Integrating new neurons into the adult olfactory bulb: joining the network, life–death decisions, and the effects of sensory experience Pierre-Marie Lledo and Armen Saghatelyan Laboratory of Perception and Memory, Centre National de la Recherche Scientifique, Unite ´ de Recherche Associe ´ e 2182, Pasteur Institute, 25 rue du Docteur Roux, 75724 Paris Cedex 15, France 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 net- work, allowing a continuous adjustment of information processing in response to an ever-changing external word. Introduction Over the past few years it has become clear that newborn neurons continue to be added to some regions of the adult nervous system [1–6]. Understanding the functional meaning of this phenomenon represents a challenging task. Today, it is believed that the generation of new neurons in adult circuits belongs to a large repertoire of neuroadaptive responses [7], with the continuous replace- ment of old neurons by the newcomers bringing to neuronal networks a degree of circuit adaptation that might depend on neuronal activity. This form of plasticity, however, occurs only in discrete regions of the adult brain, including the olfactory bulb, which receives interneurons issued from the subventricular zone (SVZ) of the fore- brain, and the dentate gyrus of the hippocampus. Other areas, such as the substantia nigra [8] and the neocortex [9], also have been thought to incorporate newborn neurons. However, this issue is still highly debated [10,11]. We currently lack confirmation that commonly used markers of neurogenesis (e.g. bromodeoxyuridine, BrdU) do not simply reflect DNA synthesis occurring during pathological conditions (e.g. trauma and ischemia) in these regions [12–14]. Once adult-generated neurons are produced in the SVZ, they proceed towards the olfactory bulb along an intricate path of migration, up to 5 mm long in rodents, called the rostral migratory stream (RMS) [15,16]. In contrast to the situation in the developing CNS, the newborn neurons in adults are not guided by radial glia but migrate tangen- tially in chains through tubular structures formed by specialized astrocytes [17] (Figure 1a). When migrating cells have reached the bulb, they turn radially away from the migratory path to invade the overlaying layers, where they differentiate into two local interneuron subtypes: granule cells and periglomerular neurons [2]. In contrast to most parts of the brain, it is noteworthy that the majority of interneurons in the olfactory bulb are generated postnatally [18]. Although the origin of stem cells and the factors controlling proliferation of neuronal precursors in the mature brain have been extensively studied [19,20], very little was known until recently about how neuronal progenitors migrate and integrate into the appropriate target area to become truly functional neurons. We also knew little concerning the factors regulating the recruit- ment and survival of newborn neurons in already functioning adult neuronal networks. However, new data from the olfactory bulb have begun to address these issues. Here, after brief description of the origin and fate specification of neuronal precursors, we will review new evidence about the role of neuronal activity in pre-existing circuits in controlling the migration, maturation, inte- gration and survival of newborn neurons. We propose that continuous neurogenesis adjusts functioning of the adult bulbar network to new flows of relevant odor information. We also discuss evidence that neurogenesis acts on information processing in a specific and functional manner, and question whether it prepares the bulb for specific behavioral challenges. Origin and generation of new neurons In the adult SVZ, periventricular astrocytes (B cells) have been proposed to act as self-renewing neural stem cells Corresponding author: Lledo, P.-M. (pmlledo@pasteur.fr). Available online 24 March 2005 Review TRENDS in Neurosciences Vol.28 No.5 May 2005 www.sciencedirect.com 0166-2236/$ - see front matter Q 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.tins.2005.03.005