Functional Anatomy of the Olfactory System II: Central Relays, Pathways, and their Function
Introduction
The first steps of central olfactory processing are accomplished in phylogenetically old brain structures located in the basal forebrain and medial temporal lobe, which are activated simultaneously or consecutively. Higher order olfactory processes, including conscious olfactory perception, convergence, lateral inhibition, adaptation/habituation, and central integration of olfactory inputs with other sensory stimuli (e.g., gustatory, trigeminal, mechanosensory, auditory, and visual afferents), are mediated in the mentioned brain structures as well as in neocortical areas that are not specific for olfactory processing. Collectively, these processes enable an individual to create adequate reaction patterns to a changing external environment.
This chapter aims to provide insights into the anatomical brain structures involved in olfactory processing. Most canonical features of the central olfactory anatomy were studied in animals in a laboratory setting; data derived from observations in humans are mentioned when necessary. Moreover, the authors intend to link the respective functionality of a brain area to its anatomical features.
Key Hypotheses of Central Olfactory Processing
In contrast to other ascending sensory systems, olfactory fibers project directly to the telencephalon, mainly without a thalamic relay. Thus, incoming olfactory information is not filtered and monitored in the thalamus before entering neocortical areas.
The main central gate for olfactory inputs is the olfactory bulb, in which the first topical map for odor representation is generated.
The olfactory system is organized in an anatomically unilateral manner. Very few, if any, canonical olfactory fibers use commissural tracts to enter contralateral brain areas.
Evidence of olfactory lateralization (i.e., representation of specific olfactory tasks within one hemisphere) is provided.
Outline of Olfactory Pathways
Olfactory pathways subdivide into bulbofugal fibers originating in the olfactory bulb (OB) and terminating in cortical areas and corticofugal fibers in reversed orientation (arising in the cortex and projecting to the OB). The latter probably mediate top-down modulation of olfactory perception at an early processing level.
Bulbofugal Fibers
Axons of olfactory receptor neurons (ORNs) collect into ~20 bundles, the olfactory fila, which pass through 1- to 2-mm-wide holes in the cribriform plate and connect to mitral/tufted cells in the OB. Collectively, these projections make up the olfactory nerve (cranial nerve I). Axons of mitral/tufted cells form the olfactory tract. The fact that the olfactory tract divides into a medial, an intermedial, and a lateral portion, or stria, has been derived from animal observation and cannot be found in humans.1 Therefore, in humans, the lateral olfactory tract (LOT) is considered the only projection from the OB terminating in a set of structures. The commonly used terminology, primary/secondary/tertiary olfactory cortex, for projection areas from the OB is somewhat misleading, as the OB already comprises typical cortical layers and accomplishes functional processes comparable to those of primary cortices in other modalities.2 Therefore, in our opinion, the OB should be considered a primary olfactory structure. The target areas of the bulbar mitral/tufted cells as secondary olfactory structures are the anterior olfactory nucleus (AON), piriform cortex (pirC), medial nuclei of the amygdala, periamygdaloid cortex, and the entorhinal cortex ( Figs. 3.1 and 3.2 ). The entorhinal cortex occupies the anterior part of the parahippocampal gyrus (Brodmann area 28), and probably targets an area underlying the anterior perforated substance, namely the ventral striatum, especially its major structure, the nucleus accumbens.3 The entities of those areas are commonly named “olfactory cortex.”
Fiber connections from the above-mentioned structures project to associated neocortical areas, tertiary olfactory structures, which are not exclusively specific olfactory areas: the orbitofrontal gyri and, in close proximity, the anterior insula, which is reached either directly or through a relay in the dorsomedial thalamic nucleus.4 A series of either diencephalic or telencephalic structures is reached from the amygdala or entorhinal cortices, for example, septal nuclei, bed nucleus of stria terminalis (BNST) in the hypothalamus, and hippocampal formation.
Furthermore, a subset of mitral cell collaterals project from the anterior olfactory nucleus to the contralateral olfactory bulb using the anterior commissure.
The entity of the olfactory fila in the olfactory epithelium in the upper nose is termed the nervus olfactorius or first cranial nerve.
