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1.
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
2.
PLoS One ; 15(10): e0237204, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33075046

RESUMO

The amygdala, a subcortical structure known for social and emotional processing, consists of multiple subnuclei with unique functions and connectivity patterns. Tracer studies in adult macaques have shown that the basolateral subnuclei differentially connect to parts of visual cortex, with stronger connections to anterior regions and weaker connections to posterior regions; infant macaques show robust connectivity even with posterior visual regions. Do these developmental differences also exist in the human amygdala, and are there specific functional regions that undergo the most pronounced developmental changes in their connections with the amygdala? To address these questions, we explored the functional connectivity (from resting-state fMRI data) of the basolateral amygdala to occipitotemporal cortex in human neonates scanned within one week of life and compared the connectivity patterns to those observed in young adults. Specifically, we calculated amygdala connectivity to anterior-posterior gradients of the anatomically-defined occipitotemporal cortex, and also to putative occipitotemporal functional parcels, including primary and high-level visual and auditory cortices (V1, A1, face, scene, object, body, high-level auditory regions). Results showed a decreasing gradient of functional connectivity to the occipitotemporal cortex in adults-similar to the gradient seen in macaque tracer studies-but no such gradient was observed in neonates. Further, adults had stronger connections to high-level functional regions associated with face, body, and object processing, and weaker connections to primary sensory regions (i.e., A1, V1), whereas neonates showed the same amount of connectivity to primary and high-level sensory regions. Overall, these results show that functional connectivity between the amygdala and occipitotemporal cortex is not yet differentiated in neonates, suggesting a role of maturation and experience in shaping these connections later in life.


Assuntos
Tonsila do Cerebelo/fisiologia , Complexo Nuclear Basolateral da Amígdala/fisiologia , Mapeamento Encefálico/métodos , Córtex Cerebral/fisiologia , Conectoma , Vias Neurais/fisiologia , Lobo Occipital/fisiologia , Adulto , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Recém-Nascido , Imagem por Ressonância Magnética , Masculino , Adulto Jovem
3.
Annu Int Conf IEEE Eng Med Biol Soc ; 2020: 3625-3628, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-33018787

RESUMO

Several studies have shown that direct brain stimulation can enhance memory in humans and animal models. Investigating the neurophysiological changes induced by brain stimulation is an important step towards understanding the neural processes underlying memory function. Furthermore, it paves the way for developing more efficient neuromodulation approaches for memory enhancement. In this study, we utilized a combination of unsupervised and supervised machine learning approaches to investigate how amygdala stimulation modulated hippocampal network activities during the encoding phase. Using a sliding window in time, we estimated the hippocampal dynamic functional network connectivity (dFNC) after stimulation and during sham trials, based on the covariance of local field potential recordings in 4 subregions of the hippocampus. We extracted different network states by combining the dFNC samples from 5 subjects and applying k-means clustering. Next, we used the between-state transition numbers as the latent features to classify between amygdala stimulation and sham trials across all subjects. By training a logistic regression model, we could differentiate stimulated from sham trials with 67% accuracy across all subjects. Using elastic net regularization as a feature selection method, we identified specific patterns of hippocampal network state transition in response to amygdala stimulation. These results offer a new approach to better understanding of the causal relationship between hippocampal network dynamics and memory-enhancing amygdala stimulation.


Assuntos
Tonsila do Cerebelo , Estimulação Encefálica Profunda , Animais , Hipocampo , Humanos , Memória
4.
Proc Natl Acad Sci U S A ; 117(37): 22962-22966, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32868418

RESUMO

Gonadal hormones are linked to mechanisms that govern appetitive behavior and its suppression. Estrogens are synthesized from androgens by the enzyme aromatase, highly expressed in the ovaries of reproductive-aged women and in the brains of men and women of all ages. We measured aromatase availability in the amygdala using positron emission tomography (PET) with the aromatase inhibitor [11C]vorozole in a sample of 43 adult, normal-weight, overweight, or obese men and women. A subsample of 27 also completed personality measures to examine the relationship between aromatase and personality traits related to self-regulation and inhibitory control. Results indicated that aromatase availability in the amygdala was negatively associated with body mass index (BMI) (in kilograms per square meter) and positively correlated with scores of the personality trait constraint independent of sex or age. Individual variations in the brain's capacity to synthesize estrogen may influence the risk of obesity and self-control in men and women.


