Mating-induced release of oxytocin in the mouse lateral septum: Implications for social fear extinction.

In mammals, some physiological conditions are associated with the high brain oxytocin (OXT) system activity. These include lactation in females and mating in males and females, both of which have been linked to reduced stress responsiveness and anxiolysis. Also, in a murine model of social fear conditioning (SFC), enhanced brain OXT signaling in lactating mice, specifically in the lateral septum (LS), was reported to underlie reduced social fear expression. Here, we studied the effects of mating in male mice on anxiety-related behaviour, social (and cued) fear expression and its extinction, and the activity of OXT neurons reflected by cFos expression and OXT release in the LS and amygdala. We further focused on the involvement of brain OXT in the mating-induced facilitation of social fear extinction. We could confirm the anxiolytic effect of mating in male mice irrespective of the occurrence of ejaculation. Further, we found that only successful mating resulting in ejaculation (Ej+) facilitated social fear extinction, whereas mating without ejaculation (Ej-) did not. In contrast, mating did not affect cues fear expression. Using the cellular activity markers cFos and pErk, we further identified the ventral LS (vLS) as a potential region participating in the effect of ejaculation on social fear extinction. In support, microdialysis experiments revealed a rise in OXT release within the LS, but not the amygdala, during mating. Finally, infusion of an OXT receptor antagonist into the LS before mating or into the lateral ventricle (icv) after mating demonstrated a significant role of brain OXT receptor-mediated signaling in the mating-induced facilitation of social fear extinction.

Repeated Lacrimal Gland Biopsies.

INTRODUCTION: To examine the indications for repeated lacrimal gland biopsies, and the rate of detection of a new diagnosis. METHODS: A single-center, retrospective review of patients who underwent more than 1 lacrimal gland biopsy, either ipsilateral or contralateral, between 2000 and 2022. RESULTS: One hundred and twenty-three patients (80 female; 65%) had repeated lacrimal gland biopsy. The commonest diagnosis on initial biopsy was chronic nonspecific dacryoadenitis (NSD) (49/123; 40%). Indications for repeated biopsy were uncertainty in making a histopathological diagnosis (16/123; 13%), poorly-responsive or recurrent ipsilateral disease (61/123; 50%), new or continued/worsening contralateral disease (30 patients; 24%), and planned tumor resection after initial biopsy (16/123; 13%). Of the 40 patients (33%) with a different histopathological diagnosis after repeated lacrimal biopsy, 4 (10%) had lymphoma, initially reported as NSD (4/49 with NSD; 8%), and 7/40 (18%) (14% of the 49 NSD patients) were reclassified as having specific inflammations (including 2 with granulomatous polyangiitis); of the 7 having reclassification as a specific dacryoadenitis, 6/7 had ipsilateral disease failing to respond to primary treatment, and 1/7 had new onset or progression of contralateral disease. All histology after the primary biopsy of 16 patients with lacrimal gland malignancies retained the same tissue diagnosis. CONCLUSION: Repeated biopsy for lacrimal gland disease in this study revealed a diagnosis of malignancy in 20%, including lymphoma in 8% of those initially diagnosed with NSD. There was a 14% rate of diagnostic progression from "non-specific" dacryoadenitis to a more specific inflammatory disease.

Monitoring oxytocin signaling in the brain: More than a love story.

More than any other neuropeptide, oxytocin (OXT) is attracting the attention of neurobiologists, psychologists, psychiatrists, evolutionary biologists and even economists. It is often called a "love hormone" due to its many prosocial functions described in vertebrates including mammals and humans, especially its ability to support "bonding behaviour". Oxytocin plays an important role in female reproduction, as it promotes labour during parturition, enables milk ejection in lactation and is essential for related reproductive behaviours. Therefore, it particularly attracts the interest of many female researchers. In this short narrative review I was invited to provide a personal overview on my scientific journey closely linked to my research on the brain OXT system and the adventures associated with starting my research career behind the Iron Curtain.

Functional involvement of septal miR-132 in extinction and oxytocin-mediated reversal of social fear.

