The findings that brain-derived neurotrophic factor (BDNF) promotes in vitro the survival and/or differentiation of postnatal subventricular zone (SVZ) progenitor cells and increases in vivo the number of the newly generated neurons in the adult rostral migratory stream and olfactory bulb prompted us to investigate whether the infusion of BDNF influences the proliferation and/or differentiation of cells in other regions of the adult forebrain. We examined the distribution and phenotype of newly generated cells in the adult rat forebrain 16 d after intraventricular administration of BDNF in conjunction with the cell proliferation marker bromodeoxyuridine (BrdU) for 12 d. BDNF infusion resulted in numerous BrdU(+) cells, not only in the SVZ lining the infused lateral ventricle, but moreover, in specific parenchymal structures lining the lateral and third ventricles, including the striatum and septum, as well as the thalamus and hypothalamus, in which neurogenesis had never been demonstrated previously during adulthood. In each region, newly generated cells expressed the neuronal marker microtubule-associated protein-2, or neuron-specific tubulin, identified by the antibody TuJ1. The percentage of the newly generated cells expressing TuJ1 ranged from 27 to 42%, suggesting that the adult forebrain has a more profound capacity to produce neurons than recognized previously. The extent of cell proliferation after BDNF infusion was correlated with the level of expression of full-length TrkB, the high-affinity receptor for BDNF, despite the fact that the BrdU(+) cells were not themselves TrkB(+). Collectively, our results demonstrate that the adult brain parenchyma may recruit and/or generate new neurons, which could replace those lost as a result of injury or disease.

This study analyzed the topographic organization of the associational fibers within the olfactory cortex of the rat, by using the autoradiographic method. Small injections of 3H-leucine were placed in all of the subdivisions of the olfactory cortex, to label selectively the fibers arising in each area. Intracortical fibers were identified from all of the olfactory cortical areas except the olfactory tubercle and were classified into two major systems (the layer Ib system and the layer II-deep Ib system) on the basis of their laminar pattern of termination (see Luskin and Price, '83). The layer Ib fiber system arises in the anterior olfactory nucleus, piriform cortex, and lateral entorhinal area, and is broadly organized in relation to the lateral olfactory tract. Cortical areas deep to or near the lateral olfactory tract are preferentially interconnected with areas near the tract, while parts of the cortex lateral and caudal to the lateral olfactory tract are most heavily interconnected with areas lateral, caudal, and medial to the tract. Commissural projections from the anterior olfactory nucleus and the anterior piriform cortex match some (but not all) components of the ipsilateral layer Ib fiber system. The layer II-deep Ib fiber system arises in three small areas--the ventral tenia tecta, the dorsal peduncular cortex, and the periamygdaloid cortex. The fibers from the ventral tenia tecta terminate in layer II of the anterior olfactory nucleus and are topographically organized. The fibers from the dorsal peduncular cortex and the periamygdaloid cortex are more widely distributed, especially in the lateral and caudal parts of the cortex. Two other intracortical projections do not fit into either of these fiber systems. The nucleus of the lateral olfactory tract projects bilaterally to the islands of Calleja and the medial edge of the anterior piriform cortex. The anterior cortical nucleus projects to many parts of the olfactory cortex, but the fibers end in both superficial and deep parts of layer I (layer Ia and Ib). There are projections from several of the olfactory cortical areas to the cortical areas surrounding the olfactory cortex. Virtually all of the olfactory areas also project to the ventral and dorsal endopiriform nuclei deep to the piriform cortex and/or to the polymorph zone deep to the olfactory tubercle. In addition, projections have been demonstrated to the deep amygdaloid nuclei, especially from the more ventromedial and caudal parts of the olfactory cortex.

We have used a monoclonal antibody against the neuron-specific class III beta-tubulin (TuJ1; Lee et al., 1990b) to study the distribution and morphology of immature neurons in the proliferative ventricular and subventricular zones of the developing telencephalon. Mouse brains from embryonic day 12 (E12) to postnatal day 5 (P5) were fixed either with a non-cross-linking agent, HistoChoice, or with 4% paraformaldehyde, and processed for TuJ1 immunohistochemistry. TuJ1 immunoreactivity first appeared in the proliferative zones of the developing cerebral cortex at E13-E14 as the cortical plate was emerging. After E14, tangentially oriented TuJ1-positive cells were abundant at the interface between the ventricular and subventricular zones. This tangential pattern was less conspicuous in the developing striatum. Within the cortical and striatal ventricular zone TuJ1-positive cells were less numerous and displayed a variety of orientations and morphologies. Postnatally, after the period of neurogenesis has ended, TuJ1 immunoreactivity continued to increase in the subventricular zone and remained high until the last developmental stage examined (P5). Anti-MAP2, another neuron-specific marker, never labeled the cells of the ventricular and subventricular zones, pre- or postnatally. To determine the birthdates of TuJ1-positive cells in the cortical-ventricular and subventricular zones, brains were double labeled with TuJ1 and bromodeoxyuridine according to different pulse-chase schedules. TuJ1-positive cells were postmitotic and generated throughout the period of cortical neurogenesis. Collectively, the results suggest that TuJ1 immunoreactivity distinguishes two neuronal populations: those that remain for an indefinite period of time in the proliferative zones, and those that leave the proliferative zones soon after being generated. Although the fate of the TuJ1-positive cells that reside in the proliferative zones remains unclear, their tangentially aligned orientation and their distribution suggest that they migrate independent of radial glial fibers.

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