Grinevich V. DFG - Deutsche Forschungsgemeinschaft DFG GR 3619/25-1: EU ERANET-NEURON "Pain and the social brain: the role of oxytocin in socio-emotional regulation of chronic pain. 02/2025-01/2028.
Chronic neuropathic pain, affecting both central and peripheral nervous systems, is highly prevalent and debilitating, impacting up to 8% of the general population and 25% of chronic pain patients. Despite extensive research over the past two decades, effective management options remain limited, with few medications proving efficacious. Pain is a complex sensation influenced by the brain's modulation of the body's nociceptive system, illustrating bidirectional brain-body interactions. Emotional disorders such as distress, anxiety, and depression are frequently accompanied by chronic pain, while chronic pain sufferers are predisposed to developing these conditions. Notably, social and emotional states significantly influence chronic pain development and outcomes, highlighting pain as a social phenomenon. The brain's "pain matrix," particularly "emotional centers" such as the amygdala and prefrontal cortex, plays a crucial role in pain perception. Non-pharmacological approaches targeting these centers are increasingly advocated. Social interactions strongly impact these emotional centers, underscoring the need to explore neurobiological mechanisms linking social behavior and pain perception in both humans and animals. Oxytocin, a neuropeptide produced and distributed within the central nervous system, modulates various behaviors and emotions, including social memory, anxiety, and pain perception. While oxytocin has demonstrated analgesic effects on acute pain in animals and humans, its direct role in the interaction between social behavior and pain perception remains unclear. Our hypothesis posits oxytocin as pivotal in mediating the interaction between socio-emotional states and chronic pain via its influence on the brain's pain matrix. Our consortium, comprising leading experts in oxytocin systems, social behavior, and pain research, plans to elucidate these neurobiological mechanisms using advanced chemogenetic, optogenetic, pharmacological and electrophysiological techniques. We aim to investigate how oxytocin release in different pain matrix stations affects socio-emotional states and chronic pain. Additionally, we will use sophisticated behavioral assays, employing the Spare Nerve Injury model in rats, to explore the reciprocal effects of chronic pain and social behavior and their modulation by OT. The human part of the project will examine the relationship between oxytocin receptor signaling genetic variants and pain perception in a lrage sample. Ultimately, this research aims to uncover the role of the brain's oxytocin system in chronic pain modulation and its influence on the interplay between chronic pain and social interactions. Our findings may pave the way for novel pharmacological and behavioral treatments targeting the oxytocin system, potentially alleviating both chronic pain and its associated psychological symptoms in the future.
Grinevich V. DFG - Deutsche Forschungsgemeinschaft GR 3619/19-1: Touched or detached: neurobiological mechanisms of loneliness. 01/2023-12/2027.
Social isolation is associated with devastating effects on mental and physical health. Emerging evidence related to the effects of the COVID-19 pandemic implicates quarantine-related social isolation as a risk factor for psychiatric disorders. Moreover, even perceived social isolation, termed “loneliness”, increases the risk for coronary heart disease, stroke, depression, cognitive decline and dementia. Therefore, understanding the biological mechanisms underlying the detrimental effects of social isolation will be extremely beneficial and will facilitate the design of interventions that can augment the influence of the limited social interactions experienced by many individuals.
