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Hippocampal Subregion Transcriptomic Profiles Associated with Age-Related Changes in Spatial Pattern Separation

ABSTRACT: Previous studies of age-related transcriptional changes indicate that cognitive impairments are associated with differentially expressed genes DEGs linked to defined neural systems; however, studies that examine multiple regions of the hippocampus fail to find major links between behavior and transcription in the dentate gyrus DG. The DG is implicated in pattern separation PS and exhibits multiple age-related changes that may affect PS performance. We hypothesize that an age-related decline in PS performance is associated with distinct changes in transcriptional profile, most strongly within the DG compared to other hippocampal subregions. We used a water maze beacon discrimination task to characterize PS in young 5 mo and middle-age 12 mo male F344 rats, followed by a spatial reference memory test. Middle-age rats showed consistent deficits in discriminating two identical beacons compared to young. Reference memory was not different between these two age groups. Interestingly, with increasing spatial overlap between the cues, older animals appeared to compensate for impaired PS performance though greater reliance on spatial reference memory. mRNA sequencing of hippocampal subregions DG, CA1, and CA3 indicated that the DG of middle-age rats expressed more genes correlated with PS performance. In contrast, reliance on a spatial reference memory was associated with differential expression of genes in regions CA1 and CA3. These results indicate that the beacon task is sensitive to PS impairment as early as middle-age, and distinct gene profiles are observed in neural circuits that underlie different strategies used to solve the task.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE140420 | GEO | 2020/05/22

REPOSITORIES: GEO

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Project description:Aging is often associated with cognitive decline, but many elderly individuals maintain a high level of function throughout life. Here we studied outbred rats, which also exhibit individual differences across a spectrum of outcomes that includes both preserved and impaired spatial memory. Previous work in this model identified the CA3 subfield of the hippocampus as a region critically affected by age and integral to differing cognitive outcomes. Earlier microarray profiling revealed distinct gene expression profiles in the CA3 region, under basal conditions, for aged rats with intact memory and those with impairment. Because prominent age-related deficits within the CA3 occur during neural encoding of new information, here we used microarray analysis to gain a broad perspective of the aged CA3 transcriptome under activated conditions. Behaviorally induced CA3 expression profiles differentiated aged rats with intact memory from those with impaired memory. In the activated profile, we observed substantial numbers of genes (greater than 1000) exhibiting increased expression in aged unimpaired rats relative to aged impaired, including many involved in synaptic plasticity and memory mechanisms. This unimpaired aged profile also overlapped significantly with a learning induced gene profile previously acquired in young adults. Alongside the increased transcripts common to both young learning and aged rats with preserved memory, many transcripts behaviorally-activated in the current study had previously been identified as repressed in the aged unimpaired phenotype in basal expression. A further distinct feature of the activated profile of aged rats with intact memory is the increased expression of an ensemble of genes involved in inhibitory synapse function, which could control the phenotype of neural hyperexcitability found in the CA3 region of aged impaired rats. These data support the conclusion that aged subjects with preserved memory recruit adaptive mechanisms to retain tight control over excitability under both basal and activated conditions. RNA profiles from cognitively unimpaired and impaired aged rats were compared under 2 conditions: spatial learning task and a non-spatial learning task.

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Hippocampal Subregion Transcriptomic Profiles Associated with Age-Related Changes in Spatial Pattern Separation

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