Olfaction Part I: The Work
Who: Kevin Bolding
What: Postdoctoral Fellow in Olfaction and Memory
Where: Duke University
Years in the Game: 2
Education: BS in Biochemistry and Genetics
In this installment of IWA$, Kevin Bolding, PhD tells us about his research as a postdoc. His work focuses on deciphering memory through the olfactory system.
“ There are really chains, sequences, or hierarchies of memory.”
Q&A:
Q. What do you work on?
A. I’m trying to determine how neuronal cell groups differ in their representation of odors, how they can decode complex odors, and how this information is stored to make a memory. We are presented with odors all the time, and also associate odors with memories and emotions. The olfactory pathway is very well characterized from the odor receptor neurons to the first synapse, but it gets murkier as it reaches deeper into the brain. This is the area that we are trying to uncover using electrophysiology. We are working on circuit level analysis, which is seeing how different types of neurons interact with input and feed information to the next stage of processing.
Q. What are the basics of olfaction?
A. Odorants are molecules, usually floating in the air. Unlike other senses (sounds or colors), there is no natural ordering or spectrum of odors, so you can’t make one all-purpose receptor. A disproportionately large part of the genome goes to encoding the thousands of odor receptor proteins that evolution has decided capture a sufficient variety of molecules your nose might encounter. We can map some of the odors we perceive to specific molecules (isoamyl acetate, for instance, smells like bananas), but real odors that we perceive are probably made up of a pattern of activation of many different odor receptors. We sometimes pick out specific odors in a complex mixture, like naming the “notes” in a wine, but also very often experience odors more holistically which means that the olfactory system eventually combines the various received signals into a stable pattern or odor object that we can identify with an experience or real-world object.
Q. What are some details of olfactory system cell interactions?
A. Odor information progresses from the olfactory receptor neurons in the nasal epithelia to the olfactory bulb, and then to the piriform cortex in the forebrain. Olfactory responses occur after an odor receptor in the nasal epithelium catches one type of odor molecule. Olfactory receptor neurons connect in a very specific way to sets of neurons in the olfactory bulb. The olfactory bulb is the first place where we can measure the olfactory response of a population of neurons. Neurons in the bulb should be more-or-less odor specific because they receive input from only one type of receptor neuron. Information passes from the bulb to the piriform cortex but the odor-specificity is not maintained. Piriform cortex is where distinct odor pathways combine for the first time to represent complex odor mixtures. The piriform cortex has architecture similar to the hippocampus, with many neurons connecting locally to each other, suggesting local processing and storage. Other areas of the brain get odor messages, but we focus on the transformation of odor information from bulb to piriform and storage of odor mixture representations.
Q. How do you choose which odors to work on?
A. Choosing a specific odor is arbitrary in my work because the olfactory system is set up to encode anything (except that it needs to be detected by our research model).There are others who are more concerned with etiologically important stuff like predator smells. It is typical now in other physiology-related studies on olfaction to use pure odor; individual molecules like anything lemony or piney. These simple odors are usually diluted and presented to the animal subject with in a stream of air. For my research the choice is based somewhat on availability and what has already been used in related studies, and I’m not sure how they were initially chosen from a historical perspective.
Q. Do you consider the strength of an odor?
A. The intensity of odor perception scales with the concentration of odorant. We control concentration by diluting pure odorants in mineral oil. Others use air dilution, mixing the odorant air flow with a larger or smaller portion of neutral air. The point is always to control the number of odor molecules reaching the nose. We can measure relative concentration using a photoionization detector, which blows odorant molecules apart with a UV lamp and detects the tiny voltage changes resulting from the charged remnants bumping into a detector.
“We could drop a chip in the brain and fix the problem”
Q. Why is your research important?
A. A long term goal is understanding memory formation and memory. At a relatively abstract level, this is a good model system for studying spontaneously or automatically acquired memories because the olfactory system has to generate a distinct, stable, long-lasting representation for each ‘odor object’ experience in a lifetime. This contrasts with motivated learning where someone might associate a certain smell with a positive or negative outcome. The idea of automatic generation of a memory draws another parallel to the hippocampus, which is responsible for storing the memories of our everyday experiences. The question is the same in both areas - how do groups of neurons code and store a whole experience made up of distinct parts? The piriform cortex may provide some advantages over the hippocampus as a memory model though because we can more precisely control what is going into the circuit. The hippocampus distills information from all the senses and integrates these with navigation information, such that the best way to study hippocampal networks is to have animals move around and correlate neural signals with movements. With the piriform, since we know it cares almost exclusively about odors we don’t have to account for other senses to the same extent and we can drive the circuit with simple stimuli. That is a long-winded way to say, this is a basic research approach to understanding memory. Memory is obviously important from a quality of life perspective and failures of memory are symptoms in some of our most horrific diseases.
Q. How do you see memory research unfolding?
A. I’m interested in the organization of memories. Right now we often study memory for one item, but there are really chains, sequences, or hierarchies of memory. Also, I remain interested in molecular mechanisms of memory. Given our unprecedented ability to manipulate neural circuits we could ask more about how neurons associate with one another. Studies of activity-dependent plasticity could be done in intact circuits with realistic activity patterns instead of in tissue slices isolated from the rest of the brain.
Q. Are there any potential therapies that are based off of this system?
A. A long long time from now but maybe sooner than you think we can use our knowledge of the neural code to create more and more refined neuronal prostheses. We could drop a chip in the brain and fix the problem (replace the parts that break). People are, for instance, continually refining our understanding of the neural code in the motor cortex and using this to develop technologies to be used by paraplegics or those who have lost limbs. This is the probably the most fully-realized version of a neural prosthesis but others, like Ted Berger’s lab and collaborators are working on a hippocampus replacement by studying the transform function between hippocampus inputs and outputs. They can cut connections between brain areas and then replace them with a silicon chip interface and animals can still perform hippocampus dependent tasks.
Keep your nose down and check out Olfaction Part II: The Life where Dr. Bolding discusses the life of a postdoc in science.
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