Assuntos
Apetite/fisiologia , Estrogênios/metabolismo , Obesidade/metabolismo , Adulto , Idoso , Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/metabolismo , Androgênios , Aromatase/análise , Inibidores da Aromatase , Índice de Massa Corporal , Encéfalo/metabolismo , Estrogênios/fisiologia , Feminino , Humanos , Lipogênese , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons/métodos , Autocontrole
5.
J Vis Exp ; (162)2020 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-32925887

RESUMO

In vivo real-time monitoring of neuronal activities in freely moving animals is one of key approaches to link neuronal activity to behavior. For this purpose, an in vivo imaging technique that detects calcium transients in neurons using genetically encoded calcium indicators (GECIs), a miniaturized fluorescence microscope, and a gradient refractive index (GRIN) lens has been developed and successfully applied to many brain structures1 , 2 , 3 , 4 , 5 , 6. This imaging technique is particularly powerful because it enables chronic simultaneous imaging of genetically defined cell populations for a long-term period up to several weeks. Although useful, this imaging technique has not been easily applied to brain structures that locate deep within the brain such as amygdala, an essential brain structure for emotional processing and associative fear memory7. There are several factors that make it difficult to apply the imaging technique to the amygdala. For instance, motion artifacts usually occur more frequently during the imaging conducted in the deeper brain regions because a head-mount microscope implanted deep in the brain is relatively unstable. Another problem is that the lateral ventricle is positioned close to the implanted GRIN lens and its movement during respiration may cause highly irregular motion artifacts that cannot be easily corrected, which makes it difficult to form a stable imaging view. Furthermore, because cells in the amygdala are usually quiet at a resting or anesthetized state, it is hard to find and focus the target cells expressing GECI in the amygdala during baseplating procedure for later imaging. This protocol provides a helpful guideline for how to efficiently target cells expressing GECI in the amygdala with head-mount miniaturized microscope for successful in vivo calcium imaging in such a deeper brain region. It is noted that this protocol is based on a particular system (e.g., Inscopix) but not restricted to it.


Assuntos
Tonsila do Cerebelo/diagnóstico por imagem , Comportamento Animal/fisiologia , Cálcio/metabolismo , Microscopia/instrumentação , Miniaturização/instrumentação , Estimulação Acústica , Animais , Artefatos , Proteínas de Ligação ao Cálcio/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Cabeça , Lentes , Camundongos Endogâmicos C57BL , Movimento , Neuroimagem , Neurônios/metabolismo , Refratometria , Reprodutibilidade dos Testes , Técnicas Estereotáxicas
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.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 36(2): 138-142, 2020 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-32744007

RESUMO

Objective: To investigate the effects of butylphthalide (NBP) on learning and memory related ability, hydrogen sulfide (H2S) content in hippocampus and amygdala, cystathionine-ß-synthase (CBS) expression and mitochondrial ATPase activity in rats with chronic alcoholism. Methods: Ninety SD male rats were randomly divided into three groups: normal control group (NC), model group (M) and butylphthalide remedy group (BR). Except for the control group, the water solution containing 6% (v/v) alcohol was used as the sole source of drinking water in the other two groups. After 14 days of feeding, the butylphthalide remedy group was injected with NBP intraperitoneally at the dose of 5 mg/kg once a day for 14 consecutive days, and the remaining two groups were injected with the same dose of normal saline. The control group subsequently used the Morris water maze method to observe and record the animals after entering the water. The time required for the underwater platform, their strategies and their swimming trajectories could analyze and infer the animal's ability to learn and remember. H2S concentration, CBS expression and mitochondrial ATPase activity in hippocampus and amygdale were dectected. Results: Compared with NC group, the latency period and swimming distance of M group were increased, the content of H2S and the mean optical density of CBS in hippocampus and amygdala were increased, and the activity of mitochondrial ATPase in hippocampus and amygdala was decreased significantly (P<0. 01) . Compared with the M group, the latency period and swimming distance of learning and memory performance of BR group were decreased, the content of H2S and the mean optical density of CBS in hippocampus and amygdala were decreased, and the activity of mitochondrial ATPase in hippocampus and amygdala was increased significantly (P<0. 01) . Conclusion: NBP can alleviate the effect of ethanol on learning and memory in rats, which may be related to the effect of NBP on the concentration of H2S and the expression of CBS in the amygdala of hippocampus and the increase of ATPase activity.


