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.

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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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