Neurobiology of Stress最新文献

Dopamine and D1 receptor in hippocampal dentate gyrus involved in chronic stress-induced alteration of spatial learning and memory in rats 多巴胺和海马齿状回中的 D1 受体参与慢性应激诱导的大鼠空间学习和记忆改变

IF 4.3 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2024-10-24 DOI: 10.1016/j.ynstr.2024.100685

There is increasing evidence that chronic stress (CS), which occurs when the body is exposed to prolonged stressors, significantly impairs learning and memory. Dopamine (DA) plays a critical role in learning and memory in the hippocampus through the activation of D1-like receptors (D1R). However, the specific roles of DA and D1R in the hippocampal dentate gyrus (DG), particularly in CS-induced changes in spatial learning and memory, are not well understood. In this study, we established a CS rat model through the random application of various stressors. We assessed spatial learning and memory using the Morris water maze (MWM) and measured DA concentration and the amplitude of field excitatory postsynaptic potentials (fEPSP) in the DG during the MWM test in freely moving rats. We also examined the involvement of D1R in spatial learning and memory by microinjecting its antagonist (SCH23390) into the DG, and then analyzed the expressions of phosphorylated (p-) Ca²⁺/calmodulin-dependent protein kinase II (CaMKII), protein kinase A (PKA), and cAMP-response element binding protein (CREB) in the DG using Western blot. During the MWM test, compared with the control group, the escape latency was increased, and the percentage of distance in target quadrant and the number of platform crossings were decreased, in addition, the increase of fEPSP amplitude in the DG was significantly attenuated in CS group. In the control group, the DA concentration in the DG was significantly increased during the MWM test, and this response was enhanced in the CS group. Microinjection of SCH23390 into the DG significantly improved the spatial learning and memory impairments in CS rats, and reversed the inhibitory effect of CS on increase of fEPSP amplitude in the DG during the MWM test. Furthermore, SCH23390 partially reversed the inhibitory effects of CS on the expressions of p-CaMKII, p-PKA, and p-CREB in the DG. Our findings suggest that overactivation of the DA-D1R system in the hippocampal DG impairs spatial learning and memory and related synaptic plasticity in CS rats via downregulation of PKA-CREB signaling pathway.

越来越多的证据表明，慢性应激（CS），即人体长期处于应激状态时发生的现象，会严重损害学习和记忆能力。多巴胺（DA）通过激活 D1 类受体（D1R）在海马的学习和记忆中发挥着关键作用。然而，DA和D1R在海马齿状回（DG）中的具体作用，尤其是在CS诱导的空间学习和记忆变化中的作用，还不是很清楚。在本研究中，我们通过随机施加各种应激源建立了 CS 大鼠模型。我们利用莫里斯水迷宫（MWM）评估了大鼠的空间学习和记忆能力，并测量了自由活动的大鼠在MWM测试中DG的DA浓度和场兴奋突触后电位（fEPSP）的振幅。我们还通过向DG显微注射D1R拮抗剂（SCH23390）研究了D1R参与空间学习和记忆的情况，然后用Western印迹分析了DG中磷酸化（p-）的Ca2+/钙调蛋白依赖性蛋白激酶II（CaMKII）、蛋白激酶A（PKA）和cAMP反应元件结合蛋白（CREB）的表达。在MWM试验中，与对照组相比，CS组的逃逸潜伏期增加，目标象限距离百分比和平台穿越次数减少，此外，DG中fEPSP振幅的增加在CS组明显减弱。在MWM测试中，对照组DG中的DA浓度明显增加，而在CS组中这一反应增强。向DG显微注射SCH23390可明显改善CS组大鼠的空间学习和记忆障碍，并逆转CS对MWM测试中DG中fEPSP振幅增加的抑制作用。此外，SCH23390还部分逆转了CS对DG中p-CaMKII、p-PKA和p-CREB表达的抑制作用。我们的研究结果表明，海马DG中DA-D1R系统的过度激活会通过下调PKA-CREB信号通路损害CS大鼠的空间学习和记忆以及相关的突触可塑性。

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引用次数: 0

Basal cortisol level modulates stress-induced opioid-seeking behavior 基础皮质醇水平调节应激诱导的阿片寻求行为

