Perinatal neurodevelopment represents the period with the greatest neuroplastic potential. Orchestration of several programmed cellular processes during early critical periods is necessary for homeostatic brain development as it leads to the emergence of adaptive behaviors that allow an organism to interact harmoniously with its environment. Brain tissue growth is marked by massive neuro- and gliogenesis which peaks during late embryogenesis. Following cellular proliferation and neuronal differentiation, axonal connections are established through synaptogenesis to facilitate neurotransmission. Neurotransmission during the brain growth spurt is primarily excitatory in nature and results in an over-abundance of working synapses which are supported by astrocytic processes at the tripartite synapse. Neural circuits imperative for survival and early-life functions such as suckling, vision, and audition are almost immediately myelinated by oligodendrocytes. However, redundant connections are phagocytosed by microglia during the phase of synaptic pruning which occurs during a sensitive period in late childhood and early adolescence, closing the perinatal period of elevated neuroplastic potential. The refined neural circuitry is then further myelinated to strengthen and optimize salient brain connections which are required for efficient adult cognitive processing. As such, glial proliferation and function are major constituents of proper neurodevelopment and are imperative for sustaining extraordinary neuroplastic potential during the perinatal and adolescent periods.

Mammalian neurodevelopment is a gradual process that continues well into the third decade of life in humans and, consequently, is susceptible to experience-driven alteration (Pujol et al., 1993; Lebel and Beaulieu, 2011; Miller et al., 2012). In this review, we discuss how several forms of early-life adversity (ELA), experiences that deviate from the expected and cause stress, lead to immediate changes in critical period onset and progression and cause downstream deficits in sensitive period ontogeny. ELA exposure, also referred to as exposure to “adverse childhood experiences (ACE),” has a high prevalence in the US and is comorbid with other environmental effectors including socioeconomic status, nutrition, and prenatal drug exposure which lead to several negative behavioral outcomes and the emergence of neuropsychiatric disorders later in life (Hambrick et al., 2019).

The amount and timing of ELA exposure are key factors which determine the effect of a stressful event on behavior and the potential emergence of a neuropsychiatric disorder in adolescence or young adulthood. The effect of ELA on brain development is modulated, in part, by the Stress Hyporesponsive Period (SHRP) which prevents an infant’s hypothalamic-pituitary-adrenal (HPA) axis from becoming overstimulated and producing an abundance of glucocorticoids during critical periods in neurodevelopment which may be damaging. The SHRP begins about 36 h after parturition and reduces basal corticosterone levels from between 15 and 25 μg/100 ml during late gestation to 1–3 μg/100 ml which is sustained until the end of the brain growth spurt around postnatal day 15 in the rat (Sapolsky and Meaney, 1986). A similar period is observed during the human brain growth spurt (Loman and Gunnar, 2010). Short and predictable periods of early-life stress do not lead to HPA axis over-activation, and instead result in the development of adaptive behaviors as early exposure to low levels of glucocorticoids induces HPA axis maturation (Popoli et al., 2011; Guan et al., 2020). However, ELA often presents as a prolonged or unpredictable stressor that has the potential to lower the SHRP threshold and elevate HPA axis activity, disrupting normative neurodevelopment, and ultimately leading to the emergence of maladaptive behaviors (Nelson and Gabard-Durnam, 2020). It should be noted that the amount of stress needed to lower the stress reactivity threshold varies by individual due to certain genetic predispositions and history of in utero exposure to stress and other teratogens. Not all ELA paradigms immediately raise levels of corticosterone during the SHRP, but instead increase stress-sensitivity in adulthood (Lajud et al., 2012). For example, prenatal alcohol exposure is highly comorbid with ELA exposure in early childhood (up to 70%) and has been shown to increase the risk of developing maladaptive behaviors later in life due to the synergistic effects of the prenatal and early-life stressors on the HPA axis regulation in early childhood (Kambeitz et al., 2019; Lebel et al., 2019). In such cases, teratogenic exposure likely reduces the SHRP threshold or prevents the onset of the SHRP during perinatal development which increases the vulnerability of the brain to the damaging effects of ELA on early circuit development and glia proliferation. Finally, ELA resulting from malnutrition or poverty indirectly influences neurodevelopment by affecting overall growth and peripheral organ development which has been linked to neurodevelopmental delays (Nelson and Gabard-Durnam, 2020).

