Age-related Learning Deficits Research Articles

Bioinformatics Analysis and Experimental Verification of Exercise for Aging Mice in Different Brain Regions Based on Transcriptome Sequencing.

Physical exercise mitigates the effects of aging and cognitive decline. However, the precise neurobiological mechanisms underlying this phenomenon remain unclear. The primary aim of this study was to investigate the protective effect of exercise on age-related memory deficits in the prefrontal cortex (PFC) and hippocampus using bioinformatic analysis and biochemical verification. Young and aging mice were subjected to natural feeding or treadmill exercise (12 m/min, 8 weeks). Cognitive function was accessed using the Barnes maze and novel object recognition. Bioinformatic analysis was performed to identify co-expressed genes in different groups and brain regions. The selected genes and pathways were validated using RT-qPCR. Regular exercise significantly ameliorated age-related cognitive deficits. Four up-regulated targets (Ifi27l2a, Irf7, Oas1b, Ifit1) and one down-regulation (Septin2) were reversed by exercise, demonstrating the underlying mechanisms of cognitive functions induced by aging with exercise in the hippocampus and PFC. The Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses indicated that the NOD-like receptor signaling pathway was inhibited in the neuroinflammation effects of exercise in aging mice in both brain regions. Exercise enhances age-related learning and memory deficits. This beneficial effect may be attributed to the changes in five up/down-regulated genes and the NOD-like receptor signaling pathway in both the hippocampus and PFC. These findings establish the modulation of neuroinflammation as a pivotal molecular mechanism supporting exercise intervention in the brain aging process.

Differential Epigenetic Changes in the Dorsal Hippocampus of Male and Female SAMP8 Mice: A Preliminary Study.

Alzheimer's disease (AD) is the most common age-related neurodegenerative disease characterized by memory loss and cognitive impairment. The causes of the disease are not well understood, as it involves a complex interaction between genetic, environmental, and epigenetic factors. SAMP8 mice have been proposed as a model for studying late-onset AD, since they show age-related learning and memory deficits as well as several features of AD pathogenesis. Epigenetic changes have been described in SAMP8 mice, although sex differences have never been evaluated. Here we used western blot and qPCR analyses to investigate whether epigenetic markers are differentially altered in the dorsal hippocampus, a region important for the regulation of learning and memory, of 9-month-old male and female SAMP8 mice. We found that H3Ac was selectively reduced in male SAMP8 mice compared to male SAMR1 control mice, but not in female mice, whereas H3K27me3 was reduced overall in SAMP8 mice. Moreover, the levels of HDAC2 and JmjD3 were increased, whereas the levels of HDAC4 and Dnmt3a were reduced in SAMP8 mice compared to SAMR1. In addition, levels of HDAC1 were reduced, whereas Utx and Jmjd3 were selectively increased in females compared to males. Although our results are preliminary, they suggest that epigenetic mechanisms in the dorsal hippocampus are differentially regulated in male and female SAMP8 mice.

Narrative Review: Edible Plants as a Source of Valuable Flavonoids and Their Role as Neuroprotector Agents

Background: Neurodegenerative disorder is a consequence of the gradual and progressive deterioration of the function and structure of the peripheral nervous system or central nervous system or both. Currently does not exist an effective treatment for this neurodegenerative disease, thus flavonoids abundant in fruits and vegetables have attracted attention as potential neuroprotective agents. Objective: The aim of this review was to discuss the existing scientific literature data regarding flavonoids, from edible plants and their potential as neuroprotective agents, to provide constituent compound and pharmacological relevance in the prevention or treatment of age-related deficits in learning, memory, and Alzheimer’s disorder. Methods: Exhaustive bibliographic investigation on phytochemistry and pharmacology associated with flavonoids from edible plants was performed using scientific databases like Science Direct, PubMed, Google Scholar, Scopus, EMBASE, Google Scholar, ChemSpider. “Cognitive deficits”, “age-related cognitive”, “Alzheimer disease” “flavonoids” and “phenolic compounds” utilized as keywords in the search in the databases. Published articles from 1992 to 2022 were collected and studied. Results: The finding indicated that flavonoids contained in edible plants can exert powerful effects on cognition and consequently can reverse the age-related deficit in learning and memory and retard the development of Alzheimer’s disorder due to their capacity to interact with the molecular architecture of the brain responsible of the memory. Mechanisms of actions were analyzed including the effect on neuroinflammation, synaptic plasticity, signaling pathways, Aβ peptides, and hippocampus among others. Conclusion: This manuscript can be used as scientific support for the development of alternative drugs, food supplements, and nutraceuticals, to prevent, maintain and enhance the neurophysiological status.

