RESUMO
Failure to appropriately predict and titrate reactivity to threat is a core feature of fear and anxiety-related disorders and is common following early life adversity (ELA). A population of neurons in the lateral central amygdala (CeAL) expressing corticotropin releasing factor (CRF) have been proposed to be key in processing threat of different intensities to mediate active fear expression. Here, we use in vivo fiber photometry to show that ELA results in sex-specific changes in the activity of CeAL CRF+ neurons, yielding divergent mechanisms underlying the augmented startle in ELA mice, a translationally relevant behavior indicative of heightened threat reactivity and hypervigilance. Further, chemogenic inhibition of CeAL CRF+ neurons selectively diminishes startle and produces a long-lasting suppression of threat reactivity. These findings identify a mechanism for sex-differences in susceptibility for anxiety following ELA and have broad implications for understanding the neural circuitry that encodes and gates the behavioral expression of fear.
Assuntos
Ansiedade , Núcleo Central da Amígdala , Hormônio Liberador da Corticotropina , Medo , Neurônios , Reflexo de Sobressalto , Animais , Hormônio Liberador da Corticotropina/metabolismo , Medo/fisiologia , Neurônios/metabolismo , Neurônios/fisiologia , Camundongos , Feminino , Masculino , Ansiedade/fisiopatologia , Núcleo Central da Amígdala/metabolismo , Reflexo de Sobressalto/fisiologia , Camundongos Endogâmicos C57BL , Comportamento Animal/fisiologia , Estresse PsicológicoRESUMO
Activity of central amygdala (CeA) PKCδ expressing neurons has been linked to appetite regulation, anxiety-like behaviors, pain sensitivity, and addiction-related behaviors. Studies of the role that CeA PKCδ+ neurons play in these behaviors have largely been carried out in mice, and genetic tools that would allow selective manipulation of PKCδ+ cells in rats have been lacking. Here, we used a CRISPR/Cas9 strategy to generate a transgenic Prkcd-cre knock-in rat and characterized this model using anatomical, electrophysiological, and behavioral approaches in both sexes. In the CeA, Cre was selectively expressed in PKCδ+ cells. Anterograde projections of PKCδ+ neurons to cortical regions, subcortical regions, several hypothalamic nuclei, the amygdala complex, and midbrain dopaminergic regions were largely consistent with published mouse data. In a behavioral screen, we found no differences between Cre+ rats and Cre- wild-type littermates. Optogenetic stimulation of CeA PKCδ+ neurons in a palatable food intake assay resulted in an increased latency to first feeding and decreased total food intake, once again replicating published mouse findings. Lastly, using a real-time place preference task, we found that stimulation of PKCδ+ neurons promoted aversion, without affecting locomotor activity. Collectively, these findings establish the novel Prkcd-Cre rat line as a valuable tool that complements available mouse lines for investigating the functional role of PKCδ+ neurons.
Assuntos
Proteína Quinase C-delta , Animais , Proteína Quinase C-delta/genética , Proteína Quinase C-delta/metabolismo , Ratos , Masculino , Feminino , Ratos Transgênicos , Neurônios/fisiologia , Núcleo Central da Amígdala/fisiologia , Integrases/genética , Optogenética/métodos , Ratos Sprague-DawleyRESUMO
OBJECTIVE: In Japan, intravenous injection of a 7 % solution of sodium bicarbonate (NaHCO3) had been originally developed to inhibit motion sickness and then have long been used to treat vertigo. Previously, we reported that Fos-positive neurons appear in the amygdala after hypergravity stimulation in rats. In the present study, we examined whether injection of 7 % NaHCO3 inhibits hypergravity-induced Fos expression in the neurons in the central nucleus of the amygdala in rats. METHODS: Rats were exposed to 2 G hypergravity in an animal centrifuge device for 3 h. A solution of 7 % NaHCO3 at a dose of 4 mM/kg was injected intraperitoneally before 2 G hypergraviy. Fos-positive neurons in the amygdala were stained immunohistochemically. RESULTS: The number of Fos-positive neurons in the central nucleus of the amygdala was significantly increased after 2 G hypergravity in rats that received no drugs or saline, compared to that in rats exposed only to the noise of the centrifuge and received 7 % NaHCO3 solution. The number of Fos-positive neurons in the central nucleus of the amygdala after 2 G hypergravity was significantly decreased in rats that received 7 % NaHCO3 solution, compared to that in rats that received no drugs or saline. CONCLUSION: Since Fos expression is a marker of activated neurons, the present findings suggest that hypergravity activates the amygdala and that administration of 7 % NaHCO3 suppresses hypergravity-induced activation of the amygdala. Hypergravity disturbs spatial orientation to produce motion sickness and the amygdala is involved in fear response. Recently, Ziemann et al. suggested that fear-evoking stimuli reduce the pH in the amygdala to activate it, leading to induction of fear behavior and that administering HCO3- attenuates fear behavior [Cell 2009; 139: 1012-1021]. Therefore, it is possible that hypergravity reduces the pH in the amygdala to activate it, thereby inducing the fear associated with motion sickness and that administration of 7 % NaHCO3 increases the brain pH thereby suppressing hypergravity-induced activation of the amygdala and inhibiting the fear associated with motion sickness. In patients with vertigo, 7 % NaHCO3 therapy may increase the brain pH thereby suppressing the activation of the amygdala and inhibiting the fear associated with vertigo to elicit a beneficial clinical effect.
