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1.
Nat Commun ; 12(1): 2438, 2021 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-33903596

RESUMO

Cortical and limbic brain areas are regarded as centres for learning. However, how thalamic sensory relays participate in plasticity upon associative learning, yet support stable long-term sensory coding remains unknown. Using a miniature microscope imaging approach, we monitor the activity of populations of auditory thalamus (medial geniculate body) neurons in freely moving mice upon fear conditioning. We find that single cells exhibit mixed selectivity and heterogeneous plasticity patterns to auditory and aversive stimuli upon learning, which is conserved in amygdala-projecting medial geniculate body neurons. Activity in auditory thalamus to amygdala-projecting neurons stabilizes single cell plasticity in the total medial geniculate body population and is necessary for fear memory consolidation. In contrast to individual cells, population level encoding of auditory stimuli remained stable across days. Our data identifies auditory thalamus as a site for complex neuronal plasticity in fear learning upstream of the amygdala that is in an ideal position to drive plasticity in cortical and limbic brain areas. These findings suggest that medial geniculate body's role goes beyond a sole relay function by balancing experience-dependent, diverse single cell plasticity with consistent ensemble level representations of the sensory environment to support stable auditory perception with minimal affective bias.


Assuntos
Vias Auditivas/fisiologia , Plasticidade Celular/fisiologia , Aprendizagem/fisiologia , Plasticidade Neuronal/fisiologia , Tálamo/fisiologia , Estimulação Acústica , Tonsila do Cerebelo/citologia , Tonsila do Cerebelo/fisiologia , Animais , Percepção Auditiva/fisiologia , Condicionamento Clássico/fisiologia , Medo/fisiologia , Corpos Geniculados/citologia , Corpos Geniculados/fisiologia , Camundongos Endogâmicos C57BL , Neurônios/fisiologia , Tálamo/citologia
2.
Nat Commun ; 12(1): 2100, 2021 04 08.
Artigo em Inglês | MEDLINE | ID: mdl-33833228

RESUMO

The ventral striatum (VS) is considered a key region that flexibly updates recent changes in reward values for habit learning. However, this update process may not serve to maintain learned habitual behaviors, which are insensitive to value changes. Here, using fMRI in humans and single-unit electrophysiology in macaque monkeys we report another role of the primate VS: that the value memory subserving habitual seeking is stably maintained in the VS. Days after object-value associative learning, human and monkey VS continue to show increased responses to previously rewarded objects, even when no immediate reward outcomes are expected. The similarity of neural response patterns to each rewarded object increases after learning among participants who display habitual seeking. Our data show that long-term memory of high-valued objects is retained as a single representation in the VS and may be utilized to evaluate visual stimuli automatically to guide habitual behavior.


Assuntos
Condicionamento Clássico/fisiologia , Comportamento de Procura de Droga/fisiologia , Memória de Longo Prazo/fisiologia , Rememoração Mental/fisiologia , Estriado Ventral/fisiologia , Adulto , Animais , Mapeamento Encefálico/métodos , Feminino , Hábitos , Humanos , Macaca mulatta , Imagem por Ressonância Magnética , Masculino , Recompensa , Adulto Jovem
3.
Nat Neurosci ; 24(3): 391-400, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33589832

RESUMO

Experimental research controls for past experience, yet prior experience influences how we learn. Here, we tested whether we could recruit a neural population that usually encodes rewards to encode aversive events. Specifically, we found that GABAergic neurons in the lateral hypothalamus (LH) were not involved in learning about fear in naïve rats. However, if these rats had prior experience with rewards, LH GABAergic neurons became important for learning about fear. Interestingly, inhibition of these neurons paradoxically enhanced learning about neutral sensory information, regardless of prior experience, suggesting that LH GABAergic neurons normally oppose learning about irrelevant information. These experiments suggest that prior experience shapes the neural circuits recruited for future learning in a highly specific manner, reopening the neural boundaries we have drawn for learning of particular types of information from work in naïve subjects.


