Effects of stress across the lifespan

Stress is a known precipitant for metabolic and neurological diseases, with sensitive periods identified across the developmental continuum from conception to old age. However, the effects of stress may vary depending on the point or points along the developmental trajectory when adversity strikes. Past research has emphasized the consequences of stress on fully developed physiological systems in the brain and periphery, but more recent studies have explored the impact of stress on systems at different stages of maturation, with differential effects being revealed. This review provides an overview of the diverse effects of stress at critical developmental stages and the potential outcomes that may be associated with experiencing environmental adversity during ontogeny.     

认知神经心理学简介

认知神经心理学是认知心理学的一个分支。它的目的是探讨当人们执行认知活动的时候,心理信息加工过程是怎样的,所采用的手段是研究这些认知功能受损的病人。它与认知神经科学的不同在于：认知神经心理学关注的是心理（mind）,而认知神经科学关注的是大脑（特别是关注与认知有关的大脑机制）。研究认知神经心理学的方法也可以用于研究发展性认知障碍,如阅读障碍,或者特殊的语言损伤,这就是发展性认知神经心理学。这些方法还可以用于高级认知发面的研究,如信念形成和心理理论。这些高级认知方面的障碍是精神病学的范畴,因此这类研究错觉、幻想或虚构等的认知神经心理学叫做认知神经精神病学。认知神经心理学的典型特征有：1）研究症状,而不是并发症;2）采用个案研究,而不是群体研究;3）主要数据来源是症状间的双分离;4）致力于模块化认知模型的建立。     

Neuropeptide S: a novel modulator of stress and arousal

Neuropeptide S (NPS) is a recently identified bioactive peptide that modulates stress and arousal. NPS is expressed in a few discrete nuclei in the brainstem, such as the pericoerulear (locus coeruleus (LC)) area and the parabrachial nucleus. NPS activates its cognate G protein-coupled receptor at low nanomolar agonist concentrations and induces elevation of intracellular Ca2+ and cAMP, therefore acting as an excitatory transmitter. The NPS receptor is widely expressed in the brain, including regions known to regulate stress responses such as hypothalamus, thalamus, amygdala and limbic cortex. We have recently reported that the NPS system can modulate stress responses and induce wakefulness based on a battery of behavioral tests. Activation of NPS receptors induces arousal and reduces all sleep stages. At the same time, NPS produces anxiolytic-like effects in rodents. These studies indicate that the NPS system has a unique pharmacological profile to promote both anxiolytic and arousal effects. NPS might interact with other hypothalamic neuropeptide systems that are known to be involved in stress and appetite control and thus might be a valuable target for development of a new class of drugs to treat anxiety disorders.     

The neuroendocrinology of posttraumatic stress disorder: new directions

Studies of the hypothalamic-pituitary-adrenal (HPA) axis in persons with posttraumatic stress disorder (PTSD) have produced variable findings. This review focuses on the factors likely to have affected the outcome of these studies, including population characteristics and experimental design. Also discussed is a possible role for the adrenal neurosteroid dehydroepiandrosterone (DHEA) as a mediator of HPA axis adaptation to extreme stress and the psychiatric symptoms associated with PTSD. The antiglucocorticoid properties of DHEA may contribute to an upregulation of HPA axis responses as well as mitigate possible deleterious effects of high cortisol levels on the brain in some PTSD subpopulations. The neuromodulatory effects of DHEA and its metabolite DHEAS at gamma-aminobutyric acid and N-methyl-D-aspartate receptors in the brain may contribute to psychiatric symptoms associated with PTSD. The possible importance of other neurohormone systems in modulating HPA axis and symptom responses to traumatic stress is also discussed. Understanding the complex interactions of these stress-responsive neurosteroid and peptide systems may help explain the variability in patterns of HPA axis adaptation, brain changes, and psychiatric symptoms observed in PTSD and lead to better targeting of preventive and therapeutic interventions.     

