Cross references: Cortisol Corticotropin-releasing hormone (CRH) CRH & Testosterone CRH & Vassopressin CRH & Serotonin Criminal Corticotropin-Releasing Hormone HPA Axis Hypothalamus Paraventricular nucleus (PVN) Pituitary Gland Stress Evolution Glucocorticoids Serotonin Serotonin Receptors Pain Fear Limbic System Locus Ceruleus (LC) Dorsal Raphe Nucleus NOTES: 1. Although Stress , Fear and Pain are not identical, there's enough similarity between them that it's informative to extrapolate from one to the others. 2. Although the sections from the 'Brain from Top to Bottom (BTB)' website that I've copied after the Wikipedia excerpts, below, do not use a lot of technical language, many of the other references do. I've provided links for most, but not all, of the technical terms. I may come back later and provide links for at least some of the technical terms which are currently unlinked, but for the moment, I want to move on. 3. The Direct Serotonin Pathway allows or prevents behavior through its input to the Nucleus Accumbens Septi. The Direct Cortisol Pathway provides the energy for behavior through its control of blood glucose levels. Since stress increases both blood glucose and accumbens inhibition, the default response to threat or environmental stress seems to be highly energized motionlessness. Stress (biology) (Wiki) "Although the basic neurochemistry of the stress response is now well understood, much remains to be discovered about how the components of this system interact with one another, in the brain and throughout the body. In response to a stressor, neurons with cell bodies in the Paraventricular nucleus (PVN) of the Hypothalamus secrete Corticotropin-releasing hormone (CRH) and Arginine Vasopressin (AVP) into the hypophyseal portal system. The locus ceruleus and other noradrenergic cell groups of the adrenal medulla and pons, collectively known as the LC/NE system, also become active and use brain epinephrine to execute autonomic and neuroendocrine responses, serving as a global alarm system.[7] The autonomic nervous system provides the rapid response to stress commonly known as the fight-or-flight response, engaging the sympathetic nervous system and withdrawing the parasympathetic nervous system, thereby enacting cardiovascular, respiratory, gastrointestinal, renal, and endocrine changes.[7] The HPA axis, a major part of the neuroendocrine system involving the interactions of the hypothalamus, the pituitary gland, and the adrenal glands, is also activated by release of CRH and AVP. This results in release of adrenocorticotropic hormone (ACTH) from the pituitary into the general bloodstream, which results in secretion of cortisol and other glucocorticoids from the adrenal cortex. " My comment: This discussion of stress only considers the Direct Cortisol Pathway . It does not consider the Direct Serotonin Pathway . The 'Brain from Top to Bottom' (BTB) website has an unusual structure. Each topic is presented at three levels of difficulty (Beginner, Intermediate and Advanced) from five different viewpoints (Social, Psychological, Neurological, Cellular and Molecular). The next two BTB sections are actually the same page. 'SEEKING PLEASURE AND AVOIDING PAIN' is from the Psychological viewpoint and 'THE PLEASURE CENTERS' is from the Neurological viewpoint. Both are at the Advanced level of difficulty.