Assuntos
Hipergravidade , Neurônios , Bicarbonato de Sódio , Vertigem , Animais , Ratos , Masculino , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Bicarbonato de Sódio/farmacologia , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/efeitos dos fármacos , Núcleo Central da Amígdala/efeitos dos fármacos , Núcleo Central da Amígdala/metabolismo , Ratos Wistar , Proteínas Proto-Oncogênicas c-fos/metabolismo , Imuno-Histoquímica , CentrifugaçãoRESUMO
The dorsomedial striatum (DMS) is associated with flexible goal seeking, as opposed to routinized habits. Whether local mechanisms brake this function, for instance when habits may be adaptive, is incompletely understood. We find that a sub-population of dopamine D1 receptor-containing striatal neurons express the melanocortin-4 receptor (MC4R) for α-melanocyte stimulating hormone. These neurons within the DMS are necessary and sufficient for controlling the capacity of mice to flexibly adjust actions based on the likelihood that they will be rewarded. In investigating MC4R function, we found that it suppresses immediate-early gene levels in the DMS and concurrently, flexible goal seeking. MC4R+ neurons receive input from the central nucleus of the amygdala, and behavioral experiments indicate that they are functionally integrated into an amygdalo-striatal circuit that suppresses action flexibility in favor of routine. Publicly available spatial transcriptomics datasets were analyzed for gene transcript correlates of Mc4r expression across the striatal subregions, revealing considerable co-variation in dorsal structures. This insight led to the discovery that the function of MC4R in the dorsolateral striatum complements that in the DMS, in this case suppressing habit-like behavior. Altogether, our findings suggest that striatal MC4R controls the capacity for goal-directed and inflexible actions alike.
Assuntos
Núcleo Central da Amígdala , Corpo Estriado , Objetivos , Receptor Tipo 4 de Melanocortina , Animais , Receptor Tipo 4 de Melanocortina/metabolismo , Camundongos , Núcleo Central da Amígdala/metabolismo , Núcleo Central da Amígdala/fisiologia , Corpo Estriado/metabolismo , Corpo Estriado/fisiologia , Masculino , Receptores de Dopamina D1/metabolismo , Melanocortinas/metabolismo , Camundongos Endogâmicos C57BL , Vias Neurais/fisiologia , Vias Neurais/metabolismoRESUMO
Chronic restraint stress induces cognitive abnormalities through changes in synapses and oxidant levels in the amygdala and hippocampus. Given the neuroprotective effects of fruit of Terminalia chebula (Halileh) in different experimental models, the present investigation aimed to address whether Terminalia chebula is able to reduce chronic restraint stress-induced behavioral, synaptic and oxidant markers in the rat model. Thirty-two male Wistar rats were randomly divided into four groups as follows: control (did not receive any treatment and were not exposed to stress), stress (restraint stress for 2â¯h a day for 14 consecutive days), Terminalia chebula (received 200â¯mg/kg hydroalcoholic extract of Terminalia chebula), and stress + Terminalia chebula groups (received 200â¯mg/kg extract of Terminalia chebula twenty minutes before stress) (n = 8 in each group). We used the shuttle box test to assess learning and memory, Golgi-Cox staining to examine dendritic spine density in the dentate gyrus region of the hippocampus and the basolateral and central nuclei of the amygdala, and total antioxidant capacity (TAC) and total oxidant status (TOS) in the brain. The shuttle box test results demonstrated that Terminalia chebula treatment had a profound positive effect on memory parameters, including step-through latency (STL) and time spent in the dark room, when compared to the stress group. Daily oral treatment with Terminalia chebula effectively suppressed the loss of neural spine density in the dentate gyrus region of the hippocampus and the basolateral and central nuclei of the amygdala caused by chronic restraint stress, as demonstrated by Golgi-Cox staining. Additionally, the results indicate that Terminalia chebula significantly reduced the TOS and increased TAC in the brain compared to the stress group. In conclusion, our results suggest that Terminalia chebula improved memory impairment and synaptic loss in the dentate gyrus of the hippocampus and the basolateral and central nuclei of the amygdala induced by restraint stress via inhibiting oxidative damage.
