Early Adversity and the Immune Hypothesis: Call for a Dialogue between Basic and Clinical Neuroscience

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: 30 June 2024 | Viewed by 3894

Special Issue Editors


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Guest Editor
Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06517, USA
Interests: early adversity; microglia; neuroinflammation; microbiome; psychopathology

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Guest Editor
Department of Psychological Science, School of Social Ecology, University of California, Irvine, CA 92697, USA
Interests: early adversity; systemic inflammation; developmental psychopathology; adolescence; depression

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Guest Editor
Department of Psychology, University of California, Los Angeles, CA 90024, USA
Interests: early adversity; microglia; neuroinflammation; microbiome; psychopathology

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Guest Editor
Institute of Medical Psychology, Charité—Universitätsmedizin, 10117 Berlin, Germany
Interests: early adversity; microglia; neuroinflammation; microbiome; psychopathology

Special Issue Information

Dear Colleagues,

A growing body of work has implicated the immune system in mediating key developmental, cognitive, and behavioral outcomes associated with early adversity. In this Special Issue, we seek input from preclinical and clinical researchers to assess current progress, challenges, and unresolved questions. Topics of particular interest include ways to improve cross talk between preclinical and clinical studies, the unbiased search for peripheral and central immune mediators (beyond cytokines), advantages and limitations of current animal models, the gut microbiome and brain–blood barrier dysregulation as potential key players, sex differences, imaging microglial activity and neuroinflammation, and therapeutic implications.

Dr. Arie Kaffman
Dr. Kate Ryan Kuhlman
Dr. Bridget L. Callaghan
Dr. Christine Heim
Guest Editors

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Keywords

  • early adversity
  • microglia
  • neuroinflammation
  • microbiome
  • psychopathology

Published Papers (4 papers)

