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1.
Behav Processes ; 184: 104319, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33450315

RESUMO

Two Pavlovian appetitive conditioning experiments with rats assessed extinction cue (EC) transfer using spontaneous recovery tests. In each experiment, after conditioned stimulus (CS) A-US pairings, an EC (X) was presented during A-extinction, followed by spontaneous recovery testing with A. Experiment 1 tested for transfer between ECs; the additional CS (B) was conditioned and then was extinguished with a second EC (Y). CS A was tested with X and with Y (the possible transfer EC). Experiment 2 tested for transfer between an EC and an explicitly trained serial negative occasion setter (OS). Prior to testing with A, Y was trained in a serial Y→C-, C + discrimination; a Z→B-, B + discrimination was also trained. A was tested with X and with Y (with Y as the possible transfer OS). X and Y were also tested with B (where X with B tests possible EC-OS transfer). In each experiment Y did not reduce spontaneous recovery to A, showing no transfer of one EC to another (Experiment 1) and no transfer of a serial negative OS to a CS (A) extinguished with an EC (X; Experiment 2). X did not reduce responding to B, showing no transfer of an EC to the target CS of a serial negative OS discrimination, although Y did transfer to B (Experiment 2) showing transfer between serial OSs. X did reduce responding to the CS (A) it had occurred with during extinction (Experiments 1 and 2). The results are discussed in terms of EC characteristics and regarding theories of an EC's possible mechanisms.


Assuntos
Sinais (Psicologia) , Extinção Psicológica , Animais , Condicionamento Clássico , Condicionamento Operante , Condicionamento Psicológico , Ratos
2.
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
3.
Elife ; 92020 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-33325370

RESUMO

AKT is implicated in neurological disorders. AKT has three isoforms, AKT1/AKT2/AKT3, with brain cell type-specific expression that may differentially influence behavior. Therefore, we examined single Akt isoform, conditional brain-specific Akt1, and double Akt1/3 mutant mice in behaviors relevant to neuropsychiatric disorders. Because sex is a determinant of these disorders but poorly understood, sex was an experimental variable in our design. Our studies revealed AKT isoform- and sex-specific effects on anxiety, spatial and contextual memory, and fear extinction. In Akt1 mutant males, viral-mediated AKT1 restoration in the prefrontal cortex rescued extinction phenotypes. We identified a novel role for AKT2 and overlapping roles for AKT1 and AKT3 in long-term memory. Finally, we found that sex-specific behavior effects were not mediated by AKT expression or activation differences between sexes. These results highlight sex as a biological variable and isoform- or cell type-specific AKT signaling as potential targets for improving treatment of neuropsychiatric disorders.


Assuntos
Comportamento Animal/fisiologia , Encéfalo/metabolismo , Extinção Psicológica/fisiologia , Transtornos Mentais/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Memória Espacial/fisiologia , Animais , Feminino , Masculino , Memória de Longo Prazo/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Isoformas de Proteínas , Caracteres Sexuais , Comportamento Espacial/fisiologia
4.
Nat Commun ; 11(1): 5180, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-33057013

RESUMO

Fear and extinction learning are adaptive processes caused by molecular changes in specific neural circuits. Neurons expressing the corticotropin-releasing hormone gene (Crh) in central amygdala (CeA) are implicated in threat regulation, yet little is known of cell type-specific gene pathways mediating adaptive learning. We translationally profiled the transcriptome of CeA Crh-expressing cells (Crh neurons) after fear conditioning or extinction in mice using translating ribosome affinity purification (TRAP) and RNAseq. Differential gene expression and co-expression network analyses identified diverse networks activated or inhibited by fear vs extinction. Upstream regulator analysis demonstrated that extinction associates with reduced CREB expression, and viral vector-induced increased CREB expression in Crh neurons increased fear expression and inhibited extinction. These findings suggest that CREB, within CeA Crh neurons, may function as a molecular switch that regulates expression of fear and its extinction. Cell-type specific translational analyses may suggest targets useful for understanding and treating stress-related psychiatric illness.


