RESUMEN
The paraventricular nucleus of the thalamus (PVT) sends dense projections to the shell of the nucleus accumbens (NAcSh), dorsolateral region of the bed nucleus of the stria terminalis (BSTDL) and the lateral region of central nucleus of the amygdala (CeL). Projection specific modulation of these pathways has been shown to regulate appetitive and aversive behavioral responses. The present investigation applied an intersectional monosynaptic rabies tracing approach to quantify the brain-wide sources of afferent input to PVT neurons that primarily project to the NAcSh, BSTDL and CeL. The results demonstrate that these projection neurons receive monosynaptic input from similar brain regions. The prefrontal cortex and the ventral subiculum of the hippocampus were major sources of input to the PVT projection neurons. In addition, the lateral septal nucleus, thalamic reticular nucleus and the hypothalamic medial preoptic area, dorsomedial, ventromedial, and arcuate nuclei were sources of input. The subfornical organ, parasubthalamic nucleus, periaqueductal gray matter, lateral parabrachial nucleus, and nucleus of the solitary tract were consistent but lesser sources of input. This input-output relationship is consistent with recent observations that PVT neurons have axons that bifurcate extensively to divergently innervate the NAcSh, BSTDL and CeL.
Asunto(s)
Núcleo Amigdalino Central , Núcleo Accumbens , Núcleo Hipotalámico Paraventricular , Hipotálamo , Neuronas , Vías Nerviosas/fisiologíaRESUMEN
As yawning is often observed in stressful or emotional situations such as tension and anxiety, this suggests that yawning can be considered to be an emotional behavior. However, the neural mechanisms underlying emotion-induced yawning remain unclear. It is well known that the hypothalamic paraventricular nucleus (PVN) is the most important brain structure for induction of yawning behavior. We previously showed that induction of yawning involves the central nucleus of the amygdala (CeA), as well as the PVN. Therefore, emotion-induced yawning could potentially be induced through activation of the direct/indirect neural pathways from the CeA to the PVN. Our present study used a combination of retrograde tracing (injection of Fluoro-Gold (FG) into the PVN) and c-Fos immunohistochemistry to examine the neural pathways that evoke emotion-induced yawning. We additionally performed lesion experiments on the CeA using ibotenic acid, a neurotoxin, to determine whether the CeA is involved in the induction of emotion-induced yawning. Emotional stress by fear conditioning induced yawning behavior, and induced expression of double-labeled cells for c-Fos and FG in the bed nucleus of the stria terminalis (BNST), but not in the CeA. Furthermore, the CeA lesions caused by ibotenic acid abolished the induction of emotion-induced yawning. These results suggest that a neural pathway from the CeA to the PVN via the BNST may be primarily involved in the induction of emotion-induced yawning behavior.
Asunto(s)
Núcleo Amigdalino Central , Distrés Psicológico , Bostezo , Animales , Núcleo Amigdalino Central/metabolismo , Hipotálamo/metabolismo , Ácido Iboténico/farmacología , Vías Nerviosas/metabolismo , Neurotoxinas/farmacología , Núcleo Hipotalámico Paraventricular/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Estilbamidinas , Bostezo/fisiologíaRESUMEN
Heightened wakefulness in response to stressors is essential for survival but can also lead to sleep disorders like insomnia. The paraventricular thalamus (PVT) is both a critical thalamic area for wakefulness and a stress-sensitive brain region. However, whether the PVT and its neural circuitries are involved in controlling wakefulness in stress conditions remains unknown. Here, we find that PVT neurons projecting to the central amygdala (CeA) are activated by different stressors. These neurons are wakefulness-active and increase their activities upon sleep to wakefulness transitions. Optogenetic activation of the PVT-CeA circuit evokes transitions from sleep to wakefulness, whereas selectively silencing the activity of this circuit decreases time spent in wakefulness. Specifically, chemogenetic inhibition of CeA-projecting PVT neurons not only alleviates stress responses but also attenuates the acute stress-induced increase of wakefulness. Thus, our results demonstrate that the PVT-CeA circuit controls physiological wakefulness and modulates acute stress-induced heightened wakefulness.
