The link between volumetric changes associated with early life stress and neuromodulator expression
Poster No:
886
Submission Type:
Abstract Submission
Authors:
Megan Sheppard1, Niall Duncan2, Marta Litwinczuk1, Rebecca Elliott1, Elizabeth McManus-Day1, Eduardo Garza-Villarreal3, Nils Muhlert1
Institutions:
1University of Manchester, Manchester, UK, 2Taipei Medical University, Taiwan, Taipei, 3Universidad Nacional Autónoma de México, Mexico City, Mexico
First Author:
Co-Author(s):
Introduction:
An individual's early life experiences play a key role in the development of the brain as plasticity is disrupted in those who have experienced early life stress (ELS) (Teicher et al., 2016). Specifically, grey matter volumes throughout the brain are known to change following ELS including in regions such as the prefrontal cortex, amygdala, and the caudate nucleus (Lee et al., 2011; DeBellis & Zisk, 2014).
The function of neurotransmitters and neuroendocrine responses are thought to be dysregulated in those who have experienced ELS, specifically impacting catecholamines (Somaini et al., 2011). However, it is unclear whether this change is specific to catecholamine dysregulation or whether this relationship is also true for the wider group of neuromodulators. Therefore, this study aimed to investigate a potential relationship between volumetric changes associated with ELS and genetic expression of the four key neuromodulators: dopamine, serotonin, acetylcholine, and noradrenaline.
The function of neurotransmitters and neuroendocrine responses are thought to be dysregulated in those who have experienced ELS, specifically impacting catecholamines (Somaini et al., 2011). However, it is unclear whether this change is specific to catecholamine dysregulation or whether this relationship is also true for the wider group of neuromodulators. Therefore, this study aimed to investigate a potential relationship between volumetric changes associated with ELS and genetic expression of the four key neuromodulators: dopamine, serotonin, acetylcholine, and noradrenaline.
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. This constituted the ELS measure, with those who scored highly comprising the high ELS group with scores ranging from 7-20. The second group had no previous experience of ELS. For demographics, see Table 1.
A voxel-based morphometry (VBM) model was conducted to identify regions that display volumetric grey matter changes associated with ELS whilst controlling for age and sex to prevent potential confounds. The Allen Human Brain Atlas gene expression maps for each neuromodulator subunit (serotonin, noradrenaline, acetylcholine, and dopamine) were then correlated against any morphometric changes identified in the VBM.
A voxel-based morphometry (VBM) model was conducted to identify regions that display volumetric grey matter changes associated with ELS whilst controlling for age and sex to prevent potential confounds. The Allen Human Brain Atlas gene expression maps for each neuromodulator subunit (serotonin, noradrenaline, acetylcholine, and dopamine) were then correlated against any morphometric changes identified in the VBM.
Results:
Results:
Six regions displayed volumetric increases associated with ELS after controlling for false positives using false discovery rate (FDR) correction. These regions include the inferior occipital lobe, inferior temporal lobe, cerebellum, an anterior portion of the superior frontal gyrus and the putamen. Two further regions displayed volumetric decreases associated with ELS: a more dorsal aspect of the superior frontal gyrus and the cingulate.
The gene expression maps of all neuromodulator subunits significantly (p <0.001) negatively correlated with the volumetric increases identified in the VBM associated with ELS. However, only a select number of subunits correlate with the identified ELS-associated volumetric decreases (p <0.05). These include four serotonin subunits (5HT1B, 5HT1D, 5HT2C and 5HT3A), three cholinergic subunits (CHRNA2, CHRNA3 and CHRNA6), two dopaminergic receptors (D2 and D3) and two noradrenergic receptors (ADRA2B and ADRB3). These subunits all positively correlated with the volumetric decreases except for the serotonin receptor 5HT2C which significantly (p<0.001) negatively correlated with these ELS associated volumetric reductions.
Six regions displayed volumetric increases associated with ELS after controlling for false positives using false discovery rate (FDR) correction. These regions include the inferior occipital lobe, inferior temporal lobe, cerebellum, an anterior portion of the superior frontal gyrus and the putamen. Two further regions displayed volumetric decreases associated with ELS: a more dorsal aspect of the superior frontal gyrus and the cingulate.
The gene expression maps of all neuromodulator subunits significantly (p <0.001) negatively correlated with the volumetric increases identified in the VBM associated with ELS. However, only a select number of subunits correlate with the identified ELS-associated volumetric decreases (p <0.05). These include four serotonin subunits (5HT1B, 5HT1D, 5HT2C and 5HT3A), three cholinergic subunits (CHRNA2, CHRNA3 and CHRNA6), two dopaminergic receptors (D2 and D3) and two noradrenergic receptors (ADRA2B and ADRB3). These subunits all positively correlated with the volumetric decreases except for the serotonin receptor 5HT2C which significantly (p<0.001) negatively correlated with these ELS associated volumetric reductions.
Conclusions:
Our findings suggest that there are distinct morphometric alterations associated with early life stress. The volumetric increases associated with ELS are related to expression of all neuromodulator subunits, whereas there is a more specific relationship between neuromodulators and reductions in grey matter volume associated with ELS. Future research will use rodent models aim to further define this relationship by investigating the relationship between potential volumetric changes in targeted brain regions associated with the acute stress response (for example, the amygdala) and genetic expression of these key neuromodulators.
Disorders of the Nervous System:
Neurodevelopmental/ Early Life (eg. ADHD, autism)
Genetics:
Transcriptomics 1
Lifespan Development:
Early life, Adolescence, Aging
Neuroanatomy, Physiology, Metabolism and Neurotransmission:
Transmitter Receptors 2
Novel Imaging Acquisition Methods:
Anatomical MRI
Keywords:
Acetylcholine
CHEMOARCHITECTURE
Dopamine
Morphometrics
MRI
Neurotransmitter
Noradrenaline
Norpinephrine
RECEPTORS
STRUCTURAL MRI
1|2Indicates the priority used for review
Provide references using author date format
Lee, H.-Y., Tae, W. S., Yoon, H.-K., Lee, B.-T., Paik, J.-W., Son, K.-R., Oh, Y.-W., Lee, M.-S., & Ham, B.-J. (2011). Demonstration of decreased gray matter concentration in the midbrain encompassing the dorsal raphe nucleus and the limbic subcortical regions in major depressive disorder: An optimized voxel-based morphometry study. Journal of Affective Disorders, 133(1–2), 128–136. https://doi.org/10.1016/j.jad.2011.04.006
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.
Teicher, M. H., Samson, J. A., Anderson, C. M., & Ohashi, K. (2016). The effects of childhood maltreatment on brain structure, function, and connectivity. Nature Reviews Neuroscience, 17(10), 652–666. https://doi.org/10.1038/nrn.2016.111