Biology subjects

Peterson, S.

Publications and source records attributed to Peterson, S..

16 recordsLinked to original sources

bioRxiv2026

Sex-specific gene and isoform expression characterizes hippocampal aging in rhesus macaques

Aging produces widespread transcriptomic alterations that extend beyond changes in gene expression to include changes at the isoform level. Declining splicing fidelity, including increased intron retention and aberrant isoform expression, has been proposed to contribute to cellular dysfunction; however, the extent and biological significance of isoform-specific changes in the aging brain remain poorly understood. Age-related cognitive decline has also been associated with neuroinflammation and the development of a chronic inflammatory state, or ''inflammaging,'' within the brain. Here, we used short- and long-read RNA sequencing to characterize gene- and isoform-level changes associated with hippocampal aging across sex in 24 rhesus macaques. We identified 594 age-associated differential isoform expression events, comprising both shared and sex-specific changes. Inflammatory pathways, including TNF- -- NF-{kappa}B signaling, interferon responses, and complement pathways, were enriched across both sexes. Weighted gene co-expression network analysis (WGCNA) further identified sex-specific modules associated with inflammatory, glial, mitochondrial, and hormone-responsive processes. Notably, several age-associated changes were detected at the isoform level despite limited or absent corresponding gene-level differences, highlighting transcript-level regulation as an additional dimension of brain aging that may be overlooked by gene-level analyses. To investigate the relationship between aging and Alzheimer's disease (AD), we independently performed WGCNA on the rhesus macaque cohort and a publicly available human hippocampal AD single-nucleus RNA-sequencing dataset (GSE268609). Cross-species module preservation and gene overlap analyses identified shared genes between age-associated and AD-associated networks, with pathway enrichment implicating glial function, inflammation, and mitochondrial biology. Together, these findings highlight sex-associated differences in hippocampal transcriptomic aging, underscore the importance of isoform-level regulation, and identify shared transcriptional signatures between normal aging and AD-associated pathways.

neuroscience↗

bioRxiv2026

Breaking the link between demyelination and axon loss: SARM1 inhibition as a neuroprotective strategy for multiple sclerosis

Axonal degeneration is a principal driver of irreversible neurological disability in multiple sclerosis (MS), yet current treatments fail to target this neurodegenerative phase directly. Sterile alpha and TIR domain-containing protein 1 (SARM1) has emerged as an executioner of programmed axon destruction and is overexpressed in grey and white matter MS tissue, making its inhibition a promising therapeutic strategy. However, the effects of SARM1 inhibition on localized neurodegeneration versus systemic and central inflammation remain poorly understood in complex autoimmune environments like MS. Here, we investigated SARM1 pathology using global SARM1-/- knockout (SARM1-/-) mice, AAV-mediated CRISPR knockdown and overexpression of SARM1 in retinal ganglion cells (RGCs), and the small-molecule SARM1 inhibitor 5-iodoisoquinoline (5IIQ), across optic nerve crush (ONC) and experimental autoimmune encephalomyelitis (EAE) models. While global SARM1-/- did not alter the overall clinical course of EAE, it revealed a complex phenotype characterized by an altered peripheral inflammatory cytokine profile and persistent CNS immune infiltration, alongside preserved axonal and myelin integrity. RGC-restricted SARM1 knockdown partially preserved RGCs and axons during EAE, whereas SARM1 overexpression worsened both retinal function and axonal injury. Pharmacological inhibition with 5IIQ preserved axonal integrity and restored visual function in both the ONC and EAE models, as confirmed by electrophysiology, and reduced serum neurofilament light chain (NfL) in EAE, without affecting demyelination. Together, these findings demonstrate that SARM1 inhibition uncouples axonal self-destruction from demyelination and gross neuroinflammation while providing robust structural and functional neuroprotection. This study establishes SARM1 as a viable target for neuroprotective co-therapies designed to complement existing immunomodulatory and remyelinating regimens in MS and related neurodegenerative disorders.

neuroscience↗

bioRxiv2026

Adaptation of white adipocytes to cooler temperatures: impacts on energy metabolism and protein acetylation

