Biomedical subjects

Armen Saghatelyan

Publications and source records attributed to Armen Saghatelyan.

10 recordsLinked to original sources

PubMed2006

Delayed onset of odor detection in neonatal mice lacking tenascin-C.

The olfactory bulb is one of the few regions in the adult mammalian forebrain in which neurons are constitutively replaced throughout life. New neurons generated in the subventricular zone migrate long distances along the rostral migratory stream to the olfactory bulb where they differentiate into interneurons. Neuronal precursor generation, migration and incorporation into the bulbar network occur in an environment rich in extracellular matrix molecules. We investigated the potential role of one of the constituents of the extracellular matrix, tenascin-C (TNC), in bulbar neurogenesis and olfactory performance using TNC-deficient mice. We found that TNC deficiency resulted in a delayed onset of olfactory responses in neonatal animals. This delay normalized at around postnatal day 10. Interestingly, this delay in early olfactory performance was not due to impaired bulbar neurogenesis as proliferation, migration, incorporation and fate determination of newborn bulbar interneurons were normal in TNC-deficient animals. Thus, we conclude that a constitutive lack of TNC does not affect bulbar neurogenesis, but instead leads to ontogenetically early impairments in olfactory detection.

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PubMed2005

Neonatal and adult neurogenesis provide two distinct populations of newborn neurons to the mouse olfactory bulb.

In mammals, the olfactory bulb (OB) constitutes one of two regions of the postnatal brain with continuous neurogenesis throughout life. Despite intense explorations of neuronal replacement in the adult OB, little is known about the mechanisms that operate at earlier postnatal stages. This question is particularly pertinent, because the majority of local interneurons are born in the neonate, when olfaction controls vital functions. Here, we analyzed the recruitment of newborn cells to the granule cell (GC) layer (GCL) and found that the postnatal mouse OB is supplied with two spatiotemporally distinct populations of newborn interneurons. Early born [postnatal day 3 (P3) to P7] GCs constitute a threefold larger population compared with those generated later (P14-P60), and some of them are produced locally within the OB itself. Newborn interneurons generated at P3-P7 were predominantly targeted to the external edge of the GCL, whereas newly generated cells were positioned deeper in older mice. Additionally, although approximately 50% of adult newborn cells were eliminated within a few weeks of reaching the OB, almost the entire population of early born GCs survived until adulthood. Importantly, early olfactory experience specifically modifies the number of newborn GCs in neonates but leaves unaltered the amount of neurons generated during adulthood. Together, these results demonstrate that early postnatal neurogenesis endows the neonate bulbar circuit with newborn GCs that differ morphologically and functionally from those produced in the adult.

Age Factors↗

PubMed2005

Activity-dependent adjustments of the inhibitory network in the olfactory bulb following early postnatal deprivation.

The first-order sensory relay for olfactory processing, the main olfactory bulb (MOB), retains the ability to acquire new interneurons throughout life. It is therefore a particularly appropriate region for studying the role of experience in sculpting neuronal networks. We found that nostril closure decreased the number of newborn granule cells in the MOB, the complexity of their dendritic arborization, and their spine density, without affecting the preexisting population of granule cells. Accordingly, the frequency of miniature synaptic inhibitory events received by mitral cells was reduced. However, due to a compensatory increase in newborn granule cell excitability, action potential-dependent GABA release was dramatically enhanced, thus counteracting the reduction in spine density and leading to an unaltered synchronization of mitral cell firing activity. Together, this study reveals a unique form of adaptive response brought about exclusively by the cohort of newborn cells and used to maintain normal functioning of the MOB.

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PubMed2005

Integrating new neurons into the adult olfactory bulb: joining the network, life-death decisions, and the effects of sensory experience.

In contrast to the situation in the developing brain, neurons born during adulthood must integrate into established neuronal networks characterized by ongoing activity. For sensory systems, this neuronal activity is driven mainly by external stimuli that can lead to experience-dependent morpho-functional changes in adult circuits. Here, we describe new insights into the mechanisms by which sensory experience might govern the targeting of adult-generated neurons to appropriate regions, their differentiation into distinct neuronal subtypes, and finally their survival in the adult olfactory bulb. We propose not only that neurogenesis depends on the degree of sensory experience, but also that new neurons bring unique features to the operational network, allowing a continuous adjustment of information processing in response to an ever-changing external word.

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PubMed2005

Neuronal fate determinants of adult olfactory bulb neurogenesis.

Adult neurogenesis in mammals is restricted to two small regions, including the olfactory bulb, where GABAergic and dopaminergic interneurons are newly generated throughout the entire lifespan. However, the mechanisms directing them towards a specific neuronal phenotype are not yet understood. Here, we demonstrate the dual role of the transcription factor Pax6 in generating neuronal progenitors and also in directing them towards a dopaminergic periglomerular phenotype in adult mice. We present further evidence that dopaminergic periglomerular neurons originate in a distinct niche, the rostral migratory stream, and are fewer derived from precursors in the zone lining the ventricle. This regionalization of the adult precursor cells is further supported by the restricted expression of the transcription factor Olig2, which specifies transit-amplifying precursor fate and opposes the neurogenic role of Pax6. Together, these data explain both extrinsic and intrinsic mechanisms controlling neuronal identity in adult neurogenesis.

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PubMed2004

Nicotinic receptors regulate the survival of newborn neurons in the adult olfactory bulb.