Assuntos
Giro Denteado , Transtornos da Memória , Estresse Oxidativo , Extratos Vegetais , Ratos Wistar , Restrição Física , Estresse Psicológico , Terminalia , Animais , Terminalia/química , Masculino , Estresse Psicológico/metabolismo , Ratos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Giro Denteado/metabolismo , Extratos Vegetais/farmacologia , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Sinapses/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Hipocampo/efeitos dos fármacos , Complexo Nuclear Basolateral da Amígdala/metabolismo , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Núcleo Central da Amígdala/metabolismo , Núcleo Central da Amígdala/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Espinhas Dendríticas/efeitos dos fármacos , Tonsila do Cerebelo/metabolismoRESUMO
Fentanyl is a powerful painkiller that elicits euphoria and positive reinforcement1. Fentanyl also leads to dependence, defined by the aversive withdrawal syndrome, which fuels negative reinforcement2,3 (that is, individuals retake the drug to avoid withdrawal). Positive and negative reinforcement maintain opioid consumption, which leads to addiction in one-fourth of users, the largest fraction for all addictive drugs4. Among the opioid receptors, µ-opioid receptors have a key role5, yet the induction loci of circuit adaptations that eventually lead to addiction remain unknown. Here we injected mice with fentanyl to acutely inhibit γ-aminobutyric acid-expressing neurons in the ventral tegmental area (VTA), causing disinhibition of dopamine neurons, which eventually increased dopamine in the nucleus accumbens. Knockdown of µ-opioid receptors in VTA abolished dopamine transients and positive reinforcement, but withdrawal remained unchanged. We identified neurons expressing µ-opioid receptors in the central amygdala (CeA) whose activity was enhanced during withdrawal. Knockdown of µ-opioid receptors in CeA eliminated aversive symptoms, suggesting that they mediate negative reinforcement. Thus, optogenetic stimulation caused place aversion, and mice readily learned to press a lever to pause optogenetic stimulation of CeA neurons that express µ-opioid receptors. Our study parses the neuronal populations that trigger positive and negative reinforcement in VTA and CeA, respectively. We lay out the circuit organization to develop interventions for reducing fentanyl addiction and facilitating rehabilitation.
Assuntos
Fentanila , Receptores Opioides mu , Reforço Psicológico , Animais , Feminino , Masculino , Camundongos , Analgésicos Opioides/farmacologia , Analgésicos Opioides/administração & dosagem , Núcleo Central da Amígdala/citologia , Núcleo Central da Amígdala/efeitos dos fármacos , Núcleo Central da Amígdala/metabolismo , Dopamina/metabolismo , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Fentanila/farmacologia , Camundongos Endogâmicos C57BL , Núcleo Accumbens/citologia , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Transtornos Relacionados ao Uso de Opioides/metabolismo , Transtornos Relacionados ao Uso de Opioides/patologia , Optogenética , Receptores Opioides mu/metabolismo , Síndrome de Abstinência a Substâncias/metabolismo , Síndrome de Abstinência a Substâncias/patologia , Área Tegmentar Ventral/citologia , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/metabolismoRESUMO
BACKGROUND: Postpartum depression (PPD) is a serious psychiatric disorder that has significantly adverse impacts on maternal health. Metabolic abnormalities in the brain are associated with numerous neurological disorders, yet the specific metabolic signaling pathways and brain regions involved in PPD remain unelucidated. METHODS: We performed behavioral test in the virgin and postpartum mice. We used mass spectrometry imaging (MSI) and targeted metabolomics analyses to investigate the metabolic alternation in the brain of GABAAR Delta-subunit-deficient (Gabrd-/-) postpartum mice, a specific preclinical animal model of PPD. Next, we performed mechanism studies including qPCR, Western blot, immunofluorescence staining, electron microscopy and primary astrocyte culture. In the specific knockdown and rescue experiments, we injected the adeno-associated virus into the central amygdala (CeA) of female mice. RESULTS: We identified that prostaglandin D2 (PGD2) downregulation in the CeA was the most outstanding alternation in PPD, and then validated that lipocalin-type prostaglandin D synthase (L-PGDS)/PGD2 downregulation plays a causal role in depressive behaviors derived from PPD in both wild-type and Gabrd-/- mice. Furthermore, we verified that L-PGDS/PGD2 signaling dysfunction-induced astrocytes atrophy is mediated by Src phosphorylation both in vitro and in vivo. LIMITATIONS: L-PGDS/PGD2 signaling dysfunction may be only responsible for the depressive behavior rather than maternal behaviors in the PPD, and it remains to be seen whether this mechanism is applicable to all depression types. CONCLUSION: Our study identified abnormalities in the L-PGDS/PGD2 signaling in the CeA, which inhibited Src phosphorylation and induced astrocyte atrophy, ultimately resulting in the development of PPD in mice.