Adipocytes throughout the body reside in distinct thermal environments. Visceral adipocytes within the body core are maintained near 37 {degrees}C, whereas those in bone marrow, subcutaneous, and dermal depots occupy cooler regions within the peripheral shell. While brown and beige adipocyte responses to cold stress are well characterized, much less is known about how white adipocytes adapt to moderately reduced temperatures below 37 {degrees}C. Our recent work revealed that cultured adipocytes exposed to 31 {degrees}C, a temperature representative of distal adipose regions, exhibit enhanced mitochondrial function, including increased substrate oxidation and ATP turnover, yet the mechanisms underlying this upregulation remain unclear. Here we show that adaptation to cool temperatures leads to a widespread decrease in protein acetylation in both undifferentiated and differentiated adipocytes, independent of nutrient status, and that this change is readily reversible upon rewarming. Subcellular fractionation and immunoblotting demonstrate that the hypoacetylation coincides with a compartment-specific enrichment of acetylated proteins within mitochondria, indicating selective remodeling of the mitochondrial acetylome. Transcriptomic and biochemical analyses reveal that these temperature-dependent changes occur without alterations in acetyltransferase or deacetylase expression, NAD concentration, or acetyl-CoA availability, suggesting regulation through alternative mechanisms affecting acetyl-CoA flux or enzyme activity. Integrative acetyl-proteomic and metabolomic profiling identifies mitochondrial enzymes, including serine hydroxymethyltransferase 2 (SHMT2) and propionyl-CoA carboxylase (PCCA), whose acetylation correlates closely with changes in associated metabolite pools. Together, these findings establish physiologically relevant cooling as a cell-autonomous regulator of mitochondrial protein acetylation and metabolic adaptation in adipocytes.

cell biology↗

bioRxiv2026

Orbitofrontal circuits for context-gated reward predictions

The orbitofrontal cortex (OFC) is essential for the contextual regulation of reward predictions, yet the circuit mechanisms underlying this function remain unclear. Here, we dissected the roles of two major OFC efferent pathways --projections to the central dorsal striatum (CDS) and the mediodorsal thalamus (MDT)-- in contextual regulation. Male and female rats performed a context-dependent discrimination task in which the reward-predictive status of two auditory target cues (X and Y) was determined by a visual contextual cue (A). Using temporally precise optogenetic inhibition of OFC terminals, we found that silencing OFC[->]CDS profoundly disrupted contextual gating, virtually abolishing the negatively gated component (A:Y- / Y+) while producing modest effects on the positively gated component (A:X+ / X-). In contrast, OFC[->]MDT inhibition produced modest and qualitatively distinct effects, characterized by a generalized increase in responding in context A and a decrease in context noA. These effects were reproduced in a connectionist model in which context influenced predictions either additively (via elemental representations) or by acting as a gatekeeper (via configural cue/context representations). Disrupting the configural pathway mimicked OFC[->]CDS silencing, whereas amplifying additive contextual inputs replicated OFC[->]MDT inhibition. Together, these findings reveal complementary circuit mechanisms through which the OFC shapes context-appropriate reward seeking.

neuroscience↗

bioRxiv2025

Integration of Multiomic and Multi-phenotypic Data Identifies Biological Pathways Associated with Physical Fitness

Unraveling the complex associations between human phenotypes and molecular pathways can pave the way to improved health and performance, but faces a fundamental challenge: the measurable genes, proteins, and metabolites vastly outnumber the participants in even the largest studies, yielding spurious correlations. To address this imbalance, we have developed a bioinformatic framework and computational approach ("PhenoMol") to discover biological drivers of phenotypic characteristics that integrates all available phenotypic data predictive of outcomes and reduces multi-omic data dimensionality by generating "expression circuits" via graph theory constrained by prior biological knowledge of molecular interactions. We applied PhenoMol to analyze causal patterns and predict elite physical performance in a healthy cohort with deep physiological, physical, behavioral, cognitive, and molecular characterization. PhenoMol outperforms regression models based on equivalent analytic methodologies that do not employ network biology for dimensionality reduction. The PhenoMol software is provided for future studies.

bioinformatics↗

bioRxiv2025

Pollen diet, more than geographic distance, shapes provision microbiome composition in two species of cavity-nesting bees

The microbial composition of stored food can influence its stability and determine the microbial species consumed by the organism feeding on it. Many bee species store nectar and pollen in provisions constructed to feed developing offspring. Previous work has shown variation in provision microbiome among bee populations, yet whether this variation is determined by the pollen types within provisions, variation between bee species at the same nesting sites, or geographic distance was unclear. Here, we sampled two species of co-occurring cavity nesting bees in the genus Osmia at 13 sites across the Sierra foothills in California and examined the composition of pollen, fungi and bacteria found in their provisions across sites. As expected, pollen, bacterial and fungal composition exhibited significant turnover between bees and sites, with bee species characterized by particular pollen and microbial species. Pollen composition explained 15% of variation in bacterial composition and [~]30% of variation in fungal composition, whereas spatial distance among sites explained minimal additional variation. Symbiotic or bee-specialized microbe genera Ascosphaera, Sodalis and Wolbachia showed contrasting patterns of association with pollen composition, suggesting distinct acquisition and transmission routes for each. Comparing provisions from both bee species comprised of the same pollens points to environmental acquisition rather than bee species as a key factor shaping the early stages of the bee microbiome in Osmia. The patterns we observed also contrast with Apilactobacillus-dominated provision microbiome in other solitary bee species, suggesting variable mechanisms of microbial assembly in stored food among bee species.

