How memory for personal interactions declines with age – Neuroscience News

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Summary: Researchers have identified a new mechanism within neurons that causes memories associated with social interactions to decline with age. Furthermore, they were able to reverse memory loss in mouse models.

Source: University of Maryland

One of the most annoying aspects of age-related memory decline is not being able to remember the face that goes with the name of a person you just talked to hours before. Although researchers do not understand why this dysfunction occurs, a new study conducted at the University of Maryland School of Medicine (UMSOM) has provided some important new clues.

The study was published on September 8 a Aging cell.

Using aged mice, researchers have identified a new mechanism in neurons that causes memories associated with these social interactions to decline with age. Furthermore, they were able to reverse this memory loss in the lab.

The researchers report that their findings identified a specific target in the brain that could one day be used to develop therapies that could prevent or reverse memory loss due to typical aging. The memory problems of aging are different from those caused by diseases such as Alzheimer’s or dementia. At this time, there are no medications that can prevent or reverse cognitive decline due to typical aging.

“If an older adult attends a cocktail party, he or she would likely recognize the names or faces of other attendees afterward, but might have trouble remembering which name went with which face,” said study leader Michy Kelly, Ph.D. . ., Associate Professor of Anatomy and Neurobiology at UMSOM.

These types of memories that associate multiple pieces of information within a personal interaction, called social associative memories, require an enzyme known as PDE11A in a part of the brain responsible for memory involving life experiences.

Last year, Dr. Kelly published research on PDE11A showing that mice with genetically similar versions of the PDE11 enzyme were more likely to interact than those mice with a different type of PDE11A.

In this new study, Dr. Kelly and her team sought to determine the role of PDE11A in social associative memory in the aging brain and whether manipulation of this enzyme could be used to prevent this memory loss.

Researchers can study the mouse’s “social interactions” with its neighbors by seeing if they will be willing to try a new food, based on their memories of finding it on another mouse’s breath.

Mice do not like to eat new food to avoid getting sick or even dying. When they smell food on another mouse’s breath, the mice make an association between the food odor and the other mouse’s pheromone odor, the memory of which serves as a safety cue that any food with this smell is safe to eat in the future.

Dr. Kelly and her colleagues found that while old mice could recognize food odors and social odors separately, they were unable to remember the association between the two, similar to the cognitive decline of the elderly

They also found that PDE11A levels increased with age in both people and mice, specifically in a brain region responsible for many types of learning and memory known as the hippocampus.

This extra PDE11A in the hippocampus was simply not found where it was normally found in young mice; instead, it preferentially accumulated as small filaments in neuronal compartments.

The researchers wondered if having too much PDE11A in these filaments was why the older mice forgot their social associative memories and would no longer eat the safe food they smelled on another mouse’s breath. To answer this question, they prevented these age-related increases in PDE11A by genetically knocking out the PDE11A gene in mice.

Without PDE11A, the older mice no longer forgot the social associative memory, meaning they ate the safe food that smelled like another mouse’s breath. When the researchers added PDE11A back into the hippocampus of these old mice, the mice once again forgot the social associative memory and would no longer eat the safe food.

A potential avenue for drug development to prevent this memory loss in people lies in an additional finding: The researchers learned that the concentrated filaments of PDE11A had an additional chemical modification at a specific site on the enzyme that other PDE11 diffused throughout the neuron no. to own. When they prevented this chemical modification, it reduced PDE11 levels and also prevented it from accumulating as filaments.

The researchers report that their findings identified a specific target in the brain that could one day be used to develop therapies that could prevent or reverse memory loss due to typical aging. The image is in the public domain

“PDE11 is involved in more things than just remembering, including preferences for who you prefer to be around. So if we were to develop a therapy to help with cognitive decline, we wouldn’t want to get rid of it entirely or it could cause other effects negative side effects,” said Dr. Kelly.

She and her colleagues joke that any drug that knocks out PDE11 will make sure you remember your friends and family, but you might not like them anymore.

“So our goal is to find a way to specifically target the bad form of PDE11A, so as not to interfere with the normal, healthy function of the enzyme.”

Dean Mark T. Gladwin, MD, executive vice president for Medical Affairs, UM Baltimore, and John Z. and Akiko K. Bowers Distinguished Professor at UMSOM, said, “We are at the tip of the iceberg when it comes to understanding how the brain ages, so it’s crucial to have basic research studies like these to help us improve our understanding and ultimately find ways to prevent cognitive decline.”

Other study authors include students Nicole Gorny, MS and Siena Petrolle from UMSOM, as well as co-authors from the University of South Carolina.

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About this aging and memory research news

Author: Press Office
Source: University of Maryland
Contact: Press Office – University of Maryland
Image: The image is in the public domain

Original research: Closed access
“Conserved age-related increases in hippocampal PDE11A4 cause unexpected proteinopathies and cognitive decline in social associative memories” by Katy Pilarzyk et al. Aging cell


Summary

Preserved age-related increases in hippocampal PDE11A4 cause unexpected proteinopathies and cognitive decline in social associative memories.

In humans, associative memories are more susceptible to age-related cognitive decline (ARCD) than recognition memories. Reduced cAMP/cGMP signaling in the hippocampus may contribute to ARCD.

Here, we found that both aging and dementia associated with traumatic brain injury increased the expression of the cAMP/cGMP-degrading enzyme phosphodiesterase 11A (PDE11A) in the human hippocampus.

Furthermore, age-related increases in hippocampal PDE11A4 mRNA and protein were preserved in mice, as was the increased vulnerability of associative versus recognition memories in ARCD. Interestingly, mouse PDE11A4 protein in the aged ventral hippocampus (VHIPP) accumulated ectopically in the membrane fraction and filamentous structures that we call “ghost axons.”

These age-related increases in expression were driven by reduced exoribonuclease-mediated degradation of PDE11A mRNA and increased PDE11A4-pS117/pS124, the latter of which also drove the accumulation point of PDE11A4. In contrast, PDE11A4-pS162 caused scattering.

Importantly, prevention of age-related increases in PDE11 expression by genetic deletion of ARCD protected mice from associative long-term and remote memory (aLTM) in the social transmission of food preference test , albeit at the expense of recent aLTM.

Furthermore, mimicking age-related overexpression of PDE11A4 in CA1 of old KO mice resulted in aging-like impairments in remote social, but not nonsocial, CREB function and LTM. RNA sequencing and phosphoproteomic analyzes of VHIPP identified cGMP-PKG, as opposed to cAMP-PKA, as well as circadian entrainment, glutamatergic/cholinergic synapses, calcium signaling, oxytocin, and retrograde endocannabinoid signaling as mechanisms by which PDE11A suppression protects against ARCD.

Taken together, these data suggest that PDE11A4 proteinopathies acutely impair signaling in the aging brain and contribute to ARCD of social memories.

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