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Núcleo Amigdalino Central , Vigilia , Tálamo/fisiología , Optogenética , Neuronas/fisiología , Vías Nerviosas/fisiologíaRESUMEN
Perception of threats is essential for survival. Previous findings suggest that parallel pathways independently relay innate threat signals from different sensory modalities to multiple brain areas, such as the midbrain and hypothalamus, for immediate avoidance. Yet little is known about whether and how multi-sensory innate threat cues are integrated and conveyed from each sensory modality to the amygdala, a critical brain area for threat perception and learning. Here, we report that neurons expressing calcitonin gene-related peptide (CGRP) in the parvocellular subparafascicular nucleus in the thalamus and external lateral parabrachial nucleus in the brainstem respond to multi-sensory threat cues from various sensory modalities and relay negative valence to the lateral and central amygdala, respectively. Both CGRP populations and their amygdala projections are required for multi-sensory threat perception and aversive memory formation. The identification of unified innate threat pathways may provide insights into developing therapeutic candidates for innate fear-related disorders.
Asunto(s)
Núcleo Amigdalino Central , Núcleos Parabraquiales , Péptido Relacionado con Gen de Calcitonina/metabolismo , Núcleo Amigdalino Central/metabolismo , Señales (Psicología) , Núcleos Parabraquiales/metabolismo , Tálamo/metabolismoRESUMEN
Background: Orexin-A (OrxA) administration in the posterior paraventricular nucleus of the thalamus (pPVT) reinstates extinguished cocaine-seeking behaviour following extended access to the drug (a model of dependence). The pPVT receives and integrates information associated with emotionally salient events and sends excitatory inputs to brain regions involved in the expression of emotional states, such as those driving cocaine-seeking behaviour (i.e., the nucleus accumbens, the central nucleus of the amygdala [CeA], the basolateral amygdala, the bed nucleus of the stria terminalis [BNST] and the prefrontal cortex). Methods: We monitored the activation pattern of these regions (measured by Fos) during cocaine-seeking induced by OrxA administered to the pPVT. The BNST and CeA emerged as being selectively activated. To test whether the functionality of these regions was pivotal during OrxA-induced cocaine-seeking behaviour, we transiently inactivated these regions concomitantly with OrxA administration to the pPVT. We then tested the participation of corticotropin-releasing factor receptors (CRF1) in the CeA during OrxA-induced cocaine-seeking using the CRF1 antagonist CP154526. Results: We observed selective activation of the CeA and BNST during cocaine-seeking induced by OrxA administered to the pPVT, but only transient inactivation of the CeA prevented cocaine-seeking behaviour. Administration of CP154526 to the CeA prevented OrxAinduced cocaine-seeking behaviour. Limitations: The use of only male rats could have been a limitation. Other limitations could have been the use of an indirect approach to test the hypothesis that administration of OrxA to the pPVT drives cocaine-seeking via CRF1 signalling in the CeA, and a lack of analysis of the participation of CeA subregions. Conclusion: Cocaine-seeking behaviour induced by OrxA administered to the pPVT is driven by activation of the CeA via CRF1 signalling.
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Núcleo Amigdalino Central/efectos de los fármacos , Trastornos Relacionados con Cocaína/prevención & control , Cocaína , Orexinas/farmacología , Núcleo Hipotalámico Paraventricular/efectos de los fármacos , Receptores de Hormona Liberadora de Corticotropina/antagonistas & inhibidores , Tálamo/efectos de los fármacos , Animales , Cocaína/farmacología , Masculino , Orexinas/administración & dosificación , RatasRESUMEN
Methamphetamine (METH) enhances dopamine (DA) transmission in the mesolimbic system implicated in its reinforcing effects. Our previous studies have shown that acupuncture attenuates drug-seeking behaviors by modulating GABAergic transmission in the ventral tegmental area and DA release in the nucleus accumbens (NAc) of the striatum. The effects of acupuncture on METH-induced behaviors and its mediation by neural pathways remain a relatively understudied area of research. The central amygdala (CeA) plays a critical role in physiological and behavioral responses to somatosensory and drug stimuli and has been implicated in negative reinforcement. Thus, we evaluated the role of the CeA in acupuncture effects on locomotor activity, positive affective states, and DA release in the NAc following acute administration of METH. Acupuncture at acupoint HT7 reduced locomotor activity, 50-kHz ultrasonic vocalizations (USVs), and NAc DA release following systemic injection of METH, which was prevented by electrolytic lesions or optogenetic inhibition of the CeA. Acupuncture alone excited CeA neurons and reversed the suppression of CeA neurons induced by METH. These results suggest that acupuncture can relieve psychomotor responses and positive affective states following METH by inhibiting NAc DA release and this effect is mediated by activation of CeA neurons.
