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G protein-coupled receptor 120 (GPR120, Ffar4) is a sensor for long-chain fatty acids including omega-3 polyunsaturated fatty acids (n-3 PUFAs) known for beneficial effects on inflammation, metabolism, and mood. GPR120 mediates the anti-inflammatory and insulin-sensitizing effects of n-3 PUFAs in peripheral tissues. The aim of this study was to determine the impact of GPR120 stimulation on microglial reactivity, neuroinflammation and sickness- and anxiety-like behaviors by acute proinflammatory insults. We found GPR120 mRNA to be enriched in  both murine and human microglia, and in situ hybridization revealed GPR120 expression in microglia of the nucleus accumbens (NAc) in mice. In a manner similar to or exceeding n-3 PUFAs, GPR120 agonism (Compound A, CpdA) strongly attenuated lipopolysaccharide (LPS)-induced proinflammatory marker expression in primary mouse microglia, including tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β), and inhibited nuclear factor-ĸB translocation to the nucleus. Central administration of CpdA to adult mice blunted LPS-induced hypolocomotion and anxiety-like behavior and reduced TNF-α, IL-1β and IBA-1 (microglia marker) mRNA in the NAc, a brain region modulating anxiety and motivation and implicated in neuroinflammation-induced mood deficits. GPR120 agonist pre-treatment attenuated NAc microglia reactivity and alleviated sickness-like behaviors elicited by central injection TNF-α and IL-1β. These findings suggest that microglial GPR120 contributes to neuroimmune regulation and behavioral changes in response to acute infection and elevated brain cytokines. GPR120 may participate in the protective action of n-3 PUFAs at the neural and behavioral level and offers potential as treatment target for neuroinflammatory conditions. Highlights GPR120 is enriched in murine and human microglia. Central GPR120 agonism decreases microglia activation and anxiety- and sickness-like behaviors in response to LPS. GPR120 agonism attenuates nucleus accumbens microglia reactivity and behavioral responses to central cytokine administration.

It is well established that stress induces reinstatement of drug seeking in an animal model of relapse. Here we studied the role of the medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC) in foot-shock stress-induced reinstatement of cocaine seeking. Groups of rats were trained to self-administer cocaine (0.5 mg/kg per infusion, i.v., 3 h/day for 9 days) and after ten drug-free days were exposed to extinction and reinstatement test sessions. Each 60 min of extinction was separated by a 30-min time-out period after which the lever and stimulus lights were reintroduced. Rats were given four 1-h extinction sessions on day 1 and then on subsequent days were given two to three 1-h extinction sessions that were followed by a 3-h test for reinstatement. Tests were run every 48 h. In one set of experiments, the effects of inactivation of the prelimbic (PL), infralimbic (IL) or OFC by tetrodotoxin (TTX, 5 ng/0.5 micro l per side) on reinstatement induced by foot shock (5 min, intermittent, 1 mA) or priming injections of cocaine (20 mg/kg, i.p.) were determined. In a second set, the effects of infusions of the D1-like and D2-like dopamine receptor antagonists (SCH 23390 and raclopride) were studied using the same methods. TTX infusions into the PL cortex blocked both foot shock and cocaine-induced reinstatement. TTX into OFC attenuated foot-shock-induced, but not cocaine-induced reinstatement. Infusions into IL were ineffective. Infusions of SCH 22390 (0.25 micro g/0.5 micro l per side) into either PL or OFC blocked foot-shock-induced reinstatement, but infusions into PL had no effect on cocaine-induced reinstatement. Raclopride (5 micro g/0.5 micro l per side) had no effect on foot-shock-induced reinstatement in either PL or OFC or on cocaine-induced reinstatement when infused into PL. Neither TTX nor SCH23390 infusions into PL or OFC had any effect on lever pressing for sucrose. These results suggest that the PL and OFC regions form part of the circuitry mediating the effects of foot shock stress on reinstatement of drug seeking and that the PL region may be a common pathway for cue, drug and foot-shock stress-induced reinstatement of drug seeking.