My comment: Since the Brain from Top to Bottom (BTB) website from which this is taken avoids the more technical levels of discussion, such as specific hormones, nerve tracts, nuclei, etc., it's not possible to say for sure, but I'd like to offer a guess. My hunch is that the middle column headed "Action required by danger" is roughly equivalent to the Direct Cortisol Pathway while the column on the right headed "Action inhibited" is roughly equivalent to the Direct Serotonin Pathway . THE PLEASURE CENTRES NOTE: This is only a very small portion of the page. To read the whole thing, click on the link. Aversive stimuli that provoke fight or flight responses activate the brain’s punishment circuit (the periventricular system, or PVS), which enables us to cope with unpleasant situations. The PVS ... includes various brain structures, such as the hypothalamus, the thalamus, and the central grey substance surrounding the aqueduct of Sylvius. Some secondary centres of this circuit are found in the amygdala and the hippocampus. The punishment circuit functions by means of acetylcholine, which stimulates the secretion of adrenal cortico-trophic hormone (ACTH). ACTH in turn stimulates the adrenal glands to release adrenalin to prepare the body’s organs for fight or flight. The situation is quite different for the third circuit, the behavioural inhibition system (BIS). This system ... is associated with the septo-hippocampal system, the amygdala, and the basal nuclei. It receives inputs from the prefrontal cortex and transmits its outputs via the noradrenergic fibres of the locus coeruleus and the serotininergic fibres of the medial Raphe nuclei. Some authors believe that serotonin plays a major role in this system. My comments: 1. This says that the PVS includes the Hypothalamus , which is consistent with my guess that the PVS is what I have called the Direct Cortisol Pathway and includes, in particular, the Paraventricular nucleus (PVN) . 2. However, it also includes the Thalamus , Periaquiductal Gray , Amygdala and Hippocampus in the PVS. I have not considered any of these to be part of the Direct Cortisol Pathway . 3. Most surprisingly, it says that it is Acetylcholine , rather than Corticotropin-releasing hormone (CRH) , which stimulates the release of ACTH from the pituitary. Could it be that the Acetylcholine stimulates the release of CRH which then stimulates the release of ACTH? 4. Since it includes Serotonin , the Raphe nuclei, presumably the (Dorsal Raphe Nucleus ), the Hippocampus and the Amygdala in its description of the BIS, this is consistent with my understanding of the Direct Serotonin Pathway . SEROTONIN AND OTHER MOLECULES INVOLVED IN DEPRESSION See full page at: Serotonin . "The body's response from the time it perceives a danger to the time it secretes the hormones to prepare to deal with it involves the following structures, in the following order: 1) the Limbic System, 2) the Hypothalamus, 3) the Pituitary Gland, and 4) the adrenal glands; see: Adrenal Cortex . The Adrenal Cortex secretes Glucocorticoids (such as Cortisol, in human beings), which interact with the Serotonin Receptors in the brain." "In rats, chronic stress and/or a high level of Glucocorticoids alters certain Serotonin Receptors (increases the 5-HT2A receptors in the Cerebral Cortex and reduces the 5-HT1A receptors in the Hippocampus). These same changes have been observed in humans who have committed suicide or suffered from diseases that cause hypersecretion of Glucocorticoids . The continued administration of antidepressants causes changes in the Serotonin Receptors that are the opposite of the changes produced by chronic stress. It also reverses the hypersecretion of stress hormones." "Thus, all indications are that the end products of the HPA Axis — Glucocorticoids — play a role in depression by influencing several neurotransmitter systems, including those for Serotonin, Norepinephrine, and Dopamine , all three of which are involved in depression." My comment: Although it mentions Serotonin Receptors , and therefore indirectly Serotonin , this discussion is primarily focused on the Direct Cortisol Pathway . Since it does not consider the Dorsal Raphe Nucleus , it doesn't consider the Direct Serotonin Pathway . Stressors, stress, and neuroendocrine integration (Biosis) - 1998 No Abstract. I got the PDF through the library. NOTE: This is a very difficult article with a lot of information packed into a few short paragraphs. In order to clarify the information, I've numbered the components listed. "The central components of the stress system are located in the Hypothalamus and the Brainstem and include (my numbers): 1. the parvocellular Corticotropin-releasing hormone (CRH) and Arginine Vasopressin (AVP) neurons of the Paraventricular nucleus (PVN) of the Hypothalamus and the 2. Corticotropin-releasing hormone (CRH) neurons of the paragigantocellular