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1.
Nat Commun ; 12(1): 1200, 2021 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-33619256

RESUMO

Learning-activated engram neurons play a critical role in memory recall. An untested hypothesis is that these same neurons play an instructive role in offline memory consolidation. Here we show that a visually-cued fear memory is consolidated during post-conditioning sleep in mice. We then use TRAP (targeted recombination in active populations) to genetically label or optogenetically manipulate primary visual cortex (V1) neurons responsive to the visual cue. Following fear conditioning, mice respond to activation of this visual engram population in a manner similar to visual presentation of fear cues. Cue-responsive neurons are selectively reactivated in V1 during post-conditioning sleep. Mimicking visual engram reactivation optogenetically leads to increased representation of the visual cue in V1. Optogenetic inhibition of the engram population during post-conditioning sleep disrupts consolidation of fear memory. We conclude that selective sleep-associated reactivation of learning-activated sensory populations serves as a necessary instructive mechanism for memory consolidation.


Assuntos
Medo/fisiologia , Consolidação da Memória/fisiologia , Memória/fisiologia , Sono/fisiologia , Animais , Condicionamento Psicológico/fisiologia , Sinais (Psicologia) , Eletrodos , Tecnologia de Fibra Óptica , Camundongos Transgênicos , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Optogenética , Privação do Sono/fisiopatologia , Córtex Visual/fisiopatologia
2.
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
3.
Science ; 371(6525): 153-159, 2021 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-33414216

RESUMO

Empathy is an essential component of social communication that involves experiencing others' sensory and emotional states. We observed that a brief social interaction with a mouse experiencing pain or morphine analgesia resulted in the transfer of these experiences to its social partner. Optogenetic manipulations demonstrated that the anterior cingulate cortex (ACC) and its projections to the nucleus accumbens (NAc) were selectively involved in the social transfer of both pain and analgesia. By contrast, the ACC→NAc circuit was not necessary for the social transfer of fear, which instead depended on ACC projections to the basolateral amygdala. These findings reveal that the ACC, a brain area strongly implicated in human empathic responses, mediates distinct forms of empathy in mice by influencing different downstream targets.


Assuntos
Analgesia/psicologia , Comunicação , Empatia/fisiologia , Giro do Cíngulo/fisiologia , Núcleo Accumbens/fisiologia , Dor/psicologia , Animais , Complexo Nuclear Basolateral da Amígdala/fisiologia , Medo/fisiologia , Feminino , Masculino , Camundongos , Morfina/administração & dosagem , Optogenética , Dor/tratamento farmacológico
4.
Neuron ; 109(5): 823-838.e6, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33476548

RESUMO

The circuit mechanisms underlying fear-induced suppression of feeding are poorly understood. To help fill this gap, mice were fear conditioned, and the resulting changes in synaptic connectivity among the locus coeruleus (LC), the parabrachial nucleus (PBN), and the central nucleus of amygdala (CeA)-all of which are implicated in fear and feeding-were studied. LC neurons co-released noradrenaline and glutamate to excite PBN neurons and suppress feeding. LC neurons also suppressed inhibitory input to PBN neurons by inducing heterosynaptic, endocannabinoid-dependent, long-term depression of CeA synapses. Blocking or knocking down endocannabinoid receptors in CeA neurons prevented fear-induced depression of CeA synaptic transmission and fear-induced suppression of feeding. Altogether, these studies demonstrate that LC neurons play a pivotal role in modulating the circuitry that underlies fear-induced suppression of feeding, pointing to new ways of alleviating stress-induced eating disorders.


Assuntos
Medo/fisiologia , Comportamento Alimentar/fisiologia , Locus Cerúleo/fisiologia , Neurônios/fisiologia , Animais , Núcleo Central da Amígdala/fisiologia , Condicionamento Clássico , Feminino , Ácido Glutâmico/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Vias Neurais/fisiologia , Norepinefrina/fisiologia , Núcleos Parabraquiais/fisiologia , Transmissão Sináptica
5.
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
6.
J Ethnopharmacol ; 264: 113265, 2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-32858198

