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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

Viewed by 1247

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 [...] Read more.

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)

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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

Viewed by 1616

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

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

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Graphical abstract

Graphical abstract
Full article ">Figure 1
The timeline of the treatments and experimental design are shown. Ages in postnatal day (P) are shown with the ages of different manipulations identified. The bold indicates when the animals were assessed for behavior or immunohistochemistry. Full article ">Figure 2
Inflammatory pathways disrupted by maternal separation (MS). (a) Schematic showing signaling pathways associated with inflammation. Most research focuses on the TLR pathway. CB2 receptor-associated pathways also modulate MARCH7/axotropin and NLRP3 as shown here. The gray box insert shows the observed changes following MS, where CB2 overexpression leads to a down-regulation followed by disinhibition of NLRP3. Modified figure from DOI: 10.1097/HRP.0000000000000325). (b,c) Female rats underwent MS or were controls (Con). At P40, the prelimbic prefrontal cortex was analyzed with Western immunoblots for MARCH7 and NLRP3 with VCP or actin as controls, respectively. (b) MS rats have a significant decrease (red arrow) in the regulatory enzyme MARCH7. (c) NLRP3 expression increases (green arrow) in MS females relative to controls (* p < 0.05). Means ± SE are presented (n = 6/5 for MARCH7 and 5/5 for NLRP3). A second cohort replicated this finding. Full article ">Figure 3
Immunohistochemistry of parvalbumin (PV) neurons and CB2 receptors in the prelimbic cortex of control (Con) and maternally separated (MS) female rats at 25 (juvenile), 40 (adolescent), and 100 (adult) days of age. (a) The white arrows identify a double-labeled CB2/PV neuron; the yellow arrow indicates the PV-labeled neuron in Con subjects or (b) MS subjects; (c) a CB2 immunopositive neuron faintly stained in gray (i.e., DAB/nickel). Magnification is 20×, and the bar represents 100 µm. Stereological assessment of (d) PV neurons without additional labeling; means ± SE for n = 4/condition. * p < 0.05 for a main effect of age. (e) The total number of PV immunopositive neurons (PV single and CB2/PV counted cells). Both the main effect of age and the condition × age interaction were marginally significant (p’s = 0.05 and 0.06, respectively); and (f) counted cells immunoreactive for CB2 and PV double labeling across age and condition in MS females relative to controls. Means ± SE for n = 4/condition. * p < 0.05 indicates a significant interaction of Age × Condition; # p < 0.05: P25 vs. P100 in the MS group were significantly different. (g) Confocal imaging of CB2-immunoreactive neurons (green; 488 λ) and PV-immunoreactive neurons (red; 560 λ). The white arrows show CB2/PV interactions, with CB2-immunoreactive neurons wrapped around the PV-immunoreactive cell, indicating that these markers are not co-localized. The far-right picture illustrates the z-plane of the image. Full article ">Figure 4
A triple-label image of CB2-immunoreactive cells (green; 488 λ; upper left), PV-immunoreactive neurons (red; 560 λ; upper right), the microglia marker, iba-1 (blue; 660 λ; middle left); this picture has an inset in the white box showing a microglia cell, CB2/PV image (middle right) as indicated in yellow; and their combined image (CB2/PV/iba-1; lower right). The white arrow points to the same cell in each image. Pink arrows and pink on the image indicate a CB2/iba-1 co-expression (lower left and lower right). Full article ">Figure 5
CB2 activity and depressive-like behaviors. (a) Timeline showing how maternally separated (MS) females were treated every other day with the CB2 agonist, HU-308 (2.5 mg/kg), or DMSO vehicle and tested for behavior. (b) Sucrose preference for a 1% sucrose solution was not significantly affected by HU-308. (c,d) While HU-308 did not significantly reduce the latency to escape, MS females treated with HU-308 had fewer escape fails than vehicle-treated females; * p < 0.05. Means ± SE for n = 8/group. Full article ">Figure 6
CB2 activity and depressive-like behaviors in maternally separated female rats at 40 days of age. (a,b) A CB2-EGFP or EGFP-alone expressing lentiviral vector with an EGFP reporter into the prelimbic cortex; (a) placements shown with blue indicating the CB2-EGFP virus, green the EGFP virus at the AP position of 3.7 or 3.2. (b) the cloning map used for plasmid construction for the CB2-EGFP virus. (c) Representative section showing the viral-mediated expression of the CB2-EGFP virus in the prelimbic cortex at 1.5×. Top picture shows background immunofluorescence in a control section compared with (bottom) CB2-EGFP expression one week following transduction; Image at 40×. (d) Quantitation of immunofluorescence 1 day after injection (0 weeks), 1 week, or 2 weeks after injection of the CB2-EGFP virus. Data are expressed as a percentage of the control injection at time 0. * p < 0.05; Means ± SE for n = 3/group. (e) MS females were given a two-bottle choice (water vs. 0, 0.25, 0.5, and 1% sucrose solutions) for two days each. Animals with CB2-EGFP overexpression drank more sucrose (less anhedonia) than EGFP-alone controls (* p < 0.05). Means ± SE for n = 8/group. (f,g) Prelimbic overexpression of the CB2 receptor significantly reduced the latency to escape and had fewer escape fails than subjects expressing the EGFP-alone virus; * p < 0.05. Means ± SE for n = 8/group. Full article ">

