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Corticostriatal projection neurons from prelimbic medial prefrontal cortex to the nucleus accumbens core critically regulate drug-seeking behaviors, yet the underlying encoding dynamics whereby these neurons contribute to drug seeking remain elusive. Here we use two-photon calcium imaging to visualize the activity of corticostriatal neurons in mice from the onset of heroin use to relapse. We find that the activity of these neurons is highly heterogeneous during heroin self-administration and seeking, with at least 8 distinct neuronal ensembles that display both excitatory and inhibitory encoding dynamics. These neuronal ensembles are particularly apparent during relapse, where excitatory responses are amplified compared to heroin self-administration. Moreover, we find that optogenetic inhibition of corticostriatal projection neurons attenuates heroin seeking regardless of the relapse trigger. Our results reveal the precise corticostriatal activity dynamics underlying drug-seeking behaviors and support a key role for this circuit in mediating relapse to drug seeking.
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Lack of behavioral suppression typifies substance use disorders, yet the neural circuit underpinnings of drug-induced behavioral disinhibition remain unclear. Here, we employ deep-brain two-photon calcium imaging in heroin self-administering mice, longitudinally tracking adaptations within a paraventricular thalamus to nucleus accumbens behavioral inhibition circuit from the onset of heroin use to reinstatement. We find that select thalamo-accumbal neuronal ensembles become profoundly hypoactive across the development of heroin seeking and use. Electrophysiological experiments further reveal persistent adaptations at thalamo-accumbal parvalbumin interneuronal synapses, whereas functional rescue of these synapses prevents multiple triggers from initiating reinstatement of heroin seeking. Finally, we find an enrichment of µ-opioid receptors in output- and cell-type-specific paraventricular thalamic neurons, which provide a mechanism for heroin-induced synaptic plasticity and behavioral disinhibition. These findings reveal key circuit adaptations that underlie behavioral disinhibition in opioid dependence and further suggest that recovery of this system would reduce relapse susceptibility.
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Heroína , Transtornos Relacionados ao Uso de Opioides , Ratos , Camundongos , Animais , Heroína/farmacologia , Ratos Sprague-Dawley , Autoadministração/métodos , Neurônios , Núcleo Accumbens/fisiologiaRESUMO
OBJECTIVE: An environmental context, which reliably predicts food availability, can increase the appetitive food drive within the same environment context. However, hunger is required for the development of such a context-induced feeding (CIF) response, suggesting the neural circuits sensitive to hunger link an internal energy state with a particular environment context. Since Agouti related peptide (AgRP) neurons are activated by energy deficit, we hypothesised that AgRP neurons are both necessary and sufficient to drive CIF. METHODS: To examine the role of AgRP neurons in the CIF process, we used fibre photometry with GCaMP7f, chemogenetic activation of AgRP neurons, as well as optogenetic control of AgRP neurons to facilitate acute temporal control not permitted with chemogenetics. RESULTS: A CIF response at test was only observed when mice were fasted during context training and AgRP population activity at test showed an attenuated inhibitory response to food, suggesting increased food-seeking and/or decreased satiety signalling drives the increased feeding response at test. Intriguingly, chemogenetic activation of AgRP neurons during context training did not increase CIF, suggesting precise temporal firing properties may be required. Indeed, termination of AgRP neuronal photostimulation during context training (ON-OFF in context), in the presence or absence of food, increased CIF. Moreover, photoinhibition of AgRP neurons during context training in fasted mice was sufficient to drive a subsequent CIF in the absence of food. CONCLUSIONS: Our results suggest that AgRP neurons regulate the acquisition of CIF when the acute inhibition of AgRP activity is temporally matched to context exposure. These results establish acute AgRP inhibition as a salient neural event underscoring the effect of hunger on associative learning.
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BACKGROUND: A greater understanding of how the brain controls appetite is fundamental to developing new approaches for treating diseases characterized by dysfunctional feeding behavior, such as obesity and anorexia nervosa. METHODS: By modeling neural network dynamics related to homeostatic state and body mass index, we identified a novel pathway projecting from the medial prefrontal cortex (mPFC) to the lateral hypothalamus (LH) in humans (n = 53). We then assessed the physiological role and dissected the function of this mPFC-LH circuit in mice. RESULTS: In vivo recordings of population calcium activity revealed that this glutamatergic mPFC-LH pathway is activated in response to acute stressors and inhibited during food consumption, suggesting a role in stress-related control over food intake. Consistent with this role, inhibition of this circuit increased feeding and sucrose seeking during mild stressors, but not under nonstressful conditions. Finally, chemogenetic or optogenetic activation of the mPFC-LH pathway is sufficient to suppress food intake and sucrose seeking in mice. CONCLUSIONS: These studies identify a glutamatergic mPFC-LH circuit as a novel stress-sensitive anorexigenic neural pathway involved in the cortical control of food intake.