Assuntos
Condicionamento Clássico/fisiologia , Medo/fisiologia , Neurônios GABAérgicos/fisiologia , Região Hipotalâmica Lateral/fisiologia , Aprendizagem/fisiologia , Animais , Sinais (Psicologia) , Feminino , Masculino , Vias Neurais/fisiologia , Ratos , Ratos Long-Evans , Ratos Transgênicos , Recompensa
4.
Int J Mol Sci ; 22(2)2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33467450

RESUMO

Fear extinction requires coordinated neural activity within the amygdala and medial prefrontal cortex (mPFC). Any behavior has a transcriptomic signature that is modified by environmental experiences, and specific genes are involved in functional plasticity and synaptic wiring during fear extinction. Here, we investigated the effects of optogenetic manipulations of prelimbic (PrL) pyramidal neurons and amygdala gene expression to analyze the specific transcriptional pathways associated to adaptive and maladaptive fear extinction. To this aim, transgenic mice were (or not) fear-conditioned and during the extinction phase they received optogenetic (or sham) stimulations over photo-activable PrL pyramidal neurons. At the end of behavioral testing, electrophysiological (neural cellular excitability and Excitatory Post-Synaptic Currents) and morphological (spinogenesis) correlates were evaluated in the PrL pyramidal neurons. Furthermore, transcriptomic cell-specific RNA-analyses (differential gene expression profiling and functional enrichment analyses) were performed in amygdala pyramidal neurons. Our results show that the optogenetic activation of PrL pyramidal neurons in fear-conditioned mice induces fear extinction deficits, reflected in an increase of cellular excitability, excitatory neurotransmission, and spinogenesis of PrL pyramidal neurons, and associated to strong modifications of the transcriptome of amygdala pyramidal neurons. Understanding the electrophysiological, morphological, and transcriptomic architecture of fear extinction may facilitate the comprehension of fear-related disorders.


Assuntos
Tonsila do Cerebelo/fisiologia , Condicionamento Clássico/fisiologia , Extinção Psicológica/fisiologia , Medo/fisiologia , Células Piramidais/fisiologia , Transcriptoma/genética , Tonsila do Cerebelo/citologia , Tonsila do Cerebelo/metabolismo , Animais , Fenômenos Eletrofisiológicos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Medo/psicologia , Masculino , Memória/fisiologia , Camundongos Transgênicos , Vias Neurais/citologia , Vias Neurais/metabolismo , Vias Neurais/fisiologia , Optogenética/métodos , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiologia , Células Piramidais/metabolismo , Transmissão Sináptica/fisiologia
5.
Drug Alcohol Depend ; 219: 108471, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33385691

RESUMO

BACKGROUND: Childhood trauma is associated with the development of adult mental health and substance use disorders, with females generally being more at risk. Alcohol is commonly used for coping with trauma, and alcohol use disorder (AUD) affects ∼14.4 million adult Americans annually. Research investigating sex differences in the environmental modification of anxiety and alcohol use following childhood trauma will extend our understanding of the etiology of AUD. Here, we sought to model the interacting effects of a single-episode late childhood trauma with post-trauma environment on adult alcohol use using male and female mice. METHODS: C57Bl6/J mice (d22) exposed to predator odor (TMT) or water were reared in standard environments (SE) or environmental enrichment (EE). Mice were assessed for adolescent anxiety and conditioned fear, and for adult alcohol use in a limited access, response non-contingent, alcohol exposure paradigm. RESULTS: A single exposure to predator odor was an effective stressor, inducing long-term sex-dependent changes in conditioned fear and alcohol behaviors that interacted with post-trauma environment. Adolescent EE females showed more conditioned freezing to the trauma-associated context. Adult EE mice consumed less total alcohol than SE mice. However, alcohol use across time differed for males and females. Exposure to a childhood stressor increased alcohol use significantly in females, but not males. EE males, but not EE females, drank less than SE counterparts. CONCLUSIONS: Findings from this model recapitulate greater vulnerability to childhood trauma in females and support sex differences in post-trauma development of conditioned fear and alcohol use that are modified by environment.


