Tamoxifen exerts direct and microglia-mediated effects preventing neuroinflammatory changes in the adult mouse hippocampal neurogenic niche.

Tamoxifen-inducible systems are widely used in research to control Cre-mediated gene deletion in genetically modified animals. Beyond Cre activation, tamoxifen also exerts off-target effects, whose consequences are still poorly addressed. Here, we investigated the impact of tamoxifen on lipopolysaccharide (LPS)-induced neuroinflammatory responses, focusing on the neurogenic activity in the adult mouse dentate gyrus. We demonstrated that a four-day LPS treatment led to an increase in microglia, astrocytes and radial glial cells with concomitant reduction of newborn neurons. These effects were counteracted by a two-day tamoxifen pre-treatment. Through selective microglia depletion, we elucidated that both LPS and tamoxifen influenced astrogliogenesis via microglia mediated mechanisms, while the effects on neurogenesis persisted even in a microglia-depleted environment. Notably, changes in radial glial cells resulted from a combination of microglia-dependent and -independent mechanisms. Overall, our data reveal that tamoxifen treatment per se does not alter the balance between adult neurogenesis and astrogliogenesis but does modulate cellular responses to inflammatory stimuli exerting a protective role within the adult hippocampal neurogenic niche.

Sex Steroids and the Shaping of the Peripubertal Brain: The Sexual-Dimorphic Set-Up of Adult Neurogenesis.

Steroid hormones represent an amazing class of molecules that play pleiotropic roles in vertebrates. In mammals, during postnatal development, sex steroids significantly influence the organization of sexually dimorphic neural circuits underlying behaviors critical for survival, such as the reproductive one. During the last decades, multiple studies have shown that many cortical and subcortical brain regions undergo sex steroid-dependent structural organization around puberty, a critical stage of life characterized by high sensitivity to external stimuli and a profound structural and functional remodeling of the organism. Here, we first give an overview of current data on how sex steroids shape the peripubertal brain by regulating neuroplasticity mechanisms. Then, we focus on adult neurogenesis, a striking form of persistent structural plasticity involved in the control of social behaviors and regulated by a fine-tuned integration of external and internal cues. We discuss recent data supporting that the sex steroid-dependent peripubertal organization of neural circuits involves a sexually dimorphic set-up of adult neurogenesis that in turn could be relevant for sex-specific reproductive behaviors.

Neurogranin Regulates Adult-Born Olfactory Granule Cell Spine Density and Odor-Reward Associative Memory in Mice.

Neurogranin (Ng) is a brain-specific postsynaptic protein, whose role in modulating Ca2+/calmodulin signaling in glutamatergic neurons has been linked to enhancement in synaptic plasticity and cognitive functions. Accordingly, Ng knock-out (Ng-ko) mice display hippocampal-dependent learning and memory impairments associated with a deficit in long-term potentiation induction. In the adult olfactory bulb (OB), Ng is expressed by a large population of GABAergic granule cells (GCs) that are continuously generated during adult life, undergo high synaptic remodeling in response to the sensory context, and play a key role in odor processing. However, the possible implication of Ng in OB plasticity and function is yet to be investigated. Here, we show that Ng expression in the OB is associated with the mature state of adult-born GCs, where its active-phosphorylated form is concentrated at post-synaptic sites. Constitutive loss of Ng in Ng-ko mice resulted in defective spine density in adult-born GCs, while their survival remained unaltered. Moreover, Ng-ko mice show an impaired odor-reward associative memory coupled with reduced expression of the activity-dependent transcription factor Zif268 in olfactory GCs. Overall, our data support a role for Ng in the molecular mechanisms underlying GC plasticity and the formation of olfactory associative memory.

Striatal astrocytes produce neuroblasts in an excitotoxic model of Huntington's disease.

In the adult brain, subsets of astrocytic cells residing in well-defined neurogenic niches constitutively generate neurons throughout life. Brain lesions can stimulate neurogenesis in otherwise non-neurogenic regions, but whether local astrocytic cells generate neurons in these conditions is unresolved. Here, through genetic and viral lineage tracing in mice, we demonstrate that striatal astrocytes become neurogenic following an acute excitotoxic lesion. Similar to astrocytes of adult germinal niches, these activated parenchymal progenitors express nestin and generate neurons through the formation of transit amplifying progenitors. These results shed new light on the neurogenic potential of the adult brain parenchyma.