Assuntos
Alcoolismo , Tonsila do Cerebelo/efeitos dos fármacos , Benzofuranos/farmacologia , Cistationina beta-Sintase/metabolismo , Hipocampo/efeitos dos fármacos , Sulfeto de Hidrogênio/metabolismo , Animais , Aprendizagem , Masculino , Memória , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
8.
Proc Natl Acad Sci U S A ; 117(34): 20868-20873, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32764147

RESUMO

Adaptive social behavior and mental well-being depend on not only recognizing emotional expressions but also, inferring the absence of emotion. While the neurobiology underwriting the perception of emotions is well studied, the mechanisms for detecting a lack of emotional content in social signals remain largely unknown. Here, using cutting-edge analyses of effective brain connectivity, we uncover the brain networks differentiating neutral and emotional body language. The data indicate greater activation of the right amygdala and midline cerebellar vermis to nonemotional as opposed to emotional body language. Most important, the effective connectivity between the amygdala and insula predicts people's ability to recognize the absence of emotion. These conclusions extend substantially current concepts of emotion perception by suggesting engagement of limbic effective connectivity in recognizing the lack of emotion in body language reading. Furthermore, the outcome may advance the understanding of overly emotional interpretation of social signals in depression or schizophrenia by providing the missing link between body language reading and limbic pathways. The study thus opens an avenue for multidisciplinary research on social cognition and the underlying cerebrocerebellar networks, ranging from animal models to patients with neuropsychiatric conditions.


Assuntos
Emoções/fisiologia , Cinésica , Transtornos Mentais/fisiopatologia , Adulto , Tonsila do Cerebelo/fisiologia , Encéfalo/fisiologia , Mapeamento Encefálico/métodos , Córtex Cerebral/fisiologia , Expressão Facial , Humanos , Imagem por Ressonância Magnética/métodos , Masculino , Vias Neurais/fisiologia , Estimulação Luminosa/métodos
10.
Adv Exp Med Biol ; 1284: 43-48, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32852739

RESUMO

Social behavior is a complex behavior that requires processing of sensory cues and integration of internal states. Social interaction involves two or more individuals to approach each other and engage communications. Although sensory, motivational, emotional, or reward cues may all play roles in directing the sociability and social preference during social interaction, how neural activities from different brain regions are modulated during the behavioral process of social interaction are only beginning to be studied. Multiple brain regions including prefrontal cortex, hippocampus, and amygdala contain active neurons during social interaction. This review examines the neural responses in behaving rodents during social behavior and discusses how manipulation of specific neural pathways can modulate social behavior. Neural activities during social interaction provide direct measurements about how social information is coded and are beneficial in understanding the neural mechanisms underlying social behavior.


Assuntos
Neurônios/fisiologia , Comportamento Social , Tonsila do Cerebelo/citologia , Tonsila do Cerebelo/fisiologia , Animais , Modelos Animais , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/fisiologia , Recompensa
11.
Neuron ; 107(4): 597-599, 2020 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-32818473

RESUMO

Many brain areas represent aspects of learned behavior. How do representations differ between regions? In this issue of Neuron, Kyriazi et al. (2020) show how the amygdala and prefrontal cortex use distinct strategies to code features of a complex task.


