Role Of Hippocampal Neurogenesis Research Articles

Role of Apolipoprotein E in the Hippocampus and Its Impact following Ionizing Radiation Exposure.

Apolipoprotein E (ApoE) is a lipid carrier in both the peripheral and the central nervous systems (CNSs). Lipid-loaded ApoE lipoprotein particles bind to several cell surface receptors to support membrane homeostasis and brain injury repair. In the brain, ApoE is produced predominantly by astrocytes, but it is also abundantly expressed in most neurons of the CNS. In this study, we addressed the role of ApoE in the hippocampus in mice, focusing on its role in response to radiation injury. To this aim, 8-week-old, wild-type, and ApoE-deficient (ApoE-/-) female mice were acutely whole-body irradiated with 3 Gy of X-rays (0.89 Gy/min), then sacrificed 150 days post-irradiation. In addition, age-matching ApoE-/- females were chronically whole-body irradiated (20 mGy/d, cumulative dose of 3 Gy) for 150 days at the low dose-rate facility at the Institute of Environmental Sciences (IES), Rokkasho, Japan. To seek for ApoE-dependent modification during lineage progression from neural stem cells to neurons, we have evaluated the cellular composition of the dentate gyrus in unexposed and irradiated mice using stage-specific markers of adult neurogenesis. Our findings indicate that ApoE genetic inactivation markedly perturbs adult hippocampal neurogenesis in unexposed and irradiated mice. The effect of ApoE inactivation on the expression of a panel of miRNAs with an established role in hippocampal neurogenesis, as well as its transcriptional consequences in their target genes regulating neurogenic program, have also been analyzed. Our data show that the absence of ApoE-/- also influences synaptic functionality and integration by interfering with the regulation of mir-34a, mir-29b, and mir-128b, leading to the downregulation of synaptic markers PSD95 and synaptophysin mRNA. Finally, compared to acute irradiation, chronic exposure of ApoE null mice yields fewer consequences except for the increased microglia-mediated neuroinflammation. Exploring the function of ApoE in the hippocampus could have implications for developing therapeutic approaches to alleviate radiation-induced brain injury.

The Mef2c Gene Dose-Dependently Controls Hippocampal Neurogenesis and the Expression of Autism-Like Behaviors.

Mutations in the activity-dependent transcription factor MEF2C have been associated with several neuropsychiatric disorders. Among these, autism spectrum disorder (ASD)-related behavioral deficits are manifested. Multiple animal models that harbor mutations in Mef2c have provided compelling evidence that Mef2c is indeed an ASD gene. However, studies in mice with germline or global brain knock-out of Mef2c are limited in their ability to identify the precise neural substrates and cell types that are required for the expression of Mef2c-mediated ASD behaviors. Given the role of hippocampal neurogenesis in cognitive and social behaviors, in this study we aimed to investigate the role of Mef2c in the structure and function of newly generated dentate granule cells (DGCs) in the postnatal hippocampus and to determine whether disrupted Mef2c function is responsible for manifesting ASD behaviors. Overexpression of Mef2c (Mef2cOE ) arrested the transition of neurogenesis at progenitor stages, as indicated by sustained expression of Sox2+ in Mef2cOE DGCs. Conditional knock-out of Mef2c (Mef2ccko ) allowed neuronal commitment of Mef2ccko cells; however, Mef2ccko impaired not only dendritic arborization and spine formation but also synaptic transmission onto Mef2ccko DGCs. Moreover, the abnormal structure and function of Mef2ccko DGCs led to deficits in social interaction and social novelty recognition, which are key characteristics of ASD behaviors. Thus, our study revealed a dose-dependent requirement of Mef2c in the control of distinct steps of neurogenesis, as well as a critical cell-autonomous function of Mef2c in newborn DGCs in the expression of proper social behavior in both sexes.

