RESUMEN
Serotonin (also known as 5-hydroxytryptamine (5-HT)) is a neurotransmitter that has an essential role in the regulation of emotion. However, the precise circuits have not yet been defined through which aversive states are orchestrated by 5-HT. Here we show that 5-HT from the dorsal raphe nucleus (5-HTDRN) enhances fear and anxiety and activates a subpopulation of corticotropin-releasing factor (CRF) neurons in the bed nucleus of the stria terminalis (CRFBNST) in mice. Specifically, 5-HTDRN projections to the BNST, via actions at 5-HT2C receptors (5-HT2CRs), engage a CRFBNST inhibitory microcircuit that silences anxiolytic BNST outputs to the ventral tegmental area and lateral hypothalamus. Furthermore, we demonstrate that this CRFBNST inhibitory circuit underlies aversive behaviour following acute exposure to selective serotonin reuptake inhibitors (SSRIs). This early aversive effect is mediated via the corticotrophin-releasing factor type 1 receptor (CRF1R, also known as CRHR1), given that CRF1R antagonism is sufficient to prevent acute SSRI-induced enhancements in aversive learning. These results reveal an essential 5-HTDRNâCRFBNST circuit governing fear and anxiety, and provide a potential mechanistic explanation for the clinical observation of early adverse events to SSRI treatment in some patients with anxiety disorders.
Asunto(s)
Amígdala del Cerebelo/metabolismo , Ansiedad/metabolismo , Hormona Liberadora de Corticotropina/metabolismo , Miedo/fisiología , Serotonina/metabolismo , Tálamo/metabolismo , Amígdala del Cerebelo/efectos de los fármacos , Animales , Ansiedad/inducido químicamente , Trastornos de Ansiedad/inducido químicamente , Núcleo Dorsal del Rafe/efectos de los fármacos , Núcleo Dorsal del Rafe/metabolismo , Miedo/efectos de los fármacos , Femenino , Fluoxetina/efectos adversos , Fluoxetina/farmacología , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Masculino , Ratones , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Optogenética , Receptores de Hormona Liberadora de Corticotropina/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Tálamo/efectos de los fármacos , Área Tegmental Ventral/efectos de los fármacos , Área Tegmental Ventral/metabolismoRESUMEN
Across mammalian species, new mothers undergo considerable behavioral changes to nurture their offspring and meet the caloric demands of milk production1-5. While many neural circuits underlying feeding and parenting behaviors are well characterized6-9, it is unclear how these different circuits interact and adapt during lactation. Here, we characterized the transcriptomic changes in the arcuate nucleus (ARC) and the medial preoptic area (MPOA) of the mouse hypothalamus in response to lactation and hunger. Furthermore, we showed that heightened appetite in lactating mice was accompanied by increased activity of hunger-promoting agouti-related peptide (AgRP) neurons in the ARC. To assess the strength of hunger versus maternal drives, we designed a conflict assay where female mice chose between a food source or a chamber containing pups and nesting material. Although food-deprived lactating mothers prioritized parenting over feeding, hunger reduced the duration and disrupted the sequences of parenting behaviors in both lactating and virgin females. We discovered that ARCAgRP neurons directly inhibit bombesin receptor subtype-3 (BRS3) neurons in the MPOA, a population that governs both parenting and satiety. Selective activation of this ARCAgRP to MPOABRS3 circuit shifted behaviors from parenting to food-seeking. Thus, hypothalamic networks are modulated by physiological states and work antagonistically during the prioritization of competing motivated behaviors.
