Neural regeneration and the peripheral olfactory system

Little is known about how normal aging affects the brain. Recent evidence suggests that neuronal loss is not ubiquitous in aging neocortex. Instead, subtle and still controversial, region-and layerspecific alterations of neuron morphology and synapses are reported during aging, leading to the notion that discrete changes in neural circuitry may underlie age-related cognitive deficits. Although deficits in sensory function suggest that primary sensory cortices are affected by aging, our understanding of the age-related cellular and molecular changes is sparse. To assess the effect of aging on the organization of olfactory bulb (OB) circuitry, we carried out quantitative morphometric analyses in the mouse OB at 2, 6, 12, 18, and 24 mo. Our data establish that the volumes of the major OB layers do not change during aging. Parallel to this, we are unique in demonstrating that the stereotypic glomerular convergence of M72-GFP OSN axons in the OB is preserved during aging. We then provide unique evidence of the stability of projection neurons and interneurons subpopulations in the aging mouse OB, arguing against the notion of an age-dependent widespread loss of neurons. Finally, we show ultrastructurally a significant layer-specific loss of synapses; synaptic density is reduced in the glomerular layer but not the external plexiform layer, leading to an imbalance in OB circuitry. These results suggest that reduction of afferent synaptic input and local modulatory circuit synapses in OB glomeruli may contribute to specific age-related alterations of the olfactory function.aging | axodendritic synapses | dendrodendritic synapses | mitral cells A ge-related neurodegenerative diseases, such as Parkinson and Alzheimer's, involve localized or widespread neuronal loss, but little is known about the changes occurring in the brain during normal aging. A growing consensus argues against widespread neuronal loss and atrophy during aging (1, 2). Rather, subtle region-and layer-specific alterations of neuronal morphology and synaptic connections are reported in the neocortex and hippocampus, where they may contribute to age-related cognitive deficits.The laminar organization of olfactory bulb (OB) neurons and synapses provides a simplified cortical model in which we can probe principles of neuronal and synaptic organization during aging. Sensory functions are affected by aging, including alterations in olfactory acuity, discrimination, and memory (3-12). The OB is the first central relay in the pathway processing odor information: it receives afferent input from olfactory sensory neurons (OSNs) located in the olfactory epithelium (OE) and is responsible for detecting odors in the nasal cavity. OSN axons synapse on mitral/tufted cell dendrites in OB glomerular neuropils. OB local interneurons modulate the activity of mitral/tufted cells, contributing to odor signal integration, before propagation to the piriform cortex. Projections from the OE to the OB are organized in an odor receptor (OR) map; each subpopulation of OSNs expressin...

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“…Adult neurogenesis occurs in both the OE and OB (28,29,35). In the OE, progenitors give rise to new OSNs that send an axon to the OB.…”

Section: Discussionmentioning

confidence: 99%

Age-induced disruption of selective olfactory bulb synaptic circuits

Richard

Taylor²,

Greer³

2010

Proc. Natl. Acad. Sci. U.S.A.

121

125

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“…On the one hand, that capacity underlies the ability of the system to recover anatomically after injury, as documented previously in numerous studies by numerous investigators (for review, see Graziadei and Monti Graziadei, 1985;Costanzo, 1991;Schwob, 2002). For example, passive inhalation of the selective olfactotoxin methyl bromide (MeBr) destroys olfactory sensory neurons (OSNs) and sustentacular cells in Ͼ95% of the olfactory epithelium (OE) (Hurtt et al, 1987(Hurtt et al, , 1988Schwob et al, 1995Schwob et al, , 1999.…”

Section: Introductionmentioning

confidence: 91%

“…Previous research has defined the presence of a sharp boundary between the dorsomedial epithelium and the ventrolateral epithelium via the expression of the Ig superfamily member olfactory cell adhesion molecule/mammalian homolog 6 fasciclin II (OCAM/mamFas II) or anonymous antigens such as that recognized by the monoclonal antibody CC2 (Schwob andGottlieb, 1986, 1988;Schwarting and Crandall, 1991;Miyawaki et al, 1996;Yoshihara et al, 1997;Norlin et al, 2001). Our results do not contradict the existence of a boundary delimited by differential expression of these markers; however, we do find that the some of Figure 10.…”

Section: Or-positive Osn Distribution Patterns In Normal Oementioning

confidence: 99%

Odorant Receptor Expression Patterns Are Restored in Lesion-Recovered Rat Olfactory Epithelium

