In one ear, out the other: The limitations of memory research

Hartford, Connecticut, 1953 — Patient H.M. experienced severe epileptic seizures that could not be controlled by medication. After undergoing experimental neurosurgery, his epilepsy was under control, but with one problem: his ability to recall and form memories had been severely impacted.

H.M. underwent a bilateral medial temporal lobectomy to remove parts of his brain — notably the majority of his hippocampus.

Today, we understand that the hippocampus, a seahorse-shaped brain structure, plays a crucial role in memory formation and storage.

Though H.M.’s case helped us gain critical insight into how memory functions, researchers generally can’t just remove parts of people’s brains to learn what happens. That leaves researchers, including those at UBC, with the need to innovate alternative approaches to researching memory formation.

While scientists have made immense progress in memory formation research, so much is still unknown.

What’s keeping us from fully understanding this aspect of the human brain, and what are memory researchers doing to overcome these obstacles?

Do we remember like rats?

Animal modelling is a gold standard method in neuroscience research. It involves using animals to study biological and physiological processes or mimic human diseases and test potential treatments.

Dr. Mark Cembrowski, a UBC cellular and physiological sciences assistant professor, uses a computational approach which integrates diverse datasets to map and interpret the brain while combining behavioural assessments in rodents to investigate memory formation.

Cembrowski said his ultimate goal is to “understand memory in a way that we can treat a variety of debilitating memory-related disorders and diseases, including PTSD, Alzheimer’s and other forms of dementia.”

The Cembrowski lab’s current research uses rodent models to study fear memory, the memory of traumatic events that causes fear and avoidance, and recognition memory, the ability to identify a previously encountered stimulus or situation as familiar.

But do rodents form and retain memories in the same way humans do?

According to Cembrowski, the underlying assumption of animal research is “what is going on in this animal model is something that generalizes to humans.”

There are limits to this assumption of translatability between animal models and the human brain, and capturing the complexities of human behaviour in simpler animals can be difficult. However, researchers like Cembrowski are attempting to narrow the gap between animal models and humans.

“We’re starting to be able to show what specifically is different in the brain[s] of humans versus animals,” he said.

Cembrowski and his lab aim to overcome the barriers associated with animal modelling through a new research project in collaboration with Vancouver General Hospital.

The project uses donated brain tissue removed from consenting epilepsy patients. This tissue is then kept alive in Cembrowski’s lab and used to analyze the human brain’s organization on a cellular and molecular level.

By using live, functioning human tissue, they hope to solve the problem of translatability.

“We start from a living human brain [and] identify what we think are really important cells and molecules there for memory,” said Cembrowski. “[We] test those in rodents, and then if [our hypotheses are correct], then we can then bring this back into clinical trials in humans and hopefully begin to understand and treat memory related impairments.”

“When you can actually start with things like living human brain tissue, there is no need to translate anything.”

A genetic framework

A common approach to researching memory formation involves studying it from a cellular perspective, which means looking closely at how individual cells interact and work with each other.

Dr. Jason Snyder, a UBC associate psychology professor, aims to understand the impact of neurogenesis, the production of new brain cells, on memory-related processes. Snyder is particularly interested in investigating memories formed in infancy, their relationship to neurogenesis and their impacts on future behaviour.

One method in cell biology involves researchers expressing genes in specific brain cells. Alterations in gene expression impact what proteins a neuron can manufacture and can have diverse effects on neuronal functioning. These effects range from how efficiently a neuron sends out its messages to what neurotransmitters it can synthesize.

Researchers use genetic tools such as promoters for optogenetic proteins, which activate or inhibit the ion channels neurons use to conduct electrical impulses by shining a specific colour of light onto the neuron through an implanted optic fibre connected to a laser or LED.

However, different cells require different types of promoters and researchers don’t have genetic tools for every type of brain cell, which can limit how much we can understand about the process of neurogenesis.

“These molecular genetic tools are one of the current things that are really allowing us to identify functions of specific brain regions,” said Snyder.

Historically, researchers utilized chemicals that would overexcite and kill neurons in a brain region for memory research, allowing researchers to analyze how the loss of those neurons affects function, similar to how they studied H.M. following his surgery.

However, issues arose as these neurotoxins were relatively imprecise. New molecular genetic tools allow researchers to overcome this problem.

For example, Synder’s lab uses viruses to specifically infect dividing cells. After an adult animal is injected with one of these viruses, none of their existing brain cells will be affected. Instead, the viral genes will only occur in the newborn cells, which can be manipulated to visualize their structure.

Like learning how to ride a bike

Imagine you were given a list of words and half of them were relevant to your personal identity and the other half were not. If you were tested on your memory of these words later, you would likely have better memory of the self-relevant words.

This behavioural observation provides some insight into how memory works and, when coupled with brain imaging techniques, shows how the brain supports this aspect of memory.

Dr. Daniela Palombo, an associate psychology professor at UBC, investigates autobiographical memory formation in human participants. Autobiographical memories come from real-life personal events, such as learning to ride a bike for the first time.

Palombo’s research projects aim to understand how negative emotions impact people’s memories of certain events, as well as how memories can change over time.

Using human participants may be the only option for certain research topics concerning memory formation, such as more complex types of memory like autobiographical memory. However, studying memory formation in humans presents its own challenges.

Functional magnetic resonance imaging (fMRI) measures the changes in blood flow to specific brain regions, and researchers can then use this information to make assumptions about human neural activity.

Palombo noted in a statement to The Ubyssey that fMRI “does not tell [researchers] how cells and circuits are operating during remembering versus forgetting.”

“It is not a direct measure of neural activity,” Palombo wrote. “We need other approaches to drill down further if we want to understand mechanisms.”

Palombo’s research combines neuroimaging with behavioural assessments such as autobiographical interviews where participants recall events from various life experiences to get a “richer picture into what and how people remember” and bridge the gaps in each method.

When behavioural output aligns with neural activity, “that might tell us a bit about how the brain supports certain aspects of memory,” wrote Palombo.

Each method has its own strengths and most researchers use a combination of techniques in order to support their findings. Developments in one research method, such as improved brain imaging quality, can ripple out to others to help the entire field of memory research gain further understanding of the mechanisms of memory.