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Running Head: CORTICOSTRIATAL REWARD SYSTEM

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INHIBITION IN DEPRESSION CORRELATED WITH INFLAMMATION

Corticostriatal Reward System Inhibition in Depression Correlated With Inflammation
Lowell Smith (V00842063)
University of Victoria

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Corticostriatal Reward System Inhibition in Depression
Correlated With Inflammation
In the news article, written by the faculty of Health Sciences at Emory University (2015),
on how “inflammation is associated with decreased functional connectivity within corticostriatal
reward circuitry in depression” it is suggested that inflammation may be responsible for cases of
depression that remain persistent in spite of pharmacotherapy. A main point that is brought up is
how anhedonia, although not definitive of, is a prevalent symptom of chronic depression and
more specifically a symptom that commonly eludes relief from medications (Emory Health
Sciences, 2015). In conjuncture of these points, this article alludes to how inflammation may be
responsible for the lack of pleasure in normally pleasurable activities, or anhedonia, in cases of
chronic depression. Furthermore, with this relation in mind, it is stated that the treatment of
inflammation may result in relief of anhedonian symptoms (Emory Health Sciences, 2015).
Giving credence to what the news article wrote, the original journal article written by
Felger, J. C., et. al. (2015) observed and reported on the activity in the reward system in various
individuals with varying levels of inflammation to determine the relationship, if any. The
communication between the ventromedial prefrontal cortex (VPC) and ventral striatum (VS),
two important regions of the reward system, were measured using magnetic resonance imaging
(MRI) in patients with either high or low levels of C-reactive protein (CRP); CRP being used as
an indirect measure of inflammation and poor communication between the two regions being
linked to anhedonian symptoms (Felger, J. C., et. al., 2015, pg. 2). It was found consistently that
individuals with high CRP levels had inhibited communication between the VPC and the VS.
Thus it was concluded that inflammation has a connection to anhedonian symptoms (Felger, J.

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C., et. al., 2015, pg. 5). Alternatively individuals with low levels of CRP had relatively much
more activity between the VPC and the VS suggesting unhindered communication and therefore
the absence of anhedonian symptoms (Felger, J. C., et. al., 2015, pg. 5). These results were also
supported by subjective reports of anhedonian symptoms in individuals with either high or low
levels of CRP (Emory Health Sciences, 2015).
Coinciding and elaborating on the hypothesis that inflammation and persistent depression
may be linked is an article titled “suicidal ideation is associated with elevated inflammation in
patients with major depressive disorder” by O’Donovan, A., et .al. (2013). This articles intention
is to provide evidence on how inflammation and major depressive disorder with varying levels of
suicidal ideations are associated. However to come to developing this hypothesis some pertinent
information was drawn upon, such as the link between symptoms of fatigue, anhedonia, and
social withdrawal being associated with inflammation in non-human studies (O’Donovan, A., et.
al. 2013, pg. 308). As well as the findings suggesting that inflammation could be predicted by
the presence or absence of depressive symptoms. Inflammation however was not found to be a
predictor of depression (O’Donovan, A., et. al. 2013, pg. 308). More interestingly perhaps is the
discovery on how depression effectively sensitizes the brains inflammatory response to day to
day stressors; which gives rise to the question of how would the brain react, in regards to an
inflammatory response, to the impending notion of suicidal ideation (O’Donovan, A., et. al.
2013, pg. 308)?
By comparing the inflammatory markers of individuals in a hospital setting whom were
diagnosed with major depressive disorder that were either exhibiting high or low levels of
suicidal ideation, measured via The Mini International Neuropsychiatric Instrument, with healthy
nondepressed individuals this journal article’s objective was to answer that very question

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(O’Donovan, A., et. al. 2013, pg. 310). Using an inflammatory index to compare individuals with
a score derived from a measure of several inflammatory markers located in the blood it was
found that there was a significant difference in inflammation of individuals in the in the high
suicidal ideation group compared to both the low suicidal ideation and baseline groups
(O’Donovan, A., et. al. 2013, pg. 311). Furthermore there was no significant difference found
between the low suicidal ideations group and the baseline. Additionally severity of depressive
symptoms increased with higher reports of suicidal ideations. In whole, when considering that
high levels of suicidal ideations are characteristic of chronic major depressive disorders, this
adds to surmounting evidence for the link between persistent forms of depression and
inflammation (O’Donovan, A., et. al. 2013, pg. 312).
To bring all of this information together, how inflammation is related to not only increased
suicidal ideations, but also a potential differentiating characteristic of persistent major depressive
disorder, we must look at the commonality between these things. Each of these factors is related
to stress in one way or another. Either by stress increasing inflammation in the brain, the lack of
ability to deal with everyday levels of stress being a symptom of persistent depressive disorders,
or how inflammation decreases how well we handle stressors in our day-to-day lives. Stress,
although an important biological response, can be very detrimental when a dysfunction occurs.
The hypothalamic-pituitary-adrenal (HPA) axis is a system that has become quite revered in
understanding stress as well as depression as of recent; possibly more so than we currently
realize (McKim, W. A., & Hancock, S. D., 2013, pg. 299). In simplest of terms the HPA axis
functions initially by the hypothalamus receiving excitatory or inhibitory stimulus from the
prefrontal cortex, amygdala, and hippocampus which given enough stimulation will result in the
secretion of corticotropin-releasing hormone (CRH) which than finds its way to the anterior