Rice-memolin, a novel peptide derived from rice bran, improves cognitive function after oral administration in mice

Many people eat polished rice, while rice bran, a by-product known to be rich in protein and expected to have potential functions for health benefits, has not been effectively utilized. In this study, we determined that orally administered Val-Tyr-Thr-Pro-Gly (VYTPG) derived from rice bran protein improved cognitive decline in mice fed a high-fat diet (HFD). It was demonstrated that VYTPG was released from model peptides corresponding to fragment sequences of original rice proteins (Os01g0941500, Os01g0872700, and allergenic protein) after treatment with thermolysin, a microorganism-derived enzyme often used in industrial scale processes. The thermolysin digest also improved cognitive decline after oral administration in mice. Because VYTPG (1.0 mg/kg) potently improved cognitive decline and is enzymatically produced from the rice bran, we named it rice-memolin. Next, we investigated the mechanisms underlying the cognitive decline improvement associated with rice-memolin. Methyllycaconitine, an antagonist for α7 nicotinic acetylcholine receptor, suppressed the rice-memolin-induced effect, suggesting that rice-memolin improved cognitive decline coupled to the acetylcholine system. Rice-memolin increased the number of 5-bromo-2’-deoxyuridine (BrdU)-positive cells and promoted the mRNA expression of EGF and FGF-2 in the hippocampus, implying that these neurotropic factors play a role in hippocampal neurogenesis after rice-memolin administration. Epidemiologic studies demonstrated that diabetes is a risk factor for dementia; therefore, we also examined the effect of rice-memolin on glucose metabolism. Rice-memolin improved glucose intolerance. In conclusion, we identified a novel rice-derived peptide that can improve cognitive decline. The mechanisms are associated with acetylcholine and hippocampal neurogenesis. Rice-memolin is the first rice-brain-derived peptide able to improve cognitive decline.

416 LRP1 as a modulator of hippocampal neurogenesis and neurodegeneration

OBJECTIVES/GOALS: This project aims to elucidate the mechanism by which LRP1 governs hippocampal neurogenesis with a particular focus on its relevance in brain aging and memory loss. We are specifically interested in further discerning the intricacies of a novel relationship we have discovered between LRP1 and CXCR4 in adult neural stem cells. METHODS/STUDY POPULATION: For the in vivo studies, we are using a triple-transgenic mouse model in which we knockout LRP1 in adult neural stem cells. This is accomplished using a nestin-driven Cre-ER system in animals with floxed LRP1 and a floxed stop codon preceding a td-tomato reporter. The reporter allows for visualization of cells with the knockout and for trafficking and differentiation assays to be easily accomplished. We study stroke recovery using the middle cerebral artery occlusion model and brain aging by inducing the knockout and allowing the mice to age. We perform behavioral batteries and histological analysis on these mice to elucidate functional changes in neurogenesis. We also incorporate in vitro studies using primary neural stem cell cultures to mechanistically test the role of LRP1 in neural stem cell function. RESULTS/ANTICIPATED RESULTS: We have discovered that neural stem cell LRP1 knockout caused a 10-fold loss of CXCR4 expression in conjunction with deficits in ischemia-stimulated migration from the subventricular zone. We also found that uninjured aged mice lacking neural stem cell LRP1 displayed spatial memory deficits at 9 months of age (6 months after knockout), suggesting dysregulated hippocampal function. Given this, we hypothesize that LRP1 regulates CXCR4 in the subgranular zone NSCs to enhance hippocampal memory function. Ongoing research is testing our hypothesis via hippocampal functional tests and in vitro trafficking/expression assays. We expect our research to elucidate a previously unknown link between three independently identified effectors of neurodegenerative disease: LRP1, CXCR4, and neurogenesis. DISCUSSION/SIGNIFICANCE: The role of LRP1 in Alzheimers disease has long eluded clarity despite its known role in trafficking many major disease players – ApoE, amyloid beta and tau. Elucidating its role in hippocampal neurogenesis, a potential disease-modifying process, could lead to novel therapeutic approaches in diseases that cause the death of 1/3 of senior citizens.

Adult Hippocampal Neurogenesis and Alzheimer's Disease: Novel Application of Mesenchymal Stem Cells and their Role in Hippocampal Neurogenesis.

