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Adult Neurogenesis in the Olfactory System Shapes Odor Memory and Perception

6

Gilles Gheusi*,{,{, Pierre-Marie Lledo*,{,1 *

Laboratory for Perception and Memory, Department of Neurosciences, Institut Pasteur, Paris, France { Centre National de la Recherche Scientifique (CNRS), Unite´ Mixte de Recherche, Paris, France { LEEC, University of Paris, Villetaneuse, France 1 Corresponding author: Tel.: þ33 (0)1 45 68 88 03; Fax: þ33 (0)1 45 68 83 69, e-mail address: [email protected]

Abstract The olfactory system is a dynamic place. In mammals, not only are sensory neurons located in the sensory organ renewed through adult life, but also its first central relay is reconstructed by continuous neuronal recruitment. Despite these numerous morphological and physiological changes, olfaction is a unique sensory modality endowed with a privileged link to memory. This raises a clear conundrum; how does the olfactory system balance its neuronal turnover with its participation in long-term memory? This review concentrates on the functional aspects of adult neurogenesis, addressing how the integration of late-born neurons participates in olfactory perception and memory. After outlining the properties of adult neurogenesis in the olfactory system, and after describing their regulation by internal and environmental factors, we ask how the process of odorant perception can be influenced by constant neuronal turnover. We then explore the possible functional roles that newborn neurons might have for olfactory memory. Throughout this review, and as we concentrate almost exclusively on mammalian models, we stress the idea that adult neurogenesis is yet another form of plasticity used by the brain to copes with a constantly changing olfactory world.

Keywords neural stem cells, olfaction, odor discrimination, circuits, GABA, interneurons, oscillations

Progress in Brain Research, Volume 208, ISSN 0079-6123, http://dx.doi.org/10.1016/B978-0-444-63350-7.00006-1 © 2014 Elsevier B.V. All rights reserved.

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1 INTRODUCTION In the adult mammal, the vast majority of neuronal circuits found in the central nervous system are established before birth. While dendritic arborization and synaptic connections retain a certain degree of plasticity after birth, in most regions, the ability to produce new neurons ceases. Only two areas of the adult brain are exceptions to this general rule: the subventricular zone of the lateral ventricle and the dentate gyrus of the hippocampus. While adult neurogenesis has been extensively investigated in both these regions, its consequences on circuit function and behavior are highly debated. Adult neurogenesis in the olfactory bulb is thought to modulate early information processing, and is possibly involved in olfactory-related memory as well (Breton-Provencher and Saghatelyan, 2012; Kelsch et al., 2010; Lazarini and Lledo, 2011; Lepousez et al., 2013; Sahay et al., 2011, Whitman and Greer, 2009). In the hippocampus, adult neurogenesis has been linked to memory formation, pattern discrimination (Aimone et al., 2011; Kheirbek et al., 2012; Marı´n-Burgin and Schinder, 2012; Ming and Song, 2011; Song et al., 2012) and adaptation to the challenges encountered throughout life by the individual (Kemperman, 2012; Wojtowicz, 2012). However, most of these conclusions were established from correlative studies rather than from causal inferences because researchers lacked tools that could specifically manipulate adult-born neurons in vivo. Traditional methods of studying the processes of adult neurogenesis involve electrophysiology, irradiation and chemical ablation of newborn neurons, conditional genetic models and genetically labeling newborn neurons in order to study their migration, differentiation, and integration into mature circuitry, all while correlating these manipulations with behavioral changes (Adam and Mizrahi, 2010, 2011; Bardy et al., 2010; Belluzzi et al., 2003; Belvindrah et al., 2011; Carleton et al., 2003; Katagiri et al., 2011; Kelsch et al., 2008, 2009; Lazarini et al., 2009; Livneh and Mizrahi, 2012; Livneh et al., 2009; Lledo and Saghatelyan, 2005; Panzanelli et al., 2009; Valley et al., 2009, 2013). More recent advances based on developmental biology, imaging, and optogenetics, have made this area of neuroscience a fruitful avenue for deciphering the causal links between neuronal circuit functioning and behaviors (reviewed in Lepousez et al., 2013). Before discussing these new set of evidence, briefly we present the circuit organization of the olfactory bulb.

2 EARLY STAGES IN THE OLFACTORY SYSTEM In mammals, the initial event of odor detection takes place within the sensory neurons that reside in the olfactory epithelium of the nasal cavity located at the posterior end of the nose. After sensory transduction, information flows from the olfactory sensory neurons to the first central relay of the olfactory system, the olfactory bulb. There, thousands of glomeruli positioned in the superficial layer of the olfactory bulb receive the terminals of sensory neuron axons that impinge onto dendrites of several neuronal subtypes, including output neurons (the second-order relay neurons called

2 Early Stages in the Olfactory System

mitral and tufted cells) and local interneurons made of periglomerular neurons and short-axon cells (Fig. 1). Upon reaching the olfactory bulb, each sensory neuron axon enters a specific glomerulus and arborizes to form approximately 15 synapses with their target dendrites. About 20–50 output neurons emanate from each glomerulus and project to a number of higher centers, including the olfactory cortex. Axonal projections from the sensory neurons to the olfactory bulb form reproducible patterns of glomeruli in two widely separated regions of each olfactory bulb, creating two mirror-symmetric maps of odorant receptor projections. Importantly, it has been shown that the identity of odorant receptors expressed by epithelial neurons determines glomerular convergence and function, meaning that the functional organization of the sensory neuron projections to the olfactory bulb is largely specified by the genetics of olfactory receptor expression. There is no strict spatial relationship between the arrangement of olfactory sensory neuron projections to the olfactory bulb and the regions of mucosa from which they originate. This feature contrasts dramatically with the spatial organization of other sensory systems where afferent inputs are organized in a rather precise topographical mode. Similarly, as described below, much evidence indicates that olfactory bulb outputs do not have point-to-point topographical projections to their target structures (Murthy, 2011), which are characteristic of other sensory systems. In mammals, the convergence ratio of sensory neurons-to-olfactory bulb output neurons is very large: about 1000:1. A bulbar output neuron thus forms its response to odorants from very large number of converging inputs, enabling postsynaptic averaging to increase the signal-to-noise ratio. To achieve this performance, target finding of receptor neuron axons uses several mechanisms: large-scale arrangement is accomplished by two chemotopic gradients, and small-scale refinement has been reported to depend on the degree of sensory experience (Mori and Sakano, 2011). Because of its relatively simple anatomical organization and easy accessibility, the olfactory bulb has been a favored model system for investigating neural processing of sensory information. The main output neurons of the olfactory bulb, the socalled mitral and tufted cells (hereafter collectively called mitral cells), are located in a single lamina (Fig. 1). In mammals, their primary and apical dendrite, extending vertically from its soma, contacts one glomerulus, where massive interactions with interneurons and olfactory nerve terminals take place. Most of the local interneurons have dendrites restricted to one glomerulus and impinge onto olfactory nerve terminals or mitral cell primary dendrites. This local interneuron population found near glomeruli is composed of periglomerular neurons and short-axon cells. In contrast to the primary dendrite, mitral cell secondary and basal dendrites radiate horizontally, up to 1000 mm, to span almost the entire circumference of the olfactory bulb (Mori et al., 1983; Orona et al., 1984). In the external plexiform layer, the mitral/ tufted cell secondary dendrites interact with inhibitory axonless interneurons, the granule cells, the most numerous cellular population of the olfactory bulb (e.g., granule cells greatly outnumber output mitral/tufted cells by at least two orders). Both sensory inputs and the intrabulbar circuit mediated by output mitral/tufted cells are excitatory and mediated by glutamatergic signaling. These excitatory events

