Throughout adulthood, the brain continuously generates new neurons in two neurogenic regions: the subgranular zone of the hippocampus and the subventricular zone on the lateral wall of the lateral ventricles. These neurons have been shown to integrate into hippocampal and olfactory bulb circuitry, respectively. Nevertheless, their specific contribution to hippocampal or olfactory function remains unclear. Previous studies have tried to assess adult born neuron contribution to memory function by suppressing neurogenesis and examining the impact on memory acquisition. Although ablation of neurogenesis has been shown to impair performance in hippocampus dependent and olfactory tasks, many studies fail to see an effect. Compensation from residual cells in either system after ablation may underlie these contradictory findings. Thus, a more direct approach to answer this question would be to ablate adult born neurons after their incorporation into the memory trace. To do this, we established a double transgenic strategy to tag and selectively ablate adult born neurons with temporal control. Ablation of a population of predominantly mature, adult generated dentate granule cells did not prevent acquisition of contextual fear conditioning or Morris Water Maze memories. Removal of that same population of cells after training, however, led to memory degradation in three hippocampus dependent tasks. Similarly, post-training ablation of a population of adult generated olfactory interneurons iii impaired performance in an associative odour memory task, whereas pre-training ablation had no impact. Together, these data show that adult generated neurons form a crucial component of both hippocampal and olfactory memory traces.

Although once thought to be incapable of regeneration, the adult mammalian brain generates new neurons in two regions: the SVZ of the lateral ventricle and the DG of the hippocampus. While the cell types involved in adult neurogenesis have been broadly characterized, the transcriptional regulation of this process remains poorly understood. Here, we demonstrate that transcription factor Cux2 is important for normal postnatal hippocampal neurogenesis. Cux2neo/neo mutant mice generated fewer Dcx-positive neuroblasts, Tbr2-positive transit amplifers, and Calretinin-positive immature neurons, without affecting gliogenesis. Moreover, we show that Cux2 is principally expressed in Type1/Type2a cells. Using cultured embryonic NPCs we show that Cux2 mutants generate fewer neurons. Indeed, Cux2 plays a pro-neuronal role in both the postnatal hippocampus and in cultured embryonic NPCs. Cux2 may thus serve as an important regulator of the neuronal fate and may be a novel marker for neuronally committed Type 1/2a NPCs in the postnatal DG.

Adult neurogenesis is a conserved feature of the central nervous system across the animal kingdom. This process takes place in restricted neurogenic niches of the brain, where active populations of adult stem/progenitor cells are capable of producing newborn neurons. The niche is tightly controlled by intrinsic signals within the microenvironment and from stimuli arising from the external world, which together determine the cellular behaviour of the niche and neuronal output. Currently, our understanding of the biological properties of adult neurogenesis rests mainly on two niches of the vertebrate forebrain. To broaden our view of the diversity of this trait comparative models and new niches must be explored. Here, I have taken advantage of the robust neurogenic capacity of the adult zebrafish brain to examine differences in forebrain and sensory neurogenic niches in regards to cytoarchitectural organization, neurogenic plasticity, and regulation. Five principle findings emerge: (1) up to six morphologically distinct cell types compose forebrain and sensory niches, and are devoid of ependymal cells; (2) heterogeniety in the phenotype of the stem/progenitor cell exists across niches; some having radial glial characteristics; (3) active populations of proliferating stem/progenitor cells reside within primary sensory structures of the adult brain, forming a “sensory neurogenic niche”; different from other models of adult neurogenesis; (4) changes in the social environment induce neurogenic plasticity in sensory niches more readily than integrative niches of the forebrain, and occur independently of cortisol levels; (5) modality-specific stimulation influences stages of adult neurogenesis exclusively in corresponding primary sensory niches as a result of sensory-dependent neurogenic plasticity. Additionally, I have shown that Fibroblast Growth Factor signalling may not be involved in maintaining cell proliferation in sensory niches. These studies showcase the diverse properties of forebrain and sensory neurogenic niches and provide a new perspective concerning the functional role of adult neurogenesis.

