Nucleus accumbens D1- and D2-expressing neurons control the balance between feeding and activity-mediated energy expenditure

Accumulating evidence points to dysregulations of the Nucleus Accumbens (NAc) in eating disorders (ED), however its precise contribution to ED symptomatic dimensions remains unclear. Using chemogenetic manipulations in male mice, we found that activity of dopamine D1 receptor-expressing neurons of the NAc core subregion facilitated effort for a food reward as well as voluntary exercise, but decreased food intake, while D2-expressing neurons have opposite effects. These effects are congruent with D2-neurons being more active than D1-neurons during feeding while it is the opposite during running. Chronic manipulations of each subpopulations had limited effects on energy balance. However, repeated activation of D1-neurons combined with inhibition of D2-neurons biased behavior toward activity-related energy expenditure, whilst the opposite manipulations favored energy intake. Strikingly, concomitant activation of D1-neurons and inhibition of D2-neurons precipitated weight loss in anorexia models. These results suggest that dysregulations of NAc dopaminoceptive neurons might be at the core of EDs

Activation du MPF dans l'ovocyte de Xénope (rôle du Cdc2 monomérique)

PARIS-BIUSJ-Thèses (751052125) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Prevention of Stress-Induced Depressive-like Behavior by Saffron Extract Is Associated with Modulation of Kynurenine Pathway and Monoamine Neurotransmission

Depressive disorders are a major public health concern. Despite currently available treatment options, their prevalence steadily increases, and a high rate of therapeutic failure is often reported, together with important antidepressant-related side effects. This highlights the need to improve existing therapeutic strategies, including by using nutritional interventions. In that context, saffron recently received particular attention for its beneficial effects on mood, although the underlying mechanisms are poorly understood. This study investigated in mice the impact of a saffron extract (Safr’Inside™; 6.25 mg/kg, per os) on acute restraint stress (ARS)-induced depressive-like behavior and related neurobiological alterations, by focusing on hypothalamic–pituitary–adrenal axis, inflammation-related metabolic pathways, and monoaminergic systems, all known to be altered by stress and involved in depressive disorder pathophysiology. When given before stress onset, Safr’Inside administration attenuated ARS-induced depressive-like behavior in the forced swim test. Importantly, it concomitantly reversed several stress-induced monoamine dysregulations and modulated the expression of key enzymes of the kynurenine pathway, likely reducing kynurenine-related neurotoxicity. These results show that saffron pretreatment prevents the development of stress-induced depressive symptoms and improves our understanding about the underlying mechanisms, which is a central issue to validate the therapeutic relevance of nutritional interventions with saffron in depressed patients

Neuroinflammation and aging: influence of dietary n-3 polyunsaturated fatty acid*

The innate immune system of the brain is principally composed of microglial cells and astrocytes, which, once activated, protect neurons against noxious agents or lesions. Activated glial cells produce inflammatory cytokines that act specifically through receptors expressed in the brain, leading to the development of altered emotional and cognitive behavior. These behavioral alterations cease along with the synthesis of brain cytokines. When the level of expression of these cytokines remains high, they become toxic to neurons possibly leading to neuronal death, as observed in neurodegenerative disorders such as Alzheimer’s disease. Omega-3 (n-3) type polyunsaturated fatty acids (PUFAs) are essential nutrients and fundamental components of neuronal and glial cell membranes. Additionally, they have immunomodulatory properties. They accumulate in the brain during the perinatal period in a dietary supply-dependant fashion. Their brain levels diminish with age, but can be corrected by a diet enriched in n-3 PUFAs. The increasing exposure of the population to diets unbalanced in n-3 PUFAs could contribute to the deleterious effect of inflammatory cytokines in the brain

Neuroinflammation and aging: influence of dietary n-3 polyunsaturated fatty acid

The innate immune system of the brain is principally composed of microglial cells and astrocytes, which, once activated, protect neurons against noxious agents or lesions. Activated glial cells produce inflammatory cytokines that act specifically through receptors expressed in the brain, leading to the development of altered emotional and cognitive behavior. These behavioral alterations cease along with the synthesis of brain cytokines. When the level of expression of these cytokines remains high, they become toxic to neurons possibly leading to neuronal death, as observed in neurodegenerative disorders such as Alzheimer’s disease. Omega-3 (n-3) type polyunsaturated fatty acids (PUFAs) are essential nutrients and fundamental components of neuronal and glial cell membranes. Additionally, they have immunomodulatory properties. They accumulate in the brain during the perinatal period in a dietary supply-dependant fashion. Their brain levels diminish with age, but can be corrected by a diet enriched in n-3 PUFAs. The increasing exposure of the population to diets unbalanced in n-3 PUFAs could contribute to the deleterious effect of inflammatory cytokines in the brain

Respective roles of the distinct populations of Medium Spiny Neurons of the Nucleus Accumbens in reward processing

National audienceThe nucleus accumbens (NAc) is a major structure that plays a key role in action selection and execution as well as reward processing and reward-dependent learning. It is largely composed of GABAergic Medium Spiny Neurons (MSN) that are divided into two distinct subpopulations, those expressing the dopamine D1 receptor (D1R; dMSNs), and those expressing the D2 receptor (D2R; iMSNs). Based on the model of the dorsal striatum, it has been proposed that dMSNs and iMSNs of the NAc play antagonistic effects on reward processing, but their respective roles are still largely debated (Carvalho Poyraz et al. 2016; Soares-Cunha et al. 2016). Herein, we aimed at deeper exploring the implication of these two populations of MSNs of the NAc core on various components of reward processing. Using operant conditioning tasks and pharmacogenetic approaches we show that activation of iMSNs decreases motivation to obtain a food reward but increases food consumption, while inhibition had the opposite effect, with no impact on hedonic reactivity. Interestingly, in vivo electrophysiology experiments in anesthetized animals revealed that the increased iMSN excitability boosts the activity of dopaminergic VTA neurons. Surprisingly, we observed that both inhibition and activation of dMSNs led to a decrease in performance in motivational tasks, likely related to a strong modulation of consummatory processes. Our data shed light on the complex function of dMSNs and iMSNs of the NAc core in reward processing and highlight differential effects on consummatory vs. motivational processes

