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Sample records for adult hippocampal neural

  1. CD44 Transmembrane Receptor and Hyaluronan Regulate Adult Hippocampal Neural Stem Cell Quiescence and Differentiation.

    PubMed

    Su, Weiping; Foster, Scott C; Xing, Rubing; Feistel, Kerstin; Olsen, Reid H J; Acevedo, Summer F; Raber, Jacob; Sherman, Larry S

    2017-03-17

    Adult neurogenesis in the hippocampal subgranular zone (SGZ) is involved in learning and memory throughout life but declines with aging. Mice lacking the CD44 transmembrane receptor for the glycosaminoglycan hyaluronan (HA) demonstrate a number of neurological disturbances including hippocampal memory deficits, implicating CD44 in the processes underlying hippocampal memory encoding, storage, or retrieval. Here, we found that HA and CD44 play important roles in regulating adult neurogenesis, and we provide evidence that HA contributes to age-related reductions in neural stem cell (NSC) expansion and differentiation in the hippocampus. CD44-expressing NSCs isolated from the mouse SGZ are self-renewing and capable of differentiating into neurons, astrocytes, and oligodendrocytes. Mice lacking CD44 demonstrate increases in NSC proliferation in the SGZ. This increased proliferation is also observed in NSCs grown in vitro, suggesting that CD44 functions to regulate NSC proliferation in a cell-autonomous manner. HA is synthesized by NSCs and increases in the SGZ with aging. Treating wild type but not CD44-null NSCs with HA inhibits NSC proliferation. HA digestion in wild type NSC cultures or in the SGZ induces increased NSC proliferation, and CD44-null as well as HA-disrupted wild type NSCs demonstrate delayed neuronal differentiation. HA therefore signals through CD44 to regulate NSC quiescence and differentiation, and HA accumulation in the SGZ may contribute to reductions in neurogenesis that are linked to age-related decline in spatial memory.

  2. Hippocampal adult neurogenesis is maintained by Neil3-dependent repair of oxidative DNA lesions in neural progenitor cells.

    PubMed

    Regnell, Christine Elisabeth; Hildrestrand, Gunn Annette; Sejersted, Yngve; Medin, Tirill; Moldestad, Olve; Rolseth, Veslemøy; Krokeide, Silje Zandstra; Suganthan, Rajikala; Luna, Luisa; Bjørås, Magnar; Bergersen, Linda H

    2012-09-27

    Accumulation of oxidative DNA damage has been proposed as a potential cause of age-related cognitive decline. The major pathway for removal of oxidative DNA base lesions is base excision repair, which is initiated by DNA glycosylases. In mice, Neil3 is the main DNA glycosylase for repair of hydantoin lesions in single-stranded DNA of neural stem/progenitor cells, promoting neurogenesis. Adult neurogenesis is crucial for maintenance of hippocampus-dependent functions involved in behavior. Herein, behavioral studies reveal learning and memory deficits and reduced anxiety-like behavior in Neil3(-/-) mice. Neural stem/progenitor cells from aged Neil3(-/-) mice show impaired proliferative capacity and reduced DNA repair activity. Furthermore, hippocampal neurons in Neil3(-/-) mice display synaptic irregularities. It appears that Neil3-dependent repair of oxidative DNA damage in neural stem/progenitor cells is required for maintenance of adult neurogenesis to counteract the age-associated deterioration of cognitive performance.

  3. Methylglyoxal Causes Cell Death in Neural Progenitor Cells and Impairs Adult Hippocampal Neurogenesis.

    PubMed

    Chun, Hye Jeong; Lee, Yujeong; Kim, Ah Hyun; Lee, Jaewon

    2016-04-01

    Methylglyoxal (MG) is formed during normal metabolism by processes like glycolysis, lipid peroxidation, and threonine catabolism, and its accumulation is associated with various degenerative diseases, such as diabetes and arterial atherogenesis. Furthermore, MG has also been reported to have toxic effects on hippocampal neurons. However, these effects have not been studied in the context of neurogenesis. Here, we report that MG adversely affects hippocampal neurogenesis and induces neural progenitor cell (NPC) death. MG significantly reduced C17.2 NPC proliferation, and high concentration of MG (500 μM) induced cell death and elevated oxidative stress. Further, MG was found to activate the ERK signaling pathway, indicating elevated stress response. To determine the effects of MG in vivo, mice were administrated with vehicle or MG (0.5 or 1 % in drinking water) for 4 weeks. The numbers of BrdU-positive cells in hippocampi were significantly lower in MG-treated mice, indicating impaired neurogenesis, but MG did not induce neuronal damage or glial activations. Interestingly, MG reduced memory retention when administered to mice at 1 % but not at 0.5 %. In addition, the levels of hippocampal BDNF and synaptophysin were significantly lower in the hippocampi of mice treated with MG at 1 %. Collectively, our findings suggest MG could be harmful to NPCs and to hippocampal neurogenesis.

  4. Cyclin E marks quiescent neural stem cells and caspase-3-positive newborn cells during adult hippocampal neurogenesis in mice.

    PubMed

    Ikeda, Yayoi; Ikeda, Masa-Aki

    2015-10-21

    Cyclin E is a key regulator of progression through the G1-phase of the cell cycle. Recently, a cell cycle-independent role for cyclin E in the adult mouse central nervous system has been suggested. In the present study, we examined expression of cyclin E in the mouse hippocampal dentate gyrus (DG), a region of neurogenesis in adulthood, using immunofluorescence. In the adult DG, cyclin E-immunoreactive (cyclin E+) cells was limited to postmitotic cells. In the subgranular zone, cyclin E was detected in the vertical process of radial glia-like cells, which were marked by the neural stem cell markers nestin and GFAP. Cyclin E was also detected in the nucleus of cells, which were labeled with stage-specific neuronal cell markers, including Pax6, Sox2, NeuroD, doublecortin, and NeuN. The densities of cyclin E+ cells in the DG reduced and increased with age and running, respectively. Furthermore, the majority of cyclin E+ cells co-expressed active caspase-3, a marker of apoptosis. Together, the results indicate that cyclin E is expressed in the process of quiescent neural stem cells and in the nucleus of active caspase-3+ cells during neuronal cell differentiation, suggesting that cyclin E has a Cdk-independent function, which might be important for the mechanisms regulating adult hippocampal neurogenesis.

  5. Neural stem cell deforestation as the main force driving the age-related decline in adult hippocampal neurogenesis.

    PubMed

    Encinas, Juan M; Sierra, Amanda

    2012-02-14

    Newborn neurons derived from radial glia-like stem cells located in the dentate gyrus integrate into the adult hippocampal circuitry and participate in memory formation, spatial learning, pattern separation, fear conditioning, and anxiety. This process takes place throughout the life span of mammals, including humans; however, it follows a sharp declining curve. New neurons are generated abundantly during youth but very scarcely in the aged brain. The absolute number of newly generated neurons, or neurogenic output, is determined at different levels along the neurogenic cascade: the activation of quiescent stem cells; the mitotic potential of proliferating precursors; and the survival of neuronal fate-committed precursors. A continuous depletion of the hippocampal neural stem cell pool has been recently proposed as the main force underlying the age-related decline of neurogenesis, in contrast to the previous view of population of neural stem cells whose number remains constant but loses its ability to bear fruit. Nevertheless, the diminished neurogenic output may be reflecting other phenomena such as decreased mitotic capability of proliferating progenitors, decreased survival or changes in differentiation. We describe herein the most important events in determining the amount of neurogenesis in the dentate gyrus and examine the literature to understand the effects of age throughout the cascade.

  6. Melatonin restores hippocampal neural precursor cell proliferation and prevents cognitive deficits induced by jet lag simulation in adult mice.

    PubMed

    Iggena, Deetje; Winter, York; Steiner, Barbara

    2017-05-01

    Frequent flyers and shift workers undergo circadian dysrhythmia with adverse impact on body and mind. The circadian rhythm disorder "jet lag" disturbs hippocampal neurogenesis and spatial cognition, which represent morphological and functional adult brain plasticity. This raises the question if pro-neurogenic stimuli might prevent those consequences. However, suitable measures to mitigate jet lag-induced adverse effects on brain plasticity have been neglected so far. Here, we used adult C57Bl6 mice to investigate the pro-neurogenic stimuli melatonin (8 mg/kg i.p.) as well as environmental enrichment as potential measures. We applied photoperiod alterations to simulate "jet lag" by shortening the dark period every third day by 6 hours for 3 weeks. We found that "jet lag" simulation reduced hippocampal neural precursor cell proliferation by 24% and impaired spatial memory performance in the water maze indicated by a prolonged swim path to the target (~23%). While melatonin prevented both the cellular (~1%) as well as the cognitive deficits (~5%), environmental enrichment only preserved precursor cell proliferation (~12%). Our results indicate that lifestyle interventions are insufficient to completely compensate jet lag-induced consequences. Instead, melatonin is required to prevent cognitive impairment caused by the same environmental factors to which frequent flyers and shift workers are typically exposed to.

  7. Mediation of Autophagic Cell Death by Type 3 Ryanodine Receptor (RyR3) in Adult Hippocampal Neural Stem Cells

    PubMed Central

    Chung, Kyung Min; Jeong, Eun-Ji; Park, Hyunhee; An, Hyun-Kyu; Yu, Seong-Woon

    2016-01-01

    Cytoplasmic Ca2+ actively engages in diverse intracellular processes from protein synthesis, folding and trafficking to cell survival and death. Dysregulation of intracellular Ca2+ levels is observed in various neuropathological states including Alzheimer’s and Parkinson’s diseases. Ryanodine receptors (RyRs) and inositol 1,4,5-triphosphate receptors (IP3Rs), the main Ca2+ release channels located in endoplasmic reticulum (ER) membranes, are known to direct various cellular events such as autophagy and apoptosis. Here we investigated the intracellular Ca2+-mediated regulation of survival and death of adult hippocampal neural stem (HCN) cells utilizing an insulin withdrawal model of autophagic cell death (ACD). Despite comparable expression levels of RyR and IP3R transcripts in HCN cells at normal state, the expression levels of RyRs—especially RyR3—were markedly upregulated upon insulin withdrawal. While treatment with the RyR agonist caffeine significantly promoted the autophagic death of insulin-deficient HCN cells, treatment with its inhibitor dantrolene prevented the induction of autophagy following insulin withdrawal. Furthermore, CRISPR/Cas9-mediated knockout of the RyR3 gene abolished ACD of HCN cells. This study delineates a distinct, RyR3-mediated ER Ca2+ regulation of autophagy and programmed cell death in neural stem cells. Our findings provide novel insights into the critical, yet understudied mechanisms underlying the regulatory function of ER Ca2+ in neural stem cell biology. PMID:27199668

  8. Growth and differentiation of adult hippocampal arctic ground squirrel neural stem cells.

    PubMed

    Drew, Kelly L; McGee, Rebecca C; Wells, Matthew S; Kelleher-Andersson, Judith A

    2011-01-07

    Arctic ground squirrels (Urocitellus parryii, AGS) are unique in their ability to hibernate with a core body temperature near or below freezing. These animals also resist ischemic injury to the brain in vivo and oxygen-glucose deprivation in vitro. These unique qualities provided the impetus to isolate AGS neurons to examine inherent neuronal characteristics that could account for the capacity of AGS neurons to resist injury and cell death caused by ischemia and extremely cold temperatures. Identifying proteins or gene targets that allow for the distinctive properties of these cells could aid in the discovery of effective therapies for a number of ischemic indications and for the study of cold tolerance. Adult AGS hippocampus contains neural stem cells that continue to proliferate, allowing for easy expansion of these stem cells in culture. We describe here methods by which researchers can utilize these stem cells and differentiated neurons for any number of purposes. By closely following these steps the AGS neural stem cells can be expanded through two passages or more and then differentiated to a culture high in TUJ1-positive neurons (~50%) without utilizing toxic chemicals to minimize the number of dividing cells. Ischemia induces neurogenesis and neurogenesis which proceeds via MEK/ERK and PI3K/Akt survival signaling pathways contributes to ischemia resistance in vivo and in vitro (Kelleher-Anderson, Drew et al., in preparation). Further characterization of these unique neural cells can advance on many fronts, using some or all of these methods.

  9. Calpain Determines the Propensity of Adult Hippocampal Neural Stem Cells to Autophagic Cell Death Following Insulin Withdrawal.

    PubMed

    Chung, Kyung Min; Park, Hyunhee; Jung, Seonghee; Ha, Shinwon; Yoo, Seung-Jun; Woo, Hanwoong; Lee, Hyang Ju; Kim, Seong Who; Kim, Eun-Kyoung; Moon, Cheil; Yu, Seong-Woon

    2015-10-01

    Programmed cell death (PCD) has significant effects on the function of neural stem cells (NSCs) during brain development and degeneration. We have previously reported that adult rat hippocampal neural stem (HCN) cells underwent autophagic cell death (ACD) rather than apoptosis following insulin withdrawal despite their intact apoptotic capabilities. Here, we report a switch in the mode of cell death in HCN cells with calpain as a critical determinant. In HCN cells, calpain 1 expression was barely detectable while calpain 2 was predominant. Inhibition of calpain in insulin-deprived HCN cells further augmented ACD. In contrast, expression of calpain 1 switched ACD to apoptosis. The proteasome inhibitor lactacystin blocked calpain 2 degradation and elevated the intracellular Ca(2+) concentration. In combination, these effects potentiated calpain activity and converted the mode of cell death to apoptosis. Our results indicate that low calpain activity, due to absence of calpain 1 and degradation of calpain 2, results in a preference for ACD over apoptosis in insulin-deprived HCN cells. On the other hand, conditions leading to high calpain activity completely switch the mode of cell death to apoptosis. This is the first report on the PCD mode switching mechanism in NSCs. The dynamic change in calpain activity through the proteasome-mediated modulation of the calpain and intracellular Ca(2+) levels may be the critical contributor to the demise of NSCs. Our findings provide a novel insight into the complex mechanisms interconnecting autophagy and apoptosis and their roles in the regulation of NSC death.

  10. The MMP-1/PAR-1 Axis Enhances Proliferation and Neuronal Differentiation of Adult Hippocampal Neural Progenitor Cells

    PubMed Central

    Valente, Maria Maddalena; Allen, Megan; Bortolotto, Valeria; Lim, Seung T.; Conant, Katherine; Grilli, Mariagrazia

    2015-01-01

    Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that play a role in varied forms of developmental and postnatal neuroplasticity. MMP substrates include protease-activated receptor-1 (PAR-1), a G-protein coupled receptor expressed in hippocampus. We examined proliferation and differentiation of adult neural progenitor cells (aNPCs) from hippocampi of mice that overexpress the potent PAR-1 agonist MMP-1. We found that, as compared to aNPCs from littermate controls, MMP-1 tg aNPCs display enhanced proliferation. Under differentiating conditions, these cells give rise to a higher percentage of MAP-2+ neurons and a reduced number of oligodendrocyte precursors, and no change in the number of astrocytes. The fact that these results are MMP and PAR-1 dependent is supported by studies with distinct antagonists. Moreover, JSH-23, an inhibitor of NF-κB p65 nuclear translocation, counteracted both the proliferation and differentiation changes seen in MMP-1 tg-derived NPCs. In complementary studies, we found that the percentage of Sox2+ undifferentiated progenitor cells is increased in hippocampi of MMP-1 tg animals, compared to wt mice. Together, these results add to a growing body of data suggesting that MMPs are effectors of hippocampal neuroplasticity in the adult CNS and that the MMP-1/PAR-1 axis may play a role in neurogenesis following physiological and/or pathological stimuli. PMID:26783471

  11. High neuronal/astroglial differentiation plasticity of adult rat hippocampal neural stem/progenitor cells in response to the effects of embryonic and adult cerebrospinal fluids

    PubMed Central

    Peirouvi, T.; Yekani, F.; Azarnia, M.; Massumi, M.

    2015-01-01

    Hippocampal neural stem/progenitor cells (hipp-NS/PCs) of the adult mammalian brain are important sources of neuronal and gial cell production. In this study, the main goal is to investigate the plasticity of these cells in neuronal/astroglial differentiations. To this end, the differentiation of the hipp-NS/PCs isolated from 3-month-old Wistar rats was investigated in response to the embryonic cerebrospinal fluid (E-CSF) including E13.5, E17-CSF and the adult cerebrospinal fluid (A-CSF), all extracted from rats. CSF samples were selected based on their effects on cell behavioral parameters. Primary cell culture was performed in the presence of either normal or high levels of KCL in a culture medium. High levels of KCL cause cell depolarization, and thus the activation of quiescent NSCs. Results from immunocytochemistry (ICC) and semi-quantitative RT-PCR (sRT-PCR) techniques showed that in E-CSF-treated groups, neuronal differentiation increased (E17>E13.5). In contrast, A-CSF decreased and increased neuronal and astroglial differentiations, respectively. Cell survivability and/or proliferation (S/P), evaluated by an MTT assay, increased by E13.5 CSF, but decreased by both E17 CSF and A-CSF. Based on the results, it is finally concluded that adult rat hippocampal proliferative cells are not restricted progenitors but rather show high plasticity in neuronal/astroglial differentiation according to the effects of CSF samples. In addition, using high concentrations of KCL in the primary cell culture led to an increase in the number of NSCs, which in turn resulted in the increase in neuronal or astroglial differentiations after CSF treatment. PMID:27175157

  12. Neural activity and the levels of high energy phosphates during deprivation of oxygen and/or glucose in hippocampal slices of immature and adult rats.

    PubMed

    Nabetani, M; Okada, Y; Kawai, S; Nakamura, H

    1995-02-01

    To investigate the relationship between neural activity and cerebral energy metabolism during anoxia or ischemia in neural tissue of different ages, hippocampal slices were prepared from four-, seven- and 10-day-old and adult rats. For the index of the neural activity, the population spikes were recorded in the pyramidal cell layer of the CA3 area. ATP and phosphocreatine levels in the slices were measured during oxygen and/or glucose deprivation. After deprivation of both oxygen and glucose, population spikes of the slices from four, seven- and 10-day-old and adult rats ceased completely in 14.2, 11.8, 9.4 and 5.3 min, respectively. The level of ATP at the time of cessation of population spike in four-, seven- and 10-day-old and adult rats was 37.4, 30.2, 28.5 and 56.4% of the original concentrations. After deprivation of glucose only, the decay time of the population spikes of the slices from four-, seven- and 10-day-old and adult rats was 17.8, 14.5, 9.0 and 10.0 min and at the time of population spikes cessation the level of ATP was 99.8, 84.2, 79.3 and 49%, respectively. After deprivation of oxygen only, population spikes of the slices from four, seven- and 10-day old and adult rats ceased completely in 257, 283, 109 and 8.5 min, respectively. The level of ATP at the time of population spikes cessation was 50, 40, 36.6 and 94.4% of the initial values, respectively. These results indicate that the immature rat is extremely resistant to oxygen deprivation from a functional and a metabolic view, whereas in the adult rat, preservation of neural activity depends much on both oxygen and glucose. During glucose deprivation, population spikes of the slices of immature and mature rats ceased rapidly although the level of ATP is preserved at high levels. This suggests that glucose plays an important role in the preservation of neural activity in addition to its major function as an energy substrate especially in immature animals.

  13. Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation.

    PubMed

    Sahay, Amar; Scobie, Kimberly N; Hill, Alexis S; O'Carroll, Colin M; Kheirbek, Mazen A; Burghardt, Nesha S; Fenton, André A; Dranovsky, Alex; Hen, René

    2011-04-28

    Adult hippocampal neurogenesis is a unique form of neural circuit plasticity that results in the generation of new neurons in the dentate gyrus throughout life. Neurons that arise in adults (adult-born neurons) show heightened synaptic plasticity during their maturation and can account for up to ten per cent of the entire granule cell population. Moreover, levels of adult hippocampal neurogenesis are increased by interventions that are associated with beneficial effects on cognition and mood, such as learning, environmental enrichment, exercise and chronic treatment with antidepressants. Together, these properties of adult neurogenesis indicate that this process could be harnessed to improve hippocampal functions. However, despite a substantial number of studies demonstrating that adult-born neurons are necessary for mediating specific cognitive functions, as well as some of the behavioural effects of antidepressants, it is unknown whether an increase in adult hippocampal neurogenesis is sufficient to improve cognition and mood. Here we show that inducible genetic expansion of the population of adult-born neurons through enhancing their survival improves performance in a specific cognitive task in which two similar contexts need to be distinguished. Mice with increased adult hippocampal neurogenesis show normal object recognition, spatial learning, contextual fear conditioning and extinction learning but are more efficient in differentiating between overlapping contextual representations, which is indicative of enhanced pattern separation. Furthermore, stimulation of adult hippocampal neurogenesis, when combined with an intervention such as voluntary exercise, produces a robust increase in exploratory behaviour. However, increasing adult hippocampal neurogenesis alone does not produce a behavioural response like that induced by anxiolytic agents or antidepressants. Together, our findings suggest that strategies that are designed to increase adult hippocampal

  14. Updating stored memory requires adult hippocampal neurogenesis

    PubMed Central

    Suárez-Pereira, Irene; Carrión, Ángel M

    2015-01-01

    Adult hippocampal neurogenesis appears to influence hippocampal functions, such as memory formation for example. While adult hippocampal neurogenesis is known to be involved in hippocampal-dependent learning and consolidation processes, the role of such immature neurons in memory reconsolidation, a process involved in the modification of stored memories, remains unclear. Here, using a novel fast X-ray ablation protocol to deplete neurogenic cells, we have found that adult hippocampal neurogenesis is required to update object recognition stored memory more than to reinforce it. Indeed, we show that immature neurons were selectively recruited to hippocampal circuits during the updating of stored information. Thus, our data demonstrate a new role for neurogenesis in cognitive processes, adult hippocampal neurogenesis being required for the updating of stored OR memories. These findings suggest that manipulating adult neurogenesis may have a therapeutic application in conditions associated with traumatic stored memory, for example. PMID:26358557

  15. Updating stored memory requires adult hippocampal neurogenesis.

    PubMed

    Suárez-Pereira, Irene; Carrión, Ángel M

    2015-09-11

    Adult hippocampal neurogenesis appears to influence hippocampal functions, such as memory formation for example. While adult hippocampal neurogenesis is known to be involved in hippocampal-dependent learning and consolidation processes, the role of such immature neurons in memory reconsolidation, a process involved in the modification of stored memories, remains unclear. Here, using a novel fast X-ray ablation protocol to deplete neurogenic cells, we have found that adult hippocampal neurogenesis is required to update object recognition stored memory more than to reinforce it. Indeed, we show that immature neurons were selectively recruited to hippocampal circuits during the updating of stored information. Thus, our data demonstrate a new role for neurogenesis in cognitive processes, adult hippocampal neurogenesis being required for the updating of stored OR memories. These findings suggest that manipulating adult neurogenesis may have a therapeutic application in conditions associated with traumatic stored memory, for example.

  16. Tet1 Regulates Adult Hippocampal Neurogenesis and Cognition

    PubMed Central

    Zhang, Run-Rui; Cui, Qing-Yan; Murai, Kiyohito; Lim, Yen Ching; Smith, Zachary D.; Jin, Shengnan; Ye, Peng; Rosa, Luis; Lee, Yew Kok; Wu, Hai-Ping; Liu, Wei; Xu, Zhi-Mei; Yang, Lu; Ding, Yu-Qiang; Tang, Fuchou; Meissner, Alexander; Ding, Chunming; Shi, Yanhong; Xu, Guo-Liang

    2015-01-01

    SUMMARY DNA hydroxylation catalyzed by Tet dioxygenases occurs abundantly in embryonic stem cells and neurons in mammals. However, its biological function in vivo is largely unknown. Here we demonstrate that Tet1 plays an important role in regulating neural progenitor cell proliferation in adult mouse brain. Mice lacking Tet1 exhibit impaired hippocampal neurogenesis accompanied by poor learning and memory. In adult neural progenitor cells deficient in Tet1, a cohort of genes involved in progenitor proliferation were hypermethylated and down-regulated. Our results indicate that Tet1 is positively involved in the epigenetic regulation of neural progenitor cell proliferation in the adult brain. PMID:23770080

  17. Prospective and Episodic Memory in Relation to Hippocampal Volume in Adults with Spina Bifida Myelomeningocele

    PubMed Central

    Treble-Barna, Amery; Juranek, Jenifer; Stuebing, Karla K.; Cirino, Paul T.; Dennis, Maureen; Fletcher, Jack M.

    2014-01-01

    The present study examined prospective and episodic memory in relation to age, functional independence, and hippocampal volume in younger to middle-aged adults with spina bifida myelomeningocele (SBM) and typically developing (TD) adults. Prospective and episodic memory, as well as hippocampal volume, were reduced in adults with SBM relative to TD adults. Neither memory performance nor hippocampal volume showed greater decrements in older adults. Lower hippocampal volume was associated with reduced prospective memory in adults with SBM, and this relation was specific to the hippocampus and not to a contrast structure, the amygdala. Prospective memory mediated the relation between hippocampal volume and functional independence in adults with SBM. The results add to emerging evidence for reduced memory function in adults with SBM, and provide quantitative evidence for compromised hippocampal macrostructure as a neural correlate of reduced memory in this population. PMID:25068670

  18. Global rhythmic activities in hippocampal neural fields and neural coding.

    PubMed

    Ventriglia, Francesco

    2006-01-01

    Global oscillations of the neural field represent some of the most interesting expressions of the hippocampal activity, being related also to learning and memory. To study oscillatory activities of the CA3 field in theta range, a model of this sub-field of Hippocampus has been formulated. The model describes the firing activity of CA3 neuronal populations within the frame of a kinetic theory of neural systems and it has been used for computer simulations. The results show that the propagation of activities induced in the neural field by hippocampal afferents occurs only in narrow time windows confined by inhibitory barrages, whose time-course follows the theta rhythm. Moreover, during each period of a theta wave, the entire CA3 field bears a firing activity with peculiar space-time patterns, a sort of specific imprint, which can induce effects with similar patterns on brain regions driven by the hippocampal formation. The simulation has also demonstrated the ability of medial septum to influence the global activity of the CA3 pyramidal population through the control of the population of inhibitory interneurons. At last, the possible involvement of global population oscillations in neural coding has been discussed.

