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1.
Nat Commun ; 11(1): 6218, 2020 12 04.
Artigo em Inglês | MEDLINE | ID: mdl-33277492

RESUMO

Marked deficits in glucose availability, or glucoprivation, elicit organism-wide counter-regulatory responses whose purpose is to restore glucose homeostasis. However, while catecholamine neurons of the ventrolateral medulla (VLMCA) are thought to orchestrate these responses, the circuit and cellular mechanisms underlying specific counter-regulatory responses are largely unknown. Here, we combined anatomical, imaging, optogenetic and behavioral approaches to interrogate the circuit mechanisms by which VLMCA neurons orchestrate glucoprivation-induced food seeking behavior. Using these approaches, we found that VLMCA neurons form functional connections with nucleus accumbens (NAc)-projecting neurons of the posterior portion of the paraventricular nucleus of the thalamus (pPVT). Importantly, optogenetic manipulations revealed that while activation of VLMCA projections to the pPVT was sufficient to elicit robust feeding behavior in well fed mice, inhibition of VLMCA-pPVT communication significantly impaired glucoprivation-induced feeding while leaving other major counterregulatory responses intact. Collectively our findings identify the VLMCA-pPVT-NAc pathway as a previously-neglected node selectively controlling glucoprivation-induced food seeking. Moreover, by identifying the ventrolateral medulla as a direct source of metabolic information to the midline thalamus, our results support a growing body of literature on the role of the PVT in homeostatic regulation.


Assuntos
Catecolaminas/metabolismo , Comportamento Alimentar/fisiologia , Glucose/metabolismo , Bulbo/fisiologia , Neurônios/fisiologia , Núcleos Ventrais do Tálamo/fisiologia , Animais , Feminino , Homeostase/fisiologia , Masculino , Bulbo/citologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Núcleos da Linha Média do Tálamo/citologia , Núcleos da Linha Média do Tálamo/fisiologia , Neurônios/metabolismo , Núcleo Accumbens/citologia , Núcleo Accumbens/fisiologia , Núcleos Ventrais do Tálamo/citologia
2.
Neuron ; 108(3): 568-581.e6, 2020 11 11.
Artigo em Inglês | MEDLINE | ID: mdl-32758424

RESUMO

Rodent studies have demonstrated the role of the mesoaccumbal circuit in reinforcement-based learning. Importantly, however, while phasic activity of the ventral tegmental area (VTA) contributes to reinforcement learning, rodent evidence suggests that slow changes in tonic VTA activity and associated accumbal dopamine release help regulate motivational behavior. Nonetheless, the consequences of sustained blockage of the mesoaccumbal circuit for motivation and reinforcement learning have not yet been examined in primates. Using a double-infection viral vector technique, we demonstrate that selective, unidirectional, and reversible blockage of the primarily dopaminergic mesoaccumbal circuit in monkeys increased network-level functional connectivity, especially in fronto-temporal cortex. These global network changes were not associated with deficits in reinforcement learning during an object discrimination reversal task. In contrast, sustained mesoaccumbal inactivation greatly reduced motivation for performing a motivation-based decision-making task. Thus, the mesoaccumbal pathway in primates is critical for high-effort motivation but not for all forms of reinforcement-based learning.


Assuntos
Aprendizagem/fisiologia , Motivação/fisiologia , Vias Neurais/fisiologia , Núcleo Accumbens/fisiologia , Área Tegmentar Ventral/fisiologia , Animais , Macaca mulatta , Reforço Psicológico
3.
Nat Neurosci ; 23(10): 1267-1276, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32778791

RESUMO

The nervous system is hypothesized to compute reward prediction errors (RPEs) to promote adaptive behavior. Correlates of RPEs have been observed in the midbrain dopamine system, but the extent to which RPE signals exist in other reward-processing regions is less well understood. In the present study, we quantified outcome history-based RPE signals in the ventral pallidum (VP), a basal ganglia region functionally linked to reward-seeking behavior. We trained rats to respond to reward-predicting cues, and we fit computational models to predict the firing rates of individual neurons at the time of reward delivery. We found that a subset of VP neurons encoded RPEs and did so more robustly than the nucleus accumbens, an input to the VP. VP RPEs predicted changes in task engagement, and optogenetic manipulation of the VP during reward delivery bidirectionally altered rats' subsequent reward-seeking behavior. Our data suggest a pivotal role for the VP in computing teaching signals that influence adaptive reward seeking.