GABA(A) receptor neurotransmission dysfunction in a mouse model of social isolation-induced stress: possible insights into a non-serotonergic mechanism of action of SSRIs in mood and anxiety disorders

Protracted social isolation in laboratory animals causes stress, which induces a variety of behavioral abnormalities including increased aggressiveness, anxiety-related behaviors, cognitive deficits and hyper locomotion. Many of these disorders are similar to the symptoms found in psychiatric disorders, such as depression, anxiety, premenstrual dysphoria and posttraumatic stress disorders (PTSD). Recent studies have demonstrated that male mice that have been socially isolated for more than 4 weeks show: (a) reduced responsiveness of GABA(A) receptors (GABA(A)-R) to the administrations of GABA mimetic drugs at GABA(A)-R; (b) downregulated biosynthesis of 3alpha,5alpha-tetrahydroprogesterone (3alpha,5alpha-THP) (allopregnanolone: ALLO), a neurosteroid with a potent positive allosteric modulatory effect on the action of GABA on GABA(A)-R; and (c) alterations in the expression of GABA(A)-R subunits (i.e. a decrease of alpha1/alpha2 and gamma2 subunits and an increase of alpha4 and alpha5 subunits). The selective serotonin reuptake inhibitor (SSRI) fluoxetine (FLX) and its congener norfluoxetine (Nor-FLX), when administered systemically at nmol/kg doses, normalize the reduced content of brain ALLO and the reduced responsiveness of GABA(A)-R to GABA mimetic drugs (i.e. pentobarbital) and also attenuate aggressive behavior in socially isolated mice in a stereospecific manner. Although these compounds inhibit ex vivo serotonin reuptake into brain tissue, their SSRI activities require high micromol/kg dose ranges and are not stereospecific. These studies suggest that in socially isolated mice, abnormalities of GABA(A)-R signal transduction are attributable to the downregulation of ALLO production and to a switch in heteropentameric GABA(A)-R subunit assembly composition. Hence, the normalization of ALLO biosynthesis may be a new target for the development of drugs effective for psychiatric disorders related to neurosteroid biosynthesis downregulation.     

CRF受体对五羟色胺系统的调节作用及早期环境因素的影响

早期环境因素持续影响脑与行为的发展,增加个体成年后应激相关精神疾病患病的易感性.应激反应的中枢启动因子促肾上腺皮质激素释放因子(corticotropin-releasing factor,CRF)通过两种受体CRF1和CRF2调节中缝背核(dorsal raphe nucleus,DRN)-五-羟色胺(serotonin,5-HT)系统,后者已被证实在应激相关情绪疾患发病和治疗过程中发挥重要作用.已知CRF受体以相互影响相互拮抗的方式动态调节DRN-5-HT系统,提示这两种受体相对作用的调节对于协调复杂环境中DRN-5-HT系统的应激反应过程起着关键性作用.早期环境因素和遗传因素交互作用导致CRF受体的分布和反应性持续改变并造成DRN-5-HT系统反应异常,可能是导致应激反应和精神疾病易感性个体差异的重要神经基础.     

Learning under stress: A role for the neural cell adhesion molecule NCAM

Stress is known to be a potent modulator of brain function and cognition. While prolonged and/or excessive stress generally exerts negative effects on learning and memory processes, acute stress can have differential effects on memory function depending on a number of factors (such as stress duration, stress intensity, timing and the source of the stress, as well as the learning type under study). Here, we have focused on the effects of ‘acute’ stress, and examined the literature attending to whether the “source of stress” is ‘intrinsic’ (i.e., when stress is originated by the cognitive task) or ‘extrinsic’ (i.e., when stress is induced by elements not related to the cognitive task). We have questioned here whether the neural cell adhesion molecule of the immunoglobulin superfamily (NCAM) contributes to the neurobiological mechanisms that translate the effects of these two different stress sources into the different behavioral and cognitive outcomes. NCAM is a cell adhesion macromolecule known to play a critical role in development and plasticity of the nervous system. NCAM and its post-translational modified form PSA-NCAM are critically involved in mechanisms of learning and memory and their expression levels are known to be highly susceptible to modulation by stress. Whereas available data are insufficient to conclude as to whether NCAM mediates extrinsic stress effects on learning and memory processes, we present systematic evidence supporting a key mediating role for both NCAM and PSA-NCAM in the facilitation of memory consolidation induced by intrinsic stress. Furthermore, NCAM is suggested to participate in some of the bidirectional effects of stress on memory processes, with its enhanced synaptic expression involved in facilitating stress actions while its reduced expression being related to impairing effects of stress on memory function.     

