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Nature Sep 2023Oxytocin is a neuropeptide that is important for maternal physiology and childcare, including parturition and milk ejection during nursing. Suckling triggers the release...
Oxytocin is a neuropeptide that is important for maternal physiology and childcare, including parturition and milk ejection during nursing. Suckling triggers the release of oxytocin, but other sensory cues-specifically, infant cries-can increase the levels of oxytocin in new human mothers, which indicates that cries can activate hypothalamic oxytocin neurons. Here we describe a neural circuit that routes auditory information about infant vocalizations to mouse oxytocin neurons. We performed in vivo electrophysiological recordings and photometry from identified oxytocin neurons in awake maternal mice that were presented with pup calls. We found that oxytocin neurons responded to pup vocalizations, but not to pure tones, through input from the posterior intralaminar thalamus, and that repetitive thalamic stimulation induced lasting disinhibition of oxytocin neurons. This circuit gates central oxytocin release and maternal behaviour in response to calls, providing a mechanism for the integration of sensory cues from the offspring in maternal endocrine networks to ensure modulation of brain state for efficient parenting.
Topics: Animals; Female; Mice; Cues; Hypothalamus; Maternal Behavior; Neural Pathways; Neurons; Oxytocin; Photometry; Thalamic Nuclei; Vocalization, Animal; Wakefulness
PubMed: 37730989
DOI: 10.1038/s41586-023-06540-4 -
Comprehensive Psychoneuroendocrinology Nov 2023This narrative describes a personal journey that led to the discovery of a profound connection between microbial symbionts and oxytocin. Pivotal oxytocin discoveries... (Review)
Review
This narrative describes a personal journey that led to the discovery of a profound connection between microbial symbionts and oxytocin. Pivotal oxytocin discoveries began to emerge in 2011 while this researcher's multidisciplinary team explored gut microbial priming of the immune system and perinatal health. Inspired by oxytocin's role in early life events of milk release, neural connections, and social bonding, the team hypothesized a symbiotic relationship between microbes and oxytocin. Scientific experiments demonstrated that specific milk-borne microbes boosted oxytocin levels through a vagus nerve-mediated gut-brain pathway, affecting immune functions and wound healing capacity in the host animal. The exploration then expanded to microbial impacts on reproductive fitness, body weight, and even mental health. Overarching hypotheses envisioned a nurturing symbiosis promoting survival and societal advancement. Ultimately, this oxytocin-mediated partnership between microbes and mammals is portrayed as a harmonious legacy of neurological stability, empathy, and universal wisdom, transcending generations. The author's personal journey underscores the beauty and inspiration found in her scientific exploration.
PubMed: 38108028
DOI: 10.1016/j.cpnec.2023.100212 -
American Journal of Obstetrics and... Mar 2024Oxytocin is a peptide hormone that plays a key role in regulating the female reproductive system, including during labor and lactation. It is produced primarily in the... (Review)
Review
Oxytocin is a peptide hormone that plays a key role in regulating the female reproductive system, including during labor and lactation. It is produced primarily in the hypothalamus and secreted by the posterior pituitary gland. Oxytocin can also be administered as a medication to initiate or augment uterine contractions. To study the effectiveness and safety of oxytocin, previous studies have randomized patients to low- and high-dose oxytocin infusion protocols either alone or as part of an active management of labor strategy along with other interventions. These randomized trials demonstrated that active management of labor and high-dose oxytocin regimens can shorten the length of labor and reduce the incidence of clinical chorioamnionitis. The safety of high-dose oxytocin regimens is also supported by no associated differences in fetal heart rate abnormalities, postpartum hemorrhage, low Apgar scores, neonatal intensive care unit admissions, and umbilical artery acidemia. Most studies reported no differences in the cesarean delivery rates with active management of labor or high-dose oxytocin regimens, thereby further validating its safety. Oxytocin does not have a predictable dose response, thus the pharmacologic effects and the amplitude and frequency of uterine contractions are used as physiological parameters for oxytocin infusion titration to achieve adequate contractions at appropriate intervals. Used in error, oxytocin can cause patient harm, highlighting the importance of precise administration using infusion pumps, institutional safety checklists, and trained nursing staff to closely monitor uterine activity and fetal heart rate changes. In this review, we summarize the physiology, pharmacology, infusion regimens, and associated risks of oxytocin.
