Increased brain cytokine level associated impairment of vigilance and memory in aged rats can be alleviated by alpha7 nicotinic acetylcholine receptor agonist treatment

Abstract

Age-related neurocognitive disorders are common problems in developed societies. Aging not only affects memory processes, but may also disturb attention, vigilance, and other executive functions. In the present study, we aimed to investigate age-related cognitive deficits in rats and associated molecular alterations in the brain. We also aimed to test the effects of the alpha7 nicotinic acetylcholine receptor (nAChR) agonist PHA-543613 on memory as well as on the sustained attention and vigilance of aged rats. Short- and long-term spatial memories of the rats were tested using the Morris water maze (MWM) task. To measure attention and vigilance, we designed a rat version of the psychomotor vigilance task (PVT) that is frequently used in human clinical examinations. At the end of the behavioral experiments, mRNA and protein expression of alpha7 nAChRs, cytokines, and brain-derived neurotrophic factor (BDNF) were quantitatively measured in the hippocampus, frontal cortex, striatum, and cerebellum. Aged rats showed marked cognitive deficits in both the MWM and the PVT. The deficit was accompanied by increased IL-1beta and TNFalpha mRNA expression and decreased BDNF protein expression in the hippocampus. PHA-543613 significantly improved the reaction time of aged rats in the PVT, especially for unexpectedly appearing stimuli, while only slightly (non-significantly) alleviating spatial memory deficits in the MWM. These results indicate that targeting alpha7 nAChRs may be an effective strategy for the amelioration of attention and vigilance deficits in age-related neurocognitive disorders.

Keywords: Aging; Alpha7 nicotinic acetylcholine receptor; Memory; Neurocognitive disorders; Neuroinflammation; Vigilance.

Fig. 1

Performance of aged and young rats in the Morris water maze (MWM). A: Time needed to find the platform (escape latency) in the four trials of the first training day. B: Average escape latency on the four days of the training process. C: Performance in the probe trial (5th day) when the platform was not placed in the pool. D: Extinction of memory for platform location in four consecutive probe trials (platform is absent). Asterisks mark significant differences between aged and young rats: * p < 0.05, *** p < 0.001

Fig. 2

Effects of alpha7 nicotinic acetylcholine receptor agonist PHA-543613 on the memory performance of aged rats in the water maze. A: Time needed to find the platform (escape latency) in the four trials of the first training day. B: Average escape latency on the four days of the training process. C: Performance in the probe trial (5th day) when the platform was not placed in the pool. Asterisks mark significant differences between experimental groups: (*) p < 0.1, * p < 0.05, *** p < 0.001

Fig. 3

Performance of aged and young rats in the psychomotor vigilance task. A: Total reaction time (from the cue until pressing the lever) as a function of foreperiod length. B: Total reaction time averaged over all trials. C: Time elapsed from cue presentation until pulling the nose out of the feeder trough (noseout) as a function of foreperiod length. D: Noseout part of the reaction time averaged over all trials. E: Time elapsed from pulling the nose out of the feeder trough until pressing the lever (lever-pressing) as a function of foreperiod length. F: Lever-pressing part of the reaction time averaged over all trials. G: Number of premature responses as a function of foreperiod length. H: Total number of premature responses. Asterisks mark significant differences between aged and young rats: * p < 0.05, ** p < 0.01, *** p < 0.001

Fig. 4

Effects of alpha7 nicotinic acetylcholine receptor agonist PHA-543613 on the performance of aged rats in the psychomotor vigilance task. A: Total reaction time (from the cue until pressing the lever) as a function of foreperiod length. B: Total reaction time averaged over all trials. C: Time elapsed from cue presentation until pulling the nose out of the feeder trough (noseout) as a function of foreperiod length. D: Noseout part of the reaction time averaged over all trials. E: Time elapsed from pulling the nose out of the feeder trough until pressing the lever (lever-pressing) as a function of foreperiod length. F: Lever-pressing part of the reaction time averaged over all trials. G: Number of premature responses as a function of foreperiod length. H: Total number of premature responses. Asterisk marks significant differences between treatments at the level of p < 0.05

Fig. 5

Number of missed trials in the psychomotor vigilance task experiments comparing the performance of aged and young rats (A), and effects of different doses of alpha7 nicotinic acetylcholine receptor agonist PHA-543613 on aged rats (B). Asterisks mark significant differences: ** p < 0.01

Fig. 6

mRNA expression of cytokines, NFκB, BDNF, and alpha7 nicotinic acetylcholine receptor (CHRNA7) in different brain regions of aged and young rats measured with quantitative real-time PCR. Data are expressed in arbitrary units that indicate the mRNA expression of target genes normalized to CycA housekeeping gene expression. Asterisks mark significant differences between aged and young rats: (*) p < 0.1, ** p < 0.01

Fig. 7

Expression of IL-1β, BDNF, and alpha7 nicotinic acetylcholine receptor (CHRNA7) proteins in different brain regions of aged and young rats measured with sandwich ELISA. Asterisk marks a significant difference between aged and young rats at the level of p < 0.05