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.