Childhood maltreatment (CM) is a broad term used to define a heterogenous group of early adversities that range from severe bullying to physical, emotional, and/or sexual abuse (White and Kaffman, 2019a; Teicher and Samson, 2016). Exposure to CM increases the risk for the development of multiple psychopathologies and medical conditions over the lifespan (Anda et al., 2006; Nemeroff, 2016; Teicher and Samson, 2016; Kaffman and Meaney, 2007), with an estimated annual economic burden of $2 trillion in the United States alone (Peterson et al., 2018). While CM is recognized as a significant risk factor for abnormal brain development in industrialized countries, a thorough understanding of how CM impacts neurodevelopment and psychopathology in males and females is lacking (White and Kaffman, 2019b; Bath, 2020; Bale and Epperson, 2015; Cameron et al., 2017; Gobinath et al., 2014). Given that 30–40% of the adult population have experienced some form of CM (Agorastos et al., 2019), clarifying these issues is necessary in order to effectively diagnose and treat the enormous clinical and economic burden associated with CM (White and Kaffman, 2019a).

The study of CM-associated outcomes is generally framed from a cumulative risk perspective, where the risk of negative outcomes raises linearly with the number of maltreatment exposures (Kessler et al., 1997; Anda et al., 2006; Chen et al., 2010; Evans et al., 2013). Newer models have expanded this framework to highlight that different forms of CM fall along multiple dimensions, and this in turn more directly impacts later outcomes than number of CM instances per se (McLaughlin et al., 2014; McLaughlin and Sheridan, 2016). However, neither of these models has addressed the potential role that sex plays in moderating CM-associated outcomes (Bath, 2020; White and Kaffman, 2019b). Further, much of the focus in the field to date has been on the role that sex plays in influencing the rate of psychopathology with little consensus and/or replication of findings (White and Kaffman, 2019b; Cameron et al., 2017; Bale and Epperson, 2015). Briefly, some studies report similar outcomes in males and females, some found females to be more sensitive to CM, while others see effects only in males (White and Kaffman, 2019b). A more nuanced approach suggests that sex-specific effects may depend on genetic vulnerability, the circuit involved, and the developmental stage when the stress occurred, or outcomes were assessed (White and Kaffman, 2019b; Bath, 2020; Demaestri et al., 2020).

Importantly, similar clinical presentation may be driven by different underlying mechanisms in males and females as reported for depression (Labonté et al., 2017) and neuropathic pain (Sorge et al., 2015). These findings suggest that sex-specific interventions might be needed to more effectively treat psychiatric and medical consequences of CM (Bath, 2020; White and Kaffman, 2019b). Promising progress on this issue comes from advanced imaging techniques (Lerch et al., 2017; Le Bihan, 2003; Biswal, 2012; Moldrich et al., 2010). The most reproducible findings are from structural MRI studies which show reduced hippocampal and corpus callosum volume in those exposed to CM, with a hint that these effects are larger in males compared to age-matched females (Teicher and Samson, 2016). A recent multi-center study using a large cohort of 3036 individuals did not find any significant changes in hippocampal size but noted reduced caudate size in females that was not seen in males exposed to CM (Frodl et al., 2017). Few studies have had sufficient power to directly test for CM by sex interactions on task mediated fMRI activation and connectivity using resting state fMRI (rsfMRI), or diffusion MRI (dMRI) (White and Kaffman, 2019b). Even within these studies, there is no agreement with regard to a specific pattern of task-mediated neuronal activation (Crozier et al., 2014; Colich et al., 2017; Dannlowski et al., 2012) or connectivity (Herringa et al., 2013; Ohashi et al., 2019).