Glia proliferation, differentiation, and function are highly vulnerable to changes in HPA axis activity during development. However, a comprehensive discussion on how early HPA axis dysregulation affects astrocyte, microglia, and oligodendrocyte function is lacking. In this review, we explore the synergistic and overlapping effects of altered HPA axis development on glial function and neuron-glial communication which are imperative for synaptic pruning and myelination. Specifically, we theorize that ELA-induced stress often lowers the threshold of stress reactivity in early life leading to irregular HPA axis activity and an accumulation of glucocorticoids. Consequently, this alters neuronal excitability and synaptogenesis and induces lasting changes to glia production and function. In turn, these changes are detrimental to brain circuit refinement and optimization in the juvenile period. A detailed review of these underlying neurobiological mechanisms is critical for establishing ELA as a risk factor for psychiatric disorder development and will highlight specific targets for intervention.

Furthermore, ELA-induced HPA axis dysregulation causes unique changes to hippocampal (HPC) and prefrontal cortex (PFC) development which contribute to the emergence of specific behavioral phenotypes (Woolley et al., 1990; Nguyen et al., 2015; Guan et al., 2020). The effect of stress-induced extracellular glucocorticoid accumulation on neuronal excitability varies by brain region in development. Glucocorticoid-activated upregulation of neuronal excitability during the brain growth spurt drives the production of redundant synapses and alters glial number and function in HPC (Paolicelli et al., 2011; Schafer et al., 2012). Elevated levels of extracellular glutamate may be maintained into the juvenile period which delays or prevents effective synaptic pruning and disrupts the myelination of refined circuits (Parellada and Gassó, 2021). In contrast, elevated glutamatergic exposure represses glutamatergic and GABAergic neuronal excitability in the PFC leading to alterations in cortical disinhibition (Green et al., 2010; Ghosal et al., 2017). Due to the reciprocal connections of PFC with the hypothalamus and other subcortical regions including HPC and thalamus, alterations to PFC signaling lead to reduced inhibitory control over the HPA axis (Diorio et al., 1993; Herman, 2020). Consequently, a feed-forward loop is initiated wherein glucocorticoid production is further potentiated and this impairs synaptic pruning and myelination. We postulate that ELA contributes to an individual’s propensity towards either resilient or maladaptive behaviors by disrupting the delicate balance of synaptic pruning and axonal myelination which is necessary for adult brain circuitry refinement in and between these brain regions. Collective analysis of preclinical and clinical literature suggests targets for effective intervention to promote adaptive and resilient behaviors.

Critical periods are windows of heightened neuroplasticity during which the lack of certain stimuli or experiences has a dramatic, and often irreversible, effect on the development and function of the brain. They are characterized by experience-expectant processes that control the naissance and adequate maturation of brain circuits necessary for vision, hearing, language, and social and emotional development during infancy and early childhood (Nelson and Gabard-Durnam, 2020). Indeed, Nobel-prize winning studies conducted by Drs. David Hubel and Torsten Wiesel were some of the first to demonstrate that the absence of visual stimuli during a perinatal critical period results in lifelong visual impairments (Hubel and Wiesel, 1962). Following the closure of a critical period, the affected brain circuits become more resistant to future neuroplastic alteration. Biological processes occurring during early critical periods include cellular proliferation and differentiation, synaptogenesis, and the onset of myelination. As such, critical periods occur in infancy and early childhood. The specific length of critical periods depends on the rate of development of the putative circuit and varies in length from weeks to months (reviewed in Hensch, 2004).

Biomolecular processes occurring during perinatal critical periods lay the groundwork for optimizing neural circuitry in adolescence and refining brain circuitry in adulthood. Sensitive periods begin in late childhood and occur across a longer span of neurodevelopment. Experiences that occur during adolescent sensitive periods alter brain structure and function in an experience-dependent manner such that input is not required for, but may have a significant effect on, circuit refinement. Unlike critical periods, sensitive periods may be reopened to facilitate the refinement of brain circuitry that occurs as a result of synaptic pruning. However, this residual plasticity is limited (Knudsen, 2004). During this process, redundant synapses are removed from the brain and functionally-relevant connections are conserved and optimized through myelination to support adult cognition (Chechik et al., 1999; Knudsen, 2004). As such, the biological processes surrounding adolescent neurodevelopment necessitate proper glial function.

