Memory and the Aging brain: Defying Dementia

What is memory? Where is it stored? How does it work? Will we experience memory loss as older adults? Dr. Carol Barnes. Ph.D. unveils the mystery and proves to us that dementia is not inevitable.

One of the greatest scientific puzzles is how the brain captures and preserves the unique experiences of each individual. This organ gives us our own identity and the ability to understand other great mysteries that exist around us.

The Hippocampus Role in Memory

It’s been known since the 1950s that the brain structure called the hippocampus plays a very special role in memory.

The neuropsychologist Brenda Milner studied a patient whose hippocampus had been removed because he suffered from severe epilepsy. She discovered that he could no longer permanently store most information. The destruction of the hippocampus produced amnesia for new or recent memories but left earlier memories intact.

This focused a spotlight on the hippocampus as a structure actively involved in laying down lasting memories. And questions began to arise about why damage to this structure had such a profound effect on memory.

Where is Memory Stored in the Brain?

In 1948, Tollman developed the idea of a cognitive map as an organizer of cognitive processes (memories) in the brain. In the early 1970s, O’Keefe and Nadel proposed that the hippocampus was the neural basis of such cognitive mapping. Like a framework in which items and events could be represented in space and time.

In the same decade, David Marr laid out the theory of hippocampus or, as he called it, the “archicortex”. Basically, the idea was that the hippocampus could rapidly form memory traces by strengthening connections between neurons. A memory trace is a change in the brain that represents something (such as an experience) encoded as a memory.

In summary, we knew:

• a role that the hippocampus played in memory,
• that the hippocampus was similar in structure across all mammals, and
• that the biological basis of human experience could be studied in animals.

This was the right time to ask questions about how memories are laid down in the brain and what is the cause of cognitive decline or age related changes in memory.

Memory and the Aging Brain: Do we Lose our Brain Cells with Age?

There are two main categories of cells in the nervous system: glial cells and neurons. In human brains there are 86 billion neurons and 85 billion glia. Even though glia/neuron interactions are critical for brain function, we are going to focus on neurons.

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A Little History on Brain Research

In the early 70s, we were still influenced by the Aristotelian views of how memory changes with age: “If you live long enough dementia was inevitable”.

This reflects, in part, an influence from stereotypic views on aging that have roots in our social fabric. Not in scientific works.

So, what was known about the brain aging then?

These are the kinds of example cells that I found from people across different ages.

These are cortical neurons. You see the progression of what scientists thought happened to these neurons during the aging process. By the time you get to the example cell from a 90 year old, it would be very shriveled.

It is a very disturbing picture of brain aging because neurons are “postmitotic”. That means no new cells would replace the worn out ones, like what happens with your skin or liver cells. The neurons you are born with die with you at the end of your life (except for neurogenesis). This misconception of cell degeneration in normal aging would support Aristotle’s idea that dementia was inevitable.

Neurogenesis is the process of creation of new neurons. Scientists know that it happens, but it doesn’t seem to happen throughout the brain, and it is currently under investigation.

What do we Know about Brain Cell Loss in the Aging Brain Now?

More recent and rigorous experiments show that there is no cell loss in the principal cells in the hippocampus during normal aging. Not in rats, mice, dogs, monkeys or humans. Of all animals, humans develop Alzheimer’s disease, but other animals do not.

• We also know now that many functional properties don’t change in hippocampal neurons in the aging brain.
• And that the cells’ membrane properties in old animals are mostly similar to those in younger animals.

So, not only is there little cell loss in aging but cell physiology is not dramatically altered. Thus, high levels of brain function is a normative part of aging.

Reaching a very old age does not imply having a neurodegenerative disease that results in dementia. In the United States, only 14% of people over 71 years of age have dementia. The most prevalent being Alzheimer’s disease followed by vascular dementia. This means that 86% of people over 71 years old, do not have dementia.

How do we Know only Humans Develop Dementia?

To know this, we had to be able to test memory across all species and across age.

Spatial memory is the kind of memory that allows us to find our way through our environment. To know where the library is or the way to our favorite restaurant.

Also, spatial memory has no need for language and it has been shown to change at the age that is considered to be old in a given species. Thus, we can examine spatial memory under similar conditions across species and across age.

It is also a specific type of memory that involves the hippocampus.

Navigation and Spatial Memory Testing Across Species

Data from humans, monkeys and rats all support the idea that the hippocampus is fully engaged in spatial navigation.

1. Human Navigation Memory Experiment.

In 1997, Eleanor Maguire and her colleagues in London conducted an experiment with taxi drivers. They asked them to recall a route and imagine they were traveling with a passenger. All the while, they were in a Positron Emission Tomography (PET) scanner to measure their brain activity. The right posterior hippocampus was shown to be powerfully activated.

2. Monkeys Spatial Memory Experiment.

In my experiment, monkeys engaged in behaviors involving navigation. For example, walking back and forth for a food reward on a 6 meter track. They also showed the highest activity in the right posterior hippocampus. And this is true for both younger and older monkeys.

3. Rats Spatial Memory Experiment.

John O’Keefe tracked the activity of a single cell in the hippocampus of rats as they moved through particular places within a box. He tracked their movement trajectory and where the cells were active, calling them “place cells”. O’Keefe and Nadel called this cell firing pattern a “cognitive map”.

Navigation and Spatial Memory Testing Across Ages

For rodents, an example spatial memory task is the Barnes circular platform developed in the mid-1970s for old rats.