Assuntos
Consumo de Bebidas Alcoólicas/epidemiologia , Transtornos Relacionados a Trauma e Fatores de Estresse/epidemiologia , Adolescente , Consumo de Bebidas Alcoólicas/psicologia , Animais , Criança , Condicionamento Clássico/fisiologia , Meio Ambiente , Etanol , Medo/psicologia , Feminino , Humanos , Masculino , Memória , Camundongos , Camundongos Endogâmicos C57BL , Caracteres Sexuais
6.
J Vis Exp ; (167)2021 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-33491674

RESUMO

Fear- and anxiety-related behaviors significantly contribute to an organism's survival. However, exaggerated defensive responses to perceived threat are characteristic of various anxiety disorders, which are the most prevalent form of mental illness in the United States. Discovering the neurobiological mechanisms responsible for defensive behaviors will aid in the development of novel therapeutic interventions. Pavlovian fear conditioning is a widely used laboratory paradigm to study fear-related learning and memory. A major limitation of traditional Pavlovian fear conditioning paradigms is that freezing is the only defensive behavior monitored. We recently developed a modified Pavlovian fear conditioning paradigm that allows us to study both conditioned freezing and flight (also known as escape) behavior within individual subjects. This model employs higher intensity footshocks and a greater number of pairings between the conditioned stimulus and unconditioned stimulus. Additionally, this conditioned flight paradigm utilizes serial presentation of pure tone and white noise auditory stimuli as the conditioned stimulus. Following conditioning in this paradigm, mice exhibit freezing behavior in response to the tone stimulus, and flight responses during the white noise. This conditioning model can be applied to the study of rapid and flexible transitions between behavioral responses necessary for survival.


Assuntos
Comportamento Animal , Condicionamento Clássico/fisiologia , Reação de Fuga/fisiologia , Medo/fisiologia , Reação de Congelamento Cataléptica/fisiologia , Animais , Extinção Psicológica , Feminino , Congelamento , Masculino , Memória/fisiologia , Camundongos Endogâmicos C57BL , Gravação em Vídeo
7.
Neurosci Lett ; 745: 135551, 2021 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-33346074

RESUMO

BACKGROUND: Previous studies suggest that muscarinic cholinergic receptors might act upon the dopamine release in the mesolimbic system and alter drug-reinforcing values related to drug craving. AIMS: We examined the effects of systemic biperiden administration, a muscarinic cholinergic (M1/M4) receptor antagonist, on ethanol (dose of 2 g/Kg) conditioned place preference (CPP), neuronal activation, dopamine and its metabolites levels in the nucleus accumbens. METHODS: Thirty minutes before the ethanol-induced CPP test, mice received saline or biperiden at doses of 1.0, 5.0, or 10.0 mg/kg. The time spent in each compartment was recorded for 15 min. After the CPP protocol, animals were euthanized, and we investigated the activation of the nucleus accumbens by immunohistochemistry for Fos. We also quantified dopamine, homovanillic acid (HVA), and dihydroxyphenylacetic acid (DOPAC) levels in the nucleus accumbens by high-performance liquid chromatography (HPLC). Additionally, the rotarod was employed to evaluate the effects of biperiden on motor coordination. RESULTS: Biperiden at different doses (1.0, 5.0, and 10.0 mg/kg) blocked the expression of ethanol-induced CPP. These biperiden doses increased the number of Fos-positive cells and the dopamine turnover in the nucleus accumbens. None of the doses affected the motor coordination evaluated by the rotarod. CONCLUSIONS: Our results show that biperiden can modulate the effect of alcohol reward, and its mechanism of action may involve a change in dopamine and cholinergic mesolimbic neurotransmission.