Delays in the Reticulospinal System Are Associated With a Reduced Capacity to Learn a Simulated Feeding Task in Older Adults.

Learning declines with age. Recent evidence indicates that the brainstem may play an important role in learning and motor skill acquisition. Our objective was to determine if delays in the reticular formation, measured via the startle reflex, correspond to age-related deficits in learning and retention. We hypothesized that delays in the startle reflex would be linearly correlated to learning and retention deficits in older adults. To determine if associations were unique to the reticulospinal system, we also evaluated corticospinal contributions with transcranial magnetic stimulation. Our results showed a linear relationship between startle onset latency and percent learning and retention but no relationship between active or passive motor-evoked potential onsets or peak-to-peak amplitude. These results lay the foundation for further study to evaluate if (1) the reticular formation is a subcortical facilitator of skill acquisition and (2) processing delays in the reticular formation contribute to age-related learning deficits.

A candidate gene of Alzheimer diseases was mutated in senescence-accelerated mouse prone (SAMP) 8 mice

The senescence-accelerated mouse prone (SAMP) 8 strain exhibits age-related learning and memory deficits (LMD) at 2 months of age. We have found strong association of chromosome 12 locus with learning memory deficit (LMD) phenotype in SAMP8 strain. In the course of searching candidate gene, here we identified solute carrier family 24 sodium/potassium/calcium exchanger member 4 (Slc24a4) in SAMP8 chromosome 12 LMD possessing one single nucleotide polymorphism causing amino acid replacement of Threonine at 413 position with Methionine. Since SLC24A4 has been postulated as a candidate of late onset Alzheimer's diseases (LOAD), we further analyze the functional importance of this polymorphism. By expressing Slc24a4 protein in HEK293 cells, here we showed polymorphic SAMP8 type Slc24a4-T413 M causing significant loss of calcium ion (Ca2+) transporter activity in cells compared with that of wild type mouse (Slc24a4-WT). However, no study yet shows any functional association of human SLC24A4 polymorphism with the onset of LOAD pathogenesis. Thus, our present finding may further help to clarify the importance of this ion exchanger with age related cognitive dysfunction.

Increased Hippocampal Excitability and Altered Learning Dynamics Mediate Cognitive Mapping Deficits in Human Aging.

Learning the spatial layout of a novel environment is associated with dynamic activity changes in the hippocampus and in medial parietal areas. With advancing age, the ability to learn spatial environments deteriorates substantially but the underlying neural mechanisms are not well understood. Here, we report findings from a behavioral and a fMRI experiment where healthy human older and younger adults of either sex performed a spatial learning task in a photorealistic virtual environment (VE). We modeled individual learning states using a Bayesian state-space model and found that activity in retrosplenial cortex (RSC)/parieto-occipital sulcus (POS) and anterior hippocampus did not change systematically as a function learning in older compared with younger adults across repeated episodes in the environment. Moreover, effective connectivity analyses revealed that the age-related learning deficits were linked to an increase in hippocampal excitability. Together, these results provide novel insights into how human aging affects computations in the brain's navigation system, highlighting the critical role of the hippocampus.SIGNIFICANCE STATEMENT Key structures of the brain's navigation circuit are particularly vulnerable to the deleterious consequences of aging, and declines in spatial navigation are among the earliest indicators for a progression from healthy aging to neurodegenerative diseases. Our study is among the first to provide a mechanistic account about how physiological changes in the aging brain affect the formation of spatial knowledge. We show that neural activity in the aging hippocampus and medial parietal areas is decoupled from individual learning states across repeated episodes in a novel spatial environment. Importantly, we find that increased excitability of the anterior hippocampus might constitute a potential neural mechanism for cognitive mapping deficits in old age.

