RESUMO
Obesity is one of the leading health concerns in the United States. Studies from human and rodent models suggest that inherent differences in the function of brain motivation centers, including the nucleus accumbens (NAc), contribute to overeating and thus obesity. For example, there are basal enhancements in the excitability of NAc GABAergic medium spiny neurons (MSN) and reductions in basal expression of AMPA-type glutamate receptors in obesity-prone vs obesity-resistant rats. However, very little is known about the regulation of extracellular glutamate and GABA within the NAc of these models. Here we gave obesity-prone and obesity-resistant rats stable isotope-labeled glucose (13 C6 -glucose) and used liquid chromatography mass spectrometry (LC-MS) analysis of NAc dialysate to examine the real-time incorporation of 13 C6 -glucose into glutamate, glutamine, and GABA. This novel approach allowed us to identify differences in glucose utilization for neurotransmitter production between these selectively bred lines. We found that voluntarily ingested or gastrically infused 13 C6 -glucose rapidly enters the NAc and is incorporated into 13 C2 -glutamine, 13 C2 -glutamate, and 13 C2 -GABA in both groups within minutes. However, the magnitude of increases in NAc 13 C2 -glutamine and 13 C2 -GABA were lower in obesity-prone than in obesity-resistant rats, while basal levels of glutamate were elevated. This suggested that there may be differences in the astrocytic regulation of these analytes. Thus, we next examined NAc glutamine synthetase, GAD67, and GLT-1 protein expression. Consistent with reduced 13 C2 -glutamine and 13 C2 -GABA, NAc glutamine synthetase and GLT-1 protein expression were reduced in obesity-prone vs obesity-resistant groups. Taken together, these data show that NAc glucose utilization differs dramatically between obesity-prone and obesity-resistant rats, favoring glutamate over GABA production in obesity-prone rats and that reductions in NAc astrocytic recycling of glutamate contribute to these differences. These data are discussed in light of established differences in NAc function between these models and the role of the NAc in feeding behavior.
Assuntos
Ácido Glutâmico , Núcleo Accumbens , Humanos , Ratos , Animais , Ácido Glutâmico/metabolismo , Núcleo Accumbens/metabolismo , Glutamina/metabolismo , Glutamato-Amônia Ligase/metabolismo , Obesidade/metabolismo , Ácido gama-Aminobutírico/metabolismo , Glucose/metabolismoRESUMO
Overconsumption of sugar contributes to obesity in part by changing the activity of brain areas that drive the motivation to seek out and consume food. Sugar-sweetened beverages are the most common source of excess dietary sugar and contribute to weight gain. However, very few studies have assessed the effects of liquid sucrose consumption on motivation. This is due in part to the need for novel approaches to assess motivation in pre-clinical models. To address this, we developed a within-session behavioral economics procedure to assess motivation for liquid sucrose. We first established and validated the procedure: we tested several sucrose concentrations, evaluated sensitivity of the procedure to satiety, and optimized several testing parameters. We then applied this new procedure to determine how intermittent vs. continuous access to liquid sucrose (1 M) in the home cage affects sucrose motivation. We found that intermittent liquid sucrose access results in an escalation of sucrose intake in the home cage, without altering motivation for liquid sucrose during demand testing (1 M or 0.25 M) compared to water-maintained controls. In contrast, continuous home cage access selectively blunted motivation for 1 M sucrose, while motivation for 0.25 M sucrose was similar to intermittent sucrose and control groups. Thus, effects of continuous home cage liquid sucrose access were selective to the familiar sucrose concentration. Finally, effects of sucrose on motivation recovered after removal of liquid sucrose from the diet. These data provide a new approach to examine motivation for liquid sucrose and show that escalation of intake and motivation for sucrose are dissociable processes.
