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.
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
Signaling and Gene Regulation
Integrative Stress Physiology
Modeling, Computation and Clinical Components