Throughout adulthood, the brain continuously generates new neurons in two neurogenic regions: the subgranular zone of the hippocampus and the subventricular zone on the lateral wall of the lateral ventricles. These neurons have been shown to integrate into hippocampal and olfactory bulb circuitry, respectively. Nevertheless, their specific contribution to hippocampal or olfactory function remains unclear. Previous studies have tried to assess adult born neuron contribution to memory function by suppressing neurogenesis and examining the impact on memory acquisition. Although ablation of neurogenesis has been shown to impair performance in hippocampus dependent and olfactory tasks, many studies fail to see an effect. Compensation from residual cells in either system after ablation may underlie these contradictory findings. Thus, a more direct approach to answer this question would be to ablate adult born neurons after their incorporation into the memory trace. To do this, we established a double transgenic strategy to tag and selectively ablate adult born neurons with temporal control. Ablation of a population of predominantly mature, adult generated dentate granule cells did not prevent acquisition of contextual fear conditioning or Morris Water Maze memories. Removal of that same population of cells after training, however, led to memory degradation in three hippocampus dependent tasks. Similarly, post-training ablation of a population of adult generated olfactory interneurons iii impaired performance in an associative odour memory task, whereas pre-training ablation had no impact. Together, these data show that adult generated neurons form a crucial component of both hippocampal and olfactory memory traces.

Neurogenesis is the process by which functionally integrated neurons are generated from progenitor cells. In the adult mammalian brain two sites of high density cell division have been identified that contain neural progenitor cells retaining the ability to generate new neurons: the subgranular zone of the hippocampus (SGZ) and the subventricular zone (SVZ) lining the lateral ventricles in the forebrain. Several studies have suggested that SVZ neural progenitor cells in the adult brain can migrate into regions other than the olfactory bulb after either administration of growth factors, induction of neuronal cell loss or injury. Brain-derived neurotrophic factor (BDNF) and fibroblast growth factor (FGF-2) play major roles in regulating the survival and fate of progenitor cells in the adult mammalian brain. To determine the effect of BDNF or FGF-2 on neurogenesis in the injured adult brain, BDNF or FGF-2 were over-expressed in the subventricular zone (SVZ) via recombinant adeno-associated virus (AAV1/2) delivery and newly generated cells were identified using bromodeoxyuridine (BrdU; 150mg/kg intraperitoneal) labelling. Selective striatal cell loss was induced in a subgroup of rats by unilateral striatal injection of the excitotoxin quinolinic acid (QA) 21 days after AAV1/2 injection and 24 hours prior to BrdU labeling. The results of this thesis demonstrate that BDNF augments the recruitment, neuronal differentiation and survival of progenitor cells in both neurogenic and non-neurogenic regions of the unlesioned or QA lesioned brain. BDNF also appears to contribute to the persistence of newly generated neurons in the QA lesioned striatum. Our results provide the first evidence demonstrating the neurogenic effect of BDNF on compensatory striatal neurogenesis in the injured adult brain and suggest that enhanced BDNF expression may be a viable strategy for inducing or augmenting endogenous neural progenitor cell neurogenesis. Unlike the effect of BDNF, FGF-2 appears to have no effect on proliferation and/or survival of neural progenitor cells in either the normal or damaged brain. FGF-2 appears to be unable to act as a positive mediator of SVZ progenitor cell proliferation and neurogenesis in this study. However, FGF-2 may be having an inhibitory effect on progenitor cell differentiation. The negative result of the FGF-2 study may be of major significance in indicating the potential requirement of additional factors interacting with FGF-2 to influence neurogenesis. The results from the FGF-2 study contribute to the research field in highlighting the complexity of the mammalian neurogenic process. This thesis highlights the need for further investigation into multiple factor interactions, tighter regulation of the transgenic protein expression from the AAV1/2 delivery vector or alternative progenitor cell labelling paradigms. However, it does show that if neurogenesis can be induced or augmented exogenously, neural progenitor cells may provide a substrate for repair in the adult brain and dramatically change therapeutic approaches towards the treatment of neurodegenerative diseases.

