Submit to Special Issue Submit Abstract to Special Issue Review for Biomolecules Propose a Special Issue

Journal Menu

Journal Browser

► Journal Browser

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

Print Special Issue Flyer
Special Issue Editors
Special Issue Information
Keywords
Benefits of Publishing in a Special Issue
Published Papers

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

Deadline for manuscript submissions: 30 June 2025 | Viewed by 19032

Share This Special Issue

Special Issue Editors

Dr. Arie Kaffman

E-Mail Website
Guest Editor

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

Dr. Kate Ryan Kuhlman

E-Mail Website
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

Dr. Bridget L. Callaghan

E-Mail Website
Guest Editor

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

Dr. Christine Heim

E-Mail Website
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

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

early adversity
microglia
neuroinflammation
microbiome
psychopathology

Benefits of Publishing in a Special Issue

Ease of navigation: Grouping papers by topic helps scholars navigate broad scope journals more efficiently.
Greater discoverability: Special Issues support the reach and impact of scientific research. Articles in Special Issues are more discoverable and cited more frequently.
Expansion of research network: Special Issues facilitate connections among authors, fostering scientific collaborations.
External promotion: Articles in Special Issues are often promoted through the journal's social media, increasing their visibility.
e-Book format: Special Issues with more than 10 articles can be published as dedicated e-books, ensuring wide and rapid dissemination.

Further information on MDPI's Special Issue policies can be found here.

Published Papers (10 papers)

Download All Papers

Order results

Result details

Show export options Show export options

Select all

Export citation of selected articles as:

Research

Jump to: Review

26 pages, 5685 KiB

Open AccessArticle

Prenatal Maternal Immune Activation with Lipopolysaccharide Accelerates the Developmental Acquisition of Neonatal Reflexes in Rat Offspring Without Affecting Maternal Care Behaviors

by Mary Beth Hall, Elise A. Lemanski and Jaclyn M. Schwarz

Biomolecules 2025, 15(3), 347; https://doi.org/10.3390/biom15030347 - 27 Feb 2025

Viewed by 393

Abstract

Maternal immune activation (MIA)—infection with an immunogen during pregnancy—is linked to an increased risk of neurodevelopmental disorders (NDDs) in offspring. Both MIA and NDDs are associated with developmental delays in offsprings’ motor behavior. Therefore, the current study examined the effects of MIA on neonatal reflex development in male and female offspring. Sprague Dawley rats were administered lipopolysaccharide (LPS; 50 μg/mL/kg, i.p.) or saline on embryonic day (E)15 of gestation. The offspring were then tested daily from postnatal day (P)3–P21 to determine their neonatal reflex abilities. The maternal care behaviors of the dam were also quantified on P1–P5, P10, and P15. We found that, regardless of sex, the E15 LPS offspring were able to forelimb grasp, cliff avoid, and right with a correct posture at an earlier postnatal age than the E15 saline offspring did. The E15 LPS offspring also showed better performance of forelimb grasping, hindlimb grasping, righting with correct posture, and walking with correct posture than the E15 saline offspring did. There were no significant differences in maternal licking/grooming, arched-back nursing, non-arched-back nursing, or total nursing across the E15 groups. Overall, these findings suggest that MIA with LPS on E15 accelerates reflex development in offspring without affecting maternal care. This may be explained by the stress acceleration hypothesis, whereby early-life stress accelerates development to promote survival. Full article

(This article belongs to the Special Issue Early Adversity and the Immune Hypothesis: Call for a Dialogue between Basic and Clinical Neuroscience)

► Show Figures

Figure 1

16 pages, 685 KiB

Open AccessArticle

Altered Gut Microbiota Patterns in Young Children with Recent Maltreatment Exposure

by Gergana Karaboycheva, Melanie L. Conrad, Peggy Dörr, Katja Dittrich, Elena Murray, Karolina Skonieczna-Żydecka, Mariusz Kaczmarczyk, Igor Łoniewski, Heiko Klawitter, Claudia Buss, Sonja Entringer, Elisabeth Binder, Sibylle M. Winter and Christine Heim

