkeys. Our findings demonstrate that pallidothalamic terminals in VApc and CM undergo major ultrastructural changes in parkinsonian monkeys: (1) increased terminal volume in both nuclei, (2) increased surface area of synapses in both nuclei, (3) increased number of synapses/GPi terminals in the CM, but not VApc, (4) increased total volume of mitochondria/terminals in both nuclei but not in the number of mitochondria. In contrast, the ultrastructure of putative GABAergic terminals from the reticular thalamic nucleus was not affected in both the VApc and CM of parkinsonian monkeys. Our findings also show striking morphological differences in terminal volume, number/area of synapses and volume/number of mitochondria between GPi terminals in VApc and CM of control monkeys. In conclusion, results of this study demonstrate that GABAergic pallidothalamic terminals are endowed with a high level of structural plasticity that may contribute to the development and maintenance of the abnormal increase in pallidal GABAergic outflow to the thalamus in the parkinsonian state. Furthermore, the evidence for ultrastructural differences between GPi terminals in VApc and CM suggests that Morphologically distinct pallidothalamic terminals underlie specific physiological properties of pallidal inputs to VApc and CM in normal and diseased states.

neuroscience↗

bioRxiv2023

Tyrosinase-induced neuromelanin accumulation triggers rapid dysregulation and degeneration of the mouse locus coeruleus

The locus coeruleus (LC), the major source of norepinephrine (NE) in the brain, is among the first sites of pathology in both Alzheimers disease (AD) and Parkinsons disease (PD), and it undergoes catastrophic degeneration later in both disorders. Dysregulation of the LC is thought to contribute to early behavioral symptoms of AD and PD such as anxiety and sleep disturbances, while frank LC loss promotes cognitive decline. However, the mechanisms responsible for this selective vulnerability are unknown. It has been suggested that neuromelanin (NM) pigment contributes to LC susceptibility, but a causal relationship has been difficult to test because rodents do not naturally produce NM. Here, we report that viral-mediated expression of human tyrosinase-induced pigmentation in male and female mouse LC neurons recapitulated key macroscopic and ultrastructural features of natural primate NM. One week of NM accumulation resulted in LC neuron hyperactivity, reduced tissue NE levels, transcriptional changes, and anxiety-like behavior. By 6 weeks, NM accumulation was associated with severe cell-autonomous LC neuron degeneration, neuroinflammation, and microglial engulfment of the pigment granules, while the anxiety-like behavior abated. These phenotypes are reminiscent of LC dysfunction and cell death in AD and PD, validating this model for studying the consequences of NM accumulation in the LC as it relates to neurodegenerative diseases. Significance StatementAlzheimers disease (AD) and Parkinsons disease (PD) are the most common neurodegenerative diseases worldwide. Because therapies that cure or prevent their progression are lacking, research is focused on the identifying the earliest signs of disease as targets for diagnosis and treatment. The locus coeruleus (LC), the main source of norepinephrine (NE) in the brain, is one of the first brain regions affected in both AD and PD. Early on, LC dysregulation promotes behavioral symptoms of AD and PD, while its subsequent degeneration accelerates disease progression. Here we identify neuromelanin (NM) pigment as an LC vulnerability factor that induces neuronal hyperactivity followed by cell death. Approaches that mitigate NM accumulation and toxicity may target the earliest phases of neurodegenerative disease.

neuroscience↗

bioRxiv2023

RGS14 is neuroprotective against seizure-induced mitochondrial oxidative stress and pathology in hippocampus

RGS14 is a complex multifunctional scaffolding protein that is highly enriched within pyramidal cells (PCs) of hippocampal area CA2. There, RGS14 suppresses glutamate-induced calcium influx and related G protein and ERK signaling in dendritic spines to restrain postsynaptic signaling and plasticity. Previous findings show that, unlike PCs of hippocampal areas CA1 and CA3, CA2 PCs are resistant to a number of neurological insults, including degeneration caused by temporal lobe epilepsy (TLE). While RGS14 is protective against peripheral injury, similar roles for RGS14 during pathological injury in hippocampus remain unexplored. Recent studies show that area CA2 modulates hippocampal excitability, generates epileptiform activity and promotes hippocampal pathology in animal models and patients with TLE. Because RGS14 suppresses CA2 excitability and signaling, we hypothesized that RGS14 would moderate seizure behavior and early hippocampal pathology following seizure activity. Using kainic acid (KA) to induce status epilepticus (KA-SE) in mice, we show loss of RGS14 (RGS14 KO) accelerated onset of limbic motor seizures and mortality compared to wild type (WT) mice, and that KA-SE upregulated RGS14 protein expression in CA2 and CA1 PCs of WT. Utilizing proteomics, we saw loss of RGS14 impacted the expression of a number of proteins at baseline and after KA-SE, many of which associated unexpectedly with mitochondrial function and oxidative stress. RGS14 was shown to localize to the mitochondria in CA2 PCs of mice and reduce mitochondrial respiration in vitro. As a readout of oxidative stress, we found RGS14 KO dramatically increased 3-nitrotyrosine levels in CA2 PCs, which was greatly exacerbated following KA-SE and correlated with a lack of superoxide dismutase 2 (SOD2) induction. Assessing for hallmarks of seizure pathology in RGS14 KO, we observed worse neuronal injury in area CA3 (but none in CA2 or CA1), and a lack of microgliosis in CA1 and CA2 compared to WT. Together, our data demonstrates a newly appreciated neuroprotective role for RGS14 against intense seizure activity in hippocampus. Our findings are consistent with a model where, after seizure, RGS14 is upregulated to support mitochondrial function and prevent oxidative stress in CA2 PCs, limit seizure onset and hippocampal neuronal injury, and promote microglial activation in hippocampus.

