A large number of variables regulate adult hippocampal cell proliferation and neurogenesis such as age, strain, gender, hormones, environment, exercise and learning.25
One of the most consistent reports throughout the literature is that acute and chronic stress produce a decrease in cell proliferation and neurogenesis.
These findings are of considerable interest to both basic and clinical researchers studying depression. This is because there are a large number of stress-based hypotheses of depression,26
and almost all of the animal models of depression have a stress component.27
Multiple acute and chronic physical and psychosocial stress paradigms have been shown to reduce cell proliferation and neurogenesis. In the rat, a single exposure to predator odour decreases cell proliferation, as demonstrated by using either [3
H]-thymidine or BrdU as a marker for cell proliferation.28,29
Acute exposure to inescapable shock produces a decrease in BrdU cell counts that is still detectable when the BrdU is injected 7 days after the exposure to shock.30
Pham et al31
have demonstrated that restraint stress negatively affects cell proliferation, but a longer period of exposure (21 days) is necessary to produce downregulation.
A single 1-hour exposure to a psychosocial stressor, the resident–intruder paradigm, reduces cell proliferation and neurogenesis in marmosets and tree shrews.32,33
Chronic psychosocial stress paradigms also produce decreases in cell proliferation. Exposure to 35 days of the social defeat paradigm caused a decrease in hippocampal cell proliferation in tree shrews, along with decreases in hippocampal volume and cerebral metabolite levels.34
Similarly, rats exposed to 18 days of a social defeat paradigm showed a decrease in cell proliferation.35
Although 1 study has reported that acute stressors affect both cell proliferation and neurogenesis,32
other studies have demonstrated that a stress-induced downregulation of cell proliferation does not always translate into a decrease in neurogenesis. For example, rats exposed to inescapable shock had a decrease in BrdU-positive cells when sacrificed 2 hours after a BrdU injection (proliferation) compared with nonshocked controls, but no change in staining was detected when animals were sacrificed 28 days after BrdU administration.30
This is in agreement with the findings of Tanapat et al,29
who reported a stress-induced decrease in cell proliferation at short time points after BrdU administration (1 and 7 days) but no effect of stress on the number of cells at a later time point (28 days). This indicates that a compensatory change may occur between the 2 time points investigated.30
In this case, in the animals exposed to inescapable shock stress, the compensatory change may have induced a greater number of BrdU-positive cells to survive to the later time point, compared with the percentage that survived in control animals. Therefore, in these animals, fewer cells were born compared with nonstressed controls, but a greater percentage survived to the 28-day time point. This compensatory effect produces the same net number of cells at a later time point.
Stress has also been shown to affect cell survival. It has been shown that 18 days' exposure to the social defeat paradigm after BrdU injection decreased cell survival in the rat.35
In addition, 3 or 6 weeks of restraint stress after BrdU administration produced a decrease in BrdU-positive cell numbers.31
In contrast, a single week of restraint at either days 4–9 or days 10–17 after BrdU injection was not sufficient to decrease the number of BrdU-positive cells.36
Taken together, these studies indicate that, in contrast to the short-term effects of stress on cell proliferation, long-term exposure to a stressor is necessary to affect cell survival.
On the basis of these studies, it can be concluded that both acute and chronic stress have effects on cell proliferation, survival and neurogenesis. To date, there is no reported effect of stress on differentiation of BrdU- positive cells into mature phenotypes. Chronic exposure to stress, which may be more applicable to a real-world situation than an acute stressor paradigm, may work through multiple mechanisms to regulate neurogenesis. One hypothesis is that the cumulative effects of stress on proliferation, neurogenesis and survival produce the changes in dendritic remodelling that may be involved in the pathophysiology of chronic depressive disorder.
Other stressors, such as prenatal stress, have also been shown to produce a decrease in cell proliferation in the adult rat.37,38
This has been shown to be a gender-specific effect, with female rats being more sensitive to some of the effects of stress on cell proliferation and dendritic spine density.39,40
The incidence of depression is higher in females than males,41
and estrogen has been shown to be a regulator of cell proliferation.42
Clearly, there may be important functional differences in the stress and cell proliferation responses between males and females. However, most basic research studies have been performed on male rats. Further studies investigating sex-specific differences are needed, and caution must be used when extrapolating data from males to females.
The deleterious effect of stress on the brain is not specific to hippocampal cell proliferation. Before studies of neurogenesis were performed, it was well established that stress affected brain restructuring and reorganization in the adult animal.43,44
Repeated stress results in atrophy of CA3 pyramidal neurons,45,46
which is reversed by the atypical antidepressant tianeptine.47
Chronic social stress also reduces dendritic arborization of CA3 neurons.48
It has been proposed by McEwen43
and by Sapolsky49
that the effect of stress on the dentate gyrus granule cells, as well as CA3 pyramidal neurons, may be the result of hypersecretion of glucocorticoids (GCs) such as corticosterone (CORT) and overproduction of excitatory amino acids. Stress increases serum bound and free CORT levels,46
and exogenous administration of CORT produces a decrease in cell proliferation that can be prevented by the N
-methyl-D-aspartate (NMDA) antagonist MK-801.50
CORT-induced decreases in cell proliferation can also be prevented by administering the dehydroepiandrosterone steroid (DHEA) or by performing adrenalectomy on the animals.29
All of the stress paradigms mentioned here also increase CORT levels in intact animals. This stress- induced increase in CORT may be responsible for the decrease in cell proliferation. Although CORT is a potent downregulator of cell proliferation, a study using [3
H]-thymidine autoradiography combined with immunohistochemistry has shown that newborn hippocampal cells have neither type I nor type II GC receptors.51
Therefore, although CORT is released during stress and cell proliferation is decreased, this is not because of a direct effect of CORT on the cells but must occur as a result of an additional regulatory pathway on the hippocampal stem cells. In addition, one study has demonstrated that decreases in cell proliferation can be seen even in the absence of elevated CORT levels.30
The many factors underlying stress-induced effects on hippocampal reorganization and hippocampal cell proliferation are currently being studied.
Although stress decreases cell proliferation, this downregulation is not solely responsible for depressive symptoms and the pathophysiology of depression. Stress and depression constitute a multifaceted picture, and decreased cell proliferation is merely 1 part of a long path leading from the first stress exposure to the manifestation of depression.52
The response of the individual organism to a stressful (or thus perceived nonstressful) situation, along with a possible genetic predisposition to affective disorders, may also play a large role in stress-induced changes in cell proliferation and neurogenesis. The study of the effects of stress on neurogenesis is still an emerging field, and currently the mechanism by which decreased cell proliferation is associated with depressive symptoms is unknown.