Distinct structural plasticity in the hippocampus and amygdala of the middle-aged common marmoset (Callithrix jacchus)

Adult neurogenesis in the primate brain is generally accepted to occur primarily in two specific areas; the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG) and the subventricular zone (SVZ) of the lateral ventricles. Hippocampal neurogenesis is well known to be downregulated by stress and aging in rodents, however there is less evidence documenting the sensitivity of neuroblasts generated in the SVZ. In primates, migrating cells generated in the SVZ travel via a unique temporal stream (TS) to the amygdala and entorhinal cortex. Using adult common marmoset monkeys (Callithrix jacchus), we examined whether i) adult-generated cells in the marmoset amygdala differentiate into doublecortin-positive (DCX+) neuroblasts, and ii) whether lasting changes occur in DCX-expressing cells in the DG or amygdala when animals are exposed to 2 weeks of psychosocial stress.A surprisingly large population of DCX+ immature neurons was found in the amygdala of these 4-year-old monkeys with an average density of 163,000 DCX+ cells per mm³. Co-labeling of these highly clustered cells with PSA-NCAM supports that a subpopulation of these cells are migratory and participate in chain-migration from the SVZ to the amygdala in middle-aged marmosets. Exposure to 2 weeks of isolation and social defeat stress failed to alter the numbers of BrdU+, or DCX+ cells in the hippocampus or amygdala when evaluated 2 weeks after psychosocial stress, indicating that the current stress paradigm has no long-term consequences on neurogenesis in this primate.     

The FGF-2/FGFRs neurotrophic system promotes neurogenesis in the adult brain

Neurogenesis occurs in two regions of the adult brain, namely, the subventricular zone (SVZ) throughout the wall of the lateral ventricle and the subgranular zone (SGZ) of the dentate gyrus (DG) in hippocampal formation. Adult neurogenesis requires several neurotrophic factors to sustain and regulate the proliferation and differentiation of the adult stem cell population. In the present review, we examine the cellular and functional aspects of a trophic system mediated by fibroblast growth factor-2 (FGF-2) and its receptors (FGFRs) related to neurogenesis in the SVZ and SGZ of the adult rat brain. In the SVZ, FGF-2 is expressed in GFAP-positive cells of SVZ but is not present in proliferating precursor cells, which instead express FGFR-1 and FGFR-2, but not FGFR-3 mRNA, although expressed in the SVZ, and FGFR-4. Therefore, it seems that in the SVZ FGF-2 may be released by GFAP-positive cells, different from the precursor cell lineage, and via volume transmission it reaches the proliferating precursor cells. FGFR-1 mRNA is also expressed in the SGZ and is localized in BrdU-labeled precursor cells, whereas FGFR-2 and FGFR-3 mRNA, although expressed in the SGZ, are not located within proliferating precursor cells. An aged-related decline of proliferating precursor cells in the SVZ and DG of old rats has been well documented, and there is the suggestion that in part it could be the consequence of alterations in growth factor expression levels. Thus, the old precursors may respond to growth factors, suggesting that during aging the basic components for neuronal precursor cell proliferation are retained and the capacity to increase neurogenesis after appropriate stimulation is still preserved. In conclusion, the trophic system mediated by FGF-2 and its receptors contributes to create an important micro-environmental niche that promotes neurogenesis in the adult and aged brain. This article is dedicated to the special issue Brain Plasticity: Aging and Neuropychiatric Disorders.     

Conditional ablation and recovery of forebrain neurogenesis in the mouse

Forebrain neurogenesis persists throughout life in the rodent subventricular zone (SVZ) and hippocampal dentate gyrus (DG). Several strategies have been employed to eliminate adult neurogenesis and thereby determine whether depleting adult‐born neurons disrupts specific brain functions, but some approaches do not specifically target neural progenitors. We have developed a transgenic mouse line to reversibly ablate adult neural stem cells and suppress neurogenesis. The nestin‐tk mouse expresses herpes simplex virus thymidine kinase (tk) under the control of the nestin 2nd intronic enhancer, which drives expression in neural progenitors. Administration of ganciclovir (GCV) kills actively dividing cells expressing this transgene. We found that peripheral GCV administration suppressed SVZ‐olfactory bulb and DG neurogenesis within 2 weeks but caused systemic toxicity. Intracerebroventricular GCV infusion for 28 days nearly completely depleted proliferating cells and immature neurons in both the SVZ and DG without systemic toxicity. Reversibility of the effects after prolonged GCV infusion was slow and partial. Neurogenesis did not recover 2 weeks after cessation of GCV administration, but showed limited recovery 6 weeks after GCV that differed between the SVZ and DG. Suppression of neurogenesis did not inhibit antidepressant responsiveness of mice in the tail suspension test. These findings indicate that SVZ and DG neural stem cells differ in their capacity for repopulation, and that adult‐born neurons are not required for antidepressant responses in a common behavioral test of antidepressant efficacy. The nestin‐tk mouse should be useful for studying how reversible depletion of adult neurogenesis influences neurophysiology, other behaviors, and neural progenitor dynamics. J. Comp. Neurol. 514:567–582, 2009. © 2009 Wiley‐Liss, Inc.     