Assuntos
Prosencéfalo Basal/fisiologia , Motivação/fisiologia , Neurônios/fisiologia , Recompensa , Animais , Sinais (Psicologia) , Preferências Alimentares/fisiologia , Masculino , Modelos Neurológicos , Núcleo Accumbens/fisiologia , Optogenética , Ratos Long-Evans
4.
J Neurosci ; 40(36): 6888-6895, 2020 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-32727819

RESUMO

Hedonic processing plays an integral role in directing appropriate behavior, but disrupted hedonic processing is associated with psychiatric disorders such as depression. The infralimbic cortex (IL) is a key structure in affective processing in rodents and activation of its human homolog, the ventromedial prefrontal cortex, has been implicated in suppressing aversive states. Here, we tested whether optogenetic activation of glutamatergic projections from the IL to the nucleus accumbens shell (NAcSh) suppresses the aversive impact of sucrose devalued using the conditioned taste aversion paradigm in males and female rats. In naive rats, no significant differences in appetitive or aversive taste reactivity (TR) to sucrose was observed indicating that initial sucrose palatability was equivalent across sex. However, we found that optical activation of the IL-NAcSh pathway during intraoral infusion of devalued sucrose inhibited aversive TR in male but not female rats. Interestingly, when allowed to freely ingest water and sucrose in a two-bottle test both males and females with a history of IL-NAcSh stimulation exhibited greater preference for sucrose. Optical pathway activation failed to alter TR to innately bitter quinine in either sex. Finally, both sexes lever pressed to self-stimulate the IL-NAcSh pathway. These results indicate that the IL-NAcSh pathway plays an important role in suppressing learned aversive states selectively in males but spares hedonic processing of innately aversive tastants. Further, pathway activation is reinforcing in both sexes, indicating that suppression of conditioned aversive TR can be dissociable from the effects of unconditioned rewarding properties of IL-NAcSh pathway activation.SIGNIFICANCE STATEMENT Negative emotional states contribute to psychiatric disorders including depression and substance use disorders. In this study, we examined whether brain circuitry previously implicated in suppressing negative emotional states in humans can inhibit learned aversion in male and female rats. We found that optical activation of the infralimbic to nucleus accumbens shell pathway attenuates learned aversive responses in male but not female rats, indicating an important sex difference in the function of this brain pathway. Furthermore, we found that pathway stimulation was reinforcing in both sexes. Collectively, these findings support the role of the infralimbic cortex and its projection to the nucleus accumbens shell in suppressing learned negative emotional states and highlight an important sex-specific function of this pathway.


Assuntos
Condicionamento Clássico , Sistema Límbico/fisiologia , Núcleo Accumbens/fisiologia , Percepção Gustatória , Animais , Agentes Aversivos , Feminino , Masculino , Vias Neurais/fisiologia , Quinina , Ratos , Ratos Sprague-Dawley , Fatores Sexuais
5.
J Neurosci ; 40(33): 6409-6427, 2020 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-32669355

RESUMO

The mesolimbic dopamine system comprises distinct compartments supporting different functions in learning and motivation. Less well understood is how complex addiction-related behaviors emerge from activity patterns across these compartments. Here we show how different forms of relapse to alcohol-seeking in male rats are assembled from activity across the VTA and the nucleus accumbens. First, we used chemogenetic approaches to show a causal role for VTA TH neurons in two forms of relapse to alcohol-seeking: renewal (context-induced reinstatement) and reacquisition. Then, using gCaMP fiber photometry of VTA TH neurons, we identified medial and lateral VTA TH neuron activity profiles during self-administration, renewal, and reacquisition. Next, we used optogenetic inhibition of VTA TH neurons to show distinct causal roles for VTA subregions in distinct forms of relapse. We then used dLight fiber photometry to measure dopamine binding across the ventral striatum (medial accumbens shell, accumbens core, lateral accumbens shell) and showed complex and heterogeneous profiles of dopamine binding during self-administration and relapse. Finally, we used representational similarity analysis to identify mesolimbic dopamine signatures of self-administration, extinction, and relapse. Our results show that signatures of relapse can be identified from heterogeneous activity profiles across the mesolimbic dopamine system and that these signatures are unique for different forms of relapse.SIGNIFICANCE STATEMENT It is axiomatic that the actions of dopamine are critical to drug addiction. Yet how relapse to drug-seeking is assembled from activity across the mesolimbic dopamine system is poorly understood. Here we show how relapse to alcohol-seeking relates to activity in specific VTA and accumbens compartments, how these change for different forms of relapse, and how relapse-associated activity relates to activity during self-administration and extinction. We report the mesolimbic dopamine activity signatures for relapse and show that these signatures are unique for different forms of relapse.