Cocoa improves age-associated health and extends lifespan in C. elegans

BACKGROUND: Cocoa, one of the richest dietary sources of polyphenols has been studied for its health promoting effects, but how long-term consumption of cocoa affects age-associated health and lifespan is not well defined. OBJECTIVE: The objective of this study was to determine the effects of long-term cocoa consumption on age-associated health and lifespan in C. elegans METHODS: The standard E. coli OP50 diet of wild type C. elegans was supplemented with cocoa powder starting from L1 stage until they die. Body length and area were measured as indicators of worm nutrition. Age associated health was determined at different stages of life as day 4, day 8 and day 12 using worm locomotion, thermotolerance, cognition and mitochondrial function. In addition, lifespan was evaluated. RESULTS: Cocoa improved age-associated decline in neuromuscular function. Both mean and median lifespan were extended by cocoa supplementation. However, maximum lifespan was not affected. Cocoa showed beneficial effects on thermotolerance at all ages (more prominent effects at young (day 4) and middle (day 8) age). Further, consumption of cocoa improved age-related learning deficits, short-term memory loss and mitochondrial dysfunction. CONCLUSIONS: Long-term cocoa consumption seemed to improve age-associated health and extends lifespan in C. elegans

Conditioning learning in an attentional task relates to age and ventricular expansion in a nonhuman primate (Microcebus murinus)

The grey mouse lemur (Microcebus murinus) is a promising nonhuman primate model for brain ageing and neurodegenerative diseases. Age-related cognitive decline in this model is well described, however, data on possible relations between attention and age, as they are known from humans, are missing.We tested 10 mouse lemurs in a touchscreen-based version of the 5-choice-serial-reaction-time-task (5CSRTT) on visuo-spatial attention: subjects had to interact with a briefly presented stimulus occurring unpredictably in one out of five locations on the touchscreen. Animals were trained to an 80 % performance at a four seconds stimulus presentation duration (SPD) and subsequently challenged by a SPD of two seconds. Additionally, ventricular expansion was assessed using structural magnetic resonance imaging.Trials to the 80 % criterion at four seconds SPD correlated significantly with age and with ventricular expansion, especially around the occipital lobe. Once criterion performance was reached, two seconds challenge performance was independent of age. In four subjects that were additionally challenged with 1.5, 1.0, 0.8, or 0.6 s SPDs or variable delays preceding stimulus presentation, performance linearly declined with decreasing SPD, i.e. increasing attentional demand.In conclusion, this is the first report of 5CSRTT data in mouse lemurs and demonstrates the general applicability of this task of visuo-spatial attention to this nonhuman primate model. Results further demonstrate age-related deficits in learning during acquisition of the 5CSRTT and suggest that both may be linked through age-related atrophy of occipital structures and a resulting deficit in central visual processes.

OPA1 deficiency accelerates hippocampal synaptic remodelling and age-related deficits in learning and memory.

A healthy mitochondrial network is essential for the maintenance of neuronal synaptic integrity. Mitochondrial and metabolic dysfunction contributes to the pathogenesis of many neurodegenerative diseases including dementia. OPA1 is the master regulator of mitochondrial fusion and fission and is likely to play an important role during neurodegenerative events. To explore this, we quantified hippocampal dendritic and synaptic integrity and the learning and memory performance of aged Opa1 haploinsufficient mice carrying the Opa1Q285X mutation (B6; C3-Opa1Q285STOP; Opa1+/−). We demonstrate that heterozygous loss of Opa1 results in premature age-related loss of spines in hippocampal pyramidal CA1 neurons and a reduction in synaptic density in the hippocampus. This loss is associated with subtle memory deficits in both spatial novelty and object recognition. We hypothesize that metabolic failure to maintain normal neuronal activity at the level of a single spine leads to premature age-related memory deficits. These results highlight the importance of mitochondrial homeostasis for maintenance of neuronal function during ageing.