This ambiguity highlights the difficulty of studying long-term consequences of complex adversity in human populations where the nature and severity of the CM may be different between and within studies and findings may be confounded with other psychological or medical co-morbidities; for a thorough review on this topic, see Herringa, 2017. Preclinical studies in rodents can bypass many obstacles faced in clinical research by precisely controlling the genetic composition of the animals, and the severity, duration, and complexity of the stress. Human imaging techniques, such as high-resolution MRI, dMRI, and rsfMRI, can be used in rodent models to characterize structural and functional outcomes that can be more directly compared to humans. Further, the contribution of structural and functional changes, measured via imaging, to behavioral alterations can be rigorously tested using optogenetics and chemogenetic tools (Kaffman et al., 2019). Although rodents and non-human primates exposed to early life stress (ELS) show similar behavioral and physiological outcomes reported in human studies, the vast majority of work has been done only in males (White and Kaffman, 2019b; Bath, 2020). Specifically, the few studies that used imaging to characterize outcomes in rodent models of ELS were done exclusively in males (Bolton et al., 2018; Molet et al., 2016; Carlyle et al., 2012; Yan et al., 2017; Guadagno et al., 2018a; Sarabdjitsingh et al., 2017; Johnson et al., 2018), with only one imaging study examining outcomes in both sexes (Honeycutt et al., 2020). The need to extend these findings to females is highlighted by a report of considerable neuroanatomical sex differences in the postnatal mouse brain (Qiu et al., 2018) and a recent study showing that maternal separation leads to sex-specific effects in amygdala (AMY) connectivity with the prefrontal cortex (PFC) in adolescent rats (Honeycutt et al., 2020).

Our lab has modified and built upon the widely used limited bedding and nesting (LBN) paradigm developed by Tallie Baram’s lab (Walker et al., 2017) by extending the time frame dam and pups are exposed to LBN (from PND2-9 to PND0-25) and adding brief, 1 hr, bouts of maternal separation on an unpredictable schedule, that is, PND 14, 16, 17, 21, 22, and 25, followed by nest disruption. This ELS paradigm is termed unpredictable postnatal stress (UPS) and was designed to represent both a cumulative and multidimensional subtype of CM that allows us to test how complex adversity can alter neurodevelopment and behavioral outcomes in both male and female mice (White and Kaffman, 2019b). Balb/cByj mice were used due to their high sensitivity to stress (Caldji et al., 2004; Zaharia et al., 1996; Francis et al., 2003; Carola et al., 2004; Tractenberg et al., 2016; Wei et al., 2010; Wei et al., 2012; McWhirt et al., 2019; Malki et al., 2015; Flint and Tinkle, 2001; Wei et al., 2014; Wei et al., 2015; Delpech et al., 2016) and the ability of Balb/cByj dams to reliably maintain their litters in the complete absence of nesting material (Wei et al., 2010). Further, we have previously shown that UPS produces an elevated anxiety phenotype in both adolescent and adult Balb/cByj offspring (Johnson et al., 2018). Using rsfMRI we found increased fronto-limbic connectivity in UPS male mice that included increased AMY–PFC and AMY–hippocampus connectivity, the strength of which was highly correlated with anxiety-like behaviors (Johnson et al., 2018). Interestingly, females did not show an elevated anxiety phenotype, suggesting that UPS may affect males and females differently. This original study did not include females in rs-fMRI analysis and is thus unable to speak to potential ELS by sex interactions on fronto-limbic connectivity patterns.

The current study aimed to replicate and extend our understanding of UPS-induced behavioral phenotypes and brain connectivity patterns in adult male and female mice. Our first objective was to replicate our previous findings that UPS increases anxiety-like behavior in male, but not female mice and to examine the effects of UPS, sex and their interaction on other exploratory behaviors (i.e. novel object) and contextual and cued fear conditioning. The second goal was to assess the effects of UPS and sex on local volumetric changes, microstructural alterations in white matter tracts, and structural connectivity using high resolution dMRI. Finally, we sought to replicate our fronto-limbic hyper connectivity rsfMRI findings in UPS male mice using dMRI tractography and to test whether similar changes would also be seen in female mice exposed to UPS.

