The corticotropin-releasing factor (CRF) system, including the urocortin peptides, is a key regulator of how the body responds to stress. A large amount of preclinical data in rodents and nonhuman primates implicates the CRF system in mediating the various physiological and psychological responses to stress. Importantly, alterations in the CRF system are associated with depression and anxiety disorders in humans. The goal of this chapter is to review what is known about the molecular mechanisms that regulate the activity of the CRF system. The role of the CRF system in stress-induced psychopathology is initially reviewed. Stress-induced molecular changes that are associated with activation of the CRF system are then described, along with the effects of manipulations that mimic or block the effects of stress. CRF receptor regulation is outlined in detail including an overview of recent data implicating the role of G-protein receptor kinase 3 in the phosphorylation and desensitization of the CRF1 receptor. The limited data on the regulation of the CRF2 receptors is also described. Finally, preliminary data from the use of microarrays and gene chips aimed at identifying stress-induced changes in gene expression that are CRF receptor dependent or independent will be described. A detailed understanding of the molecular mechanisms that mediate the stress-induced changes in the CRF system will enable identification of novel targets for the treatment and prevention of stress-related disorders.
Central integration of the hypothalamo–pituitary–adrenocortical (HPA) axis stress response is controlled by neurosecretory neurons in the medial parvocellular paraventricular nucleus (PVN). Activation of the PVN is a complex process regulated by both direct and indirect neuronal connections, as well as communication with blood-borne messengers. Ascending brainstem pathways from the nucleus of the solitary tract (both catecholaminergic and noncatecholaminergic systems) and serotonergic midbrain raphe nuclei provide direct neuronal excitation of PVN neurons. Stimulation of the HPA axis is also mediated by transsynaptic inputs from the medial and central amygdaloid nuclei, which disinhibit the PVN by way of GABAergic relay neurons in the hypothalamus and bed nucleus of the stria terminalis (BST), and perhaps enhance excitatory input from the brainstem. Inhibition of the HPA axis is controlled by PVN-projecting GABA neurons in the hypothalamus and BST, which are driven in part by descending stimulatory inputs from ventral subiculum and infralimbic cortex. The PVN is profoundly affected by blood-borne factors (including peptides and cytokines); these messengers communicate with the PVN through interactions with circumventricular organs or by induction of perivascular prostaglandin synthesis. Finally, glucocorticoids can directly inhibit PVN neurons, by diffusion from the dense vascular beds localized in this region. Thus, activation of the HPA axis is controlled by a wide variety of signals from both brain and periphery, which are thence effectively integrated into a net secretory signal at the level of the hypophysiotrophic PVN neuron.
Preclinical and clinical data indicate that corticotropin-releasing factor (CRF) and CRF-related peptides play an important role in stress-related disorders, including psychiatric disorders, such as anxiety disorder, major depression, eating disorders and drug abuse, gastrointestinal disorders, such as irritable bowel syndrome, and immunological disorders, amongst others. Two major CRF receptor subtypes have been identified (CRF1 and CRF2, with its prevailing splice variants CRF2α and CRF2β), which differ in their pharmacology and expression patterns. The recent discovery of selective small-molecule, non-peptidergic CRF1 antagonists and of peptidergic CRF2 agonists and antagonists has broadened our understanding of the role of CRF and related peptides in physiological and pathophysiological processes, and opened novel avenues for the development of innovative pharmacological approaches to treat these stress-related disorders, including anxiety and depression, which will be the focus of this chapter.