and parabranchial (these are both components of the very complex Reticular Activating Sytem ) nuclei of the Medulla Oblongata, as well as the 3. Locus Ceruleus (LC) and other mostly Norepinephrine (NE) cell groups of the Medulla Oblongata and pons (LC/NE-Sympathetic Nervous System), referred to henceforth as the LC/NE system. The peripheral limbs of the stress system are (my numbers): 1. the HPA Axis, together with 2, the efferent Sympathetic Nervous System / Adrenal Medulla system, 3. and components of the Parasympathetic Nervous System." "Corticotropin-releasing hormone (CRH), a 41 amino acid peptide, is the principal Hypothalamus regulator of the HPA Axis. ... Corticotropin-releasing hormone (CRH) and CRH Receptors were found in many extrahypothalamic sites of the brain, including (my numbers): 1. parts of the Limbic System, 2. the basal forebrain, 3. and the LC/NE system in the brainstem and spinal cord. ... There are apparently multiple sites of interaction among the various components of the stress system. Reciprocal reverberatory neural connections exist between the Paraventricular nucleus (PVN) Corticotropin-releasing hormone (CRH) neurons and Brainstem Norepinephrine neurons of the central stress system, with Corticotropin-releasing hormone (CRH) and Norepinephrine stimulating each other, the latter primarily through α1-Norepinephrine receptors. Autoregulatory ultrashort negative-feedback loops are also present in both the Paraventricular nucleus (PVN) Corticotropin-releasing hormone (CRH) neurons and Brainstem Norepinephrine neurons, with collateral fibers inhibiting CRH and Catecholamine secretion, respectively, via presynaptic CRH and α2-Norepinephrine receptors. Both the CRH neurons and Catecholamine neurons also receive stimulatory innervation from the Serotonin and Acetylcholine systems and inhibitory input from the γ-aminobutyric acid (GABA) / benzodiazepine (BZD) and the opioid peptide neuronal systems of the brain, as well as by the end product of the HPA Axis, Glucocorticoids ."  FIGURE 1. A simplified representation of the central and peripheral components of the stress system, their functional interrelations, and their relations to other central systems involved in the stress response. CRH, Corticotropin-releasing hormone; LC/NE Symp. Syst.,Locus Ceruleus (LC) / Norepinephrine - Sympathetic Nervous System; POMC, proopiomelanocortin; AVP, Arginine Vasopressin; GABA, γ-aminobutyric acid; BZD, benzodiazepine; ACTH, corticotropin; NPY, neuropeptide Y; SP, substance P. Activation is represented by solid lines, and inhibition by dashed lines. "A subset of Paraventricular nucleus (PVN) parvocellular neurons synthesize and secrete both Corticotropin-releasing hormone (CRH) and Arginine Vasopressin, while another subset secretes Arginine Vasopressin only." "Corticotropin-releasing hormone (CRH) , released into the hypophyseal portal system, is the principal regulator of anterior Pituitary Gland corticotroph ACTH secretion .., it appears that there is a reciprocal positive interaction between Corticotropin-releasing hormone (CRH) and Arginine Vasopressin at the level of the Hypothalamus with each Neuropeptides stimulating the secretion of the other. In nonstressful situations, both Corticotropin-releasing hormone (CRH) and Arginine Vasopressin are secreted in the Pituitary Gland in a circadian and highly concordant pulsatile fashion. The amplitude of the Corticotropin-releasing hormone (CRH) and Arginine Vasopressin pulses increase in the early morning hours, resulting eventually in increases of both the amplitude and apparent frequency of ACTH and Cortisol secretory bursts in the general circulation." "The Adrenal Cortex is the principal target organ of Pituitary-derived circulating ACTH . The latter is the key regulator of Glucocorticoids and adrenal Androgen secretion by the zonae fasciculata and reticularis, respectively (see: Adrenal Cortex )." "Glucocorticoids are the final effectors of the HPA Axis . These Hormones are pleiotropic and exert their effects through their ubiquitously distributed intracellular receptors. The nonactivated Glucocorticoid Receptor resides in the cytosol in the form of a heterooligomer with heat-shock proteins and immunophilins. Upon ligand binding, the Glucocorticoid Receptors dissociate from the rest of the heterooligomer and translocate into the nucleus, where they interact as homodimers with specific glucocorticoid-responsive elements (GREs) within the DNA to transactivate appropriate hormone-responsive genes." "The reproductive axis is inhibited at all levels by various components of the HPA Axis (FIG. 2A). Thus, either directly or via arcuate POMC neuron β-endorphin, Corticotropin-releasing hormone (CRH) suppresses the Gonadotropin-Releasing Hormone (GnRH) neurons of the arcuate and preoptic nuclei. Glucocorticoids , on the other hand, exert inhibitory effects at the levels of the GnRH neuron, the Pituitary gonadotroph, influencing primarily the secretion of Luteinizing Hormone , and the gonads themselves, and render target tissues of sex steroids resistant to these hormones."  