The goal is for the rat to find the one place underneath this brightly lit platform and escape into it.

We consistently found that older rats did not remember the location of the goal tunnel from day to day as well as the younger rats.

In fact, not only rats, but older monkeys and older humans also show spatial memory impairments.

These spatial memory problems due to hippocampal dysfunction exist at whatever age a species is considered to be old.

Thus, it appears that there’s a fundamental biological process that occurs in tissues of the body and also in the brain as we age. And this process is essentially sped up in rodents and in monkeys compared to humans.

So, changes in memory are a normative part of the aging process.

But, if there’s little cell loss in the hippocampus and the basic physiological properties of these cells are preserved, why do we have memory problems as we age?

The Mystery Unveiled: Why does our Memory Worsen with Age?

The answers likely lie with the synapses and the hundred trillion connections made by them onto neurons. These connections are fundamental to network communication, and ultimately, to behavior.

We will analyze three reasons why our memory worsens with age.

1. We have Fewer Synapses As We Age

The number and functional state of synapses change with age. There are either fewer actual synapses or fewer functional synaptic contacts. Both losses could lead to failures in network communication and changes in behavior.

2. There are Changes with Age in Brain Plasticity and Memory

Another factor that contributes to memory change when we get older is the synapse’s loss of plasticity. That is, their ability to be modified.

In 1949, the famous Canadian psychologist Donald Hebb attempted to explain how neural pathways are developed based on experiences.

According to Hebb’s theory, more frequent use of certain connections will make them stronger. Something often described as “cells that fire together, wire together.”

Thus, alterations in strength of these synaptic connections IS the change in the brain that is the basis of memory.

But it wasn’t until 1973 when the Norwegian physiologist Terje Lømo discovered a biological process that proved Hebb’s theory. This process was called long-term potentiation (LTP). It can be produced by delivering electrical stimulation to axons thus mimicking normal neuron firing in the brain.

When we studied LTP at hippocampal synapses in older rats, we found faster decay in their synaptic plasticity. The change in this plasticity or decay of LTP correlates with faster forgetting in older rats. (Barnes, 1979)

The plasticity mechanism used for information storage in the brain is compromised in old rats. And this correlates with individual differences in memory performance.

Maintaining brain plasticity is paramount to brain health.

3. Changes to the Hippocampal Network Function

The third change, has to do with the fact that neurons do not function individually but rather as a network to produce behavior. Earlier I shared about hippocampal “place cells” and how firing many of them contribute and form a cognitive map. 

These two panels illustrate a young rat’s “place cell” recordings on two different sessions in the same day. Different colors reflect the different cells firing pattern. And you see that the young rat retrieves the same hippocampal map on both sessions.

So, the young rats retrieve the same maps from session to session. And, most of the time, older rats also show accurate map retrieval.

But about a third of the time, a completely different place cell distribution appears when an old rat goes back into the same familiar room. It is as though the old rat had retrieved the wrong map.

This occasional failure of hippocampal network function may contribute to changes in memory with age.

Memory and Aging: Defying Dementia

There’s been a fundamental shift in thinking about brain aging over the past several decades. The picture of normative aging that we have now is very different than in the 1970s.

• We know that memory does change with age and that we are not all headed for Alzheimer’s or vascular dementia.
• We also know that with age we lose synaptic connections and functions but there’s no widespread neurons loss.
• There is also evidence that the aging brain adapts at a network level. That even though there is a loss in synapses, the remaining synapses are more powerful, as though they were ‘compensating’ for fewer actual synapses.
• We know that there is reduced brain plasticity but change can still happen when we are older.
• And we know that there are changes in network dynamics as we age.

But experiments clearly show that older individuals can recruit additional brain circuits to achieve memory retrieval that is as accurate as that of younger individuals.

The older ideas that the brain ages passively is simply the wrong way to understand the changes that occur with age.

What can the 86% of us with healthy brains do now to maintain optimal cognition? Keep those synapses active by learning new things. Like you are doing today by reading this article.

The Precision Aging Approach: Maximizing Brain and Cognitive Healthspan

Many of the insights that we have today about brain aging and cognition come from basic science work in rodents and non-human primates as it has been the focus of my laboratory. But we need to begin to translate our knowledge of the aging brain and what factors impact cognitive trajectories into solutions for people.

At the University of Arizona and in conjunction with the McKnight Brain Research Foundation we are beginning to harness the power of Precision Medicine to predict health risks and personalized brain health interventions to maximize cognitive healthspan.

This Precision Aging approach aims to close a gap that currently exists between optimal cognition and lifespan. To increase the quality of life.

Dr. Carol Barnes is a Regents Professor in the Departments of Psychology, Neurology and Neuroscience, the Evelyn F. McKnight Endowed Chair for Learning and Memory in Aging, Director of the Evelyn F. McKnight Brain Institute and  Director of the Division of Neural Systems, Memory & Aging at the University of Arizona, Tucson, AZ. Dr. Barnes is past-president of the 42,000 member Society for Neuroscience, an elected Fellow of the American Association for the Advancement of Science, and an Elected Foreign Member of the Royal Norwegian Society of Sciences and Letters.

She earned her B.A. in psychology from the University of California at Riverside, and her M.A. and Ph.D. from Carleton University in Ottawa, Canada. She did postdoctoral training in neuropsychology and neurophysiology in the Department of Psychology at Dalhousie University, The Institute of Neurophysiology, University of Oslo, and in the Cerebral Functions Group at University College London.