Developmental and adult stress: effects of steroids and neurosteroids.

In humans, exposure to early life adversity has profound implications for susceptibility to developing neuropsychiatric disorders later in life. Studies in rodents have shown that stress experienced during early postnatal life can have lasting effects on brain development. Glucocorticoids and sex steroids are produced in endocrine glands and the brain from cholesterol; these molecules bind to nuclear and membrane-associated steroid receptors. Unlike other steroids that can also be made in the brain, neurosteroids bind specifically to neurotransmitter receptors, not steroid receptors. The relationships among steroids, neurosteroids, and stress are multifaceted and not yet fully understood. However, studies demonstrating altered levels of progestogens, androgens, estrogens, glucocorticoids, and their neuroactive metabolites in both developmental and adult stress paradigms strongly suggest that these molecules may be important players in stress effects on brain circuits and behavior. In this review, we discuss the influence of developmental and adult stress on various components of the brain, including neurons, glia, and perineuronal nets, with a focus on sex steroids and neurosteroids. Gaining an enhanced understanding of how early adversity impacts the intricate systems of brain steroid and neurosteroid regulation could prove instrumental in identifying novel therapeutic targets for stress-related conditions.

Scn2a deletion disrupts oligodendroglia function: Implication for myelination, neural circuitry, and auditory hypersensitivity in ASD.

Autism spectrum disorder (ASD) is characterized by a complex etiology, with genetic determinants significantly influencing its manifestation. Among these, the Scn2a gene emerges as a pivotal player, crucially involved in both glial and neuronal functionality. This study elucidates the underexplored roles of Scn2a in oligodendrocytes, and its subsequent impact on myelination and auditory neural processes. The results reveal a nuanced interplay between oligodendrocytes and axons, where Scn2a deletion causes alterations in the intricate process of myelination. This disruption, in turn, instigates changes in axonal properties and neuronal activities at the single cell level. Furthermore, oligodendrocyte-specific Scn2a deletion compromises the integrity of neural circuitry within auditory pathways, leading to auditory hypersensitivity-a common sensory abnormality observed in ASD. Through transcriptional profiling, we identified alterations in the expression of myelin-associated genes, highlighting the cellular consequences engendered by Scn2a deletion. In summary, the findings provide unprecedented insights into the pathway from Scn2a deletion in oligodendrocytes to sensory abnormalities in ASD, underscoring the integral role of Scn2a -mediated myelination in auditory responses. This research thereby provides novel insights into the intricate tapestry of genetic and cellular interactions inherent in ASD.

Why is concealment associated with health and wellbeing? An investigation of potential mechanisms.

RATIONALE: Many members of stigmatized groups face health and wellbeing deficits relative to their non-stigmatized peers. Ample evidence suggests that one method used by some members of stigmatized groups to manage the stigma they face-concealing their stigmatized identities-may contribute to these health and wellbeing disparities. However, precisely why concealment may contribute to these disparities is less clear. OBJECTIVE: The present work seeks to identify and distinguish between plausible explanations for why concealment may contribute to worse health and wellbeing. METHODS: In the present work, we explore a large number of plausible mechanisms that may explain why concealment is associated with worse health and wellbeing. In three studies (N = 2304) using cross-sectional (Studies 1 and 2) and longitudinal (Study 3) methods, participants were recruited from an online recruitment pool (Studies 1-3) and from an institutional recruitment pool (Study 2). Participants reported on their concealment, health and wellbeing, and constructs related to plausible explanations for the relationships between concealment and health and wellbeing. RESULTS: We find that concealment is associated with worse health and wellbeing, with generally small effect sizes. We further find that lower feelings of belonging, less social support, and lower self-esteem are the most plausible mechanisms for explaining why concealment is associated with worse health and wellbeing. When between- and within-subjects effects were distinguishable (i.e., Study 3), we observed only between-subjects relationships. CONCLUSION: Because people's choices to engage in self-protection through concealment should be respected, potential avenues for intervention to reduce minority health disparities may be more appropriately targeted at the mechanisms that account for why concealment may undermine health and wellbeing than at concealment itself. The present work makes strides towards identifying those mechanisms and thus towards addressing them.

Identity Concealment May Discourage Health-Seeking Behaviors: Evidence From Sexual-Minority Men During the 2022 Global Mpox Outbreak.