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Comportamento Alimentar , Região Hipotalâmica Lateral , Córtex Pré-Frontal , Estresse Psicológico , Animais , Humanos , Camundongos , Comportamento Alimentar/fisiologia , Região Hipotalâmica Lateral/fisiologia , Córtex Pré-Frontal/fisiologia , Estresse Psicológico/fisiopatologiaRESUMO
Suppression of dangerous or inappropriate reward-motivated behaviors is critical for survival, whereas therapeutic or recreational opioid use can unleash detrimental behavioral actions and addiction. Nevertheless, the neuronal systems that suppress maladaptive motivated behaviors remain unclear, and whether opioids disengage those systems is unknown. In a mouse model using two-photon calcium imaging in vivo, we identify paraventricular thalamostriatal neuronal ensembles that are inhibited upon sucrose self-administration and seeking, yet these neurons are tonically active when behavior is suppressed by a fear-provoking predator odor, a pharmacological stressor, or inhibitory learning. Electrophysiological, optogenetic, and chemogenetic experiments reveal that thalamostriatal neurons innervate accumbal parvalbumin interneurons through synapses enriched with calcium permeable AMPA receptors, and activity within this circuit is necessary and sufficient for the suppression of sucrose seeking regardless of the behavioral suppressor administered. Furthermore, systemic or intra-accumbal opioid injections rapidly dysregulate thalamostriatal ensemble dynamics, weaken thalamostriatal synaptic innervation of downstream neurons, and unleash reward-seeking behaviors in a manner that is reversed by genetic deletion of thalamic µ-opioid receptors. Overall, our findings reveal a thalamostriatal to parvalbumin interneuron circuit that is both required for the suppression of reward seeking and rapidly disengaged by opioids.
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Analgésicos Opioides , Parvalbuminas , Camundongos , Animais , Analgésicos Opioides/farmacologia , Cálcio , Recompensa , SacaroseRESUMO
The ventromedial hypothalamic (VMH) nucleus is a well-established hub for energy and glucose homeostasis. In particular, VMH neurons are thought to be important for initiating the counterregulatory response to hypoglycemia, and ex vivo electrophysiology and immunohistochemistry data indicate a clear role for VMH neurons in sensing glucose concentration. However, the temporal response of VMH neurons to physiologically relevant changes in glucose availability in vivo has been hampered by a lack of available tools for measuring neuronal activity over time. Since the majority of neurons within the VMH are glutamatergic and can be targeted using the vesicular glutamate transporter Vglut2, we expressed cre-dependent GCaMP7s in Vglut2 cre mice and examined the response profile of VMH to intraperitoneal injections of glucose, insulin, and 2-deoxyglucose (2DG). We show that reduced available glucose via insulin-induced hypoglycemia and 2DG-induced glucoprivation, but not hyperglycemia induced by glucose injection, inhibits VMH Vglut2 neuronal population activity in vivo. Surprisingly, this inhibition was maintained for at least 45 minutes despite prolonged hypoglycemia and initiation of a counterregulatory response. Thus, although VMH stimulation, via pharmacological, electrical, or optogenetic approaches, is sufficient to drive a counterregulatory response, our data suggest VMH Vglut2 neurons are not the main drivers required to do so, since VMH Vglut2 neuronal population activity remains suppressed during hypoglycemia and glucoprivation.
