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Social isolation postweaning alters reward-related dopamine dynamics in a region-specific manner in adolescent male rats 断奶后的社会隔离会以特定区域的方式改变青春期雄性大鼠与奖赏相关的多巴胺动态变化
IF 5 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-03-02 DOI: 10.1016/j.ynstr.2024.100620
Valeria Lallai , Cristina Congiu , Giulia Craig , Letizia Manca , Yen-Chu Chen , Angeline J. Dukes , Christie D. Fowler , Laura Dazzi

Early development is characterized by dynamic transitions in brain maturation, which may be impacted by environmental factors. Here, we sought to determine the effects of social isolation from postweaning and during adolescence on reward behavior and dopaminergic signaling in male rats. Subjects were socially isolated or group housed at postnatal day 21. Three weeks later, extracellular dopamine concentrations were examined in the medial prefrontal cortex (mPFC) and nucleus accumbens shell (NAc) during a feeding bout. Surprisingly, opposing effects were found in which increased mPFC dopamine concentrations were observed in group housed, but not isolated, rats. In stark contrast, increased dopamine levels were found in the NAc of isolated, but not group housed, rats. Moreover, the absence of an effect in the mPFC of the isolated rats could not be reversed by subsequent group housing, demonstrating the remarkable long-term effects on dopamine signaling dynamics. When provided a highly palatable food, the isolated subjects exhibited a dramatic increase in mPFC dopamine levels when the chocolate was novel, but no effects following chronic chocolate consumption. In contrast, the group housed subjects showed significantly increased dopamine levels only with chronic chocolate consumption. The dopamine changes were correlated with differences in behavioral measures. Importantly, the deficit in reward-related behavior during isolation could be reversed by microinjection of either dopamine or cocaine into the mPFC. Together, these data provide evidence that social isolation from postweaning and during adolescence alters reward-induced dopamine levels in a brain region-specific manner, which has important functional implications for reward-related behavior.

早期发育的特点是大脑成熟的动态过渡,这可能会受到环境因素的影响。在此,我们试图确定断奶后和青春期的社会隔离对雄性大鼠奖励行为和多巴胺能信号传导的影响。受试者在出生后第 21 天被隔离或集体饲养。三周后,在喂食过程中检测内侧前额叶皮层(mPFC)和伏隔核(NAc)的细胞外多巴胺浓度。令人惊讶的是,研究人员发现,分组饲养的大鼠(而非隔离饲养的大鼠)mPFC多巴胺浓度增加,而分组饲养的大鼠(而非隔离饲养的大鼠)则相反。与此形成鲜明对比的是,隔离饲养的大鼠多巴胺水平升高,而非分组饲养的大鼠多巴胺水平升高。此外,隔离大鼠的 mPFC 没有受到影响,但随后的分组饲养却无法逆转,这表明多巴胺信号动态受到了显著的长期影响。当提供一种高适口性食物时,当巧克力是一种新奇的食物时,隔离受试者表现出 mPFC 多巴胺水平的急剧上升,但长期食用巧克力后则没有任何影响。相比之下,群居受试者只有在长期食用巧克力时多巴胺水平才会显著增加。多巴胺的变化与行为测量的差异相关。重要的是,在多巴胺或可卡因显微注射到mPFC后,隔离期间奖赏相关行为的缺失可以逆转。总之,这些数据提供了证据,表明从断奶后到青春期的社会隔离会以特定脑区的方式改变奖赏诱导的多巴胺水平,这对奖赏相关行为具有重要的功能影响。
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引用次数: 0
The role of brain serotonin signaling in excessive alcohol consumption and withdrawal: A call for more research in females 大脑血清素信号在过度饮酒和戒酒中的作用:呼吁对女性进行更多研究
IF 5 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-02-20 DOI: 10.1016/j.ynstr.2024.100618
Megan E. Castle, Meghan E. Flanigan

Alcohol Use Disorder (AUD) is a leading cause of death and disability worldwide, but current treatments are insufficient in fully addressing the symptoms that often lead to relapses in alcohol consumption. The brain's serotonin system has been implicated in AUD for decades and is a major regulator of stress-related behaviors associated with increased alcohol consumption. This review will discuss the current literature on the association between neurobiological adaptations in serotonin systems and AUD in humans as well as the effectiveness of serotonin receptor manipulations on alcohol-related behaviors like consumption and withdrawal. We will further discuss how these findings in humans relate to findings in animal models, including a comparison of systemic pharmacological manipulations modulating alcohol consumption. We next provide a detailed overview of brain region-specific roles for serotonin and serotonin receptor signaling in alcohol-related behaviors in preclinical animal models, highlighting the complexity of forming a cohesive model of serotonin function in AUD and providing possible avenues for more effective therapeutic intervention. Throughout the review, we discuss what is known about sex differences in the sequelae of AUD and the role of serotonin in these sequelae. We stress a critical need for additional studies in women and female animals so that we may build a clearer path to elucidating sex-specific serotonergic mechanisms and develop better treatments.