The present study demonstrates that UPS, a complex model of ELS in the mouse, produces long-lasting behavioral and central anatomical changes, some of which are moderated by sex. The role that sex plays in CM-associated outcomes is a growing area of interest (White and Kaffman, 2019b; Bath, 2020), and it is becoming increasingly clear that the influence of sex may only be seen in certain behaviors, neurodevelopmental processes, and/or specific circuits (White and Kaffman, 2019b; Bath, 2020; Demaestri et al., 2020). This is in line with the findings reported here. For example, here we report similar impact of UPS on body weight, object exploration, contextual conditioning, and global connectivity in males and females. Male and female UPS mice also showed similar changes in local volumetric and FA, but our sample size for these measures (n = 6) was not sufficiently powered to detect significant sex by rearing interactions after correcting for multiple testing. Nevertheless, this sample size revealed robust moderating effects of sex on UPS-induced outcomes in fronto-limbic connectivity and AMY nodal efficiency, findings that were further confirmed using a larger cohort of mice.

To the best of our knowledge this is the first paper to utilize high resolution dMRI to assess the effects of ELS on brain structure in both males and females. Using these methods, we demonstrated that males and females exposed to UPS showed several changes that are consistent with those previously reported in human and animal literature. Specifically, UPS leads to reduced global network efficiency and increased small-worldness that resemble those seen in a large cohort of individuals exposed to CM (Ohashi et al., 2019). Global efficiency, the ability of a network to propagate parallel information, increases during brain development and is associated with improved cognition (Bassett and Bullmore, 2017; Farahani et al., 2019; Huang et al., 2015; Bullmore and Sporns, 2009). The reduced global efficiency seen in UPS mice suggests abnormal maturation of this feature and is consistent with the cognitive deficits seen in the same animals. Small-worldness, a highly conserved network pattern across species, decreases during development (Bassett and Bullmore, 2017; Bullmore and Sporns, 2009; Lupfer et al., 2013). Thus, the increased small-worldness seen in UPS animals is further support of a premature network.

In terms of volumetric changes, UPS mice showed several outcomes that were also reported in humans (summarized in Supplementary file 3). These include reduced volumes in the frontal cortex (Carrion et al., 2001; De Bellis et al., 2002; Heim et al., 2013), reduced corpus callosum volume (Teicher and Samson, 2016), increased anterior cingulate (Zuo et al., 2019), and increased AMY volume (Pechtel et al., 2014; Mehta et al., 2009; Tottenham et al., 2010). It is important to note, however, that increased anterior cingulate and AMY volumes have not been consistently reported in humans (Teicher and Samson, 2016; Frodl et al., 2017), but increased AMY volumes are seen in non-human primates (Coplan et al., 2014) and juvenile rats exposed to LBN (Guadagno et al., 2018b). With regard to FA changes, UPS mice showed reduced FA in the corpus callosum which is one of the most robust findings in the human literature (Teicher and Samson, 2016; McCarthy-Jones et al., 2018). In contrast, the increased vHC volume seen in UPS mice is diametrically opposite to a large body of work showing reduced hippocampal volume in individuals exposed to CM (Baker et al., 2013; Cohen et al., 2006; Teicher and Samson, 2016). However, a recent analysis using over 3000 subjects found no statistical differences in hippocampal volume (Frodl et al., 2017), underscoring the challenges involved in conducting this work in humans. Inconsistent outcomes have also been reported in rats exposed to LBN, with one report indicating increased volume (Guadagno et al., 2018a) and a second publication noting reduced hippocampal volume (Molet et al., 2016). Additional work is therefore needed to replicate our findings, clarify mechanisms, and the contribution of this expansion in vHC to connectivity and behavioral outcomes.

