Michael Hoppa's Lab Identifies 'Volume Control' in the Brain

Whether you have a photographic memory, the memory of an elephant, or just a plain old bad memory, your brain relies on the complex functioning of electrical signals and neurotransmitters to bring the past to life.

New research has added to the understanding of how memories are formed and how learning happens.

A research team from the Hoppa Lab in the Department of Biological Sciences has identified a "molecular volume knob" that regulates electrical signals, controlling the width of electrical signals that flow across synapses in the brain.

The finding of the control mechanism, and the identification of the molecule that regulates it, could help researchers in their search for ways to manage neurological disorders, including Alzheimer's disease, Parkinson's disease and epilepsy.

"The synapses in our brain are highly dynamic and speak in a range of whispers and shouts," says Michael Hoppa, an assistant professor of biological sciences, who led the research team. "This finding puts us on a straighter path toward being able to cure stubborn neurological disorders."

The research, published in Proceedings of the National Academy of Sciences, describes the first-ever study of how the shapes of electrical signals contribute to the functioning of synapses.

Synapses are tiny contact points that allow neurons in the brain to communicate at different frequencies. The brain converts electrical inputs from the neurons into chemical neurotransmitters that travel across these synaptic spaces. The number of neurotransmitters released changes the numbers and patterns of neurons activated within circuits of the brain. That reshaping of synaptic connection strength is how learning happens and how memories are formed.

Two functions support these processes of memory and learning. One, known as facilitation, is a series of increasingly rapid spikes that amplifies the signals that change a synapse's shape. The other, depression, reduces the signals. Together, these two forms of plasticity keep the brain in balance and prevent neurological disorders such as seizures.

"As we age, its critical to be able to maintain strengthened synapses. We need a good balance of plasticity in our brain, but also stabilization of synaptic connections," says Hoppa.

The research focuses on the hippocampus, the center of the brain that is responsible for learning and memory.

In the study, the research team found that the electric spikes are delivered as analog signals whose shape affects the magnitude of chemical neurotransmitter released across the synapses. This mechanism functions like a light dimmer with variable settings. Previous research considered the spikes to be delivered as a digital signal, more akin to a light switch that operates only in the "on" and "off" positions.

"The finding that these electric spikes are analog unlocks our understanding of how the brain works to form memory and learning," says In Ha Cho, a postdoctoral fellow and lead author of the study. "The use of analog signals provides an easier pathway to modulate the strength of brain circuits."

Beyond discovering that the electrical signals that flow across synapses in the brain's hippocampus are analog, the Dartmouth research also identifies the molecule that regulates the electrical signals.

According to the research team, the molecule—known as Kvβ1—was previously shown to regulate potassium currents but was not known to have any role in the synapse controlling the shape of electrical signals. These findings help explain why loss of Kvβ1 molecules had previously been demonstrated to negatively affect learning, memory, and sleep in mice and fruit flies.

The research also reveals the processes that allow the brain to have high computational power at low energy. A single, analog electrical impulse can carry multi-bit information, allowing greater control with low frequency signals.

"This helps our understanding of how our brain is able to work at supercomputer levels with much lower rates of electrical impulses and the energy equivalent of a refrigerator light bulb. The more we learn about these levels of control, it helps us learn how our brains are so efficient," says Hoppa.

According to the research team, the molecular system exists in an area of the brain that is easily targeted by pharmaceuticals and could lend itself to the development of drug therapies.

Funding for this research was provided through a National Science CAREER award and from the Klingenstein-Simons Fellowship.

David Hirsch can be reached at david.s.hirsch@dartmouth.edu.