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Hipoglicemia , Insulina , Animais , Glicemia , Desoxiglucose/farmacologia , Glucose/farmacologia , Insulina/farmacologia , Masculino , Camundongos , Neurônios , Fotometria , Ratos , Ratos Sprague-Dawley , Núcleo Hipotalâmico VentromedialRESUMO
Agouti-related peptide (AgRP) neurons increase motivation for food, however, whether metabolic sensing of homeostatic state in AgRP neurons potentiates motivation by interacting with dopamine reward systems is unexplored. As a model of impaired metabolic-sensing, we used the AgRP-specific deletion of carnitine acetyltransferase (Crat) in mice. We hypothesised that metabolic sensing in AgRP neurons is required to increase motivation for food reward by modulating accumbal or striatal dopamine release. Studies confirmed that Crat deletion in AgRP neurons (KO) impaired ex vivo glucose-sensing, as well as in vivo responses to peripheral glucose injection or repeated palatable food presentation and consumption. Impaired metabolic-sensing in AgPP neurons reduced acute dopamine release (seconds) to palatable food consumption and during operant responding, as assessed by GRAB-DA photometry in the nucleus accumbens, but not the dorsal striatum. Impaired metabolic-sensing in AgRP neurons suppressed radiolabelled 18F-fDOPA accumulation after ~30 min in the dorsal striatum but not the nucleus accumbens. Impaired metabolic sensing in AgRP neurons suppressed motivated operant responding for sucrose rewards during fasting. Thus, metabolic-sensing in AgRP neurons is required for the appropriate temporal integration and transmission of homeostatic hunger-sensing to dopamine signalling in the striatum.
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Proteína Relacionada com Agouti/genética , Corpo Estriado/fisiologia , Dopamina/fisiologia , Homeostase , Neurônios/fisiologia , Transdução de Sinais , Proteína Relacionada com Agouti/metabolismo , Animais , Camundongos , Camundongos KnockoutRESUMO
Intake of processed foods has increased markedly over the past decades, coinciding with increased microvascular diseases such as chronic kidney disease (CKD) and diabetes. Here, we show in rodent models that long-term consumption of a processed diet drives intestinal barrier permeability and an increased risk of CKD. Inhibition of the advanced glycation pathway, which generates Maillard reaction products within foods upon thermal processing, reversed kidney injury. Consequently, a processed diet leads to innate immune complement activation and local kidney inflammation and injury via the potent proinflammatory effector molecule complement 5a (C5a). In a mouse model of diabetes, a high resistant starch fiber diet maintained gut barrier integrity and decreased severity of kidney injury via suppression of complement. These results demonstrate mechanisms by which processed foods cause inflammation that leads to chronic disease.
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Inflamação , Insuficiência Renal Crônica , Animais , Dieta , Feminino , Alimentos , Humanos , Inflamação/etiologia , Masculino , Camundongos , PermeabilidadeRESUMO
Feeding is critical for survival, and disruption in the mechanisms that govern food intake underlies disorders such as obesity and anorexia nervosa. It is important to understand both food intake and food motivation to reveal mechanisms underlying feeding disorders. Operant behavioral testing can be used to measure the motivational component to feeding, but most food intake monitoring systems do not measure operant behavior. Here, we present a new solution for monitoring both food intake and motivation in rodent home-cages: the Feeding Experimentation Device version 3 (FED3). FED3 measures food intake and operant behavior in rodent home-cages, enabling longitudinal studies of feeding behavior with minimal experimenter intervention. It has a programmable output for synchronizing behavior with optogenetic stimulation or neural recordings. Finally, FED3 design files are open-source and freely available, allowing researchers to modify FED3 to suit their needs.
Obesity and anorexia nervosa are two health conditions related to food intake. Researchers studying these disorders in animal models need to both measure food intake and assess behavioural factors: that is, why animals seek and consume food. Measuring an animal's food intake is usually done by weighing food containers. However, this can be inaccurate due to the small amount of food that rodents eat. As for studying feeding motivation, this can involve calculating the number of times an animal presses a lever to receive a food pellet. These tests are typically conducted in hour-long sessions in temporary testing cages, called operant boxes. Yet, these tests only measure a brief period of a rodent's life. In addition, it takes rodents time to adjust to these foreign environments, which can introduce stress and may alter their feeding behaviour. To address this, Matikainen-Ankney, Earnest, Ali et al. developed a device for monitoring food intake and feeding behaviours around the clock in rodent home cages with minimal experimenter intervention. This 'Feeding Experimentation Device' (FED3) features a pellet dispenser and two 'nose-poke' sensors to measure total food intake, as well as motivation for and learning about food rewards. The battery-powered, wire-free device fits in standard home cages, enabling long-term studies of feeding behaviour with minimal intervention from investigators and less stress on the animals. This means researchers can relate data to circadian rhythms and meal patterns, as Matikainen-Ankney did here. Moreover, the device software is open-source so researchers can customise it to suit their experimental needs. It can also be programmed to synchronise with other instruments used in animal experiments, or across labs running the same behavioural tasks for multi-site studies. Used in this way, it could help improve reproducibility and reliability of results from such studies. In summary, Matikainen-Ankney et al. have presented a new practical solution for studying food-related behaviours in mice and rats. Not only could the device be useful to researchers, it may also be suitable to use in educational settings such as teaching labs and classrooms.
