Aging mice show impaired memory updating in the novel OUL updating paradigm

Abstract

Memories do not persist in a permanent, static state but instead must be dynamically modified in response to new information. Although new memory formation is typically studied in a laboratory setting, most real-world associations are modifications to existing memories, particularly in the aging, experienced brain. To date, the field has lacked a simple behavioral paradigm that can measure whether original and updated information is remembered in a single test session. To address this gap, we have developed a novel memory updating paradigm, called the Objects in Updated Locations (OUL) task that is capable of assessing memory updating in a non-stressful task that is appropriate for both young and old rodents. We first show that young mice successfully remember both the original memory and the updated information in OUL. Next, we demonstrate that intrahippocampal infusion of the protein synthesis inhibitor anisomycin disrupts both the updated information and the original memory at test, suggesting that memory updating in OUL engages the original memory. To verify this, we used the Arc CatFISH technique to show that the OUL update session reactivates a largely overlapping set of neurons as the original memory. Finally, using OUL, we show that memory updating is impaired in aging, 18-m.o. mice. Together, these results demonstrate that hippocampal memory updating is impaired with aging and establish that the OUL paradigm is an effective, sensitive method of assessing memory updating in rodents.

Investigating Memory Updating in Mice Using the Objects in Updated Locations Task

“…For example, we have previously shown that OLM is impaired in 18‐month‐old C57BL/6J mice (Kwapis et al., ). In order to study memory updating in these mice, we increased the amount of training from one 10‐min session to three 10‐min sessions (one session per day for 3 days) and verified that old mice successfully learn the original object locations under this increased training protocol (Kwapis et al., ). If necessary for a particular age or strain, the training protocol could be additionally modified by lengthening the training session or increasing the number of training sessions to ensure acquisition of the training information.…”

“…We have shown that OUL is hippocampus dependent and, like OLM, is acutely sensitive to manipulations in dorsal CA1 (Kwapis et al., ). We have also confirmed that the update session in OUL engages the original memory, rather than forming a new, discrete memory (Kwapis et al., ).…”

“…We have shown that OUL is hippocampus dependent and, like OLM, is acutely sensitive to manipulations in dorsal CA1 (Kwapis et al., ). We have also confirmed that the update session in OUL engages the original memory, rather than forming a new, discrete memory (Kwapis et al., ). First, we demonstrated that postupdate anisomycin infusion into the dorsal hippocampus impairs memory for the both the update location and the original training object locations, indicating that the original memory is destabilized in response to the update session.…”

“…If mice remember the original training locations, they should preferentially explore the moved object. Although young C57BL/6J mice reliably show robust long‐term memory following a 10‐min OLM training session (Kwapis et al., ; McQuown & Wood, ; Vogel‐Ciernia et al., ; Current Protocols article: Vogel‐Ciernia & Wood, ), other strains and ages may need more training. For example, we have previously shown that OLM is impaired in 18‐month‐old C57BL/6J mice (Kwapis et al., ).…”

“…(Bizon, Foster, Alexander, & Glisky, 2012;Kwapis et al, 2020;Schoenbaum, Nugent, Saddoris, & Gallagher, 2002), the mechanisms that underlie age-related impairments in memory updating are currently unclear. To improve our mechanistic understanding of memory updating across the lifespan, we have developed a novel paradigm termed the objects in updated locations (OUL) task that can assess memory updating in a simple but sensitive and powerful manner (Kwapis et al, 2020). This task is based on the object location memory (OLM) task (see Current Protocols article: Vogel-Ciernia & Wood, 2014) and therefore relies on hippocampus-dependent spatial memory.…”