A Melancholic Tune: The Dynamics of Neuroinflammation and Depression
Thomas Doyle
Illustrations by Ava Sclafani
At some point in your life, you have probably felt blue, down in the dumps, or bummed out. To be depressed in the colloquial sense — generally sad or unhappy — is a familiar emotion, such that the English language provides us with plenty of words and phrases to describe the feeling. However, clinical depression is a mood disorder that goes beyond being in low spirits. Depression is characterized by a limited ability to feel pleasure, changes in appetite or sleep, low energy, diminished self-worth, and impaired concentration [1, 2]. The causes of depression vary from person to person and may entail psychological, social, and biological factors [3]. In recent years, one biological factor has been widely studied as a potential cause: neuroinflammation [4]. Inflammation is a bodily defense mechanism that protects the body from infections, damaged cells, and toxins [5]. When inflammation occurs in the brain and spinal cord, it is called neuroinflammation [2]. While neuroinflammation is often protective, in some cases, it contributes to increased depressive symptoms [2]. Understanding the role of neuroinflammation in depression may help us gain further insight into biological contributions to depression as well as types of potential treatments [4].
The Brain Inflamed: What is Neuroinflammation?
Neuroinflammation is facilitated through the coordination of microglia and astrocytes [2]. Microglia and astrocytes are types of glial cells that are in the nervous system but are not neurons [6]. Glial cells play an important role in supporting brain activity and providing an environment suitable for neurons to function [6]. Microglia maintain the conditions of their surroundings by performing regulatory functions, such as eliminating toxic substances [7]. Astrocytes carry out essential roles for proper neural functioning, such as regulating the brain’s breakdown of glucose to produce energy [8]. Additionally, astrocytes have branching extensions that radiate from their cell body, allowing them to interact with neurons at multiple distances, remove cellular debris, and respond to neural damage [9, 10]. The relationship between microglia and astrocytes in neuroinflammation resembles a jazz ensemble. By controlling the pace of the music, the pianist modulates the tempo of the entire group. Similarly, microglia regulate brain development, maintain neuronal networks, release signaling molecules to regulate cellular activity, and play a role in injury repair and immune response [2, 11]. Astrocytes mirror the ensemble’s trumpets, which support the other instruments by enriching the overall sound. Astrocytes support other cells’ functions by clearing debris and regulating the barrier between brain tissue and the blood [10].
Stressors in the brain, such as damaged tissues or viruses, trigger an immune response and induce neuroinflammation [2]. In the inflammatory response, microglia and astrocytes become more reactive to respond more effectively to stressors in the brain [12, 13]. Reactive microglia and astrocytes trigger increased cellular growth and reproduction [14, 15]. Reactive glial cells release cytokines, which are signaling molecules that influence the activity of recipient cells upon binding [13, 14, 15]. Pro-inflammatory cytokines increase the activity of recipient cells and increase levels of neuroinflammation, whereas anti-inflammatory cytokines decrease the activity of recipient cells and lower levels of neuroinflammation [13].
As the brain’s primary immune cells, microglia consume stressors in the brain to eliminate them from their environment [2, 11]. Reactive microglia can be classified as M1 and M2, while nonreactive microglia are labeled M0 [16, 17]. M1 and M2 microglia are not distinct subtypes — they exist on a continuum of states and can shift between them [16]. M1 microglia release pro-inflammatory cytokines, while M2 microglia release anti-inflammatory cytokines [16, 18]. Much like how M1 microglia increase neuroinflammation, the pianist raises the tempo, signaling the other musicians to follow suit. Conversely, in the same way that M2 microglia decrease neuroinflammation, the pianist slows down to signal other ensemble members to lower the tempo. Similar to microglia, reactive astrocytes are categorized as either A1 or A2 astrocytes, with nonreactive astrocytes labeled as A0 [19]. A1 astrocytes tend to release pro-inflammatory cytokines to perpetuate neuroinflammation, whereas A2 astrocytes mostly release anti-inflammatory cytokines, dampening neuroinflammation [19]. Astrocytes increase their activity level as part of the immune response when they receive pro-inflammatory cytokines, like how a musician would increase their tempo when signaled by the pianist [20]. Reactive astrocytes form glial scars, increase their branching to surround damaged tissue, and direct repair cells to the area [21]. While glial scars can form barriers between damaged and healthy cells to limit the spread of neuroinflammation, they can also introduce problems by preventing cell growth [21, 22].