Quiescent neuronal progenitors are activated in the juvenile guinea pig lateral striatum and give rise to transient neurons.

In the adult brain, active stem cells are a subset of astrocytes residing in the subventricular zone (SVZ) and the dentate gyrus (DG) of the hippocampus. Whether quiescent neuronal progenitors occur in other brain regions is unclear. Here, we describe a novel neurogenic system in the external capsule and lateral striatum (EC-LS) of the juvenile guinea pig that is quiescent at birth but becomes active around weaning. Activation of neurogenesis in this region was accompanied by the emergence of a neurogenic-like niche in the ventral EC characterized by chains of neuroblasts, intermediate-like progenitors and glial cells expressing markers of immature astrocytes. Like neurogenic astrocytes of the SVZ and DG, these latter cells showed a slow rate of proliferation and retained BrdU labeling for up to 65 days, suggesting that they are the primary progenitors of the EC-LS neurogenic system. Injections of GFP-tagged lentiviral vectors into the SVZ and the EC-LS of newborn animals confirmed that new LS neuroblasts originate from the activation of local progenitors and further supported their astroglial nature. Newborn EC-LS neurons existed transiently and did not contribute to neuronal addition or replacement. Nevertheless, they expressed Sp8 and showed strong tropism for white matter tracts, wherein they acquired complex morphologies. For these reasons, we propose that EC-LS neuroblasts represent a novel striatal cell type, possibly related to those populations of transient interneurons that regulate the development of fiber tracts during embryonic life.

Odour enrichment increases adult-born dopaminergic neurons in the mouse olfactory bulb.

The olfactory bulb (OB) is the first brain region involved in the processing of olfactory information. In adult mice, the OB is highly plastic, undergoing cellular/molecular dynamic changes that are modulated by sensory experience. Odour deprivation induces down-regulation of tyrosine hydroxylase (TH) expression in OB dopaminergic interneurons located in the glomerular layer (GL), resulting in decreased dopamine in the OB. Although the effect of sensory deprivation is well established, little is known about the influence of odour enrichment on dopaminergic cells. Here we report that prolonged odour enrichment on C57BL/6J strain mice selectively increases TH-immunopositive cells in the GL by nearly 20%. Following odour enrichment on TH-green fluorescent protein (GFP) transgenic mice, in which GFP identified both mature TH-positive cells and putative immature dopaminergic cells expressing TH mRNA but not TH protein, we found a similar 20% increase in GFP-expressing cells, with no changes in the ratio between TH-positive and TH-negative cells. These data suggest that enriched conditions induce an expansion in the whole dopaminergic lineage. Accordingly, by using 5-bromo-2-deoxyuridine injections to label adult-generated cells in the GL of TH-GFP mice, we found an increase in the percentage of 5-bromo-2-deoxyuridine-positive dopaminergic cells in enriched compared with control conditions, whereas no differences were found for calretinin- and calbindin-positive subtypes. Strikingly, the fraction of newborn cells among the dopaminergic population doubled in enriched conditions. On the whole, our results demonstrate that odour enrichment drives increased integration of adult-generated dopaminergic cells that could be critical to adapt the OB circuits to the environmental incoming information.

The interplay between reproductive social stimuli and adult olfactory bulb neurogenesis.

Adult neurogenesis is a striking form of structural plasticity that adapts the brain to the changing world. Accordingly, new neuron production is involved in cognitive functions, such as memory, learning, and pattern separation. Recent data in rodents indicate a close link between adult neurogenesis and reproductive social behavior. This provides a key to unravel the functional meaning of adult neurogenesis in biological relevant contexts and, in parallel, opens new perspectives to explore the way the brain is processing social stimuli. In this paper we will summarize some of the major achievements on cues and mechanisms modulating adult neurogenesis during social behaviors related to reproduction and possible role/s played by olfactory newborn neurons in this context. We will point out that newborn interneurons in the accessory olfactory bulb (AOB) represent a privileged cellular target for social stimuli that elicit reproductive behaviors and that such cues modulate adult neurogenesis at two different levels increasing both proliferation of neuronal progenitors in the germinative regions and integration of newborn neurons into functional circuits. This dual mechanism provides fresh neurons that can be involved in critical activities for the individual fitness, that is, the processing of social stimuli driving the parental behavior and partner recognition.

NR2F1 shapes mitochondria in the mouse brain, providing new insights into Bosch-Boonstra-Schaaf optic atrophy syndrome.

The nuclear receptor NR2F1 acts as a strong transcriptional regulator in embryonic and postnatal neural cells. In humans, mutations in the NR2F1 gene cause Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS), a rare neurodevelopmental disorder characterized by multiple clinical features including vision impairment, intellectual disability and autistic traits. In this study, we identified, by genome-wide and in silico analyses, a set of nuclear-encoded mitochondrial genes as potential genomic targets under direct NR2F1 transcriptional control in neurons. By combining mouse genetic, neuroanatomical and imaging approaches, we demonstrated that conditional NR2F1 loss of function within the adult mouse hippocampal neurogenic niche results in a reduced mitochondrial mass associated with mitochondrial fragmentation and downregulation of key mitochondrial proteins in newborn neurons, the genesis, survival and functional integration of which are impaired. Importantly, we also found dysregulation of several nuclear-encoded mitochondrial genes and downregulation of key mitochondrial proteins in the brain of Nr2f1-heterozygous mice, a validated BBSOAS model. Our data point to an active role for NR2F1 in the mitochondrial gene expression regulatory network in neurons and support the involvement of mitochondrial dysfunction in BBSOAS pathogenesis.

Adult neurogenesis in mammals--a theme with many variations.

Investigations of adult neurogenesis in recent years have revealed numerous differences among mammalian species, reflecting the remarkable diversity in brain anatomy and function of mammals. As a mechanism of brain plasticity, adult neurogenesis might also differ due to behavioural specialization or adaptation to specific ecological niches. Because most research has focused on rodents and only limited data are available on other mammalian orders, it is hotly debated whether, in some species, adult neurogenesis also takes place outside of the well-characterized subventricular zone of the lateral ventricle and subgranular zone of the dentate gyrus. In particular, evidence for the functional integration of new neurons born in 'non-neurogenic' zones is controversial. Considering the promise of adult neurogenesis for regenerative medicine, we posit that differences in the extent, regional occurrence and completion of adult neurogenesis need to be considered from a species-specific perspective. In this review, we provide examples underscoring that the mechanisms of adult neurogenesis cannot simply be generalized to all mammalian species. Despite numerous similarities, there are distinct differences, notably in neuronal maturation, survival and functional integration in existing synaptic circuits, as well as in the nature and localization of neural precursor cells. We also propose a more appropriate use of terminology to better describe these differences and their relevance for brain plasticity under physiological and pathophysiological conditions. In conclusion, we emphasize the need for further analysis of adult neurogenesis in diverse mammalian species to fully grasp the spectrum of variation of this adaptative mechanism in the adult CNS.

DCX and PSA-NCAM expression identifies a population of neurons preferentially distributed in associative areas of different pallial derivatives and vertebrate species.

In adult rodents, doublecortin (DCX) and polysialylated neural cell adhesion molecule (PSA-NCAM) expression is mostly restricted to newly generated neurons. These molecules have also been described in prenatally generated cells of the piriform cortex and, to a lesser extent, neocortex (NC) of the rat. In addition, PSA-NCAM+ cells have been identified in several telencephalic regions of the lizard. Here, through immunohistochemistry and 3-dimensional reconstruction, we have investigated distribution, morphology, and phenotype of DCX/PSA-NCAM-expressing cells in the pallium of different mammals and in lizard. In all species, a population of nonnewly-generated pallial DCX+/PSA-NCAM+ cells shows common morphological and phenotypic characteristics, including expression of Tbr-1, a transcription factor expressed in pallial projection neurons, and preferential distribution in associative areas. In the guinea pig and rabbit, DCX+/PSA-NCAM+ elements are also abundant in the NC, particularly in areas implicated in nonspatial learning and memory networks. In reptiles, DCX+/PSA-NCAM+ cells are located in the lateral and medial cortex and dorsal ventricular ridge but not in the dorsal cortex. These data support the fact that coexpression of DCX+/PSA-NCAM+/Tbr-1+ in the adult brain identifies evolutionary conserved cell populations shared by different pallial derivatives including the mammalian NC.

HPG-Dependent Peri-Pubertal Regulation of Adult Neurogenesis in Mice.

