Memory disorders are probably the most common symptom after any process that disrupts normal medial temporal lobe functioning. The most severe form of disorder involves the loss of ability to form new memories (anterograde amnesia) and the loss of memories from before the damage (retrograde amnesia). Three experiments with rats are proposed which address fundamental properties of the neural mechanisms of retrograde amnesia. The first evaluates the temporal dependence of retrograde amnesia produced by nearly complete, selective hippocampal formation damage caused by multiple microinjections of N-methyl-Daspartate. Using both a between- and within-subject design, we evaluate the severity of retrograde amnesia for 4 types of information, spatial map, contextual conditioning, configural discriminations, and socially transmitted diet preference. Several intervals between training and hippocampal damage are sampled, between 1 and 64 weeks. Further, we independently test the effects of memory reactivations and subject age at the time of remote learning. Second, we compare the selectivity of the retrograde deficits with anterograde deficits for certain types of information. Anterograde amnesia affects declarative/relational/configural information and not nondeclarative/nonrelational/elemental information. Using variants of 4 tasks involving Morris water task, Pavlovian fear conditioning, socially transmitted diet preference, and transverse patterning we examine this distinction in retrograde amnesia after hippocampal damage. Third, we compare the retrograde gradients and the task specificity with different extents of hippocampal damage, using varying numbers of NMDA microinjections and colchicine dentate gyrus microinjections. The comparisons will address the hypotheses that temporal gradients in retrograde amnesia are related to the amount of spared hippocampal circuitry and that dentate gyrus circuitry contributes only at the time of initial memory acquisition. The results bear upon fundamental aspects of hippocampal dependent, long-term memory consolidation theories and will delineate a more precise role for the hippocampus formation in long-term memory.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH061460-04
Application #
6929248
Study Section
Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
Program Officer
Anderson, Kathleen C
Project Start
2002-08-08
Project End
2007-05-31
Budget Start
2005-06-21
Budget End
2006-05-31
Support Year
4
Fiscal Year
2005
Total Cost
$160,569
Indirect Cost
Name
University of Lethbridge
Department
Type
DUNS #
208275701
City
Lethbridge
State
AB
Country
Canada
Zip Code
T1 3-M4
Sparks, Fraser T; Lehmann, Hugo; Hernandez, Khadaryna et al. (2011) Suppression of neurotoxic lesion-induced seizure activity: evidence for a permanent role for the hippocampus in contextual memory. PLoS One 6:e27426
Lehmann, H; Sparks, F T; O'Brien, J et al. (2010) Retrograde amnesia for fear-potentiated startle in rats after complete, but not partial, hippocampal damage. Neuroscience 167:974-84
Sutherland, Robert J; Sparks, Fraser T; Lehmann, Hugo (2010) Hippocampus and retrograde amnesia in the rat model: a modest proposal for the situation of systems consolidation. Neuropsychologia 48:2357-69
Lehmann, Hugo; Sparks, Fraser T; Spanswick, Simon C et al. (2009) Making context memories independent of the hippocampus. Learn Mem 16:417-20
Epp, Jonathan; Keith, Julian R; Spanswick, Simon C et al. (2008) Retrograde amnesia for visual memories after hippocampal damage in rats. Learn Mem 15:214-21
Sutherland, Robert J; O'Brien, Jamus; Lehmann, Hugo (2008) Absence of systems consolidation of fear memories after dorsal, ventral, or complete hippocampal damage. Hippocampus 18:710-8
Keith, Julian R; Wu, Ying; Epp, Jonathon R et al. (2007) Fluoxetine and the dentate gyrus: memory, recovery of function, and electrophysiology. Behav Pharmacol 18:521-31
O'Brien, Jamus; Sutherland, Robert J (2007) Evidence for episodic memory in a pavlovian conditioning procedure in rats. Hippocampus 17:1149-52
Lehmann, Hugo; Lacanilao, Samuel; Sutherland, Robert J (2007) Complete or partial hippocampal damage produces equivalent retrograde amnesia for remote contextual fear memories. Eur J Neurosci 25:1278-86
Spanswick, Simon C; Epp, Jonathan R; Keith, Julian R et al. (2007) Adrenalectomy-induced granule cell degeneration in the hippocampus causes spatial memory deficits that are not reversed by chronic treatment with corticosterone or fluoxetine. Hippocampus 17:137-46

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