Sloand T Joseph, Dunham Benjamin P, Niedringhaus Mark, West Elizabeth A
Department of Neuroscience, School of Osteopathic Medicine and School of Translational Biomedical Engineering and Sciences, Virtua Health College of Medicine and Life Sciences, Rowan University, Stratford, NJ 08084.
bioRxiv. 2025 Jul 15:2025.07.10.664159. doi: 10.1101/2025.07.10.664159.
Cognitive deficits, including deficits in the ability to shift behavior following negative consequences, often precede the accumulation of canonical neuropathological markers (Aβ plaques and tauopathy) and severe dementia in Alzheimer's disease (AD) patients. The Tg-F344-AD rat model exhibits age-dependent AD pathology and memory deficits that recapitulate AD, However, it is unknown how medial prefrontal cortex activity is altered in awake and behaving AD rats during learning and/or flexible behavior. Here we determine the ability of in 6-7month-old TgF344-AD rats to learn reward predictive cues and to shift behavior away from reward-predictive cues following outcome devaluation while recording mPFC neurons. Specifically, AD rats (n=17) and wild-type littermates (n=17) were presented with two distinct cues as conditioned stimuli (CS+) predicting distinct outcomes. A conditioned taste aversion to one outcome was induced, after which the rats were tested post-devaluation to evaluate their ability to avoid the CS+ associated with the devalued outcome. We found a loss of motivated behavior during learning and a loss of flexible behavior during testing in 6-7-month-old AD rats relative to WT littermate controls. In addition, there was differential aberrant mPFC encoding of cue-outcome associations in AD rats during conditioning and following outcome devaluation. Specifically, AD animals show fewer neurons during conditioning that encode both the cue and the outcome than WT animals. Also, AD animals also showed a greater proportion of neurons that exhibited an excited response to reward predictive cues post-outcome devaluation. Together, these data contribute to our understanding of alterations in mPFC that may underline prodromal AD behavioral deficits to inform future treatments.
认知缺陷，包括在负面后果后改变行为的能力缺陷，通常先于典型神经病理标志物（Aβ斑块和tau病变）的积累以及阿尔茨海默病（AD）患者出现严重痴呆。Tg-F344-AD大鼠模型表现出与年龄相关的AD病理和记忆缺陷，可重现AD情况。然而，尚不清楚在学习和/或灵活行为期间，清醒且有行为表现的AD大鼠内侧前额叶皮质活动是如何改变的。在此，我们在记录内侧前额叶皮质（mPFC）神经元的同时，确定6-7月龄TgF344-AD大鼠学习奖励预测线索以及在结果贬值后将行为从奖励预测线索转移开的能力。具体而言，给AD大鼠（n = 17）和野生型同窝仔鼠（n = 17）呈现两种不同的线索作为条件刺激（CS+），以预测不同的结果。诱导对一种结果的条件性味觉厌恶，之后在贬值后对大鼠进行测试，以评估它们避免与贬值结果相关的CS+的能力。我们发现，相对于野生型同窝对照，6-7月龄AD大鼠在学习期间出现动机行为丧失，在测试期间出现灵活行为丧失。此外，在条件作用期间和结果贬值后，AD大鼠在提示-结果关联的mPFC编码方面存在差异异常。具体而言，与野生型动物相比，AD动物在条件作用期间编码线索和结果的神经元较少。而且，AD动物在结果贬值后对奖励预测线索表现出兴奋反应的神经元比例也更高。这些数据共同有助于我们理解mPFC的改变，这些改变可能是前驱AD行为缺陷的基础，为未来治疗提供信息。