酒精使用障碍(AUD)是导致全球死亡和残疾的一个主要原因,但目前的治疗方法不足以完全解决经常导致酒精消费复发的症状。几十年来,大脑的血清素系统一直与 AUD 有关,它是与酒精消费增加有关的压力相关行为的主要调节器。本综述将讨论血清素系统的神经生物学适应性与人类 AUD 之间关联的现有文献,以及操纵血清素受体对酒精相关行为(如饮酒和戒酒)的有效性。我们将进一步讨论这些人类研究结果与动物模型研究结果之间的关系,包括对调节酒精消耗的系统药理作用进行比较。接下来,我们将详细概述临床前动物模型中血清素和血清素受体信号传导在酒精相关行为中的脑区特异性作用,突出强调在 AUD 中形成血清素功能凝聚模型的复杂性,并为更有效的治疗干预提供可能的途径。在整篇综述中,我们讨论了有关 AUD 后遗症的性别差异以及血清素在这些后遗症中的作用的已知情况。我们强调亟需在女性和雌性动物中开展更多研究,从而为阐明性别特异性血清素能机制和开发更好的治疗方法开辟一条更清晰的道路。
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引用次数: 0
Sex-specific threat responding and neuronal engagement in carbon dioxide associated fear and extinction: Noradrenergic involvement in female mice 与二氧化碳相关的恐惧和消退中的性别特异性威胁反应和神经元参与:雌性小鼠去甲肾上腺素能的参与
IF 5 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-02-20 DOI: 10.1016/j.ynstr.2024.100617
Rebecca Ahlbrand , Allison Wilson , Patrick Woller , Yuv Sachdeva , Jayden Lai , Nikki Davis , James Wiggins , Renu Sah

Difficulty in appropriately responding to threats is a key feature of psychiatric disorders, especially fear-related conditions such as panic disorder (PD) and posttraumatic stress disorder (PTSD). Most prior work on threat and fear regulation involves exposure to external threatful cues. However, fear can also be triggered by aversive, within-the-body, sensations. This interoceptive signaling of fear is highly relevant to PD and PTSD but is not well understood, especially in the context of sex. Using female and male mice, the current study investigated fear-associated spontaneous and conditioned behaviors to carbon dioxide (CO2) inhalation, a potent interoceptive threat that induces fear and panic. We also investigated whether behavioral sensitivity to CO2 is associated with delayed PTSD-relevant behaviors. CO2 evoked heterogenous freezing behaviors in both male and female animals. However, active, rearing behavior was significantly reduced in CO2-exposed male but not female mice. Interestingly, behavioral sensitivity to CO2 was associated with compromised fear extinction, independent of sex. However, in comparison to CO2-exposed males, females elicited less freezing and higher rearing during extinction suggesting an engagement of active versus passive defensive coping. Persistent neuronal activation marker ΔFosB immuno-mapping revealed attenuated engagement of infralimbic-prefrontal areas in both sexes but higher activation of brain stem locus coeruleus (LC) area in females. Inter-regional co-activation mapping revealed sex-independent disruptions in the infralimbic-amygdala associations but altered LC associations only in CO2-exposed female mice. Lastly, dopamine β hydroxylase positive (DβH + ve) noradrenergic neuronal cell counts in the LC correlated with freezing and rearing behaviors during CO2 inhalation and extinction only in female but not male mice. Collectively, these data provide evidence for higher active defensive responding to interoceptive threat CO2-associated fear in females that may stem from increased recruitment of the brainstem noradrenergic system. Our findings reveal distinct contributory mechanisms that may promote sex differences in fear and panic associated pathologies.

难以对威胁做出适当反应是精神疾病的一个主要特征,尤其是与恐惧相关的疾病,如惊恐障碍(PD)和创伤后应激障碍(PTSD)。之前关于威胁和恐惧调节的研究大多涉及暴露于外部威胁线索的情况。然而,身体内部的厌恶感觉也会引发恐惧。这种恐惧的感知间信号与帕金森病和创伤后应激障碍高度相关,但人们对其了解不多,尤其是在性别背景下。本研究使用雌性和雄性小鼠,调查了吸入二氧化碳(CO2)时与恐惧相关的自发行为和条件行为。我们还研究了对二氧化碳的行为敏感性是否与创伤后应激障碍相关的延迟行为有关。二氧化碳会诱发雄性和雌性动物出现不同的冻结行为。然而,暴露于二氧化碳的雄性小鼠的主动饲养行为明显减少,而雌性小鼠则没有。有趣的是,对二氧化碳的行为敏感性与恐惧消退能力受损有关,与性别无关。然而,与暴露于二氧化碳的雄性小鼠相比,雌性小鼠在熄灭过程中引起的冻结更少,饲养程度更高,这表明雌性小鼠参与了主动与被动的防御应对。持续性神经元激活标记物ΔFosB免疫图谱显示,雌雄动物的下边缘-前额叶区的参与程度都有所降低,但雌性动物的脑干定位区(LC)的激活程度更高。区域间共同激活图谱显示,下边缘-杏仁核关联的中断与性别无关,但只有暴露于二氧化碳的雌性小鼠的LC关联发生了改变。最后,LC 中多巴胺 β 羟化酶阳性(DβH + ve)去甲肾上腺素能神经元细胞数量与吸入二氧化碳时的冻结和饲养行为相关,只有雌性小鼠与之相关,雄性小鼠则不然。总之,这些数据提供了证据,证明雌性小鼠对二氧化碳相关恐惧的感知威胁做出了更高的主动防御反应,这可能源于脑干去甲肾上腺素能系统招募的增加。我们的研究结果揭示了可能导致恐惧和恐慌相关病症的性别差异的不同机制。
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引用次数: 0
Isolation of the differential effects of chronic and acute stress in a manner that is not confounded by stress severity 以不受压力严重程度影响的方式隔离慢性和急性压力的不同影响
IF 5 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-02-10 DOI: 10.1016/j.ynstr.2024.100616
Michael A. Conoscenti , Daniel B. Weatherill , Yuqing Huang , Raphael Tordjman , Michael S. Fanselow