Our sample size was not sufficiently powered to identify sexually dimorphic changes after rigorous correction for multiple comparisons, and the relatively lower resolution of dMRI compared to T1/T2-weighted MRI and differences in tissue contrasts may have also limited our ability to capture these differences. Nevertheless, we have identified several of the previously known sexually dimorphic brain regions including the BNST and medial preoptic area in the hypothalamus, hippocampus, thalamus, OB, striatum, and the sensory cortex (Figure 3—figure supplement 1). These findings are consistent with a previous study in C57BL/6 mice (Qiu et al., 2018) and in humans (Gillies and McArthur, 2010; Ruigrok et al., 2014; Goldstein et al., 2001), underscoring the conserved nature of these sexual dimorphic alterations.

Our dMRI tractography shows good agreement with anterograde viral tracing reported by the Allen Mouse Brain Connectivity Atlas (Figure 5—figure supplement 1), suggesting that the tractography data shown here represents true anatomical projections. Using this approach we found a robust increase in fronto-limbic connectivity in males exposed to UPS (Figures 5 and 6).These structural changes are consistent with our previous resting-state fMRI findings in UPS males (Johnson et al., 2018) and those reported in male rats exposed to LBN (Bolton et al., 2018). Similar patterns were seen in both the left and the right hemispheres (Figure 5—figure supplements 1 and 2 and Figure 6—figure supplement 1) and were further confirmed using a larger cohort of mice (Figure 10). The observation that the hyper connectivity is unique to males and is not seen in females reveals a novel sex-dependent effect of UPS on this specific circuit. Sex-specific alterations in connectivity have been reported in adolescents and young adults exposed to ELS (Crozier et al., 2014; Herringa et al., 2013; Colich et al., 2017) but not in adult subjects (Ohashi et al., 2019; Dannlowski et al., 2012). Nevertheless, increased AMY connectivity was associated with higher levels of symptomatology including anxiety and depression in adulthood (Ohashi et al., 2019), suggesting that findings in UPS males may have translational utility for some types of ELS in humans. Exposure to maternal separation also induced sex-specific changes in the connectivity between the basolateral AMY and the PFC in juvenile rats; however, these changes appear to be more prominent in females (Honeycutt et al., 2020). Together, these findings highlight intriguing sex-dependent effects of varying ELS paradigms on fronto-limbic connectivity in rodents.

Despite clear differences in UPS-induced fronto-limbic connectivity between males and females, their behavioral profiles were remarkably similar and raise the possibility that alterations in connectivity may lead to different behavioral outcomes in males and females. To address this issue, we conducted a moderated-mediation analysis to test whether sex was moderating the relationships between UPS-induced changes in connectivity between the AMY and the vHC and their resulting influence on freezing behavior. We focused on these connections for several reasons, that is, UPS induced opposing outcomes in males and females (increased in males and reduction in females, Figure 6D), there were clear volumetric changes in both areas, and these areas play an important role in fear learning. Our analysis suggests that alterations in connectivity in males, but not females, is in part responsible for the reduced freezing behavior seen in UPS mice (Figure 7). Future work should use optogenetic or chemogenetic approaches to further test the conclusions drawn from this moderated-mediation model, but the findings reported here are consistent with other examples showing that similar behavioral outcomes can be driven by different mechanisms in males and females (Labonté et al., 2017; Sorge et al., 2015).

Previous work has shown that ELS alters brain laterality (Denenberg et al., 1980; Sherman et al., 1980; Zhang et al., 2005; Guadagno et al., 2018a; Sullivan and Gratton, 2002), but the exact mechanisms responsible for these changes are yet to be elucidated. Most of our findings were seen on both the left and the right hemispheres. Nevertheless, we report three interesting findings, all of which are related to laterality within the AMY–vHC connections. First, there was a significant increase in connectivity on the left compared to the right regardless of sex. Second, there was a significant effect of sex on the right hemisphere with females showing reduced connections compared to males. Third, moderated-mediation analysis found higher number of projections between the AMY and vHC on the left, but not the right, predicting male freezing behavior in the contextual fear conditioning.