Assuntos
Sacarose Alimentar , Economia Comportamental , Motivação , Motivação/efeitos dos fármacos , Sacarose Alimentar/administração & dosagem , Sacarose Alimentar/química , Sacarose Alimentar/farmacologia , Ratos Sprague-Dawley , Masculino , Animais , Ratos , Reprodutibilidade dos Testes , Resposta de Saciedade/efeitos dos fármacos , Abrigo para Animais , FomeRESUMO
Human fMRI studies show that insulin influences brain activity in regions that mediate reward and motivation, including the nucleus accumbens (NAc). Insulin receptors are expressed by NAc medium spiny neurons (MSNs), and studies of cultured cortical and hippocampal neurons suggest that insulin influences excitatory transmission via presynaptic and postsynaptic mechanisms. However, nothing is known about how insulin influences excitatory transmission in the NAc. Furthermore, insulin dysregulation accompanying obesity is linked to cognitive decline, depression, anxiety, and altered motivation that rely on NAc excitatory transmission. Using whole-cell patch-clamp and biochemical approaches, we determined how insulin affects NAc glutamatergic transmission in nonobese and obese male rats and the underlying mechanisms. We find that there are concentration-dependent, bidirectional effects of insulin on excitatory transmission, with insulin receptor activation increasing and IGF receptor activation decreasing NAc excitatory transmission. Increases in excitatory transmission were mediated by activation of postsynaptic insulin receptors located on MSNs. However, this effect was due to an increase in presynaptic glutamate release. This suggested feedback from MSNs to presynaptic terminals. In additional experiments, we found that insulin-induced increases in presynaptic glutamate release are mediated by opioid receptor-dependent disinhibition. Furthermore, obesity resulted in a loss of insulin receptor-mediated increases in excitatory transmission and a reduction in NAc insulin receptor surface expression, while preserving reductions in transmission mediated by IGF receptors. These results provide the first insights into how insulin influences excitatory transmission in the adult brain, and evidence for a previously unidentified form of opioid receptor-dependent disinhibition of NAc glutamatergic transmission.SIGNIFICANCE STATEMENT Data here provide the first insights into how insulin influences excitatory transmission in the adult brain, and identify previously unknown interactions between insulin receptor activation, opioids, and glutamatergic transmission. These data contribute to our fundamental understanding of insulin's influence on brain motivational systems and have implications for the use of insulin as a cognitive enhancer and for targeting of insulin receptors and IGF receptors to alter motivation.
Assuntos
Endorfinas/farmacologia , Ácido Glutâmico/metabolismo , Insulina/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/fisiologia , Receptor de Insulina/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Animais , Dieta Hiperlipídica , Masculino , Neurônios/efeitos dos fármacos , Obesidade/genética , Técnicas de Patch-Clamp , Terminações Pré-Sinápticas/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptor IGF Tipo 1/agonistas , Receptores de Dopamina D1/efeitos dos fármacos , Receptores de Dopamina D2/efeitos dos fármacosRESUMO
The nucleus accumbens (NAc) plays critical roles in motivated behaviors, including food seeking and feeding. Differences in NAc function contribute to overeating that drives obesity, but the underlying mechanisms are poorly understood. In addition, there is a fair degree of variation in individual susceptibility versus resistance to obesity that is due in part to differences in NAc function. For example, using selectively bred obesity-prone and obesity-resistant rats, we have found that excitability of medium spiny neurons (MSNs) within the NAc core is enhanced in obesity-prone versus -resistant populations, before any diet manipulation. However, it is unknown whether consumption of sugary, fatty "junk food" alters MSN excitability. Here whole cell patch-clamp recordings were conducted to examine MSN intrinsic excitability in adult male obesity-prone and obesity-resistant rats with and without exposure to a sugary, fatty junk food diet. We replicated our initial finding that basal excitability is enhanced in obesity-prone versus obesity-resistant rats and determined that this is due to a lower fast transient potassium current (IA) in prone versus resistant groups. In addition, the junk food diet had opposite effects on excitability in obesity-prone versus obesity-resistant rats. Specifically, junk food enhanced excitability in MSNs of obesity-resistant rats; this was mediated by a reduction in IA. In contrast, junk food reduced excitability in MSNs from obesity-prone rats; this was mediated by an increase in inward-rectifying potassium current. Thus individual differences in obesity susceptibility influence both basal excitability and how MSN excitability adapts to junk food consumption.NEW & NOTEWORTHY Medium spiny neurons (MSNs) in the nucleus accumbens of obesity-prone rats are hyperexcitable compared with MSNs from obesity-resistant rats. We found that 10 days of "junk food" exposure reduces MSN excitability in obesity-prone rats by increasing inward-rectifying potassium current and increases MSN excitability in obesity-resistant rats by decreasing fast transient potassium current. These data show that there are basal and junk food diet-induced differences in MSN excitability in obesity-prone and obesity-resistant individuals; this may contribute to previously observed differences in incentive motivation.