  19. Wnt signaling in the regulation of adult hippocampal neurogenesis

    PubMed Central

    Varela-Nallar, Lorena; Inestrosa, Nibaldo C.

    2013-01-01

    In the adult brain new neurons are continuously generated mainly in two regions, the subventricular zone (SVZ) of the lateral ventricles and the subgranular zone (SGZ) in the hippocampal dentate gyrus. In the SGZ, radial neural stem cells (NSCs) give rise to granule cells that integrate into the hippocampal circuitry and are relevant for the plasticity of the hippocampus. Loss of neurogenesis impairs learning and memory, suggesting that this process is important for adult hippocampal function. Adult neurogenesis is tightly regulated by multiple signaling pathways, including the canonical Wnt/β-catenin pathway. This pathway plays important roles during the development of neuronal circuits and in the adult brain it modulates synaptic transmission and plasticity. Here, we review current knowledge on the regulation of adult hippocampal neurogenesis by the Wnt/β-catenin signaling cascade and the potential mechanisms involved in this regulation. Also we discuss the evidence supporting that the canonical Wnt pathway is part of the signaling mechanisms involved in the regulation of neurogenesis in different physiological conditions. Finally, some unsolved questions regarding the Wnt-mediated regulation of neurogenesis are discussed. PMID:23805076

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

    PubMed

    Costa, Veronica; Lugert, Sebastian; Jagasia, Ravi

    2015-01-01

    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.

  1. TAM receptor deficiency affects adult hippocampal neurogenesis

    PubMed Central

    Ji, Rui; Meng, Lingbin; Li, Qiutang; Lu, Qingxian

    2014-01-01

    The Tyro3, Axl and Mertk (TAM) subfamily of receptor protein tyrosine kinases functions in cell growth, differentiation, survival, and most recently found, in the regulation of immune responses and phagocytosis. All three receptors and their ligands, Gas6 (growth arrest-specific gene 6) and protein S, are expressed in the central nervous system (CNS). TAM receptors play pivotal roles in adult hippocampal neurogenesis. Loss of these receptors causes a comprised neurogenesis in the dentate gyrus of adult hippocampus. TAM receptors have a negative regulatory effect on microglia and peripheral antigen-presenting cells, and play a critical role in preventing overproduction of pro-inflammatory cytokines detrimental to the proliferation, differentiation, and survival of adult neuronal stem cells (NSCs). Besides, these receptors also play an intrinsic trophic function in supporting NSC survival, proliferation, and differentiation into immature neurons. All these events collectively ensure a sustained neurogenesis in adult hippocampus. PMID:25487541

  2. Spatial Relational Memory Requires Hippocampal Adult Neurogenesis

    PubMed Central

    Koehl, Muriel; Ichas, François; De Giorgi, Francesca; Costet, Pierre; Abrous, Djoher Nora; Piazza, Pier Vincenzo

    2008-01-01

    The dentate gyrus of the hippocampus is one of the few regions of the mammalian brain where new neurons are generated throughout adulthood. This adult neurogenesis has been proposed as a novel mechanism that mediates spatial memory. However, data showing a causal relationship between neurogenesis and spatial memory are controversial. Here, we developed an inducible transgenic strategy allowing specific ablation of adult-born hippocampal neurons. This resulted in an impairment of spatial relational memory, which supports a capacity for flexible, inferential memory expression. In contrast, less complex forms of spatial knowledge were unaltered. These findings demonstrate that adult-born neurons are necessary for complex forms of hippocampus-mediated learning. PMID:18509506

  3. Tau Protein and Adult Hippocampal Neurogenesis

    PubMed Central

    Fuster-Matanzo, Almudena; Llorens-Martín, María; Jurado-Arjona, Jerónimo; Avila, Jesús; Hernández, Félix

    2012-01-01

    Tau protein is a microtubule-associated protein found in the axonal compartment that stabilizes neuronal microtubules under normal physiological conditions. Tau metabolism has attracted much attention because of its role in neurodegenerative disorders called tauopathies, mainly Alzheimer disease. Here, we review recent findings suggesting that axonal outgrowth in subgranular zone during adult hippocampal neurogenesis requires a dynamic microtubule network and tau protein facilitates to maintain that dynamic cytoskeleton. Those functions are carried out in part by tau isoform with only three microtubule-binding domains (without exon 10) and by presence of hyperphosphorylated tau forms. Thus, tau is a good marker and a valuable tool to study new axons in adult neurogenesis. PMID:22787440

  4. REST regulation of gene networks in adult neural stem cells

    PubMed Central

    Mukherjee, Shradha; Brulet, Rebecca; Zhang, Ling; Hsieh, Jenny

    2016-01-01

    Adult hippocampal neural stem cells generate newborn neurons throughout life due to their ability to self-renew and exist as quiescent neural progenitors (QNPs) before differentiating into transit-amplifying progenitors (TAPs) and newborn neurons. The mechanisms that control adult neural stem cell self-renewal are still largely unknown. Conditional knockout of REST (repressor element 1-silencing transcription factor) results in precocious activation of QNPs and reduced neurogenesis over time. To gain insight into the molecular mechanisms by which REST regulates adult neural stem cells, we perform chromatin immunoprecipitation sequencing and RNA-sequencing to identify direct REST target genes. We find REST regulates both QNPs and TAPs, and importantly, ribosome biogenesis, cell cycle and neuronal genes in the process. Furthermore, overexpression of individual REST target ribosome biogenesis or cell cycle genes is sufficient to induce activation of QNPs. Our data define novel REST targets to maintain the quiescent neural stem cell state. PMID:27819263

  5. REST regulation of gene networks in adult neural stem cells.

    PubMed

    Mukherjee, Shradha; Brulet, Rebecca; Zhang, Ling; Hsieh, Jenny

    2016-11-07

    Adult hippocampal neural stem cells generate newborn neurons throughout life due to their ability to self-renew and exist as quiescent neural progenitors (QNPs) before differentiating into transit-amplifying progenitors (TAPs) and newborn neurons. The mechanisms that control adult neural stem cell self-renewal are still largely unknown. Conditional knockout of REST (repressor element 1-silencing transcription factor) results in precocious activation of QNPs and reduced neurogenesis over time. To gain insight into the molecular mechanisms by which REST regulates adult neural stem cells, we perform chromatin immunoprecipitation sequencing and RNA-sequencing to identify direct REST target genes. We find REST regulates both QNPs and TAPs, and importantly, ribosome biogenesis, cell cycle and neuronal genes in the process. Furthermore, overexpression of individual REST target ribosome biogenesis or cell cycle genes is sufficient to induce activation of QNPs. Our data define novel REST targets to maintain the quiescent neural stem cell state.

  6. The influence of electric fields on hippocampal neural progenitor cells.

    PubMed

    Ariza, Carlos Atico; Fleury, Asha T; Tormos, Christian J; Petruk, Vadim; Chawla, Sagar; Oh, Jisun; Sakaguchi, Donald S; Mallapragada, Surya K

    2010-12-01

    The differentiation and proliferation of neural stem/progenitor cells (NPCs) depend on various in vivo environmental factors or cues, which may include an endogenous electrical field (EF), as observed during nervous system development and repair. In this study, we investigate the morphologic, phenotypic, and mitotic alterations of adult hippocampal NPCs that occur when exposed to two EFs of estimated endogenous strengths. NPCs treated with a 437 mV/mm direct current (DC) EF aligned perpendicularly to the EF vector and had a greater tendency to differentiate into neurons, but not into oligodendrocytes or astrocytes, compared to controls. Furthermore, NPC process growth was promoted perpendicularly and inhibited anodally in the 437 mV/mm DC EF. Yet fewer cells were observed in the DC EF, which in part was due to a decrease in cell viability. The other EF applied was a 46 mV/mm alternating current (AC) EF. However, the 46 mV/mm AC EF showed no major differences in alignment or differentiation, compared to control conditions. For both EF treatments, the percent of mitotic cells during the last 14 h of the experiment were statistically similar to controls. Reported here, to our knowledge, is the first evidence of adult NPC differentiation affected in an EF in vitro. Further investigation and application of EFs on stem cells is warranted to elucidate the utility of EFs to control phenotypic behavior. With progress, the use of EFs may be engineered to control differentiation and target the growth of transplanted cells in a stem cell-based therapy to treat nervous system disorders.

  7. Alcohol and adult hippocampal neurogenesis: promiscuous drug, wanton effects.

    PubMed

    Geil, Chelsea R; Hayes, Dayna M; McClain, Justin A; Liput, Daniel J; Marshall, S Alex; Chen, Kevin Y; Nixon, Kimberly

    2014-10-03

    Adult neurogenesis is now widely accepted as an important contributor to hippocampal integrity and function but also dysfunction when adult neurogenesis is affected in neuropsychiatric diseases such as alcohol use disorders. Excessive alcohol consumption, the defining characteristic of alcohol use disorders, results in a variety of cognitive and behavioral impairments related wholly or in part to hippocampal structure and function. Recent preclinical work has shown that adult neurogenesis may be one route by which alcohol produces hippocampal neuropathology. Alcohol is a pharmacologically promiscuous drug capable of interfering with adult neurogenesis through multiple mechanisms. This review will discuss the primary mechanisms underlying alcohol-induced changes in adult hippocampal neurogenesis including alcohol's effects on neurotransmitters, CREB and its downstream effectors, and the neurogenic niche.

  8. Signal dispersion within a hippocampal neural network

    NASA Technical Reports Server (NTRS)

    Horowitz, J. M.; Mates, J. W. B.

    1975-01-01

    A model network is described, representing two neural populations coupled so that one population is inhibited by activity it excites in the other. Parameters and operations within the model represent EPSPs, IPSPs, neural thresholds, conduction delays, background activity and spatial and temporal dispersion of signals passing from one population to the other. Simulations of single-shock and pulse-train driving of the network are presented for various parameter values. Neuronal events from 100 to 300 msec following stimulation are given special consideration in model calculations.

  9. Risk assessment for the combinational effects of food color additives: neural progenitor cells and hippocampal neurogenesis.

    PubMed

    Park, Mikyung; Park, Hee Ra; Kim, So Jung; Kim, Min-Sun; Kong, Kyoung Hye; Kim, Hyun Soo; Gong, Ein Ji; Kim, Mi Eun; Kim, Hyung Sik; Lee, Byung Mu; Lee, Jaewon

    2009-01-01

    In 2006, the Korea Food and Drug Administration reported that combinations of dietary colors such as allura red AC (R40), tartrazine (Y4), sunset yellow FCF (Y5), amaranth (R2), and brilliant blue FCF (B1) are widely used in food manufacturing. Although individual tar food colors are controlled based on acceptable daily intake (ADI), there is no apparent information available for how combinations of these additives affect food safety. In the current study, the potencies of single and combination use of R40, Y4, Y5, R2, and B1 were examined on neural progenitor cell (NPC) toxicity, a biomarker for developmental stage, and neurogenesis, indicative of adult central nervous system (CNS) functions. R40 and R2 reduced NPC proliferation and viability in mouse multipotent NPC, in the developing CNS model. Among several combinations tested in mouse model, combination of Y4 and B1 at 1000-fold higher than average daily intake in Korea significantly decreased numbers of newly generated cells in adult mouse hippocampus, indicating potent adverse actions on hippocampal neurogenesis. However, other combinations including R40 and R2 did not affect adult hippocampal neurogenesis in the dentate gyrus. Evidence indicates that single and combination use of most tar food colors may be safe with respect to risk using developmental NPC and adult hippocampal neurogenesis. However, the response to excessively high dose combination of Y4 and B1 is suggestive of synergistic effects to suppress proliferation of NPC in adult hippocampus. Data indicated that combinations of tar colors may adversely affect both developmental and adult hippocampal neurogenesis; thus, further extensive studies are required to assess the safety of these additive combinations.

  10. The role of microglia in adult hippocampal neurogenesis.

    PubMed

    Gemma, Carmelina; Bachstetter, Adam D

    2013-11-22

    Our view of microglia has dramatically changed in the last decade. From cells being "silent" in the healthy brain, microglia have emerged to be actively involved in several brain physiological functions including adult hippocampal neurogenesis, and cognitive and behavioral function. In light of recent discoveries revealing a role of microglia as important effectors of neuronal circuit reorganization, considerable attention has been focused on how microglia and hippocampal neurogenesis could be an interdependent phenomenon. In this review the role of microglia in the adult hippocampal neurogenesis under physiological condition is discussed.

  11. Rhesus monkey neural stem cell transplantation promotes neural regeneration in rats with hippocampal lesions.

    PubMed

    Ye, Li-Juan; Bian, Hui; Fan, Yao-Dong; Wang, Zheng-Bo; Yu, Hua-Lin; Ma, Yuan-Ye; Chen, Feng

    2016-09-01

    Rhesus monkey neural stem cells are capable of differentiating into neurons and glial cells. Therefore, neural stem cell transplantation can be used to promote functional recovery of the nervous system. Rhesus monkey neural stem cells (1 × 10(5) cells/μL) were injected into bilateral hippocampi of rats with hippocampal lesions. Confocal laser scanning microscopy demonstrated that green fluorescent protein-labeled transplanted cells survived and grew well. Transplanted cells were detected at the lesion site, but also in the nerve fiber-rich region of the cerebral cortex and corpus callosum. Some transplanted cells differentiated into neurons and glial cells clustering along the ventricular wall, and integrated into the recipient brain. Behavioral tests revealed that spatial learning and memory ability improved, indicating that rhesus monkey neural stem cells noticeably improve spatial learning and memory abilities in rats with hippocampal lesions.

  12. The amyloid precursor protein controls adult hippocampal neurogenesis through GABAergic interneurons.

    PubMed

    Wang, Baiping; Wang, Zilai; Sun, Lu; Yang, Li; Li, Hongmei; Cole, Allysa L; Rodriguez-Rivera, Jennifer; Lu, Hui-Chen; Zheng, Hui

    2014-10-01

    Impaired neurogenesis in the adult hippocampus has been implicated in AD pathogenesis. Here we reveal that the APP plays an important role in the neural progenitor proliferation and newborn neuron maturation in the mouse dentate gyrus. APP controls adult neurogenesis through a non cell-autonomous mechanism by GABAergic neurons, as selective deletion of GABAergic, but not glutamatergic, APP disrupts adult hippocampal neurogenesis. APP, highly expressed in the majority of GABAergic neurons in the dentate gyrus, enhances the inhibitory tone to granule cells. By regulating both tonic and phasic GABAergic inputs to dentate granule cells, APP maintains excitatory-inhibitory balance and preserves cognitive functions. Our studies uncover an indispensable role of APP in the GABAergic system for controlling adult hippocampal neurogenesis, and our findings indicate that APP dysfunction may contribute to impaired neurogenesis and cognitive decline associated with AD.

  13. Increasing Adult Hippocampal Neurogenesis is Sufficient to Reduce Anxiety and Depression-Like Behaviors.

    PubMed

    Hill, Alexis S; Sahay, Amar; Hen, René

    2015-09-01

    Adult hippocampal neurogenesis is increased by antidepressants, and is required for some of their behavioral effects. However, it remains unclear whether expanding the population of adult-born neurons is sufficient to affect anxiety and depression-related behavior. Here, we use an inducible transgenic mouse model in which the pro-apoptotic gene Bax is deleted from neural stem cells and their progeny in the adult brain, and thereby increases adult neurogenesis. We find no effects on baseline anxiety and depression-related behavior; however, we find that increasing adult neurogenesis is sufficient to reduce anxiety and depression-related behaviors in mice treated chronically with corticosterone (CORT), a mouse model of stress. Thus, neurogenesis differentially affects behavior under baseline conditions and in a model of chronic stress. Moreover, we find no effect of increased adult hippocampal neurogenesis on hypothalamic-pituitary-adrenal (HPA) axis regulation, either at baseline or following chronic CORT administration, suggesting that increasing adult hippocampal neurogenesis can affect anxiety and depression-related behavior through a mechanism independent of the HPA axis. The use of future techniques to specifically inhibit BAX in the hippocampus could be used to augment adult neurogenesis, and may therefore represent a novel strategy to promote antidepressant-like behavioral effects.

  14. Transient elevation of adult hippocampal neurogenesis after dopamine depletion

    PubMed Central

    Park, June-Hee; Enikolopov, Grigori

    2010-01-01

    Degeneration of the midbrain dopaminergic neurons during Parkinson's disease (PD) may affect remote regions of the brain that are innervated by the projections of these neurons. The dentate gyrus (DG), a site of continuous production of new neurons in the adult hippocampus, receives dopaminergic inputs from the neurons of the substantia nigra (SN). Thus, depletion of the SN neurons during disease or in experimental settings may directly affect adult hippocampal neurogenesis. We show that experimental ablation of dopaminergic neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydopyridine (MPTP) mouse model of PD results in a transient increase in cell division in the subgranular zone (SGZ) of the DG. This increase is evident for the amplifying neural progenitors and for their postmitotic progeny; our results also indicate that MPTP treatment affects division of the normally quiescent stem cells in the SGZ. We also show that L-DOPA, used in the clinical treatment of PD, while attenuating the MPTP-induced death of dopaminergic neurons, does not alter the effect of MPTP on cell division in the DG. Our results suggest that a decrease in dopaminergic signaling in the hippocampus leads to a transient activation of stem and progenitor cells in the DG. PMID:20079351

  15. Stress, glucocorticoid hormones, and hippocampal neural progenitor cells: implications to mood disorders

    PubMed Central

    Kino, Tomoshige

    2015-01-01

    The hypothalamic-pituitary-adrenal (HPA) axis and its end-effectors glucocorticoid hormones play central roles in the adaptive response to numerous stressors that can be either internal or external. Thus, this system has a strong impact on the brain hippocampus and its major functions, such as cognition, memory as well as behavior, and mood. The hippocampal area of the adult brain contains neural stem cells or more committed neural progenitor cells, which retain throughout the human life the ability of self-renewal and to differentiate into multiple neural cell lineages, such as neurons, astrocytes, and oligodendrocytes. Importantly, these characteristic cells contribute significantly to the above-indicated functions of the hippocampus, while various stressors and glucocorticoids influence proliferation, differentiation, and fate of these cells. This review offers an overview of the current understanding on the interactions between the HPA axis/glucocorticoid stress-responsive system and hippocampal neural progenitor cells by focusing on the actions of glucocorticoids. Also addressed is a further discussion on the implications of such interactions to the pathophysiology of mood disorders. PMID:26347657

  16. Disrupting neural activity related to awake-state sharp wave-ripple complexes prevents hippocampal learning.

    PubMed

    Nokia, Miriam S; Mikkonen, Jarno E; Penttonen, Markku; Wikgren, Jan

    2012-01-01

    Oscillations in hippocampal local-field potentials (LFPs) reflect the crucial involvement of the hippocampus in memory trace formation: theta (4-8 Hz) oscillations and ripples (~200 Hz) occurring during sharp waves are thought to mediate encoding and consolidation, respectively. During sharp wave-ripple complexes (SPW-Rs), hippocampal cell firing closely follows the pattern that took place during the initial experience, most likely reflecting replay of that event. Disrupting hippocampal ripples using electrical stimulation either during training in awake animals or during sleep after training retards spatial learning. Here, adult rabbits were trained in trace eyeblink conditioning, a hippocampus-dependent associative learning task. A bright light was presented to the animals during the inter-trial interval (ITI), when awake, either during SPW-Rs or irrespective of their neural state. Learning was particularly poor when the light was presented following SPW-Rs. While the light did not disrupt the ripple itself, it elicited a theta-band oscillation, a state that does not usually coincide with SPW-Rs. Thus, it seems that consolidation depends on neuronal activity within and beyond the hippocampus taking place immediately after, but by no means limited to, hippocampal SPW-Rs.

  17. Role of adult hippocampal neurogenesis in stress resilience

    PubMed Central

    Levone, Brunno R.; Cryan, John F.; O'Leary, Olivia F.

    2014-01-01

    There is a growing appreciation that adult hippocampal neurogenesis plays a role in emotional and cognitive processes related to psychiatric disorders. Although many studies have investigated the effects of stress on adult hippocampal neurogenesis, most have not focused on whether stress-induced changes in neurogenesis occur specifically in animals that are more resilient or more susceptible to the behavioural and neuroendocrine effects of stress. Thus, in the present review we explore whether there is a clear relationship between stress-induced changes in adult hippocampal neurogenesis, stress resilience and antidepressant-induced recovery from stress-induced changes in behaviour. Exposure to different stressors is known to reduce adult hippocampal neurogenesis, but some stressors have also been shown to exert opposite effects. Ablation of neurogenesis does not lead to a depressive phenotype, but it can enhance responsiveness to stress and affect stress susceptibility. Monoaminergic-targeted antidepressants, environmental enrichment and adrenalectomy are beneficial for reversing stress-induced changes in behaviour and have been shown to do so in a neurogenesis-dependant manner. In addition, stress and antidepressants can affect hippocampal neurogenesis, preferentially in the ventral hippocampus. Together, these data show that adult hippocampal neurogenesis may play a role in the neuroendocrine and behavioural responses to stress, although it is not yet fully clear under which circumstances neurogenesis promotes resilience or susceptibility to stress. It will be important that future studies carefully examine how adult hippocampal neurogenesis can contribute to stress resilience/susceptibility so that it may be appropriately exploited for the development of new and more effective treatments for stress-related psychiatric disorders. PMID:27589664

  18. Involvement of Adult Hippocampal Neurogenesis in Learning and Forgetting

    PubMed Central

    Yau, Suk-yu; Li, Ang; So, Kwok-Fai

    2015-01-01

    Adult hippocampal neurogenesis is a process involving the continuous generation of newborn neurons in the hippocampus of adult animals. Mounting evidence has suggested that hippocampal neurogenesis contributes to some forms of hippocampus-dependent learning and memory; however, the detailed mechanism concerning how this small number of newborn neurons could affect learning and memory remains unclear. In this review, we discuss the relationship between adult-born neurons and learning and memory, with a highlight on recently discovered potential roles of neurogenesis in pattern separation and forgetting. PMID:26380120

  19. Rescue of Adult Hippocampal Neurogenesis in a Mouse Model of HIV Neurologic Disease

    PubMed Central

    Lee, Myoung-Hwa; Wang, Tongguang; Jang, Mi-Hyeon; Steiner, Joseph; Haughey, Norman; Ming, Guo-li; Song, Hongjun; Nath, Avindra; Venkatesan, Arun

    2011-01-01

    The prevalence of central nervous system (CNS) neurologic dysfunction associated with human immunodeficiency virus (HIV) infection continues to increase, despite the use of antiretroviral therapy. Previous work has focused on the deleterious effects of HIV on mature neurons and on development of neuroprotective strategies, which have consistently failed to show a meaningful clinical benefit. It is now well established that new neurons are continuously generated in discrete regions in the adult mammalian brain, and accumulating evidence supports important roles for these neurons in specific cognitive functions. In a transgenic mouse model of HIV neurologic disease with glial expression of the HIV envelope protein gp120, we demonstrate a significant reduction in proliferation of hippocampal neural progenitors in the dentate gyrus of adult animals, resulting in a dramatic decrease in the number of newborn neurons in the adult brain. We identify amplifying neural progenitor cells (ANPs) as the first class of progenitors affected by gp120, and we also demonstrate that newly generated neurons exhibit aberrant dendritic development. Furthermore, voluntary exercise and treatment with a selective serotonin reuptake inhibitor increase the ANP population and rescue the observed deficits in gp120 transgenic mice. Thus, during HIV infection, the envelope protein gp120 may potently inhibit adult hippocampal neurogenesis, and neurorestorative approaches may be effective in ameliorating these effects. Our study has significant implications for the development of novel therapeutic approaches for HIV-infected individuals with neurologic dysfunction and may be applicable to other neurodegenerative diseases in which hippocampal neurogenesis is impaired. PMID:21146610

  20. Stochastic neural network model for spontaneous bursting in hippocampal slices.

    PubMed

    Biswal, B; Dasgupta, C

    2002-11-01

    A biologically plausible, stochastic, neural network model that exhibits spontaneous transitions between a low-activity (normal) state and a high-activity (epileptic) state is studied by computer simulation. Brief excursions of the network to the high-activity state lead to spontaneous population bursting similar to the behavior observed in hippocampal slices bathed in a high-potassium medium. Although the variability of interburst intervals in this model is due to stochasticity, first return maps of successive interburst intervals show trajectories that resemble the behavior expected near unstable periodic orbits (UPOs) of systems exhibiting deterministic chaos. Simulations of the effects of the application of chaos control, periodic pacing, and anticontrol to the network model yield results that are qualitatively similar to those obtained in experiments on hippocampal slices. Estimation of the statistical significance of UPOs through surrogate data analysis also leads to results that resemble those of similar analysis of data obtained from slice experiments and human epileptic activity. These results suggest that spontaneous population bursting in hippocampal slices may be a manifestation of stochastic bistable dynamics, rather than of deterministic chaos. Our results also question the reliability of some of the recently proposed, UPO-based, statistical methods for detecting determinism and chaos in experimental time-series data.

  1. Adult hippocampal neurogenesis and memory interference.

    PubMed

    Winocur, Gordon; Becker, Suzanna; Luu, Paul; Rosenzweig, Shira; Wojtowicz, J Martin

    2012-02-14

    Rats, subjected to low-dose irradiation that suppressed hippocampal neurogenesis, or a sham treatment, were administered a visual discrimination task under conditions of high, or low interference. Half of the rats engaged in running activity and the other half did not. In the non-runners, there was no effect of irradiation on learning, or remembering the discrimination response under low interference, but irradiation treatment increased their susceptibility to interference, resulting in loss of memory for the previously learned discrimination. Irradiated rats that engaged in running activity exhibited increased neuronal growth and protection from memory impairment. The results, which show that hippocampal cells generated in adulthood play a role in differentiating between conflicting, context-dependent memories, provide further evidence of the importance of neurogenesis in hippocampus-sensitive memory tasks. The results are consistent with computational models of hippocampal function that specify a central role for neurogenesis in the modulation of interfering influences during learning and memory.

