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Sex differences in the structure and organization of the corpus callosum (CC) can be attributed to genetic, hormonal, or environmental effects, or a combination of these factors. To address the role of gonadal hormones on axon myelination functional axon conduction and immunohistochemistry analysis of the CC in intact, gonadectomized, and hormone-replaced gonadectomized animals were used. These groups were subjected to cuprizone diet-induced demyelination followed by remyelination. The myelinated component of callosal compound action potential was significantly decreased in ovariectomized and castrated animals. Compared to gonadally intact cohorts, both gonadectomized groups displayed more severe demyelination and inhibited remyelination. Castration in males was more deleterious than ovariectomy in females. Callosal conduction in estradiol-supplemented ovariectomized females was significantly increased during normal myelination less attenuated during demyelination and increased beyond placebo-treated ovariectomized or intact female levels during remyelination. In castrated males, the non-aromatizing steroid dihydrotestosterone was less efficient than testosterone and estradiol in restoring normal myelination/axon conduction and remyelination to levels of intact males. Furthermore, in both sexes, estradiol supplementation in gonadectomized groups increased the number of oligodendrocytes. These studies suggest an essential role of estradiol to bring forth efficient CC myelination and axon conduction in both sexes.

BACKGROUND: There are robust sex differences in the prevalence of depression. Inflammation and anhedonia may play a role in understanding these sex differences. Indeed, sex differences in inflammation-induced neural responses to reward may provide insight into the sex gaps in depression, but no study has examined this question. METHODS: As such, the current study examined whether there were sex differences in reward-related neural activity (i.e., ventral striatum [VS] activity) in response to an experimental inflammatory challenge. Human participants (N = 115; 69 female) were randomly assigned to receive either placebo or low-dose endotoxin, which increases inflammation in a safe, time-limited manner. Two hours after receiving placebo or endotoxin (the height of the inflammatory response to endotoxin), participants completed a task in which they anticipated monetary reward in a functional magnetic resonance imaging scanner. RESULTS: Results demonstrated that endotoxin (vs. placebo) led to reduced VS activity in anticipation of reward and that there were sex differences in this effect. Specifically, in female participants, endotoxin (vs. placebo) led to decreased VS activity in anticipation of reward, but this effect was not present in male participants. In addition, within the endotoxin condition, decreases in VS activity in anticipation of reward were related to increases in inflammation for female but not male participants. CONCLUSIONS: These findings may have implications for understanding how inflammation may contribute to sex differences in rates of depression.

Neuroimaging studies of mentalizing (i.e., theory of mind) consistently implicate the default mode network (DMN). Nevertheless, the social cognitive functions of individual DMN regions remain unclear, perhaps due to limited spatiotemporal resolution in neuroimaging. Here we use electrocorticography (ECoG) to directly record neuronal population activity while 16 human participants judge the psychological traits of themselves and others. Self- and other-mentalizing recruit near-identical cortical sites in a common spatiotemporal sequence. Activations begin in the visual cortex, followed by temporoparietal DMN regions, then finally in medial prefrontal regions. Moreover, regions with later activations exhibit stronger functional specificity for mentalizing, stronger associations with behavioral responses, and stronger self/other differentiation. Specifically, other-mentalizing evokes slower and longer activations than self-mentalizing across successive DMN regions, implying lengthier processing at higher levels of representation. Our results suggest a common neurocognitive pathway for self- and other-mentalizing that follows a complex spatiotemporal gradient of functional specialization across DMN and beyond.

Background: Social cognitive impairments, specifically in mentalizing and emotion recognition, are common and debilitating symptoms of posttraumatic stress disorder (PTSD). Despite this, little is known about the neurobiology of these impairments, as there are currently no published neuroimaging investigations of social inference in PTSD.Methods: Trauma-exposed veterans with and without PTSD (n = 20 each) performed the Why/How social inference task during functional magnetic resonance imaging (fMRI). Patients with PTSD had two fMRI sessions, between which they underwent affect labeling training. We probed the primary networks of the "social brain"-the default mode network (DMN) and mirror neuron system (MNS)-by examining neural activity evoked by mentalizing and action identification prompts, which were paired with emotional and nonemotional targets.Results: Hyperactivation to emotional stimuli differentiated PTSD patients from controls, correlated with symptom severity, and predicted training outcomes.Critically, these effects were nonsignificant or marginal for nonemotional stimuli.Results were generally consistent throughout DMN and MNS. Unexpectedly, effects were nonsignificant in core affect regions, but robust in regions that overlap with the dorsal attention, ventral attention, and frontoparietal control networks. Conclusions:The array of social cognitive processes subserved by DMN and MNS appear to be inordinately selective for emotional stimuli in PTSD. However, core affective processes do not appear to be the primary instigators of such selectivity. Instead, we propose that affective attentional biases may instigate widespread affect-selectivity throughout the social brain. Affect labeling training may inhibit such biases. These accounts align with numerous reports of affect-biased attentional processes in PTSD.