RESUMEN
Estradiol treatment of ovariectomized rodents is known to affect the morphology of dendritic spines and produce behavioral and cognitive effects. Kalirin-7 (Kal7), a postsynaptic density (PSD)-localized Rho-guanine nucleotide exchange factor, is important for dendritic spine formation and stability. Male Kal7 knockout [Kal7(KO)] mice exhibit a number of abnormal behavioral and biochemical phenotypes. Given that chronic 17ß-estradiol (E2) replacement of ovariectomized rats enhanced Kal7 expression in the hippocampus and primary hippocampal cultures, we assessed the behavioral and biochemical effects of chronic E2 treatment of ovariectomized female wild-type and Kal7(KO) mice. Both intact and ovariectomized Kal7(KO) female mice exhibited decreased anxiety-like behavior compared with the corresponding wild type in the elevated zero maze and were unaffected by E2 treatment. Chronic E2 decreased locomotor activity in the open field and enhanced performance in a passive-avoidance fear conditioning task, which were both unaffected by genotype. Kal7(KO) female mice engaged in significantly more object exploration, both familiar and novel, than did wild-type females. E2 enhanced the acute locomotor response to cocaine, with no significant effect of genotype. Similar to Kal7(KO) males, Kal7(KO) females had decreased levels of N-methyl-d-aspartate receptor 2B in hippocampal PSD fractions with no effect of E2 treatment. The differing behavioral effects of Kal7 ablation in female and male mice may offer insight into the molecular underpinnings of these differences.
Asunto(s)
Conducta Animal/fisiología , Factores de Intercambio de Guanina Nucleótido/deficiencia , Factores de Intercambio de Guanina Nucleótido/metabolismo , Actividad Motora/fisiología , Animales , Ansiedad/genética , Ansiedad/metabolismo , Ansiedad/fisiopatología , Conducta Animal/efectos de los fármacos , Cocaína/farmacología , Estradiol/farmacología , Estrógenos/farmacología , Miedo/efectos de los fármacos , Miedo/fisiología , Femenino , Factores de Intercambio de Guanina Nucleótido/genética , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/fisiología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Actividad Motora/efectos de los fármacos , Actividad Motora/genética , Ovariectomía/métodos , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismoRESUMEN
Fear is an adaptive state that drives defensive behavioral responses to specific and imminent threats. The central nucleus of the amygdala (CeA) is a critical site of adaptations that are required for the acquisition and expression of fear, in part due to alterations in the activity of inputs to the CeA. Here, we characterize a novel GABAergic input to the CeA from the ventral periaqueductal gray (vPAG) using fiber photometry and ex vivo whole-cell slice electrophysiology combined with optogenetics and pharmacology. GABA transmission from this ascending vPAG-CeA input was enhanced by serotonin via activation of serotonin type 2 C (5HT2C) receptors. Results suggest that these receptors are presynaptic. Interestingly, we found that GABA release from the vPAG-CeA input is enhanced following fear learning via activation of 5HT2C receptors and that this pathway is dynamically engaged in response to aversive stimuli. Additionally, we characterized serotonin release in the CeA during fear learning and recall for the first time using fiber photometry coupled to a serotonin biosensor. Together, these findings describe a mechanism by which serotonin modulates GABA release from ascending vPAG GABA inputs to the CeA and characterize a role for this pathway in fear.
Asunto(s)
Núcleo Amigdalino Central , Sustancia Gris Periacueductal , Sustancia Gris Periacueductal/fisiología , Serotonina , Ácido gamma-AminobutíricoRESUMEN
Recent data demonstrate that noradrenergic neurons of the locus coeruleus (LC-NE) are required for fear-induced suppression of feeding, but the role of endogenous LC-NE activity in natural, homeostatic feeding remains unclear. Here, we found that LC-NE activity was suppressed during food consumption, and the magnitude of this neural response was attenuated as mice consumed more pellets throughout the session, suggesting that LC responses to food are modulated by satiety state. Visual-evoked LC-NE activity was also attenuated in sated mice, suggesting that satiety state modulates LC-NE encoding of multiple behavioral states. We also found that food intake could be attenuated by brief or longer durations of LC-NE activation. Last, we found that activation of the LC to the lateral hypothalamus pathway suppresses feeding and enhances avoidance and anxiety-like responding. Our findings suggest that LC-NE neurons modulate feeding by integrating both external cues (e.g., anxiogenic environmental cues) and internal drives (e.g., satiety).
