Experience-dependent persistent expression of zif268during rest is preserved in the aged dentate gyrus

Abstract

BackgroundAging is typically accompanied by memory decline and changes in hippocampal function. Among these changes is a decline in the activity of the dentate gyrus (DG) during behavior. Lasting memory, however, is thought to also require recapitulation of recent memory traces during subsequent rest – a phenomenon, termed memory trace reactivation, which is compromised in hippocampal CA1 with progressive age. This process has yet to be assessed in the aged DG, despite its prominent role in age-related memory impairment. Using zif268 transcription to measure granule cell recruitment, DG activity in adult and aged animals was assessed both during spatial exploration and as animals remained at rest in the home cage in order to detect potential memory-related replay.ResultsConsistent with the observation of memory trace reactivation in DG, the probability that an individual granule cell transcribes zif268 during rest in the animal’s home cage is increased by recent experience in a novel environment. Surprisingly, a comparable increase was observed in the probability of granule cells in the aged DG expressing zif268 during rest. Moreover, no significant age-related difference was observed in the number of granule cells expressing zif268 during rest. Thus, the number and pattern of granule cell expression of zif268 during rest is preserved in aged animals, despite a significant decline in exploration-related zif268 expression.ConclusionsThese data lead to the hypothesis that the input the aged DG receives from backprojections from CA3 (the region widely hypothesized to mediate reactivation) remains functionally intact despite loss of innervation from the perforant path.

Experience-dependent effects of muscimol-induced hippocampal excitation on mnemonic discrimination

“…In particular, based on human neuroimaging data linking CA3/DG activity to accuracy in distinguishing highly similar visual stimuli (Kirwan and Stark, 2007;Bakker et al, 2008;Yassa and Stark, 2011;Reagh and Yassa, 2014;Reagh et al, 2018), we sought to determine if disrupting neural activity in the rodent CA3/DG with intrahippocampal infusions of muscimol would selectively impair discrimination of a target object from highly similar lure objects. However, in verifying the effects of muscimol on neural activity, we discovered infusion of this GABAA agonist at the coordinates used here produced excitation throughout the DG granule cell layer (Fig.1C), which typically shows sparse levels of activation assessed with the same methods (Small et al, 2004;Marrone et al, 2011Marrone et al, , 2012Penner et al, 2011;Gheidi et al, 2013). A subsequent experiment confirmed that, relative to vehicle, muscimol infusions robustly increased expression of the activity-dependent immediate-early genes Arc and Homer1a in DG (Fig.3).…”

Age-related Deficits in Recognition Memory are Protocol-Dependent

“…Although post-hoc analyses indicate that aged animals took significantly longer than both middle-aged and young animals to reach the visible platform on day 1 (p = 0.01), much smaller differences in the average distance swam to reach the platform were observed on day 2. Consistent with this observation, post-hoc tests showed no significant difference was observed in the distance travelled between aged and middle-aged rats, consistent with previous reports [ 7 , 29 , 30 , 33 ], nor between middle-aged and young rats. A significant difference remained between young and aged rats (p = 0.04).…”

Cellular compartment analysis of temporal activity by fluorescent in situ hybridization (catFISH) in the transcardially perfused rat brain

“…Interestingly, our c-Fos mRNA positive cell quantification revealed that the number of cells activated in response to both tone and home cage far exceeded that expected by random chance. This may reflect ‘replay’ of the previous experience with tone, as has been previously reported with both in vivo electrophysiology in freely moving rats (Wilson & McNaughton, 1994) and IEG detection methods in animals during spatial navigation (Gheidi, Azzopardi, Adams, & Marrone, 2013). The finding lends support to the notion that “background” IEG expression is not mere random activity and may represent mnemonic replay of previous experiences.…”