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 1637

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 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)

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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 2 | Viewed by 2010

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

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

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Figure 1
Early life adversity is positively associated with peripheral inflammation. First principal component of IL-6, CRP, and TNF-a was positively and significantly associated with early life stress, controlling for sex, age, total fat percentage, and time of blood draw. PI = previously institutionalized group, NA = non-adopted group. Full article ">Figure 2
Early life adversity was associated with increased IgD− memory B cells and senescent B cells. The presented p-value is from the multiple regression model that controlled for sex, age, total fat percentage, time of blood draw, IL-6, and CRP for: (a) IgD− memory B cells, (b) senescent B cells. PI = previously institutionalized group, NA = non-adopted group. Full article ">Figure 3
Early life stress exposure was associated with fewer Helper T cells and naïve helper T cells and increased effector memory helper T cells. The presented p-value is from the multiple regression model that controlled for sex, age, total fat percentage, time of blood draw, IL-6, and CRP for (a) helper T cells, (b) effector memory helper T cells, and (c) naïve helper T cells. PI = previously institutionalized group, NA = non-adopted group. Full article ">Figure 4
Early life stress exposure was associated with fewer naive cytotoxic T cells and effector memory cytotoxic T cells. The presented p-value is from the multiple regression model that controlled for sex, age, total fat percentage, time of blood draw, IL-6, and CRP for (a) naive cytotoxic T cells and (b) effector memory cytotoxic T cells. PI = previously institutionalized group, NA = non-adopted group. Full article ">Figure 5
Early life stress exposure was associated with more senescent T cells. The presented p-value is from the multiple regression model that controlled for sex, age, total fat percentage, time of blood draw, IL-6, and CRP. PI = previously institutionalized group, NA = non-adopted group. Full article ">

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 2 | Viewed by 2416

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

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

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Review

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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 125

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 [...] Read more.

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)

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16 pages, 963 KiB

Open AccessReview

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 1801

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 [...] Read more.

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)