It is important to note that we were unable to replicate our UPS-induced anxiety-like behavior in the open field or the EPM (Johnson et al., 2018). One possible explanation for this failure to replicate may be due to differences in the implementation of the paradigm. For instance, the current studies were conducted in a room that was roughly 10 times quieter than the room utilized in previous work (see Animals heading within the Materials and methods section) and the work was conducted by different individuals. These outcomes also highlight the sensitivity of the OF and the EPM tests to multiple variables such as sex of the experimenter, phase of the light/dark cycle, degree of illumination in the arena, noise, smells, and order of behavioral testing (Tractenberg et al., 2016; Alves et al., 2019; Murthy and Gould, 2018; Lehmann and Feldon, 2000). Our inability to replicate behavioral outcomes in the EPM in the first and second cohorts underscores the challenges of using this test even under practically identical conditions (Supplementary file 1) and highlights the need to develop more robust behavioral tests of anxiety; see Oberrauch et al., 2019; Meyer et al., 2019; Prevot et al., 2019 for some encouraging examples. Reduced baseline corticosterone levels were seen in males, but not female UPS mice (Figure 1E). This outcome is consistent with a recent meta-analysis showing an overall blunted corticosterone levels in individuals exposed to early adversity (Bunea et al., 2017) and might be due to sex-specific changes in connectivity between the AMY and the hypothalamus (Figure 9A).

Additional work is also needed to characterize maternal care in UPS and its potential for inducing sex-specific changes; see Bath, 2020 for a comprehensive review on this topic. Consistent with our previous work (Johnson et al., 2018) we found that UPS caused a robust reduction in weight across different ages (Figure 1). Moreover, male and female UPS mice spent less time exploring novel objects and showed reduced contextual freezing, findings that were replicated in two independent cohorts (Figure 2 and Supplementary file 1) and in additional studies conducted in the lab (Figure 2—figure supplement 2).

All imaging data are deposited at https://doi.org/10.35092/yhjc.12367658.

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Author details

1. Jordon D White

   Department of Psychiatry, Yale University School of Medicine, New Haven, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing - original draft, Project administration, Writing - review and editing

   Competing interests

   No competing interests declared

2. Tanzil M Arefin

   Bernard and Irene Schwartz Center for Biomedical Imaging, Department of Radiology, New York University School of Medicine, New York, United States

   Contribution

   Conceptualization, Data curation, Software, Formal analysis, Supervision, Funding acquisition, Investigation, Methodology, Writing - original draft, Project administration, Writing - review and editing

   Competing interests

   No competing interests declared

3. Alexa Pugliese

   Department of Psychiatry, Yale University School of Medicine, New Haven, United States

   Contribution

   Data curation, Software, Formal analysis, Investigation, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

4. Choong H Lee

   Bernard and Irene Schwartz Center for Biomedical Imaging, Department of Radiology, New York University School of Medicine, New York, United States

   Contribution

   Data curation, Investigation

   Competing interests

   No competing interests declared

5. Jeff Gassen

   Department of Psychology, Texas Christian University, Fort Worth, United States

   Contribution

   Software, Formal analysis, Investigation, Writing - review and editing

   Competing interests

   No competing interests declared

6. Jiangyang Zhang

   Bernard and Irene Schwartz Center for Biomedical Imaging, Department of Radiology, New York University School of Medicine, New York, United States

   Contribution

   Conceptualization, Data curation, Software, Formal analysis, Supervision, Funding acquisition, Investigation, Methodology, Project administration, Writing - review and editing

   Competing interests

   No competing interests declared

7. Arie Kaffman

   Department of Psychiatry, Yale University School of Medicine, New Haven, United States

   Contribution

   Conceptualization, Data curation, Software, Formal analysis, Supervision, Funding acquisition, Validation, Investigation, Visualization, Methodology, Writing - original draft, Project administration, Writing - review and editing

   For correspondence

   arie.kaffman@yale.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-7028-8869

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