Author: Zachary René

Mentor: Elise Adamson

Institution: Duke University

Highlights

·      Cellular immune factors regarding corticosterone contribute to depression

·      Chronic stress and CORT as factors in the pathogenesis of depression

·      A model of depression underpinned by dynamic immunocellular processes.

·      Decreased natural killer cells and elevated interleukin-6 cytokines as depressive indicators

·      Elevated levels of corticosterone as a regulator of the molecular mechanism of depression

Abstract

The hormone corticosterone (CORT) is a validated stressor in rodents, and when present in high levels, CORT has been linked to a stress-induced depressive-like state. While CORT treatment does induce depressive-like behavior, the connections between the cellular and immunological responses of CORT and depression have not been fully established. This review suggests that the physiological effects of elevated CORT levels may contribute to understanding the molecular mechanisms that characterize depression. Considering the neurobiological impact of decreased natural killer (NK) cells and elevated interleukin-6 (IL-6) cytokines which are characteristics of a depressive state and related to high CORT levels, it is possible to explore an association between the two variables. Additionally, decreased receptor functionality and activity in the prefrontal cortex are indicative of overexpression of CORT in stress-induced depressive-like subjects. Based on this review, using elevated CORT levels as a possible regulator of the cellular and immunological responses in depression may lead to better understanding the molecular mechanisms that characterize this condition.

Introduction

Stress impacts everyone and its lasting strain on the body can result in serious health problems. According to the American Institute of Stress, about 33 percent of people report feeling extreme stress that can be disruptive to daily behavior and functioning. Prolonged stress over a period of time is known as chronic stress and can cause physiological health problems like elevated hormone levels or mental health problems depression. Elevated levels of the hormone corticosterone (CORT) have been linked to stress-induced depressive-like states and are used as a model for stress in rodents (Kvarta, 2015). This literature review explores the link between elevated CORT levels and their negative impact on immune responses and brain regions associated with depression. Investigating elevated CORT levels could lead to building a case for this variable as a factor in the pathogenesis of depression, the development of future antidepressant drugs, and the experimental modeling of depression.

NK cells and inflammation as immunological responses

CORT in high levels can decrease the cytolytic activity of natural killer (NK) cells, promote increased rates of inflammation, and impair brain functioning in the prefrontal cortex (Yuen, 2013) (Wang, 2018). These physiological effects of corticosterone under chronic conditions impact the regulation of the same cellular and immunological responses that characterize depression (Blume,2010). An excess of CORT in chronically stressed species has been found to suppress important immunological responses. Chronic stress leads to decreased immediate immune responses carried out by natural killer (NK) cells and causes an increased rate of inflammation. NK cells are a type of lymphocyte that defend the body against pathogens, thus aiding in an efficient immune response (Dragos, 2010). Experimental evidence has indicated that the administration of the chemical stressor CORT causes the suppression of NK cell activity. Exogenous corticosterone was administered by subcutaneous injection to mice in a vehicle of 2% beta-cyclodextrin in phosphate-buffered saline at dosages of 3, 9, or 18 mg/kg body weight. Twelve hours after injections, samples were obtained to analyze NK cell activity and revealed maximal suppression of NK cell cytolytic activity (Pruett, 1999). Glucocorticoid treatment of NK cells was shown to reduce NK cell cytolytic activity by reduction of histone promoter acetylation for genes encoding perforin and granzyme B. These reductions in gene expression corresponded with reduced mRNA and protein for each resulting in a decrease of vital NK cellular activity (Eddy,2014). A decrease in natural killer cells has also been linked to depression. It was found through experimentation that there were reductions in absolute NK-cell counts in patients diagnosed with depression. In research from (Zorrilla et al., 2001), a negative correlation was found between NK cells and depression, meaning that as depression increased, the number of NK cells decreased. Findings from (Zorrilla et al., 2001) also concluded that depressed patients are likely to have reductions in NK cell cytotoxicity or decreased functioning of the NK cells. Thus, the reduced NK cells in depressed patients, which are also a key physiological effect of corticosterone, could be used to study and target immune responses in depression.

