Stress


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. 


SEEKING PLEASURE AND AVOIDING PAIN (BTB) 
   

    Our most powerful motivations come from behaviours that have proven beneficial to our species from an evolutionary standpoint. Specialized systems in the brain have thus evolved to give us pleasure when we engage in these behaviours.

    The brain has two major pathways that help to activate behaviours: the reward circuit, which is part of the medial forebrain bundle (MFB); and the punishment circuit, or periventricular system (PVS).

     Both the MFB, through the desire/action/satisfaction cycle, and the PVS, through the successful fight or flight response, lead the organism to behave in a way that preserves its homeostasis. Together, they form the behavioural approach system (BAS).

     Opposing the BAS is the behavioural inhibition system (BIS), characterized by Henri Laborit in the early 1970s. Stimulation of the BIS causes an overall inhibition of behaviour, thus working against the BAS.

    Under natural conditions, the BIS is activated when we observe that our actions will be ineffective. When fight or flight appears impossible, very often the only choice left to ensure survival is to submit and accept things as they are. The BIS is the result of an evolutionary history in which this system made itself useful by operating intermittently, temporarily preventing any useless actions that could only have made matters worse.

    For example, consider a small mammal in the middle of a field who suddenly sees a bird of prey flying overhead. The best thing to do is not to move, in the hope of not being seen. In human societies based on competition, many people activate their behavioural inhibition system continually, to avoid reprisals.

    In such cases, the inhibition of behaviour is no longer merely an adaptive interval between approach and avoidance behaviours, but instead becomes a chronic source of anxiety. This sense of uneasiness gradually undermines the individual’s health. Indeed, the inhibition of behaviour has many negative consequences, and they have been abundantly documented. The most obvious ones are psychosomatic illnesses, stomach ulcers, and arterial hypertension. But prolonged activation of the BIS can also lead to more serious genetic disorders such as cancers and all of the pathologies associated with impaired immune function.




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
An external file that holds a picture, illustration, etc. Object name is nihms294476f1.jpg Object name is nihms294476f1.jpg
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. "     

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