Patterns matter: differential effects of stress‐inducing and novelty‐associated locus coeruleus firing on pretangle tau pathophysiology in a rat model

Abstract

AbstractBackgroundThe brainstem locus coeruleus (LC), the main source of brain norepinephrine (NE), is critically involved in several functions including wakefulness, vigilance, attention, learning and memory. LC functioning is firing pattern‐dependent. Phasic pattern promotes novelty and learning, while high tonic activity associates with stress and anxiety. LC has been identified as a key structure in Alzheimer’s disease (AD) development. Braak and colleagues propose that soluble abnormally phosphorylated tau (pretangle tau) originates in the LC early in life. The spreading of pretangle tau to other neuromodulatory areas and transentorhinal cortex constitutes Braak’s pretangle AD stages. Pretangle stages appear to be universal in human, however, only a portion of us develop AD. The selective vulnerability of individuals for AD is not understood. We hypothesized that differential LC activity patterns, influence the pretangle tau pathophysiology and the development of AD.MethodIn this study, an AAV carrying pseudo‐phosphorylated human tau (AAV9‐DIO‐EGFP‐htauE14) was infused into the LC of 2‐3 month‐old TH‐CRE rats, mimicking the onset of tauopathy during puberty in humans. Another AAV containing ChR2 opsin (AAVdj‐DIO‐ChR2‐mCherry) was co‐infused with htauE14. Chronic light stimulation of the LC of either a 10 Hz phasic pattern or a 25 Hz tonic pattern was carried out for 6 weeks. The performance of ChR2 rats in a battery of behavioral assays was compared with control groups without ChR2 (AAVdj‐DIO‐mCherry), 10 months following the AAV infusion. This was followed by immunohistochemistry and Western blotting comparing different biomarkers.ResultPhasic LC activation improved spatial and olfactory discrimination of the htauE14 rats, while chronic tonic activation increased stress level of the rats and led to anhedonia. Phasic pattern rescued axonal degeneration observed in the control htauE14 rats, showing higher density of LC fibers in the piriform cortex and hippocampal dentate gyrus. Tonic LC activation did not rescue LC fiber degeneration, instead, worsened LC neuronal health indexed by elevated level of active caspase 3. The learning performance was positively correlated with the LC fiber density.ConclusionThese results argue that variations in environmental experiences associated with differing LC activity patterns may account for individual susceptibility to development of AD in humans.