Having a traumatic childhood increases the risk a person will develop anxiety disorders later in life. Early life adversity affects men and women differently, but scientists do not yet know why. Learning more could help scientists develop better ways to prevent or treat anxiety disorders in men and women who experienced childhood trauma.

Anxiety occurs when threat-detecting brain circuits turn on. These circuits begin working in infancy, and during childhood and adolescence, experiences shape the brain to hone the body’s responses to perceived threats. Two areas of the brain that are important hubs for anxiety-related brain circuits include the basolateral amygdala (BLA) and the prefrontal cortex (PFC).

Now, Honeycutt et al. show that rats that experience early life adversity develop stronger connections between the BLA and PFC, and these changes occur earlier in female rats. In the experiments, one group of rats was repeatedly separated from their mothers and littermates (an early life trauma), while a second group was not. Honeycutt et al. examined the connections between the BLA and PFC in the two groups at three different time periods during their development: the juvenile stage, early adolescence, and late adolescence.

The experiments showed stronger connections between the BLA and PFC begin to appear earlier in juvenile traumatized female rats. But these changes did not appear in their male counterparts until adolescence. Lastly, the rats that developed these strengthened BLA-PFC connections also behaved more anxiously later in life. This may mean that the ideal timing for interventions may be different for males and females. More work is needed to see if these results translate to humans and then to find the best times and methods to help people who experienced childhood trauma.

Exposure to early life adversity (ELA) increases vulnerability to various psychiatric disorders across the lifespan (Smyke et al., 2007; McEwen, 2008; Maccari et al., 2014; Callaghan and Tottenham, 2016; Hane and Fox, 2016; Krugers et al., 2017). Males and females appear to be affected differently by ELA, with females more prone to developing disorders including anxiety and depression (Hammen et al., 2000; Heim et al., 2008; Davis and Pfaff, 2014). Importantly, these sequelae often emerge later in childhood or adolescence, providing an opportunistic window for intervention before psychopathology takes hold. Thus, development of effective intervention strategies requires biological and developmental targets specific to individuals based on factors including sex and timing of stress exposure (Lupien et al., 2009). Evidence suggests that ELA in humans leads to life-long changes in connectivity and/or functionality of limbic and cortical regions (Choi et al., 2009; VanTieghem and Tottenham, 2018), with consequential deficits in emotion regulation and cognition (Tyrka et al., 2013). Both human and animal studies highlight the importance of corticolimbic circuitry in affective behavior regulation, its disruption in mental disorders (Herringa et al., 2013; Bangasser and Valentino, 2014; Killgore et al., 2014), and alterations directly related to ELA (Kaiser et al., 2018). Specifically, Tottenham and colleagues illustrated that normative developmental changes in task-based functional connectivity (FC) between amygdala and medial prefrontal cortex (mPFC) are accelerated after ELA with associated changes in anxiety (Gee et al., 2013a) and are particularly evident in females (Dickie and Armony, 2008). Indeed, children institutionalized during the first two years of life in orphanages display precocial development of amygdala-mPFC FC, though the anatomical substrates for this accelerated connectivity remain unknown.

In rats, the basolateral amygdala (BLA) sends inputs to the mPFC and modulates anxiety-related behaviors (Felix-Ortiz et al., 2016), recall of emotionally salient information (McGaugh, 2004), decision-making (St Onge et al., 2012), and goal-directed behavior (Schoenbaum et al., 2000). Notably, two subpopulations of BLA neurons project to different regions of the mPFC (Senn et al., 2014): projections to the dorsal (prelimbic; PL) region of the mPFC are active during threat-associated fear learning and expression, whereas projections from the BLA to the ventral (infralimbic; IL) region of the mPFC are active upon extinction of fear, or learning about safety signals. In typically developing male rats, BLA innervation of mPFC increases through adolescence (Cunningham et al., 2002), likely contributing to healthy maturation of threat and safety appraisal. Notably, BLA-mPFC axonal innervation has not yet been evaluated in females, nor has any study examined the effects of ELA on BLA-derived innervation of PL or IL.

Evidence in both the human and rodent literature supports the role of amygdala-PFC circuitry in the regulation of anxiety-like behaviors (Likhtik et al., 2014; Arruda-Carvalho and Clem, 2015; Fragale et al., 2016). However, the neurobiological mechanisms are ill-defined and therefore require investment in translational animal research to pinpoint neural contributions to affective pathology (Shackman and Wager, 2019). Emerging evidence in rodents suggests that perturbations of this circuit – particularly following various models of ELA – may be implicated in maladaptive maintenance of anxiety-like behaviors (Chocyk et al., 2013; Maccari et al., 2014; Krugers et al., 2017). ELA via chronic stress has been shown to increase BLA-derived glutamatergic release within the PFC, a finding that can be recapitulated via BLA-PFC stimulation in typical mice and is associated with increased anxiety-like behavior (Lowery-Gionta et al., 2018). This is in line with reports of altered excitatory:inhibitory balance within the BLA-PFC circuit that is associated with changes in affective behaviors (Arruda-Carvalho and Clem, 2014). For example, excitatory latencies of PFC neurons to amygdalar stimulation in adult rats were significantly longer in animals with a history of ELA (Ishikawa et al., 2015). It is likely that ELA-induced changes in plasticity lead to increased BLA-derived excitatory signaling into the PFC, with insufficient reciprocal PFC-driven anxiolytic signals returning to the BLA. However, there is presently insufficient evidence to determine the neuroanatomical time-course of this developing circuit, and a lack of evidence evaluating its modulation by additional factors (i.e. sex, development).

Clinical evidence points to striking sex differences in the clinical time-course and symptomology of ELA effects (Wainwright and Surtees, 2002; Martin et al., 2014). Moreover, several studies in animals over the past two decades have revealed sex-specific effects of ELA on anxiety-like behaviors (Tractenberg et al., 2016; Bonapersona et al., 2019b) and adolescent or adult corticolimbic measures (Salzberg et al., 2007; Holland et al., 2014; Farrell et al., 2016; Blaze and Roth, 2017; Bonapersona et al., 2019a), however little is known about the interaction of sex and ELA on corticolimbic development. Notably, typically developing females display earlier maturation of the PFC (Lenroot et al., 2007; Lenroot and Giedd, 2010). Identifying how ELA affects these sex-dependent trajectories is crucial to understanding sex differences in vulnerability and to developing individually targeted intervention strategies. Therefore, we used anterograde tracing to examine ELA effects on BLA-PFC innervation over development in male and female rats. We hypothesized that if heightened anxiety-like behaviors following ELA are associated with increased BLA-derived PFC innervation, then rats exposed to ELA via repeated isolation from dam and littermates will display anxiety-like behavior and increased BLA-PFC innervation that will be more robust in females.

While task-based FC illustrates coordinated responsivity to anxiety-provoking stimuli (Gee et al., 2013a), resting-state FC (rsFC) is excellent for probing the functional integrity of the amygdala-PFC circuit independent of task demands (Thomason et al., 2011a; Thomason et al., 2011b; Alarcón et al., 2015; Gabard-Durnam et al., 2016). ELA effects on corticolimbic rsFC in humans are inconsistent, likely because of reliance on autobiographical questionnaires, different ages of measurement, and different ELA criteria. In rats, maternal separation results in early emergence of both adult-like fear learning based in fronto-amygdala circuitry (Callaghan and Richardson, 2011) and early amygdala structural maturation (Ono et al., 2008). rsFC has recently been utilized in rats to characterize ELA (via limited bedding) induced changes in BLA-PFC connectivity in preweanling males, revealing an association between decreased rsFC and adult fear behaviors (Guadagno et al., 2018). Early or blunted maturation of corticolimbic connectivity likely has deleterious consequences because a sufficient degree of PFC immaturity during juvenility is critical for learning anxiolytic cues (safety signals) in adulthood (Yang et al., 2012). Therefore, we provide a back-translation to examine whether ELA-exposed rats display accelerated maturation of amygdala-PFC connectivity to parallel humans with a history of adversity, with increased BLA-PFC innervation as a potential anatomical substrate driving sex-specific developmental effects. This multi-level approach aims to elucidate the neurobiological underpinnings of ELA-attributable vulnerability through the use of mechanistic neural tracing paired with a translational imaging investigation: an approach which enhances our ability to develop a cross-species understanding of ELA-associated pathology (Fox and Shackman, 2019).

