Stress and the Neuroendocrinology of Anxiety Disorders (original) (raw)
Related papers
European Journal of Neuroscience, 1999
The amygdala plays a pivotal role in the generation of appropriate responses to emotional stimuli. In the case of emotional stressors, these responses include activation of the hypothalamic±pituitary±adrenal (HPA) axis. This effect is generally held to depend upon the central nucleus of the amygdala, but recent evidence suggests a role for the medial nucleus. In the present study, c-fos expression, amygdala lesion and retrograde tracing experiments were performed on adult rats in order to re-evaluate the role of the central as opposed to the medial amygdala in generating neuroendocrine responses to an emotional stressor. Brief restraint (15 min) was used as a representative emotional stressor and was found to elicit c-fos expression much more strongly in the medial than central nucleus of the amygdala; relatively few Fos-positive cells were seen in other amygdala nuclei. Subsequent experiments showed that ibotenic acid lesions of the medial amygdala, but not the central amygdala, greatly reduced restraint-induced activation of cells of the medial paraventricular nucleus, the site of the tuberoinfundibular corticotropin-releasing factor cells that constitute the apex of the HPA axis. Medial amygdala lesions also reduced the activation of supraoptic and paraventricular nucleus oxytocinergic neurosecretory cells that commonly accompanies stress-induced HPA axis activation in rodents. To assess whether the role of the medial amygdala in the control of neuroendocrine cell responses to emotional stress might involve a direct projection to such cells, retrograde tracing of amygdala projections to the paraventricular nucleus was performed in combination with Fos immunolabelling. This showed that although some medial amygdala cells activated by exposure to an emotional stressor project directly to the paraventricular nucleus, the number is very small. These ®ndings provide the ®rst direct evidence that it is the medial rather than the central amygdala that is critical to hypothalamic neuroendocrine cell responses during an emotional response, and also provide the ®rst evidence that the amygdala governs oxytocin as well as HPA axis responses to an emotional stressor.
Neurobiological links between stress and anxiety
Neurobiology of Stress, 2019
Stress and anxiety have intertwined behavioral and neural underpinnings. These commonalities are critical for understanding each state, as well as their mutual interactions. Grasping the mechanisms underlying this bidirectional relationship will have major clinical implications for managing a wide range of psychopathologies. After briefly defining key concepts for the study of stress and anxiety in pre-clinical models, we present circuit, as well as cellular and molecular mechanisms involved in either or both stress and anxiety. First, we review studies on divergent circuits of the basolateral amygdala (BLA) underlying emotional valence processing and anxietylike behaviors, and how norepinephrine inputs from the locus coeruleus (LC) to the BLA are responsible for acute-stress induced anxiety. We then describe recent studies revealing a new role for mitochondrial function within the nucleus accumbens (NAc), defining individual trait anxiety in rodents, and participating in the link between stress and anxiety. Next, we report findings on the impact of anxiety on reward encoding through alteration of circuit dynamic synchronicity. Finally, we present work unravelling a new role for hypothalamic corticotropin-releasing hormone (CRH) neurons in controlling anxiety-like and stress-induce behaviors. Altogether, the research reviewed here reveals circuits sharing subcortical nodes and underlying the processing of both stress and anxiety. Understanding the neural overlap between these two psychobiological states, might provide alternative strategies to manage disorders such as post-traumatic stress disorder (PTSD).
Central Amygdaloid Involvement in Neuroendocrine Correlates of Conditioned Stress Responses
Journal of Neuroendocrinology, 1992
The purpose of this study was to examine the effects of bilateral electrolytic lesions of the central nucleus of the amygdala (CEA) in comparison with sham lesions on neuroendocrine responses during conditioned emotional stress in male Wistar rats. Lesions in the CEA, made either before or after the single learning trial of inescapable footshock, failed to affect the conditioned response of plasma epinephrine levels. Plasma levels of norepinephrine showed neither a conditioned stress effect nor were influenced by lesioning. Pre-training CEA lesions, but not post-training intervention, abolished the conditioned elevations of circulating plasma corticosterone and prolactin. These results suggest that the CEA is involved in the conditioning rather than the retention of neuroendocrine stress responses. The effects of pre-training lesioning of the CEA can possibly be explained by a reduced feedback of all these neuroendocrine factors during or shortly after acquisition. In addition, there is a remarkable differentiation between various hormonal correlates of conditioned stress following CEA lesioning. Only corticosterone and prolactin, that appear to be correlates of a passive behavioural stress response, were abolished. The lesions failed to affect the sympatho-active stress parameters (epinephrine and norepinephrine). Relations between coping strategy-active and passive behaviour-and physiology in connection with CEA functioning are discussed.