ecology↗

bioRxiv2024

Partially dissociable roles of the Orbitofrontal cortex and dorsal Hippocampus in context-dependent (hierarchical) reward predictions and contextual inference in learning

Reward cues are often ambiguous; what is good in one context is not necessarily good in another context. To solve this ambiguity, animals form hierarchical associations in which the context acts as a gatekeeper in the retrieval of the appropriate cue-evoked memory, ensuring context-appropriate behavior. These hierarchical associative structures also influence future learning by promoting the formation of new context-dependent associations (leading to the inference of context-dependency for new associations). The orbitofrontal cortex (OFC) and the dorsal hippocampus (DH) are both proposed to encode a "cognitive map" that includes the representation of hierarchical, context-dependent, associations. However the causal role of the OFC and DH in the different functional properties of hierarchical associations remains controversial. Here we used chemogenetic inactivations, in rats, to examine the role of OFC and DH in 1) the contextual regulation of performance, and 2) the contextual learning bias conferred by hierarchical associations. We show that OFC is required for both manifestations of hierarchical associations. In contrast, DH contribution appears limited to the contextual learning bias. This study provides novel insight into the different functional properties of context-dependent hierarchical associations, and establishes the OFC as a critical orchestrator of these different contextual effects.

neuroscience↗

bioRxiv2023

Sex differences in discrimination behavior and orbitofrontal engagement during context-gated reward prediction

Animals, including humans, rely on contextual information to interpret ambiguous stimuli. Impaired context processing is a hallmark of several neuropsychiatric disorders, including schizophrenia, autism spectrum disorders, post-traumatic stress disorder, and addiction. While sex differences in the prevalence and manifestations of these disorders are well established, potential sex differences in context processing remain uncertain. Here we examined sex differences in the contextual control over cue-evoked reward seeking and its neural correlates, in rats. Male and female rats were trained in a bidirectional occasion-setting preparation in which the validity of two auditory reward-predictive cues was informed by the presence, or absence, of a visual contextual feature (LIGHT: X+ / DARK: X- / LIGHT: Y- / DARK: Y+). Females were significantly slower to acquire contextual control over cue-evoked reward seeking. However, once established, the contextual control over behavior was more robust in female rats; it showed less within-session variability (less influence of prior reward) and greater resistance to acute stress. This superior contextual control achieved by females was accompanied by an increased activation of the orbitofrontal cortex compared to males. Critically, these behavioral and neural sex differences were specific to the contextual modulation process and not observed in simple, context-independent, reward prediction tasks. These results indicate a sex-biased trade-off between the speed of acquisition and the robustness of performance in the contextual modulation of cued reward seeking. The different distribution of sexes along the fast learning {leftrightarrow} steady performance continuum might reflect different levels of engagement of the orbitofrontal cortex, and might have implications for our understanding of sex differences in psychiatric disorders.

neuroscience↗

bioRxiv2023

A naturally occurring variant of MBD4 causes maternal germline hypermutation in primates

As part of an ongoing genome sequencing project at the Oregon National Primate Research Center, we identified a rhesus macaque with a rare homozygous frameshift mutation in the gene Methyl-CpG binding domain 4 (MBD4). MBD4 is responsible for the repair of C>T deamination mutations at CpG locations and has been linked to somatic hypermutation and cancer predisposition in humans. We show here that MBD4-associated hypermutation also affects the germline: the 6 offspring of the MBD4-null dam have a 4-6 fold increase in de novo mutation burden. This excess burden was predominantly C>T mutations at CpG locations consistent with MBD4 loss-of-function in the dam. There was also a significant excess of C>T at CpA sites, indicating an important, underappreciated role for MBD4 to repair deamination in CpA contexts. The MBD4-null dam developed sustained eosinophilia later in life, but we saw no other signs of neoplastic processes associated with MBD4 loss-of-function in humans, nor any obvious disease in the hypermutated offspring. This work provides what is likely the first evidence for a genetic factor causing hypermutation in the maternal germline of a mammal, and adds to the very small list of naturally occurring variants known to modulate germline mutation rates in mammals.