Firm conclusions regarding the differential effects of the maladaptive consequences of acute versus chronic stress on the etiology and symptomatology of stress disorders await a model that isolates chronicity as a variable for studying the differential effects of acute versus chronic stress. This is because most previous studies have confounded chronicity with the total amount of stress. Here, we have modified the stress-enhanced fear learning (SEFL) protocol, which models some aspects of posttraumatic stress disorder (PTSD) following an acute stressor, to create a chronic variant that does not have this confound. Comparing results from this new protocol to the acute protocol, we found that chronic stress further potentiates enhanced fear-learning beyond the nonassociative enhancement induced by acute stress. This additional component is not observed when the unconditional stimulus (US) used during subsequent fear learning is distinct from the US used as the stressor, and is enhanced when glucose is administered following stressor exposure, suggesting that it is associative in nature. Furthermore, extinction of stressor-context fear blocks this additional associative component of SEFL as well as reinstatement of generalized fear, suggesting reinstatement of generalized fear may underlie this additional SEFL component.

关于急性和慢性压力对应激障碍的病因学和症状学所产生的不良后果的不同影响,还有待于建立一个模型,将慢性化作为研究急性和慢性压力的不同影响的一个变量。这是因为之前的大多数研究都将慢性应激与应激总量混为一谈。在这里,我们修改了应激增强恐惧学习(SEFL)方案(该方案模拟了急性应激后创伤后应激障碍(PTSD)的某些方面),创建了一个没有这种混淆的慢性变体。将这种新方案的结果与急性方案的结果进行比较后,我们发现,慢性应激进一步增强了恐惧学习能力,超出了急性应激引起的非联想增强。如果在随后的恐惧学习过程中使用的无条件刺激(US)与作为应激源的US不同,就不会观察到这种额外的成分,而如果在暴露于应激源后给予葡萄糖,这种额外的成分就会增强,这表明它在本质上是联想性的。此外,应激源-情境恐惧的消退会阻止 SEFL 的这种额外联想成分以及泛化恐惧的恢复,这表明泛化恐惧的恢复可能是 SEFL 这种额外成分的基础。
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引用次数: 0
Integrating and fragmenting memories under stress and alcohol 压力和酒精下的记忆整合与碎片化
IF 5 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-02-08 DOI: 10.1016/j.ynstr.2024.100615
Krystian B. Loetscher , Elizabeth V. Goldfarb

Stress can powerfully influence the way we form memories, particularly the extent to which they are integrated or situated within an underlying spatiotemporal and broader knowledge architecture. These different representations in turn have significant consequences for the way we use these memories to guide later behavior. Puzzlingly, although stress has historically been argued to promote fragmentation, leading to disjoint memory representations, more recent work suggests that stress can also facilitate memory binding and integration. Understanding the circumstances under which stress fosters integration will be key to resolving this discrepancy and unpacking the mechanisms by which stress can shape later behavior. Here, we examine memory integration at multiple levels: linking together the content of an individual experience, threading associations between related but distinct events, and binding an experience into a pre-existing schema or sense of causal structure. We discuss neural and cognitive mechanisms underlying each form of integration as well as findings regarding how stress, aversive learning, and negative affect can modulate each. In this analysis, we uncover that stress can indeed promote each level of integration. We also show how memory integration may apply to understanding effects of alcohol, highlighting extant clinical and preclinical findings and opportunities for further investigation. Finally, we consider the implications of integration and fragmentation for later memory-guided behavior, and the importance of understanding which type of memory representation is potentiated in order to design appropriate interventions.

