The Olfactory System

Olfactory System Chemical sensing system with receptor organs in the nasal passages Receptors synapse directly into the brain; heavy connections with the limbic system Different from other sensory systems in many ways

Olfactory System: Peripheral Structure Olfactory receptors are located on the olfactory (or nasal) epithelium. The epithelium hangs down from the roof of the nasal sinus. The epithelium contains olfactory receptor cells and supporting cells. Dendrites of olfactory receptor cells extend into the mucus coating of the epithelium; odorant molecules bind to receptors on the dendrites. Axons of the olfactory receptor cells enter the brain and synapse on cells in the olfactory bulb. BRAIN SINUS

Olfactory sensory neurons There are about 10 million receptors per side in humans

Olfactory sensory neurons No circuitry or synapses in the epithelium; receptors have axons (thin, unmyelinated, slow) which project directly to the brain. Receptors die and are replaced about every 60 days. Stem cell To olfactory bulb

Olfactory receptors use a G-protein coupled transduction mechanism similar to visual receptors

Kinase Adjust sensitivity Olfactory receptors show strong adaptation Mechanisms: 1. Kinase phosphorolation of receptor protein (desensitization to odorant molecules); 2. Adjustment of channel sensitivity to cAMP (up or down depending on odorant concentration)

What exactly do receptors code? How odors are encoded by the olfactory receptors was a long-standing mystery Early olfactory researchers suggested that a small number of receptor types could encode a large number of natural odors, similar to 3 cones coding all perceived colors: The “Prime Odor” theory (7 primes was a popular number) Difficult to determine what those “prime odors” might be and how they would be combined to give the smell of a natural substance

Richard Axel and Linda Buck used molecular techniques to determine the number of different olfactory receptor types. The concept and strategy: 1. SPECIFICITY WOULD BE BASED ON STRUCTURE OF RECEPTOR-G PROTEIN COMPLEX; THEREFORE, IF YOU DETERMINE THE NUMBER OF DIFFERENT RECEPTOR STRUCTURES, YOU KNOW THE NUMBER OF DIFFERENT FUNCTIONAL TYPES, AND THEREFORE THE NUMBER OF DIFFERENT “PRIME ODORS” 2. STRUCTURALLY DIFFERENT RECEPTOR PROTEINS WOULD BE CODED BY DIFFERENT GENES; CLONE, SEQUENCE, CHARACTERIZE GENES EXPRESSED IN THE OLFACTORY EPITHELIUM, LOOK FOR SYSTEMATIC VARIATION ON G-PROTEIN TYPES 3. LOCALIZE THE EXPRESSED GENES BACK TO THE OLFACTORY RECEPTOR CELLS

Result: There are 1000 different genes in 4 families; each codes 7-transmembrane domain G-protein coupled receptor protein that is expressed in olfactory receptors in mice About 350 of these are functional genes in humans; the rest are present as “pseudogenes” Each receptor cell in the epithelium expresses only one receptor gene Therefore, each receptor is best “tuned” to one of 1000 different chemical “types” What these types are is still not clear, nor is how the code gets turned into a “smell”

The olfactory epithelium is “mapped”, but not in a familiar way The 4 gene families are expressed in different zones of the epithelium Within a zone, different receptor types appear to be randomly scattered

Examples of odorant coding; note that relative levels of activation in the different receptors might also be important in coding the odor

A combinatorial code means that receptors can contribute to the perception of very different smells

Output of the olfactory epithelium goes to the Olfactory Bulb: Olfactory bulb is a three layered structure. Mitral cells are the principal neurons of the olfactory bulb.

Olfactory Bulb Circuitry: The glomerulus is the basic processing component of the olfactory bulb Olfactory Bulb Circuitry: Periglomerular cells in the glomerulus and granular cells in the deeper layers mediate local and lateral inhibition

Cells expressing a single type of receptor are widely scattered across the olfactory epithelium. Axons of all these cells converge on a single place (glomerulus) in the olfactory bulb.

All the axons terminating in a glomerulus are from the same type olfactory receptors. Therefore each glomerulus codes one odorant type. Axons from each olfactory receptor type terminate in very few (maybe only 1 or 2) glomeruli at one point in the olfactory bulb.

