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Oxytocin signaling cascades lead to LTP and behavioral changes. OXTRs are G-protein-coupled-receptors that can activate a number of downstream pathways upon ligand binding. Here we highlight two such pathways that drive LTP in the mammalian brain.
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An essential characteristic of nervous systems is their capacity to reshape functional connectivity in response to physiological and environmental cues. Endogenous signals, including neuropeptides, governs nervous system plasticity. Particularly, oxytocin has been recognized for its role in mediating activity-dependent circuit changes. These oxytoc...
Citations
... 45,49 In addition, oxytocin receptors are distributed on some specific neurons in important brain regions related to social behaviour (e.g., anterior cingulate cortex [ACC], basolateral amygdala [BLA], nucleus accumbens [NAc], hippocampus). 5,[50][51][52] Despite advances in empathy research, further work is needed to explore how various forms of empathy rely on distinct brain regions and neural circuits involved in the sensory -emotional transformation process, the process by which an individual observes the behavioural state of another and elicits a behaviour that matches the emotional state. 14,15,53 Thus, we sought to compare the similarities and differences in the brain regions associated with empathy-like behaviour of fear induced by electric shock and those associated with empathy-like behaviour of pain induced by complete Freund's adjuvant. ...
... However, the contribution of oxytocin receptor activation in astrocytes to rescuing AD pathology remains elusive. These findings support the notion that oxytocin can exert cell typespecific effects ranging from increased neurogenesis and neuromodulation [3,29,30] to modulation of acute and chronic inflammatory responses [12,28]. Thus, dissecting the cell type specific effects of oxytocin receptor activation will help understand the orchestrated effects of oxytocin in the brain. ...
Alzheimer’s disease is a multi-factorial disease that disrupts many aspects of human behavior. In this comment, we highlight the work by Koulousakis et al. published in a recent issue of the Journal of Alzheimer’s Disease. In this study, the authors tested the therapeutic potential of the neuropeptide oxytocin in a pre-clinical model of Alzheimer’s disease and found positive behavioral outcomes on memory assessments. We discuss these findings in the context of oxytocin research in the field of Alzheimer’s disease and the literature regarding oxytocin-based therapeutics, including administration protocols and potential underlying cellular and molecular mechanisms.
... The pregnancies introduced by subsequent mice can be aborted if the scent of the first mouse is imprinted in the female. Thus, basal mechanisms including enhancement of LTP and neural plasticity may be in play when learning is supported by oxytocin (Pekarek et al., 2020). This may also apply to the improvement of social cognition and spatial orientation that may occur with birth and lactation (Monks et al., 2003). ...
Oxytocin supports reproduction by promoting sexual- and nursing behavior. Moreover, it stimulates reproductive organs by different avenues. Oxytocin is released to the blood from terminals of oxytocinergic neurons which project from the hypothalamus to the pituitary gland. Concomitantly, the dendrites of these neurons discharge oxytocin into neighboring areas of the hypothalamus. At this location it affects other neuroendocrine systems by autocrine and paracrine mechanisms. Moreover, sensory processing, affective functions, and reward circuits are influenced by oxytocinergic neurons that reach different sites in the brain. In addition to its facilitating impact on various aspects of reproduction, oxytocin is revealed to possess significant anti-inflammatory, restoring, and tranquilizing properties. This has been demonstrated both in many in-vivo and in-vitro studies. The oxytocin system may therefore have the capacity to alleviate detrimental physiological- and mental stress reactions. Thus, high levels of endogenous oxytocin may counteract inadequate inflammation and malfunctioning of neurons and supportive cells in the brain. A persistent low-grade inflammation increasing with age—referred to as inflammaging—may lead to a cognitive decline but may also predispose to neurodegenerative diseases such as Alzheimer’s and Parkinson. Interestingly, animal studies indicate that age-related destructive processes in the body can be postponed by techniques that preserve immune- and stem cell functions in the hypothalamus. It is argued in this article that sexual activity—by its stimulating impact on the oxytocinergic activity in many regions of the brain—has the capacity to delay the onset of age-related cerebral decay. This may also postpone frailty and age-associated diseases in the body. Finally, oxytocin possesses neuroplastic properties that may be applied to expand sexual reward. The release of oxytocin may therefore be further potentiated by learning processes that involves oxytocin itself. It may therefore be profitable to raise the consciousness about the potential health benefits of sexual activity particularly among the seniors.
... Critical for human reproduction, oxytocin drives parturition and parental attachment including establishment and maintenance of mother-child bonding in response to social cues [34][35][36]. It also plays a role in sensory network plasticity [37]. Oxytocin signals through G-protein-coupled receptors as the mechanism for enhancing connectivity of the social brain across vertebrate species. ...
... In addition to EGF, several growth factors and hormones regulate the proliferation and birth of new neurons in vivo and in vitro isolated from neurogenic niches in mammals, which are controlled by behavioral changes, sociosexual stimuli, stress, stroke injury, lactation, pregnancy, among others (see the review for steroid hormones [46,47], prolactin [48,49], brain-derived neurotrophic factor [50], progesterone [51] and oxytocin [52]). Next, we evaluated the formation and differentiation of SVZ-derived neurospheres under single treatments with brain-derived neurotrophic (BDNF) (50, 100, and 200 ng/mL) (Fig. 8), estradiol (E2) (0.5, 1, and 2 µM) (Fig. 9), prolactin (PRL) (50, 100, and 200 ng/ mL) (Fig. 10), oxytocin (OXY) (1 and 2 µM) (Fig. 11) and progesterone (P4) (1 and 2 µM) (Fig. 12). ...
Background
The prairie vole ( Microtus ochrogaster ) is a socially monogamous rodent that establishes an enduring pair bond after cohabitation, with (6 h) or without (24 h) mating. Previously, we reported that social interaction and mating increased cell proliferation and differentiation to neuronal fate in neurogenic niches in male voles. We hypothesized that neurogenesis may be a neural plasticity mechanism involved in mating-induced pair bond formation. Here, we evaluated the differentiation potential of neural progenitor cells (NPCs) isolated from the subventricular zone (SVZ) of both female and male adult voles as a function of sociosexual experience. Animals were assigned to one of the following groups: (1) control (Co), sexually naive female and male voles that had no contact with another vole of the opposite sex; (2) social exposure (SE), males and females exposed to olfactory, auditory, and visual stimuli from a vole of the opposite sex, but without physical contact; and (3) social cohabitation with mating (SCM), male and female voles copulating to induce pair bonding formation. Subsequently, the NPCs were isolated from the SVZ, maintained, and supplemented with growth factors to form neurospheres in vitro.
Results
Notably, we detected in SE and SCM voles, a higher proliferation of neurosphere-derived Nestin + cells, as well as an increase in mature neurons (MAP2 +) and a decrease in glial (GFAP +) differentiated cells with some sex differences. These data suggest that when voles are exposed to sociosexual experiences that induce pair bonding, undifferentiated cells of the SVZ acquire a commitment to a neuronal lineage, and the determined potential of the neurosphere is conserved despite adaptations under in vitro conditions. Finally, we repeated the culture to obtain neurospheres under treatments with different hormones and factors (brain-derived neurotrophic factor, estradiol, prolactin, oxytocin, and progesterone); the ability of SVZ-isolated cells to generate neurospheres and differentiate in vitro into neurons or glial lineages in response to hormones or factors is also dependent on sex and sociosexual context.
Conclusion
Social interactions that promote pair bonding in voles change the properties of cells isolated from the SVZ. Thus, SE or SCM induces a bias in the differentiation potential in both sexes, while SE is sufficient to promote proliferation in SVZ-isolated cells from male brains. In females, proliferation increases when mating is performed. The next question is whether the rise in proliferation and neurogenesis of cells from the SVZ are plastic processes essential for establishing, enhancing, maintaining, or accelerating pair bond formation.
Highlights Sociosexual experiences that promote pair bonding (social exposure and social cohabitation with mating) induce changes in the properties of neural stem/progenitor cells isolated from the SVZ in adult prairie voles.
Social interactions lead to increased proliferation and induce a bias in the differentiation potential of SVZ-isolated cells in both male and female voles.
The differentiation potential of SVZ-isolated cells is conserved under in vitro conditions, suggesting a commitment to a neuronal lineage under a sociosexual context.
Hormonal and growth factors treatments (brain-derived neurotrophic factor, estradiol, prolactin, oxytocin, and progesterone) affect the generation and differentiation of neurospheres, with dependencies on sex and sociosexual context.
Proliferation and neurogenesis in the SVZ may play a crucial role in establishing, enhancing, maintaining, or accelerating pair bond formation.
... The hippocampus is a key structure for most of these emotional, behavioral, and cognitive functions (Sweatt, 2004;Immordino-Yang and Singh, 2013;Rubin et al., 2014), it receives input from hypothalamic OT-expressing fibers, and subgroups of hippocampal cells expresses OT receptors. OT influences hippocampus at multiple levels by modulating processes of learning and memory (Chini et al., 2014;Rajamani et al., 2018;Pekarek et al., 2020) and social behavior (Raam et al., 2017;Bertoni et al., 2021), remodeling the intrinsic hippocampal circuit in newborn autism models (Raam et al., 2017;Bertoni et al., 2021), and stimulating adult hippocampal neurogenesis (Leuner et al., 2012;Lin et al., 2017). The action of OT in the hippocampus relies on a precise, finely tuned, and timely modulation of specific neurons in each hippocampal subregion. ...