Regulatory interactions of stress and reward on rat forebrain opioidergic and GABAergic circuitry

Palatable food intake reduces stress responses, suggesting that individuals may consume such ?comfort? food as self-medication for stress relief. The mechanism by which palatable foods provide stress relief is not known, but likely lies at the intersection of forebrain reward and stress regulatory circuits. Forebrain opioidergic and gamma-aminobutyric acid ergic signaling is critical for both reward and stress regulation, suggesting that these systems are prime candidates for mediating stress relief by palatable foods. Thus, the present study (1) determines how palatable ?comfort? food alters stress-induced changes in the mRNA expression of inhibitory neurotransmitters in reward and stress neurocircuitry and (2) identifies candidate brain regions that may underlie comfort food-mediated stress reduction. We used a model of palatable ?snacking? in combination with a model of chronic variable stress followed by in situ hybridization to determine forebrain levels of pro-opioid and glutamic acid decarboxylase (GAD) mRNA. The data identify regions within the extended amygdala, striatum, and hypothalamus as potential regions for mediating hypothalamic-pituitary-adrenal axis buffering following palatable snacking. Specifically, palatable snacking alone decreased pro-enkephalin-A (ENK) mRNA expression in the anterior bed nucleus of the stria terminalis (BST) and the nucleus accumbens, and decreased GAD65 mRNA in the posterior BST. Chronic stress alone increased ENK mRNA in the hypothalamus, nucleus accumbens, amygdala, and hippocampus; increased dynorphin mRNA in the nucleus accumbens; increased GAD65 mRNA in the anterior hypothalamus and BST; and decreased GAD65 mRNA in the dorsal hypothalamus. Importantly, palatable food intake prevented stress-induced gene expression changes in subregions of the hypothalamus, BST, and nucleus accumbens. Overall, these data suggest that complex interactions exist between brain reward and stress pathways and that palatable snacking can mitigate many of the neurochemical alterations induced by chronic stress.     

Histamine reverses a memory deficit induced in rats by early postnatal maternal deprivation

Early partial maternal deprivation causes long-lasting neurochemical, behavioral and brain structural effects. In rats, it causes a deficit in memory consolidation visible in adult life. Some of these deficits can be reversed by donepezil and galantamine, which suggests that they may result from an impairment of brain cholinergic transmission. One such deficit, representative of all others, is an impairment of memory consolidation, clearly observable in a one-trial inhibitory avoidance task. Recent data suggest a role of brain histaminergic systems in the regulation of behavior, particularly inhibitory avoidance learning. Here we investigate whether histamine itself, its analog SKF-91844, or various receptor-selective histamine agonists and antagonists given into the CA1 region of the hippocampus immediately post-training can affect retention of one-trial inhibitory avoidance in rats submitted to early postnatal maternal deprivation. We found that histamine, SKF-91844 and the H2 receptor agonist, dimaprit enhance consolidation on their own and reverse the consolidation deficit induced by maternal deprivation. The enhancing effect of histamine was blocked by the H2 receptor antagonist, ranitidine, but not by the H1 receptor antagonist pyrilamine or by the H3 antagonist thioperamide given into CA1 at doses known to have other behavioral actions, without altering locomotor and exploratory activity or the anxiety state of the animals. The present results suggest that the memory deficit induced by early postnatal maternal deprivation in rats may in part be due to an impairment of histamine mediated mechanisms in the CA1 region of the rat hippocampus.     

