Involvement of the oxytocin system in sex-specific regulation of social behavior and sex-specific brain activation

Thesis advisor: Alexa H. VeenemaThe poorly understood, but robust sex differences in prevalence, symptom severity, and treatment responses of many psychiatric disorders characterized by social dysfunction signifies the importance of understanding the neurobiological mechanisms underlying sex differences in the regulation of social behaviors. One potential system involved is the oxytocin (OT) system. OT is an evolutionarily conserved neuropeptide that has been implicated in the regulation of a variety of social behaviors in rodents and humans. This thesis aims to clarify the role of OT in sex-specific regulation of social behavior and brain function in rats. Study 1 characterized sex differences in the OT system in the brain, and found that males show higher OT receptor (OTR) binding densities in several forebrain regions compared to females. Studies 2 and 3 then determined the relevance of these sex differences in OTR binding densities for the sex-specific regulation of social behavior using pharmacological manipulations of the OTR and in vivo measurement of OT release. Study 2 focused on the function of the OT system in the posterior bed nucleus of the stria terminalis (BNSTp), because this region showed the largest sex difference in OTR binding density, and is part of the core social behavior network. Results show that endogenous OT in the BNSTp is important for social recognition in both sexes, but that exogenous OT facilitated social recognition in males only. Furthermore, social recognition in males, but not in females, was associated with higher endogenous OT release in BNSTp. This study is the first to provide a link between sex differences in OTR binding density and OT release with sex-specific regulation of social recognition by OT. Study 3 focused on amygdala subregions because these regions were found to show sex-specific correlations of OTR binding density with social interest. Results show that the OT system modulates social interest in the central amygdala (CeA), but not the medial amygdala, in sex-specific ways, with activation of the OTR in the CeA facilitating social interest in males, but not in females. These results provide evidence that the CeA is a brain region involved in the sex-specific processing of social stimuli by the OT system. Finally, Study 4 examined whether sex differences in OTR binding densities in forebrain regions lead to sex-specific brain activation in response to OT. Functional magnetic resonance imaging was used to examine blood oxygen level-dependent (BOLD) activation in awake male and female rats following central or peripheral administration of OT. Central OT administration induced sex differences in BOLD activation in numerous brain regions (including several regions with denser OTR binding in males), in which males showed predominantly higher activation compared to females. Peripheral OT administration also induced sex differences in BOLD activation, but in fewer brain regions and in different brain regions compared to central OT, indicating that the pattern and the magnitude of sex differences in neural activation induced by OT strongly depend on the route of administration. Together, outcomes of this thesis provide novel insight into the sexual dimorphic structure and function of the OT system in rats, and highlights the fact that research seeking a full understanding of the role of the OT system in behavioral and brain responses is incomplete without the inclusion of both sexes. These results may be informative given the increasing popularity of the use of OT as a potential therapeutic agent in the treatment of social dysfunction in sex-biased psychiatric disorders.Thesis (PhD) — Boston College, 2016.Submitted to: Boston College. Graduate School of Arts and Sciences.Discipline: Psychology

Maternal depression is associated with DNA methylation changes in cord blood T lymphocytes and adult hippocampi

Depression affects 10-15% of pregnant women and has been associated with preterm delivery and later developmental, behavioural and learning disabilities. We tested the hypothesis that maternal depression is associated with DNA methylation alterations in maternal T lymphocytes, neonatal cord blood T lymphocytes and adult offspring hippocampi. Genome-wide DNA methylation of CD3+ T lymphocytes isolated from 38 antepartum maternal and 44 neonatal cord blood samples were analyzed using Illumina Methylation 450 K microarrays. Previously obtained methylation data sets using methylated DNA immunoprecipitation and array-hybridization of 62 postmortem hippocampal samples of adult males were re-analyzed to test associations with history of maternal depression. We found 145 (false discovery rate (FDR) q<0.05) and 2520 (FDR q<0.1) differentially methylated CG-sites in cord blood T lymphocytes of neonates from the maternal depression group as compared with the control group. However, no significant DNA methylation differences were detected in the antepartum maternal T lymphocytes of our preliminary data set. We also detected 294 differentially methylated probes (FDR q<0.1) in hippocampal samples associated with history of maternal depression. We observed a significant overlap (P=0.002) of 33 genes with changes in DNA methylation in T lymphocytes of neonates and brains of adult offspring. Many of these genes are involved in immune system functions. Our results show that DNA methylation changes in offspring associated with maternal depression are detectable at birth in the immune system and persist to adulthood in the brain. This is consistent with the hypothesis that system-wide epigenetic changes are involved in life-long responses to maternal depression in the offspring. © 2015 Translational Psychiatry

