Biology subjects

Thompson, J. M.

Publications and source records attributed to Thompson, J. M..

6 recordsLinked to original sources

bioRxiv2025

Reduced SK channel control of mesolimbic dopamine neuron firing drives reward seeking adaptations in chronic pain

Patients with chronic neuropathic pain typically experience affective symptoms that drive reduced quality of life and negatively impact pain management. Mesolimbic dopamine is necessary for reward valuation and learning, and the existence of a hypodopaminergic state has been proposed to underlie these affective symptoms of chronic pain. However, direct functional evidence for this hypodopaminergic state is lacking, and the mechanisms underlying its emergence over the acute to chronic pain transition are unknown. Here, we find a selective deficit in the ability of mesolimbic dopamine neurons to sustain burst firing, which is apparent uniquely at chronic timepoints following neuropathic injury. As a result, animals are unable to sustain effortful pursuit of rewards under conditions of high effort or time costs. Convergent biophysical modeling and experimental electrophysiology establish that in a spared nerve injury (SNI) model of chronic neuropathic pain, calcium-activated, small-conductance potassium (SK) channel function is impaired, resulting in lower peak firing and earlier entry into depolarization block of mesolimbic dopamine neurons. Critically, dopamine dependent reward learning, formation of cue-reward associations and locomotor activity remain intact, arguing against the interpretation of a generalized hypodopaminergic state. These results elucidate a circuit-level basis for selective motivational deficits emerging in chronic neuropathic pain.

neuroscience↗

bioRxiv2025

Single-nucleus analysis of thoracic perivascular adipose tissue reveals critical changes in cell composition, communication, and gene regulatory networks induced by a high fat hypertensive diet

Perivascular adipose tissue (PVAT), an intriguing layer of fat surrounding blood vessels, regulates vascular tone and mediates vascular dysfunction through mechanisms that are not well understood. Here we show with single nucleus RNA-sequencing of thoracic aortic PVAT from Dahl SS rats that a high-fat (HF) hypertensive diet induces coordinated changes in gene expression across the diverse cell types within PVAT. HF diet produced sex-specific alterations in cell-type proportions and genes related to remodeling of extracellular matrix dynamics and vascular integrity and stiffness, as well as changes in cell-cell communication pathways involved in angiogenesis, vascular remodeling, and mechanotransduction. Gene regulatory network analysis with virtual transcription factor knockout in adipocytes identified specific nuclear receptors that could be targeted for suppression or potential reversal of HF diet-induced changes. Interestingly, generative deep learning models were able to predict cross-cell-type perturbations in gene expression, indicating a hypertensive disease signature that characterizes HF-diet-induced perturbations in PVAT.

bioinformatics↗

bioRxiv2024

A simple action reduces food intake and obesity in mice

Diets that are high in fat cause over-eating and weight gain in multiple species of animals, suggesting that high dietary fat is sufficient to cause obesity. However, high-fat diets are typically provided freely to animals in obesity experiments, so it remains unclear if high-fat diets would still cause obesity if they required more effort to obtain. We hypothesized that unrestricted and easy access is necessary for high-fat diet induced over-eating, and the corollary that requiring mice to perform small amounts of work to obtain high-fat diet would reduce high-fat diet intake and associated weight gain. To test this hypothesis, we developed a novel home-cage based feeding device that either provided high-fat diet freely, or after mice poked their noses into a port one time - a simple action that is easy for them to do. We tested the effect of this intervention for six weeks, with mice receiving all daily calories from high-fat diet, modifying only how they accessed it. Requiring mice to nose-poke to access high-fat diet reduced intake and nearly completely prevented the development of obesity. In follow up experiments, we observed a similar phenomenon in mice responding for low-fat grain-based pellets that do not induce obesity, suggesting a general mechanism whereby animals engage with and consume more food when it is freely available vs. when it requires a simple action to obtain. We conclude that unrestricted access to food promotes overeating, and that a simple action such as a nose-poke can reduce over-eating and weight gain in mice. This may have implications for why over-eating and obesity are common in modern food environments, which are often characterized by easy access to low-cost unhealthy foods.