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Criação de Animais Domésticos , Condicionamento Operante , Desenho de Equipamento/instrumentação , Comportamento Alimentar , Abrigo para Animais , Roedores/fisiologia , Animais , Ingestão de Alimentos , Feminino , Masculino , CamundongosRESUMO
Emerging evidence from human imaging studies suggests that obese individuals have altered connectivity between the hypothalamus, the key brain region controlling energy homeostasis, and cortical regions involved in decision-making and reward processing. Historically, animal studies have demonstrated that the lateral hypothalamus is the key hypothalamic region involved in feeding and reward. The lateral hypothalamus is a heterogeneous structure comprised of several distinct types of neurons which are scattered throughout. In addition, the lateral hypothalamus receives inputs from a number of cortical brain regions suggesting that it is uniquely positioned to be a key integrator of cortical information and metabolic feedback. In this review, we summarize how human brain imaging can inform detailed animal studies to investigate neural pathways connecting cortical regions and the hypothalamus. Here, we discuss key cortical brain regions that are reciprocally connected to the lateral hypothalamus and are implicated in decision-making processes surrounding food.
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Córtex Cerebral/fisiologia , Corpo Estriado/fisiologia , Comportamento Alimentar/fisiologia , Hipotálamo/fisiologia , Rede Nervosa/fisiologia , Obesidade/fisiopatologia , Animais , Córtex Cerebral/fisiopatologia , Corpo Estriado/fisiopatologia , Humanos , Hipotálamo/fisiopatologia , Rede Nervosa/fisiopatologiaRESUMO
Monounsaturated (MUFA) fatty acids have been shown to induce greater meal-induced thermogenesis (MIT) than saturated fatty acids (SFA) in some studies, however, the effect of SFA chain length has not been examined. We hypothesized that a meal rich in short- to medium-chain SFA would elicit a greater MIT than one rich in long-chain SFA, and that MIT responses would be comparable between the short- to medium-chain SFA and the MUFA rich meal. A 3-arm crossover study was conducted with healthy overweight men, aged 18 to 40 years. Participants consumed either an iso-energetic (3780 ± 4.3 kJ), high fat (45%) meal rich in short-/medium-chain SFA (SMCSFA) (2-12 carbons); long-chain SFA (LCSFA) (14-24 carbons), and MUFA. MIT, fat oxidation, triglyceride and subjective appetite were measured for 6 hours post-prandial. Data were analyzed as total area under the curve and compared using a one-way repeated-measures ANOVA. The mean BMI of participants (n =13) was 29.3 ± 0.6 kg/m2 and mean age 23.8±1.4 years. MIT was not different between the meals: MUFA (204.2 ± 20.5 kJ/6 h), SMCSFA (192.6 ± 21.8 kJ/6 h), LCSFA (198.1 ± 21.5 kJ/6 h) (P = .888). Fat oxidation, plasma triglyceride, and hunger and fullness were similar after each meal (P > .05 all values). This study demonstrated that in healthy overweight men, SFA chain length, and fatty acid saturation have no acute differential effect on MIT, fat oxidation, triglyceride, or subjective appetite responses.