Both preclinical and clinical evidence suggest that atypical antipsychotics may modulate the stress response in a manner that is distinct from conventional agents. For example, atypical antipsychotics have anxiolytic-like actions in a number of animal models. The mechanisms underlying these anxiolytic effects are not clear, but it is possible that antipsychotic-induced alterations in GABAergic neurosteroids play a role. Atypical antipsychotics also demonstrate unique effects in prefrontal cortex stress paradigms focusing on dopamine alterations. Data that mild stress also increases extracellular GABA levels in prefrontal cortex but not striatum, with no concurrent effects on glycine levels is presented. Neurosteroids may be relevant to these prefrontal cortex investigations. The authors review the emerging stress-modulatory profile of atypical antipsychotics and discuss potential ramifications of these findings for the therapeutic efficacy of these compounds. In addition to their well-established roles in the treatment of schizophrenia core symptoms, atypical antipsychotics also have utility in the treatment of depression- and anxiety-spectrum symptoms that frequently accompany the illness. Atypical antipsychotics also appear to have efficacy in the treatment of stress-sensitive anxiety disorders such as post-traumatic stress disorder (PTSD) and obsessive–compulsive disorder (OCD), underscoring the possibility that these agents may have stress-modulatory actions that are clinically therapeutic. As the knowledge of the stress-modulatory actions of atypical antipsychotics evolves, it may be possible to target these properties in the development of novel agents in the treatment of schizophrenia and other psychiatric disorders.
ntegrity of the hypothalamo–pituitary–adrenal (HPA) axis is essential to survival of vertebrate species. This neuroendocrine axis functions to coordinate neural, endocrine and immune responses to diverse stressful stimuli that threaten homeostasis. The final products of activation of the HPA axis are the glucocorticoids that exert widespread effects on body functions, including cellular metabolism and immune function. Inappropriate secretion of endogenous glucocorticoids is potentially damaging and may predispose to disease. Homeostatic regulation of the HPA axis is complex and involves coordination of multiple systems of the body, in part mediated by the bi-directional communication network between the brain, endocrine and immune systems. Health and integrity of the individual relies on the appropriate integration of stress signals, including pro-inflammatory messages, generated at central and peripheral sites. Functional balance between pro- and anti-inflammatory mediators is fundamental to the appropriate control of the HPA axis and the prevention of dysregulation in its activity, a characteristic of numerous stress-related disorders including chronic inflammatory disease.
Depression is characterized by a group of varying symptoms and encompasses a number of clinical diagnosis. External stressors usually trigger the onset of depression and the hypothalamic–pituitary–adrenocortical (HPA) axis is activated. Moreover, genetic influences play a substantial role. A large number of clinical and preclinical studies investigating the stress system in depth have led to the formulation of the corticosteriod receptor (CR) hypothesis that implies that a disturbed CR signalling is a pathological mechanism leading to enhanced CRH release. Almost all antidepressants irrespective of their pharmacology at the receptor level have an influence on the HPA system suggesting a common mode of action. Therefore the stress system is a promosing candidate for further development of new drug targets for the treatment of depression and other stress-related disorders.
The corticotropin-releasing factor (CRF) family constitutes a primary system that mediates adaptive neuroendocrine, autonomic, and behavioral responses to stress, a process known as allostasis. Genetically engineered mice provide a powerful tool for dissection of corticotropin pathways. A collection of models have been generated that harbor specific alterations in ligands, receptors, and the binding protein. In this review, we describe prominent neuroendocrine and behavioral features of these genetic mouse models that have led to new insights of allostatic regulation and associated pathology.
The secretion of glucocorticoids from the adrenal cortex is considered an essential adaptive component of the response to stress. Although adrenocorticotropic hormone (ACTH) regulates adrenal steroidogenesis, the dissociation between changes in plasma ACTH and glucocorticoids under nonstress and stress conditions has prompted the search for alternative non-ACTH mechanisms. The innervation of the adrenal cortex and the intermingling of adrenal cortical and medullary cells form the anatomical substrate for regulation of adrenocortical secretion by neural elements. In vitro studies demonstrate the effectiveness of a variety of neurotransmitters to affect adrenal steroidogenesis. In vivo experiments show that adrenal denervation alters glucocorticoid secretion under nonstress and stress conditions. Further investigations are required to reveal the full extent of neural control of adrenal steroidogenesis and to delineate the mechanisms that underlie it. Nonetheless, the collective results suggest that the brain can control glucocorticoid production by at least two complimentary mechanisms, by stimulation of the neuroendocrine hypothalamic–pituitary–adrenal axis and through direct activation of adrenal neural elements.