Corticofugal Fibers
Though not entirely established in humans, animal data provide evidence for several glutamatergic, adrenergic, cholinergic, and serotonergic projections terminating in the AON and OB. They are believed to partly take the same route as the “medial olfactory tract (stria)” in animals, although its existence in humans has been questioned (see above). The functional significance of corticofugal fibers has not been investigated yet; however, they are assumed to mediate top-down modulation of olfactory information, such as olfactory learning or memory.5
Cortical Olfactory Areas and their Function
The First Olfactory Processing Relay: Olfactory Bulb
The OB is the first relay for incoming ORNs and is responsible for a condensation and amplification of olfactory information. It is located bilaterally upon the cribriform plate and is surrounded by the subarachnoid space filled with cerebrospinal fluid. In humans, its size varies considerably (ranging from 0.5 to 1.5 mm; Fig. 3.3 ) depending on individual olfactory performance.6,7 As an extension of the prosencephalon, the OB presents a laminar structure that is similar to the laminar structure of cortical areas ( Fig. 3.4 ). Occasionally, a vesicle may be preserved as a developmental relict.8,9
Cell Layers
As mentioned above, the OB shows a cortical lamination. It mainly consists of the olfactory nerve layer, the glomerular layer, the internal plexiform layer, the mitral/tufted cell layer, the external plexiform layer, and the granule cell layer ( Fig. 3.4 ). ORNs assemble on the OB′s surface and immerse in easily detectable spherical structures, glomeruli, in which they connect with dendrites of mitral cells. Glomeruli are surrounded by two major groups of inhibitory interneurons, periglomerular cells and short axon (SA) cells, which are responsible for fine tuning olfactory information mediated through mitral cells. The deepest cortex layer consists of columnar arrangements of another cell type—granular cells—derived from precursor neurons that migrate from the rostral migratory stream and the subventricular zone. The regenerative capacity of those interneurons is extraordinarily high. Genetic tracer studies suggest the arrival of ~30,000 new neurons per day in the OB.10 However, only a subset of these neurons climbs up to convert to the interneurons mentioned above.11 Both kinds of OB interneurons are also target neurons for inhibitory projections from the contralateral anterior olfactory nucleus through the anterior portion of the anterior commissure.
Convergence
From rodent studies it is known that several olfactory neurons expressing the same receptor converge onto two glomeruli. In consequence, a given odorant elicits a characteristic spatial pattern of glomerular activities,12,13 initiating an odor-specific activation pattern already at the OB level. Odor-related spatial positions are conserved across different individuals of the same species. However, this topographic organization has not yet been demonstrated in neocortical brain areas.
Processes of GABAergic periglomerular cells project to a single glomerulus for intraglomerular processing, whereas GABA- and dopaminergic SA cells extend to multiple glomeruli, thus providing interglomerular crosstalk.14 Local circuits among large projection neurons (mitral/tufted cells) and small OB interneurons mediate lateral inhibition among glomerular units to enhance contrast related to odor information that is forwarded to higher order olfactory structures.2
The olfactory bulb is the first relay for incoming olfactory information. Lateral inhibition and convergence at the level of the olfactory bulb seem to be important for contrasting different olfactory perceptions against each other.
What is Special about the Human Olfactory Bulb?
Compared with laboratory animals, the volume of the human OB is much smaller relative to total brain size ( Figs. 3.3 and 3.5 ). Furthermore, data obtained from 42 human autopsies (mean age 77 years) revealed a remarkable interindividual variability in OB size (mean: 83 µL; range: 50 to 142 µL).8 As mentioned above, magnetic resonance imaging (MRI) studies revealed a strong correlation between OB size and olfactory performance.6 However, precise information on wiring, presorting of individual ORNs in the periphery, and receptor-specific glomerular unit organization has not yet been determined in humans.
Besides this, the number of glomeruli in the human OB is considerably higher than animal models would predict. Animal studies provide evidence that ORNs expressing one particular receptor project to only two receptor-specific glomeruli. This 2:1 model (two glomeruli per receptor) assumes that if 1,000 functional receptor genes exist (as in mice), there are 2,000 glomeruli per OB.15 In humans, however, who have only ~340 to 400 functional receptor genes,16,17 one might predict 680 to 800 glomeruli, which is clearly contradicted by histomorphological estimations ranging from 2,975 to 9,325 glomeruli per human OB.18,19 Thus the 2:1 ratio originating from other mammals is greater by a factor of eight (16:1) in humans. These results suggest that the convergence described for rodents or other mammals might be distinct from that in humans, pointing to a fundamental difference in human OB organization.19
Projection Targets of Mitral Cells in the Olfactory Bulb (“Secondary Olfactory Structures”)
Anterior olfactory nucleus
Anterior perforated substance and underlying ventral striatum (nucleus accumbens)
Piriform cortex
Periamygdalar cortex/medial amygdala
Entorhinal cortex
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