Background The effect of prolonged hypoxemia in early life on systemic arterial blood pressure at maturity was assessed in Sprague–Dawley rats. Methods Animals hypoxic in early life (12 males, 10 females) were raised in hypoxia (FiO2 = 0.12) for the first 10 days of life and subsequently raised in normoxia, along with age-matched controls (11 males, 9 females). At 2 months of age, arterial blood pressure was recorded intravascularly using telemetry in awake and unrestrained animals over two 12-h night-time (active) and daytime (resting) periods. Aortic pulse wave velocity was assessed in six additional hypoxic pretreated and five control anesthetized 2-month-old male rats. Results Systolic, mean, and pulse pressures were significantly greater in the hypoxic pretreated group compared to the control group during resting and active periods in both sexes (P ≤ 0.05). Diastolic pressure and heart rate did not differ between the two groups. Hypoxic pretreated males displayed significantly increased blood pressure variability during the resting period. Aortic pulse wave velocity was also found to be elevated in the hypoxic pretreated rats. Conclusions Prolonged hypoxic stress in early life in the rat is associated with increased systolic arterial pressure at maturity very likely due to decreased arterial compliance. These findings suggest that a nutrient-independent, postnatal stress may lead to long-lasting vascular alterations predisposing to increased arterial pressure at maturity. This raises the possibility that adult survivors of congenital cyanotic cardiac disease may be at risk for secondary cardiovascular morbidity unrelated to surgical repair or residual cardiac defects.

Overconsumption of dietary fat is increasingly linked with motivational and emotional impairments. Human and animal studies demonstrate associations between obesity and blunted reward function at the behavioral and neural level, but it is unclear to what degree such changes are a consequence of an obese state and whether they are contingent on dietary lipid class. We sought to determine the impact of prolonged ad libitum intake of diets rich in saturated or monounsaturated fat, separate from metabolic signals associated with increased adiposity, on dopamine (DA)-dependent behaviors and to identify pertinent signaling changes in the nucleus accumbens (NAc). Male rats fed a saturated (palm oil), but not an isocaloric monounsaturated (olive oil), high-fat diet exhibited decreased sensitivity to the rewarding (place preference) and locomotor-sensitizing effects of amphetamine as compared with low-fat diet controls. Blunted amphetamine action by saturated high-fat feeding was entirely independent of caloric intake, weight gain, and plasma levels of leptin, insulin, and glucose and was accompanied by biochemical and behavioral evidence of reduced D1R signaling in the NAc. Saturated high-fat feeding was also tied to protein markers of increased AMPA receptor-mediated plasticity and decreased DA transporter expression in the NAc but not to alterations in DA turnover and biosynthesis. Collectively, the results suggest that intake of saturated lipids can suppress DA signaling apart from increases in body weight and adiposity-related signals known to affect mesolimbic DA function, in part by diminishing D1 receptor signaling, and that equivalent intake of monounsaturated dietary fat protects against such changes.

Glial cells have emerged as key players in the central control of energy balance and etiology of obesity. Astrocytes play a central role in neural communication via the release of gliotransmitters. Acyl-CoA binding protein (ACBP)-derived endozepines are secreted peptides that modulate the GABAA receptor. In the hypothalamus, ACBP is enriched in arcuate nucleus (ARC) astrocytes, ependymocytes and tanycytes. Central administration of the endozepine octadecaneuropeptide (ODN) reduces feeding and improves glucose tolerance, yet the contribution of endogenous ACBP in energy homeostasis is unknown. We demonstrated that ACBP deletion in GFAP+ astrocytes, but not in Nkx2.1-lineage neural cells, promoted diet-induced hyperphagia and obesity in both male and female mice, an effect prevented by viral rescue of ACBP in ARC astrocytes. ACBP-astrocytes were observed in apposition with proopiomelanocortin (POMC) neurons and ODN selectively activated POMC neurons through the ODN-GPCR but not GABAA, and supressed feeding while increasing carbohydrate utilization via the melanocortin system. Similarly, ACBP overexpression in ARC astrocytes reduced feeding and weight gain. Finally, the ODN-GPCR agonist decreased feeding and promoted weight loss in ob/ob mice. These findings uncover ACBP as an ARC gliopeptide playing a key role in energy balance control and exerting strong anorectic effects via the central melanocortin system.

