|  Mood
disorders continue to be major medical problems that affect up to 17%
of the population at some point in life and can result in loss of life.
Although effective treatments exist, not all patients respond to available
medications and there is a time lag of weeks to months in the therapeutic
response to antidepressants. The pathophysiology underlying mood disorders
has not been identified. Recent advances in neurobiology provide a new
conceptual framework for investigating both the pathophysiology and the
treatment of mood disorders. These studies demonstrate that regulation
of brain function can occur via structural remodeling or synaptic plasticity
of the cellular components of the brain. This includes neurogenesis (addition
of new neurons) in the adult brain. In this review, the concept of structural
remodeling will be discussed and evidence that the pathophysiology and
treatment of mood disorders may be influenced by structural remodeling,
particularly neurogenesis, will be examined. Additional reviews of these
topics are listed at the end of this article.
Over
the past 30 years, there has been a revolution in our understanding of
how the brain works and consequently in our studies of the pathophysiology
of disorders of the brain. During this time we have discovered that communication
between the different cellular components of the brain is controlled by
a number of neurotransmitter systems. These neurotransmitter systems control
neuronal activity by regulating complex intracellular signaling pathways
and expression of specific genes. Elucidation of these extracellular and
intracellular pathways has led to the widely accepted notion that major
psychiatric illnesses result from disruption of these neurochemical pathways,
and a tremendous effort has been placed on identification of these specific
neurochemical alterations.
In
addition to neurochemical control of the brain, more recent studies demonstrate
that structural remodeling of the cellular components of the brain also
controls communication between neurons. Structural remodeling, often referred
to as neuronal plasticity, can occur in several different ways. This includes
a change in the number or shape of dendritic spines, the primary location
for synapse formation, as well as alterations in the number and length
of dendritic branch points. Moreover, contrary to what used to be considered
dogma, the total number of neurons in certain brain regions can be altered
in the adult brain.
Until
recently, it was thought that after the brain reached an adult stage the
capacity for adding new neurons was lost. However, neurogenesis has now
been demonstrated in the brains of a variety of different adult species,
including bird, rodent, monkey, and human. New cells are derived from
neural progenitor cells that are localized to a few restricted brain regions.
One region is the subventricular zone that gives rise to cells that migrate
to the olfactory system. The other is the subgranular zone in the hippocampus,
where new cells are added that mature into granule neurons in the dentate
gyrus of the hippocampus. The hippocampus is a limbic brain structure
that plays a role in learning and memory and control of several vegetative
processes. It is also a structure that has been implicated in mood disorders,
including depression and posttraumatic stress disorder (PTSD).
New
cells added to the hippocampus differentiate and mature into adult neurons
within a period of several weeks. The cells display characteristics of
adult neurons, including physiological properties of mature cells. Evidence
that adult neurogenesis contributes to brain function has come mostly
from correlative studies. For example, the rate of neurogenesis is increased
by a variety of stimuli including exercise, hippocampal-dependent learning,
and estrogen. This suggests that there is activity-dependent regulation
of neurogenesis that increases the functional capacity of the hippocampus.
This possibility is supported by a study demonstrating that chemical inhibition
of neurogenesis in adult rodents blocks hippocampal-dependent learning,
indicating that new neurons have a functional role in the adult brain.
However, it is important to point out that the extent of neurogenesis
in the adult human brain has not been determined and the functional relevance
of this process in primates remains to be established.
Neuronal
remodeling and neurogenesis provide additional mechanisms for regulation
of neurotransmission in the brain. The mechanisms for control of remodeling
and neurogenesis have not been fully identified, but they are likely to
involve extracellular and intracellular pathways, thereby linking neurochemical
and structural changes in the brain.
In
contrast to the positive effects of exercise and learning, neurogenesis
can also be regulated in a negative manner. This has been demonstrated
most dramatically by exposure to stress, which results in a robust down-regulation
of adult neurogenesis in the hippocampus of rodents and nonhuman primates
(Fig. 1). Several
different types of stress have been examined, including both physical
and social stressors. One of the first reports demonstrated that exposure
of a marmoset monkey to a resident animal in its home cage, referred to
as intruder stress, decreases the rate of neurogenesis in the hippocampus
of the intruder. Although this is considered a stressful condition for
these very territorial animals, the time of exposure was very short (1
hour) and the two animals were never in physical contact because they
were separated by a wire mesh. Similar effects have been observed in tree
shrews with the resident–intruder stress model. Exposure to predator
stress (e.g., fox odor) or foot shock is also reported to decrease neurogenesis
in the hippocampus of adult rodents.
