Heightened impulsivity is associated with substance abuse disorders, gambling, and obesity. The ventral hippocampus (vHPC) has recently been linked with impulse control, yet the neurobiological and behavioral mechanisms through which this occurs are unknown. A subset of vHPC neurons projects to the nucleus accumbens shell (ACBsh), a brain region known for regulating reward and motivation. Here, we evaluated the role of vHPC-ACBsh signaling in food-directed impulsivity using fiber photometry and transsynaptic chemogenetic and behavioral approaches. Male and female rats were trained in the differential reinforcement of low rates of responding (DRL) test of impulsive action, where they learn to withhold lever presses for 20 s to obtain a palatable food reward. Photometry recordings during DRL revealed elevations in calcium-dependent activity in the vHPC during the 5 s immediately prior to a non-impulsive vs. an impulsive response in males but not females. Chemogenetic silencing of ACBsh-projecting vHPC neurons elevated impulsive responses in DRL relative to vehicle treatment in males but not females, yet had no effect on home cage food intake, operant-based motivation to work for palatable food, impulsive choice, or anxiety-like behavior. To determine whether this impulse control circuit requires vHPC->ACBsh communication independent of collateral targets of ACBsh-projecting vHPC neurons, we utilized a novel transsynaptic viral approach to selectively silence ACB neurons that receive synaptic glutamatergic signaling from the vHPC. Results reveal that inhibition of ACBsh neurons receiving vHPC signaling elevates impulsive action in the DRL task relative to vehicle treatment. Collective results reveal a sex-specific hippocampal-striatal circuit that regulates impulsivity.

The brain regulates choices such as when and how much food to consume, and pathway that regulate food consumption sometimes overlap with pathways that regulate intake of drugs of abuse, like alcohol. The lateral hypothalamic neuropeptide melanin-concentrating hormone (MCH) has been shown to increase ingestive behavior for both food and alcohol in male rats. Similarly, activation of the MCH neurons increases food intake, and some research has shown that these effects may depend on sex. Here, we use a rat model to investigate whether MCH neuronal signaling increases voluntary alcohol drinking and reward choice behavior in female Wistar rats. We further investigate whether the effects of MCH neuronal signaling is via an MCH receptor mediated mechanism. Results reveal that centrally administered MCH neuropeptide increases chow consumption but not alcohol drinking when either option is offered alone or when offered concurrently. By contrast, chemogenetic activation of MCH neurons increases alcohol drinking and selectively increases alcohol consumption when offered concurrently with either chow or a quinine-adulterated sucrose solution isocaloric to alcohol. Finally, pretreatment with a centrally administered MCH-1 receptor (MCH1R) antagonist had no effect on MCH neuron-mediated increases in alcohol consumption. We conclude that under the conditions tested MCH neuronal activation increases alcohol intake in females possibly through an MCH1R-independent mechanism.

Adolescent obesity is a chronic disease associated with early cardiometabolic dysfunction and long-term health risk. Behavioral interventions alone produce modest and unsustained weight loss, leading to increasing use of pharmacotherapy. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as highly effective treatments for obesity, producing clinically significant reductions in body weight and improvements in glycemic control. Short-term safety profiles are characterized primarily by transient gastrointestinal symptoms and low rates of serious adverse events or psychiatric symptoms. However, the developmental implications and long-term effects have yet to be evaluated. The purpose of this review is to summarize existing literature concerning the use of GLP-1RAs for adolescents with obesity and to discuss the implications of GLP-1RA use in the adolescent population. This review serves to both identify areas of potential concern and to highlight the need for continued research. Although GLP-1RAs demonstrate robust efficacy for the treatment of adolescent obesity, adolescence is a sensitive period of development and critical knowledge gaps remain regarding long-term effects of GLP-1RAs on growth, pubertal development, cognition, neural reward processing, and lifelong energy balance regulation. Longitudinal and mechanistic studies are needed to determine the long-term effects on development and to guide safe, developmentally informed clinical use.

