Small molecule cognitive enhancer reverses age-related memory decline in mice
- University of California, San Francisco, United States
- Fundación Ciencia & Vida, Chile
- Howard Hughes Medical Institute, University of California, San Francisco, United States
Abstract
With increased life expectancy age-associated cognitive decline becomes a growing concern, even in the absence of recognizable neurodegenerative disease. The integrated stress response (ISR) is activated during aging and contributes to age-related brain phenotypes. We demonstrate that treatment with the drug-like small-molecule ISR inhibitor ISRIB reverses ISR activation in the brain, as indicated by decreased levels of activating transcription factor 4 (ATF4) and phosphorylated eukaryotic translation initiation factor eIF2. Furthermore, ISRIB treatment reverses spatial memory deficits and ameliorates working memory in old mice. At the cellular level in the hippocampus, ISR inhibition i) rescues intrinsic neuronal electrophysiological properties, ii) restores spine density and iii) reduces immune profiles, specifically interferon and T cell-mediated responses. Thus, pharmacological interference with the ISR emerges as a promising intervention strategy for combating age-related cognitive decline in otherwise healthy individuals.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Funding
National Institute on Aging (F32AG054126)
- Karen Krukowski
National Institutes of Health (R01AG056770)
- Susanna Rosi
National Center for Advancing Translational Sciences (TL1 TR001871)
- Amber Nolan
National Institute of Neurological Disorders and Stroke (K08NS114170)
- Amber Nolan
Howard Hughes Medical Institute
- Peter Walter
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols of the University of California, San Francisco.(Protocol 170302).
Copyright
© 2020, Krukowski et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 48,996
- views
-
- 4,491
- downloads
-
- 101
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Small molecule cognitive enhancer reverses age-related memory decline in mice
eLife 9:e62048.
https://doi.org/10.7554/eLife.62048
Further reading
-
- Neuroscience
Motor systems operate over a range of frequencies and relative timing (phase). We studied the role of the hyperpolarization-activated inward current (Ih) in regulating these features in the pyloric rhythm of the stomatogastric ganglion (STG) of the crab, Cancer borealis, as temperature was altered from 11°C to 21°C. Under control conditions, rhythm frequency increased monotonically with temperature, while the phases of the pyloric dilator (PD), lateral pyloric (LP), and pyloric (PY) neurons remained constant. Blocking Ih with cesium (Cs+) phase advanced PD offset, LP onset, and LP offset at 11°C, and the latter two further advanced as temperature increased. In Cs+ the frequency increase with temperature diminished and the Q10 of the frequency dropped from ~1.75 to ~1.35. Unexpectedly in Cs+, the frequency dynamics became non-monotonic during temperature transitions; frequency initially dropped as temperature increased, then rose once temperature stabilized, creating a characteristic ‘jag’. Interestingly, these jags persisted during temperature transitions in Cs+ when the pacemaker was isolated by picrotoxin, although the temperature-induced change in frequency recovered to control levels. Overall, these data suggest that Ih plays an important role in maintaining smooth transitory responses and persistent frequency increases by different mechanisms in the pyloric circuitry during temperature fluctuations.
-
- Neuroscience
Perceiving emotions from the movements of other biological entities is critical for human survival and interpersonal interactions. Here, we report that emotional information conveyed by point-light biological motion (BM) triggered automatic physiological responses as reflected in pupil size. Specifically, happy BM evoked larger pupil size than neutral and sad BM, while sad BM induced a smaller pupil response than neutral BM. Moreover, this happy over sad pupil dilation effect is negatively correlated with individual autistic traits. Notably, emotional BM with only local motion features retained could also exert modulations on pupils. Compared with intact BM, both happy and sad local BM evoked stronger pupil responses than neutral local BM starting from an earlier time point, with no difference between the happy and sad conditions. These results revealed a fine-grained pupil-related emotional modulation induced by intact BM and a coarse but rapid modulation by local BM, demonstrating multi-level processing of emotions in life motion signals. Taken together, our findings shed new light on BM emotion processing, and highlight the potential of utilizing the emotion-modulated pupil response to facilitate the diagnosis of social cognitive disorders.