  2. Adult hippocampal neurogenesis inversely correlates with microglia in conditions of voluntary running and aging

    PubMed Central

    Gebara, Elias; Sultan, Sebastien; Kocher-Braissant, Jacqueline; Toni, Nicolas

    2013-01-01

    Adult hippocampal neurogenesis results in the formation of new neurons and is a process of brain plasticity involved in learning and memory. The proliferation of adult neural stem or progenitor cells is regulated by several extrinsic factors such as experience, disease or aging and intrinsic factors originating from the neurogenic niche. Microglia is very abundant in the dentate gyrus (DG) and increasing evidence indicates that these cells mediate the inflammation-induced reduction in neurogenesis. However, the role of microglia in neurogenesis in physiological conditions remains poorly understood. In this study, we monitored microglia and the proliferation of adult hippocampal stem/progenitor cells in physiological conditions known to increase or decrease adult neurogenesis, voluntary running and aging respectively. We found that the number of microglia in the DG was strongly inversely correlated with the number of stem/progenitor cells and cell proliferation in the granule cell layer. Accordingly, co-cultures of decreasing neural progenitor/glia ratio showed that microglia but not astroglia reduced the number of progenitor cells. Together, these results suggest that microglia inhibits the proliferation of neural stem/progenitor cells despite the absence of inflammatory stimulus. PMID:23970848

  3. Stage-specific functions of Semaphorin7A during adult hippocampal neurogenesis rely on distinct receptors.

    PubMed

    Jongbloets, Bart C; Lemstra, Suzanne; Schellino, Roberta; Broekhoven, Mark H; Parkash, Jyoti; Hellemons, Anita J C G M; Mao, Tianyi; Giacobini, Paolo; van Praag, Henriette; De Marchis, Silvia; Ramakers, Geert M J; Pasterkamp, R Jeroen

    2017-03-10

    The guidance protein Semaphorin7A (Sema7A) is required for the proper development of the immune and nervous systems. Despite strong expression in the mature brain, the role of Sema7A in the adult remains poorly defined. Here we show that Sema7A utilizes different cell surface receptors to control the proliferation and differentiation of neural progenitors in the adult hippocampal dentate gyrus (DG), one of the select regions of the mature brain where neurogenesis occurs. PlexinC1 is selectively expressed in early neural progenitors in the adult mouse DG and mediates the inhibitory effects of Sema7A on progenitor proliferation. Subsequently, during differentiation of adult-born DG granule cells, Sema7A promotes dendrite growth, complexity and spine development through β1-subunit-containing integrin receptors. Our data identify Sema7A as a key regulator of adult hippocampal neurogenesis, providing an example of how differential receptor usage spatiotemporally controls and diversifies the effects of guidance cues in the adult brain.

  4. Stage-specific functions of Semaphorin7A during adult hippocampal neurogenesis rely on distinct receptors

    PubMed Central

    Jongbloets, Bart C.; Lemstra, Suzanne; Schellino, Roberta; Broekhoven, Mark H.; Parkash, Jyoti; Hellemons, Anita J. C. G. M.; Mao, Tianyi; Giacobini, Paolo; van Praag, Henriette; De Marchis, Silvia; Ramakers, Geert M. J.; Pasterkamp, R. Jeroen

    2017-01-01

    The guidance protein Semaphorin7A (Sema7A) is required for the proper development of the immune and nervous systems. Despite strong expression in the mature brain, the role of Sema7A in the adult remains poorly defined. Here we show that Sema7A utilizes different cell surface receptors to control the proliferation and differentiation of neural progenitors in the adult hippocampal dentate gyrus (DG), one of the select regions of the mature brain where neurogenesis occurs. PlexinC1 is selectively expressed in early neural progenitors in the adult mouse DG and mediates the inhibitory effects of Sema7A on progenitor proliferation. Subsequently, during differentiation of adult-born DG granule cells, Sema7A promotes dendrite growth, complexity and spine development through β1-subunit-containing integrin receptors. Our data identify Sema7A as a key regulator of adult hippocampal neurogenesis, providing an example of how differential receptor usage spatiotemporally controls and diversifies the effects of guidance cues in the adult brain. PMID:28281529

  5. Adult Hippocampal Neurogenesis, Fear Generalization, and Stress

    PubMed Central

    Besnard, Antoine; Sahay, Amar

    2016-01-01

    The generalization of fear is an adaptive, behavioral, and physiological response to the likelihood of threat in the environment. In contrast, the overgeneralization of fear, a cardinal feature of posttraumatic stress disorder (PTSD), manifests as inappropriate, uncontrollable expression of fear in neutral and safe environments. Overgeneralization of fear stems from impaired discrimination of safe from aversive environments or discernment of unlikely threats from those that are highly probable. In addition, the time-dependent erosion of episodic details of traumatic memories might contribute to their generalization. Understanding the neural mechanisms underlying the overgeneralization of fear will guide development of novel therapeutic strategies to combat PTSD. Here, we conceptualize generalization of fear in terms of resolution of interference between similar memories. We propose a role for a fundamental encoding mechanism, pattern separation, in the dentate gyrus (DG)–CA3 circuit in resolving interference between ambiguous or uncertain threats and in preserving episodic content of remote aversive memories in hippocampal–cortical networks. We invoke cellular-, circuit-, and systems-based mechanisms by which adult-born dentate granule cells (DGCs) modulate pattern separation to influence resolution of interference and maintain precision of remote aversive memories. We discuss evidence for how these mechanisms are affected by stress, a risk factor for PTSD, to increase memory interference and decrease precision. Using this scaffold we ideate strategies to curb overgeneralization of fear in PTSD. PMID:26068726

  6. Secreted frizzled-related protein 3 regulates activity-dependent adult hippocampal neurogenesis.

    PubMed

    Jang, Mi-Hyeon; Bonaguidi, Michael A; Kitabatake, Yasuji; Sun, Jiaqi; Song, Juan; Kang, Eunchai; Jun, Heechul; Zhong, Chun; Su, Yijing; Guo, Junjie U; Wang, Marie Xun; Sailor, Kurt A; Kim, Ju-Young; Gao, Yuan; Christian, Kimberly M; Ming, Guo-li; Song, Hongjun

    2013-02-07

    Adult neurogenesis, the process of generating mature neurons from adult neural stem cells, proceeds concurrently with ongoing neuronal circuit activity and is modulated by various physiological and pathological stimuli. The niche mechanism underlying the activity-dependent regulation of the sequential steps of adult neurogenesis remains largely unknown. Here, we report that neuronal activity decreases the expression of secreted frizzled-related protein 3 (sFRP3), a naturally secreted Wnt inhibitor highly expressed by adult dentate gyrus granule neurons. Sfrp3 deletion activates quiescent radial neural stem cells and promotes newborn neuron maturation, dendritic growth, and dendritic spine formation in the adult mouse hippocampus. Furthermore, sfrp3 reduction is essential for activity-induced adult neural progenitor proliferation and the acceleration of new neuron development. Our study identifies sFRP3 as an inhibitory niche factor from local mature dentate granule neurons that regulates multiple phases of adult hippocampal neurogenesis and suggests an interesting activity-dependent mechanism governing adult neurogenesis via the acute release of tonic inhibition.

  7. Tetrahydrohyperforin increases adult hippocampal neurogenesis in wild-type and APPswe/PS1ΔE9 mice.

    PubMed

    Abbott, Ana C; Calderon Toledo, Carla; Aranguiz, Florencia C; Inestrosa, Nibaldo C; Varela-Nallar, Lorena

    2013-01-01

    Tetrahydrohyperforin (IDN5706), a semi-synthetic derivative of hyperforin, has shown neuroprotective properties preventing the impairment of synaptic plasticity and cognitive decline in an in vivo model of Alzheimer's disease (AD). Considering the reported role of adult neurogenesis in the plasticity of the hippocampal network, we investigated whether IDN5706 affects adult neurogenesis and hippocampal function. In hippocampal progenitors cultured from adult rats, IDN5706 increased proliferation. Moreover, treatment with IDN5706 for 4 weeks increased cell proliferation in the subgranular zone (SGZ) of the hippocampus in 2 month-old wild-type mice in vivo. As determined by double labeling with BrdU and neuronal markers, IDN5706 treatment increased the number of immature neurons and newborn mature neurons in the adult dentate gyrus. In addition, IDN5706 treatment improved long-term memory in a hippocampal-dependent spatial memory task. Finally, IDN5706 treatment increased cell proliferation and neural commitment in the SGZ of the double transgenic APPswe/PS1ΔE9 mouse model of AD. These results indicate that IDN5706 increases adult hippocampal neurogenesis and may have therapeutic value in neurological disorders in which adult neurogenesis is impaired.

  8. Comparison of Neurite Outgrowth Induced by Erythropoietin (EPO) and Carbamylated Erythropoietin (CEPO) in Hippocampal Neural Progenitor Cells.

    PubMed

    Oh, Dong Hoon; Lee, In Young; Choi, Miyeon; Kim, Seok Hyeon; Son, Hyeon

    2012-08-01

    A previous animal study has shown the effects of erythropoietin (EPO) and its non-erythropoietic carbamylated derivative (CEPO) on neurogenesis in the dentate gyrus. In the present study, we sought to investigate the effect of EPO on adult hippocampal neurogenesis, and to compare the ability of EPO and CEPO promoting dendrite elongation in cultured hippocampal neural progenitor cells. Two-month-old male BALB/c mice were given daily injections of EPO (5 U/g) for seven days and were sacrificed 12 hours after the final injection. Proliferation assays demonstrated that EPO treatment increased the density of bromodeoxyuridine (BrdU)-labeled cells in the subgranular zone (SGZ) compared to that in vehicle-treated controls. Functional differentiation studies using dissociated hippocampal cultures revealed that EPO treatment also increased the number of double-labeled BrdU/microtubule-associated protein 2 (MAP2) neurons compared to those in vehicle-treated controls. Both EPO and CEPO treatment significantly increased the length of neurites and spine density in MAP2(+) cells. In summary, these results provide evidences that EPO and CEPO promote adult hippocampal neurogenesis and neuronal differentiation. These suggest that EPO and CEPO could be a good candidate for treating neuropsychiatric disorders such as depression and anxiety associated with neuronal atrophy and reduced hippocampal neurogenesis.

  9. Norbin ablation results in defective adult hippocampal neurogenesis and depressive-like behavior in mice.

    PubMed

    Wang, Hong; Warner-Schmidt, Jennifer; Varela, Santiago; Enikolopov, Grigori; Greengard, Paul; Flajolet, Marc

    2015-08-04

    Adult neurogenesis in the hippocampus subgranular zone is associated with the etiology and treatment efficiency of depression. Factors that affect adult hippocampal neurogenesis have been shown to contribute to the neuropathology of depression. Glutamate, the major excitatory neurotransmitter, plays a critical role in different aspects of neurogenesis. Of the eight metabotropic glutamate receptors (mGluRs), mGluR5 is the most highly expressed in neural stem cells. We previously identified Norbin as a positive regulator of mGluR5 and showed that its expression promotes neurite outgrowth. In this study, we investigated the role of Norbin in adult neurogenesis and depressive-like behaviors using Norbin-deficient mice. We found that Norbin deletion significantly reduced hippocampal neurogenesis; specifically, the loss of Norbin impaired the proliferation and maturation of newborn neurons without affecting cell-fate specification of neural stem cells/neural progenitor cells (NSCs/NPCs). Norbin is highly expressed in the granular neurons in the dentate gyrus of the hippocampus, but it is undetectable in NSCs/NPCs or immature neurons, suggesting that the effect of Norbin on neurogenesis is likely caused by a nonautonomous niche effect. In support of this hypothesis, we found that the expression of a cell-cell contact gene, Desmoplakin, is greatly reduced in Norbin-deletion mice. Moreover, Norbin-KO mice show an increased immobility in the forced-swim test and the tail-suspension test and reduced sucrose preference compared with wild-type controls. Taken together, these results show that Norbin is a regulator of adult hippocampal neurogenesis and that its deletion causes depressive-like behaviors.

  10. Norbin ablation results in defective adult hippocampal neurogenesis and depressive-like behavior in mice

    PubMed Central

    Wang, Hong; Warner-Schmidt, Jennifer; Varela, Santiago; Enikolopov, Grigori; Greengard, Paul; Flajolet, Marc

    2015-01-01

    Adult neurogenesis in the hippocampus subgranular zone is associated with the etiology and treatment efficiency of depression. Factors that affect adult hippocampal neurogenesis have been shown to contribute to the neuropathology of depression. Glutamate, the major excitatory neurotransmitter, plays a critical role in different aspects of neurogenesis. Of the eight metabotropic glutamate receptors (mGluRs), mGluR5 is the most highly expressed in neural stem cells. We previously identified Norbin as a positive regulator of mGluR5 and showed that its expression promotes neurite outgrowth. In this study, we investigated the role of Norbin in adult neurogenesis and depressive-like behaviors using Norbin-deficient mice. We found that Norbin deletion significantly reduced hippocampal neurogenesis; specifically, the loss of Norbin impaired the proliferation and maturation of newborn neurons without affecting cell-fate specification of neural stem cells/neural progenitor cells (NSCs/NPCs). Norbin is highly expressed in the granular neurons in the dentate gyrus of the hippocampus, but it is undetectable in NSCs/NPCs or immature neurons, suggesting that the effect of Norbin on neurogenesis is likely caused by a nonautonomous niche effect. In support of this hypothesis, we found that the expression of a cell–cell contact gene, Desmoplakin, is greatly reduced in Norbin-deletion mice. Moreover, Norbin-KO mice show an increased immobility in the forced-swim test and the tail-suspension test and reduced sucrose preference compared with wild-type controls. Taken together, these results show that Norbin is a regulator of adult hippocampal neurogenesis and that its deletion causes depressive-like behaviors. PMID:26195764

  11. Microbats appear to have adult hippocampal neurogenesis, but post-capture stress causes a rapid decline in the number of neurons expressing doublecortin.

    PubMed

    Chawana, R; Alagaili, A; Patzke, N; Spocter, M A; Mohammed, O B; Kaswera, C; Gilissen, E; Bennett, N C; Ihunwo, A O; Manger, P R

    2014-09-26

    A previous study investigating potential adult hippocampal neurogenesis in microchiropteran bats failed to reveal a strong presence of this neural trait. As microchiropterans have a high field metabolic rate and a small body mass, it is possible that capture/handling stress may lead to a decrease in the detectable presence of adult hippocampal neurogenesis. Here we looked for evidence of adult hippocampal neurogenesis using immunohistochemical techniques for the endogenous marker doublecortin (DCX) in 10 species of microchiropterans euthanized and perfusion fixed at specific time points following capture. Our results reveal that when euthanized and perfused within 15 min of capture, abundant putative adult hippocampal neurogenesis could be detected using DCX immunohistochemistry. Between 15 and 30 min post-capture, the detectable levels of DCX dropped dramatically and after 30 min post-capture, immunohistochemistry for DCX could not reveal any significant evidence of putative adult hippocampal neurogenesis. Thus, as with all other mammals studied to date apart from cetaceans, bats, including both microchiropterans and megachiropterans, appear to exhibit substantial levels of adult hippocampal neurogenesis. The present study underscores the concept that, as with laboratory experiments, studies conducted on wild-caught animals need to be cognizant of the fact that acute stress (capture/handling) may induce major changes in the appearance of specific neural traits.

  12. Adult hippocampal neurogenesis in natural populations of mammals.

    PubMed

    Amrein, Irmgard

    2015-05-01

    This review will discuss adult hippocampal neurogenesis in wild mammals of different taxa and outline similarities with and differences from laboratory animals. It begins with a review of evidence for hippocampal neurogenesis in various mammals, and shows the similar patterns of age-dependent decline in cell proliferation in wild and domesticated mammals. In contrast, the pool of immature neurons that originate from proliferative activity varies between species, implying a selective advantage for mammals that can make use of a large number of these functionally special neurons. Furthermore, rapid adaptation of hippocampal neurogenesis to experimental challenges appears to be a characteristic of laboratory rodents. Wild mammals show species-specific, rather stable hippocampal neurogenesis, which appears related to demands that characterize the niche exploited by a species rather than to acute events in the life of its members. Studies that investigate adult neurogenesis in wild mammals are not numerous, but the findings of neurogenesis under natural conditions can provide new insights, and thereby also address the question to which cognitive demands neurogenesis may respond during selection.

  13. Linking adult hippocampal neurogenesis with human physiology and disease.

    PubMed

    Bowers, Megan; Jessberger, Sebastian

    2016-07-01

    We here review the existing evidence linking adult hippocampal neurogenesis and human brain function in physiology and disease. Furthermore, we aim to point out where evidence is missing, highlight current promising avenues of investigation, and suggest future tools and approaches to foster the link between life-long neurogenesis and human brain function. Developmental Dynamics 245:702-709, 2016. © 2016 Wiley Periodicals, Inc.

  14. GABAergic Interneuron Dysfunction Impairs Hippocampal Neurogenesis in Adult Apolipoprotein E4 Knock-in Mice

    PubMed Central

    Li, Gang; Bien-Ly, Nga; Andrews-Zwilling, Yaisa; Xu, Qin; Bernardo, Aubrey; Ring, Karen; Halabisky, Brian; Deng, Changhui; Mahley, Robert W.; Huang, Yadong

    2010-01-01

    SUMMARY Apolipoprotein (apo) E has important and diverse functions in neurobiology, and apoE4 is the major known genetic risk factor for Alzheimer’s disease. Here we report that adult neural stem/progenitor cells (NSCs) express apoE. In apoE knockout mice, neurogenesis in the hippocampus was ~60% lower than in wildtype mice, and most newborn cells developed into astrocytes rather than into neurons as in wildtype mice. This impairment was not observed in human apoE3 knock-in mice. In apoE4 knock-in mice, however, the maturation and dendritic development of newborn hippocampal neurons was significantly impaired as a result of apoE4 and its fragment-caused GABAergic interneuron dysfunction. This impairment was fully rescued by treatment with a GABAA receptor potentiator. These findings demonstrate the importance of apoE in adult hippocampal neurogenesis and show that apoE4 inhibits hippocampal neurogenesis by impairing neuronal maturation mediated by GABA signaling. PMID:19951691

  15. The development of spatial behaviour and the hippocampal neural representation of space

    PubMed Central

    Wills, Thomas J.; Muessig, Laurenz; Cacucci, Francesca

    2014-01-01

    The role of the hippocampal formation in spatial cognition is thought to be supported by distinct classes of neurons whose firing is tuned to an organism's position and orientation in space. In this article, we review recent research focused on how and when this neural representation of space emerges during development: each class of spatially tuned neurons appears at a different age, and matures at a different rate, but all the main spatial responses tested so far are present by three weeks of age in the rat. We also summarize the development of spatial behaviour in the rat, describing how active exploration of space emerges during the third week of life, the first evidence of learning in formal tests of hippocampus-dependent spatial cognition is observed in the fourth week, whereas fully adult-like spatial cognitive abilities require another few weeks to be achieved. We argue that the development of spatially tuned neurons needs to be considered within the context of the development of spatial behaviour in order to achieve an integrated understanding of the emergence of hippocampal function and spatial cognition. PMID:24366148

  16. Hippocampal lesion prevents spatial relational learning in adult macaque monkeys.

    PubMed

    Lavenex, Pamela Banta; Amaral, David G; Lavenex, Pierre

    2006-04-26

    The role of the hippocampus in spatial learning and memory has been extensively studied in rodents. Comparable studies in nonhuman primates, however, are few, and findings are often contradictory. This may be attributable to the failure to distinguish between allocentric and egocentric spatial representations in experimental designs. For this experiment, six adult monkeys received bilateral hippocampal ibotenic acid lesions, and six control subjects underwent sham surgery. Freely moving monkeys then foraged for food located in two arrays of three distinct locations among 18 locations distributed in an open-field arena. Multiple goals and four pseudorandomly chosen entrance points precluded the monkeys' ability to rely on an egocentric strategy to identify food locations. Monkeys were tested in two conditions. First, local visual cues marked the food locations. Second, no local cues marked the food locations, so that monkeys had to rely on an allocentric (spatial relational) representation of the environment to discriminate these locations. Both hippocampal-lesioned and control monkeys discriminated the food locations in the presence of local cues. However, in the absence of local cues, control subjects discriminated the food locations, whereas hippocampal-lesioned monkeys were unable to do so. Interestingly, histological analysis of the brain of one control monkey whose behavior was identical to that of the experimentally lesioned animals revealed a bilateral ischemic lesion restricted to the hippocampus. These findings demonstrate that the adult monkey hippocampal formation is critical for the establishment or use of allocentric spatial representations and that selective damage of the hippocampus prevents spatial relational learning in adult nonhuman primates.

  17. Natural variation and genetic covariance in adult hippocampal neurogenesis

    SciTech Connect

    Kempermann, Gerd; Chesler, Elissa J; Lu, Lu; Williams, Robert; Gage, Fred

    2006-01-01

    Adult hippocampal neurogenesis is highly variable and heritable among laboratory strains of mice. Adult neurogenesis is also remarkably plastic and can be modulated by environment and activity. Here, we provide a systematic quantitative analysis of adult hippocampal neurogenesis in two large genetic reference panels of recombinant inbred strains (BXD and AXB?BXA, n ? 52 strains). We combined data on variation in neurogenesis with a new transcriptome database to extract a set of 190 genes with expression patterns that are also highly variable and that covary with rates of (i) cell proliferation, (ii) cell survival, or the numbers of surviving (iii) new neurons, and (iv) astrocytes. Expression of a subset of these neurogenesis-associated transcripts was controlled in cis across the BXD set. These self-modulating genes are particularly interesting candidates to control neurogenesis. Among these were musashi (Msi1h) and prominin1?CD133 (Prom1), both of which are linked to stem-cell maintenance and division. Twelve neurogenesis-associated transcripts had significant cis-acting quantitative trait loci, and, of these, six had plausible biological association with adult neurogenesis (Prom1, Ssbp2, Kcnq2, Ndufs2, Camk4, and Kcnj9). Only one cis- cting candidate was linked to both neurogenesis and gliogenesis, Rapgef6, a downstream target of ras signaling. The use of genetic reference panels coupled with phenotyping and global transcriptome profiling thus allowed insight into the complexity of the genetic control of adult neurogenesis.

  18. Wnt signaling in neuropsychiatric disorders: ties with adult hippocampal neurogenesis and behavior

    PubMed Central

    Hussaini, Syed Mohammed Qasim; Choi, Chan-Il; Cho, Chang Hoon; Kim, Hyo Jin; Jun, Heechul; Jang, Mi-Hyeon

    2014-01-01

    In an effort to better understand and treat mental disorders, the Wnt pathway and adult hippocampal neurogenesis have received increased attention in recent years. One is a signaling pathway regulating key aspects of embryonic patterning, cell specification, and adult tissue homeostasis. The other is the generation of newborn neurons in adulthood that integrate into the neural circuit and function in learning and memory, and mood behavior. In this review, we discuss the growing relationship between Wnt signaling-mediated regulation of adult hippocampal neurogenesis as it applies to neuropsychiatric disorders. Evidence suggests dysfunctional Wnt signaling may aberrantly regulate new neuron development and cognitive function. Indeed, altered expression of key Wnt pathway components are observed in the hippocampus of patients suffering from neuropsychiatric disorders. Clinically-utilized mood stabilizers also proceed through modulation of Wnt signaling in the hippocampus, while Wnt pathway antagonists can regulate the antidepressant response. Here, we review the role of Wnt signaling in disease etiology and pathogenesis, regulation of adult neurogenesis and behavior, and the therapeutic targeting of disease symptoms. PMID:25263701

  19. Ghrelin directly stimulates adult hippocampal neurogenesis: implications for learning and memory.

    PubMed

    Li, Endan; Chung, Hyunju; Kim, Yumi; Kim, Dong Hyun; Ryu, Jong Hoon; Sato, Takahiro; Kojima, Masayasu; Park, Seungjoon

    2013-01-01

    Adult hippocampal neurogenesis is important in mediating hippocampal-dependent learning and memory. Exogenous ghrelin is known to stimulate progenitor cell proliferation in the dentate gyrus of adult hippocampus. The aim of this study was to investigate the role of endogenous ghrelin in regulating the in vivo proliferation and differentiation of the newly generating cells in the adult hippocampus using ghrelin knockout (GKO) mice. Targeted deletion of ghrelin gene resulted in reduced numbers of progenitor cells in the subgranular zone (SGZ) of the hippocampus, while ghrelin treatment restored progenitor cell numbers to those of wild-type controls. We also found that not only the number of bromodeoxyuridine (BrdU)-positive cells but also the fraction of immature neurons and newly generated neurons were decreased in the GKO mice, which were increased by ghrelin replacement. Additionally, in the GKO mice, we observed impairment of memory performance in Y-maze task and novel object recognition test. However, these functional deficiencies were attenuated by ghrelin administration. These results suggest that ghrelin directly induces proliferation and differentiation of adult neural progenitor cells in the SGZ. Our data suggest ghrelin may be a plausible therapeutic potential to enhance learning and memory processes.

  20. Role of adult hippocampal neurogenesis in persistent pain.

    PubMed

    Apkarian, A Vania; Mutso, Amelia A; Centeno, Maria V; Kan, Lixin; Wu, Melody; Levinstein, Marjorie; Banisadr, Ghazal; Gobeske, Kevin T; Miller, Richard J; Radulovic, Jelena; Hen, René; Kessler, John A

    2016-02-01

    The full role of adult hippocampal neurogenesis (AHN) remains to be determined, yet it is implicated in learning and emotional functions, and is disrupted in negative mood disorders. Recent evidence indicates that AHN is decreased in persistent pain consistent with the idea that chronic pain is a major stressor, associated with negative moods and abnormal memories. Yet, the role of AHN in development of persistent pain has remained unexplored. In this study, we test the influence of AHN in postinjury inflammatory and neuropathic persistent pain-like behaviors by manipulating neurogenesis: pharmacologically through intracerebroventricular infusion of the antimitotic AraC; ablation of AHN by x-irradiation; and using transgenic mice with increased or decreased AHN. Downregulating neurogenesis reversibly diminished or blocked persistent pain; oppositely, upregulating neurogenesis led to prolonged persistent pain. Moreover, we could dissociate negative mood from persistent pain. These results suggest that AHN-mediated hippocampal learning mechanisms are involved in the emergence of persistent pain.