This work identifies sex-specific neuroanatomical development and corresponding functional maturation of the BLA-PFC circuit following ELA. The data reveal newly uncovered aberrations to PFC innervation that can be interpreted in the context of atypical behavior and FC that has been observed in humans (Gee et al., 2013a; Philip et al., 2013; Thomason et al., 2015; Teicher et al., 2016) and in animals (Yan et al., 2017; Johnson et al., 2018). These findings are the first description of sex-specific developmental trajectories following ELA, using a juxtaposition of rsFC as assessed in humans with an anatomically discrete measurement of monosynaptic innervation. We observed sex- and age-dependent effects on BLA innervation in PL and IL regions of the PFC following ELA in a rat model of caregiver deprivation. It is important to note here, especially given the current need for more transparency in reporting of ELA paradigms (Kentner et al., 2019; Brenhouse and Bath, 2019) that pregnant dams were shipped to our facility, therefore all animals in our study underwent shipping stress during gestation. It is thus possible that effects of maternal separation reported here are a consequence of both prenatal and postnatal stress, which is common amongst human instances of early life stress (Pedersen et al., 2018). Our findings suggest that females may be particularly vulnerable to neuroanatomical consequences of early adversity, with innervation effects seen earlier in females compared to a later effect observed in males. This is in line with human studies describing sex-dependent effects of early adversity where female participants appear to exhibit more severe adolescent and later-life consequences, especially with regard to affective disorders (Humphreys et al., 2015). Rodent studies investigating potential sex differences have also largely revealed female-specific increases in adolescent anxiety-like behavior following ELA (e.g. Salberg et al., 2019; Manzano-Nieves et al., 2018; Jin et al., 2018; Viola et al., 2019; but see Bonapersona et al. (2019b) for further examination), though some studies have failed to show any anxiety-like effects in adolescence (e.g., Doherty et al., 2017). Little, however, has been known to date regarding biological substrates for sex-specific consequences on anxiety-like behaviors.

Our data indicate that BLA-IL innervation increases through adolescence in a bilaminar manner across development, with more dramatic increases following ELA in both males and females. Importantly, these main effects of age support previous work in male rats (Cunningham et al., 2002) and now characterize a similar trajectory in female rats. Interestingly, increased innervation to the IL in PD28 females and PD38 males occurred in IL2, whereas previous work has shown that in wild-type adult mice, the BLA preferentially targets amygdala-projecting neurons in IL5 over IL2 (Cheriyan et al., 2016). Since IL2 projection neurons do also project back to the BLA (Gabbott et al., 2005; Little and Carter, 2013), it is possible that atypical hyper-innervation after maternal separation aberrantly targets layer 2, which may drive the altered maturation of BLA-IL functional connectivity we observed in the present work.

While IL innervation showed a developmental increase through adolescence, PL innervation appeared to reach adult-like levels in both sexes earlier than was previously captured (Van Eden and Uylings, 1985; Bouwmeester et al., 2002). Following ELA, however, our data indicate that aberrant effects on innervation were apparent at PD28 in females, but not until PD38 in males; this finding was observed across both the PL and IL. However, while ELA conferred a similar age-dependent influx of BLA axonal innervation in both regions, the long-term neuroanatomical alterations were different depending on the region examined. In IL there was evidence of precocial maturation, such that ELA induced BLA-IL innervation that was comparable to more mature (PD48) patterns in female juveniles (PD28) and male early adolescents (PD38). Interestingly, in PL we saw a transient effect of ELA that was age- and sex-dependent. Indeed, within the PL we observed that both male and female rats showed an unexpected transient spike in innervation that appeared to resolve at the following developmental timepoint. It is possible that reversal of the innervation seen at earlier time points may be due to pruning mechanisms (Koss et al., 2014) that typically occur in adolescence, and these mechanisms may serve to mediate excess innervation (Rakic et al., 1994; Spear, 2000; Riccomagno and Kolodkin, 2015). Prior work has shown a peak in BLA-PL connectivity, specifically at PD30 (Pattwell et al., 2016), that may contribute to the present findings of transient ELA-exacerbated hyper-innervation. However, this does not explain why innervation to the PL spiked at PD28, was reduced to CON levels at PD38, and then spiked again by PD48 in female ELA. It is possible that the temporary (one week) isolation following surgery may have acted as a secondary stressor acting in conjunction with pubertal changes to produce a resurgence of this ELA-specific phenotype (Andersen and Teicher, 2008; Tzanoulinou and Sandi, 2016). Relatedly, surgery itself during peripubertal development compared to other time periods may have differentially interacted with ELA.

Importantly, the ages at which ELA-exposed females and males first displayed increased BLA-IL innervation (PD28 and PD38, respectively) were the ages at which higher innervation correlated with higher anxiety-like behavior (less time spent in open arms of the EPM). Since monosynaptic input from the BLA to the medial PFC drives aversion to anxiogenic stimuli as measured in the EPM (Felix-Ortiz et al., 2016), these data suggest that hypertrophic effects of ELA at the BLA-IL circuit lead to heightened anxiety-like behavior in ELA-exposed animals. However, we were surprised that group-wise comparisons only showed higher anxiety-like behaviors in ELA females at PD38, but not at PD28 when innervation was increased (see Figure 3). Group comparisons also failed to reveal higher anxiety-like behaviors in ELA-exposed males at any age. Our group and others have previously observed increased anxiety-like behaviors in male and female rats following ELA (e.g., Holland et al., 2014; Ganguly et al., 2015; Jin et al., 2018), therefore further work will reveal whether more sensitive assays can more reliably demonstrate anxiety-like behavior in ELA-exposed rats. Here we demonstrate that, regardless of mean differences, ELA experience can forge a relationship between heightened innervation and anxiety-like behavior at distinct developmental time-points that could suggest mechanistic ties between early hypertrophy of inputs and behavior.

Transient effects of ELA on innervation and behavior are notable because adolescent perturbations have been shown to have lasting consequences on later life function. Multiple lines of evidence from both clinical and animal studies suggest that physiological or experiential anomalies during critical periods of development can program the central nervous system for susceptibility or resilience to future environments (Andersen, 2003; Nederhof and Schmidt, 2012). One example is seen in an animal model utilizing prenatal treatment with the mitotoxin MAM, which produces adolescent-specific corticolimbic and mesolimbic dysfunctions that drive a hyperresponsivity to stress with anxiety-like and psychosis-like behavior. If conversion to the dysfunctional phenotype in adolescence is prevented by relieving stress in adolescence, MAM-treated animals will still be more susceptible to affective dysfunction in adulthood (Gomes et al., 2019). Moreover, ELA reportedly leads to adolescent alterations in PFC NMDA receptor subunit composition that regulate anxiety-like behaviors in males (Ganguly et al., 2015); future work will reveal whether increased glutamatergic input from the BLA drives these receptor changes in the PFC. Since the PFC can serve reciprocally as a modulator of BLA activity (Rosenkranz and Grace, 2002), it is therefore possible that transient innervation changes lead to long-term receptor alterations and subsequent changes to the efficiency of BLA-PFC functional connectivity. Indeed, we observed an effect of rearing in female anxiety-like behavior and functional connectivity after the age when innervation to the PL and IL2 was increased (PD28). Together, the early increases in innervation after ELA reported here may perturb normal critical period maturation, leading to late-onset effects on functional connectivity and affective dysregulation.

