Steven C. Fordahl

Anemia in aging is multifaceted and may be in part caused by increased inflammation and oxidative stress. Almonds contain nutrients that may improve inflammation or antioxidant activity, which can improve red blood cell (RBC) integrity and mitigate anemia. The aim of this study is to investigate the effects of almond consumption on hematologic markers in a mouse model of aging. Forty-eight 18-month-old male and female C57BL/6 mice were randomized to receive a control diet or an almond-supplemented diet (15% calories from almond meal) for 12 or 21 weeks (four groups, n = 12/group). Blood and tissues were collected after respective intervention periods for analyses of hematologic markers (complete blood count analysis) and antioxidant status (RBC alpha-tocopherol concentration and superoxide dismutase activity). Mice consuming the almond-supplemented diet had significantly lower red cell distribution width at 12 weeks (p = 0.05) and significantly higher RBC count at 21 weeks (p = 0.04). Regression analyses indicated that almond intake resulted in higher RBC count (β = 0.82, p = 0.026) and lower odds of anemia (OR = 0.20, p = 0.046) after adjusting for sex of mice and length of intervention. These findings suggest that almond intake in aging mice improved selected hematologic markers and reduced anemia risk.

Objective: This cross‐sectional study examined associations between sleep, body weight, body composition, appetite, and food reward after bariatric surgery. Methods: A single 7‐day study period in 22 female adults (age, 53.5 ± 9.3 years; BMI, 35.5 ± 8.5 kg/m ² ; body fat: 44.9% ± 8.6%) who underwent bariatric surgery ≥ 1 year prior to enrollment assessed: actigraphy‐measured sleep (duration, efficiency, midpoint, and variability [coefficient of variation]) and activity energy expenditure (AEE); sleep architecture and apnea‐hypopnea index (AHI) via in‐home polysomnography; energy intake via food diaries; resting EE via indirect calorimetry; fasting appetite via visual analog scales; and food reward via Leeds Food Preference Questionnaire. Results: Weight regain was 10.6% relative to nadir postsurgery weight. Rapid eye movement (REM) sleep duration was associated with lower body fat percentage ( r = −0.52, p = 0.02). Participants with AHI ≥ 5 had a greater waist to hip ratio compared to those with AHI < 5 (mean difference = 0.09, p = 0.01). Sleep timing and duration variability was associated with fasting prospective food consumption ( r = 0.44, p = 0.05 and r = 0.47, p = 0.03, respectively). Greater sleep duration was associated with lower AEE ( r = −0.62, p < 0.01) and explicit liking for sweet foods ( r = 0.45, p = 0.04). Conclusions: Our exploratory results underscore the need to evaluate whether sleep behaviors, including total and REM sleep duration, AHI, and sleep regularity, predict long‐term weight loss maintenance after bariatric surgery.

Alcohol use disorder is marked by disrupted behavioral and emotional states which persist into abstinence. The enduring synaptic alterations that remain despite the absence of alcohol are of interest for interventions to prevent relapse. Here, 28 male rhesus macaques underwent over 20 months of alcohol drinking interspersed with three 30-day forced abstinence periods. After the last abstinence period, we paired direct sub-second dopamine monitoring via ex vivo voltammetry in nucleus accumbens core with RNA-sequencing of the ventral tegmental area. We found persistent augmentation of dopamine transporter function, kappa opioid receptor sensitivity, and putative dynorphin release – all inhibitory regulators which act to decrease extracellular dopamine. Surprisingly, though transcript expression was not altered, the relationship between gene expression and functional readouts of these encoded proteins was highly dynamic and altered by drinking history. These results outline the long-lasting synaptic impact of alcohol use and suggest that assessment of transcript-function relationships is critical for the rational design of precision therapeutics.

Objective: The objective of this study was to determine the influence of sex and strain on striatal and nucleus accumbens dopamine neurochemistry and dopamine-related behavior due to a high-saturated-fat diet (HFD). Methods: Male and female C57B6/J (B6J) and Balb/cJ (Balb/c) mice were randomly assigned to a control-fat diet (CFD) containing 10% kcal fat/g or a mineral-matched HFD containing 60% kcal fat/g for 12 weeks. Results: Intraperitoneal glucose tolerance testing (IPGTT) and elevated plus maze experiments (EPM) confirmed that an HFD produced marked blunting of glucose clearance and increased anxiety-like behavior, respectively, in male and female B6J mice. Electrically evoked dopamine release in the striatum and reuptake in the nucleus accumbens (NAc), as measured by ex vivo fast scan cyclic voltammetry, was reduced for HFD-fed B6J females. Impairment in glucose metabolism explained HFD-induced changes in dopamine neurochemistry for B6J males and, to a lesser extent, Balb/c males. The relative expressions of protein markers associated with the activation of microglia, ionized calcium binding adaptor molecule (Iba1) and cluster of differentiation molecule 11b (CD11b) in the striatum were increased due to an HFD for B6J males but were unchanged or decreased amongst HFD-fed Balb/c mice. Conclusions: Our findings demonstrate that strain and sex influence the insulin- and microglia-dependent mechanisms of alterations to dopamine neurochemistry and associated behavior due to an HFD.