Assuntos
Biperideno/administração & dosagem , Condicionamento Clássico/efeitos dos fármacos , Etanol/administração & dosagem , Antagonistas Muscarínicos/administração & dosagem , Receptor Muscarínico M1/antagonistas & inibidores , Receptor Muscarínico M4/antagonistas & inibidores , Animais , Condicionamento Clássico/fisiologia , Dopamina/metabolismo , Relação Dose-Resposta a Droga , Ácido Homovanílico/metabolismo , Injeções Intraperitoneais , Masculino , Camundongos , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Receptor Muscarínico M1/metabolismo , Receptor Muscarínico M4/metabolismo
8.
Nat Commun ; 11(1): 5207, 2020 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-33060630

RESUMO

Fear conditioning is a form of associative learning that is known to involve different brain areas, notably the amygdala, the prefrontal cortex and the periaqueductal grey (PAG). Here, we describe the functional role of pathways that link the cerebellum with the fear network. We found that the cerebellar fastigial nucleus (FN) sends glutamatergic projections to vlPAG that synapse onto glutamatergic and GABAergic vlPAG neurons. Chemogenetic and optogenetic manipulations revealed that the FN-vlPAG pathway controls bi-directionally the strength of the fear memories, indicating an important role in the association of the conditioned and unconditioned stimuli, a function consistent with vlPAG encoding of fear prediction error. Moreover, FN-vlPAG projections also modulate extinction learning. We also found a FN-parafascicular thalamus pathway, which may relay cerebellar influence to the amygdala and modulates anxiety behaviors. Overall, our results reveal multiple contributions of the cerebellum to the emotional system.


Assuntos
Sistema Nervoso Central/fisiologia , Medo/fisiologia , Memória/fisiologia , Vias Neurais/fisiologia , Substância Cinzenta Periaquedutal/fisiologia , Tonsila do Cerebelo/fisiologia , Animais , Sistema Nervoso Central/patologia , Cerebelo/diagnóstico por imagem , Cerebelo/fisiologia , Condicionamento Clássico/fisiologia , Condicionamento Operante/fisiologia , Aprendizagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Optogenética
9.
Proc Natl Acad Sci U S A ; 117(40): 25116-25127, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-32958652

RESUMO

The ventromedial prefrontal cortex (vmPFC) is a key brain structure implicated in mood and anxiety disorders, based primarily on evidence from correlational neuroimaging studies. Composed of a number of brain regions with distinct architecture and connectivity, dissecting its functional heterogeneity will provide key insights into the symptomatology of these disorders. Focusing on area 14, lying on the medial and orbital surfaces of the gyrus rectus, this study addresses a key question of causality. Do changes in area 14 activity induce changes in threat- and reward-elicited responses within the nonhuman primate, the common marmoset, similar to that seen in mood and anxiety disorders? Area 14 overactivation was found to induce heightened responsivity to uncertain, low-imminence threat while blunting cardiovascular and behavioral anticipatory arousal to high-value food reward. Conversely, inactivation enhanced the arousal to high-value reward cues while dampening the acquisition of cardiovascular and behavioral responses to a Pavlovian threat cue. Basal cardiovascular activity, including heart rate variability and sympathovagal balance, which are dysfunctional in mood and anxiety disorders, are insensitive to alterations in area 14 activity as is the extinction of conditioned threat responses. The distinct pattern of dysregulation compared to neighboring region area 25 highlights the heterogeneity of function within vmPFC and reveals how the effects of area 14 overactivation on positive and negative reactivity mirror symptoms of anhedonia and anxiety that are so often comorbid in mood disorders.


