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What are current strengths in the department? What gaps need to be filled?
HUGANIR: We’re very strong at molecular and cellular neuroscience, and we’re also strong on the systems side. What we’re missing are the people who work in the middle, building the bridge between molecules and mind. Perception is really a big black box. We don’t understand the basic mechanisms involved.
Are the methodologies for exploring perception evolving?
HUGANIR: Lately, we’ve developed much better imaging methods—functional MRI, two-photon imaging and multi-electrode recording. You can actually see how neurons respond when an animal is learning something, forming new circuits, for example. Targeted genetic manipulations of receptors that we think are important in learning and memory are also providing a great deal of information.
HUGANIR: Learning creates new circuits in the brain by sculpting connections between neurons—making new connections, strengthening some connections, weakening or removing others. We’ve found that you can remove receptors from a synapse or add them to a synapse, and that actually affects the strength of the connection. One of our papers out a couple of years ago showed that if you knock out this one specific mechanism for adding receptors to a synapse, you can affect memory retention in mice. They become forgetful; they can’t retain memories for very long.
Aside from learning and memory, what are some of the other hot topics in neuroscience these days?
HUGANIR: Development. The brain has an incredibly complex wiring diagram and we need to understand how it forms. Of course, understanding those basic mechanisms will enable us to promote regeneration and repair of the nervous system. We’ve come a long way in understanding what regulates nerve regeneration, and if we could relieve the inhibition of regeneration in the peripheral nervous system, that would be incredibly important therapeutically.
There’s a black notebook on the shelf in your office that dates from 1970 and details science experiments you conducted in high school during an ambitious investigation entitled “Memory and Protein Synthesis.” Could you please recall some particulars?
HUGANIR: When I was a senior at Germantown Friends, a Quaker school in Pennsylvania, I was training goldfish onto light; they needed to “learn” to respond to light by swimming over a little barrier. If they didn’t respond to the light, they would get shocked. I then tried blocking their memory of what they learned by using protein synthesis inhibitors. The idea was to show that making new proteins in the brain was very important to learning and memory.
Your professional focus – on neuroscience – has been life-long. Where did it originate?
HUGANIR: I always wanted to understand how the brain worked. In high school, I started paying attention to my changing emotions. I was taking chemistry at the time and thought that these intense emotions I was experiencing must have a biological basis. I wanted to know how that occurred.
Fast forward a few decades: What are the big questions now?
HUGANIR: How do we perceive, understand, react and remember? How does an experience – like looking at a painting – literally sculpt your brain? How does emotional status determine whether an experience will change the connections between neurons for days, years or a lifetime?
What is known about how we learn and remember?
HUGANIR: Learning and memory happen when communication channels between nerve cells are weakened or strengthened, a process called synaptic plasticity. For example, a burst of an excitatory chemical called glutamate from one nerve to the next will make it harder for that particular connection to "fire" again for a certain amount of time. The sheer number of possible connections gives the brain unfathomable flexibility--each of the brain's trillion nerve cells can have a thousand connections to other nerves. My lab is investigating exactly how these nerve-to-nerve communications happen and what molecules are involved in weakening or strengthening two neurons' ability to talk to one another.
Our approach has been to study molecular and cellular mechanisms that regulate neurotransmitter receptors. These receptors mediate the response of neurons to neurotransmitters released at synapses and are a central convergence point for transmission of signals between neurons. Modulation of the function of these receptors is a powerful and efficient way to modulate synaptic communication and synaptic plasticity.
Over the years we have shown that receptor protein phosphorylation and the regulation of the synaptic targeting of receptors are dynamically regulated and regulate the efficiency of synaptic transmission. While it’s not well understood how neuronal connections are made, lost or changed, the process involves the movement of the AMPA receptor protein to and from these connections.
Do you still use goldfish in your experiments?
HUGANIR: The goldfish are long gone. We’ve generated a “forgetful” mouse. We discovered a critically important step in storing new memories. When a phosphate group couldn't be hooked onto one part of the animal's glutamate receptor, the mice quickly forgot the location of a platform in a pool of water. These phosphorylation-blocked forgetful mice can be used to better understand the mechanisms that regulate so-called AMPA receptors which mediate about 70 percent of synaptic transmission in the brain.
In addition to directly linking modification of receptor function to plasticity/learning/memory retention, we also detected defects in the emotional memories of these forgetful rodents.
Your lab also created a mouse with the opposite mutation?
HUGANIR: Yes: By mimicking constant phosphorylation, we created an animal model in which the AMPA receptor is always primed, resulting in a mouse that is very smart but also very anxious – and likely prone to drug addiction.
Most recently, your team reported watching learning in real time?
HUGANIR: We’re using special acrylic windows to peer in the brains of live, anesthetized mice and can image about 500 microns into the surface of the brain. It’s not quite there yet, but within a year, we’ll be stimulating their whiskers in a learning paradigm and watching receptors move in and out of dendrites – watching learning in real time.
Richard Huganir on how learning rewires the brain
- Scientists View Effect of Whisker Tickling on Mouse Brains
- Brain Scientists Figure Out How A Protein Crucial To Learning And Memory Works
- Gene Found To Be Crucial For Formation Of Certain Brain Circuitry
- Gene Found To Foster Synapse Formation In The Brain
- Newly Discovered ‘Switch’ Plays Dual Role In Memory Formation
- Study Refutes Accepted Model of Memory Formation
- Johns Hopkins Scientists Reveal Molecular Sculptor of Memories
- Researchers discover how to erase memory
- Luring prospective faculty
- Picking apart how neurons learn
- What emotional memories are made of
- Watching memories form in real time
- This is your brain on fatty acids