Biomolecules 2024, 14(10), 1313; https://doi.org/10.3390/biom14101313 - 16 Oct 2024

Cited by 1 | Viewed by 1474

Abstract

Background: The brain and the intestinal microbiota are highly interconnected and especially vulnerable to disruptions in early life. Emerging evidence indicates that psychosocial adversity detrimentally impacts the intestinal microbiota, affecting both physical and mental health. This study aims to investigate the gut microbiome in young children in the immediate aftermath of maltreatment exposure. Methods: Maltreatment exposure was assessed in 88 children (ages 3–7) using the Maternal Interview for the Classification of Maltreatment [MICM]. Children were allocated to three groups according to the number of experienced maltreatment categories: no maltreatment, low maltreatment, and high maltreatment exposures. Stool samples were collected and analyzed by 16S rRNA sequencing. Results: Children subjected to high maltreatment exposure exhibited lower alpha diversity in comparison to those with both no and low maltreatment exposure (Simpson Index, Tukey post hoc, p = 0.059 and p = 0.007, respectively). No significant distinctions in beta diversity were identified. High maltreatment exposure was associated with the enrichment of several genera from the class Clostridia (Clostridium, Intestinibacter, Howardella and Butyrivibrio) and the depletion of the genus Phocaeicola (class Bacteriodia). Conclusions: Severe maltreatment exposure is associated with alterations in the gut microbiota of young children. Longitudinal trajectories of intestinal microbiota composition in the context of maltreatment may reveal important insights related to psychiatric and somatic health outcomes. Full article

(This article belongs to the Special Issue Early Adversity and the Immune Hypothesis: Call for a Dialogue between Basic and Clinical Neuroscience)

► Show Figures

Figure 1

20 pages, 4953 KiB

Open AccessArticle

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

Cited by 1 | Viewed by 1763

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 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

(This article belongs to the Special Issue Early Adversity and the Immune Hypothesis: Call for a Dialogue between Basic and Clinical Neuroscience)

► Show Figures

Graphical abstract

26 pages, 3717 KiB

Open AccessArticle

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 - 9 Apr 2024

Cited by 1 | Viewed by 1751

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 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 CD56^bright 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 CD56^dim lineages. The NK cell repertoire revealed lingering immune effects of early rearing while still maintaining an overall integrity and resilience. Full article

(This article belongs to the Special Issue Early Adversity and the Immune Hypothesis: Call for a Dialogue between Basic and Clinical Neuroscience)

► Show Figures

Figure 1

19 pages, 2445 KiB

Open AccessFeature PaperEditor’s ChoiceArticle

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 3 | Viewed by 2171

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 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

(This article belongs to the Special Issue Early Adversity and the Immune Hypothesis: Call for a Dialogue between Basic and Clinical Neuroscience)

► Show Figures

Figure 1

15 pages, 825 KiB

Open AccessArticle

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

Cited by 4 | Viewed by 2600

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 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

(This article belongs to the Special Issue Early Adversity and the Immune Hypothesis: Call for a Dialogue between Basic and Clinical Neuroscience)

► Show Figures

Figure 1

Review

Jump to: Research

13 pages, 273 KiB

Open AccessReview

Sex Differences in the Associations Among Early Life Adversity, Inflammation, and Cognition

by Erin Logue and Charles B. Nemeroff

Biomolecules 2025, 15(2), 161; https://doi.org/10.3390/biom15020161 - 22 Jan 2025

Viewed by 807

Abstract

Early life adversity (ELA) has long been recognized to negatively impact a variety of health outcomes, with increasingly recognized long-term implications for neurocognitive function. ELA may affect the brain through multiple mechanisms, including chronic inflammation. One potential moderator of the pathway from ELA to neuroinflammation to cognitive dysfunction is sex. ELA may leave females potentially even more vulnerable to cognitive impairment in later life. This review discusses the influence of ELA on cognitive function across much of the lifespan, how inflammation is implicated in this process, and the current state of knowledge regarding sex differences in these relationships. We conclude with a discussion of unanswered questions and suggestions for future research, including the incorporation of genetic data. Full article

(This article belongs to the Special Issue Early Adversity and the Immune Hypothesis: Call for a Dialogue between Basic and Clinical Neuroscience)

