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1.
Mol Psychiatry ; 25(3): 640-654, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31758092

RESUMEN

Norepinephrine (NE) plays a central role in the acquisition of aversive learning via actions in the lateral nucleus of the amygdala (LA) [1, 2]. However, the function of NE in expression of aversively-conditioned responses has not been established. Given the role of the central nucleus of the amygdala (CeA) in the expression of such behaviors [3-5], and the presence of NE axons projections in this brain nucleus [6], we assessed the effects of NE activity in the CeA on behavioral expression using receptor-specific pharmacology and cell- and projection-specific chemogenetic manipulations. We found that inhibition and activation of locus coeruleus (LC) neurons decreases and increases freezing to aversively conditioned cues, respectively. We then show that locally inhibiting or activating LC terminals in CeA is sufficient to achieve this bidirectional modulation of defensive reactions. These findings support the hypothesis that LC projections to CeA are critical for the expression of defensive responses elicited by conditioned threats.


Asunto(s)
Reacción de Prevención/fisiología , Núcleo Amigdalino Central/fisiología , Norepinefrina/fisiología , Animales , Complejo Nuclear Basolateral/fisiología , Tronco Encefálico/fisiología , Condicionamiento Clásico/fisiología , Miedo/fisiología , Locus Coeruleus/metabolismo , Masculino , Neuronas/metabolismo , Norepinefrina/metabolismo , Ratas , Ratas Sprague-Dawley
2.
Learn Mem ; 27(7): 270-274, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32540916

RESUMEN

In signaled active avoidance (SigAA), rats learn to suppress Pavlovian freezing and emit actions to remove threats and prevent footshocks. SigAA is critical for understanding aversively motivated instrumental behavior and anxiety-related active coping. However, with standard protocols ∼25% of rats exhibit high freezing and poor avoidance. This has dampened enthusiasm for the paradigm and stalled progress. We demonstrate that reducing shock imminence with long-duration warning signals leads to greater freezing suppression and perfect avoidance in all subjects. This suggests that instrumental SigAA mechanisms evolved to cope with distant harm and protocols that promote inflexible Pavlovian reactions are poorly designed to study avoidance.


Asunto(s)
Adaptación Psicológica/fisiología , Reacción de Prevención/fisiología , Conducta Animal/fisiología , Condicionamiento Clásico/fisiología , Condicionamiento Operante/fisiología , Desempeño Psicomotor/fisiología , Animales , Femenino , Masculino , Ratas , Ratas Sprague-Dawley , Factores de Tiempo
3.
Learn Mem ; 25(11): 564-568, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-30322888

RESUMEN

Signaled active avoidance (SigAA) is the key experimental procedure for studying the acquisition of instrumental responses toward conditioned threat cues. Traditional analytic approaches (e.g., general linear model) often obfuscate important individual differences, although individual differences in learned responses characterize both animal and human learning data. However, individual differences models (e.g., latent growth curve modeling) typically require large samples and onerous computational methods. Here, we present an analytic methodology that enables the detection of individual differences in SigAA performance at a high accuracy, even when a single animal is included in the data set (i.e., n = 1 level). We further show an online software that enables the easy application of our method to any SigAA data set.


Asunto(s)
Reacción de Prevención , Individualidad , Modelos Estadísticos , Pruebas Psicológicas , Programas Informáticos , Animales , Condicionamiento Psicológico , Interpretación Estadística de Datos , Masculino , Ratas Sprague-Dawley , Tiempo de Reacción , Reproducibilidad de los Resultados
4.
Learn Mem ; 24(1): 55-58, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-27980076

RESUMEN

Distinguishing threatening from nonthreatening stimuli is essential for survival and stimulus generalization is a hallmark of anxiety disorders. While auditory threat learning produces long-lasting plasticity in primary auditory cortex (Au1), it is not clear whether such Au1 plasticity regulates memory specificity or generalization. We used muscimol infusions in rats to show that discriminatory threat learning requires Au1 activity specifically during memory acquisition and retrieval, but not during consolidation. Memory specificity was similarly disrupted by infusion of PKMζ inhibitor peptide (ZIP) during memory storage. Our findings show that Au1 is required at critical memory phases and suggest that Au1 plasticity enables stimulus discrimination.


