The integrated stress response: From mechanism to disease

Protein quality control is essential for the proper function of cells and the organisms that they make up. The resulting loss of proteostasis, the processes by which the health of the cell’s proteins is monitored and maintained at homeostasis, is associated with a wide range of age-related human diseases. Here, we highlight how the integrated stress response (ISR), a central signaling network that responds to proteostasis defects by tuning protein synthesis rates, impedes the formation of long-term memory. In addition, we address how dysregulated ISR signaling contributes to the pathogenesis of complex diseases, including cognitive disorders, neurodegeneration, cancer, diabetes, and metabolic disorders. The development of tools through which the ISR can be modulated promises to uncover new avenues to diminish pathologies resulting from it for clinical benefit.

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The Integrated Stress Response in Memory and Cognitive Disorders

The Oxford Handbook of Neuronal Protein Synthesis ◽

10.1093/oxfordhb/9780190686307.013.2 ◽

2020 ◽

Author(s):

Jacqunae L. Mays ◽

Mauro Costa-Mattioli

Keyword(s):

Protein Synthesis ◽

Stress Response ◽

Cognitive Disorders ◽

Memory Formation ◽

Model Systems ◽

Long Term Memory ◽

Integrated Stress Response ◽

Term Memory ◽

Wide Range

The integrated stress response (ISR) is an evolutionarily conserved intracellular signaling network that responds to proteostasis defects and stress conditions by tuning protein synthesis rates. While it has been long recognized that long-term memory formation requires new protein synthesis, our understanding of the central translational control mechanisms that regulate memory formation has advanced vastly. Indeed, novel causal and convergent evidence across different species and model systems shows that the ISR serves as a universal regulator of long-term memory formation. This chapter discusses the evidence explaining how inhibition of the ISR enhances long-term memory formation while activation of the ISR prevents it. In addition, it highlights the role of the ISR in different forms of long-lasting synaptic plasticity in the brain. Finally, the chapter addresses how dysregulated ISR signaling contributes to the pathogenesis of a wide range of cognitive and neurodegenerative disorders and discusses the future prospects for therapeutically targeting the ISR for the treatment of cognitive disorders.

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A Multivariate Assessment of Age-Related Cognitive Impairment in Octodon degus

Frontiers in Integrative Neuroscience ◽

10.3389/fnint.2021.719076 ◽

2021 ◽

Vol 15 ◽

Author(s):

Daniela S. Rivera ◽

Carolina B. Lindsay ◽

Carolina A. Oliva ◽

Francisco Bozinovic ◽

Nibaldo C. Inestrosa

Keyword(s):

Recognition Memory ◽

Cognitive Performance ◽

Natural Aging ◽

Long Term Memory ◽

Barnes Maze ◽

Short Term ◽

Term Memory ◽

Age Related ◽

Age Dependent

Aging is a progressive functional decline characterized by a gradual deterioration in physiological function and behavior. The most important age-related change in cognitive function is decline in cognitive performance (i.e., the processing or transformation of information to make decisions that includes speed of processing, working memory, and learning). The purpose of this study is to outline the changes in age-related cognitive performance (i.e., short-term recognition memory and long-term learning and memory) in long-lived Octodon degus. The strong similarity between degus and humans in social, metabolic, biochemical, and cognitive aspects makes it a unique animal model for exploring the mechanisms underlying the behavioral and cognitive deficits related to natural aging. In this study, we examined young adult female degus (12- and 24-months-old) and aged female degus (38-, 56-, and 75-months-old) that were exposed to a battery of cognitive-behavioral tests. Multivariate analyses of data from the Social Interaction test or Novel Object/Local Recognition (to measure short-term recognition memory), and the Barnes maze test (to measure long-term learning and memory) revealed a consistent pattern. Young animals formed a separate group of aged degus for both short- and long-term memories. The association between the first component of the principal component analysis (PCA) from short-term memory with the first component of the PCA from long-term memory showed a significant negative correlation. This suggests age-dependent differences in both memories, with the aged degus having higher values of long-term memory ability but poor short-term recognition memory, whereas in the young degus an opposite pattern was found. Approximately 5% of the young and 80% of the aged degus showed an impaired short-term recognition memory; whereas for long-term memory about 32% of the young degus and 57% of the aged degus showed decreased performance on the Barnes maze test. Throughout this study, we outlined age-dependent cognitive performance decline during natural aging in degus. Moreover, we also demonstrated that the use of a multivariate approach let us explore and visualize complex behavioral variables, and identified specific behavioral patterns that allowed us to make powerful conclusions that will facilitate further the study on the biology of aging. In addition, this study could help predict the onset of the aging process based on behavioral performance.