Nearly half of all CNS synapses created during the perinatal critical period are phagocytosed by microglia during the phase of synaptic pruning (Schafer et al., 2012; Zhan et al., 2014). Synaptic pruning results from the coordinated activity of all three major CNS glia. As aforementioned, microglia are the primary cells responsible for coordinating and performing synaptic pruning through the phagocytosis of synaptic material (Paolicelli et al., 2011) and the initiation of programmed cell death (Wakselman et al., 2008; Sominsky et al., 2018). Chemokine fractalkine signaling, via complement component cascade proteins and associated receptors, is a central mechanism by which microglia communicate with neurons to coordinate the removal of redundant synapses. During this process, excess synapses are tagged with C1 and C3 complement cascade proteins which bind to the Cx3cr1 receptor on microglia to facilitate pruning of weak, surplus synapses. Synaptic pruning occurs earlier in PFC than HPC (Mallya et al., 2019). The repression of Cx3cr1 receptor expression delays the onset of synaptic pruning and prevents microglia proliferation in the adolescent HPC. As a result, hyperconnectivity is observed in the HPC and consists of immature spines which form many weak synapses (Paolicelli and Gross, 2011; Zhan et al., 2014). An overabundance of circuit input from weak synapses disrupts neuronal synchrony, ultimately affecting functional connectivity of the HPC and PFC circuits (Pattwell et al., 2016; Honeycutt et al., 2020). Moreover, astrocytes play a pivotal role in coordinating synaptic pruning. Primarily, astrocytic processes monitor synapse strength and support excitatory signaling through glutamate recycling. However, astrocytes reserve the capacity to tag redundant synapses and directly phagocytose synapses (Stevens et al., 2007; Fair et al., 2008; Schafer et al., 2012; López-Murcia et al., 2015; Sultan et al., 2015; Bosworth and Allen, 2017). Reduced proliferation of astrocytes and/or disruption to astrocytic activity weakens mature synapses, prevents synapse maturation, and reduces synaptic pruning. Finally, oligodendrocyte precursor cells share the capacity to engulf synapses and aid in synaptic pruning (Buchanan et al., 2021). Interestingly, the proliferation, migration, and activity of OPCs bear a striking similarity to microglia.

The next phase of circuit refinement is axonal myelination, the process by which mature, myelinating oligodendrocyte (mOL) processes ensheath axons to support axonal survival and fine-tune axonal conduction velocity. The ontogenesis of mOLs in the mammalian brain is complex and varies by brain region and an organism’s age. Briefly, OPCs proliferate in three distinct gestational phases (Cui et al., 2012; Bergles and Richardson, 2016) and the differentiation of OPCs to mOLs occurs during the mammalian brain growth spurt; axons lengthen and myelination of functionally-relevant synapses is needed to support the emergence of early behaviors, such as suckling and vision. Much like neuro- and synaptogenesis, myelination begins in subcortical structures with HPC fiber tracts myelinated before cortical PFC axons. Myelination is arguably the longest neurodevelopmental process, with the fastest peak of myelination occurring in adolescence; this aligns with and follows the aforementioned process of synaptic pruning (Downes and Mullins, 2014; Kwon et al., 2020). One mOL may myelinate up to 50 axons in the CNS (Pfeiffer et al., 1993). Thus, abnormalities in OPC differentiation or mOL survival pose a major threat to axonal survival and circuit function. The onset and progression of these processes are critical for brain circuit optimization. Environmental experiences that alter adolescent myelination are known risk factors for the development of several psychiatric disorders including anxiety, schizophrenia, and depression (Makinodan et al., 2012; Forbes and Gallo, 2017).

All three major types of CNS glia work synergistically to facilitate myelination of axons with terminals serving functionally-relevant synapses. Following synaptic pruning in late childhood and early adolescence, microglia engulf viable OPCs as mediated by fractalkine signaling. Inadequate reduction of the OPC population prior to the onset of peak myelination in adolescence alters the OPC-mOL ratio, favoring mOLs, and leads to disruptions in typical axonal myelination patterns (i.e., mistargeted ensheathment of neuronal cell bodies and a thinning of the axonal myelin sheath). Thus, precise regulation of myelin content to axonal number is integral for proper myelination, and this balance is directly affected by microglial activity (Almeida et al., 2018; Nemes-Baran et al., 2020). Moreover, microglia are directly involved in myelin sheath pruning for refinement (Hughes and Appel, 2020) and microglia-OPC interactions mediate OPC differentiation to mOL (Wlodarczyk et al., 2017; Giera et al., 2018). Additionally, in an in vitro study, Pang et al. (2013) showed that astrocytes support long-term survival of OPCs, whereas microglia support oligodendrocyte differentiation and myelination. Astrocyte and oligodendrocyte communication has been shown to play an important role in myelin production. Astrocytes secrete platelet-derived growth factor (PDGF) which supports OPC proliferation and also inhibits immediate OPC differentiation (Raff et al., 1988; Richardson et al., 1988; McKinnon et al., 2005; Traiffort et al., 2020). Brain-derived neurotrophic factor (Bdnf) is also secreted by astrocytes, and Bdnf supports myelination during the brain growth spurt (Fletcher et al., 2018; Traiffort et al., 2020). Furthermore, astrocytes control the concentrations of Sonic hedgehog (Shh) produced which has a direct effect on OPC production throughout the forebrain (Traiffort et al., 2016).

