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Science Overview

How does the Brain Respond to Stress?

Questions that would be addressed by Sangam


How Does the Brain Respond to Stress


          Stress triggers a sequence of events in the brain that ultimately produces a global, coordinated, whole-body response.  First, the body senses a stressful stimulus using either internal (e.g., nausea, low-blood sugar, infection) or external (e.g., pain, hot or cold, trauma) sensors.  Next, the signals produced by these sensors are then picked up by brain circuits that converge upon a small, paired cluster of nerve cells (neurons), located near the base of the mammalian brain.  These neurons are responsible for the brain’s adaptive responses to all types of stress.  They are located in a brain subregion known as the paraventricular nucleus of the hypothalamus (PVH).  Third, upon receiving these signals, PVH neurons release a hormone known as corticotropin releasing hormone (CRH) in the vicinity of the anterior pituitary gland.  Because these PVH neurons are specialized to release CRH hormone, they are often referred to as CRH neuroendocrine neurons.  Fourth, The anterior pituitary, in turn, responds by secreting another hormone, called ACTH, into the general blood circulation of the body.  The ACTH travels to the adrenal glands, located just above the kidneys, where it causes the glands to release a third hormone, called corticosterone (cortisol in humans; abbreviated CORT) into the bloodstream.  Finally, CORT acts on various tissues to mobilize the body’s energy stores and thereby initiate a whole body response to the stressor.


        In summary, brain signals conveying stress reach the CRH neurons of the hypothalamus, which in turn release CRH to activate the anterior pituitary, which in turn release ACTH to activate the adrenal gland.  These regulatory elements are collectively referred to as the hypothalamus-pituitary-adrenal axis, or HPA axis.  Much evidence now exists in support of the idea that stress disorders are directly linked to abnormalities in HPA axis function.  Some of these findings are highlighted in Table 1.




HPA Axis Related Findings

Major Depression

Elevated plasma cortisol

Elevated cortisol metabolites

Enlarged adrenal glands

Elevated CRH in plasma/CSF

Reduced CRH receptor binding sites

Blunted ACTH response to CRH administration

Elevated 24-hour urinary-free cortisol

Posttraumatic Stress Disorder

Elevated CRH in CSF

Blunted ACTH response to CRH administration

Low basal and stress-induced cortisol output

Atypical depression/seasonal affective disorder

Elevated 24-hour urinary-free cortisol

Low CRH in CSF

Low plasma ACTH, normal plasma cortisol

Eating disorders

Elevated plasma cortisol

Elevated 24-hour urinary free cortisol

Elevated CRH in CSF

Table 1. HPA Axis Abnormalities Associated With Mental Illness



CRH Neuroendocrine Neurons of the PVH Respond in Two Distinct Ways to Stress-Related Signals:


         As described earlier, CRH neuroendocrine neurons are responsible for integrating all signals from the brain that are salient for the stress response.  Accordingly, these neurons constitute a “final common pathway” which funnels all stress-related neural signals into a well-defined patterned output, namely release of CRH hormone.  However, in addition to secreting hormone, there is a second way in which CRH neuroendocrine neurons respond to incoming signals related to stress: they begin synthesizing more CRH hormone.  This is achieved within the nucleus of each CRH neuroendocrine neuron, where chemical reactions take place to turn on the gene sequence encoding the CRH hormone.  The gene, once turned on, is used as a blueprint by the cell to produce more CRH protein.  Thus, in response to stress, CRH neurons: 1) release CRH hormone and 2) begin synthesizing more CRH hormone using the CRH gene within the nucleus as a template.





How Do Incoming Stress Signals Arriving at the Surface of CRH Neurons Turn on the CRH Gene Deep Inside the Nucleus of These Neurons?


        The nucleus, where the CRH gene resides, is situated deep inside the CRH neuroendocrine neuron’s  react with receptors located on the surface of the neuron, triggering an intracellular cascade of reactions that ultimately lead to CRH gene activation.  Depending on the incoming chemical signal, different receptors, coupled to different intracellular cascades, can each produce a similar effect of activating the CRH gene.


Questions that would be addressed by Sangam           

       When designing a computer system to solve scientific problems, computer scientists often find themselves unsure of how to help domain experts in their chosen discipline.  One way for them to do so is to address specific problems given to them by those experts  (See the keynote address, “20 Questions to a Better Application” by Dr. Jim Gray at the Microsoft SciData'04 Workshop).

         Sangam is designed to bring together information concerned with the stress response in mammals. Within our research discipline of neuroendocrinology, the following questions are of particular interest to us and focus the development of Sangam.



Cellular and Systems-Level Anatomy   

  1. What are the chemically defined inputs to CRH neuroendocrine neurons?
  2. What is the chemically defined output from these neurons?
  3. What glial types are in proximity to these neurons? How do they modulate the activation of these neurons?
  4. What are the gross morphological characteristics of these neurons?
  5. What are ultrastructural morphological characteristics of these neurons?
  6. What is the structure of microcircuits for these neurons (i.e. synaptic interactions)?
  7. What is the full complement of receptive machinery on CRH neuron plasma membranes? Where exactly are they located? What are their characteristics?


Molecular Properties

  1. What is the structure of the CRH gene?
  2. What is the macrostructure of the CRH gene in the nucleus?
  3. Which mechanisms regulate the CRH gene?
  4. On which chromosome is the CRH gene located in humans? Rats? What flanks this gene on the chromosome? What mutations effect more than one locus associated with these chromosomes?
  5. What are major differences that have been found, if any, between rats and humans for this system?


Biophysical Properties

  1. What are the membrane (intrinsic) properties of these neurons?
  2. What patterns of electricity activity correlate with hormone release events for these neurons?
  3. What are the kinetic (biophysical) properties of the signaling intermediates responsible for turning genes on in these neurons?


Signaling and Gene Regulation

  1. What signaling pathways are capable of activating the CRH gene in these neurons?
  2. What electrical events are directly coupled to CRH gene expression in these neurons?
  3. When are release events and gene induction coordinated in these neurons? When are they not?
  4. What intracellular transcription factors control CRH transcription? What are their characteristics?
  5. What is the subcellular localization of each major macromolecule involved in gene activation in these neurons over time?


Integrative Stress Physiology

  1. What is the (basal) state of the neurons in unstressed conditions over the circadian cycle?
  2. Which inputs are activating these neurons under various types of stress?
  3. What is the time course of CRH gene activation during acute and sustained hypoglycemic stress?
  4. How do circulation factors feed back to control CRH release?
  5. What are all the known genes activated in these neurons under various types of stress? What are their structures?


Modeling, Computation and Clinical Components

  1. What are some hypotheses put forward by investigators concerning this system and its role in physiology?
  2. What experimental models have been developed to study these neurons?
  3. What computational models have been developed to study these neurons?
  4. Which components of this system are potential targets for therapeutics?
  5. What genetic mutations in the CRH gene lead to clinical pathologies in humans?