Brain Research, 1999
The central administration of corticotropin-releasing hormone CRH to experimental animals sets into motion a coordinated series of physiological and behavioral events that promote survival during threatening situation. A large body of evidence suggest that CRH in the Ž. central nucleus of the amygdala CEA induces fear-related behaviors and is essential to fear conditioning; however, evidence of CRH-mediated activation of the amygdala under physiological situation is still limited. We report here a study of the impact of a psychological stressor on hypothalamic and amygdala CRH systems in the rat. Non-footshocked rats placed in a floored compartment surrounded by footshocked rats were defined as the psychological stress group. Rats were exposed to psychological stress for 15 min, and then sacrificed 1.5 and 3 h after cessation of stress. We found that our psychological stressor induced an increase in both CRH mRNA levels, as assessed by in situ hybridization histochemistry, and CRH content, as assessed by micropunch RIA, in the CEA. Exposure to the psychological stressor also caused a significant increase in CRH mRNA levels with a trend for an increase in CRH content in the Ž. dorsolateral subdivision of the bed nucleus of the stria terminalis BNST which is anatomically associated with the CEA. In contrast, Ž. psychological stress induced a small, but significant increase in type-1 CRH receptor CRHR-1 mRNA in the hypothalamic Ž. paraventricular nucleus PVN , while it failed to elevate either PVN CRH mRNA levels or content, CRH content in the median eminence Ž. Ž. ME , or levels of plasma ACTH or corticosterone CORT. Thus, in the context of a psychological stressor, the activation of the amygdala CRH system can occur without robust activation of the hypothalamic CRH system. In the light of previous data that the psychological stress-induced loss of sleep was reversed by the central administration of a CRH antagonist, these data suggest that CRH in the CEA may contribute to the psychological stress-evoked fear-related behavior such as hyperarousal. These data also indicate that in response to a psychological stressor, the amygdala CRH system is much more sensitive than is the CRH system emanating from the PVN.
Neural circuits mediating stress
Biological Psychiatry, 1999
Stress has been linked to the pathophysiology and pathogenesis of mood and anxiety disorders. Over the past few years, our understanding of the brain and neuroendocrine circuits that are linked to the stress response have increased dramatically. This article reviews a series of animal and human studies aimed at understanding what are the pathways by which stress is perceived, processed, and transduced into a neuroendocrine response. We focus on the classic stress circuit: the limbic-hypothalamicpituitary-adrenal (LHPA) axis. These studies indicate that the LHPA stress circuit is a complex system with multiple control mechanisms and that these mechanisms are altered in pathological states, such as chronic stress and depression. These studies also suggest that the interactions between the LHPA and other neurotransmitters, such as serotonin, may provide the neurobiological substrate by which stress may affect mood.
The Interacting Neuroendocrine Network in Stress-Inducing Mood Disorders
Extensive research studies showed the existing interaction between different systems of the body that maintain the stability of homeostatic processes and which allow species to adapt to its environment in response to stressors. Adaptive responses to stressors activates adaptive-mechanisms, that result in the synthesis and release of several brain neurotransmitters, peptide hormones, proinflammatory cytokines and adrenal steroids from neural, neuroendocrine and immune cells which prepared the organism to alert its systems to adopt the proper behavioral responses against stressful events. Neurotransmitters, peptide hormones and cytokines act through the HPA axis forming a regulatory loop that maintains homeostasis in response to different stressors. One route to understand the interactions between brain transmitters, neurosecretory peptide-hormones, adrenal steroids and immune-borne cytokines, including neurotrophic factors is when body`s systems and chemical communication between cells appear to be disrupted during stressful events as occurs in mood-related disorders and depression. Thus, this review will described the functional interactions between HPA axis activity and the projecting neural pathways (DRN-5HT neurons; LC-NA neurons) and brain neurotransmitters (NE, 5-HT, DA, GLU) that impinge on forebrain-limbic structures (hypothalamus, hippocampus, mPFCx) that drive the release of the CRH and CRH-dependent secretion of ACTH from anterior hypophysis and cortisol from adrenal glands, under stressful conditions. Moreover, interactions between immune-borne cytokines and HPA axis activity, and glucocorticoid receptors have been shown to be extremely important to understand the pathophysiological mechanisms that operate in mood-related disorders and MDD, including the stress-inducing altered changes in brain morphology, neuronal atrophy and neurogenesis in brain areas involved in learning processing and memory functions.