Social interactions are critical for mammalian survival and evolution. Dysregulation of social behavior often leads to psychopathologies such as social anxiety disorder, denoted by intense fear and avoidance of social situations. Using the social fear conditioning (SFC) paradigm, we analyzed expression levels of miR-132-3p and miR-124-3p within the septum, a brain region essential for social preference and avoidance behavior, after acquisition and extinction of social fear. Here, we found that SFC dynamically altered both microRNAs. Functional in vivo approaches using pharmacological strategies, inhibition of miR-132-3p, viral overexpression of miR-132-3p, and shRNA-mediated knockdown of miR-132-3p specifically within oxytocin receptor-positive neurons confirmed septal miR-132-3p to be critically involved not only in social fear extinction, but also in oxytocin-induced reversal of social fear. Moreover, Argonaute-RNA-co-immunoprecipitation-microarray analysis and further in vitro and in vivo quantification of target mRNA and protein, revealed growth differentiation factor-5 (Gdf-5) as a target of miR-132-3p. Septal application of GDF-5 impaired social fear extinction suggesting its functional involvement in the reversal of social fear. In summary, we show that septal miR-132-3p and its downstream target Gdf-5 regulate social fear expression and potentially mediate oxytocin-induced reversal of social fear.

Detection, processing and reinforcement of social cues: regulation by the oxytocin system.

Many social behaviours are evolutionarily conserved and are essential for the healthy development of an individual. The neuropeptide oxytocin (OXT) is crucial for the fine-tuned regulation of social interactions in mammals. The advent and application of state-of-the-art methodological approaches that allow the activity of neuronal circuits involving OXT to be monitored and functionally manipulated in laboratory mammals have deepened our understanding of the roles of OXT in these behaviours. In this Review, we discuss how OXT promotes the sensory detection and evaluation of social cues, the subsequent approach and display of social behaviour, and the rewarding consequences of social interactions in selected reproductive and non-reproductive social behaviours. Social stressors - such as social isolation, exposure to social defeat or social trauma, and partner loss - are often paralleled by maladaptations of the OXT system, and restoring OXT system functioning can reinstate socio-emotional allostasis. Thus, the OXT system acts as a dynamic mediator of appropriate behavioural adaptations to environmental challenges by enhancing and reinforcing social salience and buffering social stress.

Oxytocin Receptor Expression in Hair Follicle Stem Cells: A Promising Model for Biological and Therapeutic Discovery in Neuropsychiatric Disorders.

The intricate nature of the human brain and the limitations of existing model systems to study molecular and cellular causes of neuropsychiatric disorders represent a major challenge for basic research. The promising progress in patient-derived stem cell technology and in our knowledge on the role of the brain oxytocin (OXT) system in health and disease offer new possibilities in that direction. In this study, the rat hair follicle stem cells (HFSCs) were isolated and expanded in vitro. The expression of oxytocin receptors (OXTR) was evaluated in these cells. The cellular viability was assessed 12 h post stimulation with OXT. The activation of OXTR-coupled intracellular signaling cascades, following OXT treatment was determined. Also, the influence of OXT on neurite outgrowth and cytoskeletal rearrangement were defined. The assessment of OXTR protein expression revealed this receptor is expressed abundantly in HFSCs. As evidenced by the cell viability assay, no adverse or cytotoxic effects were detected following 12 h treatment with different concentrations of OXT. Moreover, OXTR stimulation by OXT resulted in ERK1/2, CREB, and eEF2 activation, neurite length alterations, and cytoskeletal rearrangements that reveal the functionality of this receptor in HFSCs. Here, we introduced the rat HFSCs as an easy-to-obtain stem cell model that express functional OXTR. This cell-based model can contribute to our understanding of the progression and treatment of neuropsychiatric disorders with oxytocinergic system deficiency.

Selective breeding of rats for high (HAB) and low (LAB) anxiety-related behaviour: A unique model for comorbid depression and social dysfunctions.

Animal models of selective breeding for extremes in emotionality are a strong experimental approach to model psychopathologies. They became indispensable in order to increase our understanding of neurobiological, genetic, epigenetic, hormonal, and environmental mechanisms contributing to anxiety disorders and their association with depressive symptoms or social deficits. In the present review, we extensively discuss Wistar rats selectively bred for high (HAB) and low (LAB) anxiety-related behaviour on the elevated plus-maze. After 30 years of breeding, we can confirm the prominent differences between HAB and LAB rats in trait anxiety, which are accompanied by consistent differences in depressive-like, social and cognitive behaviours. We can further confirm a single nucleotide polymorphism in the vasopressin promotor of HAB rats causative for neuropeptide overexpression, and show that low (or high) anxiety and fear levels are unlikely due to visual dysfunctions. Thus, HAB and LAB rats continue to exist as a reliable tool to study the multiple facets underlying the pathology of high trait anxiety and its comorbidity with depression-like behaviour and social dysfunctions.