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Dissociating refreshing and elaboration and their impacts on memory

10.1101/423277 ◽

2018 ◽

Author(s):

Lea M. Bartsch ◽

Vanessa M. Loaiza ◽

Lutz Jäncke ◽

Klaus Oberauer ◽

Jarrod A. Lewis-Peacock

Keyword(s):

Older Adults ◽

Memory Performance ◽

Ethics Committees ◽

Fmri Data ◽

Ethical Review ◽

Long Term Memory ◽

List Type ◽

Term Memory ◽

Age Related

AbstractMaintenance of information in working memory (WM) is assumed to rely on refreshing and elaboration, but clear mechanistic descriptions of these cognitive processes are lacking, and it is unclear whether they are simply two labels for the same process. This fMRI study investigated the extent to which refreshing, elaboration, and repeating of items in WM are distinct neural processes with dissociable behavioral outcomes in WM and long-term memory (LTM). Multivariate pattern analyses of fMRI data revealed differentiable neural signatures for these processes, which we also replicated in an independent sample of older adults. In some cases, the degree of neural separation within an individual predicted their memory performance. Elaboration improved LTM, but not WM, and this benefit increased as its neural signature became more distinct from repetition. Refreshing had no impact on LTM, but did improve WM, although the neural discrimination of this process was not predictive of the degree of improvement. These results demonstrate that refreshing and elaboration are separate processes that differently contribute to memory performance.HighlightsRepeated reading, refreshing, and elaboration are differentiable in brain activation patterns in both young and older adults.Elaboration selectively improved long-term memory for young adults, and the size of the benefit was related to the neural separability of elaboration from other processes.Older adults implemented a sub-optimal form of elaboration, and this may be a factor contributing to age-related deficits in long-term memory.Ethics statementThe study was approved by the ethical review board of the canton of Zurich (BASEC-No. 2017-00190) and all subjects gave informed written consent in accordance with the Declaration of Helsinki.Data and code availability statementAll behavioral data and analysis scripts can be assessed on the Open Science Framework (osf.io/p2h8b/). The fMRI data that support the findings of this study are available on request from the corresponding author, LMB. The fMRI data are not publicly available due to restrictions of the Swiss Ethics Committees on research involving humans regarding data containing information that could compromise the privacy of research participants.

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Individual differences in positive affect moderate age-related declines in episodic long-term memory

Journal of Cognitive Psychology ◽

10.1080/20445911.2011.570254 ◽

2011 ◽

Vol 23 (6) ◽

pp. 768-779 ◽

Cited By ~ 13

Author(s):

Philip A. Allen ◽

Kevin Kaut ◽

Elsa Baena ◽

Mei-Ching Lien ◽

Eric Ruthruff

Keyword(s):

Individual Differences ◽

Positive Affect ◽

Long Term Memory ◽

Term Memory ◽

Age Related

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Closing the Capacity-Ability Gap: Using Technology to Support Aging With Disability

Innovation in Aging ◽

10.1093/geroni/igy008 ◽

2018 ◽

Vol 2 (1) ◽

Cited By ~ 12

Author(s):

Tracy L Mitzner ◽

Jon A Sanford ◽

Wendy A Rogers

Keyword(s):

Great Promise ◽

User Requirements ◽

Intervention Model ◽

Current State ◽

Age Related ◽

Wide Range ◽

Technology Intervention ◽

Bridge Models ◽

Age Related Changes

Abstract There is a critical need to develop supports for older adults who have a wide range of abilities, including those aging with long-term impairments. Without appropriate support, many individuals will be functioning below optimal levels and will face participation barriers. Technology holds great promise to provide individualized support for a wide range of abilities and for a variety of domains. To ensure technology interventions are designed well and meet research-documented user requirements, we need more specific, actionable models to provide guidance for those developing and designing interventions. In this paper, we present the TechSAge Aging and Disability Model to bridge models from the aging and disability literatures and to disambiguate the population of individuals aging into disability from those aging with disability (i.e., pre-existing impairments). We also present the TechSAge Technology Intervention Model to support aging with pre-existing impairments, which provides direction and touch points for technology interventions. These models reflect the complex and dynamic interaction between age-related changes and an individual’s prior capabilities and limitations. We describe the need for these models with respect to filling a gap in the disability and aging literature by highlighting the importance of differentiating between age-related changes and long-term impairments when designing interventions. We also show the need for quantitative and qualitative data to refine the models given complexities of the current state of the literature and survey data. The TechSAge Technology Intervention Model can be used to drive and inform technology redesign and development.