Considering that social connectedness is as an innate need, it is likely to involve behavioral, physiological and molecular adaptations. Yet, the neural and hormonal systems that support social connectedness have yet to be identified and described. A central player at the interface of social isolation and connectedness is the hypothalamic neuropeptide oxytocin, the release of which is regulated as a function of social interactions, especially somatosensory stimuli delivered by social touch. This proposed translational project is aimed at probing the behavioral, neural and molecular sequelae of social isolation by carrying out a set of complementary experiments (WPs 1-5) on animal and human models of social isolation. While social isolation includes physical isolation in the animal model (rats), in humans, we will focus on loneliness as a subjective experience of isolation. In rats, we aim to reveal the molecular and neural changes that take place in the brain during social isolation and resocialization by using unbiased transcriptomic and proteomic analyses as well as in vivo electrophysiology at both the system and single cells levels (WP1). Specifically, we aim to reveal anatomical, electrophysiological and molecular modifications induced in the oxytocin system during social isolation and resocialization (WP2). Additionally, we will explore the effects of social isolation at the group level by correlating these modifications across pairs of animals as a proxy for inter-brain coupling. Critically, we will evaluate the possibility of reversing these changes by enhancing endogenous oxytocin system activity using chemogenetic manipulations as well as social touch (WP3). Following these detailed analyses in the rat model, we will explore the effects of loneliness in humans by comparing inter-brain coupling, social connectedness and oxytocin levels of individuals experiencing states of either high or low loneliness (WP4). Specifically, we will take advantage of the high temporal resolution of state-of-the-art dual-functional Near-Infrared Spectroscopy (fNIRS) to examine how inter-brain networks reconfigure during real-life interactions of dyads composed of high loneliness and low loneliness participants. We will further use this system to test whether social touch normalizes the levels of oxytocin, social connectedness and inter-brain coupling in dyads comprised of lonely participants. Finally, we will examine touch as a therapeutic tool for individuals suffering from loneliness (WP5) and characterize the effects of touch treatment on oxytocin levels and brain function. This set of experiments will lay the foundation for a new theory that views dysregulation of oxytocin and inter-brain coupling at the heart of deficient connectedness and loneliness. Our central goal of determining the neurobiological basis and mechanisms of social isolation combined with the unconventional methodological approaches it employs will offer a novel behavioral as well as neural model for understanding and treating human loneliness.
Meyer-Lindenberg A. BMBF - Bundesministerium für Bildung und Forschung 01EE2304A: DZPG Aufbauförderung - Standort Mannheim. 05/2023-04/2025.
Grinevich V. New York University : Oxytocin Modulation of Neural Circuit Function and Behavior – Renewal/Molecular Tools Core. 09/2023-07/2024.
SFB 1158-2: From nociception to chronic pain: Structure-function properties of neural pathways and their reorganization: Project: Social influence on acute and chronic pain: Role of oxytocin-dependent mechanisms with a focus on insular cortical circuitry. 01/2019-12/2023.
Our work focuses on psychoneuroendocrine and social factors, which modulate pain, and particularly on the effects of the neuropeptide oxytocin (OT) on supportive and stressful social effects in interaction with the pain experience. During the 1st funding period, we uncovered pathways via which endogenous OT as well as exogenously-applied OT modulates nociception and pain. In particular, we found OT-effects on pain to be closely related to the insular (IS) cortex: OT reduced pain sensitization across repeated application of thermal pain stimuli via the anterior IS and enhanced associative learning via the posterior IS in humans. Positive social interactions and particularly social support are known to reduce pain experiences to acute pain stimuli and our previous research in humans and rodents suggests that OT-ergic mechanisms play a critical role in this process. In contrast, social stress seems to enhance pain experiences; however, this may vary with sex, pain dynamics and the context in everyday life. While chronic stress has been shown to induce sensitization to pain (allodynia), initial studies in rats suggest that OT inhibits this effect. Of note, central vs. peripheral OT mechanisms in relation to social influences on pain processing in chronic pain disorders have not been investigated yet.
Grinevich V. Georgia State University : Inverse neurovascular coupling in the hypothalamus and its role in positive feedback regulation of Vasopressin neurons in health and disease. 12/2022-11/2023.
SFB 1158: B02 - Central oxytocin effects on acute and chronic pain processing. 07/2019-06/2023.
DFG - Deutsche Forschungsgemeinschaft GR 3619/13-1: Oxytocin signaling in the ventral hippocampus: from modulation of the local circuit to socio-sexual behavior. 01/2019-12/2022.