Assuntos
Tonsila do Cerebelo , Córtex Pré-Frontal , Encéfalo , Neurônios
12.
Nat Neurosci ; 23(9): 1111-1124, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32719562

RESUMO

Sexual and aggressive behaviors are fundamental to animal survival and reproduction. The medial preoptic nucleus (MPN) and ventrolateral part of the ventromedial hypothalamus (VMHvl) are essential regions for male sexual and aggressive behaviors, respectively. While key inhibitory inputs to the VMHvl and MPN have been identified, the extrahypothalamic excitatory inputs essential for social behaviors remain elusive. Here we identify estrogen receptor alpha (Esr1)-expressing cells in the posterior amygdala (PA) as a main source of excitatory inputs to the hypothalamus and key mediators for mating and fighting in male mice. We find two largely distinct PA subpopulations that differ in connectivity, gene expression, in vivo responses and social behavior relevance. MPN-projecting PAEsr1+ cells are activated during mating and are necessary and sufficient for male sexual behaviors, while VMHvl-projecting PAEsr1+ cells are excited during intermale aggression and promote attacks. These findings place the PA as a key node in both male aggression and reproduction circuits.


Assuntos
Agressão/fisiologia , Tonsila do Cerebelo/fisiologia , Vias Neurais/fisiologia , Comportamento Sexual Animal/fisiologia , Tonsila do Cerebelo/citologia , Animais , Hipotálamo/citologia , Hipotálamo/fisiologia , Masculino , Camundongos , Vias Neurais/citologia , Neurônios/citologia , Neurônios/fisiologia
13.
J Pharmacol Sci ; 144(1): 57-59, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32624301

RESUMO

Some psychiatric diseases are associated with disruptions in the circadian clock system. Ziprasidone (ZIP), a second-generation antipsychotic, is widely used for psychiatry-related pharmacotherapy but its mechanism has not been clearly elucidated. We measured clock gene fluctuation patterns in the hippocampus and the amygdala in ZIP-treated mice. ZIP significantly increased Per1, Per2, and Bmal1 mRNA 2 h after the lights were turned off (ZT14) in the hippocampus, but not in the amygdala. These results suggest that ZIP might affect clock gene regulation, which could represent the pathway underlying symptom amelioration.


Assuntos
Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Antipsicóticos/farmacologia , Relógios Biológicos/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Expressão Gênica/efeitos dos fármacos , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Piperazinas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Tiazóis/farmacologia , Tonsila do Cerebelo/metabolismo , Animais , Hipocampo/metabolismo , Luz , Masculino , Camundongos Endogâmicos C57BL
14.
Neuron ; 107(6): 1113-1123.e4, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32679036

RESUMO

Disrupting memories that associate environmental cues with drug experiences holds promise for treating addiction, yet accessing the distributed neural network that stores such memories is challenging. Here, we show that the paraventricular nucleus of the thalamus (PVT) orchestrates the acquisition and maintenance of opiate-associated memories via projections to the central nucleus of the amygdala (CeA) and nucleus accumbens (NAc). PVT→CeA activity associates morphine reward to the environment, whereas transient inhibition of the PVT→NAc pathway during retrieval causes enduring protection against opiate-primed relapse. Using brain-wide activity mapping, we revealed distributed network activities that are altered in non-relapsing mice, which enabled us to find that activating the downstream NAc→lateral hypothalamus (LH) pathway also prevents relapse. These findings establish the PVT as a key node in the opiate-associated memory network and demonstrate the potential of targeting the PVT→NAc→LH pathway for treating opioid addiction.


Assuntos
Tonsila do Cerebelo/fisiopatologia , Núcleo Accumbens/fisiopatologia , Transtornos Relacionados ao Uso de Opioides/fisiopatologia , Núcleo Hipotalâmico Paraventricular/fisiopatologia , Priming de Repetição , Animais , Sinais (Psicologia) , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Vias Neurais/fisiopatologia
15.
Neuron ; 107(5): 909-923.e6, 2020 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-32649865

RESUMO

The parabrachial nucleus (PBN) is one of the major targets of spinal projection neurons and plays important roles in pain. However, the architecture of the spinoparabrachial pathway underlying its functional role in nociceptive information processing remains elusive. Here, we report that the PBN directly relays nociceptive signals from the spinal cord to the intralaminar thalamic nuclei (ILN). We demonstrate that the spinal cord connects with the PBN in a bilateral manner and that the ipsilateral spinoparabrachial pathway is critical for nocifensive behavior. We identify Tacr1-expressing neurons as the major neuronal subtype in the PBN that receives direct spinal input and show that these neurons are critical for processing nociceptive information. Furthermore, PBN neurons receiving spinal input form functional monosynaptic excitatory connections with neurons in the ILN, but not the amygdala. Together, our results delineate the neural circuit underlying nocifensive behavior, providing crucial insight into the circuit mechanism underlying nociceptive information processing.