genetics↗

bioRxiv2023

Parallel Neurodegenerative Phenotypes in Sporadic Parkinsons Disease Fibroblasts and Midbrain Dopamine Neurons

Understanding the mechanisms causing Parkinsons disease (PD) is vital to the development of much needed early diagnostics and therapeutics for this debilitating condition. Here, we report cellular and molecular alterations in skin fibroblasts of late-onset sporadic PD subjects, that were recapitulated in matched induced pluripotent stem cell (iPSC)-derived midbrain dopamine (DA) neurons, reprogrammed from the same fibroblasts. Specific changes in growth, morphology, reactive oxygen species levels, mitochondrial function, and autophagy, were seen in both the PD fibroblasts and DA neurons, as compared to their respective controls. Additionally, significant alterations in alpha synuclein expression and electrical activity were also noted in the PD DA neurons. Interestingly, although the fibroblast and neuronal phenotypes were similar to each other, they also differed in their nature and scale. Furthermore, statistical analysis revealed novel associations between various clinical measures of the PD subjects and the different fibroblast and neuronal data. In essence, these findings encapsulate spontaneous, in-tandem, disease-related phenotypes in both sporadic PD fibroblasts and iPSC-based DA neurons, from the same patient, and generates an innovative model to investigate PD mechanisms with a view towards rational disease stratification and precision treatments.

neuroscience↗

bioRxiv2023

CTCF is essential for proper mitotic spindle structure and anaphase segregation

Mitosis is an essential process in which the duplicated genome is segregated equally into two daughter cells. CTCF has been reported to be present in mitosis but its importance for mitotic fidelity remains to be determined. To evaluate the importance of CTCF in mitosis, we tracked mitotic behaviors in wild type and two different CTCF CRISPR-based genetic knockdowns. We find that knockdown of CTCF results in prolonged mitoses and failed anaphase segregation via time lapse imaging of SiR-DNA. CTCF knockdown did not alter cell cycling or the mitotic checkpoint, which was activated upon nocodazole treatment. Immunofluorescence imaging of the mitotic spindle in CTCF knockdowns revealed disorganization via tri/tetrapolar spindles and chromosomes behind the spindle pole. Imaging of interphase nuclei showed that nuclear size increased drastically, consistent with failure to divide the duplicated genome in anaphase. Population measurements of nuclear shape in CTCF knockdowns do not display decreased circularity or increased nuclear blebbing relative to wild type. However, failed mitoses do display abnormal nuclear morphologies relative to successful mitoses, suggesting population images do not capture individual behaviors. Thus, CTCF is important for both proper metaphase organization and anaphase segregation which impacts the size and shape of the interphase nucleus.

cell biology↗

bioRxiv2021

Kismet/CHD7/CHD8 affects gut biomechanics, the gut microbiome, and gut-brain axis in Drosophila melanogaster

The gut-brain axis may contribute to the pathophysiology of neurodevelopmental disorders, yet it is often unclear how risk genes associated with these disorders affect gut physiology in a manner that could impact microbial colonization. We addressed this question using Drosophila melanogaster with a null mutation in kismet, the ortholog of chromodomain helicase DNA-binding protein (CHD) family members CHD7 and CHD8. In humans, CHD7 and CHD8 are risk genes for neurodevelopmental disorders with co-occurring gastrointestinal symptoms. We found kismet mutant flies have a significant increase in gastrointestinal transit time, indicating functional homology of kismet with CHD7/CHD8 in vertebrates. To measure gut tissue mechanics, we used a high-precision force transducer and length controller, capable of measuring forces to micro-Newton precision, which revealed significant changes in the mechanics of kismet mutant guts, in terms of elasticity, strain stiffening, and tensile strength. Using 16S rRNA metagenomic sequencing, we also found kismet mutants have reduced diversity of gut microbiota at every taxonomic level and an increase in pathogenic taxa. To investigate the connection between the gut microbiome and behavior, we depleted gut microbiota in kismet mutant and control flies and measured courtship behavior. Depletion of gut microbiota rescued courtship defects of kismet mutant flies, indicating a connection between gut microbiota and behavior. In striking contrast, depletion of gut microbiome in the control strain reduced courtship activity. This result demonstrated that antibiotic treatment can have differential impacts on behavior that may depend on the status of microbial dysbiosis in the gut prior to depletion. We propose that Kismet influences multiple gastrointestinal phenotypes that contribute to the gut-brain axis to influence behavior. Based on our results, we also suggest that gut tissue mechanics should be considered as an element in the gut-brain communication loop, both influenced by and potentially influencing the gut microbiome and neuronal development.