  1. Role of adult hippocampal neurogenesis in persistent pain

    PubMed Central

    Apkarian, A. Vania; Mutso, Amelia A.; Centeno, Maria V.; Kan, Lixin; Wu, Melody; Levinstein, Marjorie; Banisadr, Ghazal; Gobeske, Kevin T.; Miller, Richard J.; Radulovic, Jelena; Hen, René; Kessler, John A.

    2016-01-01

    The full role of adult hippocampal neurogenesis (AHN) remains to be determined, yet it is implicated in learning and emotional functions, and is disrupted in negative mood disorders. Recent evidence indicates that AHN is decreased in persistent pain consistent with the idea that chronic pain is a major stressor, associated with negative moods and abnormal memories. Yet, the role of AHN in development of persistent pain has remained unexplored. In this study, we test the influence of AHN in postinjury inflammatory and neuropathic persistent pain-like behaviors by manipulating neurogenesis: pharmacologically through intracerebroventricular infusion of the antimitotic AraC; ablation of AHN by x-irradiation; and using transgenic mice with increased or decreased AHN. Downregulating neurogenesis reversibly diminished or blocked persistent pain; oppositely, upregulating neurogenesis led to prolonged persistent pain. Moreover, we could dissociate negative mood from persistent pain. These results suggest that AHN-mediated hippocampal learning mechanisms are involved in the emergence of persistent pain. PMID:26313405

  2. Neural repair in the adult brain

    PubMed Central

    Jessberger, Sebastian

    2016-01-01

    Acute or chronic injury to the adult brain often results in substantial loss of neural tissue and subsequent permanent functional impairment. Over the last two decades, a number of approaches have been developed to harness the regenerative potential of neural stem cells and the existing fate plasticity of neural cells in the nervous system to prevent tissue loss or to enhance structural and functional regeneration upon injury. Here, we review recent advances of stem cell-associated neural repair in the adult brain, discuss current challenges and limitations, and suggest potential directions to foster the translation of experimental stem cell therapies into the clinic. PMID:26918167

  3. Fractalkine and CX 3 CR1 regulate hippocampal neurogenesis in adult and aged rats.

    PubMed

    Bachstetter, Adam D; Morganti, Josh M; Jernberg, Jennifer; Schlunk, Andrea; Mitchell, Staten H; Brewster, Kaelin W; Hudson, Charles E; Cole, Michael J; Harrison, Jeffrey K; Bickford, Paula C; Gemma, Carmelina

    2011-11-01

    Microglia have neuroprotective capacities, yet chronic activation can promote neurotoxic inflammation. Neuronal fractalkine (FKN), acting on CX(3)CR1, has been shown to suppress excessive microglia activation. We found that disruption in FKN/CX(3)CR1 signaling in young adult rodents decreased survival and proliferation of neural progenitor cells through IL-1β. Aged rats were found to have decreased levels of hippocampal FKN protein; moreover, interruption of CX(3)CR1 function in these animals did not affect neurogenesis. The age-related loss of FKN could be restored by exogenous FKN reversing the age-related decrease in hippocampal neurogenesis. There were no measureable changes in young animals by the addition of exogenous FKN. The results suggest that FKN/CX(3)CR1 signaling has a regulatory role in modulating hippocampal neurogenesis via mechanisms that involve indirect modification of the niche environment. As elevated neuroinflammation is associated with many age-related neurodegenerative diseases, enhancing FKN/CX(3)CR1 interactions could provide an alternative therapeutic approach to slow age-related neurodegeneration.

  4. Implications of adult hippocampal neurogenesis in antidepressant action

    PubMed Central

    Malberg, Jessica E.

    2004-01-01

    In the dentate gyrus of the hippocampus, cell birth and maturation into neurons, or neurogenesis, occur throughout the lifetime of animals and humans. Multiple factors have been shown to regulate adult neurogenesis, and a number of findings in this field have had a large impact on basic and clinical research in depression. It has been reported that both physical and psychosocial stress paradigms, as well as some animal models of depression, produce a decrease in hippocampal cell proliferation and neurogenesis. Conversely, long-term, but not short-term, treatment with different classes of antidepressant drug increases cell proliferation and neurogenesis. Patients with depressive disorders or post-traumatic stress disorder have reduced hippocampal volume. Given this interaction of stress, depression and neurogenesis, a current hypothesis is that reduced adult hippocampal cell proliferation or neurogenesis may be involved in the pathophysiology of depression and that reversal or prevention of the decrease in neurogenesis may be one way in which the antidepressant drugs exert their effects. Research from this emerging field will further our understanding of the effects of stress and depression on the brain and the mechanism of action of antidepressant drugs. Dans le gyrus denté de l'hippocampe, la naissance des cellules et leur maturation en neurones, ou neurogenèse, se produisent pendant toute la vie des animaux et des êtres humains. On a démontré que de multiples facteurs régularisent la neurogenèse chez l'adulte, et de nombreuses constatations dans ce domaine ont eu un effet important sur la recherche fondamentale et clinique sur la dépression. On a signalé que des paradigmes de stress à la fois physique et psychosocial, ainsi que certains modèles animaux de dépression, entraÎnent une diminution de la prolifération des cellules dans l'hippocampe et une baisse de la neurogenèse. Par ailleurs, le traitement avec différentes catégories d

  5. A neural extracellular matrix-based method for in vitro hippocampal neuron culture and dopaminergic differentiation of neural stem cells

    PubMed Central

    2013-01-01

    Background The ability to recreate an optimal cellular microenvironment is critical to understand neuronal behavior and functionality in vitro. An organized neural extracellular matrix (nECM) promotes neural cell adhesion, proliferation and differentiation. Here, we expanded previous observations on the ability of nECM to support in vitro neuronal differentiation, with the following goals: (i) to recreate complex neuronal networks of embryonic rat hippocampal cells, and (ii) to achieve improved levels of dopaminergic differentiation of subventricular zone (SVZ) neural progenitor cells. Methods Hippocampal cells from E18 rat embryos were seeded on PLL- and nECM-coated substrates. Neurosphere cultures were prepared from the SVZ of P4-P7 rat pups, and differentiation of neurospheres assayed on PLL- and nECM-coated substrates. Results When seeded on nECM-coated substrates, both hippocampal cells and SVZ progenitor cells showed neural expression patterns that were similar to their poly-L-lysine-seeded counterparts. However, nECM-based cultures of both hippocampal neurons and SVZ progenitor cells could be maintained for longer times as compared to poly-L-lysine-based cultures. As a result, nECM-based cultures gave rise to a more branched neurite arborization of hippocampal neurons. Interestingly, the prolonged differentiation time of SVZ progenitor cells in nECM allowed us to obtain a purer population of dopaminergic neurons. Conclusions We conclude that nECM-based coating is an efficient substrate to culture neural cells at different stages of differentiation. In addition, neural ECM-coated substrates increased neuronal survival and neuronal differentiation efficiency as compared to cationic polymers such as poly-L-lysine. PMID:23594371

  6. Effective connectivity of hippocampal neural network and its alteration in Mg2+-free epilepsy model.

    PubMed

    Gong, Xin-Wei; Li, Jing-Bo; Lu, Qin-Chi; Liang, Pei-Ji; Zhang, Pu-Ming

    2014-01-01

    Understanding the connectivity of the brain neural network and its evolution in epileptiform discharges is meaningful in the epilepsy researches and treatments. In the present study, epileptiform discharges were induced in rat hippocampal slices perfused with Mg2+-free artificial cerebrospinal fluid. The effective connectivity of the hippocampal neural network was studied by comparing the normal and epileptiform discharges recorded by a microelectrode array. The neural network connectivity was constructed by using partial directed coherence and analyzed by graph theory. The transition of the hippocampal network topology from control to epileptiform discharges was demonstrated. Firstly, differences existed in both the averaged in- and out-degree between nodes in the pyramidal cell layer and the granule cell layer, which indicated an information flow from the pyramidal cell layer to the granule cell layer during epileptiform discharges, whereas no consistent information flow was observed in control. Secondly, the neural network showed different small-worldness in the early, middle and late stages of the epileptiform discharges, whereas the control network did not show the small-world property. Thirdly, the network connectivity began to change earlier than the appearance of epileptiform discharges and lasted several seconds after the epileptiform discharges disappeared. These results revealed the important network bases underlying the transition from normal to epileptiform discharges in hippocampal slices. Additionally, this work indicated that the network analysis might provide a useful tool to evaluate the neural network and help to improve the prediction of seizures.

  7. Exploration of the Brn4-regulated genes enhancing adult hippocampal neurogenesis by RNA sequencing.

    PubMed

    Guo, Jingjing; Cheng, Xiang; Zhang, Lei; Wang, Linmei; Mao, Yongxin; Tian, Guixiang; Xu, Wenhao; Wu, Yuhao; Ma, Zhi; Qin, Jianbing; Tian, Meiling; Jin, Guohua; Shi, Wei; Zhang, Xinhua

    2017-02-18

    Adult hippocampal neurogenesis is essential for learning and memory, and its dysfunction is involved in neurodegenerative diseases. However, the molecular mechanisms underlying adult hippocampal neurogenesis are still largely unknown. Our previous studies indicated that the transcription factor Brn4 was upregulated and promoted neuronal differentiation of neural stem cells (NSCs) in the surgically denervated hippocampus in rats. In this study, we use high-throughput RNA sequencing to explore the molecular mechanisms underlying the enhancement of adult hippocampal neurogenesis induced by lentivirus-mediated Brn4 overexpression in vivo. After 10 days of the lentivirus injection, we found that the expression levels of genes related to neuronal development and maturation were significantly increased and the expression levels of genes related to NSC maintenance were significantly decreased, indicating enhanced neurogenesis in the hippocampus after Brn4 overexpression. Through RNA sequencing, we found that 658 genes were differentially expressed in the Brn4-overexpressed hippocampi compared with GFP-overexpressed controls. Many of these differentially expressed genes are involved in NSC division and differentiation. By using quantitative real-time PCR, we validated the expression changes of three genes, including Ctbp2, Notch2, and Gli1, all of which are reported to play key roles in neuronal differentiation of NSCs. Importantly, the expression levels of Ctbp2 and Notch2 were also significantly changed in the hippocampus of Brn4 KO mice, which indicates that the expression levels of Ctbp2 and Notch2 may be directly regulated by Brn4. Our current study provides a solid foundation for further investigation and identifies Ctbp2 and Notch2 as possible downstream targets of Brn4. © 2017 Wiley Periodicals, Inc.

  8. Impaired adult hippocampal neurogenesis and its partial reversal by chronic treatment of fluoxetine in a mouse model of Angelman syndrome.

    PubMed

    Godavarthi, Swetha K; Dey, Parthanarayan; Sharma, Ankit; Jana, Nihar Ranjan

    2015-09-04

    Angelman syndrome (AS) is a neurodevelopmental disorder characterized by severe cognitive and motor deficits, caused by the loss of function of maternally inherited Ube3a. Ube3a-maternal deficient mice (AS model mice) recapitulate many essential features of AS, but how the deficiency of Ube3a lead to such behavioural abnormalities is poorly understood. Here we have demonstrated significant impairment of adult hippocampal neurogenesis in AS mice brain. Although, the number of BrdU and Ki67-positive cell in the hippocampal DG region was nearly equal at early postnatal days among wild type and AS mice, they were significantly reduced in adult AS mice compared to wild type controls. Reduced number of doublecortin-positive immature neurons in this region of AS mice further indicated impaired neurogenesis. Unaltered BrdU and Ki67-positive cells number in the sub ventricular zone of adult AS mice brain along with the absence of imprinted expression of Ube3a in the neural progenitor cell suggesting that Ube3a may not be directly linked with altered neurogenesis. Finally, we show that the impaired hippocampal neurogenesis in these mice can be partially rescued by the chronic treatment of antidepressant fluoxetine. These results suggest that the chronic stress may lead to reduced hippocampal neurogenesis in AS mice and that impaired neurogenesis could contribute to cognitive disturbances observed in these mice.

  9. Microglia shape adult hippocampal neurogenesis through apoptosis-coupled phagocytosis

    PubMed Central

    Sierra, Amanda; Encinas, Juan M.; Deudero, Juan JP; Chancey, Jessica H.; Enikolopov, Grigori; Overstreet-Wadiche, Linda S.; Tsirka, Stella E.; Maletic-Savatic, Mirjana

    2010-01-01

    Summary In the adult hippocampus, neuroprogenitor cells in the subgranular zone (SGZ) of the dentate gyrus give rise to newborn neuroblasts. However, only a small subset of these cells integrates into the hippocampal circuitry as mature neurons at the end of a four-week period. Here, we show that the majority of the newborn cells undergo death by apoptosis in the first one to four days of their life, during the transition from amplifying neuroprogenitors to neuroblasts. These apoptotic newborn cells are rapidly cleared out through phagocytosis by unchallenged microglia present in the adult SGZ niche. Phagocytosis by the microglia is efficient and undeterred by increased age or inflammatory challenge. Our results suggest that the main critical period of newborn cell survival occurs within a few days of birth and reveal a new role for microglia in maintaining the homeostasis of the baseline neurogenic cascade. PMID:20887954

  10. Notch1 is required for maintenance of the reservoir of adult hippocampal stem cells

    PubMed Central

    Ables, Jessica L.; DeCarolis, Nathan A.; Johnson, Madeleine A.; Rivera, Phillip D.; Gao, Zhengliang; Cooper, Don C.; Radtke, Freddy; Hsieh, Jenny; Eisch, Amelia J.

    2010-01-01

    Notch1 regulates neural stem cell (NSC) number during development, but its role in adult neurogenesis is unclear. We generated nestin-CreERT2/R26R-YFP/Notch1loxP/loxP (Notch1 iKO) mice to allow tamoxifen (TAM)-inducible elimination of Notch1 and concomitant expression of yellow fluorescent protein (YFP) in nestin-expressing Type-1 NSCs and their progeny in the adult hippocampal subgranular zone (SGZ). Consistent with previous research, YFP+ cells in all stages of neurogenesis were evident in the subgranular zone (SGZ) of wild type mice (WT; nestin-CreERT2/R26R-YFP/Notch1wt/wt) after tamoxifen (post-TAM), producing adult-generated YFP+ dentate gyrus neurons. Compared to WT littermates, Notch1 iKO mice had similar numbers of total SGZ YFP+ cells 13 and 30 days post-TAM but had significantly fewer SGZ YFP+ cells 60 and 90 days post-TAM. Significantly fewer YFP+ Type-1 NSCs and transiently-amplifying progenitors (TAPs) resulted in generation of fewer YFP+ granule neurons in Notch1 iKO mice. Strikingly, 30 days of running rescued this deficit, as the total YFP+ cell number in Notch iKO mice was equivalent to WT levels. This was even more notable given the persistent deficits in the Type-1 NSC and TAP reservoirs. Our data show that Notch1 signaling is required to maintain a reservoir of undifferentiated cells and ensure continuity of adult hippocampal neurogenesis, but that alternative Notch1- and Type-1 NSC-independent pathways compensate in response to physical activity. These data shed light on the complex relationship between Type-1 NSCs, adult neurogenesis, the neurogenic niche, and environmental stimuli. PMID:20685991

  11. Generalized Potential of Adult Neural Stem Cells

    NASA Astrophysics Data System (ADS)

    Clarke, Diana L.; Johansson, Clas B.; Wilbertz, Johannes; Veress, Biborka; Nilsson, Erik; Karlström, Helena; Lendahl, Urban; Frisén, Jonas

    2000-06-01

    The differentiation potential of stem cells in tissues of the adult has been thought to be limited to cell lineages present in the organ from which they were derived, but there is evidence that some stem cells may have a broader differentiation repertoire. We show here that neural stem cells from the adult mouse brain can contribute to the formation of chimeric chick and mouse embryos and give rise to cells of all germ layers. This demonstrates that an adult neural stem cell has a very broad developmental capacity and may potentially be used to generate a variety of cell types for transplantation in different diseases.

  12. The postnatal origin of adult neural stem cells and the effects of glucocorticoids on their genesis.

    PubMed

    Ortega-Martínez, Sylvia; Trejo, José L

    2015-02-15

    The relevance of adult neurogenesis in hippocampal function is well documented, as is the potential impact stress has on the adult neurogenic niche. Adult born neurons are generated from neural precursors in the dentate gyrus (DG), although the point in postnatal development that these cell precursors originate is not known. This is particularly relevant if we consider the effects stress may have on the development of neural precursors, and whether such effects on adult neurogenesis and behavior may persist in the long-term. We have analyzed the proportion of neural precursors in the adult murine hippocampus born on specific days during postnatal development using a dual birth-dating analysis, and we assessed their sensitivity to dexamethasone (DEX) on the peak day of cell generation. We also studied the consequences of postnatal DEX administration on adult hippocampal-dependent behavior. Postnatal day 6 (P6) is a preferred period for proliferating neural stem cells (NSCs) to become the precursors that remain in a proliferative state throughout adulthood. This window is independent of gender, the cell's location in the DG granule cell layer or their rostro-caudal position. DEX administration at P6 reduces the size of the adult NSC pool in the DG, which is correlated with poor learning/memory capacity and increased anxiety-like behavior. These results indicate that aNSCs are generated non-uniformly during postnatal development, with peak generation on day P6, and that stress receptor activation during the key period of postnatal NSC generation has a profound impact on both adult hippocampal neurogenesis and behavior.

  13. Neural Activity Propagation in an Unfolded Hippocampal Preparation with a Penetrating Micro-electrode Array

    PubMed Central

    Gonzales-Reyes, Luis E.; Durand, Dominique M.

    2015-01-01

    This protocol describes a method for preparing a new in vitro flat hippocampus preparation combined with a micro-machined array to map neural activity in the hippocampus. The transverse hippocampal slice preparation is the most common tissue preparation to study hippocampus electrophysiology. A longitudinal hippocampal slice was also developed in order to investigate longitudinal connections in the hippocampus. The intact mouse hippocampus can also be maintained in vitro because its thickness allows adequate oxygen diffusion. However, these three preparations do not provide direct access to neural propagation since some of the tissue is either missing or folded. The unfolded intact hippocampus provides both transverse and longitudinal connections in a flat configuration for direct access to the tissue to analyze the full extent of signal propagation in the hippocampus in vitro. In order to effectively monitor the neural activity from the cell layer, a custom made penetrating micro-electrode array (PMEA) was fabricated and applied to the unfolded hippocampus. The PMEA with 64 electrodes of 200 µm in height could record neural activity deep inside the mouse hippocampus. The unique combination of an unfolded hippocampal preparation and the PMEA provides a new in-vitro tool to study the speed and direction of propagation of neural activity in the two-dimensional CA1-CA3 regions of the hippocampus with a high signal to noise ratio. PMID:25868081

  14. Impact of actin filament stabilization on adult hippocampal and olfactory bulb neurogenesis.

    PubMed

    Kronenberg, Golo; Gertz, Karen; Baldinger, Tina; Kirste, Imke; Eckart, Sarah; Yildirim, Ferah; Ji, Shengbo; Heuser, Isabella; Schröck, Helmut; Hörtnagl, Heide; Sohr, Reinhard; Djoufack, Pierre Chryso; Jüttner, René; Glass, Rainer; Przesdzing, Ingo; Kumar, Jitender; Freyer, Dorette; Hellweg, Rainer; Kettenmann, Helmut; Fink, Klaus Benno; Endres, Matthias

    2010-03-03

    Rearrangement of the actin cytoskeleton is essential for dynamic cellular processes. Decreased actin turnover and rigidity of cytoskeletal structures have been associated with aging and cell death. Gelsolin is a Ca(2+)-activated actin-severing protein that is widely expressed throughout the adult mammalian brain. Here, we used gelsolin-deficient (Gsn(-/-)) mice as a model system for actin filament stabilization. In Gsn(-/-) mice, emigration of newly generated cells from the subventricular zone into the olfactory bulb was slowed. In vitro, gelsolin deficiency did not affect proliferation or neuronal differentiation of adult neural progenitors cells (NPCs) but resulted in retarded migration. Surprisingly, hippocampal neurogenesis was robustly induced by gelsolin deficiency. The ability of NPCs to intrinsically sense excitatory activity and thereby implement coupling between network activity and neurogenesis has recently been established. Depolarization-induced [Ca(2+)](i) increases and exocytotic neurotransmitter release were enhanced in Gsn(-/-) synaptosomes. Importantly, treatment of Gsn(-/-) synaptosomes with mycotoxin cytochalasin D, which, like gelsolin, produces actin disassembly, decreased enhanced Ca(2+) influx and subsequent exocytotic norepinephrine release to wild-type levels. Similarly, depolarization-induced glutamate release from Gsn(-/-) brain slices was increased. Furthermore, increased hippocampal neurogenesis in Gsn(-/-) mice was associated with a special microenvironment characterized by enhanced density of perfused vessels, increased regional cerebral blood flow, and increased endothelial nitric oxide synthase (NOS-III) expression in hippocampus. Together, reduced filamentous actin turnover in presynaptic terminals causes increased Ca(2+) influx and, subsequently, elevated exocytotic neurotransmitter release acting on neural progenitors. Increased neurogenesis in Gsn(-/-) hippocampus is associated with a special vascular niche for neurogenesis.

  15. Active dentate granule cells encode experience to promote the addition of adult-born hippocampal neurons.

    PubMed

    Kirschen, Gregory W; Shen, Jia; Tian, Mu; Schroeder, Bryce; Wang, Jia; Man, Guoming; Wu, Song; Ge, Shaoyu

    2017-04-03

    The continuous addition of new dentate granule cells, exquisitely regulated by brain activity, renders the hippocampus plastic. However, how neural circuits encode experiences to impact the addition of adult-born neurons remains unknown. Here, we used endoscopic Ca(2+) imaging to track the real-time activity of individual dentate granule cells in freely-behaving mice. For the first time, we found that active dentate granule cells responded to a novel experience by preferentially increasing their Ca(2+) event frequency. This elevated activity, which we found to be associated with object exploration, returned to baseline by one hour in the same environment, but could be dishabituated via introduction to a novel environment. To seamlessly transition between environments, we next established a freely-controllable virtual reality system for unrestrained mice. We again observed increased firing of active neurons in a virtual enriched environment. Interestingly, multiple novel virtual experiences accumulatively increased the number of newborn neurons when compared to a single experience. Finally, optogenetic silencing of existing dentate granule cells during novel environmental exploration perturbed experience-induced neuronal addition. Together, our study shows that the adult brain conveys novel, enriched experiences to increase the addition of adult-born hippocampal neurons by increasing the firing of active dentate granule cells.SIGNIFICANCE STATEMENTAdult brains are constantly reshaping themselves from synapses to circuits as we encounter novel experiences from moment to moment. Importantly, this reshaping includes the addition of newborn hippocampal neurons. However, it remains largely unknown how our circuits encode experience-induced brain activity to govern the addition of new hippocampal neurons. By coupling in vivo Ca(2+) imaging of dentate granule neurons with a novel unrestrained virtual reality system for rodents, we discovered that a new experience rapidly

  16. Adult hippocampal neurogenesis and its role in Alzheimer's disease.

    PubMed

    Mu, Yangling; Gage, Fred H

    2011-12-22

    The hippocampus, a brain area critical for learning and memory, is especially vulnerable to damage at early stages of Alzheimer's disease (AD). Emerging evidence has indicated that altered neurogenesis in the adult hippocampus represents an early critical event in the course of AD. Although causal links have not been established, a variety of key molecules involved in AD pathogenesis have been shown to impact new neuron generation, either positively or negatively. From a functional point of view, hippocampal neurogenesis plays an important role in structural plasticity and network maintenance. Therefore, dysfunctional neurogenesis resulting from early subtle disease manifestations may in turn exacerbate neuronal vulnerability to AD and contribute to memory impairment, whereas enhanced neurogenesis may be a compensatory response and represent an endogenous brain repair mechanism. Here we review recent findings on alterations of neurogenesis associated with pathogenesis of AD, and we discuss the potential of neurogenesis-based diagnostics and therapeutic strategies for AD.

  17. Adult hippocampal neurogenesis and its role in Alzheimer's disease

    PubMed Central

    2011-01-01

    The hippocampus, a brain area critical for learning and memory, is especially vulnerable to damage at early stages of Alzheimer's disease (AD). Emerging evidence has indicated that altered neurogenesis in the adult hippocampus represents an early critical event in the course of AD. Although causal links have not been established, a variety of key molecules involved in AD pathogenesis have been shown to impact new neuron generation, either positively or negatively. From a functional point of view, hippocampal neurogenesis plays an important role in structural plasticity and network maintenance. Therefore, dysfunctional neurogenesis resulting from early subtle disease manifestations may in turn exacerbate neuronal vulnerability to AD and contribute to memory impairment, whereas enhanced neurogenesis may be a compensatory response and represent an endogenous brain repair mechanism. Here we review recent findings on alterations of neurogenesis associated with pathogenesis of AD, and we discuss the potential of neurogenesis-based diagnostics and therapeutic strategies for AD. PMID:22192775

  18. Osthole Upregulates BDNF to Enhance Adult Hippocampal Neurogenesis in APP/PS1 Transgenic Mice.

    PubMed

    Liu, Hong; Xue, Xinhong; Shi, Huijian; Qi, Lifeng; Gong, Dianrong

    2015-01-01

    Adult hippocampal neurogenesis occurs in the dentate gyrus (DG) of the mouse hippocampus, and plays roles in learning and memory progresses. In amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mice, a rodent model of Alzheimer's disease (AD), severe impairment of neurogenesis in the dentate subgranular zone (SGZ) of the DG has been reported. Osthole, an active constituent of Cnidium monnieri (L.) CUSSON, has been reported to exert neuroprotective effects and may promote neural stem cell proliferation. However, whether osthole ameliorates spatial memory deficits and improves hippocampal neurogenesis in APP/PS1 mice remains unknown. In this study we found that osthole (30 mg/kg intraperitoneally (i.p.) once daily) treatment dramatically ameliorated the cognitive impairments by Morris Water Maze test and passive avoidance test, and augmented neurogenesis in the DG of hippocampus in APP/PS1 mice. Furthermore, osthole treatment upregulated expression of brain-derived neurotrophic factor (BDNF) and enhanced activation of the BDNF receptor tyrosine receptor kinase B (TrkB) following increased phosphorylation of cyclic AMP response element-binding protein (CREB), indicating that osthole improves neurogenesis via stimulating BDNF/TrkB/CREB signaling in APP/PS1 transgenic mice.