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Terapia por Acupuntura , Núcleo Amigdalino Central/metabolismo , Comportamiento de Búsqueda de Drogas/fisiología , Metanfetamina/metabolismo , Animales , Estimulantes del Sistema Nervioso Central/metabolismo , Dopamina/metabolismo , Locomoción , Masculino , Neuronas/metabolismo , Núcleo Accumbens/metabolismo , Ratas , Ratas Sprague-Dawley , Refuerzo en Psicología , Área Tegmental Ventral/metabolismoRESUMEN
Pre-clinical and human neuroimaging research implicates the extended-amygdala (ExtA) (including the bed nucleus of the stria terminalis [BST] and central nucleus of the amygdala [CeA]) in networks mediating negative emotional states associated with stress and substance-use behaviours. The extent to which individual ExtA structures form a functionally integrated unit is controversial. We utilised a large sample (n > 1,000 healthy young adult humans) to compare the intrinsic functional connectivity networks (ICNs) of the BST and CeA using task-free functional magnetic resonance imaging (fMRI) data from the Human Connectome Project. We assessed whether inter-individual differences within these ICNs were related to two principal components representing negative disposition and alcohol use. Building on recent primate evidence, we tested whether within BST-CeA intrinsic functional connectivity (iFC) was heritable and further examined co-heritability with our principal components. We demonstrate the BST and CeA to have discrete, but largely overlapping ICNs similar to previous findings. We found no evidence that within BST-CeA iFC was heritable; however, post hoc analyses found significant BST iFC heritability with the broader superficial and centromedial amygdala regions. There were no significant correlations or co-heritability associations with our principal components either across the ICNs or for specific BST-Amygdala iFC. Possible differences in phenotype associations across task-free, task-based, and clinical fMRI are discussed, along with suggestions for more causal investigative paradigms that make use of the now well-established ExtA ICNs.
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Núcleo Amigdalino Central/fisiología , Conectoma/métodos , Red Nerviosa/fisiología , Núcleos Septales/fisiología , Adulto , Núcleo Amigdalino Central/diagnóstico por imagen , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/fisiología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Herencia Multifactorial/fisiología , Red Nerviosa/diagnóstico por imagen , Linaje , Núcleos Septales/diagnóstico por imagen , Tálamo/diagnóstico por imagen , Tálamo/fisiologíaRESUMEN
The paraventricular nucleus of the thalamus (PVT), which serves as a hub, receives dense projections from the medial prefrontal cortex (mPFC) and projects to the lateral division of central amygdala (CeL). The infralimbic (IL) cortex plays a crucial role in encoding and recalling fear extinction memory. Here, we found that neurons in the PVT and IL were strongly activated during fear extinction retrieval. Silencing PVT neurons inhibited extinction retrieval at recent time point (24 h after extinction), while activating them promoted extinction retrieval at remote time point (7 d after extinction), suggesting a critical role of the PVT in extinction retrieval. In the mPFC-PVT circuit, projections from IL rather than prelimbic cortex to the PVT were dominant, and disrupting the IL-PVT projection suppressed extinction retrieval. Moreover, the axons of PVT neurons preferentially projected to the CeL. Silencing the PVT-CeL circuit also suppressed extinction retrieval. Together, our findings reveal a new neural circuit for fear extinction retrieval outside the classical IL-amygdala circuit.
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Núcleo Amigdalino Central , Miedo , Extinción Psicológica , Corteza Prefrontal , TálamoRESUMEN
The insular cortex (INS) is extensively connected to the central nucleus of the amygdala (CEA), and both regions send convergent projections into the caudal lateral hypothalamus (LHA) encompassing the parasubthalamic nucleus (PSTN). However, the organization of the network between these structures has not been clearly delineated in the literature, although there has been an upsurge in functional studies related to these structures, especially with regard to the cognitive and psychopathological control of feeding. We conducted tract-tracing experiments from the INS and observed a pathway to the PSTN region that runs parallel to the canonical hyperdirect pathway from the isocortex to the subthalamic nucleus (STN) adjacent to the PSTN. In addition, an indirect pathway with a relay in the central amygdala was also observed that is similar in its structure to the classic indirect pathway of the basal ganglia that also targets the STN. C-Fos experiments showed that the PSTN complex reacts to neophobia and sickness induced by lipopolysaccharide or cisplatin. Chemogenetic (designer receptors exclusively activated by designer drugs [DREADD]) inhibition of tachykininergic neurons (Tac1) in the PSTN revealed that this nucleus gates a stop "no-eat" signal to refrain from feeding when the animal is subjected to sickness or exposed to a previously unknown source of food. Therefore, our anatomical findings in rats and mice indicate that the INS-PSTN network is organized in a similar manner as the hyperdirect and indirect basal ganglia circuitry. Functionally, the PSTN is involved in gating feeding behavior, which is conceptually homologous to the motor no-go response of the adjacent STN.