Assuntos
Ansiedade/diagnóstico por imagem , Mapeamento Encefálico , Callithrix/fisiologia , Córtex Pré-Frontal/diagnóstico por imagem , Animais , Ansiedade/fisiopatologia , Condicionamento Clássico/fisiologia , Frequência Cardíaca/fisiologia , Humanos , Imagem por Ressonância Magnética , Córtex Pré-Frontal/fisiologia , Recompensa
10.
Nat Commun ; 11(1): 3845, 2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32737295

RESUMO

Many experimental studies suggest that animals can rapidly learn to identify odors and predict the rewards associated with them. However, the underlying plasticity mechanism remains elusive. In particular, it is not clear how olfactory circuits achieve rapid, data efficient learning with local synaptic plasticity. Here, we formulate olfactory learning as a Bayesian optimization process, then map the learning rules into a computational model of the mammalian olfactory circuit. The model is capable of odor identification from a small number of observations, while reproducing cellular plasticity commonly observed during development. We extend the framework to reward-based learning, and show that the circuit is able to rapidly learn odor-reward association with a plausible neural architecture. These results deepen our theoretical understanding of unsupervised learning in the mammalian brain.


Assuntos
Condicionamento Clássico/fisiologia , Rede Nervosa , Plasticidade Neuronal/fisiologia , Condutos Olfatórios/fisiologia , Percepção Olfatória/fisiologia , Olfato/fisiologia , Animais , Teorema de Bayes , Simulação por Computador , Mamíferos , Neurônios/citologia , Neurônios/fisiologia , Odorantes/análise , Bulbo Olfatório/fisiologia , Recompensa
11.
Neuron ; 108(1): 209-224.e6, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-32827456

RESUMO

The representation of odor in olfactory cortex (piriform) is distributive and unstructured and can only be afforded behavioral significance upon learning. We performed 2-photon imaging to examine the representation of odors in piriform and in two downstream areas, the orbitofrontal cortex (OFC) and the medial prefrontal cortex (mPFC), as mice learned olfactory associations. In piriform, we observed that odor responses were largely unchanged during learning. In OFC, 30% of the neurons acquired robust responses to conditioned stimuli (CS+) after learning, and these responses were gated by internal state and task context. Moreover, direct projections from piriform to OFC can be entrained to elicit learned olfactory behavior. CS+ responses in OFC diminished with continued training, whereas persistent representations of both CS+ and CS- odors emerged in mPFC. Optogenetic silencing indicates that these two brain structures function sequentially to consolidate the learning of appetitive associations.


Assuntos
Comportamento Apetitivo/fisiologia , Aprendizagem por Associação/fisiologia , Neurônios/fisiologia , Odorantes , Condutos Olfatórios/fisiologia , Córtex Piriforme/fisiologia , Córtex Pré-Frontal/fisiologia , Animais , Condicionamento Clássico/fisiologia , Microscopia Intravital , Camundongos , Microscopia de Fluorescência por Excitação Multifotônica , Optogenética , Córtex Piriforme/citologia , Córtex Pré-Frontal/citologia
12.
Nat Commun ; 11(1): 3764, 2020 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-32724058

RESUMO

Context can influence reactions to environmental cues and this elemental process has implications for substance use disorder. Using an animal model, we show that an alcohol-associated context elevates entry into a fluid port triggered by a conditioned stimulus (CS) that predicted alcohol (CS-triggered alcohol-seeking). This effect persists across multiple sessions and, after it diminishes in extinction, the alcohol context retains the capacity to augment reinstatement. Systemically administered eticlopride and chemogenetic inhibition of ventral tegmental area (VTA) dopamine neurons reduce CS-triggered alcohol-seeking. Chemogenetically silencing VTA dopamine terminals in the nucleus accumbens (NAc) core reduces CS-triggered alcohol-seeking, irrespective of context, whereas silencing VTA dopamine terminals in the NAc shell selectively reduces the elevation of CS-triggered alcohol-seeking in an alcohol context. This dissociation reveals new roles for divergent mesolimbic dopamine circuits in the control of responding to a discrete cue for alcohol and in the amplification of this behaviour in an alcohol context.


