title: Deficits in hippocampal-dependent transfer generalization learning accompany synaptic dysfunction in a mouse model of amyloidosis.
abstract: Elevated β-amyloid and impaired synaptic function in hippocampus are among the earliest manifestations of Alzheimer's disease (AD). Most cognitive assessments employed in both humans and animal models, however, are insensitive to this early disease pathology. One critical aspect of hippocampal function is its role in episodic memory, which involves the binding of temporally coincident sensory information (e.g., sights, smells, and sounds) to create a representation of a specific learning epoch. Flexible associations can be formed among these distinct sensory stimuli that enable the "transfer" of new learning across a wide variety of contexts. The current studies employed a mouse analog of an associative "transfer learning" task that has previously been used to identify risk for prodromal AD in humans. The rodent version of the task assesses the transfer of learning about stimulus features relevant to a food reward across a series of compound discrimination problems. The relevant feature that predicts the food reward is unchanged across problems, but an irrelevant feature (i.e., the context) is altered. Experiment 1 demonstrated that C57BL6/J mice with bilateral ibotenic acid lesions of hippocampus were able to discriminate between two stimuli on par with control mice; however, lesioned mice were unable to transfer or apply this learning to new problem configurations. Experiment 2 used the APPswe PS1 mouse model of amyloidosis to show that robust impairments in transfer learning are evident in mice with subtle β-amyloid-induced synaptic deficits in the hippocampus. Finally, Experiment 3 confirmed that the same transfer learning impairments observed in APPswePS1 mice were also evident in the Tg-SwDI mouse, a second model of amyloidosis. Together, these data show that the ability to generalize learned associations to new contexts is disrupted even in the presence of subtle hippocampal dysfunction and suggest that, across species, this aspect of hippocampal-dependent learning may be useful for early identification of AD-like pathology.
authors.affiliation: Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center, Bryan, Texas.
authors.forename: Karienn S
authors.initials: KS
authors.lastname: Montgomery
authors.affiliation: Department of Neurology, Mitchell Center for Alzheimer's Disease and Related Brain Disorders, University of Texas Health Science Center in Houston, Houston, Texas.
authors.forename: George
authors.initials: G
authors.lastname: Edwards
authors.affiliation: Department of Neuroscience, University of Florida, Gainesville, Florida.
authors.forename: Yona
authors.initials: Y
authors.lastname: Levites
authors.affiliation: Department of Neuroscience, University of Florida, Gainesville, Florida.
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
authors.affiliation: Neurobehavioral Research Lab, New Jersey Health Care System, East Orange, New Jersey.|Department of Pharmacology, Physiology & Neuroscience, New Jersey Medical School, Rutgers University, Newark, New Jersey.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Myers
authors.affiliation: Center for Molecular & Behavioral Neuroscience, Department of Neuroscience, Rutgers University, Newark, New Jersey.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Gluck
authors.affiliation: Department of Psychiatry, University of Florida, Gainesville, Florida.
authors.forename: Barry
authors.initials: B
authors.lastname: Setlow
authors.affiliation: Department of Neuroscience, University of Florida, Gainesville, Florida.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Bizon
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000686:Amyloidosis / Q000473:pathology / Q000503:physiopathology* / Q000523:psychology*; D000818:Animals; D001244:Association; D004195:Disease Models, Animal; D005260:Female; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D007051:Ibotenic Acid; D007859:Learning Disabilities / Q000473:pathology / Q000503:physiopathology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055696:Olfactory Perception / Q000502:physiology; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000473:pathology / Q000502:physiology*; D046509:Tissue Culture Techniques; D014163:Transfer, Psychology / Q000502:physiology*
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; C508853:PSEN1 protein, human; D053764:Presenilin-1; D007051:Ibotenic Acid
keywords: APPswePS1; Alzheimer's disease; LTP; Tg-SwDI; amyloid; associative learning; memory; mice; synaptic function