Modulation of in vivo oxidative status by exogenous corticosterone and restraint stress in rats

Physical and psychological stressors not only enhance activity of the hypothalamo-pituitary-adrenocortical axis, but also cause oxidative damage by inducing an imbalance between the in vivo pro-oxidant and antioxidant status. The involvement of adrenal steroid stress hormones in oxidative damage associated with these stressors has not been extensively investigated. Therefore, this study was designed to probe any direct role of glucocorticoids on induction of oxidative processes by comparing the effects of low, intermediate and high doses of exogenously administered corticosterone, without other applied stressors, on a wide range of key components of the antioxidant defence system. The data presented here indicate a substantial decline in antioxidant defences by actions of corticosterone, evidenced by coordinate decreases in the activities in the brain, liver and heart of free-radical scavenging enzymes superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST) and glutathione reductase (GR), as well as the non-enzymatic antioxidants glutathione (GSH) and serum urate. Also, lipid peroxidation and protein carbonyl contents, oxidative stress markers, were found to be significantly increased in brain, liver and heart. The compromised in vivo antioxidant status was strikingly analogous to the deleterious effects of restraint stress, indicating a direct effect of stress hormones on induction of oxidative damage during physical or psychological stress. A dose-dependent decrease of SOD and CAT, and increase in protein oxidation was observed between the high (40 mg/kg) and low (10 mg/kg) doses of corticosterone. The findings have fundamental implications for oxidative stress as a major pathological mechanism in the maladaptation to chronic stress. Thus, the study suggests that stress hormones have a causal role in impacting oxidative processes induced during the adaptive response. This may hold important implications for pharmacological interventions targeting cellular antioxidants as a promising strategy for protecting against oxidative insults in various psychiatric and non-psychiatric conditions induced by physical or psychological stress.     

背景应激对静息态下大脑自发神经活动的影响

本研究试图探究背景应激对应激相关大脑自发神经活动的影响。使用日常应激水平作为背景应激的量化指标,同时,使用静息态fMRI技术采集了个体在静息态下的大脑自发神经活动,并使用局部一致性(ReHo)作为指标。结果发现,背景应激越高的个体,右侧海马(扩展到丘脑和脑干)静息态下局部一致性水平越高。结果提示,经历了高背景应激的个体会表现出边缘系统脑区自发神经活动的持续活跃状态。     

Clinical Perspectives on Neurobiological Effects of Psychological Trauma

Physical trauma to the brain has always been known to affect brain functions and subsequent neurobiological development. Research primarily since the early 1990s has shown that psychological trauma can have detrimental effects on brain function that are not only lasting but that may alter patterns of subsequent neurodevelopment, particularly in children although developmental effects may be seen in adults as well. Childhood trauma produces a diverse range of symptoms and defining the brain's response to trauma and the factors that mediate the body's stress response systems is at the forefront of scientific investigation. This paper reviews the current evidence relating psychological trauma to anatomical and functional changes in the brain and discusses the need for accurate diagnosis and treatment to minimize such effects and to recognize their existence in developing treatment programs.     

Estrogen treatment alleviates NMDA-antagonist induced hippocampal LTP blockade and cognitive deficits in ovariectomized mice

Estrogen is implicated in hippocampus-dependent spatial learning as well as structural organization and electrophysiological properties of the rat hippocampus but little is known about its mechanisms of action in mice. In this study, we investigated pharmacologically whether estrogen interacts with the hippocampal N-methyl-D-aspartate (NMDA) receptors in ovariectomized mice as postulated for rats. Female C57BL/6J mice were ovariectomized at 5 months, and 2 weeks before testing at 12 months, half of them received subcutaneous estrogen pellets containing 0.18 mg of 17 beta-estradiol. The competitive NMDA-antagonist, 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), was administered at 5.0 and 10.0 microM to block induction of long-term potentiation (LTP) in the hippocampal slice and intraperitoneally at 0.5, 2.0, and 5.0 mg/kg to impair spatial learning in the water maze. Estrogen treatment shifted the dose-response curve to CPP in both experiments. First, 10 microM CPP blocked the initiation of LTP in all mice, but 5 microM only in ovariectomized non-estrogen-treated mice. Second, final level of acquisition and probe trial performance in the water maze were less affected by high doses of CPP in the estrogen-treated ovariectomized mice than in non-treated group. In control tests for motor side effects, estrogen treatment did not reduce the tendency of CPP to decrease locomotor activity in the open field and impair balance on a rotating rod, and estrogen by itself decreased swimming speed as did CPP, but these effects did not interact. Our findings support the notion that estrogen treatment increases the number of active NMDA-receptors in the mouse hippocampus.     