Assuntos
Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/fisiologia , Comportamento de Procura de Droga/fisiologia , Etanol/administração & dosagem , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/fisiologia , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/fisiologia , Animais , Comportamento Aditivo/fisiopatologia , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Dopamina/metabolismo , Masculino , Potenciais da Membrana , Optogenética , Ratos Long-Evans , Recidiva , Tirosina 3-Mono-Oxigenase/metabolismo
6.
Nat Commun ; 11(1): 3688, 2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32703948

RESUMO

Zeta inhibitory peptide (ZIP), a PKMζ inhibitor, is widely used to interfere with the maintenance of acquired memories. ZIP is able to erase memory even in the absence of PKMζ, via an unknown mechanism. We found that ZIP induces redistribution of the AMPARGluA1 in HEK293 cells and primary cortical neurons, and decreases AMPAR-mediated currents in the nucleus accumbens (NAc). These effects were mimicked by free arginine or by a modified ZIP in which all but the arginine residues were replaced by alanine. Redistribution was blocked by a peptidase-resistant version of ZIP and by treatment with the nitric oxide (NO)-synthase inhibitor L-NAME. ZIP increased GluA1-S831 phosphorylation and ZIP-induced redistribution was blocked by nitrosyl-mutant GluA1-C875S or serine-mutant GluA1-S831A. Introducing the cleavable arginine-alanine peptide into the NAc attenuated expression of cocaine-conditioned reward. Together, these results suggest that ZIP may act as an arginine donor, facilitating NO-dependent downregulation of AMPARs, thereby attenuating learning and memory.


Assuntos
Peptídeos Penetradores de Células/farmacologia , Condicionamento Psicológico/efeitos dos fármacos , Lipopeptídeos/farmacologia , Memória de Longo Prazo/efeitos dos fármacos , Óxido Nítrico/metabolismo , Receptores de AMPA/metabolismo , Animais , Cocaína/administração & dosagem , Regulação para Baixo , Endocitose/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Células HEK293 , Humanos , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Camundongos , Modelos Animais , NG-Nitroarginina Metil Éster/farmacologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Óxido Nítrico/antagonistas & inibidores , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/fisiologia , Fosforilação , Cultura Primária de Células , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Ratos , Receptores de AMPA/genética , Recompensa , Técnicas Estereotáxicas
7.
Nat Neurosci ; 23(7): 869-880, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32483349

RESUMO

Besides generating vision, light modulates various physiological functions, including mood. While light therapy applied in the daytime is known to have anti-depressive properties, excessive light exposure at night has been reportedly associated with depressive symptoms. The neural mechanisms underlying this day-night difference in the effects of light are unknown. Using a light-at-night (LAN) paradigm in mice, we showed that LAN induced depressive-like behaviors without disturbing the circadian rhythm. This effect was mediated by a neural pathway from retinal melanopsin-expressing ganglion cells to the dorsal perihabenular nucleus (dpHb) to the nucleus accumbens (NAc). Importantly, the dpHb was gated by the circadian rhythm, being more excitable at night than during the day. This indicates that the ipRGC→dpHb→NAc pathway preferentially conducts light signals at night, thereby mediating LAN-induced depressive-like behaviors. These findings may be relevant when considering the mental health effects of the prevalent nighttime illumination in the industrial world.


Assuntos
Ritmo Circadiano/fisiologia , Ritmo Circadiano/efeitos da radiação , Depressão/fisiopatologia , Luz/efeitos adversos , Vias Visuais/fisiologia , Animais , Depressão/etiologia , Habenula/fisiologia , Habenula/efeitos da radiação , Camundongos , Núcleo Accumbens/fisiologia , Núcleo Accumbens/efeitos da radiação , Células Ganglionares da Retina/fisiologia , Células Ganglionares da Retina/efeitos da radiação , Vias Visuais/efeitos da radiação
8.
J Neurosci ; 40(24): 4750-4760, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32381486

