A novel touchscreen-automated paired-associate learning (PAL) task sensitive to pharmacological manipulation of the hippocampus: a translational rodent model of cognitive impairments in neurodegenerative disease
- 1.7k Downloads
Paired-associate learning (PAL), as part of the Cambridge Neuropsychological Test Automated Battery, is able to predict who from an at-risk population will develop Alzheimer’s disease. Schizophrenic patients are also impaired on this same task. An automated rodent model of PAL would be extremely beneficial in further research into Alzheimer’s disease and schizophrenia.
The objective of this study was to develop a PAL task using touchscreen-equipped operant boxes and test its sensitivity to manipulations of the hippocampus, a brain region of interest in both Alzheimer’s disease and schizophrenia.
Materials and methods
Previous work has shown that spatial and non-spatial memory can be tested in touchscreen-equipped operant boxes. Using this same apparatus, rats were trained on two variants of a PAL task differing only in the nature of the S− (the unrewarded stimuli, a combination of image and location upon the screen). Rats underwent cannulation of the dorsal hippocampus, and after recovery were tested under the influence of intra-hippocampally administered glutamatergic and cholinergic antagonists while performing the PAL task.
Impairments were seen after the administration of glutamatergic antagonists, but not cholinergic antagonists, in one of the two versions of PAL.
De-activation of the hippocampus caused impairments in a PAL task. The selective nature of this effect (only one of the two tasks was impaired), suggests the effect is specific to cognition and cannot be attributed to gross impairments (changes in visual learning). The pattern of results suggests that rodent PAL may be suitable as a translational model of PAL in humans.
KeywordsLidocaine MK-801 CNQX Scopolamine Mecamylamine Schizophrenia Alzheimer’s disease Direct administration
This work was supported by a grant to TJB and LMS from the Wellcome Trust, Number 071493/Z/03/Z. John Talpos was funded by a Merck, Sharp, & Dohme Ph.D. fellowship.
- Bussey TJ, Muir JL, Robbins TW (1994) A novel automated touchscreen procedure for assessing learning in the rat using a computer graphic stimuli. Neurosci Res Commun 15:365–374Google Scholar
- Bussey TJ, Clea WE, Aggleton JP, Muir JL (1998) Fornix lesions can facilitate acquisition of the transverse patterning task: a challenge for “configural” theories of hippocampal function. J Neurosci 18:1622–1631Google Scholar
- de Rover M, Pironti V (2008) Hippocampal dysfunction in patients suffering from Mild Cognitive Impairment (MCI): a functional neuroimaging study.Google Scholar
- Janisiewicz AM, Baxter MG (2003) Transfer effects and conditional learning in rats with selective lesions of medial septal/diagonal band cholinergic neurons. Behav Neurosci 117:1342–1352Google Scholar
- Paxinos G, Watson C (1998) The rat brain. Academic Press, New YorkGoogle Scholar
- Robbins TW, Semple J, Kumar R, Truman MI, Shorter J, Ferraro A, Fox B, McKay G, Matthews K (1997) Effects of scopolamine on delayed-matching-to-sample and paired associates tests of visual memory and learning in human subjects: comparison with diazepam and implications for dementia. Psychopharmacology (Berl) 134:95–106CrossRefGoogle Scholar
- Saksida L, Bartko S, Wess J, Bussey T (2008) Investigating Cholinergic function in muscarinic receptor-deficient mice in a novel automated computer touchscreen task battery. Society for Neuroscience, Washington DCGoogle Scholar
- Talpos JC (2006) Modelling cognitive disorders associated with hippocampal dysfunction: a novel automated test battery. Experimental Psychology. University of Cambridge, Cambridge, p 181Google Scholar
- Tse D, Langston R, Kakeyama M, Wood E, Morris R (2006) Schema and memory consolidation: paired associate memory can rapidly consolidate and become hippocampal independent. Federation of European Neuroscience Socities, ViennaGoogle Scholar
- Winters BD, Forwood SE, Cowell RA, Saksida LM, Bussey TJ (2004) Double dissociation between the effects of peri-postrhinal cortex and hippocampal lesions on tests of object recognition and spatial memory: heterogeneity of function within the temporal lobe. J Neurosci 24:5901–5908PubMedCrossRefGoogle Scholar
- Wood SJ, Proffitt T, Mahony K, Smith DJ, Buchanan JA, Brewer W, Stuart GW, Velakoulis D, McGorry PD, Pantelis C (2002) Visuospatial memory and learning in firstepisode schizophreniform psychosis and established schizophrenia: a functional correlate of hippocampal pathology? Psychol Med 32:429–438PubMedCrossRefGoogle Scholar