In the field of early-life experience, the advantage of studying laboratory animals is that it allows you to compare alternative rearing conditions with respect to the standard conditions commonly used in animal facilities. To do so, neuroscientists developed standardized approaches to mimic positive or negative environmental conditions affecting early-life development. Specifically, the impact of the positive experience was mostly studied using environmental enrichment (EE) paradigms (Cancedda et al., 2004). In opposition with EE, with the idea of exploring the consequences of the lack of a stimulating environment, some laboratories have investigated the effect of environmental impoverishment (EI) (Narducci et al., 2018). Finally, the study of early-life adversities (eLA) required several alternative approaches, as the quality of ACEs can present in a spectrum of different insults (Center for disease control and prevention [CDC], 1998; Felitti et al., 1998; Brenhouse and Bath, 2019; Figure 1). A common feature of all these approaches is the critical mediation of maternal care. Dams are single-handedly responsible for the pups’ survival during the first 2 weeks of offspring’s life, providing nutrition, hygiene care, and preventing hypothermia. Manipulation of rearing conditions drastically impact the mothers’ neurobiology and behavior, disrupting the quality of maternal care and resulting in long-lasting neurobiological and behavioral consequences for the offspring’s life (Guzzetta et al., 2009; Sale et al., 2014; Luchetti et al., 2015; Couto-Pereira et al., 2016, 2019; Walker et al., 2017; Narducci et al., 2018; Brenhouse and Bath, 2019; Gallo et al., 2019; Sparling et al., 2020).

Following early theories of psychosocial development (Baltes et al., 1980), animal studies confirmed the central dogma where positive caregiving and stimulating early-life predisposes to a healthier life. Specifically, early-life experiences were shown to impact postnatal CPs drastically. Not surprisingly, bidirectional impact on CPs occurs in animals exposed to eEE, eEI, or eLA. For instance, exposure to an eEE promotes the maturation of primary sensory systems (visual, somatosensory, and auditory) from a molecular and functional point of view. In some cases, this maturation is accompanied by enhanced perceptual capacity compared to standard-reared controls (Coq and Xerri, 2001; Cancedda et al., 2004; Cai et al., 2009; Xu et al., 2009; Baroncelli et al., 2010; Zennou-Azogui et al., 2016). Better cognitive performances (Baroncelli et al., 2010; Sale et al., 2014) and reduced anxiety (Baldini et al., 2013; Hegde and Mitra, 2020) generally accompany these effects, providing beneficial consequences in the rodent’s model of neurodevelopmental disorders (Lonetti et al., 2010; Chakrabarti et al., 2011; Sale et al., 2014; Yamaguchi et al., 2017; Consorti et al., 2019) and cognitive decline (Petrosini et al., 2009). Cortical development is consistently delayed in animals reared in eEI, coherently with impaired cognitive performances (Narducci et al., 2018).

Given these findings, the protracted consequences of eLA on adulthood emotional regulation are less intuitive. On one hand, increased anxiogenic behaviors and altered fear regulation are consistently detected in adult rodents with history of eLA, irrespectively from the kind of stressors (Brenhouse and Bath, 2019; Guadagno et al., 2020; Manzano Nieves et al., 2020; Tsotsokou et al., 2021). On the other hand, surprising findings are observed in the cortico-limbic pathway. For instance, an increased density of PV interneurons in the basolateral amygdala was reported in young mice reared with LBN (Manzano Nieves et al., 2020). Similarly, MS resulted in increased density of PNNs enveloping PV-cells in adult male mice prefrontal cortex (Gildawie et al., 2020). Consistently, another study found hypertrophic dendritic branching in adult mice exposed to MS, an abnormality that was successfully rescued by pre-weaning EE (Koe et al., 2016). Notably, optogenetic studies showed that correcting PV-function in LBN animals was able to re-instate conditioned fear behavior analogous to standard reared mice (Manzano Nieves et al., 2020).

These findings show that postnatal stress directly impacts some of the key factors contributing to CPs of development (namely, PV-cells and PNNs), qualifying them as primary candidates to mediate long-lasting behavioral abnormalities. Moreover, most of these studies show a gain-of-function in both PV and PNNs, suggesting that eLA might trigger an early and empowered maturation of limbic regions, analogous to what is seen in sensory regions in response to eEE. In light of these evidence, we postulate that early-life experiences might not induce, per se, substantial changes in the levels of specific cellular factors, but rather bias the allocation of resources in favor of targeted systems under the direct guidance of external cues.