RESUMO

Fear is adaptive when the level of the response rapidly scales to degree of threat. Using a discrimination procedure consisting of danger, uncertainty, and safety cues, we have found rapid fear scaling (within 2 s of cue presentation) in male rats. Here, we examined a possible role for the nucleus accumbens core (NAcc) in the acquisition and expression of fear scaling. In experiment 1, male Long-Evans rats received bilateral sham or neurotoxic NAcc lesions, recovered, and underwent fear discrimination. NAcc-lesioned rats were generally impaired in scaling fear to degree of threat, and specifically impaired in rapid uncertainty-safety discrimination. In experiment 2, male Long-Evans rats received NAcc transduction with halorhodopsin (Halo) or a control fluorophore. After fear scaling was established, the NAcc was illuminated during cue or control periods. NAcc-Halo rats receiving cue illumination were specifically impaired in rapid uncertainty-safety discrimination. The results reveal a general role for the NAcc in scaling fear to degree of threat, and a specific role in rapid discrimination of uncertain threat and safety.SIGNIFICANCE STATEMENT Rapidly discriminating cues for threat and safety is essential for survival and impaired threat-safety discrimination is a hallmark of stress and anxiety disorders. In two experiments, we induced nucleus accumbens core (NAcc) dysfunction in rats receiving fear discrimination consisting of cues for danger, uncertainty, and safety. Permanent NAcc dysfunction, via neurotoxic lesion, generally disrupted the ability to scale fear to degree of threat, and specifically impaired one component of scaling: rapid discrimination of uncertain threat and safety. Reversible NAcc dysfunction, via optogenetic inhibition, specifically impaired rapid discrimination of uncertain threat and safety. The results reveal that the NAcc is essential to scale fear to degree of threat, and is a plausible source of dysfunction in stress and anxiety disorders.


Assuntos
Discriminação Psicológica/fisiologia , Medo/fisiologia , Núcleo Accumbens/fisiologia , Animais , Condicionamento Clássico/fisiologia , Masculino , Optogenética , Ratos , Ratos Long-Evans
9.
Proc Natl Acad Sci U S A ; 117(20): 11076-11084, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32381740

RESUMO

Pair-bond formation depends vitally on neuromodulatory signaling within the nucleus accumbens, but the neuronal dynamics underlying this behavior remain unclear. Using 1-photon in vivo Ca2+ imaging in monogamous prairie voles, we found that pair bonding does not elicit differences in overall nucleus accumbens Ca2+ activity. Instead, we identified distinct ensembles of neurons in this region that are recruited during approach to either a partner or a novel vole. The partner-approach neuronal ensemble increased in size following bond formation, and differences in the size of approach ensembles for partner and novel voles predict bond strength. In contrast, neurons comprising departure ensembles do not change over time and are not correlated with bond strength, indicating that ensemble plasticity is specific to partner approach. Furthermore, the neurons comprising partner and novel-approach ensembles are nonoverlapping while departure ensembles are more overlapping than chance, which may reflect another key feature of approach ensembles. We posit that the features of the partner-approach ensemble and its expansion upon bond formation potentially make it a key neuronal substrate associated with bond formation and maturation.


Assuntos
Neurônios/fisiologia , Núcleo Accumbens/fisiologia , Ligação do Par , Comportamento Sexual Animal/fisiologia , Animais , Arvicolinae/fisiologia , Feminino , Masculino , Preferência de Acasalamento Animal/fisiologia , Núcleo Accumbens/diagnóstico por imagem , Comportamento Social
10.
J Neurosci ; 40(24): 4727-4738, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32354856

RESUMO

Decades of research have shown that the NAc is a critical region influencing addiction, mood, and food consumption through its effects on reinforcement learning, motivation, and hedonic experience. Pharmacological studies have demonstrated that inhibition of the NAc shell induces voracious feeding, leading to the hypothesis that the inhibitory projections that emerge from the NAc normally act to restrict feeding. While much of this work has focused on projections to the lateral hypothalamus, the role of NAc projections to the VTA in the control food intake has been largely unexplored. Using a retrograde viral labeling technique and real-time monitoring of neural activity with fiber photometry, we find that medial NAc shell projections to the VTA (mNAc→VTA) are inhibited during food-seeking and food consumption in male mice. We also demonstrate that this circuit bidirectionally controls feeding: optogenetic activation of NAc projections to the VTA inhibits food-seeking and food intake (in both sexes), while optogenetic inhibition of this circuit potentiates food-seeking behavior. Additionally, we show that activity of the NAc to VTA pathway is necessary for adaptive inhibition of food intake in response to external cues. These data provide new insight into NAc control over feeding in mice, and contribute to an emerging literature elucidating the role of inhibitory midbrain feedback within the mesolimbic circuit.SIGNIFICANCE STATEMENT The medial NAc has long been known to control consummatory behavior, with particular focus on accumbens projections to the lateral hypothalamus. Conversely, NAc projections to the VTA have mainly been studied in the context of drug reward. We show that NAc projections to the VTA bidirectionally control food intake, consistent with a permissive role in feeding. Additionally, we show that this circuit is normally inactivated during consumption and food-seeking. Together, these findings elucidate how mesolimbic circuits control food consumption.