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

Sex differences in default mode and dorsal attention network engagement

Focusing on sex differences is necessary to fully understand basic neurobiological processes such as the engagement of large-scale brain networks involved in attention. Prior work suggests that women show enhanced attention during tasks of reward/punishment relative to men. Yet, sex differences in the engagement of neural networks sub serving internal and external focus has been unexplored in regard to reward and punishment. Using data from a large sample (n = 190) of healthy participants from the Human Connectome Project, we investigated sex differences in default mode network (DMN), dorsal attention network (DAN), and frontal parietal network (FPN) activation during exposure to reward and punishment. To determine if sex differences are specific to valenced stimuli, we analyzed network activation during working memory. Results indicate that, relative to men, women have increased suppression of the DMN and greater activation of the DAN during exposure to reward and punishment. Given the relative roles of these networks in internal (DMN) and external (DAN) attention, this pattern of activation suggests that women have enhanced external attention to reward and punishment. In contrast, there were no sex differences in network activation during working memory, indicating that this sex difference is specific to the processing of reward and punishment. These findings suggest a neurobiological explanation for prior work showing women have greater sensitivity to reward/punishment and are more prone to psychiatric disorders characterized by enhanced attention to such stimuli. Furthermore, given the large sample from the Human Connectome Project, the current findings provide general implications for the study of sex as a biological variable in investigation of reward processes

Sex-specific modulation of juvenile social play behavior by vasopressin and oxytocin depends on social context

We recently demonstrated that vasopressin (AVP) in the lateral septum modulates social play behavior differently in male and female juvenile rats. However, the extent to which different social contexts (i.e., exposure to an unfamiliar play partner in different environments) affect the regulation of social play remains largely unknown. Given that AVP and the closely related neuropeptide oxytocin (OXT) modulate social behavior as well as anxiety-like behavior, we hypothesized that these neuropeptides may regulate social play behavior differently in novel (novel cage) as opposed to familiar (home cage) social environments. Administration of the specific AVP V1a receptor (V1aR) antagonist (CH2)5Tyr(Me2)AVP into the lateral septum enhanced home cage social play behavior in males but reduced it in females, confirming our previous findings. These effects were context-specific because V1aR blockade did not alter novel cage social play behavior in either sex. Furthermore, social play in females was reduced by AVP in the novel cage and by OXT in the home cage. Additionally, females administered the specific OXT receptor antagonist desGly-NH2,d(CH2)5-[Tyr(Me)2,Thr4]OVT showed less social play in the novel as compared to the home cage. AVP enhanced anxiety-related behavior in males (tested on the elevated plus-maze), but failed to do so in females, suggesting that exogenous AVP alters social play and anxiety-related behavior via distinct and sex-specific mechanisms. Moreover, none of the other drug treatments that altered social play had an effect on anxiety, suggesting that these drug-induced behavioral alterations are relatively specific to social behavior. Overall, we showed that AVP and OXT systems in the lateral septum modulate social play in juvenile rats in neuropeptide-, sex- and social context-specific ways. These findings underscore the importance of considering not only sex, but also social context, in how AVP and OXT modulate social behavior

Network activation during reward and punishment trials of the incentive processing task.

<p>Females show greater suppression of the default mode network (DMN) and greater activation of the dorsal attention network (DAN) during reward and punishment trials compared to males. There is no sex difference in frontoparietal control network (FPN) activation. * p < 0.05, **p<0.01, t-tests with non-parametric permutation testing via Permutation Analysis of Linear Models (PALM). Bars represent mean ± SEM.</p

Participant demographics.

<p>Participant demographics.</p

Network ICA maps.

<p>Sagittal, coronal and axial images showing the independent components from the MELODIC analysis that correspond to the default mode network (DMN), dorsal attention network (DAN) and frontoparietal control network (FPN). Because two DMN sub-networks and two FPN networks (left and right) were identified, the maps of these networks were added together to show a single DMN and FPN. Networks are shown overlaid on the MNI standard brain image.</p

Distinct BOLD activation profiles following central and peripheral oxytocin administration in awake rats

A growing body of literature has suggested that intranasal oxytocin (OT) or other systemic routes of administration can alter prosocial behavior, presumably by directly activating OT sensitive neural circuits in the brain. Yet there is no clear evidence that OT given peripherally can cross the blood-brain-barrier at levels sufficient to engage the OT receptor. To address this issue we examined changes in blood oxygen level dependent (BOLD) signal intensity in response to peripheral OT injections (0.1, 0.5 or 2.5 mg/kg) during functional magnetic resonance (fMRI) in awake rats imaged at 7.0 tesla. These data were compared to OT (1ug/5 µl) given directly to the brain via the lateral cerebroventricle. Using a 3D annotated MRI atlas of the rat brain segmented into 171 brain areas and computational analysis we reconstructed the distributed integrated neural circuits identified with BOLD fMRI following central and peripheral OT. Both routes of administration caused significant changes in BOLD signal within the first 10 min of administration. As expected, central OT activated a majority of brain areas known to express a high density of OT receptors e.g., lateral septum, subiculum, shell of the accumbens, bed nucleus of the stria terminalis. This profile of activation was not matched by peripheral OT. The change in BOLD signal to peripheral OT did not show any discernible dose-response. Interestingly, peripheral OT affected all subdivisions of the olfactory bulb, in addition to the cerebellum and several brainstem areas relevant to the autonomic nervous system, including the solitary tract nucleus. The results from this imaging study do not support a direct central action of peripheral OT on the brain. Instead, the patterns of brain activity suggest that peripheral OT may interact at the level of the olfactory bulb and through sensory afferents from the autonomic nervous system to influence brain activity