Importantly, cellular and synaptogenesis occur during the SHRP, a perinatal neuroprotective period wherein HPA axis activation, and subsequently, glucocorticoid reactivity is significantly reduced (Schmidt et al., 2005; Slattery and Neumann, 2008). Alterations to neuronal physiology are harmful to cellular proliferation and synaptogenesis, and glia are most vulnerable to stress-induced changes to glucocorticoid exposure and glutamatergic signaling (Jauregui-Huerta et al., 2010). Glia express stress hormone and/or glutamate receptors and are thus directly impacted by the HPA axis and neuronal hyperactivity. For example, astrocytes replenish excitatory neurons with glutamate through glutamate recycling (Pfrieger and Barres, 1996; Sonnewald et al., 1997; Bélanger et al., 2011). Therefore, stress-induced changes to neuronal excitability directly affect astrocytic activity. Similarly, OPCs increase voltage-gated sodium channel expression in response to elevated glutamatergic signaling, which upregulates OPC-neuron communication and stimulates precocial OPC differentiation (Cheli et al., 2015). Moreover, mOL have a high bioenergetic consumption and are highly susceptible to glutamate-induced oxidative stress which can lead to apoptosis (Rosko et al., 2019; Meyer and Rinholm, 2021; Nakamura et al., 2021). Prolonged, unpredictable periods of ELA exposure are known to overwhelm the HPA axis, leading to a lowering of the stress threshold. Significant challenges to this threshold lead to lasting changes to glia proliferation and function and are correlated with altered brain connectivity and the emergence of maladaptive behaviors later in life. It should be noted that shorter, predictable periods of ELA prime the brain to experience future stress, and ultimately lead to the emergence of resilient and adaptive behaviors. In effect, increases to stress reactivity during the SHRP are quickly recovered.

ELA reduces the volume of HPC and PFC in adolescence and adulthood. Specifically, as a result of normative synaptic pruning, cortical and subcortical gray matter (composed of cell bodies and axons) is thinned in adolescence (Gorka et al., 2014; Hanson et al., 2015; Underwood et al., 2019; Monninger et al., 2020). However, ELA disrupts this process and leads to alterations in PFC and HPC that do not follow the predetermined developmental trajectory of these regions (Sapolsky, 1996; Kim and Yoon, 1998; Gorka et al., 2014; Hanson et al., 2015; Calem et al., 2017). For example, many prominent hippocampal subregions (CA1, CA3, and the granule cell layer of the dentate gyrus) are smaller in children with ELA exposure (Teicher et al., 2012). PFC volume is similarly reduced following ELA exposure. We expect that ELA-related changes in HPC or PFC volume may be attributed to cellular apoptosis and/or hypomyelination as opposed to normative synaptic pruning. It should be noted that ELA exposure causes lateralization in the growth of these structures and is correlated with circulating cortisol levels (Dahmen et al., 2018).

ELA alters the connectivity between brain regions important for impulse control, emotional regulation, and memory (Miller and Cohen, 2001; Arnsten, 2009; Jin and Maren, 2015). As previously described and summarized in Figure 3, glial dysregulation prevents appropriate synaptic pruning and results in increased axonal connectivity between some structures. The discovery of increased connectivity was first observed between the PFC, HPC, and the amygdala of institutionalized children using magnetic resonance imaging and was correlated with disruptions in circuit function (Sullivan and Holman, 2010). Rearing of children in orphanages is a known risk factor for reaching appropriate neurodevelopmental milestones (Theoretical Empirical Practical Rationale, 2008; Hostinar et al., 2012) likely due to the reduction in personalized care and lack of routine in some homes. Specifically, formerly institutionalized children exhibited precocial amygdala-PFC connectivity, a pattern atypical of their developmental stage, which is correlated with an increase in anxiety-like behaviors and reduced inhibitory control (Gee et al., 2013; Silvers et al., 2016). Indeed, preclinical studies using rodent models of perinatal maternal separation indicate that amygdala-HPC and amygdala-PFC functional connectivity is increased in adolescence and is correlated with an upregulation in anxiety-like behaviors (Johnson and Kaffman, 2018). Histological assessment of brain tissue samples collected from these animals confirms that maternal separation stress leads to the precocial innervation of medial PFC from the basolateral amygdala in adolescence. Interestingly, the increased connectivity was observed earliest in the female adolescent brain (Honeycutt et al., 2020).