What's parenting got to do with it: emotional autonomy and brain and behavioral responses to emotional conflict in children and adolescents

Healthy parenting may be protective against the development of emotional psychopathology, particularly for children reared in stressful environments. Little is known, however, about the brain and behavioral mechanisms underlying this association, particularly during childhood and adolescence, when emotional disorders frequently emerge. Here, we demonstrate that psychological control, a parenting strategy known to limit socioemotional development in children, is associated with altered brain and behavioral responses to emotional conflict in 27 at‐risk (urban, lower income) youth, ages 9–16. In particular, youth reporting higher parental psychological control demonstrated lower activity in the left anterior insula, a brain area involved in emotion conflict processing, and submitted faster but less accurate behavioral responses—possibly reflecting an avoidant pattern. Effects were not replicated for parental care, and did not generalize to an analogous nonemotional conflict task. We also find evidence that behavioral responses to emotional conflict bridge the previously reported link between parental overcontrol and anxiety in children. Effects of psychological control may reflect a parenting style that limits opportunities to practice self‐regulation when faced with emotionally charged situations. Results support the notion that parenting strategies that facilitate appropriate amounts of socioemotional competence and autonomy in children may be protective against social and emotional difficulties.     

Stress-induced relapse to drug seeking in the rat: role of the bed nucleus of the stria terminalis and amygdala

There is growing interest in the role that the bed nucleus of the stria terminalis (BNST) and central nucleus of the amygdala (CeA), components of the extended amygdala, play in drug addiction. Within the BNST and CeA, there is an extensive system of intrinsic, primarily GABAergic, interconnections known to synthesize a variety of neuropeptides, including corticotrophin-releasing factor (CRF). The actions of CRF at extrahypothalamic sites,including the BNST and CeA, have been implicated in stress responses and in the aversive effects of withdrawal from drugs of abuse. Most recently, we have shown a critical role for extrahypothalamic CRF in stress-induced reinstatement of drug seeking in rats. In attempting to determine which brain circuitry mediates the effect of stress on relapse and, more specifically, where in the brain CRF acts to initiate the behaviours involved in relapse, we focused on the BNST and CeA. In the present paper, we summarize studies we have conducted that explore the role of these brain sites in stress-induced relapse to heroin and cocaine seeking, and then consider how our findings can be understood within the more general context of what is known about the role of the BNST and CeA in stress-related and general approach behaviours, such as drug seeking.     

The role of neuropeptide Y in the amygdala on corticotropin-releasing factor receptor-mediated behavioral stress responses in the rat

Neuropeptide Y (NPY) is one of the most abundant peptides in the brain and has been shown to be a critical regulator of emotionality, most notably for its effect in decreasing anxiety-like behaviors. The stress response in both humans and animals has been shown to involve a cascade of biological events initiated by corticotropin releasing factor (CRF), another centrally acting peptide. Interestingly, NPY and CRF are present in similar brain regions mediating stress responses and may act in an opposing fashion. The basolateral nucleus of the amygdala (BLA) is a distinct division of the amygdala and contains CRF receptors and the highest concentration of NPY neurons. The current study investigates the behavioral effects in rodents when NPY is injected directly into the BLA prior to the pharmacological stressor, urocortin I (Ucn; a CRF receptor agonist) or the emotional stressor, restraint. The animals that underwent restraint were evaluated in the social interaction (SI) test, while those injected with Ucn into the BLA were assessed in the two floor choice test, a modified version of the conditioned-place avoidance paradigm. The results showed that injections of NPY into the BLA prior to Ucn significantly blocked the development of the avoidance behavior in the two floor choice test and the decrease in SI time that is usually seen following restraint stress. These results provide further support that an interaction between NPY and CRF within the BLA may be critical for maintaining a normal homeostatic emotional state.     