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Ganglios Basales/fisiología , Corteza Cerebral/patología , Conducta Alimentaria/fisiología , Hipotálamo/fisiología , Corteza Olfatoria/fisiología , Animales , Conducta Animal , Núcleo Amigdalino Central , Masculino , Ratones , Modelos Animales , Vías Nerviosas/fisiología , Neuronas/metabolismo , Ratas , Ratas Sprague-Dawley , Núcleo SubtalámicoRESUMEN
OBJECTIVE: To explore the effect of γ-aminobutyric acid (GABA)ergic neuronal circuit of the central amygdaloid nucleus (CeA) and the paraventricular nucleus of hypothalamus (PVN) on electroacupuncture (EA)-induced regulation of gastric function by way of CeA-PVN projection. METHODS: The present study included 3 parts: 1) C57BL/6 mice were randomly divided into control and EA groups (n=6 in each group). EA was applied to right "Weishu"(BL21, Back-shu point) and "Zhongwan"(CV12, Front-mu point) for 20 min, followed by detecting the expression of c-fos in the CeA and PVN by using immunofluorescence staining; 2) Microinjection of anterograde tracer (rAAV-EF1α-DIO-mcherry-WPRE-pA) into the CeA was conducted in GAD2-Cre mice for confirming the projection of GABAergic neurons from CeA to PVN; 3) GAD2-Cre mice were randomly divided into rAAV-DIO-mcherry (intra-CeA injection of rAAV-EF1α-DIO-mcherry-WPRE-pA), rAAV-DIO-hM3Dï¼Gqï¼-mcherry(intra-CeA injection of rAAV-EF1α-DIO-hM3D(Gq)-mcherry-WPRE-pA) and rAAV-DIO-hM3Dï¼Gqï¼-mcherry+EA groups(n=6 in each group). The food intake and gastric empty were detected, and the concentration of GABA in the PVN was assayed by using high performance liquid chromatography on the 28th day after intra-CeA injection. RESULTS: 1) The expression of c-fos in the CeA and PVN was significantly increased in the EA group relevant to the control group(P<0.01), suggesting an activation of neurons in both CeA and PVN after EA. 2) Following CeA injection of rAAV-EF1α-DIO-mcherry-WPRE-pA, the densely expressed virus GABAergic neurons were found in CeA and large number of projection fibers found in the PVN, suggesting a direct connection between CeA and PVN. 3) After activating the GABAergic neurons of CeA, the concentration of GABA in the PVN was obviously increased (P<0.01), the food intake and the gastric empty were considerably decreased relevant to the rAAV-DIO-mcherry group(P<0.01). Following EA interventionï¼the concentration of GABA in the PVN was obviously decreased(P<0.01), the food intake and the gastric empty were significantly increased relevant to the rAAV-DIO-hM3Dï¼Gqï¼-mcherry group (P<0.01). CONCLUSION: EA of BL21 and CV12 (Back-shu and Front-mu acupoints) can increase food intake and gastric empty in GAD2-Cre mice, which may be achieved by suppressing the release of GABA in PVN through CeA-PVN GABAergic neural circuit.
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Núcleo Amigdalino Central , Electroacupuntura , Hipotálamo , Núcleo Hipotalámico Paraventricular , Animales , Integrasas , Ratones , Ratones Endogámicos C57BLRESUMEN
Increasing evidence suggests that long-term opioids and pain induce similar adaptive changes in the brain's reward circuits, however, how pain alters the addictive properties of opioids remains poorly understood. In this study using a rat model of morphine self-administration (MSA), we found that short-term pain, induced by an intraplantar injection of complete Freund's adjuvant (CFA), acutely decreased voluntary morphine intake, but not food intake, only at a morphine dose that did not affect pain itself. Pre-treatment with indomethacin, a non-opioid inhibitor of pain, before the pain induction blocked the decrease in morphine intake. In rats with steady MSA, the protein level of GluA1 subunits of glutamate AMPA receptors (AMPARs) was significantly increased, but that of GluA2 was decreased, resulting in an increased GluA1/GluA2 ratio in central nucleus of the amygdala (CeA). In contrast, pain decreased the GluA1/GluA2 ratio in the CeA of rats with MSA. Microinjection of NASPM, a selective inhibitor of homomeric GluA1-AMPARs, into CeA inhibited morphine intake. Furthermore, viral overexpression of GluA1 protein in CeA maintained morphine intake at a higher level than controls and reversed the pain-induced reduction in morphine intake. These findings suggest that CeA GluA1 promotes opioid use and its upregulation is sufficient to increase opioid consumption, which counteracts the acute inhibitory effect of pain on opioid intake. These results demonstrate that the CeA GluA1 is a shared target of opioid and pain in regulation of opioid use, which may aid in future development of therapeutic applications in opioid abuse.