HDAC1-mediated regulation of GABA signaling within the lateral septum facilitates long-lasting social fear extinction in male mice.

Social anxiety disorder (SAD) is caused by traumatic social experiences. It is characterized by intense fear and avoidance of social contexts, which can be robustly mimicked by the social fear conditioning (SFC) paradigm. The extinction phase of the SFC paradigm is akin to exposure therapy for SAD and requires learning to disassociate the trauma with the social context. Learning-induced acetylation of histones is critical for extinction memory formation and its endurance. Although class I histone deacetylases (HDACs) regulate the abovementioned learning process, there is a lack of clarity in isoforms and spatial specificity in HDAC function in social learning. Utilizing the SFC paradigm, we functionally characterized the role of HDAC1, specifically in the lateral septum (LS), in regulating the formation of long-term social fear extinction memory. We measured a local increase in activity-inducing HDAC1 phosphorylation at serine residues of social fear-conditioned (SFC+) mice in response to the extinction of social fear. We also found that LS-HDAC1 function negatively correlates with acute social fear extinction learning using pharmacological and viral approaches. Further, inhibition of LS-HDAC1 enhanced the expression of the GABA-A receptor ß1 subunit (Gabrb1) in SFC+ mice, and activation of GABA-A receptors facilitated acute extinction learning. Finally, the facilitation of extinction learning by HDAC1 inhibition or GABA-A receptor activation within the LS led to the formation of long-lasting extinction memory, which persisted even 30 days after extinction. Our results show that HDAC1-mediated regulation of GABA signaling in the LS is crucial for the formation of long-lasting social fear extinction memory.

Rare periorbital, pseudocystic metastasis of squamous cell carcinoma of the bladder: Case report and review of the literature.

We present the case of a man in his fifties with a history of bladder carcinoma who presented with a large periorbital cystic lesion that was found to be a metastasis. Bladder carcinomas are a very rare cause of peri-/orbital metastasis. The primary tumor in this case predominately showed squamous cell differentiation and small areas of adenoid differentiation. To our knowledge only one previous case of orbital metastasis from squamous cell carcinoma of the bladder has been reported. Cyst formation in bladder cancer metastasis has not been reported and is very rare for orbital metastases in general. The pathogenesis of metastatic cyst development is not fully understood and may vary from case to case. A biopsy of an atypical cyst is indicated.

Treatment of periocular lentigo maligna with topical 5% Imiquimod: a review.

Lentigo Maligna is a benign subtype of melanoma in situ and can progress to lentigo maligna melanoma, which is invasive. Complete surgical excision is the gold standard of treatment but requires large margins. If affecting the peri-ocular region, surgical excision leads to extensive defects, complex reconstructions, and functional impairment of the protection of the ocular surface. Here we review the reported literature about the use of Imiquimod 5% topical cream for lentigo maligna of the eyelid, the treatment outcomes, side effects and tolerance. In addition, the side effects of imiquimod treatment of non-LM lesions are described to help better inform the decision-making process. Treatment for peri-ocular Lentigo maligna showed a 56-86% complete treatment response and a 90% tolerability rate. However, reported treatment protocols vary and histopathological confirmation of clearance was only obtained in 56%. Further studies are required to determine the optimal treatment protocol to maximise clearance rates. Overall, Imiquimod was well tolerated in the peri-ocular area.

Advances in human oxytocin measurement: challenges and proposed solutions.

Oxytocin, a neuropeptide known for its role in reproduction and socioemotional processes, may hold promise as a therapeutic agent in treating social impairments in patient populations. However, research has yet to uncover precisely how to manipulate this system for clinical benefit. Moreover, inconsistent use of standardized and validated oxytocin measurement methodologies-including the design and study of hormone secretion and biochemical assays-present unresolved challenges. Human studies measuring peripheral (i.e., in plasma, saliva, or urine) or central (i.e., in cerebrospinal fluid) oxytocin concentrations have involved very diverse methods, including the use of different assay techniques, further compounding this problem. In the present review, we describe the scientific value in measuring human endogenous oxytocin concentrations, common issues in biochemical analysis and study design that researchers face when doing so, and our recommendations for improving studies using valid and reliable methodologies.