Assuntos
Potenciais de Ação/fisiologia , Dieta da Carga de Carboidratos , Dieta Hiperlipídica , Suscetibilidade a Doenças/fisiopatologia , Núcleo Accumbens/fisiologia , Obesidade/fisiopatologia , Canais de Potássio de Abertura Dependente da Tensão da Membrana/fisiologia , Animais , Masculino , Técnicas de Patch-Clamp , RatosRESUMO
Naturally occurring alterations in estradiol influence food intake in females. However, how motivational responses to food cues are affected by the estrous cycle or ovarian hormones is unknown. In addition, while individual susceptibility to obesity is accompanied by enhanced incentive motivational responses to food cues and increased NAc intrinsic excitability in males, studies in females are absent. Therefore, we examined basal differences in intrinsic NAc excitability of obesity-prone vs. obesity-resistant females and determined how conditioned approach (a measure of cue-triggered motivation), food intake, and motivation for food vary with the cycle in naturally cycling female obesity-prone, obesity-resistant, and outbred Sprague-Dawley rats. Finally, we used ovariectomy followed by hormone treatment to determine the role of ovarian hormones in cue-triggered motivation in selectively-bred and outbred female rats. We found that intrinsic excitability of NAc MSNs and conditioned approach are enhanced in female obesity-prone vs. obesity-resistant rats. These effects were driven by greater MSN excitability and conditioned approach behavior during metestrus/diestrus vs. proestrus/estrus in obesity-prone but not obesity-resistant rats, despite similar regulation of food intake and food motivation by the cycle in these groups. Furthermore, estradiol and progesterone treatment reduced conditioned approach behavior in obesity-prone and outbred Sprague-Dawley females. To our knowledge, these data are the first to demonstrate cycle- and hormone-dependent effects on the motivational response to a food cue, and the only studies to date to determine how individual susceptibility to obesity influences NAc excitability, cue-triggered food-seeking, and differences in the regulation of these neurobehavioral responses by the estrous cycle.
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Ciclo Estral/fisiologia , Hormônios Gonadais/farmacologia , Motivação/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Animais , Comportamento Apetitivo/efeitos dos fármacos , Comportamento Apetitivo/fisiologia , Comportamento de Escolha/efeitos dos fármacos , Comportamento de Escolha/fisiologia , Sinais (Psicologia) , Comportamento Alimentar/efeitos dos fármacos , Comportamento Alimentar/fisiologia , Feminino , Alimentos , Hormônios Gonadais/metabolismo , Masculino , Motivação/fisiologia , Neurônios/fisiologia , Núcleo Accumbens/citologia , Obesidade/patologia , Obesidade/fisiopatologia , Ovário/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
Signals of energy homeostasis interact closely with neural circuits of motivation to control food intake. An emerging hypothesis is that the transition to maladaptive feeding behavior seen in eating disorders or obesity may arise from dysregulation of these interactions. Focusing on key brain regions involved in the control of food intake (ventral tegmental area, striatum, hypothalamus, and thalamus), we describe how activity of specific cell types embedded within these regions can influence distinct components of motivated feeding behavior. We review how signals of energy homeostasis interact with these regions to influence motivated behavioral output and present evidence that experience-dependent neural adaptations in key feeding circuits may represent cellular correlates of impaired food intake control. Future research into mechanisms that restore the balance of control between signals of homeostasis and motivated feeding behavior may inspire new treatment options for eating disorders and obesity.
Assuntos
Regulação do Apetite/fisiologia , Encéfalo/fisiologia , Ingestão de Alimentos/fisiologia , Metabolismo Energético/fisiologia , Homeostase/fisiologia , Motivação/fisiologia , Animais , Peso Corporal/fisiologia , HumanosRESUMO
Neuroadaptive responses to chronic ethanol, such as behavioral sensitization, are associated with N-methyl-D-aspartate receptor (NMDAR) recruitment. Ethanol enhances GluN2B-containing NMDAR function and phosphorylation (Tyr-1472) of the GluN2B-NMDAR subunit in the dorsal medial striatum (DMS) through a protein kinase A (PKA)-dependent pathway. Ethanol-induced phosphorylation of PKA substrates is partially mediated by calcium-stimulated adenylyl cyclase 1 (AC1), which is enriched in the dorsal striatum. As such, AC1 is poised as an upstream modulator of ethanol-induced DMS neuroadaptations that promote drug responding, and thus represents a therapeutic target. Our hypothesis is that loss of AC1 activity will prevent ethanol-induced locomotor sensitization and associated DMS GluN2B-NMDAR adaptations. We evaluated AC1's contribution to ethanol-evoked locomotor responses and DMS GluN2B-NMDAR phosphorylation and function using AC1 knockout (AC1KO) mice. Results were mechanistically validated with the AC1 inhibitor, NB001. Acute ethanol (2.0 g/kg) locomotor responses in AC1KO and wild-type (WT) mice pretreated with NB001 (10 mg/kg) were comparable to WT ethanol controls. However, repeated ethanol treatment (10 days, 2.5 g/kg) failed to produce sensitization in AC1KO or NB001 pretreated mice, as observed in WT ethanol controls, following challenge exposure (2.0 g/kg). Repeated exposure to ethanol in the sensitization procedure significantly increased pTyr-1472 GluN2B levels and GluN2B-containing NMDAR transmission in the DMS of WT mice. Loss of AC1 signaling impaired ethanol-induced increases in DMS pGluN2B levels and NMDAR-mediated transmission. Together, these data support a critical and specific role for AC1 in striatal signaling that mediates ethanol-induced behavioral sensitization, and identify GluN2B-containing NMDARs as an important AC1 target.