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Luffa operculata (L.) Cogn (Cucurbitaceae) is a traditional plant popularly used in the abortion induction, against sinusitis and is toxic. AIM OF THE STUDY: To verify the influence of the aqueous extract obtained from the dry fruit of L. operculata (BNE) on the male rats vertically exposed to a subabortive dose of BNE, by evaluating alterations in behavior and neurochemical features in hypothalamus, striatum and frontal cortex, at a juvenile age, after receiving a stress challenge given by the use of the "New York subway stress" technique (NYS). MATERIALS AND METHODS: Pregnant female rats (F0 generation) received 1.0 mg/kg BNE, or distilled water (100 mL/kg), by gavage, between gestation days GD17 and GD21. The pups were weaned at PND21 and were kept up to PND60 (juvenile age) in controlled environmental conditions. Four groups were obtained: control (CG), experimental (EG), stress control (SCG) and stress experimental (SEG) After being stressed, the animals were behavioral screened for in the open field (OF) and in light-dark box (LDB) apparatuses. They were euthanized, and the liver, kidneys and brain were removed for both macroscopic and microscopic analyses, and for quantification of vanillylmandelic acid (VMA), norepinephrine (NE), dopamine (DA) and its metabolite, 3,4-dihydroxyphenylacetic acid (DOPAC) and the serotonin (5-HT) and its metabolite 5-hydroxyindolylacetic acid (5-HIAA) were accessed in the hypothalamus, frontal cortex and striatum. RESULTS AND DISCUSSION: although most of the behavior changes were due to the stress challenge, the rats spent more time in the dark side of the LDB and were less likely to explore the light side, indicating that the treatment with BNE induced to fear. Interferences of BNE over behavior were due to impairment of VMA, NE, 5-HT and DA and increasing of DOPAC in the hypothalamus, and an increase of 5-HIAA in the frontal cortex, indicating alterations in the hypothalamic-hypophysis-adrenal axis (HHAA). No macroscopic or histopathological changes were observed in the liver, kidneys, or brain, although GFAP was diminished in the SCG, as expected for stressed rats. CONCLUSION: the vertical exposition of juvenile rats to BNE led to the manifestation of fear and to a down regulation of the hypothalamic-hypophysis-adrenal axis.


Assuntos
Medo/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Luffa , Neurotransmissores/metabolismo , Extratos Vegetais/administração & dosagem , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Fatores Etários , Animais , Dopamina/metabolismo , Medo/fisiologia , Medo/psicologia , Feminino , Ácido Hidroxi-Indolacético/metabolismo , Masculino , Extratos Vegetais/isolamento & purificação , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/psicologia , Ratos , Ratos Wistar , Serotonina/metabolismo
7.
Neuroimage ; 227: 117686, 2021 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-33359340

RESUMO

Processing of fear is of crucial importance for human survival and it can generally occur at explicit and implicit conditions. It is worth noting that explicit and implicit fear processing produces different behavioral and neurophysiological outcomes. The present study capitalizes on the Activation Likelihood Estimation (ALE) method of meta-analysis to identify: (a) the "core" network of fear processing in healthy individuals; (b) common and specific neural activations associated with explicit and implicit processing of fear. Following PRISMA guidelines, a total of 92 fMRI and PET studies were included in the meta-analysis. The overall analysis show that the core fear network comprises the amygdala, pulvinar, and fronto-occipital regions. Both implicit and explicit fear processing activated amygdala, declive, fusiform gyrus, and middle frontal gyrus, suggesting that these two types of fear processing share a common neural substrate. Explicit fear processing elicited more activations at the pulvinar and parahippocampal gyrus, suggesting visual attention/orientation and contextual association play important roles during explicit fear processing. In contrast, implicit fear processing elicited more activations at the cerebellum-amygdala-cortical pathway, indicating an 'alarm' system underlying implicit fear processing. These findings have shed light on the neural mechanism underlying fear processing at different levels of awareness.


Assuntos
Encéfalo/fisiologia , Medo/fisiologia , Adulto , Mapeamento Encefálico/métodos , Feminino , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Tomografia por Emissão de Pósitrons/métodos
8.
Elife ; 92020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33319747

RESUMO

In many cases of trauma, the same environmental stimuli that become associated with aversive events are experienced on other occasions without adverse consequence. We examined neural circuits underlying partially reinforced fear (PRF), whereby mice received tone-shock pairings on half of conditioning trials. Tone-elicited freezing was lower after PRF conditioning than fully reinforced fear (FRF) conditioning, despite an equivalent number of tone-shock pairings. PRF preferentially activated medial prefrontal cortex (mPFC) and bed nucleus of the stria terminalis (BNST). Chemogenetic inhibition of BNST-projecting mPFC neurons increased PRF, not FRF, freezing. Multiplexing chemogenetics with in vivo neuronal recordings showed elevated infralimbic cortex (IL) neuronal activity during CS onset and freezing cessation; these neural correlates were abolished by chemogenetic mPFC→BNST inhibition. These data suggest that mPFC→BNST neurons limit fear to threats with a history of partial association with an aversive stimulus, with potential implications for understanding the neural basis of trauma-related disorders.