While the current work did not directly address the causal relationship between innervation and rsFC, results from the rsFC analyses in females supported the idea that early maturation of BLA-IL innervation disrupts later functional relationships between these regions (Tottenham and Galván, 2016). Specifically, we report here that females exposed to ELA displayed dampened maturation of BLA-IL rsFC compared to female CON; while no effects of rearing were apparent at PD28, ELA female rats failed to display the increase in BLA-IL rsFC by PD48 that was observed in female CON. This is in line with previous work showing reduced BLA-mPFC connectivity following a limited bedding model (Guadagno et al., 2018). Interestingly, increased [more mature] rsFC BLA-IL connectivity in female ELA at PD28 correlated with decreased anxiety-like behavior at that age, as well as 20 days later. This suggests that more mature connectivity in female juveniles may confer enduring behavioral resilience, which is consistent with previous reports that dampened connectivity is associated with increased anxiety in adolescence (Kim et al., 2011; Nooner et al., 2013). While ELA exposure in males appeared to result in lower juvenile (PD28) rsFC between the BLA and the PL, no effects on the magnitude of change between PD28-PD48 were noted, therefore altered maturation per se was not observed in males. Interestingly, ELA affected male BLA-PL rsFC at an age that preceded any ELA-attributable increase in innervation, suggesting that the reciprocal connectivity between the two regions was altered without the influence of aberrant amygdalofugal innervation.

ELA experience resulted in dampened maturation of BLA-IL rsFC in females, in contrast to the precocial maturation we observed in axonal innervation of the IL from the BLA, as well as the accelerated maturation of task-based FC reported following childhood maltreatment in humans (Gee et al., 2013a). While BLA-mPFC rsFC in humans has been observed to increase towards more positive connectivity through adolescent development (Gabard-Durnam et al., 2014), task-based FC during fearful face presentations declines from positive connectivity to a negative connectivity (Gee et al., 2013b). This task-based FC was further found to reach mature (more negative) levels in previously institutionalized children (Gee et al., 2013a). In contrast, girls who express higher basal cortisol levels at 4.5 years display lower rsFC between the ventromedial PFC and the amygdala at 18 years (Burghy et al., 2012), corroborating our current findings in PD48 females (see Figure 5). rsFC reflects an intrinsic alternate resonance between different brain areas connected at large scale, in contrast to the more isolated activation of the corresponding brain areas during a task (Rasero et al., 2018). Therefore, it appears that early hyperinnervation to the PFC may alter the stability of the functional BLA-PFC network as it develops, leading to increased anxiety when innervation arises and disrupted maturation of rsFC; though how these effects in rats relate to task-based FC is currently unknown. It is also possible that early maturation of BLA-PFC projections may overwhelm the slow-maturing reciprocal projections to the BLA that dampen anxiety-related circuit activity in mature brains (Arruda-Carvalho et al., 2017; Selleck et al., 2018).

The present findings support previous work indicating the distinct functional relationship between the BLA and PL and IL regions of mPFC (Calhoon and Tye, 2015), with PL connectivity related to anxiogenic effects (Felix-Ortiz et al., 2016) and IL connectivity promoting anxiolytic effects (Maroun et al., 2012). Furthermore, these findings are in line with the idea that altered neuroanatomy and functionality of PL and IL, along with BLA, likely have reciprocal effects on one another, further contributing to the exacerbation of ELA-induced anxiety-like phenotypes in adolescence and early adulthood (Likhtik and Paz, 2015; Zimmermann et al., 2019).

Taken together, maternal separation in rats was found to disrupt normative development of both anatomical (axonal innervation) and functional (rsFC) connectivity within a circuit regulating emotional processing, with sex-specific effects and evidence of resilience in individuals with precocial maturation of rsFC. Future work will investigate the physiological consequences of increased innervation that underlies rsFC and behavioral effects, as well as the potential impact of puberty on increased innervation, since females also reportedly display accelerated puberty initiation following ELA (Grassi-Oliveira et al., 2016). The present findings have implications for intervention based on experience, age, and sex – three functionally interactive factors that uniquely define risk in every individual.

All data generated for Figures 1, 2, 3, 4, and Figure 6—figure supplement 1 are provided as source data files. Data generated for Figures 5 and 6 will be made available once an ongoing additional analysis is completed for another research report. Data deposited to Dryad, https://doi.org/10.5061/dryad.jdfn2z371.

1. 1. Brenhouse HC

   (2020) Dryad Digital Repository

   Data from: Altered corticolimbic connectivity reveals sex-specific adolescent outcomes in a rat model of early life adversity.

   https://doi.org/10.5061/dryad.jdfn2z371

1. 1. Alarcón G
   2. Cservenka A
   3. Rudolph MD
   4. Fair DA
   5. Nagel BJ

   (2015) Developmental sex differences in resting state functional connectivity of amygdala sub-regions

   NeuroImage 115:235–244.

   https://doi.org/10.1016/j.neuroimage.2015.04.013

   • PubMed
   • Google Scholar
2. 1. Andersen SL

   (2003) Trajectories of brain development: point of vulnerability or window of opportunity?

   Neuroscience & Biobehavioral Reviews 27:3–18.

   https://doi.org/10.1016/S0149-7634(03)00005-8

   • PubMed
   • Google Scholar
3. 1. Andersen SL
   2. Teicher MH

   (2008) Stress, sensitive periods and maturational events in adolescent depression

   Trends in Neurosciences 31:183–191.

   https://doi.org/10.1016/j.tins.2008.01.004

   • PubMed
   • Google Scholar
4. 1. Arruda-Carvalho M
   2. Wu WC
   3. Cummings KA
   4. Clem RL

   (2017) Optogenetic examination of Prefrontal-Amygdala synaptic development

   The Journal of Neuroscience 37:2976–2985.

   https://doi.org/10.1523/JNEUROSCI.3097-16.2017

   • PubMed
   • Google Scholar
5. 1. Arruda-Carvalho M
   2. Clem RL

   (2014) Pathway-selective adjustment of prefrontal-amygdala transmission during fear encoding

   Journal of Neuroscience 34:15601–15609.

   https://doi.org/10.1523/JNEUROSCI.2664-14.2014

   • PubMed
   • Google Scholar
6. 1. Arruda-Carvalho M
   2. Clem RL

   (2015) Prefrontal-amygdala fear networks come into focus

   Frontiers in Systems Neuroscience 9:145.

   https://doi.org/10.3389/fnsys.2015.00145

   • PubMed
   • Google Scholar
7. 1. Bangasser DA
   2. Valentino RJ

   (2014) Sex differences in stress-related psychiatric disorders: neurobiological perspectives

   Frontiers in Neuroendocrinology 35:303–319.

   https://doi.org/10.1016/j.yfrne.2014.03.008

   • PubMed
   • Google Scholar
8. 1. Blaze J
   2. Roth TL

   (2017) Caregiver maltreatment causes altered neuronal DNA methylation in female rodents

   Development and Psychopathology 29:477–489.

   https://doi.org/10.1017/S0954579417000128

   • PubMed
   • Google Scholar
9. 1. Bonapersona V
   2. Damsteegt R
   3. Adams ML
   4. van Weert L
   5. Meijer OC
   6. Joëls M
   7. Sarabdjitsingh RA

   (2019a) Sex-Dependent modulation of acute stress reactivity after early life stress in mice: relevance of mineralocorticoid receptor expression

   Frontiers in Behavioral Neuroscience 13:181.

   https://doi.org/10.3389/fnbeh.2019.00181

   • PubMed
   • Google Scholar
10. 1. Bonapersona V
    2. Kentrop J
    3. Van Lissa CJ
    4. van der Veen R
    5. Joëls M
    6. Sarabdjitsingh RA

