Oxytocin-ergic Control of Social Anxiety: An Interplay between Periaqueductal Gray and Central Amygdala
Experimental and Theoretical Network Neuroscience
Final Report Abstract
Oxytocin (OT) serves dual roles as a hormone, influencing functions like uterine contractions and lactation, and as a neuropeptide within the intricate brain-wide network known as the OT system. This system plays a crucial role in the neural regulation of diverse behaviours, especially social behaviours. It does this by connecting with numerous brain structures through synaptic inputs and axonal outputs. The release of OT from axons in target areas changes the activity of neurons expressing the specific OT receptor (OTR), thus modulating local circuit activity. The midbrain's periaqueductal gray (PAG), a recognized OT system target, serves as a central hub in the limbic system, influencing emotional and behavioural functions such as fear, pain processing, sexual behaviours, aggression, play, vocalizations, and various social behaviours. However, the behavioural functions of the OT-PAG projection are still little understood. My main hypothesis was that it balances a pro-social versus an anti-social behavioural disposition. As the OT projection to the central amygdala (CeA) conveys an anxiolytic function in a non-social context, and as the PAG is strongly interconnected with the CeA, I posited that the OT-PAG pathways might reduce social anxiety-like behaviours. To study this, I used a novel transgenic rat to gain specific genetic access to OTR neurons. To understand the network connectivity of the PAG OTR neurons, I systematically mapped their brain-wide inputs and outputs. I found connections with many socially relevant limbic forebrain areas such as preoptic area and lateral hypothalamus as well as premotor hindbrain areas likely controlling the final behavioural “output”. These results will significantly advance our understanding of the functional organization of the OT-PAG system. Using chemogenetics, I studied the effects of PAG OTR activation on anxiety-like behaviours and free social interactions. Contrary to my hypothesis, this neither changed general anxiety, nor did it increase total social interaction time, while it decreased proactive sociability. Interestingly, my recent results suggest a hitherto entirely unexplored role of PAG-OTR neurons in playfulness and in social communication. In summary, my results have opened several novel avenues of research, which will significantly advance our understanding of how neuropeptides, especially OT, regulate social and other behaviours via modulation of distinct circuits throughout the brain.
Publications
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Oxytocinergic Feedback Circuitries: An Anatomical Basis for Neuromodulation of Social Behaviors. Frontiers in Neural Circuits, 15.
Lefevre, Arthur; Benusiglio, Diego; Tang, Yan; Krabichler, Quirin; Charlet, Alexandre & Grinevich, Valery
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Analysis of the hypothalamic oxytocin system and oxytocin receptor‐expressing astrocytes in a mouse model of Prader–Willi syndrome. Journal of Neuroendocrinology, 34(12).
Althammer, Ferdinand; Wimmer, Moritz Claudius; Krabichler, Quirin; Küppers, Stephanie; Schimmer, Jonas; Fröhlich, Henning; Dötsch, Laura; Gruber, Tim; Wunsch, Selina; Schubert, Tim; Kirchner, Matthew K.; Stern, Javier E.; Charlet, Alexandre; Grinevich, Valery & Schaaf, Christian P.
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Oxytocin-induced astrocyte remodelling promote neuronal activity in the central amygdala. French Glial Cell Club Meeting 2022. Sète, France.
Baudon, A.; Krabichler, Q.; Althammer, F.; Clauss—Creusot, E.; Grinevich, V. & Charlet, A.
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An analgesic pathway from parvocellular oxytocin neurons to the periaqueductal gray in rats. Nature Communications, 14(1).
Iwasaki, Mai; Lefevre, Arthur; Althammer, Ferdinand; Clauss, Creusot Etienne; Łąpieś, Olga; Petitjean, Hugues; Hilfiger, Louis; Kerspern, Damien; Melchior, Meggane; Küppers, Stephanie; Krabichler, Quirin; Patwell, Ryan; Kania, Alan; Gruber, Tim; Kirchner, Matthew K.; Wimmer, Moritz; Fröhlich, Henning; Dötsch, Laura; Schimmer, Jonas ... & Charlet, Alexandre
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Editorial: Molecular mechanisms underlying pain relief and drug tolerance. Frontiers in Molecular Neuroscience, 16.
Krabichler, Quirin & Reynders, Ana
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Generation of iPSCs derived Oxytocin specific hypothalamic organoids and transplantation into rat brains. Interdisciplinary Center for Neurosciences (IZN) Retreat 2023. Schöntal, Germany.
Zovko, A.; Munoz, E.; Sierra Garcia, D.; Horschitz, S.; Krabichler, Q.; Koch, P. & Grinevich, V.
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High-calorie diets uncouple hypothalamic oxytocin neurons from a gut-to-brain satiation pathway via κ-opioid signaling. Cell Reports, 42(10), 113305.
Gruber, Tim; Lechner, Franziska; Murat, Cahuê; Contreras, Raian E.; Sanchez-Quant, Eva; Miok, Viktorian; Makris, Konstantinos; Le, Thuc Ophélia; González-García, Ismael; García-Clave, Elena; Althammer, Ferdinand; Krabichler, Quirin; DeCamp, Lisa M.; Jones, Russell G.; Lutter, Dominik; Williams, Rhiannan H.; Pfluger, Paul T.; Müller, Timo D.; Woods, Stephen C. ... & García-Cáceres, Cristina
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Oxytocin action in the periaqueductal gray is involved in social habituation by heterospecific play in rats. Interdisciplinary Center for Neurosciences (IZN) Retreat 2023. Schöntal, Germany.
Krabichler, Q.; Maier, E.; Bechthold, L.; Liu, H.-J.; Zovko, A.; Brecht, M.; Ishiyama, S. & Grinevich, V.
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Oxytocin receptor expressing neurons in the periaqueductal gray control spectro-temporal characteristics of rat ultrasonic vocalizations during social habituation gated heterospecific play. Neurobiology of Social Behaviors Meeting, September 9-14, 2023. Erice, Sicily, Italy.
Maier, E.; Krabichler, Q.; Bechthold, L.; Liu, H.-J.; Brecht, M.; Ishiyama, S. & Grinevich, V.
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Using a novel transgenic AVP-Cre rat to dissect arginine-vasopressin circuits in the brain and their behavioral roles. PANAM Physiological Sciences Meeting 2023, November 27-30, 2023, Puerto Varas, Chile.
Krabichler, Q.; Lefevre, A.; Kania, A. Hagiwara, D.; Afordakos, K.; Schönig, K.; Bartsch, D. & Grinevich, V.