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Gorduras na Dieta/farmacologia , Ácidos Graxos/farmacologia , Refeições , Obesidade/metabolismo , Termogênese/efeitos dos fármacos , Adolescente , Adulto , Análise de Variância , Apetite/efeitos dos fármacos , Índice de Massa Corporal , Estudos Cross-Over , Ingestão de Energia , Ácidos Graxos/química , Ácidos Graxos Monoinsaturados/farmacologia , Humanos , Metabolismo dos Lipídeos , Masculino , Sobrepeso/metabolismo , Período Pós-Prandial , Valores de Referência , Triglicerídeos/sangue , Adulto JovemRESUMO
AgRP neurons control peripheral substrate utilization and nutrient partitioning during conditions of energy deficit and nutrient replenishment, although the molecular mechanism is unknown. We examined whether carnitine acetyltransferase (Crat) in AgRP neurons affects peripheral nutrient partitioning. Crat deletion in AgRP neurons reduced food intake and feeding behavior and increased glycerol supply to the liver during fasting, as a gluconeogenic substrate, which was mediated by changes to sympathetic output and peripheral fatty acid metabolism in the liver. Crat deletion in AgRP neurons increased peripheral fatty acid substrate utilization and attenuated the switch to glucose utilization after refeeding, indicating altered nutrient partitioning. Proteomic analysis in AgRP neurons shows that Crat regulates protein acetylation and metabolic processing. Collectively, our studies highlight that AgRP neurons require Crat to provide the metabolic flexibility to optimize nutrient partitioning and regulate peripheral substrate utilization, particularly during fasting and refeeding.
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Proteína Relacionada com Agouti/metabolismo , Carnitina O-Acetiltransferase/metabolismo , Ácidos Graxos/metabolismo , Animais , Colecistocinina/administração & dosagem , Ingestão de Alimentos , Jejum , Comportamento Alimentar , Deleção de Genes , Glucose/metabolismo , Teste de Tolerância a Glucose , Injeções Intraperitoneais , Injeções Intraventriculares , Insulina/administração & dosagem , Integrases/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos Knockout , Proteômica , Reprodutibilidade dos TestesRESUMO
Diet is one of the largest modifiable risk factors for chronic kidney disease (CKD)-related death and disability. CKD is largely a progressive disease; however, it is increasingly appreciated that hallmarks of chronic kidney disease such as albuminuria can regress over time. The factors driving albuminuria resolution remain elusive. Since albuminuria is a strong risk factor for GFR loss, modifiable lifestyle factors that lead to an improvement in albuminuria would likely reduce the burden of CKD in high-risk individuals, such as patients with diabetes. Dietary therapy such as protein and sodium restriction has historically been used in the management of CKD. Evidence is emerging to indicate that other nutrients may influence kidney health, either through metabolic or haemodynamic pathways or via the modification of gut homeostasis. This review focuses on the role of diet in the pathogenesis and progression of CKD and discusses the latest findings related to the mechanisms of diet-induced kidney disease. It is possible that optimizing diet quality or restricting dietary intake could be harnessed as an adjunct therapy for CKD prevention or progression in susceptible individuals, thereby reducing the burden of CKD.
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Dieta Saudável , Medicina Baseada em Evidências , Estilo de Vida Saudável , Rim/fisiologia , Insuficiência Renal Crônica/prevenção & controle , Animais , Terapia Combinada/efeitos adversos , Efeitos Psicossociais da Doença , Dieta com Restrição de Proteínas/efeitos adversos , Dieta Hipossódica/efeitos adversos , Suplementos Nutricionais , Progressão da Doença , Humanos , Rim/fisiopatologia , Insuficiência Renal Crônica/dietoterapia , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/terapia , Fatores de RiscoRESUMO
Dietary advanced glycation end-products (AGEs) form during heating and processing of food products and are widely prevalent in the modern Western diet. Recent systematic reviews indicate that consumption of dietary AGEs may promote inflammation, oxidative stress and insulin resistance. Experimental evidence indicates that dietary AGEs may also induce renal damage, however, this outcome has not been considered in previous systematic reviews. The purpose of this review was to examine the effect of consumption of a high AGE diet on biomarkers of chronic disease, including chronic kidney disease (CKD), in human randomized controlled trials (RCTs). Six databases (SCOPUS, CINHAL, EMBASE, Medline, Biological abstracts and Web of Science) were searched for randomised controlled dietary trials that compared high AGE intake to low AGE intake in adults with and without obesity, diabetes or CKD. Twelve dietary AGE interventions were identified with a total of 293 participants. A high AGE diet increased circulating tumour necrosis factor-alpha and AGEs in all populations. A high AGE diet increased 8-isoprostanes in healthy adults, and vascular cell adhesion molecule-1 (VCAM-1) in patients with diabetes. Markers of CKD were not widely assessed. The evidence presented indicates that a high AGE diet may contribute to risk factors associated with chronic disease, such as inflammation and oxidative stress, however, due to a lack of high quality randomised trials, more research is required.