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Research

20 pages, 4953 KiB  
Article
Increasing CB2 Receptor Activity after Early Life Stress Prevents Depressive Behavior in Female Rats
by Susan L. Andersen
Biomolecules 2024, 14(4), 464; https://doi.org/10.3390/biom14040464 - 10 Apr 2024
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Abstract
Early adversity, the loss of the inhibitory GABAergic interneuron parvalbumin, and elevated neuroinflammation are associated with depression. Individuals with a maltreatment history initiate medicinal cannabis use earlier in life than non-maltreated individuals, suggesting self-medication. Female rats underwent maternal separation (MS) between 2 and [...] Read more.
Early adversity, the loss of the inhibitory GABAergic interneuron parvalbumin, and elevated neuroinflammation are associated with depression. Individuals with a maltreatment history initiate medicinal cannabis use earlier in life than non-maltreated individuals, suggesting self-medication. Female rats underwent maternal separation (MS) between 2 and 20 days of age to model early adversity or served as colony controls. The prelimbic cortex and behavior were examined to determine whether MS alters the cannabinoid receptor 2 (CB2), which has anti-inflammatory properties. A reduction in the CB2-associated regulatory enzyme MARCH7 leading to increased NLRP3 was observed with Western immunoblots in MS females. Immunohistochemistry with stereology quantified numbers of parvalbumin-immunoreactive cells and CB2 at 25, 40, and 100 days of age, revealing that the CB2 receptor associated with PV neurons initially increases at P25 and subsequently decreases by P40 in MS animals, with no change in controls. Confocal and triple-label microscopy suggest colocalization of these CB2 receptors to microglia wrapped around the parvalbumin neuron. Depressive-like behavior in MS animals was elevated at P40 and reduced with the CB2 agonist HU-308 or a CB2-overexpressing lentivirus microinjected into the prelimbic cortex. These results suggest that increasing CB2 expression by P40 in the prelimbic cortex prevents depressive behavior in MS female rats. Full article
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26 pages, 3717 KiB  
Article
Lingering Effects of Early Institutional Rearing and Cytomegalovirus Infection on the Natural Killer Cell Repertoire of Adopted Adolescents
by Elizabeth K. Wood, Brie M. Reid, Dagna S. Sheerar, Bonny Donzella, Megan R. Gunnar and Christopher L. Coe
Biomolecules 2024, 14(4), 456; https://doi.org/10.3390/biom14040456 - 09 Apr 2024
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Abstract
Adversity during infancy can affect neurobehavioral development and perturb the maturation of physiological systems. Dysregulated immune and inflammatory responses contribute to many of the later effects on health. Whether normalization can occur following a transition to more nurturing, benevolent conditions is unclear. To [...] Read more.
Adversity during infancy can affect neurobehavioral development and perturb the maturation of physiological systems. Dysregulated immune and inflammatory responses contribute to many of the later effects on health. Whether normalization can occur following a transition to more nurturing, benevolent conditions is unclear. To assess the potential for recovery, blood samples were obtained from 45 adolescents adopted by supportive families after impoverished infancies in institutional settings (post-institutionalized, PI). Their immune profiles were compared to 39 age-matched controls raised by their biological parents (non-adopted, NA). Leukocytes were immunophenotyped, and this analysis focuses on natural killer (NK) cell populations in circulation. Cytomegalovirus (CMV) seropositivity was evaluated to determine if early infection contributed to the impact of an atypical rearing. Associations with tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ), two cytokines released by activated NK cells, were examined. Compared to the NA controls, PI adolescents had a lower percent of CD56bright NK cells in circulation, higher TNF-α levels, and were more likely to be infected with CMV. PI adolescents who were latent carriers of CMV expressed NKG2C and CD57 surface markers on more NK cells, including CD56dim lineages. The NK cell repertoire revealed lingering immune effects of early rearing while still maintaining an overall integrity and resilience. Full article
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19 pages, 2445 KiB  
Article
Early Life Stress Is Associated with Alterations in Lymphocyte Subsets Independent of Increased Inflammation in Adolescents
by Brie M. Reid, Christopher Desjardins, Bharat Thyagarajan, Michael A. Linden and Megan Gunnar
Biomolecules 2024, 14(3), 262; https://doi.org/10.3390/biom14030262 - 22 Feb 2024
Cited by 1 | Viewed by 972
Abstract
Early life stress (ELS) is linked to an elevated risk of poor health and early mortality, with emerging evidence pointing to the pivotal role of the immune system in long-term health outcomes. While recent research has focused on the impact of ELS on [...] Read more.
Early life stress (ELS) is linked to an elevated risk of poor health and early mortality, with emerging evidence pointing to the pivotal role of the immune system in long-term health outcomes. While recent research has focused on the impact of ELS on inflammation, this study examined the impact of ELS on immune function, including CMV seropositivity, inflammatory cytokines, and lymphocyte cell subsets in an adolescent cohort. This study used data from the Early Life Stress and Cardiometabolic Health in Adolescence Study (N = 191, aged 12 to 21 years, N = 95 exposed to ELS). We employed multiple regression to investigate the association between ELS, characterized by early institutional care, cytomegalovirus (CMV) seropositivity (determined by chemiluminescent immunoassay), inflammation (CRP, IL-6, and TNF-a determined by ELISA), and twenty-one immune cell subsets characterized by flow cytometry (sixteen T cell subsets and five B cell subsets). Results reveal a significant association between ELS and lymphocytes that was independent of the association between ELS and inflammation: ELS was associated with increased effector memory helper T cells, effector memory cytotoxic T cells, senescent T cells, senescent B cells, and IgD− memory B cells compared to non-adopted youth. ELS was also associated with reduced percentages of helper T cells and naive cytotoxic T cells. Exploratory analyses found that the association between ELS and fewer helper T cells and increased cytotoxic T cells remained even in cytomegalovirus (CMV) seronegative youth. These findings suggest that ELS is associated with cell subsets that are linked to early mortality risk in older populations and markers of replicative senescence, separate from inflammation, in adolescents. Full article
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15 pages, 825 KiB  
Article
Childhood Maltreatment and Immune Cell Gene Regulation during Adolescence: Transcriptomics Highlight Non-Classical Monocytes
by Kate R. Kuhlman, Steve W. Cole, Ece N. Tan, James A. Swanson and Uma Rao
Biomolecules 2024, 14(2), 220; https://doi.org/10.3390/biom14020220 - 13 Feb 2024
Viewed by 1307
Abstract
Childhood maltreatment has been repeatedly linked to a higher incidence of health conditions with an underlying proinflammatory component, such as asthma, chronic obstructive pulmonary disease, stroke, and cardiovascular disease. Childhood maltreatment has also been linked to elevated systemic inflammation prior to the onset [...] Read more.
Childhood maltreatment has been repeatedly linked to a higher incidence of health conditions with an underlying proinflammatory component, such as asthma, chronic obstructive pulmonary disease, stroke, and cardiovascular disease. Childhood maltreatment has also been linked to elevated systemic inflammation prior to the onset of disease. However, childhood maltreatment is highly comorbid with other risk factors which have also been linked to inflammation, namely major depression. The present analysis addresses this issue by assessing the association of maltreatment with genome-wide transcriptional profiling of immune cells collected from four orthogonal groups of adolescents (aged 13–17): maltreated and not maltreated in childhood, with and without major depressive disorder. Maltreatment and psychiatric history were determined using semi-structured clinical interviews and cross-validated using self-report questionnaires. Dried whole blood spots were collected from each participant (n = 133) and assayed to determine the extent to which maltreatment in childhood was associated with a higher prevalence of transcriptional activity among differentially expressed genes, specific immune cell subtypes, and up- or down-regulation of genes involved in immune function after accounting for current major depression. Maltreatment was associated with increased interferon regulatory factor (IRF) transcriptional activity (p = 0.03), as well as nuclear factor erythroid-2 related factor 1 (NRF1; p = 0.002) and MAF (p = 0.01) among up-regulated genes, and increased activity of nuclear factor kappa beta (NF-κB) among down-regulated genes (p = 0.01). Non-classical CD16+ monocytes were implicated in both the up- and down-regulated genes among maltreated adolescents. These data provide convergent evidence supporting the role of maltreatment in altering intracellular and molecular markers of immune function, as well as implicate monocyte/macrophage functions as mechanisms through which childhood maltreatment may shape lifelong immune development and function. Full article
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