Vitamin E status and quality of life in the elderly: influence of inflammatory processes.: Nutrition, Inflammation and Quality of life

International audienceChronic low-grade inflammation is a characteristic of ageing that may lead to alterations in health status and quality of life. In addition to intrinsic biological factors, recent data suggest that poor nutritional habits may largely contribute to this condition. The present study aimed at assessing mental and physical components of quality of life and at determining their relationship to vitamin E status, inflammation and tryptophan (TRP) metabolism in the elderly. Sixty-nine elderly subjects recruited from the Three-City cohort study participated in the study. Quality of life was assessed using the medical outcomes study thirty-six-item short-form health survey (SF-36). Biological assays included the measurement of plasma vitamin E (alpha-tocopherol), inflammatory markers, including IL-6 and C-reactive protein, and TRP metabolism. Results showed that participants with poor physical health status, as assessed by the SF-36, exhibited lower circulating concentrations of alpha-tocopherol together with increased concentrations of inflammatory markers. Similarly, poor mental health scores on the SF-36 were associated with lower concentrations of alpha-tocopherol, but also with decreased concentrations of TRP. These findings indicate that nutritional status, notably as it relates to vitamin E, is associated with immune function and quality of life in the elderly

Role of corticosteroid binding globulin in emotional reactivity sex differences in mice

Sex differences exist for stress reactivity as well as for the prevalence of depression, which is more frequent in women of reproductive age and often precipitated by stressful events. In animals, the differential effect of stress on male's and female's emotional behavior has been well documented. Crosstalk between the gonadal and stress hormones, in particular between estrogens and glucocorticoids, underlie these sex differences on stress vulnerability. We have previously shown that corticosteroid binding globulin (CBG) deficiency in a mouse model (Cbg k.o.) leads, in males, to an increased despair-like behavior caused by suboptimal corticosterone stress response. Because CBG displays a sexual dimorphism and is regulated by estrogens, we have now investigated whether it plays a role in the sex differences observed for emotional reactivity in mice. By analyzing Cbg k.o. and wild-type (WT) animals of both sexes, we detected sex differences in despair-like behavior in WT mice but not in Cbg k.o. animals. We showed through ovariectomy and estradiol (E2) replacement that E2 levels explain the sex differences found in WT animals. However, the manipulation of E2 levels did not affect the emotional behavior of Cbg k.o. females. As Cbg k.o. males, Cbg k.o. females have markedly reduced corticosterone levels across the circadian cycle and also after stress. Plasma free corticosterone levels in Cbg k.o. mice measured immediately after stress were blunted in both sexes compared to WT mice. A trend for higher mean levels of ACTH in Cbg k.o. mice was found for both sexes. The turnover of a corticosterone bolus was increased in Cbg k.o. Finally, the glucocorticoid-regulated immediate early gene early growth response 1 (Egr1) showed a blunted mRNA expression in the hippocampus of Cbg k.o. mutants while mineralocorticoid and glucocorticoid receptors presented sex differences but equivalent mRNA expression between genotypes. Thus, in our experimental conditions, sex differences for despair-like behavior in WT mice are explained by estrogens levels. Also, in both sexes, the presence of CBG is required to attain optimal glucocorticoid concentrations and normal emotional reactivity, although in females this is apparent only under low E2 concentrations. These findings suggest a complex interaction of CBG and E2 on emotional reactivity in females

Vulnerability of the nucleus accumbens neuronal network to developmental n-3 PUFA deficiency: consequences on the reward and motivation system

National audienceVarious, though distinct psychiatric disorders, such as Schizophrenia, bipolar disorder or major depression are associated with a dysfunction of the reward system linked to an alteration of dopamine transmission. Furthermore, these pathologies are also accompanied by changes in lipid metabolism and in particular a decrease in the brain content n-3 polyunsaturated fatty acid (PUFA) in the nervous system. However, the implication of brain lipid composition in the etiology of psychiatric endophenotypes has been overlooked. The aim of this study was to investigate a potential causal link between n-3 PUFA deficiency and deficits in reward processing. Using operant conditioning tasks in mice, we showed that developmental n-3 PUFA deficiency leads to a selective motivational deficit at adulthood that is reversed by n-3 PUFA supplementation starting at birth. In parallel, we showed that n-3 PUFA deficiency leads to alterations in electrophysiological properties of medium spiny neurons (MSNs) in the nucleus accumbens, main actors for motivational processes. MSNs from the direct pathway (dMSNs) displayed a decrease in excitability paralleled with an increase of inhibitory input onto these neurons. Using pharmacogenetic and transgenic approaches, we showed that 1) alterations in dMSNs directly results from increased inhibitory input from MSNs of the indirect pathway (iMSNs), called lateral inhibition and 2) rescuing appropriate PUFA levels in D2R-expressing neurons selectively (including iMSNs), was sufficient to reverse both alterations in electrophysiological properties of dMSNs and motivational deficit observed in n-3 PUFA deficient mice