  19. Epigenetic modulation of adult hippocampal neurogenesis by extremely low-frequency electromagnetic fields.

    PubMed

    Leone, Lucia; Fusco, Salvatore; Mastrodonato, Alessia; Piacentini, Roberto; Barbati, Saviana Antonella; Zaffina, Salvatore; Pani, Giovambattista; Podda, Maria Vittoria; Grassi, Claudio

    2014-06-01

    Throughout life, adult neurogenesis generates new neurons in the dentate gyrus of hippocampus that have a critical role in memory formation. Strategies able to stimulate this endogenous process have raised considerable interest because of their potential use to treat neurological disorders entailing cognitive impairment. We previously reported that mice exposed to extremely low-frequency electromagnetic fields (ELFEFs) showed increased hippocampal neurogenesis. Here, we demonstrate that the ELFEF-dependent enhancement of hippocampal neurogenesis improves spatial learning and memory. To gain insights on the molecular mechanisms underlying ELFEFs' effects, we extended our studies to an in vitro model of neural stem cells (NSCs) isolated from the hippocampi of newborn mice. We found that ELFEFs enhanced proliferation and neuronal differentiation of hippocampal NSCs by regulation of epigenetic mechanisms leading to pro-neuronal gene expression. Upon ELFEF stimulation of NSCs, we observed a significant enhancement of expression of the pro-proliferative gene hairy enhancer of split 1 and the neuronal determination genes NeuroD1 and Neurogenin1. These events were preceded by increased acetylation of H3K9 and binding of the phosphorylated transcription factor cAMP response element-binding protein (CREB) on the regulatory sequence of these genes. Such ELFEF-dependent epigenetic modifications were prevented by the Cav1-channel blocker nifedipine, and were associated with increased occupancy of CREB-binding protein (CBP) to the same loci within the analyzed promoters. Our results unravel the molecular mechanisms underlying the ELFEFs' ability to improve endogenous neurogenesis, pointing to histone acetylation-related chromatin remodeling as a critical determinant. These findings could pave the way to the development of novel therapeutic approaches in regenerative medicine.

  20. Neural correlates of autobiographical memory retrieval in children and adults.

    PubMed

    Bauer, Patricia J; Pathman, Thanujeni; Inman, Cory; Campanella, Carolina; Hamann, Stephan

    2017-04-01

    Autobiographical memory (AM) is a critically important form of memory for life events that undergoes substantial developmental changes from childhood to adulthood. Relatively little is known regarding the functional neural correlates of AM retrieval in children as assessed with fMRI, and how they may differ from adults. We investigated this question with 14 children ages 8-11 years and 14 adults ages 19-30 years, contrasting AM retrieval with semantic memory (SM) retrieval. During scanning, participants were cued by verbal prompts to retrieve previously selected recent AMs or to verify semantic properties of words. As predicted, both groups showed AM retrieval-related increased activation in regions implicated in prior studies, including bilateral hippocampus, and prefrontal, posterior cingulate, and parietal cortices. Adults showed greater activation in the hippocampal/parahippocampal region as well as prefrontal and parietal cortex, relative to children; age-related differences were most prominent in the first 8 sec versus the second 8 sec of AM retrieval and when AM retrieval was contrasted with semantic retrieval. This study is the first to characterise similarities and differences during AM retrieval in children and adults using fMRI.

  1. Neonatal administration of phencyclidine decreases the number of putative inhibitory interneurons and increases neural excitability to auditory paired clicks in the hippocampal CA3 region of freely moving adult mice.

    PubMed

    Okamoto, M; Katayama, T; Suzuki, Y; Hoshino, K-Y; Yamada, H; Matsuoka, N; Jodo, E

    2012-11-08

    Animals exposed to phencyclidine (PCP) during the neonatal period have fewer GABAergic interneurons in the corticolimbic area, including the hippocampus, and exhibit abnormal behaviors after attaining maturation that correspond with schizophrenic symptoms. Since a lack of inhibitory interneurons in the hippocampus has also been reported in postmortem studies of patients with schizophrenia, the deficit may induce abnormal activity of hippocampal neurons that underlies pathological states in schizophrenia. However, it remains unclear how PCP treatment during the neonatal period affects the discharge activity of hippocampal neurons in adulthood. In the current study, single unit responses of hippocampal CA3 neurons to paired auditory clicks were recorded in freely moving mice repeatedly injected with PCP or saline during the neonatal period. The recorded neurons were classified into two subpopulations, narrow-spike neurons and broad-spike neurons, based on the spike width. The spontaneous discharge rate was higher in the narrow-spike neurons than in the broad-spike neurons, indicating that the narrow-spike neurons correspond with hippocampal inhibitory neurons. The proportion of narrow-spike neurons was significantly smaller in neonatally PCP-treated mice than in saline-treated mice. The broad-spike neurons that exhibited a response magnitude to the second click as large as that to the first click (E/E-type response) showed longer response duration to the paired clicks in PCP-treated mice than in the saline-treated mice. Further, the number of neurons with E/E-type response was higher in the PCP-treated mice than in the saline-treated mice. Finally, the attenuation of an auditory-evoked potential component, N40, to the second click (sensory gating) was blunted in the PCP-treated mice when compared with that in the saline-treated mice. These results suggest that the neonatal administration of PCP induced a deficit of inhibitory interneurons and altered discharge

  2. Thermal dependence of neural activity in the hamster hippocampal slice preparation

    NASA Technical Reports Server (NTRS)

    Horowitz, J. M.; Thomas, M. P.; Eckerman, P.

    1987-01-01

    1. Neural activity was recorded in an in vitro hamster hippocampal slice preparation while the temperature of the Ringer's solution bathing in the slice was controlled at selected levels. 2. The amplitude of the population spike (action potentials from a group of pyramidal cells) was measured as bath temperature was lowered from 35 degrees C to temperatures where a response could not be evoked. 3. Plots of population spike amplitude versus temperature have bell-shaped curves. The population spikes increased in amplitude as temperature was lowered from 35 degrees C, reached a peak amplitude between 25 and 20 degrees C, and then decreased until a response could not be evoked when temperature was further lowered. 4. These in vitro results obtained in the slice preparation are related to in vivo hippocampal studies. Results are interpreted as consistent with the proposal reviewed here that neural activity in the hippocampus plays a role at specific stages of entrance into and arousal from hibernation.

  3. Hippocampal Brain Volume Is Associated with Faster Facial Emotion Identification in Older Adults: Preliminary Results

    PubMed Central

    Szymkowicz, Sarah M.; Persson, Jonas; Lin, Tian; Fischer, Håkan; Ebner, Natalie C.

    2016-01-01

    Quick correct identification of facial emotions is highly relevant for successful social interactions. Research suggests that older, compared to young, adults experience increased difficulty with face and emotion processing skills. While functional neuroimaging studies suggest age differences in neural processing of faces and emotions, evidence about age-associated structural brain changes and their involvement in face and emotion processing is scarce. Using structural magnetic resonance imaging (MRI), this study investigated the extent to which volumes of frontal and temporal brain structures were related to reaction time in accurate identification of facial emotions in 30 young and 30 older adults. Volumetric segmentation was performed using FreeSurfer and gray matter volumes from frontal and temporal regions were extracted. Analysis of covariances (ANCOVAs) models with response time (RT) as the dependent variable and age group and regional volume, and their interaction, as independent variables were conducted, controlling for total intracranial volume (ICV). Results indicated that, in older adults, larger hippocampal volumes were associated with faster correct facial emotion identification. These preliminary observations suggest that greater volume in brain regions associated with face and emotion processing contributes to improved facial emotion identification performance in aging. PMID:27610082

  4. Influences of NR2B-containing NMDA receptors knockdown on neural activity in hippocampal newborn neurons.

    PubMed

    Li, Zhi-jun; Zhang, Hui-wen; Tang, Na

    2013-08-01

    Adult-born neurons undergo a transient period of plasticity during their integration into the neural circuit. This transient plasticity may involve NMDA receptors containing NR2B, the major subunit expressed at early developmental stages. The main objective of the present study was to investigate the effects of NR2B gene knockdown on the functional integration of the adult-born granule cells generated from the subgranule zone (SGZ) in the hippocampus. The small interfering RNA (siRNA) was used to knock down the NR2B gene in the adult-born hippocampal neurons. In the functional integration test, the mice were exposed to a novel environment (open field arena), and the expression of c-fos was immunohistochemically detected in the hippocampus. After exposure to the novel environment, siRNA-NR2B mice were significantly different from control mice in either the number of squares or the number of rears they crossed, showing decreased horizontal and vertical activity (P<0.05). Moreover, the c-fos expression was increased in both control and siRNA-NR2B mice after open field test. But, it was significantly lower in siRNA-NR2B neurons than in control neurons. It was concluded that the neural activity of newborn neurons is regulated by their own NR2B-containing NMDA glutamate receptors during a short, critical period after neuronal birth.

  5. The effects of erdosteine, N-acetylcysteine, and vitamin E on nicotine-induced apoptosis of hippocampal neural cells.

    PubMed

    Demiralay, Rezan; Gürsan, Nesrin; Erdem, Havva

    2008-08-01

    This study investigated the frequency of apoptosis in rat hippocampal neural cells after intraperitoneal nicotine injection, examining the roles of the inflammatory markers myeloperoxidase (MPO) and tumor necrosis factor alpha (TNF-alpha) in nicotine-induced brain damage and the protective effects of three known antioxidant agents, N-acetylcysteine (NAC), erdosteine, and vitamin E. Female Wistar rats were divided into seven groups, each composed of nine rats: 2 negative control groups, 2 positive control groups, one erdosteine-treated group (500 mg/kg), one NAC-treated group (500 mg/kg), and one vitamin E-treated group (500 mg/kg). Nicotine was intraperitoneally injected at a dosage of 0.6 mg/kg for 21 days. Following nicotine injection, the antioxidants were administered orally; treatment was continued until the rats were killed. Apoptosis level in hippocampal neural cells was determined by using TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick endlabeling) method. Staining of cytoplasmic TNF-alpha in hippocampal neural cells and hippocampus MPO activity were evaluated by immunohistochemistry. Nicotine administration had no effect on local TNF-alpha production, or hippocampal MPO activity. The treatments with erdosteine, NAC and vitamin E significantly reduced the rate of nicotine-induced hippocampal neural cell apoptosis. This findings suggest that erdosteine and NAC can be as effective as vitamin E in protecting against nicotine-induced hippocampal neural cell apoptosis.

  6. Impaired Memory in OT-II Transgenic Mice Is Associated with Decreased Adult Hippocampal Neurogenesis Possibly Induced by Alteration in Th2 Cytokine Levels

    PubMed Central

    Jeon, Seong Gak; Kim, Kyoung Ah; Chung, Hyunju; Choi, Junghyun; Song, Eun Ji; Han, Seung-Yun; Oh, Myung Sook; Park, Jong Hwan; Kim, Jin-il; Moon, Minho

    2016-01-01

    Recently, an increasing number of studies have focused on the effects of CD4+ T cell on cognitive function. However, the changes of Th2 cytokines in restricted CD4+ T cell receptor (TCR) repertoire model and their effects on the adult hippocampal neurogenesis and memory are not fully understood. Here, we investigated whether and how the mice with restricted CD4+ repertoire TCR exhibit learning and memory impairment by using OT-II mice. OT-II mice showed decreased adult neurogenesis in hippocampus and short- and long- term memory impairment. Moreover, Th2 cytokines in OT-II mice are significantly increased in peripheral organs and IL-4 is significantly increased in brain. Finally, IL-4 treatment significantly inhibited the proliferation of cultured adult rat hippocampal neural stem cells. Taken together, abnormal level of Th2 cytokines can lead memory dysfunction via impaired adult neurogenesis in OT-II transgenic. PMID:27432189

  7. Impaired Memory in OT-II Transgenic Mice Is Associated with Decreased Adult Hippocampal Neurogenesis Possibly Induced by Alteration in Th2 Cytokine Levels.

    PubMed

    Jeon, Seong Gak; Kim, Kyoung Ah; Chung, Hyunju; Choi, Junghyun; Song, Eun Ji; Han, Seung-Yun; Oh, Myung Sook; Park, Jong Hwan; Kim, Jin-Il; Moon, Minho

    2016-08-31

    Recently, an increasing number of studies have focused on the effects of CD4+ T cell on cognitive function. However, the changes of Th2 cytokines in restricted CD4+ T cell receptor (TCR) repertoire model and their effects on the adult hippocampal neurogenesis and memory are not fully understood. Here, we investigated whether and how the mice with restricted CD4+ repertoire TCR exhibit learning and memory impairment by using OT-II mice. OT-II mice showed decreased adult neurogenesis in hippocampus and short- and long- term memory impairment. Moreover, Th2 cytokines in OT-II mice are significantly increased in peripheral organs and IL-4 is significantly increased in brain. Finally, IL-4 treatment significantly inhibited the proliferation of cultured adult rat hippocampal neural stem cells. Taken together, abnormal level of Th2 cytokines can lead memory dysfunction via impaired adult neurogenesis in OT-II transgenic.

  8. Intense Exercise Promotes Adult Hippocampal Neurogenesis But Not Spatial Discrimination

    PubMed Central

    So, Ji H.; Huang, Chao; Ge, Minyan; Cai, Guangyao; Zhang, Lanqiu; Lu, Yisheng; Mu, Yangling

    2017-01-01

    Hippocampal neurogenesis persists throughout adult life and plays an important role in learning and memory. Although the influence of physical exercise on neurogenesis has been intensively studied, there is controversy in regard to how the impact of exercise may vary with its regime. Less is known about how distinct exercise paradigms may differentially affect the learning behavior. Here we found that, chronic moderate treadmill running led to an increase of cell proliferation, survival, neuronal differentiation, and migration. In contrast, intense running only promoted neuronal differentiation and migration, which was accompanied with lower expressions of vascular endothelial growth factor, brain-derived neurotrophic factor, insulin-like growth factor 1, and erythropoietin. In addition, the intensely but not mildly exercised animals exhibited a lower mitochondrial activity in the dentate gyrus. Correspondingly, neurogenesis induced by moderate but not intense exercise was sufficient to improve the animal’s ability in spatial pattern separation. Our data indicate that the effect of exercise on spatial learning is intensity-dependent and may involve mechanisms other than a simple increase in the number of new neurons. PMID:28197080

  9. Recruitment and replacement of hippocampal neurons in young and adult chickadees: an addition to the theory of hippocampal learning.

    PubMed Central

    Barnea, A; Nottebohm, F

    1996-01-01

    We used [3H]thymidine to document the birth of neurons and their recruitment into the hippocampal complex (HC) of juvenile (4.5 months old) and adult blackcapped chickadees (Parus atricapillus) living in their natural surroundings. Birds received a single dose of [3H]thymidine in August and were recaptured and killed 6 weeks later, in early October. All brains were stained with Cresyl violet, a Nissl stain. The boundaries of the HC were defined by reference to the ventricular wall, the brain surface, or differences in neuronal packing density. The HC of juveniles was as large as or larger than that of adults and packing density of HC neurons was 31% higher in juveniles than in adults. Almost all of the 3H-labeled HC neurons were found in a 350-m-wide layer of tissue adjacent to the lateral ventricle. Within this layer the fraction of 3H-labeled neurons was 50% higher in juveniles than in adults. We conclude that the HC of juvenile chickadees recruits more neurons and has more neurons than that of adults. We speculate that juveniles encounter greater environmental novelty than adults and that the greater number of HC neurons found in juveniles allows them to learn more than adults. At a more general level, we suggest that (i) long-term learning alters HC neurons irreversibly; (ii) sustained hippocampal learning requires the periodic replacement of HC neurons; (iii) memories coded by hippocampal neurons are transferred elsewhere before the neurons are replaced. Images Fig. 1 Fig. 2 PMID:11607626

  10. Closing the Loop for Memory Prostheses: Detecting the Role of Hippocampal Neural Ensembles Using Nonlinear Models

    PubMed Central

    Hampson, Robert E.; Song, Dong; Chan, Rosa H.M.; Sweatt, Andrew J.; Riley, Mitchell R.; Goonawardena, Anushka V.; Marmarelis, Vasilis Z.; Gerhardt, Greg A.; Berger, Theodore W.; Deadwyler, Sam A.

    2012-01-01

    A major factor involved in providing closed loop feedback for control of neural function is to understand how neural ensembles encode online information critical to the final behavioral endpoint. This issue was directly assessed in rats performing a short-term delay memory task in which successful encoding of task information is dependent upon specific spatiotemporal firing patterns recorded from ensembles of CA3 and CA1 hippocampal neurons. Such patterns, extracted by a specially designed nonlinear multi-input multi-output (MIMO) nonlinear mathematical model, were used to predict successful performance online via a closed loop paradigm which regulated trial difficulty (time of retention) as a function of the “strength” of stimulus encoding. The significance of the MIMO model as a neural prosthesis has been demonstrated by substituting trains of electrical stimulation pulses to mimic these same ensemble firing patterns. This feature was used repeatedly to vary “normal” encoding as a means of understanding how neural ensembles can be “tuned” to mimic the inherent process of selecting codes of different strength and functional specificity. The capacity to enhance and tune hippocampal encoding via MIMO model detection and insertion of critical ensemble firing patterns shown here provides the basis for possible extension to other disrupted brain circuitry. PMID:22498704

  11. Low-intensity daily walking activity is associated with hippocampal volume in older adults.

    PubMed

    Varma, Vijay R; Chuang, Yi-Fang; Harris, Gregory C; Tan, Erwin J; Carlson, Michelle C

    2015-05-01

    Hippocampal atrophy is associated with memory impairment and dementia and serves as a key biomarker in the preclinical stages of Alzheimer's disease. Physical activity, one of the most promising behavioral interventions to prevent or delay cognitive decline, has been shown to be associated with hippocampal volume; specifically increased aerobic activity and fitness may have a positive effect on the size of the hippocampus. The majority of older adults, however, are sedentary and have difficulty initiating and maintaining exercise programs. A modestly more active lifestyle may nonetheless be beneficial. This study explored whether greater objectively measured daily walking activity was associated with larger hippocampal volume. We additionally explored whether greater low-intensity walking activity, which may be related to leisure-time physical, functional, and social activities, was associated with larger hippocampal volume independent of exercise and higher-intensity walking activity. Segmentation of hippocampal volumes was performed using Functional Magnetic Resonance Imaging of the Brain's Software Library (FSL), and daily walking activity was assessed using a step activity monitor on 92, nondemented, older adult participants. After controlling for age, education, body mass index, cardiovascular disease risk factors, and the Mini Mental State Exam, we found that a greater amount, duration, and frequency of total daily walking activity were each associated with larger hippocampal volume among older women, but not among men. These relationships were specific to hippocampal volume, compared with the thalamus, used as a control brain region, and remained significant for low-intensity walking activity, independent of moderate- to vigorous-intensity activity and self-reported exercise. This is the first study, to our knowledge, to explore the relationship between objectively measured daily walking activity and hippocampal volume in an older adult population. Findings

  12. Distinct Effects of Chronic Dopaminergic Stimulation on Hippocampal Neurogenesis and Striatal Doublecortin Expression in Adult Mice

    PubMed Central

    Salvi, Rachele; Steigleder, Tobias; Schlachetzki, Johannes C. M.; Waldmann, Elisabeth; Schwab, Stefan; Winner, Beate; Winkler, Jürgen; Kohl, Zacharias

    2016-01-01

    While adult neurogenesis is considered to be restricted to the hippocampal dentate gyrus (DG) and the subventricular zone (SVZ), recent studies in humans and rodents provide evidence for newly generated neurons in regions generally considered as non-neurogenic, e.g., the striatum. Stimulating dopaminergic neurotransmission has the potential to enhance adult neurogenesis in the SVZ and the DG most likely via D2/D3 dopamine (DA) receptors. Here, we investigated the effect of two distinct preferential D2/D3 DA agonists, Pramipexole (PPX), and Ropinirole (ROP), on adult neurogenesis in the hippocampus and striatum of adult naïve mice. To determine newly generated cells in the DG incorporating 5-bromo-2′-deoxyuridine (BrdU) a proliferation paradigm was performed in which two BrdU injections (100 mg/kg) were applied intraperitoneally within 12 h after a 14-days-DA agonist treatment. Interestingly, PPX, but not ROP significantly enhanced the proliferation in the DG by 42% compared to phosphate buffered saline (PBS)-injected control mice. To analyze the proportion of newly generated cells differentiating into mature neurons, we quantified cells co-expressing BrdU and Neuronal Nuclei (NeuN) 32 days after the last of five BrdU injections (50 mg/kg) applied at the beginning of 14-days DA agonist or PBS administration. Again, PPX only enhanced neurogenesis in the DG significantly compared to ROP- and PBS-injected mice. Moreover, we explored the pro-neurogenic effect of both DA agonists in the striatum by quantifying neuroblasts expressing doublecortin (DCX) in the entire striatum, as well as in the dorsal and ventral sub-regions separately. We observed a significantly higher number of DCX+ neuroblasts in the dorsal compared to the ventral sub-region of the striatum in PPX-injected mice. These results suggest that the stimulation of hippocampal and dorsal striatal neurogenesis may be up-regulated by PPX. The increased generation of neural cells, both in constitutively active

  13. Melatonin attenuates methamphetamine-induced inhibition of proliferation of adult rat hippocampal progenitor cells in vitro.

    PubMed

    Ekthuwapranee, Kasima; Sotthibundhu, Areechun; Govitrapong, Piyarat

    2015-05-01

    Methamphetamine (METH) is an extremely addictive stimulatory drug. A recent study suggested that METH may cause an impairment in the proliferation of hippocampal neural progenitor cells, but the underlying mechanism of this effect remains unknown. Blood and cerebrospinal levels of melatonin derive primarily from the pineal gland, and that performs many biological functions. Our previous study demonstrated that melatonin promotes the proliferation of progenitor cells originating from the hippocampus. In this study, hippocampal progenitor cells from adult Wistar rats were used to determine the effects of METH on cell proliferation and the mechanisms underlying these effects. We investigated the effects of melatonin on the METH-induced alteration in cell proliferation. The results demonstrated that 500 μm METH induced a decrease (63.0%) in neurosphere cell proliferation and altered the expression of neuronal phenotype markers in the neurosphere cell population. Moreover, METH induced an increase in the protein expression of the tumor suppressor p53 (124.4%) and the cell cycle inhibitor p21(CIP) (1) (p21) (128.1%), resulting in the accumulation of p21 in the nucleus. We also found that METH altered the expression of the N-methyl-d-aspartate (NMDA) receptor subunits NR2A (79.6%) and NR2B (126.7%) and Ca(2+) /calmodulin-dependent protein kinase II (CAMKII) (74.0%). In addition, pretreatment with 1 μm melatonin attenuated the effects induced by METH treatment. According to these results, we concluded that METH induces a reduction in cell proliferation by upregulating the cell cycle regulators p53/p21 and promoting the accumulation of p21 in the nucleus and that melatonin ameliorates these negative effects of METH.

  14. Expression of familial Alzheimer's disease-linked human presenilin 1 variants impair enrichment-induced adult hippocampal neurogenesis.

    PubMed

    Veeraraghavalu, Karthikeyan; Choi, Se Hoon; Sisodia, Sangram S

    2010-01-01

    Presenilin 1 (PS1) plays a critical role in neurogenesis both during development and in the adult. We recently reported that ubiquitous expression of familial, early-onset Alzheimer's disease-linked PS1 mutants impairs enrichment-induced proliferation and neurogenesis of hippocampal neural progenitor cells (NPCs) in a non-cell autonomous manner. The impairments in proliferation and neurogenesis are, at least in part, due to alterations in the levels of specific chemokines and growth factors secreted from microglia expressing familial Alzheimer's disease-linked PS1 variants. To test our hypothesis that the fate of hippocampal NPCs in PS1 mutant mice is largely determined by cellular factors produced within the niche itself, we are examining the fate of NPCs from hippocampi of wild-type human PS1 or PS1 mutant mice that are marked with green fluorescent protein and BrdU following transplantation into heterologous hosts. In parallel, we have generated transgenic mice that harbor a transgene encoding the PS1DeltaE9 variant flanked with loxP sites that can be conditionally deleted in a temporal and/or spatial manner using specific cre driver lines. These studies will allow us to assess the contributions of varying cell types within the hippocampal stem cell niche that express mutant PS1 to NPC proliferation and differentiation.

  15. Content-based retrieval using MPEG-7 visual descriptor and hippocampal neural network

    NASA Astrophysics Data System (ADS)

    Kim, Young Ho; Joung, Lyang-Jae; Kang, Dae-Seong

    2005-12-01

    As development of digital technology, many kinds of multimedia data are used variously and requirements for effective use by user are increasing. In order to transfer information fast and precisely what user wants, effective retrieval method is required. As existing multimedia data are impossible to apply the MPEG-1, MPEG-2 and MPEG-4 technologies which are aimed at compression, store and transmission. So MPEG-7 is introduced as a new technology for effective management and retrieval for multimedia data. In this paper, we extract content-based features using color descriptor among the MPEG-7 standardization visual descriptor, and reduce feature data applying PCA(Principal Components Analysis) technique. We remodel the cerebral cortex and hippocampal neural networks as a principle of a human's brain and it can label the features of the image-data which are inputted according to the order of hippocampal neuron structure to reaction-pattern according to the adjustment of a good impression in Dentate gyrus region and remove the noise through the auto-associate- memory step in the CA3 region. In the CA1 region receiving the information of the CA3, it can make long-term or short-term memory learned by neuron. Hippocampal neural network makes neuron of the neural network separate and combine dynamically, expand the neuron attaching additional information using the synapse and add new features according to the situation by user's demand. When user is querying, it compares feature value stored in long-term memory first and it learns feature vector fast and construct optimized feature. So the speed of index and retrieval is fast. Also, it uses MPEG-7 standard visual descriptors as content-based feature value, it improves retrieval efficiency.