Functional implications of hypothalamic neurogenesis in the adult mammalian brain

Adult neurogenesis represents a striking example of structural plasticity in the mature brain. Research on adult mammalian neurogenesis today focuses almost exclusively on two areas: the subgranular zone (SGZ) in the dentate gyrus of the hippocampus, and the subventricular zone (SVZ) of the lateral ventricles. Numerous studies, however, have also reported adult neurogenesis in the hypothalamus, a brain structure that serves as a central homeostatic regulator of numerous physiological and behavioral functions, such as feeding, metabolism, body temperature, thirst, fatigue, aggression, sleep, circadian rhythms, and sexual behavior. Recent studies on hypothalamic neurogenesis have identified a progenitor population within a dedicated hypothalamic neurogenic zone. Furthermore, adult born hypothalamic neurons appear to play a role in the regulation of metabolism, weight, and energy balance. It remains to be seen what other functional roles adult hypothalamic neurogenesis may play. This review summarizes studies on the identification and characterization of neural stem/progenitor cells in the mammalian hypothalamus, in what contexts these stem/progenitor cells engage in neurogenesis, and potential functions of postnatally generated hypothalamic neurons.     

Forebrain neurogenesis after focal Ischemic and traumatic brain injury

Neural stem cells persist in the adult mammalian forebrain and are a potential source of neurons for repair after brain injury. The two main areas of persistent neurogenesis, the subventricular zone (SVZ)-olfactory bulb pathway and hippocampal dentate gyrus, are stimulated by brain insults such as stroke or trauma. Here we focus on the effects of focal cerebral ischemia on SVZ neural progenitor cells in experimental stroke, and the influence of mechanical injury on adult hippocampal neurogenesis in models of traumatic brain injury (TBI). Stroke potently stimulates forebrain SVZ cell proliferation and neurogenesis. SVZ neuroblasts are induced to migrate to the injured striatum, and to a lesser extent to the peri-infarct cortex. Controversy exists as to the types of neurons that are generated in the injured striatum, and whether adult-born neurons contribute to functional restoration remains uncertain. Advances in understanding the regulation of SVZ neurogenesis in general, and stroke-induced neurogenesis in particular, may lead to improved integration and survival of adult-born neurons at sites of injury. Dentate gyrus cell proliferation and neurogenesis similarly increase after experimental TBI. However, pre-existing neuroblasts in the dentate gyrus are vulnerable to traumatic insults, which appear to stimulate neural stem cells in the SGZ to proliferate and replace them, leading to increased numbers of new granule cells. Interventions that stimulate hippocampal neurogenesis appear to improve cognitive recovery after experimental TBI. Transgenic methods to conditionally label or ablate neural stem cells are beginning to further address critical questions regarding underlying mechanisms and functional significance of neurogenesis after stroke or TBI. Future therapies should be aimed at directing appropriate neuronal replacement after ischemic or traumatic injury while suppressing aberrant integration that may contribute to co-morbidities such as epilepsy or cognitive impairment.     

Adult neurogenesis and neurite outgrowth are impaired in LRRK2 G2019S mice

The generation and maturation of adult neural stem/progenitor cells are impaired in many neurodegenerative diseases, among them is Parkinson's disease (PD). In mammals, including humans, adult neurogenesis is a lifelong feature of cellular brain plasticity in the hippocampal dentate gyrus (DG) and in the subventricular zone (SVZ)/olfactory bulb system. Hyposmia, depression, and anxiety are early non-motor symptoms in PD. There are parallels between brain regions associated with non-motor symptoms in PD and neurogenic regions. In autosomal dominant PD, mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are frequent. LRRK2 homologs in non-vertebrate systems play an important role in chemotaxis, cell polarity, and neurite arborization. We investigated adult neurogenesis and the neurite development of new neurons in the DG and SVZ/olfactory bulb system in bacterial artificial chromosome (BAC) human Lrrk2 G2019S transgenic mice. We report that mutant human Lrrk2 is highly expressed in the hippocampus in the DG and the SVZ of adult Lrrk2 G2019S mice. Proliferation of newly generated cells is significantly decreased and survival of newly generated neurons in the DG and olfactory bulb is also severely impaired. In addition, after stereotactic injection of a GFP retrovirus, newly generated neurons in the DG of Lrrk2 G2019S mice exhibited reduced dendritic arborization and fewer spines. This loss in mature, developed spines might point towards a decrease in synaptic connectivity. Interestingly, physical activity partially reverses the decrease in neuroblasts observed in Lrrk2 G2010S mice. These data further support a role for Lrrk2 in neuronal morphogenesis and provide new insights into the role of Lrrk2 in adult neurogenesis.     