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FIGURE 1 (Left) Detailed of a cresyl-violet stained coronal section of the main olfactory bulb, showing the layer organisation. (Right) Olfactory sensory neurons in the olfactory epithelium project their axons (white) to one of the glomeruli that form the glomerular layer (GL). In the GL, sensory neuron terminals synapse onto the apical dendrites of glutamatergic projection neurons, namely the mitral cells (MC) and the tufted cells (TC; glutamatergic cells are depicted in orange). In addition, GABAergic periglomerular cells (PGC; GABAergic cells are depicted in blue), glutamatergic superficial short-axon cells (sSAC), and glutamatergic external tufted cells (ETC) act on glomerular synaptic transmission. In the external plexiform layer (EPL), the lateral dendrites of mitral and tufted cells interact with the spines of granule cells (GC) and local parvalbumin expressing GABAergic short-axon cells (PV þ SAC) across a dendrodendritic reciprocal synapse. The soma of MC are aligned and delineate the mitral cell layer (MCL), and the soma of tufted cells are scattered in the EPL. GC somas and GABAergic deep short-axon cells (dSAC) compose the granule cell layer (GCL). Adult neurogenesis gives rise to two types of GABAergic interneurons: PGC and GC (labeled abPGC and abGC; green). Centrifugal inputs from neuromodulatory centers (red) and top-down cortical inputs from the olfactory cortex (violet) innervate specific layers of the olfactory bulb, notably adult-born cells. ONL denotes olfactory nerve layer. Bottom inset: in the dendrodendritic reciprocal synapse (bottom, inset), local calcium entry within MC and TC lateral dendrites triggers glutamate release, which activates both AMPA and NMDA receptors on GC spines. This postsynaptic activation can directly increase local calcium concentration in the GC spines. In addition, propagating action potentials can trigger calcium entry via voltage-gated calcium channels (VGCC). This calcium increase triggers GABA release and postsynaptic inhibition of MC dendrites via GABAA receptors.

2 Early Stages in the Olfactory System

originate mainly from two distinct connections: between primary dendrites and periglomerular cells or short-axon cells, and between secondary dendrites and granule cells. The main difference between periglomerular and granule cells is that the former mediate mostly interactions between cells affiliated with the same glomerulus, while granule cells mostly mediate interactions between output neurons projecting to many different glomeruli. The functional consequences of this synaptic organization will be further described. The synaptic mechanisms that play a key role in the olfactory bulb circuits exhibit three special features. First, many bulbar neurons communicate via reciprocal dendrodendritic synapses (Price and Powell, 1970; Rall et al., 1966). The reciprocal circuit provides inhibition that forms the basis for a reliable, spatially localized, recurrent inhibition (Rall et al., 1966). A mitral/tufted cell’s synaptic depolarization driven by the long-lasting excitatory input from the sensory neurons triggers glutamate release by dendrites and thus depolarizes interneuron dendrites and spines. This, in turn, elicits the release of GABA directly back onto output neurons (Isaacson and Strowbridge, 1998; Jahr and Nicoll, 1982; Nowycky et al., 1981; Schoppa et al., 1998). Second, several olfactory bulb neuronal subtypes are known to modulate their own activity through the transmitters that they themselves release (Isaacson, 1999; Smith and Jahr, 2002; Schoppa and Urban, 2003) and transmitter release might occur, in some cell types, through an action potential-independent manner (Isaacson and Strowbridge, 1998; Jahr and Nicoll, 1982; Schoppa et al., 1998). Third, since secondary dendrites have large projection fields and receive massive reciprocal connections with local interneurons, each interneuron may contact the dendrites of numerous output neurons. This indicates that not only do dendrodendritic interactions provide a fast and graded feedback inhibition onto the activated output neurons, but they also offer a unique device for spreading lateral inhibition of output neurons that contact different glomeruli. Consequently, it has been demonstrated that bulbar output neurons connected to different glomerular units, and which respond to a wide range of related odor molecules, also receive inhibitory inputs from neighboring glomerular units via lateral inhibition at dendrodendritic connections. Thus, the propagation of action potentials into the lateral dendrites, and the possible spread of excitation through granule cell dendrites, both contribute to a “spatial” contrast mechanism that sharpens the tuning of output neuron odorant receptive fields. This interglomerular inhibitory network, along with the mitral–granule–mitral inhibitory circuit described above, forms a serial, two-stage inhibitory circuit that could modify the spatiotemporal responses to odors. In this case, information is transmitted not only vertically across the glomerular relay between sensory neurons and output neurons but also horizontally through local interneuron connections that are activated in odorspecific patterns. Both anatomical and functional analyses support the existence of lateral inhibitory mechanisms through which activity in few stimulated output neurons may lead to suppression of other neurons innervating distinct glomeruli. For instance, examination of the responses of individual bulbar neurons to inhalation of aliphatic aldehydes reveals that many individual cells are excited by one subset of these odorants, inhibited by another subset, and unaffected by yet a third subset. Thus, the quality

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of the odor stimulus is first encoded in the olfactory bulb by a specific combination of activated mitral cells that critically depend on GABAergic inhibition. Because of this unique connectivity within the olfactory bulb, a novel perspective has emerged recently that views the long-range projections of secondary dendrites as supporting a nonlinear dynamical system. According to this view, the olfactory bulb transforms stationary input patterns into time-varying output patterns, moving along input-specific trajectories in coding space. Within this framework, the main function of bulbar microcircuits would be to enable odor-specific dynamics that can decorrelate input patterns (Sahay et al., 2011; Wiechert et al., 2010). Such a decorrelative function would distribute clustered input patterns more evenly in coding space, thus optimizing the use of the coding space for discrimination and other olfactory tasks. In other words, since secondary dendrites project to long distances, the olfactory bulb networks aim to reformat combinatorial representations so as to facilitate their readout by downstream olfactory centers. This model is consistent with experiments showing that GABAergic reciprocal inhibition from granule cells contributes to synchronizing output neuron activity. The local inhibitory networks in the olfactory bulb are highly diverse in terms of cellular markers (Batista-Brito et al., 2008), morphology (Kosaka and Kosaka, 2008), and physiology (Tan et al., 2010). Two recent studies investigated the circuit properties of a subset of these populations of olfactory bulb interneurons, the parvalbumin-containing GABAergic neurons. They reported that this category of neurons is a key regulator of gain control in the olfactory system by providing a broad feedback control of the olfactory bulb output neurons (Kato et al., 2013; Miyamichi et al., 2013). This inhibitory function normalizes neural responses to adjust their sensitivity according to task demands, facilitating intensity-invariant information processing in the olfactory system. Taking into account the complex action of local circuit networks, the balance between excitation and inhibition in the olfactory bulb, and thus the interplay between local interneurons and output neurons, may produce a combinatorial device that encodes olfactory information. Two combinatorial encoders of olfactory information should be distinguished. The first consists of the olfactory receptor repertoire expressed by the sensory neuron ensemble that transduces receptor activation patterns into glomerular odor maps using highly reliable synaptic transmission (stimulus space). The secondary encoder lies in the intricate interneuron network that extracts higher order features from the odor stimulus and encodes these features as timing relationships across the firing output neuron ensemble (representation space). This second encoder is subjected to continuous readjustment throughout life by adult neurogenesis.