FIGURE 2A. Interactions between the HPA Axis and the reproductive system. GnRH, Gonadotropin-Releasing Hormone; LH, Luteinizing Hormone; FSH, follicle stimulating hormone. My comment: This discussion of stress only considers the Direct Cortisol Pathway . It does not consider the Direct Serotonin Pathway . Although Figure 1 shows Serotonin in some sort of ambiguous connection between the HPA Axis and the Locus Ceruleus (LC) / Norepinephrine system, it makes no mention of the Dorsal Raphe Nucleus . Neurobiology of the stress response early in life: evolution of a concept and the role of corticotropin releasing hormone (PubMed) - 2001 Full length HTML available online for free. from the abstract "Corticotropin-releasing hormone (CRH) has been shown to contribute critically to molecular and neuroendocrine responses to stress during development. In turn the expression of this Neuropeptides in both Hypothalamus and Amygdala is differentially modulated by single and recurrent stress, and is determined also by the type of stress (eg, psychological or physiological). A likely transcriptional regulatory factor for modulating Corticotropin-releasing hormone (CRH) gene expression, the cAMP responsive element binding protein CREB, is phosphorylated (activated) in the developing Hypothalamus within seconds of stress onset, preceding the transcription of the Corticotropin-releasing hormone (CRH) gene and initiating the activation of stress-induced cellular and neuroendocrine cascades. Finally, early life stress may permanently modify the HPA Axis and the response to further stressful stimuli, and recent data suggest that Corticotropin-releasing hormone (CRH) may play an integral role in the mechanisms of these long-term changes." My comments on the Abstract: 1. Although I'm very interested in the transcription of genes, I don't know much about it. So " transcriptional regulatory factor for modulating CRH gene expression, the cAMP responsive element binding protein CREB" is pretty much Greek to me. 2. The review seems mostly concerned with the effects that early life experiences have later in life. 3. Although this abstract does mention the Amygdala which might be part of the Direct Serotonin Pathway , it does not mention either Serotonin itself or the Dorsal Raphe Nucleus . Like the other articles, above, it seems to be mostly focused on the Direct Cortisol Pathway . from the HTML "The neuronal networks comprising the stress response in developing and mature rodents and primates include several major circuits. The first is the neuroendocrine circuit, the HPA Axis (Figure 1a). It has been well established that stress-induced activation of this circuit is dependent on secretion of the hypothalamic hormone Corticotropin-releasing hormone (CRH).8,15 Within seconds of exposure to stress, CRH, located in peptidergic neurons in the hypothalamic Paraventricular nucleus (PVN), is secreted from nerve terminals to influence rapid secretion of adrenocorticotrophic hormone (ACTH) from the corticotrophs of the anterior Pituitary Gland. Subsequent to its secretion, ACTH travels through the bloodstream and acts on the Adrenal Cortex to release Glucocorticoids." Clicking on the image, below, will not only enlarge it so that you can easily read the labels, you will also be able to grab hold of the image and move it around so you can look more closely at whatever you're interested in. Way cool! Click on image to enlarge
 Figure 1
The
neuroendocrine (a), Limbic System (b), and Brainstem (c) inter-related, stress-activated Corticotropin-releasing hormone (CRH) loops. (a) Stress-conveying signals rapidly activate immediate early genes in CRH-expressing neurons of the central nucleus of the Amygdala (ACe). Rapid CRH release in the ACe is is thought to activate CRH expressing neurons in the hypothalamic Paraventricular nucleus (PVN) to secrete Corticotropin-releasing hormone (CRH) into the hypothalamo-pituitary portal system, inducing ACTH and Glucocorticoid secretion from the Pituitary and Adrenal Cortex, respectively. In response to stress, CRH expression is also activated rapidly in these neurons. Glucocorticoids exert a negative feedback on PVN (directly and via Hippocampus), yet activate CRH gene expression in the Amygdala, potentially promoting further Corticotropin-releasing hormone (CRH) release in this region. (b) Stressors involving ‘psychological’ or multi-modal elements activate the Limbic circuit. This consists of Amygdala (ACe), which conveys information both to the Hypothalamus and to the Hippocampal formation via pathways that likely do not utilize CRH as a neurotransmitter. Within the Hippocampus, CRH-expressing GABAergic interneurons (in purple) in the principal cell layers of the Hippocampal CA1, CA3 and the dentate gyrus (DG) are positioned to control information flow in the major, tri-synaptic Hippocampal pathway. (c) Sensory information regarding physical, somatic and visceral elements of stress is conveyed from sensory organs via a neuroanatomically defined Brainstem pathway. Within this general circuit, a chemically defined loop, utilizing Corticotropin-releasing hormone (CRH) (or a similar Ligand ) as a Neurotransmitter which activates the CRF2 receptor may be considered. This afferent pathway contributes to the integration of stress signals, resulting in behavioral and neuroendocrine responses. For panels (a) and (b), red and blue arrows denote established or putative potentiating and inhibitory actions, respectively. Thick arrows do not imply monosynaptic connections. For panel (c), blue frames indicate CRF2 mRNA expression. Red shading over a region indicates the presence of CRH-expressing neurons. Red arrows denote established CRH-containing pathways. CEA = ACe-bed nucleus of the stria terminalis continuum; NTS = nucleus of the solitary tract; PBN = parabrachial nucleus; SCN = suprachiasmatic hypothalamic nucleus; PVT = thalamic paraventricular nucleus; VMH = ventromedial hypothalamic nucleus; MEA and BMA = medial and basomedial amygdalaoid nucleus, respectively. My comment on the Figure: Note the absence of the Dorsal Raphe Nucleus . "Corticotropin-releasing hormone (CRH) , in addition to acting as a neuroendocrine releasing factor for ACTH, plays an important role as a Neuromodulator in brain regions involved in anxiety, mood and learning/memory. The long-term deleterious effects observed after early life stress may involve sustained alteration of CRH expression in these key Limbic System regions, resulting in dysfunction of the behavioral, molecular and neuroendocrine aspects of the responses to stress throughout life." My comments on the HTML: This review features the HPA Axis prominently. Although it highlights the Amygdala as being important in the stress response, discusses the role of the Hippocampus and even gives a role to the Bed Nucleus of the Stria Terminalis , it mentions Serotonin only in passing and doesn't mention the Dorsal Raphe Nucleus at all. Therefore, I think it's fair to say that, while it takes a broader view than just a narrow interpretation of the Direct Cortisol Pathway , it hasn't managed to incorporate the Direct Serotonin Pathway . It is my hypothesis that it's the Direct Serotonin Pathway which regulates Impulsivity . 2013 Dysfunctional astrocytic and synaptic regulation of hypothalamic glutamatergic transmission in a mouse model of early-life adversity: relevance to neurosteroids and programming of the stress response. http://www.ncbi.nlm.nih.gov/pubmed/24336719 "Adverse early-life experiences, such as poor maternal care, program an abnormal stress response that may involve an altered balance between excitatory and inhibitory signals. Here, we explored how early-life stress (ELS) affects excitatory and inhibitory transmission in corticotrophin-releasing factor (CRF)-expressing dorsal-medial (mpd) neurons of the neonatal mouse hypothalamus. We report that ELS associates with enhanced excitatory glutamatergic transmission that is manifested as an increased frequency of synaptic events and increased extrasynaptic conductance, with the latter associated with dysfunctional astrocytic regulation of glutamate levels. The neurosteroid 5α-pregnan-3α-ol-20-one (5α3α-THPROG) is an endogenous, positive modulator of GABAA receptors (GABAARs) that is abundant during brain development and rises rapidly during acute stress, thereby enhancing inhibition to curtail stress-induced activation of the hypothalamic-pituitary-adrenocortical axis. In control mpd neurons, 5α3α-THPROG potently suppressed neuronal discharge, but this action was greatly compromised by prior ELS exposure. This neurosteroid insensitivity did not primarily result from perturbations of GABAergic inhibition, but rather arose functionally from the increased excitatory drive onto mpd neurons. Previous reports indicated that mice (dams) lacking the GABAAR δ subunit (δ(0/0)) exhibit altered maternal behavior. Intriguingly, δ(0/0) offspring showed some hallmarks of abnormal maternal care that were further exacerbated by ELS. Moreover, in common with ELS, mpd neurons of δ(0/0) pups exhibited increased synaptic and extrasynaptic glutamatergic transmission and consequently a blunted neurosteroid suppression of neuronal firing. This study reveals that increased synaptic and tonic glutamatergic transmission may be a common maladaptation to ELS, leading to enhanced excitation of CRF-releasing neurons, and identifies neurosteroids as putative early regulators of the stress neurocircuitry. " 117 Related citations:
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