Assuntos
Núcleo Central da Amígdala/fisiologia , Condicionamento Psicológico/fisiologia , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Extinção Psicológica/fisiologia , Medo/fisiologia , Animais , Comportamento Animal , Núcleo Central da Amígdala/citologia , Hormônio Liberador da Corticotropina/genética , Hormônio Liberador da Corticotropina/metabolismo , Feminino , Masculino , Camundongos , Camundongos Transgênicos , Modelos Animais , Neurônios/metabolismo , RNA-Seq
5.
Life Sci ; 260: 118430, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32931800

RESUMO

AIMS: Previous investigations demonstrated that tramadol, as a painkiller, similar to morphine induces tolerance and dependence. Furthermore, the cannabinoid receptor 1 (CB1R) located in the nucleus accumbens (NAc) plays a critical role in morphine-induced conditioning. Therefore, the main objective of this study was to evaluate the role of NAc CB1R in tramadol induced conditioning and reinstatement. MAIN METHODS: In the present experiment, the effect of NAc CB1 receptors on tramadol induced conditioning was tested by microinjecting of arachidonylcyclopropylamide (ACPA, CB1R agonist) and AM 251 (CB1R inverse agonist) in the NAc during tramadol-induced conditioning in the adult male Wistar rats. In addition, the role of NAc CB1R in the reinstatement was also evaluated by injecting ACPA and AM 251 after a 10-days extinction period. KEY FINDINGS: The obtained data revealed that the administration of tramadol (1,2, and 4 mg/kg, ip) dose-dependently produced conditioned place preference (CPP). Moreover, intra-NAc administration of ACPA (0.25, 0.5, and 1 µg/rat) dose-dependently induced conditioning, while the administration of AM-251 (30, 60, and 120 ng/rat) induced a significant aversion. In addition, the administration of a non-effective dose of AM251 during tramadol conditioning inhibited conditioning induced by tramadol. On the other hand, the administration of ACPA after extinction induced a significant reinstatement. Notably, the locomotor activity did not change among groups. SIGNIFICANCE: Previous studies have shown that tramadol-induced CPP occurs through µ-opioid receptors. The data obtained in the current study indicated that CB1R located in the NAc is involved in mediating conditioning induced by tramadol. Besides, CB1R also plays a vital role in the reinstatement of tramadol-conditioned animals. It might be due to the effect of opioids on enhancing the level of CB1R.


Assuntos
Analgésicos Opioides/efeitos adversos , Condicionamento Psicológico/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Receptor CB1 de Canabinoide/fisiologia , Tramadol/efeitos adversos , Analgésicos Opioides/administração & dosagem , Animais , Condicionamento Clássico , Relação Dose-Resposta a Droga , Extinção Psicológica/efeitos dos fármacos , Masculino , Núcleo Accumbens/metabolismo , Piperidinas/administração & dosagem , Piperidinas/farmacologia , Pirazóis/administração & dosagem , Pirazóis/farmacologia , Ratos Wistar , Receptor CB1 de Canabinoide/agonistas , Tramadol/administração & dosagem
6.
Nat Commun ; 11(1): 4358, 2020 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-32868768

RESUMO

Learned fear and safety are associated with distinct oscillatory states in the basolateral amygdala (BLA) and medial prefrontal cortex (mPFC). To determine if and how these network states support the retrieval of competing memories, we mimicked endogenous oscillatory activity through optogenetic stimulation of parvalbumin-expressing interneurons in mice during retrieval of contextual fear and extinction memories. We found that exogenously induced 4 Hz and 8 Hz oscillatory activity in the BLA exerts bi-directional control over conditioned freezing behavior in an experience- and context-specific manner, and that these oscillations have an experience-dependent ability to recruit distinct functional neuronal ensembles. At the network level we demonstrate, via simultaneous manipulation of BLA and mPFC, that experience-dependent 4 Hz resonance across BLA-mPFC circuitry supports post-extinction fear memory retrieval. Our findings reveal that post-extinction fear memory retrieval is supported by local and interregional experience-dependent resonance, and suggest novel approaches for interrogation and therapeutic manipulation of acquired fear circuitry.


