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Head: STRESS ON HIPPOCAMPAL FUNCTIONS: RISK FOR CLINICAL DEPRESSION 1

Affect of Stress on Hippocampal Functions: A Risk Factor for Clinical Depression

Megan Wiltshire
Christopher Newport University

STRESS ON HIPPOCAMPAL FUNCTIONS: RISK FOR CLINICAL DEPRESSION

Abstract
A part of the limbic system, the hippocampus is key in the regulation of emotion, learning and
memory. In studies of patients with depression, many correlates have been found to the
impairment of hippocampal functioning. Suggesting that such impairment could be a leading
risk factor to the development of major depression. Also, recent studies have discovered a
connection between chronic stress and the impairment of the hippocampus. This further suggests
that the effects of chronic stress on the hippocampus then lead to depression and/or depressivelike symptoms.
Keywords: depression, stress, hippocampus, emotion, neurogenesis, synaptic plasticity,
dendritic spine density, volume

STRESS ON HIPPOCAMPAL FUNCTIONS: RISK FOR CLINICAL DEPRESSION

Affects of Stress on Hippocampal Functions: Risk Factor for Clinical Depression

I. Introduction
Depression is quickly becoming a common mental disorder, with an estimated 18% of the
population experiencing at least one episode of depression in their lifetime (Depression is
Underdiagnosed and Undertreated, 2004, p. 1). However it remains one of the most underaddressed conditions in the clinical setting. Assessments for depression consist of evaluating the
patient based on nine symptoms: reduced mood, absence of interest or pleasure in activities,
indecisiveness, feelings of worthlessness and guilt, disturbances in sleep and food intake,
restlessness or sluggishness, fatigue, lack of concentration, and thoughts of death or suicide
(Nelson, 2011). These symptoms commonly overlap with numerous other health conditions and
therefore, are overlooked in terms of major depression (Depression is Underdiagnosed, 2004, p.
1). Frequently associated with the diagnosis of major depression is stress. Chronic stress has
been found to have multiple damaging affects on the body, specifically the brain. Prolonged
exposure to stress and the hormones involved in stress response has been shown to have
impairing effects on brain function and even alter the structure of certain areas of the brain,
namely the hippocampus (Nelson, 2011, p. 594). The hippocampus, located in the medial
temporal lobe, is apart of the limbic system, which functions to mediate emotional responses
(Carlson, 2012, p. 85). Specifically, the hippocampus is known to be involved in learning,
memory formation and consolidation (Byrne & Roberts, 2009, p. 541). Long-term memory,
spatial navigation and spatial memory, along with behavioral inhibition are the potential
functions damaged by chronic stress. The physical effects of stress on the hippocampus may

STRESS ON HIPPOCAMPAL FUNCTIONS: RISK FOR CLINICAL DEPRESSION

lead to possible risk factors for the diagnosis of clinical depression and could also lead to
innovative treatments for major depression.
II. Hippocampal impairments
Major impairments observed in patients with depression include a reduced hippocampal
volume, decrease in hippocampal neurogenesis, and a reduction in dendritic arbor and spine
density (Jols et al., 2004, p. 223)
Hippocampal Volume
One of the effects of stress on the hippocampus is seen in the overall volume of the
hippocampus within the adult brain. In a study presented in the American Journal of Psychiatry,
patients with depression exhibited a significant 19% smaller left hippocampal volume than
comparison subjects without smaller volumes of other comparison regions (Bremner, Narayan,
Anderson, Staib, Miller, & Charner, 2000, p. 116). In an estimated 40-50% of patients, high
levels of cortisol have been associated with depressive episodes. In addition increased levels of
glucocorticoids associated with high levels of stress have been correlated to damage of
hippocampal neurons resulting in diminished volume of the hippocampus. Neuroimaging studies
have shown the enlargement of the ventricles and a widening of the cortical sulci in patients with
depression (Bremner et al., 2000, p. 115-117). A study by Booij (2015, p. 1), investigated the
role of serotonin (5-HT) in hippocampal development since the hippocampus is dense with
serotonergic receptors and important in stress-regulation. The results of the study show that sitespecific serotonin transporter methylation could be used as a marker for the development of
serotonin associated disorders, such as depression. This implies that there are biological