IF 4.3 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2024-10-24 DOI: 10.1016/j.ynstr.2024.100684

In preclinical studies and our human laboratory, the α₂-noradrenergic autoreceptor antagonist yohimbine was found to promote drug-seeking behavior. This study evaluated effects of dose-combinations of yohimbine and the glucocorticoid receptor agonist hydrocortisone to model intensity-dependent effects of stimulating each neurochemical system, alone and together, on stress-reactivity and opioid-seeking. Twelve regular heroin-using participants diagnosed with opioid use disorder (OUD) were stabilized on sublingual buprenorphine (8-mg/day), then passed a hydromorphone 18-mg vs. placebo intramuscular reinforcement screen. Across 9 experimental conditions (3 × 3 within-subject, randomized crossover, placebo-controlled, double-blind design) during inpatient buprenorphine maintenance, combinations of oral pretreatment doses of yohimbine (0, 27, 54-mg; t = 0 min) then hydrocortisone (0, 20, 40-mg; t = 45 min) were administered. In each condition, subjective drug and mood effects, cardiovascular responses, and saliva cortisol and α-amylase levels were assessed to evaluate stress-reactivity, and participants completed a 12-trial choice progressive ratio task during which they could earn units of hydromorphone (1.5-mg intramuscular) and/or money ($2.00). Yohimbine dose-dependently increased blood pressure, α-amylase, and anxiety scores, and decreased opioid agonist symptoms; hydrocortisone dose-dependently increased cortisol levels. Yohimbine/hydrocortisone dose-combinations significantly shifted within-session responding from money to opioid-seeking among participants with lower basal cortisol levels. These findings replicate yohimbine effects on stress biomarkers and demonstrate that noradrenergic/glucocorticoid-potentiated opioid-seeking is modulated by basal cortisol level. In persons with OUD stabilized on buprenorphine, basal HPA-axis activity and acute stressors can enhance opioid relative reinforcing efficacy. These factors may limit OUD treatment efficacy and highlight the need for novel interventions that prevent stress-induced opioid-seeking.

在临床前研究和我们的人体实验室中，发现α2-去甲肾上腺素能自体受体拮抗剂育亨宾能促进觅药行为。本研究评估了育亨宾和糖皮质激素受体激动剂氢化可的松的剂量组合效应，以模拟单独或同时刺激每种神经化学系统对应激反应和阿片觅药行为的强度依赖效应。12 名被诊断为阿片类药物使用障碍（OUD）的定期吸食海洛因的参与者在舌下含服丁丙诺啡（8 毫克/天）稳定后，通过了 18 毫克氢吗啡酮与安慰剂的肌肉注射强化筛选。在住院丁丙诺啡维持治疗期间的 9 个实验条件（3 × 3 受试者内、随机交叉、安慰剂对照、双盲设计）中，分别给予口服预处理剂量育亨宾（0、27、54 毫克；t = 0 分钟）和氢化可的松（0、20、40 毫克；t = 45 分钟）的组合。在每种条件下，都会对主观药物和情绪效应、心血管反应、唾液皮质醇和α-淀粉酶水平进行评估，以评价应激反应性，参与者还完成了一项 12 次选择累进比率任务，在该任务中，他们可以获得氢吗啡酮单位（1.5 毫克肌肉注射）和/或金钱（2 美元）。育亨宾剂量依赖性地增加了血压、α-淀粉酶和焦虑评分，并减少了阿片激动症状；氢化可的松剂量依赖性地增加了皮质醇水平。在基础皮质醇水平较低的参与者中，育亨宾/氢化可的松的剂量组合能显著地将会话期内的反应从金钱转向阿片寻求。这些发现复制了育亨宾对应激生物标志物的影响，并证明了去甲肾上腺素能/糖皮质激素促进的阿片类药物寻求受基础皮质醇水平的调节。对于服用丁丙诺啡后病情稳定的 OUD 患者，基础 HPA 轴活动和急性应激因素会增强阿片类药物的相对强化效果。这些因素可能会限制对 OUD 的治疗效果，并凸显了对新型干预措施的需求，以防止压力引起的阿片类药物寻求。

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引用次数: 0

Stress resilience is an active and multifactorial process manifested by structural, functional, and molecular changes in synapses 压力复原力是一个活跃的多因素过程，表现为突触的结构、功能和分子变化