Heightened impulsivity is attributed with substance abuse disorders, gambling, and obesity. The ventral hippocampus (vHPC) has recently been linked with impulse control, yet the neurobiological and behavioral mechanisms through which this control occurs are unknown. A subset of vHPC neurons project to the nucleus accumbens (ACB), a brain region known for regulating reward and motivation. Here, we evaluated the role of vHPC-ACB signaling in food-directed impulsivity using fiber photometry and transsynaptic chemogenetic and behavioral approaches. Male and female rats were trained in the differential reinforcement of low rates of responding (DRL) test of impulsive action, where they learn to withhold lever presses for 20 seconds to obtain a palatable food reward. Photometry recordings during DRL revealed analogous elevations in calcium-dependent activity in the vHPC and ACB during the 5s immediately prior to a non-impulsive vs. an impulsive response. Chemogenetic silencing of ACB-projecting vHPC neurons elevated impulsive responses in DRL relative to vehicle treatment in males but not females, yet had no effect on home cage food intake, operant-based motivation to work for palatable food, impulsive choice, or anxiety-like behavior. To determine whether this impulse control circuit requires vHPC->ACB communication independent of collateral targets of ACB-projecting vHPC neurons, we utilized a novel transsynaptic viral approach to selectively silence ACB neurons that receive synaptic glutamatergic signaling from the vHPC. Results reveal that inhibition of ACB neurons receiving vHPC signaling elevates impulsive action in the DRL task relative to vehicle treatment. Collective results reveal a hippocampal-striatal circuit that regulates impulsive action in males.

Exogenous cannabinoids have long been known to promote eating. However, the underlying mechanisms have not been completely elucidated, which is critical to understanding their utility. The orexin/hypocretin (OH) system of the lateral hypothalamus (LHA) has known anatomical, biochemical, and physiological interactions with the endocannabinoid system, and has an established role in promoting appetitive behavior; yet, it is still unknown if the OH system mediates food intake following cannabinoid administration. Herein, we validated an oral method of cannabinoid receptor agonist, CP55940, administration via gelatin-based edibles, showing that voluntarily consumed cannabinoid-containing edibles produce acute hyperphagia via an increase in meal number in male rats. Following cannabinoid administration, rats displayed an upregulation in the immediate early gene c-Fos in OH neurons compared to vehicle-treated animals. We further employed a within-subjects design to investigate whether orexin-1 (OX1) receptor signaling was necessary for cannabinoid-induced hyperphagia by coadministering a subeffective dose of an OX1 receptor antagonist, SB334867, with the cannabinoid-containing edible. Data were collected from metabolic monitoring cages, simultaneously capturing chow intake, locomotor activity, and metabolic variables. Results showed that the OX1 receptor antagonist blocked cannabinoid-induced hyperphagia and the transient increase in locomotor activity following cannabinoid administration. Furthermore, both the edible cannabinoid receptor agonist and the OX1 receptor antagonist individually reduced energy expenditure several hours following administration. Taken together, we conclude that the OX1 receptor is required for the hyperphagic response to exogenous cannabinoid administration.

Approximately 14% of U.S. households are food insecure. The neurocognitive and metabolic impacts of unpredictable food access during early-life periods of development are poorly understood. To address these gaps we devised a novel rat model of food insecurity to control the timing, type, and quantity of accessible food using programmable feeders. Male rats were divided into 3 groups: Secure-chow (SC), a control group given 100% of daily estimated caloric intake, distributed evenly across 4 daily meals of standard chow at set mealtimes; Secure-mixed (SM), a 2nd control group identical to the SC group except that the food type predictably alternated daily between chow and a high-fat, high-sugar diet (HFHS); and Insecure-mixed (IM), the experimental group given randomly alternating daily access to either chow or HFHS at either 85% or 115% of daily estimated caloric intake, distributed evenly across 3 daily meals with unpredictable mealtimes. These feeding schedules were implemented from postnatal days (PNs) 26-45, after which all groups received chow ad libitum. Metabolic assessments performed in adulthood revealed no group differences in caloric intake, body weight, or body composition when maintained on either chow (PN46-149) or a cafeteria diet (PN150-174). Behavioral measures (PN66-126) revealed no group differences in anxiety-like, exploratory, or impulsive behavior (zero maze, open field, differential reinforcement of low rates of responding procedures). However, the IM group exhibited hippocampus-dependent memory impairments compared to both control groups in the novel location recognition test. These findings suggest that early-life food insecurity may contribute to long-term impairments in memory function.