Endocrine Factors in Stress and Psychiatric Disorders
Annals of the New York Academy of Sciences, 2008
Glucocorticoids and other steroids produced in the adrenal cortex are altered in chronic stress situations associated with enhanced anxiety. A useful tool to evaluate changes in adrenal steroids during stress and anxiety under both laboratory and real‐life stress situations is determination of steroids in saliva. The main advantages of this technique are its noninvasiveness and its measurement of biologically active free hormone levels. Salivary cortisol is a valuable indicator of the activity of the hypothalamic‐pituitary‐adrenocortical axis, which is known to be altered in psychiatric disorders. Measurements of salivary cortisol helped to reveal changes that would otherwise remained undetected, such as increase in cortisol release in spontaneously occurring panic attacks. By selecting only the subjects with high and low trait anxiety, we have brought evidence confirmed by others that high trait anxiety may be associated with an inability to respond with adequate cortisol release d...
The brain and the stress axis: The neural correlates of cortisol regulation in response to stress
Neuroimage, 2009
The hypothalamic-pituitary-adrenal (HPA) axis is the major endocrine stress axis of the human organism. Cortisol, the final hormone of this axis, affects metabolic, cardiovascular and central nervous systems both acutely and chronically. Recent advances in neuroimaging techniques have led to the investigation of regulatory networks and mechanisms of cortisol regulation in the central nervous system in human populations. In the following review, results from human and animal studies are being presented that investigate the specific role of hippocampus (HC), amygdala (AG), prefrontal cortex (PFC), and brainstem nuclei in cortisol regulation in response to stress. In general, the types of stressors need to be distinguished when discussing the contributions of these structures in regulating the HPA axis. We propose a basic framework on how these structures communicate as a network to regulate cortisol secretion in response to psychological stress. Furthermore, we review critical studies that have substantially contributed to the literature. Possible future research avenues in the field of neuroimaging of cortisol regulation are discussed. In combination with investigations on genetic and environmental factors that influence the development of the HPA axis, this emerging new research will eventually allow the formulation of a more comprehensive framework of functional neuroanatomy of cortisol regulation.
Role of stress, corticotrophin releasing factor (CRF) and amygdala plasticity in chronic anxiety
Stress: The International Journal on the Biology of Stress, 2005
Stress initiates a series of neuronal responses that prepare an organism to adapt to new environmental challenges. However, chronic stress may lead to maladaptive responses that can result in psychiatric syndromes such as anxiety and depressive disorders. Corticotropin-releasing factor (CRF) has been identified as a key neuropeptide responsible for initiating many of the endocrine, autonomic and behavioral responses to stress. The amygdala expresses high concentrations of CRF receptors and is itself a major extrahypothalamic source of CRF containing neurons. Within the amygdala, the basolateral nucleus (BLA) has an important role in regulating anxiety and affective responses. During periods of stress, CRF is released into the amygdala and local CRF receptor activation has been postulated as a substrate for stress-induced alterations in affective behavior. Previous studies have suggested that synaptic plasticity in the BLA contributes to mechanisms underlying long-term changes in the regulation of affective behaviors. Several studies have shown that acute glutamate receptor-mediated activation, by either GABA-mediated disinhibition or CRF-mediated excitation, induces long-term synaptic plasticity and increases the excitability of BLA neurons. This review summarizes some of the data supporting the hypotheses that stress induced plasticity within the amygdala may be a critical step in the pathophysiology of the development of chronic anxiety states. It is further proposed that such a change in the limbic neural circuitry is involved in the transition from normal vigilance responses to pathological anxiety, leading to syndromes such as panic and post-traumatic stress disorders.
Progress in Neuro-psychopharmacology & Biological Psychiatry, 2004
Altered stress responsiveness has been repeatedly related to mood and anxiety disorders. In a traditional view, a reduction of the stress response has been thought favorable. The goal of the present study was to verify the hypothesis that high anxiety is accompanied by enhanced hormone release during stress. Healthy subjects at the upper (anxious, n=15) and lower (non-anxious, n=12) limits of the normal range of a trait anxiety scale (State trait anxiety inventory) were exposed to psychosocial stress procedure based on public speech. Hormone levels, cardiovascular activation and skin conductance were measured. Exposure to psychosocial stress was associated with significant increases of all parameters measured. During the stress procedure, subjects with high trait anxiety exhibited lower levels of hormones of the hypothalamo-pituitary-adrenocortical axis, namely ACTH and cortisol in plasma, as well as cortisol in saliva. Similarly, the stress-induced activation of epinephrine, norepinephrine and prolactin secretion was significantly lower in anxious subjects in comparison with that in nonanxious subjects. Thus, in contrast to the traditional view, high anxiousness was not associated with exaggerated stress response. Our findings suggest that high trait anxiety may be associated with an inability to respond with adequate hormone release to acute stress stimuli. D