压力会有力地影响我们形成记忆的方式,尤其是记忆在多大程度上被整合或置于潜在的时空和更广泛的知识架构中。这些不同的表征反过来又会对我们利用这些记忆指导以后行为的方式产生重大影响。令人费解的是,虽然压力在历史上一直被认为会促进记忆的分裂,导致记忆表征的脱节,但最近的研究表明,压力也能促进记忆的结合和整合。了解压力在何种情况下会促进记忆整合,将是解决这一差异并揭示压力影响日后行为的机制的关键。在这里,我们将从多个层面来研究记忆整合:将单个经验的内容联系在一起,在相关但不同的事件之间建立联系,以及将经验与预先存在的图式或因果结构感结合在一起。我们将讨论每种整合形式背后的神经和认知机制,以及有关压力、厌恶学习和负面情绪如何调节每种整合形式的研究结果。在这一分析中,我们发现压力确实可以促进每种形式的整合。我们还展示了记忆整合如何应用于理解酒精的影响,强调了现有的临床和临床前研究结果以及进一步研究的机会。最后,我们探讨了整合和分裂对以后记忆引导行为的影响,以及了解哪种类型的记忆表征会被强化以设计适当干预措施的重要性。
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引用次数: 0
Does sleep promote adaptation to acute stress: An experimental study 睡眠是否能促进对急性压力的适应:一项实验研究
IF 5 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-02-04 DOI: 10.1016/j.ynstr.2024.100613
Emil Hein , Risto Halonen , Thomas Wolbers , Tommi Makkonen , Markus Kyllönen , Liisa Kuula , Ilmari Kurki , Philipp Stepnicka , Anu-Katriina Pesonen

Objectives

Evidence of the impact of chronic stress on sleep is abundant, yet experimental sleep studies with a focus on acute stress are scarce and the results are mixed. Our study aimed to fill this gap by experimentally investigating the effects of pre-sleep social stress on sleep dynamics during the subsequent night, as measured with polysomnography (PSG).

Methods

Thirty-four healthy individuals (65% females, Mage = 25.76 years SD = 3.35) underwent a stress-inducing (SC) or neutral control condition (CC) in virtual reality (VR). We used overnight EEG measurements to analyze the basic sleep parameters and power spectral density (PSD) across the sleep cycles, and measured heart rate and its variability (HRV), skin electrodermal activity (EDA), and salivary cortisol to capture physiological arousal during the VR task and the pre-sleep period.

Results

Following acute stress (SC), the amount of slow-wave sleep (SWS) was higher and N2 sleep lower relative to CC, specifically in the first sleep cycle. In SC, PSD was elevated in the beta-low (16–24 Hz) and beta-high (25–35 Hz) frequency ranges during both stages N2 and SWS over the entire night.

Conclusions

Sleep promoted adaptation to acute social stress by a longer duration of SWS in the subsequent sleep period, especially in early sleep. A similar homeostatic effect towards restorative sleep is well-evidenced in animal model stress studies but has not been previously reported in experimental human studies. Whether the high-frequency PSD activity during stages N2 and SWS also serves in the resolution of transient stress, remains open.

目的有大量证据表明慢性压力对睡眠有影响,但以急性压力为重点的实验性睡眠研究却很少,而且结果也不尽相同。我们的研究旨在通过多导睡眠图(PSG)的测量,实验性地研究睡前社会压力对随后一夜睡眠动态的影响,从而填补这一空白。方法34名健康人(65%为女性,年龄:25.76岁,平均年龄:3.35岁)在虚拟现实(VR)中接受了压力诱导(SC)或中性控制条件(CC)。我们使用通宵脑电图测量来分析各睡眠周期的睡眠结构和功率谱密度(PSD),并测量了心率及其变异性(HRV)、皮肤电活动(EDA)和唾液皮质醇,以捕捉 VR 任务期间和睡眠前的生理唤醒。在SC中,整夜N2和SWS阶段的β-低(16-24Hz)和β-高(25-35Hz)频率范围内的PSD都升高了。结论在随后的睡眠期,尤其是在早期睡眠中,睡眠通过延长SWS的持续时间促进了对急性社会压力的适应。类似的恢复性睡眠平衡效应在动物应激模型研究中得到了充分证实,但在人类实验研究中却未见报道。N2和SWS阶段的高频PSD活动是否也能起到缓解瞬时压力的作用,目前尚无定论。
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引用次数: 0
Prenatal and postnatal influences on behavioral development in a mouse model of preconceptional stress 产前和产后对受孕前应激小鼠模型行为发育的影响
IF 5 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-02-03 DOI: 10.1016/j.ynstr.2024.100614
Joseph Scarborough , Monica Iachizzi , Sina M. Schalbetter , Flavia S. Müller , Ulrike Weber-Stadlbauer , Juliet Richetto

Depression during pregnancy is detrimental for the wellbeing of the expectant mother and can exert long-term consequences on the offspring's development and mental health. In this context, both the gestational environment and the postpartum milieu may be negatively affected by the depressive pathology. It is, however, challenging to assess whether the contributions of prenatal and postnatal depression exposure are distinct, interactive, or cumulative, as it is unclear whether antenatal effects are due to direct effects on fetal development or because antenatal symptoms continue postnatally. Preclinical models have sought to answer this question by implementing stressors that induce a depressive-like state in the dams during pregnancy and studying the effects on the offspring. The aim of our present study was to disentangle the contribution of direct stress in utero from possible changes in maternal behavior in a novel model of preconceptional stress based on social isolation rearing (SIR). Using a cross-fostering paradigm in this model, we show that while SIR leads to subtle changes in maternal behavior, the behavioral changes observed in the offspring are driven by a complex interaction between sex, and prenatal and postnatal maternal factors. Indeed, male offspring are more sensitive to the prenatal environment, as demonstrated by behavioral and transcriptional changes driven by their birth mother, while females are likely affected by more complex interactions between the pre and the postpartum milieu, as suggested by the important impact of their surrogate foster mother. Taken together, our findings suggest that male and female offspring have different time-windows and behavioral domains of susceptibility to maternal preconceptional stress, and thus underscore the importance of including both sexes when investigating the mechanisms that mediate the negative consequences of exposure to such stressor.