Assuntos
Comportamento Consumatório/fisiologia , Ingestão de Alimentos/fisiologia , Núcleo Accumbens/fisiologia , Área Tegmentar Ventral/fisiologia , Animais , Condicionamento Operante/fisiologia , Masculino , Camundongos , Atividade Motora/fisiologia , Vias Neurais/fisiologia , Optogenética , Recompensa
11.
Nat Hum Behav ; 4(5): 531-543, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32231281

RESUMO

Curiosity is often portrayed as a desirable feature of human faculty. However, curiosity may come at a cost that sometimes puts people in harmful situations. Here, using a set of behavioural and neuroimaging experiments with stimuli that strongly trigger curiosity (for example, magic tricks), we examine the psychological and neural mechanisms underlying the motivational effect of curiosity. We consistently demonstrate that across different samples, people are indeed willing to gamble, subjecting themselves to electric shocks to satisfy their curiosity for trivial knowledge that carries no apparent instrumental value. Also, this influence of curiosity shares common neural mechanisms with that of hunger for food. In particular, we show that acceptance (compared to rejection) of curiosity-driven or incentive-driven gambles is accompanied by enhanced activity in the ventral striatum when curiosity or hunger was elicited, which extends into the dorsal striatum when participants made a decision.


Assuntos
Corpo Estriado/fisiologia , Tomada de Decisões/fisiologia , Comportamento Exploratório , Fome/fisiologia , Estriado Ventral/diagnóstico por imagem , Estriado Ventral/fisiologia , Corpo Estriado/diagnóstico por imagem , Eletrochoque/psicologia , Comportamento Exploratório/fisiologia , Feminino , Jogo de Azar/diagnóstico por imagem , Jogo de Azar/fisiopatologia , Humanos , Magia/psicologia , Imagem por Ressonância Magnética , Masculino , Motivação/fisiologia , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/fisiologia , Neuroimagem , Núcleo Accumbens/diagnóstico por imagem , Núcleo Accumbens/fisiologia , Adulto Jovem
12.
Nat Commun ; 11(1): 1957, 2020 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-32327644

RESUMO

Action control is a key brain function determining the survival of animals in their environment. In mammals, neurons expressing dopamine D2 receptors (D2R) in the dorsal striatum (DS) and the nucleus accumbens (Acb) jointly but differentially contribute to the fine regulation of movement. However, their region-specific molecular features are presently unknown. By combining RNAseq of striatal D2R neurons and histological analyses, we identified hundreds of novel region-specific molecular markers, which may serve as tools to target selective subpopulations. As a proof of concept, we characterized the molecular identity of a subcircuit defined by WFS1 neurons and evaluated multiple behavioral tasks after its temporally-controlled deletion of D2R. Consequently, conditional D2R knockout mice displayed a significant reduction in digging behavior and an exacerbated hyperlocomotor response to amphetamine. Thus, targeted molecular analyses reveal an unforeseen heterogeneity in D2R-expressing striatal neuronal populations, underlying specific D2R's functional features in the control of specific motor behaviors.


Assuntos
Neostriado/citologia , Neurônios/fisiologia , Núcleo Accumbens/citologia , Receptores de Dopamina D2/metabolismo , Anfetamina/farmacologia , Animais , Biomarcadores/metabolismo , Corpo Estriado/citologia , Corpo Estriado/metabolismo , Corpo Estriado/fisiologia , Dopaminérgicos/farmacologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Atividade Motora/genética , Neostriado/metabolismo , Neostriado/fisiologia , Vias Neurais , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Núcleo Accumbens/metabolismo , Núcleo Accumbens/fisiologia , Receptores de Dopamina D2/genética
13.
Proc Natl Acad Sci U S A ; 117(12): 6936-6941, 2020 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-32152105

RESUMO

The growth of the internet has spawned new "attention markets," in which people devote increasing amounts of time to consuming online content, but the neurobehavioral mechanisms that drive engagement in these markets have yet to be elucidated. We used functional MRI (FMRI) to examine whether individuals' neural responses to videos could predict their choices to start and stop watching videos as well as whether group brain activity could forecast aggregate video view frequency and duration out of sample on the internet (i.e., on youtube.com). Brain activity during video onset predicted individual choice in several regions (i.e., increased activity in the nucleus accumbens [NAcc] and medial prefrontal cortex [MPFC] as well as decreased activity in the anterior insula [AIns]). Group activity during video onset in only a subset of these regions, however, forecasted both aggregate view frequency and duration (i.e., increased NAcc and decreased AIns)-and did so above and beyond conventional measures. These findings extend neuroforecasting theory and tools by revealing that activity in brain regions implicated in anticipatory affect at the onset of video viewing (but not initial choice) can forecast time allocation out of sample in an internet attention market.