Assuntos
Transtornos Relacionados ao Uso de Álcool/psicologia , Dopamina/metabolismo , Etanol/administração & dosagem , Extinção Psicológica/fisiologia , Área Tegmentar Ventral/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Sinais (Psicologia) , Modelos Animais de Doenças , Antagonistas de Dopamina/administração & dosagem , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Comportamento de Procura de Droga/efeitos dos fármacos , Comportamento de Procura de Droga/fisiologia , Extinção Psicológica/efeitos dos fármacos , Feminino , Humanos , Masculino , Ratos , Salicilamidas/administração & dosagem , Técnicas Estereotáxicas , Área Tegmentar Ventral/citologia
13.
Nat Commun ; 11(1): 3318, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620879

RESUMO

Decision-making is guided by memories of option values. However, retrieving items from memory renders them malleable. Here, we show that merely retrieving values from memory and making a choice between options is sufficient both to induce changes to stimulus-reward associations in the hippocampus and to bias future decision-making. After allowing participants to make repeated choices between reward-conditioned stimuli, in the absence of any outcome, we observe that participants prefer stimuli they have previously chosen, and neglect previously unchosen stimuli, over otherwise identical-valued options. Using functional brain imaging, we show that decisions induce changes to hippocampal representations of stimulus-outcome associations. These changes are correlated with future decision biases. Our results indicate that choice-induced preference changes are partially driven by choice-induced modification of memory representations and suggest that merely making a choice - even without experiencing any outcomes - induces associative plasticity.


Assuntos
Comportamento de Escolha/fisiologia , Tomada de Decisões/fisiologia , Hipocampo/fisiologia , Memória/fisiologia , Adulto , Algoritmos , Viés , Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Condicionamento Clássico/fisiologia , Hipocampo/diagnóstico por imagem , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Desempenho Psicomotor/fisiologia , Recompensa , Adulto Jovem
14.
Nat Neurosci ; 23(8): 968-980, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32541962

RESUMO

The ventral tegmental area (VTA) is important for reward processing and motivation. The anatomic organization of neurotransmitter-specific inputs to the VTA remains poorly resolved. In the present study, we mapped the major neurotransmitter projections to the VTA through cell-type-specific retrograde and anterograde tracing. We found that glutamatergic inputs arose from a variety of sources and displayed some connectivity biases toward specific VTA cell types. The sources of GABAergic projections were more widespread, displayed a high degree of differential innervation of subregions in the VTA and were largely biased toward synaptic contact with local GABA neurons. Inactivation of GABA release from the two major sources, locally derived versus distally derived, revealed distinct roles for these projections in behavioral regulation. Optogenetic manipulation of individual distal GABAergic inputs also revealed differential behavioral effects. These results demonstrate that GABAergic projections to the VTA are a major contributor to the regulation and diversification of the structure.


Assuntos
Neurônios GABAérgicos/metabolismo , Transmissão Sináptica/fisiologia , Área Tegmentar Ventral/metabolismo , Animais , Condicionamento Clássico/fisiologia , Condicionamento Operante/fisiologia , Neurônios Dopaminérgicos/fisiologia , Medo/fisiologia , Feminino , Masculino , Camundongos , Atividade Motora/fisiologia , Vias Neurais/metabolismo , Optogenética , Recompensa , Autoestimulação
15.
Psychopharmacology (Berl) ; 237(8): 2305-2316, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32506233