3 ADULT NEUROGENESIS IN THE OLFACTORY BULB Adult neurogenesis complicates the simple view that considers the olfactory bulb as a mere relay station that connects the sensory organ to the olfactory cortex. Adult-born neurons originate from astrocytes at the edge of the subventricular zone of the

3 Adult Neurogenesis in the Olfactory Bulb

forebrain and migrating through the rostral migratory stream toward the olfactory bulb. As small subset of these neurons mediate intraglomerular and interglomerular connectivity (periglomerular neurons) and utilize both GABA and dopamine to mediate their inhibitory function. The second population which makes up approximately 90% of adult-born neurons in the olfactory bulb is called granule cells, which all use GABA as a neurotransmitter. Granule cells form dendrodendritic synapses onto the large lateral dendrites of mitral cells and inhibit mitral cell activity when activated. In sum, the intrabulbar circuit includes two categories of inhibitory interneurons that together actively process odor information and are continuously regenerated. While periglomerular neurons regulate sensory input patterns in this first central relay, granule cells provide a variety of inhibitory functions (i.e., graded, recurrent, lateral, and feedforward) that are necessary for complex olfactory network dynamics. Finally, a small number of adult-born neurons turn into short-axon cells (Yang, 2008), whose contribution to olfactory circuit function is unclear. Nevertheless, due to recent technical improvements, today we have a clear quantitative and qualitative picture of adult neurogenesis. Adult-born neurons in the nervous system have been mostly studied by introducing cell-specific labels. In the developing nervous system which is comprised entirely of newborn cells, lineage tracing using genetic markers such as transcription factors, has been a successful way to label and study developing neurons (Sur and Rubenstein, 2005). In the adult olfactory bulb, however, newborn neurons are much less common and several methods taking advantage of this fact have been used to label these populations. First, nucleotide analogues such as bromodeoxyuridine (5-bromo-20 -deoxyuridine or BrdU) or iododeoxyuridine (IUdR) have been injected into adult animals in order to specifically label dividing cells at the injection time. These thymidine analogues incorporate into the nuclear DNA during the S-phase of the cell cycle, thus targeting any newborn neurons in the brain (Rochefort et al., 2002; Winner et al., 2002). However, since DNA synthesis can be initiated independently of mitosis (e.g., during gene duplication, repair, or apoptosis), both BrdU and IUdR labeling are indicators of only DNA synthesis and not of cell division. To be certain that a given population labeled with BrdU (or IUdR) reflects indeed a genuine population of newly generated cells, data should be compared with immunostaining labeling obtained with endogenous cell division markers such as the proliferation-associated nuclear antigen Ki-67. In all cases, these methods give an approximation of the numbers of newborn neurons being generated and how many remain after defined time periods. Once it has been demonstrated that a given cell type divides, a second useful method for labeling cells is immunostaining for the cell markers they express upon terminal differentiation or those related to their recent genesis, including doublecortin, PSA-NCAM, calbindin, calretinin, NeuN, and tyrosine hydroxlyase, among others (Alonso et al., 2008; Alvarez-Buylla et al., 2008; Espo´sito et al., 2005; Winner et al., 2002). Combining immunostaining with BrdU allows for the identification of newborn neurons at various stages of development and integration into the existing neural circuitry. A more recent derivative of this technique combines Cre recombinase driven by the promoters for common developmental transcription

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factors with floxed reporters, allowing researchers to asses the developmental regions producing different types of newborn neurons (see for instance, Kohwi et al., 2007; Young et al., 2007). Another method of labeling newborn cells in the olfactory system takes advantage of the fact that they are generated in the subventricular zone before migrating through the rostral migrating stream into the olfactory bulb. By injecting retroviruses or lentiviruses encoding GFP into the subventricular zone, or the rostral migrating stream, newborn cells can be genetically labeled far from the site of their eventual integration. This technique improves on other methods in that it allows for labeling of newborn cells in vivo, which can then be followed by electrophysiological assessment of their activity as they begin to form functional connections in the olfactory bulb (Grubb et al., 2008; Livneh et al., 2009; Nissant et al., 2009; Saghatelyan et al., 2005; reviewed in Adam and Mizrahi, 2010). An alternative and faster way to transduce cells with a given gene is electroporation (i.e., Belvindrah et al., 2011). Embryonic or neonatal mice can be injected with the plasmids directly into the lateral ventricle. Application of brief pulses of current causes the injected plasmid to be taken up into the cells lining the injected ventricle, which include the entire stem cell niche for adult-born olfactory neurons. These cells will then express the gene of interest in the electroporated plasmid. Using this method, we have introduced both GFP and a short-hairpin RNA against doublecortin and were able to link expression of this developmental gene to proper migration and maturation. Reducing doublecortin levels caused significant migration defects in newborn neurons, leaving many in the migratory stream or the core of the olfactory bulb with defective polarity and morphology and randomized direction of movement. This study shows that electroporation, even when performed postnatally, is a viable means of introducing genes into newborn neurons and indicates the necessity of doublecortin for normal newborn neuron migration and development (Belvindrah et al., 2011). With the use of a monosynaptic rabies virus-based tracing technique, Deshpande and colleagues reported for the first time the dynamics of inputs that the adult-born interneurons receive soon after their arrival into the OB (Deshpande et al., 2013). Interestingly, adult-born interneurons first receive local inputs from GABAergic interneurons before being connected by long-range axons from the anterior olfactory nucleus and the piriform cortex that form synapses onto the basolateral dendrites of granule cells. The use of the above methods applied to study adult neurogenesis in the olfactory bulb has allowed researchers to detail newborn neurons’ developmental steps from birth to their integration into existing neural circuitry. For a thorough discussion of the breadth of this field of research, the reader should refer to previous reviews (Adam and Mizrahi, 2010; Alvarez-Buylla et al., 2008; Kelsch et al., 2010; Lepousez et al., 2013; Lledo et al., 2008), which go into greater detail regarding the development and integration of adult-born neurons. While much progress has been made understanding how synapses form onto new neurons, few studies have unraveled the nature of output signals from new neurons.