孕期抑郁症不利于孕妇的健康,并可能对后代的发育和心理健康造成长期影响。在这种情况下,妊娠环境和产后环境都可能受到抑郁病理的负面影响。然而,评估产前和产后抑郁暴露的贡献是不同的、交互的还是累积的,是一项挑战,因为目前还不清楚产前影响是由于对胎儿发育的直接影响,还是因为产前症状在产后仍在继续。临床前模型试图回答这个问题,方法是在母体妊娠期间施加能诱发类似抑郁状态的压力,并研究其对后代的影响。我们本研究的目的是在一种基于社会隔离饲养(SIR)的新型孕前压力模型中,将子宫内的直接压力与母体行为的可能变化区分开来。通过在该模型中使用交叉寄养范式,我们发现虽然社会隔离饲养会导致母体行为的微妙变化,但在后代身上观察到的行为变化是由性别、产前和产后母体因素之间复杂的相互作用所驱动的。事实上,雄性后代对产前环境更敏感,其行为和转录变化由生母驱动,而雌性后代则可能受到产前和产后环境之间更复杂的相互作用的影响,代养母亲的重要影响也说明了这一点。总之,我们的研究结果表明,男性和女性的后代易受孕前母体压力影响的时间窗口和行为领域不同,因此在研究介导暴露于这种压力的负面影响的机制时,将两性都包括在内非常重要。
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引用次数: 0
Genetic disruption of dopamine β-hydroxylase dysregulates innate responses to predator odor in mice 基因干扰多巴胺β-羟化酶会导致小鼠对捕食者气味的先天反应失调
IF 5 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-02-02 DOI: 10.1016/j.ynstr.2024.100612
Joyce Liu , Daniel J. Lustberg , Abigail Galvez, L. Cameron Liles, Katharine E. McCann, David Weinshenker

In rodents, exposure to predator odors such as cat urine acts as a severe stressor that engages innate defensive behaviors critical for survival in the wild. The neurotransmitters norepinephrine (NE) and dopamine (DA) modulate anxiety and predator odor responses, and we have shown previously that dopamine β-hydroxylase knockout (Dbh −/−), which reduces NE and increases DA in mouse noradrenergic neurons, disrupts innate behaviors in response to mild stressors such as novelty. We examined the consequences of Dbh knockout on responses to predator odor (bobcat urine) and compared them to Dbh-competent littermate controls. Over the first 10 min of predator odor exposure, controls exhibited robust defensive burying behavior, whereas Dbh −/− mice showed high levels of grooming. Defensive burying was potently suppressed in controls by drugs that reduce NE transmission, while excessive grooming in Dbh −/− mice was blocked by DA receptor antagonism. In response to a cotton square scented with a novel “neutral” odor (lavender), most control mice shredded the material, built a nest, and fell asleep within 90 min. Dbh −/− mice failed to shred the lavender-scented nestlet, but still fell asleep. In contrast, controls sustained high levels of arousal throughout the predator odor test and did not build nests, while Dbh −/− mice were asleep by the 90-min time point, often in shredded bobcat urine-soaked nesting material. Compared with controls exposed to predator odor, Dbh −/− mice demonstrated decreased c-fos induction in the anterior cingulate cortex, lateral septum, periaqueductal gray, and bed nucleus of the stria terminalis, but increased c-fos in the locus coeruleus and medial amygdala. These data indicate that relative ratios of central NE and DA signaling coordinate the type and valence of responses to predator odor.

对于啮齿类动物来说,暴露于捕食者气味(如猫尿)是一种严重的应激反应,会引发对野外生存至关重要的先天防御行为。神经递质去甲肾上腺素(NE)和多巴胺(DA)调节焦虑和捕食者气味反应,我们之前已经证明,多巴胺β-羟化酶敲除(Dbh -/-)会减少小鼠去甲肾上腺素能神经元中的NE,增加DA,从而破坏对新奇事物等轻度应激源的先天性行为。我们研究了Dbh基因敲除(Dbh -/-)对捕食者气味(山猫尿液)反应的影响,并将其与Dbh功能正常的同窝对照组进行了比较。在暴露于捕食者气味的最初10分钟内,对照组小鼠表现出强烈的防御性掩埋行为,而Dbh -/-小鼠则表现出高水平的梳理行为。降低NE传递的药物可有效抑制对照组的防御性掩埋行为,而Dbh -/-小鼠的过度梳理行为可被DA受体拮抗剂阻断。对于带有新奇 "中性 "气味(薰衣草)的棉花方块,大多数对照组小鼠会在90分钟内将其撕碎、筑巢并入睡。Dbh -/-小鼠未能撕碎薰衣草香味的小窝,但仍然睡着了。相比之下,对照组在整个捕食者气味测试过程中都保持着高水平的唤醒,并且没有筑巢,而Dbh -/-小鼠在90分钟的时间点前就已经睡着了,通常是在山猫尿液浸泡过的碎巢材料中睡着的。与暴露于捕食者气味的对照组相比,Dbh -/-小鼠在前扣带回皮层、外侧隔膜、丘脑周围灰质和纹状体末端床核中的c-fos诱导减少,但在脑室和内侧杏仁核中的c-fos诱导增加。这些数据表明,中枢NE和DA信号的相对比例协调了对捕食者气味的反应类型和情绪。
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引用次数: 0
Frontal cortical volume deficits as enduring evidence of childhood abuse in community adults with AUD and HIV infection comorbidity 额叶皮质体积缺陷是社区成人中合并有 AUD 和 HIV 感染者童年受虐待的持久证据
IF 5 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-01-22 DOI: 10.1016/j.ynstr.2024.100608
Stephanie A. Sassoon , Rosemary Fama , Kilian M. Pohl , Adolf Pfefferbaum , Edith V. Sullivan