    (2019b) The behavioral phenotype of early life adversity: a 3-level meta-analysis of rodent studies

    Neuroscience & Biobehavioral Reviews 102:299–307.

    https://doi.org/10.1016/j.neubiorev.2019.04.021

    • PubMed
    • Google Scholar
11. 1. Bouwmeester H
    2. Wolterink G
    3. van Ree JM

    (2002) Neonatal development of projections from the basolateral amygdala to prefrontal, Striatal, and thalamic structures in the rat

    The Journal of Comparative Neurology 442:239–249.

    https://doi.org/10.1002/cne.10084

    • PubMed
    • Google Scholar
12. 1. Brenhouse HC
    2. Bath KG

    (2019) Bundling the haystack to find the needle: challenges and opportunities in modeling risk and resilience following early life stress

    Frontiers in Neuroendocrinology 54:100768.

    https://doi.org/10.1016/j.yfrne.2019.100768

    • PubMed
    • Google Scholar
13. 1. Burghy CA
    2. Stodola DE
    3. Ruttle PL
    4. Molloy EK
    5. Armstrong JM
    6. Oler JA
    7. Fox ME
    8. Hayes AS
    9. Kalin NH
    10. Essex MJ
    11. Davidson RJ
    12. Birn RM

    (2012) Developmental pathways to amygdala-prefrontal function and internalizing symptoms in adolescence

    Nature Neuroscience 15:1736–1741.

    https://doi.org/10.1038/nn.3257

    • PubMed
    • Google Scholar
14. 1. Calhoon GG
    2. Tye KM

    (2015) Resolving the neural circuits of anxiety

    Nature Neuroscience 18:1394–1404.

    https://doi.org/10.1038/nn.4101

    • PubMed
    • Google Scholar
15. 1. Callaghan BL
    2. Richardson R

    (2011) Maternal separation results in early emergence of adult-like fear and extinction learning in infant rats

    Behavioral Neuroscience 125:20–28.

    https://doi.org/10.1037/a0022008

    • Google Scholar
16. 1. Callaghan BL
    2. Tottenham N

    (2016) The stress acceleration hypothesis: effects of early-life adversity on emotion circuits and behavior

    Current Opinion in Behavioral Sciences 7:76–81.

    https://doi.org/10.1016/j.cobeha.2015.11.018

    • PubMed
    • Google Scholar
17. 1. Cheriyan J
    2. Kaushik MK
    3. Ferreira AN
    4. Sheets PL

    (2016) Specific targeting of the basolateral amygdala to projectionally defined pyramidal neurons in Prelimbic and infralimbic cortex

    Eneuro 3:ENEURO.0002-16.2016.

    https://doi.org/10.1523/ENEURO.0002-16.2016

    • PubMed
    • Google Scholar
18. 1. Chocyk A
    2. Majcher-Maślanka I
    3. Dudys D
    4. Przyborowska A
    5. Wędzony K

    (2013) Impact of early-life stress on the medial prefrontal cortex functions - a search for the pathomechanisms of anxiety and mood disorders

    Pharmacological Reports 65:1462–1470.

    https://doi.org/10.1016/S1734-1140(13)71506-8

    • PubMed
    • Google Scholar
19. 1. Choi J
    2. Jeong B
    3. Rohan ML
    4. Polcari AM
    5. Teicher MH

    (2009) Preliminary evidence for white matter tract abnormalities in young adults exposed to parental verbal abuse

    Biological Psychiatry 65:227–234.

    https://doi.org/10.1016/j.biopsych.2008.06.022

    • Google Scholar
20. 1. Coley EJL
    2. Demaestri C
    3. Ganguly P
    4. Honeycutt JA
    5. Peterzell S
    6. Rose N
    7. Ahmed N
    8. Holschbach M
    9. Trivedi M
    10. Brenhouse HC

    (2019) Cross-Generational transmission of early life stress effects on HPA regulators and bdnf are mediated by sex, lineage, and upbringing

    Frontiers in Behavioral Neuroscience 13:101.

    https://doi.org/10.3389/fnbeh.2019.00101

    • PubMed
    • Google Scholar
21. 1. Cunningham MG
    2. Bhattacharyya S
    3. Benes FM

    (2002) Amygdalo-cortical sprouting continues into early adulthood: implications for the development of normal and abnormal function during adolescence

    The Journal of Comparative Neurology 453:116–130.

    https://doi.org/10.1002/cne.10376

    • PubMed
    • Google Scholar
22. 1. Davis EP
    2. Pfaff D

    (2014) Sexually dimorphic responses to early adversity: implications for affective problems and autism spectrum disorder

    Psychoneuroendocrinology 49:11–25.

    https://doi.org/10.1016/j.psyneuen.2014.06.014

    • Google Scholar
23. 1. Dickie EW
    2. Armony JL

    (2008) Amygdala responses to unattended fearful faces: interaction between sex and trait anxiety

    Psychiatry Research: Neuroimaging 162:51–57.

    https://doi.org/10.1016/j.pscychresns.2007.08.002

    • PubMed
    • Google Scholar
24. 1. Doherty TS
    2. Blaze J
    3. Keller SM
    4. Roth TL

    (2017) Phenotypic outcomes in adolescence and adulthood in the scarcity-adversity model of low nesting resources outside the home cage

    Developmental Psychobiology 59:703–714.

    https://doi.org/10.1002/dev.21547

    • PubMed
    • Google Scholar
25. 1. Farrell MR
    2. Holland FH
    3. Shansky RM
    4. Brenhouse HC

    (2016) Sex-specific effects of early life stress on social interaction and prefrontal cortex dendritic morphology in young rats

    Behavioural Brain Research 310:119–125.

    https://doi.org/10.1016/j.bbr.2016.05.009

    • PubMed
    • Google Scholar
26. 1. Felix-Ortiz AC
    2. Burgos-Robles A
    3. Bhagat ND
    4. Leppla CA
    5. Tye KM

    (2016) Bidirectional modulation of anxiety-related and social behaviors by amygdala projections to the medial prefrontal cortex

    Neuroscience 321:197–209.

    https://doi.org/10.1016/j.neuroscience.2015.07.041

    • PubMed
    • Google Scholar
27. 1. Fox AS
    2. Shackman AJ

    (2019) The central extended amygdala in fear and anxiety: closing the gap between mechanistic and neuroimaging research

    Neuroscience Letters 693:58–67.

    https://doi.org/10.1016/j.neulet.2017.11.056

    • PubMed
    • Google Scholar
28. 1. Fragale JEC
    2. Khariv V
    3. Gregor DM
    4. Smith IM
    5. Jiao X
    6. Elkabes S
    7. Servatius RJ
    8. Pang KCH
    9. Beck KD

    (2016) Dysfunction in amygdala–prefrontal plasticity and extinction-resistant avoidance: A model for anxiety disorder vulnerability

    Experimental Neurology 275:59–68.

    https://doi.org/10.1016/j.expneurol.2015.11.002

    • Google Scholar
29. 1. Gabard-Durnam LJ
    2. Flannery J
    3. Goff B
    4. Gee DG
    5. Humphreys KL
    6. Telzer E
    7. Hare T
    8. Tottenham N

    (2014) The development of human amygdala functional connectivity at rest from 4 to 23 years: a cross-sectional study

    NeuroImage 95:193–207.

    https://doi.org/10.1016/j.neuroimage.2014.03.038

    • PubMed
    • Google Scholar
30. 1. Gabard-Durnam LJ
    2. Gee DG
    3. Goff B
    4. Flannery J
    5. Telzer E
    6. Humphreys KL
    7. Lumian DS
    8. Fareri DS
    9. Caldera C
    10. Tottenham N

    (2016) Stimulus-Elicited connectivity influences Resting-State connectivity years later in human development: a prospective study

    Journal of Neuroscience 36:4771–4784.