People who conceal their stigmatized identities often experience worse physical health. One possibility for why is that concealment may render certain health-seeking behaviors more difficult. We tested this possibility during the 2022 global mpox outbreak, a public-health emergency that disproportionately affected sexual-minority men. We recruited adult sexual-minority men from Prolific at two time points near the outbreak's peak and attenuation (n = 864 and n = 685, respectively). We found that men who concealed their minority sexual orientations were less likely to (a) receive a vaccine to protect against mpox, (b) receive an mpox test, and (c) report having received an mpox vaccine. The relationship between concealment and vaccine receipt was serially mediated by reduced community connectedness and reduced knowledge of mpox resources. We call for thoughtful consideration of how to reach stigmatized groups with public-health resources, inclusive of those who conceal.

Which Identities Are Concealable? Individual Differences in Concealability.

Concealment is a common and consequential identity management strategy. But which identities are concealable? In three studies (n = 468; obs = 4,068), we find substantial individual differences in which identities people experience as concealable. These individual differences in concealability manifest as Person × Identity interactions, such that people experience varying levels of concealability for each of their individual identities. In two additional studies (n = 465; obs = 3,784), we find that these individual differences predict the frequency and efficacy of concealment. We conclude that it is inaccurate to label entire categories of identities as either concealable or conspicuous and urge intergroup researchers to consider people's unique experiences of concealability. Pre-registrations for Studies 1 to 4 and open materials, code, and data for all studies are available on the Open Science Framework: https://osf.io/m95qu/.

Development of the hippocampal CA2 region and the emergence of social recognition.

Social memories formed in early life, like those for family and unrelated peers, are known to contribute to healthy social interactions throughout life, although how the developing brain supports social memory remains relatively unexplored. The CA2 subregion of the hippocampus is involved in social memory function, but most literature on this subject is restricted to studies of adult rodents. Here, we review the current literature on the embryonic and postnatal development of hippocampal subregion CA2 in mammals, with a focus on the emergence of its unusual molecular and cellular characteristics, including its notably high expression of plasticity-suppressing molecules. We also consider the connectivity of the CA2 with other brain areas, including intrahippocampal regions, such as the dentate gyrus, CA3, and CA1 regions, and extrahippocampal regions, such as the hypothalamus, ventral tegmental area, basal forebrain, raphe nuclei, and the entorhinal cortex. We review developmental milestones of CA2 molecular, cellular, and circuit-level features that may contribute to emerging social recognition abilities for kin and unrelated conspecifics in early life. Lastly, we consider genetic mouse models related to neurodevelopmental disorders in humans in order to survey evidence about whether atypical formation of the CA2 may contribute to social memory dysfunction.

Activation of the CA2-ventral CA1 pathway reverses social discrimination dysfunction in Shank3B knockout mice.

Mutation or deletion of the SHANK3 gene, which encodes a synaptic scaffolding protein, is linked to autism spectrum disorder and Phelan-McDermid syndrome, conditions associated with social memory impairments. Shank3B knockout mice also exhibit social memory deficits. The CA2 region of the hippocampus integrates numerous inputs and sends a major output to the ventral CA1 (vCA1). Despite finding few differences in excitatory afferents to the CA2 in Shank3B knockout mice, we found that activation of CA2 neurons as well as the CA2-vCA1 pathway restored social recognition function to wildtype levels. vCA1 neuronal oscillations have been linked to social memory, but we observed no differences in these measures between wildtype and Shank3B knockout mice. However, activation of the CA2 enhanced vCA1 theta power in Shank3B knockout mice, concurrent with behavioral improvements. These findings suggest that stimulating adult circuitry in a mouse model with neurodevelopmental impairments can invoke latent social memory function.

Postnatal development of hippocampal CA2 structure and function during the emergence of social recognition of peers.