Neurogenesis is the process by which functionally integrated neurons are generated from progenitor cells. In the adult mammalian brain two sites of high density cell division have been identified that contain neural progenitor cells retaining the ability to generate new neurons: the subgranular zone of the hippocampus (SGZ) and the subventricular zone (SVZ) lining the lateral ventricles in the forebrain. Several studies have suggested that SVZ neural progenitor cells in the adult brain can migrate into regions other than the olfactory bulb after either administration of growth factors, induction of neuronal cell loss or injury. Brain-derived neurotrophic factor (BDNF) and fibroblast growth factor (FGF-2) play major roles in regulating the survival and fate of progenitor cells in the adult mammalian brain. To determine the effect of BDNF or FGF-2 on neurogenesis in the injured adult brain, BDNF or FGF-2 were over-expressed in the subventricular zone (SVZ) via recombinant adeno-associated virus (AAV1/2) delivery and newly generated cells were identified using bromodeoxyuridine (BrdU; 150mg/kg intraperitoneal) labelling. Selective striatal cell loss was induced in a subgroup of rats by unilateral striatal injection of the excitotoxin quinolinic acid (QA) 21 days after AAV1/2 injection and 24 hours prior to BrdU labeling. The results of this thesis demonstrate that BDNF augments the recruitment, neuronal differentiation and survival of progenitor cells in both neurogenic and non-neurogenic regions of the unlesioned or QA lesioned brain. BDNF also appears to contribute to the persistence of newly generated neurons in the QA lesioned striatum. Our results provide the first evidence demonstrating the neurogenic effect of BDNF on compensatory striatal neurogenesis in the injured adult brain and suggest that enhanced BDNF expression may be a viable strategy for inducing or augmenting endogenous neural progenitor cell neurogenesis. Unlike the effect of BDNF, FGF-2 appears to have no effect on proliferation and/or survival of neural progenitor cells in either the normal or damaged brain. FGF-2 appears to be unable to act as a positive mediator of SVZ progenitor cell proliferation and neurogenesis in this study. However, FGF-2 may be having an inhibitory effect on progenitor cell differentiation. The negative result of the FGF-2 study may be of major significance in indicating the potential requirement of additional factors interacting with FGF-2 to influence neurogenesis. The results from the FGF-2 study contribute to the research field in highlighting the complexity of the mammalian neurogenic process. This thesis highlights the need for further investigation into multiple factor interactions, tighter regulation of the transgenic protein expression from the AAV1/2 delivery vector or alternative progenitor cell labelling paradigms. However, it does show that if neurogenesis can be induced or augmented exogenously, neural progenitor cells may provide a substrate for repair in the adult brain and dramatically change therapeutic approaches towards the treatment of neurodegenerative diseases.

