Behavioral dysregulation and monoaminergic deficits precede memory impairments in human tau-overexpressing (htau) mice

Alzheimers disease (AD) poses an ever-increasing public health concern as the population ages, affecting more than 6 million Americans. AD patients present with mood and sleep changes in the prodromal stages that may be partly driven by loss of monoaminergic neurons in brainstem, but a causal relationship has not been firmly established. The goal of the present study was to evaluate depressive and anxiety-like behaviors in a mouse model of human tauopathy (htau mice) at 4 and 6 months of age prior to the onset of cognitive impairments and correlate these behavior changes with tau pathology, neuroinflammation, and monoaminergic dysregulation in the DRN and LC. We observed depressive-like behaviors at 4 months of age in male and female htau mice and hyperlocomotion in male htau mice. At 6 months, male htau mice developed anxiety-like behavior in the EZM, whereas hyperlocomotion had resolved by this time point. Depressive-like behaviors in the social interaction test persisted at 6 months but were resolved in the sucrose preference test. There was also a significant reduction in number and density of 5-HT-immunoreactive neurons in the rostral DRN in htau mice at 4 months and 5-HT neuronal density was negatively correlated with the intensity of phosphorylated tau staining in this subregion. Additionally, we found evidence of microglial activation in the mid and caudal DRN and astrocytic activation in the rostral DRN. 5-HT neuronal activity was reduced in the DRN and accompanied by downregulation of Tph2 and Sert, whereas genes that promote neuroinflammation and tau phosphorylation were upregulated. Finally, there was enhanced ptau202/205 staining and microglial activity in the LC of htau mice and reduced TH optical density, although the number and density of TH+ neurons were not altered. In total, these results suggest that tau pathology in the DRN and the resulting loss of serotonergic neurotransmission may drive depressive-like behaviors in the early stages of AD, whereas anxiety-like behaviors develop later and may result from neurodegeneration in other regions. ### Competing Interest Statement The authors have declared no competing interest.