Negative emotion regulation in alcohol use disorder - (Epi)Genetic modulation of fear extinction, negative emotion, reward and stress processing
Final Report Abstract
The primary aim of this research project was to study the role and interaction of (epi)genetic factors, early life stress (ELS) exposure, and alcohol use disorder (AUD) on neuronal mechanisms of fear conditioning and extinction.Therefore, individuals with and without AUD were evaluated for fear conditioning and extinction using a two-day shock conditioning paradigm (combining fMRI imaging that utilizes galvanic skin response). Processing of negative emotions, reward and stress was further assessed in all participants by neuroimaging. Additionally, all participants underwent genotyping of variants in candidate genes, and whole-genome methylome analyses to assess genome wide methylation patterns. For the first time investigating FCE in AUD by combining both functional and structural neuroimaging, as well as psychophysiological data and clinical measures, our main results show during fear conditioning and renewal significantly blunted functional amygdala BOLD responses as a core region within the emotional brain circuit in alcohol-dependent individuals (ALC) compared with healthy controls (HC). Here, the degree of threat-related amygdala activation was strongly correlated with various clinically relevant negative emotion-related outcomes in ALC, including trait anxiety, depressive symptoms, and perceived stress. Further, investigating the emotional face matching task, we did not observe any association between SLC6A4 promoter methylation variation and threat-related amygdala activation in HCs or ALC; also, methylation in the promoter region of SLC6A4 did not significantly differ between the groups. In another study, we focused on structural differences in prefrontal regions and its associations with aspects of self-control. Here, ALC had significantly less gray matter volume (GM) in bilateral middle frontal gyrus (MFG) and right medial prefrontal cortex as well as in the right anterior cingulate compared to HC. While a significant positive correlation between right lateralized MFG-GM and Sensation Seeking Total Score and the Thrill and Adventure Seeking Subscore was observed in ALC only, furher stratification by lifetime alcohol intake revealed that this was driven by the low-consuming ALC. Particularly, larger MFG-GM correlated with greater Thrill and Adventure Seeking supporting a potential protective role of this self-control aspect in stress-related psychopathologies like AUD. In another investigation, we evaluated the effects of heavy, chronic alcohol consumption on epigenetic age acceleration (EAA) using clinical biomarkers, including liver function test enzymes (LFTs) and clinical measures. We found a significant 2.22-year age acceleration in ALC compared to HC after adjusting for gender and blood cell composition. Secondary analyses showed more pronounced EAA in individuals with more severe AUD-associated phenotypes, including elevated gammaglutamyl transferase (GGT) and alanine aminotransferase (ALT), and higher number of heavy drinking days. EAA was further associated with genetic variation in APOL2 (SNP rs916264), suggesting potential novel biological mechanisms for age acceleration in AUD. Furthermore, we found high-impact binge drinking (consuming 2 or more times the binge threshold of alcohol as defined by the NIAAA) significantly associated with increased odds for clinically high levels of lipids and LFTs. Studying the potential underlying liver-brain connecting mechanism, we finally targeted proprotein convertase subtilisin/kexin 9 (PCSK9). PCSK9 plays a major role in hepatic function and lipid regulation, and recent studies have shown that alcohol use affects the regulation and expression of PCSK9. Now, our data showed that PCSK9 is elevated in the CSF of individuals with AUD, and plasma PCSK9 levels were further correlated positively with CSF PCSK9 levels in AUD, which in total may support a potential role of PCSK9 in AUD. In sum, these findings encourage 1) future use of AUD-relevant neuroimaging tasks like the FCE paradigm in ALC populations to further investigate functional and structural dysregulations in fear/ negative emotion neurocircuitry. 2) Given that the number of imaging epigenetics studies in AUD is very limited to date, our results indicate that future research is needed to clarify epigenetic changes in severe psychopathologies like AUD. Thus, improving our understanding of the structures and functions mediating crucial regulatory mechanisms in AUD might inform the development of promising novel treatment approaches for individuals with AUD.
Publications
- (2018). Imaging resilience and recovery in alcohol dependence. Addiction, 113(10):1933-1950
Charlet K, Rosenthal A, Lohoff FW, Heinz A, Beck A
(See online at https://doi.org/10.1111/add.14259) - (2019). Association of High-Intensity Binge Drinking With Lipid and Liver Function Enzyme Levels. JAMA Network Open, 2(6):e195844
Rosoff DB, Charlet K, Jung J, Lee J, Muench C, Luo A, Longley M, Mauro KL, Lohoff FW
(See online at https://doi.org/10.1001/jamanetworkopen.2019.5844) - (2019). Epigenetic aging is accelerated in alcohol use disorder and regulated by genetic variation in APOL2. Neuropsychopharmacology
Luo A, Jung J, Longley M, Rosoff DB, Charlet K, Muench C, Lee J, Hodgkinson CA, Goldman D, Horvath S, Kaminsky ZA, Lohoff FW
(See online at https://doi.org/10.1038/s41386-019-0500-y) - (2019). Fear conditioning and extinction in alcohol dependence: evidence for abnormal amygdala reactivity. Addiction Biology, e12835
Muench C, Charlet K, Balderston NL, Grillon C, Heilig M, Cortes CR, Momenan R, Lohoff FW
(See online at https://doi.org/10.1111/adb.12835) - (2019). Lack of Association Between Serotonin Transporter Gene (SLC6A4) Promoter Methylation and Amygdala Response During Negative Emotion Processing in Individuals With Alcohol Dependence. Alcohol Alcoholism, 54(3):209-215
Muench C, Luo A, Charlet K, Lee J, Rosoff DB, Sun H, Fede SJ, Jung J, Momenan R, Lohoff FW
(See online at https://doi.org/10.1093/alcalc/agz032) - (2019). PCSK9 is Increased in Cerebrospinal Fluid of Individuals With Alcohol Use Disorder. Alcoholism: Clinical and Experimental Research, 43(6):1163-1169
Lee JS, Rosoff D, Luo A, Longley M, Phillips M, Charlet K, Muench C, Jung J, Lohoff FW
(See online at https://doi.org/10.1111/acer.14039) - (2019). Volumetric prefrontal cortex alterations in patients with alcohol dependence and the involvement of self-control. Alcoholism: Clinical and Experimental Research
Rosenthal A, Beck A, Zois E, Vollstaedt-Klein S, Walter H, Kiefer F, Lohoff FW, Charlet K
(See online at https://doi.org/10.1111/acer.14211)