Assuntos
Atenção/fisiologia , Encéfalo/fisiologia , Comportamento de Escolha , Internet/estatística & dados numéricos , Fenômenos Fisiológicos do Sistema Nervoso , Mídias Sociais , Gravação em Vídeo , Adulto , Córtex Cerebral/fisiologia , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Núcleo Accumbens/fisiologia , Córtex Pré-Frontal/fisiologia
14.
Sci Rep ; 10(1): 1838, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-32020036

RESUMO

The medial prefrontal cortex (mPFC) is a critical component of a cortico-basal ganglia-thalamo-cortical loop regulating limbic and cognitive functions. Within this circuit, two distinct nucleus accumbens (NAc) output neuron types, dopamine D1 or D2 receptor-expressing neurons, dynamically control the flow of information through basal ganglia nuclei that eventually project back to the mPFC to complete the loop. Thus, chronic dysfunction of the NAc may result in mPFC transcriptomal changes, which in turn contribute to disease conditions associated with the mPFC and basal ganglia. Here, we used RNA sequencing to analyse differentially expressed genes (DEGs) in the mPFC following a reversible neurotransmission blocking technique in D1 or D2 receptor-expressing NAc neurons, respectively (D1-RNB, or D2-RNB). Gene Set Enrichment Analysis revealed that gene sets of layer 5b and 6 pyramidal neurons were enriched in DEGs of the mPFC downregulated in both NAc D1- and D2-RNB mice. In contrast, gene sets of layer 5a pyramidal neurons were enriched in upregulated DEGs of the mPFC in D1-RNB mice, and downregulated DEGs of the mPFC in D2-RNB mice. These findings reveal for the first time that NAc output pathways play an important role in controlling mPFC gene expression.


Assuntos
Vias Neurais/metabolismo , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/metabolismo , Animais , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/fisiologia , Regulação da Expressão Gênica , Camundongos , Vias Neurais/fisiologia , Núcleo Accumbens/fisiologia , Células Piramidais/metabolismo , Células Piramidais/fisiologia , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismo , Transcriptoma
15.
Nat Commun ; 11(1): 782, 2020 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-32034128

RESUMO

Food addiction is linked to obesity and eating disorders and is characterized by a loss of behavioral control and compulsive food intake. Here, using a food addiction mouse model, we report that the lack of cannabinoid type-1 receptor in dorsal telencephalic glutamatergic neurons prevents the development of food addiction-like behavior, which is associated with enhanced synaptic excitatory transmission in the medial prefrontal cortex (mPFC) and in the nucleus accumbens (NAc). In contrast, chemogenetic inhibition of neuronal activity in the mPFC-NAc pathway induces compulsive food seeking. Transcriptomic analysis and genetic manipulation identified that increased dopamine D2 receptor expression in the mPFC-NAc pathway promotes the addiction-like phenotype. Our study unravels a new neurobiological mechanism underlying resilience and vulnerability to the development of food addiction, which could pave the way towards novel and efficient interventions for this disorder.


Assuntos
Dependência de Alimentos/fisiopatologia , Núcleo Accumbens/fisiologia , Córtex Pré-Frontal/fisiologia , Receptores de Dopamina D2/genética , Animais , Modelos Animais de Doenças , Comportamento Alimentar/fisiologia , Dependência de Alimentos/genética , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Camundongos Knockout , Vias Neurais/fisiologia , Receptor CB1 de Canabinoide/genética , Transmissão Sináptica , Regulação para Cima
16.
Sci Adv ; 6(7): eaay1502, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32095523

RESUMO

Adolescence represents a developmental period with the highest risk for initiating cannabis use. Little is known about whether genetic variation in the endocannabinoid system alters mesolimbic reward circuitry to produce vulnerability to the rewarding properties of the exogenous cannabinoid Δ9-tetrahydrocannabinol (THC). Using a genetic knock-in mouse model (FAAHC/A) that biologically recapitulates the human polymorphism associated with problematic drug use, we find that in adolescent female mice, but not male mice, this FAAH polymorphism enhances the mesolimbic dopamine circuitry projecting from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) and alters cannabinoid receptor 1 (CB1R) levels at inhibitory and excitatory terminals in the VTA. These developmental changes collectively increase vulnerability of adolescent female FAAHC/A mice to THC preference that persists into adulthood. Together, these findings suggest that this endocannabinoid genetic variant is a contributing factor for increased susceptibility to cannabis dependence in adolescent females.