Assuntos
Vias Aferentes , Lateralidade Funcional/fisiologia , Núcleos Intralaminares do Tálamo , Nociceptividade/fisiologia , Núcleos Parabraquiais , Vias Aferentes/citologia , Vias Aferentes/fisiologia , Tonsila do Cerebelo , Animais , Núcleos Intralaminares do Tálamo/citologia , Núcleos Intralaminares do Tálamo/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neurônios/citologia , Neurônios/fisiologia , Núcleos Parabraquiais/citologia , Núcleos Parabraquiais/fisiologia , Medula Espinal/citologia , Medula Espinal/fisiologia
16.
Mol Pharmacol ; 98(4): 454-461, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32606204

RESUMO

Endogenous opioid peptides in the amygdala regulate many of our behaviors and emotional responses. In particular, the endogenous opioid enkephalin plays a significant role in regulating amygdala activity, but its action is strongly limited by peptidases, which degrade enkephalin into inactive fragments. Inhibiting peptidases may be an attractive method to enhance endogenous opioid signaling; however, we do not know which specific peptidase(s) to target. Using inhibition of glutamate release onto the intercalated cells of the amygdala as an assay for enkephalin activity, we applied specific peptidase inhibitors to determine which peptidase(s) regulate enkephalin signaling in this region. Thiorphan (10 µM), captopril (1 µM), or bestatin (10 µM) were used to inhibit the activity of neprilysin, angiotensin-converting enzyme, or aminopeptidase N, respectively. In rat brain slices containing the intercalated cells, we found that inhibition of glutamate release by a submaximal concentration of enkephalin was doubled by application of all three peptidase inhibitors combined. Then, we tested inhibitors individually and found that inhibition of neprilysin alone could enhance enkephalin responses to the same extent as inhibitors of all three peptidases combined. This indicates neprilysin is the predominant peptidase responsible for degrading enkephalins in the intercalated cells of the amygdala. This differs from the striatum, locus coeruleus, and spinal cord, where multiple peptidases metabolize enkephalin. These data highlight the importance of knowing which specific peptidase(s) control opioid actions in the relevant neural circuit and how they change in disease states to allow rational choices of drugs targeting the specific peptidase of interest. SIGNIFICANCE STATEMENT: Endogenous opioids modulate many of our emotional and behavioral responses. In the amygdala, they modulate our pain, fear, and addictive behaviors. Their actions are terminated when they are catabolized into inactive fragments by at least three different peptidases. In this study, we found that neprilysin selectively controls endogenous opioid concentrations at synapses in the intercalated cells of the amygdala. This peptidase may be a target for regulation of endogenous opioid modulation of amygdala-mediated emotional and behavioral responses.


Assuntos
Tonsila do Cerebelo/metabolismo , Encefalinas/metabolismo , Neprilisina/metabolismo , Inibidores de Proteases/farmacologia , Animais , Captopril/farmacologia , Sinapses Elétricas/efeitos dos fármacos , Sinapses Elétricas/metabolismo , Ácido Glutâmico/metabolismo , Leucina/análogos & derivados , Leucina/farmacologia , Masculino , Neprilisina/antagonistas & inibidores , Proteólise/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Tiorfano/farmacologia
17.
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
18.
Proc Natl Acad Sci U S A ; 117(28): 16475-16480, 2020 07 14.
Artigo em Inglês | MEDLINE | ID: mdl-32601180