In
addition to these types of stress, a recent study demonstrated that exposure
of animals to a behavioral model of depression can decrease adult neurogenesis
in the hippocampus. In this model, referred to as the learned helplessness
model, animals are exposed to an inescapable stress condition that results
in a state of “helplessness.” That is, animals exposed to
the inescapable stress are no longer capable of escaping upon subsequent
testing even though escape is now possible, and administration of an antidepressant
can reinstate the ability to escape. We have found that exposure to inescapable
stress results in down-regulation of neurogenesis in the hippocampus that
correlates with behavioral helplessness. Taken together, these studies
demonstrate that different types of stress, including social, physical,
and psychological stress, can decrease neurogenesis in the adult hippocampus.
The
mechanism underlying the down-regulation of neurogenesis in the hippocampus
by stress has not been fully characterized. Activation of the hypothalamic-pituitary-adrenal
axis clearly plays a role, however. Administration of a high dose of adrenal
glucocorticoids similar to what would be observed under stressful conditions
decreases the rate of neurogenesis in the adult hippocampus. A role for
glucocorticoids in the regulation of neurogenesis has also been demonstrated
in a study of neurogenesis in aging. Neurogenesis continues to occur in
aged animals, although at a reduced rate. If the adrenal hormones are
removed, the rate of neurogenesis returns to that seen in young animals.
The results demonstrate that aging-induced elevation of glucocorticoids
can account for the decreased rate of neurogenesis that is observed with
age. The exact molecular and cellular mechanisms underlying the effect
of glucocorticoids on neurogenesis are currently being studied and may
involve regulation of excitatory amino acid neurotransmission.
In
addition to decreased neurogenesis, repeated stress also alters the dendritic
morphology of a major population of neurons in the hippocampus, termed
CA3 pyramidal cells (see
Fig. 1). McEwen and colleagues have found that exposure to restraint
stress for 2 weeks decreases the dendritic arborization of CA3 neurons.
This includes a decrease in the number and length of the apical dendrites.
Combined with a reduction in neurogenesis of granule cells, the atrophy
of CA3 neurons could result in a significant reduction in the function
of the hippocampus.
These
studies clearly demonstrate that stress can negatively regulate neurogenesis
and cause neuronal atrophy in the adult hippocampus. However, there is
little or no information on how stress influences neurogenesis and dendritic
morphology in a developing brain. Given the high degree of stress that
children and adolescents may be exposed to and the increasing awareness
of psychiatric disorders in these age groups, it will be important to
investigate this relationship in future studies.
Stress
is known to play a major role in mood disorders, often being involved
in either the precipitation or worsening of depression as well as other
illnesses. On the basis of preclinical studies demonstrating that stress
can reduce neurogenesis and can cause atrophy of neurons in the hippocampus,
clinical investigators began asking whether structural alterations might
be found in the brains of patients with illnesses related to stress. Magnetic
resonance spectroscopy imaging studies demonstrate that the volume of
the hippocampus is significantly decreased in patients with depression
or PTSD. Several independent investigators have confirmed these findings
in different patient populations. These findings raise the possibility
that a reduction in hippocampal volume, as well as hippocampal function,
contributes to the cognitive and vegetative abnormalities observed in
depressed patients.
The
reduction in hippocampal volume has been shown to correlate directly with
the duration of depressive illness, but not the age of the individual.
This suggests that depression may cause a reduction in hippocampal volume,
and not that decreased volume leads to depression. However, it is possible
that small changes in hippocampal volume contribute to the formation of
depression and there is then a continued progression of the volumetric
change. This could result from continued stress associated with illness.
Additional studies will be needed to determine whether decreased hippocampal
volume is a trait or state marker. It will also be important to determine
whether the effect is reversible with antidepressant treatment.