4 Dead or Alive: A Matter of Choice

To unambiguously identify the nature of targeted cells onto which the newly formed neurons impinge, optogenetic tools have proven useful. Optogenetics, or controlling neuronal activity with light, has been facilitating prominent research for over half a decade (Zhang et al., 2008). Using viral-vector gene transfection of the photosensitive channelrhodopsin2 (ChR2), one can examine specifically the synaptic outputs of new neurons in the adult OB (Bardy et al., 2010). As a proof of principal, in this study, newborn neurons infected with ChR2 were reliably responding to light stimulation by 1 week postinjection. By recording other olfactory neuron subtypes, it was possible to describe the functional integration of newborn neurons which surprisingly revealed synaptic connections not only onto output neurons (mitral and tufted cells) but also onto short-axon, juxtaglomerular, and even other granule cells. Three major breakthroughs came from applying optogenetics to the study of olfactory bulb adult neurogenesis. First, it was possible to identify unambiguously the nature of the neurotransmitter being released by the adult-born neurons and the impact they have on the output patterns of the olfactory bulb. Second, it was reported that both spikedependent and spike-independent mechanisms support synaptic GABA release from newborn neurons. Finally, the functional impacts of the newborn neuron synaptic outputs onto various target cells were revealed. Therefore, optogenetics has provided new insight into the contribution of the newly generated interneurons-to-olfactory bulb function. What remains still unknown, however, is the exact role of adult neurogenesis in the olfactory bulb as relates to olfactory perception and memory. Behavioral experiments suggest that adult neurogenesis is affected by environmental factors (Alonso et al., 2006) and has roles in neuron survival, olfactory discrimination or pattern recognition, and olfactory memory (Gheusi et al., 2000; Mouret et al., 2009; Rochefort et al., 2002; Sultan et al., 2010). However, how these cells function in the existing neuronal circuitry has not been clearly determined. Several recent methods being applied to this system, however, are beginning to provide new insight into exactly what newborn neurons do in the olfactory bulb circuitry. We discuss this issue in detail below.

4 DEAD OR ALIVE: A MATTER OF CHOICE Overall, three interrelated pathways have been identified that mediate the survival of adult-born neurons: sensory activity that drives dendrodendritic synaptic input, topdown glutamatergic inputs originating from cortical regions such as the olfactory cortex and centrifugal modulation by neuroamines and neuropeptides locally released in the olfactory bulb. It is now clearly established that sensory experience influences the rate of survival of the new interneurons that populate the adult olfactory bulb (Petreanu and Alvarez-Buylla, 2002; Rochefort et al., 2002). Odor enrichment and olfactory learning for instance enhance both the survival and the integration of newborn neurons in the olfactory bulb (Bovetti et al., 2009; Miwa and Storm, 2005; Moreno et al., 2009; Rochefort et al., 2002; Veyrac et al., 2009). Conversely,

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a blockade of odor signal transduction in sensory neurons, a naris occlusion or a diazepam-enhanced inhibition in the olfactory bulb, have all been reported to decrease the survival of newly generated neurons (Corotto et al., 1994; Petreanu and Alvarez-Buylla, 2002; Yamaguchi and Mori, 2005). In basal conditions, almost one half of the adult-born neurons originating from the SVZ will survive (Petreanu and Alvarez-Buylla, 2002; Winner et al., 2002), and the elimination of new neurons occurs during a critical window, ranging from 14 to 28 days after cell birth (Yamaguchi and Mori, 2005). Interestingly, this time window coincides with the period of maturation for glutamatergic input synapses during granule cells development (Kelsch et al., 2008) that undergo LTP (Nissant et al., 2009), much before the newborn neurons establish their dendrodendritic synapses with mitral/tufted cells (Carleton et al., 2003; Whitman and Greer, 2007). Regarding the role of centrifugal neuromodulation, the olfactory bulb is known to receive a rich noradrenergic innervation from the locus coeruleus (Nicholas et al., 1993; Shipley et al., 1985), and noradrenaline has been reported to promote newborn neuron survival (Bauer et al., 2003). Interestingly, odor enrichment has been shown to trigger noradrenergic-dependent mechanisms that promote the survival of olfactory newborn neurons (Veyrac et al., 2009). In addition, Moreno et al. (2012) reported that olfactory perceptual learning rescues a large proportion of adult-born neurons from death and showed that noradrenaline is required for olfactory perceptual learning. Overall, these results are reminiscent to the findings that a significant increase of noradrenaline originating from the locus coeruleus occurs during olfactory learning (Brennan et al., 1998; Le´vy et al., 1990; Rosser and Keverne, 1995; Sullivan et al., 2000), and that olfactory associative learning also promotes the survival of adult-born neurons in the olfactory bulb (Alonso et al., 2006; Kermen et al., 2010; Mouret et al., 2008; Sultan et al., 2010, 2011). A recent experiment elegantly illustrates how the selection of olfactory adultborn interneurons is modulated by both olfactory sensory experience and the topdown inputs originated from the pyramidal cells of the olfactory cortex (Yokoyama et al., 2011). The authors reported a massive wave of apoptotic adultborn granule cells within a few hours after eating, that is, the postprandial period, in food-restricted mice, and from these results they have drawn several conclusions. First, most of the apoptotic newborn cells were 14–28-day-old granule cells. Second, apoptosis mainly occurred during postprandial slow-wave sleep. The authors demonstrated that the combination feeding and sleeping times was essential to observe the increase the elimination of granule cells. The olfactory sensory experience that occurred during the feeding episode was a key process that influenced the survival and death decision of adult-born interneurons, since the elimination of granule cells increased dramatically during the postprandial period in olfactory-deprived mice. The authors suggested that a subset of newly generated interneurons ranging from 14 to 28 days after their birth receive strong synaptic inputs (“survival tag”) during the feeding episode and are rescued from apoptosis by a “reorganizing signal” supported by a synchronized top-down synaptic inputs from olfactory cortex pyramidal cells. In addition, neuromodulatory inputs involving changes in noradrenergic,

5 The Potential Functions of Olfactory Bulb Adult Neurogenesis

cholinergic, and serotoninergic tones during the circadian cycle and/or behavioral activities could contribute to the selection of the sensory experience-activated adult-born neurons (Banasr et al., 2004; Cooper-Kuhn et al., 2004; Devore et al., 2012; Sullivan et al., 1989; Veyrac et al., 2009). Although it is still debated, we shall examine in the next section how newly generated bulbar neurons contribute to olfactory bulb function.

5 THE POTENTIAL FUNCTIONS OF OLFACTORY BULB ADULT NEUROGENESIS We have little knowledge about how precisely adult-born neurons influence the preexisting circuitry within the olfactory bulb and what functions emerge from restructuring the olfactory bulb. One way to resolve this issue is to accumulate information on the specific properties exhibited by the newly generated interneurons. For instance, it has been proposed that newborn interneurons might specifically contribute in shaping responses during olfactory processing. First, adult-born neurons tend to occupy a deepest position in the granule cell layer than the early postnatally born granule cells (Lemasson et al., 2005). Second, young adult-born neurons receive excitatory inputs originating from the piriform cortex, anterior olfactory nucleus, and cortical amygdala nuclei on the proximal segment of their apical dendrite (de Olmos et al., 1978; Matsutani and Yamamoto, 2008), much before they establish GABAergic outputs (Bardy et al., 2010; Carleton et al., 2003; Kelsch et al., 2008). Third, electrophysiological recordings showed that some glutamatergic inputs impinging onto young adult-born neurons, but not onto mature interneurons, exhibit LTP when the glutamatergic synaptic transmission is activated by theta-burst stimuli, demonstrating that young granule cells are more excitable than their more mature counterparts (Nissant et al., 2009). Fourth, Valley et al. (2013) reported that adult-born granule cells exhibit uniquely strong synaptic output compared to those born during early postnatal development. In this study, GABA release from adult-born neurons was resistant to GABAB-mediated suppression of GABA release, and this resistance reflected an internalization of GABAB receptors away from the plasma membrane. Resistance to GABAB signaling suggests that adult-born neurons have a stronger control over controlling the mitral cells firing activity, and potentially in the generation of network synchrony. Fifth, adult-born granule cells are most responsive to novel odors soon after their synaptic integration (Magavi et al., 2005). Sixth, adult-born interneurons seem to have a critical contribution toward the rate of olfactory learning compared to mature interneurons born just after birth (Alonso et al., 2012). Collectively, because adult-born neurons display unique properties, it is reasonable to propose they make a special contribution at the network level, and ultimately at the behavioral level. What is the functional contribution of adult-born neurons once integrated into the olfactory bulb circuit? Unfortunately, studies that have been carried out to specifically address this question have yielded several conflicting results. As a result, our