It is now well-established that the hippocampal CA2 region plays an important role in social recognition memory in adult mice. The CA2 is also important for the earliest social memories, including those that mice have for their mothers and littermates, which manifest themselves as a social preference for familiarity over novelty. The role of the CA2 in the development of social memory for recently encountered same-age conspecifics, that is, peers, has not been previously reported. Here, we used a direct social interaction test to characterize the emergence of novelty preference for peers during development and found that at the end of the second postnatal week, pups begin to significantly prefer novel over familiar peers. Using chemogenetic inhibition at this time, we showed that CA2 activity is necessary for the emergence of novelty preference and for the ability to distinguish never encountered from recently encountered peers. In adulthood, the CA2 region is known to integrate a large number of inputs from various sources, many of which participate in social recognition memory, but previous studies have not determined whether these afferents are present at adult levels by the end of the second postnatal week. To explore the development of CA2 inputs, we used immunolabeling and retrograde adenovirus circuit tracing and found that, by the end of the second postnatal week, the CA2 is innervated by many regions, including the dentate gyrus, supramammillary nucleus of the hypothalamus, the lateral entorhinal cortex, and the median raphe nucleus. Using retroviral labeling of postnatally generated granule cells in the dentate gyrus, we found that mossy fiber projections to the CA2 mature faster during development than those generated in adulthood. Together, our findings indicate that the CA2 is partially mature in afferent connectivity by the end of the second postnatal week, connections that likely facilitate the emergence of social recognition memory and preference for novel peers.

The estrous cycle modulates early-life adversity effects on mouse avoidance behavior through progesterone signaling.

Early-life adversity (ELA) increases the likelihood of neuropsychiatric diagnoses, which are more prevalent in women than men. Since changes in reproductive hormone levels can also increase the probability of anxiety disorders in women, we examined the effects of ELA on adult female mice across the estrous cycle. We found that during diestrus, when progesterone levels are relatively high, ELA mice exhibit increased avoidance behavior and increased theta oscillation power in the ventral hippocampus (vHIP). We also found that diestrus ELA mice had higher levels of progesterone and lower levels of allopregnanolone, a neurosteroid metabolite of progesterone, in the vHIP compared with control-reared mice. Progesterone receptor antagonism normalized avoidance behavior in ELA mice, while treatment with a negative allosteric modulator of allopregnanolone promoted avoidance behavior in control mice. These results suggest that altered vHIP progesterone and allopregnanolone signaling during diestrus increases avoidance behavior in ELA mice.

Perineuronal Nets in the Dorsomedial Striatum Contribute to Behavioral Dysfunction in Mouse Models of Excessive Repetitive Behavior.

Background: Excessive repetitive behavior is a debilitating symptom of several neuropsychiatric disorders. Parvalbumin-positive inhibitory interneurons in the dorsal striatum have been linked to repetitive behavior, and a sizable portion of these cells are surrounded by perineuronal nets (PNNs), specialized extracellular matrix structures. Although PNNs have been associated with plasticity and neuropsychiatric disease, no previous studies have investigated their involvement in excessive repetitive behavior. Methods: We used histochemistry and confocal imaging to investigate PNNs surrounding parvalbumin-positive cells in the dorsal striatum of 4 mouse models of excessive repetitive behavior (BTBR, Cntnap2, Shank3, prenatal valproate treatment). We then investigated one of these models, the BTBR mouse, in detail, with DiI labeling, in vivo and in vitro recordings, and behavioral analyses. We next degraded PNNs in the dorsomedial striatum (DMS) using the enzyme chondroitinase ABC and assessed dendritic spine density, electrophysiology, and repetitive behavior. Results: We found a greater percentage of parvalbumin-positive interneurons with PNNs in the DMS of all 4 mouse models of excessive repetitive behavior compared with control mice. In BTBR mice, we found fewer dendritic spines on medium spiny neurons (targets of parvalbumin-positive interneurons) and differences in neuronal oscillations as well as inhibitory postsynaptic potentials compared with control mice. Reduction of DMS PNNs in BTBR mice altered dendritic spine density and inhibitory responses and normalized repetitive behavior. Conclusions: These findings suggest that cellular abnormalities in the DMS are associated with maladaptive repetitive behaviors and that manipulating PNNs can restore normal levels of repetitive behavior while altering DMS dendritic spines and inhibitory signaling.

Early Life Adversity and Neuropsychiatric Disease: Differential Outcomes and Translational Relevance of Rodent Models.