The neurogenesis can occur in two regions of the adult mammalian brain throughout the lifespan: the subgranular zone of the hippocampal dentate gyrus, and the subventricular zone of the lateral ventricle. The proliferation and maturation of neural progenitor cells are tightly regulated through intrinsic and extrinsic factors. The integration of maturated cells into the circuitry of the adult hippocampus emphasizes the importance of adult hippocampal neurogenesis in learning and memory. There is a large body of evidence demonstrating that alteration in the neurogenesis process in the adult hippocampus results in an early event in the course of Alzheimer's disease (AD). In AD condition, the number and maturation of neurons declines progressively in the hippocampus. Innovative therapies are required to modulate brain homeostasis. Mesenchymal stem cells (MSCs) hold an immense potential to regulate the neurogenesis process, and are currently tested in some brain-related disorders, such as AD. Therefore, the aim of this review is to discuss the use of MSCs to regulate endogenous adult neurogenesis and their significant impact on future strategies for the treatment of AD.

Role of Hippocampal Neurogenesis in Alcohol Withdrawal Seizures.

Chronic alcohol consumption results in alcohol use disorder (AUD). Interestingly, however, sudden alcohol withdrawal (AW) after chronic alcohol exposure also leads to a devastating series of symptoms, referred to as alcohol withdrawal syndromes. One key feature of AW syndromes is to produce phenotypes that are opposite to AUD. For example, while the brain is characterized by a hypoactive state in the presence of alcohol, AW induces a hyperactive state, which is manifested as seizure expression. In this review, we discuss the idea that hippocampal neurogenesis and neural circuits play a key role in neuroadaptation and establishment of allostatic states in response to alcohol exposure and AW. The intrinsic properties of dentate granule cells (DGCs), and their contribution to the formation of a potent feedback inhibitory loop, endow the dentate gyrus with a “gate” function, which can limit the entry of excessive excitatory signals from the cortex into the hippocampus. We discuss the possibility that alcohol exposure and withdrawal disrupts structural development and circuitry integration of hippocampal newborn neurons, and that this altered neurogenesis impairs the gate function of the hippocampus. Failure of this gate function is expected to alter the ratio of excitatory to inhibitory (E/I) signals in the hippocampus and to induce seizure expression during AW. Recent functional studies have shown that specific activation and inhibition of hippocampal newborn DGCs are both necessary and sufficient for the expression of AW-associated seizures, further supporting the concept that neurogenesis-induced neuroadaptation is a critical target to understand and treat AUD and AW-associated seizures.

Hippocampal neurogenesis and memory in adolescence following intrauterine growth restriction.

Intrauterine growth restriction (IUGR) is associated with hippocampal alterations that can increase the risk of short-term memory impairments later in life. Despite the role of hippocampal neurogenesis in learning and memory, research into the long-lasting impact of IUGR on these processes is limited. We aimed to determine the effects of IUGR on neuronal proliferation, differentiation and morphology, and on memory function at adolescent equivalent age. At embryonic day (E) 18 (term ∼E22), placental insufficiency was induced in pregnant Wistar rats via bilateral uterine vessel ligation to generate IUGR offspring (n = 10); control offspring (n = 11) were generated via sham surgery. From postnatal day (P) 36-44, spontaneous location recognition (SLR), novel object location and recognition (NOL, NOR), and open field tests were performed. Brains were collected at P45 to assess neurogenesis (immunohistochemistry), dendritic morphology (Golgi staining), and brain-derived neurotrophic factor expression (BDNF; Western blot analysis). In IUGR versus control rats there was no difference in object preference in the NOL or NOR, the similar and dissimilar condition of the SLR task, or in locomotion and anxiety-like behavior in the open field. There was a significant increase in the linear density of immature neurons (DCX+) in the subgranular zone (SGZ) of the dentate gyrus (DG), but no difference in the linear density of proliferating cells (Ki67+) in the SGZ, nor in areal density of mature neurons (NeuN+) or microglia (Iba-1+) in the DG in IUGR rats compared to controls. Dendritic morphology of dentate granule cells did not differ between groups. Protein expression of the BDNF precursor (pro-BDNF), but not mature BDNF, was increased in the hippocampus of IUGR compared with control rats. These findings highlight that while the long-lasting prenatal hypoxic environment may impact brain development, it may not impact hippocampal-dependent learning and memory in adolescence.