IF 4.3 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2024-10-22 DOI: 10.1016/j.ynstr.2024.100683

Stress resilience is the ability of neuronal networks to maintain their function despite the stress exposure. Using a mouse model we investigate stress resilience phenomenon. To assess the resilient and anhedonic behavioral phenotypes developed after the induction of chronic unpredictable stress, we quantitatively characterized the structural and functional plasticity of excitatory synapses in the hippocampus using a combination of proteomic, electrophysiological, and imaging methods. Our results indicate that stress resilience is an active and multifactorial process manifested by structural, functional, and molecular changes in synapses. We reveal that chronic stress influences palmitoylation of synaptic proteins, whose profiles differ between resilient and anhedonic animals. The changes in palmitoylation are predominantly related with the glutamate receptor signaling thus affects synaptic transmission and associated structures of dendritic spines. We show that stress resilience is associated with structural compensatory plasticity of the postsynaptic parts of synapses in CA1 subregion of the hippocampus.

应激恢复能力是指神经元网络在面临应激时仍能保持其功能的能力。我们利用小鼠模型研究了应激恢复现象。为了评估小鼠在长期不可预测的应激诱导后产生的恢复能力和失调行为表型，我们结合使用了蛋白质组学、电生理学和成像方法，对海马兴奋性突触的结构和功能可塑性进行了定量表征。我们的研究结果表明，应激复原力是一个活跃的多因素过程，表现为突触的结构、功能和分子变化。我们发现，慢性应激会影响突触蛋白的棕榈酰化，而有应激恢复能力的动物和无应激恢复能力的动物的棕榈酰化情况各不相同。棕榈酰化的变化主要与谷氨酸受体信号传导有关，从而影响突触传递和树突棘的相关结构。我们的研究表明，应激恢复能力与海马 CA1 亚区突触后部分的结构补偿可塑性有关。

引用次数: 0

Stress-induced cortisol response predicts empathy for pain: The role of task-based connectivity between the insula and sensorimotor cortex during acute stress 压力引起的皮质醇反应可预测对疼痛的移情作用急性应激期间脑岛和感觉运动皮层之间基于任务的连接的作用

IF 4.3 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2024-10-18 DOI: 10.1016/j.ynstr.2024.100682

Empathy for pain is a key driver of prosocial behavior and is influenced by acute psychosocial stress. However, the role of task-based brain connectivity during acute stress have been neglected. Hence, we aimed to explore the relationship between the magnitude of cortisol response to acute stress and empathy for pain, as well as the neural connectivity mechanisms involved. In this study, 80 healthy participants (37 women and 43 men) were exposed to the acute psychosocial stress paradigm (ScanSTRESS) and were scanned by functional magnetic resonance imaging. Saliva samples were collected to measure the magnitude of cortisol stress response. Subsequently, the participants took part in a pain-video task to assess their empathy for pain. Six participants were excluded because of physical discomfort or excessive head movement in all runs during the task-dependent fMRI scan. Therefore, 33 women and 41 men were included in data analysis. We found that empathy for pain was negatively correlated with the magnitude of cortisol stress response (r = -0.268, p = 0.018) and that the task-based connectivity between the salience network and sensorimotor network, including its sub-network and sub-region, was negatively correlated with the magnitude of cortisol stress response, and positively correlated with empathy for pain. Furthermore, task-based connectivity between the insula and the paracentral lobule mediates the effect of the stress-induced cortisol response on empathy for pain (indirect effect = -0.0152, 95% CI = [-0.036, -0.001], p = 0.036). Our research suggests that empathy is not only correlated with stress-induced glucocorticoids but also tied to the stress-induced reduced communication between basic and higher brain regions.