ELA-induced alterations to regional volume and circuit functional connectivity lead to the emergence of maladaptive behaviors (Roceri et al., 2004; Holmes and Wellman, 2009; van Harmelen et al., 2010; Moriguchi and Hiraki, 2013; Gorka et al., 2014; Van Harmelen et al., 2014a, b). Notable impairments to executive function are observed in preclinical (Lovic and Fleming, 2004; Roceri et al., 2004; Holmes and Wellman, 2009; Liston and Gan, 2011) and clinical studies (Moriguchi and Hiraki, 2013). Thus, ELA-exposed adolescents and adults exhibit impaired future planning, abstract conceptualization, and emotional gating (Hostinar et al., 2012; French and Carp, 2016). Moreover, alterations to HPC volume and connectivity are associated with increased risk for developing depression (Baaré et al., 2010; Rao et al., 2010) and stress-related disorders (Geuze et al., 2005; Kitayama et al., 2005; Smith, 2005; Anda et al., 2006; Etkin and Wager, 2007). Structural and functional alterations within the PFC and HPC as a consequence of ELA also affect communication between these structures, contributing to the emergence of maladaptive behaviors. Patients with neuropsychiatric and stress-related disorders showed altered functional connectivity in PFC-HPC circuitry which contributes to deficits in working memory (Genzel et al., 2015; Jin and Maren, 2015; Poletti et al., 2016; Calabro et al., 2020). Lambert et al. (2019) showed that children with ELA exposure exhibited HPC-dependent learning deficits and this impairment increases with age. Increased middle frontal gyrus and reduced intraparietal sulcus activation during the encoding phase of learning emerge with increasing age in children exposed to violence and may reflect the greater effort required to maintain attention due to less efficient short-term memory storage.

Furthermore, ELA exposure results in enhanced sensitivity to stress hormones via impairments to negative feedback loops which control stress reactivity in HPC and PFC (Maniam et al., 2014; Van Bodegom et al., 2017). Glucocorticoids are essential for cellular and behavioral responsiveness to stressful situations and bind to mineralocorticoid receptors (MRs) and glucocorticoid receptors (GRs) on neurons and glia. These two receptors have different affinities for glucocorticoids and their expression is brain-region specific. Increased expression of GRs with limited MR colocalization in the HPC, PFC, hypothalamus, and pituitary facilitates homeostatic regulation of the HPA axis via negative feedback loops (Reul and De Kloet, 1986; Sapolsky and Meaney, 1986; Fuxe et al., 1987; Van Eekelen et al., 1988; Meaney et al., 1996; Jankord and Herman, 2009). However, ELA leads to a lasting reduction in GR expression in the adolescent and adult HPC which plays a major role in alterations to functional connectivity and contributes to behavioral impairment associated with heightened stress reactivity (Champagne, 2013; Liu and Nusslock, 2018). As such, pharmaceutical intervention with a GR antagonist is not recommended. It should be noted that some amount of glucocorticoid exposure is necessary for the development of brain circuits underlying the neurobiological response to stress and fear and their regulation. Thus, blockade of GR in certain brain regions during the SHRP may be harmful to brain development and would have increasingly detrimental effects on neurodevelopment in organisms exposed to ELA due to the reduction in GR expression. Schmidt et al. (2005) demonstrated that blockade of glucocorticoid receptors during the SHRP led to increased basal corticosterone levels, suggesting an impairment in the self-regulation of the HPA axis following GR receptor antagonism. When administered during an ELA paradigm, GR antagonism had a synergistic effect on basal corticosterone levels during the SHRP—corticosterone levels were four times greater than in pups just exposed to the ELA paradigm. It may be predicted that antagonism of such receptors on glia cells, namely microglia, severely upregulates the neuroimmune system and is therefore disadvantageous. Pharmaceutical interventions providing partial antagonism or competitive inhibition may be more suitable solutions for preventing the lowering of the stress reactivity threshold during ELA exposure. Reductions to GR expression are associated with alterations to functional connectivity in adolescence (Arnett et al., 2015). More research is needed to identify how ELA alters GR expression on glia, specifically.