Assuntos
Adenilil Ciclases/deficiência , Corpo Estriado/metabolismo , Etanol/administração & dosagem , Locomoção/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Corpo Estriado/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação/efeitos dos fármacos , Fosforilação/fisiologiaRESUMO
Brain-derived neurotrophic factor (BDNF) contributes to diverse types of plasticity, including cocaine addiction. We investigated the role of BDNF in the rat nucleus accumbens (NAc) in the incubation of cocaine craving over 3 months of withdrawal from extended access cocaine self-administration. First, we confirmed by immunoblotting that BDNF levels are elevated after this cocaine regimen on withdrawal day 45 (WD45) and showed that BDNF mRNA levels are not altered. Next, we explored the time course of elevated BDNF expression using immunohistochemistry. Elevation of BDNF in the NAc core was detected on WD45 and further increased on WD90, whereas elevation in shell was not detected until WD90. Surface expression of activated tropomyosin receptor kinase B (TrkB) was also enhanced on WD90. Next, we used viral vectors to attenuate BDNF-TrkB signaling. Virus injection into the NAc core enhanced cue-induced cocaine seeking on WD1 compared with controls, whereas no effect was observed on WD30 or WD90. Attenuating BDNF-TrkB signaling in shell did not affect cocaine seeking on WD1 or WD45 but significantly decreased cocaine seeking on WD90. These results suggest that basal levels of BDNF transmission in the NAc core exert a suppressive effect on cocaine seeking in early withdrawal (WD1), whereas the late elevation of BDNF protein in NAc shell contributes to incubation in late withdrawal (WD90). Finally, BDNF protein levels in the NAc were significantly increased after ampakine treatment, supporting the novel hypothesis that the gradual increase of BDNF levels in NAc accompanying incubation could be caused by increased AMPAR transmission during withdrawal.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/fisiologia , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Cocaína/administração & dosagem , Inibidores da Captação de Dopamina/administração & dosagem , Núcleo Accumbens/metabolismo , Síndrome de Abstinência a Substâncias/metabolismo , Animais , Cocaína/efeitos adversos , Condicionamento Operante/efeitos dos fármacos , Sinais (Psicologia) , Masculino , Núcleo Accumbens/efeitos dos fármacos , Fosforilação , Ratos , Ratos Sprague-Dawley , Receptor trkB/metabolismo , AutoadministraçãoRESUMO
While sign-tracking, also known as autoshaping, has been studied for many decades, only recently has the tendency to show sign-tracking behavior been linked to the development and persistence of addiction. Sign-tracking is dependent upon dopamine activity in the nucleus accumbens (NAc). The NAc is comprised predominantly of medium spiny projection neurons (MSN) that can be differentiated by their D1-like or D2-like dopamine receptor expression. Here we determined how reducing activity of D1-type MSNs in the NAc affects the expression and extinction of sign-tracking. To address this, we transfected the NAc of transgenic male and female rats that selectively express Cre recombinase in D1-type MSNs with a DIO viral vector expressing hM4Di. Cre- rats were given the same viral infusion but did not express the hM4Di receptor and therefore served as controls. Rats were then conditioned to associate lever presentations with pellet delivery. After sign-tracking was established, all rats were administered clozapine-n-oxide (CNO) prior to three additional conditioning sessions to assess the effects of NAc D1-MSNs inhibition on sign-tracking in the presence of reward. CNO treatment did not alter the expression of sign-tracking in Cre+ or Cre- rats. Next rats underwent extinction training where lever presentations occurred without pellet delivery and all rats received a CNO injection prior to each extinction session. In these extinction conditions, Cre+ rats exhibited robust extinction of sign-tracking across sessions, whereas Cre- rats did not. To determine if D1-MSN inhibition merely produced a temporary cessation of sign-tracking or instead had facilitated a persistent loss of sign-tracking, we evaluated the reemergence of sign-tracking in a test for reconditioning. During testing, reintroduction of the CS-US pairing did not promote the reemergence of sign-tracking in Cre+ rats, but restored sign-tracking in Cre- rats. Thus, chemogenetic inhibition of NAc D1-MSNs promoted extinction of sign-tracking. Collectively, these data suggest that D1-MSNs play an important role in resistance to extinction that typifies sign-tracking behavior.