Iwema¹,

Fang²,

Kurtz³

et al. 2004

J. Neurosci.

133

112

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Lesions of the olfactory periphery provide a means for examining the reconstitution of a diverse and highly regulated population of sensory neurons and the growth, en masse, of nascent axons to the bulb. The olfactory epithelium and its projection onto the bulb are reconstituted after ablation by methyl bromide gas, and some measure of olfactory function is restored. The extent to which the system regenerates the full repertoire of odorant receptor-expressing neurons, particularly their spatially restricted distribution across the epithelial sheet, is unknown, however, and altered odorant receptor expression might contribute to the persistent distortion of odorant quality that is observed in the lesioned-recovered animals. To address the question of receptor expression in the recovered epithelium, we performed in situ hybridization with digoxigenin-labeled riboprobes for eight odorant receptors on the olfactory epithelium from unilaterally methyl bromide-lesioned and control rats. The data demonstrate that the distribution of sensory neuron types, as identified and defined by odorant receptor expression, is restored to normal or nearly so by 3 months after lesion. Likewise, the numbers of probe-labeled neurons in the lesioned-recovered epithelium are nearly equivalent to the unlesioned side at this time. Finally, our evidence suggests that odorant receptors are distributed in multiple overlapping bands in the normal, unlesioned, and lesioned-recovered epithelium rather than in the conventionally accepted three or four zones. Thus, the primary sensory elements required for functional recovery of the olfactory system after damage are restored, and altered function implies the persistence of a more central failure in regeneration.

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“…The age-related decrease in the number of labeled basal cells have been attributed to a number of factors including age-related decrease in the concentration of growth-associated factors (Weiler and Farbman, 1998), longer cell cycle time in older animals Farbman, 1997, 1998), and greater rate of expansion of the olfactory area in the younger than in the older animals (Weiler and Farbman, 1997). In the basal region of the OE, multipotent basal cell progenitors give rise to immature neuronal and supporting cells that migrate with the passage of time to take defined positions in the apical region of the epithelium (Graziadei and Graziadei, 1979; Williams, 1995;Schwob, 2002). This apical migration of maturing neuronal cells has actually made it possible to determine the neuronal age by position (Graziadei and Monti-Graziadei, 1979;Farbman and Margolis, 1980).…”

Section: Postnatal Morphology Of Olfactory Mucosa In Rabbitsmentioning

confidence: 99%

Morphofunctional Adaptations of the Olfactory Mucosa in Postnatally Developing Rabbits

Kavoi

Makanya

Plendl

et al. 2012

The Anatomical Record

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Rabbits are born blind and deaf and receive unusually limited maternal care. Consequently, their suckling young heavily rely on the olfactory cue for nipple attachment. However, the postnatal morphofunctional adaptations of olfactory mucosa (OM) are not fully elucidated. To clarify on the extent and the pattern of refinement of the OM following birth in the rabbit, morphologic and morphometric analysis of the mucosa were done at neonatal (0-1 days), suckling (2 weeks), weanling (4 weeks), and adult (6-8 months) stages of postnatal development. In all the age groups, the basic components of the OM were present. However, proliferative activity of cells of the mucosal epithelium decreased with increasing age as revealed by Ki-67 immunostaining. Diameters of axon bundles, packing densities of olfactory cells, and cilia numbers per olfactory cell knob increased progressively with age being 5.5, 2.1, and 2.6 times, respectively, in the adult as compared with the neonate. Volume fraction values for the bundles increased by 5.3% from birth to suckling age and by 7.4% from weaning to adulthood and the bundle cores were infiltrated with blood capillaries in all ages except in the adult where such vessels were lacking. The pattern of cilia projection from olfactory cell knobs also showed age-related variations, that is, arose as a tuft from the tips of the knobs in neonates and sucklings and in a radial pattern from the knob bases in weanlings and adults. These morphological changes may be attributed to the high olfactory functional demand associated with postnatal development in the rabbit.

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Neural regeneration and the peripheral olfactory system

Cited by 452 publications

References 159 publications

Age-induced disruption of selective olfactory bulb synaptic circuits

Age-induced disruption of selective olfactory bulb synaptic circuits

Odorant Receptor Expression Patterns Are Restored in Lesion-Recovered Rat Olfactory Epithelium

Morphofunctional Adaptations of the Olfactory Mucosa in Postnatally Developing Rabbits

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