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Analgésicos Opioides/farmacología , Núcleo Amigdalino Central/efectos de los fármacos , Dolor Crónico/tratamiento farmacológico , Morfina/farmacología , Receptores AMPA/efectos de los fármacos , Animales , Núcleo Amigdalino Central/metabolismo , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Ácido Glutámico/metabolismo , Masculino , Ratas Wistar , Receptores AMPA/metabolismo , Receptores de Glutamato/metabolismo , Recompensa , Regulación hacia Arriba/efectos de los fármacosRESUMEN
Survival relies on optimizing behavioral responses through experience. Animals often react to acute stress by switching to passive behavioral responses when coping with environmental challenge. Despite recent advances in dissecting mammalian circuitry for Pavlovian fear, the neuronal basis underlying this form of non-Pavlovian anxiety-related behavioral plasticity remains poorly understood. Here, we report that aversive experience recruits the posterior paraventricular thalamus (PVT) and corticotropin-releasing hormone (CRH) and sensitizes a Pavlovian fear circuit to promote passive responding. Site-specific lesions and optogenetic manipulations reveal that PVT-to-central amygdala (CE) projections activate anxiogenic neuronal populations in the CE that release local CRH in response to acute stress. CRH potentiates basolateral (BLA)-CE connectivity and antagonizes inhibitory gating of CE output, a mechanism linked to Pavlovian fear, to facilitate the switch from active to passive behavior. Thus, PVT-amygdala fear circuitry uses inhibitory gating in the CE as a shared dynamic motif, but relies on different cellular mechanisms (postsynaptic long-term potentiation vs. presynaptic facilitation), to multiplex active/passive response bias in Pavlovian and non-Pavlovian behavioral plasticity. These results establish a framework promoting stress-induced passive responding, which might contribute to passive emotional coping seen in human fear- and anxiety-related disorders.
Asunto(s)
Hormona Liberadora de Corticotropina/metabolismo , Miedo/fisiología , Estrés Psicológico/metabolismo , Adaptación Psicológica/fisiología , Afecto , Amígdala del Cerebelo/metabolismo , Animales , Ansiedad/metabolismo , Trastornos de Ansiedad/metabolismo , Núcleo Amigdalino Central/metabolismo , Emociones/fisiología , Humanos , Potenciación a Largo Plazo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Núcleos Talámicos de la Línea Media/fisiopatología , Neuronas/metabolismo , Tálamo/fisiopatologíaRESUMEN
High rates of relapse are a chronic and debilitating obstacle to effective treatment of alcohol use disorder (AUD); however, no effective treatments are available to treat symptoms induced by protracted abstinence. In the first part of this 2-part review series, we examine the literature supporting the effects of alcohol exposure within the extended amygdala (EA) neural circuitry. In Part 2, we focus on a potential way to combat negative affect associated with AUD, by exploring the therapeutic potential of the endogenous cannabinoid (eCB) system. The eCB system is a potent modulator of neural activity in the brain, and its ability to mitigate stress and negative affect has long been an area of interest for developing novel therapeutics. This review details the recent advances in our understanding of eCB signaling in 2 key regions of the EA, the central nucleus of the amygdala and the bed nucleus of the stria terminalis (BNST), and their role in regulating negative affect. Despite an established role for EA eCB signaling in reducing negative affect, few studies have examined the potential for eCB-based therapies to treat AUD-associated negative affect. In this review, we present an overview of studies focusing on eCB signaling in EA and cannabinoid modulation on EA synaptic activity. We further discuss studies suggesting dysregulation of eCB signaling in models of AUD and propose that pharmacological augmentation of eCB could be a novel approach to treat aspects of AUD. Lastly, future directions are proposed to advance our understanding of the relationship between AUD-associated negative affect and the EA eCB system that could yield new pharmacotherapies targeting negative affective symptoms associated with AUD.