    https://doi.org/10.1523/JNEUROSCI.0598-16.2016

    • PubMed
    • Google Scholar
31. 1. Gabbott PL
    2. Warner TA
    3. Jays PR
    4. Salway P
    5. Busby SJ

    (2005) Prefrontal cortex in the rat: projections to subcortical autonomic, motor, and limbic centers

    The Journal of Comparative Neurology 492:145–177.

    https://doi.org/10.1002/cne.20738

    • PubMed
    • Google Scholar
32. 1. Ganguly P
    2. Holland FH
    3. Brenhouse HC

    (2015) Functional uncoupling NMDAR NR2A subunit from PSD-95 in the prefrontal cortex: effects on behavioral dysfunction and parvalbumin loss after Early-Life stress

    Neuropsychopharmacology 40:2666–2675.

    https://doi.org/10.1038/npp.2015.134

    • PubMed
    • Google Scholar
33. 1. Ganguly P
    2. Honeycutt JA
    3. Rowe JR
    4. Demaestri C
    5. Brenhouse HC

    (2019) Effects of early life stress on cocaine conditioning and AMPA receptor composition are sex-specific and driven by TNF

    Brain, Behavior, and Immunity 78:41–51.

    https://doi.org/10.1016/j.bbi.2019.01.006

    • PubMed
    • Google Scholar
34. 1. Gee DG
    2. Gabard-Durnam LJ
    3. Flannery J
    4. Goff B
    5. Humphreys KL
    6. Telzer EH
    7. Hare TA
    8. Bookheimer SY
    9. Tottenham N

    (2013a) Early developmental emergence of human amygdala-prefrontal connectivity after maternal deprivation

    PNAS 110:15638–15643.

    https://doi.org/10.1073/pnas.1307893110

    • PubMed
    • Google Scholar
35. 1. Gee DG
    2. Humphreys KL
    3. Flannery J
    4. Goff B
    5. Telzer EH
    6. Shapiro M
    7. Hare TA
    8. Bookheimer SY
    9. Tottenham N

    (2013b) A developmental shift from positive to negative connectivity in human amygdala-prefrontal circuitry

    Journal of Neuroscience 33:4584–4593.

    https://doi.org/10.1523/JNEUROSCI.3446-12.2013

    • PubMed
    • Google Scholar
36. 1. Gomes FV
    2. Zhu X
    3. Grace AA

    (2019) Stress during critical periods of development and risk for schizophrenia

    Schizophrenia Research 213:107–113.

    https://doi.org/10.1016/j.schres.2019.01.030

    • PubMed
    • Google Scholar
37. 1. Grassi-Oliveira R
    2. Honeycutt JA
    3. Holland FH
    4. Ganguly P
    5. Brenhouse HC

    (2016) Cognitive impairment effects of early life stress in adolescents can be predicted with early biomarkers: impacts of sex, experience, and cytokines

    Psychoneuroendocrinology 71:19–30.

    https://doi.org/10.1016/j.psyneuen.2016.04.016

    • PubMed
    • Google Scholar
38. 1. Guadagno A
    2. Kang MS
    3. Devenyi GA
    4. Mathieu AP
    5. Rosa-Neto P
    6. Chakravarty M
    7. Walker CD

    (2018) Reduced resting-state functional connectivity of the basolateral amygdala to the medial prefrontal cortex in preweaning rats exposed to chronic early-life stress

    Brain Structure and Function 223:3711–3729.

    https://doi.org/10.1007/s00429-018-1720-3

    • PubMed
    • Google Scholar
39. 1. Gundersen HJ
    2. Jensen EB
    3. Kiêu K
    4. Nielsen J

    (1999) The efficiency of systematic sampling in Stereology--reconsidered

    Journal of Microscopy 193:199–211.

    https://doi.org/10.1046/j.1365-2818.1999.00457.x

    • PubMed
    • Google Scholar
40. 1. Gundersen HJ
    2. Jensen EB

    (1987) The efficiency of systematic sampling in Stereology and its prediction

    Journal of Microscopy 147:229–263.

    https://doi.org/10.1111/j.1365-2818.1987.tb02837.x

    • PubMed
    • Google Scholar
41. 1. Hammen C
    2. Henry R
    3. Daley SE

    (2000) Depression and sensitization to stressors among young women as a function of childhood adversity

    Journal of Consulting and Clinical Psychology 68:782–787.

    https://doi.org/10.1037/0022-006X.68.5.782

    • PubMed
    • Google Scholar
42. 1. Hane AA
    2. Fox NA

    (2016) Early caregiving and human biobehavioral development: a comparative physiology approach

    Current Opinion in Behavioral Sciences 7:82–90.

    https://doi.org/10.1016/j.cobeha.2015.12.002

    • PubMed
    • Google Scholar
43. 1. Heim C
    2. Newport DJ
    3. Mletzko T
    4. Miller AH
    5. Nemeroff CB

    (2008) The link between childhood trauma and depression: insights from HPA Axis studies in humans

    Psychoneuroendocrinology 33:693–710.

    https://doi.org/10.1016/j.psyneuen.2008.03.008

    • PubMed
    • Google Scholar
44. 1. Herringa RJ
    2. Birn RM
    3. Ruttle PL
    4. Burghy CA
    5. Stodola DE
    6. Davidson RJ
    7. Essex MJ

    (2013) Childhood maltreatment is associated with altered fear circuitry and increased internalizing symptoms by late adolescence

    PNAS 110:19119–19124.

    https://doi.org/10.1073/pnas.1310766110

    • PubMed
    • Google Scholar
45. 1. Holland FH
    2. Ganguly P
    3. Potter DN
    4. Chartoff EH
    5. Brenhouse HC

    (2014) Early life stress disrupts social behavior and prefrontal cortex parvalbumin interneurons at an earlier time-point in females than in males

    Neuroscience Letters 566:131–136.

    https://doi.org/10.1016/j.neulet.2014.02.023

    • PubMed
    • Google Scholar
46. 1. Humphreys KL
    2. Gleason MM
    3. Drury SS
    4. Miron D
    5. Nelson CA
    6. Fox NA
    7. Zeanah CH

    (2015) Effects of institutional rearing and foster care on psychopathology at age 12 years in Romania: follow-up of an open, randomised controlled trial

    The Lancet Psychiatry 2:625–634.

    https://doi.org/10.1016/S2215-0366(15)00095-4

    • PubMed
    • Google Scholar
47. 1. Ishikawa J
    2. Nishimura R
    3. Ishikawa A

    (2015) Early-life stress induces anxiety-like behaviors and activity imbalances in the medial prefrontal cortex and amygdala in adult rats

    European Journal of Neuroscience 41:442–453.

    https://doi.org/10.1111/ejn.12825

    • PubMed
    • Google Scholar
48. 1. Jin S
    2. Zhao Y
    3. Jiang Y
    4. Wang Y
    5. Li C
    6. Zhang D
    7. Lian B
    8. Du Z
    9. Sun H
    10. Sun L

    (2018) Anxiety-like behaviour assessments of adolescent rats after repeated maternal separation during early life

    NeuroReport 29:643–649.

    https://doi.org/10.1097/WNR.0000000000001010

    • PubMed
    • Google Scholar
49. 1. Johnson FK
    2. Delpech JC
    3. Thompson GJ
    4. Wei L
    5. Hao J
    6. Herman P
    7. Hyder F
    8. Kaffman A

    (2018) Amygdala hyper-connectivity in a mouse model of unpredictable early life stress

    Translational Psychiatry 8:49.

    https://doi.org/10.1038/s41398-018-0092-z

    • PubMed
    • Google Scholar
50. 1. Kaiser RH
    2. Clegg R
    3. Goer F
    4. Pechtel P
    5. Beltzer M
    6. Vitaliano G
    7. Olson DP
    8. Teicher MH
    9. Pizzagalli DA