We reported previously that bilateral injection of a corticotropin-releasing factor (CRF)-receptor antagonist, D-Phe CRF(12-41), into the bed nucleus of the stria terminalis (BNST) blocks the reinstatement of cocaine seeking induced by footshock, whereas the injection of CRF into the same region induces reinstatement. One source of CRF in the BNST arises from a CRF-containing projection originating in the central nucleus of the amygdala (CeA). To determine whether the CRF-containing projection from the amygdala to the BNST is involved in the mediation of stress-induced reinstatement of cocaine seeking by functionally interrupting the pathway. Rats trained to self-administer cocaine (1 mg/kg, IV, 9 days) were given extinction sessions after a 10- to 11-day drug-free period, followed by tests for stress-induced reinstatement (footshock: 15 min intermittent 0.8-mA footshocks given immediately before presentation of the previously active lever). Before the tests, animals were pretreated with either: (1) TTX (2.5 ng) in amygdala (including the CeA) in one hemisphere and D-Phe CRF(12-41) (50 ng) in BNST in the other, (2) unilateral TTX, or (3) unilateral D-Phe. Footshock reinstated cocaine seeking following unilateral injections of either TTX in amygdala or D-Phe in BNST, but following the injection of both TTX in amygdala and D-Phe in BNST the effects of footshock were greatly attenuated. These results suggest that the CRF-containing pathway from CeA to BNST is involved in mediating the effects of CRF and its receptor antagonist in the BNST on the reinstatement of cocaine seeking.

Lipids are essential for neuron development and physiology. Yet, the central hubs that coordinate lipid supply and demand in neurons remain unclear. Here, we combine invertebrate and vertebrate models to establish the presence and functional significance of neuronal lipid droplets (LD) . We find that LD are normally present in neurons in a non-uniform distribution across the brain, and demonstrate triglyceride metabolism enzymes and lipid droplet-associated proteins control neuronal LD formation through both canonical and recently-discovered pathways. Appropriate LD regulation in neurons has conserved and male-biased effects on whole-body energy homeostasis across flies and mice, specifically neurons that couple environmental cues with energy homeostasis. Mechanistically, LD-derived lipids support neuron function by providing phospholipids to sustain mitochondrial and endoplasmic reticulum homeostasis. Together, our work identifies a conserved role for LD as the organelle that coordinates lipid management in neurons, with implications for our understanding of mechanisms that preserve neuronal lipid homeostasis and function in health and disease.

Acyl-CoA Binding Protein (ACBP), also known as Diazepam Binding Inhibitor (DBI), has recently emerged as a hypothalamic and brainstem gliopeptide regulating energy balance. Previous work has shown that the ACBP-derived octadecaneuropeptide exerts strong anorectic action via POMC neuron activation and the melanocortin-4 receptor. Importantly, targeted ACBP loss-of-function in astrocytes promotes hyperphagia and diet-induced obesity while its overexpression in arcuate astrocytes reduces feeding and body weight. Despite this knowledge, the role of astroglial ACBP in adaptive feeding and metabolic responses to acute metabolic challenges has not been investigated. Using different paradigms, we found that ACBP deletion in Glial Fibrillary Acidic Protein (GFAP)-positive astrocytes does not affect diet-induced weight loss in obese male mice nor metabolic parameters in chow-fed mice (e.g. energy expenditure, body temperature) during fasting, cold exposure and at thermoneutrality. In contrast, astroglial ACBP deletion impairs meal pattern and feeding responses during refeeding after a fast and during cold exposure, thereby showing that ACBP is required to mount an appropriate feeding response in states of increased energy demand. These findings challenge the general view that astroglial ACBP exerts anorectic effects and suggest that regulation of feeding by ACBP is dependent on metabolic status. Competing Interest Statement The authors have declared no competing interest.