对疼痛的同情是亲社会行为的一个关键驱动因素，并受到急性社会心理压力的影响。然而，基于任务的大脑连通性在急性应激中的作用却一直被忽视。因此，我们旨在探索皮质醇对急性应激反应的程度与对疼痛的移情之间的关系，以及其中涉及的神经连接机制。在这项研究中，80 名健康参与者（37 名女性和 43 名男性）接受了急性社会心理应激范式（ScanSTRESS）的训练，并进行了功能磁共振成像扫描。采集唾液样本以测量皮质醇应激反应的程度。随后，参与者参加了疼痛视频任务，以评估他们对疼痛的移情能力。有六名参与者因身体不适或在任务相关的 fMRI 扫描过程中头部过度移动而被排除在外。因此，33 名女性和 41 名男性被纳入数据分析。我们发现，对疼痛的移情与皮质醇应激反应的程度呈负相关（r = -0.268，p = 0.018），并且显著性网络和感觉运动网络（包括其子网络和子区域）之间基于任务的连通性与皮质醇应激反应的程度呈负相关，而与对疼痛的移情呈正相关。此外，脑岛和旁中心小叶之间基于任务的连接介导了压力引起的皮质醇反应对疼痛移情的影响（间接效应 = -0.0152，95% CI = [-0.036，-0.001]，p = 0.036）。我们的研究表明，移情不仅与压力诱导的糖皮质激素相关，还与压力诱导的基础脑区和高级脑区之间的交流减少有关。

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引用次数: 0

Intra-BLA alteration of interneurons’ modulation of activity in rats, reveals a dissociation between effects on anxiety symptoms and extinction learning 大鼠神经元间活动调节的 BLA 内改变揭示了对焦虑症状和消退学习的不同影响

IF 4.3 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2024-10-17 DOI: 10.1016/j.ynstr.2024.100681

The basolateral amygdala (BLA) is a dynamic brain region involved in emotional experiences and subject to long-term plasticity. The BLA also modulates activity, plasticity, and related behaviors associated with other brain regions, including the mPFC and hippocampus. Accordingly, intra-BLA plasticity can be expected to alter both BLA-dependent behaviors and behaviors mediated by other brain regions. Lasting intra-BLA plasticity may be considered a form of metaplasticity, since it will affect subsequent plasticity and response to challenges later on. Activity within the BLA is tightly modulated by GABAergic interneurons, and thus inducing lasting alteration of GABAergic modulation of principal neurons may have an impactful metaplastic effect on BLA functioning. Previously, we demonstrated that intra-BLA knockdown (KD) of neurofascin (NF) reduced GABAergic synapses exclusively at the axon initial segment (AIS). Here, by reducing the expression of the tyrosine kinase receptor ephrin A7 (EphA7), we selectively impaired the modulatory function of a different subpopulation of interneurons, specifically targeting the soma and proximal dendrites of principal neurons. This perturbation induced an expected reduction in the spontaneous inhibitory synaptic input and an increase in the excitatory spontaneous synaptic activity, most probably due to the reduction of inhibitory tone. Moreover, this increased synaptic activity was followed by a reduction in intrinsic excitability. While intra-BLA NF-KD resulted in impaired extinction learning, without increased symptoms of anxiety, intra-BLA reduction of EphA7 expression resulted in increased symptoms of anxiety, as measured in the elevated plus maze, but without affecting fear conditioning or extinction learning. These results confirm the role of the BLA and intra-BLA metaplasticity in stress-induced increased anxiety symptoms and in impaired fear extinction learning but reveals a difference in intra-BLA mechanisms involved. The results also confirm the contribution of GABAergic interneurons to these effects but indicate selective roles for different subpopulations of intra-BLA interneurons.

杏仁基底外侧（BLA）是一个动态脑区，参与情绪体验并具有长期可塑性。基底外侧杏仁核还能调节其他脑区的活动、可塑性和相关行为，包括前脑皮质和海马。因此，BLA内部的可塑性可望改变依赖于BLA的行为和由其他脑区介导的行为。BLA内的持久可塑性可被视为一种元可塑性，因为它将影响以后的可塑性和对挑战的反应。BLA内的活动受到GABA能中间神经元的严格调控，因此诱导持久改变GABA能对主要神经元的调控可能会对BLA的功能产生影响。此前，我们曾证实，在BLA内敲除（KD）神经瀑蛋白（NF）会减少GABA能突触，而这种突触只出现在轴突起始节段（AIS）。在这里，通过减少酪氨酸激酶受体ephrin A7（EphA7）的表达，我们选择性地损害了不同亚群中间神经元的调节功能，特别是针对主神经元的体节和近端树突。这种扰动引起了自发抑制性突触输入的预期减少和兴奋性自发突触活动的增加，这很可能是由于抑制张力的降低。此外，突触活动增加后，内在兴奋性也随之降低。BLA内的NF-KD会导致消减学习受损，但不会增加焦虑症状，而BLA内减少EphA7的表达会导致焦虑症状增加，这是在高架加迷宫中测得的结果，但不会影响恐惧条件反射或消减学习。这些结果证实了BLA和BLA内变态反应在应激诱导的焦虑症状加重和恐惧消退学习受损中的作用，但揭示了BLA内机制的不同。这些结果还证实了GABA能中间神经元对这些效应的贡献，但表明了BLA内中间神经元不同亚群的选择性作用。