  16. When is adult hippocampal neurogenesis necessary for learning? evidence from animal research.

    PubMed

    Castilla-Ortega, Estela; Pedraza, Carmen; Estivill-Torrús, Guillermo; Santín, Luis J

    2011-01-01

    The hippocampus is a key brain structure involved in the short- and long-term processing of declarative memory. Since adult hippocampal neurogenesis was first found, numerous studies have tried to establish the contribution of newborn neurons to hippocampus-dependent cognitive functions. However, this large amount of research has generated contradictory results. In this paper, we review the body of evidence investigating the relationship between hippocampal neurogenesis and learning to conclude the functional role of adult-born hippocampal neurons. First, factors that could explain discrepancies among experiments are taken into account. Then, in addition to methodological differences, we emphasize the importance of the age of the newborn neurons studied, as to how their maturation influences both their properties and potential functionality. Next, we discuss which declarative memory components could require involvement of adult hippocampal neurogenesis, taking into consideration the representational demands of the task, its difficulty and the level of performance reached by the subject. Finally, other factors that could modulate neurogenesis and memory, such as stress levels or previous experience of the animal, should also be taken into consideration in interpreting experiments focused on neurogenesis. In conclusion, our analysis of published studies suggests that new adult-born neurons, under certain circumstances, have a crucial and irreplaceable role in hippocampal learning.

  17. Hippocampal learning, memory, and neurogenesis: Effects of sex and estrogens across the lifespan in adults.

    PubMed

    Duarte-Guterman, Paula; Yagi, Shunya; Chow, Carmen; Galea, Liisa A M

    2015-08-01

    This article is part of a Special Issue "Estradiol and Cognition". There are sex differences in hippocampus-dependent cognition and neurogenesis suggesting that sex hormones are involved. Estrogens modulate certain forms of spatial and contextual memory and neurogenesis in the adult female rodent, and to a lesser extent male, hippocampus. This review focuses on the effects of sex and estrogens on hippocampal learning, memory, and neurogenesis in the young and aged adult rodent. We discuss how factors such as the type of estrogen, duration and dose of treatment, timing of treatment, and type of memory influence the effects of estrogens on cognition and neurogenesis. We also address how reproductive experience (pregnancy and mothering) and aging interact with estrogens to modulate hippocampal cognition and neurogenesis in females. Given the evidence that adult hippocampal neurogenesis plays a role in long-term spatial memory and pattern separation, we also discuss the functional implications of regulating neurogenesis in the hippocampus.

  18. Hippocampal neural activity reflects the economy of choices during goal-directed navigation.

    PubMed

    Tryon, Valerie L; Penner, Marsha R; Heide, Shawn W; King, Hunter O; Larkin, Joshua; Mizumori, Sheri J Y

    2017-02-27

    Distinguishing spatial contexts is likely essential for the well-known role of the hippocampus in episodic memory. We studied whether types of hippocampal neural organization thought to underlie context discrimination are impacted by learned economic considerations of choice behavior. Hippocampal place cells and theta activity were recorded as rats performed a maze-based probability discounting task that involved choosing between a small certain reward or a large probabilistic reward. Different spatial distributions of place fields were observed in response to changes in probability, the outcome of the rats' choice, and whether or not rats were free to make that choice. The degree to which the reward location was represented by place cells scaled with the expected probability of rewards. Theta power increased around the goal location also in proportion to the expected probability of signaled rewards. Furthermore, theta power dynamically varied as specific econometric information was obtained "on the fly" during task performance. Such an economic perspective of memory processing by hippocampal place cells expands our view of the nature of context memories retrieved by hippocampus during adaptive navigation.

  19. Formation of hippocampal mHTT aggregates leads to impaired spatial memory, hippocampal activation and adult neurogenesis.

    PubMed

    Schwab, L C; Richetin, K; Barker, R A; Déglon, N

    2017-03-09

    Huntington's disease (HD) is a genetic neurodegenerative disorder characterized by a triad of motor, psychiatric and cognitive deficits with the latter classically attributed to disruption of fronto-striatal circuits. However, emerging evidence suggests that some of the cognitive deficits in HD may have their origin in other structures including the hippocampus. Hippocampal abnormalities have been reported in HD mouse models particularly in terms of performance on the Morris Water Maze. However, in these animals, it is difficult to be certain whether the spatial memory deficits are due to local pathology within this structure or their poor mobility and motivation. Thus, a better model of hippocampal dysfunction in HD is needed especially given that we have previously shown that patients with HD have hippocampal-related problems from the very earliest stages of disease. In this study, our aim was therefore to understand the cellular and behavioural consequences of local overexpression of mutant huntingtin (mHTT) in the hippocampus of adult mice. We found that a targeted injection of a lentivirus, encoding an N-terminal of mHTT with 82 CAG repeats, into the murine hippocampus led to the focal formation of mHTT aggregates, long-term spatial memory impairments with decreased neurogenesis and expression of the immediate early gene c-fos. This study has therefore shown for the first time that local expression of mHTT in the dentate gyrus has deleterious effects, including its neurogenic capacity, with functional behavioural consequences, which fits well with recent data on hippocampal deficits seen in patients with HD.

  20. Mouse model of CADASIL reveals novel insights into Notch3 function in adult hippocampal neurogenesis.

    PubMed

    Ehret, Fanny; Vogler, Steffen; Pojar, Sherin; Elliott, David A; Bradke, Frank; Steiner, Barbara; Kempermann, Gerd

    2015-03-01

    Could impaired adult hippocampal neurogenesis be a relevant mechanism underlying CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy)? Memory symptoms in CADASIL, the most common hereditary form of vascular dementia, are usually thought to be primarily due to vascular degeneration and white matter lacunes. Since adult hippocampal neurogenesis, a process essential for the integration of new spatial memory occurs in a highly vascularized niche, we considered dysregulation of adult neurogenesis as a potential mechanism for the manifestation of dementia in CADASIL. Analysis in aged mice overexpressing Notch3 with a CADASIL mutation, revealed vascular deficits in arteries of the hippocampal fissure but not in the niche of the dentate gyrus. At 12 months of age, cell proliferation and survival of newborn neurons were reduced not only in CADASIL mice but also in transgenic controls overexpressing wild type Notch3. At 6 months, hippocampal neurogenesis was altered in CADASIL mice independent of overt vascular abnormalities in the fissure. Further, we identified Notch3 expression in hippocampal precursor cells and maturing neurons in vivo as well as in cultured hippocampal precursor cells. Overexpression and knockdown experiments showed that Notch3 signaling negatively regulated precursor cell proliferation. Notch3 overexpression also led to deficits in KCl-induced precursor cell activation. This suggests a cell-autonomous effect of Notch3 signaling in the regulation of precursor proliferation and activation and a loss-of-function effect in CADASIL. Consequently, besides vascular damage, aberrant precursor cell proliferation and differentiation due to Notch3 dysfunction might be an additional independent mechanism for the development of hippocampal dysfunction in CADASIL.

  1. Hippocampal volume is as variable in young as in older adults: implications for the notion of hippocampal atrophy in humans.

    PubMed

    Lupien, S J; Evans, A; Lord, C; Miles, J; Pruessner, M; Pike, B; Pruessner, J C

    2007-01-15

    Previous studies in humans have shown the presence of an age-related reduction of hippocampal (HC) volume, as well as the presence of reduced HC volume in psychiatric populations suffering from schizophrenia, depression or post-traumatic stress disorder. Altogether, these data suggested that aging or psychiatric disease can have neurotoxic effects on the hippocampus, and lead to HC atrophy. However, these two sets of findings imply that HC volume in young healthy adults should present less variability than HC volume in older adults and psychiatric populations. In the present study, we assessed HC volume in 177 healthy men and women aged from 18 to 85 years of age. We show that the dispersion around the mean of HC volume is not different in young and older adults, so that 25% of young healthy adults present HC volume as small as the average participants aged 60 to 75 years. This shows that HC volume is as variable in young as in older adults and suggests that smaller HC volume attributed to the aging process in previous studies could in fact represent HC volume determined early in life. We also report that within similar age groups, the percentage of difference in HC volume between the individuals with the smallest HC volume (smallest quartile) and the group average is greater than the percentage of difference reported to exist between psychiatric populations and normal control in recent meta-analyses. Taken together, these results confront the notion of hippocampal atrophy in humans and raise the possibility that pre-determined inter-individual differences in HC volume in humans may determine the vulnerability for age-related cognitive impairments or psychopathology throughout the lifetime.

  2. Gene expression profiling of the hippocampal dentate gyrus in an adult toxicity study captures a variety of neurodevelopmental dysfunctions in rat models of hypothyroidism.

    PubMed

    Shiraki, Ayako; Saito, Fumiyo; Akane, Hirotoshi; Akahori, Yumi; Imatanaka, Nobuya; Itahashi, Megu; Yoshida, Toshinori; Shibutani, Makoto

    2016-01-01

    We previously found that developmental hypothyroidism changed the expression of genes in the rat hippocampal dentate gyrus, a brain region where adult neurogenesis is known to occur. In the present study, we performed brain region-specific global gene expression profiling in an adult rat hypothyroidism model to see if it reflected the developmental neurotoxicity we saw in the developmental hypothyroidism model. Starting when male rats were 5 weeks old, we administered 6-propyl-2-thiouracil at a doses of 0, 0.1 and 10 mg kg(-1) body weight by gavage for 28 days. We selected four brain regions to represent both cerebral and cerebellar tissues: hippocampal dentate gyrus, cerebral cortex, corpus callosum and cerebellar vermis. We observed significant alterations in the expression of genes related to neural development (Eph family genes and Robo3) in the cerebral cortex and hippocampal dentate gyrus and in the expression of genes related to myelination (Plp1 and Mbp) in the hippocampal dentate gyrus. We observed only minor changes in the expression of these genes in the corpus callosum and cerebellar vermis. We used real-time reverse-transcription polymerase chain reaction to confirm Chrdl1, Hes5, Mbp, Plp1, Slit1, Robo3 and the Eph family transcript expression changes. The most significant changes in gene expression were found in the dentate gyrus. Considering that the gene expression profile of the adult dentate gyrus closely related to neurogenesis, 28-day toxicity studies looking at gene expression changes in adult hippocampal dentate gyrus may also detect possible developmental neurotoxic effects.

  3. Neuroinflammation negatively affects adult hippocampal neurogenesis and cognition: can exercise compensate?

    PubMed

    Ryan, Sinéad M; Nolan, Yvonne M

    2016-02-01

    Adult hippocampal neurogenesis is believed to be integral for certain forms of learning and memory. Dysregulation of hippocampal neurogenesis has been shown to be an important mechanism underlying the cognitive impairment associated with normal aging, as well as the cognitive deficits evident in preclinical models of Alzheimer's disease and other neurodegenerative diseases. Neuroinflammation is a significant pathological feature of these conditions; it contributes to the observed cognitive decline, and recent evidence demonstrates that it also negatively affects hippocampal neurogenesis. Conversely, during the past twenty years, it has been robustly shown that exercise is a potent inducer of hippocampal neurogenesis, and it is believed that the positive beneficial effect of exercise on cognitive function is likely due to its pro-neurogenic effects. However, the interplay between exercise- and neuroinflammatory-induced changes in hippocampal neurogenesis and associated cognitive function has only recently begun to receive attention. Here we review the current literature on exercise-induced effects on hippocampal neurogenesis, cognitive function and neuroinflammation, and consider exercise as a potential pro-neurogenic and anti-inflammatory intervention for cognition.

  4. Alzheimer's Disease and Hippocampal Adult Neurogenesis; Exploring Shared Mechanisms

    PubMed Central

    Hollands, Carolyn; Bartolotti, Nancy; Lazarov, Orly

    2016-01-01

    New neurons incorporate into the granular cell layer of the dentate gyrus throughout life. Neurogenesis is modulated by behavior and plays a major role in hippocampal plasticity. Along with older mature neurons, new neurons structure the dentate gyrus, and determine its function. Recent data suggest that the level of hippocampal neurogenesis is substantial in the human brain, suggesting that neurogenesis may have important implications for human cognition. In support of that, impaired neurogenesis compromises hippocampal function and plays a role in cognitive deficits in Alzheimer's disease mouse models. We review current work suggesting that neuronal differentiation is defective in Alzheimer's disease, leading to dysfunction of the dentate gyrus. Additionally, alterations in critical signals regulating neurogenesis, such as presenilin-1, Notch 1, soluble amyloid precursor protein, CREB, and β-catenin underlie dysfunctional neurogenesis in Alzheimer's disease. Lastly, we discuss the detectability of neurogenesis in the live mouse and human brain, as well as the therapeutic implications of enhancing neurogenesis for the treatment of cognitive deficits and Alzheimer's disease. PMID:27199641

  5. Neural Progenitor Cell Transplantation Promotes Neuroprotection, Enhances Hippocampal Neurogenesis, and Improves Cognitive Outcomes after Traumatic Brain Injury

    PubMed Central

    Blaya, Meghan O.; Tsoulfas, Pantelis; Bramlett, Helen M.; Dietrich, W. Dalton

    2014-01-01

    Transplantation of neural progenitor cells (NPCs) may be a potential treatment strategy for traumatic brain injury (TBI) due to their intrinsic advantages, including the secretion of neurotrophins. Neurotrophins are critical for neuronal survival and repair, but their clinical use is limited. In this study, we hypothesized that pericontusional transplantation of NPCs genetically modified to secrete a synthetic, human multineurotrophin (MNTS1) would overcome some of the limitations of traditional neurotrophin therapy. MNTS1 is a multifunctional neurotrophin that binds all three tropomyosin-related kinase (Trk) receptors, recapitulating the prosurvival activity of 3 endogenous mature neurotrophins. NPCs obtained from rat fetuses at E15 were transduced with lentiviral vectors containing MNTS1 and GFP constructs (MNTS1-NPCs) or fluorescent constructs alone (control GFP-NPCs). Adult rats received fluid percussion-induced TBI or sham surgery. Animals were transplanted 1 week later with control GFP-NPCs, MNTS1-NPCs, or injected with saline (vehicle). At five weeks, animals were evaluated for hippocampal-dependent spatial memory. Six weeks post surgery, we observed significant survival and neuronal differentiation of MNTS1-NPCs and injury-activated tropism towards contused regions. NPCs displayed processes that extended into several remote structures, including the hippocampus and contralateral cortex. Both GFP- and MNTS1-NPCs conferred significant preservation of pericontusional host tissues and enhanced hippocampal neurogenesis. NPC transplantation improved spatial memory capacity on the Morris water maze (MWM) task. Transplant recipients exhibited escape latencies approximately half that of injured vehicle controls. While we observed greater transplant survival and neuronal differentiation of MNTS1-NPCs, our collective findings suggest that MNTS1 may be superfluous in terms of preserving the cytoarchitecture and rescuing behavioral deficits given the lack of significant

  6. Neural progenitor cell transplantation promotes neuroprotection, enhances hippocampal neurogenesis, and improves cognitive outcomes after traumatic brain injury.

    PubMed

    Blaya, Meghan O; Tsoulfas, Pantelis; Bramlett, Helen M; Dietrich, W Dalton

    2015-02-01

    Transplantation of neural progenitor cells (NPCs) may be a potential treatment strategy for traumatic brain injury (TBI) due to their intrinsic advantages, including the secretion of neurotrophins. Neurotrophins are critical for neuronal survival and repair, but their clinical use is limited. In this study, we hypothesized that pericontusional transplantation of NPCs genetically modified to secrete a synthetic, human multineurotrophin (MNTS1) would overcome some of the limitations of traditional neurotrophin therapy. MNTS1 is a multifunctional neurotrophin that binds all three tropomyosin-related kinase (Trk) receptors, recapitulating the prosurvival activity of 3 endogenous mature neurotrophins. NPCs obtained from rat fetuses at E15 were transduced with lentiviral vectors containing MNTS1 and GFP constructs (MNTS1-NPCs) or fluorescent constructs alone (control GFP-NPCs). Adult rats received fluid percussion-induced TBI or sham surgery. Animals were transplanted 1week later with control GFP-NPCs, MNTS1-NPCs, or injected with saline (vehicle). At five weeks, animals were evaluated for hippocampal-dependent spatial memory. Six weeks post-surgery, we observed significant survival and neuronal differentiation of MNTS1-NPCs and injury-activated tropism toward contused regions. NPCs displayed processes that extended into several remote structures, including the hippocampus and contralateral cortex. Both GFP- and MNTS1-NPCs conferred significant preservation of pericontusional host tissues and enhanced hippocampal neurogenesis. NPC transplantation improved spatial memory capacity on the Morris water maze (MWM) task. Transplant recipients exhibited escape latencies approximately half that of injured vehicle controls. While we observed greater transplant survival and neuronal differentiation of MNTS1-NPCs, our collective findings suggest that MNTS1 may be superfluous in terms of preserving the cytoarchitecture and rescuing behavioral deficits given the lack of significant

  7. Functional Integration of Adult-Born Hippocampal Neurons after Traumatic Brain Injury

    PubMed Central

    Villasana, Laura E.; Kim, Kristine N.

    2015-01-01

    Abstract Traumatic brain injury (TBI) increases hippocampal neurogenesis, which may contribute to cognitive recovery after injury. However, it is unknown whether TBI-induced adult-born neurons mature normally and functionally integrate into the hippocampal network. We assessed the generation, morphology, and synaptic integration of new hippocampal neurons after a controlled cortical impact (CCI) injury model of TBI. To label TBI-induced newborn neurons, we used 2-month-old POMC-EGFP mice, which transiently and specifically express EGFP in immature hippocampal neurons, and doublecortin-CreERT2 transgenic mice crossed with Rosa26-CAG-tdTomato reporter mice, to permanently pulse-label a cohort of adult-born hippocampal neurons. TBI increased the generation, outward migration, and dendritic complexity of neurons born during post-traumatic neurogenesis. Cells born after TBI had profound alterations in their dendritic structure, with increased dendritic branching proximal to the soma and widely splayed dendritic branches. These changes were apparent during early dendritic outgrowth and persisted as these cells matured. Whole-cell recordings from neurons generated during post-traumatic neurogenesis demonstrate that they are excitable and functionally integrate into the hippocampal circuit. However, despite their dramatic morphologic abnormalities, we found no differences in the rate of their electrophysiological maturation, or their overall degree of synaptic integration when compared to age-matched adult-born cells from sham mice. Our results suggest that cells born after TBI participate in information processing, and receive an apparently normal balance of excitatory and inhibitory inputs. However, TBI-induced changes in their anatomic localization and dendritic projection patterns could result in maladaptive network properties. PMID:26478908

  8. HIPPOCAMPAL ADULT NEUROGENESIS: ITS REGULATION AND POTENTIAL ROLE IN SPATIAL LEARNING AND MEMORY

    PubMed Central

    Lieberwirth, Claudia; Pan, Yongliang; Liu, Yan; Zhang, Zhibin; Wang, Zuoxin

    2016-01-01

    Adult neurogenesis, defined here as progenitor cell division generating functionally integrated neurons in the adult brain, occurs within the hippocampus of numerous mammalian species including humans. The present review details various endogenous (e.g., neurotransmitters) and environmental (e.g., physical exercise) factors that have been shown to influence hippocampal adult neurogenesis. In addition, the potential involvement of adult-generated neurons in naturally-occurring spatial learning behavior is discussed by summarizing the literature focusing on traditional animal models (e.g., rats and mice), non-traditional animal models (e.g., tree shrews), as well as natural populations (e.g., chickadees and Siberian chipmunk). PMID:27174001

  9. Adult Mammalian Neural Stem Cells and Neurogenesis: Five Decades Later

    PubMed Central

    Bond, Allison M.; Ming, Guo-li; Song, Hongjun

    2015-01-01

    Summary Adult somatic stem cells in various organs maintain homeostatic tissue regeneration and enhance plasticity. Since its initial discovery five decades ago, investigations of adult neurogenesis and neural stem cells have led to an established and expanding field that has significantly influenced many facets of neuroscience, developmental biology and regenerative medicine. Here we review recent progress and focus on questions related to adult mammalian neural stem cells that also apply to other somatic stem cells. We further discuss emerging topics that are guiding the field toward better understanding adult neural stem cells and ultimately applying these principles to improve human health. PMID:26431181

  10. Cardiorespiratory Fitness, Hippocampal Volume and Frequency of Forgetting in Older Adults

    PubMed Central

    Szabo, Amanda N.; McAuley, Edward; Erickson, Kirk I.; Voss, Michelle; Prakash, Ruchika S.; Mailey, Emily L.; Wójcicki, Thomas R.; White, Siobhan M.; Gothe, Neha; Olson, Erin A.; Kramer, Arthur F.

    2011-01-01

    Objective The purpose of this study was to extend our earlier work to determine the extent to which cardiorespiratory fitness is associated with the frequency of memory problems via its effects on the hippocampus and spatial working memory. We hypothesized that age, sex, education, body composition, and physical activity were direct determinants of fitness which, in turn, influenced frequency of forgetting indirectly through hippocampal volume and spatial working memory. Method We conducted assessments of hippocampal volume, spatial working memory, frequency of forgetting, BMI, physical activity, demographic characteristics, and cardiorespiratory fitness in 158 older adults (M age = 66.49). Path analyses within a covariance modeling framework were used to examine relationships among these constructs. Results Sex, age, BMI, and education were all significant determinants of cardiorespiratory fitness. The hypothesized path models testing the effects of fitness on frequency of forgetting through hippocampal volume and accuracy and speed of spatial working memory all fit the data well. Conclusions Our findings suggest that older adults with higher levels of fitness show greater preservation of hippocampal volume which, in turn, is associated with more accurate and faster spatial memory and fewer episodes of forgetting. Given the proportion of older adults reporting memory problems, it is necessary to determine whether improvements in fitness brought about by physical activity interventions can result in subsequent attenuation of memory problems or potentially improvements in memory. PMID:21500917

  11. Epigenetic (de)regulation of adult hippocampal neurogenesis: implications for depression

    PubMed Central

    2011-01-01

    Adult neurogenesis represents a dynamic level of modulation upon the neuroplastic properties of the mature nervous system, that is essential to the homeostatic brain function. The adult neurogenic process comprises several sequential steps, all of which subjected to an assortment of cell-intrinsic and neurogenic-niche complex regulatory mechanisms. Among these, epigenetic regulation is now emerging as a crucial regulator of several neurogenesis steps. In particular, the active regulation of hippocampal neurogenesis and its repercussions in global hippocampal function are of special interest for the biomedical field, since imbalances at this level have been strongly related to the precipitation of several neuropsychyatric disorders, such as depression. Indeed, growing evidence supports that the detrimental effects on adult hippocampal neurogenesis, that have been associated with depression, might be epigenetically-mediated. Therefore, understanding the epigenetic regulation of the neurogenic process may provide a link between neurogenesis imbalances and the deterioration of the behavioural and cognitive domains frequently affected in depression, thus contributing to unravel the complex pathophysiology of this disorder. Here, we outline some of the major epigenetic mechanisms contributing to the regulation of hippocampal neurogenesis and discuss several lines of evidence supporting their involvement on the development of imbalances in the neurogenic process, often correlated to behavioural and cognitive deficits commonly observed in major depressive disorder. PMID:22414227

  12. α2δ ligands act as positive modulators of adult hippocampal neurogenesis and prevent depression-like behavior induced by chronic restraint stress.

    PubMed

    Valente, Maria Maddalena; Bortolotto, Valeria; Cuccurazzu, Bruna; Ubezio, Federica; Meneghini, Vasco; Francese, Maria Teresa; Canonico, Pier Luigi; Grilli, Mariagrazia

    2012-08-01

    Although the role of adult hippocampal neurogenesis remains to be fully elucidated, several studies suggested that the process is involved in cognitive and emotional functions and is deregulated in various neuropsychiatric disorders, including major depression. Several psychoactive drugs, including antidepressants, can modulate adult neurogenesis. Here we show for the first time that the α2δ ligands gabapentin [1-(aminomethyl)cyclohexaneacetic acid] and pregabalin (PGB) [(S)-(+)-3-isobutyl-GABA or (S)-3-(aminomethyl)-5-methylhexanoic acid] can produce concentration-dependent increases in the numbers of newborn mature and immature neurons generated in vitro from adult hippocampal neural progenitor cells and, in parallel, a decrease in the number of undifferentiated precursor cells. These effects were confirmed in vivo, because significantly increased numbers of adult cell-generated neurons were observed in the hippocampal region of mice receiving prolonged treatment with PGB (10 mg/kg i.p. for 21 days), compared with vehicle-treated mice. We demonstrated that PGB administration prevented the appearance of depression-like behaviors induced by chronic restraint stress and, in parallel, promoted hippocampal neurogenesis in adult stressed mice. Finally, we provided data suggesting involvement of the α2δ1 subunit and the nuclear factor-κB signaling pathway in drug-mediated proneurogenic effects. The new pharmacological activities of α2δ ligands may help explain their therapeutic activity as supplemental therapy for major depression and depressive symptoms in post-traumatic stress disorder and generalized anxiety disorders. These data contribute to the identification of novel molecular pathways that may represent potential targets for pharmacological modulation in depression.

  13. Attractor neural networks storing multiple space representations: A model for hippocampal place fields

    NASA Astrophysics Data System (ADS)

    Battaglia, F. P.; Treves, A.

    1998-12-01

    A recurrent neural network model storing multiple spatial maps, or ``charts,'' is analyzed. A network of this type has been suggested as a model for the origin of place cells in the hippocampus of rodents. The extremely diluted and fully connected limits are studied, and the storage capacity and the information capacity are found. The important parameters determining the performance of the network are the sparsity of the spatial representations and the degree of connectivity, as found already for the storage of individual memory patterns in the general theory of autoassociative networks. Such results suggest a quantitative parallel between theories of hippocampal function in different animal species, such as primates (episodic memory) and rodents (memory for space).