Finally, it has been argued that increased circuit connectivity might be adaptive and promote some resilient behaviors. For example, increased connectivity and reactivity to novel stimuli may provide institutionalized children with a better means of interacting with the unpredictable and stressful nature of their environments (Tottenham, 2012). Moreover, previously institutionalized children exhibit more effective aversive learning during a threat-discrimination task that may be beneficial for survival (Silvers et al., 2016). Increased activation of the amygdala, HPC, and PFC circuits in institutionalized children and adolescents likely contributes to greater assessment of potential threats in their environment, increasing their capacity for self-preservation. However, extreme hyperconnectivity is linked to the onset of neuropsychiatric disorders.

Environmental and pharmacological therapies mitigate ELA-induced structural and functional alterations to HPC and PFC in adolescence and adulthood. While human studies allow us to explore the effect of ELA on behavioral outcomes, epigenetic modifications, functional connectivity, and HPA axis function, animal models facilitate the investigation of the neurobiological underpinnings supporting these behavioral alterations. As a result, novel targets for intervention are discovered. We have highlighted several glia-centric mechanisms as targets for intervention: preventing HPA axis dysregulation during critical and sensitive periods of neurodevelopment, mitigating changes to glia proliferation, and restoring normative glia function in adolescence. These therapies are summarized in Figure 4 and described in more detail below.

Aberrant glial proliferation and function resulting from exposure to ELA delays the onset of synaptic pruning in adolescence, with consequential precocial formation of redundant, immature synapses. This feed-forward loop of impaired adolescent circuit refinement results in the incomplete myelination of an abundance of weak synapses, ultimately leading to the emergence of maladaptive behaviors. Indeed, dysregulated synaptic pruning and myelination in adolescence is correlated with changes in behavior and cognitive capacity. In most cases, ELA exposure leads to a prolonged elevation in HPA axis activity during critical periods of neurodevelopment. Immediate changes to glia proliferation and function ultimately cause downstream impairments to glia function during later adolescent sensitive periods of neurodevelopment.

ELA-induced alterations to neural circuits are region-specific as the development of certain structures is not uniform across gestation and early childhood (Dobbing and Sands, 1973). We describe how the disruption of circuit refinement at the cellular level contributes to aberrant functional connectivity between and within the HPC and PFC. Our review of the literature has uncovered that ELA leads to hyperconnectivity of HPC and PFC-dependent circuits in adolescence and young adulthood due to reduced synaptic pruning. Consequently, the abundance of weak, immature synapses produces a disorganized landscape for myelination. Moreover, ELA exposure prevents the production of myelin basic protein in the adolescent brain, reducing the thickness of existing myelin sheaths. As a result, functional connectivity within and between HPC and PFC is impaired resulting in the emergence of maladaptive behaviors. These include increased anxiety-like behaviors and reduced capacity for impulse control, emotional regulation, and memory encoding.

Our review of glia-derived mechanisms underlying impairments to circuit refinement in adolescence following ELA exposure highlights several targets for effective therapeutic intervention. Moreover, behavioral interventions, which are accessible and affordable, strongly benefit structural and functional repair of HPC and PFC by preventing hyperactivation of the HPA axis in children and upregulating myelination in adolescents exposed to ELA. These include therapies which strengthen the caregiver-child bond such as the ABC intervention (Dozier et al., 2006) and the MTFC-P program (Fisher et al., 1999). At the neurobiological level, these interventions interact with the genome and increase the expression of growth factors which support normative glial function. Additionally, exposure to a complex environment or increased voluntary aerobic exercise are predicted to have a significant effect on mitigating the reduction in glia proliferation and maturation resulting from ELA. Future research would benefit from validating that these behavioral manipulations affect synaptic pruning or myelination in the ELA-exposed adolescent brain. Continued work under this lens will help us better understand preventative measures and interventions to improve the quality of life for children and families overall.

All authors collaboratively conceived the focus of this review and contributed to the draft and final versions of the manuscript. KM, NC, TR, and AK edited the manuscript and interpreted the collective findings of the preclinical and clinical research to understand the immediate and lasting effects of early-life adversity on glia-driven processes in neurodevelopment. KM, TC, and SK conducted the majority of the literature review and created the four included figures. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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