Biology subjects

Small, D. M.

Publications and source records attributed to Small, D. M..

10 recordsLinked to original sources

bioRxiv2025

Neutrophil arrest in myocardial capillaries drives hypoxia and impairs diastolic function in a mouse model of heart failure with preserved ejection fraction

Impairments in myocardial blood flow have been recognized for decades in human patients with and animal models of heart failure with preserved ejection fraction (HFpEF), but the underlying mechanisms and roles in pathogenesis remain poorly understood. Using intravital cardiac microcopy in a two-hit mouse model of HFpEF that combines high fat diet and inhibition of nitric oxide synthase, we identified an increase in slow or non-flowing neutrophils in capillaries compared to Control mice. In other mouse models of disease (e.g., in the brain of Alzheimers Disease mice), the presence of such stalled neutrophils leads to organ-wide decreases in perfusion and oxygenation. Administration of antibodies against the neutrophil surface protein Ly6G to deplete neutrophils reduced the number of arrested neutrophils in myocardial capillaries, leading to improvements in myocardial hypoxia, diastolic function, and exercise capacity. This study identifies a previously uncharacterized cellular mechanism that explains myocardial blood flow deficits in mouse models of HFpEF, and demonstrates that improving myocardial blood flow improves cardiac function, without necessitating reversal of pathologic remodeling. Restoring myocardial perfusion by decreasing neutrophil arrest in myocardial capillaries may provide a strategy for improving heart function in HFpEF patients in the future.

physiology↗

bioRxiv2025

A lateralized pathway for associating nutrients with flavors

Animals learn about the external world, in part, via interoceptive signals1,2. For example, the nutrient content of food is first estimated in the mouth, in the form of flavor, and then measured again via slower signals from the gut. How these signals from the mouth and gut are integrated to drive learning is unknown. Here we identify a lateralized dopamine pathway that is specialized for learning about the nutrient content of food. We show that dopamine neurons in the ventral tegmental area (VTADA) are necessary for associating nutrients with flavors, and that post-ingestive nutrients trigger DA release selectively in a small region of the anterior basolateral amygdala (BLA) but not canonical DA targets in striatum. Remarkably, this nutrient-triggered DA release occurs preferentially on the left side of the brain in both mice and humans, revealing that the DA system is functionally lateralized. We identify the gut sensors that are responsible for nutrient-triggered DA release; show that they activate BLA-projecting DA neurons defined by expression of cholecystokinin (CCK); and demonstrate that stimulation of DA axon terminals in the anterior BLA drives flavor-nutrient learning but not other aspects of feeding behavior. Two-photon imaging of neurons in the left anterior BLA reveals that they integrate gustatory and post-ingestive cues, and silencing these neurons prevents flavor-nutrient learning. These findings establish a neural basis for how animals learn about the nutrient content of their food. They also reveal unexpectedly that post-ingestive nutrients are differentially represented on the right and left sides of the brain.

neuroscience↗

bioRxiv2023

Odor imagery but not perception drives risk for food cue reactivity and increased adiposity

Mental imagery has been proposed to play a critical role in the amplification of cravings. Here we tested whether olfactory imagery drives food cue reactivity strength to promote adiposity in 45 healthy individuals. We measured odor perception, odor imagery ability, and food cue reactivity using self-report, perceptual testing, and neuroimaging. Adiposity was assessed at baseline and one year later. Brain responses to real and imagined odors were analyzed with univariate and multivariate decoding methods to identify pattern-based olfactory codes. We found that the accuracy of decoding imagined, but not real, odor quality correlated with a perceptual measure of odor imagery ability and with greater adiposity changes. This latter relationship was mediated by cue-potentiated craving and intake. Collectively, these findings establish odor imagery ability as a risk factor for weight gain and more specifically as a mechanism by which exposure to food cues promotes craving and overeating.