Assuntos
Medo/fisiologia , Córtex Pré-Frontal/fisiologia , Núcleos Septais/fisiologia , Animais , Condicionamento Clássico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/fisiologia , Reforço Psicológico , Incerteza
9.
Mayo Clin Proc ; 95(11): 2487-2498, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33153636

RESUMO

In light of the coronavirus disease 2019 pandemic, we explore the role of stress, fear, and the impact of positive and negative emotions on health and disease. We then introduce strategies to help mitigate stress within the health care team, and provide a rationale for their efficacy. Additionally, we identify strategies to optimize patient care and explain their heightened importance in today's environment.


Assuntos
Infecções por Coronavirus/psicologia , Medo/psicologia , Pessoal de Saúde/psicologia , Pneumonia Viral/psicologia , Relações Profissional-Paciente , Estresse Psicológico/etiologia , Adaptação Psicológica , Ansiedade/etiologia , Ansiedade/fisiopatologia , Ansiedade/prevenção & controle , Estado Terminal , Medo/fisiologia , Saúde Global , Humanos , Relações Interpessoais , Saúde Mental , Saúde do Trabalhador , Pandemias , Resiliência Psicológica , Estresse Psicológico/fisiopatologia , Estresse Psicológico/prevenção & controle
10.
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
11.
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
12.
J Vis Exp ; (162)2020 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-32894260

RESUMO

Emotional memory has been primarily studied with fear-conditioning paradigms. Fear conditioning is a form of learning through which individuals learn the relationships between aversive events and otherwise neutral stimuli. The most-widely utilized procedures for studying emotional memories entail fear conditioning in rats. In these tasks, the unconditioned stimulus (US) is a footshock presented once or several times across single or several sessions, and the conditioned response (CR) is freezing. In a version of these procedures, called cued fear conditioning, a tone (conditioned stimulus, CS) is paired with footshocks (US) during the training phase. During the first test, animals are exposed to the same context in which training took place, and freezing responses are tested in the absence of footshocks and tones (i.e., a context test). During the second test, freezing is measured when the context is changed (e.g., by manipulating the smell and walls of the experimental chamber) and the tone is presented in the absence of footshocks (i.e., a cue test). Most cued fear conditioning procedures entail few tone-shock pairings (e.g., 1-3 trials in a single session). There is a growing interest in less common versions involving an extensive number of pairings (i.e., overtraining) related to the long-lasting effect called fear incubation (i.e., fear responses increase over time without further exposure to aversive events or conditioned stimuli). Extended fear-conditioning tasks have been key to the understanding of fear incubation's behavioral and neurobiological aspects, including its relationship with other psychological phenomena (e.g., post-traumatic stress disorder). Here, we describe an extended fear-conditioning protocol that produces overtraining and fear incubation in rats. This protocol entails a single training session with 25 tone-shock pairings (i.e., overtraining) and a comparison of conditioned freezing responses during context and cue tests 48 h (short-term) and 6 weeks (long-term) after training.


Assuntos
Condicionamento Psicológico , Medo/fisiologia , Estimulação Acústica , Animais , Sinais (Psicologia) , Masculino , Memória/fisiologia , Ratos , Fatores de Tempo
13.
Nat Commun ; 11(1): 4819, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32968048

RESUMO

In many parts of the nervous system, experience-dependent refinement of neuronal circuits predominantly involves synapse elimination. The role of sleep in this process remains unknown. We investigated the role of sleep in experience-dependent dendritic spine elimination of layer 5 pyramidal neurons in the visual (V1) and frontal association cortex (FrA) of 1-month-old mice. We found that monocular deprivation (MD) or auditory-cued fear conditioning (FC) caused rapid spine elimination in V1 or FrA, respectively. MD- or FC-induced spine elimination was significantly reduced after total sleep or REM sleep deprivation. Total sleep or REM sleep deprivation also prevented MD- and FC-induced reduction of neuronal activity in response to visual or conditioned auditory stimuli. Furthermore, dendritic calcium spikes increased substantially during REM sleep, and the blockade of these calcium spikes prevented MD- and FC-induced spine elimination. These findings reveal an important role of REM sleep in experience-dependent synapse elimination and neuronal activity reduction.


