14‐3‐3ζ is crucial for the conversion of labile short‐term object recognition memory into stable long‐term memory

Abstract

The consolidation of new memories into long‐lasting memories is multistage process characterized by distinct temporal dynamics. However, our understanding on the initial stage of transformation of labile memory of recent experience into stable memory remains elusive. Here, with the use of rats and mice overexpressing a memory enhancer called regulator of G protein signaling 14 of 414 amino acids (RGS14414) as a tool, we show that the expression of RGS14414 in male rats' perirhinal cortex (PRh), which is a brain area crucial for object recognition memory (ORM), enhanced the ORM to the extent that it caused the conversion of labile short‐term ORM (ST‐ORM) expected to last for 40 min into stable long‐term ORM (LT‐ORM) traceable after a delay of 24 hr, and that the temporal window of 40 to 60 min after object exposure not only was key for this conversion but also was the time frame when a surge in 14‐3‐3ζ protein was observed. A knockdown of 14‐3‐3ζ gene abrogated both the increase in 14‐3‐3ζ protein and the formation of LT‐ORM. Furthermore, this 14‐3‐3ζ upregulation increased brain‐derived growth factor (BDNF) levels in the time frame of 60 min and 24 hr and 14‐3‐3ζ knockdown decreased the BDNF levels, and a deletion of BDNF gene produced loss in mice ability to form LT‐ORM. Thus, within 60 min of object exposure, 14‐3‐3ζ facilitated the conversion of labile ORM into stable ORM, whereas beyond the 60 min, it mediated the consolidation of the stable memory into long‐lasting ORM by regulating BDNF signaling.

Increased cortical plasticity leads to memory interference and enhanced hippocampal-cortical interactions

“…Previous experiments using the plasticity-enhancer RGS14 in the peri-rhinal and visual cortex, showed increased conversion of short-term memory (40 min) to long-term memory (24 hr) ( Navarro-Lobato et al, 2021 ; Masmudi-Martín et al, 2019 ). As in this study, treatment did not affect other behavioral parameters such as overall exploration times in a simple object exploration paradigm.…”

“…Prelimbic plasticity was increased by the overexpression of RGS14414 ( Navarro-Lobato et al, 2021 ; Masmudi-Martín et al, 2019 ; Navarro-Lobato et al, 2022 ; Masmudi-Martín et al, 2020 ; López-Aranda et al, 2009 ; Figure 1A and B ) and initially two behavioral experiments were performed using the Object Space task ( Genzel et al, 2019 ). In this task, the condition Overlapping tests for the extraction of an underlying structure across five training trials, while the Stable condition tests for the simple memory of the last experience ( Figure 1C ).…”

“…To test if naturally restricted plasticity in the neocortex protects from memory interference, we artificially increased plasticity in the prelimbic cortex via the overexpression of an established plasticity-enhancer called regulator of G protein signaling 14 of 414 amino acids (RGS14414) ( Navarro-Lobato et al, 2021 ; Masmudi-Martín et al, 2019 ). The overexpression of RGS14414 is known to lead to increased BNDF and dendritic branching in the targeted area ( Navarro-Lobato et al, 2021 ; Masmudi-Martín et al, 2019 ) and thereby increase plasticity locally. This increased local plasticity makes memories, that usually would not be retained, last longer and can rescue memory-deficits accompanying aging or diseases ( Navarro-Lobato et al, 2022 ; Masmudi-Martín et al, 2020 ; López-Aranda et al, 2009 ).…”

Learning Fast and Slow: Increased cortical plasticity leads to memory interference and enhanced hippocampal-cortical interactions

“…Prelimbic plasticity was increased by the overexpression of RGS14414 [5][6][7][8][9] (Fig. 1A, B) and initially two behavioral experiments were performed using the Object Space task 10 .…”

“…To test if naturally restricted plasticity in the neocortex protects from memory interference, we artificially increased plasticity in the prelimbic cortex via the overexpression of an established plasticity-enhancer called regulator of G protein signaling 14 of 414 amino acids (RGS14414) 5,6 . The overexpression of RGS14414 is known to lead to increased BNDF and dendritic branching in the targeted area 5,6 and thereby increase plasticity locally. This increased local plasticity makes memories, that usually would not be retained, last longer and can rescue memory-deficits accompanying aging or diseases [7][8][9] .…”