RESUMEN
Maintaining healthy body weight is increasingly difficult in our obesogenic environment. Dieting efforts are often overpowered by the internal drive to consume energy-dense foods. Although the selection of calorically rich substrates over healthier options is identifiable across species, the mechanisms behind this choice remain poorly understood. Using a passive devaluation paradigm, we found that exposure to high-fat diet (HFD) suppresses the intake of nutritionally balanced standard chow diet (SD) irrespective of age, sex, body mass accrual and functional leptin or melanocortin-4 receptor signaling. Longitudinal recordings revealed that this SD devaluation and subsequent shift toward HFD consumption is encoded at the level of hypothalamic agouti-related peptide neurons and mesolimbic dopamine signaling. Prior HFD consumption vastly diminished the capacity of SD to alleviate the negative valence associated with hunger and the rewarding properties of food discovery even after periods of HFD abstinence. These data reveal a neural basis behind the hardships of dieting.
Asunto(s)
Núcleo Arqueado del Hipotálamo/fisiología , Conducta Consumatoria/fisiología , Dieta Alta en Grasa , Preferencias Alimentarias/fisiología , Neuronas/fisiología , Área Tegmental Ventral/fisiología , Proteína Relacionada con Agouti/fisiología , Animales , Dopamina/fisiología , Femenino , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Vías Nerviosas/fisiología , OptogenéticaRESUMEN
Food palatability is one of many factors that drives food consumption, and the hedonic drive to feed is a key contributor to obesity and binge eating. In this study, we identified a population of prepronociceptin-expressing cells in the central amygdala (PnocCeA) that are activated by palatable food consumption. Ablation or chemogenetic inhibition of these cells reduces palatable food consumption. Additionally, ablation of PnocCeA cells reduces high-fat-diet-driven increases in bodyweight and adiposity. PnocCeA neurons project to the ventral bed nucleus of the stria terminalis (vBNST), parabrachial nucleus (PBN), and nucleus of the solitary tract (NTS), and activation of cell bodies in the central amygdala (CeA) or axons in the vBNST, PBN, and NTS produces reward behavior but did not promote feeding of palatable food. These data suggest that the PnocCeA network is necessary for promoting the reinforcing and rewarding properties of palatable food, but activation of this network itself is not sufficient to promote feeding.
Asunto(s)
Núcleo Amigdalino Central/metabolismo , Conducta Alimentaria/fisiología , Neuronas/metabolismo , Precursores de Proteínas/metabolismo , Receptores Opioides/metabolismo , Recompensa , Adiposidad , Animales , Peso Corporal , Núcleo Amigdalino Central/fisiología , Dieta Alta en Grasa , Ratones , Vías Nerviosas , Neuronas/fisiología , Núcleos Parabraquiales/metabolismo , Núcleos Parabraquiales/fisiología , Técnicas de Placa-Clamp , Precursores de Proteínas/genética , Receptores Opioides/genética , Núcleos Septales/metabolismo , Núcleos Septales/fisiología , Núcleo Solitario/metabolismo , Núcleo Solitario/fisiologíaRESUMEN
Emotional behavioral responses related to anxiety and fear comprise the negative valence systems domain as defined by the Research Domain Criteria (RDoC) approach to categorizing related emotional behavioral constructs that are compromised in mental health disorders. Here, we evaluate the role of GABA neurons of the ventral periaqueductal gray (vPAG) in emotional behavioral responses related to anxiety and fear using a chemogenetic approach in Vgat-ires-Cre mice. Functional inhibition of vPAG GABA neurons using selective expression of inhibitory Gi-coupled Designer Receptors Exclusively Activated by Designer Drugs (Gi-DREADDs) enhanced anxiety-like behavior in the light-dark exploration and open-field tests. Functional inhibition of vPAG GABA neurons during the acquisition of conditioned fear impaired later performance of conditioned fear responses to the fear-associated context. No effects on spontaneous freezing behavior, fear generalization, or conditioned fear responses to the fear-associated cue were observed. Together, these data suggest that activity of vPAG GABA neurons underlies emotional behavioral responses related to anxiety and conditioned fear. As such, vPAG GABA neurons are a common neurophysiological correlate of the negative valence system and dysregulation of this population may contribute to the etiology of mental health disorders in which the negative valence systems domain is compromised.