The Role of Hippocampal Neurogenesis in ANT-DBS for LiCl-Pilocarpine-Induced Epileptic Rats

Purpose: Abnormal neurogenesis in the hippocampus after status epilepticus (SE) has been suggested as a key pathogeny of temporal lobe epilepsy. This study aimed to investigate the effect of deep brain stimulation of the anterior thalamic nucleus (ANT-DBS) on hippocampal neurogenesis in LiCl-pilocarpine-induced epileptic rats and to analyze its relationship with postoperative spontaneous recurrent seizures (SRS) and anxiety. Method: SE was induced by a systemic LiCl-pilocarpine injection in adult male rats. Rats in the DBS group underwent ANT-DBS immediately after successful SE induction. SRS was only recorded during the chronic stage. An elevated plus maze was used to evaluate the level of anxiety in rats 7, 28, and 60 days after SE onset. After the elevated plus-maze experiment, rats were sacrificed under anesthesia in order to evaluate hippocampal neurogenesis. Doublecortin (DCX) was used as a marker for neurogenesis. Results: During the chronic stage, SRS in rats in the DBS group were significantly decreased. The level of anxiety was increased significantly in rats in the DBS group 28 days after SE, while no significant differences in anxiety levels were found 7 and 60 days after SE. The number of DCX-positive cells in the hippocampus was significantly increased 7 days after SE and was significantly decreased 60 days after SE in all rats in which SE was induced. However, the number of DCX-positive cells in the DBS group was significantly lower than that in the other groups 28 days after SE. Conclusions: ANT-DBS may suppress SRS and increase the postoperative anxiety of epileptic rats by influencing hippocampal neurogenesis.

Orally administered milk-derived tripeptide improved cognitive decline in mice fed a high-fat diet.

The functions of the brain, which is thought of as an organ highly independent from the periphery, are often affected by the peripheral environment. Indeed, epidemiologic studies demonstrated that diabetes was a risk factor for dementia. It was also reported that the intake of dairy products, such as milk, reduces the risk of developing dementia. We found that mice on a short-term high-fat diet (HFD) for 1 wk had reduced cognitive function. Thus, using this acute model, we investigated the effects of milk-derived peptide on cognitive decline induced by HFD. Tyr-Leu-Gly (YLG), a tripeptide derived from αS1-casein, a major bovine milk protein, is released by gastrointestinal proteases. We found that orally administered YLG improved cognitive decline induced by 1-wk HFD intake in the object recognition test. YLG also improved cognitive decline in the object location test. Thus, we found that YLG improved cognitive decline induced by HFD. Next, we examined the effects of YLG on the hippocampus, a brain area essential for cognitive function. HFD intake decreased the number of 5-bromo-2'-deoxyuridine (BrdU)-positive cells, and this decrease was improved by YLG administration. HFD intake decreased nerve growth factor (NGF) and glial cell line-derived neurotrophic factor, whereas YLG increased NGF and ciliary neurotrophic factor, suggesting that these neurotropic factors play a role in hippocampal neurogenesis after YLG administration. In conclusion, we demonstrated that 1-wk HFD reduced cognitive function. Furthermore, we found that YLG, a milk-derived tripeptide, improved cognitive decline in mice on HFD. The HFD reduced neural stem cell proliferation, and YLG improved this reduction. YLG is the first reported milk peptide to improve cognitive decline induced by HFD intake.-Nagai, A., Mizushige, T., Matsumura, S., Inoue, K., Ohinata, K. Orally administered milk-derived tripeptide improved cognitive decline in mice fed a high-fat diet.