RESUMO

Autism spectrum disorder (ASD) is characterized by impaired social interactions and communication. The pathogenesis of ASD is not known, but it involves activation of microglia. We had shown that the peptide neurotensin (NT) is increased in the serum of children with ASD and stimulates cultured adult human microglia to secrete the proinflammatory molecules IL-1ß and CXCL8. This process is inhibited by the cytokine IL-37. Another cytokine, IL-38, has been reported to have antiinflammatory actions. In this report, we show that pretreatment of cultured adult human microglia with recombinant IL-38 (aa3-152, 1-100 ng/mL) inhibits (P < 0.0001) NT-stimulated (10 nM) secretion of IL-1ß (at 1 ng/mL) and CXCL8 (at 100 ng/mL). In fact, IL-38 (aa3-152, 1 ng/mL) is more potent than IL-37 (100 ng/mL). Here, we report that pretreatment with IL-38 (100 ng/mL) of embryonic microglia (HMC3), in which secretion of IL-1ß was undetectable, inhibits secretion of CXCL8 (P = 0.004). Gene expression of IL-38 and its receptor IL-36R are decreased (P = 0.001 and P = 0.04, respectively) in amygdala from patients with ASD (n = 8) compared to non-ASD controls (n = 8), obtained from the University of Maryland NeuroBioBank. IL-38 is increased (P = 0.03) in the serum of children with ASD. These findings indicate an important role for IL-38 in the inhibition of activation of human microglia, thus supporting its development as a treatment approach for ASD.


Assuntos
Tonsila do Cerebelo/imunologia , Transtorno do Espectro Autista/imunologia , Interleucinas/imunologia , Microglia/imunologia , Adolescente , Transtorno do Espectro Autista/sangue , Células Cultivadas , Criança , Pré-Escolar , Humanos , Interleucina-16/sangue , Interleucina-16/imunologia , Interleucina-1beta/sangue , Interleucina-1beta/imunologia , Interleucina-8/imunologia , Interleucinas/sangue , Masculino , Neurotensina/sangue , Neurotensina/imunologia
19.
Zhen Ci Yan Jiu ; 45(7): 517-23, 2020 Jul 25.
Artigo em Chinês | MEDLINE | ID: mdl-32705823

RESUMO

OBJECTIVE: To observe the effect of electroacupuncture (EA) on the expression of cAMP-response element binding protein (CREB, a key protein for BDNF-TrkB signaling) and it's blinding ability to synaptic key protein in the amygdala and hippocampus of rats with post-traumatic stress disorder (PTSD), so as to lay a foundation for further study of the interaction mechanism between BDNF-TrkB signaling and synaptic plasticity. METHODS: Twenty-four male SD rats were randomly divided into blank, model and electroacupuncture (EA) groups, with 8 rats in each group. The PTSD model was established by psychological stress (bondage) and physiological stress (forced swimming and anesthesia). After modeling, EA (2 Hz/100 Hz, 1 mA) was applied to "Baihui"(GV20) "Shenting"(GB24) and bilateral "Shenshu"(BL23) for 20 min, once daily for 21 days. The behavioral changes (spontaneous locomotor within 30 min and contextual fear conditioning tests in 7 days) were detected by using a spontaneous locomotor detection box, and a conditioned fear response test chamber, respectively. The expression of CREB was detected by immunohistochemistry and Western blot, separately. The binding abilities of CREB to synaptic proteins (post synaptic density 95 [PSD95], synaptophysin [SYN] and growth-associated protein 43 [GAP43]) were verified by chromatin-immunoprecipitation (CHIP) technique. RESULTS: After modeling, the spontaneous locomotor distance, the expression levels of CREB and the binding ability of CREB to PSD95 protein in the amygdala and hippocampus were significantly decreased (P<0.01), and the percentage of freezing time significantly increased in the model group relevant to the blank group (P<0.01). Following the intervention, the spontaneous locomotor distance, and the expression levels of CREB and the binding ability of CREB to PSD95 protein were considerably increased in the EA group relevant to the model group (P<0.05,P<0.01). No significant changes were found in the binding abilities of CREB to SYN and GAP43 after modeling and after EA intervention (P>0.05). CONCLUSION: EA can improve the motor activity in PTSD rats, which may be associated with its effect in increasing the binding ability of CREB to the synaptic key protein PSD95 to regulate the interaction between the synaptic plasticity and BDNF-TrkB signaling pathway of the amygdala and hippocampus.


Assuntos
Eletroacupuntura , Transtornos de Estresse Pós-Traumáticos , Tonsila do Cerebelo , Animais , Proteína de Ligação a CREB , Hipocampo , Masculino , Ratos , Ratos Sprague-Dawley
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