Abnormal cholesterol metabolism can lead to oxidative stress in the brain. Low-density lipoprotein receptor (LDLr) knockout mice are models for studying altered cholesterol metabolism and oxidative stress onset in the brain. Carbon nanodots are a new class of carbon nanomaterials that possess antioxidant properties. The goal of our study was to evaluate the effectiveness of carbon nanodots in preventing brain lipid peroxidation. LDLr knockout mice and wild-type C57BL/6J mice were treated with saline or 2.5 mg/kg bw of carbon nanodots for a 16-week period. Brains were removed and dissected into the cortex, midbrain, and striatum. We measured lipid peroxidation in the mouse brain tissues using the Thiobarbituric Acid Reactive Substances Assay and iron and copper concentrations using Graphite Furnace Atomic Absorption Spectroscopy. We focused on iron and copper due to their association with oxidative stress. Iron concentrations were significantly elevated in the midbrain and striatum of the LDLr knockout mice compared to the C57BL/6J mice, whereas lipid peroxidation was greatest in the midbrain and cortex of the LDLr knockout mice. Treatment with carbon nanodots in the LDLr knockout mice attenuated both the rise in iron and lipid peroxidation, but they had no negative effect in the C57BL/6J mice, indicating the anti-oxidative stress properties of carbon nanodots. We also assessed locomotor and anxiety-like behaviors as functional indicators of lipid peroxidation and found that treatment with carbon nanodots prevented the anxiety-like behaviors displayed by the LDLr knockout mice. Overall, our results show that carbon nanodots are safe and may be an effective nanomaterial for combating the harmful effects caused by lipid peroxidation.

Chronic low-grade inflammation is associated with a state of diet-induced obesity that impacts systemic tissues and can cross the blood–brain barrier to act directly on the brain. The extent to which pro-inflammatory cytokines released in these conditions affect dopamine presynaptic neurotransmission has not been previously investigated. The purpose of this study was to examine how dopamine terminals are affected by pro-inflammatory cytokines, and to determine if dietary fat consumption potentiates cytokine effects on dopamine release and reuptake rate in the nucleus accumbens (NAc). Male and female C57BL/6J mice were fed high, medium, or low-fat diets (60%, 30%, or 10% total kcals from fat, respectively) for six weeks. Fast scan cyclic voltammetry (FSCV) was used to measure dopamine release and reuptake rate in the NAc core from ex vivo coronal brain slices. Electrically evoked dopamine release and the maximal rate of dopamine reuptake (V_max) were significantly lower in mice fed the 30% and 60% high-fat diets compared to the 10% low-fat group (p < 0.05). IL-6 5 or 10 nM or TNFα 30 or 300 nM was added to artificial cerebrospinal fluid (aCSF) bathed over brain slices during FSCV. No effect on dopamine release or V_max was observed with lower concentrations. However, 10 nM IL-6 and 300 nM TNFα significantly reduced dopamine release in the 60% fat group (p < 0.05). No effect of added cytokine was observed on V_max. Overall, these data provide evidence that dietary fat increases neural responsiveness to cytokines, which may help inform comorbidities between diet-induced obesity and depression or other mood disorders.

Obesity has been linked to behavioral and biochemical changes, such as reduced physical activity, dysregulated dopamine metabolism, and gene expression alterations in the brain. The impact of a con...

Diet-induced obesity reduces dopaminergic neurotransmission in the nucleus accumbens (NAc), and stressful weight loss interventions could promote cravings for palatable foods high in fat and sugar that stimulate dopamine. Activation of κ-opioid receptors (KORs) reduces synaptic dopamine, but contribution of KORs to lower dopamine tone after dietary changes is unknown. Therefore, the purpose of this study was to determine the function of KORs in C57BL/6 mice that consumed a 60% high-fat diet (HFD) for six weeks followed by replacement of HFD with a control 10% fat diet for one day or one week. HFD replacement induced voluntary caloric restriction and weight loss. However, fast-scan cyclic voltammetry revealed no differences in baseline dopamine parameters, whereas sex effects were revealed during KOR stimulation. NAc core dopamine release was reduced by KOR agonism after one day of HFD replacement in females but after one week of HFD replacement in males. Further, elevated plus-maze testing revealed no diet effects during HFD replacement on overt anxiety. These results suggest that KORs reduce NAc dopamine tone and increase food-related anxiety during dietary weight loss interventions that could subsequently promote palatable food cravings and inhibit weight loss.

The aim of this review is to explore how metabolic changes induced by diets high in saturated fat (HFD) affect nucleus accumbens (NAc) dopamine neurotransmission and food intake, and to explore how stress and inflammation influence this process. Recent evidence linked diet-induced obesity and HFD with reduced dopamine release and reuptake. Altered dopamine neurotransmission could disrupt satiety circuits between NAc dopamine terminals and projections to the hypothalamus. The NAc directs learning and motivated behaviours based on homeostatic needs and psychological states. Therefore, impaired dopaminergic responses to palatable food could contribute to weight gain by disrupting responses to food cues or stress, which impacts type and quantity of food consumed. Specifically, saturated fat promotes neuronal resistance to anorectic hormones and activation of immune cells that release proinflammatory cytokines. Insulin has been shown to regulate dopamine neurotransmission by enhancing satiety, but less is known about effects of diet-induced stress. Therefore, changes to dopamine signalling due to HFD warrant further examination to characterise crosstalk of cytokines with endocrine and neurotransmitter signals. A HFD promotes a proinflammatory environment that may disrupt neuronal endocrine function and dopamine signalling that could be exacerbated by the hypothalamic–pituitary–adrenal and κ-opioid receptor stress systems. Together, these adaptive changes may dysregulate eating by changing NAc dopamine during hedonic versus homeostatic food intake. This could drive palatable food cravings during energy restriction and hinder weight loss. Understanding links between HFD and dopamine neurotransmission will inform treatment strategies for diet-induced obesity and identify molecular candidates for targeted therapeutics.