Total Full-Thickness Upper Eyelid Reconstruction: Combination of Mustardé Eyelid Switch Flap with a Bipedicled Periosteal and Tenzel Flap Technique.

INTRODUCTION: In recent decades, two techniques for large full-thickness upper eyelid reconstruction have been described, the Cutler-Beard lid sharing flap and the Mustardé eyelid switch flap. In the literature, modifications are being introduced to improve those techniques. Here, we present our approach for the reconstruction of total full-thickness upper eyelid defects and compare it with these established upper lid reconstruction techniques. METHODS: Three patients presented with upper eyelid tumors and required extensive excision resulting in total full-thickness upper eyelid defects. Reconstruction consisted of a two-stage procedure: a Mustardé eyelid switch flap was performed followed by division of the rotation flap and lateral canthoplasty using a periosteal bipedicled flap and Tenzel flap. Patients were followed-up every 3 months for at least 1 year. During every preoperative and postoperative check-up, palpebral fissure height, levator function, margin reflex distance, and presence of lagophthalmos were measured. RESULTS: Histopathological examination revealed a Merkel cell carcinoma in two cases and a Basal cell carcinoma in one case. Postoperatively, all patients showed a stable reconstructed upper eyelid with preserved motility and satisfying aesthetic results when compared to the fellow eye. In one case, a lagophthalmos of 1.5 mm was observed, which was treated conservatively to prevent exposure keratopathy. CONCLUSION: The eyelid switch flap combined with a bipedicled periosteal and a Tenzel flap is a good alternative for the reconstruction of total upper eyelid defects with the advantage of leaving the contralateral eye untouched. It achieves satisfying anatomical results, including an upper eyelid margin with eyelashes and well-matched skin color.

Brain-derived neurotrophic factor expression in serotonergic neurons improves stress resilience and promotes adult hippocampal neurogenesis.

The neurotrophin brain-derived neurotrophic factor (BDNF) stimulates adult neurogenesis, but also influences structural plasticity and function of serotonergic neurons. Both, BDNF/TrkB signaling and the serotonergic system modulate behavioral responses to stress and can lead to pathological states when dysregulated. The two systems have been shown to mediate the therapeutic effect of antidepressant drugs and to regulate hippocampal neurogenesis. To elucidate the interplay of both systems at cellular and behavioral levels, we generated a transgenic mouse line that overexpresses BDNF in serotonergic neurons in an inducible manner. Besides displaying enhanced hippocampus-dependent contextual learning, transgenic mice were less affected by chronic social defeat stress (CSDS) compared to wild-type animals. In parallel, we observed enhanced serotonergic axonal sprouting in the dentate gyrus and increased neural stem/progenitor cell proliferation, which was uniformly distributed along the dorsoventral axis of the hippocampus. In the forced swim test, BDNF-overexpressing mice behaved similarly as wild-type mice treated with the antidepressant fluoxetine. Our data suggest that BDNF released from serotonergic projections exerts this effect partly by enhancing adult neurogenesis. Furthermore, independently of the genotype, enhanced neurogenesis positively correlated with the social interaction time after the CSDS, a measure for stress resilience.

Synthetic Oxytocin and Vasopressin Act Within the Central Amygdala to Exacerbate Aggression in Female Wistar Rats.

Exacerbated aggression is a high-impact, but poorly understood core symptom of several psychiatric disorders, which can also affect women. Animal models have successfully been employed to unravel the neurobiology of aggression. However, despite increasing evidence for sex-specificity, little is known about aggression in females. Here, we studied the role of the oxytocin (OXT) and arginine vasopressin (AVP) systems within the central amygdala (CeA) on aggressive behavior displayed by virgin female Wistar rats using immunohistochemistry, receptor autoradiography, and neuropharmacology. Our data show that CeA GABAergic neurons are activated after an aggressive encounter in the female intruder test. Additionally, neuronal activity (pERK) negatively correlated with the display of aggression in low-aggressive group-housed females. Binding of OXT receptors, but not AVP-V1a receptors, was increased in the CeA of high-aggressive isolated and trained (IST) females. Finally, local infusion of either synthetic OXT or AVP enhanced aggression in IST females, whereas blockade of either of these receptors did not affect aggressive behavior. Altogether, our data support a moderate role of the CeA in female aggression. Regarding neuropeptide signaling, our findings suggest that synthetic, but not endogenous OXT and AVP modulate aggressive behavior in female Wistar rats.