Assuntos
Astrócitos , Atrofia , Depressão Pós-Parto , Modelos Animais de Doenças , Prostaglandina D2 , Transdução de Sinais , Animais , Astrócitos/patologia , Astrócitos/metabolismo , Feminino , Depressão Pós-Parto/patologia , Depressão Pós-Parto/metabolismo , Camundongos , Transdução de Sinais/fisiologia , Prostaglandina D2/metabolismo , Núcleo Central da Amígdala/metabolismo , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/metabolismo , Lipocalinas/genética , Lipocalinas/metabolismo , Quinases da Família src/metabolismo , Camundongos KnockoutRESUMO
Neuroplasticity in the central nucleus of the amygdala (CeA) plays a key role in the modulation of pain and its aversive component. The dynorphin/kappa opioid receptor (KOR) system in the amygdala is critical for averse-affective behaviors in pain conditions, but its mechanisms are not well understood. Here, we used chemogenetic manipulations of amygdala KOR-expressing neurons to analyze the behavioral consequences in a chronic neuropathic pain model. For the chemogenetic inhibition or activation of KOR neurons in the CeA, a Cre-inducible viral vector encoding Gi-DREADD (hM4Di) or Gq-DREADD (hM3Dq) was injected stereotaxically into the right CeA of transgenic KOR-Cre mice. The chemogenetic inhibition of KOR neurons expressing hM4Di with a selective DREADD actuator (deschloroclozapine, DCZ) in sham control mice significantly decreased inhibitory transmission, resulting in a shift of inhibition/excitation balance to promote excitation and induced pain behaviors. The chemogenetic activation of KOR neurons expressing hM3Dq with DCZ in neuropathic mice significantly increased inhibitory transmission, decreased excitability, and decreased neuropathic pain behaviors. These data suggest that amygdala KOR neurons modulate pain behaviors by exerting an inhibitory tone on downstream CeA neurons. Therefore, activation of these interneurons or blockade of inhibitory KOR signaling in these neurons could restore control of amygdala output and mitigate pain.
Assuntos
Tonsila do Cerebelo , Camundongos Transgênicos , Neuralgia , Neurônios , Receptores Opioides kappa , Animais , Receptores Opioides kappa/metabolismo , Receptores Opioides kappa/genética , Neuralgia/metabolismo , Neuralgia/fisiopatologia , Neurônios/metabolismo , Camundongos , Tonsila do Cerebelo/metabolismo , Comportamento Animal , Masculino , Clozapina/análogos & derivados , Clozapina/farmacologia , Núcleo Central da Amígdala/metabolismoRESUMO
Prepulse inhibition (PPI) of the auditory startle response, a key measure of sensorimotor gating, diminishes with age and is impaired in various neurological conditions. While PPI deficits are often associated with cognitive impairments, their reversal is routinely used in experimental systems for antipsychotic drug screening. Yet, the cellular and circuit-level mechanisms of PPI remain unclear, even under non-pathological conditions. We recently showed that brainstem neurons located in the caudal pontine reticular nucleus (PnC) expressing the glycine transporter type 2 (GlyT2±) receive inputs from the central nucleus of the amygdala (CeA) and contribute to PPI but via an uncharted pathway. Here, using tract-tracing, immunohistochemistry and in vitro optogenetic manipulations coupled to field electrophysiological recordings, we reveal the neuroanatomical distribution of GlyT2± PnC neurons and PnC-projecting CeA glutamatergic neurons and we provide mechanistic insights on how these glutamatergic inputs suppress auditory neurotransmission in PnC sections. Additionally, in vivo experiments using GlyT2-Cre mice confirm that optogenetic activation of GlyT2± PnC neurons enhances PPI and is sufficient to induce PPI in young mice, emphasizing their role. However, in older mice, PPI decline is not further influenced by inhibiting GlyT2± neurons. This study highlights the importance of GlyT2± PnC neurons in PPI and underscores their diminished activity in age-related PPI decline.