animal behavior and cognition↗

bioRxiv2024

Delivering large genes using adeno-associated virus and the CRE-lox DNA recombination system

Adeno-associated virus (AAV) is a safe and efficient gene delivery vehicle for gene therapies. However, its relatively small packaging capacity limits its use as a gene transfer vector. Here, we describe a strategy to deliver large genes that exceed the AAVs packaging capacity using up to four AAV vectors and the CRE-lox DNA recombination system. We devised novel lox sites by combining non-compatible and reaction equilibrium-modifying lox site variants. These lox sites facilitate sequence-specific and near-unidirectional recombination of AAV vector genomes, enabling efficient reconstitution of up to 16 kb of therapeutic genes in a pre-determined configuration. Using this strategy, we have developed AAV gene therapy vectors to deliver IFT140, PCDH15, CEP290, and CDH23 and demonstrate efficient production of full-length proteins in cultured mammalian cells and mouse retinas. Notably, this approach significantly surpasses the trans-splicing and split-intein-based reconstitution methods in efficiency, requiring lower doses, minimizing or eliminating the production of truncated protein products, and offering flexibility in selecting splitting positions. The CRE-lox approach described here provides a simple and effective platform for producing AAV gene therapy vectors beyond AAVs packaging capacity.

molecular biology↗

bioRxiv2023

A Cell Atlas of Thoracic Aortic Perivascular Adipose Tissue: a focus on mechanotransducers

Perivascular adipose tissue (PVAT) is increasingly recognized for its function in mechanotransduction. To examine the cell-specificity of recognized mechanotransducers we used single nuclei RNA sequencing (snRNAseq) of the thoracic aorta PVAT (taPVAT) from male Dahl SS rats compared to subscapular brown adipose tissue (BAT). Approximately 30,000 nuclei from taPVAT and BAT each were characterized by snRNAseq, identifying 8 major cell types expected and one unexpected (nuclei with oligodendrocyte marker genes). Cell-specific differential gene expression analysis between taPVAT and BAT identified up to 511 genes (adipocytes) with many ([≥]20%) being unique to individual cell types. Piezo1 was the most highly, widely expressed mechanotransducer. Presence of PIEZO1 in the PVAT was confirmed by RNAscope(R) and IHC; antagonism of PIEZO1 impaired the PVATs ability to hold tension. Collectively, the cell compositions of taPVAT and BAT are highly similar, and PIEZO1 is likely a mechanotransducer in taPVAT.

molecular biology↗

bioRxiv2017

Discordant association of the CREBRF rs373863828 minor allele with increased body mass index and protection from type 2 diabetes in Maori and Pacific (Polynesian) people living in New Zealand

Aim/HypothesesThe minor allele of CREBRF rs373863828 associates with increased body mass index (BMI) and reduced risk of type 2 diabetes (T2D) in the Samoan population of Samoa and American Samoa. Our aim was to test rs373863828 for association with BMI and odds of T2D, gout and chronic kidney disease (CKD) in M[a]ori and Pacific (Polynesian) people living in Aotearoa New Zealand in 2,286 adults.\n\nMethodsAssociation analyses were performed by linear and logistic regression with BMI, log-transformed BMI, waist circumference, T2D, gout and CKD. Analyses were adjusted for age, sex, the first four genome-wide principal components, and (when appropriate) BMI, waist circumference and T2D.\n\nResultsFor the minor allele of rs373863828 the effect size for log-transformed BMI was 0.038 (95% CI [0.022-0.055], P=4.8x10-6) and for T2D was OR=0.59 (95% CI [0.47-0.73], P=1.9x10-6). There was no evidence for association of genotype with variance in BMI (P=0.13). Nor was there evidence for association with serum urate ({beta}=0.012 mmol/L, Pc=0.10), gout (OR=1.00, P=0.98) or CKD (OR=0.91, P=0.59).\n\nConclusions/interpretationOur results replicated, with very similar effect sizes, association of the minor allele of rs373863828 with higher BMI but lower odds of T2D among New Zealand Polynesian adults, as in Samoan adults living in Samoa and American Samoa.

genetics↗