As seen in Psychology Today.

Coping with depression is no easy task no matter how mild the condition may be. Depression is a mood disorder characterized by feelings of hopelessness, emptiness, loneliness, and excessive guilt for extended periods of time. Individuals with major depressive disorder will experience episodes lasting at least two weeks. Individuals with persistent depressive disorder experience episodes lasting significantly longer—more than two years in adults and more than one year in children and adolescents.

The symptoms of depression extend beyond low mood. Patients may also have a lack of motivation, find it difficult to concentrate, be unable to anticipate feelings of fulfillment or happiness, and have recurrent thoughts of death or suicidal ideation. Depression can also bring on feelings of fatigue and may alter sleeping and eating habits. Taken together, these symptoms can disrupt patients’ social lives and careers.

Depression is distinct from sadness or bereavement caused by a major life event such as the death of a loved one, though those who are prone to depressive disorders may experience a depressive episode because of such an event. For those with major depressive disorder or persistent depressive disorder (also known as dysthymia), depressive episodes are not always tied to a specific event and may seem to arise for no discernible reason. However, when one is experiencing a depressive episode, one may begin to view the world through a depressive schema.

Such a schema is not merely an analog to the medieval melancholic or the eternal pessimist who sees the proverbial glass as always half empty. There may be neurobiological evidence to support what many individuals who have struggled with depression have experienced. It may also support the claim of Aaron Beck, the father of cognitive therapy, who proposed that depression could be described as a cognitive disorder wherein negative information is given a higher priority than positive or neutral information.

What Causes Depression?

Despite being one of the most widespread forms of psychiatric pathology, the simple answer is that researchers are not certain. As noted above, some depressive episodes may be triggered by trauma, but other factors—including one’s neurochemistry, one’s neural architecture, and how well one’s brain responds to stress—can have an impact on how susceptible an individual is to depression.

While is clear is that genetics play a key role in determining one’s risk of developing depression, there does not appear to be a single neurobiological cause for depression. Researchers have identified more than 100 candidate genes and their alleles that can affect an individual’s neurochemistry, neural architecture, or ability to effectively process stress. This has led to multiple theories to explain the onset of depressive episodes and the reason why some individuals are more prone to them than others.

The latter may seem surprising, since stress is not typically associated with depression. However, excessive stress or the body’s response to perceived stress appears to play a crucial role in the development of depression and may even alter neural architecture. Stress can affect specific regions of the brain, particularly the limbic system (which includes the amygdala, thalamus, and hippocampus), and may lead to physical changes in brain structure, including impaired nerve growth.

A study published in the Journal of Neuroscience found that the hippocampus was between 9 percent and 13 percent smaller in depressed women when compared to women who did not suffer from depression. Furthermore, hippocampus volume was more pronounced among women who had experienced more depressive episodes throughout their lifetimes, suggesting a correlation between the number of depressive episodes and hippocampus volume. Other studies have proposed that impaired neurogenesis in or an underdevelopment of the hippocampus is not a consequence of depression, but rather its antecedent.

Negative Memory Storage and the Hippocampus

The hippocampus plays a central role in recollection and the encoding of episodic memories. Episodic memories are believed to be stored in clusters of neurons known as engrams, and individual engrams are believed to be associated with individual memory traces. Specific engrams corresponding to individual pieces of information, researchers have found, can be tagged using Ca2+ imaging. Consequently, one can observe a pattern that corresponds with memory creation, memory processing, and memory retrieval.

The hippocampus also plays a role in processing negative or stressful information, which suggests that it could be possible to test the cognitive theory of depression proposed by Beck in a lab. Using murine models, researchers at the Douglas Hospital Research Centre at McGill University in Montreal recently did just that.

The experiment utilized the chronic social defeat stress (CSDS) model to observe engrams in the hippocampi of mice believed to be susceptible to stress and a separate group believed to be resilient. The team hypothesized that susceptible animals would have a hippocampus that is more sensitive to stress, that these animals would have more hippocampal engram cells related to stress, and that depressive behavior would be observed by reactivating the engram cells corresponding with stressful experiences. Resilient animals, they reasoned, would not have an increase in hippocampal engram cells related to stress.

The team, Zhang et al, published their findings in the Journal of Neuroscience in August. They discovered that, “Compared to resilient or non-stressed control mice, susceptible mice exhibited a higher reactivation of social defeat-related…engram cells…in both the dorsal and ventral hippocampal CA1 regions. The density of CA1 engram cells correlated with the level of social avoidance.” The team also wrote that, “Our findings that negative memory engrams are increased in mice that are susceptible to CSDS suggested that these engrams could mechanistically contribute to the negative bias of memory formation in depression.” In other words, mice that retained more negative information were more likely to revisit the negative memory and behave in a depressed manner, whereas mice that were retained less negative information were less likely to revisit the memory and behave in a depressed manner.

While this major study may not answer our questions about the direction of causality between negative memory bias and depression, it does indicate that the hippocampus does play a significant role in reinforcing depressive behaviors and does give greater credence to Beck’s contention that depression can viewed as a cognitive disorder, though it does not necessarily negate any theoretical paradigm about depression. Consequently, the team concluded their paper on an optimistic note about what this study could mean for patients: “Inhibiting negative memory engrams in the hippocampus could be a novel therapeutic approach for treating cognitive symptoms in depression.”

More studies are needed to confirm these results and to explore how negative memory engrams could be successfully inhibited, but this could potentially be a step in providing new forms of treatment for one of the most widespread and debilitating mental illnesses in the world. These novel approaches may also allow us to better understand the complex web of biological and psychological components that are the underlying causes of depression and take more proactive steps to prevent it.

Dr. Ahmad reports no conflict of interest. He is not a speaker, advisor, or consultant and has no financial or commercial relationship with any biopharmaceutical entity whose product/device may have been mentioned in this article.

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