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引用次数: 0

Transcriptomic analysis of rat prefrontal cortex following chronic stress induced by social isolation – Relevance to psychiatric and neurodevelopmental illness, and implications for treatment 社会隔离诱发慢性压力后大鼠前额叶皮层的转录组分析--与精神病和神经发育疾病的相关性以及对治疗的影响

IF 4.3 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2024-10-17 DOI: 10.1016/j.ynstr.2024.100679

Social isolation is an established risk factor for psychiatric illness, and became increasingly topical with the spread of SARS-CoV-2. We used RNA sequencing (RNA-Seq) to enable unbiased assessment of transcriptomic changes within the prefrontal cortex (PFC) of isolation-reared rats. To provide insight into the relevance of this manipulation for studying human illness, we compared differentially expressed genes (DEGs) and enriched biological functions against datasets involving post-mortem frontal cortical tissue from patients with psychiatric and neurodevelopmental illnesses. Sixteen male Sprague-Dawley rats were reared in groups of four or individually from weaning on postnatal day (PND) 22–24 until PFC tissue collection for RNA-Seq (PND64-66). We identified a total of 183 DEGs in isolates, of which 128 mirrored those in PFC tissue from patients with stress-related mental illnesses and/or neurodevelopmental conditions featuring social deficits. Seventy-one encode proteins classed as druggable by the gene-drug interaction database. Interestingly there are antagonists or inhibitors for the products of three of these up-regulated DEGs (Hrh3, Snca and Sod1) and agonists or activators for products of six of these down-regulated DEGs (Chrm4, Klf2, Lrrk2, Nr4a1, Nr4a3 and Prkca). Some have already undergone pre-clinical and clinical evaluation, and studies with the remainder may be warranted. Changes to Hrh3, Sod1, Chrm4, Lrrk2, Nr4a1 and Prkca were replicated in an independent cohort of sixteen male Sprague-Dawley rats via quantitative reverse transcription polymerase chain reaction (qRT-PCR). Our findings support the continued use of post-weaning isolation rearing to investigate the neurobiology of stress-related disorders and evaluate therapeutic targets.

社会隔离是导致精神疾病的一个既定风险因素，随着SARS-CoV-2的传播，这一问题日益受到关注。我们利用 RNA 测序（RNA-Seq）技术对隔离饲养大鼠前额叶皮层（PFC）的转录组变化进行了无偏见的评估。为了深入了解这种操作对研究人类疾病的意义，我们将差异表达基因（DEGs）和富集的生物功能与精神疾病和神经发育疾病患者的死后额叶皮层组织数据集进行了比较。16只雄性Sprague-Dawley大鼠从出生后第22-24天断奶到收集额叶皮质组织进行RNA-Seq分析（第64-66天）期间，每4只一组或单独饲养。我们在分离物中共鉴定出 183 个 DEGs，其中 128 个与压力相关精神疾病和/或具有社交缺陷的神经发育状况患者的 PFC 组织中的 DEGs 一致。71个编码蛋白被基因-药物相互作用数据库归类为可药用蛋白。有趣的是，其中三个上调 DEGs（Hrh3、Snca 和 Sod1）的产物有拮抗剂或抑制剂，六个下调 DEGs（Chrm4、Klf2、Lrrk2、Nr4a1、Nr4a3 和 Prkca）的产物有激动剂或激活剂。其中一些已经进行了临床前和临床评估，其余的可能需要进行研究。通过定量反转录聚合酶链反应 (qRT-PCR)，Hrh3、Sod1、Chrm4、Lrrk2、Nr4a1 和 Prkca 的变化在十六只雄性 Sprague-Dawley 大鼠的独立队列中得到了复制。我们的研究结果支持继续使用断奶后隔离饲养来研究应激相关疾病的神经生物学并评估治疗目标。