Neurogenesis is the process by which functionally integrated neurons are generated from progenitor cells. In the adult mammalian brain two sites of high density cell division have been identified that contain neural progenitor cells retaining the ability to generate new neurons: the subgranular zone of the hippocampus (SGZ) and the subventricular zone (SVZ) lining the lateral ventricles in the forebrain. Several studies have suggested that SVZ neural progenitor cells in the adult brain can migrate into regions other than the olfactory bulb after either administration of growth factors, induction of neuronal cell loss or injury. Brain-derived neurotrophic factor (BDNF) and fibroblast growth factor (FGF-2) play major roles in regulating the survival and fate of progenitor cells in the adult mammalian brain. To determine the effect of BDNF or FGF-2 on neurogenesis in the injured adult brain, BDNF or FGF-2 were over-expressed in the subventricular zone (SVZ) via recombinant adeno-associated virus (AAV1/2) delivery and newly generated cells were identified using bromodeoxyuridine (BrdU; 150mg/kg intraperitoneal) labelling. Selective striatal cell loss was induced in a subgroup of rats by unilateral striatal injection of the excitotoxin quinolinic acid (QA) 21 days after AAV1/2 injection and 24 hours prior to BrdU labeling. The results of this thesis demonstrate that BDNF augments the recruitment, neuronal differentiation and survival of progenitor cells in both neurogenic and non-neurogenic regions of the unlesioned or QA lesioned brain. BDNF also appears to contribute to the persistence of newly generated neurons in the QA lesioned striatum. Our results provide the first evidence demonstrating the neurogenic effect of BDNF on compensatory striatal neurogenesis in the injured adult brain and suggest that enhanced BDNF expression may be a viable strategy for inducing or augmenting endogenous neural progenitor cell neurogenesis. Unlike the effect of BDNF, FGF-2 appears to have no effect on proliferation and/or survival of neural progenitor cells in either the normal or damaged brain. FGF-2 appears to be unable to act as a positive mediator of SVZ progenitor cell proliferation and neurogenesis in this study. However, FGF-2 may be having an inhibitory effect on progenitor cell differentiation. The negative result of the FGF-2 study may be of major significance in indicating the potential requirement of additional factors interacting with FGF-2 to influence neurogenesis. The results from the FGF-2 study contribute to the research field in highlighting the complexity of the mammalian neurogenic process. This thesis highlights the need for further investigation into multiple factor interactions, tighter regulation of the transgenic protein expression from the AAV1/2 delivery vector or alternative progenitor cell labelling paradigms. However, it does show that if neurogenesis can be induced or augmented exogenously, neural progenitor cells may provide a substrate for repair in the adult brain and dramatically change therapeutic approaches towards the treatment of neurodegenerative diseases.

Neurogenesis is the process by which functionally integrated neurons are generated from progenitor cells. In the adult mammalian brain two sites of high density cell division have been identified that contain neural progenitor cells retaining the ability to generate new neurons: the subgranular zone of the hippocampus (SGZ) and the subventricular zone (SVZ) lining the lateral ventricles in the forebrain. Several studies have suggested that SVZ neural progenitor cells in the adult brain can migrate into regions other than the olfactory bulb after either administration of growth factors, induction of neuronal cell loss or injury. Brain-derived neurotrophic factor (BDNF) and fibroblast growth factor (FGF-2) play major roles in regulating the survival and fate of progenitor cells in the adult mammalian brain. To determine the effect of BDNF or FGF-2 on neurogenesis in the injured adult brain, BDNF or FGF-2 were over-expressed in the subventricular zone (SVZ) via recombinant adeno-associated virus (AAV1/2) delivery and newly generated cells were identified using bromodeoxyuridine (BrdU; 150mg/kg intraperitoneal) labelling. Selective striatal cell loss was induced in a subgroup of rats by unilateral striatal injection of the excitotoxin quinolinic acid (QA) 21 days after AAV1/2 injection and 24 hours prior to BrdU labeling. The results of this thesis demonstrate that BDNF augments the recruitment, neuronal differentiation and survival of progenitor cells in both neurogenic and non-neurogenic regions of the unlesioned or QA lesioned brain. BDNF also appears to contribute to the persistence of newly generated neurons in the QA lesioned striatum. Our results provide the first evidence demonstrating the neurogenic effect of BDNF on compensatory striatal neurogenesis in the injured adult brain and suggest that enhanced BDNF expression may be a viable strategy for inducing or augmenting endogenous neural progenitor cell neurogenesis. Unlike the effect of BDNF, FGF-2 appears to have no effect on proliferation and/or survival of neural progenitor cells in either the normal or damaged brain. FGF-2 appears to be unable to act as a positive mediator of SVZ progenitor cell proliferation and neurogenesis in this study. However, FGF-2 may be having an inhibitory effect on progenitor cell differentiation. The negative result of the FGF-2 study may be of major significance in indicating the potential requirement of additional factors interacting with FGF-2 to influence neurogenesis. The results from the FGF-2 study contribute to the research field in highlighting the complexity of the mammalian neurogenic process. This thesis highlights the need for further investigation into multiple factor interactions, tighter regulation of the transgenic protein expression from the AAV1/2 delivery vector or alternative progenitor cell labelling paradigms. However, it does show that if neurogenesis can be induced or augmented exogenously, neural progenitor cells may provide a substrate for repair in the adult brain and dramatically change therapeutic approaches towards the treatment of neurodegenerative diseases.