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pituitary. Upon contact with the anterior pituitary it will cause a release of adrenocorticotropic
hormone (ACTH) which results in the adrenal glands releasing cortisol (McKim, W. A., &
Hancock, S. D., 2013, pg. 300). The excretion of cortisol into the bloodstream results in various
functions; the ones of interest include immune responses, anti-inflammation, and CNS activation.
Furthermore the release of cortisol must be shut off, this is possible by cortisol forming a
negative feedback loop with the pituitary, hypothalamus, and the hippocampus by binding to
glucocorticoid receptors ultimately results in a termination signal being sent to the hypothalamus
to stop excreting CRH (McKim, W. A., & Hancock, S. D., 2013, pg. 300).
The hippocampus, amygdala, and the prefrontal cortex are just a few of the regions that
make up the limbic system. The limbic system is a network of nerves that spread throughout the
brain. It is responsible for anything involved with emotion, mood, and instinct (McKim, W. A., &
Hancock, S. D., 2013, pg. 300). It so happens that CRH receptors have been found in many
regions of the limbic system; not restricted to the areas listed previously. Bringing all of this
information together we might see how a dysfunction could lead to disrupting countless
functions in between these systems (McKim, W. A., & Hancock, S. D., 2013, pg. 300). For
example, it has been found that high concentrations of cortisol in the blood stream for extended
periods of time results in physiological changes in many areas of the limbic systems, specifically
an increase in volume of the amygdala and decrease in volumes of both the hippocampus and
prefrontal cortex; this in itself will have a compounding effect (McKim, W. A., & Hancock, S.
D., 2013, pg. 300). Since the amygdala is responsible for stimulating the hypothalamus, which
ultimately leads to the signaling of cortisol to be released, as well as the hippocampus and
prefrontal cortex being responsible for inhibiting the hypothalamus. These structural changes

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will caused by high levels of cortisol will maintain or increase these levels (McKim, W. A., &
Hancock, S. D., 2013, pg. 300).
Discussion
Between the cortisol and the structural changes throughout the limbic system we see
quickly how inflammation in the brain may occur. With inflammation, as discussed earlier,
results in decreased communications between particular regions in the brain, explaining
anhedonian symptoms. In addition inflammation causes sensitization to stress. When the HPA
axis becomes overly sensitized and traumatically stressful experiences are encountered, such as
suicidal ideations, it is quite reasonable to see how this could become an unbearable distress to
not only the mind but the body. Furthermore the reason why we see suicidal ideations, as well as
higher inflammation levels particularly in chronic depressive disorders could be due to the long
lasting effects of the structural changes in the limbic system caused by the over active HPA axis.
When we consider this, with how the typical symptoms of chronic depressions elude
treatment via antidepressants and that antidepressants function by regulating the levels of
monoamines in our brain; we may come to the conclusion, although a bit of a stretch, that the
monoamine theory of depression may be more suited for explaining acute cases of depression
where the glucocorticoid theory of depression may be better for explaining chronic cases of
depression. Although these two systems interact a great deal, if we contemplate the function of
the monoamine and glucocorticoid systems in addition to how chronic and acute depressions
differ we may see that the severity of the dysfunction of one or each of the systems is associated
with the type of depression experienced.

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References
Emory Health Sciences (2015). Inflammation linked to weakened reward circuits in depression:
Brain imaging shows distinctive aspects of high-inflammation depression. ScienceDaily.
Retrieved from: www.sciencedaily.com/releases/2015/11/151120182942.htm
Felger, J. C., Li, Z., Haroon, E., Woolwine, B. J., Jung, M. Y., Hu, X., & Miller, A. H. (2015).
Inflammation is associated with decreased functional connectivity within corticostriatal
reward circuitry in depression. Molecular Psychiatry. 1-8. doi:10.1038/mp.2015.168
McKim, W. A., & Hancock, S. D. (2013). Drugs and behavior: An introduction to behavioral
pharmacology (7th ed.). New Jersey: Pearson Education.
O’Donovan, A., Rush, G., Hughes, B. M., McCrohan, A., Kelleher, C., O’Farrelly, C., & Malone,
K. M. (2013). Suicidal ideation is associated with elevated inflammation in patients with
major depressive disorder. Depress. Anxiety, 30: 307-314. doi: 10.1002/da.22087