RESUMO

RATIONAL: The ability of conditioned stimuli to affect instrumental responding is a robust finding from animal as well as human research and is assumed as a key factor regarding the development and maintenance of addictive behaviour. OBJECTIVES: While it is well known that stress is an important factor for relapse after treatment, little is known about the impact of stress on conditioned substance-associated stimuli and their influence on instrumental responding. METHODS: We administered in the present study a Pavlovian-to-instrumental transfer (PIT) paradigm with stimuli associated with smoking- and chocolate-related rewards using points in a token economy to light to moderate smokers who also indicated to like eating chocolate. After completion of the first two phases of the PIT paradigm (i.e. Pavlovian training and instrumental trainings), participants were randomly allocated to the socially evaluated cold pressor test or a control condition before the final phase of the PIT paradigm, the transfer phase, was administered. RESULTS: The presentation of a smoking-related stimulus enhanced instrumental responding for a smoking-related reward (i.e. 'smoking-PIT' effect) and presentation of a chocolate-related stimulus for a chocolate-related reward (i.e. 'chocolate-PIT' effect) in participants aware of the experimental contingencies as indicated by expectancy ratings. However, acute stress did not change (i.e. neither enhanced nor attenuated) the 'smoking-PIT' effect or the 'chocolate-PIT' effect, and no overall effect of acute stress on tobacco choice was observed in aware participants. CONCLUSIONS: The established role of stress in addiction appears not to be driven by an augmenting effect on the ability of drug stimuli to promote drug-seeking.


Assuntos
Condicionamento Clássico/fisiologia , Recompensa , Estresse Psicológico/psicologia , Transtornos Relacionados ao Uso de Substâncias/psicologia , Transferência de Experiência/fisiologia , Doença Aguda , Adolescente , Adulto , Animais , Comportamento Aditivo/metabolismo , Comportamento Aditivo/psicologia , Temperatura Baixa/efeitos adversos , Feminino , Humanos , Hidrocortisona/análise , Hidrocortisona/metabolismo , Masculino , Distribuição Aleatória , Estresse Psicológico/metabolismo , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Adulto Jovem
16.
PLoS One ; 15(5): e0232108, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32379766

RESUMO

Influential theoretical accounts take the position that classical conditioning can induce placebo effects through conscious expectancies. In the current study two different conditioning procedures (hidden and open) were used to separate expectancy from conditioning in order to reveal the role of expectancy in the formation of nocebo hyperalgesia. Eighty-seven healthy females were randomly assigned to three groups (hidden conditioning, open conditioning, and control). Participants were selected according to the Fear of Pain Questionnaire scores and assigned to two subgroups: high and low level of fear of pain (trait). They received electrocutaneous pain stimuli preceded by either an orange or blue color. During the conditioning phase, one color was paired with pain stimuli of moderate intensity (control stimuli) and the other color was paired with pain stimuli of high intensity (nocebo stimuli) in both hidden and open conditioning groups. Only participants in the open conditioning group were informed about this association, however just before the testing phase the expectancy of hyperalgesia induced in this way was withdrawn. In the control group, both colors were followed by control pain stimuli. During the testing phase all participants received a series of stimuli of the same intensity, regardless of the preceding color. Participants rated pain intensity, expectancy of pain intensity and fear (state). We found that nocebo hyperalgesia was induced by hidden rather than open conditioning. The hidden conditioning procedure did not produce conscious expectancies related to pain. Nocebo hyperalgesia was induced in participants with low and high fear of pain and there was no difference in the magnitude of the nocebo effect between both groups. Nocebo hyperalgesia was not predicted by the fear of upcoming painful stimuli.


Assuntos
Condicionamento Clássico/fisiologia , Hiperalgesia/fisiopatologia , Efeito Nocebo , Adulto , Medo/fisiologia , Medo/psicologia , Feminino , Humanos , Motivação/fisiologia , Dor/fisiopatologia , Dor/psicologia , Medição da Dor/métodos , Medição da Dor/psicologia , Limiar da Dor/fisiologia , Limiar da Dor/psicologia
17.
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
18.
Psychopharmacology (Berl) ; 237(7): 2161-2172, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32363439

