Spatial reference learning deficits in absence of dysfunctional working memory in the TgF344‐AD rat model of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is characterized by cognitive disorders and alterations of behavioral traits such as anhedonia and anxiety. Contribution of nonphysiological forms of amyloid and tau peptides to the onset of neurological dysfunctions remains unclear because most preclinical models only present one of those pathological AD‐related biomarkers. A more recently developed model, the TgF344‐AD rat has the advantage of overexpressing amyloid and naturally developing tauopathy, thus making it close to human familial forms of AD. We showed the presence of a learning dysfunction in a reference memory test, without spatial working memory impairment but with an increase in anxiety levels and a decrease in motivation to participate in the test. In the sucrose preference test, TgF344‐AD rats did not show signs of anhedonia but did not increase the volume of liquid consumed when the water was replaced by sucrose solution. These behavioral phenomena were observed at an age when tau accumulation are absent, and where amyloid deposits are predominant in the hippocampus and the entorhinal cortex. Within the hippocampus itself, amyloid accumulation is heterogenous between the subiculum, the dorsal hippocampus and the ventral hippocampus. Thus, our data demonstrated heterogeneity in the appearance of various behavioral and neurochemical markers in the TgF344‐AD rat. This multivariate analysis will therefore make it possible to define the stage of the pathology, to measure its evolution and the effects of future therapeutic treatments.

Heightened Hippocampal β-Adrenergic Receptor Function Drives Synaptic Potentiation and Supports Learning and Memory in the TgF344-AD Rat Model during Prodromal Alzheimer's Disease

“…ns, not significant. *p 0.05, **p 0.01. memory in a Y-maze (Tournier et al, 2020). Together, these data suggest that compensatory mechanisms must be maintaining function, but certain tasks may be more vulnerable to deterioration.…”

Heightened β-adrenergic receptor function in the TgF344-AD rat model drives synaptic potentiation and supports learning and memory

“…Despite significant AD pathology and altered synaptic function beginning at 6 months of age in TgF344-AD rats (23, 34), performance in hippocampus dependent spatial tasks such as Morris Water Maze or Barnes Maze is surprisingly not different from Wt (61–63). At 9-months of age reference memory in a T-maze is altered, but not working memory in a Y-maze (64). Together, these data suggest compensatory mechanisms must be maintaining function, but certain tasks may be more vulnerable to deterioration.…”

Alterations in dopamine system and in its connectivity with serotonin in a rat model of Alzheimer’s disease

“…The recent report showing a reduction in the participation of TgF344-AD rats in behavioural tests also supports the presence of a deficit in the dopaminergic system. 50 As it was previously reported that SSRI treatment can alter the activity of DA neurons, 69 we tested the impact of chronic exposure to citalopram on the response to quinpirole alone or in combination with MDLl00.907. The SSRI treatment appeared to be effective on reducing anxiety levels, and on the control of 5HT 2A R on the locomotor response to presynaptic quinpirole, but does not allow a normalization of the hyper-sensitivity of D 2 -autoreceptors.…”