Chronic stress also promotes inflammation, a process usually framed as immune activating, but has been proven to suppress innate and adaptive cellular immunity under chronically stressful conditions (Blume,2010). Psychological or physiological stressors may lead to initial inflammatory responses, but a repeated stressor can impair the immune system’s ability to coordinate effective intermediary responses, thus leaving the body compromised. Interleukin-6 is part of a group of cytokines, that are important for cell signaling in the immune system and can be elevated with inflammation. Studies have shown that heightened levels of the interleukin-6 are consistently found in individuals suffering from chronic stress, depression, and anxiety (Hodes, 2003). In one experiment, four groups of mice: wildtype-stress, wildtype-control, interleukin-6-knockout-stress, and interleukin-6-knockout-control were tested for depressive-like behaviors using social avoidance and open field tests. In addition to this testing, samples were taken from bone marrow, blood, and brain tissue to track Interleukin-6 levels.  Collections showed that elevated levels of interleukin-1-beta, which is linked to depressive-like behaviors, were observed in the wildtype but not in interleukin-6-knockout mice in the stress condition, suggesting that interleukin-6-knockout mice are protected from the induction of interleukin-1-beta in response to stress. It was also found that stress-induced increases in interleukin-6 circulation releases corticosterone and pushes white blood cells towards an inflammatory state, causing increased interleukin concentrations in the brain resulting in a depressive phenotype (Niraula, 2018). Studies have indicated that IL-6 is the most consistently elevated cytokine in the blood of patients with major depressive disorder (Hodes, 2003). The high levels of the interleukin-6 that cause an increase in CORT provide evidence that in depressive patients, there is a connection between elevated CORT and key immunological responses that characterize depression.  

Cellular responses to CORT and chronic stress

When stress is persistent or chronic, it leads to a buildup of glucocorticoids like cortisone, cortisol, and prednisone, which can cause decreased brain function and cell activity in specific brain regions. These high levels of glucocorticoid, such as CORT result in atrophy of cells in the prefrontal cortex (Wang, 2018). This atrophy results in structural changes in the medial prefrontal cortex consistent with decreased activity in these areas in the brains of depressed patients. The prefrontal cortex (PFC) is responsible for cognitive responses, social behavior, and decision-making, which are defining features of how an organism behaves. Experimental evidence has shown that chronic stress (CS) causes atrophy in superficial and deep regions of the brain. CS induces volumetric reductions in the mPFC in the layers of the cingulum, prelimbic and infralimbic regions, diminishing their ability to carry our much-needed cognitive and behavioral functions like processing emotions or thoughts (Bessa, 2008). Stressors that damage this area can leave lasting reductions and have detrimental effects on social cognition and behavior like those seen in depressed species. Chronic stress exposure has also been shown to cause atrophy of dendrites on pyramidal cells in the medial PFC leading to cell death and decreased cognitive function. Correspondingly, reductions in the -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR)- and N-methyl-D-aspartate receptor (NMDAR)-mediated synaptic transmission and glutamate receptor expression were found in PFC pyramidal neurons of these stressed species (Anacker,2012). In an experiment to examine the impact of CORT on these brain regions, repeated injections of CORT into the PFC (0.87 nmol/g, 7d) produced a significant reduction of AMPAR- mediated synaptic currents (Yuen, 2013). These findings may suggest that repeated stress down-regulates glutamatergic transmission via glucocorticoid receptors and causes deactivation in the PFC. This decreased glucocorticoid receptor function has been linked to the development of depressive symptoms. (Anacker,2012). The Prefrontal cortex receives and projects signals from the amygdala, hypothalamus, midbrain, and pons, so excessive damage in this area can impair the executive functioning of the PFC and its associated cortical regions. These regions can integrate higher-order brain functions like decision making and cognitive processing that the PFC mediates with more fundamental brain activities such as emotion and motor functions. (Siddiqui, 2008). The elevated CORT levels caused by chronic stress lead to damage in receptors and brain areas that are consistent with those suffering from depression and should be considered for antidepressant drug research.

Conclusion

Elevated corticosterone levels are proven to be associated with some of the same detrimental cellular and immunological responses that characterize depression. Excess CORT in chronically stressed species causes decreased immediate immune response like reduced natural killer cell activity which mirrors the reduced natural killer cell activity in patients with depression. Additionally, stress can cause increased immunosuppressive rates of inflammation that result in increased interleukin concentrations in the brain. In patients with depression, IL-6 is the most consistently elevated cytokine in the blood and is a known factor of this disease. Lastly, persistent stress and high levels of CORT also result in the atrophy of PFC cells, causing decreased glucocorticoid receptor functions of the AMPA in this brain region(Kvarta, 2015). This is consistent with the reduced receptor functions and reductions of AMPAR- mediated synaptic activity that is linked to depressive symptoms. (Anacker,2012).  Using elevated corticosterone levels as a possible regulator of the cellular and immunological responses characterized in depression could lead to developments in the pathogenesis of depression, the development of future antidepressant drugs, and the experimental modeling of depression.

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