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引用次数: 0

Cholecystokinin-expressing interneurons mediated inhibitory transmission and plasticity in basolateral amygdala modulate stress-induced anxiety-like behaviors in mice 胆囊收缩素表达的中间神经元介导的杏仁核基底外侧抑制性传导和可塑性调节小鼠应激诱发的焦虑样行为

IF 4.3 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2024-10-16 DOI: 10.1016/j.ynstr.2024.100680

The basolateral amygdala (BLA) hyperactivity has been implicated in the pathophysiology of anxiety disorders. We recently found that enhancing inhibitory transmission in BLA by chemo-genetic activation of local interneurons (INs) can reduce stress-induced anxiety-like behaviors in mice. Cholecystokinin interneurons (CCK-INs) are a major part of INs in BLA. It remains unknown whether CCK-INs modulated inhibition in BLA can mediate anxiety. In the present study, we found that BLA CCK-INs project extensively to most local excitatory neurons. Activating these CCK-INs using chemo-genetics and optogenetics can both effectively suppress electrical-induced neuronal activity within the BLA. Additionally, we observed that direct and sustained activation of CCK-INs within the BLA via chemo-genetics can mitigate stress-induced anxiety-like behaviors in mice and reduce stress-induced hyperactivity within the BLA itself. Furthermore, augmenting inhibitory plasticity within the BLA through a brief, 10-min high-frequency laser stimulation (HFLS) of CCK-INs also reduce stress-induced anxiety-like behaviors in mice. Collectively, these findings underscore the pivotal role of BLA CCK-IN-mediated inhibitory transmission and plasticity in modulating anxiety.

杏仁基底外侧（BLA）的过度活跃与焦虑症的病理生理学有关。我们最近发现，通过化学基因激活局部中间神经元（INs）来增强杏仁基底外侧的抑制性传导，可以减少小鼠由压力诱发的焦虑样行为。胆囊收缩素中间神经元（CCK-INs）是BLA中INs的主要组成部分。CCK-INs调节BLA中的抑制作用是否能介导焦虑仍是一个未知数。在本研究中，我们发现 BLA CCK-INs 广泛投射到大多数局部兴奋性神经元。利用化学遗传学和光遗传学激活这些 CCK-INs 都能有效抑制 BLA 内电诱导的神经元活动。此外，我们还观察到，通过化学遗传学直接、持续地激活 BLA 内的 CCK-INs 可以减轻应激诱导的小鼠焦虑样行为，并降低应激诱导的 BLA 自身的过度活跃性。此外，通过对CCK-INs进行10分钟的短暂高频激光刺激（HFLS）来增强BLA内的抑制可塑性，也能减少小鼠应激诱发的焦虑样行为。总之，这些发现强调了BLA CCK-IN介导的抑制性传递和可塑性在调节焦虑中的关键作用。

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引用次数: 0

Emotional comorbidities in epilepsy result from seizure-induced corticosterone activity 癫痫患者的情感并发症源于癫痫发作引起的皮质酮活动

IF 4.3 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2024-10-11 DOI: 10.1016/j.ynstr.2024.100678

People with epilepsy often have psychiatric comorbidities that can significantly impair their quality of life. We previously reported that repeated seizure activity persistently alters endocannabinoid (eCB) signaling in the amygdala which accounts for comorbid emotional dysregulation in rats, however, the mechanism by which these alterations in eCB signaling within the epileptic brain occur is unclear. Endocannabinoid signaling is influenced by corticosterone (CORT) to modulate cognitive and emotional processes and a hyperactive hypothalamic-pituitary-adrenal (HPA) axis occurs in both people with epilepsy and nonhuman animal models of epilepsy.

We employed selective pharmacological tools and a variety of approaches including whole-cell patch-clamp electrophysiology, behavioural paradigms and biochemical assays in amygdala kindled adult male Long-Evans rats. We aimed to determine whether seizures induce hypersecretion of CORT and the role this plays in eCB system dysregulation, impaired fear memory, and anxiety-like behaviours associated with seizure activity.