During the last decade, the availability of genomic databases has provided a resource where biological questions can be addressed in an unprecedented manner. Based on searches of homologous sequences, paralogous † genes from individual species or orthologous † genes from different species can be identified. The function of paralogous or orthologous genes can be inferred or predicted based on their degree of similarity to known genes, thereby augmenting our understanding of the gene functions that coevolved during evolution. Recent studies on human genomic sequences have led to the discovery of novel type 2 corticotropin-releasing factor (CRF) receptor-selective agonists that are related to CRF by structural and functional characteristics. In addition, analysis of vertebrate genomes showed that the CRF peptide family in mammals includes four distinct genes, CRF, Urocortin 1, Urocortin 3/stresscopin (SCP), and Urocortin 2/stresscopin-related peptide (SRP). Phylogenetic analysis suggested that the origin of each of these peptides predated the separation of tetrapods and teleosts. It is likely that CRF family genes in modern vertebrates evolved from an ancestor gene that gave rise to the CRF/Urocortin 1 and Urocortin 3(SCP)/Urocortin 2(SRP) branches through a gene duplication event. These two ancestor genes then gave rise to additional paralogs through a second round of gene duplication. Each of these four genes is tightly conserved ranging from the > 96% identity found for CRF to the > 55% for Urocortin 3/SCP, thus suggesting that these peptides played essential signaling roles over the 550 million years of vertebrate evolution. The finding of type 2 CRF receptor-selective Urocortin 3/SCP and Urocortin 2/SRP not only provided an opportunity to understand the physiology regulated by these novel ligands but also that of related peptides. The present review focuses on the recent findings of selective CRF receptor ligands, the evolution of signaling molecules associated with the CRF pathway as well as the implications of a complete inventory of CRF family ligands, receptors, and binding proteins in genomes of different organisms. In addition, new findings on CRF receptor subtype-dependent functions derived from studies using Urocortin 3/SCP and Urocortin 2/SRP are discussed. Instead of the traditional analysis of single-gene function in endocrine research, the complete assembly of CRF-associated signaling molecules throughout evolution can provide an integrated view for understanding the physiology and pathophysiology of all CRF family peptides and their receptors, thereby providing new therapeutic approaches for the pathology associated with stress.
Exposure to stress can lead to both adaptive and maladaptive changes that control neuronal function and behavior. The mechanisms underlying these adaptive changes include regulation of synaptic transmission, intracellular signal transduction, gene expression, and even structural alterations. Because acute and chronic exposure to stress can lead to long-term changes in neuronal function, special emphasis has been placed on regulation of transcription factors and patterns of gene expression that could underlie these changes. In this chapter, the basic mechanisms that regulate transcription factors and gene expression, including cis- and trans-acting factors, are discussed. The influence of stress on three major classes of transcription factors, activating transcription factor (ATF) (e.g., the cAMP response elementbinding protein or CREB), activator protein-1 (AP-1) (e.g., c-Fos and c-Jun), and nuclear factor kappa B (NF-κB) is examined. Characterization of the transcription factors and target genes underlying the actions of stress will provide critical information for understanding stress-related neurobiological disorders and ultimately better treatment interventions.