Assuntos
Tonsila do Cerebelo/fisiologia , Extinção Psicológica , Medo/fisiologia , Memória/fisiologia , Animais , Complexo Nuclear Basolateral da Amígdala/fisiologia , Condicionamento Psicológico , Eletrofisiologia/métodos , Aprendizagem/fisiologia , Camundongos , Optogenética/métodos , Córtex Pré-Frontal/fisiologia
7.
Proc Natl Acad Sci U S A ; 117(36): 22514-22521, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32848057

RESUMO

Learning to fear danger is essential for survival. However, overactive, relapsing fear behavior in the absence of danger is a hallmark of disabling anxiety disorders that affect millions of people. Its suppression is thus of great interest, but the necessary brain components remain incompletely identified. We studied fear suppression through a procedure in which, after acquiring fear of aversive events (fear learning), subjects were exposed to fear-eliciting cues without aversive events (safety learning), leading to suppression of fear behavior (fear extinction). Here we show that inappropriate, learning-resistant fear behavior results from disruption of brain components not previously implicated in this disorder: hypothalamic melanin-concentrating hormone-expressing neurons (MNs). Using real-time recordings of MNs across fear learning and extinction, we provide evidence that fear-inducing aversive events elevate MN activity. We find that optogenetic disruption of this MN activity profoundly impairs safety learning, abnormally slowing down fear extinction and exacerbating fear relapse. Importantly, we demonstrate that the MN disruption impairs neither fear learning nor related sensory responses, indicating that MNs differentially control safety and fear learning. Thus, we identify a neural substrate for inhibition of excessive fear behavior.


Assuntos
Extinção Psicológica/fisiologia , Medo/fisiologia , Hormônios Hipotalâmicos/metabolismo , Hipotálamo/citologia , Melaninas/metabolismo , Neurônios/metabolismo , Hormônios Hipofisários/metabolismo , Animais , Hipotálamo/metabolismo , Masculino , Camundongos , Optogenética
8.
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
9.
PLoS One ; 15(6): e0234160, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32559202

RESUMO

Pain is evolutionarily hardwired to signal potential danger and threat. It has been proposed that altered pain-related associative learning processes, i.e., emotional or fear conditioning, might contribute to the development and maintenance of chronic pain. Pain in or near the face plays a special role in pain perception and processing, especially with regard to increased pain-related fear and unpleasantness. However, differences in pain-related learning mechanisms between the face and other body parts have not yet been investigated. Here, we examined body-site specific differences in associative emotional conditioning using electrical stimuli applied to the face and the hand. Acquisition, extinction, and reinstatement of cue-pain associations were assessed in a 2-day emotional conditioning paradigm using a within-subject design. Data of 34 healthy subjects revealed higher fear of face pain as compared to hand pain. During acquisition, face pain (as compared to hand pain) led to a steeper increase in pain-related negative emotions in response to conditioned stimuli (CS) as assessed using valence ratings. While no significant differences between both conditions were observed during the extinction phase, a reinstatement effect for face but not for hand pain was revealed on the descriptive level and contingency awareness was higher for face pain compared to hand pain. Our results indicate a stronger propensity to acquire cue-pain-associations for face compared to hand pain, which might also be reinstated more easily. These differences in learning and resultant pain-related emotions might play an important role in the chronification and high prevalence of chronic facial pain and stress the evolutionary significance of pain in the head and face.


Assuntos
Condicionamento Clássico , Face , Mãos , Dor/psicologia , Adulto , Sinais (Psicologia) , Estimulação Elétrica , Extinção Psicológica , Medo/psicologia , Feminino , Humanos , Masculino , Rememoração Mental , Percepção da Dor/fisiologia , Limiar da Dor
10.
Psychopharmacology (Berl) ; 237(7): 2007-2018, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32382781

RESUMO

RATIONALE: The beta-lactam antibiotic ceftriaxone reliably attenuates the reinstatement of cocaine seeking. While the restoration of nucleus accumbens core (NA core) GLT-1 expression is necessary for ceftriaxone to attenuate reinstatement, AAV-mediated GLT-1 overexpression is not sufficient to attenuate reinstatement and does not prevent glutamate efflux during reinstatement. AIMS: Here, we test the hypothesis that ceftriaxone attenuates reinstatement through interactions with glutamate autoreceptors mGlu2 and mGlu3 in the NA core. METHODS: Male and female rats self-administered cocaine for 12 days followed by 2-3 weeks of extinction training. During the last 6-10 days of extinction, rats received ceftriaxone (200 mg/kg IP) or vehicle. In experiment 1, rats were killed, and NA core tissue was biotinylated for assessment of total and surface expression of mGlu2 and mGlu3 via western blotting. In experiment 2, we tested the hypothesis that mGlu2/3 signaling is necessary for ceftriaxone to attenuate cue- and cocaine-primed reinstatement by administering bilateral intra-NA core infusion of mGlu2/3 antagonist LY341495 or vehicle immediately prior to reinstatement testing. RESULTS: mGlu2 expression was reduced by cocaine and restored by ceftriaxone. There were no effects of cocaine or ceftriaxone on mGlu3 expression. We observed no effects of estrus on expression of either protein. The antagonism of mGlu2/3 in the NA core during both cue- and cocaine-primed reinstatement tests prevented ceftriaxone from attenuating reinstatement. CONCLUSIONS: These results indicate that ceftriaxone's effects depend on mGlu2/3 function and possibly mGlu2 receptor expression. Future work will test this hypothesis by manipulating mGlu2 expression in pathways that project to the NA core.