neuroscience↗

bioRxiv2022

The addiction-susceptibility TaqIA/Ankyrin repeat and kinase domain containing 1 kinase (ANKK1) controls reward and metabolism through dopamine receptor type 2 (DR2)-expressing neurons

Significant evidence highlights the importance of genetic variants in the development of psychiatric and metabolic conditions. Among these, the Taq1A polymorphism is one of the most commonly studied in psychiatry. TaqIA is located in the gene that codes for the Ankyrin repeat and kinase domain containing 1 kinase (ANKK1) near the dopamine D2 dopamine receptor (DR2) gene. Depending on race it affects 30 to 80% of the population and its homozygous expression of the A1 allele correlates with a 30 to 40% reduction of striatal DR2, a typical feature of addiction, over-eating and other psychiatric pathologies. The mechanisms by which the variant influences dopamine signaling and behavior is unknown. Here we used transgenic and viral-mediated strategies to reveal the role of ANKK1 in the regulation of activity and functions of the striatum. We found that Ankk1 is preferentially enriched in striatal DR2 expressing neurons and that Ankk1 loss-of-function in dorsal and ventral striatum leads to alteration in learning, impulsive, and flexible behaviors resembling the endophenotypes described in A1 carriers. We also observed an unsuspected role of ANKK1 in striatal DR2-expressing neurons in the ventral striatum in the regulation of energy homeostasis and documented differential nutrient partitioning in humans with versus without the A1 allele. Overall, our data demonstrate that the Ankk1 gene is necessary for the integrity of striatal functions and reveal a new role for ANKK1 in the regulation of body metabolism.

neuroscience↗

bioRxiv2022

Olfactory decoding is positively associated with ad libitum food intake in sated humans

The role of olfaction in eating behavior and body weight regulation is controversial. Here we used functional magnetic resonance imaging to test whether central olfactory coding is associated with internal state, food intake, and change in body weight over one year in healthy human adults. Since odor quality and category are coded across distributed neural patterns that are not discernible with traditional univariate analyses, we used multi-voxel pattern analyses to decode patterns of brain activation to food versus nonfood odors. We found that decoding accuracies in the piriform cortex and amygdala were greater in the sated compared to hungry state. Sated decoding accuracies in these and other regions were also associated with post-scan ad libitum food intake, but not with weight change. These findings demonstrate that the fidelity of olfactory decoding is influenced by internal state and is associated with immediate food intake, but not longer-term body weight regulation.

neuroscience↗

bioRxiv2021

Fat and carbohydrate interact to potentiate food reward in healthy weight but not in overweight or obesity

Prior work suggests that actual, but not estimated, energy density drives the reinforcing value of food [1,2] and that energy from fat and carbohydrate can interact to potentiate reward [2]. Here we sought to replicate these findings in an American sample and to determine if the effects are influenced by body mass index (BMI). Thirty participants with healthy weight (HW; BMI 21.92 {+/-} 1.77; M {+/-} SD) and 30 participants with overweight/obesity (OW/OB; BMI 29.42 {+/-} 4.44) rated pictures of common American snacks in 120-kcal portions for liking, familiarity, frequency of consumption, expected satiety, healthiness, energy content, energy density, and price. Participants then completed an auction task where they bid for the opportunity to consume each food. Snacks contained either primarily carbohydrate, primarily fat, or roughly equal portions of fat and carbohydrate (combo). Replicating prior work, we found that participants with HW bid the most for combo foods in linear mixed model analyses. This effect was not observed among individuals with OW/OB. Additionally, in contrast with previous reports [1,2], our linear regression analyses revealed a negative relationship between the actual energy density of the snacks and bid amount that was mediated by food price. Our findings support altered macronutrient reinforcement in obesity and highlight potential influences of the food environment on the regulation of food reward.

