GLYCOPROTEIN COMPONENTS OF MYELIN PROTEIN IN EXPERIMENTAL MODELS OF STRESS INTRODUCTION

ACUTE STRESS RESPONSE:

The acute stress response has a time course of 1-2 h. Exposure to acute stress generates an adaptive individual response, such as ‘‘fight or flight’’ (McEwen, 1998). Adrenaline production occurs in response to many forms of acute stress. It mobilizes energy stores and alters blood flow, thereby allowing the body to effectively deal with a range of stresses. Its release is essential to survival (Sapolsky et al., 2000).

During acute stress response, the stress is perceived by the hypothalamus stimulating the nerves of the sympathetic nervous system thereby stimulating the body's organs directly (through noradrenaline synapses), and then by a slow release of adrenaline from the adrenal medulla. When there is no longer stress, adrenaline stops being released and the body slowly returns to normal over the next few minutes.

 

CHRONIC STRESS RESPONSE:

The chronic stress response in the other hand takes one day to weeks. Chronic stress is generally thought of as the chronic load of day-to-day stressors. Researchers have long recognized that stress may protect the body, but when more chronic, can also damage it (McEwen, 1998).

Cortisol is produced in response to many forms of stress, and likewise helps the body cope effectively with adverse situations. It also mobi­lizes energy stores, as well as suppresses immune responses, when it is released acutely. Longer- term effects of cortisol include regulation of gene expression in neural circuits involved in modulating stress responsiveness, emotion, and memory (Sapolsky et al., 2000).

Increases in the level of cortisol in the brain ac­tually can turn specific genes “on” or “off” at specific times and locations (De Kloet et al., 1996). Examples include regulation of the glucocorticoid receptor gene, which affects the long-term responsiveness of the brain to stress-induced cortisol release, and the myelin basic protein gene, which is involved in regulating the development of the “insula­tion” that increases the efficiency of nerve signal transmission (Gunnar and Vazquez, 2006; Weaver et al., 2004).

High, sustained levels of cortisol or corticotro­pin-releasing hormone (CRH), which is the brain chemical that regulates the HPA system, result in damage to a part of the brain called the hippocam­pus. This can lead to impairments in learning, memory, and the ability to regulate certain stress responses in both young and adult animals (Brunson et al., 2002).

Individual responses to early stressful experiences can vary dramatically. This variability is thought to be related to differences among animals in the expression of so-called “vulnerability genes,” which make it more likely that early stressors will lead to subsequent problems in stress hormone regulation and behavioural difficulties. In such cas­es, positive early care giving can decrease the like­lihood of these adverse outcomes, demonstrat­ing that beneficial environmental influences can moderate the impact of genetic vulnerability (Barr et al., 2004).

The consequences of chronic stress are serious, particularly as it contributes to anxiety and depression (Anderson and Anderson, 2003). Research has shown that chronic stress is treatable with appropriate interventions such as therapy or medication (McEwen, 2004).

DEPRESSION:

Depression is a state of low mood and aversion to activity that can have a negative effect on a person's thoughts, behaviour, feelings, world view and physical well-being (Sandra Salmans, 1997). Stressful life experiences play an important role in the etiology of depressive complaints. Depression may be conceived as a component of chronic stress (Herbert and Cohen, 1993).

THE AREAS OF THE BRAIN AFFECTED IN DEPRESSION:

Many areas of the brain appear to be involved in depression including the frontal and temporal lobes and parts of the limbic system including the cingulate gyrus. However, it is not clear if the changes in these areas cause depression or if the disturbance occurs as a result of the etiology of psychiatric disorders.

THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS IN DEPRESSION:

In depression, the hypothalamic-pituitary-adrenal (HPA) axis is upregulated with a down-regulation of its negative feedback controls. Corticotropin-releasing factor (CRF) is hypersecreted from the hypothalamus and induces the release of adrenocorticotropin hormone (ACTH) from the pituitary. ACTH interacts with receptors on adrenocortical cells and cortisol is released from the adrenal glands; adrenal hypertrophy can also occur. Release of cortisol into the circulation has a number of effects, including elevation of blood glucose. The negative feedback of cortisol to the hypothalamus, pituitary and immune system is impaired. This leads to continual activation of the HPA axis and excess cortisol release. Cortisol receptors become desensitized leading to increased activity of the pro-inflammatory immune mediators and disturbances in neurotransmitter transmission.

THE SEROTONIN PATHWAYS IN DEPRESSION:

The neurotransmitter serotonin is involved in depression. Serotonin transmission from both the caudal raphe nuclei and rostral raphe nuclei is reduced in patients with depression compared with non-depressed controls. Increasing the levels of serotonin in these pathways, by reducing serotonin reuptake and hence increasing serotonin function, is one of the therapeutic approaches to treating depression (Barker, 1999). Some common SSRIs (Selective serotonin reuptake inhibitors) are Prozac, Zoloft, and Paxil (Dubuc, 2002). 

NEUROENDOCRINE RESPONSE TO STRESS:

Stress, both physical and psychological, results in neuroendocrine signals being released from the brain that can affect immune function. The main two neuroendocrine pathways activated in response to stress that control the immune system are the HPA axis which results in release of glucocorticoid, and the sympathetic nervous system which results in release of catecholamines, epinephrine and norepinephrine. However, there are other neuroendocrine factors that are released following stress that also regulate the immune system, including prolactin, growth hormone (GH) and nerve growth factor (NGF)     (Figure-1).

 

Figure 1: Stress- associated modulation of the hormone response by the central nervous system. Upon experiencing a stressor, the hypothalamic–pituitary–adrenal (HPA) axis and the sympathetic nervous system are activated resulting in release of glucocorticoid and catecholamines which are able to modulate various aspects of the immune system. In addition, the pituitary hormones prolactin and growth hormone are also released which also can modulate the immune system. Figure reproduced from (Glaser and Kiecolt-Glaser, 2005).