It is now well-established that early life adversity (ELA) predisposes individuals to develop several neuropsychiatric conditions, including anxiety disorders, and major depressive disorder. However, ELA is a very broad term, encompassing multiple types of negative childhood experiences, including physical, sexual and emotional abuse, physical and emotional neglect, as well as trauma associated with chronic illness, family separation, natural disasters, accidents, and witnessing a violent crime. Emerging literature suggests that in humans, different types of adverse experiences are more or less likely to produce susceptibilities to certain conditions that involve affective dysfunction. To investigate the driving mechanisms underlying the connection between experience and subsequent disease, neuroscientists have developed several rodent models of ELA, including pain exposure, maternal deprivation, and limited resources. These studies have also shown that different types of ELA paradigms produce different but somewhat overlapping behavioral phenotypes. In this review, we first investigate the types of ELA that may be driving different neuropsychiatric outcomes and brain changes in humans. We next evaluate whether rodent models of ELA can provide translationally relevant information regarding links between specific types of experience and changes in neural circuits underlying dysfunction.

Satisfying singlehood as a function of age and cohort: Satisfaction with being single increases with age after midlife.

A growing body of research suggests that despite the stereotype of being dissatisfied with their relationship status, there is variability in how single (unpartnered) individuals feel about singlehood. The current research examined how satisfaction with singlehood varies (linearly or nonlinearly) with age. In Study 1, we analyzed five cross-sectional samples of single individuals (N = 3,304; collected in 2020-2021) using an integrative data analysis (IDA) approach. In Study 2, we used Dutch longitudinal data (N = 3,193; collected in 2008-2019) to more precisely separate the effect of age from that of birth cohort. Study 1 demonstrated that satisfaction with singlehood was positively associated with age after midlife whereas desire for a partner was negatively associated with age. Study 2 provided conceptually consistent evidence for age-related increases in satisfaction with singlehood during mid to late adulthood (around 40s-80s). Some evidence was found in Study 2 that more recent cohorts were higher in satisfaction with singlehood, but this effect did not hold when accounting for differences in marital status. These results provide evidence for potential age effects in well-being related outcomes for singles and suggest that midlife may be an important turning point. Understanding what makes singles satisfied with singlehood at older age may be a promising approach to gain insights into how to promote well-being of the rising single population. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Interpersonal traits and the neural representations of cognitive control in the prefrontal cortex.

Adaptive interpersonal functioning relies on the effectiveness of behavioral and neural systems involved in cognitive control. Whether different subcomponents of cognitive control and their neural representations are associated with distinctive interpersonal dispositions has yet to be determined. The present study investigated the relationships between prefrontal cortex (PFC) activation associated with two subcomponents of cognitive control and individual differences in interpersonally relevant traits and facets within the Five-Factor Model of personality. Undergraduate participants (n = 237) provided self-ratings of interpersonal traits and underwent functional near-infrared spectroscopy to measure activation in regions-of-interest linked to subcomponents of cognitive control: the right lateral PFC and its involvement in response selection and inhibition/suppression (RS) during a go/no-go task, and the left lateral PFC associated with goal selection, updating, representation, and maintenance (GS) on a tower planning task. Multilevel models revealed that during both RS and GS, Neuroticism and Extraversion were associated with lower and higher levels of activation, respectively. Higher Agreeableness was related to lower activation during RS but also with greater activation during GS. More narrowly defined interpersonal facets subsumed within the broader trait domains were differentially associated with RS- and GS-related neural responses. Taken together, these findings highlight potential avenues of future research to better understand the ways in which the neural processes that subserve cognitive control may underlie interpersonal dispositions.

Inhibition of adult neurogenesis reduces avoidance behavior in male, but not female, mice subjected to early life adversity.

Early life adversity (ELA) increases the risk of developing neuropsychiatric illnesses such as anxiety disorders. However, the mechanisms connecting these negative early life experiences to illness later in life remain unclear. In rodents, plasticity mechanisms, specifically adult neurogenesis in the ventral hippocampus, have been shown to be altered by ELA and important for buffering against detrimental stress-induced outcomes. The current study sought to explore whether adult neurogenesis contributes to ELA-induced changes in avoidance behavior. Using the GFAP-TK transgenic model, which allows for the inhibition of adult neurogenesis, and CD1 littermate controls, we subjected mice to an ELA paradigm of maternal separation and early weaning (MSEW) or control rearing. We found that mice with intact adult neurogenesis showed no behavioral changes in response to MSEW. After reducing adult neurogenesis, however, male mice previously subjected to MSEW had an unexpected decrease in avoidance behavior. This finding was not observed in female mice, suggesting that a sex difference exists in the role of adult-born neurons in buffering against ELA-induced changes in behavior. Taken together with the existing literature on ELA and avoidance behavior, this work suggests that strain differences exist in susceptibility to ELA and that adult-born neurons may play a role in regulating adaptive behavior.