Assuntos
Tronco Encefálico , Proteínas da Membrana Plasmática de Transporte de Glicina , Glicina , Neurônios , Inibição Pré-Pulso , Reflexo de Sobressalto , Animais , Inibição Pré-Pulso/fisiologia , Neurônios/fisiologia , Neurônios/metabolismo , Reflexo de Sobressalto/fisiologia , Camundongos , Tronco Encefálico/fisiologia , Tronco Encefálico/metabolismo , Proteínas da Membrana Plasmática de Transporte de Glicina/metabolismo , Masculino , Glicina/metabolismo , Optogenética , Camundongos Transgênicos , Camundongos Endogâmicos C57BL , Transmissão Sináptica/fisiologia , Núcleo Central da Amígdala/fisiologia , Núcleo Central da Amígdala/metabolismoRESUMO
BACKGROUND: The central nucleus of the amygdala (CeA) is part of the dopaminergic reward system and controls energy balance. Recently, a cluster of neurons was identified as responsive to the orexigenic effect of ghrelin and fasting. However, the signaling pathway by which ghrelin and fasting induce feeding is unknown. AMP-activated protein kinase (AMPK) is a cellular energy sensor, and its Thr172 phosphorylation (AMPKThr172) in the mediobasal hypothalamus regulates food intake. However, whether the expression and activation of AMPK in CeA could be one of the intracellular signaling activated in response to ghrelin and fasting eliciting food intake is unknown. AIM: To evaluate the activation of AMPK into CeA in response to ghrelin, fasting, and 2-deoxy-D-glucose (2DG) and whether feeding accompanied these changes. In addition, to investigate whether the inhibition of AMPK into CeA could decrease food intake. METHODS: On a chow diet, eight-week-old Wistar male rats were stereotaxically implanted with a cannula in the CeA to inject several modulators of AMPKα1/2Thr172 phosphorylation, and we performed physiological and molecular assays. KEY FINDINGS: Fasting increased, and refeeding reduced AMPKThr172 in the CeA. Intra-CeA glucose injection decreased feeding, whereas injection of 2DG, a glucoprivation inductor, in the CeA, increased food intake and blood glucose, despite faint increases in AMPKThr172. Intra-CeA ghrelin injection increased food intake and AMPKThr172. To further confirm the role of AMPK in the CeA, chronic injection of Melanotan II (MTII) in CeA reduced body mass and food intake over seven days together with a slight decrease in AMPKThr172. SIGNIFICANCE: Our findings identified that AMPK might be part of the signaling machinery in the CeA, which responds to nutrients and hormones contributing to feeding control. The results can contribute to understanding the pathophysiological mechanisms of altered feeding behavior/consumption, such as binge eating of caloric-dense, palatable food.
Assuntos
Proteínas Quinases Ativadas por AMP , Núcleo Central da Amígdala , Ingestão de Alimentos , Jejum , Grelina , Ratos Wistar , Animais , Masculino , Grelina/metabolismo , Grelina/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Fosforilação/efeitos dos fármacos , Núcleo Central da Amígdala/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Ratos , Transdução de Sinais/efeitos dos fármacos , Desoxiglucose/farmacologia , Desoxiglucose/metabolismo , Comportamento Alimentar/efeitos dos fármacos , Glucose/metabolismoRESUMO
It is adaptive to restrict eating under uncertainty, such as during habituation to novel foods and unfamiliar environments. However, sustained restrictive eating can become maladaptive. Currently, the neural substrates of restrictive eating are poorly understood. Using a model of feeding avoidance under novelty, our recent study identified forebrain activation patterns and found evidence that the central nucleus of the amygdala (CEA) is a core integrating node. The current study analyzed the activity of CEA inputs in male and female rats to determine if specific pathways are recruited during feeding under novelty. Recruitment of direct inputs from the paraventricular nucleus of the thalamus (PVT), the infralimbic cortex (ILA), the agranular insular cortex (AI), the hippocampal ventral field CA1, and the bed nucleus of the stria terminals (BST) was assessed with combined retrograde tract tracing and Fos induction analysis. The study found that during consumption of a novel food in a novel environment, larger number of neurons within the PVTp and the CA1 that send monosynaptic inputs to the CEA were recruited compared to controls that consumed familiar food in a familiar environment. The ILA, AI, and BST inputs to the CEA were similarly recruited across conditions. There were no sex differences in activation of any of the pathways analyzed. These results suggest that the PVTp-CEA and CA1-CEA pathways underlie feeding inhibition during novelty and could be potential sites of malfunction in excessive food avoidance.