Plasma CORT levels were significantly and consistently elevated following seizures over the course of kindling. Pre-seizure administration with the CORT synthesis inhibitor metyrapone prevented this seizure-induced CORT increase, prevented amygdala anandamide downregulation, and synaptic alteration induced by seizure activity. Moreover, treatment with metyrapone or combined glucocorticoid receptor (GR)/mineralocorticoid receptor (MR) antagonists prior to each elicited seizure were equally effective in preventing chronically altered anxiety-like behaviour and fear memory responses.

Inhibiting seizure-induced corticosterone synthesis, or directly blocking the effects of CORT at GR/MR prevents deleterious changes in emotional processing and could be a treatment option for emotional comorbidities in epilepsy.

癫痫患者往往合并有精神疾病，这会严重影响他们的生活质量。我们以前曾报道，反复发作的癫痫活动会持续改变杏仁核中的内源性大麻素（eCB）信号传导，从而导致大鼠合并情绪失调，然而，癫痫患者大脑中 eCB 信号传导发生改变的机制尚不清楚。内源性大麻素信号传导受皮质酮（CORT）的影响，可调节认知和情绪过程，癫痫患者和非人类癫痫动物模型都会出现下丘脑-垂体-肾上腺（HPA）轴亢进。我们的目的是确定癫痫发作是否会诱发 CORT 分泌过多，以及这在 eCB 系统失调、恐惧记忆受损和与癫痫发作活动相关的焦虑样行为中所起的作用。癫痫发作前服用CORT合成抑制剂甲萘醌可防止癫痫发作引起的CORT升高，防止杏仁核anandamide下调和癫痫活动引起的突触改变。此外，在每次诱发癫痫发作前使用甲泼尼龙或糖皮质激素受体（GR）/矿质皮质激素受体（MR）联合拮抗剂治疗，对防止长期改变的焦虑样行为和恐惧记忆反应同样有效。

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引用次数: 0

Dynamic changes of media prefrontal cortex astrocytic activity in response to negative stimuli in male mice 雄性小鼠中前额叶皮层星形胶质细胞活动对负面刺激的动态变化

IF 4.3 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2024-10-04 DOI: 10.1016/j.ynstr.2024.100676

Astrocytes play significant roles in regulating the central stress response. Chronic stress impairs the structure and function of astrocytes in many brain regions such as media prefrontal cortex (mPFC) in multiple neuropsychiatric conditions, but the astrocytic dynamics on the timescale of behavior remains unclear. Here, we recorded mPFC astrocytic activity in freely behaving mice and found that astrocytes are activated immediately by different aversive stimuli. Astrocyte specific GCaMP6s calcium indicator were virally expressed in mPFC astrocytes and fiber photometry experiments revealed that astrocytes are activated by tail-restraint (TRT), foot shock (FS), open arm exploration, stressor of height, predator odor and social defeat (SD) stress. ΔF/F analyses demonstrated that an unpredictable stimulus such as elevated platform stress (EPS) at the initial encounter induced the most intense and rapid changes in astrocytic calcium activity, while a predictable 2,5-dihydro-2,4,5-trimethylthiazoline (TMT) stimulus resulted in the weakest response with a longer peak latency. In TRT, FS or SD test, a somatic stimulus led to higher average calcium activity level and faster average peak latency in repeated trails. Similar to TMT stimulus, astrocytic calcium activity in elevated plus maze (EPM) test exhibited a smaller average change in amplitude and the longest peak latency during open arm exploration. Moreover, astrocytic calcium activity exhibited different changes across behavioral states in SD tests. Our findings show that mPFC astrocytes exhibit distinct patterns of calcium activity in response to various negative stimuli, indicating that the dynamic activity of astrocytes may reflect the stress-related behavioral state under different stimulus conditions.