    (2018) Childhood stress, grown-up brain networks: corticolimbic correlates of threat-related early life stress and adult stress response

    Psychological Medicine 48:1157–1166.

    https://doi.org/10.1017/S0033291717002628

    • PubMed
    • Google Scholar
51. 1. Kentner AC
    2. Bilbo SD
    3. Brown AS
    4. Hsiao EY
    5. McAllister AK
    6. Meyer U
    7. Pearce BD
    8. Pletnikov MV
    9. Yolken RH
    10. Bauman MD

    (2019) Maternal immune activation: reporting guidelines to improve the rigor, reproducibility, and transparency of the model

    Neuropsychopharmacology 44:245–258.

    https://doi.org/10.1038/s41386-018-0185-7

    • PubMed
    • Google Scholar
52. 1. Killgore WD
    2. Britton JC
    3. Schwab ZJ
    4. Price LM
    5. Weiner MR
    6. Gold AL
    7. Rosso IM
    8. Simon NM
    9. Pollack MH
    10. Rauch SL

    (2014) Cortico-limbic responses to masked affective faces across ptsd, panic disorder, and specific phobia

    Depression and Anxiety 31:150–159.

    https://doi.org/10.1002/da.22156

    • PubMed
    • Google Scholar
53. 1. Kim MJ
    2. Gee DG
    3. Loucks RA
    4. Davis FC
    5. Whalen PJ

    (2011) Anxiety dissociates dorsal and ventral medial prefrontal cortex functional connectivity with the amygdala at rest

    Cerebral Cortex 21:1667–1673.

    https://doi.org/10.1093/cercor/bhq237

    • Google Scholar
54. 1. Koss WA
    2. Belden CE
    3. Hristov AD
    4. Juraska JM

    (2014) Dendritic remodeling in the adolescent medial prefrontal cortex and the basolateral amygdala of male and female rats

    Synapse 68:61–72.

    https://doi.org/10.1002/syn.21716

    • PubMed
    • Google Scholar
55. 1. Krugers HJ
    2. Arp JM
    3. Xiong H
    4. Kanatsou S
    5. Lesuis SL
    6. Korosi A
    7. Joels M
    8. Lucassen PJ

    (2017) Early life adversity: lasting consequences for emotional learning

    Neurobiology of Stress 6:14–21.

    https://doi.org/10.1016/j.ynstr.2016.11.005

    • PubMed
    • Google Scholar
56. 1. Lenroot RK
    2. Gogtay N
    3. Greenstein DK
    4. Wells EM
    5. Wallace GL
    6. Clasen LS
    7. Blumenthal JD
    8. Lerch J
    9. Zijdenbos AP
    10. Evans AC
    11. Thompson PM
    12. Giedd JN

    (2007) Sexual dimorphism of brain developmental trajectories during childhood and adolescence

    NeuroImage 36:1065–1073.

    https://doi.org/10.1016/j.neuroimage.2007.03.053

    • PubMed
    • Google Scholar
57. 1. Lenroot RK
    2. Giedd JN

    (2010) Sex differences in the adolescent brain

    Brain and Cognition 72:46–55.

    https://doi.org/10.1016/j.bandc.2009.10.008

    • PubMed
    • Google Scholar
58. 1. Likhtik E
    2. Stujenske JM
    3. Topiwala MA
    4. Harris AZ
    5. Gordon JA

    (2014) Prefrontal entrainment of amygdala activity signals safety in learned fear and innate anxiety

    Nature Neuroscience 17:106–113.

    https://doi.org/10.1038/nn.3582

    • PubMed
    • Google Scholar
59. 1. Likhtik E
    2. Paz R

    (2015) Amygdala-prefrontal interactions in (mal)adaptive learning

    Trends in Neurosciences 38:158–166.

    https://doi.org/10.1016/j.tins.2014.12.007

    • PubMed
    • Google Scholar
60. 1. Little JP
    2. Carter AG

    (2013) Synaptic mechanisms underlying strong reciprocal connectivity between the medial prefrontal cortex and basolateral amygdala

    The Journal of Neuroscience 33:15333–15342.

    https://doi.org/10.1523/JNEUROSCI.2385-13.2013

    • PubMed
    • Google Scholar
61. 1. Lowery-Gionta EG
    2. Crowley NA
    3. Bukalo O
    4. Silverstein S
    5. Holmes A
    6. Kash TL

    (2018) Chronic stress dysregulates amygdalar output to the prefrontal cortex

    Neuropharmacology 139:68–75.

    https://doi.org/10.1016/j.neuropharm.2018.06.032

    • PubMed
    • Google Scholar
62. 1. Lupien SJ
    2. McEwen BS
    3. Gunnar MR
    4. Heim C

    (2009) Effects of stress throughout the lifespan on the brain, behaviour and cognition

    Nature Reviews Neuroscience 10:434–445.

    https://doi.org/10.1038/nrn2639

    • PubMed
    • Google Scholar
63. 1. Maccari S
    2. Krugers HJ
    3. Morley-Fletcher S
    4. Szyf M
    5. Brunton PJ

    (2014) The consequences of early-life adversity: neurobiological, behavioural and epigenetic adaptations

    Journal of Neuroendocrinology 26:707–723.

    https://doi.org/10.1111/jne.12175

    • PubMed
    • Google Scholar
64. 1. Manzano-Nieves G
    2. Gaillard M
    3. Gallo M
    4. Bath KG

    (2018) Early life stress impairs contextual threat expression in female, but not male, mice

    Behavioral Neuroscience 132:247–257.

    https://doi.org/10.1037/bne0000248

    • PubMed
    • Google Scholar
65. 1. Maroun M
    2. Kavushansky A
    3. Holmes A
    4. Wellman C
    5. Motanis H

    (2012) Enhanced extinction of aversive memories by high-frequency stimulation of the rat infralimbic cortex

    PLOS ONE 7:e35853.

    https://doi.org/10.1371/journal.pone.0035853

    • PubMed
    • Google Scholar
66. 1. Martin L
    2. Viljoen M
    3. Kidd M
    4. Seedat S

    (2014) Are childhood trauma exposures predictive of anxiety sensitivity in school attending youth?

    Journal of Affective Disorders 168:5–12.

    https://doi.org/10.1016/j.jad.2014.06.035

    • Google Scholar
67. 1. McEwen BS

    (2008) Understanding the potency of stressful early life experiences on brain and body function

    Metabolism 57:S11–S15.

    https://doi.org/10.1016/j.metabol.2008.07.006

    • PubMed
    • Google Scholar
68. 1. McGaugh JL

    (2004) The amygdala modulates the consolidation of memories of emotionally arousing experiences

    Annual Review of Neuroscience 27:1–28.

    https://doi.org/10.1146/annurev.neuro.27.070203.144157

    • PubMed
    • Google Scholar
69. 1. Mouton PR
    2. Gokhale AM
    3. Ward NL
    4. West MJ

    (2002) Stereological length estimation using spherical probes

    Journal of Microscopy 206:54–64.

    https://doi.org/10.1046/j.1365-2818.2002.01006.x

    • PubMed
    • Google Scholar
70. 1. Nederhof E
    2. Schmidt MV

    (2012) Mismatch or cumulative stress: toward an integrated hypothesis of programming effects

    Physiology & Behavior 106:691–700.

    https://doi.org/10.1016/j.physbeh.2011.12.008

    • PubMed
    • Google Scholar
71. 1. Nooner KB
    2. Mennes M
    3. Brown S
    4. Castellanos FX
    5. Leventhal B
    6. Milham MP
    7. Colcombe SJ

    (2013) Relationship of trauma symptoms to amygdala-based functional brain changes in adolescents

    Journal of Traumatic Stress 26:784–787.

    https://doi.org/10.1002/jts.21873

    • PubMed
    • Google Scholar
72. 1. Ono M
    2. Kikusui T
    3. Sasaki N
    4. Ichikawa M
    5. Mori Y
    6. Murakami-Murofushi K

    (2008) Early weaning induces anxiety and precocious myelination in the anterior part of the basolateral amygdala of male balb/c mice

    Neuroscience 156:1103–1110.

    https://doi.org/10.1016/j.neuroscience.2008.07.078

    • PubMed
    • Google Scholar
73. 1. Pattwell SS
    2. Liston C
    3. Jing D
    4. Ninan I
    5. Yang RR
    6. Witztum J
    7. Murdock MH
    8. Dincheva I
    9. Bath KG
    10. Casey BJ
    11. Deisseroth K
    12. Lee FS

    (2016) Dynamic changes in neural circuitry during adolescence are associated with persistent attenuation of fear memories

    Nature Communications 7:11475.

    https://doi.org/10.1038/ncomms11475

    • PubMed
    • Google Scholar
74. Book

    1. Paxinos G
    2. Watson C

    (1997)

    The Rain Brain in Stereotaxic Coordinates

    Academic Press.

