Antidepressant Treatments Reversing the Effects of Stress on Hippocampal Neurogenesis

Megan Wiltshire
Christopher Newport University
NEUR 301
April 20th 2015

Specific Aims of Research:

The purpose of this research is to determine the extent to which hippocampal neurogenesis is
down regulated by chronic stress in adult mice. Furthermore this study will determine the extent
to which antidepressants can stop and/or reverse the down regulation of neurogenesis cause by
chronic stress in adult mice. This will provide a basis for determination of the best
pharmacological method in the treatment of major depression disorder.
Background Information:
Depression is a devastating illness that is estimated to affect about 18% of the population at some
point in an individuals lifetime (Depression is Underdiagnosed and Undertreated, 2004, p. 1).
Current treatment for major depression displays high resistance, and the probability of lasting
remission is low (Depression in Adults with a Chronic Physical Health Problem: The NICE
Guideline on Treatment and Management, 2010). From the pharmacological standpoint there
are two main classes of drugs commonly used for the treatment of depression. They are tricyclic
antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs). Both classes involve
blocking the synaptic reuptake of monoamines such as noradrenaline (NA), 5hydroxytryptymine (5-HT), and dopamine (DA). The increased presence of these
neurotransmitters in the synaptic cleft is accountable for the mood-elevating effects to combat
depression (Depression in Adults, 2010). Numerous studies have focused on the interactions
between stress and depression and their effects on the hippocampus, among other brain regions.
Stress has been found to exert a profound effect on hippocampal neurogenesis, leading to
extreme decreases in the rate of cell proliferation resulting in both short-term and long-term
impairment (Warner-Schmidt & Duman, 2006, p. 240-241). In addition, brain-imaging studies
demonstrate that hippocampal volume is decreased in patients with stress-associated depression

and post-traumatic stress disorder (Astur et al., 2006, p. 234).

The hippocampus is one of only a few brain regions where production of new neurons occurs
throughout the lifetime of animals, including humans (Carlson, 2012). Hippocampal
neurogenesis can be influenced by several environmental factors and stimuli. Most importantly,
it has been shown that stressful experiences, including both physical and psychosocial stress,
suppress the formation of hippocampal cells (McKittrick et al., 2000, p. 85).
Hypotheses:
When exposed to chronic stress, adult rats will display significant down regulation in
hippocampal neurogenesis compared to the control group not exposed to stress. Nortriptyline, a
commonly prescribed TCA, will increase neurogenesis in both the control group and the stress
treatment group. Sertraline, a commonly prescribed SSRI, will also increase neurogenesis in
both the control and treatment groups. When comparing the effects of nortriptyline to those of
sertraline, sertraline will have a greater reversal effect on down regulated hippocampal
neurogenesis caused by exposure to chronic stress.
Proposed Methodologies:
The first experiment will consist of two groups, a control group of 15 adult male rats and a
treatment group of 25 adult male rats. In the control group, each rat will be housed individually
and food and water will be provided ad libitum. In the treatment group, each rat will be housed
individually and food and water will be provided ad libitum. A tail shock will be randomly
applied at different times to the treatment group to simulate chronic unpredictable stress.
The second experiment will consist of three groups, a control group of consisting of 10 adult
male rats from the first experiments control group and two treatment groups each consisting of
10 adult male rats from the first experiments treatment group. All rats will be housed

individually and food and water will be provided ad libitum. One treatment group will receive
daily nortriptyline injections, the other treatment group will receive daily sertraline injections,
and the control group will receive daily placebo injections.
Proposed Analyses:
BrdU labeling will be used to analyze hippocampal neurogenesis in each group.
10 rats, 5 from the control and 5 from the treatment group, will be administered BrdU after week
three of experiment one. Twenty-four hours after BrdU injection, the rats will be killed and
immunohistochemistry will be used to quantify BrdU-positive cells.
All of the rats from the second experiment will be administered BrdU after three weeks of
antidepressant or placebo injection. Twenty-four hours after BrdU injection, the rats will be
killed and immunohistochemistry will be used to quantify BrdU-positive cells.
ANOVA statistical analysis will then be performed to determine statistically significant
differences in BrdU-positive cells.
Possible Outcomes:
The first experiment will hopefully show the expected significant reduction in BrdU-positive
cells, indicating the down regulation of hippocampal neurogenesis, in the treatment group
exposed to chronic unpredictable stress when compared with the control group. This result is
needed to proceed to the second experiment to test antidepressant effects on the reversal of
reduced neurogenesis seen in rats exposed to chronic stress.
For the second experiment, the predicted reversal in the reduction of hippocampal neurogenesis
in the treatment groups compared to continual impairment in the control group would support the
theory that the impairment of the hippocampus due to stress is in fact a risk factor for depression,
and that prescribed antidepressants can reverse the impairment. Furthermore, if sertraline

significantly increased hippocampal neurogenesis when compared to nortriptyline, it can be

concluded that SSRIs are a better treatment for depression than TCAs, when stress is involved.
Other outcomes to the second experiment, such as showing no significant increase in
hippocampal neurogenesis, would the support the basis that stress and depression are not
associated through hippocampal neurogenesis as previously thought.

References
Astur, R. S., St. Germain, S. A., Tolin, D., Ford, J., Russell, D., & Stevens, M. (2006). Hippocampus
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Carlson, N. R. (2012). Physiology of Behavior (11th ed., p. 85; 601612). Boston: Prentice Hall.
Depression in Adults with a Chronic Physical Health Problem: The NICE Guideline on Treatment
and Management. (2010). London: British Psychological Society and the Royal College of
Psychiatrists.
Depression is Underdiagnosed and Undertreated. (2004). The Medical Wellness Association, 1(1).
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