Neurogenesis in the adult brain: association with stress and depression

This press release issued by eurekalert
was presented at the 21st Congress of the European College of
Neuropsychopharmacology 2008, Barcelona, Spain.

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.