Adult neurogenesis, a striking form of neural plasticity, is involved in the modulation of social stimuli driving reproduction. Previous studies on adult neurogenesis have shown that this process is significantly modulated around puberty in female mice. Puberty is a critical developmental period triggered by increased secretion of the gonadotropin releasing hormone (GnRH), which controls the activity of the hypothalamic-pituitary-gonadal axis (HPG). Secretion of HPG-axis factors at puberty participates to the refinement of neural circuits that govern reproduction. Here, by exploiting a transgenic GnRH deficient mouse model, that progressively loses GnRH expression during postnatal development (GnRH::Cre;Dicer loxP/loxP mice), we found that a postnatally-acquired dysfunction in the GnRH system affects adult neurogenesis selectively in the subventricular-zone neurogenic niche in a sexually dimorphic way. Moreover, by examining adult females ovariectomized before the onset of puberty, we provide important evidence that, among the HPG-axis secreting factors, the circulating levels of gonadal hormones during pre-/peri-pubertal life contribute to set-up the proper adult subventricular zone-olfactory bulb neurogenic system.

Radial glial origin of the adult neural stem cells in the subventricular zone.

Adult neurogenesis persists within restricted areas of the mammalian brain, giving rise prevalently to neuronal precursors that integrate inside the hippocampus and olfactory bulb. The source of this continuous cell production consists of neural stem cells which have been identified as elements of the astroglial lineage. This counterintuitive finding overlaps with the recent discovery that embryonic radial glia can themselves act as stem cells, capable of producing both neurons and glia during development. Although radial glia was thought to disappear early postnatally at the end of neurogenesis by transformation into parenchymal astrocytes, it has recently been demonstrated that some radial glial cells somehow persist within the adult forebrain subventricular zone, hidden among astrocytes of the glial tubes. This transformation occurs in parallel with overall morphological and molecular changes within the neurogenic site, whose specific steps, mechanisms, and outcomes are not yet fully understood. The modified radial glia appear to be neural progenitor cells belonging to the astroglial lineage (type B cells) assuring both stem cell self-renewal and production of a differentiated progeny in the adult subventricular zone, and also playing regulatory roles in stem cell niche maintenance.

Activation of the Wnt-beta catenin pathway in a cell population on the surface of the forebrain is essential for the establishment of olfactory axon connections.

A variety of signals governing early extension, guidance, and connectivity of olfactory receptor neuron (ORN) axons has been identified; however, little is known about axon-mesoderm and forebrain (FB)-mesoderm signals. Using Wnt-beta catenin reporter mice, we identify a novel Wnt-responsive resident cell population, located in a Frizzled7 expression domain at the surface of the embryonic FB, along the trajectory of incoming ORN axons. Organotypic slice cultures that recapitulate olfactory-associated Wnt-beta catenin activation show that the beta catenin response depends on a placode-derived signal(s). Likewise, in Dlx5-/- embryos, in which the primary connections fail to form, Wnt-beta catenin response on the surface of the FB is strongly reduced. The olfactory placode expresses a number of beta catenin-activating Wnt genes, and the Frizzled7 receptor transduces the "canonical" Wnt signal; using Wnt expression plasmids we show that Wnt5a and Wnt7b are sufficient to rescue beta catenin activation in the absence of incoming axons. Finally, blocking the canonical Wnt pathway with the exogenous application of the antagonists Dikkopf-1 or secreted-Frizzled-receptor protein-2 prevents ORN axon contact to the FB. These data reveal a novel function for Wnt signaling in the establishment of periphery-CNS olfactory connections and highlight a complex interplay between cells of different embryonic origin for ORN axon connectivity.

Generation of distinct types of periglomerular olfactory bulb interneurons during development and in adult mice: implication for intrinsic properties of the subventricular zone progenitor population.

The subventricular zone (SVZ) of the lateral ventricle develops from residual progenitors of the embryonic lateral ganglionic eminence (LGE) and maintains neurogenic activity throughout life. Precursors from LGE/SVZ migrate to the olfactory bulb (OB) where they differentiate into local interneurons, principally in the granule layer and glomerular layer (GL). By in situ dye labeling, we show that neonatal and adult SVZ progenitors differentially contribute to neurochemically distinct types of periglomerular interneurons in the GL. Namely, calbindin-positive periglomerular cells are preferentially generated during early life, whereas calretinin- and tyrosine hydroxylase-expressing neurons are mainly produced at later ages. Furthermore, homochronic/heterochronic transplantation demonstrates that progenitor cells isolated from the LGE or SVZ at different stages (embryonic day 15 and postnatal days 2 and 30) engraft into the SVZ of neonatal or adult mice, migrate to the OB, and differentiate into local interneurons, including granule and periglomerular cells as well as other types of interneurons. The total number of integrated cells and the relative proportion of granule or periglomerular neurons change, according to the donor age, whereas they are weakly influenced by the recipient age. Analysis of the neurochemical phenotypes acquired by transplanted cells in the GL shows that donor cells of different ages also differentiate according to their origin, regardless of the host age. This suggests that progenitor cells at different ontogenetic stages are intrinsically directed toward specific lineages. Neurogenic processes occurring during development and in adult OB are not equivalent and produce different types of periglomerular interneurons as a consequence of intrinsic properties of the SVZ progenitors.

