Sex Differences in Affective Dysfunction and Alterations in Parvalbumin in Rodent Models of Early Life Adversity

Abstract

The early life environment markedly influences brain and behavioral development, with adverse experiences associated with increased risk of anxiety and depressive phenotypes, particularly in females. Indeed, early life adversity (ELA) in humans (i.e., caregiver deprivation, maltreatment) and rodents (i.e., maternal separation, resource scarcity) is associated with sex-specific emergence of anxious and depressive behaviors. Although these disorders show clear sex differences in humans, little attention has been paid toward evaluating sex as a biological variable in models of affective dysfunction; however, recent rodent work suggests sex-specific effects. Two widely used rodent models of ELA approximate caregiver deprivation (i.e., maternal separation) and resource scarcity (i.e., limited bedding). While these approaches model aspects of ELA experienced in humans, they span different portions of the pre-weaning developmental period and may therefore differentially contribute to underlying mechanistic risk. This is borne out in the literature, where evidence suggests differences in trajectories of behavior depending on the type of ELA and/or sex; however, the neural underpinning of these differences is not well understood. Because anxiety and depression are thought to involve dysregulation in the balance of excitatory and inhibitory signaling in ELA-vulnerable brain regions (e.g., prefrontal cortex, amygdala, hippocampus), outcomes are likely driven by alterations in local and/or circuit-specific inhibitory activity. The most abundant GABAergic subtypes in the brain, accounting for approximately 40% of inhibitory neurons, contain the calcium-binding protein Parvalbumin (PV). As PV-expressing neurons have perisomatic and proximal dendritic targets on pyramidal neurons, they are well-positioned to regulate excitatory/inhibitory balance. Recent evidence suggests that PV outcomes following ELA are sex, age, and region-specific and may be influenced by the type and timing of ELA. Here, we suggest the possibility of a combined role of PV and sex hormones driving differences in behavioral outcomes associated with affective dysfunction following ELA. This review evaluates the literature across models of ELA to characterize neural (PV) and behavioral (anxiety- and depressive-like) outcomes as a function of sex and age. Additionally, we detail a putative mechanistic role of PV on ELA-related outcomes and discuss evidence suggesting hormone influences on PV expression/function which may help to explain sex differences in ELA outcomes.

Chronic hM3Dq-DREADD mediated chemogenetic activation of parvalbumin-positive inhibitory interneurons in postnatal life alters anxiety and despair-like behavior in adulthood in a task and sex-dependent manner

“…These chemogenetic and optogenetic studies targeting PV-positive inhibitory interneurons in specific circuits in juvenile and adult animals, highlight an important role in modulation of anxio-depressive behaviors. It also underscores the importance of addressing the role of this subclass of inhibitory interneurons in critical early postnatal temporal windows (Medendorp et al ., 2021), which are particularly important given the large body of evidence indicating that PV-interneuron number and function is perturbed in both models of early adversity and neurodevelopmental disorders (Rodriguez et al ., 2018; Ellis and Honeycutt, 2021).…”

“…This was also apparent with regards to despair-like behavior on the TST and FST, with PNCNO-treated male, but not female, mice exhibiting a decline in despair-like behavior. This raises the intriguing possibility that postnatal chemogenetic activation of PV-positive interneurons could differentially impact neurocircuits that regulate approach-avoidance behavior and active/passive coping strategies which may underlie the heterogeneity noted in behavioral responses, with a strong influence of biological sex as a key variable (Goodwill et al ., 2018; Gildawie et al ., 2020; Ellis and Honeycutt, 2021). Given the differences in the age of onset of treatment, timing, duration and mode of chemogenetic activation, neurocircuit in which PV-positive inhibitory interneurons were targeted, as well as specific behavioral tests performed, it is difficult to directly draw comparisons across our findings and prior studies (Zou et al ., 2016; Mukherjee et al ., 2019; Nawreen et al ., 2020; Huang et al ., 2021).…”

“…The temporal windows used in multiple early adversity models overlaps with the time-window used for chemogenetic manipulations of PV-positive interneurons (Katahira et al ., 2018; Gomes et al ., 2019; Reh et al ., 2020; Tiwari et al ., 2021), and this opens up the possibility that such postnatal modulation of PV-positive interneuron activity during critical periods could directly impinge on the manner in which local microcircuit rhythmogenesis is shaped (Sohal et al ., 2009; Moran et al ., 2017; Murthy et al ., 2019), with biological sex playing a key role given that PV interneurons also express sex hormone receptors (Wu et al ., 2014). A recent review raises the intriguing possibility that “estrogens may serve a protective role” resulting in the “blunting” of some of the impact of early adversity in females (Ellis and Honeycutt, 2021; Woodward and Coutellier, 2021). Our results further highlight that biological sex is a key variable to keep in mind when assessing the impact of PV-positive interneuron manipulations in the shaping of adult emotionality.…”

Non-human contributions to personality neuroscience – from fish through primates. An introduction to the special issue

“…Importantly for personality neuroscience, the amygdala, hippocampus, and endocrine system are substrates of these responses to early adversity (Ellis & Honeycutt, 2021;Qin et al, 2021) with similar brain changes apparent in humans (Pollok et al, 2022). The comparison of strain selection and environmental experiments in nonhumans with confirmatory, albeit correlational, human imaging is a powerful solution to the problems facing each approach separately.…”

Early life adversity impaired dorsal striatal synaptic transmission and behavioral adaptability to appropriate action selection in a sex-dependent manner

“…To this end, our study begins to explore three questions that remain unanswered: (i) whether ELA impacts corticostriatal glutamate transmission in a manner that explains behavioral impairments; (ii) whether ELA affects the flexibility of mice to adopt different action selection strategies; and (iii) whether ELA impairs reversal learning. We also aim to address these questions in a sex-dependent manner on the basis of a plethora of studies showing differences in cognitive and emotional behaviors between male and female mice subjected to ELA (Colich et al, 2017 ; Ellis and Honeycutt, 2021 ; Bondar et al, 2018 ; Ruigrok et al, 2021a , b ). The sex-dependent differences in behaviors can be attributed to discrepancies in maternal care, where male mice receive more care than their female siblings (Oomen et al, 2009 ; van Hasselt et al, 2012 ).…”