Nestin Null Mice Show Improved Reversal Place Learning

The intermediate filament protein nestin is expressed by neural stem cells, but also by some astrocytes in the neurogenic niche of the hippocampus in the adult rodent brain. We recently reported that nestin-deficient (Nes−/−) mice showed increased adult hippocampal neurogenesis, reduced Notch signaling from Nes−/− astrocytes to the neural stem cells, and impaired long-term memory. Here we assessed learning and memory of Nes−/− mice in a home cage set up using the IntelliCage system, in which the mice learn in which cage corner a nose poke earns access to drinking water. Nes−/− and wildtype mice showed comparable place learning assessed as the incorrect corner visit ratio and the incorrect nose poke ratio. However, during reversal place learning, a more challenging task, Nes−/− mice, compared to wildtype mice, showed improved learning over time demonstrated by the incorrect visit ratio and improved memory extinction over time assessed as nose pokes per visit to the previous drinking corner. In addition, Nes−/− mice showed increased explorative activity as judged by the increased total numbers of corner visits and nose pokes. We conclude that Nes−/− mice exhibit improved reversal place learning and memory extinction, a finding which together with the previous results supports the concept of the dual role of hippocampal neurogenesis in cognitive functions.

Lgl1 deficiency disrupts hippocampal development and impairs cognitive performance in mice.

Cellular polarity is crucial for brain development and morphogenesis. Lethal giant larvae 1 (Lgl1) plays a crucial role in the establishment of cell polarity from Drosophila to mammalian cells. Previous studies have found the importance of Lgl1 in the development of cerebellar, olfactory bulb, and cerebral cortex. However, the role of Lgl1 in hippocampal development during the embryonic stage and function in adult mice is still unknown. In our study, we created Lgl1-deficient hippocampus mice by using Emx1-Cre mice. Histological analysis showed that the Emx1-Lgl1-/- mice exhibited reduced size of the hippocampus with severe malformations of hippocampal cytoarchitecture. These defects mainly originated from the disrupted hippocampal neuroepithelium, including increased cell proliferation, abnormal interkinetic nuclear migration, reduced differentiation, increased apoptosis, gradual disruption of adherens junctions, and abnormal neuronal migration. The radial glial scaffold was disorganized in the Lgl1-deficient hippocampus. Thus, Lgl1 plays a distinct role in hippocampal neurogenesis. In addition, the Emx1-Lgl1-/- mice displayed impaired behavioral performance in the Morris water maze and fear conditioning test.

SU104 - EXPERIMENTAL MODEL OF DISRUPTED IN SCHIZOPHRENIA 1 GENE IN A STEM CELL BASED NEURONAL MODEL

Background Induced Pluripotent Stem Cells (IPSCs) have the capability to differentiate into any kind of cell types, such as Neuronal Progenitor Cells (NPCs), and then to mature neurons. By this new approach we can investigate neuronal differentiation processes or the role of specific genes using genome editing techniques (e.g., ZFN, TALEN, or CRISPR). For example, the neuron-specific roles of the disrupted in schizophrenia 1 (DISC1) can be studied in a simple, Petri-dish based model. The DISC1gene has been intensively studied over the last decades after the description of a balanced translocation of t(1;11)(q42.1;q14.3) in a multigenerational Scottish family with several cases of psychosis and affective disorders, followed by the identification of a frameshift DISC1 mutation in an American family affected with schizophrenia. Previous molecular biological experiments have shown that DISC1 scaffold protein can affect neuronal proliferation and migration, and synapse maintenance. Animal model findings also pointed to its role in hippocampal neurogenesis, which is a crucial neuronal mechanism affected in several psychiatric disorders. Methods We aimed to characterize the possible roles of DISC1 in vitro neuronal cell culture. We applied an isogenic IPSC line in a model of hippocampal dentate gyrus neurogenesis, given that impaired hippocampal neurogenesis has been implicated in the pathogenesis of both schizophrenia and affective disorders. IPSC line XCL1 was engineered using zinc finger nuclease technology to produce an isogenic DISC1 exon-2 biallelic knockout cell line (XCL1 DISC1 exon-2 KO/KO). The locus of the genetic engineering was selected because of the frameshift mutation. The isogenic IPSC pair was characterized in terms of pluripotency and spontaneous differentiation potential. Following this, IPSC lines were differentiated into neuronal lineages using established protocols to generate hippocampal dentate gyrus granule cells. The dentate gyrus protocol is founded on dual SMAD inhibition, Wnt- and SHH inhibition, after generating free-floated embryoid bodies from pluripotent stem cells, which results in forebrain NPCs. Results We have successfully derived and characterized NPCs and then matured neurons from human IPSC XCL1 and deletion pair, which were differentiated according to the DG PROX1 protocol. There was no significant difference at the spontaneous differentiation potential between the isogenic IPSC XCL1 lines. The immunofluorescence staining showed that NPCs express Nestin and Sox2. This intermediate cell type can be further differentiated into PROX1 and MAP2 positive functional neurons which have dendritic spines. Till now we have not found significant differences between wild type and knock out cell lines based on induced outgrowth measurement and structure of ICC. We have found some alteration in Ca-dynamics between the two cell lines, however these measurements need further investigation. Discussion The generated neuronal progenitor cells and mature neurons carrying biallelic knockout of the DISC1 gene were amenable for assays comparing the isogenic pairs by immunofluorescence microscopy, and transcriptomics. Functional studies, such as calcium-imaging assays, single cell patch-clamp electrophysiology and real-time live cell visualization of induced neurite outgrowth are under way to further. These investigations may help to explore the role of DISC1 in hippocampal neurogenesis and the etiology of psychiatric disorders.

Effect of aerobic exercise on BDNF/proBDNF expression in the ischemic hippocampus and depression recovery of rats after stroke

BDNF and proBDNF play an opposite role in hippocampal neurogenesis. What remains to be known is the effect of balance between BDNF and proBDNF in the ischemic hippocampus on pathogenesis of post-stroke depression (PSD) and the potential mechanisms of aerobic exercise (AE) on PSD. Wistar rats were randomly divided into control, Sham, Sedentary and AE groups. After PSD model was successful made, the blood lactate threshold corresponding speed (SLT) were measured. The behavioral tests (open field, forced swimming and sucrose preference tests) were performed before and after 4 weeks of aerobic treadmill training. HE staining and immunostaining for doublecortin (DCX)+ neurons were used to observe the changes of neuronal cell morphology and proliferation, migration of the neural progenitor cells (NPCs). The expression of mature brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), precursor BDNF (proBDNF), pan-neurotrophin receptor 75 (p75NTR) proteins, BDNF mRNA in the ischemic hippocampus and serum adrenocorticotropic hormone (ACTH) and corticosterone (CORT) were detected by Western blotting, immunohistochemistry, RT-PCR and ELISA. Higher immobility time and levels of proBDNF, p75NTR, ACTH, CORT proteins and lower sucrose preference, total distance, climbing frequency and levels of BDNF, TrkB proteins, BDNF mRNA were observed in the Sedentary group. Neuronal cells in the ischemic hippocampus were loosely arranged and expression of DCX reduced in the Sedentary group. There were significant differences in above results between Sedentary and AE groups after 4 weeks of aerobic exercise. The balance between BDNF and proBDNF in the ischemic hippocampus are likely to play an important role in the pathogenesis of PSD. And AE could improve depression, hippocampal neurogenesis, and increase BDNF/proBDNF ratio in the ischemic hippocampus of the PSD rats.

Progranulin Protects Hippocampal Neurogenesis via Suppression of Neuroinflammatory Responses Under Acute Immune Stress.

Immune stress is well known to suppress adult neurogenesis in the hippocampus. We have demonstrated that progranulin (PGRN) has a mitogenic effect on neurogenesis under several experimental conditions. We have also shown that PGRN suppresses excessive neuroinflammatory responses after traumatic brain injury. However, the role of PGRN in modulating neurogenesis under acute immune stress is yet to be elucidated. In the present study, we evaluated the involvement of PGRN in neurogenesis and inflammatory responses in the hippocampus using a lipopolysaccharide (LPS)-induced immune stress model. Treatment of mice with LPS significantly increased the expression of PGRN in activated microglia and decreased neurogenesis in the dentate gyrus of the hippocampus. PGRN deficiency increased CD68-immunoreactive area and exacerbated suppression of neurogenesis following LPS treatment. The expression levels of lysosomal genes including lysozyme M, macrophage expressed gene 1, and cathepsin Z were higher in PGRN-deficient than in wild-type mice, while PGRN deficiency decreased mammalian target of rapamycin (mTOR) mRNA levels, suggesting that PGRN suppresses excessive lysosomal biogenesis by promoting mTOR signaling. LPS treatment also increased the expression of proinflammatory genes such as interleukin (IL)-1β, tumor necrosis factor-α, and microsomal prostaglandin E synthase-1 (mPGES-1) in the hippocampus, and PGRN deficiency further enhanced gene expression of IL-6 and mPGES-1. These results suggest that PGRN plays a protecting role in hippocampal neurogenesis at least partially by attenuating neuroinflammatory responses during LPS-induced acute immune stress.

Role of Hippocampal Neurogenesis in Drug Addiction

Methamphetamine, a psychostimulant and neurotoxic drug, has been shown to inhibit neurogenesis in the hippocampal region of the brain. The hippocampus is responsible for functions such as short‐term and long‐term memory, spatial orientation, and connecting emotions and senses. Also the hippocampus is involved in forming context‐specific memories associated with reinstatement of drug‐seeking. Neurogenesis is the process of stem‐like precursor cells that proliferate into preneuronal progenitor cells that then differentiate into immature neurons that become granule cell neurons in the dentate gyrus. This process is impaired by methamphetamine and other drugs of abuse. The objective of this study is to determine the role of spontaneous neurogenesis in the dentate gyrus in drug addiction. To address this, we took a genetic approach using GFAP‐TK transgenic animals to conditionally inhibit the process of neurogenesis. GFAP‐TK+ and TK− (wild‐type controls) were submitted to intravenous surgery to implant a catheter to the jugular vein for intravenous drug self‐administration. The self‐administration behavior was divided in 5 phases: drug acquisition, forced abstinence from drug (withdrawal), extinction, and context‐ and cue‐ induced reinstatement. During withdrawal GFAP‐TK+ animals received valganciclovir diet (valcyte) to inhibit the proliferation and differentiation of neural precursor cells in the dentate gyrus. Controls received vehicle diet. One hour following reinstatement session, TK+ and TK− animals were sacrificed and the brain was processed for immunohistochemistry. Valcyte treatment in TK+ rats reduced the number of Ki‐67 and NeuroD cells in the hippocampus compared to vehicle TK− controls. In parallel, TK+ rats showed impaired lever discrimination during extinction sessions and context‐induced reinstatement, but not cue‐induced reinstatement, indicating enhanced motivation to seek methamphetamine in the absence of the drug. These results indicate that hippocampal neurogenesis plays a role in extinguishing drug seeking behavior and suppresses motivation during context induced reinstatement.Support or Funding InformationThe study was supported by funds from the National Institute on Drug Abuse (DA022473 and DA034140 to CDM) and National Science Foundation (DGE‐1144086) to MG

Role of Hippocampal Neurogenesis in Regulation of Feeding Behavior during Withdrawal Period in Socialized and Isolated Rats

Role of Hippocampal Neurogenesis in Regulation of Feeding Behavior during Withdrawal Period in Socialized and Isolated Rats

Role of adult hippocampal neurogenesis in cognition in physiology and disease: pharmacological targets and biomarkers.

Adult hippocampal neurogenesis is a remarkable form of brain structural plasticity by which new functional neurons are generated from adult neural stem cells/precursors. Although the precise role of this process remains elusive, adult hippocampal neurogenesis is important for learning and memory and it is affected in disease conditions associated with cognitive impairment, depression, and anxiety. Immature neurons in the adult brain exhibit an enhanced structural and synaptic plasticity during their maturation representing a unique population of neurons to mediate specific hippocampal function. Compelling preclinical evidence suggests that hippocampal neurogenesis is modulated by a broad range of physiological stimuli which are relevant in cognitive and emotional states. Moreover, multiple pharmacological interventions targeting cognition modulate adult hippocampal neurogenesis. In addition, recent genetic approaches have shown that promoting neurogenesis can positively modulate cognition associated with both physiology and disease. Thus the discovery of signaling pathways that enhance adult neurogenesis may lead to therapeutic strategies for improving memory loss due to aging or disease. This chapter endeavors to review the literature in the field, with particular focus on (1) the role of hippocampal neurogenesis in cognition in physiology and disease; (2) extrinsic and intrinsic signals that modulate hippocampal neurogenesis with a focus on pharmacological targets; and (3) efforts toward novel strategies pharmacologically targeting neurogenesis and identification of biomarkers of human neurogenesis.

The microtubule destabilizing protein stathmin controls the transition from dividing neuronal precursors to postmitotic neurons during adult hippocampal neurogenesis.

The hippocampus is one of the two areas in the mammalian brain where adult neurogenesis occurs. Adult neurogenesis is well known to be involved in hippocampal physiological functions as well as pathophysiological conditions. Microtubules (MTs), providing intracellular transport, stability, and transmitting force, are indispensable for neurogenesis by facilitating cell division, migration, growth, and differentiation. Although there are several examples of MT-stabilizing proteins regulating different aspects of adult neurogenesis, relatively little is known about the function of MT-destabilizing proteins. Stathmin is such a MT-destabilizing protein largely restricted to the CNS, and in contrast to its developmental family members, stathmin is also expressed at significant levels in the adult brain, notably in areas involved in adult neurogenesis. Here, we show an important role for stathmin during adult neurogenesis in the subgranular zone of the mouse hippocampus. After carefully mapping stathmin expression in the adult dentate gyrus (DG), we investigated its role in hippocampal neurogenesis making use of stathmin knockout mice. Although hippocampus development appears normal in these animals, different aspects of adult neurogenesis are affected. First, the number of proliferating Ki-67+ cells is decreased in stathmin knockout mice, as well as the expression of the immature markers Nestin and PSA-NCAM. However, newborn cells that do survive express more frequently the adult marker NeuN and have a more mature morphology. Furthermore, our data suggest that migration in the DG might be affected. We propose a model in which stathmin controls the transition from neuronal precursors to early postmitotic neurons.

Huperzine A promotes hippocampal neurogenesis in vitro and in vivo

Huperzine A (Hup A) is a lycopodium alkaloid from Huperzia serrata, which has been used as a therapeutic agent in several neurological disorders. Despite the diverse pharmacological activities Hup A has, its role in hippocampal neurogenesis remains to be established. This study showed that Hup A not only promoted the proliferation of cultured mouse embryonic hippocampal neural stem cells (NSCs), but also increased the newly generated cells in the subgranular zone (SGZ) of the hippocampus in adult mice. Furthermore, the in vitro findings indicated that low concentrations of Hup A stimulated the proliferation of cultured NSCs, whereas extremely high concentration of it decreased the cell proliferation. Hup A activated mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway, which was a well-known regulator of biological processes including cell proliferation and differentiation. ERK inhibitor dramatically inhibited the proliferative effect of Hup A on NSCs. Administration of Hup A to adult mice significantly enhanced the cell proliferation in dentate gyrus of hippocampus, and increased the remaining newborn cells 4 weeks after the drug administration. Moreover, the newly generated BrdU+/NeuN+ neurons were also increased by Hup A treatment. These findings suggest a novel role of Hup A in neurogenesis and provide a new insight into its therapeutic effects in neurological disorders via a neurogenesis-related mechanism.

The Pivotal Role of Hippocampal Neurogenesis

Several lines of evidence support the role of hippocampal neurogenesis in the successful treatment of depression. Two recent translational studies add