Assuntos
Envelhecimento/fisiologia , Dronabinol/farmacologia , Endocanabinoides/genética , Variação Genética , Recompensa , Amidoidrolases/genética , Animais , Axônios/metabolismo , Comportamento de Escolha/efeitos dos fármacos , Feminino , Masculino , Camundongos Endogâmicos C57BL , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/fisiologia , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/fisiologia , Polimorfismo de Nucleotídeo Único/genética , Receptor CB1 de Canabinoide/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismo , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/fisiologia
17.
J Neurosci ; 40(13): 2737-2752, 2020 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-32075899

RESUMO

Microinjections of a glutamate AMPA antagonist (DNQX) in medial shell of nucleus accumbens (NAc) can cause either intense appetitive motivation (i.e., 'desire') or intense defensive motivation (i.e., 'dread'), depending on site along a flexible rostrocaudal gradient and on environmental ambience. DNQX, by blocking excitatory AMPA glutamate inputs, is hypothesized to produce relative inhibitions of NAc neurons. However, given potential alternative explanations, it is not known whether neuronal inhibition is in fact necessary for NAc DNQX microinjections to generate motivations. Here we provide a direct test of whether local neuronal inhibition in NAc is necessary for DNQX microinjections to produce either desire or dread. We used optogenetic channelrhodopsin (ChR2) excitations at the same local sites in NAc as DNQX microinjections to oppose relative neuronal inhibitions induced by DNQX in female and male rats. We found that same-site ChR2 excitation effectively reversed the ability of NAc DNQX microinjections to generate appetitive motivation, and similarly reversed ability of DNQX microinjections to generate defensive motivation. Same-site NAc optogenetic excitations also attenuated recruitment of Fos expression in other limbic structures throughout the brain, which was otherwise elevated by NAc DNQX microinjections that generated motivation. However, to successfully reverse motivation generation, an optic fiber tip for ChR2 illumination needed to be located within <1 mm of the corresponding DNQX microinjector tip; that is, both truly at the same NAc site. Thus, we confirm that localized NAc neuronal inhibition is required for AMPA-blocking microinjections in medial shell to induce either positively-valenced 'desire' or negatively-valenced 'dread'.SIGNIFICANCE STATEMENT A major hypothesis posits neuronal inhibitions in nucleus accumbens generate intense motivation. Microinjections in nucleus accumbens of glutamate antagonist, DNQX, which might suppress local neuronal firing, generate either appetitive or defensive motivation, depending on site and environmental factors. Is neuronal inhibition in nucleus accumbens required for such pharmacologically-induced motivations? Here we demonstrate that neuronal inhibition is necessary to generate appetitive or defensive motivations, using local optogenetic excitations to oppose putative DNQX-induced inhibitions. We show that excitation at the same site prevents DNQX microinjections from recruiting downstream limbic structures into neurobiological activation, and simultaneously prevents generation of either appetitive or defensive motivated behaviors. These results may be relevant to roles of nucleus accumbens mechanisms in pathological motivations, including addiction and paranoia.


Assuntos
Inibição Psicológica , Motivação/fisiologia , Núcleo Accumbens/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Masculino , Microinjeções , Motivação/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Optogenética , Quinoxalinas/farmacologia , Ratos , Ratos Long-Evans , Ratos Sprague-Dawley
18.
Neuromodulation ; 23(2): 167-176, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32103594

RESUMO

OBJECTIVE: The role of the nucleus accumbens (NAc) in chronic neuropathic pain has been suggested, but the role of the NAc in dorsal root ganglion (DRG) neuropathic pain remains unclear. The objective of this study was to determine whether optogenetic stimulation of the NAc influences DRG compression-induced neuropathic pain. MATERIALS AND METHODS: We established sham or DRG lesions in female Sprague-Dawley rats by L4-5 DRG root compression, and the animals received unilateral injections of optogenetic virus in the NAc core. We employed reflexive pain tests to assess the alterations between the groups at the light on/off states. To determine thalamic firing, we performed single-unit in vivo extracellular recording. For statistical analysis, we used one- or two-way repeated-measures analysis of variance. RESULTS: Compared to sham-operated rats, chronic compressed DRG rats showed elevated behavioral sensitivity and sustained neuronal hyperexcitability in the thalamus. NAc optic stimulation improved pain behaviors and lowered thalamic discharge from ventral posterolateral thalamic nuclei. CONCLUSIONS: The NAc core impacts the reward and motivational aspects of chronic neuropathic pain influenced by limbic behaviors to thalamic discharge. Increased thalamic firing activity may result in chronic compressed DRG-induced neuropathic pain, and optogenetic neuromodulation of the NAc can ease chronic pain and thalamic discharge.