When an individual encounters stressors such as physical pain, internal malaise, or drought conditions, a constellation of physiological and behavioral responses are evoked that aid the individual in coping with the stressors and learning strategies to minimize exposure to these stressors. Vasopressin (VP) plays an important role in modulating these responses and this role is complex. Acute painful stimuli such as electric footshock stimulate hormonal and neural release of VP and this in turn can contribute to analgesia and facilitate maintenance of behaviors that allow the individual to avoid future painful encounters in the same environmental context. The effect of VP on avoidance maintenance is consistent no matter when during the stressful situation it is released. Two hypotheses have emerged to account for the action of VP on shock avoidance maintenance. One states that central VP is necessary for optimal mnemonic processing of aversive environmental stimuli and the other states that VP produces nonspecific effects on arousal systems that modulate memory processes. There is evidence to support both positions. Internal malaise induced by consumption of toxic substances also stimulates hormonal release of VP and this in turn facilitates a reduction in exposure to the toxic substance and modulates maintenance of behaviors that avoid future contact with the toxic substance. The hormonal and neural release of low levels of VP promotes relinquishing avoidance behavior when it is present after the first exposure to the stressor but the release of high levels of VP facilitates maintenance. It is suggested that low doses of VP reduce the sensory impact of toxins while high doses of VP have aversive stimulus properties that are additive with the properties of toxins. Finally, scarcity of water stimulates hormonal release of VP, which directly promotes water retention. The neural changes in VP release during the conditions of water restriction can affect avoidance behavior maintenance when an individual encounters other stressors. It facilitates maintaining avoidance behavior for physical pain stressors and relinquishing avoidance behavior for internal malaise stressors. The picture emerging is that VP has variable effects on learning and memory processes. Some of these effects are due to its direct action on the neural systems mediating these processes while other effects are due to its action on modulatory neural systems, such as those mediating the aversive properties of VP and those mediating arousal.
In this chapter, we review evidence derived from studies in animals and humans implicating the medial prefrontal cortex in the regulation of the autonomic, neuroendocrine, and behavioral responses to stress. The main focus of the review is on the functional differences that have been uncovered between the prelimbic and infralimbic subregions of the prefrontal cortex. We also discuss at some length, the mounting evidence of hemispheric specialization of medial prefrontal cortical function as it relates to the regulation of the autonomic and neuroendocrine responses to stress as well as of emotional reactivity and stress-related behaviors. The last section of the chapter deals with some of the long-term consequences of early developmental perturbations on medial prefrontal cortical function and their implications for stress-related psychopathologies. The discussion here centers primarily on the lasting effects of early postnatal maternal separation and handling on medial prefrontal cortex-mediated stress reactivity and their potential role in the development of major depression.
Depression is now one of the most common human illnesses and is of immense clinical and economic importance. Considerable preclinical research efforts have been made to establish animal models of depression, and more recently the human evidence derived from brain imaging studies has provided important insights into the functional neuroanatomical correlates of depression. Despite this, knowledge of the neurobiology of both depression and its pharmacological treatment is limited and so, consequently, is the efficacy of antidepressant pharmacology. In terms of etiology, whilst evidence for specific factors and mechanisms is sparse, it is well established from human epidemiological and clinical studies that genetic and environmental factors, and of course their interaction, are involved. With regard to the environment, acute stressors induce adaptive behavioral and physiological changes in adult mammals that resemble the symptoms of depression but are transient, whereas chronic stressors lead to chronic changes in these behavioral and physiological states, such that they constitute the symptoms, e.g. low mood, helplessness, anhedonia, hyposomnia, and associated abnormalities of depression, e.g. elevated catecholamine output, hypercortisolemia. The environment in which human infants and children develop is fundamental to how they develop, and it is clear that parental loss but also infant or child exposure to emotional or physical neglect or abuse, impact on development including increased vulnerability to depression and associated physiological abnormalities, across the life span. It would be important to establish the mechanisms mediating specific forms of abnormal offspring-parent relationship and development, including whether this early experience induces depressed traits per se and/or traits of increased vulnerability to depression that are triggered by events in later life. Studies of early-life environmental manipulations in rodents and primates can potentially yield evidence that abnormal developmental experience leading to dysfunction of the neurobiology, physiology and behavior of emotion is a general mammalian characteristic, and therefore that this approach can be used to develop animal models for depression research.