STRESS ON HIPPOCAMPAL FUNCTIONS: RISK FOR CLINICAL DEPRESSION

mechanisms by which gene interactions influence hippocampal development and, through brain
development, make individuals more vulnerable to developing depression or other stress-related
disorders (Booij et al., 2015, p. 3, 9, 11). Also elevated levels of glucocorticoids seen in stress
responses were previously associated with post-traumatic stress disorder (PTSD), in which
patients have abnormal brain structures within the hippocampus (Astur et al., 2006, p. 234).
Symptoms of PTSD include those of depression, such as sleeplessness, fatigue, and deficits in
declarative memory function (Bremner et al., 2000, p. 115). Thus, chronic stress leading to
PTSD could also be seen to have an affect on those with repeated episodes of depression leading
to increased hippocampal atrophy over time. The reduction in hippocampal volume increases the
risk for subsequent depressive relapses (Bremner et al., 2000, p. 117). Another finding shows
decreased hippocampal volume in patients with depression correlating to the number of
depressive episodes (MacQueen et al., 2003, p. 1387). Previous reports stated that hippocampal
volume decreases as age increases (Bremner et al., 2000, p. 117). In McQueen et al. (2003),
twenty subjects experiencing their fist episode of depression, along with twenty matched control
subjects, and seventeen subjects with confirmed multiple episodes of depression, along with
seventeen matched control subjects, were tested and volumetric data was collected through MRI
scans. The study found that not only did patients with depression exhibit smaller hippocampal
volume, but those who had experienced multiple episodes of depression had significantly smaller
volumes compared to both the control group and first episode patients (MacQueen et al., 2003, p.
1390). This model demonstrates that chronic repeated episodes of stress and depression may
lead to increased hippocampal atrophy, possibly increasing the risk for successive relapses of

STRESS ON HIPPOCAMPAL FUNCTIONS: RISK FOR CLINICAL DEPRESSION

major depression. Early treatment of stress through various coping mechanisms would aid in the
reduction of glucocorticoids in the body, which in turn would stop and potentially reverse this
hippocampal impairment, allowing for the treatment depression.
Neurogenesis
Associated with hippocampal volume, neurogenesis, the growth and development of new
nervous tissue, also has a role in depression. Stress has been found to exert a profound effect on
neurogenesis, leading to extreme decreases in the rate of cell proliferation resulting in both shortterm and long-term impairment (Warner-Schmidt & Duman, 2006, p. 240-241). Numerous
studies are now present that consistently report the decrease in adult neurogenesis due to
exposure to chronic stress. Chronic inescapable stress offers time line correlates to the
behavioral despair model of depression. Liu, Dang, and Liu (2015, p. 8415), studied the
effects of hippocampal neurogenesis in antidepressant-like behavioral effects of the SIRT2
protein. Sirtuins (SIRTs) modulate biological pathways such as stress response, protein
aggregation, and inflammatory processes. They found that neurogenesis increased the
antidepressant-like behavioral effects of SIRT2, increasing test performance, and concluded that
neurogenesis may be required for the behavioral effects of antidepressant drugs to take place
(Liu et al., 2015). SIRT2 also may be a potential therapeutic target for the prevention of
depression and other neurological disorders. Other studies have shown that common treatment
with antidepressants has the ability to block the down-regulation of neurogenesis in the
hippocampus caused by stress, resulting in increased mood and memory functioning (WarnerSchmidt & Duman, 2006, p. 243). Further study is needed however to form a direct link

STRESS ON HIPPOCAMPAL FUNCTIONS: RISK FOR CLINICAL DEPRESSION

between neurogenesis and depression. Since neurogenesis can be affected also by other factors,
it could pose challenges in discerning the role of stress specifically in this mechanism.
Dendritic Arbor/Spine Density
The dendritic arbor and spine density in the hippocampus is extensive due to its role in
long-term potentiation (LTP) through the hippocampal circuit (Byrne & Roberts, 2009, p. 541544). During a stress response the hypothalamic-pituitary-adrenal (HPA) axis is activated and
causes the release of glucocorticoids, catecholamines, and enkephalins (Nelson, 2011, p. 695).
Studies have shown differential effects of stress on the hippocampus and the amygdala (Kim et
al., 2006, p. 6). This release of hormones from the HPA axis has been found to impair LTP and
decrease dendritic arborization in the hippocampus, while facilitating LTP and increasing
dendritic arborization of amygdalar neurons. This accounts for the decrease in declarative
memory function and increase in mood fluctuations seen in patients with depression (Kim et al.,
2006, p.1-2). A study on chronic social stress performed on male rats resulted in a decrease in
the number of branch points and total dendritic length in the arbors of CA3 pyramidal neurons
(McKittrick et al., 2000, p. 85). It is also believed that the mechanisms, which underlie dendritic
alterations in the hippocampus, involve the stress-induced changes in glucocorticoids, 5-HT and
other neurotransmitters (Warner-Schmidt & Duman, 2006, p. 246). One interesting study
showed contrasting effects of stress on dendritic spine density (Shors, Chua, & Falduto, 2001, p.
6292). The difference was seen between the male versus the female hippocampus. The study
utilized a tail shock stressor and found that the exposure to stress enhanced spine density in the
male hippocampus, but reduced spine density in the female hippocampus. When measured they