RESUMO

The ability to discriminate between danger and safety is crucial for survival across species. Whereas danger signals predict the onset of a potentially threatening event, safety signals indicate the non-occurrence of an aversive event, thereby reducing fear and stress responses. While the neural basis of conditioned safety remains to be elucidated, fear extinction studies provide evidence that the infralimbic cortex (IL) modulates fear inhibition. In the current study, the IL was temporarily inactivated with local muscimol injections in male and female rats. The effect of IL inactivation on the acquisition and expression of conditioned safety was investigated utilizing the startle response. Temporary inactivation of the IL prior to conditioning did not affect the acquisition of conditioned safety, whereas IL inactivation during the expression test completely blocked the expression of conditioned safety in male and female rats. Inactivation of the neighboring prelimbic (PL) cortex during the expression test did not affect the expression of safety memory. Our findings suggest that the IL is a critical brain region for the expression of safety memory. Because patients suffering from anxiety disorders are often unable to make use of safety cues to inhibit fear, the present findings are of clinical relevance and could potentially contribute to therapy optimization of anxiety-related psychiatric disorders.


Assuntos
Condicionamento Clássico/fisiologia , Medo/fisiologia , Inibição Psicológica , Memória/fisiologia , Córtex Pré-Frontal/metabolismo , Reflexo de Sobressalto/fisiologia , Animais , Condicionamento Clássico/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Extinção Psicológica/fisiologia , Medo/efeitos dos fármacos , Medo/psicologia , Feminino , Agonistas de Receptores de GABA-A/farmacologia , Masculino , Memória/efeitos dos fármacos , Muscimol/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Reflexo de Sobressalto/efeitos dos fármacos
19.
Proc Natl Acad Sci U S A ; 117(20): 10983-10988, 2020 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-32366650

RESUMO

Allergies are highly prevalent, and allergic responses can be triggered even in the absence of allergens due to Pavlovian conditioning to a specific cue. Here we show in humans suffering from allergic rhinitis that merely reencountering the environmental context in which an allergen was administered a week earlier is sufficient to trigger an allergic response-but only if participants had slept after allergen exposure. This context-conditioning effect was entirely absent when participants stayed awake the night after allergen exposure or were tested in a different context. Unlike in context conditioning, cue conditioning (to an odor stimulus) occurred independently of sleep, a differential pattern that is likewise observed for conditioning in the behavioral domain. Our findings provide evidence that allergic responses can be conditioned to contextual information alone, even after only a single-trial conditioning procedure, and that sleep is necessary to consolidate this rapidly acquired maladaptive response. The results unravel a mechanism that could explain part of the strong psychological impact on allergic responses.


Assuntos
Alérgenos/imunologia , Rinite Alérgica/imunologia , Sono/imunologia , Sono/fisiologia , Adulto , Condicionamento Clássico/fisiologia , Feminino , Humanos , Aprendizagem/fisiologia , Masculino , Propilenoglicol , Vigília , Adulto Jovem
20.
Nat Neurosci ; 23(5): 625-637, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32284608

RESUMO

Decades of research support the idea that associations between a conditioned stimulus (CS) and an unconditioned stimulus (US) are encoded in the lateral amygdala (LA) during fear learning. However, direct proof for the sources of CS and US information is lacking. Definitive evidence of the LA as the primary site for cue association is also missing. Here, we show that calretinin (Calr)-expressing neurons of the lateral thalamus (Calr+LT neurons) convey the association of fast CS (tone) and US (foot shock) signals upstream from the LA in mice. Calr+LT input shapes a short-latency sensory-evoked activation pattern of the amygdala via both feedforward excitation and inhibition. Optogenetic silencing of Calr+LT input to the LA prevents auditory fear conditioning. Notably, fear conditioning drives plasticity in Calr+LT neurons, which is required for appropriate cue and contextual fear memory retrieval. Collectively, our results demonstrate that Calr+LT neurons provide integrated CS-US representations to the LA that support the formation of aversive memories.


Assuntos
Condicionamento Clássico/fisiologia , Medo/fisiologia , Vias Neurais/fisiologia , Plasticidade Neuronal/fisiologia , Animais , Complexo Nuclear Basolateral da Amígdala/fisiologia , Calreticulina/metabolismo , Sinais (Psicologia) , Memória/fisiologia , Camundongos , Neurônios/fisiologia , Transdução de Sinais/fisiologia , Tálamo/fisiologia
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