neuroscience↗

bioRxiv2021

Genetically Engineered Strains for Combinatorial Cardiovascular Optobiology

Optogenetic effectors and sensors provide a novel real-time window into complex physiological processes, enabling determination of molecular signaling processes within functioning cellular networks. However, the combination of these optical tools in mice is made practical by construction of genetic lines that are optically compatible and genetically tractable. We present a new toolbox of 21 mouse lines with lineage -specific expression of optogenetic effectors and sensors for direct biallelic combination, avoiding the multiallelic requirement of Cre recombinase -mediated DNA recombination, focusing on models relevant for cardiovascular biology. Optogenetic effectors (11 lines) or Ca2+ sensors (10 lines) were selectively expressed in cardiac pacemaker cells, cardiomyocytes, vascular endothelial and smooth muscle cells, alveolar epithelial cells, lymphocytes, glia, and other cell types. Optogenetic effector and sensor function was demonstrated in numerous tissues. Arterial/arteriolar tone was modulated by optical activation of the second messengers InsP3 (opto1AR) and cAMP (opto{beta}2AR), or Ca2+- permeant membrane channels (CatCh2) in smooth muscle (Acta2) and endothelium (Cdh5). Cardiac activation was separately controlled through activation of nodal/conducting cells or cardiac myocytes. We demonstrate combined effector and sensor function in biallelic mouse crosses: optical cardiac pacing and simultaneous cardiomyocyte Ca2+ imaging in HCN4BAC-CatCh2/MHC-GCaMP8 crosses. These experiments highlight the potential of these mice to explore cellular signaling in vivo, in complex tissue networks.

physiology↗

bioRxiv2019

Short-term consumption of sucralose with, but not without, carbohydrate impairs neural and metabolic sensitivity to sugar

There is a general consensus that overconsumption of sugar sweetened beverages contributes to the prevalence of obesity and related comorbidities such as type 2 diabetes (T2D). Whether a similar relationship exists for no, or low-calorie "diet" drinks is a subject of intensive debate and controversy. Here, we show that metabolic dysfunction, coupled with reduced central sensitivity to sweet, but not sour, salty or bitter taste, occurs when sucralose is repeatedly consumed with, but not without, a carbohydrate over a two-week period in healthy humans. A similar exposure to sucralose, with, but not without, a carbohydrate altered substrate utilization in mice. More specifically, greater energy intake was required for the animals to shift from fatty acid to carbohydrate oxidation, indicating a reduced sensitivity to carbohydrate. These findings demonstrate that consumption of sucralose in the presence of a carbohydrate rapidly impairs glucose metabolism and may contribute to the rise in T2D.

physiology↗

bioRxiv2019

Fingerprinting Adiposity and Metabolic Function in the Brains of Overweight and Obese Humans

The brain plays a central role in the pathophysiology of obesity. Connectome-based Predictive Modeling (CPM) is a newly developed, data-driven approach that exploits whole-brain functional connectivity to predict a behavior or trait that varies across individuals. We used CPM to determine whether brain "fingerprints" evoked during milkshake consumption could be isolated for common measures of adiposity in 67 overweight and obese adults. We found that a CPM could be identified for waist circumference, but not percent body fat or BMI, the most frequently used measures to assess brain correlates of obesity. In an exploratory analysis, we were also able to derive a largely distinct CPM predicting fasting blood insulin. These findings demonstrate that brain network patterns are more tightly coupled to waist circumference than BMI or percent body fat and that adiposity and glucose tolerance are associated with distinct maps, pointing to dissociable central pathophysiological phenotypes for obesity and diabetes.

neuroscience↗

bioRxiv2018

In vivo multiphoton microscopy of cardiomyocyte calcium dynamics in the beating mouse heart

We demonstrated intravital multiphoton microscopy in the beating heart in an intact mouse and optically measured action potentials with GCaMP6f, a genetically-encoded calcium indicator. Images were acquired at 30 fps with spontaneous heart beat and continuously running ventilated breathing. The data were reconstructed into three-dimensional volumes showing tissue structure, displacement, and GCaMP activity in cardiomyocytes as a function of both the cardiac and respiratory cycle.

physiology↗