Neurogenesis is the process by which functionally integrated neurons are generated from progenitor cells. In the adult mammalian brain two sites of high density cell division have been identified that contain neural progenitor cells retaining the ability to generate new neurons: the subgranular zone of the hippocampus (SGZ) and the subventricular zone (SVZ) lining the lateral ventricles in the forebrain. Several studies have suggested that SVZ neural progenitor cells in the adult brain can migrate into regions other than the olfactory bulb after either administration of growth factors, induction of neuronal cell loss or injury. Brain-derived neurotrophic factor (BDNF) and fibroblast growth factor (FGF-2) play major roles in regulating the survival and fate of progenitor cells in the adult mammalian brain. To determine the effect of BDNF or FGF-2 on neurogenesis in the injured adult brain, BDNF or FGF-2 were over-expressed in the subventricular zone (SVZ) via recombinant adeno-associated virus (AAV1/2) delivery and newly generated cells were identified using bromodeoxyuridine (BrdU; 150mg/kg intraperitoneal) labelling. Selective striatal cell loss was induced in a subgroup of rats by unilateral striatal injection of the excitotoxin quinolinic acid (QA) 21 days after AAV1/2 injection and 24 hours prior to BrdU labeling. The results of this thesis demonstrate that BDNF augments the recruitment, neuronal differentiation and survival of progenitor cells in both neurogenic and non-neurogenic regions of the unlesioned or QA lesioned brain. BDNF also appears to contribute to the persistence of newly generated neurons in the QA lesioned striatum. Our results provide the first evidence demonstrating the neurogenic effect of BDNF on compensatory striatal neurogenesis in the injured adult brain and suggest that enhanced BDNF expression may be a viable strategy for inducing or augmenting endogenous neural progenitor cell neurogenesis. Unlike the effect of BDNF, FGF-2 appears to have no effect on proliferation and/or survival of neural progenitor cells in either the normal or damaged brain. FGF-2 appears to be unable to act as a positive mediator of SVZ progenitor cell proliferation and neurogenesis in this study. However, FGF-2 may be having an inhibitory effect on progenitor cell differentiation. The negative result of the FGF-2 study may be of major significance in indicating the potential requirement of additional factors interacting with FGF-2 to influence neurogenesis. The results from the FGF-2 study contribute to the research field in highlighting the complexity of the mammalian neurogenic process. This thesis highlights the need for further investigation into multiple factor interactions, tighter regulation of the transgenic protein expression from the AAV1/2 delivery vector or alternative progenitor cell labelling paradigms. However, it does show that if neurogenesis can be induced or augmented exogenously, neural progenitor cells may provide a substrate for repair in the adult brain and dramatically change therapeutic approaches towards the treatment of neurodegenerative diseases.

Adult neurogenesis is a process that produces neurons in the adult brain and garners potential for the development of novel therapeutic interventions to combat neurodegenerative and other brain related diseases. With the hope of increasing neurogenesis, active investigations are defining the cellular and molecular mechanisms that regulate adult neural precursor cell (NPC) survival, and thus maintain neurogenesis. Recently, autophagy, an intracellular recycling pathway, has been implicated in regulating adult NPCs in embryonic knockout mice models. Whether autophagy has a similar effect within the adult and how autophagy regulates development of adult NPC remains unknown. Here, we investigate the role of Beclin1, a gene responsible for autophagy induction, in adult hippocampal NPC function in mice. Retroviral-mediated removal of Beclin1 from proliferating adult NPCs in vivo led to a reduction in the survival of adult-born neurons. In addition, Beclin1 was removed specifically from nestin-expressing adult neural stem- and progenitor-cells through the development of a Beclin1 nestin-inducible knockout mouse. Beclin1 nKO mice had a reduction in NPC proliferation and development, and overall fewer adult-generated neurons. Together, these findings reveal Beclin1 is required for adult hippocampal neurogenesis through regulating the proliferation and survival of the NPCs, in the absence of changing NPC fate.