Herbert Covington Co-Authors Study Unveiling the Epigenetic Impact of Stress on Antidepressant Response

(SARATOGA SPRINGS, NY – AUGUST 6, 2024) Herbert Covington, Assistant Professor in the School of Social and Behavioral Science, co-authored a research paper that was recently published in Nature Communications.

The paper, titled “Histone serotonylation in dorsal raphe nucleus contributes to stress – and antidepressant – mediated gene expression and behavior,” examines a potentially novel clinical interaction between stressful life experiences and the efficacy of conventional antidepressants.

Covington said the research provides unique insight into how the therapeutic potential of common medications often prescribed for managing mood disorders like depression and anxiety might relate to an individual’s experiential history and ‘epigenetic’ landscape within monoaminergic neurons, specifically those containing serotonin. Despite decades of research, Covington said there is still more to learn about the impact drugs like selective serotonin reuptake inhibitors (SSRIs) and common stress experiences have on the molecular architecture of brain cells involved in clinically relevant mental processes.

“Even after at least 75 years of recognizing their clinical benefits in some individuals, studies like this one exploring serotonylation provide clear evidence that the fingerprint our experiences leave behind on DNA may have much to do with the emergence of not only a particular symptomology associated with the clinical course of depression, but also a later responsivity to antidepressants,” Covington said. “This study demonstrates that more science needs to happen to fully appreciate how ‘experiential fingerprints’ carved into the chromatin landscape of some neuron populations in brain relate to all the clinical variations in exogenous depression –and for establishing a reliable course of treatment tailored to an individual.”

Covington said scientists have become increasingly interested in relating specific behavioral responses to patterns of gene expression that are tied to the epigenome at distinctive landmarks like “histone methylation sites” examined in this piece. He said peering into a single neuron provides a powerful degree of resolution when examining the incredible efforts neurons commit to their ongoing orchestration of molecular dynamics.

“Many investigators in the scientific community recognize that slow and steady cellular processes like those determining broadscale patterns of gene expression are a sizeable force towards inflexible and consistent patterns of behavior,” Covington said. “Tons of evidence supports this hypothesis, but what we are noticing is that molecular mechanisms controlling behavioral stability are buried very deep within the epigenetic landscape of each and every brain cell.” 

Discussions about mental health, and the aid of prescription drugs as treatment, have only become more prevalent. Covington said he hopes this research can better demonstrate how brain cells react to these drugs and give insight into the exact processes that take place at a cellular level.

“I hope this work helps amplify an understanding that a desire for behavioral change is only accomplished by concurrent slow changes in brain,” Covington said. “Adaptive responses at the level of gene expression programs in brain cells are not only incorporated slowly but require frequent pulses of influence to the biochemical environment most stably represented within them through behavioral practice. Thus, behavioral change is an effortful day-by-day process requiring all the ingredients for allowing positive outcomes in brain as well. For example, making sure that variables like decent nutritional resources, an appropriate temperature, sleep quality, and an enriched cellular environment are crucial for maintaining the brain’s adaptability. Mental health progress is a facet of physical wellbeing.”

Covington also noted that, as this relationship between molecular dynamics, mood disorders, and medication is studied, there is often a misunderstanding about the speed and impact of neurotransmitters like dopamine and serotonin, molecules that regulate movement, coordination, motivational states, and perhaps feelings of well-being.  “It has become easy to think that these neurotransmitters produce immediate sensations like pleasure, or elevated mood. However, most of the receptors for these neurotransmitters produce very slow and gradual cellular effects,” Covington said. “Dopamine and serotonin are much more involved in the enduring process or ‘learning’ to accurately associate people, places, and things with their most probable outcomes, whether those outcomes are positive or negative. We rely on these so-called ‘associative processes’ significantly when later navigating our moment-to-moment experiences.”