Assuntos
Núcleo Accumbens , Receptores de Dopamina D1 , Ratos , Masculino , Feminino , Animais , Camundongos , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Neurônios Espinhosos Médios , Dopamina/metabolismo , Camundongos Endogâmicos C57BLRESUMO
In rats, eating obesogenic diets increases calcium-permeable AMPA receptor (CP-AMPAR) transmission in the nucleus accumbens (NAc) core, and enhances food-motivated behavior. Interestingly, these diet-induced alterations in NAc transmission are pronounced and sustained in obesity-prone (OP) male rats and absent in obesity-resistant (OR) populations. However, effects of diet manipulation on food motivation, and the mechanisms underlying this NAc plasticity in OPs is unknown. Using male selectively-bred OP and OR rats, we assessed food-motivated behavior following ad lib access to chow (CH), junk-food (JF), or 10d of JF followed by a return to chow diet (JF-Dep). Motivation for food was greater in OP than OR rats, as expected. However, JF-Dep only produced enhancements in food-seeking in OP groups, while continuous JF access reduced food-seeking in both OPs and ORs. Additionally, optogenetic, chemogenetic, and pharmacological approaches were used to examine NAc CP-AMPAR recruitment following diet manipulation and ex vivo treatment of brain slices. Reducing excitatory transmission in the NAc was sufficient to recruit CP-AMPARs to synapses in OPs, but not ORs. In OPs, JF-induced increases in CP-AMPARs occurred in mPFC-, but not BLA-to-NAc inputs. Together results show that diet differentially affects behavioral and neural plasticity in obesity susceptible populations. We also identify conditions for acute recruitment of NAc CP-AMPARs; these results suggest that synaptic scaling mechanisms contribute to NAc CP-AMPAR recruitment. Overall, this work helps elucidate how diet interacts with obesity susceptibility to influence food-motivated behavior and extends our fundamental understanding of NAc CP-AMPAR recruitment.
Assuntos
Cálcio , Receptores de AMPA , Ratos , Masculino , Animais , Receptores de AMPA/metabolismo , Cálcio/metabolismo , Ratos Sprague-Dawley , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/farmacologia , Ácido Glutâmico/farmacologia , Núcleo Accumbens , ObesidadeRESUMO
Analyzing social behaviors is critical for many fields, including neuroscience, psychology, and ecology. While computational tools have been developed to analyze videos containing animals engaging in limited social interactions under specific experimental conditions, automated identification of the social roles of freely moving individuals in a multi-animal group remains unresolved. Here we describe a deep-learning-based system - named LabGym2 - for identifying and quantifying social roles in multi-animal groups. This system uses a subject-aware approach: it evaluates the behavioral state of every individual in a group of two or more animals while factoring in its social and environmental surroundings. We demonstrate the performance of subject-aware deep-learning in different species and assays, from partner preference in freely-moving insects to primate social interactions in the field. Our subject-aware deep learning approach provides a controllable, interpretable, and efficient framework to enable new experimental paradigms and systematic evaluation of interactive behavior in individuals identified within a group.
RESUMO
In April 2023, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), in partnership with the National Institute of Child Health and Human Development, the National Institute on Aging, and the Office of Behavioral and Social Sciences Research, hosted a 2-day online workshop to discuss neural plasticity in energy homeostasis and obesity. The goal was to provide a broad view of current knowledge while identifying research questions and challenges regarding neural systems that control food intake and energy balance. This review includes highlights from the meeting and is intended both to introduce unfamiliar audiences with concepts central to energy homeostasis, feeding, and obesity and to highlight up-and-coming research in these areas that may be of special interest to those with a background in these fields. The overarching theme of this review addresses plasticity within the central and peripheral nervous systems that regulates and influences eating, emphasizing distinctions between healthy and disease states. This is by no means a comprehensive review because this is a broad and rapidly developing area. However, we have pointed out relevant reviews and primary articles throughout, as well as gaps in current understanding and opportunities for developments in the field.
