Attenuated IEG reactivation in aged animals correlates with memory deficits.
1. ARL NSMA;
2. Evelyn F. McKnight Brain Inst., Univ. Arizona, Tucson, AZ;
3. Neurosci. and Neurol., Johns Hopkins Univ., Baltimore, MD
Abundant evidence suggests that the hippocampus facilitates the consolidation of episodic memories. One strongly supportive observation is that patterns of hippocampal ensemble activity expressed among pyramidal cells during behaviour persist during subsequent “off-line” resting states [i.e., quiet waking states, slow wave sleep (Wilson & McNaughton, 1994; Kudrimoti et al., 1999)]. Recently, the catFISH method has been expanded to permit detection of three episodes of activity by visualizing the expression of immediate-early genes (IEGs) Arc and Homer1a (H1a). Although both IEGS are transcribed immediately following neuronal activity, nuclear Arc appears within 5 min., while H1a is detected only after 30 min., due to its unusually large intron. Cytoplasmic accumulation of these IEGs is similarly staggered: Arc accumulates in the cytoplasm 30 min. following activity, while H1a requires 60 min. Using this technique, we examined IEG expression in hippocampal CA1 using a spatial exploration paradigm with the addition of a third rest episode in three groups. In one group (pre-rest), the rest episode occurred prior to two explorations in the same space; while in a second group (post-rest), the rest episode occurred between the two explorations. Using this paradigm, a subpopulation of cells active during exploration expresses IEGs again during a subsequent period of rest. Thus, reactivation of spatial activity-induced ensembles also reactivates IEG expression. The next critical step is to understand how gene mis-regulation may occur with aging, since defects in reactivation could lead to poorer consolidation, and thus contribute to age-related memory decline. Although electrophysiological recording suggests that reactivation is compromised in old animals, these differences are remarkably subtle (Gerrard et al., 2001). The sampling capability of IEG techniques, however, may permit discrimination of differences in consolidation-related activity not discernible with the sample sizes possible through electrophysiology. During rest, both young and aged rats recapitulate IEG expression patterns induced during previous exploration. However, ensemble-specific IEG reactivation occurs in fewer cells in aged animals relative to young ones. Moreover, the size of the ensemble reactivating IEG expression predicts the animal’s performance in the Morris Swim Task and the reliability with which the same cells are activated during a return to the same environment. These data are consistent with the hypothesis that IEG reactivation captures a molecular correlate of memory consolidation and that this process is deficient in aged, memory-impaired animals.
Grant/Other Support: AG009219; McKnight Brain Research Foundation; state of Arizona and ADHS; NSERC
Keyword (Complete): aging; Arc; Homer1a; immediate-early genes; reactivation