Axons from 25,000 olfactory receptors STRUCTURE OF THE OLFACTORY GLOMERULUS Dendrites from 25 mitral cells Periglomerular cells form inhibitory connections between glomeruli A glomerulus is a self- contained zone of synaptic interactions. There are about 2000 glomeruli in the olfactory bulb of each side. 10,000,000 RECEPTORS 2,000 GLOMERULI

Olfactory system codes “odors” based on chemical structure of molecules; specificity is for a molecular structural characteristic, not a particular molecule. SCIENCE VOL OCTOBER 1999

Dendrodendritic reciprocal synapses form between PG cells and MT dendritic tufts, and between granular cells and MT basal dendrites. These both result in local dendritic inhibition following excitation of the mitral cells by olfactory nerve inputs. (NOTE: This is in addition to lateral inhibition of neighboring mitral cells.)

Lateral inhibition through periglomerular cells: Looking down on glomerular level; connections form +/- center surround receptive field + _ Oscillations induced through dendrodendritic connections: Mitral EPSP Mitral AP Odorant present

Numerous connections to limbic system areas. Connections to cortical areas do not depend on relay through a thalamic nucleus Olfactory pathways out of the bulb are all uncrossed. The piriform cortex is considered the olfactory sensory cortex.

SCIENCE VOL NOVEMBER 2001 Single glomeruli project to multiple locations in olfactory cortex. Cortical representation of olfactory information

Glomeruli projections overlap in olfactory cortex, and individual cortical neurons receive input from multiple glomeruli (and hence receive input from multiple odorants).

QUESTION: Why remix inputs after you have gone through all the trouble of separating them out so effectively? ANSWER: Olfaction may be based on pattern detection: Cortical neurons are concerned with specific combinations of inputs, with each combination corresponding to a percept.

The Vomeronasal System A second olfactory system is present in most vertebrates. It is separate from the main olfactory system anatomically and functionally.

The vomeronasal organ is separate from the main olfactory epithelium in the nasal cavity

Vomeronasal receptors use a different signal transduction pathway than main olfactory receptors About 100 different receptor types in two gene families; these families are different from the four in which main olfactory receptors are coded Vomeronasal receptors are different from main olfactory receptors

The vomeronasal system is specialized for detecting high molecular weight, relatively nonvolatile chemicals. Its presence is often accompanied by morphological or behavioral specializations for moving such odorants to the vomeronasal epithelium. LOCATION NEAR NARES, OR OPENING INTO MOUTH CAVITY VASCULAR “PUMPS” STEREOTYPED BEHAVIORS: TONGUE FLICKING IN SNAKES “FLEHMEN” RESPONSE IN HORSES

The vomeronasal receptors project to a separate “accessory olfactory bulb” via a separate “accessory olfactory nerve” Organization of the AOB is similar to that of the MOB. Outputs are different: the AOB output target only subcortical limbic areas that connect in turn to the hypothalamus

Accessory Olfactory Bulb Main Olfactory Bulb Vomeronasal OrganMain Olfactory Organ Septal nuclei AmygdalaOlfactory tubercle Olfactory Cortex PHEROMONES PREY ODORS GENERAL ODORS Entorhinal Cortex Hippocampus PARALLEL OLFACTORY PATHWAYS Medial, BNST Cortical Hypothalamus

The vomeronasal system is specialized for detecting and processing biologically important odors, especially chemical communication signals (“pheromones”) Chemical communication is a preeminent social communication channel in most mammals Courtship, sexual behavior, aggression, maternal behavior, kin recognition, pair bonding, territoriality, fear and predator avoidance all involve chemical signaling and are controlled by the reception of chemical signals in most mammals Lesions of the vomeronasal system at various levels interfere with normal social behavior mediated by pheromonal communication

Vomeronasal and Main Olfactory System May Both Participate in Chemical Signaling Depending on Experience In virgin male rodents, lesioning VNO blocks sex with a female; lesioning OE has no effect X X X X NO COPULATION WITH A FEMALE NORMAL COPULATION WITH A FEMALE X X In male rodents with 1 previous sexual experience, lesioning VNO or OE alone has no effect; both must be lesioned to block copulation

Is Chemical Communication Important in Humans? Do we have a vomeronasal organ? Probably not (nor do Old World primates generally) – but does that mean anything? What can we recognize by odor alone? The “t-shirt” experiments Can odors affect reproductive function? The menstrual synchrony experiments If human pheromones were controlling our behavior, would we even know it? Look where accessory olfactory information is sent in the brain – it’s all subcortical