... These two effects improve the fidelity and temporal precision of the information transfer through this area. Pekarek et al., 2020;Hu et al., 2021). OT application on cultured glutamatergic hippocampal neurons drives dendritic and synaptic remodeling confirming that plasticity processes occur at these synapses (Ripamonti et al., 2017). ...
Oxytocin (OT) is a neuropeptide widely known for its peripheral hormonal effects (i.e., parturition and lactation) and central neuromodulatory functions, related especially to social behavior and social, spatial, and episodic memory. The hippocampus is a key structure for these functions, it is innervated by oxytocinergic fibers, and contains OT receptors (OTRs). The hippocampal OTR distribution is not homogeneous among its subregions and types of neuronal cells, reflecting the specificity of oxytocin’s modulatory action. In this review, we describe the most recent discoveries in OT/OTR signaling in the hippocampus, focusing primarily on the electrophysiological oxytocinergic modulation of the OTR-expressing hippocampal neurons. We then look at the effect this modulation has on the balance of excitation/inhibition and synaptic plasticity in each hippocampal subregion. Additionally, we review OTR downstream signaling, which underlies the OT effects observed in different types of hippocampal neuron. Overall, this review comprehensively summarizes the advancements in unraveling the neuromodulatory functions exerted by OT on specific hippocampal networks.
... Hence, by modifying the calcium gradient, OXT could block the burstiness of PIR SP cells. It has also been described that OXT can activate inward rectifying potassium channels in neurons (Pekarek et al., 2020). Thus, another possible mechanism would be a change in the membrane potential of SP cells that would indirectly disrupt the burstiness of these cells in the presence of TGOT. ...
La respiration est un processus hautement dynamique qui varie en fréquence et en amplitude. Ces variations sont liées à l’état émotionnel et cognitif de l’animal mais aussi au recrutement de son système olfactif pour la détection de molécules odorantes, comme c’est le cas lors d’interactions sociales entre individus. De plus, un nombre croissant de données montre que la respiration influence les rythmes neuronaux dans certaines régions du cerveau. Dans ce contexte, disposer d’un outil précis et fiable de l’activité respiratoire chez l’animal libre de ses mouvements qui soit également compatible avec des enregistrements neuronaux semble plus que jamais pertinent. Nous avons mis au point une technique d’enregistrement de la pression nasale chez la souris libre de ses mouvements et avons caractérisé ce signal en fonction de l’état de vigilance de l’animal (éveil – sommeil lent – sommeil paradoxal). Nos recherches montrent que chaque état est associé à une combinaison spécifique de paramètres caractérisant son signal respiratoire. De plus, la précision de cette technique nous a permis de mettre en évidence la présence de pauses dans ce signal (c’est-à-dire des absences transitoires de flux d’air). Ces pauses ne sont pas anodines puisque ce sont elles qui dictent la fréquence de la respiration, les autres composantes du cycle respiratoire (inhalation et exhalation) formant des unités de durée relativement fixe. Enfin, sur la base de ce signal, nous avons construit un réseau de neurones artificiels à partir de données annotées, capable de prédire l’état de vigilance d’autres souris à partir d’enregistrements de leur pression nasale.Dans une deuxième partie de cette thèse, nous nous sommes intéressés au rôle de l’ocytocine dans le cortex piriforme au cours des comportements sociaux. En effet, l’ocytocine a été amplement décrite comme un neuropeptide pro-social qui favorise les interactions et la mémoire sociale. Chez le rongeur, l’olfaction est la modalité sensorielle principale, dont le cortex olfactif piriforme représente un substrat neuronal majeur. Le piriforme présente une anatomie semblable à celle de l’hippocampe et est impliqué dans les processus de mémoire olfactive. Parce que le cortex piriforme exprime une forte densité des récepteurs à l’ocytocine et parce qu’il reçoit des afférences ocytocinergiques, nous avons testé l’hypothèse que l’ocytocine dans le cortex piriforme module la sociabilité et surtout la mémoire sociale. Avec une approche pharmacologique ciblée sur ce cortex, nous avons montré que l’ocytocine induit des effets subtils mais étonnants. En effet, le blocage de son récepteur entraine une augmentation sélective de certains types d’interactions sociales et semble augmenter l’attraction envers des stimuli sociaux olfactifs. Cependant aucun effet n’a été observé dans nos conditions sur la mémoire sociale.Enfin, dans une troisième partie nous avons commencé à disséquer les mécanismes d’action de l’ocytocine sur la physiologie du cortex piriforme. Nous montrons que l’agoniste des récepteurs à l’ocytocine entraine une diminution de la burstiness d’un sous-type de neurones excitateurs à la fois in vitro et in vivo. Nous montrons par ailleurs que l’ocytocine diminue l’entrainement des neurones du cortex piriforme par la respiration.