Adolescence represents a life stage in which vast physiological and neuroendocrine changes contribute to rapid growth and development. Throughout this transition from childhood to adulthood, the adolescent brain is in a critical developmental period. This is especially true for the prefrontal cortex and hippocampus, essential areas for executive functioning. The formation of lasting synaptic connections and dynamic plasticity within the adolescent brain make it especially vulnerable to environmental insults, such as a poor-quality diet. Herein, we review research pertaining to the period of adolescence with respect to food intake control as well as the impact of the modern food environment on the development of the prefrontal cortex and hippocampus and discuss implications for ingestive behaviors throughout rest of life.

Astrocytes have risen as stars in the field of energy homeostasis and neurocognitive function, acting as a bridge of communication between the periphery and the brain, providing metabolic support, signaling via gliotransmitters, and altering synaptic communication. Dietary factors and energy state have a profound influence on hippocampal function, and the hippocampus is critical for appropriate behavioral responses associated with feeding and internal hunger cues (being in the fasted or full state), but how the hippocampus senses periprandial status and is impacted by diet is largely unknown. Periprandial hormones act within the hippocampus to modulate processes involved in hippocampal-dependent learning and memory function and astrocytes likely play an important role in modulating this signaling. In addition to periprandial hormones, astrocytes are positioned to respond to changes in circulating nutrients like glucose. Here, we review literature investigating how astrocytes mediate changes in hippocampal function, highlighting astrocyte location, morphology, and function in the context of integrating glucose metabolism, neuroendocrine hormone action, and/or cognitive function in the hippocampus. Specifically, we discuss research findings on the effects of insulin, ghrelin, leptin, and GLP-1 on glucose homeostasis, neural activity, astrocyte function, and behavior in the hippocampus. Because obesogenic diets impact neuroendocrine hormones, astrocytes, and cognitive function, we also discuss the effects of diet and diet-induced obesity on these parameters.

Cannabinoid receptor agonists increase eating in a dose-dependent manner. However, the behavioral mechanisms by which cannabinoids modulate food intake control aren't clear, particularly in females. We utilized a rodent model of cannabinoid administration modeling a common route of cannabinoid consumption in humans: edibles. Herein, we administered the dual cannabinoid receptor agonist CP55940 in edible form to female rats and observed acute increases in standard chow intake due to an increase in meal size with no change in meal number. We further observed that the hyperphagic dose of edible CP55940 increases impulsive responding for sucrose, but this did not coincide with changes in motivation for sucrose. Finally, cannabinoids can affect anxiety-like behavior, but the acutely hyperphagic dose used in our studies had no effect on anxiety-like behavior. We conclude that edible cannabinoid administration delays satiation and increases impulsive eating behavior without impacting food motivation, potentially by reducing inhibitory control.

Deleting leptin receptors from VMH steroidogenic factor 1-expressing neurons exaggerates diet-induced obesity in mice. Experiments described here tested whether VMH leptin receptors prevent obesity in rats. Male, but not female, Sprague-Dawley rats increased energy intake for 3 days when offered a 45% kcal fat high-fat (HF) diet. There was no change in body composition of either sex during 60 days of HF feeding. Basal leptin signaling was not changed during overeating, but hindbrain leptin activity was downregulated when HF-fed rats corrected energy intake. Male and female rats exhibited increased sensitivity to VMH leptin only during the early days of being offered an HF diet. Deletion of VMH leptin receptor-expressing cells using leptin-saporin (Lep-Sap) prevented the initial hyperphagia in males but did not change subsequent energy intake, expenditure, adiposity, or glucose clearance compared with rats fed a 10% kcal fat diet. Surprisingly, HF-fed Lep-Sap rats responded to peripheral injection of leptin, whereas LF-fed Lep-Sap rats did not. Male Lep-Sap rats showed increased preference for a 2% sucrose solution but were more accurate than control blank-Sap rats in compensating for consumption of a 10% sucrose solution. Similarly, Lep-Sap rats offered a choice diet of lard, 30% sucrose, and chow increased energy intake and body fat mass but consumed less than blank-Sap rats during the first 4 days on the diet by decreasing chow intake. These results suggest that VMH leptin receptors in rats contribute to the early overconsumption of palatable diets and that this is reversed when leptin signaling in the nucleus tractus solitarius and VMH is downregulated.NEW & NOTEWORTHY When rats are offered a high-fat diet, they overeat for the first few days, and then energy intake decreases to a lower, stable level. Experiments described here demonstrate that leptin receptors in the ventromedial hypothalamus of rats are required for this overeating. Loss of these receptors appears to result in an increased preference for sucrose solution but a greater precision of the control of energy intake.