Our hypothesis calls for some underlying mediators to control resource allocation across different brain regions in an experience-dependent manner. A primary candidate for this role is the neuroendocrine system. The endocrine glands secrete systemic hormones in response to stress (corticosterone) or pleasure (oxytocin) and activate selected cellular programs upon targeted cellular signaling. Transversal evidence corroborates this hypothesis: levels of oxytocin are found to increase in female mice reared under eEE conditions (Cutuli et al., 2019; Faraji et al., 2022), while intranasal administration of oxytocin reverses the impairment in social behavior consequent to MS (Joushi et al., 2021). On the contrary, enriched early-life experience significantly reduces the expression of corticosterone in peripheral blood coherently with accelerated cortical development (Guzzetta et al., 2009). Moreover, a higher level of corticosterone is observed in pups exposed to LBN, MS, and SR (Heun-Johnson and Levitt, 2016; Walker et al., 2017; Joushi et al., 2021).

The role of neurotrophins and growth factors is less clear. While molecules such as brain-derived neurotrophic factor (BDNF) and insulin-like growth factor 1 (IGF-1) were established as positive modulators of eEE in sensory systems’ development (Cancedda et al., 2004; Guzzetta et al., 2009; Baroncelli et al., 2010), their role in response to eLA is still unclear. According to the findings of accelerated maturation of limbic regions as a consequence of LBN and MS, it is reasonable to hypothesize a targeted increase of BDNF and IGF-1 in the cortico-limbic pathway. Two separate studies on MS-rats corroborate this hypothesis: one showing widespread cortical elevation of both BDNF and IGF-1 (Lee et al., 2012); another reporting elevated BDNF levels in the prefrontal cortex (Poleksic et al., 2021). In the amygdala, however, no significant changes in BDNF expression were observed (Hegde et al., 2020). Given the controversy, further investigation is required to determine the specific contribution of growth and neurotrophic factors to the development of cortico-limbic pathway in eLA models (Studies showing early-life experience impact on CPs are summarized in Supplementary Table 1).

Another additional aspect, potentially contributing to the consequence of eLA onto developmental process, is the involvement of multi-systemic inflammation and oxidative stress, two interconnected factors that have gained central attention in neuropsychiatric research over the past decade (Schafer and Stevens, 2010; Sekar et al., 2016; Devlin et al., 2021; Dziabis and Bilbo, 2021). On the one hand, the involvement of the immune system has been extensively described in a variety of brain disorders (Aw et al., 2021). On top of that, the intimate and bidirectional relationship between neuroinflammation and oxidative stress was shown to have a mechanistic implication on PV-cells and PNNs (Cabungcal et al., 2013; Soares et al., 2020). Indeed, elevated levels of pro-inflammatory molecules were extensively described in people with a history of ACE (Dutcher et al., 2020). For instance, a very elegant study described an association between ACEs and impaired pro-inflammatory glucocorticoid signaling (Danese et al., 2007). Thanks to this study, it is estimated that around 10% of cases of low-grade inflammation within the population, measured with C-reactive protein (CRP) levels in the blood, could be attributed to childhood maltreatment. Moreover, the elevated blood level of interleukin (IL) 6 and CRP were found in people with a history of ACE, when exposed to acute stressful events (Baumeister et al., 2016). Similarly, a systematic review established that mice exposed to MS present a short-term increased in the expression of IL-6, tumor necrosis factor-alpha (TNF), and IL-10 in non-blood tissues. At the same time, the levels of these molecules did not change in the blood (Dutcher et al., 2020). However, when further stress was applied, MS animals showed significant overexpression of IL-6, IL-1β, TNF, and IL-10 in the blood, closely matching previous findings in humans (Dimatelis et al., 2012). Despite the limited viability of studies in this area, a similar tendency of increased neuro-inflammation was observed in LBN animals; a clear example of this shows altered immune responses to amyloid plaques in a mouse model Alzheimer’s disease previously exposed to LBN (Hoeijmakers et al., 2015, 2017; Lesuis et al., 2016). On the other hand, eEE has extensively been described as protective against neuroinflammation (Jurgens and Johnson, 2012; Muscat and Barrientos, 2020; Reddaway and Brydges, 2020). Hence, converging findings from the human population and animal models suggest that eLA contributes to the onset of chronic inflammatory processes, representing an instrumental vulnerability factor leading to the development of a broad spectrum of neuropathological conditions in adulthood.

We would like to emphasize that, as nefarious as inflammation is for neurodevelopment, it also offers valuable therapeutic landscapes. Attenuating inflammatory processes might be a beneficial clinical option during early developmental stages, in conjunction with non-pharmacological approaches such as cognitive-behavioral therapies. This concept was empirically confirmed by a recent work showing early administration of N-acetylcysteine in conjunction with eEE significantly reduces neuroinflammation, rescuing abnormalities of GABAergic function and PNNs in a mouse model with an early oxidative insult (Dwir et al., 2021).

Results here described are graphically summarized in Figure 2.