The European College of Neuropsychopharmacology has released the
following statement:

Neurogenesis in the adult brain: The association with stress and depression
Presented at the 21st Congress of the European College of
Neuropsychopharmacology 2008, Barcelona, Spain

This release is available in Spanish.

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 (Czeh 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.

References

1. Wittchen HU, Hofler M, Meister W. Depressionen in der
Allgemeinpraxis. Die bundesweite Depressionsstudie. Stuttgart:
Schattauer, 2000
2. Moussavi S, Chatterji S, Verdes E, et al. Depression, chronic
diseases, and decrements in health: results from the World Health
Surveys. Lancet 2007;370:851-858
3. World Health Organisation (WHO). The World Health Report 2001.
Mental Health: New Understanding, New Hope. Download http://www.who.int/
whr/2001/en/whr01_en.pdf
4. Sahay A, Hen R. Adult hippocampal neurogenesis in depression.
Nature Neuroscience 2007;10:1110-1115
5. Ramon y Cajal, SR. Degeneration and regeneration of the nervous
system. London, Oxford University Press, 1928
6. Czeh B, Muller-Keuker JIH, Rygula R, et al. Chronic social stress
inhibits cell proliferation in the adult medial prefrontal cortex:
hemispheric asymmetry and reversal by fluoxetine treatment.
Neuropsychopharmacology 2007;32:1490-1503

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