... With regard to pharmacological interventions that may be implemented within a learning paradigm, oxytocin has recently been found to modulate plastic brain circuits and increase neural representation of sensory stimuli (Pekarek, Hunt, & Arenkiel, 2020). Research has demonstrated anxiolytic effects of oxytocin for negative self-judgment during social tasks and self-referential bias (Zhao et al., 2020), or threat processing with decreased fear-associated amygdala activity (Radke et al., 2017). ...
Social interactions are dynamic, context-dependent, and reciprocal events that influence prospective strategies and require constant practice and adaptation. This complexity of social interactions creates several research challenges. We propose a new framework encouraging future research to investigate not only individual differences in capacities relevant for social functioning and their underlying mechanisms, but also the flexibility to adapt or update one's social abilities. We suggest three key capacities relevant for social functioning: (1) social perception, (2) sharing emotions or empathizing, and (3) mentalizing. We elaborate on how adaptations in these capacities may be investigated on behavioral and neural levels. Research on these flexible adaptations of one's social behavior is needed to specify how humans actually “learn to be social”. Learning to adapt implies plasticity of the relevant brain networks involved in the underlying social processes, indicating that social abilities are malleable for different contexts. To quantify such measures, researchers need to find ways to investigate learning through dynamic changes in adaptable social paradigms and examine several factors influencing social functioning within the three aformentioned social key capacities. This framework furthers insight concerning individual differences, provides a holistic approach to social functioning, and may improve interventions for ameliorating social abilities in patients.
... Taken together, perinatal oxytocin was found to be essential for shaping adult behaviours, but moderate levels are required. Noteworthy, oxytocin receptors can couple to Gi or Gq/11 and generate a plethora of downstream activities depending on the oxytocin levels that are present [159]. ...
Autism spectrum disorder (ASD) and associated neurodevelopmental disorders share similar pathogenesis and clinical features. Pathophysiological changes in these diseases are rooted in early neuronal stem cells in the uterus. Several genetic and environmental factors potentially perturb neurogenesis and synaptogenesis processes causing incomplete or altered maturation of the brain that precedes the symptomology later in life. In this review, the impact of several endogenous neuromodulators and pharmacological agents on the foetus during pregnancy, manifested on numerous aspects of neurodevelopment is discussed. Within this context, some possible insults that may alter these modulators and therefore alter their role in neurodevelopment are high-lighted. Sometimes, a particular insult could influence several neuromodulator systems as is supported by recent research in the field of ASD and associated disorders. Dopaminergic hy-pothesis prevailed on the table for discussion of the pathogenesis of schizophrenia (SCH), atten-tion-deficit hyperactivity disorder (ADHD) and ASD for a long time. However, recent cumulative evidence suggests otherwise. Indeed, the neuromodulators that are dysregulated in ASD and comorbid disorders are as diverse as the causes and symptoms of this disease. Additionally, these neuromodulators have roles in brain development, further complicating their involvement in comorbidity. This review will survey the current understanding of the neuromodulating systems to serve the pharmacological field during pregnancy and to minimize drug-related insults in pa-tients with ASD and associated comorbidity disorders, e.g., SCH or ADHD.
... These findings not only suggest that different trainings induce differential plasticity in mental faculties, but further indicate social adaptability. With regard to pharmacological interventions that may be implemented within a learning paradigm, oxytocin has recently been found to modulate plastic brain circuits and increase neural representation of sensory stimuli [116]. Research has demonstrated anxiolytic effects of oxytocin for negative self-judgement during social tasks and self-referential bias [175], or threat processing with decreased fear-associated amygdala activity [123]. ...
Social interactions are dynamic, context-dependent, and reciprocal events that influence prospective strategies and require constant practice and adaptation. This complexity of social interactions creates several research challenges. We propose a new framework encouraging future research to investigate not only individual differences in capacities relevant for social functioning and their underlying mechanisms, but also the flexibility to adapt or update one's social abilities. We suggest three key capacities relevant for social functioning: (1) social perception, (2) sharing emotions or empathizing, and (3) mentalizing. We elaborate on how adaptations in these capacities may be investigated on behavioral and neural levels. Research on these flexible adaptations of one's social behavior is needed to specify how humans actually "learn to be social". Learning to adapt implies plasticity of the relevant brain networks involved in the underlying social processes, indicating that social abilities are malleable for different contexts. To quantify such measures, researchers need to find ways to investigate learning through dynamic changes in adaptable social paradigms and examine several factors influencing social functioning within the three aforementioned social key capacities. This framework furthers insight concerning individual differences, provides a holistic approach to social functioning, and may improve interventions for ameliorating social abilities in patients.