Neurogenesis in the caudate nucleus of the adult rabbit.

Stem cells with the potential to give rise to new neurons reside in different regions of the adult rodents CNS, but in vivo only the hippocampal dentate gyrus and the subventricular zone-olfactory bulb system are neurogenic under physiological condition. Comparative analyses have shown that vast species differences exist in the way the mammalian brain is organized and in its neurogenic capacity. Accordingly, we have demonstrated recently that, in the adult rabbit brain, striking structural plasticity persists in several cortical and subcortical areas. Here, by using markers for immature and mature neuronal and glial cell types, endogenous and exogenously administered cell-proliferation markers, intraventricular cell tracer injections coupled to confocal analysis, three-dimensional reconstructions, and in vitro tissue cultures, we demonstrate the existence of newly formed neurons in the caudate nucleus of normal, untreated, adult rabbit. Our results suggest that neurogenesis in the caudate nucleus is a phenomenon independent from that occurring in the adjacent subventricular zone, mostly attributable to the activity of clusters of proliferating cells located within the parenchyma of this nucleus. These clusters originate chains of neuroblasts that ultimately differentiate into mature neurons, which represent only a small percentage of the total neuronal precursors. These results indicate that striatum of rabbit represents a favorable environment for genesis rather than survival of newly formed neurons.

Spatio-temporal specification of olfactory bulb interneurons.

Olfactory bulb (OB) interneurons are continuously generated throughout development and in adulthood, and are derived from different progenitor zones. Once integrated in the OB circuits, interneurons play essential roles in olfactory information processing by modulating the activity of major output neurons. These functions are performed by multiple classes of neurons that differ in their spatial distribution, morphology, neurochemical and synaptic properties. This diversity, and the continuous neurogenesis make the understanding of the specification mechanisms in the OB a challenging task. New studies suggest that both intrinsic and extrinsic cues are involved in fate determination of OB interneurons. In both development and adulthood the expression of specific transcription factors not only defines different progenitor regions but also precise interneuronal phenotypes. Here we discuss recent findings on the molecular mechanisms regulating production and diversity of OB interneurons with respect to the spatial and temporal parameters.

The role of Dlx homeogenes in early development of the olfactory pathway.

Development of the olfactory pathway requires interaction between cells and signals of different origin. Olfactory receptor neurons (ORN) in the olfactory placodes (OP) extend axons towards the forebrain (FB); with innervation taking place at a later time following degradation of the basement membrane. Cells from the OP migrate along ORN axons and differentiate into various elements, including ensheathing and Gonadotropin Releasing Hormone (GnRH)+ cells. The importance of the olfactory connection and migration is highlighted by the severe endocrine phenotype in Kallmann's patients who lack this migratory pathway. Little is known about the genetic control of intrinsic ORN properties. Inactivation of the distalless-related Dlx5 prevents connections between ORNs and FB. Using a grafting approach we show that misguidance and lack of connectivity is due to intrinsic defects in ORN neurites and migratory cells (MgC), and not to environmental factors. These data point to a cell-autonomous function of Dlx5 in providing ORN axons with their connectivity properties. Dlx5 also marks a population of early MgC that partly overlaps with the GnRH+ population. In the absence of Dlx5 MgCs of the Dlx5+ lineage migrate, associated with PSA-NCAM+ axons, but fail to reach the FB as a consequence of the lack of axonal connection and not an inability to migrate. These data suggests that Dlx5 is not required to initiate migration and differentiation of MgCs.

Activity Dependent Modulation of Granule Cell Survival in the Accessory Olfactory Bulb at Puberty.