Background

Childhood abuse is an underappreciated source of stress, associated with adverse mental and physical health consequences. Childhood abuse has been directly associated with risky behavior thereby increasing the likelihood of alcohol misuse and risk of HIV infection, conditions associated with brain structural and functional deficits. Here, we examined the neural and behavioral correlates of childhood trauma history in alcohol use disorder (AUD), HIV infection (HIV), and their comorbidity (AUD+HIV).

Methods

Occurrence of childhood trauma was evaluated by retrospective interview. Cortical (frontal, temporal, parietal, and occipital), subcortical (hippocampus, amygdala), and regional frontal volumes were derived from structural MRI, adjusted for intracranial volume and age. Test scores of executive functioning, attention/working memory, verbal/visual learning, verbal/visual memory, and motor speed functional domains were standardized on age and education of a laboratory control group.

Results

History of childhood abuse was associated with smaller frontal lobe volumes regardless of diagnosis. For frontal subregional volumes, history of childhood abuse was selectively associated with smaller orbitofrontal and supplementary motor volumes. In participants with a child abuse history, poorer verbal/visual memory performance was associated with smaller orbitofrontal and frontal middle volumes, whereas in those without childhood abuse, poorer verbal/visual memory performance was associated with smaller orbitofrontal, frontal superior, and supplemental motor volumes.

Conclusions

Taken together, these results comport with and extend the findings that childhood abuse is associated with brain and behavioral sequelae in AUD, HIV, and AUD+HIV comorbidity. Further, these findings suggest that sequelae of abuse in childhood may be best conceptualized as a spectrum disorder as significant deficits may be present in those who may not meet criteria for a formal trauma-related diagnosis yet may be suffering enduring stress effects on brain structural and functional health.

背景童年虐待是一种未被充分认识的压力来源,与不良的身心健康后果相关。童年虐待与危险行为直接相关,从而增加了酗酒的可能性和感染艾滋病病毒的风险,这些情况与大脑结构和功能缺陷有关。在此,我们研究了酗酒障碍(AUD)、艾滋病病毒感染(HIV)及其合并症(AUD+HIV)中童年创伤史的神经和行为相关性。皮质(额叶、颞叶、顶叶和枕叶)、皮质下(海马、杏仁核)和区域额叶体积由结构性核磁共振成像得出,并根据颅内体积和年龄进行了调整。执行功能、注意力/工作记忆、言语/视觉学习、言语/视觉记忆和运动速度等功能领域的测试得分根据实验室对照组的年龄和教育程度进行了标准化处理。就额叶亚区体积而言,童年虐待史选择性地与眶额叶和辅助运动区体积较小有关。在有儿童虐待史的参与者中,较差的言语/视觉记忆表现与较小的眶额叶和额叶中部体积有关,而在没有儿童虐待史的参与者中,较差的言语/视觉记忆表现与较小的眶额叶、额叶上部和辅助运动体积有关。此外,这些研究结果表明,童年受虐后遗症最好被概念化为一种谱系障碍,因为那些可能不符合正式创伤相关诊断标准,但可能对大脑结构和功能健康造成持久应激影响的人可能存在明显缺陷。
{"title":"Frontal cortical volume deficits as enduring evidence of childhood abuse in community adults with AUD and HIV infection comorbidity","authors":"Stephanie A. Sassoon ,&nbsp;Rosemary Fama ,&nbsp;Kilian M. Pohl ,&nbsp;Adolf Pfefferbaum ,&nbsp;Edith V. Sullivan","doi":"10.1016/j.ynstr.2024.100608","DOIUrl":"10.1016/j.ynstr.2024.100608","url":null,"abstract":"<div><h3>Background</h3><p>Childhood abuse is an underappreciated source of stress, associated with adverse mental and physical health consequences. Childhood abuse has been directly associated with risky behavior thereby increasing the likelihood of alcohol misuse and risk of HIV infection, conditions associated with brain structural and functional deficits. Here, we examined the neural and behavioral correlates of childhood trauma history in alcohol use disorder (AUD), HIV infection (HIV), and their comorbidity (AUD+HIV).</p></div><div><h3>Methods</h3><p>Occurrence of childhood trauma was evaluated by retrospective interview. Cortical (frontal, temporal, parietal, and occipital), subcortical (hippocampus, amygdala), and regional frontal volumes were derived from structural MRI, adjusted for intracranial volume and age. Test scores of executive functioning, attention/working memory, verbal/visual learning, verbal/visual memory, and motor speed functional domains were standardized on age and education of a laboratory control group.</p></div><div><h3>Results</h3><p>History of childhood abuse was associated with smaller frontal lobe volumes regardless of diagnosis. For frontal subregional volumes, history of childhood abuse was selectively associated with smaller orbitofrontal and supplementary motor volumes. In participants with a child abuse history, poorer verbal/visual memory performance was associated with smaller orbitofrontal and frontal middle volumes, whereas in those without childhood abuse, poorer verbal/visual memory performance was associated with smaller orbitofrontal, frontal superior, and supplemental motor volumes.</p></div><div><h3>Conclusions</h3><p>Taken together, these results comport with and extend the findings that childhood abuse is associated with brain and behavioral sequelae in AUD, HIV, and AUD+HIV comorbidity. Further, these findings suggest that sequelae of abuse in childhood may be best conceptualized as a spectrum disorder as significant deficits may be present in those who may not meet criteria for a formal trauma-related diagnosis yet may be suffering enduring stress effects on brain structural and functional health.</p></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"29 ","pages":"Article 100608"},"PeriodicalIF":5.0,"publicationDate":"2024-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352289524000043/pdfft?md5=7ff3b4d56cbe3ab090853e523d58eebc&pid=1-s2.0-S2352289524000043-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139523287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Imaging a putative marker of brain cortisol regulation in alcohol use disorder 酒精使用障碍中大脑皮质醇调节的假定标记成像
IF 5 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-01-21 DOI: 10.1016/j.ynstr.2024.100609
Terril L. Verplaetse , Ansel T. Hillmer , Shivani Bhatt , Aleksandra Rusowicz , Songye Li , Nabeel Nabulsi , David Matuskey , Yiyun Huang , Sherry A. McKee , Kelly P. Cosgrove

Background

Stress is a potent activator of the hypothalamic-pituitary-adrenal (HPA) axis, initiating the release of glucocorticoid hormones, such as cortisol. Alcohol consumption can lead to HPA axis dysfunction, including altered cortisol levels. Until recently, research has only been able to examine peripheral cortisol associated with alcohol use disorder (AUD) in humans. We used positron emission tomography (PET) brain imaging with the radiotracer [18F]AS2471907 to measure 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), a cortisol-regenerating enzyme, in people with AUD compared to healthy controls.

Methods

We imaged 9 individuals with moderate to severe AUD (5 men, 4 women; mean age = 38 years) and 12 healthy controls (8 men, 4 women; mean age = 29 years). Participants received 93.5 ± 15.6 MBq of the 11β-HSD1 inhibitor radiotracer [18F]AS2471907 as a bolus injection and were imaged for 150–180 min on the High-Resolution Research Tomograph. 11β-HSD1 availability was quantified by [18F]AS2471907 volume of distribution (VT; mL/cm3). A priori regions of interest included amygdala, anterior cingulate cortex (ACC), hippocampus, ventromedial PFC (vmPFC) and caudate.

Results

Individuals with AUD consumed 52.4 drinks/week with 5.8 drinking days/week. Healthy controls consumed 2.8 drinks/week with 1.3 drinking days/week. Preliminary findings suggest that [18F]AS2471907 VT was higher in amygdala, ACC, hippocampus, vmPFC, and caudate of those with AUD compared to healthy controls (p < 0.05). In AUD, vmPFC [18F]AS2471907 VT was associated with drinks per week (r = 0.81, p = 0.01) and quantity per drinking episode (r = 0.75, p = 0.02).

Conclusions

This is the first in vivo examination of 11β-HSD1 availability in individuals with AUD. Our data suggest higher brain availability of the cortisol-regenerating enzyme 11β-HSD1 in people with AUD (vs. controls), and that higher vmPFC 11β-HSD1 availability is related to greater alcohol consumption. Thus, in addition to the literature suggesting that people with AUD have elevated peripheral cortisol, our findings suggest there may also be heightened central HPA activity. These findings set the foundation for future hypotheses on mechanisms related to HPA axis function in this population.