Assuntos
Núcleo Central da Amígdala , Comportamento Alimentar , Hipocampo , Vias Neurais , Tálamo , Animais , Masculino , Feminino , Comportamento Alimentar/fisiologia , Núcleo Central da Amígdala/fisiologia , Vias Neurais/fisiologia , Tálamo/fisiologia , Hipocampo/fisiologia , Ratos , Comportamento Exploratório/fisiologia , Neurônios/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Sprague-Dawley , Ratos Long-EvansRESUMO
Alcohol use and anxiety disorders occur in both males and females, but despite sharing similar presentation and classical symptoms, the prevalence of alcohol use disorder (AUD) is lower in females. While anxiety is a symptom and comorbidity shared by both sexes, the common underlying mechanism that leads to AUD and the subsequent development of anxiety is still understudied. Using a rodent model of adolescent intermittent ethanol (AIE) exposure in both sexes, we investigated the epigenetic mechanism mediated by enhancer of zeste 2 (EZH2), a histone methyltransferase, in regulating both the expression of activity-regulated cytoskeleton-associated protein (Arc) and an anxiety-like phenotype in adulthood. Here, we report that EZH2 protein levels were significantly higher in PKC-δ positive GABAergic neurons in the central nucleus of amygdala (CeA) of adult male and female rats after AIE. Reducing protein and mRNA levels of EZH2 using siRNA infusion in the CeA prevented AIE-induced anxiety-like behavior, increased H3K27me3, decreased H3K27ac at the Arc synaptic activity response element (SARE) site, and restored deficits in Arc mRNA and protein expression in both male and female adult rats. Our data indicate that an EZH2-mediated epigenetic mechanism in the CeA plays an important role in regulating anxiety-like behavior and Arc expression after AIE in both male and female rats in adulthood. This study suggests that EZH2 may serve as a tractable drug target for the treatment of adult psychopathology after adolescent alcohol exposure.
Assuntos
Ansiedade , Núcleo Central da Amígdala , Proteína Potenciadora do Homólogo 2 de Zeste , Epigênese Genética , Etanol , Animais , Masculino , Feminino , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Núcleo Central da Amígdala/metabolismo , Núcleo Central da Amígdala/efeitos dos fármacos , Ratos , Ansiedade/metabolismo , Ansiedade/genética , Etanol/farmacologia , Modelos Animais de Doenças , Alcoolismo/genética , Alcoolismo/metabolismo , Neurônios GABAérgicos/metabolismo , Neurônios GABAérgicos/efeitos dos fármacos , Ratos Sprague-Dawley , Proteínas do Citoesqueleto/genética , Proteínas do Citoesqueleto/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismoRESUMO
The central amygdaloid nucleus (CeA) has an ancient phylogenetic development and functions relevant for animal survival. Local cells receive intrinsic amygdaloidal information that codes emotional stimuli of fear, integrate them, and send cortical and subcortical output projections that prompt rapid visceral and social behavior responses. We aimed to describe the morphology of the neurons that compose the human CeA (N = 8 adult men). Cells within CeA coronal borders were identified using the thionine staining and were further analyzed using the "single-section" Golgi method followed by open-source software procedures for two-dimensional and three-dimensional image reconstructions. Our results evidenced varied neuronal cell body features, number and thickness of primary shafts, dendritic branching patterns, and density and shape of dendritic spines. Based on these criteria, we propose the existence of 12 morphologically different spiny neurons in the human CeA and discuss the variability in the dendritic architecture within cellular types, including likely interneurons. Some dendritic shafts were long and straight, displayed few collaterals, and had planar radiation within the coronal neuropil volume. Most of the sampled neurons showed a few to moderate density of small stubby/wide spines. Long spines (thin and mushroom) were observed occasionally. These novel data address the synaptic processing and plasticity in the human CeA. Our morphological description can be combined with further transcriptomic, immunohistochemical, and electrophysiological/connectional approaches. It serves also to investigate how neurons are altered in neurological and psychiatric disorders with hindered emotional perception, in anxiety, following atrophy in schizophrenia, and along different stages of Alzheimer's disease.