Assuntos
Dieta , Metabolismo Energético , Plasticidade Neuronal , Obesidade , Humanos , Metabolismo Energético/fisiologia , Plasticidade Neuronal/fisiologia , Obesidade/fisiopatologia , Obesidade/metabolismo , Homeostase/fisiologia , Ingestão de Alimentos/fisiologia , Comportamento Alimentar/fisiologia , AnimaisRESUMO
Alterations in the function and expression of NMDA receptors are observed after in vivo and in vitro traumatic brain injury. We recently reported that mechanical stretch injury in cortical neurons transiently increases the contribution of NMDA receptors to network activity and results in an increase in calcium-permeable AMPA (CP-AMPA) receptor-mediated transmission 4 h postinjury (Goforth et al. 2011). Here, we evaluated changes in the function of synaptic vs. extrasynaptic GluN2B-containing NMDA receptors after injury. We also determined whether postinjury treatment with the GluN2B-selective antagonist Ro 25-6981 or memantine prevents injury-induced increases in CP-AMPA receptor activity. We found that injury increased extrasynaptic, GluN2B-containing NMDA receptor-mediated whole cell currents. In contrast, we found no differences in synaptic NMDA receptor-mediated transmission after injury. Furthermore, treatment with Ro 25-6981 or memantine after injury prevented injury-induced increases in CP-AMPA receptor-mediated activity. Together, our data suggest that increased NMDA receptor activity after injury is predominantly due to alterations in extrasynaptic, GluN2B-containing NMDA receptors and that activation of these receptors may contribute to the appearance of CP-AMPA receptors after injury.
Assuntos
Córtex Cerebral/fisiologia , Neurônios/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Células Cultivadas , Ratos , Ratos Sprague-Dawley , Receptores de AMPA/metabolismo , Estresse MecânicoRESUMO
In rats, eating obesogenic diets increase calcium-permeable AMPA receptor (CP-AMPAR) transmission in the nucleus accumbens (NAc) core, and enhances food-motivated behavior. Interestingly these diet-induced alterations in NAc transmission are pronounced in obesity-prone (OP) rats and absent in obesity-resistant (OR) populations. However, effects of diet manipulation on food motivation, and the mechanisms underlying NAc plasticity in OPs is unknown. Using male selectively-bred OP and OR rats, we assessed food-motivated behavior following ad lib access to chow (CH), junk-food (JF), or 10d of JF followed by a return to chow diet (JF-Dep). Behavioral tests included conditioned reinforcement, instrumental responding, and free consumption. Additionally, optogenetic, chemogenetic, and pharmacological approaches were used to examine NAc CP-AMPAR recruitment following diet manipulation and ex vivo treatment of brain slices. Motivation for food was greater in OP than OR rats, as expected. However, JF-Dep only produced enhancements in food-seeking in OP groups, while continuous JF access reduced food-seeking in both OPs and ORs. Reducing excitatory transmission in the NAc was sufficient to recruit CP-AMPARs to synapses in OPs, but not ORs. In OPs, JF-induced increases in CP-AMPARs occurred in mPFC-, but not BLA-to-NAc inputs. Diet differentially affects behavioral and neural plasticity in obesity susceptible populations. We also identify conditions for acute recruitment of NAc CP-AMPARs; these results suggest that synaptic scaling mechanisms contribute to NAc CP-AMPAR recruitment. Overall, this work improves our understanding of how sugary, fatty food consumption interacts with obesity susceptibility to influence food-motivated behavior. It also extends our fundamental understanding of NAc CP-AMPAR recruitment; this has important implications for motivation in the context of obesity as well as drug addiction.
RESUMO
RATIONALE: Compared to obesity-resistant rats, obesity-prone rats consume more food, work harder to obtain food, show greater motivational responses to food-cues, and show greater striatal plasticity in response to eating sugary/fatty foods. Therefore, it is possible that obesity-prone rats may also be more sensitive to the motivational properties of cocaine and cocaine-paired cues, and to plasticity induced by cocaine. OBJECTIVE: To examine baseline differences in motivation for cocaine and effects of intermittent access (IntA) cocaine self-administration on cocaine motivation, neurobehavioral responsivity to cocaine-paired cues, and locomotor sensitization in male obesity-prone vs obesity-resistant rats. METHODS: Intravenous cocaine self-administration was used to examine drug-taking and drug-seeking in males. Motivation for cocaine was measured using a within session threshold procedure. Cue-induced c-Fos expression in mesocorticolimbic regions was measured. RESULTS: Drug-taking and drug-seeking, cue-induced c-Fos, locomotor sensitization, and preferred level of cocaine consumption (Q0) were similar between obesity-prone and obesity-resistant groups. Maximal responding during demand testing (Rmax) was lower in obesity-prone rats. IntA experience enhanced motivation for cocaine (Pmax) in obesity-prone rats. CONCLUSIONS: The results do not support robust inherent differences in motivation for cocaine, cue-induced cocaine seeking, or neurobehavioral plasticity induced by IntA in obesity-prone vs obesity-resistant rats. This contrasts with previously established differences seen for food and food cues in these populations and shows that inherent enhancements in motivation for food and food-paired cues do not necessarily transfer to drugs and drug-paired cues.
