Early life stress associated volume loss in the amygdala & neuromodulator gene expression
Poster No:
973
Submission Type:
Abstract Submission
Authors:
Meg Sheppard1, Rebecca Elliott2, Niall Duncan3, Nils Muhlert4
Institutions:
1University of Manchester, Manchester, Gt. Manchester, 2University of Manchester, Manchester, Greater Manchester, 3Graduate Institute of Mind Brain and Consciousness, Taipei, Taipei, 4The University of Manchester, Manchester, Greater Manchester
First Author:
Co-Author(s):
Introduction:
An individual's early life experiences play a key role in the development of the brain; stress (ELS) during this period is known to affect plasticity (Teicher et al., 2016). For example, ELS has been shown to affect grey matter volumes in the amygdala, but the direction and magnitude of these changes are disputed (Tottenham et al., 2010; Mehta et al., 2009; Hanson et al., 2015). In addition, neurotransmitter function and neuroendocrine responses may be dysregulated following ELS, specifically disrupting catecholaminergic activity (Somaini et al., 2011). Recent work has suggested that the noradrenergic system may be particularly vulnerable to stress-related changes (Sheppard et al., 2024). In this project we used a random forest model to investigate whether ELS-induced volume change in the amygdala relates to (1) local expression of noradrenergic genes, or (2) other neuromodulator genes (dopamine, serotonin and acetylcholine).
Methods:
Data from the UK Biobank (2022 release) were used in this analysis. Participants with any previous neurological illness or injury were excluded. Two groups were defined by their responses to questions assessing the individual's environment growing up including any instances of abuse and neglect. We identified N=350 people who scored highly on the ELS measure ("high ELS" group; scores from 7-20), and N=365 who had no previous experience of ELS ("No ELS group", see Table 1).
A voxel-based morphometry (VBM) region of interest (ROI) analysis was conducted using SPM12 in MATLAB to identify volume changes in the amygdala associated with ELS whilst controlling for the nuisance covariates of age and sex. A Random Forest regression was then conducted in R to identify which neuromodulator subunits best predicted the volume change in the amygdala associated with ELS identified in the ROI VBM. Normalised gene expression maps from the Allen Human Brain Atlas were used in this analysis for the four neuromodulators of interest: serotonin, noradrenaline, acetylcholine, and dopamine.
A voxel-based morphometry (VBM) region of interest (ROI) analysis was conducted using SPM12 in MATLAB to identify volume changes in the amygdala associated with ELS whilst controlling for the nuisance covariates of age and sex. A Random Forest regression was then conducted in R to identify which neuromodulator subunits best predicted the volume change in the amygdala associated with ELS identified in the ROI VBM. Normalised gene expression maps from the Allen Human Brain Atlas were used in this analysis for the four neuromodulators of interest: serotonin, noradrenaline, acetylcholine, and dopamine.
Results:
Significant voxel-wise reductions in grey matter in the bilateral amygdalae were identified in the VBM ROI analysis (p<.05, small volume corrected), see Figure 1.
The Random Forest regression model was able to predict the data with a reasonable variance explained (R2 of 28.7%) and model fit (RMSE of 0.012).
The Random Forest model indicated that genes expressed on serotonergic and cholinergic receptors, namely 5HT3A, CHRNA5 and HT2B, were the most important features for predicting amygdala volume loss associated with ELS, with importance scores of 6.03, 4.07 and 3.74, respectively. Conversely, dopaminergic and noradrenergic subunits were ranked much lower, with the highest contribution score of noradrenaline being 2.15 for ADRB3 and the lowest being 0.9 for ADRA1b. For dopaminergic subunits, the highest importance value was 2.08 for D4 and the lowest being 1.33 for D5, indicating minimal contribution to the model. Figure 2 illustrates the different levels of variable importance for each subunit
The Random Forest regression model was able to predict the data with a reasonable variance explained (R2 of 28.7%) and model fit (RMSE of 0.012).
The Random Forest model indicated that genes expressed on serotonergic and cholinergic receptors, namely 5HT3A, CHRNA5 and HT2B, were the most important features for predicting amygdala volume loss associated with ELS, with importance scores of 6.03, 4.07 and 3.74, respectively. Conversely, dopaminergic and noradrenergic subunits were ranked much lower, with the highest contribution score of noradrenaline being 2.15 for ADRB3 and the lowest being 0.9 for ADRA1b. For dopaminergic subunits, the highest importance value was 2.08 for D4 and the lowest being 1.33 for D5, indicating minimal contribution to the model. Figure 2 illustrates the different levels of variable importance for each subunit
Conclusions:
Our findings demonstrate that amygdala volume decreases associated with ELS are predicted by the regional distribution of serotonergic and cholinergic gene subunits. Overall, neuromodulator subunits explained 28.7% of variability of this volume loss. Our results argue against a potential heightened role of noradrenergic gene expression in conferring vulnerability to ELS but are in line with the literature on serotonin changes being a key mechanism for (or a result of) these effects. Future work can address whether these findings align with receptor densities, as can be estimated from relevant PET ligands.
Genetics:
Genetic Modeling and Analysis Methods
Lifespan Development:
Early life, Adolescence, Aging 1
Modeling and Analysis Methods:
Classification and Predictive Modeling
Neuroanatomy, Physiology, Metabolism and Neurotransmission:
Anatomy and Functional Systems
Physiology, Metabolism and Neurotransmission:
Pharmacology and Neurotransmission 2
Keywords:
Acetylcholine
Dopamine
Neurotransmitter
Noradrenaline
Norpinephrine
RECEPTORS
Seretonin
Statistical Methods
STRUCTURAL MRI
Other - Stress
1|2Indicates the priority used for review
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Provide references using APA citation style.
Mehta, M.A., Golembo, N.I., Nosarti, C., Colvert, E., Mota, A., Williams, S.C., Rutter, M., Sonuga-Barke, S. (2009). Amygdala, hippocampal and corpus callosum size following severe early institutional deprivation: the English and Romanian adoptees study pilot. J. Child Psychol. Psychiatry, 50 (8) (2009), pp. 943-951, doi: 10.1111/j.1469-7610.2009.02084.x
Sheppard, M., Rasgado-Toledo, J., Duncan, N., Elliott, R., Garza-Villarreal, E. A., & Muhlert, N. (2024). Noradrenergic alterations associated with early life stress. Neuroscience & Biobehavioral Reviews, 164, 105832. https://doi.org/10.1016/j.neubiorev.2024.105832
Somaini, L. et al. (2011) ‘Adverse childhood experiences (ACES), genetic polymorphisms and neurochemical correlates in experimentation with psychotropic drugs among adolescents’, Neuroscience &; Biobehavioral Reviews, 35(8), pp. 1771–1778. doi: 10.1016/j.neubiorev.2010.11.008.
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