Assuntos
Comportamento Aditivo/metabolismo , Ceftriaxona/administração & dosagem , Cocaína/administração & dosagem , Núcleo Accumbens/metabolismo , Receptores de Glutamato Metabotrópico/metabolismo , Animais , Comportamento Aditivo/tratamento farmacológico , Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Inibidores da Captação de Dopamina/administração & dosagem , Extinção Psicológica/efeitos dos fármacos , Extinção Psicológica/fisiologia , Feminino , Masculino , Núcleo Accumbens/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Autoadministração
11.
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
12.
J Neurosci ; 40(25): 4881-4887, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32430298

RESUMO

Understanding how disruption of prefrontal cortex (PFC) maturation during adolescence is crucial to reveal which neural processes could contribute to the onset of psychiatric disorders that display frontal cortical deficits. Of particular interest is the gain of GABAergic function in the PFC during adolescence and its susceptibility to the impact of transient blockade of NMDA receptor function. Here we assessed whether exposure to MK-801 during adolescence in male rats triggers a state of excitatory-inhibitory imbalance in the PFC that limits its functional capacity to regulate behavior in adulthood. Recordings from PFC brain slices revealed that MK-801 exposure during adolescence preferentially reduces the presynaptic functionality of GABAergic activity over that of excitatory synapses. As a result, an imbalance of excitatory-inhibitory synaptic activity emerges in the PFC that correlates linearly with the GABAergic deficit. Notably, the data also suggest that the diminished prefrontal GABAergic function could arise from a deficit in the recruitment of fast-spiking interneurons by excitatory inputs during adolescence. At the behavioral level, MK-801 exposure during adolescence did not disrupt the acquisition of trace fear conditioning, but markedly increased the level of freezing response during extinction testing. Infusion of the GABAA receptor-positive allosteric modulator Indiplon into the PFC before extinction testing reduced the level of freezing response in MK-801-treated rats to control levels. Collectively, the results indicate NMDA receptor signaling during adolescence enables the gain of prefrontal GABAergic function, which is required for maintaining proper excitatory-inhibitory balance in the PFC and its control of behavioral responses.SIGNIFICANCE STATEMENT A developmental disruption of prefrontal cortex maturation has been implicated in the pathophysiology of cognitive deficits in psychiatric disorders. Of particular interest is the susceptibility of the local GABAergic circuit to the impact of transient disruption of NMDA receptors. Here we found that NMDA receptor signaling is critical to enable the gain of prefrontal GABAergic transmission during adolescence for maintaining proper levels of excitatory-inhibitory balance in the PFC and its control of behavior.


Assuntos
Medo/fisiologia , Córtex Pré-Frontal/crescimento & desenvolvimento , Córtex Pré-Frontal/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Transmissão Sináptica/fisiologia , Animais , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Extinção Psicológica/fisiologia , Medo/efeitos dos fármacos , Interneurônios/efeitos dos fármacos , Interneurônios/metabolismo , Masculino , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transmissão Sináptica/efeitos dos fármacos
13.
J Neurosci ; 40(24): 4739-4749, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32393533