Asunto(s)
Ansiedad/fisiopatología , Miedo/fisiología , Neuronas GABAérgicas/fisiología , Sustancia Gris Periacueductal/fisiopatología , Animales , Condicionamiento Clásico , Masculino , Ratones Endogámicos C57BL , Ratones TransgénicosRESUMEN
BACKGROUND: Corticotropin-releasing factor (CRF) signaling at the CRF1 receptor (CRF1R) in the ventral tegmental area (VTA) can modulate ethanol consumption in rodents. However, the effects of binge-like ethanol drinking on this system have not been thoroughly characterized, and little is known about the role of CRF2R or the CRF neurocircuitry involved. METHODS: The effects of binge-like ethanol consumption on the VTA CRF system were assessed following drinking-in-the-dark procedures. Intra-VTA infusions of selective CRF1R and/or CRF2R compounds were employed to assess the contributions of these receptors in modulating binge-like ethanol consumption (n = 89). To determine the potential role of CRF projections from the bed nucleus of the stria terminalis (BNST) to the VTA, CRF neurons in this circuit were chemogenetically inhibited (n = 32). Binge-induced changes in VTA CRF system protein and messenger RNA were also assessed (n = 58). RESULTS: Intra-VTA antagonism of CRF1R and activation of CRF2R resulted in decreased ethanol intake, which was eliminated by simultaneous blockade of both receptors. Chemogenetic inhibition of local CRF neurons in the VTA did not alter binge-like ethanol drinking, but inhibition of VTA-projecting CRF neurons from the BNST significantly reduced intake. CONCLUSIONS: We provide novel evidence that 1) blunted binge-like ethanol consumption stemming from CRF1R blockade requires intact CRF2R signaling, and CRF2R activation reduces binge-like drinking; 2) inhibiting VTA-projecting BNST CRF neurons attenuates binge-like drinking; and 3) binge-like ethanol drinking alters protein and messenger RNA associated with the VTA-CRF system. These data suggest that ethanol-induced activation of BNST-to-VTA CRF projections is critical in driving binge-like ethanol intake.
Asunto(s)
Consumo Excesivo de Bebidas Alcohólicas/fisiopatología , Hormona Liberadora de Corticotropina/fisiología , Vías Nerviosas/fisiopatología , Receptores de Hormona Liberadora de Corticotropina/fisiología , Área Tegmental Ventral/fisiopatología , Acenaftenos/farmacología , Animales , Clozapina/análogos & derivados , Clozapina/farmacología , Hormona Liberadora de Corticotropina/genética , Drogas de Diseño , Masculino , Ratones , Ratones Transgénicos , Pirimidinas/farmacología , Pirroles/farmacología , Receptores de Hormona Liberadora de Corticotropina/agonistas , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Núcleos Septales/efectos de los fármacos , Núcleos Septales/fisiopatología , Urocortinas/farmacología , Área Tegmental Ventral/efectos de los fármacosRESUMEN
It was recently reported that activation of a subset of lateral hypothalamus (LH) GABAergic neurons induced both appetitive (food-seeking) and consummatory (eating) behaviors in vGat-ires-cre mice, while inhibition or deletion of GABAergic neurons blunted these behaviors. As food and caloric-dense liquid solutions were used, the data reported suggest that these LH GABAergic neurons may modulate behaviors that function to maintain homeostatic caloric balance. Here we report that chemogenetic activation of this GABAergic population in vGat-ires-cre mice increased consummatory behavior directed at any available stimulus, including those entailing calories (food, sucrose, and ethanol), those that do not (saccharin and water), and those lacking biological relevance (wood). Chemogenetic inhibition of these neurons attenuated consummatory behaviors. These data indicate that LH GABAergic neurons modulate consummatory behaviors regardless of the caloric content or biological relevance of the consumed stimuli.