A model for the social neuroscience of music production begins on a dubious note: Commentary on Greenberg et al. (2021).

Group singing and music-making behaviors that were rapidly adapted to the coronavirus disease (COVID-19) pandemic context suggest to Greenberg et al. (2021) not only a musical solution to pandemic-related social isolation but also the importance of the social neuroscientific side of music. They propose a model of the social neuroscience of music production premised on the view that group singing leads to increased levels of oxytocin (a neuropeptide associated with empathy and social bonding), citing data of Schladt et al. (2017) and Keeler et al. (2015) as support. The present commentary points out that Schladt et al. reported a decrease rather than an increase in oxytocin level following group singing. Further, reference to the work by Keeler et al. (2015) is only partially accurate, and evidence contrary to the oxytocin premise is ignored. Similar inaccuracy is associated with claims for cortisol, another primary component of their model. While the authors are applauded for directing attention to both the social neuroscience of music and the value of group singing, tempering the stated premises associated with the oxytocin and cortisol channels of the model is recommended. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Modelling sexual violence in male rats: the sexual aggression test (SxAT).

Sexual assault and rape are crimes that impact victims worldwide. Although the psychosocial and eco-evolutionary factors associated with this antisocial behavior have repeatedly been studied, the underlying neurobiological mechanisms are still largely unknown. Here, we established a novel paradigm to provoke and subsequently assess sexual aggression (SxA) in adult male Wistar rats: the sexual aggression test (SxAT). Briefly, male Wistar rats are sexually aroused by a receptive female, which is exchanged by a non-receptive female immediately after the first intromission. This protocol elicits forced mounting and aggressive behavior toward the non-receptive female to different degrees, which can be scored. In a series of experiments we have shown that SxA behavior is a relatively stable trait in rats and correlates positively with sexual motivation. Rats with innate abnormal anxiety and aggressive behavior also show abnormal SxA behavior. In addition, central infusion of oxytocin moderately inhibits aggressive behavior, but increases forced mounting. Finally, we identified the agranular insular cortex to be specifically activated by SxA, however, inhibition of this region did not significantly alter behavior in the SxAT. Altogether, the SxAT is a paradigm that can be readily implemented in behavioral laboratories as a valuable tool to find answers regarding the biological mechanisms underlying SxA in humans, as well as social decision-making in general.

Translocator protein (18kDa) TSPO: a new diagnostic or therapeutic target for stress-related disorders?

Efficient treatment of stress-related disorders, such as depression, is still a major challenge. The onset of antidepressant drug action is generally quite slow, while the anxiolytic action of benzodiazepines is considerably faster. However, their long-term use is impaired by tolerance development, abuse liability and cognitive impairment. Benzodiazepines act as positive allosteric modulators of É£-aminobutyric acid type A (GABAA) receptors. 3α-reduced neurosteroids such as allopregnanolone also are positive allosteric GABAA receptor modulators, however, through a site different from that targeted by benzodiazepines. Recently, the administration of neurosteroids such as brexanolone or zuranolone has been shown to rapidly ameliorate symptoms in post-partum depression or major depressive disorder. An attractive alternative to the administration of exogenous neurosteroids is promoting endogenous neurosteroidogenesis via the translocator protein 18k Da (TSPO). TSPO is a transmembrane protein located primarily in mitochondria, which mediates numerous biological functions, e.g., steroidogenesis and mitochondrial bioenergetics. TSPO ligands have been used in positron emission tomography (PET) studies as putative markers of microglia activation and neuroinflammation in stress-related disorders. Moreover, TSPO ligands have been shown to modulate neuroplasticity and to elicit antidepressant and anxiolytic therapeutic effects in animals and humans. As such, TSPO may open new avenues for understanding the pathophysiology of stress-related disorders and for the development of novel treatment options.