STRESS ON HIPPOCAMPAL FUNCTIONS: RISK FOR CLINICAL DEPRESSION

also found that females had higher levels of corticosterone than males (Shors, Chua, & Falduto,
2001, p. 6294-6296). These opposite effects of stress on spine density in males versus females
correspond to the effect of stress on learning in males versus females (Wood et al., 2001). This
information could be used to explain the difference in the percentage of men diagnosed each
year, 6%, versus the percentage of women, 12% (Depression is Underdiagnosed, 2004, p. 1).
III. Current treatment
Today treatment for depression is still widely unknown. Both pharmacological and
psychological treatments are used at a relatively even ratio for the treatment and control of
depressive symptoms. However, treatment resistance is high, 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).
Pharmacological
Tricyclic antidepressants (TCAs) are the main class of antidepressant drugs. They were
introduced in the 1950s and have the ability to block the synaptic reuptake of monoamines such
as noradrenaline (NA), 5-hydroxytryptymine (5-HT), and dopamine (DA) (Depression in Adults,
2010). The increased presence of these neurotransmitters is accountable for the mood-elevating
effects to combat depression. Because of the influence of these neurotransmitters of
anticholinergic, histaminergic and other receptor systems, the side effects made the drugs not
accepted initially. With further identification of specific treatments the proper TCA could be
prescribed to adequately control and reduce an individuals depression. Another problem seen
with TCAs is that an overdose has high mortality and morbidity rates, which are extremely

STRESS ON HIPPOCAMPAL FUNCTIONS: RISK FOR CLINICAL DEPRESSION

problematic when treating those who already have suicidal thoughts and intentions. Because of
the side effects of TCAs, a new class of antidepressants called selective serotonin reuptake
inhibitors (SSRIs) was developed (Depression in Adults, 2010). Chemically related to TCAs,
SSRIs also work through increasing the concentration of monoamines in the synaptic cleft. Side
effects seen in SSRIs vary greatly between individuals, therefore prescriptions are highly
monitored and altered between drug and dosage to accommodate an individuals needs
(Depression in Adults, 2010). Other drugs used less commonly are antipsychotics, which are
generally reserved for those with severe psychotic or chronic depressions.
Psychological
As far as psychological treatments, Freud published the first modern psychological theory
that described the causes and treatment of depression in 1917 (Depression in Adults, 2010).
Since then many other theories and methods for psychological treatment have developed;
however treatments specifically for depression have only developed over the last half of the 20th
century. Most methodologies are adapted from Freudian psychoanalysis and are catered toward
the needs of the depressed individuals. Current treatments claiming efficacy include: cognitive
behavioral therapies, behavioral activation, interpersonal therapy, problem-solving therapy,
counseling, short-term psychodynamic psychotherapy and couples therapy (Depression in
Adults, 2010). The growth of psychological treatments in the primary care for depression has
only occurred recently in the last 15 years. Further research on the benefits of coupling
psychological treatments with pharmacological treatments is still being done, but they show
great promise.

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IV. Conclusion
Substantial information has been presented reporting the detrimental effects of stress on
the hippocampus and how the hippocampus plays a role in depressive symptoms. Therefore
advances in the understanding of the relationship between all three could provide critical
information for the diagnosis and treatment of depression. Further, if a strong correlation is
found, chronic unpredictable stress could be a prospective risk factor used in the prediction of the
development of major depression before symptoms begin. This could reduce greatly reduce the
number of people who suffer from major repeated episodes of depression, or eliminate repeated
episodes all together.

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