Biology subjects

Smart, S.

Publications and source records attributed to Smart, S..

7 recordsLinked to original sources

bioRxiv2026

A hippocampal neuroimaging signature of neurovascular insulin signalling links metabolism to mood

Depression is a leading cause of global disability and is increasingly linked to systemic metabolic dysfunctions, including insulin resistance. However, the biological pathways connecting metabolic state to affective symptoms are unresolved. A growing body of evidence indicates that insulin, beyond its role in systemic glucose homeostasis, supports brain metabolism, synaptic function and cognition, yet its contribution to mood regulation remains unclear. Here, we identify a human hippocampal metabolic signature associated with glycaemic variation in individuals with depression. Using multimodal neuroimaging, we show that hippocampal concentrations of GABA and lactate correlate with HbA1c and with mood severity, while functional connectivity between the hippocampus and the default mode network tracks affective symptoms independently of adiposity. To causally probe these relationships, we generated a mouse model of hippocampus-specific insulin receptor depletion. Unexpectedly, reducing insulin signalling at the blood brain barrier enhanced neuronal metabolism and attenuated anxiety-like behaviour. Notably, hippocampal lactate and GABA levels similarly tracked anxiety-related behaviour in mice, mirroring their association with symptom severity in humans. Together, these findings identify a conserved neurometabolic signature linking hippocampal insulin signalling to affective state, and reveal that brain insulin resistance exerts context- and cell-type-specific effects on behaviour. This work establishes a mechanistic basis for brain insulin resistance in depression and highlights the hippocampus as a critical hub for metabolic modulation of mood.

neuroscience↗

bioRxiv2024

In vivo quantification of creatine kinase kinetics in mouse brain using 31P-MRS at 7 Tesla

31P-MRS is a method of choice for studying neuroenergetics in vivo, but its application in the mouse brain have been limited, often restricted to ultra-high field (>7 Tesla) MRI scanners. Establishing its feasibility on more readily available preclinical 7 Tesla (T) scanners would create new opportunities to study metabolism and physiology in murine models of brain disorders. Here, we demonstrate that the apparent forward rate constant (kf) of creatine kinase (CK) can be accurately quantified using a progressive saturation-transfer approach in the mouse brain at 7T. We also find that a reduction of approximately 20% in the breathing rate of anesthetized mice can lead to a 36% increase in kf attributable to a drop in intracellular pH and mitochondrial ATP production. To achieve this, we used a test-retest analysis to assess the reliability and repeatability of 31P-MRS acquisition, analysis and experimental design protocols. We report that most 31P-containing metabolites can be reliably measured using a localized 3D-ISIS sequence, which showed highest SNR amplitude, SNR consistency and minimal T2 relaxation signal loss. Using this protocol, our study identifies, for the first time, key physiological factors influencing mouse brain energy homeostasis in vivo and provides a methodological basis that will guide future studies interested in implementing 31P-MRS on preclinical 7T scanners.

neuroscience↗

bioRxiv2022

Metabolic clearance rate modeling: A translational approach to quantifying cerebral metabolism using hyperpolarized pyruvate.

Hyperpolarized carbon-13 MRI is a promising technique for in vivo metabolic interrogation of alterations between health and disease. This study introduces a model-free formalism for quantifying the metabolic information in hyperpolarized imaging. This study investigated a novel model-free perfusion and metabolic clearance rate (MCR) model in pre-clinical stroke and in the healthy human brain. Simulations showed that the proposed model was robust to perturbations in T1, transmit B1, and kPL. A significant difference in ipsilateral vs contralateral pyruvate derived cerebral blood flow (CBF) was detected in rats (140 {+/-} 2 vs 89 {+/-} 6 mL/100g/min, p < 0.01, respectively) and pigs (139 {+/-} 12 vs 95 {+/-} 5 mL/100g/min, p = 0.04, respectively), along with an increase in fractional metabolism (26 {+/-} 5 vs 4 {+/-} 2 %, p < 0.01, respectively) in the rodent brain. In addition, a significant increase in ipsilateral vs contralateral MCR (0.034 {+/-} 0.007 vs 0.017 {+/-} 0.02 s-1, p = 0.03, respectively) and a decrease in mean transit time (MTT) (31 {+/-} 8 vs 60 {+/-} 2, p = 0.04, respectively) was observed in the porcine brain. In conclusion, MCR mapping is a simple and robust approach to the post-processing of hyperpolarized magnetic resonance imaging.

physiology↗

bioRxiv2022

CD8 T Cell Memory Inflation is Driven by Latent CMV Infection of Lymphatic Endothelial Cells

CMV, a ubiquitous herpesvirus, elicits an extraordinarily large T cell response that is sustained or increases over time, a phenomenon termed memory inflation. Remarkably, even latent, non-productive infection can drive memory inflation. Despite intense research on this phenomenon, the infected cell type(s) involved are unknown. To identify the responsible cell type(s), we designed a Cre-lox murine CMV (MCMV) system, where a spread-deficient ({Delta}gL) virus expresses recombinant SIINFEKL only in Cre+ host cells. We found that latent infection of endothelial cells (ECs), but not dendritic cells (DCs) or hepatocytes, was sufficient to drive CD8 T cell memory inflation. Infection of Lyve-1-Cre and Prox1-CreERT2 mice revealed that amongst EC subsets, infection of lymphatic ECs was sufficient. Genetic ablation of {beta}2m on lymphatic ECs did not prevent inflation, suggesting another unidentified cell type can also present antigen to CD8 T cells during latency. This novel system definitively shows that antigen presentation by lymphatic ECs drives robust CD8 T cell memory inflation. SUMMARYActive T cell immunosurveillance during latent CMV infection results in T cell memory inflation. A novel Cre-lox genetic system for cell-specific antigen expression reveals that lymphatic ECs, but not DCs or hepatocytes, can drive CD8 T cell memory inflation.