Assuntos
Gânglios Espinais/lesões , Terapia a Laser/métodos , Síndromes de Compressão Nervosa/terapia , Neuralgia/terapia , Núcleo Accumbens/fisiologia , Fibras Ópticas , Animais , Modelos Animais de Doenças , Feminino , Gânglios Espinais/fisiopatologia , Síndromes de Compressão Nervosa/fisiopatologia , Neuralgia/fisiopatologia , Manejo da Dor/métodos , Ratos , Ratos Sprague-Dawley
19.
Neuron ; 105(6): 1036-1047.e5, 2020 03 18.
Artigo em Inglês | MEDLINE | ID: mdl-31954621

RESUMO

Dopamine is involved in physiological processes like learning and memory, motor control and reward, and pathological conditions such as Parkinson's disease and addiction. In contrast to the extensive studies on neurons, astrocyte involvement in dopaminergic signaling remains largely unknown. Using transgenic mice, optogenetics, and pharmacogenetics, we studied the role of astrocytes on the dopaminergic system. We show that in freely behaving mice, astrocytes in the nucleus accumbens (NAc), a key reward center in the brain, respond with Ca2+ elevations to synaptically released dopamine, a phenomenon enhanced by amphetamine. In brain slices, synaptically released dopamine increases astrocyte Ca2+, stimulates ATP/adenosine release, and depresses excitatory synaptic transmission through activation of presynaptic A1 receptors. Amphetamine depresses neurotransmission through stimulation of astrocytes and the consequent A1 receptor activation. Furthermore, astrocytes modulate the acute behavioral psychomotor effects of amphetamine. Therefore, astrocytes mediate the dopamine- and amphetamine-induced synaptic regulation, revealing a novel cellular pathway in the brain reward system.


Assuntos
Astrócitos/fisiologia , Dopamina/fisiologia , Núcleo Accumbens/fisiologia , Transmissão Sináptica/fisiologia , Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Anfetamina/farmacologia , Animais , Astrócitos/metabolismo , Cálcio/metabolismo , Clozapina/análogos & derivados , Clozapina/farmacologia , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Masculino , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Atividade Motora/fisiologia , Optogenética , Receptores de Dopamina D1/genética , Recompensa
20.
Behav Pharmacol ; 31(2&3): 159-167, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31860563

RESUMO

Analgesia induced by stressful and painful stimuli is an adaptive response during life-threatening situations. There is no evidence linking the mechanisms underlying them, while the former depends on the activation of stress-related brain pathways, the second depends on opioidergic mechanisms in the nucleus accumbens and on nicotinic cholinergic mechanisms in the rostral ventromedial medulla. In this study, we hypothesized that stress-induced analgesia is also dependent on opioidergic mechanisms in the nucleus accumbens and on nicotinic cholinergic mechanisms in the rostral ventromedial medulla. We used immobilization, a classical procedure to induce acute stress, and evaluated its ability to decrease the nociceptive responses induced either by carrageenan or by formalin in rats. Immobilization stress significantly decreased either carrageenan-induced hyperalgesia or formalin-induced tonic nociception in a time-dependent manner. This stress-induced analgesia is similar to pain-induced analgesia, as revealed by contrasting the antinociceptive effect induced by immobilization and by a forepaw injection of capsaicin. The administration of a µ-opioid receptor antagonist (CTOP, 0.5 µg) into the nucleus accumbens, as well as that of a nicotinic cholinergic receptor antagonist (mecamylamine, 0.6 µg) into the rostral ventromedial medulla, blocked immobilization stress-induced analgesia in both pain models. These results demonstrate that supraspinal mechanisms which are known to mediate pain-induced analgesia also mediate stress-induced analgesia. Therefore both forms of analgesia have overlapping mechanisms, probably recruited in response to the perception of danger.


Assuntos
Analgesia/psicologia , Dor/fisiopatologia , Estresse Psicológico/fisiopatologia , Animais , Capsaicina/farmacologia , Neurônios Colinérgicos/fisiologia , Hiperalgesia/fisiopatologia , Masculino , Mecamilamina/farmacologia , Nicotina/farmacologia , Nociceptividade/efeitos dos fármacos , Núcleo Accumbens/fisiologia , Manejo da Dor , Medição da Dor , Ratos , Ratos Wistar
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