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Comportamento Aditivo , Transtornos Relacionados ao Uso de Cocaína , Cocaína , Dependência de Alimentos , Ratos , Masculino , Animais , Motivação , Sinais (Psicologia) , Ratos Sprague-Dawley , Obesidade , Comportamento de Procura de Droga , AutoadministraçãoRESUMO
OBJECTIVE: The nucleus accumbens (NAc) plays critical roles in eating and food seeking in rodents and humans. Diets high in fats and sugars ("junk food") produce persistent increases in NAc function in male obesity-prone rats. This study examines effects of junk food and junk food deprivation on NAc core medium spiny neuron (MSN) excitability and glutamate transmission in females. METHODS: Obesity-prone female rats were given access to ad libitum junk food for 10 days, and recordings were made from MSNs in the NAc core immediately or after a short (27-72 hours) or long (14-16 days) junk food deprivation period in which rats were returned to ad libitum standard chow. Controls remained on chow throughout. Whole-cell slice electrophysiology was used to examine MSN intrinsic membrane and firing properties and glutamatergic transmission. RESULTS: The study found that intrinsic excitability was reduced, whereas glutamatergic transmission was enhanced, after the short, but not long, junk food deprivation period. A brief junk food deprivation period was necessary for increases in NAc calcium-permeable-AMPA receptor transmission and spontaneous excitatory postsynaptic current (sEPSC) frequency, but not for increases in sEPSC amplitude. CONCLUSIONS: This study reveals that females are protected from long-lasting effects of sugary fatty foods on MSN neuronal function and provides evidence for sex-specific effects on plasticity in brain centers that influence food-seeking and feeding behavior.
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Núcleo Accumbens , Obesidade , Humanos , Ratos , Masculino , Feminino , Animais , Dieta , Comportamento Alimentar , AlimentosRESUMO
BACKGROUND: The development and persistence of addiction is mediated in part by drug-induced alterations in nucleus accumbens (NAc) function. AMPA-type glutamate receptors (AMPARs) provide the main source of excitatory drive to the NAc and enhancements in transmission of calcium-permeable AMPARs (CP-AMPARs) mediate increased cue-triggered drug-seeking following prolonged withdrawal. Cocaine treatment regimens that result in psychomotor sensitization enhance subsequent drug-seeking and drug-taking behaviors. Furthermore, cocaine-induced locomotor sensitization followed by 14 days of withdrawal results in an increase in glutamatergic synaptic transmission. However, very few studies have examined cocaine-induced alterations in synaptic transmission of females or potential effects of experimenter-administered cocaine on NAc CP-AMPAR-mediated transmission in either sex. METHODS: Male and female rats were given repeated systemic cocaine injections to induce psychomotor sensitization (15 mg/kg, i.p. 1 injection/day, 8 days). Controls received repeated saline (1 mL/kg, i.p). After 14-16 days of withdrawal brain slices were prepared and whole-cell patch-clamp approaches in the NAc core were used to measure spontaneous excitatory post-synaptic currents (sEPSC), paired pulse ratio, and CP-AMPAR transmission. Additional female rats from this same cohort were also given a challenge injection of cocaine at withdrawal day 14 to assess the expression of sensitization. RESULTS: Repeated cocaine produced psychomotor sensitization in both sexes. In males this was accompanied by an increase in sEPSC frequency, but not amplitude, and there was no effect on the paired pulse ratio. Males treated with cocaine and saline had similar sensitivity to Naspm. In contrast, in females there were no significant differences between cocaine and saline groups on any measure, despite females showing robust psychomotor sensitization both during the induction and expression phase. CONCLUSIONS: Overall, these data reveal striking sex differences in cocaine-induced NAc glutamate plasticity that accompany the induction of psychomotor sensitization. This suggests that the neural adaptations that contribute to sensitization vary by sex.