immunology↗

bioRxiv2020

PD-1 Specific 'Blocking' Antibodies That Deplete PD-1+ T Cells Present An Inconvenient Variable In Pre-clinical Immunotherapy Experiments

Therapeutic antibodies blocking PD-1-/PD-L1 interaction have achieved remarkable clinical success in cancer. In addition to blocking a target molecule, some isotypes of antibodies can activate complement, NK cells or phagocytes, resulting in death of the cell expressing the antibodys target. Human anti-PD-1 therapeutics use antibody isotypes designed to minimize such antibody-dependent lysis. In contrast, anti-PD-1 reagents used in mice are derived from multiple species, with different isotypes, and are not engineered to reduce target cell death: few studies analyze or discuss how antibody species and isotype may impact data interpretation. We demonstrate here that anti-PD-1 therapy to promote activation and proliferation of PD-1-expressing CD8 T cells sometimes led instead to a loss of antigen specific cells. This phenomenon was seen in two tumor models and a model of virus infection, and was varied with the clone of anti-PD-1 antibody. Additionally, we compared competition among anti-PD-1 clones to find a combination that allows detection of PD-1-expressing cells despite the presence of blocking anti-PD1 antibodies in vivo. These data bring attention to the possibility of unintended target cell depletion with some commonly used anti-mouse PD-1 clones, and should provide a valuable resource for the design and interpretation of anti-PD-1 studies in mice. (200)

immunology↗

bioRxiv2020

Drivers of vascular plant species area relationships in British broadleaved woodlands and their effects on the species area curve

The loss of plant biodiversity in Great Britain is a major concern, with a fifth of species endangered or vulnerable according to the latest IUCN Red List. The Governments 25 Year Plan for the environment aims to halt this loss and build new habitats, including new woodlands. To ensure that biodiversity loss is halted in existing woodlands and gain is maximised in new ones, we need to better understand which drivers have been most influential in controlling biodiversity. Here we focus on vascular plant species richness. Previous attempts to explain plant species richness have mainly focussed on alpha diversity in a consistent, fixed unit area. Here, we additionally undertake a novel analysis of the effects of environmental heterogeneity and abiotic factors on species-area relationships derived from 16 randomly placed quadrats in each of 103 semi-natural, broad-leaved woodlands across Britain. Species-area relationships were examined at two scales (4m2 to 200m2 and 200m2 to 3200m2) to explore the relationship between the drivers of species richness and the exponent z, of the canonical species-area curve, S = cAz. We also explore the use of a new metric {zeta}r, based on zeta diversity to quantify heterogeneity. Zeta diversity quantifies the number of species shared between multiple combinations of plots. Habitat heterogeneity increased species richness, as did the proximity of the woodlands to surrounding natural habitats. Higher levels of soil organic matter and the progression of woodlands to later successional stages, decreased species richness. Richness was also seen to have a unimodal response to soil acidity with a peak around pH 6. At the smaller scale, heterogeneity elements in the woodland such as riparian zones or coppicing led to an increase in the value of the exponent of the species area curve. At the larger scale, species turnover led to an increase in the exponent of the curves while succession led to a decrease. At both scales, soil organic matter content had a negative effect. {zeta}r was found to be a significant and important variable and to affect both species richness and the slope of the species accumulation curves at larger scales. SynthesisHabitat heterogeneity measures included the presence of coppicing, open areas such as rides and riparian zones and the difference between species assemblages in different plots in the woodland. Results suggest that to maximize vascular plant diversity, woodlands should be managed for heterogeneity. In addition, the increase in richness with exposure to surrounding natural habitats suggests that woodlands benefit from being embedded in more benign habitats and further, that land management surrounding woodlands has a clear role to play in supporting biodiversity within woodlands. This is an area were Agri-environment schemes have an important role.

ecology↗

bioRxiv2018

Magnetic resonance imaging of the regenerating neonatal mouse heart

We present longitudinal magnetic resonance imaging (MRI) of neonatal mouse hearts during the first three weeks following coronary artery ligation to mimic heart attack. We confirm heart regeneration in individual animals injured on post-natal day 1 (P1) while those injured on P7 show the adult response of fibrosis, scarring and impaired heart performance. We document heart growth and development of the principal functional cardiac parameters, and also remodeling during tissue regeneration as compared to fibrosis when imaging repeatedly up to 21 days after myocardial infarction (MI). We reveal compensatory changes in cardiac function with the restoration of tissue and resolution of injury for the P1 cohort and sustained injury responses for the P7 cohort. This study resolves the controversy surrounding neonatal mouse heart regeneration and establishes a functional platform for live capture of the regenerative process and for the future testing of genetic or therapeutic interventions.

biophysics↗