Asunto(s)
Corteza Auditiva/fisiología , Condicionamiento Clásico/fisiología , Miedo/fisiología , Memoria/fisiología , Análisis de Varianza , Animales , Corteza Auditiva/efectos de los fármacos , Condicionamiento Clásico/efectos de los fármacos , Discriminación en Psicología/efectos de los fármacos , Discriminación en Psicología/fisiología , Inhibidores Enzimáticos/farmacología , Miedo/efectos de los fármacos , Agonistas de Receptores de GABA-A/farmacología , Memoria/efectos de los fármacos , Muscimol/farmacología , Proteína Quinasa C/antagonistas & inhibidores , Proteína Quinasa C/metabolismo , Ratas
5.
Learn Mem ; 24(9): 432-439, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-28814469

RESUMEN

The creation of auditory threat Pavlovian memory requires an initial learning stage in which a neutral conditioned stimulus (CS), such as a tone, is paired with an aversive one (US), such as a shock. In this phase, the CS acquires the capacity of predicting the occurrence of the US and therefore elicits conditioned defense responses. Norepinephrine (NE), through ß-adrenergic receptors in the amygdala, enhances threat memory by facilitating the acquisition of the CS-US association, but the nature of this effect has not been described. Here we show that NE release, induced by the footshock of the first conditioning trial, promotes the subsequent enhancement of learning. Consequently, blocking NE transmission disrupts multitrial but not one-trial conditioning. We further found that increasing the time between the conditioning trials eliminates the amplificatory effect of NE. Similarly, an unsignaled footshock delivered in a separate context immediately before conditioning can enhance learning. These results help define the conditions under which NE should and should not be expected to alter threat processing and fill an important gap in the understanding of the neural processes relevant to the pathophysiology of stress and anxiety disorders.


Asunto(s)
Amígdala del Cerebelo/efectos de los fármacos , Condicionamiento Clásico/efectos de los fármacos , Miedo/efectos de los fármacos , Memoria a Largo Plazo/efectos de los fármacos , Norepinefrina/farmacología , Antagonistas Adrenérgicos beta/farmacología , Amígdala del Cerebelo/fisiología , Análisis de Varianza , Animales , Condicionamiento Clásico/fisiología , Electrochoque/efectos adversos , Extinción Psicológica/efectos de los fármacos , Reacción Cataléptica de Congelación/efectos de los fármacos , Reacción Cataléptica de Congelación/fisiología , Masculino , Propranolol/farmacología , Ratas , Ratas Sprague-Dawley , Factores de Tiempo
6.
J Neurosci ; 35(8): 3470-7, 2015 Feb 25.
Artículo en Inglés | MEDLINE | ID: mdl-25716846

RESUMEN

Freezing is a species-typical defensive reaction to conditioned threats. While the neural circuitry of aversive Pavlovian behavior has been extensively studied, less is known about the circuitry underlying more active responses to danger. Here we show that the flow of information between the basal amygdala (BA) and the nucleus accumbens (NAcc) is necessary for signaled active avoidance behavior. Rats trained to avoid shock by shuttling during an auditory conditioned stimulus showed increased expression of the activity-dependent protein c-Fos in the NAcc, specifically the shell subregion (NAccSh). Silencing neural activity in the NAccSh, but not in the adjacent NAcc core, disrupted avoidance behavior. Disconnection of the BA and the NAccSh was just as effective at disrupting avoidance behavior as bilateral NAccSh inactivations, suggesting learned avoidance behavior requires an intact BA-NAccSh circuit. Together, these data highlight an essential role for the amygdalar projection to the ventral striatum in aversively motivated actions.