Assuntos
Córtex Cerebral/fisiologia , Espinhas Dendríticas/fisiologia , Sono REM/fisiologia , Animais , Condicionamento Clássico , Medo/fisiologia , Camundongos , Camundongos Transgênicos , Modelos Animais , Plasticidade Neuronal/fisiologia , Neurônios/fisiologia , Células Piramidais/fisiologia , Privação Sensorial/fisiologia , Privação do Sono , Sinapses , Córtex Visual/fisiologia
14.
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
15.
PLoS One ; 15(8): e0236999, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32813734

RESUMO

Snakes have been important ambush predators of both primates and human hunter-gatherers throughout their co-evolutionary history. Viperid snakes in particular are responsible for most fatal venomous snakebites worldwide and thus represent a strong selective pressure. They elicit intense fear in humans and are easily recognizable thanks to their distinctive morphotype. In this study, we measured skin resistance (SR) and heart rate (HR) in human subjects exposed to snake pictures eliciting either high fear (10 venomous viperid species) or disgust (10 nonvenomous fossorial species). Venomous snakes subjectively evaluated as frightening trigger a stronger physiological response (higher SR amplitude) than repulsive non-venomous snakes. However, stimuli presented in a block (more intense stimulation) do not trigger a stronger emotional response compared to sequentially presented stimuli (less intense stimulation). There are significant interindividual differences as subjects with high fear of snakes confronted with images of viperid snakes show stronger, longer-lasting, and more frequent changes in SR and higher HR compared to low-fear subjects. Thus, we show that humans demonstrate a remarkable ability to discriminate between dangerous viperids and harmless fossorial snakes, which is also reflected in distinct autonomous body responses.


Assuntos
Medo/fisiologia , Medo/psicologia , Mordeduras de Serpentes/psicologia , Serpentes , Adolescente , Adulto , Animais , Sistema Nervoso Autônomo/fisiologia , Evolução Biológica , Asco , Feminino , Resposta Galvânica da Pele/fisiologia , Frequência Cardíaca/fisiologia , Humanos , Masculino , Modelos Psicológicos , Estimulação Luminosa , Psicometria , Psicofisiologia , Venenos de Serpentes/envenenamento , Adulto Jovem
16.
Adv Exp Med Biol ; 1284: 1-7, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32852735

RESUMO

Fear is defined as a fundamental emotion promptly arising in the context of threat and when danger is perceived. Fear can be innate or learned. Examples of innate fear include fears that are triggered by predators, pain, heights, rapidly approaching objects, and ancestral threats such as snakes and spiders. Animals and humans detect and respond more rapidly to threatening stimuli than to nonthreatening stimuli in the natural world. The threatening stimuli for most animals are predators, and most predators are themselves prey to other animals. Predatory avoidance is of crucial importance for survival of animals. Although humans are rarely affected by predators, we are constantly challenged by social threats such as a fearful or angry facial expression. This chapter will summarize the current knowledge on brain circuits processing innate fear responses to visual stimuli derived from studies conducted in mice and humans.


Assuntos
Encéfalo/fisiologia , Medo/fisiologia , Ira , Animais , Expressão Facial , Humanos , Serpentes , Aranhas
17.
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
18.
PLoS One ; 15(7): e0235346, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32667951