The hypothalamic-pituitary-adrenal (HPA) axis is a complex endocrine system. Its main role is maintainance of homeostasis following stress. Corticotropin releasing factor (CRF) is the major regulator of the HPA axis, controling the release of pituitary adrenocorticotropin (ACTH). CRF is cosynthesized with vasopressin (AVP) in neurons of the hypothalamic paraventricular nucleus and released into the portal0hypophyseal blood circulation, from whrer it is transported to the anterior pituitary gland. The binding of CRF to its specific receptor (CRF type 1 receptor) on pituitary corticotrophic cells results in stimulation of proopiomelanocortin (POMC) mRNA synthesis and ACTH secretion. ACTH and other biologically active peptides (N-terminal glycopeptide, γ-melanotropin, joining peptide, α-melanotropin, CLIP, β-1ipotropin, β-melanotropin and β-endorphin) are generated by posttranslational cleavage of their precursor peptide POMC. POMC gene transcription is induced by CRF-stimulated elevation in cyclic adenosine 3′,5′-momophosphate (cAMP). Several mediators of CRF-induced POMC regulation and corticotroph differentiation have been identified, such as Nur factors, TPIT, leukaemia-inhibitory factor and interleukin 6. Upon stimulation, ACTH is released into the systemic circulation in a circadian rhythm, orchestrated by the suprachiasmatic nucleus of the hypothalamus. ACTH stimulates steroidogenesis (mineralocorticoids, glucocorticoid and, in humans, adrenal androgens) via the Gs-coupled melanocortin 2 receptor (MC2R). ACTH, via cAMP, promotes the synthesis of steroidogenic acute regulatory protein (STAR), which in turn mediates the uptake of cholesterol into the mitochondria of adrenocortical cells. This is followed by coordinated action of cytochrome P 450 enzymes resulting in biosynthesis and secretion of adrenal steroids. Glucocorticoids in particular have wide-ranging effects on many organ systems, as well as a including negative feedback action at the pituitary and hypothalamic level.
The hypothalamic–pituitary–adrenal (HPA) axis is a neuroendocrine system which is vital for the organism to meet and adapt to stressful challenges and physical demands. A complex network of stimulatory and inhibitory influences from neural and endocrine origin governs the activity of the HPA axis. The regulatory setpoints (e.g. responsiveness to secretagogues, negative-feedback sensitivity, limbic and frontal cortical inhibitory and stimulatory control) within this network are not static but, on the contrary, are dynamically adjustable in response to changes in environmental conditions such as stressful events. Thus, the HPA axis does not only respond to stressful events by an acute surge in glucocorticoid hormone production, but also by adjusting its regulatory setpoints in order to adapt to the altering conditions. In recent work on voluntarily exercising mice, we obtained new insights into the regulatory control mechanisms of the HPA axis. Voluntary exercise is established by providing mice with a running wheel in their home cage. They run exuberantly (~ 7 km/day), mainly during the first half of the dark phase. Voluntary exercise has been shown to act beneficially on the organism (either animal or human) precipitating effects at the cellular, system and behavioural level. Here, we account of the “lessons” we learned from studying the HPA axis in this animal model. We found that the HPA axis of control mice is asymmetric at least at the level of the adrenal gland (i.e. the left adrenal is larger than the right one) and, possibly, at the level of the central nervous system as well. Moreover, this asymmetry is most likely associated with the asymmetry in the sympathoadrenomedullary system. Strikingly, in exercised mice, this asymmetry was abolished due to a selective potentiation of the right sympathoadrenomedullary branch and growth of the right adrenal gland. The impact of these effects of long-term voluntary exercise on regulatory components of the HPA axis and its responsiveness to different types of stressors is reviewed and discussed.