Asunto(s)
Conducta Consumatoria/fisiología , Neuronas GABAérgicas/fisiología , Hipotálamo/fisiopatología , Consumo de Bebidas Alcohólicas/fisiopatología , Animales , Bulimia/fisiopatología , Ingestión de Líquidos/fisiología , Ingestión de Energía/fisiología , Conducta Alimentaria/fisiología , Femenino , Alimentos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones TransgénicosRESUMEN
Binge eating is a dysregulated form of feeding behavior that occurs in multiple eating disorders including binge-eating disorder, the most common eating disorder. Feeding is a complex behavioral program supported through the function of multiple brain regions and influenced by a diverse array of receptor signaling pathways. Previous studies have shown the overexpression of the opioid neuropeptide nociceptin (orphanin FQ, N/OFQ) can induce hyperphagia, but the role of endogenous nociceptin receptor (NOP) in naturally occurring palatability-induced hyperphagia is unknown. In this study we adapted a simple, replicable form of binge eating of high fat food (HFD). We found that male and female C57BL/6J mice provided with daily one-hour access sessions to HFD eat significantly more during this period than those provided with continuous 24h access. This form of feeding is rapid and entrained. Chronic intermittent HFD binge eating produced hyperactivity and increased light zone exploration in the open field and light-dark assays respectively. Treatment with the potent and selective NOP antagonist SB 612111 resulted in a significant dose-dependent reduction in binge intake in both male and female mice, and, unlike treatment with the serotonin selective reuptake inhibitor fluoxetine, produced no change in total 24-h food intake. SB 612111 treatment also significantly decreased non-binge-like acute HFD consumption in male mice. These data are consistent with the hypothesis that high fat binge eating is modulated by NOP signaling and that the NOP system may represent a promising novel receptor to explore for the treatment of binge eating.
Asunto(s)
Bulimia/tratamiento farmacológico , Bulimia/etiología , Cicloheptanos/uso terapéutico , Dieta Alta en Grasa/efectos adversos , Piperidinas/uso terapéutico , Adaptación Ocular/efectos de los fármacos , Análisis de Varianza , Animales , Antidepresivos de Segunda Generación/uso terapéutico , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Conducta Exploratoria/efectos de los fármacos , Femenino , Fluoxetina/uso terapéutico , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Receptores Opioides/metabolismo , Caracteres Sexuales , Factores de Tiempo , Receptor de NociceptinaRESUMEN
Binge alcohol drinking is a tremendous public health problem because it leads to the development of numerous pathologies, including alcohol abuse and anxiety. It is thought to do so by hijacking brain systems that regulate stress and reward, including neuropeptide Y (NPY) and corticotropin-releasing factor (CRF). The central actions of NPY and CRF have opposing functions in the regulation of emotional and reward-seeking behaviors; thus, dysfunctional interactions between these peptidergic systems could be involved in the development of these pathologies. We used converging physiological, pharmacological and chemogenetic approaches to identify a precise neural mechanism in the bed nucleus of the stria terminalis (BNST), a limbic brain region involved in pathological reward and anxiety behaviors, underlying the interactions between NPY and CRF in the regulation of binge alcohol drinking in both mice and monkeys. We found that NPY Y1 receptor (Y1R) activation in the BNST suppressed binge alcohol drinking by enhancing inhibitory synaptic transmission specifically in CRF neurons via a previously unknown Gi-mediated, PKA-dependent postsynaptic mechanism. Furthermore, chronic alcohol drinking led to persistent alterations in Y1R function in the BNST of both mice and monkeys, highlighting the enduring, conserved nature of this effect across mammalian species. Together, these data provide both a cellular locus and signaling framework for the development of new therapeutics for treatment of neuropsychiatric diseases, including alcohol use disorders.
