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

Abstract

Exposure to early-life adversity (ELA) increases the risk for psychopathologies associated with amygdala-prefrontal cortex (PFC) circuits. While sex differences in vulnerability have been identified with a clear need for individualized intervention strategies, the neurobiological substrates of ELA-attributable differences remain unknown due to a paucity of translational investigations taking both development and sex into account. Male and female rats exposed to maternal separation ELA were analyzed with anterograde tracing from basolateral amygdala (BLA) to PFC to identify sex-specific innervation trajectories through juvenility (PD28) and adolescence (PD38;PD48). Resting-state functional connectivity (rsFC) was assessed longitudinally (PD28;PD48) in a separate cohort. All measures were related to anxiety-like behavior. ELA-exposed rats showed precocial maturation of BLA-PFC innervation, with females affected earlier than males. ELA also disrupted maturation of female rsFC, with enduring relationships between rsFC and anxiety-like behavior. This study is the first providing both anatomical and functional evidence for sex- and experience-dependent corticolimbic development.

Sex-Specific Effects of Early Life Stress on Brain Mitochondrial Function, Monoamine Levels and Neuroinflammation

“…Indeed, MS males in this study were more susceptible to the addictive effects of chronic ethanol intake and its adverse effects on the HPA axis stress response [ 14 ]. These sex differences in brain neurotransmitter levels and behavior could also be related to the sex-dependent disruption by ELS of the maturation of cortico-limbic circuits, as recently reported in a neuroimaging study in rats [ 73 ].…”

Early life stress causes sex-specific changes in adult fronto-limbic connectivity that differentially drive learning

“…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.…”

“…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 ).…”

Early life adversity decreases pre-adolescent fear expression by accelerating amygdala PV cell development

“…Previous research has demonstrated that ELA can alter mPFC to BLA connectivity in humans ( Fan et al, 2014 ; Gee et al, 2013 ; Herringa et al, 2016 ) (reviewed in Herzberg and Gunnar, 2020 ; VanTieghem and Tottenham, 2018 ), and BLA to mPFC anatomical ( Honeycutt et al, 2020 ), and functional ( Bolton et al, 2018 ; Guadagno et al, 2018 ; Yan et al, 2017 ) connectivity in rodents. Since LB male and female mice exhibited diminished fear expression at PND 21, and PL projections into BLA are known to promote fear learning, while IL projections into BLA support fear extinction ( Do-Monte et al, 2015a ; Giustino and Maren, 2015 ; Lee and Choi, 2012 ; Sierra-Mercado et al, 2011 ), we sought to investigate whether LB altered anatomical connectivity between mPFC and BLA in our hands.…”