星形胶质细胞在调节中枢应激反应方面发挥着重要作用。在多种神经精神疾病中，慢性应激会损害中枢前额叶皮层（mPFC）等许多脑区的星形胶质细胞的结构和功能，但行为时间尺度上的星形胶质细胞动态仍不清楚。在这里，我们记录了自由行为小鼠的 mPFC 星形胶质细胞活动，发现星形胶质细胞会在不同的厌恶刺激下立即被激活。在 mPFC 星形胶质细胞中病毒表达了星形胶质细胞特异性 GCaMP6s 钙指示剂，纤维光度测定实验显示星形胶质细胞在受到尾约束（TRT）、足部冲击（FS）、张开手臂探索、身高应激源、捕食者气味和社交失败（SD）应激时被激活。ΔF/F分析表明，初次接触高台应激（EPS）等不可预测的刺激会诱导星形胶质细胞钙活性发生最强烈和快速的变化，而可预测的2,5-二氢-2,4,5-三甲基噻唑啉（TMT）刺激会导致最微弱的反应和更长的峰值潜伏期。在TRT、FS或SD测试中，躯体刺激会导致更高的平均钙活性水平和更快的重复追踪平均峰值潜伏期。与TMT刺激类似，在高架加迷宫（EPM）测试中，星形胶质细胞钙活动在开臂探索过程中表现出较小的平均振幅变化和最长的峰值潜伏期。此外，在 SD 测试中，星形胶质细胞钙活动在不同行为状态下表现出不同的变化。我们的研究结果表明，mPFC星形胶质细胞在对各种负性刺激做出反应时表现出不同的钙活动模式，这表明星形胶质细胞的动态活动可能反映了在不同刺激条件下与应激相关的行为状态。

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引用次数: 0

Behavioral and neural correlates of diverse conditioned fear responses in male and female rats 雌雄大鼠各种条件性恐惧反应的行为和神经相关性

IF 4.3 2区医学 Q1 NEUROSCIENCES

Neurobiology of Stress

Pub Date : 2024-09-21 DOI: 10.1016/j.ynstr.2024.100675

Pavlovian fear conditioning is a widely used tool that models associative learning in rodents. For decades the field has used predominantly male rodents and focused on a sole conditioned fear response: freezing. However, recent work from our lab and others has identified darting as a female-biased conditioned response, characterized by an escape-like movement across a fear conditioning chamber. It is also accompanied by a behavioral phenotype: Darters reliably show decreased freezing compared to Non-darters and males and reach higher velocities in response to the foot shock (“shock response”). However, the relationship between shock response and conditioned darting is not known. This study investigated if this link is due to differences in general processing of aversive stimuli between Darters, Non-darters and males. Across a variety of modalities, including corticosterone measures, the acoustic startle test, and sensitivity to thermal pain, Darters were found not to be more reactive or sensitive to aversive stimuli, and, in some cases, they appear less reactive to Non-darters and males. Analyses of cFos activity in regions involved in pain and fear processing following fear conditioning identified discrete patterns of expression among Darters, Non-darters, and males exposed to low and high intensity foot shocks. The results from these studies further our understanding of the differences between Darters, Non-darters and males and highlight the importance of studying individual differences in fear conditioning as indicators of fear state.

巴甫洛夫恐惧条件反射是一种广泛使用的啮齿动物联想学习模型工具。几十年来，该领域一直主要使用雄性啮齿动物，并专注于唯一的条件性恐惧反应：冻结。然而，我们实验室和其他实验室最近的研究发现，飞奔是一种偏向雌性的条件反应，其特征是在恐惧条件反射室中进行类似逃跑的运动。它还伴随着一种行为表型：与非镖鱼和雄性镖鱼相比，镖鱼能可靠地表现出较低的凝滞性，并在脚部冲击下达到较高的速度（"冲击反应"）。然而，冲击反应与条件飞镖之间的关系尚不清楚。本研究调查了这种联系是否是由于短吻鳄、非短吻鳄和雄性短吻鳄对厌恶刺激的一般处理过程存在差异造成的。在皮质酮测量、声学惊吓试验和对热痛的敏感性等多种模式中，我们发现短吻鳄对厌恶刺激的反应性或敏感性并不更高，在某些情况下，它们的反应性似乎低于非短吻鳄和雄性短吻鳄。在恐惧条件反射后，对涉及疼痛和恐惧处理区域的 cFos 活动进行分析，发现在暴露于低强度和高强度足部冲击的短吻鳄、非短吻鳄和雄性短吻鳄中，cFos 的表达模式各不相同。这些研究结果进一步加深了我们对短吻鳄、非短吻鳄和雄性短吻鳄之间差异的理解，并强调了研究作为恐惧状态指标的恐惧条件反射中个体差异的重要性。

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引用次数: 0