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knowledge about the significance of adult neurogenesis in the olfactory system still remains fragmented and elusive. At least three main strategies have been used to assess the functional contribution of adult-born interneurons. One simple and direct way is to eliminate (or reduce) the proliferation of adult-born neurons. This has been achieved using antimitotic drugs such as cytosine arabinose (Ara-C) (Doetsch et al., 1999), focal irradiation (McGinn et al., 2008), or conditional transgenic ablation of neural precursor cells (Singer et al., 2009). Immunohistochemical approaches to quantify adult-born interneurons (i.e., that have incorporated BrdU) that express immediate early genes represents an alternative method. This technique also provides a direct comparison between the respective contributions of postnatal-born and adult-born interneurons during specific behavioral tasks. Despite substantial efforts, these approaches have yielded mixed results. For these reasons, optogenetic techniques that can control cellular signaling and neural activity in a cell-type selective manner constitutes another promising strategy to elucidate the specific functions of adult-born neurons (Alonso et al., 2012). Behavioral analysis is critical to understand how adult-born neurons contribute to the encoding and processing of odors and decision-making in different contexts. Two distinct approaches have been generally used: psychophysical studies that investigate sensory and performance variables in animals exposed to a variety of learning paradigms and ethological studies that mainly focus on natural behaviors occurring in the everyday life situations. Within the context of adult olfactory neurogenesis, most studies to date have examined the role of adult-born neurons on odor detection, discrimination, and memory processing in psychophysical settings. BretonProvencher et al. (2009) reported a reduced sensitivity of odorant perception in mice treated with Ara-C. However, Lazarini et al. (2009) found no reduction of odorant perception in mice with subventricular zone irradiation. Because these two studies involved different paradigms that triggered differential attentional and motivational processes, it is difficult to draw any definitive conclusion about the contribution of adult-born neurons in odor perception. Odor discrimination and odor memory represent the main domains in which the role of newborn interneurons in the olfactory bulb has been investigated. As highlighted previously (Sahay et al., 2011), the generation of adult-born neurons has been considered as a putative means to disambiguate perceptually similar olfactory stimuli, a process also known as “pattern separation” (Wilson, 2009). Regarding odor discrimination, we are facing a growing collection of studies that have provided conflicting results. Some authors have reported that ablation of neurogenesis in the olfactory bulb did not interfere with odor discrimination (Breton-Provencher et al., 2009; Imayoshi et al., 2008; Lazarini et al., 2009; Sultan et al., 2010). However, this assumption contrasts with others studies that have shown that a reduction of olfactory neurogenesis impairs odor discrimination (Bath et al., 2008; Enewere et al., 2004; Gheusi et al., 2000). In support of a specific contribution of adult-born neurons in improving pattern separation, one study reported that manipulations of olfactory neurogenesis affect odor discrimination between similar olfactory stimuli

References

(Moreno et al., 2009). In the same vein, Alonso et al. (2012) demonstrated that light activation of adult-born granule cells that selectively expressed ChR2 facilitated difficult odor discrimination and improved odor memory. These discrepancies between the different studies are not surprising if one considers the number of factors that may vary between protocols (i.e., procedures of ablation, specifics of experimental design, length of adult-born neuron depletion, etc.). Obviously, further experiments are needed to exactly decipher the exact contribution of adult-born neurons in olfactory acuity. Because most of the studies that focused on the role of adult neurogenesis on odor discrimination have relied on nonassociative and associative memory tasks (habituation/dishabituation, instrumental conditioning), it remains difficult to disentangle the specific contribution of olfactory neurogenesis on odor discrimination and memory. Ablation of adult-born neurons, both in the SVZ and in the hippocampus, does not induce any deficit in olfactory short-term memory (Imayoshi et al., 2008). In contrast, Breton-Provencher et al. (2009) have reported a reduction of short-term memory in Ara-C-treated mice and Valley and colleagues (2009) also reported that the short-term strength of odor-cue fear-conditioned olfactory memory critically relies on adult olfactory neurogenesis. Similarly, the examination of the contribution of adult neurogenesis on olfactory long-term memory has also raised mixed results. However, pharmacological ablation of adult-born neurons, as well as irradiation of the SVZ, produces a significant impairment in long-term retention of odorants (Lazarini et al., 2009; Sultan et al., 2010). In addition, Sultan et al. (2010) demonstrated that adult-born neurons are preferentially recruited during a recall test in response to learned odorants. As stated above, optogenetic activation of newly formed olfactory interneurons facilitated difficult odor discrimination training and improved odor memory (Alonso et al., 2012). Although some other studies do not support this view (see for instance, Breton-Provencher et al., 2009; Imayoshi et al., 2008), these results suggest a significant contribution of adult-born neurons toward olfactory learning and memory.

Acknowledgments Authors acknowledge the financial support from the life insurance company “AG2R,” the Agence Nationale de la Recherche “ANR-BLAN-SVSE4-LS-110624.” The Lledo’s lab is part of the E´cole des Neurosciences de Paris (ENP) Ile-de-France network and member of the Laboratoire d’Excellence Bio-Psy (Investissement d’Avenir, ANR-10-LABX-73).

References Adam, Y., Mizrahi, A., 2010. Circuit formation and maintenance—perspectives from the mammalian olfactory bulb. Curr. Opin. Neurobiol. 20, 134–140. Adam, Y., Mizrahi, A., 2011. Long-term imaging reveals dynamic changes in the neuronal composition of the glomerular layer. J. Neurosci. 31, 7967–7973.

169

170

CHAPTER 6 Adult Neurogenesis in the Olfactory System

Aimone, J.B., Deng, W., Gage, F.H., 2011. Resolving new memories: a critical look at the dentate gyrus, adult neurogenesis, and pattern separation. Neuron 70, 589–596. Alonso, M., Viollet, C., Gagebellec, M.-M., Meas-Yedid, V., Olivo-Marin, J.-C., Lledo, P.-M., 2006. Olfactory discrimination learning increases the survival of adult-born neurons in the olfactory bulb. J. Neurosci. 26, 10508–10513. Alonso, M., Ortega-Pe´rez, I., Grubb, M.S., Bourgeois, J.-P., Charneau, P., Lledo, P.-M., 2008. Turning astrocytes from the rostral migratory stream into neurons: a role for the olfactory sensory organ. J. Neurosci. 28, 11089–11102. Alonso, M., Lepousez, G., Wagner, S., Bardy, C., Gabellec, M.M., Torquet, N., Lledo, P.M., 2012. Activation of adult-born neurons facilitates learning and memory. Nat. Neurosci. 15, 897–904. Alvarez-Buylla, A., Kohwi, M., Nguyen, T.M., Merkle, F.T., 2008. The heterogeneity of adult neural stem cells and the emerging complexity of their niche. Cold Spring Harb. Symp. Quant. Biol. 73, 357–365. Banasr, M., Hery, M., Printemps, R., Daszuta, A., 2004. Serotonin-induced increases in adult cell proliferation and neurogenesis are mediated through different and common 5-HT receptor subtypes in the dentate gyrus and the subventicular zone. Neuropsychopharmacology 29, 450–460. Bardy, C., Alonso, M., Bouthour, W., Lledo, P.-M., 2010. How, when, and where new inhibitory neurons release neurotransmitters in the adult olfactory bulb. J. Neurosci. 30, 17023–17034. Bath, K.G., Mandairon, N., Jing, D., Rajagopal, R., Kapoor, R., Chen, Z.Y., Khan, T., Proenca, C.C., Kraemer, R., Cleland, T.A., Hempstead, B., Chaos, M.V., Lee, F.S., 2008. Variant brain-derived neurotrophic factor (Val66Met) alters adult olfactory bulb neurogenesis and spontaneous olfactory discrimination. J. Neurosci. 28, 2383–2393. Batista-Brito, R., Close, J., Machold, R., Fishell, G., 2008. The distinct temporal origins of olfactory bulb interneuron subtypes. J. Neurosci. 28, 3966–3975. Bauer, S., Moyse, E., Jourdan, F., Colpaert, F., Martel, J.C., Marien, M., 2003. Effects of the alpha 2-adrenoreceptor antagonist dexefaroxan on neurogenesis in the olfactory bulb of the adult rat in vivo: selective protection against neuronal death. Neuroscience 117, 281–291. Belluzzi, O., Benedusi, M., Ackman, J., LoTurco, J.J., 2003. Electrophysiological differentiation of new neurons in the olfactory bulb. J. Neurosci. 23, 10411–10418. Belvindrah, R., Nissant, A., Lledo, P.-M., 2011. Abnormal neuronal migration changes the fate of developing neurons in the postnatal olfactory bulb. J. Neurosci. 31, 7551–7562. Bovetti, S., Veyrac, A., Peretto, P., Fasolo, A., De Marchis, S., 2009. Olfactory enrichment influences adult neurogenesis modulating GAD67 and plasticity-related molecules expression in newborn cells of the olfactory bulb. PLoS One 4, e6359. Brennan, P.A., Schellinck, H.M., de la Riva, C., Kendrick, K.M., Keverne, E.B., 1998. Changes in neurotransmitter release in the main olfactory bulb following an olfactory conditioning procedure in mice. Neuroscience 87, 583–590. Breton-Provencher, V., Lemasson, M., Peralta, M.R. III, Seghatelyan, A., 2009. Interneurons produced in adulthood are required for the normal functioning of the olfactory bulb network and for the execution of selected olfactory behaviors. J. Neurosci. 29, 15245–15257. Breton-Provencher, V., Saghatelyan, A., 2012. Newborn neurons in the adult olfactory bulb: unique properties for specific odor behavior. Behav. Brain Res. 227, 480–489. Carleton, A., Petreanu, L.T., Lansford, R., Alvarez-Buylla, A., Lledo, P.-M., 2003. Becoming a new neuron in the adult olfactory bulb. Nat. Neurosci. 6, 507–518.

References

Cooper-Kuhn, C.M., Winkler, J., Kuhn, H.G., 2004. Decreased neurogenesis after cholinergic forebrain lesion in the adult rat. J. Neurosci. Res. 77, 155–165. Corotto, F.S., Henegar, J.R., Maruniak, J.A., 1994. Odor deprivation leads to reduced neurogenesis and reduced survival in the olfactory bulb of the adult mouse. Neuroscience 61, 739–744. de Olmos, J., Hardy, H., Heimer, L., 1978. The afferent connections of the main and the accessory olfactory bulb formations in the rat: an experimental HRP-study. J. Comp. Neurol. 181, 213–244. Deshpande, A., Bergami, M., Ghanem, A., Conzelmann, K.-K., Lepier, A., Go¨tz, M., Berninger, B., 2013. Retrograde monosynaptic tracing reveals the temporal evolution of inputs onto new neurons in the adult dentate gyrus and olfactory bulb. Proc. Natl. Acad. Sci. U. S. A. 110, E1152–E1161. Devore, S., Manella, L.C., Linster, C., 2012. Blocking muscarinic receptors in the olfactory bulb impairs performance on an olfactory short-term memory task. Front. Behav. Neurosci. 6, 59. Doetsch, F., Caille´, I., Lim, D.A., Garcia-Verdugo, J.M., Alvarez-Buylla, A., 1999. Subventricular zone astrocytes are neural stem cells in the adult mammalian brain. Cell 97, 703–716. Enewere, E., Shingo, T., Gregg, C., Fujikawa, H., Ohta, S., Weiss, S., 2004. Aging results in reduced epidermal growth factor receptor signaling, diminished olfactory neurogenesis, and deficits in fine olfactory discrimination. J. Neurosci. 24, 8354–8365. Espo´sito, M.S., Piatti, V.C., Laplagne, D.A., Morgenstern, N.A., Ferrari, C.C., Pitossi, F.J., Schinder, A.F., 2005. Neuronal differentiation in the adult hippocampus recapitulates embryonic development. J. Neurosci. 25, 10074–10086. Gheusi, G., Cremer, H., McLean, H., Chazal, G., Vincent, J.D., Lledo, P.M., 2000. Importance of newly generated neurons in the adult olfactory bulb for odor discrimination. Proc. Natl. Acad. Sci. U. S. A. 97, 1823–1828. Grubb, M.S., Nissant, A., Murray, K., Lledo, P.-M., 2008. Functional maturation of the first synapse in olfaction: development and adult neurogenesis. J. Neurosci. 28, 2919–2932. Imayoshi, I., Sakamoto, M., Ohtsuka, T., Takao, K., Miyakawa, T., Yamaguchi, M., Mori, K., Ikeda, T., Itohara, S., Kageyama, R., 2008. Roles of continuous neurogenesis in the structural and functional integrity of the adult forebrain. Nat. Neurosci. 11, 1153–1161. Isaacson, J.S., Strowbridge, B.W., 1998. Olfactory reciprocal synapses: dendritic signaling in the CNS. Neuron 20, 749–761. Isaacson, J.S., 1999. Glutamate spillover mediates excitatory transmission in the rat olfactory bulb. Neuron 23, 377–384. Jahr, C.E., Nicoll, R.A., 1982. An intracellular analysis of dendrodendritic inhibition in the turtle in vitro olfactory bulb. J. Physiol. (Lond.) 326, 213–234. Katagiri, H., Pallotto, M., Nissant, A., Murray, K., Sassoe`-Pognetto, M., Lledo, P.-M., 2011. Dynamic development of the first synapse impinging on adult-born neurons in the olfactory bulb circuit. Neural Syst. Circuits 1 (1), 6. Kato, H.K., Gillet, S.N., Peters, A.J., Isaacson, J.S., Komiyama, T., 2013. Parvalbuminexpressing interneurons linearly control olfactory bulb output. Neuron 80, 1218–1231. Kelsch, W., Lin, C.-W., Lois, C., 2008. Sequential development of synapses in dendritic domains during adult neurogenesis. Proc. Natl. Acad. Sci. U. S. A. 105, 16803–16808. Kelsch, W., Lin, C.-W., Mosley, C.P., Lois, C., 2009. A critical period for activity-dependent synaptic development during olfactory bulb adult neurogenesis. J. Neurosci. 29, 11852–11858.

