Edition 73 - May 2019 / Subject Review

Subject Review – Ed. 73

Marco A. Rivarola y Alicia Belgorosky. Servicio de Endocrinología, Hospital de Pediatría Garrahan, Buenos Aires, Argentina. 

For this issue of Endocrinología Pediátrica On Line, we have selected to comment on the following publication:

Current Molecular Pharmacology, 2018, 11, 4-31
The CRF Family of Neuropeptides and their Receptors – Mediators of the Central Stress Response.
Nina Dedic1, Alon Chen1,2,* and Jan M. Deussing1
1Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, Kraepelinstr, 2-10, 80804
Munich, Germany; 2Department of Neurobiology, Weizmann Institute of Science, 76100 Rehovot, Israel  

BACKGROUND: Dysregulated stress neurocircuits, caused by genetic and/or environmental changes, underlie the development of many neuropsychiatric disorders. Corticotropin-releasing factor (CRF) is the major physiological activator of the hypothalamic-pituitary-adrenal (HPA) axis and consequently a primary regulator of the mammalian stress response. Together with its three family members, urocortins (UCNs) 1, 2, and 3, CRF integrates the neuroendocrine, autonomic, metabolic and behavioral responses to stress by activating its cognate receptors CRFR1 and CRFR2. OBJECTIVE: Here we review the past and current state of the CRF/CRFR field, ranging from pharmacological studies to genetic mouse models and virus-mediated manipulations. RESULTS: Although it is well established that CRF/CRFR1 signaling mediates aversive responses, including anxiety and depression-like behaviors, a number of recent studies have challenged this viewpoint by revealing anxiolytic and appetitive properties of specific CRF/CRFR1 circuits. In contrast, the UCN/CRFR2 system is less well understood and may possibly also exert divergent functions on physiology and behavior depending on the brain region, underlying circuit, and/or experienced stress conditions. CONCLUSION: A plethora of available genetic tools, including conventional and conditional mouse mutants targeting CRF system components, has greatly advanced our understanding about the endogenous mechanisms underlying HPA system regulation and CRF/UCN-related neuronal circuits involved in stress-related behaviors. Yet, the detailed pathways and molecular mechanisms by which the CRF/UCN-system translates negative or positive stimuli into the final, integrated biological response are not completely understood. The utilization of future complementary methodologies, such as cell-type specific Cre-driver lines, viral and optogenetic tools will help to further dissect the function of genetically defined CRF/UCN neurocircuits in the context of adaptive and maladaptive stress responses.

Selected Contents:
1.INTRODUCTION: Stress can be discriminated on the one hand into eustress, or “positive” stress, meaning that the succeeding adaptive response is able to re-instate homeostasis, and on the other hand into distress, or “negative” stress resulting in pathological outcomes. Two closely interplaying systems are primarily responsible for orchestrating the stress response: the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis is characterized by the release of different neuropeptides and hormones, and is believed to mediate the immediate, as well as the long-lasting effects of stress. These socalled stress-mediators are broadly classified into three groups; the monoamines, neuropeptides and steroids.
Importantly, different stressors are processed by distinct circuits and/or in specific brain areas. The non-specific effects of stress are mirrored by the rapid activation of the SNS and the neuroendocrine arm of the stress response, i.e. the HPA axis, which in turn regulates the synthesis and release of glucocorticoids (GCs) from the adrenal glands. Conversely, psychological and anticipatory stressors (stress due to hypothetical events that may/may not occur) are primarily processed by the limbic system, including the hippocampus, amygdala and prefrontal cortex. W. Vale´s group discovered this central stress mediator – the neuropeptide corticotropin-releasing factor (CRF). This major breakthrough contributed significantly to the understanding of the neurobiological mechanisms underlying the stress response (Vale, W.; Science, 1981).

2.CRF (or CRH) MODULATES THE NEUROENDOCRINE STRESS RESPONSE VIA THE HPA AXIS: CRF is the major physiological activator of the HPA axis, and coordinates the neuroendocrine response to stress. The release of CRF from parvocellular neuroendocrine neurons of the paraventricular nucleus of the hypothalamus (PVN) into the hypophysial portal vasculature transports the neuropeptide to secretory corticotrope cells of the anterior pituitary, which express the CRF receptor type 1 (CRFR1), and it stimulates the release of ACTH and other pro-opiomelanocortin (POMC)-derived peptides. ACTH, in turn, triggers the synthesis and release of GCs from the adrenal cortex, which mediate numerous physiological and metabolic reactions and ultimately prepare the organism to deal with the stressful situation. In order to restore the HPA axis to its normal state and to protect it from overshooting, GCs signal back via glucocorticoid (GR) and mineralocorticoid receptors (MR) at various feedback levels (e.g. pituitary, hippocampus, periventricular nucleus and amygdala), which ultimately inhibit the secretion of CRF and consequently ACTH. It is also important to note that the HPA axis is not exclusively activated during aversive stressful situations but also after rewarding stimuli.