Properly regulated neuroinflammation facilitates the brain’s response to cellular damage by promoting the removal of injured or dysfunctional cells [23]. Removing damaged cells prevents unnecessary consumption of resources and ensures that materials are directed toward supporting healthy tissue repair and function [23]. Likewise, when the jazz ensemble’s tempo is well-regulated, the music sounds harmonious, much like how properly-regulated neuroinflammation supports healthy brain function [23]. When the musicians are all playing at different speeds, the ensemble sounds chaotic and discordant. Similarly, when neuroinflammation is dysregulated, the microglia and astrocytes continue releasing pro-inflammatory cytokines, which leads to the damage and death of brain cells [2, 13, 14]. Dysregulated neuroinflammation may eventually result in psychiatric conditions like depression [24, 25].
Playing Fast and Slow: High Reactivity and Low Mood
Understanding neuroinflammation may help identify a neurological explanation for the changes in the brain that contribute to depression [25]. Reduced inflammatory activity in microglia and astrocytes is associated with a reduction in depressive symptoms [26]. Furthermore, reactive microglia have been shown to contribute to depressive behaviors by increasing the production of pro-inflammatory cytokines [26]. When neuroinflammation increases, astrocyte reactivity and depressive behaviors also increase [27]. The antibiotic minocycline has been found to inhibit the activation of microglia by blocking cytokine signaling that would typically lead to a reactive state [28]. In both rodents and humans, there is evidence that minocycline suppresses neuroinflammation, which in turn decreases depressive behaviors [28, 29, 30]. Moreover, the drug scutellarin, traditionally used in Chinese herbal medicine, has been shown to suppress neuroinflammation and decrease levels of pro-inflammatory cytokines, also demonstrating a reduction in depressive behaviors [31, 32]. The use of minocycline and scutellarin in mitigating depressive behaviors implies that decreasing neuroinflammation could relieve depression [28, 31].
Since many neurological processes are similar between humans and rodents, animal models of depression can help researchers better understand the biological processes underlying depression and develop better treatments [33]. For example, minocycline was first tested in animal models prior to human applications [26, 27, 31]. Rodents have been a valuable tool for investigating the underlying biological mechanisms of depression [8, 26, 31]. While the brains of rodents and humans are structurally and functionally similar, there are distinct differences [34]. Human astrocytes, for instance, are larger than those of rodents and involve more complicated branching patterns [8]. Therefore, rodents serve as a model for human physiology and do not perfectly replicate human behavioral states, such as depression [8, 35]. Due to the limitations of animal models, research with human subjects is also important to translate results found in rodent studies to the treatment of human diseases [36].
Switching Up the Tempo: New Approaches to Treating Depression
Antidepressants are a standard form of depression treatment [37, 38]. However, they take time to become effective and can have negative side effects, including indigestion, sweating, and dry mouth [39]. Moreover, antidepressants are not guaranteed to effectively treat depression, leading individuals to turn to alternative forms of treatment [37, 38, 40, 41]. Transcranial magnetic stimulation (TMS) is one such treatment that could help improve our understanding of depression [42]. TMS uses a magnetic field to stimulate neurons in the outer layer of the brain, which has been shown to lessen symptoms of depression [42, 43]. People who underwent TMS treatment exhibited decreased levels of certain pro-inflammatory cytokines and demonstrated fewer depressive symptoms [43]. In addition, deep brain stimulation (DBS) could contribute to our understanding of depression in humans as well. DBS uses electricity to stimulate brain areas associated with depressive symptoms and alter their activity [42]. DBS is a promising therapy for treatment-resistant depression; however, its impact on neuroinflammation is in the early stages and has yielded inconsistent findings [42, 44]. In some cases, DBS has been able to reduce neuroinflammation by increasing levels of anti-inflammatory cytokines in conditions such as epilepsy and traumatic brain injury [42, 45, 46]. However, other studies have reported increases in the levels of pro-inflammatory cytokines after DBS treatment, suggesting that the treatment leads to increased neuroinflammation [42, 47]. The variability in findings related to the efficacy of DBS may be a result of the treatment decreasing amounts of some pro-inflammatory cytokines while not affecting other cytokines [42]. More research is needed to better understand how TMS and DBS can reduce neuroinflammation to alleviate depressive symptoms [42].
Ending on a High Note: The Research Continues
Depression is a widespread and debilitating condition [3]. Just one type of depression, major depressive disorder, affects over 300 million people and is the most prevalent cause of disability worldwide [1, 48]. The causes of depression are poorly understood, and standard treatments like antidepressants do not always relieve symptoms [48]. As a result, new treatments are needed to reach a greater proportion of the population with the condition [48]. While drugs such as minocycline and scutellarin decrease neuroinflammation and depressive behaviors in rodents, little is known about their effect in humans [28, 31]. Treatments like TMS and DBS have been administered to humans, but findings have been inconsistent as to whether they reduce neuroinflammation [42]. Gaining a more concrete understanding of the link between glial cells, neuroinflammation, and depression could help further develop TMS, DBS, and other treatments for depression, helping countless people [4, 42].
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