Females are more vulnerable to substance use disorder than males. However, preclinical studies in females are lacking, particularly in regard to the function of neural regions that mediate reward and motivation such as the nucleus accumbens (NAc). Cocaine-induced changes in excitatory transmission within the NAc play important roles in cocaine-seeking and addiction, but are under-studied in females. Here we found that cocaine treatment enhances NAc excitatory transmission in males, but has no effects on this aspect of NAc function in females. The neural processes underlying addiction may vary according to gonadal sex.
Assuntos
Cocaína , Feminino , Ratos , Masculino , Animais , Cocaína/farmacologia , Cocaína/metabolismo , Núcleo Accumbens , Ratos Sprague-Dawley , Ácido Glutâmico/metabolismo , Ácido Glutâmico/farmacologia , Transmissão Sináptica , Receptores de AMPA/metabolismoRESUMO
Quantifying animal behavior is important for biological research. Identifying behaviors is the prerequisite of quantifying them. Current computational tools for behavioral quantification typically use high-level properties such as body poses to identify the behaviors, which constrains the information available for a holistic assessment. Here we report LabGym, an open-source computational tool for quantifying animal behaviors without this constraint. In LabGym, we introduce "pattern image" to represent the animal's motion pattern, in addition to "animation" that shows all spatiotemporal details of a behavior. These two pieces of information are assessed holistically by customizable deep neural networks for accurate behavior identifications. The quantitative measurements of each behavior are then calculated. LabGym is applicable for experiments involving multiple animals, requires little programming knowledge to use, and provides visualizations of behavioral datasets. We demonstrate its efficacy in capturing subtle behavioral changes in diverse animal species.
Assuntos
Comportamento Animal , Redes Neurais de Computação , Animais , Computadores , Movimento (Física)RESUMO
Obesity is increasing at an alarming rate. The effectiveness of currently available strategies for the treatment of obesity (including pharmacologic, surgical, and behavioral interventions) is limited. Understanding the neurobiology of appetite and the important drivers of energy intake (EI) can lead to the development of more effective strategies for the prevention and treatment of obesity. Appetite regulation is complex and is influenced by genetic, social, and environmental factors. It is intricately regulated by a complex interplay of endocrine, gastrointestinal, and neural systems. Hormonal and neural signals generated in response to the energy state of the organism and the quality of food eaten are communicated by paracrine, endocrine, and gastrointestinal signals to the nervous system. The central nervous system integrates homeostatic and hedonic signals to regulate appetite. Although there has been an enormous amount of research over many decades regarding the regulation of EI and body weight, research is only now yielding potentially effective treatment strategies for obesity. The purpose of this article is to summarize the key findings presented in June 2022 at the 23rd annual Harvard Nutrition Obesity Symposium entitled "The Neurobiology of Eating Behavior in Obesity: Mechanisms and Therapeutic Targets." Findings presented at the symposium, sponsored by NIH P30 Nutrition Obesity Research Center at Harvard, enhance our current understanding of appetite biology, including innovative techniques used to assess and systematically manipulate critical hedonic processes, which will shape future research and the development of therapeutics for obesity prevention and treatment.
Assuntos
Ingestão de Alimentos , Comportamento Alimentar , Humanos , Ingestão de Alimentos/fisiologia , Comportamento Alimentar/fisiologia , Obesidade/terapia , Apetite/fisiologia , Peso CorporalRESUMO
Insulin receptors are expressed throughout the adult brain, and insulin from the periphery reaches the central nervous system. In humans and rodents, actions of insulin in the brain decrease food intake. Furthermore, insulin receptor activation alters dopamine and glutamate transmission within mesolimbic regions that influence food-seeking and feeding including the nucleus accumbens (NAc). Here we determined how intra-NAc insulin affects conditioned approach (a measure of cue-triggered food-seeking), free food intake, and the motivation to obtain food in hungry rats using Pavlovian and instrumental approaches. Intra-NAc insulin did not affect conditioned approach but did reduce home cage chow intake immediately following conditioned approach testing. Consistent with reduced chow intake, intra-NAc insulin also reduced the motivation to work for flavored food pellets (assessed by a progressive ratio procedure). This effect was partially reversed by insulin receptor blockade and was not driven by insulin-induced sickness or malaise. Taken together, these data show that insulin within the NAc does not alter behavioral responses to a food cue, but instead reduces the motivation to work for and consume food in hungry animals. These data are discussed in light of insulin's role in the regulation of feeding, and its dysregulation by obesity.