AbstractIn parallel to the legalization of cannabis for both medicinal and recreational purposes, cannabinoid use has steadily increased over the last decade in the United States. Cannabinoids, such as tetrahydrocannabinol and anandamide, bind to the central cannabinoid‐1 (CB1) receptor to impact several physiological processes relevant for body weight regulation, including appetite and energy expenditure. The hypothalamus integrates peripheral signals related to energy balance, houses several nuclei that orchestrate eating, and expresses the CB1 receptor. Herein we review literature to date concerning cannabinergic action in the hypothalamus with a specific focus on eating behaviors. We highlight hypothalamic areas wherein researchers have focused their attention, including the lateral, arcuate, paraventricular, and ventromedial hypothalamic nuclei, and interactions with the hormone leptin. This review serves as a comprehensive analysis of what is known about cannabinoid signaling in the hypothalamus, highlights gaps in the literature, and suggests future directions.

Food insecurity is defined as having limited or uncertain access to nutritious foods, and adolescent food insecurity is associated with obesity and disordered eating behaviors in humans. We developed a rodent model of adolescent food insecurity to determine whether adolescent food insecurity per se promotes increased susceptibility to diet-induced obesity and altered eating behaviors during adulthood. Female juvenile Wistar rats were singly housed and assigned to three experimental diets: food-secure with standard chow (CHOW), food-secure with a high-fat/sugar Western diet (WD), and food-insecure with WD (WD-FI). Food-secure rats (CHOW and WD) received meals at fixed feeding times (9:00, 13:00, and 16:00). WD-FI rats received meals at unpredictable intervals of the above-mentioned feeding times but had isocaloric amounts of food to WD. We investigated the impact of adolescent food insecurity on motivation for sucrose (Progressive Ratio), approach-avoidance behavior for palatable high-fat food (Approach-Avoidance task), and susceptibility to weight gain and hyperphagia when given an obesogenic choice diet. Secondary outcomes were the effects of food insecurity during development on anxiety-like behaviors (Open Field and Elevated Plus Maze) and learning and memory function (Novel Location Recognition task). Rodents with adolescent food insecurity showed a greater trend of weight gain and significantly increased fat mass and liver fat accumulation on an obesogenic diet in adulthood, despite no increases in motivation for sucrose or high-fat food. These data suggest that adolescent unpredictable food access increases susceptibility to diet-induced fat gain without impacting food motivation or food intake in female rodents. These findings are among a small group of recent studies modeling food insecurity in rodents and suggest that adolescent food insecurity in females may have long-term implications for metabolic physiology later in life.

Exercise benefits many organ systems, including having a panacea-like effect on the brain. For example, aerobic exercise improves cognition and attention and reduces the risk of brain-related diseases, such as dementia, stress, and depression. Recent advances suggest that endocrine signaling from peripheral systems, such as skeletal muscle, mediates the effects of exercise on the brain. Consequently, it has been proposed that factors secreted by all organs in response to physical exercise should be more broadly termed the "exerkines." Accumulating findings suggest that exerkines derived from skeletal muscle, liver, and adipose tissues directly impact brain mitochondrial function. Mitochondria play a pivotal role in regulating neuronal energy metabolism, neurotransmission, cell repair, and maintenance in the brain, and therefore exerkines may act via impacting brain mitochondria to improve brain function and disease resistance. Therefore, herein we review studies investigating the impact of muscle-, liver-, and adipose tissue-derived exerkines on brain cognitive and metabolic function via modulating mitochondrial bioenergetics, content, and dynamics under healthy and/or disease conditions.