  14. α-Tocopherol and Hippocampal Neural Plasticity in Physiological and Pathological Conditions

    PubMed Central

    Ambrogini, Patrizia; Betti, Michele; Galati, Claudia; Di Palma, Michael; Lattanzi, Davide; Savelli, David; Galli, Francesco; Cuppini, Riccardo; Minelli, Andrea

    2016-01-01

    Neuroplasticity is an “umbrella term” referring to the complex, multifaceted physiological processes that mediate the ongoing structural and functional modifications occurring, at various time- and size-scales, in the ever-changing immature and adult brain, and that represent the basis for fundamental neurocognitive behavioral functions; in addition, maladaptive neuroplasticity plays a role in the pathophysiology of neuropsychiatric dysfunctions. Experiential cues and several endogenous and exogenous factors can regulate neuroplasticity; among these, vitamin E, and in particular α-tocopherol (α-T), the isoform with highest bioactivity, exerts potent effects on many plasticity-related events in both the physiological and pathological brain. In this review, the role of vitamin E/α-T in regulating diverse aspects of neuroplasticity is analyzed and discussed, focusing on the hippocampus, a brain structure that remains highly plastic throughout the lifespan and is involved in cognitive functions. Vitamin E-mediated influences on hippocampal synaptic plasticity and related cognitive behavior, on post-natal development and adult hippocampal neurogenesis, as well as on cellular and molecular disruptions in kainate-induced temporal seizures are described. Besides underscoring the relevance of its antioxidant properties, non-antioxidant functions of vitamin E/α-T, mainly involving regulation of cell signaling molecules and their target proteins, have been highlighted to help interpret the possible mechanisms underlying the effects on neuroplasticity. PMID:27983697

  15. New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory?

    PubMed Central

    Deng, Wei; Aimone, James B.; Gage, Fred H.

    2010-01-01

    The integration of adult-born neurons into the circuitry of the adult hippocampus suggests an important role for adult hippocampal neurogenesis in learning and memory, but its specific function in these processes has remained elusive. In this article, we summarize recent progress in this area, including advances based on behavioural studies and insights provided by computational modelling. Increasingly, evidence suggests that newborn neurons might be involved in hippocampal functions that are particularly dependent on the dentate gyrus, such as pattern separation. Furthermore, newborn neurons at different maturation stages may make distinct contributions to learning and memory. In particular, computational studies suggest that, before newborn neurons are fully mature, they might function as a pattern integrator by introducing a degree of similarity to the encoding of events that occur closely in time. PMID:20354534

  16. Taxonomic Separation of Hippocampal Networks: Principal Cell Populations and Adult Neurogenesis

    PubMed Central

    van Dijk, R. Maarten; Huang, Shih-Hui; Slomianka, Lutz; Amrein, Irmgard

    2016-01-01

    While many differences in hippocampal anatomy have been described between species, it is typically not clear if they are specific to a particular species and related to functional requirements or if they are shared by species of larger taxonomic units. Without such information, it is difficult to infer how anatomical differences may impact on hippocampal function, because multiple taxonomic levels need to be considered to associate behavioral and anatomical changes. To provide information on anatomical changes within and across taxonomic ranks, we present a quantitative assessment of hippocampal principal cell populations in 20 species or strain groups, with emphasis on rodents, the taxonomic group that provides most animals used in laboratory research. Of special interest is the importance of adult hippocampal neurogenesis (AHN) in species-specific adaptations relative to other cell populations. Correspondence analysis of cell numbers shows that across taxonomic units, phylogenetically related species cluster together, sharing similar proportions of principal cell populations. CA3 and hilus are strong separators that place rodent species into a tight cluster based on their relatively large CA3 and small hilus while non-rodent species (including humans and non-human primates) are placed on the opposite side of the spectrum. Hilus and CA3 are also separators within rodents, with a very large CA3 and rather small hilar cell populations separating mole-rats from other rodents that, in turn, are separated from each other by smaller changes in the proportions of CA1 and granule cells. When adult neurogenesis is included, the relatively small populations of young neurons, proliferating cells and hilar neurons become main drivers of taxonomic separation within rodents. The observations provide challenges to the computational modeling of hippocampal function, suggest differences in the organization of hippocampal information streams in rodent and non-rodent species, and

  17. Memory function and hippocampal volumes in preterm born very-low-birth-weight (VLBW) young adults.

    PubMed

    Aanes, Synne; Bjuland, Knut Jørgen; Skranes, Jon; Løhaugen, Gro C C

    2015-01-15

    The hippocampi are regarded as core structures for learning and memory functions, which is important for daily functioning and educational achievements. Previous studies have linked reduction in hippocampal volume to working memory problems in very low birth weight (VLBW; ≤ 1500 g) children and reduced general cognitive ability in VLBW adolescents. However, the relationship between memory function and hippocampal volume has not been described in VLBW subjects reaching adulthood. The aim of the study was to investigate memory function and hippocampal volume in VLBW young adults, both in relation to perinatal risk factors and compared to term born controls, and to look for structure-function relationships. Using Wechsler Memory Scale-III and MRI, we included 42 non-disabled VLBW and 61 control individuals at age 19-20 years, and related our findings to perinatal risk factors in the VLBW-group. The VLBW young adults achieved lower scores on several subtests of the Wechsler Memory Scale-III, resulting in lower results in the immediate memory indices (visual and auditory), the working memory index, and in the visual delayed and general memory delayed indices, but not in the auditory delayed and auditory recognition delayed indices. The VLBW group had smaller absolute and relative hippocampal volumes than the controls. In the VLBW group inferior memory function, especially for the working memory index, was related to smaller hippocampal volume, and both correlated with lower birth weight and more days in the neonatal intensive care unit (NICU). Our results may indicate a structural-functional relationship in the VLBW group due to aberrant hippocampal development and functioning after preterm birth.

  18. Distinct stages of adult hippocampal neurogenesis are regulated by running and the running environment.

    PubMed

    Bednarczyk, Matthew R; Hacker, Lindsay C; Fortin-Nunez, Stéphanie; Aumont, Anne; Bergeron, Raynald; Fernandes, Karl J L

    2011-12-01

    Hippocampal neurogenesis continues into adulthood in mammalian vertebrates, and in experimental rodent models it is powerfully stimulated by exposure to a voluntary running wheel. In this study, we demonstrate that exposure to a running wheel environment, in the absence of running, is sufficient to regulate specific aspects of hippocampal neurogenesis. Adult mice were provided with standard housing, housing enriched with a running wheel or housing enriched with a locked wheel (i.e., an environment comparable to that of running animals, without the possibility of engaging in running). We found that mice in the running wheel and locked wheel groups exhibited equivalent increases in proliferation within the neurogenic niche of the dentate gyrus; this included comparable increases in the proliferation of radial glia-like stem cells and the number of proliferating neuroblasts. However, only running animals displayed increased numbers of postmitotic neuroblasts and mature neurons. These results demonstrate that the running wheel environment itself is sufficient for promoting proliferation of early lineage hippocampal precursors, while running per se enables newly generated neuroblasts to survive and mature into functional hippocampal neurons. Thus, both running-independent and running-dependent stimuli are integral to running wheel-induced hippocampal neurogenesis.

  19. Long-Term Fate Mapping Using Conditional Lentiviral Vectors Reveals a Continuous Contribution of Radial Glia-Like Cells to Adult Hippocampal Neurogenesis in Mice

    PubMed Central

    Aelvoet, Sarah-Ann; Pascual-Brazo, Jesus; Libbrecht, Sarah; Reumers, Veerle; Gijsbers, Rik; Van den Haute, Chris; Baekelandt, Veerle

    2015-01-01

    Newborn neurons are generated throughout life in two neurogenic regions, the subventricular zone and the hippocampal dentate gyrus. Stimulation of adult neurogenesis is considered as an attractive endogenous repair mechanism to treat different neurological disorders. Although tremendous progress has been made in our understanding of adult hippocampal neurogenesis, important questions remain unanswered, regarding the identity and the behavior of neural stem cells in the dentate gyrus. We previously showed that conditional Cre-Flex lentiviral vectors can be used to label neural stem cells in the subventricular zone and to track the migration of their progeny with non-invasive bioluminescence imaging. Here, we applied these Cre-Flex lentiviral vectors to study neurogenesis in the dentate gyrus with bioluminescence imaging and histological techniques. Stereotactic injection of the Cre-Flex vectors into the dentate gyrus of transgenic Nestin-Cre mice resulted in specific labeling of the nestin-positive neural stem cells. The labeled cell population could be detected with bioluminescence imaging until 9 months post injection, but no significant increase in the number of labeled cells over time was observed with this imaging technique. Nevertheless, the specific labeling of the nestin-positive neural stem cells, combined with histological analysis at different time points, allowed detailed analysis of their neurogenic potential. This long-term fate mapping revealed that a stable pool of labeled nestin-positive neural stem cells continuously contributes to the generation of newborn neurons in the mouse brain until 9 months post injection. In conclusion, the Cre-Flex technology is a valuable tool to address remaining questions regarding neural stem cell identity and behavior in the dentate gyrus. PMID:26600383

  20. Trim9 Deletion Alters the Morphogenesis of Developing and Adult-Born Hippocampal Neurons and Impairs Spatial Learning and Memory

    PubMed Central

    Winkle, Cortney C.; Olsen, Reid H. J.; Kim, Hyojin; Moy, Sheryl S.

    2016-01-01

    During hippocampal development, newly born neurons migrate to appropriate destinations, extend axons, and ramify dendritic arbors to establish functional circuitry. These developmental stages are recapitulated in the dentate gyrus of the adult hippocampus, where neurons are continuously generated and subsequently incorporate into existing, local circuitry. Here we demonstrate that the E3 ubiquitin ligase TRIM9 regulates these developmental stages in embryonic and adult-born mouse hippocampal neurons in vitro and in vivo. Embryonic hippocampal and adult-born dentate granule neurons lacking Trim9 exhibit several morphological defects, including excessive dendritic arborization. Although gross anatomy of the hippocampus was not detectably altered by Trim9 deletion, a significant number of Trim9−/− adult-born dentate neurons localized inappropriately. These morphological and localization defects of hippocampal neurons in Trim9−/− mice were associated with extreme deficits in spatial learning and memory, suggesting that TRIM9-directed neuronal morphogenesis may be involved in hippocampal-dependent behaviors. SIGNIFICANCE STATEMENT Appropriate generation and incorporation of adult-born neurons in the dentate gyrus are critical for spatial learning and memory and other hippocampal functions. Here we identify the brain-enriched E3 ubiquitin ligase TRIM9 as a novel regulator of embryonic and adult hippocampal neuron shape acquisition and hippocampal-dependent behaviors. Genetic deletion of Trim9 elevated dendritic arborization of hippocampal neurons in vitro and in vivo. Adult-born dentate granule cells lacking Trim9 similarly exhibited excessive dendritic arborization and mislocalization of cell bodies in vivo. These cellular defects were associated with severe deficits in spatial learning and memory. PMID:27147649

  1. Adult Hippocampal Neurogenesis in the Pathogenesis of Addiction and Dual Diagnosis Disorders

    PubMed Central

    Chambers, R. Andrew

    2013-01-01

    Background As knowledge deepens about how new neurons are born, differentiate, and wire into the adult mammalian brain, growing evidence depicts hippocampal neurogenesis as a special form of neuroplasticity that may be impaired across psychiatric disorders. This review provides an integrated-evidence based framework describing a neurogenic basis for addictions and addiction vulnerability in mental illness. Methods Basic studies conducted over the last decade examining the effects of addictive drugs on adult neurogenesis and the impact of neurogenic activity on addictive behavior were compiled and integrated with relevant neurocomputational and human studies. Results While suppression of hippocampal neurogenic proliferation appears to be a universal property of addictive drugs, the pathophysiology of addictions involves neuroadaptative processes within frontal-cortical-striatal motivation circuits that the neurogenic hippocampus regulates via direct projections. States of suppressed neurogenic activity may simultaneously underlie psychiatric and cognitive symptoms, but also confer or signify hippocampal dysfunction that heightens addiction vulnerability in mental illness as a basis for dual diagnosis disorders. Conclusions Research on pharmacological, behavioral and experiential strategies that enhance adaptive regulation of hippocampal neurogenesis holds potential in advancing preventative and integrative treatment strategies for addictions and dual diagnosis disorders. PMID:23279925

  2. Basolateral amygdala regulation of adult hippocampal neurogenesis and fear-related activation of newborn neurons

    PubMed Central

    Kirby, Elizabeth D.; Friedman, Aaron R.; Covarrubias, David; Ying, Carl; Sun, Wayne G.; Goosens, Ki A.; Sapolsky, Robert M.; Kaufer, Daniela

    2014-01-01

    Impaired regulation of emotional memory is a feature of several affective disorders, including depression, anxiety and post-traumatic stress disorder. Such regulation occurs, in part, by interactions between the hippocampus and the basolateral amygdala (BLA). Recent studies have indicated that within the adult hippocampus, newborn neurons may contribute to support of emotional memory, and that regulation of hippocampal neurogenesis is implicated in depressive disorders. How emotional information impacts newborn neurons in adults is not clear. Given the role of the BLA in hippocampus-dependent emotional memory, we investigated whether hippocampal neurogenesis was sensitive to emotional stimuli from the BLA. We show that BLA lesions suppress adult neurogenesis, while lesions of the central nucleus of the amygdala do not. Similarly, we show that reducing BLA activity through viral vector-mediated overexpression of an outwardly rectifying potassium channel suppresses neurogenesis. We also show that BLA lesions prevent selective activation of immature newborn neurons in response to a fear conditioning task. These results demonstrate that BLA activity regulates adult hippocampal neurogenesis and the fear context-specific activation of newborn neurons. Together, these findings denote functional implications for proliferation and recruitment of new neurons into emotional memory circuits. PMID:21670733

  3. MK-801 (Dizocilpine) Regulates Multiple Steps of Adult Hippocampal Neurogenesis and Alters Psychological Symptoms via Wnt/β-Catenin Signaling in Parkinsonian Rats.

    PubMed

    Singh, Sonu; Mishra, Akanksha; Srivastava, Neha; Shukla, Shubha

    2017-03-15

    Adult hippocampal neurogenesis is directly involved in regulation of stress, anxiety, and depression that are commonly observed nonmotor symptoms in Parkinson's disease (PD). These symptoms do not respond to pharmacological dopamine replacement therapy. Excitotoxic damage to neuronal cells by N-methyl-d-aspartate (NMDA) receptor activation is also a major contributing factor in PD development, but whether it regulates hippocampal neurogenesis and nonmotor symptoms in PD is yet unexplored. Herein, for the first time, we studied the effect of MK-801, an NMDA receptor antagonist, on adult hippocampal neurogenesis and behavioral functions in 6-OHDA (6-hydroxydopamine) induced rat model of PD. MK-801 treatment (0.2 mg/kg, ip) increased neural stem cell (NSC) proliferation, self-renewal capacity, long-term survival, and neuronal differentiation in the hippocampus of rat model of PD. MK-801 potentially enhanced long-term survival, improved dendritic arborization of immature neurons, and reduced 6-OHDA induced neurodegeneration via maintaining the NSC pool in hippocampus, leading to decreased anxiety and depression-like phenotypes in the PD model. MK-801 inhibited glycogen synthase kinase-3β (GSK-3β) through up-regulation of Wnt-3a, which resulted in the activation of Wnt/β-catenin signaling leading to enhanced hippocampal neurogenesis in PD model. Additionally, MK-801 treatment protected the dopaminergic (DAergic) neurons in the nigrostriatal pathway and improved motor functions by increasing the expression of Nurr-1 and Pitx-3 in the PD model. Therefore, MK-801 treatment serves as a valuable tool to enhance hippocampal neurogenesis in PD, but further studies are needed to revisit the role of MK-801 in the neurodegenerative disorder before proposing a potential therapeutic candidate.

  4. Accumulated quiescent neural stem cells in adult hippocampus of the mouse model for the MECP2 duplication syndrome

    PubMed Central

    Chen, Zhifang; Li, Xiao; Zhou, Jingjing; Yuan, Bo; Yu, Bin; Tong, Dali; Cheng, Cheng; Shao, Yinqi; Xia, Shengnan; Zhang, Ran; Lyu, Jingwen; Yu, Xiuya; Dong, Chen; Zhou, Wen-Hao; Qiu, Zilong

    2017-01-01

    Duplications of Methyl CpG binding protein 2 (MECP2) -containing segments lead to the MECP2 duplication syndrome, in which severe autistic symptoms were identified. Whether adult neurogenesis may play a role in pathogenesis of autism and the role of MECP2 on state determination of adult neural stem cells (NSCs) remain largely unclear. Using a MECP2 transgenic (TG) mouse model for the MECP2 duplication syndrome, we found that adult hippocampal quiescent NSCs were significantly accumulated in TG mice comparing to wild type (WT) mice, the neural progenitor cells (NPCs) were reduced and the neuroblasts were increased in adult hippocampi of MECP2 TG mice. Interestingly, we found that parvalbumin (PV) positive interneurons were significantly decreased in MECP2 TG mice, which were critical for determining fates of adult hippocampal NSCs between the quiescence and activation. In summary, we found that MeCP2 plays a critical role in regulating fate determination of adult NSCs. These evidences further suggest that abnormal development of NSCs may play a role in the pathogenesis of the MECP2 duplication syndrome. PMID:28139724

  5. Anisotropically organized three-dimensional culture platform for reconstruction of a hippocampal neural network

    PubMed Central

    Kim, So Hyun; Im, Sun-Kyoung; Oh, Soo-Jin; Jeong, Sohyeon; Yoon, Eui-Sung; Lee, C. Justin; Choi, Nakwon; Hur, Eun-Mi

    2017-01-01

    In native tissues, cellular and acellular components are anisotropically organized and often aligned in specific directions, providing structural and mechanical properties for actuating biological functions. Thus, engineering alignment not only allows for emulation of native tissue structures but might also enable implementation of specific functionalities. However, achieving desired alignment is challenging, especially in three-dimensional constructs. By exploiting the elastomeric property of polydimethylsiloxane and fibrillogenesis kinetics of collagen, here we introduce a simple yet effective method to assemble and align fibrous structures in a multi-modular three-dimensional conglomerate. Applying this method, we have reconstructed the CA3–CA1 hippocampal neural circuit three-dimensionally in a monolithic gel, in which CA3 neurons extend parallel axons to and synapse with CA1 neurons. Furthermore, we show that alignment of the fibrous scaffold facilitates the establishment of functional connectivity. This method can be applied for reconstructing other neural circuits or tissue units where anisotropic organization in a multi-modular structure is desired. PMID:28146148

  6. Epigallocatechin-3-gallate rescues LPS-impaired adult hippocampal neurogenesis through suppressing the TLR4-NF-κB signaling pathway in mice

    PubMed Central

    Seong, Kyung-Joo; Lee, Hyun-Gwan; Kook, Min Suk; Ko, Hyun-Mi

    2016-01-01

    Adult hippocampal dentate granule neurons are generated from neural stem cells (NSCs) in the mammalian brain, and the fate specification of adult NSCs is precisely controlled by the local niches and environment, such as the subventricular zone (SVZ), dentate gyrus (DG), and Toll-like receptors (TLRs). Epigallocatechin-3-gallate (EGCG) is the main polyphenolic flavonoid in green tea that has neuroprotective activities, but there is no clear understanding of the role of EGCG in adult neurogenesis in the DG after neuroinflammation. Here, we investigate the effect and the mechanism of EGCG on adult neurogenesis impaired by lipopolysaccharides (LPS). LPS-induced neuroinflammation inhibited adult neurogenesis by suppressing the proliferation and differentiation of neural stem cells in the DG, which was indicated by the decreased number of Bromodeoxyuridine (BrdU)-, Doublecortin (DCX)- and Neuronal Nuclei (NeuN)-positive cells. In addition, microglia were recruited with activatingTLR4-NF-κB signaling in the adult hippocampus by LPS injection. Treating LPS-injured mice with EGCG restored the proliferation and differentiation of NSCs in the DG, which were decreased by LPS, and EGCG treatment also ameliorated the apoptosis of NSCs. Moreover, pro-inflammatory cytokine production induced by LPS was attenuated by EGCG treatment through modulating the TLR4-NF-κB pathway. These results illustrate that EGCG has a beneficial effect on impaired adult neurogenesis caused by LPSinduced neuroinflammation, and it may be applicable as a therapeutic agent against neurodegenerative disorders caused by inflammation. PMID:26807022

  7. The ventral hippocampus is the embryonic origin for adult neural stem cells in the dentate gyrus.

    PubMed

    Li, Guangnan; Fang, Li; Fernández, Gloria; Pleasure, Samuel J

    2013-05-22

    Adult neurogenesis represents a unique form of plasticity in the dentate gyrus requiring the presence of long-lived neural stem cells (LL-NSCs). However, the embryonic origin of these LL-NSCs remains unclear. The prevailing model assumes that the dentate neuroepithelium throughout the longitudinal axis of the hippocampus generates both the LL-NSCs and embryonically produced granule neurons. Here we show that the NSCs initially originate from the ventral hippocampus during late gestation and then relocate into the dorsal hippocampus. The descendants of these cells are the source for the LL-NSCs in the subgranular zone (SGZ). Furthermore, we show that the origin of these cells and their maintenance in the dentate are controlled by distinct sources of Sonic Hedgehog (Shh). The revelation of the complexity of both the embryonic origin of hippocampal LL-NSCs and the sources of Shh has important implications for the functions of LL-NSCs in the adult hippocampus.

  8. Prolonged cultivation of hippocampal neural precursor cells shifts their differentiation potential and selects for aneuploid cells.

    PubMed

    Nguyen, The Duy; Widera, Darius; Greiner, Johannes; Müller, Janine; Martin, Ina; Slotta, Carsten; Hauser, Stefan; Kaltschmidt, Christian; Kaltschmidt, Barbara

    2013-12-01

    Neural precursor cells (NPCs) are lineage-restricted neural stem cells with limited self-renewal, giving rise to a broad range of neural cell types such as neurons, astrocytes, and oligodendrocytes. Despite this developmental potential, the differentiation capacity of NPCs has been controversially discussed concerning the trespassing lineage boundaries, for instance resulting in hematopoietic competence. Assessing their in vitro plasticity, we isolated nestin+/Sox2+, NPCs from the adult murine hippocampus. In vitro-expanded adult NPCs were able to form neurospheres, self-renew, and differentiate into neuronal, astrocytic, and oligodendrocytic cells. Although NPCs cultivated in early passage efficiently gave rise to neuronal cells in a directed differentiation assay, extensively cultivated NPCs revealed reduced potential for ectodermal differentiation. We further observed successful differentiation of long-term cultured NPCs into osteogenic and adipogenic cell types, suggesting that NPCs underwent a fate switch during culture. NPCs cultivated for more than 12 passages were aneuploid (abnormal chromosome numbers such as 70 chromosomes). Furthermore, they showed growth factor-independent proliferation, a hallmark of tumorigenic transformation. In conclusion, our findings substantiate the lineage restriction of NPCs from adult mammalian hippocampus. Prolonged cultivation results, however, in enhanced differentiation potential, which may be attributed to transformation events leading to aneuploid cells.

  9. Anti-Nogo-A Immunotherapy Does Not Alter Hippocampal Neurogenesis after Stroke in Adult Rats

    PubMed Central

    Shepherd, Daniel J.; Tsai, Shih-Yen; O'Brien, Timothy E.; Farrer, Robert G.; Kartje, Gwendolyn L.

    2016-01-01

    Ischemic stroke is a leading cause of adult disability, including cognitive impairment. Our laboratory has previously shown that treatment with function-blocking antibodies against the neurite growth inhibitory protein Nogo-A promotes functional recovery after stroke in adult and aged rats, including enhancing spatial memory performance, for which the hippocampus is critically important. Since spatial memory has been linked to hippocampal neurogenesis, we investigated whether anti-Nogo-A treatment increases hippocampal neurogenesis after stroke. Adult rats were subject to permanent middle cerebral artery occlusion followed 1 week later by 2 weeks of antibody treatment. Cellular proliferation in the dentate gyrus was quantified at the end of treatment, and the number of newborn neurons was determined at 8 weeks post-stroke. Treatment with both anti-Nogo-A and control antibodies stimulated the accumulation of new microglia/macrophages in the dentate granule cell layer, but neither treatment increased cellular proliferation or the number of newborn neurons above stroke-only levels. These results suggest that anti-Nogo-A immunotherapy does not increase post-stroke hippocampal neurogenesis. PMID:27803646

  10. Premature aging of the hippocampal neurogenic niche in adult Bmal1‐ deficient mice

    PubMed Central

    Ali, Amira A. H.; Schwarz‐Herzke, Beryl; Stahr, Anna; Prozorovski, Timour; Aktas, Orhan; von Gall, Charlotte

    2015-01-01

    Hippocampal neurogenesis undergoes dramatic age‐related changes. Mice with targeted deletion of the clock gene Bmal1 (Bmal1‐/‐) show disrupted regulation of reactive oxygen species homeostasis, accelerated aging, neurodegeneration and cognitive deficits. As proliferation of neuronal progenitor/precursor cells (NPCs) is enhanced in young Bmal1‐/‐ mice, we tested the hypothesis that this results in premature aging of hippocampal neurogenic niche in adult Bmal1‐/‐ mice as compared to wildtype littermates. We found significantly reduced pool of hippocampal NPCs, scattered distribution, enhanced survival of NPCs and an increased differentiation of NPCs into the astroglial lineage at the expense of the neuronal lineage. Immunoreaction of the redox sensitive histone deacetylase Sirtuine 1, peroxisomal membrane protein at 70kDa and expression of the cell cycle inhibitor p21 Waf1/CIP1 were increased in adult Bmal1‐/‐ mice. In conclusion, genetic disruption of the molecular clockwork leads to accelerated age‐dependent decline in adult neurogenesis presumably as a consequence of oxidative stress. PMID:26142744

  11. Premature aging of the hippocampal neurogenic niche in adult Bmal1-deficient mice.

    PubMed

    Ali, Amira A H; Schwarz-Herzke, Beryl; Stahr, Anna; Prozorovski, Timour; Aktas, Orhan; von Gall, Charlotte

    2015-06-01

    Hippocampal neurogenesis undergoes dramatic age-related changes. Mice with targeted deletion of the clock geneBmal1 (Bmal1(-/-)) show disrupted regulation of reactive oxygen species homeostasis, accelerated aging, neurodegeneration and cognitive deficits. As proliferation of neuronal progenitor/precursor cells (NPCs) is enhanced in young Bmal1(-/-) mice, we tested the hypothesis that this results in premature aging of hippocampal neurogenic niche in adult Bmal1(-/-) mice as compared to wildtype littermates. We found significantly reduced pool of hippocampal NPCs, scattered distribution, enhanced survival of NPCs and an increased differentiation of NPCs into the astroglial lineage at the expense of the neuronal lineage. Immunoreaction of the redox sensitive histone deacetylase Sirtuine 1, peroxisomal membrane protein at 70 kDa and expression of the cell cycle inhibitor p21(Waf1/CIP1) were increased in adult Bmal1(-/-) mice. In conclusion, genetic disruption of the molecular clockwork leads to accelerated age-dependent decline in adult neurogenesis presumably as a consequence of oxidative stress.