Hemispheric asymmetry in stress processing in rat prefrontal cortex and the role of mesocortical dopamine

The prefrontal cortex (PFC) is known to play an important role not only in the regulation of emotion, but in the integration of affective states with appropriate modulation of autonomic and neuroendocrine stress regulatory systems. The present review highlights findings in the rat which helps to elucidate the complex nature of prefrontal involvement in emotion and stress regulation. The medial PFC is particularly important in this regard and while dorsomedial regions appear to play a suppressive role in such regulation, the ventromedial (particularly infralimbic) region appears to activate behavioral, neuroendocrine and sympathetic autonomic systems in response to stressful situations. This may be especially true of spontaneous stress-related behavior or physiological responses to relatively acute stressors. The role of the medial PFC is somewhat more complex in conditions involving learned adjustments to stressful situations, such as the extinction of conditioned fear responses, but it is clear that the medial PFC is important in incorporating stressful experience for future adaptive behavior. It is also suggested that mesocortical dopamine plays an important adaptive role in this region by preventing excessive behavioral and physiological stress reactivity. The rat brain shows substantial hemispheric specialization in many respects, and while the right PFC is normally dominant in the activation of stress-related systems, the left may play a role in countering this activation through processes of interhemispheric inhibition. This proposed basic template for the lateralization of stress regulatory systems is suggested to be associated with efficient stress and emotional self-regulation, and also to be shaped by both early postnatal experience and gender differences.     

Inhibition of endogenous carbon monoxide production induces transient retention losses in the day-old chick when trained using a single trial passive avoidance learning task

Carbon monoxide (CO) is most often thought of as an exogenous toxin rather than as a possible endogenous nootrope. However, a limited number of studies have suggested that CO is necessary in memory processing for at least some tasks. While nitric oxide (NO) and CO are known activators of guanylyl cyclase (GC), only the effect of NO on GC has been extensively investigated as a mechanism underlying memory processing. The aim of the present study was to determine if inhibition of CO production would have an effect on memory processing. Using chicks trained on a single trial passive avoidance task, inhibition of CO production using zinc (II) deuteroporphyrin IX 2,4-bis ethylene glycol (ZnBG; 5 microM) resulted in two transient retention losses occurring at around 40 and 130 min post-training. The timing of these transient retention losses was similar to those observed following inhibition of GC, using the same species and task in a previous study. This supports the notion that CO is necessary in memory processing for this task and may act through a GC-dependent mechanism. As ZnBG also directly inhibits GC or nitric oxide synthase (NOS) at high concentrations, a second experiment was carried-out to confirm the specificity of ZnBG for heme oxygenase (HO) at the concentration used. The action of ZnBG was challenged with the HO agonist hemin (100 microM) and the transient deficits were abolished. This confirmed that the action of ZnBG on memory was through a CO-related mechanism rather than directly on GC or NOS. In this way the specificity of ZnBG (5 microM) for HO could be confirmed. The results support a role for endogenous CO in memory processing, possibly through activation of GC. In addition, the transient retention losses observed following administration of ZnBG suggest that CO may be necessary for memory retrieval and not formation as previously thought.     

The Buddha and the computer: Meditation in an age of information

Information overload is one of the factors behind current alarming statistics on stress. Meditation helps the body-mind resist the deleterious effects of the information onslaught. Though meditation is well known as a relaxation technique, its noetic value is often overlooked. Its benefits extend well beyond superficial soothing: it trains attention; it increases pattern recognition; and it reconnects us to the whole of our intelligence, enhancing coordination between its complementary poles. Meditation is a potent high-touch resource in a high-tech world.