The lateral hypothalamic area (LHA) integrates homeostatic processes and reward-motivated behaviors. Here we show that LHA neurons that produce melanin-concentrating hormone (MCH) are dynamically responsive to both food-directed appetitive and consummatory processes in male rats. Specifically, results reveal that MCH neuron Ca 2+ activity increases in response to both discrete and contextual food-predictive cues and is correlated with food-motivated responses. MCH neuron activity also increases during eating, and this response is highly predictive of caloric consumption and declines throughout a meal, thus supporting a role for MCH neurons in the positive feedback consummatory process known as appetition. These physiological MCH neural responses are functionally relevant as chemogenetic MCH neuron activation promotes appetitive behavioral responses to food-predictive cues and increases meal size. Finally, MCH neuron activation enhances preference for a noncaloric flavor paired with intragastric glucose. Collectively, these data identify a hypothalamic neural population that orchestrates both food-motivated appetitive and intake-promoting consummatory processes.

BACKGROUND:This study was designed to develop an understanding of the pathophysiology of traumatic muscle injury in the context of Western diet (WD; high fat and high sugar) and obesity. The objective was to interrogate the combination of WD and injury on skeletal muscle mass and contractile and metabolic function.METHODS:Male and female C57BL/6J mice were randomized into four groups based on a two-factor study design: (1) injury (uninjured vs. volumetric muscle loss [VML]) and (2) diet (WD vs. normal chow [NC]). Electrophysiology was used to test muscle strength and metabolic function in cohorts of uninjured + NC, uninjured + WD, VML + NC and VML + WD at 8 weeks of intervention.RESULTS:VML-injured male and female mice both exhibited decrements in muscle mass (-17%, P < 0.001) and muscle strength (-28%, P < 0.001); however, VML + WD females had a 28% greater muscle mass compared to VML + NC females (P = 0.034), a compensatory response not detected in males. VML-injured male and female mice both had lower carbohydrate- and fat-supported muscle mitochondrial respiration (JO2 ) and less electron conductance through the electron transport system (ETS); however, male VML-WD had 48% lower carbohydrate-supported JO2 (P = 0.014) and 47% less carbohydrate-supported electron conductance (P = 0.026) compared to male VML + NC, and this diet-injury phenotype was not present in females. ETS electron conductance starts with complex I and complex II dehydrogenase enzymes at the inner mitochondrial membrane, and male VML + WD had 31% less complex I activity (P = 0.004) and 43% less complex II activity (P = 0.005) compared to male VML + NC. This was a diet-injury phenotype not present in females. Pyruvate dehydrogenase (PDH), β-hydroxyacyl-CoA dehydrogenase, citrate synthase, α-ketoglutarate dehydrogenase and malate dehydrogenase metabolic enzyme activities were evaluated as potential drivers of impaired JO2 in the context of diet and injury. There were notable male and female differential effects in the enzyme activity and post-translational regulation of PDH. PDH enzyme activity was 24% less in VML-injured males, independent of diet (P < 0.001), but PDH enzyme activity was not influenced by injury in females. PDH enzyme activity is inhibited by phosphorylation at serine-293 by PDH kinase 4 (PDK4). In males, there was greater total PDH, phospho-PDHser293 and phospho-PDH-to-total PDH ratio in WD mice compared to NC, independent of injury (P ≤ 0.041). In females, PDK4 was 51% greater in WD compared to NC, independent of injury (P = 0.025), and was complemented by greater phospho-PDHser293 (P = 0.001).CONCLUSIONS:Males are more susceptible to muscle metabolic dysfunction in the context of combined WD and traumatic injury compared to females, and this may be due to impaired metabolic enzyme functions.