Asunto(s)
Conducta Animal/efectos de los fármacos , Consumo Excesivo de Bebidas Alcohólicas/metabolismo , Hormona Liberadora de Corticotropina/metabolismo , Inhibición Neural/fisiología , Neuropéptido Y/metabolismo , Receptores de Neuropéptido Y/metabolismo , Núcleos Septales/metabolismo , Transducción de Señal/fisiología , Animales , Consumo Excesivo de Bebidas Alcohólicas/tratamiento farmacológico , Ritmo Circadiano/efectos de los fármacos , Modelos Animales de Enfermedad , Macaca mulatta , Masculino , Ratones , Ratones Endogámicos C57BL , Inhibición Neural/efectos de los fármacos , Receptores de Neuropéptido Y/agonistas , Receptores de Neuropéptido Y/antagonistas & inhibidores , Núcleos Septales/efectos de los fármacosRESUMEN
DREADDs are chemogenetic tools widely used to remotely control cellular signaling, neuronal activity, and behavior. Here we used a structure-based approach to develop a new Gi-coupled DREADD using the kappa-opioid receptor as a template (KORD) that is activated by the pharmacologically inert ligand salvinorin B (SALB). Activation of virally expressed KORD in several neuronal contexts robustly attenuated neuronal activity and modified behaviors. Additionally, co-expression of the KORD and the Gq-coupled M3-DREADD within the same neuronal population facilitated the sequential and bidirectional remote control of behavior. The availability of DREADDs activated by different ligands provides enhanced opportunities for investigating diverse physiological systems using multiplexed chemogenetic actuators.
Asunto(s)
Conducta Animal/efectos de los fármacos , Diterpenos/farmacología , Neuronas/efectos de los fármacos , Receptores Opioides kappa/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Diterpenos de Tipo Clerodano , Ligandos , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Long-lasting increases in dendritic spine density and gene expression in the nucleus accumbens and in the ambulatory response to cocaine occur following chronic cocaine treatment. Despite numerous reports of these findings, the molecular mechanisms leading to these morphological, biochemical, and behavioral changes remain unclear. METHODS: We used mice genetically lacking Kalirin7 (Kal7(KO)), a Rho guanine nucleotide exchange factor that regulates dendritic spine formation and function. Both wild-type (Wt) and Kal7(KO) mice were given high-dose cocaine (20 mg/kg) for 4 or 8 consecutive days. Locomotor sensitization and conditioned place preference elicited by cocaine were evaluated. The nucleus accumbens core was diolistically labeled and spine density and morphology were quantified using confocal microscopy. RESULTS: Cocaine increased Kalirin7 messenger RNA and protein expression in the nucleus accumbens of Wt mice. The Kal7(KO) animals showed greater locomotor sensitization to cocaine than Wt mice. In contrast, Kal7(KO) mice exhibited decreased place preference for cocaine, despite displaying a normal place preference for food. While Wt mice showed a robust increase in dendritic spine density after 4 and 8 days of cocaine treatment, dendritic spine density failed to increase in cocaine-exposed Kal7(KO) mice. Wild-type mice treated with cocaine for 8 days exhibited larger dendritic spines than cocaine-treated Kal7(KO) mice. CONCLUSIONS: Kalirin7 is an essential determinant of dendritic spine formation following cocaine treatment. The absence of this single isoform of one of the many Rho guanine nucleotide exchange factors expressed in the nucleus accumbens results in enhanced locomotor sensitization and diminished place preference in response to cocaine.