Asunto(s)
Amígdala del Cerebelo/fisiología , Reacción de Prevención , Núcleo Accumbens/fisiología , Amígdala del Cerebelo/metabolismo , Animales , Condicionamiento Clásico , Miedo , Masculino , Vías Nerviosas/metabolismo , Vías Nerviosas/fisiología , Núcleo Accumbens/metabolismo , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Sprague-Dawley
7.
Proc Natl Acad Sci U S A ; 110(50): 20260-5, 2013 Dec 10.
Artículo en Inglés | MEDLINE | ID: mdl-24277819

RESUMEN

Survival in a dangerous environment requires learning about stimuli that predict harm. Although recent work has focused on the amygdala as the locus of aversive memory formation, the hypothalamus has long been implicated in emotional regulation, and the hypothalamic neuropeptide orexin (hypocretin) is involved in anxiety states and arousal. Nevertheless, little is known about the role of orexin in aversive memory formation. Using a combination of behavioral pharmacology, slice physiology, and optogenetic techniques, we show that orexin acts upstream of the amygdala via the noradrenergic locus coeruleus to enable threat (fear) learning, specifically during the aversive event. Our results are consistent with clinical studies linking orexin levels to aversive learning and anxiety in humans and dysregulation of the orexin system may contribute to the etiology of fear and anxiety disorders.


Asunto(s)
Amígdala del Cerebelo/fisiología , Miedo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Aprendizaje/fisiología , Locus Coeruleus/fisiología , Neuropéptidos/metabolismo , Estimulación Acústica , Animales , Benzoxazoles/administración & dosificación , Benzoxazoles/farmacología , Channelrhodopsins , Condicionamiento Clásico , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Masculino , Naftiridinas , Neuropéptidos/antagonistas & inhibidores , Optogenética , Orexinas , Técnicas de Placa-Clamp , Ratas , Ratas Sprague-Dawley , Urea/administración & dosificación , Urea/análogos & derivados , Urea/farmacología
8.
Learn Mem ; 20(8): 446-52, 2013 Jul 18.
Artículo en Inglés | MEDLINE | ID: mdl-23869027

RESUMEN

Active avoidance (AA) is an important paradigm for studying mechanisms of aversive instrumental learning, pathological anxiety, and active coping. Unfortunately, AA neurocircuits are poorly understood, partly because behavior is highly variable and reflects a competition between Pavlovian reactions and instrumental actions. Here we exploited the behavioral differences between good and poor avoiders to elucidate the AA neurocircuit. Rats received Sidman AA training and expression of the activity-dependent immediate-early gene c-fos was measured after a shock-free AA test. Six brain regions with known or putative roles in AA were evaluated: amygdala, periaqueductal gray, nucleus accumbens, dorsal striatum, prefrontal cortex (PFC), and hippocampus. Good avoiders showed little Pavlovian freezing and high AA rates at test, the opposite of poor avoiders. Although c-Fos activation was observed throughout the brain, differential activation was found only in subregions of amygdala and PFC. Interestingly, c-Fos correlated with avoidance and freezing in only five of 20 distinct areas evaluated: lateral amygdala, central amygdala, medial amygdala, basal amygdala, and infralimbic PFC. Thus, activity in specific amygdala-PFC circuits likely mediates the competition between instrumental actions and Pavlovian reactions after AA training. Individual differences in AA behavior, long considered a nuisance by researchers, may be the key to elucidating the AA neurocircuit and understanding pathological response profiles.


Asunto(s)
Amígdala del Cerebelo/fisiología , Reacción de Prevención/fisiología , Corteza Prefrontal/fisiología , Proteínas Proto-Oncogénicas c-fos/metabolismo , Amígdala del Cerebelo/metabolismo , Animales , Masculino , Corteza Prefrontal/metabolismo , Ratas , Ratas Sprague-Dawley
9.
bioRxiv ; 2024 Feb 13.
Artículo en Inglés | MEDLINE | ID: mdl-38370659

RESUMEN

Active avoidance responses (ARs) are instrumental behaviors that prevent harm. Adaptive ARs may contribute to active coping, whereas maladaptive avoidance habits are implicated in anxiety and obsessive-compulsive disorders. The AR learning mechanism has remained elusive, as successful avoidance trials produce no obvious reinforcer. We used a novel outcome-devaluation procedure in rats to show that ARs are positively reinforced by response-produced feedback (FB) cues that develop into safety signals during training. Males were sensitive to FB-devaluation after moderate training, but not overtraining, consistent with a transition from goal-directed to habitual avoidance. Using chemogenetics and FB-devaluation, we also show that goal-directed vs. habitual ARs depend on dorsomedial vs. dorsolateral striatum, suggesting a significant overlap between the mechanisms of avoidance and rewarded instrumental behavior. Females were insensitive to FB-devaluation due to a remarkable context-dependence of counterconditioning. However, degrading the AR-FB contingency suggests that both sexes rely on safety signals to perform goal-directed ARs.