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Figure 1
Cell-type enrichment analysis of PNN components in the dorsolateral prefrontal cortex (dlPFC) of healthy subjects. Heatmap showing the expression levels of PNN canonical components derived from post mortem dlPFC samples from 34 neurotypical individuals (16M/18F) (Maitra et al., 2023) [<a href="#B68-biomolecules-14-01087" class="html-bibr">68</a>]. The OPC cluster highly expresses VCAN, PTPRZ1 and TNR. Microglia cells barely express—if at all—canonical PNN components such as VCAN, ACAN, BCAN and TNR. The processed dataset by Maitra et al. (2023) [<a href="#B68-biomolecules-14-01087" class="html-bibr">68</a>], including the cluster annotations, was downloaded through the UCSC Cell Browser with the following link: <a href="https://cells.ucsc.edu/?ds=dlpfc-mdd" target="_blank">https://cells.ucsc.edu/?ds=dlpfc-mdd</a> (accessed on 30 June 2024) Using the R package Seurat [<a href="#B67-biomolecules-14-01087" class="html-bibr">67</a>] (v. 4.1.1, R version 4.1 [<a href="#B69-biomolecules-14-01087" class="html-bibr">69</a>]), the matrix.mtx, features.tsv, barcodes.tsv and meta.tsv files were loaded into a Seurat object. Only neurotypical subjects (n = 34) were included in the following analysis. The heatmap was generated using Seurat’s DoHeatmap function with default parameters and the following set of genes inputted as features to include: NCAN, VCAN, BCAN, ACAN, PTPRZ1, CSPG4, TNR, HAPLN1, HAPLN2, HAPLN3, HAPLN4. All the PNN components were derived from Tanti et al. (2022) [<a href="#B3-biomolecules-14-01087" class="html-bibr">3</a>]. The expression values (normalized expression) of each marker were scaled and are presented as z-scores in the colour bar of the heatmap. Expression is grouped by broad cell types. A darker colour (blue) indicates higher levels of expression. Abbreviations: Ast, Astrocytes; End, Endothelial cells; ExN, Excitatory neurons; InN, Inhibitory neurons; Mic, Microglia; Mix, Mixed expression profile; Oli, oligodendrocytes; OPCs, Oligodendrocyte precursor cells; PNN, Perineuronal net. Full article ">Figure 2
Microglial interactions with other glia cells that are pertinent to ECM-PNN regulation. Inhibitory neurons release GABA, cytokines (e.g., IL33) and chemokines (e.g., CX3CL1). The receptors for these molecules are highly expressed by microglia. The interplay between these neuronal ligands and microglial receptors initiates different signaling cascades that culminate in the engulfment of ECM-PNN components. Furthermore, non-neural cells such as astrocytes can affect the interaction between microglia and PNNs through the release of IL33. Microglia also synthesize and release enzymes such as MMP2, MMP9 and Cathepsin S that indirectly modulate the integrity of PNNs. Finally, microglia secrete several pro-inflammatory and anti-inflammatory cytokines and chemokines. These molecules can robustly regulate OPC proliferation, maturation and survival. Full article ">

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 1320

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 [...] Read more.

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)

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LB Impairs Synaptic Pruning During a Critical Period of Hippocampal Development. (A) The number of microglia and their size increase from P12 to P21 in the hippocampus (top). During this critical period, the expression of TREM2 on microglia increases, enabling the efficient removal of non-functional synapses labeled with “eat-me signals”, depicted as red circles. This process redirects limited neuronal resources to functional synapses (indicated by red arrows), enabling the formation of a more efficient network characterized by a high synaptic maturity index and improved hippocampal-dependent memory. (B) Mice were exposed to control (CTL) or LB conditions and perfused at P17 and P33 to assess microglial morphology and phagocytic activity. (C) Imaris models of P17 microglial morphology (Iba1 staining in green, left column) and synaptic engulfment (PSD95 in red, right column) and phagosome size (CD68, blue, right column). (D) LB reduced the number of PSD95 puncta inside microglia at P17, but not at P33. Note that phagocytic activity is eightfold higher at P17 compared to P33 in CTL, but not LB [<a href="#B39-biomolecules-14-00964" class="html-bibr">39</a>]. (E) Working model: LB impairs microglial-mediated synaptic pruning in both males and females, leading to reduced synaptic maturity, lower functional connectivity, and impaired contextual fear conditioning in adolescent males. Upregulation of synaptic pruning in astrocytes may protect female LB mice (in (E) but see [<a href="#B39-biomolecules-14-00964" class="html-bibr">39</a>] for details). **** p < 0.0001. Full article ">Figure 2
Recent Progress (in red font) and Unresolved Questions (black font). (A) Potential signals that drive ELA-induced microglial changes. (B) Alterations in microglial function. (C) Functional and structural changes observed in rodents exposed to ELA. Full article ">

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 2440

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 [...] Read more.

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)

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