RESUMO

High trait anxiety is associated with altered activity across emotion regulation circuitry and a higher risk of developing anxiety disorders and depression. This circuitry is extensively modulated by serotonin. Here, to understand why some people may be more vulnerable to developing affective disorders, we investigated whether serotonin-related gene expression across the brain's emotion regulation circuitry may underlie individual differences in trait anxiety using the common marmoset (Callithrix jacchus, mixed sexes) as a model. First, we assessed the association of region-specific expression of the serotonin transporter (SLC6A4) and serotonin receptor (HTR1A, HTR2A, HTR2C) genes with anxiety-like behavior; and second, we investigated their causal role in two key features of the high trait anxious phenotype: high responsivity to anxiety-provoking stimuli and an exaggerated conditioned threat response. While the expression of the serotonin receptors did not show a significant relationship with anxiety-like behavior in any of the targeted brain regions, serotonin transporter expression, specifically within the right ventrolateral prefrontal cortex (vlPFC) and most strongly in the right amygdala, was associated positively with anxiety-like behavior. The causal relationship between amygdala serotonin levels and an animal's sensitivity to threat was confirmed via direct amygdala infusions of a selective serotonin reuptake inhibitor (SSRI), citalopram. Both anxiety-like behaviors, and conditioned threat-induced responses were reduced by the blockade of serotonin reuptake in the amygdala. Together, these findings provide evidence that high amygdala serotonin transporter expression contributes to the high trait anxious phenotype and suggest that reduction of threat reactivity by SSRIs may be mediated by their actions in the amygdala.SIGNIFICANCE STATEMENT Findings here contribute to our understanding of how the serotonin system underlies an individual's expression of threat-elicited negative emotions such as anxiety and fear within nonhuman primates. Exploration of serotonergic gene expression across brain regions implicated in emotion regulation revealed that serotonin transporter gene expression in the ventrolateral prefrontal cortex (vlPFC) and most strongly in the amygdala, but none of the serotonin receptor genes, were predictive of interindividual differences in anxiety-like behavior. Targeting of amygdala serotonin reuptake with selective serotonin reuptake inhibitors (SSRIs) confirmed the causal relationship between amygdala serotonin transporter and an animal's sensitivity to threat by reversing expression of two key features of the high trait-like anxiety phenotype: high responsivity to anxiety-provoking uncertain threat and responsivity to certain conditioned threat.


Assuntos
Tonsila do Cerebelo/metabolismo , Ansiedade/metabolismo , Emoções/fisiologia , Comportamento Exploratório/fisiologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Ansiedade/genética , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Callithrix , Citalopram/farmacologia , Emoções/efeitos dos fármacos , Comportamento Exploratório/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Extinção Psicológica/fisiologia , Medo/efeitos dos fármacos , Medo/fisiologia , Feminino , Humanos , Masculino , Receptores de Serotonina/genética , Receptores de Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Inibidores de Captação de Serotonina/farmacologia
14.
J Neurosci ; 40(24): 4773-4787, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32393535

RESUMO

Flexible initiation or suppression of actions to avoid aversive events is crucial for survival. The prelimbic (PL) and infralimbic (IL) regions of the medial prefrontal cortex (mPFC) have been implicated in different aspects of avoidance and reward-seeking, but their respective contribution in instigating versus suppressing actions in aversive contexts remains to be clarified. We examined mPFC involvement in different forms of avoidance in rats well trained on different cued lever-press avoidance tasks. Active/inhibitory avoidance required flexible discrimination between auditory cues signaling foot-shock could be avoided by making or withholding instrumental responses. On a simpler active avoidance task, a single cue signaled when a lever press would avoid shock. PL inactivation disrupted active but not inhibitory avoidance on the discriminative task while having no effect on single-cued avoidance. In comparison, IL inactivation broadly impaired active and inhibitory avoidance. Conversely, on a cued appetitive go/no-go task, both IL and PL inactivation impaired inhibitory but not active reward-seeking, the latter effect being diametrically opposite to that observed on the avoidance task. These findings highlight the complex manner in which different mPFC regions aid in initiating or inhibiting actions in the service of avoiding aversive outcomes or obtaining rewarding ones. IL facilitates active avoidance but suppress inappropriate actions in appetitive and aversive contexts. In contrast, contextual valence plays a critical role in how the PL is recruited in initiating or suppressing actions, which may relate to the degree of cognitive control required to flexibly negotiate response or motivational conflicts and override prepotent behaviors.SIGNIFICANCE STATEMENT Choosing to make or withhold actions in a context-appropriate manner to avoid aversive events or obtain other goals is a critical survival skill. Different medial prefrontal cortex (mPFC) regions have been implicated in certain aspects of avoidance, but their contributions to instigating or suppressing actions remains to be clarified. Here, we show that the dorsal, prelimbic (PL) region of the medial PFC aids active avoidance in situations requiring flexible mitigation of response conflicts, but also aids in withholding responses to obtain rewards. In comparison the ventral infralimbic (IL) cortex plays a broader role in active and inhibitory avoidance as well as suppressing actions to obtain rewards. These findings provide insight into mechanisms underlying normal and maladaptive avoidance behaviors and response inhibition.


Assuntos
Aprendizagem da Esquiva/fisiologia , Cognição/fisiologia , Córtex Pré-Frontal/fisiologia , Recompensa , Animais , Condicionamento Operante/fisiologia , Sinais (Psicologia) , Extinção Psicológica/fisiologia , Masculino , Ratos , Ratos Long-Evans
15.
Nat Neurosci ; 23(6): 718-729, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32367065

RESUMO

DNA forms conformational states beyond the right-handed double helix; however, the functional relevance of these noncanonical structures in the brain remains unknown. Here we show that, in the prefrontal cortex of mice, the formation of one such structure, Z-DNA, is involved in the regulation of extinction memory. Z-DNA is formed during fear learning and reduced during extinction learning, which is mediated, in part, by a direct interaction between Z-DNA and the RNA-editing enzyme Adar1. Adar1 binds to Z-DNA during fear extinction learning, which leads to a reduction in Z-DNA at sites where Adar1 is recruited. Knockdown of Adar1 leads to an inability to modify a previously acquired fear memory and blocks activity-dependent changes in DNA structure and RNA state-effects that are fully rescued by the introduction of full-length Adar1. These findings suggest a new mechanism of learning-induced gene regulation that is dependent on proteins that recognize alternate DNA structure states, which are required for memory flexibility.


Assuntos
Adenosina Desaminase/metabolismo , Adenosina Desaminase/fisiologia , DNA Forma Z/fisiologia , Extinção Psicológica/fisiologia , Edição de RNA/fisiologia , Animais , DNA Forma Z/metabolismo , Medo , Aprendizagem/fisiologia , Camundongos , Córtex Pré-Frontal/metabolismo , RNA Interferente Pequeno/farmacologia
17.
Am J Psychiatry ; 177(5): 454-463, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32252541

RESUMO

OBJECTIVE: Although both pediatric and adult patients with anxiety disorders exhibit similar neural responding to threats, age-related differences have been found in some functional MRI (fMRI) studies. To reconcile disparate findings, the authors compared brain function in youths and adults with and without anxiety disorders while rating fear and memory of ambiguous threats. METHODS: Two hundred medication-free individuals ages 8-50 were assessed, including 93 participants with an anxiety disorder. Participants underwent discriminative threat conditioning and extinction in the clinic. Approximately 3 weeks later, they completed an fMRI paradigm involving extinction recall, in which they rated their levels of fear evoked by, and their explicit memory for, morph stimuli with varying degrees of similarity to the extinguished threat cues. RESULTS: Age moderated two sets of anxiety disorder findings. First, as age increased, healthy subjects compared with participants with anxiety disorders exhibited greater amygdala-ventromedial prefrontal cortex (vmPFC) connectivity when processing threat-related cues. Second, age moderated diagnostic differences in activation in ways that varied with attention and brain regions. When rating fear, activation in the vmPFC differed between the anxiety and healthy groups at relatively older ages. In contrast, when rating memory for task stimuli, activation in the inferior temporal cortex differed between the anxiety and healthy groups at relatively younger ages. CONCLUSIONS: In contrast to previous studies that demonstrated age-related similarities in the biological correlates of anxiety disorders, this study identified age differences. These findings may reflect this study's focus on relatively late-maturing psychological processes, particularly the appraisal and explicit memory of ambiguous threat, and inform neurodevelopmental perspectives on anxiety.


Assuntos
Envelhecimento/psicologia , Transtornos de Ansiedade/fisiopatologia , Adolescente , Adulto , Transtornos de Ansiedade/psicologia , Criança , Condicionamento Psicológico , Extinção Psicológica , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Análise e Desempenho de Tarefas , Adulto Jovem
18.
Behav Processes ; 174: 104105, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32169352

RESUMO

Resurgence is the reoccurrence of a target response when reinforcement for a more recently reinforced alternative response is eliminated or reduced. The present study arranged two successive three-phase procedures to assess whether resurgence decreases with repeated assessments. Moreover, we arranged a contextual change from the first to second assessment for some groups. Phase 1 reinforced a target response on a touchscreen computer with typically developing adults as participants according to either variable-ratio or variable-interval schedules of reinforcement. Phase 2 extinguished target responding and reinforced alternative responding. Phase 3 tested for resurgence by extinguishing alternative responding. Resurgence reliably occurred in all tests and decreased from the first to second exposure to the procedures but there were no effects of context change. Therefore, repeated exposures to resurgence tests reduced those effects but contextual changes had no effect.


Assuntos
Condicionamento Operante , Extinção Psicológica , Esquema de Reforço , Adolescente , Adulto , Feminino , Humanos , Masculino , Adulto Jovem
19.
Psychopharmacology (Berl) ; 237(6): 1709-1721, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32125483

RESUMO

RATIONALE: There is a robust relationship between anxiety disorders, including post-traumatic stress disorder (PTSD) and substance abuse. In fact, 30-50% of people seeking treatment for substance abuse have a comorbid diagnosis for PTSD. Heroin use is at epic proportions in the USA and is commonly used by people with co-occurring PTSD symptoms and substance use disorder. OBJECTIVES: Here, we combined animal assays of acute restraint stress and contingent heroin self-administration (SA) to study comorbidity between stress disorders and opioid use disorder and identify shifts in anxiety-like behaviors following stress and/or heroin in response to a stress-conditioned cue. Our objective for this approach was to determine the long-term impact of acute restraint stress and heroin self-administration on stress reactivity and basic reward processes. METHODS: We used 2-h acute restraint stress paired with an odor stimulus to condition a stress cue (CS) for testing of subsequent stress reactivity in a burying task and reinstatement and extinction to heroin seeking. Rats were also tested for social place preference for measures of social reward and anxiety-like behaviors. RESULTS: Stress rats exhibited multiple levels of disrupted behavior including enhanced acquisition of heroin intake and reinstatement in response to the stress CS, as well as delayed extinction in response to the stress CS. All rats developed a social place preference, but stress rats spent more time in nose-to-nose contact with the unfamiliar rat while heroin rats spent time exploring the chamber. In the burying task, stress shortened latencies to bury the CS and increased burying and immobility in male and female rats relative to sham counterparts. CONCLUSIONS: Acute restraint stress results in anxiety-like behaviors and a stress-associated cue is sufficient to reinstate extinguished heroin seeking. This project has the potential to elucidate the complex relationship between stress/anxiety disorders, including some PTSD-like characteristics, and the onset, maintenance, and relapse to heroin seeking.


Assuntos
Extinção Psicológica , Dependência de Heroína/psicologia , Heroína/administração & dosagem , Restrição Física/psicologia , Estresse Psicológico/psicologia , Animais , Sinais (Psicologia) , Extinção Psicológica/fisiologia , Feminino , Masculino , Odorantes , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Autoadministração
20.
Biochem Biophys Res Commun ; 525(2): 520-527, 2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32113678

RESUMO

Extremely high relapse rate is the dramatic challenge of drug abuse at present. Environmental cues play an important role in relapse of drug abuse. However, the specific mechanism underlying relapse remains unclear. Using morphine conditioned place preference (CPP) model, we show that association of neuronal nitric oxide synthase (nNOS) with postsynaptic density-95 (PSD-95) plays a significant role in morphine priming-induced reinstatement. The nNOS-PSD-95 coupling and c-Fos expression in the medial prefrontal cortex (mPFC) was significantly increased after extinction of morphine CPP. Dissociation of nNOS-PSD-95 in the mPFC by ZL006 inhibited the reinstatement of morphine CPP induced by a priming dose of morphine. Significantly reduced phosphorylation of cAMP-response element binding protein (CREB) in the mPFC was observed in the mice exposed to morphine after the extinction training. Uncoupling nNOS-PSD-95 reversed the morphine-induced CREB dysfunction. Moreover, effects of ZL006 on the reinstatement of morphine CPP and CREB activation depended on nNOS-PSD-95 target. Together, our findings suggest that nNOS-PSD-95 in the mPFC contributes to reinstatement of morphine CPP, possibly through CREB dysfunction, offering a potential target to prevent relapse of drug abuse.


Assuntos
Proteína 4 Homóloga a Disks-Large/metabolismo , Morfina/farmacologia , Entorpecentes/farmacologia , Óxido Nítrico Sintase Tipo I/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Extinção Psicológica/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal/metabolismo , Mapas de Interação de Proteínas/efeitos dos fármacos
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