10.
J Neurosci ; 30(24): 8263-73, 2010 Jun 16.
Artículo en Inglés | MEDLINE | ID: mdl-20554878

RESUMEN

The lateral hypothalamus and the nucleus accumbens shell (AcbSh) are brain regions important for food intake. The AcbSh contains high levels of receptor for melanin-concentrating hormone (MCH), a lateral hypothalamic peptide critical for feeding and metabolism. MCH receptor (MCHR1) activation in the AcbSh increases food intake, while AcbSh MCHR1 blockade reduces feeding. Here biochemical and cellular mechanisms of MCH action in the rodent AcbSh are described. A reduction of phosphorylation of GluR1 at serine 845 (pSer(845)) is shown to occur after both pharmacological and genetic manipulations of MCHR1 activity. These changes depend upon signaling through G(i/o), and result in decreased surface expression of GluR1-containing AMPA receptors (AMPARs). Electrophysiological analysis of medium spiny neurons (MSNs) in the AcbSh revealed decreased amplitude of AMPAR-mediated synaptic events (mEPSCs) with MCH treatment. In addition, MCH suppressed action potential firing MSNs through K(+) channel activation. Finally, in vivo recordings confirmed that MCH reduces neuronal cell firing in the AcbSh in freely moving animals. The ability of MCH to reduce cell firing in the AcbSh is consistent with a general model from other pharmacological and electrophysiological studies whereby reduced AcbSh neuronal firing leads to food intake. The current work integrates the hypothalamus into this model, providing biochemical and cellular mechanisms whereby metabolic and limbic signals converge to regulate food intake.


Asunto(s)
Hormonas Hipotalámicas/metabolismo , Hipotálamo/metabolismo , Melaninas/metabolismo , Núcleo Accumbens/fisiología , Hormonas Hipofisarias/metabolismo , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/genética , Animales , Compuestos de Bario/farmacología , Biotina/análogos & derivados , Biotina/metabolismo , Cloruros/farmacología , Fosfoproteína 32 Regulada por Dopamina y AMPc/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Regulación de la Expresión Génica/efectos de los fármacos , Hormonas Hipotalámicas/genética , Hormonas Hipotalámicas/farmacología , Hipotálamo/citología , Técnicas In Vitro , Masculino , Melaninas/genética , Melaninas/farmacología , Ratones , Ratones Transgénicos , Vías Nerviosas/fisiología , Neuronas/clasificación , Neuronas/citología , Neuronas/efectos de los fármacos , Neuronas/fisiología , Núcleo Accumbens/citología , Técnicas de Placa-Clamp/métodos , Hormonas Hipofisarias/genética , Hormonas Hipofisarias/farmacología , Bloqueadores de los Canales de Potasio/farmacología , Ratas , Ratas Long-Evans , Ratas Wistar , Receptores AMPA/genética , Receptores AMPA/metabolismo , Serina/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología
11.
Nat Med ; 9(12): 1539-44, 2003 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-14634645

RESUMEN

Conditional mutant techniques that allow spatial and temporal control over gene expression can be used to create mice with restricted genetic modifications. These mice serve as powerful disease models in which gene function in adult tissues can be specifically dissected. Current strategies for conditional genetic manipulation are inefficient, however, and often lack sufficient spatial control. Here we use viral-mediated RNA interference (RNAi) to generate a specific knockdown of Th, the gene encoding the dopamine synthesis enzyme tyrosine hydroxylase, within midbrain neurons of adult mice. This localized gene knockdown resulted in behavioral changes, including a motor performance deficit and reduced response to a psychostimulant. These results underscore the potential of using viral-mediated RNAi for the rapid production and testing of new genetic disease models. Similar strategies may be used in other model species, and may ultimately find applications in human gene therapy.


Asunto(s)
Encéfalo/metabolismo , Marcación de Gen/métodos , Interferencia de ARN , Animales , Secuencia de Bases , Conducta Animal , ADN/genética , Dependovirus/genética , Expresión Génica , Vectores Genéticos , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Tirosina 3-Monooxigenasa/biosíntesis , Tirosina 3-Monooxigenasa/genética
12.
Neuron ; 51(6): 801-10, 2006 Sep 21.
Artículo en Inglés | MEDLINE | ID: mdl-16982424

RESUMEN

The leptin hormone is critical for normal food intake and metabolism. While leptin receptor (Lepr) function has been well studied in the hypothalamus, the functional relevance of Lepr expression in the ventral tegmental area (VTA) has not been investigated. The VTA contains dopamine neurons that are important in modulating motivated behavior, addiction, and reward. Here, we show that VTA dopamine neurons express Lepr mRNA and respond to leptin with activation of an intracellular JAK-STAT pathway and a reduction in firing rate. Direct administration of leptin to the VTA caused decreased food intake while long-term RNAi-mediated knockdown of Lepr in the VTA led to increased food intake, locomotor activity, and sensitivity to highly palatable food. These data support a critical role for VTA Lepr in regulating feeding behavior and provide functional evidence for direct action of a peripheral metabolic signal on VTA dopamine neurons.


Asunto(s)
Conducta Alimentaria/fisiología , Neuronas/fisiología , Receptores de Superficie Celular/fisiología , Transducción de Señal/fisiología , Potenciales de Acción/efectos de los fármacos , Animales , Dopamina/metabolismo , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Conducta Alimentaria/efectos de los fármacos , Expresión Génica , Hibridación Fluorescente in Situ , Técnicas In Vitro , Infusiones Intravenosas , Leptina/administración & dosificación , Leptina/farmacología , Mesencéfalo/citología , Mesencéfalo/fisiología , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Neuronas/citología , Neuronas/metabolismo , Fosforilación/efectos de los fármacos , Interferencia de ARN , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Superficie Celular/genética , Receptores de Leptina , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Área Tegmental Ventral/citología , Área Tegmental Ventral/metabolismo
13.
Physiol Behav ; 91(5): 499-505, 2007 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-17292426

RESUMEN

Increasing rates of obesity have alarmed health officials and prompted much public dialogue. While the factors leading to obesity are numerous, an inability to control intake of freely available food is central to the problem. In order to understand this, we need to better define the mechanisms by which the brain regulates food intake, and why it is often difficult to control consumption. From this point of view, it seems valuable to consider the commonalities between food intake and drug abuse. While research in the two fields has historically emphasized different neural substrates, recent data have increased interest in better defining elements that may underlie both drug addiction and obesity. Here we discuss some of these shared elements with an emphasis on emerging areas of research that better define common mechanisms leading to overconsumption.


Asunto(s)
Conducta Adictiva/fisiopatología , Obesidad/fisiopatología , Trastornos Relacionados con Sustancias/fisiopatología , Animales , Conducta Adictiva/psicología , Encéfalo/fisiopatología , Humanos , Obesidad/psicología , Trastornos Relacionados con Sustancias/psicología
14.
eNeuro ; 4(5)2017.
Artículo en Inglés | MEDLINE | ID: mdl-29071299

RESUMEN

The neural mechanisms through which a Pavlovian conditioned stimulus (CS) elicits innate defense responses are well understood. But a Pavlovian CS can also invigorate ongoing instrumental responding, as shown by studies of aversive Pavlovian-to-instrumental transfer (PIT). While the neural circuitry of appetitive PIT has been studied extensively, little is known about the brain mechanisms of aversive PIT. We recently showed the central amygdala (CeA) is essential for aversive PIT. In the current studies, using pharmacology and designer receptors in rodents, we demonstrate that noradrenergic (NE) activity negatively regulates PIT via brainstem locus coeruleus (LC) activity and LC projections to CeA. Our results provide evidence for a novel pathway through which response modulation occurs between brainstem neuromodulatory systems and CeA to invigorate adaptive behavior in the face of threat.