RESUMO

Several studies have recently suggested that an abnormal processing of respiratory interoceptive and nociceptive (painful) stimuli may contribute to eating disorder (ED) pathophysiology. Mood and anxiety disorders (MA) are also characterized by abnormal respiratory symptoms, and show substantial comorbidity with ED. However, no studies have examined both respiratory and pain processing simultaneously within ED and MA. The present study systematically evaluated responses to perturbations of respiratory and nociceptive signals across the levels of physiology, behavior, and symptom report in a transdiagnostic ED sample (n = 51) that was individually matched to MA individuals (n = 51) and healthy comparisons (HC; n = 51). Participants underwent an inspiratory breath-holding challenge as a probe of respiratory interoception and a cold pressor challenge as a probe of pain processing. We expected both clinical groups to report greater stress and fear in response to respiratory and nociceptive perturbation than HCs, in the absence of differential physiological and behavioral responses. During breath-holding, both the ED and MA groups reported significantly more stress, feelings of suffocation, and suffocation fear than HC, with the ED group reporting the most severe symptoms. Moreover, anxiety sensitivity was related to suffocation fear only in the ED group. The heightened affective responses in the current study occurred in the absence of group differences in behavioral (breath hold duration, cold pressor duration) and physiological (end-tidal carbon dioxide, end-tidal oxygen, heart rate, skin conductance) responses. Against our expectations, there were no group differences in the response to cold pain stimulation. A matched-subgroup analysis focusing on individuals with anorexia nervosa (n = 30) produced similar results. These findings underscore the presence of abnormal respiratory interoception in MA and suggest that hyperreactivity to respiratory signals may be a potentially overlooked clinical feature of ED.


Assuntos
Anorexia Nervosa/fisiopatologia , Transtornos de Ansiedade/fisiopatologia , Transtornos da Alimentação e da Ingestão de Alimentos/fisiopatologia , Dor Nociceptiva/fisiopatologia , Adolescente , Adulto , Afeto/fisiologia , Anorexia Nervosa/complicações , Anorexia Nervosa/epidemiologia , Transtornos de Ansiedade/complicações , Transtornos de Ansiedade/epidemiologia , Asfixia/fisiopatologia , Asfixia/terapia , Comorbidade , Medo/fisiologia , Transtornos da Alimentação e da Ingestão de Alimentos/complicações , Transtornos da Alimentação e da Ingestão de Alimentos/epidemiologia , Feminino , Humanos , Masculino , Transtornos do Humor/complicações , Transtornos do Humor/epidemiologia , Transtornos do Humor/fisiopatologia , Dor Nociceptiva/complicações , Dor Nociceptiva/epidemiologia , Dor/complicações , Dor/epidemiologia , Dor/fisiopatologia , Sistema Respiratório/fisiopatologia
19.
Nat Commun ; 11(1): 3492, 2020 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-32661319

RESUMO

Ventral hippocampal CA1 (vCA1) projections to the amygdala are necessary for contextual fear memory. Here we used in vivo Ca2+ imaging in mice to assess the temporal dynamics by which ensembles of vCA1 neurons mediate encoding and retrieval of contextual fear memories. We found that a subset of vCA1 neurons were responsive to the aversive shock during context conditioning, their activity was necessary for memory encoding, and these shock-responsive neurons were enriched in the vCA1 projection to the amygdala. During memory retrieval, a population of vCA1 neurons became correlated with shock-encoding neurons, and the magnitude of synchronized activity within this population was proportional to memory strength. The emergence of these correlated networks was disrupted by inhibiting vCA1 shock responses during memory encoding. Thus, our findings suggest that networks of cells that become correlated with shock-responsive neurons in vCA1 are essential components of contextual fear memory ensembles.


Assuntos
Região CA1 Hipocampal/metabolismo , Medo/fisiologia , Memória/fisiologia , Algoritmos , Tonsila do Cerebelo/metabolismo , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL
20.
Neuron ; 107(4): 717-730.e5, 2020 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-32562662

RESUMO

The prelimbic (PL) area and basolateral amygdala (lateral [LA] and basolateral [BL] nuclei) have closely related functions and similar extrinsic connectivity. Reasoning that the computational advantage of such redundancy should be reflected in differences in how these structures represent information, we compared the coding properties of PL and amygdala neurons during a task that requires rats to produce different conditioned defensive or appetitive behaviors. Rather than unambiguous regional differences in the identities of the variables encoded, we found gradients in how the same variables are represented. Whereas PL and BL neurons represented many different parameters through minor variations in firing rates, LA cells coded fewer task features with stronger changes in activity. At the population level, whereas valence could be easily distinguished from amygdala activity, PL neurons could distinguish both valence and trial identity as well as or better than amygdala neurons. Thus, PL has greater representational capacity.


Assuntos
Potenciais de Ação/fisiologia , Tonsila do Cerebelo/fisiologia , Aprendizagem da Esquiva/fisiologia , Rede Nervosa/fisiologia , Neurônios/fisiologia , Córtex Pré-Frontal/fisiologia , Animais , Comportamento Animal/fisiologia , Medo/fisiologia , Modelos Neurológicos , Vias Neurais/fisiologia , Ratos , Recompensa
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