Topics: Pregnancy; Infant, Newborn; Humans; Female; Oxytocin; Oxytocics; Labor, Induced; Labor, Obstetric; Cesarean Section
PubMed: 37460365
DOI: 10.1016/j.ajog.2023.06.041 -
Nature Feb 2024To survive in a complex social group, one needs to know who to approach and, more importantly, who to avoid. In mice, a single defeat causes the losing mouse to stay...
To survive in a complex social group, one needs to know who to approach and, more importantly, who to avoid. In mice, a single defeat causes the losing mouse to stay away from the winner for weeks. Here through a series of functional manipulation and recording experiments, we identify oxytocin neurons in the retrochiasmatic supraoptic nucleus (SOR) and oxytocin-receptor-expressing cells in the anterior subdivision of the ventromedial hypothalamus, ventrolateral part (aVMHvl) as a key circuit motif for defeat-induced social avoidance. Before defeat, aVMHvl cells minimally respond to aggressor cues. During defeat, aVMHvl cells are highly activated and, with the help of an exclusive oxytocin supply from the SOR, potentiate their responses to aggressor cues. After defeat, strong aggressor-induced aVMHvl cell activation drives the animal to avoid the aggressor and minimizes future defeat. Our study uncovers a neural process that supports rapid social learning caused by defeat and highlights the importance of the brain oxytocin system in social plasticity.
Topics: Animals; Mice; Aggression; Avoidance Learning; Cues; Fear; Hypothalamus; Neural Pathways; Neurons; Oxytocin; Receptors, Oxytocin; Social Behavior; Social Learning; Supraoptic Nucleus; Ventromedial Hypothalamic Nucleus; Neuronal Plasticity
PubMed: 38267576
DOI: 10.1038/s41586-023-06958-w -
Proceedings of the National Academy of... Jan 2024Social anxiety disorder (SAD) is a crippling psychiatric disorder characterized by intense fear or anxiety in social situations and their avoidance. However, the...
Social anxiety disorder (SAD) is a crippling psychiatric disorder characterized by intense fear or anxiety in social situations and their avoidance. However, the underlying biology of SAD is unclear and better treatments are needed. Recently, the gut microbiota has emerged as a key regulator of both brain and behaviour, especially those related to social function. Moreover, increasing data supports a role for immune function and oxytocin signalling in social responses. To investigate whether the gut microbiota plays a causal role in modulating behaviours relevant to SAD, we transplanted the microbiota from SAD patients, which was identified by 16S rRNA sequencing to be of a differential composition compared to healthy controls, to mice. Although the mice that received the SAD microbiota had normal behaviours across a battery of tests designed to assess depression and general anxiety-like behaviours, they had a specific heightened sensitivity to social fear, a model of SAD. This distinct heightened social fear response was coupled with changes in central and peripheral immune function and oxytocin expression in the bed nucleus of the stria terminalis. This work demonstrates an interkingdom basis for social fear responses and posits the microbiome as a potential therapeutic target for SAD.
Topics: Humans; Animals; Mice; Phobia, Social; Gastrointestinal Microbiome; Oxytocin; RNA, Ribosomal, 16S; Fear; Anxiety
PubMed: 38147649
DOI: 10.1073/pnas.2308706120 -
Nature Biotechnology Jul 2023Oxytocin (OT), a peptide hormone and neuromodulator, is involved in diverse physiological and pathophysiological processes in the central nervous system and the...