Asunto(s)
Reacción de Prevención/fisiología , Núcleo Amigdalino Central/metabolismo , Condicionamiento Clásico/fisiología , Norepinefrina/metabolismo , Transferencia de Experiencia en Psicología/fisiología , Antagonistas Adrenérgicos beta/farmacología , Análisis de Varianza , Animales , Antipsicóticos/farmacología , Reacción de Prevención/efectos de los fármacos , Núcleo Amigdalino Central/efectos de los fármacos , Clozapina/análogos & derivados , Clozapina/farmacología , Condicionamiento Clásico/efectos de los fármacos , Dopamina beta-Hidroxilasa/metabolismo , Locus Coeruleus/fisiología , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Masculino , Propranolol/farmacología , Ratas , Ratas Sprague-Dawley , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Transducción Genética , Transferencia de Experiencia en Psicología/efectos de los fármacos , Proteína Fluorescente Roja
15.
Neuropsychopharmacology ; 42(4): 895-903, 2017 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-27762270

RESUMEN

Memory formation requires the temporal coordination of molecular events and cellular processes following a learned event. During Pavlovian threat (fear) conditioning (PTC), sensory and neuromodulatory inputs converge on post-synaptic neurons within the lateral nucleus of the amygdala (LA). By activating an intracellular cascade of signaling molecules, these G-protein-coupled neuromodulatory receptors are capable of recruiting a diverse profile of plasticity-related proteins. Here we report that norepinephrine, through its actions on ß-adrenergic receptors (ßARs), modulates aversive memory formation following PTC through two molecularly and temporally distinct signaling mechanisms. Specifically, using behavioral pharmacology and biochemistry in adult rats, we determined that ßAR activity during, but not after PTC training initiates the activation of two plasticity-related targets: AMPA receptors (AMPARs) for memory acquisition and short-term memory and extracellular regulated kinase (ERK) for consolidating the learned association into a long-term memory. These findings reveal that ßAR activity during, but not following PTC sets in motion cascading molecular events for the acquisition (AMPARs) and subsequent consolidation (ERK) of learned associations.


Asunto(s)
Complejo Nuclear Basolateral/metabolismo , Conducta Animal/fisiología , Condicionamiento Clásico/fisiología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Miedo/fisiología , Memoria/fisiología , Norepinefrina/metabolismo , Receptores AMPA/metabolismo , Receptores Adrenérgicos beta/metabolismo , Transducción de Señal/fisiología , Animales , Sistema de Señalización de MAP Quinasas/fisiología , Masculino , Ratas , Ratas Sprague-Dawley
16.
J Neurosci ; 25(11): 2933-40, 2005 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-15772353

RESUMEN

Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide with a prominent role in feeding and energy homeostasis. The rodent MCH receptor (MCH1R) is highly expressed in the nucleus accumbens shell (AcSh), a region that is important in the regulation of appetitive behavior. Here we establish a role for MCH and MCH1R in mediating a hypothalamic-limbic circuit that regulates feeding and related behaviors. Direct delivery of an MCH1R receptor antagonist to the AcSh blocked feeding and produced an antidepressant-like effect in the forced swim test, whereas intra-AcSh injection of MCH had the opposite effect. Expression studies demonstrated that MCH1R is present in both the enkephalin- and dynorphin-positive medium spiny neurons of the AcSh. Biochemical analysis in AcSh explants showed that MCH signaling blocks dopamine-induced phosphorylation of the AMPA glutamate receptor subunit GluR1 at Ser845. Finally, food deprivation, but not other stressors, stimulated cAMP response element-binding protein-dependent pathways selectively in MCH neurons of the hypothalamus, suggesting that these neurons are responsive to a specific set of physiologically relevant conditions. This work identifies a novel hypothalamic-AcSh circuit that influences appetitive behavior and mediates the antidepressant activity of MCH1R antagonists.