Asunto(s)
Alcoholismo/fisiopatología , Alcoholismo/terapia , Núcleo Amigdalino Central/fisiopatología , Endocannabinoides , Núcleos Septales/fisiopatología , Transducción de Señal , Animales , Depresión/inducido químicamente , Depresión/fisiopatología , Depresión/psicología , Humanos , Receptores de Cannabinoides/efectos de los fármacosRESUMEN
The amygdala plays a critical role in emotional-affective aspects of behaviors and pain modulation. The central nucleus of amygdala (CeA) serves major output functions, and neuroplasticity in the CeA is linked to pain-related behaviors in different models. Activation of Gi/o-coupled group II metabotropic glutamate receptors (mGluRs), which consist of mGluR2 and mGluR3, can decrease neurotransmitter release and regulate synaptic plasticity. Group II mGluRs have emerged as targets for neuropsychiatric disorders and can inhibit pain-related processing and behaviors. Surprisingly, site and mechanism of antinociceptive actions of systemically applied group II mGluR agonists are not clear. Our previous work showed that group II mGluR activation in the amygdala inhibits pain-related CeA activity, but behavioral and spinal consequences remain to be determined. Here we studied the contribution of group II mGluRs in the amygdala to the antinociceptive effects of a systemically applied group II mGluR agonist (LY379268) on behavior and spinal dorsal horn neuronal activity, using the kaolin/carrageenan-induced knee joint arthritis pain model. Audible and ultrasonic vocalizations (emotional responses) and mechanical reflex thresholds were measured in adult rats with and without arthritis (5-6â¯h postinduction). Extracellular single-unit recordings were made from spinal dorsal horn wide dynamic range neurons of anesthetized (isoflurane) rats with and without arthritis (5-6â¯h postinduction). Systemic (intraperitoneal) application of a group II mGluR agonist (LY379268) decreased behaviors and activity of spinal neurons in the arthritis pain model but not under normal conditions. Stereotaxic administration of LY379268 into the CeA mimicked the effects of systemic application. Conversely, stereotaxic administration of a group II mGluR antagonist (LY341495) into the CeA reversed the effects of systemic application of LY379268 on behaviors and dorsal horn neuronal activity in arthritic rats. The data show for the first time that the amygdala is the critical site of action for the antinociceptive behavioral and spinal neuronal effects of systemically applied group II mGluR agonists.
Asunto(s)
Aminoácidos/farmacología , Artritis Experimental , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Núcleo Amigdalino Central/efectos de los fármacos , Agonistas de Aminoácidos Excitadores/farmacología , Nocicepción/efectos de los fármacos , Células del Asta Posterior/efectos de los fármacos , Receptores de Glutamato Metabotrópico/agonistas , Amígdala del Cerebelo/efectos de los fármacos , Animales , Artralgia , Conducta Animal/efectos de los fármacos , Carragenina , Antagonistas de Aminoácidos Excitadores/farmacología , Caolín , Dolor/metabolismo , Ratas , Receptores de Glutamato Metabotrópico/metabolismo , Médula Espinal/citología , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Vocalización Animal/efectos de los fármacos , Xantenos/farmacologíaRESUMEN
BACKGROUND: Ethanol withdrawal (EtOHW) anxiety is a crucial risk factor for alcoholic relapse. The neuropeptide nociceptin/orphanin FQ (N/OFQ) acts upon its receptor (NOP) to antagonize corticotropin-releasing factor (CRF) and elicit anxiolytic actions. Semen Ziziphi Spinosae (SZS), a prototypical hypnotic-sedative herb in Oriental medicine, exhibits anxiolytic effects during nicotine withdrawal by improving amygdaloid CRF/CRF1 receptor (CRFR1) signaling. Therefore, we evaluated the effects of SZS on EtOHW anxiety and the involvement of amygdaloid CRF/CRFR1 and N/OFQ/NOP pathways. METHODS: Male Sprague Dawley rats received intraperitoneal injections of 2 g/kg EtOH (20% v/v) once daily for 28 d followed by a 3-d withdrawal. During EtOHW, the rats were given once-daily intragastric treatments of a methanol extract of SZS (MESZS, 60 or 180 mg/kg/d). Anxiety-like behaviors were measured with the open field (OF) and elevated plus maze (EPM) tests, and plasma corticosterone (CORT) levels were examined by an enzyme-linked immunosorbent assay. mRNA and protein expression levels of the neuropeptides and their receptors were determined by quantitative polymerase chain reaction and Western blot assays. RESULTS: MESZS increased the distance traveled in the center zone of the OF and dose-dependently elongated the duration of staying in the center zone in EtOHW rats. MESZS increased both the number of entries into and the time spent in the open arms of the EPM by EtOHW rats. And, MESZS inhibited the over secretion of plasma CORT during EtOHW. EtOHW enhanced CRF and CRFR1 gene and protein expression in the central nucleus of the amygdala (CeA), which were inhibited by 180 mg/kg/d MESZS. EtOHW increased amygdaloid NOP mRNA and protein expression but spared N/OFQ mRNA expression, and 180 mg/kg/d MESZS further promoted these increases. Additionally, a post-MESZS intra-CeA infusion of either CRF or the selective NOP antagonist UFP-101 abolished the expected anxiolytic effect of 180 mg/kg/d MESZS. CONCLUSIONS: These results suggest that MESZS ameliorates EtOHW anxiety by improving both CRF/CRFR1 and N/OFQ/NOP transmissions in the CeA.