The hypothalamic neuropeptide oxytocin (OT) modulates a plethora of socio-sexual behaviors. Due to the fact that social cognition and relationship rely on the general ability of a subject to reconstruct and relate memory representations, in this project we focused on the ventral hippocampus (vHippo), which has been recently reported as a controlling social memory hub. Intriguingly, the experimental inhibition of CA1 region of vHippo leads to disturbance of social behavior, similar to that observed in animal models lacking OT or its receptor (OTR). Therefore, we propose that social function of the vHippo is related to OT action. Although the vHippo CA1 region receives direct OT-ergic input, neuronal types underlying OT-mediated modulation of neuronal ensembles in this structure, and their functional contribution to the social behavior remains unknown. In our preliminary experiments, implementing newly generated OTR-Cre knock-in rats and viral vectors, we identified two populations of OTR+ neurons in the vHippo: parvalbumin-positive interneurons and principal cells (PCs), which reside outside the CA1 principal cell layer. Application of OTR agonist to acute vHippo slices resulted in co-activation of both OTR+ interneurons and OTR+ PCs, while OTR- PCs were silent. Further, our viral-vector based tracing studies revealed that OTR+ PCs specifically project to granule cell layer of the accessory olfactory bulb (AOB) – the hub structure of sexual (pheromonal) information processing. Knowing that OTR+ PCs target the AOB, we propose that the vHippo may tune perception of sexually valid olfactory information via selectively strengthening the connection between OTR+ PCs in the vHippo and extrinsic component of the network – the AOB. Following this hypothesis, we will perform detailed electrophysiological and anatomical analyses of neuronal components of vHippo OTR+ circuit at synaptic, neuronal and behavioral levels aiming to uncover neuronal partnership between the hypothalamic OT system, vHippo and AOB and its role in the orchestration of socio-sexual behavior. Furthermore, our results will help to better understand mechanisms of sexual and social alterations in patients afflicted with mental pathologies, such as autism spectrum disorders.
DFG - Deutsche Forschungsgemeinschaft GR 3619/8-1: Identification and functional characterization of an oxytocin neuronal population coordinating lactation. 01/2017-12/2020.
The hypothalamic neuropeptide oxytocin (OT) is an essential molecule for initiation and maintenance of lactation – a unique functional state of offspring nourishing typical for mammals. The central OT system is composed of two distinct cell types – magnocellular and parvocellular OT neurons. Magnocellular OT neurons are the main cellular components of the system due to their unique synchronous bursting activity, eliciting release of OT into blood circulatory system to induce milk let-down from the mammary glands. The basic mechanisms underlying this synchronicity are still, however, largely unknown. Our recent finding in virgin rats demonstrated that the other cellular components of the OT system, the parvocellular OT neurons, can directly control both OT magnocellular neuron activity and systemic OT release in response to sensory stimulation. Following this finding and also based on unpublished preliminary results included in the present proposal, we here aim to demonstrate that the parvocellular OT neurons also contribute to the regulation of magnocellular neuron activity during lactation. In the course of our prospective study we will use complementary expertise of our laboratories in Germany and Switzerland, using newly developed viral vectors for opto- and pharmacogenetic approaches to study the importance of parvocellular OT neurons using in vivomulti-unit opto-electrode recordings in combination with the monitoring of suckling behaviour in lactating rats. These techniques will first be implemented to perform loss-of-function chemo,- and optogenetic experiments to prove the causal relation between the activity of parvocellular OT neurons and changes in weight gain of suckling pups and bursting of magnocellular OT neurons during lactation. Next, in a gain-of-function setup we will rescue changed in breast feeding and magnocellular OT neuron firing activity that are induced by nipple sensory deprivation, via optogenetic activation of parvocellular OT neurons. Finally, applying a cocktail of monosynaptic retrogradely transmitted viruses we will reconstruct the neural pathways between mammary glands and parvocellular OT neurons and with the above described approaches, examine their functional importance for inducing lactation. Collectively, our work will dissect novel OT network initiating and/or maintaining lactation, which will be important to further our understanding of the basic mechanisms of reproductive physiology.
DFG - Deutsche Forschungsgemeinschaft GR 3619/7-1: Deciphering oxytocin circuits orchestrating socio-sexual behavior. 01/2017-12/2020.
: Reproduction is an essential feature of living organisms and is largely modulated in vertebrates by hypothalamic neuropeptide oxytocin (OT) and its homologs. In mammals, reproductive function is realized by complex socio-sexual (SS) behaviors, which can be mechanistically divided into precopulatory and copulatory behaviors, both modulated by OT. However, precise OT circuits underlying OT effects are far from clear. Although there are no doubts that OT promotes sexual behavior, the OT circuits orchestrating precopulatory behavior viaforebrain regions are largely unknown. To address these questions, we will employ a recently developed genetic technique (called “virus-based Genetic Activity-Induced Tagging” and abbreviated as vGAIT) to tag only those OT neurons which were activated during precopulatory and copulatory behaviors of rats. Using this technique, we will elucidate spatial distribution of such OT neurons in the hypothalamus, their phenotype and their projections as well as identify structures receiving input from tagged OT neurons in the forebrain, brainstem, and spinal cord. In parallel, in freely moving rats, we will record the activity of these OT neurons to elucidate their properties and excitability during SS behavior. Based on anatomical data, we will stimulate axonal OT release in those forebrain structures which are functionally related with SS behavior. At the end, using optogenetic and pharmacogenetic techniques, we will activate or inhibit entire populations of tagged OT neurons to monitor changes in SS behavior. The expected data will be entirely novel and will provide mechanistic insights into the physiology of the OT system in the context of SS behavior. Our proposal is highly relevant to human health as it will provide a basis for pathogenesis and possible pharmacological intervention in patients experiencing problems with sexual arousal and reproductive function.
Fritz Thyssen Research Foundation: Functional and therapeutical investigation of the oxytocin system in the Magel2-deficient mouse model of autism and Prader-Willi Syndrome. 01/2038-12/2020.
Prader-Willi syndrome (PWS) is one of the best-studied neurodevelopmental genetic disease. It is characterized mainly as a feeding disorder with behavioral disturbances; indeed, PWS is associated with a distinct behavioral phenotype that includes restricted and/or repetitive behaviors and social-communication impairment, overlapping, in this respect, with autism spectrum disorder (ASD). PWS results from the lack of expression of several contiguous genes, including MAGEL2. Recently, specific point mutations in MAGEL2have been identified in a cohort of patients with ASD, namely the Schaaf-Yang syndrome, underlying the role of MAGEL2in autism. Magel2-deficient mice present deficiencies in early feeding from birth, and later on, in social behavior and cognition, recapitulating the phenotype of patients with Schaaf-Yang syndrome and PWS, and thus representing a highly valuable translational animal model for these conditions.
Compelling evidence coming from humans and animal studies suggests that a deficit in the neuropeptide oxytocin (OT) plays a central role in the pathogenesis of PWS. OT is a hypotalamic neuropeptide that, for its master role in the regulation of social behavior, has been proposed as atreatmentforseveralneuropsychiatricdisorders characterizedby deficits in the social domain (Meyer-Lindenberg et al., 2011). Preliminary clinicaltrialshavebeenprimarily carriedoutinadultpatients,thatis,whentheplastic capacity of the brain is at a minimum and the social behavioral and cognitive dysfunctions are consolidated. However, it is conceivable that a treatment with OT early in life, when the plastic capacity of the brain is at a maximum and the social and behavioral dysfunctions are not consolidated, could produce longer-lasting effects. In particular, by exploiting the higher plastic capacity of the brain, OT could possibly (and hopefully) act as a true disease-modifying intervention. In line with this hypothesis, and of great relevance for this proposal, is the finding that a postnatal administration of OT restores a normal suckling activity (Schaller et al., 2010) and cures alterations in social behavior and cognition in the Magel2-deficient mice (Meziane et al., 2015),making this model particularly pertinent for understanding the mechanisms of rescue of OT and for optimizing OT-based therapeutic strategies for this neurodevelopmental disorder.
The aim of this proposal is to elucidate the mechanisms underlying rescue of PWS alterations by OT.To pursue this aim, we will:
topic 1) elucidate the role of OT signaling in Magel2KO developing neurons
topic 2) trace the development of the OT system in vivoin Magel2KOmice
topic 3) investigate the alteration in the activity of OT neurons in adult Magel2KO mice
topic 4) check for the persistence of rescue effects in offsprings of Magel2KO females treated with OT at birth.
This project will be achieved using newly created and available genetically engineered mice combined with new powerful methodological approaches. By deciphering the alterations of the central OT signaling in PWS we will provide the data for designing and evaluating the most appropriate scheme of OT administration for optimal pathophysiological treatment of human PWS patients
Grinevich V. University of California, Davis, National Institute of Mental Health 1R21MH135349-01A1: Cell types controlling social behavior in extended amygdala andnucleus accumbens.
We will investigate oxytocin neurons in the paraventricular nucleus and bed nucleus of the stria terminalis. Using the oxytocin promoter Venus virus we will conduct viral tracing in the oxytocin neurons in the anterior or posterior PVN. Using the oxytocin promoter GCaMP virus, we will perform calcium imaging in the anterior and posterior PVN as well as the bed nucleus of the stria terminalis. Finally, we will perform CRISPR-based gene editing in oxytocin neurons using the oxytocin promoter Cas9 virus. In Work Package (WP) 1 the student assistant prepares existing viral constructs (Venus and GCaMP). In WP2 the student assistant completes the validation of a new viral construct (Cas9).