Assuntos
Núcleo Central da Amígdala , Masculino , Adulto , Animais , Humanos , Filogenia , Espinhas Dendríticas/fisiologia , Neurônios/fisiologia , InterneurôniosRESUMO
Our previous studies found that the central amygdala (CeA) modulates cerebellum-dependent eyeblink conditioning (EBC) using muscimol inactivation. We also found that CeA inactivation decreases cerebellar neuronal activity during the conditional stimulus (CS) from the start of training. Based on these findings, we hypothesized that the CeA facilitates CS input to the cerebellum. The current study tested the CS facilitation hypothesis using optogenetic inhibition with archaerhodopsin (Arch) and excitation with channelrhodopsin (ChR2) of the CeA during EBC in male rats. Optogenetic manipulations were administered during the 400 ms tone CS or during a 400 ms pre-CS period. As predicted by the CS facilitation hypothesis CeA inhibition during the CS impaired EBC and CeA excitation during the CS facilitated EBC. Unexpectedly, CeA inhibition just prior to the CS also impaired EBC, while CeA excitation during the pre-CS pathway did not facilitate EBC. The results suggest that the CeA contributes to CS facilitation and vigilance during the pre-CS period. These putative functions of the CeA may be mediated through separate output pathways from the CeA to the cerebellum.
Assuntos
Núcleo Central da Amígdala , Cerebelo , Condicionamento Palpebral , Optogenética , Animais , Masculino , Cerebelo/fisiologia , Cerebelo/efeitos dos fármacos , Núcleo Central da Amígdala/fisiologia , Núcleo Central da Amígdala/efeitos dos fármacos , Condicionamento Palpebral/fisiologia , Condicionamento Palpebral/efeitos dos fármacos , Ratos , Ratos Long-Evans , Condicionamento Clássico/fisiologia , Condicionamento Clássico/efeitos dos fármacosRESUMO
The motivation to eat is suppressed by satiety and aversive stimuli such as nausea. The neural circuit mechanisms of appetite suppression by nausea are not well understood. Pkcδ neurons in the lateral subdivision of the central amygdala (CeA) suppress feeding in response to satiety signals and nausea. Here, we characterized neurons enriched in the medial subdivision (CeM) of the CeA marked by expression of Dlk1. CeADlk1 neurons are activated by nausea, but not satiety, and specifically suppress feeding induced by nausea. Artificial activation of CeADlk1 neurons suppresses drinking and social interactions, suggesting a broader function in attenuating motivational behavior. CeADlk1 neurons form projections to many brain regions and exert their anorexigenic activity by inhibition of neurons of the parabrachial nucleus. CeADlk1 neurons are inhibited by appetitive CeA neurons, but also receive long-range monosynaptic inputs from multiple brain regions. Our results illustrate a CeA circuit that regulates nausea-induced feeding suppression.
Assuntos
Proteínas de Ligação ao Cálcio , Núcleo Central da Amígdala , Comportamento Alimentar , Náusea , Neurônios , Animais , Neurônios/metabolismo , Núcleo Central da Amígdala/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , Camundongos , Náusea/metabolismo , Náusea/etiologia , Masculino , Camundongos Endogâmicos C57BL , Peptídeos e Proteínas de Sinalização Intercelular/metabolismoRESUMO
Anxiety disorders affect millions of people worldwide and impair health, happiness, and productivity on a massive scale. Developmental research points to a connection between early-life behavioral inhibition and the eventual development of these disorders. Our group has previously shown that measures of behavioral inhibition in young rhesus monkeys (Macaca mulatta) predict anxiety-like behavior later in life. In recent years, clinical and basic researchers have implicated the central extended amygdala (EAc)-a neuroanatomical concept that includes the central nucleus of the amygdala (Ce) and the bed nucleus of the stria terminalis (BST)-as a key neural substrate for the expression of anxious and inhibited behavior. An improved understanding of how early-life behavioral inhibition relates to an increased lifetime risk of anxiety disorders-and how this relationship is mediated by alterations in the EAc-could lead to improved treatments and preventive strategies. In this study, we explored the relationships between infant behavioral inhibition and peri-adolescent defensive behavior and brain metabolism in 18 female rhesus monkeys. We coupled a mildly threatening behavioral assay with concurrent multimodal neuroimaging, and related those findings to various measures of infant temperament. To score the behavioral assay, we developed and validated UC-Freeze, a semi-automated machine-learning (ML) tool that uses unsupervised clustering to quantify freezing. Consistent with previous work, we found that heightened Ce metabolism predicted elevated defensive behavior (i.e., more freezing) in the presence of an unfamiliar human intruder. Although we found no link between infant-inhibited temperament and peri-adolescent EAc metabolism or defensive behavior, we did identify infant nervous temperament as a significant predictor of peri-adolescent defensive behavior. Our findings suggest a connection between infant nervous temperament and the eventual development of anxiety and depressive disorders. Moreover, our approach highlights the potential for ML tools to augment existing behavioral neuroscience methods.