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Ansiolíticos/administración & dosificación , Ansiedad/tratamiento farmacológico , Núcleo Amigdalino Central/efectos de los fármacos , Etanol/efectos adversos , Neuropéptidos/metabolismo , Síndrome de Abstinencia a Sustancias/complicaciones , Ziziphus/química , Animales , Ansiedad/etiología , Ansiedad/genética , Ansiedad/metabolismo , Núcleo Amigdalino Central/metabolismo , Hormona Liberadora de Corticotropina/metabolismo , Humanos , Masculino , Ratas , Ratas Sprague-Dawley , Receptores de Hormona Liberadora de Corticotropina/genética , Receptores de Hormona Liberadora de Corticotropina/metabolismoRESUMEN
Threat processing is central to understanding debilitating fear- and trauma-related disorders such as posttraumatic stress disorder (PTSD). Progress has been made in understanding the neural circuits underlying the "engram" of threat or fear memory formation that complements a decades-old appreciation of the neurobiology of fear and threat involving hub structures such as the amygdala. In this review, we examine key recent findings, as well as integrate the importance of hormonal and physiological approaches, to provide a broader perspective of how bodily systems engaged in threat responses may interact with amygdala-based circuits in the encoding and updating of threat-related memory. Understanding how trauma-related memories are encoded and updated throughout the brain and the body will ultimately lead to novel biologically-driven approaches for treatment and prevention.
Asunto(s)
Encéfalo/fisiopatología , Miedo/fisiología , Memoria/fisiología , Trauma Psicológico/fisiopatología , Trastornos por Estrés Postraumático/fisiopatología , Estrés Psicológico/fisiopatología , Amígdala del Cerebelo/metabolismo , Amígdala del Cerebelo/fisiología , Amígdala del Cerebelo/fisiopatología , Encéfalo/metabolismo , Encéfalo/fisiología , Núcleo Amigdalino Central/fisiología , Núcleo Amigdalino Central/fisiopatología , Hormona Liberadora de Corticotropina/metabolismo , Miedo/psicología , Glucocorticoides/metabolismo , Hipocampo/metabolismo , Hipocampo/fisiología , Hipocampo/fisiopatología , Humanos , Hipotálamo/metabolismo , Hipotálamo/fisiología , Hipotálamo/fisiopatología , Interneuronas/metabolismo , Interneuronas/fisiología , Trauma Psicológico/metabolismo , Trauma Psicológico/psicología , Trastornos por Estrés Postraumático/metabolismo , Trastornos por Estrés Postraumático/psicología , Estrés Psicológico/metabolismo , Estrés Psicológico/psicología , Tálamo/metabolismo , Tálamo/fisiología , Tálamo/fisiopatologíaRESUMEN
Children with an extremely inhibited, anxious temperament (AT) are at increased risk for anxiety disorders and depression. Using a rhesus monkey model of early-life AT, we previously demonstrated that metabolism in the central extended amygdala (EAc), including the central nucleus of the amygdala (Ce) and bed nucleus of the stria terminalis (BST), is associated with trait-like variation in AT. Here, we use fMRI to examine relationships between Ce-BST functional connectivity and AT in a large multigenerational family pedigree of rhesus monkeys (n = 170 females and 208 males). Results demonstrate that Ce-BST functional connectivity is heritable, accounts for a significant but modest portion of the variance in AT, and is coheritable with AT. Interestingly, Ce-BST functional connectivity and AT-related BST metabolism were not correlated and accounted for non-overlapping variance in AT. Exploratory analyses suggest that Ce-BST functional connectivity is associated with metabolism in the hypothalamus and periaqueductal gray. Together, these results suggest the importance of coordinated function within the EAc for determining individual differences in AT and metabolism in brain regions associated with its behavioral and neuroendocrine components.SIGNIFICANCE STATEMENT Anxiety disorders directly impact the lives of nearly one in five people, accounting for substantial worldwide suffering and disability. Here, we use a nonhuman primate model of anxious temperament (AT) to understand the neurobiology underlying the early-life risk to develop anxiety disorders. Leveraging the same kinds of neuroimaging measures routinely used in human studies, we demonstrate that coordinated activation between the central nucleus of the amygdala and the bed nucleus of the stria terminalis is correlated with, and coinherited with, early-life AT. Understanding how these central extended amygdala regions work together to produce extreme anxiety provides a neural target for early-life interventions with the promise of preventing lifelong disability in at-risk children.