171

172

CHAPTER 6 Adult Neurogenesis in the Olfactory System

Kelsch, W., Sim, S., Lois, C., 2010. Watching synaptogenesis in the adult brain. Annu. Rev. Neurosci. 33, 131–149. Kemperman, G., 2012. New neurons for ‘survival of the fittest’. Nat. Rev. Neurosci. 13, 727–736. Kermen, F., Sultan, S., Sacquet, J., Mandairon, N., Didier, A., 2010. Consolidation of an olfactory memory trace in the olfactory bulb is required for learning-induced survival of adult-born neurons and long-term memory. PLoS One 5, e1218. Kheirbek, M.A., Klemenhagen, K.C., Sahay, A., Hen, R., 2012. Neurogenesis and generalization: a new approach to stratify and treat anxiety disorders. Nat. Neurosci. 15, 1613–1620. Kohwi, M., Petryniak, M.A., Long, J.E., Ekker, M., Obata, K., Yanagawa, Y., Rubenstein, J.L.R., Alvarez-Buylla, A., 2007. A subpopulation of olfactory bulb GABAergic interneurons is derived from Emx1- and Dlx5/6-expressing progenitors. J. Neurosci. 27, 6878–6891. Kosaka, T., Kosaka, K., 2008. Heterogeneity of parvalbumin-containing neurons in the mouse main olfactory bulb, with special reference to short-axon cells and betaIV-spectrin positive dendritic segments. Neurosci. Res. 60, 56–72. Lazarini, F., Lledo, P.-M., 2011. Is adult neurogenesis essential for olfaction? Trends Neurosci. 34, 20–30. Lazarini, F., Mouthon, M.A., Gheusi, G., de Chaumont, F., Olivo-Marin, J.C., Lamarque, S., Abrous, D.N., Boussin, F.D., Lledo, P.M., 2009. Cellular and behavioral effects of cranial irradiation of the subventricular zone in adult mice. PLoS One 4 (9), e7017. Lemasson, M., Saghatelyan, M., Olivo-Marin, J.C., Lledo, P.M., 2005. Neonatal and adult neurogenesis provide two distinct populations of newborn neurons to the mouse olfactory bulb. J. Neurosci. 25, 6816–6825. Lepousez, G., Valley, M.T., Lledo, P.M., 2013. The impact of adult neurogenesis on olfactory bulb circuits and computations. Annu. Rev. Physiol. 75, 339–363. Le´vy, F., Gervais, R., Kindermann, U., Orgeur, P., Piketty, V., 1990. Importance of betanoradrenergic receptors in the olfactory bulb of sheep for recognition of lambs. Behav. Neurosci. 104, 464–469. Livneh, Y., Mizrahi, A., 2012. Experience-dependent plasticity of mature adult-born neurons. Nat. Neurosci. 15, 26–28. Livneh, Y., Feinstein, N., Klein, M., Mizrahi, A., 2009. Sensory input enhances synaptogenesis of adult-born neurons. J. Neurosci. 29, 86–97. Lledo, P.-M., Saghatelyan, A., 2005. Integrating new neurons into the adult olfactory bulb: joining the network, life-death decisions, and the effects of sensory experience. Trends Neurosci. 28, 248–254. Lledo, P.M., Merkle, F.T., Alvarez-Buylla, A., 2008. Origin and function of olfactory bulb interneuron diversity. Trends Neurosci. 31, 392–400. Magavi, S.S.P., Bartley, D.M., Szentirmai, O., Carter, B.S., Macklis, J.D., 2005. Adult-born and preexisting olfactory granule neurons undergo distinct experience-dependent modifications of their olfactory responses in vivo. J. Neurosci. 25, 10729–10739. Marı´n-Burgin, A., Schinder, A.F., 2012. Requirement of adult-born neurons for hippocampusdependent learning. Behav. Brain Res. 227, 391–399. Matsutani, S., Yamamoto, N., 2008. Centrifugal innervation of the mammalian olfactory bulb. Anat. Sci. Int. 83, 218–227. McGinn, M.J., Sun, D., Colello, R.J., 2008. Utilizing X-irradiation to selectively eliminate neural stem/progenitor cells from neurogenic regions of the mammalian brain. J. Neurosci. Methods 170, 9–15.

References

Ming, G.-L., Song, H., 2011. Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 70, 687–702. Miwa, N., Storm, D.R., 2005. Odorant-induced activation of extracellular signal-regulated kinase/mitogen-activated protein kinase in the olfactory bulb promotes survival of newly formed granule cells. J. Neurosci. 25, 5404–5413. Miyamichi, K., Shlomai-Fuchs, Y., Shu, M., Weissbourd, B.C., Luo, L., Mizrahi, A., 2013. Dissecting local circuits: parvalbumin interneurons underlie broad feedback control of olfactory bulb output. Neuron 80, 1232–1245. Moreno, M.M., Linster, C., Escanilla, O., Sacquet, J., Didier, A., Mandairon, N., 2009. Olfactory perceptual learning requires adult neurogenesis. Proc. Natl. Acad. Sci. U. S. A. 106, 17980–17985. Moreno, M.M., Bath, K., Kuczewski, N., Sacquet, J., Didier, A., Mandairon, N., 2012. Action of noradrenergic system on adult-born cells is required for olfactory learning in mice. J. Neurosci. 32, 3748–3758. Mori, K., Sakano, H., 2011. How is the olfactory map formed and interpreted in the mammalian brain? Annu. Rev. Neurosci. 34, 467–499. Mori, K., Kishi, K., Ojima, H., 1983. Distribution of dendrites of mitral, displaced mitral, tufted, and granule cells in the rabbit olfactory bulb. J. Comp. Neurol. 219, 339–355. Mouret, A., Gheusi, G., Gabellec, M.M., de Chaumont, F., Olivo-Marin, J.C., Lledo, P.M., 2008. Learning and survival of newly generated neurons: when time matters. J. Neurosci. 28, 11511–11516. Mouret, A., Lepousez, G., Gras, J., Gabellec, M.-M., Lledo, P.-M., 2009. Turnover of newborn olfactory bulb neurons optimizes olfaction. J. Neurosci. 29, 12302–12314. Murthy, V.N., 2011. Olfactory maps in the brain. Annu. Rev. Neurosci. 34, 233–258. Nicholas, A.P., Pieribone, V.A., Hokfelt, T., 1993. Cellular localization of messenger RNA for beta-1 and beta-2 adrenergic receptors in rat brain: an in situ hybridization study. Neuroscience 56, 1023–1039. Nissant, A., Bardy, C., Katagiri, H., Murray, K., Lledo, P.-M., 2009. Adult neurogenesis promotes synaptic plasticity in the olfactory bulb. Nat. Neurosci. 12, 728–730. Nowycky, M.C., Mori, K., Shepherd, G.M., 1981. GABAergic mechanisms of dendrodendritic synapses in isolated turtle olfactory bulb. J. Neurophysiol. 46, 639–648. Orona, E., Rainer, E.C., Scott, J.W., 1984. Dendritic and axonal organization of mitral and tufted cells in the rat olfactory bulb. J. Comp. Neurol. 226, 346–356. Panzanelli, P., Bardy, C., Nissant, A., Pallotto, M., Sassoe`-Pognetto, M., Lledo, P.-M., Fritschy, J.-M., 2009. Early synapse formation in developing interneurons of the adult olfactory bulb. J. Neurosci. 29, 15039–15052. Petreanu, L., Alvarez-Buylla, A., 2002. Maturation and death of adult-born olfactory bulb granule neurons: role of olfaction. J. Neurosci. 22, 6106–6113. Price, J.L., Powell, T.P., 1970. The afferent connexions of the nucleus of the horizontal limb of the diagonal band. J. Anat. 107, 239–256. Rall, W., Shepherd, G.M., Reese, T.S., Brightman, M.W., 1966. Dendrodendritic synaptic pathway for inhibition in the olfactory bulb. Exp. Neurol. 14, 44–56. Rochefort, C., Gheusi, G., Vincent, J.-D., Lledo, P.-M., 2002. Enriched odor exposure increases the number of newborn neurons in the adult olfactory bulb and improves odor memory. J. Neurosci. 22, 2679–2689. Rosser, A.E., Keverne, E.B., 1995. The importance of central noradrenergic neurons in the formation of an olfactory memory in the prevention of pregnancy block. Neuroscience 15, 1141–1147.

