Turning Memory Off And On In Rats To Aid Alzheimer's Research
June 2, 2014

Turning Memory Off And On In Rats To Aid Alzheimer’s Research

Alan McStravick for www.redorbit.com - Your Universe online

Memory is, it could be said, one of the most important keys in the propagation of a species. Without memory, one would be unable to recall fear of a predator or recognize a situation that promises a reward, such as food or an optimal mating situation. There is a flip-side to the coin of memory, too, however. A particularly traumatic experience can too easily be remembered given an environmental catalyst. Losing memory, as is the case with Alzheimer's patients, could place an individual in dangerous and harmful situations.

A new study is focusing on the manipulation of memory in the hopes that those last two conditions can be identified and treated. As is the case with many brain studies, the subjects the researchers are focusing on are genetically-engineered rats. Rats, it is known, share many similarities with the human brain and are, therefore, ideal test subjects.

In this particular study, scientists focused on optogenetics, a relatively brand new tool available in the field of neuroscience. Using a flash of light targeted to specific neurons in the brain of the rat, the researchers were able to inactivate and then reactivate memory in their study subjects. This marks the first cause-and-effect evidence that strengthened connections between neurons are how memories are made and stored.

"Our results add to mounting evidence that the brain represents a memory by forming assemblies of neurons with strengthened connections, or synapses," explained Roberto Malinow, MD, PhD, of the University of California, San Diego (UCSD), a grantee of the NIH's National Institute of Mental Health (NIMH). "Further, the findings suggest that weakening synapses likely disassembles neuronal assemblies to inactivate a memory."

Adding to Malinow's statement, director of NIMH, Thomas R. Insel, MD stated, “Beyond potential applications in disorders of memory deficiency, such as dementia, this improved understanding of how memory works may hold clues to taking control of runaway emotional memories in mental illnesses, such as post-traumatic stress disorder.”

Until this study, despite strong belief that long-term potentiation (LTP), a term indicative of strengthened connections between neurons, was responsible for memory formation, no formal scientific proof existed.

The work performed by the Malinow team was seminal in finally proving once and for all that this relationship between LTP and memory existed. By detecting LTP when forming a memory in their subjects and then removing the memory via a process known to reverse LTP only to bring the memory back again via LTP, the relationship was proved.

Mentioned above, it was the use of optogenetics, a relatively new option in neuroscience, that allowed the team to operate with the precision required to demonstrate the cause-and-effect relationship. Optogenetics basically works with the same cellular machinery which allows even the most primitive of organisms, like algae, to be controlled by light. That light focuses on specific brain circuit components and, as in this experiment, light from a laser can affect the behavior of an animal far more complex than simple algae.

The study was conducted putting a new twist on the conventional rodent fear conditioning experiments. Where previously a tone was paired with a foot shock in the cage of the subject rat, thereby inducing fear memory of a tone, Malinow's team paired a foot shock with direct optogenetic stimulation. When the team would light up a specific group of neurons in a known auditory fear memory circuit, the rat, as in a conventional experiment, would freeze and show reduced reward-seeking behaviors.

The precision allowed by optogenetic stimulation was key for the next part of the study. The researchers were able to strengthen connections between neurons in the circuit by promoting LTP or, conversely, to weaken the connections by the promotion of a countervailing process called long-term depression (LTD). This was how the team was able to create a fear memory, remove it from the subject and, ultimately, bring it back.

Equally important to their findings above, the team performed autopsies on the brains of deceased rat subjects and were able to detect distinct changes in the sensitivity of brain chemical messenger systems. This, say the researchers, is confirmation of what was before the hypothesized role of strengthening and weakening of synaptic connections in the switching on-and-off of memory.

"We have shown that the damaging products that build up in the brains of Alzheimer's disease patients can weaken synapses in the same way that we weakened synapses to remove a memory," said Malinow. "So this line of research could suggest ways to intervene in the process."

"In addition to eliminating any doubt about a link between LTP/LTD with memories, this work highlights the staggering potential of precision targeting and circuit manipulation for alleviating maladaptive memories," said project officer Chiiko Asanuma, PhD, of the NIMH Division of Neuroscience and Basic Behavioral Science.

"This work provides a nice demonstration of how the field of neuroscience is being transformed by the types of technologies that are at the heart of President Obama's BRAIN Initiative," said Edmund Talley, PhD, program director at the NINDS.

Malinow and his colleagues at UCSD along with Roger Tsien, PhD, a grantee of the NIH's National Institute on Neurological Disorders and Stroke, have published their report in this month's edition of the journal Nature.