The neuropeptide oxytocin (OT) has emerged as an important anorexigen in the regulation of food intake and energy balance. It has been shown that the release of OT and activation of hypothalamic OT neurons coincide with food ingestion. Its effects on feeding have largely been attributed to limiting meal size through interactions in key regulatory brain regions governing the homeostatic control of food intake such as the hypothalamus and hindbrain in addition to key feeding reward areas such as the nucleus accumbens and ventral tegmental area. Furthermore, the magnitude of an anorexigenic response to OT and feeding-related activation of the brain OT circuit are modified by the composition and flavor of a diet, as well as by a social context in which a meal is consumed. OT is particularly effective in reducing consumption of carbohydrates and sweet tastants. Pharmacologic, genetic, and pair-feeding studies indicate that OT-elicited weight loss cannot be fully explained by reductions of food intake and that the overall impact of OT on energy balance is also partly a result of OT-elicited changes in lipolysis, energy expenditure, and glucose regulation. Peripheral administration of OT mimics many of its effects when it is given into the central nervous system, raising the questions of whether and to what extent circulating OT acts through peripheral OT receptors to regulate energy balance. Although OT has been found to elicit weight loss in female mice, recent studies have indicated that sex and estrous cycle may impact oxytocinergic modulation of food intake. Despite the overall promising basic research data, attempts to use OT in the clinical setting to combat obesity and overeating have generated somewhat mixed results. The focus of this mini-review is to briefly summarize the role of OT in feeding and metabolism, address gaps and inconsistencies in our knowledge, and discuss some of the limitations to the potential use of chronic OT that should help guide future research on OT as a tailor-made anti-obesity therapeutic.

Impact statementVolumetric muscle loss (VML) injuries result in deficiencies in strength and mobility, which have a severe impact on patient quality of life. Despite breakthroughs in tissue engineering, there are currently no treatments available that can restore function to the affected limb. Our data show that treatment of VML injuries with clinically available and FDA-approved formoterol (FOR), a beta-agonist, significantly improves strength and metabolism of VML-injured muscle. FOR is therefore a promising candidate for combined therapeutic approaches (i.e., regenerative rehabilitation) such as pairing FOR with structured rehabilitation or cell-seeded biomaterials as it may provide greater functional improvements than either strategy alone. Volumetric muscle loss (VML) injuries represent a majority of military service member casualties and are common in civilian populations following blunt and/or penetrating traumas. Characterized as a skeletal muscle injury with permanent functional impairments, there is currently no standard for rehabilitation, leading to lifelong disability. Toward developing rehabilitative strategies, previous research demonstrates that the remaining muscle after a VML injury lacks similar levels of plasticity or adaptability as healthy, uninjured skeletal muscle. This may be due, in part, to impaired innervation and vascularization of the remaining muscle, as well as disrupted molecular signaling cascades commonly associated with muscle adaptation. The primary objective of this study was to assess the ability of four pharmacological agents with a strong record of modulating muscle contractile and metabolic function to improve functional deficits in a murine model of VML injury. Male C57BL/6 mice underwent a 15% multimuscle VML injury of the posterior hindlimb and were randomized into drug treatment groups (formoterol [FOR], 5-aminoimidazole-4-carboxamide riboside [AICAR], pioglitazone [PIO], or sildenafil [SIL]) or untreated VML group. At the end of 60 days, the injury model was first validated by comparison to age-matched injury-naive mice. Untreated VML mice had 22% less gastrocnemius muscle mass, 36% less peak-isometric torque, and 27% less maximal mitochondrial oxygen consumption rate compared to uninjured mice (p < 0.01). Experimental drug groups were, then, compared to VML untreated, and there was minimal evidence of efficacy for AICAR, PIO, or SIL in improving contractile and metabolic functional outcomes. However, FOR-treated VML mice had 18% greater peak isometric torque (p < 0.01) and permeabilized muscle fibers had 36% greater State III mitochondrial oxygen consumption rate (p < 0.01) compared to VML untreated mice, suggesting an overall improvement in muscle condition. There was minimal evidence that these benefits came from greater mitochondrial biogenesis and/or mitochondrial complex protein content, but could be due to greater enzyme activity levels for complex I and complex II. These findings suggest that FOR treatment is candidate to pair with a rehabilitative approach to maximize functional improvements in VML-injured muscle.

For animals, survival is greatly enhanced by the ability to adapt to facilitate the meeting of physiological needs in an ever-changing world. These adaptations can be physiological, such as the shedding a heavy coat of fur in warm weather, or behavioral, such as snuggling up to another animal in cold weather. Such behavioral changes, brought about by sensory information from the environment, are facilitated by psychological shifts in motivation, attention, and emotional responses. In the current issue of Biological Psychiatry, Krieger et al.