P&S Journal: Spring 1995, Vol.15, No.2
Research & Reports
How Does the Brain Smell?
Whether a scent emanates from a floral bouquet, the beach, or fresh-ground coffee, its essence envelops us. Odors penetrate consciousness almost against reason. Smell by its nature is primal. Our nose, a direct conduit from the environment to our brain, communicates the pleasurable and offensive sensations of smells that conjure up emotions, thought, and memories.
What structure has the brain evolved to distinguish between the smell of a rose and the smell of cologne? Why do humans as a species distinguish 10,000 or so aromas? How does what happens in the sensory olfactory neurons deep in the nose get read by the higher cortex to evoke images and feelings?
Dr. Richard Axel, the Eugene Higgins Professor of Pathology and Biochemistry and Molecular Biophysics and Howard Hughes Medical Institute investigator, set out to answer these questions a few years ago. In April 1991, Dr. Axel and his research team reported in Cell the cloning of about 1,000 genes for odor receptors, cell surface molecules on neurons in the nose that could theoretically bind everything from jasmine to turpentine.
This gene family of transmembrane receptors represents the largest percentage of the genome dedicated to a single physiological function. "We use one in 100 of our genes to recognize smells," says Dr. Axel. Although the very number of genes dedicated to odor receptors partially explains how humans recognize a multitude of odors, it is not the whole picture. For the past few years, Dr. Axel and his laboratory have begun to understand how mammalian neurons situated in the nose bind aromas and how that event gets translated by the brain as odor.
Inside the nose, behind the bridge, olfactory neuron cell bodies with receptors bind odorants. Their axons synapse in the olfactory bulb, a region in the brain. Initially, Dr. Axel found that each of the 10 million neurons in the nose expresses only a single one of the thousand possible receptors. So discrimination among odorants requires the brain to determine which of the numerous receptors have been activated.
But Dr. Axel asked how the brain uses the space occupied by olfactory neurons to read the sensory information contained in an odor. In the Dec. 16, 1994, issue of Cell, he reported that neurons of a certain class, i.e., containing a unique receptor, are randomly spread out in the nose and their axons segregate to one or a few distinct points, known as glomeruli, in a lower brain region called the olfactory bulb. Then, in a way still unknown, higher parts of the brain, or the cortex, read the spatial map made by the activated glomeruli. Before Dr. Axel's studies, research showed a given odorant could stimulate a few glomeruli. But, the topological connections between the neurons in the nose and the olfactory bulb were unknown until now.
In other words, when an odorant, say the essence of a rose, enters the nose it confronts the cell body dendrites of some 10 million sensory neurons. Rose odorant molecules bind to receptors on a few different classes of neurons, which are essentially randomly located in the nose, according to these findings. The binding of rose essence alters the electrical properties of these neurons down their axons, which extend to the olfactory bulb. The axons from these activated neurons synapse to a few glomeruli in the olfactory bulb. (About 1,000 distinct glomeruli exist, since each receptor maps to one glomerulus.) The synapsing of the activated axons at these glomeruli is then spatially read by higher brain centers.
"This organization creates a two-dimensional map of receptor activation for the brain," says Dr. Axel. "Rose may activate glomeruli A, B, and G, for example, while jasmine does F, N, and Q." Moreover, the brain can identify thousands of odors through this combinatorial design.
To find this convergence of the olfactory axons on a few glomeruli, Dr. Axel's laboratory exploited in situ hybridization of messenger RNA of a given receptor in the axons of olfactory neurons. He reasoned that if neurons expressing a given receptor synapsed on a single glomerulus and if receptor mRNA is infrequently found in the axon of a given neuron, the convergence of axons should permit detection by in situ hybridization. (Receptors are found mainly in the neuronal cell bodies in the nose.) Using DNA probes from the genes for receptors identified in 1991, the lab found that neurons expressing a given receptor project their axons to one or a small number of discrete glomeruli in the olfactory bulb.
Dr. Axel and his laboratory now are trying to understand how many and which receptors are activated by a given odorant, how a given neuron knows to make only one receptor, how the neuron knows where to go in the olfactory bulb during development and in the natural turnover of olfactory neurons, and how the higher cortex reads the map on the surface of the olfactory bulb. Dr. Axel says, "This ability of the higher cortex to read and translate a sensory map into appropriate thought and behavior is the central problem in neurobiology and even psychology."