► Show Figures

Graphical abstract

16 pages, 963 KiB

Open AccessEditor’s ChoiceReview

Perineuronal Net Alterations Following Early-Life Stress: Are Microglia Pulling Some Strings?

by Reza Rahimian, Claudia Belliveau, Sophie Simard, Gustavo Turecki and Naguib Mechawar

Biomolecules 2024, 14(9), 1087; https://doi.org/10.3390/biom14091087 - 30 Aug 2024

Cited by 1 | Viewed by 2180

Abstract

The extracellular matrix plays a key role in synapse formation and in the modulation of synaptic function in the central nervous system. Recent investigations have revealed that microglia, the resident immune cells of the brain, are involved in extracellular matrix remodeling under both physiological and pathological conditions. Moreover, the dysregulation of both innate immune responses and the extracellular matrix has been documented in stress-related psychopathologies as well as in relation to early-life stress. However, the dynamics of microglial regulation of the ECM and how it can be impacted by early-life adversity have been understudied. This brief review provides an overview of the recent literature on this topic, drawing from both animal model and human post mortem studies. Direct and indirect mechanisms through which microglia may regulate the extracellular matrix—including perineuronal nets—are presented and discussed in light of the interactions with other cell types. Full article

(This article belongs to the Special Issue Early Adversity and the Immune Hypothesis: Call for a Dialogue between Basic and Clinical Neuroscience)

► Show Figures

Figure 1

15 pages, 1325 KiB

Open AccessReview

Microglia: The Drunken Gardeners of Early Adversity

by Sahabuddin Ahmed, Baruh Polis and Arie Kaffman

Biomolecules 2024, 14(8), 964; https://doi.org/10.3390/biom14080964 - 8 Aug 2024

Cited by 1 | Viewed by 1559

Abstract

Early life adversity (ELA) is a heterogeneous group of negative childhood experiences that can lead to abnormal brain development and more severe psychiatric, neurological, and medical conditions in adulthood. According to the immune hypothesis, ELA leads to an abnormal immune response characterized by high levels of inflammatory cytokines. This abnormal immune response contributes to more severe negative health outcomes and a refractory response to treatment in individuals with a history of ELA. Here, we examine this hypothesis in the context of recent rodent studies that focus on the impact of ELA on microglia, the resident immune cells in the brain. We review recent progress in our ability to mechanistically link molecular alterations in microglial function during a critical period of development with changes in synaptic connectivity, cognition, and stress reactivity later in life. We also examine recent research showing that ELA induces long-term alterations in microglial inflammatory response to “secondary hits” such as traumatic brain injury, substance use, and exposure to additional stress in adulthood. We conclude with a discussion on future directions and unresolved questions regarding the signals that modify microglial function and the clinical significance of rodent studies for humans. Full article

(This article belongs to the Special Issue Early Adversity and the Immune Hypothesis: Call for a Dialogue between Basic and Clinical Neuroscience)

► Show Figures

Figure 1

17 pages, 1443 KiB

Open AccessReview

Early Life Adversity, Microbiome, and Inflammatory Responses

by Eléonore Beurel and Charles B. Nemeroff

Biomolecules 2024, 14(7), 802; https://doi.org/10.3390/biom14070802 - 6 Jul 2024

Cited by 1 | Viewed by 2760

Abstract

Early life adversity has a profound impact on physical and mental health. Because the central nervous and immune systems are not fully mature at birth and continue to mature during the postnatal period, a bidirectional interaction between the central nervous system and the immune system has been hypothesized, with traumatic stressors during childhood being pivotal in priming individuals for later adult psychopathology. Similarly, the microbiome, which regulates both neurodevelopment and immune function, also matures during childhood, rendering this interaction between the brain and the immune system even more complex. In this review, we provide evidence for the role of the immune response and the microbiome in the deleterious effects of early life adversity, both in humans and rodent models. Full article

(This article belongs to the Special Issue Early Adversity and the Immune Hypothesis: Call for a Dialogue between Basic and Clinical Neuroscience)

► Show Figures

Journal Menu

Journal Browser

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

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Published Papers (10 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI