Neural progenitor cell differentiation and migration : Role of glutamate signaling, brain-derived neurotrophic factor, and hypoxia/acidosis

The mammalian central nervous system (CNS) develops from multipotent neural stem or progenitor cells. During development the cells proliferate actively and differentiate into all the different cell types of the brain. Neurogenesis continues in the adult brain but to a much lesser extent than during development. Adult neurogenesis is influenced by many different factors, including insults to the brain and neurodegenerative disease. Neurotransmitters have been implicated as regulators of neurogenesis. The main excitatory neurotransmitter glutamate is linked to neural progenitor cell proliferation and differentiation as well as migration of newborn neurons. Glutamate is also involved in the pathogenesis of several neurological disorders and other factors linked to brain pathogenesis, such as hypoxia and acidosis, are known to influence neural progenitor cells. Elucidating the mechanisms governing stem/progenitor cell behavior during normal and pathological conditions will aid in the development of cell-based therapies for treating insult or disease within the CNS. The aim of this thesis was to study the role of glutamate receptor agonists and antagonists in differentiation and migration of neural progenitors and their progeny to increase the understanding of how this neurotransmitter influences these cells. In addition, the effects of brain-derived neurotrophic factor (BDNF) and the reactivity of the cells to conditions associated with ischemic stroke (hypoxia/acidosis) were studied. By utilizing the neurosphere model we found that differentiating neural progenitors initially mainly expressed and responded to stimuli through metabotropic glutamate receptor 5 (mGluR5) and that the expression and functional response of the receptor corresponded with the distribution of radial glial cells. Ionotropic alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)/kainate (KA) receptors were also present during early differentiation and expressed mainly by neuron-like cells. The expression of mGluR5 decreased and the expression and functional maturity of AMPA/KA receptors increased with time in culture. Pharmacological blocking studies revealed that radial glial process extension and neuronal motility are regulated through both mGluR5 and AMPA/KA receptors, but that the receptors have opposing effects on these cellular mechanisms. After prolonged differentiation a small subpopulation of neuronal cells responding to stimulation with N-methyl-D-aspartate (NMDA) and gamma amino butyric acid (GABA) appeared. This subpopulation of cells was responsive to motogenic actions mediated by BDNF. In addition, we found that radial glial and neuron-like cells exhibited differences in resting membrane potential and intracellular pH and reacted differently when exposed to hypoxic and acidic conditions. This study contributes new information regarding neural progenitor cell characteristics and behavior when differentiated in the presence of or challenged with factors influencing neurogenesis, both during normal and pathological conditions. These findings may be useful in developing treatment programs for neurological disorders.Det centrala nervsystemet (CNS) hos mammalier utvecklas utgående från multipotenta neurala stamceller. Under utvecklingen delar sig de neurala stamcellerna aktivt och ger upphov till alla de olika celltyperna i hjärnan. Nybildning av nervceller fortsätter i den vuxna hjärnan men i mycket begränsad mån. Denna nybildning påverkas av många olika faktorer, inklusive hjärnskador och neurodegenerativa sjukdomar. Signalsubstanser i hjärnan har föreslagits påverka nybildningen av nervceller. Glutamat är den huvudsakliga excitatoriska signalsubstansen i hjärnan och har länkats till proliferation och differentiering av neurala stamceller samt migration av nybildade nervceller. Glutamat är också involverad i patogenesen av flera olika neurologiska sjukdomar och andra faktorer länkade till patologiska tillstånd i hjärnan, såsom hypoxi och acidos, har också visats påverka neurala stamceller. Klargörande av de mekanismer som styr stamcellernas beteende under normala och patologiska tillstånd kan bidra till utvecklingen av cellbaserade terapiformer för behandling av skador eller sjukdomar i CNS. Målet med denna avhandling var att studera rollen av glutamatreceptoragonister och -antagonister vid differentiering och migration av neurala stamceller och deras derivat för att öka förståelsen för hur denna signalsubstans påverkar dessa celler. Ytterligare studerades hur cellerna påverkas av den neurotrofa faktorn BDNF och förhållanden associerade med slaganfall (hypoxi/acidos). Genom att utnyttja den så kallade neurosfärmodellen fann vi att neurala stamceller vid differentiering initialt huvudsakligen uppvisade funktionella svar vid stimulering via den metabotropa glutamatreceptorn mGluR5 och att uttrycket av mGluR5 korrelerade med distributionen av radiala gliaceller. Funktionella jonotropa AMPA/KA-receptorer fanns också vara närvarande tidigt under differentieringsprocessen, främst i neuroner. Uttrycket av mGluR5 minskade medan uttrycket och den funktionella mognaden av AMPA/KA-receptorer ökade med tiden. Farmakologiska studier visade att både mGluR5 och AMPA/KA-receptorer är involverade i regleringen av neuronala cellers motilitet och radiala gliacellers processutväxt men att receptorerna har motsatta effekter på dessa cellulära mekanismer. Efter en längre periods differentiering kunde en liten subpopulation av celler som uppvisade funktionella svar vid stimulering med NMDA och GABA identifieras. BDNF ökade motiliteten av denna subpopulation. Vi fann ytterligare att radiala gliaceller och neuroner uppisade skillnader i vilomembranpotential och intracellulärt pH samt reagerade olika i hypoxiska och sura förhållanden. Denna studie bidrar med ny information angående neurala stamcellers egenskaper och beteende vid differentiering i närvaro av eller vid stimulering med faktorer som påverkar neurogenes, både under normala och patologiska förhållanden. Dessa upptäckter kan vara av nytta vid utvecklingen av behandlingsprogram för neurologiska skador och sjukdomar

Neurotrophins and neuronal plasticity in the action of antidepressants and morphine

Neuronal plasticity is a well characterized phenomenon in the developing and adult brain. It refers to capasity of a single neuron to modify morphology, synaptic connections and activity. Neuronal connections and capacity for plastic events are compromised in several pathological disorders, such as major depression. In addition, neuronal atrophy has been reported in depressive patients. Neurotrophins are a group of secretory proteins functionally classified as neuronal survival factors. Neurotrophins, especially brain derived neurotrophic factor (BDNF), have also been associated with promoting neuronal plasticity in dysfunctional neuronal networks. Chronic antidepressant treatment increases plastic events including neurogenesis and arborization and branching of neurites in distinct brain areas, such as the hippocampus. One suggested mode of action is where the antidepressants elevate the synaptic levels of BDNF thus further activating several signaling cascades via trkB-receptor. In our studies we have tried to clarify the mechanisms of action for antidepressants and to resolve the role of BDNF in this process. We found that chronic antidepressant treatment increases amount of markers of neuronal plasticity in both hippocampus and in the medial prefrontal cortex, both of which are closely linked to the etiology of major depression. Secondary actions of antidepressants include rapid activation of the trkB receptor followed by a phosphorylation of transcription factor CREB. In addition, activation of CREB by phosphorylation appears responsible for the regulation of the expression of the BDNF gene. Using transgenic mice we found that BDNF-induced trkB-mediated signaling proved crucial for the behavioral effects of antidepressants in the forced swimming test and for the survival of newly-born neurons in the adult hippocampus. Antidepressants not only increased neurogenesis in the adult hippocampus but also elevated the turnover of hippocampal neurons. During these studies we also discovered that another trkB ligand, NT-4, is involved in morphine-mediated anti-nociception and tolerance. These results present a novel role for trkB-mediated signaling in plastic events present in the opioid system. This thesis evaluates neuronal plasticity and trkB as a target for future antidepressant treatments.Hermoston muovautuvuus on hyvin kuvattu ilmiö sekä kehittyvissä että aikuisissa aivoissa. Muovautuvuus tarkoittaa hermosolun kykyä muokata rakennettaan, yhteyksiään ja toimintaansa. Hermosolujen väliset yhteydet sekä kyky muovautua ovat häiriytyneet useissa patologisissa taudeissa kuten masennuksessa. Lisäksi hermosolujen tuhoutumista on havaittu masennuksesta kärsivillä potilailla. Hermokasvutekijät ovat joukko proteiineja, jotka toimintansa perusteella luokitellaan hermosolujen toimintaa ylläpitäviksi tekijöiksi. Hermokasvutekijöistä erityisesti aivoperäinen hermokasvutekijä (BDNF) on läheisesti liitetty hermoston muovautuvuuden säätelyyn varsinkin häiriintyneissä hermoverkoissa. Pitkäkestoinen masennuslääkehoito lisää aivojen muovautuvuutta monin eri tavoin, kuten esimerkiksi lisäämällä uusien hermosolujen tuotantoa, aksonien ja dentriittien kasvua ja haaroittumista erityisesti hippokampuksen alueella. Masennuslääkkeet nostavat BDNF:n määrää hermopäätteissä joka puolestaan johtaa trkB-reseptorin kautta useiden viestikaskadien aktivoitumiseen. Tätä tapahtumaa on esitetty yhdeksi mahdollisista mekanismeista jonka avulla masennuslääkkeet välittävät vaikutuksiaan. Tutkimusten tavoitteena on ollut edelleen selventää sekä masennuslääkkeiden vaikutusmekanismeja, että BDNF:n osuutta tässä prosessissa. Havaitsimme että pitkäaikainen masennuslääkehoito lisää hermoston muovautuvuuteen liitettyjen proteiinien määrää erityisesti tietyillä aivoalueilla, hippokampuksessa ja etuaivolohkossa, jotka ovat myös läheisesti liitetty masennuksen etiologiaan. Lisäksi masennuslääkkeet aktivoivat trkB-reseptorin kautta transkription säätelytekijä CREB:iä. CREB:n aktivaatio puolestaan vastaa BDNF:n geenin säätelystä. Siirtogeenisiä hiiriä apuna käyttäen havaitsimme että BDNF välitteinen trkB-reseptorin aktivaatio tarvitaan sekä masennuslääkkeiden aiheuttamille käyttäytymisvasteille, että uusien hermosolujen selviytymiselle hippokampuksessa. Masennuslääkkeet eivät ainoastaan lisää uusien hermosolujen tuotantoa hippokampuksessa vaan myös niiden poistamista, kulloisenkin tarpeen mukaan. Tutkimuksissa havaitsimme myös että toinen trkB-reseptoriin sitoutuva hermokasvukekijä, NT-4, on osallisena morfiinin välittämässä kivunpoistossa ja opiaatti-toleranssissa. Nämä tulokset viittaavat trkB-reseptorin osallisuuteen opiaatti järjestelmien muovautuvuuteen. Väitöskirjatyössä tarkastellaan hermoston muovautuvuutta sekä trkB-reseptoria mahdollisina lääkevaikutuskohteina tulevaisuuden masennuslääkehoidoille

BDNF signaling in epilepsy: TRKB-induced JAK/STAT pathway and phosphorylation of LSF in neurons

Epilepsy is a neurological disorder that causes recurrent and unprovoked seizures due to imbalances in synaptic transmission in distinct regions of the brain. In both human patients and animal models of epilepsy, there is a marked increase in brain-derived neurotrophic factor (BDNF), a critical signaling molecule in the brain that contributes to two divergent pathways important to disease pathology: 1) the regulation of type A receptors for the major inhibitory neurotransmitter GABA (GABAARs), and 2) aberrant neurogenesis with ectopic expression of new neurons from progenitor cells that disrupt neural network activity in the hippocampus. The first part of my thesis addresses how neurons regulate levels of α1-containing GABAARs through BDNF signaling at its receptors, tropomyosin receptor kinase B (TrkB) and p75 neurotrophin receptor (p75NTR). I hypothesized and showed that BDNF, working at TrkB, rapidly activates the Janus kinase and signal transducers and activators of transcription (JAK/STAT) pathway in neurons and identified a novel intracellular receptor signaling complex composed of p75NTR and JAK2 that is present in neuronal processes, cell body, and nucleus. Based on this finding, we suggest that an intracellular p75NTR/JAK2 signalsome recruits STAT3, a transcriptional activator of the gene coding for the cAMP inducible early repressor (ICER) that blocks synthesis of α1 subunits reducing synaptic GABAARs in response to status epilepticus. This model is consistent with our collaborative studies that show a JAK2 inhibitor, WP1066, inhibits development of spontaneous seizures in an epilepsy model and my observation that WP1066 degrades JAK2 protein in primary neurons. The second part of my thesis addresses BDNF regulation of the Late SV40 Factor (LSF), a ubiquitous transcription factor that regulates cell cycle progression and survival. I show that BDNF through the mitogen-activated protein kinase pathway selectively phosphorylates LSF at serine 291 (p291LSF) and that p291LSF is present throughout neurogenesis, increases with status epilepticus in the hippocampus, and is highest in structures associated with neurogenesis (such as olfactory bulb and hippocampus when compared to cortex). Taken together, these results suggest LSF may play an important role in neuronal development and potentially in epilepsy, providing an additional target for future therapeutic intervention.2016-12-15T00:00:00

Salmeterol, a \u3b22 Adrenergic Agonist, Promotes Adult Hippocampal Neurogenesis in a Region-Specific Manner.

Neurogenesis persists in the subgranular zone of the hippocampal formation in the adult mammalian brain. In this area, neural progenitor cells (NPCs) receive both permissive and instructive signals, including neurotransmitters, that allow them to generate adult-born neurons which can be functionally integrated in the preexisting circuit. Deregulation of adult hippocampal neurogenesis (ahNG) occurs in several neuropsychiatric and neurodegenerative diseases, including major depression, and represents a potential therapeutic target. Of interest, several studies suggested that, both in rodents and in humans, ahNG is increased by chronic administration of classical monoaminergic antidepressant drugs, suggesting that modulation of this process may participate to their therapeutic effects. Since the established observation that noradrenergic innervations from locus coeruleus make contact with NPC in the dentate gyrus, we investigated the role of beta adrenergic receptor (\u3b2-AR) on ahNG both in vitro and in vivo. Here we report that, in vitro, activation of \u3b22-AR by norepinephrine and \u3b22-AR agonists promotes the formation of NPC-derived mature neurons, without affecting NPC survival or differentiation toward glial lineages. Additionally, we show that a selective \u3b22-AR agonist able to cross the blood-brain barrier, salmeterol, positively modulates hippocampal neuroplasticity when chronically administered in adult na\uefve mice. Indeed, salmeterol significantly increased number, maturation, and dendritic complexity of DCX+ neuroblasts. The increased number of DCX+ cells was not accompanied by a parallel increase in the percentage of BrdU+/DCX+ cells suggesting a potential prosurvival effect of the drug on neuroblasts. More importantly, compared to vehicle, salmeterol promoted ahNG, as demonstrated by an increase in the actual number of BrdU+/NeuN+ cells and in the percentage of BrdU+/NeuN+ cells over the total number of newly generated cells. Interestingly, salmeterol proneurogenic effects were restricted to the ventral hippocampus, an area related to emotional behavior and mood regulation. Since salmeterol is commonly used for asthma therapy in the clinical setting, its novel pharmacological property deserves to be further exploited with a particular focus on drug potential to counteract stress-induced deregulation of ahNG and depressive-like behavior

ProNGF Is a Cell-Type-Specific Mitogen for Adult Hippocampal and for Induced Neural Stem Cells

The role of proNGF, the precursor of Nerve Growth Factor (NGF), on the biology of adult neural stem cells (aNSCs) is still unclear. Here I analyzed adult hippo-campal neurogenesis in AD11 transgenic mice, in which the constitutive expression of anti-NGF antibody leads to an imbalance of proNGF over mature NGF. I found in-creased proliferation of progenitors but a reduced neurogenesis in the AD11 DG- hippocampus (HP-DG). Also in vitro, AD11 hippocampal neural stem cells (NSCs) pro-liferated more but were unable to differentiate into morphologically mature neu-rons. By treating wild-type (WT) hippocampal progenitors with the uncleavable form of proNGF (proNGF-KR) I demonstrated that proNGF acts as mitogen on aNSCs at low concentration. The mitogenic effect of proNGF was specifically addressed to the radial glia-like (RGL) neural stem cells through the induction of cyclin D1 expression. These cells express high level of p75NTR, as demonstrated by immunofluorescence analyses performed ex vivo on RGL cells isolated from freshly-dissociated HP-DG or selected in vitro from NSCs by LIF (leukemia inhibitory factor). Clonogenic assay per-formed in the absence of mitogens showed that RGLs respond to proNGF-KR by re-activating their proliferation and thus leading to neurospheres formation. The mito-genic effect of proNGF was further exploited in the expansion of mouse induced Neural Stem Cells (iNSCs). Chronic exposure of iNSCs to proNGF-KR increased their proliferation. Altogether, I demonstrated that proNGF acts as mitogen on hippo-campal and induced neural stem cells.The role of proNGF, the precursor of nerve growth factor (NGF), in the biology of adult neural stem cells (aNSCs) is still unclear. Here, we analyzed adult hippocampal neurogenesis in AD11 transgenic mice, in which the constitutive expression of anti-NGF antibody leads to an imbalance of proNGF over mature NGF. We found increased proliferation of progenitors but a reduced neurogenesis in the AD11 dentate gyrus (DG)-hippocampus (HP). Also in vitro, AD11 hippocampal neural stem cells (NSCs) proliferated more, but were unable to differentiate into morphologically mature neurons. By treating wild-type hippocampal progenitors with the uncleavable form of proNGF (proNGF-KR), we demonstrated that proNGF acts as mitogen on aNSCs at low concentration. The mitogenic effect of proNGF was specifically addressed to the radial glia-like (RGL) stem cells through the induction of cyclin D1 expression. These cells express high levels of p75NTR, as demonstrated by immunofluorescence analyses performed ex vivo on RGL cells isolated from freshly dissociated HP-DG or selected in vitro from NSCs by leukemia inhibitory factor. Clonogenic assay performed in the absence of mitogens showed that RGLs respond to proNGF-KR by reactivating their proliferation and thus leading to neurospheres formation. The mitogenic effect of proNGF was further exploited in the expansion of mouse-induced neural stem cells (iNSCs). Chronic exposure of iNSCs to proNGF-KR increased their proliferation. Altogether, we demonstrated that proNGF acts as mitogen on hippocampal and iNSCs. Stem Cells 2019;37:1223–1237

Early phase of plasticity-related gene regulation and SRF dependent transcription in the hippocampus

Hippocampal organotypic cultures are a highly reliable in vitro model for studying neuroplasticity: in this paper, we analyze the early phase of the transcriptional response induced by a 20 \ub5M gabazine treatment (GabT), a GABA-Ar antagonist, by using Affymetrix oligonucleotide microarray, RT-PCR based time-course and chromatin-immuno-precipitation. The transcriptome profiling revealed that the pool of genes up-regulated by GabT, besides being strongly related to the regulation of growth and synaptic transmission, is also endowed with neuro-protective and pro-survival properties. By using RT-PCR, we quantified a time-course of the transient expression for 33 of the highest up-regulated genes, with an average sampling rate of 10 minutes and covering the time interval [10 3690] minutes. The cluster analysis of the time-course disclosed the existence of three different dynamical patterns, one of which proved, in a statistical analysis based on results from previous works, to be significantly related with SRF-dependent regulation (p-value<0.05). The chromatin immunoprecipitation (chip) assay confirmed the rich presence of working CArG boxes in the genes belonging to the latter dynamical pattern and therefore validated the statistical analysis. Furthermore, an in silico analysis of the promoters revealed the presence of additional conserved CArG boxes upstream of the genes Nr4a1 and Rgs2. The chip assay confirmed a significant SRF signal in the Nr4a1 CArG box but not in the Rgs2 CArG box

FGFR1-5HT1AR heteroreceptor complexes differently modulate GIRK currents in the hippocampus and the raphe nucleus of control rats and of a genetic rat model of depression

The midbrain raphe serotonin neurons provide the main ascending serotonergic projection to the forebrain, including the hippocampus, which has a recognized role in the pathophysiology of depressive disorder. The activation of G protein-coupled inwardly-rectifying potassium (GIRK) channels by serotonin 5HT1A receptors at the soma-dendritic level of serotonergic raphe neurons and glutamatergic hippocampal pyramidal neurons reduces neuronal activity. The presence of FGFR1-5HT1A heteroreceptor complexes in this raphe-hippocampal serotonin neuron system has been demonstrated, but functional receptor-receptor interactions in the heterocomplexes have only been studied in CA1 pyramidal neurons of control Sprague Dawley (SD) rats. In the present research, the short-term effects of FGFR1-5HT1A complex activation were studied in hippocampal pyramidal neurons, both in CA1 and CA2 areas, and midbrain dorsal raphe serotonergic neurons of SD rats and a genetic rat model of depression, the Flinders sensitive line (FSL) rats selected from SD strain, using an electrophysiological technique. The results obtained demonstrate that FGFR1-5HT1A heteroreceptor activation by specific agonists reduced the ability of the 5HT1AR protomer to open the GIRK channels via the allosteric inhibitory interplay produced by agonist activation of the FGFR1 protomer, resulting in increased neuronal firing in the raphe-hippocampal 5HT system of SD rats. In contrast, apart from CA2 neurons, the inhibitory allosteric effects of FGFR1 agonist on the 5HT1AR protomer were unable to have this influence on GIRK channels in FSL rats. According to these data, 5HT1AR activation impaired hippocampal plasticity in both SD and FSL rats, as determined by long-term potentiation induction capability in the CA1 field, but not in SD rats following simultaneous FGFR1-5HT1A heterocomplex activation. While, due to the impairment in heterocomplex activation, long-term potentiation was precluded in FSL rats. It is thus hypothesized that in the genetic FSL model of depression, there is a considerable decrease of the allosteric inhibition mediated by the FGFR1 protomer on the 5HT1AR protomer, resulting in a reduced opening of the GIRK channels in the raphe-hippocampal serotonin pathway. The consequent increase in inhibition in dorsal raphe 5HT nerve cells and glutamatergic hippocampal CA1 pyramidal nerve cell firing may contribute to the onset of major depression