Centrally administered interleukin-1 beta sensitizes to the central pressor action of angiotensin II

Proliferating astrocytes and proliferating neuroblasts have been observed in the subgranular zone (SGZ) of the dentate gyrus (DG) in the hippocampus of adult rats under normal conditions. However, whether these proliferating cells are stimulated by running has not been determined. Using immunohistochemical techniques, we examined the effects of chronic treadmill running on proliferating astrocytes (PCNA+/GFAP+ cells), proliferating neuroblasts (PCNA+/DCX+ cells) and newly generated postmitotic neurons (DCX+/NeuN+ cells) in the DG of the hippocampus of adult rats and also characterized the morphological features of PCNA+/GFAP+ cells and PCNA+/DCX+ cells. PCNA+/GFAP+ cells with few processes and PCNA+/DCX+ cells without long processes were detected in the SGZ, and we determined that these are morphological features of the astrocytes and neuroblasts with proliferative ability. Chronic treadmill running (at a speed of 22 m/min, 30 min/days for 7 days) significantly increased the numbers of PCNA+/GFAP+ cells and DCX+/NeuN+ cells, and the number of PCNA+/DCX+ cells tended to increase by chronic treadmill running. These results indicate that chronic treadmill running stimulates the proliferation of astrocytes in the SGZ. Furthermore, the present study indicates that chronic treadmill running increases DCX+/NeuN+ cells that are detected in a transient stage during the neuronal maturation process. These events may be the cellular basis mediating both running-induced increases of new neurons in the DG of the hippocampus and running-induced improvement of learning and memory functions of adult rats.     

The role of olfactory stimulus in adult mammalian neurogenesis

Neurogenesis occurs in the adult mammalian brain in discrete regions related to olfactory sensory signaling and integration. The olfactory receptor cell population is in constant turn-over through local progenitor cells. Also, newborn neurons are added to the olfactory bulbs through a major migratory route from the subventricular zone, the rostral migratory stream. The olfactory bulbs project to different brain structures, including: piriform cortex, amygdala, entorhinal cortex, striatum and hippocampus. These structures play important roles in odor identification, feeding behavior, social interactions, reproductive behavior, behavioral reinforcement, emotional responses, learning and memory. In all of these regions neurogenesis has been described in normal and in manipulated mammalian brain. These data are reviewed in the context of a sensory-behavioral hypothesis on adult neurogenesis that olfactory input modulates neurogenesis in many different regions of the brain.     

Enhanced production and dendritic growth of new dentate granule cells in the middle-aged hippocampus following intracerebroventricular FGF-2 infusions

Declined production and diminished dendritic growth of new dentate granule cells in the middle-aged and aged hippocampus are correlated with diminished concentration of fibroblast growth factor-2 (FGF-2). This study examined whether increased FGF-2 concentration in the milieu boosts both production and dendritic growth of new dentate granule cells in the middle-aged hippocampus. The FGF-2 or vehicle was infused into the posterior lateral ventricle of middle-aged Fischer (F)344 rats for 2 weeks using osmotic minipumps. New cells born during the first 12 days of infusions were labeled via daily intraperitoneal injections of 5'-bromodeoxyuridine (BrdU) and analysed at 10 days after the last BrdU injection. Measurement of BrdU(+) cells revealed a considerably enhanced number of new cells in the subgranular zone (SGZ) and granule cell layer (GCL) of the dentate gyrus (DG) ipsilateral to FGF-2 infusions. Characterization of beta-III tubulin(+) neurons among newly born cells suggested an increased addition of new neurons to the SGZ/GCL ipsilateral to FGF-2 infusions. Quantification of DG neurogenesis at 8 days post-infusions via doublecortin (DCX) immunostaining also revealed the presence of an enhanced DG neurogenesis ipsilateral to FGF-2 infusions. Furthermore, DCX(+) neurons in FGF-2-infused rats exhibited enhanced dendritic growth compared with their counterparts in vehicle-infused rats. Thus, subchronic infusion of FGF-2 is efficacious for stimulating an enhanced DG neurogenesis from neural stem/progenitor cells in the middle-aged hippocampus. As dentate neurogenesis is important for hippocampal-dependent learning and memory and DG long-term potentiation, strategies that maintain increased FGF-2 concentration during ageing may be beneficial for thwarting some of the age-related cognitive impairments.