Cholinergic axons and nicotinic receptors are abundant in all layers of the olfactory bulb (OB), the main region of newborn neuron integration in the adult brain. Here, we report that the OB granule cell layer in mice lacking the predominant form of brain high-affinity nicotinic acetylcholine receptors (beta(2)(-/-) mice) displayed nearly 50% more newborn neurons and significantly fewer apoptotic cells than did beta(2)(+/+) mice. Conversely, in vivo chronic nicotine exposure significantly decreased the number of newborn granule cells in beta(2)(+/+) but not beta(2)(-/-) adult mice, confirming that the survival of newborn neurons can be controlled by the activation of beta(2)-containing nicotinic acetylcholine receptors. Unexpectedly, investigating the behavioral consequence of an increased number of granule cells in beta(2)(-/-) mice revealed that these animals have a less robust short-term olfactory memory than their wild-type counterparts. Taken together, these results provide evidence that high-affinity nicotinic receptors are involved in the maturation of adult OB local circuits. They also indicate that an increase in the number of granule cells does not necessarily correlate with better olfactory performance and further highlight the importance of cholinergic afferents for olfactory processing.

Aging↗

PubMed2004

Tenascin-R mediates activity-dependent recruitment of neuroblasts in the adult mouse forebrain.

Neuroblasts arising in the adult forebrain that travel to the olfactory bulb use two modes of migration: tangentially, along the rostral migratory stream, and radially, in the core of the olfactory bulb where they start to ascend to the outer layers. Although the mechanisms of tangential migration have been extensively studied, the factors controlling radial migration remain unexplored. Here we report that the extracellular matrix glycoprotein tenascin-R, expressed in the adult mouse olfactory bulb, initiates both the detachment of neuroblasts from chains and their radial migration. Expression of tenascin-R is activity dependent, as it is markedly reduced by odor deprivation. Furthermore, grafting of tenascin-R-transfected cells into non-neurogenic regions reroutes migrating neuroblasts toward these regions. The identification of an extracellular microenvironment capable of directing migrating neuroblasts provides insights into the mechanisms regulating radial migration in the adult olfactory bulb and offers promising therapeutic venues for brain repair.

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PubMed2004

Inhibitory interneurons in the olfactory bulb: from development to function.

Identifying and defining the characteristic features of the inhibitory neurons in the nervous system has become essential for achieving a cellular understanding of complex brain activities. For this, the olfactory bulb is ideally suited because it is readily accessible, it is a laminated structure where local interneurons can be easily distinguished from projecting neurons, and, more important, GABAergic interneurons are continuously replaced. How the newly generated neurons integrate into a preexisting neural network and how basic network functions are maintained when a large percentage of neurons are subjected to continuous renewal are important questions that have recently received new insights. Here, it is seen that the production of bulbar interneurons is specifically adapted to experience-dependent regulation of adult neural networks. In particular, the authors report the degree of sensitivity of the bulbar neurogenesis to the activity level of sensory inputs and, in turn, how the adult neurogenesis adjusts the neural network functioning to optimize information processing. By maintaining a constitutive neurogenesis sensitive to environmental cues, this neuronal recruitment leads to improving sensory abilities. This review brings together recently described properties and emerging principles of interneuron functions that may convey, into bulbar neuronal networks, a degree of circuit adaptation unmatched by synaptic plasticity alone.

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PubMed2002

Mice deficient for the HNK-1 sulfotransferase show alterations in synaptic efficacy and spatial learning and memory.

The HNK-1 carbohydrate structure, a sulfated glucuronyl-lactosaminyl residue carried by many neural recognition molecules, is involved in cell interactions during ontogenetic development and in synaptic plasticity in the adult. To characterize the functional role of the HNK-1 carbohydrate in vivo, we have generated mice deficient for the HNK-1 sulfotransferase (ST). The ST-/- allele is inherited with Mendelian frequencies, and the ST-/- mice are viable and fertile. The anatomy of all major brain areas appeared histologically normal. However, basal synaptic transmission in pyramidal cells in the CA1 region of the hippocampus was increased and long-term potentiation evoked by theta-burst stimulation was reduced in ST mutants. In the water maze, ST-/- mice showed an impaired long-term memory and a poorer spatial learning when a short inter-trial interval was used. These observations indicate an essential role for the sulfate group of the HNK-1 carbohydrate in synaptic plasticity of the hippocampus.

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PubMedDate not supplied

Local neurons play key roles in the mammalian olfactory bulb.

Over the past few decades, research exploring how the brain perceives, discriminates, and recognizes odorant molecules has received a growing interest. Today, olfaction is no longer considered a matter of poetry. Chemical senses entered the biological era when an increasing number of scientists started to elucidate the early stages of the olfactory pathway. A combination of genetic, biochemical, cellular, electrophysiological and behavioral methods has provided a picture of how odor information is processed in the olfactory system as it moves from the periphery to higher areas of the brain. Our group is exploring the physiology of the main olfactory bulb, the first processing relay in the mammalian brain. From different electrophysiological approaches, we are attempting to understand the cellular rules that contribute to the synaptic transmission and plasticity at this central relay. How olfactory sensory inputs, originating from the olfactory epithelium located in the nasal cavity, are encoded in the main olfactory bulb remains a crucial question for understanding odor processing. More importantly, the persistence of a high level of neurogenesis continuously supplying the adult olfactory bulb with newborn local neurons provides an attractive model to investigate how basic olfactory functions are maintained when a large proportion of local neurons are continuously renewed. For this purpose, we summarize the current ideas concerning the molecular mechanisms and organizational strategies used by the olfactory system to encode and process information in the main olfactory bulb. We discuss the degree of sensitivity of the bulbar neuronal network activity to the persistence of this high level of neurogenesis that is modulated by sensory experience. Finally, it is worth mentioning that analyzing the molecular mechanisms and organizational strategies used by the olfactory system to transduce, encode, and process odorant information in the olfactory bulb should aid in understanding the general neural mechanisms involved in both sensory perception and memory. Due to space constraints, this review focuses exclusively on the olfactory systems of vertebrates and primarily those of mammals.

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