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Noncoding RNAs and RNA Editing in Brain Development, Functional Diversification, and Neurological Disease

Physiological Reviews ◽

10.1152/physrev.00036.2006 ◽

2007 ◽

Vol 87 (3) ◽

pp. 799-823 ◽

Cited By ~ 196

Author(s):

Mark F. Mehler ◽

John S. Mattick

Keyword(s):

Nervous System ◽

Rna Editing ◽

Neurological Diseases ◽

Cell Types ◽

State Transitions ◽

Long Term Memory ◽

Protein Coding ◽

Continuous State ◽

Wide Range

The progressive maturation and functional plasticity of the nervous system in health and disease involve a dynamic interplay between the transcriptome and the environment. There is a growing awareness that the previously unexplored molecular and functional interface mediating these complex gene-environmental interactions, particularly in brain, may encompass a sophisticated RNA regulatory network involving the twin processes of RNA editing and multifaceted actions of numerous subclasses of non-protein-coding RNAs. The mature nervous system encompasses a wide range of cell types and interconnections. Long-term changes in the strength of synaptic connections are thought to underlie memory retrieval, formation, stabilization, and effector functions. The evolving nervous system involves numerous developmental transitions, such as neurulation, neural tube patterning, neural stem cell expansion and maintenance, lineage elaboration, differentiation, axonal path finding, and synaptogenesis. Although the molecular bases for these processes are largely unknown, RNA-based epigenetic mechanisms appear to be essential for orchestrating these precise and versatile biological phenomena and in defining the etiology of a spectrum of neurological diseases. The concerted modulation of RNA editing and the selective expression of non-protein-coding RNAs during seminal as well as continuous state transitions may comprise the plastic molecular code needed to couple the intrinsic malleability of neural network connections to evolving environmental influences to establish diverse forms of short- and long-term memory, context-specific behavioral responses, and sophisticated cognitive capacities.

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CREB overexpression in dorsal CA1 ameliorates long-term memory deficits in aged rats

eLife ◽

10.7554/elife.19358 ◽

2017 ◽

Vol 6 ◽

Cited By ~ 16

Author(s):

Xiao-Wen Yu ◽

Daniel M Curlik ◽

M Matthew Oh ◽

Jerry CP Yin ◽

John F Disterhoft

Keyword(s):

Molecular Mechanisms ◽

Pyramidal Neurons ◽

Dorsal Hippocampus ◽

Memory Deficits ◽

Camp Response Element Binding ◽

Intrinsic Excitability ◽

Long Term Memory ◽

Term Memory ◽

Age Related

The molecular mechanisms underlying age-related cognitive deficits are not yet fully elucidated. In aged animals, a decrease in the intrinsic excitability of CA1 pyramidal neurons is believed to contribute to age-related cognitive impairments. Increasing activity of the transcription factor cAMP response element-binding protein (CREB) in young adult rodents facilitates cognition, and increases intrinsic excitability. However, it has yet to be tested if increasing CREB expression also ameliorates age-related behavioral and biophysical deficits. To test this hypothesis, we virally overexpressed CREB in CA1 of dorsal hippocampus. Rats received CREB or control virus, before undergoing water maze training. CREB overexpression in aged animals ameliorated the long-term memory deficits observed in control animals. Concurrently, cells overexpressing CREB in aged animals had reduced post-burst afterhyperpolarizations, indicative of increased intrinsic excitability. These results identify CREB modulation as a potential therapy to treat age-related cognitive decline.

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Cognitive aging and verbal labeling in continuous visual memory

Memory & Cognition ◽

10.3758/s13421-020-01043-3 ◽

2020 ◽

Vol 48 (7) ◽

pp. 1196-1213

Author(s):

Alicia Forsberg ◽

Wendy Johnson ◽

Robert H. Logie

Keyword(s):

Older Adults ◽

Cognitive Aging ◽

Visual Memory ◽

Memory Performance ◽

Age Groups ◽

Long Term Memory ◽

Younger Adults ◽

Healthy Older Adults ◽

Age Related

Abstract The decline of working memory (WM) is a common feature of general cognitive decline, and visual and verbal WM capacity appear to decline at different rates with age. Visual material may be remembered via verbal codes or visual traces, or both. Souza and Skóra, Cognition, 166, 277–297 (2017) found that labeling boosted memory in younger adults by activating categorical visual long-term memory (LTM) knowledge. Here, we replicated this and tested whether it held in healthy older adults. We compared performance in silence, under instructed overt labeling (participants were asked to say color names out loud), and articulatory suppression (repeating irrelevant syllables to prevent labeling) in the delayed estimation paradigm. Overt labeling improved memory performance in both age groups. However, comparing the effect of overt labeling and suppression on the number of coarse, categorical representations in the two age groups suggested that older adults used verbal labels subvocally more than younger adults, when performing the task in silence. Older adults also appeared to benefit from labels differently than younger adults. In younger adults labeling appeared to improve visual, continuous memory, suggesting that labels activated visual LTM representations. However, for older adults, labels did not appear to enhance visual, continuous representations, but instead boosted memory via additional verbal (categorical) memory traces. These results challenged the assumption that visual memory paradigms measure the same cognitive ability in younger and older adults, and highlighted the importance of controlling differences in age-related strategic preferences in visual memory tasks.

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