Asunto(s)
Conducta Alimentaria/efectos de los fármacos , Hormonas Hipotalámicas/farmacología , Melaninas/farmacología , Núcleo Accumbens/efectos de los fármacos , Hormonas Hipofisarias/farmacología , Natación/fisiología , Análisis de Varianza , Animales , Conducta Animal , Benzazepinas/farmacología , Western Blotting/métodos , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Agonistas de Dopamina/farmacología , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Dinorfinas/genética , Dinorfinas/metabolismo , Ingestión de Alimentos/efectos de los fármacos , Encefalinas/genética , Encefalinas/metabolismo , Conducta Alimentaria/fisiología , Privación de Alimentos/fisiología , Regulación de la Expresión Génica/efectos de los fármacos , Hormonas Hipotalámicas/deficiencia , Inmunohistoquímica/métodos , Hibridación Fluorescente in Situ/métodos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Melaninas/deficiencia , Ratones , Ratones Transgénicos , Neuronas/metabolismo , Neuropéptidos/metabolismo , Núcleo Accumbens/citología , Núcleo Accumbens/fisiología , Receptores de Orexina , Orexinas , Hormonas Hipofisarias/deficiencia , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/genética , Receptores AMPA/metabolismo , Receptores Acoplados a Proteínas G , Receptores de Neuropéptido , Receptores de la Hormona Hipofisaria/antagonistas & inhibidores , Receptores de la Hormona Hipofisaria/metabolismo , Serina/metabolismo , Factores de Tiempo
17.
Curr Top Behav Neurosci ; 27: 171-95, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26643998

RESUMEN

Much of the early research in aversive learning concerned motivation and reinforcement in avoidance conditioning and related paradigms. When the field transitioned toward the focus on Pavlovian threat conditioning in isolation, this paved the way for the clear understanding of the psychological principles and neural and molecular mechanisms responsible for this type of learning and memory that has unfolded over recent decades. Currently, avoidance conditioning is being revisited, and with what has been learned about associative aversive learning, rapid progress is being made. We review, below, the literature on the neural substrates critical for learning in instrumental active avoidance tasks and conditioned aversive motivation.


Asunto(s)
Reacción de Prevención/fisiología , Encéfalo/fisiología , Reacción Cataléptica de Congelación/fisiología , Motivación/fisiología , Amígdala del Cerebelo/fisiología , Animales , Condicionamiento Clásico/fisiología , Condicionamiento Operante/fisiología , Miedo/fisiología , Memoria/fisiología , Refuerzo en Psicología
18.
ACS Chem Neurosci ; 6(7): 1248-58, 2015 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-26120876

RESUMEN

A feature of multiple neuropsychiatric disorders is motor impulsivity. Recent studies have implicated serotonin (5-HT) systems in medial prefrontal cortex (mPFC) in mediating individual differences in motor impulsivity, notably the 5-HT2AR receptor (5-HT2AR) and 5-HT2CR. We investigated the hypothesis that differences in the ratio of 5-HT2AR:5-HT2CR protein expression in mPFC would predict the individual level of motor impulsivity and that the engineered loss of the 5-HT2CR would result in high motor impulsivity concomitant with elevated 5-HT2AR expression and pharmacological sensitivity to the selective 5-HT2AR antagonist M100907. High and low impulsive rats were identified in a 1-choice serial reaction time task. Native protein levels of the 5-HT2AR and the 5-HT2CR predicted the intensity of motor impulsivity and the 5-HT2AR:5-HT2CR ratio in mPFC positively correlated with levels of premature responses in individual outbred rats. The possibility that the 5-HT2AR and 5-HT2CR act in concert to control motor impulsivity is supported by the observation that high phenotypic motor impulsivity associated with a diminished mPFC synaptosomal 5-HT2AR:5-HT2CR protein:protein interaction. Knockdown of mPFC 5-HT2CR resulted in increased motor impulsivity and triggered a functional disruption of the local 5-HT2AR:5-HT2CR balance as evidenced by a compensatory upregulation of 5-HT2AR protein expression and a leftward shift in the potency of M100907 to suppress impulsive behavior. We infer that there is an interactive relationship between the mPFC 5-HT2AR and 5-HT2CR, and that a 5-HT2AR:5-HT2CR imbalance may be a functionally relevant mechanism underlying motor impulsivity.