    • Google Scholar
75. 1. Pedersen JM
    2. Mortensen EL
    3. Christensen DS
    4. Rozing M
    5. Brunsgaard H
    6. Meincke RH
    7. Petersen GL
    8. Lund R

    (2018) Prenatal and early postnatal stress and later life inflammation

    Psychoneuroendocrinology 88:158–166.

    https://doi.org/10.1016/j.psyneuen.2017.12.014

    • PubMed
    • Google Scholar
76. 1. Philip NS
    2. Kuras YI
    3. Valentine TR
    4. Sweet LH
    5. Tyrka AR
    6. Price LH
    7. Carpenter LL

    (2013) Regional homogeneity and resting state functional connectivity: associations with exposure to early life stress

    Psychiatry Research: Neuroimaging 214:247–253.

    https://doi.org/10.1016/j.pscychresns.2013.07.013

    • Google Scholar
77. 1. Rakic P
    2. Bourgeois JP
    3. Goldman-Rakic PS

    (1994) Synaptic development of the cerebral cortex: implications for learning, memory, and mental illness

    Progress in Brain Research 102:227–243.

    https://doi.org/10.1016/S0079-6123(08)60543-9

    • PubMed
    • Google Scholar
78. 1. Rasero J
    2. Aerts H
    3. Ontivero Ortega M
    4. Cortes JM
    5. Stramaglia S
    6. Marinazzo D

    (2018) Predicting functional networks from region connectivity profiles in task-based versus resting-state fMRI data

    PLOS ONE 13:e0207385.

    https://doi.org/10.1371/journal.pone.0207385

    • PubMed
    • Google Scholar
79. 1. Riccomagno MM
    2. Kolodkin AL

    (2015) Sculpting neural circuits by axon and dendrite pruning

    Annual Review of Cell and Developmental Biology 31:779–805.

    https://doi.org/10.1146/annurev-cellbio-100913-013038

    • PubMed
    • Google Scholar
80. 1. Rosenkranz JA
    2. Grace AA

    (2002) Cellular mechanisms of infralimbic and prelimbic prefrontal cortical inhibition and dopaminergic modulation of basolateral amygdala neurons in vivo

    The Journal of Neuroscience 22:324–337.

    https://doi.org/10.1523/JNEUROSCI.22-01-00324.2002

    • PubMed
    • Google Scholar
81. 1. Salberg S
    2. Noel M
    3. Burke NN
    4. Vinall J
    5. Mychasiuk R

    (2019) Utilization of a rodent model to examine the neurological effects of early life adversity on adolescent pain sensitivity

    Developmental Psychobiology 42:21922.

    https://doi.org/10.1002/dev.21922

    • Google Scholar
82. 1. Salzberg M
    2. Kumar G
    3. Supit L
    4. Jones NC
    5. Morris MJ
    6. Rees S
    7. O'Brien TJ

    (2007) Early postnatal stress confers enduring vulnerability to limbic epileptogenesis

    Epilepsia 48:2079–2085.

    https://doi.org/10.1111/j.1528-1167.2007.01246.x

    • PubMed
    • Google Scholar
83. 1. Schoenbaum G
    2. Chiba AA
    3. Gallagher M

    (2000) Changes in functional connectivity in orbitofrontal cortex and basolateral amygdala during learning and reversal training

    The Journal of Neuroscience 20:5179–5189.

    https://doi.org/10.1523/JNEUROSCI.20-13-05179.2000

    • PubMed
    • Google Scholar
84. 1. Selleck RA
    2. Zhang W
    3. Samberg HD
    4. Padival M
    5. Rosenkranz JA

    (2018) Limited prefrontal cortical regulation over the basolateral amygdala in adolescent rats

    Scientific Reports 8:17171.

    https://doi.org/10.1038/s41598-018-35649-0

    • PubMed
    • Google Scholar
85. 1. Senn V
    2. Wolff SB
    3. Herry C
    4. Grenier F
    5. Ehrlich I
    6. Gründemann J
    7. Fadok JP
    8. Müller C
    9. Letzkus JJ
    10. Lüthi A

    (2014) Long-range connectivity defines behavioral specificity of amygdala neurons

    Neuron 81:428–437.

    https://doi.org/10.1016/j.neuron.2013.11.006

    • PubMed
    • Google Scholar
86. 1. Shackman AJ
    2. Wager TD

    (2019) The emotional brain: fundamental questions and strategies for future research

    Neuroscience Letters 693:68–74.

    https://doi.org/10.1016/j.neulet.2018.10.012

    • PubMed
    • Google Scholar
87. 1. Smyke AT
    2. Koga SF
    3. Johnson DE
    4. Fox NA
    5. Marshall PJ
    6. Nelson CA
    7. Zeanah CH
    8. the BEIP Core Group

    (2007) The caregiving context in institution-reared and family-reared infants and toddlers in Romania

    Journal of Child Psychology and Psychiatry 48:210–218.

    https://doi.org/10.1111/j.1469-7610.2006.01694.x

    • Google Scholar
88. 1. Spear LP

    (2000) The adolescent brain and age-related behavioral manifestations

    Neuroscience & Biobehavioral Reviews 24:417–463.

    https://doi.org/10.1016/S0149-7634(00)00014-2

    • PubMed
    • Google Scholar
89. 1. St Onge JR
    2. Stopper CM
    3. Zahm DS
    4. Floresco SB

    (2012) Separate prefrontal-subcortical circuits mediate different components of risk-based decision making

    Journal of Neuroscience 32:2886–2899.

    https://doi.org/10.1523/JNEUROSCI.5625-11.2012

    • PubMed
    • Google Scholar
90. 1. Swanson LW

    (2018) Brain maps 4.0-Structure of the rat brain: an open access atlas with global nervous system nomenclature ontology and flatmaps

    Journal of Comparative Neurology 526:935–943.

    https://doi.org/10.1002/cne.24381

    • PubMed
    • Google Scholar
91. 1. Teicher MH
    2. Samson JA
    3. Anderson CM
    4. Ohashi K

    (2016) The effects of childhood maltreatment on brain structure, function and connectivity

    Nature Reviews Neuroscience 17:652–666.

    https://doi.org/10.1038/nrn.2016.111

    • PubMed
    • Google Scholar
92. 1. Thomason ME
    2. Dennis EL
    3. Joshi AA
    4. Joshi SH
    5. Dinov ID
    6. Chang C
    7. Henry ML
    8. Johnson RF
    9. Thompson PM
    10. Toga AW
    11. Glover GH
    12. Van Horn JD
    13. Gotlib IH

    (2011a) Resting-state fMRI can reliably map neural networks in children

    NeuroImage 55:165–175.

    https://doi.org/10.1016/j.neuroimage.2010.11.080

    • PubMed
    • Google Scholar
93. 1. Thomason ME
    2. Hamilton JP
    3. Gotlib IH

