STRESS- AND AROUSAL-ASSOCIATED RELAXIN-3/RXFP3 NETWORKS AND CONTROL OF AFFECT AND COGNITION: STUDIES IN TRANSGENIC MICE  — ASN Events

STRESS- AND AROUSAL-ASSOCIATED RELAXIN-3/RXFP3 NETWORKS AND CONTROL OF AFFECT AND COGNITION: STUDIES IN TRANSGENIC MICE  (#375)

Mouna Haidar 1 , Cary Zhang 1 , Francisco Olucha-Bordonau 2 , Davor Stanic 1 3 , Matthias Dutschmann 1 3 , Craig Smith 1 3 , Andrew Gundlach 1 3
  1. The Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia
  2. Department of Anatomy and Human Embryology , University of Valencia, Valencia, Spain
  3. The Florey Department of Neuroscience and Mental Health, The University of Melbourne, Melbourne, VIC, Australia

Convergent evidence implicates stress in the pathology of Alzheimer’s disease (AD) and dementia (e.g. AD and stress disorders is characterized by hypothalamic-pituitary-adrenal dysfunction and psychological stress increases AD risk). Chronic stress and elevated glucocorticoids are associated with cognitive symptoms of dementia in elderly/AD subjects, and exacerbate β-amyloid (Aβ) accumulation and memory deficits in AD transgenic mice. Furthermore, CRF is a likely causal factor in stress-induced Aβ increases and CRF1-signalling is implicated in the pathophysiology of tau hyperphosphorylation in disease models, including mice (Tau-P301L/S) that overexpress mutant tau found in familial frontotemporal degeneration. Evidence also suggests relaxin-3/RXFP3 networks contribute to control of arousal and stress responses via interactions with other systems (e.g. 5-HT) and modulate behavioural state, affect and cognition. In this regard, the septohippocampal pathway is regulated by GABA/relaxin-3 neurons in nucleus incertus (NI) that innervate RXFP3-positive GABA neurons in medial septum (MS) and hippocampus; and RXFP3 modulation in MS alters hippocampal theta rhythm and working memory. In turn, the activity of these neurons is altered in AD patients and in Tau-P301L mice. Therefore, this study is investigating the neurochemical phenotype of RXFP3-positive neurons in the MS and hippocampus in RXFP3-reporter mice, particularly markers for GABA projection- and inter-neurons. Initial studies reveal strong RXFP3-related staining within calretinin-positive and -negative neurons in dentate gyrus and hippocampus, respectively. Secondly, we are comparing relaxin-3/RXFP3 systems in wildtype and Tau-P301L mice, in which tauopathy is detected in cortex, hippocampus and brainstem; and cognitive/affective behaviour is altered. In terms of the relative degeneration or resistance of the NI/relaxin-3 network in these mice, in initial studies in a 9-month-old Tau-P301L mouse, the majority of NI relaxin-3 neurons appeared negative for phospho-tau aggregates. Hence, the NI/relaxin-3/GABA network may represent an intact arousal system and justify studies of stress-related behavioural outputs in Tau-P301L mice and how these are impacted by RXFP3 modulation in MS and hippocampus.