Asunto(s)
Conducta Impulsiva/fisiología , Actividad Motora/fisiología , Corteza Prefrontal/metabolismo , Receptor de Serotonina 5-HT2A/metabolismo , Receptor de Serotonina 5-HT2C/metabolismo , Animales , Animales no Consanguíneos , Conducta de Elección/efectos de los fármacos , Conducta de Elección/fisiología , Función Ejecutiva/efectos de los fármacos , Función Ejecutiva/fisiología , Fluorobencenos/farmacología , Técnicas de Silenciamiento del Gen , Conducta Impulsiva/efectos de los fármacos , Masculino , Glicoproteínas de Membrana , Actividad Motora/efectos de los fármacos , Pruebas Neuropsicológicas , Fenotipo , Piperidinas/farmacología , Corteza Prefrontal/efectos de los fármacos , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT2C/genética , Receptores de Interleucina-1 , Antagonistas de la Serotonina/farmacología , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismo
19.
Prog Mol Biol Transl Sci ; 122: 263-304, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24484705

RESUMEN

Pavlovian threat conditioning is a behavioral paradigm that has been successfully utilized to define the mechanisms underlying threat (fear) memory formation. The amygdala is a temporal lobe structure required for the acquisition, consolidation, and expression of threat (fear) memories. In particular, the lateral nucleus of the amygdala (LA) is the major input structure of the amygdala and is required for all aspects of threat learning and memory. The LA expresses many neurotransmitter and neuromodulator receptors. This chapter covers the molecular mechanisms that occur downstream of these receptors and how they influence LA-dependent Pavlovian threat learning.


Asunto(s)
Amígdala del Cerebelo/metabolismo , Condicionamiento Psicológico/fisiología , Miedo/psicología , Aprendizaje/fisiología , Memoria/fisiología , Animales , Humanos
20.
Neuropsychopharmacology ; 39(2): 370-82, 2014 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-23939424

RESUMEN

Relapse vulnerability in cocaine dependence is rooted in genetic and environmental determinants, and propelled by both impulsivity and the responsivity to cocaine-linked cues ('cue reactivity'). The serotonin (5-hydroxytryptamine, 5-HT) 5-HT2C receptor (5-HT2CR) within the medial prefrontal cortex (mPFC) is uniquely poised to serve as a strategic nexus to mechanistically control these behaviors. The 5-HT2CR functional capacity is regulated by a number of factors including availability of active membrane receptor pools, the composition of the 5-HT2CR macromolecular protein complex, and editing of the 5-HT2CR pre-mRNA. The one-choice serial reaction time (1-CSRT) task was used to identify impulsive action phenotypes in an outbred rat population before cocaine self-administration and assessment of cue reactivity in the form of lever presses reinforced by the cocaine-associated discrete cue complex during forced abstinence. The 1-CSRT task reliably and reproducibly identified high impulsive (HI) and low impulsive (LI) action phenotypes; HI action predicted high cue reactivity. Lower cortical 5-HT2CR membrane protein levels concomitant with higher levels of 5-HT2CR:postsynaptic density 95 complex distinguished HI rats from LI rats. The frequency of edited 5-HT2CR mRNA variants was elevated with the prediction that the protein population in HI rats favors those isoforms linked to reduced signaling capacity. Genetic loss of the mPFC 5-HT2CR induced aggregate impulsive action/cue reactivity, suggesting that depressed cortical 5-HT2CR tone confers vulnerability to these interlocked behaviors. Thus, impulsive action and cue reactivity appear to neuromechanistically overlap in rodents, with the 5-HT2CR functional status acting as a neural rheostat to regulate, in part, the intersection between these vulnerability behaviors.


Asunto(s)
Trastornos Relacionados con Cocaína/genética , Trastornos Relacionados con Cocaína/metabolismo , Fenotipo , Receptor de Serotonina 5-HT2C/deficiencia , Receptor de Serotonina 5-HT2C/fisiología , Animales , Conducta Animal/fisiología , Trastornos Relacionados con Cocaína/fisiopatología , Masculino , Corteza Prefrontal/metabolismo , Corteza Prefrontal/fisiopatología , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT2C/genética , Recurrencia , Autoadministración
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