The role of L-type calcium channels in neuronal excitability and aging

Over the last two decades there has been significant progress towards understanding the neural substrates that underlie age-related cognitive decline. Although many of the exact molecular and cellular mechanisms have yet to be fully understood, there is consensus that alterations in neuronal calcium homeostasis contribute to age-related deficits in learning and memory. Furthermore, it is thought that the age-related changes in calcium homeostasis are driven, at least in part, by changes in calcium channel expression. In this review, we focus on the role of a specific class of calcium channels: L-type voltage-gated calcium channels (LVGCCs). We provide the reader with a general introduction to voltage-gated calcium channels, followed by a more detailed description of LVGCCs and how they serve to regulate neuronal excitability via the post burst afterhyperpolarization (AHP). We conclude by reviewing studies that link the slow component of the AHP to learning and memory, and discuss how age-related increases in LVGCC expression may underlie cognitive decline by mediating a decrease in neuronal excitability.

Emotional feedback ameliorates older adults' feedback-induced learning.

In older age, learning and feedback processing are usually impaired. This is thought to be due to impairments in the dopaminergic system and the anterior cingulate cortex. By contrast, processing of affective information seems to remain relatively intact. Recent research has also demonstrated that cognitive functioning can be influenced by affective materials or contexts and lead to an enhancement in diverse cognitive tasks. Hence, the aim of the present study was to explore, whether emotional feedback would counteract age-related learning deficits and strengthen early and later phases of feedback processing as reflected in the feedback-related negativity (FRN) and P3b of the event-related potential (ERP). Younger and older participants conducted a probabilistic reinforcement learning task in which the accurate responses had to be learned via feedback. In emotional trials, feedback stimuli consisted of faces with smiling and disgusted expressions, and in a non-emotional condition, positive and negative feedback was indicated by the background color of faces with neutral expressions. Our main results were that older adults showed better learning performance in the emotional feedback condition and a larger P3b after emotional than non-emotional feedback indexing heightened working memory updating after task relevant events.

Aberrant Expression Profiles of lncRNAs and Their Associated Nearby Coding Genes in the Hippocampus of the SAMP8 Mouse Model with AD

The senescence-accelerated mouse prone 8 (SAMP8) mouse model is a useful model for investigating the fundamental mechanisms involved in the age-related learning and memory deficits of Alzheimer’s disease (AD), while the SAM/resistant 1 (SAMR1) mouse model shows normal features. Recent evidence has shown that long non-coding RNAs (lncRNAs) may play an important role in AD pathogenesis. However, a comprehensive and systematic understanding of the function of AD-related lncRNAs and their associated nearby coding genes in AD is still lacking. In this study, we collected the hippocampus, the main area of AD pathological processes, of SAMP8 and SAMR1 animals and performed microarray analysis to identify aberrantly expressed lncRNAs and their associated nearby coding genes, which may contribute to AD pathogenesis. We identified 3,112 differentially expressed lncRNAs and 3,191 differentially expressed mRNAs in SAMP8 mice compared to SAMR1 mice. More than 70% of the deregulated lncRNAs were intergenic and exon sense-overlapping lncRNAs. Gene Ontology (GO) and pathway analyses of the AD-related transcripts were also performed and are described in detail, which imply that metabolic process reprograming was likely related to AD. Furthermore, six lncRNAs and six mRNAs were selected for further validation of the microarray results using quantitative PCR, and the results were consistent with the findings from the microarray. Moreover, we analyzed 780 lincRNAs (also called long “intergenic” non-coding RNAs) and their associated nearby coding genes. Among these lincRNAs, AK158400 had the most genes nearby (n = 13), all of which belonged to the histone cluster 1 family, suggesting regulation of the nucleosome structure of the chromosomal fiber by affecting nearby genes during AD progression. In addition, we also identified 97 aberrant antisense lncRNAs and their associated coding genes. It is likely that these dysregulated lncRNAs and their associated nearby coding genes play a role in the development and/or progression of AD.

Med Check: Alzheimer’s Therapy; Adhansia XR; Dasotraline for Binge-Eating Disorder; Somryst for Insomnia; Nuplazid

Med Check: Alzheimer’s Therapy; Adhansia XR; Dasotraline for Binge-Eating Disorder; Somryst for Insomnia; Nuplazid

Age-related deficits in motor learning are associated with altered motor exploration strategies

How is motor learning affected by aging? Although several experimental paradigms have been used to address this question, there has been limited focus on the early phase of motor learning, which involves motor exploration and the need to coordinate multiple degrees of freedom in the body. Here, we examined motor learning in a body-machine interface where we measured both age-related differences in task performance as well as the coordination strategies underlying this performance. Participants (N = 65; age range 18–72 years) wore wireless inertial measurement units on the upper body, and learned to control a cursor on a screen, which was controlled by motions of the trunk. Results showed that, consistent with prior studies, there was an age-related effect on movement time, with middle-aged and older adults taking longer to perform the task than young adults. However, we also found that these changes were associated with limited exploration in older adults. Moreover, when considering data across a majority of the lifespan (including children), longer movement times were associated with greater inefficiency of the coordination pattern, producing more task-irrelevant motion. These results suggest exploration behaviors during motor learning are affected with aging, and highlight the need for different practice strategies with aging.