In this review, we examine how differences in the activity of the hypothalamic–pituitary–adrenal (HPA) axis can influence vulnerability to drug addiction. Glucocorticoid hormones, the final step in the activation of the HPA axis, show a basal circadian secretion, and rise in response to stressful events. Studies manipulating levels of glucocorticoids show that these hormones facilitate the behavioral response to psychostimulant drugs. Thus, blockade of glucocorticoid secretion reduces drug-induced responses such as locomotor activity, self-administration and relapse, whereas an increase in glucocorticoids has opposite effects. We then describe how these behavioral effects of glucocorticoids involve an action on the dopamine system, one of the major systems mediating the addictive properties of drugs. Thus, decreasing glucocorticoid levels reduces the activity of the dopamine system, whereas an increase in the concentration of these hormones can increase dopamine transmission. The causal relationship between glucocorticoid hormones, dopamine, and behavioral response to addictive drugs suggests that inter-individual differences in glucocorticoid levels could explain inter-individual differences in drug vulnerabilities. In this review we expand this notion by suggesting that individuals with greater vulnerability to drugs may also differ in their sensitivity to glucocorticoid hormones. We propose that increased exposure to glucocorticoids, whether induced by repeated stress or increased sensitivity to these hormones, could result in the sensitization of the dopamine reward system; this would enhance reactivity to drugs and increase liability to develop addiction.
This chapter discussed how neuroendocrine findings in posttraumatic stress disorder (PTSD) potentially inform hypothalamic-pituitary-adrenal (HPA) alterations in PTSD and highlight alterations relevant to the identification of targets for drug development. Most studies demonstrate alterations consistent with an enhanced negative feedback inhibition of cortisol on the pituitary, an overall hyperreactivity of other target tissues (adrenal gland, hypothalamus), or both in PTSD. However, findings of low cortisol and increased reactivity of the pituitary in PTSD are also consistent with reduced adrenal output. The observations in PTSD are part of a growing body of neuroendocrine data providing evidence of insufficient glucocorticoid signaling in stress-related neuropsychiatric disorders.
It has long been known that cholinergic neurotransmission is intimately associated with mammalian stress responses. Inhibition of acetylcholinesterase (AChE), like stress, elevates the levels of acetylcholine (ACh) in the short term, and both conditions induce some common long-lasting behavioral symptoms. Therefore, AChE manipulations provide an interesting window onto stress responses. Like many other stimuli, both stress and inhibition of AChE cause an increase in AChE gene expression that is also associated with a shift in its pre-mRNA splicing pattern. Of the several variants of AChE that arise due to alternative splicing, it is specifically the usually rare, soluble AChE-R variant that is up-regulated. Transgenic mice that over-express AChE also show many of the same symptoms as stress: erratic behavior following circadian light/dark shift, progressive failure of learning and memory, intensified long-term potentiation (LTP), development of neuropathologies, progressive muscle fatigue and degeneration of neuromuscular junctions. Altered expression of other cholinergic proteins in these mice, e.g. protein kinase CβII choline acetyltransferase and the high affinity choline transporter, suggests chronic feedback responses to the cholinergic imbalance. Stress-associated characteristics can be ameliorated in mice and humans by treatment with antisense agents that induce selective destruction of AChE-R, which provides further support for changes in alternative splicing, and in particular the accumulation of this variant, having a role in the etiology of stress responses.
Within the last two decades, our view of the mature mammalian brain has been changed. It is far from being fixed and immutable, as a number of factors such as environmental stimulation, learning, growth factors, glucocorticoid, and sexual hormones, stress, aging, neurotransmitters such as glutamate and serotonin, and a number of drugs regulate the production of new neurons in the adult dentate gyrus. This newfound capacity has forced a new look at plasticity of the brain, an organ previously considered to have an anatomically stable structure. The presence of neuronal precursors in the adult mammalian brain suggests a new level of plasticity for brain regions, whereby neurons are constantly replaced. Moreover, it raises questions regarding the underlying mechanisms of the newly generated neurons, and how they influence the functioning of the differentiated adult brain. The evolutionary conservation of adult neurogenesis and the persistently high level of neuron production throughout adulthood suggest that this process is of fundamental biological importance. The functional implications of adult neurogenesis remain unknown, but several studies have suggested a link between the formation of new neurons in the dentate gyrus and learning.
