Neurogenesis occurs continuously in the forebrain of adult mammals, but the functional importance of adult neurogenesis is still unclear. Here, using a genetic labeling method in adult mice, we found that continuous neurogenesis results in the replacement of the majority of granule neurons in the olfactory bulb and a substantial addition of granule neurons to the hippocampal dentate gyrus. Genetic ablation of newly formed neurons in adult mice led to a gradual decrease in the number of granule cells in the olfactory bulb, inhibition of increases in the granule cell number in the dentate gyrus and impairment of behaviors in contextual and spatial memory, which are known to depend on hippocampus. These results suggest that continuous neurogenesis is required for the maintenance and reorganization of the whole interneuron system in the olfactory bulb, the modulation and refinement of the existing neuronal circuits in the dentate gyrus and the normal behaviors involved in hippocampal-dependent memory.

The mammalian olfactory system mediates various responses, including aversive behaviours to spoiled foods and fear responses to predator odours. In the olfactory bulb, each glomerulus represents a single species of odorant receptor. Because a single odorant can interact with several different receptor species, the odour information received in the olfactory epithelium is converted to a topographical map of multiple glomeruli activated in distinct areas in the olfactory bulb. To study how the odour map is interpreted in the brain, we generated mutant mice in which olfactory sensory neurons in a specific area of the olfactory epithelium are ablated by targeted expression of the diphtheria toxin gene. Here we show that, in dorsal-zone-depleted mice, the dorsal domain of the olfactory bulb was devoid of glomerular structures, although second-order neurons were present in the vacant areas. The mutant mice lacked innate responses to aversive odorants, even though they were capable of detecting them and could be conditioned for aversion with the remaining glomeruli. These results indicate that, in mice, aversive information is received in the olfactory bulb by separate sets of glomeruli, those dedicated for innate and those for learned responses.

Activation of Notch signaling induces the expression of transcriptional repressor genes such as

Olfactory sensory neurons detect a large variety of odor molecules and send information through their axons to the olfactory bulb, the first site for the processing of olfactory information in the brain. The axonal connection is precisely organized so that signals from 1000 different types of odorant receptors are sorted out in 1800 glomeruli in the mouse olfactory bulb. Individual glomerular modules presumably represent a single type of receptor and are thus tuned to specific molecular features of odorants. Local neuronal circuits in the bulb mediate lateral inhibition among glomerular modules to sharpen the tuning specificity of output neurons. They also mediate synchronized oscillatory discharges among specific combinations of output neurons and may contribute to the integration of signals from distinct odorant receptors in the olfactory cortex.

Mitral MATERIALS AND METHODS Animal Preparation. Male adult rabbits (1.8-2.6 kg, Japanese White) were anesthetized with an intravenous injection of 30% urethane (1.2 g/kg, Aldrich) and tracheotomy was performed for double cannulation, one for the animals' spontaneous respiration and the other for artificial inhalation of odor-containing air (Fig. 1). The latter cannula was connected with an artificial respirator for drawing odor-containing air through the nasal cavity periodically. Animals were mounted in a stereotaxic apparatus. Body temperature was maintained at 38.0°C by a homeothermic heat pad system (ATB-1100, Nihon Kohden, Tokyo). The cerebrospinal fluid was drained at the atlantooccipital membrane to minimize brain pulsation. After exposure of the dorsal surface of the left olfactory bulb, a recording micropipette was inserted vertically into the dorsomedial region of the MOB, while a bipolar stimulatory electrode was introduced into the lateral olfactory tract (LOT) at the anterolateral portion of the frontal neocortex. The final position of the stimulating electrode was determined by monitoring LOT-evoked field potentials and the electrode was then anchored to the skull with dental cement.Electrophysiology. Extracellular single unit responses and LOT-evoked field potentials were recorded in the MOB using a glass micropipette (-3 Mfl) filled with 2 M NaCl. Signals were taken into a conventional amplifier and monitored on an oscilloscope. The action potentials were amplified and separated using band path filters (50 Hz-3 kHz). The position of the recorded cell was judged by the profile of the LOT-evoked field potentials. Single unit responses were recorded from a M/T cell in the EPL and the mitral cell layer of the dorsomedial region in the MOB. Mitral cells were identified by their Abbreviations: GABA, y-aminobutyrate; M/T cell, mitral/tufted cell; MOB, main olfactory bulb; LOT, lateral olfactory tract; EPL, external plexiform layer; CNQX, 6-cyano-7-nitroquinoxaline-2,3-dione; D-AP5, D-(-)-2-amino-5-phosphonovalerate; AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazolepropionate.