The brain is the key organ in the response to stress. It reacts in a complex, orchestrated manner that is related to the activation and inhibition of neural structures involved in sensory, motor, autonomic, cognitive and emotional processes. It is the brain which finally determines what in the world is threatening and might be stressful for us, and which regulates the stress responses that can be either adaptive or maladaptive. Chronic stress can affect the brain and lead into depression: Environmental stressors (e.g. job and family situation, neighborhood) and especially stressful life events such as trauma or abuse are amongst the most potent factors to induce depression. Since the development of novel approaches to antidepressant treatment is based upon an improved neurobiological understanding of this condition, new information about the cellular changes that take place in the brain is required.
Depression: a growing public health burden
Depression is a chronic, recurring, multifactorial, and life-threatening disorder, which represents a collection of psychological, neuroendocrine, physiological and behavioural symptoms. Chronicity and frequency of these symptoms constitute the clinical condition. Depressive disorders affect up to 20% of people at some time in their life. In primary care, an estimated 20% of patients suffer from depression, but often are not diagnosed correctly (Wittchen, 2000).
Depressive disorders are among the most prevalent illnesses worldwide, producing significant public health and socioeconomic problems (WHO, 2001). The immense costs of depression account for approximately 1% of the gross domestic product in Europe (approximately 100 billion Euro). Depression is affecting more than 120 million people globally, and is set to rise to become one of the leading causes of disability, second only to cardiovascular disease, by the year 2015.
Brain changes induced by stress and depression
The areas of the brain that are most affected by the changes caused by depression are the prefrontal cortex, amygdala and hippocampus, which are central to emotion, memory and learning. Structural and functional changes as a consequence of stress and/or major depression are a reduction in volume, neuronal size and density, associated with changes in cerebral blood flow and glucose metabolism (see figure 1). In addition, there is a reduced density of glial support cells that are instrumental in the communication between nerve cells, which is particularly relevant to the reduced volume of the prefrontal cortex and the hippocampus. The shrinkage might explain some of the emotional changes observed in people with depression.
Neurogenesis in the adult brain
The ´stress hypothesis´ of affective disorders has stimulated the development of putative animal models of depression. Animal models today are generally regarded as invaluable in preclinical research on human psychopathology, and are thus of prime interest in studying the pathophysiology of depression and specific responses to antidepressant drug treatments. The discovery that the adult nervous system is capable of replacing its cells has attracted considerable interest in the scientific community. Up to now, neural networks in adults have been thought to be fixed and immutable, without the potential to regenerate: This assumption was prominently pronounced by the famous Spanish neuroscientist Santiago Ramon y Cajal, who postulated that „everything may die, nothing may regenerate" (Cajal, 1928). Current research has overcome this view and has shown that the formation of new nerve cells (=neurogenesis) also takes place in the adult brain. Neurogenesis can be modified by positive modulators such as learning, physical exercise, and hormonal influence, as well as negative modulators such as acute and chronic stress.
While stress has been found to inhibit adult neurogenesis in the hippocampus – a brain area that is central to emotion, memory and learning –, antidepressant treatment has the opposite effect. Moreover, patients with mood disorders often have reduced hippocampal volumes. This evidence rapidly led to the formulation of the 'neurogenesis hypothesis' of depression, which says that adult neurogenesis in the hippocampus is a candidate substrate for both the etiology and the treatment of major depressive disorders. However, according to the current view, newborn cells in the hippocampus per se may not be critical for the development of depression, but may be required for certain behavioural effects of antidepressants (Sahay & Hen, 2007).
Recent research has proven that the adult brain is capable of generating new nerve cells (neurons). Neurogenesis can be influenced by positive and negative modulators.
The role of gliogenesis
There is increasing evidence that in addition to neurogenesis, stress and antidepressant treatment also induce changes in the formation of specific glial support cells (=gliogenesis) that are critical for the survival of the neurons in the brain. There are about 100 times more glial cells than nerve cells, providing energy and nutrition to the neurons. Besides their ´housekeeping´ functions, glial cells are instrumental to neural communication and regarded as dynamic regulators of synaptic strength and synapse formation. They also possess receptors for neurotransmitters and steroid hormones that, similarly to receptors of neurons, can trigger electrical and biochemical events in the cell. Therefore, structural changes of glial cells are likely to have an important functional significance for the communication between neurons and between neurons and glial cells.
In the adult brain various antidepressant treatment strategies can not only stimulate neurogenesis, but also exert similar stimulatory effects on gliogenesis. Moreover, animal studies have recently shown that chronic stress inhibits cell proliferation not only in the hippocampus but also in the prefrontal cortex, and that this inhibitory effect can be counteracted by antidepressant treatment (Czéh et al., 2007). The significance of these observations is strengthened by in vivo neuroimaging studies in patients with mood disorders that consistently point to the involvement of prefrontal brain sites in the pathophysiology of the disease. These imaging findings are further supported by reports on human post-mortem tissues revealing that the number of glial cells in the prefrontal cortex is adversely affected in patients with mood disorders.
Experiments show that stress and depression inhibit the growth of new nerve cells as well as glial support cells, and that this inhibitory effect can be counteracted by antidepressive therapy.
Clinical implications
- Within the last two decades, the understanding of the mature brain has changed: Neuronal and glial cell networks in the brain are far from being fixed and immutable – a multitude of factors such as environmental stimulation, learning, growth factors, glucocorticoids, sexual hormones, stress, aging, and several neurotransmitters regulate the generation of new neurons. Antidepressants stimulate the growth of neurons and glial cells again so the brain changes that occur as a consequence of stress and depression are generally reversible.
- Today it is widely believed that neurogenesis in the adult brain is restricted to selected brain regions such as zones of the hippocampus and the lateral brain ventricles. However, a growing number of recent studies describe the generation of new neurons also in the adult neocortex. Although small in both number and size, these new cells could have a significant impact on neocortical function.
- Interrelation between psychiatric diseases and adult neocortical cytogenesis is suggested by preclinical studies of stress (inhibiting cytogenesis) and antidepressive treatment (stimulating cytogenesis), but so far the existence of a causative relationship remains speculative. Nevertheless these findings should encourage further studies on neocortical cytogenesis and its function in affective disorders such as depression, which may provide additional evidence that impairments of brain neuroplasticity are important features of depressive disorders.
- On the basis of this research it might be possible to develop new strategies for more effective therapies of depressive diseases.
These discoveries show that brain cells can be adversely affected by stress and depression which may lead to a new approach to antidepressant treatment.