Scientists use genetic tags to disclose secrets of memory retention in mice

Washington, Feb 22 : Researchers at the Scripps Research Institute have used genetic tags in mice to understand the cellular mechanism behind memory, and which helps in its retention over a long period of time.

This knowledge is enabled by a newfound ability to link a learning experience in a mouse to consequent changes in the inner workings of its neurons. For this, the researchers have developed a way to pinpoint the specific cellular components that sustain a specific memory in genetically-engineered mice.

The study was led by Mark Mayford, Ph.D., and Naoki Matsuo, Ph.D., at the Scripps.

"Remarkably, this research demonstrates a way to untangle precisely which cells and connections are activated by a particular memory. We are actually learning the molecular basis of learning and memory," said NIMH Director Thomas Insel, M.D.

In order to have a long-term memory, the neural connections holding it need to be strengthened by including new proteins activated by learning. Still it's not known how these new proteins, born deep inside a neuron, finally become part of the specific connections in far-off neuronal extensions that encode that memory.

The researchers traced the destinations of such migrating proteins and located the neural connections, called synapses, holding a specific fear memory. They also discovered that these synapses are distinguished by telltale molecular tags making them capture the memory-sustaining proteins.

The researchers have been applying their new technique in a series of studies that focus on progressively finer details of the molecular machinery of memory.

"Inside neurons involved in a specific memory, we're tracing molecules activated by that learning to see how it ultimately changes neural connections," explained Mayford.

In an earlier study the researchers demonstrated that the same neurons activated by a learning experience are also activated when that memory is retrieved. The more neurons involved in the learning, the stronger the memory.

This was done by genetically engineering a strain of mice with traceable neurons in the brain's fear center, called the amygdala. Inserted genes caused activated neurons to glow red when the animals learned to fear situations where they received shocks, in a process known as fear conditioning, and to glow green when the memory was later retrieved. It was revealed which circuits and neurons were involved in the specific learning experience.

In the current study, the researchers followed this approach to discover how fear learning works at a deeper level, inside neurons of the brain's memory hub, called the hippocampus. It was indicated that proteins called AMPA receptors strengthen memories by becoming part of the synapses encoding them.

The researchers genetically engineered a strain of mice to express AMPA receptors traceable by a green glow in order to identify these synapses. After fear conditioning had triggered new AMPA receptors deep in the neuron's nucleus, any further expression of the proteins was chemically suppressed. This granted time for the receptors to migrate to their appointed synapses. After some hours, green fluorescence revealed the fate of the specific AMPA receptors born in response to the learning.

Just as the researchers were hoping that the newly synthesized AMPA receptors had travelled and become part of only certain hippocampus synapses, most probably the ones holding the memory.

Synaptic connections are made onto small nubs on the neuron called spines. These spines come in three different shapes called thin, stubby and mushroom. While not much was known about the function of these differently shaped spines, they have a critical importance in mental function because of the fact that they are altered in various forms of mental retardation, like Fragile-X syndrome.

The researchers discovered the synapses that received the AMPA receptors with memory were limited to the mushroom type. The mushroom spines also prominently detected in the same neurons when the fear conditioning was reversed by repeatedly exposing the animals to the feared situation without getting shocked, a procedure called extinction learning.

This indicated that the same neurons activated when a fear is learned are also activated when it is lost. The rush in mushroom spine capture of the receptors came into sight within hours of learning and was gone after a few days, but it seemed to be critical for cementing the memory.

The report on the findings of this study appears in the recent issue of the journal Science.

ANI