The
exact role of neurogenesis in depression and reduction in hippocampal
volume has not been determined. It is conceivable that down-regulation
of neurogenesis in the adult brain could contribute to a decrease in hippocampal
volume. It has been calculated that neurogenesis adds up to 250,000 new
cells per month in the rodent hippocampus, or 6% of the total number of
existing granule cells. Although the numbers in both nonhuman primates
and humans are much lower, it is possible that inhibition of this process
could contribute to a reduction in the overall volume of the hippocampus.
It is likely that atrophy of CA3 pyramidal neurons as well as other cell
types could contribute to the overall reduction in the size of this brain
region. Additional postmortem studies will be required to determine fully
the cellular mechanisms that account for decreased hippocampal volume
in mood disorders.
In
addition to the changes observed in the hippocampus, recent studies also
demonstrate structural alterations in the cerebral cortex of patients
with mood disorders. Brain imaging studies demonstrate that the volume
of the subgenual prefrontal cortex is decreased in patients with depression
or bipolar disorder. Moreover, postmortem studies of patients with these
illnesses also find that the number and size of neurons and glia are decreased
in the cerebral cortex. Although reduced neurogenesis does not appear
to account for these cortical changes, these results demonstrate that
atrophy and cell loss in mood disorders are not restricted to the hippocampus.
Further studies will be needed to determine the cellular mechanisms underlying
the cerebral cortical changes observed in depression and bipolar disorder.
We
have also been interested in identifying the molecular and cellular mechanisms
underlying the actions of antidepressants. Toward this goal, we found
that antidepressant treatment increases the expression of brain-derived
neurotrophic factor (BDNF), a major neurotrophin in the brain. This discovery,
combined with reports that stress causes atrophy and cell loss in the
hippocampus, leads to the notion that neurotrophic actions could contribute
to the effects of antidepressants. To examine this possibility, we studied
the influence of antidepressant treatment on neurogenesis in the adult
hippocampus. We found that administration of different classes of antidepressants,
including norepinephrine and selective serotonin reuptake inhibitors,
up-regulates neurogenesis in the hippocampus of adult rodents. Increased
neurogenesis was dependent on several weeks of antidepressant administration
consistent with the time course for the therapeutic action of antidepressants.
In addition, up-regulation of neurogenesis was not observed with other
classes of psychotropic drugs, demonstrating a pharmacological specificity
for antidepressants. Several different investigators have now reported
that both chemical antidepressants and electroconvulsive seizures increase
neurogenesis in the adult rodent hippocampus.
In addition to studies in normal animals, the influence of antidepressant
treatment on the down-regulation of neurogenesis in rodents exposed to
learned helplessness has also been examined. As described above, learned
helplessness is a behavioral model of depression. We have found that helplessness
in this paradigm is associated with decreased neurogenesis. We have also
found that antidepressant treatment blocks the down-
regulation of neurogenesis and reverses the behavioral helplessness in
this paradigm. Additional studies are being designed to test directly
the role of neurogenesis in the behavioral responses observed in the learned
helplessness model. However, the results suggest that up-regulation of
neurogenesis could contribute to behavioral alterations in this model.
Moreover, increased neurogenesis would be expected to oppose the actions
of stress on the hippocampus and could help to reverse or block the atrophy
of the hippocampus observed in patients with mood disorders.
The
results discussed in this column highlight significant conceptual advances
for understanding the pathophysiology and treatment of mood disorders.
These include the astonishing discoveries that the shape and number of
neurons can be altered in the adult brain. Moreover, structural, as well
as neurochemical, alterations have been observed in the brains of patients
with mood disorders, and antidepressant treatment could oppose these structural
changes. Taken together, these findings raise the possibility that novel
therapeutic interventions targeted at neuronal number and morphology can
be developed with the hope of more efficacious and faster-acting drugs.
It is also interesting to speculate that behavioral therapy could be designed
to enhance the effects of antidepressants. For example, exercise and learning
are reported to increase neurogenesis in the adult brain, and it is possible
that a combination of drug and behavioral therapy could produce a greater
therapeutic response. This possibility is supported by clinical studies
demonstrating that exercise can produce antidepressant effects in depressed
individuals. The continued use of state-of-the-art neurobiological studies
holds a bright future for the development of better treatments, and possibly
the prevention, of mood disorders.
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