developmental biology↗

bioRxiv2021

Aldh2 dependent formaldehyde metabolism fuels purine demands in melanocyte stem cells

Melanocyte stem cells (McSCs) in zebrafish serve as an on-demand source of melanocytes during growth and regeneration, but metabolic programs associated with their activation and regenerative processes are not well known. Here, using live imaging coupled with scRNA-sequencing, we discovered that quiescent McSCs during regeneration activate a dormant embryonic neural crest transcriptional program followed by an aldehyde dehydrogenase (Aldh) 2 metabolic switch to generate progeny. Unexpectedly, while ALDH2 is well known for its aldehyde clearing mechanisms we find that in regenerating McSCs, Aldh2 activity is required to generate formate - the one-carbon (1C) building block for nucleotide biosynthesis - through formaldehyde metabolism. Consequently, we find that disrupting the 1C cycle with low-doses of methotrexate caused melanocyte regeneration defects. In the absence of Aldh2, we find that purines (but not pyrimidines) are the metabolic end product sufficient for activated McSCs to generate progeny. Together, our work reveals McSCs undergo a two-step cell state transition during regeneration, and that the reaction products of Aldh2 enzymes have tissue-specific stem cell functions that meet metabolic demands in regeneration. SUMMARY STATEMENTIn melanocyte regeneration, quiescent McSCs respond by re-expressing a neural crest identity, followed by an Aldh2-dependent metabolic switch to generate progeny.

cell biology↗

bioRxiv2021

501Y.V2 and 501Y.V3 variants of SARS-CoV-2 lose binding to Bamlanivimab in vitro

We generated several versions of the receptor binding domain (RBD) of the Spike protein with mutations existing within newly emerging variants from South Africa and Brazil. We found that the mutant RBD with K417N, E484K, and N501Y exchanges has higher binding affinity to the human receptor compared to the wildtype RBD. This mutated version of RBD also completely abolishes the binding to a therapeutic antibody, Bamlanivimab, in vitro.

biochemistry↗

bioRxiv2021

The basis of a more contagious 501Y.V1 variant of SARS-COV-2

Severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) is causing a world-wide pandemic. A variant of SARS-COV-2 (20I/501Y.V1) recently discovered in the United Kingdom has a single mutation from N501 to Y501 within the receptor binding domain (Y501-RBD), of the Spike protein of the virus. This variant is much more contagious than the original version (N501-RBD). We found that this mutated version of RBD binds to human Angiotensin Converting Enzyme 2 (ACE2) a ~10 times more tightly than the native version (N501-RBD). Modeling analysis showed that the N501Y mutation would allow a potential aromatic ring-ring interaction and an additional hydrogen bond between the RBD and ACE2. However, sera from individuals immunized with the Pfizer-BioNTech vaccine still efficiently block the binding of Y501-RBD to ACE2 though with a slight compromised manner by comparison with their ability to inhibit binding to ACE2 of N501-RBD. This may raise the concern whether therapeutic anti-RBD antibodies used to treat COVID-19 patients are still efficacious. Nevertheless, a therapeutic antibody, Bamlanivimab, still binds to the Y501-RBD as efficiently as its binds to N501-RBD.

biochemistry↗

bioRxiv2020

The molecular and metabolic program for adaptation of white adipocytesto cool physiologic temperatures

Although visceral adipocytes located within the bodys central core are maintained at ~37{degrees}C, adipocytes within bone marrow, subcutaneous, and dermal depots are found primarily within the peripheral shell, and generally exist at cooler temperatures. Responses of brown and beige/brite adipocytes to cold stress are well-studied; however, comparatively little is known about mechanisms by white adipocytes adapt to temperatures below 37{degrees}C. Here we report that adaptation of cultured adipocytes to 31{degrees}C, the temperature at which distal marrow adipose tissues and subcutaneous adipose tissues often reside, induces extensive changes in gene expression, increased anabolic and catabolic lipid metabolism, and elevated oxygen consumption with reduced reliance on glucose and preferential use of pyruvate, glutamine and fatty acids as energy sources. Cool temperatures up-regulate stearoyl-CoA desaturase-1 expression and monounsaturated lipid levels in cultured adipocytes and distal bone marrow adipose tissues, and stearoyl-CoA desaturase-1 activity is required for acquisition of maximal oxygen consumption at 31{degrees}C.

physiology↗