Assuntos
Núcleo Central da Amígdala , Humanos , Animais , Feminino , Adolescente , Macaca mulatta , Temperamento/fisiologia , Ansiedade/metabolismo , Transtornos de Ansiedade/metabolismoRESUMO
Anorexia nervosa (AN) is a serious psychiatric disease, but the neural mechanisms underlying its development are unclear. A subpopulation of amygdala neurons, marked by expression of protein kinase C-delta (PKC-δ), has previously been shown to regulate diverse anorexigenic signals. Here, we demonstrate that these neurons regulate development of activity-based anorexia (ABA), a common animal model for AN. PKC-δ neurons are located in two nuclei of the central extended amygdala (EAc): the central nucleus (CeA) and oval region of the bed nucleus of the stria terminalis (ovBNST). Simultaneous ablation of CeAPKC-δ and ovBNSTPKC-δ neurons prevents ABA, but ablating PKC-δ neurons in the CeA or ovBNST alone is not sufficient. Correspondingly, PKC-δ neurons in both nuclei show increased activity with ABA development. Our study shows how neurons in the amygdala regulate ABA by impacting both feeding and wheel activity behaviors and support a complex heterogeneous etiology of AN.
Assuntos
Núcleo Central da Amígdala , Núcleos Septais , Animais , Proteína Quinase C-delta/metabolismo , Anorexia/metabolismo , Neurônios/metabolismo , Núcleo Central da Amígdala/metabolismo , Vias Neurais/fisiologia , Núcleos Septais/fisiologiaRESUMO
The nicotine acetylcholinergic receptor (nAchR) in the central nucleus of the amygdala (CeA) is known to modulate anxiety traits as well as ethanol-induced behavioral effects. Therefore, the present study investigated the role of CeA nAChR in the tolerance to ethanol anxiolysis and withdrawal-induced anxiety-related effects in rats on elevated plus maze (EPM). To develop ethanol dependence, rats were given free access to an ethanol-containing liquid diet for 10 days. To assess the development of tolerance, separate groups of rats were challenged with ethanol (2 g/kg, i.p.) on days 1, 3, 5, 7 and 10 during the period of ethanol exposure, followed by an EPM assessment. Moreover, expression of ethanol withdrawal was induced after switching ethanol-dependent rats to a liquid diet on day 11, and withdrawal-induced anxiety-like behavior was noted at different post-withdrawal time points using the EPM test. The ethanol-dependent rats were pretreated with intra-CeA (i.CeA) (bilateral) injections of nicotine (0.25â µg/rat) or mecamylamine (MEC) (5 ng/rat) before the challenge dose of ethanol on subthreshold tolerance on the 5th day or on peak tolerance day, that is, 7th or 10th, and before assessment of postwithdrawal anxiety on the 11th day on EPM. Bilateral i.CeA preadministration of nicotine before the challenge dose of ethanol on days 5, 7 and 10 exhibited enhanced tolerance, while injection of MEC, completely mitigated the tolerance to the ethanol-induced antianxiety effect. On the other hand, ethanol-withdrawn rats pretreated i.CeA with nicotine exacerbated while pretreatment with MEC, alleviated the ethanol withdrawal-induced anxiety on all time points. Thus, the present investigation indicates that stimulation of nAChR in CeA negatively modulates the ethanol-induced chronic behavioral effects on anxiety in rats. It is proposed that nAChR antagonists might be useful in the treatment of alcohol use disorder and ethanol withdrawal-related anxiety-like behavior.