neuroscience↗

bioRxiv2020

Sexually dimorphic responses to MPTP found in microglia, inflammation and gut microbiota in a progressive monkey model of Parkinson's disease

Inflammation has been linked to the development of nonmotor symptoms in Parkinsons disease (PD), which greatly impact patients quality of life and can often precede motor symptoms. Suitable animal models are critical for our understanding of the mechanisms underlying disease and the associated prodromal disturbances. The neurotoxin 1- methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkey model is commonly seen as a "gold standard" model that closely mimics the clinical motor symptoms and the nigrostriatal dopaminergic loss of PD, however MPTP toxicity extends to other nondopaminergic regions. Yet, there are limited reports monitoring the MPTP-induced progressive central and peripheral inflammation as well as other nonmotor symptoms such as gastrointestinal function and microbiota. The main objective of this study is to gain a broader understanding of central and peripheral inflammatory dysfunction triggered by exposure to a neurotoxicant known to degenerate nigral dopaminergic neurons in order to understand the potential role of inflammation in prodromal/pre-motor features of PD-like degeneration in a progressive non-human primate model of the disease. We measured inflammatory proteins in plasma and CSF and performed [18F]FEPPA PET scans to evaluate translocator proteins (TSPO) or microglial activation in a small cohort of rhesus monkeys (n=5) given weekly low doses of MPTP (0.2-0.8 mg/kg, im). Additionally, monkeys were evaluated for working memory and executive function using various behavior tasks and for gastrointestinal hyperpermeability and microbiota composition. Monkeys were also treated with novel TNF inhibitor XPro1595 (10mg/kg, n=3) or vehicle (n=2) every three days starting 11 weeks after the initiation of MPTP to determine whether nonmotor symptoms are tied to TNF signaling and whether XPro1595 would alter inflammation and microglial behavior in a progressive model of PD. Our analyses revealed sex-dependent sensitivity to MPTP that resulted in early microglial activation by PET, acute plasma IL-6 and CSF TNF, and earlier parkinsonism as measured by motor deficits in males compared to female monkeys. Sex differences were also identified in microbiota and their metabolites and targeted short chain fatty acids at both basal levels and in response to MPTP. Both sexes displayed cognitive impairment prior to a significant motor phenotype. Importantly, XPro1595 shifted peripheral and central inflammation, and significantly reduced CD68-immunoreactivity in the colon. As such, our findings revealed a sexually dimorphic inflammatory response to chronic MPTP treatment and suggest that males may have higher vulnerability than females to inflammation-induced degeneration. If these findings reflect potential differences in humans, these sex differences have significant implications for therapeutic development of inflammatory targets in the clinic.

neuroscience↗

bioRxiv2019

Guanine content of microRNAs is associated with their tumor suppressive and oncogenic roles in lung and breast cancers

BackgroundmicroRNAs (miRNAs, miRs) are small noncoding RNAs that negatively regulate gene expression at the post-transcriptional level and fine-tune gene functions. A global repression of miRNAs expression in different types of human tumors, after exposure to cigarette-smoke, or to the hormone estrogen, have been shown to be associated with guanine (G) enrichment in the terminal loops (TLs) of their precursors. Methodswe integrated the G content of miRNA mature forms and precursor miRNA TLs with their described function in the literature, using the PubMed database. Gene Ontology term analysis was used to describe the pathways in which the G-enriched miRNA targets are involved. Resultswe show here an association between the relative G enrichment of precursor miRNAs TLs and their tendency to act as tumor suppressor miRs in human lung and breast cancers. Another association was observed between the high G content of the miRNAs 5-mature forms and their tendency to act as oncomiRs. Conclusionsthe results support previous findings showing that the G sequence content is an important feature determining miRNA expression and function, and open the way for future cancer investigations in this direction.

cancer biology↗