Oxytocin (OT), a peptide hormone and neuromodulator, is involved in diverse physiological and pathophysiological processes in the central nervous system and the periphery. However, the regulation and functional sequences of spatial OT release in the brain remain poorly understood. We describe a genetically encoded G-protein-coupled receptor activation-based (GRAB) OT sensor called GRAB. In contrast to previous methods, GRAB enables imaging of OT release ex vivo and in vivo with suitable sensitivity, specificity and spatiotemporal resolution. Using this sensor, we visualize stimulation-induced OT release from specific neuronal compartments in mouse brain slices and discover that N-type calcium channels predominantly mediate axonal OT release, whereas L-type calcium channels mediate somatodendritic OT release. We identify differences in the fusion machinery of OT release for axon terminals versus somata and dendrites. Finally, we measure OT dynamics in various brain regions in mice during male courtship behavior. Thus, GRAB provides insights into the role of compartmental OT release in physiological and behavioral functions.
Topics: Male; Mice; Animals; Oxytocin; Neurons; Brain; Signal Transduction; Central Nervous System
PubMed: 36593404
DOI: 10.1038/s41587-022-01561-2 -
Stroke Jul 2023Intracerebral hemorrhage (ICH) causes severe sensorimotor dysfunction and cognitive decline which are aggravated by secondary brain injury, yet there are no effective...
BACKGROUND
Intracerebral hemorrhage (ICH) causes severe sensorimotor dysfunction and cognitive decline which are aggravated by secondary brain injury, yet there are no effective management to alleviate these outcomes. Pyroptosis is strongly related to neuroinflammation, which plays a crucial role in the pathophysiological processes of secondary brain injury after ICH. OXT (oxytocin), as a pleiotropic neuropeptide, has multiple functions including anti-inflammation and antioxidation. This study aims to investigate the role of OXT in improving ICH outcomes and the underlying mechanisms.
METHODS
C57BL/6 mice were used to establish the ICH model by autologous blood injection. OXT was administered intranasally (0.2 μg/g) after ICH. Combing behavioral tests, Western blot, immunofluorescence staining, electron microscopy, and pharmacological approaches, we evaluated the effect of intranasal OXT application on neurological outcomes after ICH and explored the underlying mechanism.
RESULTS
Endogenous OXT level was decreased, whereas OXTR (oxytocin receptor) expression was increased after ICH. OXT treatment improved the short-term and long-term neurological functions and alleviated neuronal pyroptosis and neuroinflammation. In addition, OXT reduced excessive mitochondrial fission and mitochondrial-derived oxidative stress 3 days after ICH. OXT decreased the expression of pyroptotic and proinflammatory factors including NLRP3 (NOD-like receptor protein 3), ASC (apoptosis-associated speck-like protein containing a CARD), GSDMD (gasdermin D), caspase-1, IL (interleukin)-1β, and IL-18 and increased the expression of p-PKA (phospho-protein kinase A) and p-DRP1 (S637; DRP1 [dynamin-related protein 1] phosphorylation at Ser637). OXT-induced neuroprotective effects were blocked by either OXTR inhibitor or PKA inhibitor.
CONCLUSIONS
Intranasal application of OXT can ameliorate neurological deficits and alleviate neural pyroptosis, inflammation, and excessive mitochondrial fission via OXTR/p-PKA/DRP1 signaling pathway after ICH. Thus, OXT administration may be a potential therapeutic strategy to improve the prognosis of ICH.
Topics: Mice; Animals; Oxytocin; Pyroptosis; Neuroinflammatory Diseases; Mitochondrial Dynamics; Mice, Inbred C57BL; Cerebral Hemorrhage; Brain Injuries
PubMed: 37317879
DOI: 10.1161/STROKEAHA.123.043391 -
Comprehensive Psychoneuroendocrinology Nov 2023The neuropeptide hormone oxytocin is involved in many processes in our bodies, linking our social lives to our internal states. I started out my career studying primate... (Review)
Review
The neuropeptide hormone oxytocin is involved in many processes in our bodies, linking our social lives to our internal states. I started out my career studying primate families, an interest that expanded into the role of oxytocin in family-oriented behaviors such as pair bonding and parenting in prairie voles, humans, and other primates. Starting as a post-doc with Dr. C. Sue Carter, I also became interested in the role of oxytocin during development and the way that we manipulate oxytocin clinically. During that post-doc and then as a faculty member at the University of California, Davis, I have worked on a number of these questions.
PubMed: 38108037
DOI: 10.1016/j.cpnec.2023.100203