Background The earliest brain pathology related to Alzheimer’s disease (AD) is hyperphosphorylated soluble tau in the noradrenergic locus coeruleus (LC) neurons. Braak characterizes five pretangle tau stages preceding AD tangles. Pretangles begin in young humans and persist in the LC while spreading from there to other neuromodulatory neurons and, later, to the cortex. While LC pretangles appear in all by age 40, they do not necessarily result in AD prior to death. However, with age and pretangle spread, more individuals progress to AD stages. LC neurons are lost late, at Braak stages III–IV, when memory deficits appear. It is not clear if LC hyperphosphorylated tau generates the pathology and cognitive changes associated with preclinical AD. We use a rat model expressing pseudohyperphosphorylated human tau in LC to investigate the hypothesis that LC pretangles generate preclinical Alzheimer pathology. Methods We infused an adeno-associated viral vector carrying a human tau gene pseudophosphorylated at 14 sites common in LC pretangles into 2–3- or 14–16-month TH-Cre rats. We used odor discrimination to probe LC dysfunction, and we evaluated LC cell and fiber loss. Results Abnormal human tau was expressed in LC and exhibited somatodendritic mislocalization. In rats infused at 2–3 months old, 4 months post-infusion abnormal LC tau had transferred to the serotonergic raphe neurons. After 7 months, difficult similar odor discrimination learning was impaired. Impairment was associated with reduced LC axonal density in the olfactory cortex and upregulated β1-adrenoceptors. LC infusions in 14–16-month-old rats resulted in more severe outcomes. By 5–6 months post-infusion, rats were impaired even in simple odor discrimination learning. LC neuron number was reduced. Human tau appeared in the microglia and cortical neurons. Conclusions Our animal model suggests, for the first time, that Braak’s hypothesis that human AD originates with pretangle stages is plausible. LC pretangle progression here generates both preclinical AD pathological changes and cognitive decline. The odor discrimination deficits are similar to human odor identification deficits seen with aging and preclinical AD. When initiated in aged rats, pretangle stages progress rapidly and cause LC cell loss. These age-related outcomes are associated with a severe learning impairment consistent with memory decline in Braak stages III–IV. Electronic supplementary material The online version of this article (10.1186/s13195-019-0511-2) contains supplementary material, which is available to authorized users.
The locus coeruleus (LC) produces phasic and tonic firing patterns that are theorized to have distinct functional consequences. However, how different firing modes affect learning and valence encoding of sensory information are unknown. Here we show bilateral optogenetic activation of rat LC neurons using 10-Hz phasic trains of either 300 msec or 10 sec accelerated acquisition of a similar odor discrimination. Similar odor discrimination learning was impaired by noradrenergic blockade in the piriform cortex (PC). However, 10-Hz phasic light-mediated learning facilitation was prevented by a dopaminergic antagonist in the PC, or by ventral tegmental area (VTA) silencing with lidocaine, suggesting a LC-VTA-PC dopamine circuitry involvement. Ten hertz tonic stimulation did not alter odor discrimination acquisition, and was ineffective in activating VTA DA neurons. For valence encoding, tonic stimulation at 25 Hz induced conditioned odor aversion, while 10-Hz phasic stimulations produced an odor preference. Both conditionings were prevented by noradrenergic blockade in the basolateral amygdala (BLA). Cholera Toxin B retro-labeling showed larger engagement of nucleus accumbens-projecting neurons in the BLA with 10-Hz phasic activation, and larger engagement of central amygdala projecting cells with 25-Hz tonic light. These outcomes argue that the LC activation patterns differentially influence both target networks and behavior.
The earliest abnormality associated with Alzheimer's disease (AD) is the presence of persistently phosphorylated pretangle tau in locus coeruleus (LC) neurons. LC neuron numbers and fiber density are positive predictors of cognition prior to death. Using an animal model of LC pretangle tau, we ask if LC activity patterns influence the sequelae of pretangle tau. We seeded LC neurons with a pretangle human tau gene. We provided daily novelty‐ or stress‐associated optogenetic activation patterns to LC neurons for 6 weeks in mid‐adulthood and, subsequently, probed cognitive and anatomical changes. Prior LC phasic stimulation prevented spatial and olfactory discrimination deficits and preserved LC axonal density. A stress‐associated activation pattern increased indices of anxiety and depression, did not improve cognition, and worsened LC neuronal health. These results argue that variations in environmental experiences associated with differing LC activity patterns may account for individual susceptibility to development of AD in humans.
The locus coeruleus (LC), the main source of forebrain norepinephrine, produces phasic and tonic firing patterns that are theorized to have distinct functional consequences. However, how different firing modes affect learning and valence coding of sensory information are unknown. Here bilateral optogenetic activation of rat LC neurons using 10-Hz phasic trains of either 300 msec or 10 sec accelerates acquisition of a food-rewarded similar odor discrimination, but not a dissimilar odor discrimination, consistent with LC-supported enhanced pattern separation and plasticity. Similar odor discrimination learning is impaired by noradrenergic blockade in the piriform cortex (PC). However, here 10-Hz LC phasic light-mediated learning facilitation is prevented by a dopaminergic antagonist in the PC, or by ventral tegmental area (VTA) silencing with lidocaine, suggesting an LC-VTA-PC dopamine circuitry mediates 10-Hz phasic learning facilitation. Tonic stimulation at 10 Hz did not alter odor discrimination acquisition, and was less effective in activating VTA DA neurons. For valence encoding, tonic stimulation at 25 Hz induced freezing, anxiety and conditioned odor aversion, while 10-Hz phasic stimulation produced an odor preference consistent with positive valence. Noradrenergic blockade in the basolateral amygdala (BLA) prevented conditioned odor preference and aversion induced by 10-Hz phasic and 25-Hz tonic light respectively. CTB retro-labeling showed relatively larger engagement of nucleus accumbens projecting neurons over central amygdala projecting neurons in the BLA with 10-Hz LC phasic activation, compared to 25-Hz tonic. These outcomes argue that LC pauses, as well as LC firing frequencies, differentially influence both target networks and behaviour.
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