Microcircuit remodeling processes underlying learning in the adult

One of the most intriguing discoveries in neuroscience of the past decades has been showing that experience is able to induce structural modifications in cortical microcircuit that might underlie the formation of memories upon learning (for a review, see Caroni, Donato and Muller 2012). Hence, learning induces phases of synapse formation and elimination that are strictly regulated by a variety of mechanisms, which impact on cortical microcircuits affecting both excitatory and inhibitory neurons. Nevertheless, the extent to which specific configurations might be implemented to support specific phases of learning, as well as the impact of experience-induced structural modifications on further learning, is still largely unknown. Here, I explore how the remodeling of identified microcircuits in the mouse hippocampus and neocortex supports learning in the adult. In the first part, I identifiy a microcircuit module engaging VIP and Parvalbumin (PV) positive interneurons to regulate the state of the PV+ network upon experience. This defines states of enhanced or reduced structural plasticity and learning based on the distribution of PV intensity in the network. In the second part, I demonstrate how specific hippocampal subdivisions are exploited to learn subtasks of trial-and-errors forms of learning via the deployment of increasingly precise searching strategies, and sequential recruitment of ventral, intermediate, and dorsal hippocampus. In the third part, I highlight the existence of genetically matched subpopulations of principal cells in the hippocampus, which achieve selective connectivity across hippocampal subdivisions via matched windows of neurogenesis and synaptogenesis during development. In the fourth part, I investigate the maturation of microcircuits mediating feedforward inhibition in the hippocampus, and highlight windows during development for the establishment of the proper baseline configuration in the adult. Moreover, I identify a critical window for cognitive enhancement during hippocampal development. In the fifth part, I study how ageing affects the PV network in hippocampal CA3, providing evidence for which age related neuronal loss correlates to reduced incidental learning performances in old mice. Therefore, by manipulating the PV network early during life, I provide strategies to modulate cognitive decline

RIT GTPASE SIGNALING MEDIATES OXIDATIVE STRESS RESISTANCE AND SURVIVAL OF ADULT NEWBORN NEURONS AFTER TRAUMATIC BRAIN INJURY

The small GTPases function as molecular switches to control diverse signaling cascades. The mammalian Rit and Rin, along with Drosophila Ric, comprise an evolutionarily conserved subfamily of the Ras-related GTPases. Previous studies using cultured cell models suggested that Rit was involved in the control of cell proliferation, transformation, neuronal differentiation, morphogenesis, and cell survival, but the principal physiological function of Rit remained uncharacterized. To address this outstanding question, we employed a genetic approach, engineering a Rit knockout mouse. Using this animal model, we demonstrate a central role of Rit in governing cell survival in a p38-dependent fashion. Primary mouse embryonic fibroblasts (MEFs) derived from Rit-/- mice display increased apoptosis and selective disruption of MAPK signaling following oxidative stress. These deficits include a reduction in ROS-mediated stimulation of a novel p38-MK2-HSP27 signaling cascade, which appears to act upstream of the mTORC2 complex to control Akt-dependent cell survival. In the adult brain, proliferation of stem cells within the subgranular zone (SGZ) of the hippocampal dentate gyrus (DG), provide a lifelong supply of new neurons. Adult neurogenesis appears critical for learning and memory and is altered in animal models of brain injury and neurological diseases. Thus, a greater understanding of the regulation of adult neurogenesis will provide insight into its myriad physiological roles but also to the development of therapeutic strategies for the treatment of injury and the progression of brain diseases. Here we find that Rit plays a central role in governing the survival of hippocampal neurons in response to oxidative stress. Importantly, using a controlled cortical impact model of traumatic brain injury (TBI), we show that Rit acts to protect newborn immature neurons within the SGZ of the DG from apoptosis following TBI. Finally, studies indicate that Rit plays a significant role in directing IGF-1 signaling, a key neurotrophin known to promote neurogenesis and to protect neurons against apoptotic stress. Together, these studies establish Rit as a critical regulator of a p38 MAPKdependent signaling cascade that functions as an important survival mechanism for cells in response to oxidative stress, including the survival of newborn hippocampal neurons in the traumatically injured brain