Are age-related deficits in route learning related to control of visual attention?

Typically aged adults show reduced ability to learn a route compared to younger adults. In this experiment, we investigate the role of visual attention through eye-tracking and engagement of attentional resources in age-related route learning deficits. Participants were shown a route through a realistic virtual environment before being tested on their route knowledge. Younger and older adults were compared on their gaze behaviour during route learning and on their reaction time to a secondary probe task as a measure of attentional engagement. Behavioural results show a performance deficit in route knowledge for older adults compared to younger adults, which is consistent with previous research. We replicated previous findings showing that reaction times to the secondary probe task were longer at decision points than non-decision points, indicating stronger attentional engagement at navigationally relevant locations. However, we found no differences in attentional engagement and no differences for a range of gaze measures between age groups. We conclude that age-related changes in route learning ability are not reflected in changes in control of visual attention or regulation of attentional engagement.

Aging and the role of attention in associative learning.

In this study, we investigated whether age-related deficits in cue-outcome associative learning (e.g., Mutter, Atchley, & Plumlee, 2012; Mutter, DeCaro, & Plumlee, 2009; Mutter, Haggbloom, Plumlee, & Schirmer, 2006; Mutter & Williams, 2004) might be due to a decline in older adults' ability to modulate attention to relevant and irrelevant cues. In the first 2 experiments, we used standard blocking and highlighting tasks to indirectly measure the ability to shift attention away from irrelevant stimuli toward relevant, predictive cues (e.g., Kruschke, Kappenman, & Hetrick, 2005). Although there were age differences in prediction accuracy, like young adults, older adults learned to shift attention toward predictive stimuli and ignore irrelevant or less predictive stimuli. This attentional effect was unrelated to either working memory or executive function suggesting that it did not involve voluntary control processes. The third experiment provided further support for this idea. We alternated a category learning task with a dot probe task to more directly assess the development of automatic attentional biases. There were again age differences in category prediction, but young and older adults alike responded more rapidly to the location of a dot probe cued by a stimulus experienced as predictive during the learning task than one cued by a stimulus experienced as nonpredictive. These findings provide converging evidence that even though cue-outcome prediction declines with age, the ability to modulate attention based on the predictive relevance of cues during associative learning remains intact. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Are age-related changes in cortical motor representations linked with facilitation/inhibition in the primary motor cortex?

Are age-related changes in cortical motor representations linked with facilitation/inhibition in the primary motor cortex?

Sleep: Ever-decreasing ripples.

Slow gamma oscillations during sharp-wave ripples in hippocampus are reduced in mice expressing human APOE4 and this is associated with age-related deficits in learning and memory.

Age differences in learning emerge from an insufficient representation of uncertainty in older adults.

Healthy aging can lead to impairments in learning that affect many laboratory and real-life tasks. These tasks often involve the acquisition of dynamic contingencies, which requires adjusting the rate of learning to environmental statistics. For example, learning rate should increase when expectations are uncertain (uncertainty), outcomes are surprising (surprise) or contingencies are more likely to change (hazard rate). In this study, we combine computational modelling with an age-comparative behavioural study to test whether age-related learning deficits emerge from a failure to optimize learning according to the three factors mentioned above. Our results suggest that learning deficits observed in healthy older adults are driven by a diminished capacity to represent and use uncertainty to guide learning. These findings provide insight into age-related cognitive changes and demonstrate how learning deficits can emerge from a failure to accurately assess how much should be learned.

Neurodegenerative disease: Ever decreasing ripples.

Slow gamma oscillations during sharp-wave ripples in hippocampus are reduced in mice expressing human APOE4 and this is associated with age-related deficits in learning and memory.