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Prof. Dr. Valery Grinevich

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.

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

Zentralinstitut für Seelische Gesundheit (ZI) - https://www.zi-mannheim.de