The vomeronasal system (VNS) is specialized in the detection of salient chemical cues triggering social and neuroendocrine responses. Such responses are not always stereotyped, instead, they vary depending on age, sex, and reproductive state, yet the mechanisms underlying this variability are unclear. Here, by analyzing neuronal survival in the first processing nucleus of the VNS, namely the accessory olfactory bulb (AOB), through multiple bromodeoxyuridine birthdating protocols, we show that exposure of female mice to male soiled bedding material affects the integration of newborn granule interneurons mainly after puberty. This effect is induced by urine compounds produced by mature males, as bedding soiled by younger males was ineffective. The granule cell increase induced by mature male odor exposure is not prevented by pre-pubertal ovariectomy, indicating a lesser role of circulating estrogens in this plasticity. Interestingly, the intake of adult male urine-derived cues by the female vomeronasal organ increases during puberty, suggesting a direct correlation between sensory activity and AOB neuronal plasticity. Thus, as odor exposure increases the responses of newly born cells to the experienced stimuli, the addition of new GABAergic inhibitory cells to the AOB might contribute to the shaping of vomeronasal processing of male cues after puberty. Consistently, only after puberty, female mice are capable to discriminate individual male odors through the VNS.

Vitamin D3 protects against Aß peptide cytotoxicity in differentiated human neuroblastoma SH- SY5Y cells: A role for S1P1/p38MAPK/ATF4 axis.

Besides its classical function of bone metabolism regulation, 1alpha, 25-dihydroxyvitamin D3 (1,25(OH)2D3), acts on a variety of tissues including the nervous system, where the hormone plays an important role as neuroprotective, antiproliferating and differentiating agent. Sphingolipids are bioactive lipids that play critical and complex roles in regulating cell fate. In the present paper we have investigated whether sphingolipids are involved in the protective action of 1,25(OH)2D3. We have found that 1,25(OH)2D3 prevents amyloid-ß peptide (Aß(1-42)) cytotoxicity both in differentiated SH-SY5Y human neuroblastoma cells and in vivo. In differentiated SH-SY5Y cells, Aß(1-42) strongly reduces the sphingosine-1-phosphate (S1P)/ceramide (Cer) ratio while 1,25(OH)2D3 partially reverts this effect. 1,25(OH)2D3 reverts also the Aß(1-42)-induced reduction of sphingosine kinase activity. We have also studied the crosstalk between 1,25(OH)2D3 and S1P signaling pathways downstream to the activation of S1P receptor subtype S1P1. Notably, we found that 1,25(OH)2D3 prevents the reduction of S1P1 expression promoted by Aß(1-42) and thereby it modulates the downstream signaling leading to ER stress damage (p38MAPK/ATF4). Similar effects were observed by using ZK191784. In addition, chronic treatment with 1,25(OH)2D3 protects from aggregated Aß(1-42)-induced damage in the CA1 region of the rat hippocampus and promotes cell proliferation in the hippocampal dentate gyrus of adult mice. In conclusion, these results represent the first evidence of the role of 1,25(OH)2D3 and its structural analogue ZK191784 in counteracting the Aß(1-42) peptide-induced toxicity through the modulation of S1P/S1P1/p38MAPK/ATF4 pathway in differentiated SH-SY5Y cells.

cAMP response element-binding protein regulates differentiation and survival of newborn neurons in the olfactory bulb.

The transcription factor cAMP response element-binding protein (CREB) is involved in multiple aspects of neuronal development and plasticity. Here, we demonstrate that CREB regulates specific phases of adult neurogenesis in the subventricular zone/olfactory bulb (SVZ/OB) system. Combining immunohistochemistry with bromodeoxyuridine treatments, cell tracer injections, cell transplants, and quantitative analyses, we show that although CREB is expressed by the SVZ neuroblasts throughout the neurogenic process, its phosphorylation is transient and parallels neuronal differentiation, increasing during the late phase of tangential migration and decreasing after dendrite elongation and spine formation. In vitro, inhibition of CREB function impairs morphological differentiation of SVZ-derived neuroblasts. Transgenic mice lacking CREB, in a null CREM genetic background, show reduced survival of newborn neurons in the OB. This finding is further supported by peripheral afferent denervation experiments resulting in downregulation of CREB phosphorylation in neuroblasts, the survival of which appears heavily impaired. Together, these findings provide evidence that CREB regulates differentiation and survival of newborn neurons in the OB.