Effects of chronic psychosocial stress on the brain oxytocin (OXT) and neuropeptide S (NPS) systems, and potential stress-protective actions of chronic OXT and NPS administration

• Applicant: Professorin Dr. Inga D. Neumann
• Subject Area: Biological Psychiatry ; Cognitive, Systems and Behavioural Neurobiology
• Term: from 2013 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 234728202

• Final Report Year: 2019

Final Report Abstract

The overall aim of our project was to identify the effects of the neuropeptides oxytocin (OXT) and neuropeptide S (NPS) on brain and neuronal functions, and behavior in the context of chronic psychosocial stress. Using a clinically relevant mouse model of chronic psychosocial stress, i.e. chronic subordinate colony (CSC) housing (also know as "Four mice and a macho"), we could reveal brain region-dependent alterations in OXT receptor (OXTR), but not NPSR, binding. Down-regulation of OXTR binding may reflect continuous high presence of OXT due to stress-induced local OXT release. To further test this hypothesis, and to reveal potential anti-stress effects of OXT, we chronically applied OXT over 14 days. To our surprise, such treatment resulted in elevated levels of anxiety-related behavior and reduction in OXTR binding in several relevant brain regions in unstressed adult males, which challenges the use of intranasal OXT treatment in humans. In contrast, at lower dose, chronic OXT attenuated some behavioral and physiological maladaptations induced by chronic stress. In a translational site project, we confirmed the anxiolytic and revealed social memory effects of OXT and NPS after nasal administration, and could show that OXT is indeed taken up by the brain compartment of both rats and mice. At neuronal level, we were able to identify several novel OXTR-mediated signaling pathways, which are involved in the anxiolytic effect of OXT. These included (i) the activation of transient receptor potential vanilloid type-2 channels (TRPV2), required for increased Ca2+ signaling, (ii) attenuation of basal and stress-induced expression of the anxiogenic neuropeptide CRF via regulation of the translocation of the transcription cofactor CRTC3 into the nucleus, and (iii) modulation of protein translation via activation of the eukaryotic elongation factor 2 (eEF2), a key mediator of protein synthesis, both in a hypothalamic cell line and in vivo within the rat hypothalamus. Thus, OXT seems to recruit multiple intracellular signaling cascades to modulate gene expression and protein synthesis - processes mediating its anxiolytic effects within the brain. Based on these molecular insights of "acute" OXTR–mediated effects, we continued to study potential adaptations of OXTR signaling after "chronic" OXT stimulation and revealed the induction of an alternative splicing process of the CRFR2, which contributed to the anxiogenic effects of chronic OXT treatment. With respect to the brain NPS system, signaling pathways downstream of NPSR activation are largely unknown. In this context several studies we could show that NPS activates intra-neuronal Calcium signaling via CaM kinases and the MAP kinase pathway. Especially activation of phospholipase C signaling was found to be essential for NPS-evoked anxiolysis in an amygdala subregion. Interestingly, the OXT and NPS systems seem to interact, as the anxiolytic effect of NPS within the hypothalamus is dependent on local OXT actions. Taken together, these DFG-funded studies significantly increased our knowledge regarding neuropeptide actions in the brain in the context of anxiety and stress at behavioral, physiological and neuronal and molecular levels.

Publications

• Brain oxytocin in social fear conditioning and its extinction: Involvement of the lateral septum. Neuropsychopharmacology 2014; 39(13):3027-35
  Zoicas I, Slattery DA, Neumann ID
  
• Dose-dependent effects of chronic central infusion of oxytocin on anxiety, oxytocin receptor binding and stress-related parameters in mice. Psychoneuroendocrinology 2014; 42, 225-236
  Peters S, Slattery DA, Uschold-Schmidt N, Reber SO, Neumann ID
  
• Stress resilience-a low-anxiety genotype protects male mice from the consequences of chronic psychosocial stress. Endocrinology 2014; 155(1):117-26
  Füchsl AM, Neumann ID, Reber SO
  
• Oxytocin regulates stress-induced CRF gene transcription through CREB- regulated transcription coactivator 3 (CRTC3). J Neurosci. 2015;35(35):12248-60
  Jurek B, Slattery DA, Hiraoka Y, Liu Y, Nishimori K, Aguilera G, Neumann ID, van den Burg EH
  
• Oxytocin Stimulates Extracellular Ca2+ Influx Through TRPV2 Channels in Hypothalamic Neurons to Exert its Anxiolytic Effects. Neuropsychopharmacology 2015; 40(13):2938-47
  van den Burg EH, Stindl J, Grund T, Neumann ID, Strauss O
  
• Selective breeding for high anxiety introduces a synonymous SNP that increases neuropeptide S receptor activity. J Neurosci 2015; 35(11):4599-613
  Slattery DA, Naik RR, Grund T, Yen YC, Sartori SB, Füchsl A, Finger BC, Elfving B, Nordemann U, Guerrini R, Calo G, Wegener G, Mathé AA, Singewald N, Czibere L, Landgraf R, Neumann ID
  
• Neuropeptide S reduces fear and avoidance of conspecifics induced by social fear conditioning and social defeat, respectively. Neuropharmacology 2016; 108:284-91
  Zoicas I, Menon R, Neumann ID
  
• Neuropeptide S activates paraventricular oxytocin neurons to induce anxiolysis. J Neurosci 2017; 37(50):12214-12225
  Grund T, Goyon S, Li Y, Eliava M, Liu H, Charlet A, Grinevich V, Neumann ID
  
• Neuropeptide S Induces Acute Anxiolysis by Phospholipase C- Dependent Signaling within the Medial Amygdala. Neuropsychopharmacology 2018; 43(5):1156-63
  Grund T, Neumann ID
  
• De Novo Protein Synthesis Mediated by the Eukaryotic Elongation Factor 2 Is Required for the Anxiolytic Effect of Oxytocin. Biol Psychiatry. 2019; 85(10):802-811
  Martinetz S, Meinung CP, Jurek B, von Schack D, van den Burg EH, Slattery DA, Neumann ID