3.THE FAMILY OF CRF-RELATED NEUROPEPTIDES AND THEIR RECEPTORS. CRF also regulates neuronal activity throughout the central nervous system (CNS) including most limbic and cortical structures affecting the emotional and cognitive components of the stress response. CRF is closely related to urocortin 1 (UCN 1), both factors signal through CRFR1 and CRFR2 receptors, located in PVN, pituitary stalk, hypothalamus, and cortex. CRFR1 and CRFR2 are also highly expressed in the human brain. The activity of CRF and UCN1 can be regulated additionally by the CRF binding protein (CRF-BP). The diverse and broad expression patterns of CRF-related peptides and receptors, as well as the high level of signaling complexity, enable this circuitry to effectively integrate neuroendocrine, autonomic and behavioral responses of stress.

4.NEUROMODULATORY EFFECTS OF CENTRAL CRF-CRFR1 SIGNALING. CRF and its high affinity receptor, CRFR1, are widely distributed throughout the brain, which allows them to orchestrate autonomic and behavioral stress responses. Consequently, hyperactivity of the CRF/CRFR1 system has been linked to stress-related psychiatric disorders that involve a strong emotional component such as depression and anxiety. Alterations in HPA axis function, such as impaired negative feedback, which results in hypercortisolemia, have been reported repeatedly in a subset of depressed patients, and attributed to centrally elevated CRF levels. Increased CRF levels have also been detected in the CSF of untreated depressed patients.
4.1. Limbic System: Hippocampus and Extended Amygdala. The effects of CRF on hippocampal function and integrity with respect to learning and memory has been repeatedly investigated. The hippocampus contains scattered CRF expressing GABAergic interneurons and numerous CRFR1-expressing excitatory pyramidal neurons. It is generally proposed that a short-lived increase in CRF facilitates hippocampus-dependent learning and memory (similarly to acute stress), whereas prolonged exposure to elevated CRF impairs cognitive performance.

5.NEUROMODULATORY EFFECTS OF CENTRAL UCN/CRFR2-SIGNALING. Whereas the role of CRF/CRFR1 in the modulation of HPA axis activity, stress-induced behavior and cognitive functions is well established, the role of CRFR2 and the urocortins still remains controversial. Although still debated, it is postulated that CRF/CRFR1 signaling mediates the initial reaction to stress, whereas UCN/CRFR2 activation controls the later adaptive phase. UCN1 neurons are mainly localized in the Edinger Westphal (EW) nucleus where they constitute the centrally-projecting part of the nucleus (EWcp). UCN1 neurons are recruited following chronic stress exposure, and stay active for a prolonged period of time, suggesting that this peptide plays a prominent role in the later adaptive phase of the stress response.

Stress-related mental disorders including depression, anxiety-disorders, as well as alcohol and substance abuse, represent some of the most common and escalating health problems in today’s society. Depression tops the estimated financial burden of all psychiatric disorders, and represents the most prevalent mental illness and third leading contributor to the global disease burden. The lack of effective treatments or preventive interventions for most mental disorders partially reflects our limited understanding of the underlying brain-circuitries. This is largely owed to the substantial amount of overlapping symptoms of many psychiatric illnesses, which makes accurate diagnosis often very difficult. This overlap in disease etiology partially arises from shared genetic susceptibility factors; however environmental perturbations, such as trauma and chronic stress, are additional, well-established risk factors. Chronic stress represents a strong proximal predictor of major depressive disorder onset and can also induce recurrence of depressive symptoms. Similarly, stressful life events are associated with substance and drug abuse and are frequently reported to trigger relapse. Even adverse experiences in utero or during early childhood are increasingly associated with lifelong health disparities. But why does stress cause disease in some individuals but not in others? A common perception is that adverse environments might trigger disease onset in genetically predisposed individuals. Evidence for such gene-environment interactions have been provided by a number of studies. Consequently, altered stress-neurocircuits, either caused by genetic, and/or environmental changes, constitute a common domain of many mental disorders, and highlight the necessity to functionally dissect the brains’ most prominent stress system – the CRF/UCN/CRFR system. As summarized above, a large body of evidence has implicated CRF-family members and their receptors in the neuroendocrine and behavioral responses to stress. The ability of the CRF system to interact and modulate monoaminergic circuits is of particular importance considering the involvement of serotonergic, dopaminergic and noradrenergic systems in essentially all aspects of emotion, motivation, reward and cognition. The interaction of the CRF/CRFR-system with different neurotransmitters possibly accounts for the generation of highly specific molecular, circuit and behavioral effects under both, basal and stress conditions. Furthermore, the identity and release sites of activated CRF/UCN neurons, as well as the identity and expression sites of the responding postsynaptic CRFR neurons are likely determining specific behavioral outcomes in response to stress. Although we have substantially advanced our understanding of functional CRF circuits and their effects on stress-related behaviors, we still lack detailed knowledge about the underlying molecular mechanisms and pathways by which the brain translates stressful stimuli into the final integrated biological response under physiological and pathological conditions. Based on recent genetic and pharmacological studies, it becomes evident that CRF is losing its reputation as an “allaversive” peptide, which is not entirely surprising considering that CRF-mediated HPA axis activation also occurs during eustress – the positive stress-response. The CRF/CRFR1 system modulates very specific and partially opposing physiological and behavioral effects depending on the underlying neuronal circuits, brain regions and environmental conditions, which also most likely holds true for CRFR2. The generation of more specific mouse genetic models, viral and optogenetic tools will enhance our understanding of CRF/UCN-CRFR1/2 circuit dynamics in adaptive and maladaptive stress-related behaviors, and aid in the development of more effective treatment modalities in psychiatry.

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