The Ups and Downs of Being Us: Cross-Relationship Comparisons in Daily Life.

Cross-relationship comparisons are an integral part of relationship processes, yet little is known about the impact of these comparisons in daily life. The present research employed a dyadic experience-sampling methodology (N = 78 couples) with end-of-day surveys, end-of-week follow-up, and a 6-month follow-up to examine how individuals make cross-relationship comparisons in daily life, the cumulative impact of these comparisons over time, and the dyadic consequences of such comparisons. Participants made more downward than upward comparisons; however, upward comparisons had a more lasting impact, resulting in decreased satisfaction and optimism, and less positive self-perceptions and partner perceptions, at the end of each day and the week. Individuals who made more upward comparisons were also less satisfied 6 months later. Individuals were also affected by their partner's comparisons: On days when partners made more upward comparisons, they felt less satisfied and optimistic about their relationship and less positive about themselves and their partner.

Subjective Identity Concealability and the Consequences of Fearing Identity-Based Judgment.

In intergroup contexts, people may fear being judged negatively because of an identity they hold. For some, the prospect of concealment offers an opportunity to attenuate this fear. Therefore, believing an identity is concealable may minimize people's fears of identity-based judgment. Here, we explore the construct of subjective identity concealability: the belief that an identity one holds is concealable from others. Across four pre-registered studies and a set of internal meta-analyses, we develop and validate a scale to measure individual differences in subjective identity concealability and provide evidence that it is associated with lower levels of the psychological costs of fearing judgment in intergroup contexts. Open materials, data, and code for all studies, pre-registrations for Studies 1-4, and online supplementary materials can be found at the following link: https://osf.io/pzcf9/.

Atypical perineuronal nets in the CA2 region interfere with social memory in a mouse model of social dysfunction.

Social memory dysfunction is an especially devastating symptom of many neuropsychiatric disorders, which makes understanding the cellular and molecular processes that contribute to such abnormalities important. Evidence suggests that the hippocampus, particularly the CA2 region, plays an important role in social memory. We sought to identify potential mechanisms of social memory dysfunction in the hippocampus by investigating features of neurons, glia, and the extracellular matrix (ECM) of BTBR mice, an inbred mouse strain with deficient social memory. The CA2 is known to receive inputs from dentate gyrus adult-born granule cells (abGCs), neurons known to participate in social memory, so we examined this cell population and found fewer abGCs, as well as fewer axons from abGCs in the CA2 of BTBR mice compared to controls. We also found that BTBR mice had fewer pyramidal cell dendritic spines, in addition to fewer microglia and astrocytes, in the CA2 compared to controls. Along with diminished neuronal and glial elements, we found atypical perineuronal nets (PNNs), specialized ECM structures that regulate plasticity, in the CA2 of BTBR mice. By diminishing PNNs in the CA2 of BTBR mice to control levels, we observed a partial restoration of social memory. Our findings suggest that the CA2 region of BTBR mice exhibits multiple cellular and extracellular abnormalities and identify atypical PNNs as one mechanism producing social memory dysfunction, although the contribution of reduced abGC afferents, pyramidal cell dendritic spine, and glial cell numbers remains unexplored.

SCN2A contributes to oligodendroglia excitability and development in the mammalian brain.

Spiking immature oligodendrocytes (OLs), referred to as spiking OLs, express voltage-activated Na+ channels (Nav) and K+ (Kv) channels, endowing a subpopulation of OLs with the ability to generate Nav-driven spikes. In this study, we investigate the molecular profile of spiking OLs, using single-cell transcriptomics paired with whole-cell patch-clamp recordings. SCN2A, which encodes the channel Nav1.2, is specifically expressed in spiking OLs in the brainstem and cerebellum, both in mice and in Olive baboons. Spiking OLs express lineage markers of OL progenitor cells (OPCs) and pre-myelinating OLs, indicating they belong to a transitional stage during differentiation. Deletion of SCN2A reduces the Nav current-expressing OL population and eliminates spiking OLs, indicating that SCN2A is essential for spiking in OLs. Deletion of SCN2A does not impact global OL proliferation but disrupts maturation of a subpopulation of OLs, suggesting that Nav1.2 is involved in heterogeneity in OL lineage cells and their development.