    (2011b) Stress-induced activation of the HPA Axis predicts connectivity between subgenual cingulate and salience network during rest in adolescents

    Journal of Child Psychology and Psychiatry 52:1026–1034.

    https://doi.org/10.1111/j.1469-7610.2011.02422.x

    • PubMed
    • Google Scholar
94. 1. Thomason ME
    2. Marusak HA
    3. Tocco MA
    4. Vila AM
    5. McGarragle O
    6. Rosenberg DR

    (2015) Altered amygdala connectivity in urban youth exposed to trauma

    Social Cognitive and Affective Neuroscience 10:1460–1468.

    https://doi.org/10.1093/scan/nsv030

    • PubMed
    • Google Scholar
95. 1. Tottenham N
    2. Galván A

    (2016) Stress and the adolescent brain: amygdala-prefrontal cortex circuitry and ventral striatum as developmental targets

    Neuroscience and Biobehavioral Reviews 70:217–227.

    https://doi.org/10.1016/j.neubiorev.2016.07.030

    • PubMed
    • Google Scholar
96. 1. Tractenberg SG
    2. Levandowski ML
    3. de Azeredo LA
    4. Orso R
    5. Roithmann LG
    6. Hoffmann ES
    7. Brenhouse H
    8. Grassi-Oliveira R

    (2016) An overview of maternal separation effects on behavioural outcomes in mice: evidence from a four-stage methodological systematic review

    Neuroscience & Biobehavioral Reviews 68:489–503.

    https://doi.org/10.1016/j.neubiorev.2016.06.021

    • PubMed
    • Google Scholar
97. 1. Tyrka AR
    2. Burgers DE
    3. Philip NS
    4. Price LH
    5. Carpenter LL

    (2013) The neurobiological correlates of childhood adversity and implications for treatment

    Acta Psychiatrica Scandinavica 128:434–447.

    https://doi.org/10.1111/acps.12143

    • PubMed
    • Google Scholar
98. 1. Tzanoulinou S
    2. Sandi C

    (2016)

    Current Topics in Behavioral Neurosciences

    The programming of the social brain by stress during childhood and adolescence: from rodents to humans. Social Behavior from Rodents to Humans, Social Behavior from Rodents to Humans, Current Topics in Behavioral Neurosciences, 30, Springer, 10.1007/7854_2015_430.

    • Google Scholar
99. 1. Van Eden CG
    2. Uylings HB

    (1985) Cytoarchitectonic development of the prefrontal cortex in the rat

    The Journal of Comparative Neurology 241:253–267.

    https://doi.org/10.1002/cne.902410302

    • PubMed
    • Google Scholar
100. 1. VanTieghem MR
     2. Tottenham N

     (2018) Neurobiological programming of early life stress: functional development of amygdala-prefrontal circuitry and vulnerability for stress-related psychopathology

     Current Topics in Behavioral Neurosciences 38:117–136.

     https://doi.org/10.1007/7854_2016_42

     • PubMed
     • Google Scholar
101. 1. Viola TW
     2. Wearick-Silva LE
     3. Creutzberg KC
     4. Kestering-Ferreira É
     5. Orso R
     6. Centeno-Silva A
     7. Albrechet-Souza L
     8. Marshall PR
     9. Li X
     10. Bredy TW
     11. Riva MA
     12. Grassi-Oliveira R

     (2019) Postnatal impoverished housing impairs adolescent risk-assessment and increases risk-taking: a sex-specific effect associated with histone epigenetic regulation of Crfr1 in the medial prefrontal cortex

     Psychoneuroendocrinology 99:8–19.

     https://doi.org/10.1016/j.psyneuen.2018.08.032

     • PubMed
     • Google Scholar
102. 1. Wainwright NW
     2. Surtees PG

     (2002) Childhood adversity, gender and depression over the life-course

     Journal of Affective Disorders 72:33–44.

     https://doi.org/10.1016/S0165-0327(01)00420-7

     • PubMed
     • Google Scholar
103. 1. Wieck A
     2. Andersen SL
     3. Brenhouse HC

     (2013) Evidence for a neuroinflammatory mechanism in delayed effects of early life adversity in rats: relationship to cortical NMDA receptor expression

     Brain, Behavior, and Immunity 28:218–226.

     https://doi.org/10.1016/j.bbi.2012.11.012

     • PubMed
     • Google Scholar
104. 1. Yan CG
     2. Rincón-Cortés M
     3. Raineki C
     4. Sarro E
     5. Colcombe S
     6. Guilfoyle DN
     7. Yang Z
     8. Gerum S
     9. Biswal BB
     10. Milham MP
     11. Sullivan RM
     12. Castellanos FX

     (2017) Aberrant development of intrinsic brain activity in a rat model of caregiver maltreatment of offspring

     Translational Psychiatry 7:e1005.

     https://doi.org/10.1038/tp.2016.276

     • PubMed
     • Google Scholar
105. 1. Yang E-J
     2. Lin EW
     3. Hensch TK

     (2012) Critical period for acoustic preference in mice

     PNAS 109:17213–17220.

     https://doi.org/10.1073/pnas.1200705109

     • PubMed
     • Google Scholar
106. 1. Zimmermann K
     2. Richardson R
     3. Baker K

     (2019) Maturational changes in prefrontal and amygdala circuits in adolescence: implications for understanding fear inhibition during a vulnerable period of development

     Brain Sciences 9:65.

     https://doi.org/10.3390/brainsci9030065

     • Google Scholar

Author details

1. Jennifer A Honeycutt

   Developmental Neuropsychobiology Laboratory, Department of Psychology, Northeastern University, Boston, United States

   Contribution

   Data curation, Formal analysis, Investigation, Methodology, Project administration

   For correspondence

   j.honeycutt@northeastern.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-4879-0203

2. Camila Demaestri

   Developmental Neuropsychobiology Laboratory, Department of Psychology, Northeastern University, Boston, United States

   Contribution

   Data curation, Formal analysis, Investigation, Methodology

   Competing interests

   No competing interests declared

3. Shayna Peterzell

   Developmental Neuropsychobiology Laboratory, Department of Psychology, Northeastern University, Boston, United States

   Contribution

   Formal analysis, Investigation, Methodology

   Competing interests

   No competing interests declared

4. Marisa M Silveri

   1. Neurodevelopmental Laboratory on Addictions and Mental Health, McLean Hospital, Belmont, United States
   2. Department of Psychiatry, Harvard Medical School, Boston, United States

   Contribution

   Conceptualization, Data curation

   Competing interests

   No competing interests declared

5. Xuezhu Cai

   Center for Translational Neuroimaging, Department of Psychology, Northeastern University, Boston, United States

   Contribution

   Data curation, Formal analysis

   Competing interests

   No competing interests declared

6. Praveen Kulkarni

   Center for Translational Neuroimaging, Department of Psychology, Northeastern University, Boston, United States

   Contribution

   Data curation, Formal analysis, Validation, Investigation

   Competing interests

   No competing interests declared

7. Miles G Cunningham

   Laboratory for Neural Reconstruction, Department of Psychiatry, McLean Hospital, Belmont, United States

   Contribution

   Conceptualization, Funding acquisition, Methodology

   Competing interests

   No competing interests declared

8. Craig F Ferris

   Center for Translational Neuroimaging, Department of Psychology, Northeastern University, Boston, United States

   Contribution

   Resources, Supervision

   Competing interests

   has a financial interest in Animal Imaging Research, the company that makes the rat imaging system

9. Heather C Brenhouse

   Developmental Neuropsychobiology Laboratory, Department of Psychology, Northeastern University, Boston, United States

   Contribution

   Conceptualization, Resources, Data curation, Formal analysis, Supervision, Funding acquisition, Methodology, Project administration

   For correspondence

   h.brenhouse@neu.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-7591-4964

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