背景压力是下丘脑-垂体-肾上腺(HPA)轴的强效激活剂,可启动皮质醇等糖皮质激素的释放。饮酒会导致 HPA 轴功能紊乱,包括皮质醇水平的改变。直到最近,研究才得以检测与人类酒精使用障碍(AUD)相关的外周皮质醇。我们使用放射性示踪剂 [18F]AS2471907 进行正电子发射断层扫描(PET)脑成像,测量 AUD 患者与健康对照组的皮质醇再生酶 11β- 羟类固醇脱氢酶 1 型 (11β-HSD1)。参与者接受了 93.5 ± 15.6 MBq 的 11β-HSD1 抑制剂放射性示踪剂 [18F]AS2471907 的栓剂注射,并在高分辨率研究断层成像仪上进行了 150-180 分钟的成像。11β-HSD1的可用性通过[18F]AS2471907分布容积(VT;mL/cm3)进行量化。先验相关区域包括杏仁核、前扣带回皮层(ACC)、海马、腹内侧 PFC(vmPFC)和尾状核。健康对照组每周饮酒 2.8 次,每周饮酒天数为 1.3 天。初步研究结果表明,与健康对照组相比,AUD患者杏仁核、ACC、海马、vmPFC和尾状核的[18F]AS2471907 VT更高(p <0.05)。在 AUD 患者中,vmPFC [18F]AS2471907 VT 与每周饮酒量(r = 0.81,p = 0.01)和每次饮酒量(r = 0.75,p = 0.02)相关。我们的数据表明,在 AUD 患者(与对照组相比)中,大脑中皮质醇再生酶 11β-HSD1 的可用性较高,而且大脑皮质功能区 11β-HSD1 的可用性较高与饮酒量较大有关。因此,除了有文献表明 AUD 患者的外周皮质醇升高外,我们的研究结果还表明他们的中枢 HPA 活动也可能升高。这些发现为今后假设该人群 HPA 轴功能的相关机制奠定了基础。
{"title":"Imaging a putative marker of brain cortisol regulation in alcohol use disorder","authors":"Terril L. Verplaetse ,&nbsp;Ansel T. Hillmer ,&nbsp;Shivani Bhatt ,&nbsp;Aleksandra Rusowicz ,&nbsp;Songye Li ,&nbsp;Nabeel Nabulsi ,&nbsp;David Matuskey ,&nbsp;Yiyun Huang ,&nbsp;Sherry A. McKee ,&nbsp;Kelly P. Cosgrove","doi":"10.1016/j.ynstr.2024.100609","DOIUrl":"10.1016/j.ynstr.2024.100609","url":null,"abstract":"<div><h3>Background</h3><p>Stress is a potent activator of the hypothalamic-pituitary-adrenal (HPA) axis, initiating the release of glucocorticoid hormones, such as cortisol. Alcohol consumption can lead to HPA axis dysfunction, including altered cortisol levels. Until recently, research has only been able to examine peripheral cortisol associated with alcohol use disorder (AUD) in humans. We used positron emission tomography (PET) brain imaging with the radiotracer [<sup>18</sup>F]AS2471907 to measure 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), a cortisol-regenerating enzyme, in people with AUD compared to healthy controls.</p></div><div><h3>Methods</h3><p>We imaged 9 individuals with moderate to severe AUD (5 men, 4 women; mean age = 38 years) and 12 healthy controls (8 men, 4 women; mean age = 29 years). Participants received 93.5 ± 15.6 MBq of the 11β-HSD1 inhibitor radiotracer [<sup>18</sup>F]AS2471907 as a bolus injection and were imaged for 150–180 min on the High-Resolution Research Tomograph. 11β-HSD1 availability was quantified by [<sup>18</sup>F]AS2471907 volume of distribution (<em>V</em><sub>T</sub>; mL/cm<sup>3</sup>). <em>A priori</em> regions of interest included amygdala, anterior cingulate cortex (ACC), hippocampus, ventromedial PFC (vmPFC) and caudate.</p></div><div><h3>Results</h3><p>Individuals with AUD consumed 52.4 drinks/week with 5.8 drinking days/week. Healthy controls consumed 2.8 drinks/week with 1.3 drinking days/week. Preliminary findings suggest that [<sup>18</sup>F]AS2471907 <em>V</em><sub>T</sub> was higher in amygdala, ACC, hippocampus, vmPFC, and caudate of those with AUD compared to healthy controls (<em>p</em> &lt; 0.05). In AUD, vmPFC [<sup>18</sup>F]AS2471907 <em>V</em><sub>T</sub> was associated with drinks per week (r = 0.81, <em>p</em> = 0.01) and quantity per drinking episode (r = 0.75, <em>p</em> = 0.02).</p></div><div><h3>Conclusions</h3><p>This is the first <em>in vivo</em> examination of 11β-HSD1 availability in individuals with AUD. Our data suggest higher brain availability of the cortisol-regenerating enzyme 11β-HSD1 in people with AUD (vs. controls), and that higher vmPFC 11β-HSD1 availability is related to greater alcohol consumption. Thus, in addition to the literature suggesting that people with AUD have elevated peripheral cortisol, our findings suggest there may also be heightened central HPA activity. These findings set the foundation for future hypotheses on mechanisms related to HPA axis function in this population.</p></div>","PeriodicalId":19125,"journal":{"name":"Neurobiology of Stress","volume":"29 ","pages":"Article 100609"},"PeriodicalIF":5.0,"publicationDate":"2024-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2352289524000055/pdfft?md5=2ad0ca0c2b05a36a7d0a86365f2daa6f&pid=1-s2.0-S2352289524000055-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139539676","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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Neurobiology of Stress
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