173

174

CHAPTER 6 Adult Neurogenesis in the Olfactory System

Saghatelyan, A., Roux, P., Migliore, M., Rochefort, C., Desmaisons, D., Charneau, P., Shepherd, G.M., Lledo, P.-M., 2005. Activity-dependent adjustments of the inhibitory network in the olfactory bulb following early postnatal deprivation. Neuron 46, 103–116. Sahay, A., Wilson, D.A., Hen, R., 2011. Pattern separation: a common function for new neurons in hippocampus and olfactory bulb. Neuron 70, 582–588. Schoppa, N.E., Kinzie, J.M., Sahara, Y., Segerson, T.P., Westbrook, G.L., 1998. Dendrodendritic inhibition in the olfactory bulb is driven by NMDA receptors. J. Neurosci. 18, 6790–6802. Schoppa, N.E., Urban, N.N., 2003. Dendritic processing within olfactory bulb circuits. Trends Neurosci. 26, 501–506. Shipley, M.T., Halloran, F.J., de la Torre, J., 1985. Surprisingly rich projection from locus coeruleus to the olfactory bulb in the rat. Brain Res. 329, 294–299. Singer, B.H., Jutkiewicz, E.M., Fuller, C.L., Lichtenwalner, R.J., Zhang, H., Velander, A.J., Li, X., Gnegy, M.E., Burant, C.F., Parent, J.M., 2009. Conditional ablation and recovery of forebrain neurogenesis in the mouse. J. Comp. Neurol. 514, 567–582. Smith, T.C., Jahr, C.E., 2002. Self-inhibition of olfactory bulb neurons. Nat. Neurosci. 5, 760–766. Sullivan, R.M., Wilson, D.A., Leon, M., 1989. Norepinephrine and learning-induced plasticity in infant rat olfactory system. J. Neurosci. 9, 3998–4006. Sullivan, R.M., Stackenwalt, G., Nasr, F., Lemon, C., Wilson, D.A., 2000. Association of an odor with activation of olfactory bulb noradrenergic beta-receptors or locus coeruleus stimulation is sufficient to produce learned approach responses to that odor in neonatal rats. Behav. Neurosci. 114, 957–962. Sultan, S., Mandairon, N., Kermen, F., Garcia, S., Sacquet, J., Didier, A., 2010. Learning-dependent neurogenesis in the olfactory bulb determines long-term olfactory memory. Faseb J. 24, 2355–2363. Sultan, S., Rey, N., Sacquet, J., Mandairon, N., Didier, A., 2011. Newborn neurons in the olfactory bulb selected for long-term survival through olfactory learning are prematurely suppressed when the olfactory memory is erased. J. Neurosci. 31, 14893–14898. Sur, M., Rubenstein, J.L.R., 2005. Patterning and plasticity of the cerebral cortex. Science 310, 805–810. Tan, J., Savigner, A., Ma, M., Luo, M., 2010. Odor information processing by the olfactory bulb analyzed in gene-targeted mice. Neuron 65, 912–926. Valley, M.T., Mullen, T.R., Schultz, L.C., Sagdullaev, B.T., Firestein, S., 2009. Ablation of mouse adult neurogenesis alters olfactory bulb structure and olfactory fear conditioning. Front. Neurosci. 3, 51. Valley, M.T., Henderson, L.G., Inverso, S.A., Lledo, P.-M., 2013. Adult neurogenesis produces neurons with unique GABAergic synapses in the olfactory bulb. J. Neurosci. 33, 14660–14665. Veyrac, A., Sacquet, J., Nguyen, V., Marien, M., Jourdan, F., Didier, A., 2009. Novelty determines the effects of olfactory enrichment on memory and neurogenesis through noradrenergic mechanisms. Neuropsychopharmacology 34, 786–795. Whitman, M.C., Greer, C., 2007. Synaptic integration of adult-generated olfactory bulb granule cells: basal axodendritic centrifugal input precedes apical dendrodendritic local circuits. J. Neurosci. 27, 9951–9961. Whitman, M.C., Greer, C.A., 2009. Adult neurogenesis and the olfactory system. Prog. Neurobiol. 89, 162–175.

References

Wiechert, M.T., Judkewitz, B., Riecke, H., Friedrich, R.W., 2010. Mechanisms of pattern decorrelation by recurrent neuronal circuits. Nat. Neurosci. 13, 1003–1010. Wilson, D.A., 2009. Pattern separation and completion in olfaction. Ann. N. Y. Acad. Sci. 1170, 306–312. Winner, B., Cooper-Kuhn, C.M., Aigner, R., Winkler, J., Kuhn, H.G., 2002. Long-term survival and cell death of newly generated neurons in the adult rat olfactory bulb. Eur. J. Neurosci. 16, 1681–1689. Wojtowicz, J.M., 2012. Adult neurogenesis. From circuits to models. Behav. Brain Res. 227, 490–496. Yamaguchi, M., Mori, K., 2005. Critical period for sensory experience-dependent survival of newly generated granule cells in the adult mouse olfactory bulb. Proc. Natl. Acad. Sci. U. S. A. 102, 9697–9702. Yang, Z., 2008. Postnatal subventricular zone progenitors give rise not only to granular and periglomerular interneurons but also to interneurons in the external plexiform layer of the rat olfactory bulb. J. Comp. Neurol. 506, 347–358. Yokoyama, T.K., Mochimaru, D., Murata, K., Manabe, H., Kobayakawa, K., Kobayakawa, R., Sakano, H., Mori, K., Yamaguchi, M., 2011. Elimination of adult-born neurons in the olfactory bulb is promoted during the postprandial period. Neuron 71, 883–897. Young, K.M., Fogarty, M., Kessaris, N., Richardson, W.D., 2007. Subventricular zone stem cells are heterogeneous with respect to their embryonic origins and neurogenic fates in the adult olfactory bulb. J. Neurosci. 27, 8286–8296. Zhang, F., Prigge, M., Beyrie`re, F., Tsunoda, S.P., Mattis, J., Yizhar, O., Hegemann, P., Deisseroth, K., 2008. Red-shifted optogenetic excitation: a tool for fast neural control derived from Volvox carteri. Nat. Neurosci. 11, 631–633.

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