Background Although potential links between oxytocin (OT), vasopressin (AVP), and social cognition are well-grounded theoretically, most studies have included all male samples, and few have demonstrated consistent effects of either neuropeptide on mentalizing (i.e. understanding the mental states of others). To understand the potential of either neuropeptide as a pharmacological treatment for individuals with impairments in social cognition, it is important to demonstrate the beneficial effects of OT and AVP on mentalizing in healthy individuals. Methods In the present randomized, double-blind, placebo-controlled study (n = 186) of healthy individuals, we examined the effects of OT and AVP administration on behavioral responses and neural activity in response to a mentalizing task. Results Relative to placebo, neither drug showed an effect on task reaction time or accuracy, nor on whole-brain neural activation or functional connectivity observed within brain networks associated with mentalizing. Exploratory analyses included several variables previously shown to moderate OT's effects on social processes (e.g., self-reported empathy, alexithymia) but resulted in no significant interaction effects. Conclusions Results add to a growing literature demonstrating that intranasal administration of OT and AVP may have a more limited effect on social cognition, at both the behavioral and neural level, than initially assumed. Randomized controlled trial registrations: ClinicalTrials.gov; NCT02393443; NCT02393456; NCT02394054.

Characters in Title: 112Word Counts: Abstract = 250 Main text = 3980 AbstractBackground: Social impairments, specifically in mentalizing and emotion recognition, are common and debilitating symptoms of posttraumatic stress disorder (PTSD). Despite this, little is known about the neural underpinnings of these impairments, as there have been no published neuroimaging investigations of social inference in PTSD.Methods: Trauma-exposed veterans with and without PTSD (N = 20 each) performed the Why/How social inference task during functional magnetic resonance imaging (fMRI). The PTSD group had two fMRI sessions, between which they underwent affect labeling training. We probed the primary networks of the "social brain"-the default mode network (DMN) and mirror neuron system (MNS)-by examining neural activity evoked by mentalizing and action identification prompts, which were paired with emotional and non-emotional targets.Results: Hyperactivation to emotional stimuli differentiated PTSD patients from controls, correlated with symptom severity, and predicted training outcomes. Critically, these effects were generally non-significant for non-emotional stimuli. PTSD-related effects were widely distributed throughout DMN and MNS. Effects were strongest in regions associated with the dorsal attention, ventral attention, and frontoparietal control networks. Unexpectedly, effects were non-significant in core affect regions.Conclusions: The array of social cognitive processes subserved by DMN and MNS may be inordinately selective for emotional stimuli in PTSD. This selectivity may be tightly linked with attentional processes, as effects were strongest in attention-related regions. Putatively, wepropose an attentional account of social inference dysfunction in PTSD, in which affective attentional biases drive widespread affect-selectivity throughout the social brain. This account aligns with numerous findings of affect-biased attentional processing in PTSD.PTSD AND THE SOCIAL BRAIN 3/39

Hundreds of neuroimaging studies show that mentalizing (i.e., theory of mind) recruits default mode network (DMN) regions with remarkable consistency. Nevertheless, the social-cognitive functions of individual DMN regions remain unclear, perhaps due to the limited spatiotemporal resolution of neuroimaging. We used electrocorticography (ECoG) to record neuronal population activity while 16 human subjects judged the psychological traits of themselves and others. Self- and other-mentalizing recruited near-identical neuronal populations in a common spatiotemporal sequence: activations were earliest in visual cortex, followed by temporoparietal DMN regions, and finally medial prefrontal cortex. Critically, regions with later activations showed greater functional specificity for mentalizing, greater self/other differentiation, and stronger associations with behavioral response times. Moreover, other-mentalizing evoked slower and lengthier activations than self-mentalizing across successive DMN regions, suggesting temporally extended demands on higher-level processes. Our results reveal a common neurocognitive pathway for self- and other-mentalizing that follows a hierarchy of functional specialization across DMN regions.