Asunto(s)
Ansiedad/genética , Núcleo Amigdalino Central/fisiología , Núcleos Septales/fisiología , Temperamento/fisiología , Edad de Inicio , Animales , Ansiedad/fisiopatología , Mapeo Encefálico , Núcleo Amigdalino Central/metabolismo , Conectoma , Femenino , Hipotálamo/metabolismo , Pérdida de Tono Postural , Macaca mulatta , Imagen por Resonancia Magnética , Masculino , Modelos Animales , Neuroimagen , Linaje , Sustancia Gris Periacueductal/metabolismo , Fenotipo , Tomografía de Emisión de Positrones , Núcleos Septales/metabolismoRESUMEN
Here we studied whether descending control of mechanical nociception by glutamate in the central nucleus of the amygdala (CeA) of healthy control animals is induced by amygdaloid NMDA receptors and relayed through the midbrain periaqueductal gray (PAG). Mechanical nociception in the hind paws was assessed in rats with chronic guide cannulae for glutamate administration in the right CeA and for inducing local anesthesia in the PAG. In a separate electrophysiological study, ON-like PAG neurons giving an excitatory response to noxious pinch of the tail were recorded in anesthetized rats following glutamate administration into the CeA. A high dose of glutamate (100 microg) in the CeA induced mechanical antinociception in the contra- but not ipsilateral hind limb. Antinociception was prevented by an NMDA receptor antagonist in the CeA or local anesthesia of the PAG. Discharge rate of ON-like PAG neurons was increased by a high dose of glutamate (100 microg) in the CeA and this increase was prevented by an NMDA receptor antagonist in the CeA. The results indicate that amygdaloid NMDA receptors in the CeA may induce contralaterally mechanical antinociception through a circuitry relaying in the PAG. Activation of ON-like PAG neurons is associated with the descending antinociceptive effect. Mechanisms and causality of this association still remain to be studied.
Asunto(s)
Núcleo Amigdalino Central/fisiología , Red Nerviosa/fisiología , Dimensión del Dolor/métodos , Dolor/fisiopatología , Sustancia Gris Periacueductal/fisiología , Animales , Núcleo Amigdalino Central/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/farmacología , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Ácido Glutámico/toxicidad , Masculino , Red Nerviosa/efectos de los fármacos , Dolor/inducido químicamente , Dolor/prevención & control , Dimensión del Dolor/efectos de los fármacos , Sustancia Gris Periacueductal/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
The bed nucleus of the stria terminalis (BNST) and central amygdala (CeA) of the extended amygdala are small, anatomically interconnected brain regions. They are thought to mediate responses to sustained, unpredictable threat stimuli and phasic, predictable threat stimuli, respectively. They perform these operations largely through their interconnected networks. In two previous studies, we mapped and contrasted the resting functional connectivity networks of the BNST and CeA at 7 Tesla with high resolution. This follow-up study investigates the changes in functional connectivity of these structures during sustained anticipation of electric shock. Results show that the BNST and CeA become less strongly coupled with the ventromedial prefrontal cortex (vmPFC), cingulate, and nucleus accumbens in shock threat relative to a safety condition. In addition, the CeA becomes more strongly coupled with the thalamus under threat. An exploratory, whole-brain connectivity analysis reveals that, although the BNST/CeA exhibits generally decreased connectivity, many other cortical regions demonstrate greater coupling under threat than safety. Understanding the differential network structures of these two regions and how they contribute to processing under threat will help elucidate the building blocks of the anxious state.