  12. Physical exercise increases adult hippocampal neurogenesis in male rats provided it is aerobic and sustained

    PubMed Central

    Lensu, Sanna; Ahtiainen, Juha P.; Johansson, Petra P.; Koch, Lauren G.; Britton, Steven L.; Kainulainen, Heikki

    2016-01-01

    Key points Aerobic exercise, such as running, enhances adult hippocampal neurogenesis (AHN) in rodents.Little is known about the effects of high‐intensity interval training (HIT) or of purely anaerobic resistance training on AHN.Here, compared with a sedentary lifestyle, we report a very modest effect of HIT and no effect of resistance training on AHN in adult male rats.We found the most AHN in rats that were selectively bred for an innately high response to aerobic exercise that also run voluntarily and increase maximal running capacity.Our results confirm that sustained aerobic exercise is key in improving AHN. Abstract Aerobic exercise, such as running, has positive effects on brain structure and function, such as adult hippocampal neurogenesis (AHN) and learning. Whether high‐intensity interval training (HIT), referring to alternating short bouts of very intense anaerobic exercise with recovery periods, or anaerobic resistance training (RT) has similar effects on AHN is unclear. In addition, individual genetic variation in the overall response to physical exercise is likely to play a part in the effects of exercise on AHN but is less well studied. Recently, we developed polygenic rat models that gain differentially for running capacity in response to aerobic treadmill training. Here, we subjected these low‐response trainer (LRT) and high‐response trainer (HRT) adult male rats to various forms of physical exercise for 6–8 weeks and examined the effects on AHN. Compared with sedentary animals, the highest number of doublecortin‐positive hippocampal cells was observed in HRT rats that ran voluntarily on a running wheel, whereas HIT on the treadmill had a smaller, statistically non‐significant effect on AHN. Adult hippocampal neurogenesis was elevated in both LRT and HRT rats that underwent endurance training on a treadmill compared with those that performed RT by climbing a vertical ladder with weights, despite their significant gain in strength

  13. Young adult born neurons enhance hippocampal dependent performance via influences on bilateral networks

    PubMed Central

    Zhuo, Jia-Min; Tseng, Hua-an; Desai, Mitul; Bucklin, Mark E; Mohammed, Ali I; Robinson, Nick TM; Boyden, Edward S; Rangel, Lara M; Jasanoff, Alan P; Gritton, Howard J; Han, Xue

    2016-01-01

    Adult neurogenesis supports performance in many hippocampal dependent tasks. Considering the small number of adult-born neurons generated at any given time, it is surprising that this sparse population of cells can substantially influence behavior. Recent studies have demonstrated that heightened excitability and plasticity may be critical for the contribution of young adult-born cells for certain tasks. What is not well understood is how these unique biophysical and synaptic properties may translate to networks that support behavioral function. Here we employed a location discrimination task in mice while using optogenetics to transiently silence adult-born neurons at different ages. We discovered that adult-born neurons promote location discrimination during early stages of development but only if they undergo maturation during task acquisition. Silencing of young adult-born neurons also produced changes extending to the contralateral hippocampus, detectable by both electrophysiology and fMRI measurements, suggesting young neurons may modulate location discrimination through influences on bilateral hippocampal networks. DOI: http://dx.doi.org/10.7554/eLife.22429.001 PMID:27914197

  14. Effects of chronic exercise and treatment with the antipsychotic drug olanzapine on hippocampal volume in adult female rats.

    PubMed

    Barr, A M; Wu, C H; Wong, C; Hercher, C; Töpfer, E; Boyda, H N; Procyshyn, R M; Honer, W G; Beasley, C L

    2013-01-01

    Numerous studies have reported that the hippocampus in schizophrenia patients is reduced in volume compared to the normal population. Antipsychotic medications have had mixed benefits in maintaining hippocampal volume or reversing volume loss. Recent evidence indicates that routine aerobic exercise represents a promising intervention for reversing hippocampal loss and cognitive deficits. In the present study, we measured the effects of chronic treatment with olanzapine and daily exercise on the hippocampal volumes of rats. Adult female rats were treated during the week with either olanzapine (10mg/kg) or vehicle for 9 consecutive weeks. Subgroups of animals were provided access to exercise running wheels for 1 or 3h per day during the same period, or were sedentary. Metabolic indices, including glucose tolerance, were measured on a weekly basis. At the conclusion of the study, brains were perfused and hippocampal sections were Nissl stained. Total hippocampal volume was measured using the Cavalieri estimator. Treatment with olanzapine caused a significant decrease in hippocampal volume in sedentary rats. However, exercise was able to reverse most of this volume loss. The hippocampal sub-regions of the dentate gyrus and CA1 were most strongly affected by olanzapine and exercise. Of interest, there was a strong and highly significant negative correlation between glucose intolerance and hippocampal volume, whereby greater glucose intolerance was associated with a smaller hippocampal volume. These findings indicate that exercise may have beneficial effects on the hippocampus when antipsychotic medication can contribute to changes in volume.

  15. Stress-induced suppression of hippocampal neurogenesis in adult male rats is altered by prenatal ethanol exposure

    PubMed Central

    SLIWOWSKA, J. H.; BARKER, J. M.; BARHA, C. K.; LAN, N.; WEINBERG, J.; GALEA, L. A. M.

    2016-01-01

    In adulthood, both alcohol (ethanol) and stress are known to suppress hippocampal neurogenesis in male rats. Similarly, most studies report that prenatal alcohol exposure (PAE) reduces cell proliferation and/or cell survival in the hippocampus of adult males. Furthermore, PAE is known to have marked effects on behavioral and hypothalamic–pituitary–adrenal (HPA) responsiveness to stressors. However, no studies have examined the modulation of adult hippocampal neurogenesis by stress in PAE animals. We hypothesized that, in accordance with previous data, PAE would suppress basal levels of adult hippocampal neurogenesis, and further that stress acting on a sensitized HPA axis would have greater adverse effects on adult hippocampal neurogenesis in PAE than in control rats. Adult male offspring from PAE, pair-fed (PF) control, and ad libitum-fed control (C) groups were subjected to restraint stress (9 days, 1 h/day) or left undisturbed. Rats were then injected with bromodeoxyuridine (BrdU) on day 10, perfused 24 h (proliferation) or 3 weeks (survival) later, and brains processed for BrdU immunohistochemistry. We found that (1) under non-stressed conditions, PAE rats had a small but statistically significant suppressive effect on levels of hippocampal neurogenesis and (2) unexpectedly, repeated restraint stress significantly reduced neurogenesis in C and PF, but not PAE rats. We speculate that the failure of PAE males to mount an appropriate (i.e. suppressive) neurogenic response to stressors, implies reduced plasticity and adaptability or resilience, which could impact negatively on hippocampal structure and function. PMID:20536332

  16. Developmental effects of wheel running on hippocampal glutamate receptor expression in young and mature adult rats.

    PubMed

    Staples, M C; Somkuwar, S S; Mandyam, C D

    2015-10-01

    Recent evidence suggests that the behavioral benefits associated with voluntary wheel running in rodents may be due to modulation of glutamatergic transmission in the hippocampus, a brain region implicated in learning and memory. However, the expression of the glutamatergic ionotropic N-methyl-d-aspartate receptor (GluN) in the hippocampus in response to chronic sustained voluntary wheel running has not yet been investigated. Further, the developmental effects during young and mature adulthood on wheel running output and GluN expression in hippocampal subregions has not been determined, and therefore is the main focus of this investigation. Eight-week-old and 16-week-old male Wistar rats were housed in home cages with free access to running wheels and running output was monitored for 4weeks. Wheel access was terminated and tissues from the dorsal and ventral hippocampi were processed for Western blot analysis of GluN subunit expression. Young adult runners demonstrated an escalation in running output but this behavior was not evident in mature adult runners. In parallel, young adult runners demonstrated a significant increase in total GluN (1 and 2A) subunit expression in the dorsal hippocampus (DH), and an opposing effect in the ventral hippocampus (VH) compared to age-matched sedentary controls; these changes in total protein expression were not associated with significant alterations in the phosphorylation of the GluN subunits. In contrast, mature adult runners demonstrated a reduction in total GluN2A expression in the DH, without producing alterations in the VH compared to age-matched sedentary controls. In conclusion, differential running activity-mediated modulation of GluN subunit expression in the hippocampal subregions was revealed to be associated with developmental effects on running activity, which may contribute to altered hippocampal synaptic activity and behavioral outcomes in young and mature adult subjects.

  17. Mathematical modelling of adult hippocampal neurogenesis: effects of altered stem cell dynamics on cell counts and bromodeoxyuridine-labelled cells

    PubMed Central

    Ziebell, Frederik; Martin-Villalba, Ana; Marciniak-Czochra, Anna

    2014-01-01

    In the adult hippocampus, neurogenesis—the process of generating mature granule cells from adult neural stem cells—occurs throughout the entire lifetime. In order to investigate the involved regulatory mechanisms, knockout (KO) experiments, which modify the dynamic behaviour of this process, were conducted in the past. Evaluating these KOs is a non-trivial task owing to the complicated nature of the hippocampal neurogenic niche. In this study, we model neurogenesis as a multicompartmental system of ordinary differential equations based on experimental data. To analyse the results of KO experiments, we investigate how changes of cell properties, reflected by model parameters, influence the dynamics of cell counts and of the experimentally observed counts of cells labelled by the cell division marker bromodeoxyuridine (BrdU). We find that changing cell proliferation rates or the fraction of self-renewal, reflecting the balance between symmetric and asymmetric cell divisions, may result in multiple time phases in the response of the system, such as an initial increase in cell counts followed by a decrease. Furthermore, these phases may be qualitatively different in cells at different differentiation stages and even between mitotically labelled cells and all cells existing in the system. PMID:24598209

  18. Effect of voluntary running on adult hippocampal neurogenesis in cholinergic lesioned mice

    PubMed Central

    Ho, New Fei; Han, Siew Ping; Dawe, Gavin S

    2009-01-01

    Background Cholinergic neuronal dysfunction of the basal forebrain is observed in patients with Alzheimer's disease and dementia, and has been linked to decreased neurogenesis in the hippocampus, a region involved in learning and memory. Running is a robust inducer of adult hippocampal neurogenesis. This study aims to address the effect of running on hippocampal neurogenesis in lesioned mice, where septohippocampal cholinergic neurones have been selectively eliminated in the medial septum and diagonal band of Broca of the basal forebrain by infusion of mu-p75-saporin immunotoxin. Results Running increased the number of newborn cells in the dentate gyrus of the hippocampus in cholinergic denervated mice compared to non-lesioned mice 24 hours after injection of bromodeoxyuridine (BrdU). Although similar levels of surviving cells were present in cholinergic depleted animals and their respective controls four weeks after injection of BrdU, the majority of progenitors that proliferate in response to the initial period of running were not able to survive beyond one month without cholinergic input. Despite this, the running-induced increase in the number of surviving neurones was not affected by cholinergic depletion. Conclusion The lesion paradigm used here models aspects of the cholinergic deficits associated with Alzheimer's Disease and aging. We showed that running still increased the number of newborn cells in the adult hippocampal dentate gyrus in this model of neurodegenerative disease. PMID:19500352

  19. Exercise Can Rescue Recognition Memory Impairment in a Model with Reduced Adult Hippocampal Neurogenesis

    PubMed Central

    Lafenêtre, Pauline; Leske, Oliver; Ma-Högemeie, Zhanlu; Haghikia, Aiden; Bichler, Zoe; Wahle, Petra; Heumann, Rolf

    2009-01-01

    Running is a potent stimulator of cell proliferation in the adult dentate gyrus and these newly generated hippocampal neurons seem to be implicated in memory functions. Here we have used a mouse model expressing activated Ras under the direction of the neuronal Synapsin I promoter (named synRas mice). These mice develop down-regulated proliferation of adult hippocampal precursor cells and show decreased short-term recognition memory performances. Voluntary physical activity reversed the genetically blocked generation of hippocampal proliferating cells and enhanced the dendritic arborisation of the resulting doublecortin newly generated neurons. Moreover, running improved novelty recognition in both wild type and synRas littermates, compensating their memory deficits. Brain-derived neurotrophic factor (BDNF) has been proposed to be a potential mediator of physical exercise acting in the hippocampus on dentate neurons and their precursors. This was confirmed here by the identification of doublecortin-immunoreactive cells expressing tyrosine receptor kinase B BDNF receptor. While no difference in BDNF levels were detected in basal conditions between the synRas mice and their wild type littermates, running was associated with enhanced BDNF expression levels. Thus increased BDNF signalling is a candidate mechanism to explain the observed effects of running. Our studies demonstrate that voluntary physical activity has a robust beneficial effect even in mice with genetically restricted neurogenesis and cognition. PMID:20204139

  20. Impact of neonatal anoxia on adult rat hippocampal volume, neurogenesis and behavior.

    PubMed

    Takada, Silvia Honda; Motta-Teixeira, Lívia Clemente; Machado-Nils, Aline Vilar; Lee, Vitor Yonamine; Sampaio, Carlos Alberto; Polli, Roberson Saraiva; Malheiros, Jackeline Moraes; Takase, Luiz Fernando; Kihara, Alexandre Hiroaki; Covolan, Luciene; Xavier, Gilberto Fernando; Nogueira, Maria Inês

    2016-01-01

    Neonates that suffer oxygen deprivation during birth can have long lasting cognitive deficits, such as memory and learning impairments. Hippocampus, one of the main structures that participate in memory and learning processes, is a plastic and dynamic structure that conserves during life span the property of generating new cells which can become neurons, the so-called neurogenesis. The present study investigated whether a model of rat neonatal anoxia, that causes only respiratory distress, is able to alter the hippocampal volume, the neurogenesis rate and has functional implications in adult life. MRI analysis revealed significant hippocampal volume decrease in adult rats who had experienced neonatal anoxia compared to control animals for rostral, caudal and total hippocampus. In addition, these animals also had 55.7% decrease of double-labelled cells to BrdU and NeuN, reflecting a decrease in neurogenesis rate. Finally, behavioral analysis indicated that neonatal anoxia resulted in disruption of spatial working memory, similar to human condition, accompanied by an anxiogenic effect. The observed behavioral alterations caused by oxygen deprivation at birth might represent an outcome of the decreased hippocampal neurogenesis and volume, evidenced by immunohistochemistry and MRI analysis. Therefore, based on current findings we propose this model as suitable to explore new therapeutic approaches.

  1. GDNF facilitates differentiation of the adult dentate gyrus-derived neural precursor cells into astrocytes via STAT3

    SciTech Connect

    Boku, Shuken; Nakagawa, Shin; Takamura, Naoki; Kato, Akiko; Takebayashi, Minoru; Hisaoka-Nakashima, Kazue; Omiya, Yuki; Inoue, Takeshi; Kusumi, Ichiro

    2013-05-17

    Highlights: •GDNF has no effect on ADP proliferation and apoptosis. •GDNF increases ADP differentiation into astrocyte. •A specific inhibitor of STAT3 decreases the astrogliogenic effect of GDNF. •STAT3 knockdown by lentiviral shRNA vector also decreases the astrogliogenic effect of GDNF. •GDNF increases the phosphorylation of STAT3. -- Abstract: While the pro-neurogenic actions of antidepressants in the adult hippocampal dentate gyrus (DG) are thought to be one of the mechanisms through which antidepressants exert their therapeutic actions, antidepressants do not increase proliferation of neural precursor cells derived from the adult DG. Because previous studies showed that antidepressants increase the expression and secretion of glial cell line-derived neurotrophic factor (GDNF) in C6 glioma cells derived from rat astrocytes and GDNF increases neurogenesis in adult DG in vivo, we investigated the effects of GDNF on the proliferation, differentiation and apoptosis of cultured neural precursor cells derived from the adult DG. Data showed that GDNF facilitated the differentiation of neural precursor cells into astrocytes but had no effect on their proliferation or apoptosis. Moreover, GDNF increased the phosphorylation of STAT3, and both a specific inhibitor of STAT3 and lentiviral shRNA for STAT3 decreased their differentiation into astrocytes. Taken together, our findings suggest that GDNF facilitates astrogliogenesis from neural precursor cells in adult DG through activating STAT3 and that this action might indirectly affect neurogenesis.

  2. Hippocalcin Is Required for Astrocytic Differentiation through Activation of Stat3 in Hippocampal Neural Precursor Cells

    PubMed Central

    Kang, Min-Jeong; Park, Shin-Young; Han, Joong-Soo

    2016-01-01

    Hippocalcin (Hpca) is a neuronal calcium sensor protein expressed in the mammalian brain. However, its function in neural stem/precursor cells has not yet been studied. Here, we clarify the function of Hpca in astrocytic differentiation in hippocampal neural precursor cells (HNPCs). When we overexpressed Hpca in HNPCs in the presence or absence of bFGF, expression levels of nerve-growth factors such as neurotrophin-3 (NT-3), neurotrophin-4/5 (NT-4/5), and brain-derived neurotrophic factor (BDNF), together with the proneural basic helix loop helix (bHLH) transcription factors NeuroD and neurogenin 1 (Ngn1), increased significantly. In addition, there was an increase in the number of cells expressing glial fibrillary acidic protein (GFAP), an astrocyte marker, and in branch outgrowth, indicating astrocytic differentiation of the HNPCs. Downregulation of Hpca by transfection with Hpca siRNA reduced expression of NT-3, NT-4/5, BDNF, NeuroD, and Ngn1 as well as levels of GFAP protein. Furthermore, overexpression of Hpca increased the phosphorylation of STAT3 (Ser727), and this effect was abolished by treatment with a STAT3 inhibitor (S3I-201), suggesting that STAT3 (Ser727) activation is involved in Hpca-mediated astrocytic differentiation. As expected, treatment with Stat3 siRNA or STAT3 inhibitor caused a complete inhibition of astrogliogenesis induced by Hpca overexpression. Taken together, this is the first report to show that Hpca, acting through Stat3, has an important role in the expression of neurotrophins and proneural bHLH transcription factors, and that it is an essential regulator of astrocytic differentiation and branch outgrowth in HNPCs. PMID:27840601

  3. A ventral view on antidepressant action: roles for adult hippocampal neurogenesis along the dorsoventral axis.

    PubMed

    O'Leary, Olivia F; Cryan, John F

    2014-12-01

    Adult hippocampal neurogenesis is implicated in antidepressant action, stress responses, and cognitive functioning. The hippocampus is functionally segregated along its longitudinal axis into dorsal (dHi) and ventral (vHi) regions in rodents, and analogous posterior and anterior regions in primates, whereby the vHi preferentially regulates stress and anxiety, while the dHi preferentially regulates spatial learning and memory. Given the role of neurogenesis in functions preferentially regulated by the dHi or vHi, it is plausible that neurogenesis is preferentially regulated in either the dHi or vHi depending upon the stimulus. We appraise here the literature on the effects of stress and antidepressants on neurogenesis along the hippocampal longitudinal axis and explore whether preferential regulation of neurogenesis in the vHi/anterior hippocampus contributes to stress resilience and antidepressant action.

  4. Neural Plasticity and Proliferation in the Generation of Antidepressant Effects: Hippocampal Implication

    PubMed Central

    Pilar-Cuéllar, Fuencisla; Vidal, Rebeca; Díaz, Alvaro; Castro, Elena; dos Anjos, Severiano; Pascual-Brazo, Jesús; Linge, Raquel; Vargas, Veronica; Blanco, Helena; Martínez-Villayandre, Beatriz; Pazos, Ángel; Valdizán, Elsa M.

    2013-01-01

    It is widely accepted that changes underlying depression and antidepressant-like effects involve not only alterations in the levels of neurotransmitters as monoamines and their receptors in the brain, but also structural and functional changes far beyond. During the last two decades, emerging theories are providing new explanations about the neurobiology of depression and the mechanism of action of antidepressant strategies based on cellular changes at the CNS level. The neurotrophic/plasticity hypothesis of depression, proposed more than a decade ago, is now supported by multiple basic and clinical studies focused on the role of intracellular-signalling cascades that govern neural proliferation and plasticity. Herein, we review the state-of-the-art of the changes in these signalling pathways which appear to underlie both depressive disorders and antidepressant actions. We will especially focus on the hippocampal cellularity and plasticity modulation by serotonin, trophic factors as brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF) through intracellular signalling pathways—cAMP, Wnt/β-catenin, and mTOR. Connecting the classic monoaminergic hypothesis with proliferation/neuroplasticity-related evidence is an appealing and comprehensive attempt for improving our knowledge about the neurobiological events leading to depression and associated to antidepressant therapies. PMID:23862076

  5. Hippocampal activity mediates the relationship between circadian activity rhythms and memory in older adults.

    PubMed

    Sherman, Stephanie M; Mumford, Jeanette A; Schnyer, David M

    2015-08-01

    Older adults experience parallel changes in sleep, circadian rhythms, and episodic memory. These processes appear to be linked such that disruptions in sleep contribute to deficits in memory. Although more variability in circadian patterns is a common feature of aging and predicts pathology, little is known about how alterations in circadian activity rhythms within older adults influence new episodic learning. Following 10 days of recording sleep-wake patterns using actigraphy, healthy older adults underwent fMRI while performing an associative memory task. The results revealed better associative memory was related to more consistent circadian activity rhythms, independent of total sleep time, sleep efficiency, and level of physical activity. Moreover, hippocampal activity during successful memory retrieval events was positively correlated with associative memory accuracy and circadian activity rhythm (CAR) consistency. We demonstrated that the link between consistent rhythms and associative memory performance was mediated by hippocampal activity. These findings provide novel insight into how the circadian rhythm of sleep-wake cycles are associated with memory in older adults and encourage further examination of circadian activity rhythms as a biomarker of cognitive functioning.

  6. Perinatal programming of adult hippocampal structure and function; emerging roles of stress, nutrition and epigenetics.

    PubMed

    Lucassen, Paul J; Naninck, Eva F G; van Goudoever, Johannes B; Fitzsimons, Carlos; Joels, Marian; Korosi, Aniko

    2013-11-01

    Early-life stress lastingly affects adult cognition and increases vulnerability to psychopathology, but the underlying mechanisms remain elusive. In this Opinion article, we propose that early nutritional input together with stress hormones and sensory stimuli from the mother during the perinatal period act synergistically to program the adult brain, possibly via epigenetic mechanisms. We hypothesize that stress during gestation or lactation affects the intake of macro- and micronutrients, including dietary methyl donors, and/or impairs the dam's metabolism, thereby altering nutrient composition and intake by the offspring. In turn, this may persistently modulate gene expression via epigenetic programming, thus altering hippocampal structure and cognition. Understanding how the combination of stress, nutrition, and epigenetics shapes the adult brain is essential for effective therapies.

  7. Childhood Social Inequalities Influences Neural Processes in Young Adult Caregiving

    PubMed Central

    Kim, Pilyoung; Ho, S. Shaun; Evans, Gary W.; Liberzon, Israel; Swain, James E.

    2016-01-01

    Childhood poverty is associated with harsh parenting with a risk of transmission to the next generation. This prospective study examined the relations between childhood poverty and non-parent adults’ neural responses to infant cry sounds. While no main effects of poverty were revealed in contrasts of infant cry vs. acoustically matched white noise, a gender by childhood poverty interaction emerged. In females, childhood poverty was associated with increased neural activations in the posterior insula, striatum, calcarine sulcus, hippocampus and fusiform gyrus, while, in males, childhood poverty was associated with reduced levels of neural responses to infant cry in the same regions. Irrespective of gender, neural activation in these regions was associated with higher levels of annoyance with the cry sound and reduced desire to approach the crying infant. The findings suggest gender differences in neural and emotional responses to infant cry sounds among young adults growing up in poverty. PMID:25981334

  8. Adult hippocampal neurogenesis is impaired by transient and moderate developmental thyroid hormone disruption.

    PubMed

    Gilbert, M E; Goodman, J H; Gomez, J; Johnstone, A F M; Ramos, R L

    2017-03-01

    The hippocampus maintains a capacity for neurogenesis throughout life, a capacity that is reduced in models of adult onset hypothyroidism. The effects of developmental thyroid hormone (TH) insufficiency on neurogenesis in the adult hippocampus, however, has not been examined. Graded degrees of TH insufficiency were induced in pregnant rat dams by administration of 0, 3 or 10ppm of 6-propylthiouracil (PTU) in drinking water from gestational day (GD) 6 until weaning. Body, brain, and hippocampal weight were reduced on postnatal day (PN) 14, 21, 78 and hippocampal volume was smaller at the 10 but not 3ppm dose level. A second experiment examined adult hippocampal neurogenesis following developmental or adult onset hypothyroidism. Two male offspring from 0 and 3ppm exposed dams were either maintained on control water or exposed to 3ppm PTU to create 4 distinct treatment conditions (Control-Control; Control-PTU, PTU-Control, PTU-PTU) based on developmental and adult exposures. Beginning on the 28th day of adult exposure to 0 or 3ppm PTU, bromodeoxyuridine (BrdU, 50mg/kg, ip) was administered twice daily for 5days, and one male from each treatment was sacrificed 24h and 28days after the last BrdU dose and brains processed for immunohistochemistry. Although no volume changes were seen in the hippocampus of the neonate at 3ppm, thinning of the granule cell layer emerged in adulthood. Developmental TH insufficiency produced a reduction in newly born cells, reducing BrdU+ve cells at 1 with no further reduction at 28-days post-BrdU. Similar findings were obtained using the proliferative cell marker Ki67. Neuronal differentiations was also altered with fewer doublecortin (Dcx) expressing cells and a higher proportion of immature Dcx phenotypes seen after developmental but not adult TH insufficiency. An impaired capacity for neurogenesis may contribute to impairments in synaptic plasticity and cognitive deficits previously reported by our laboratory and others following

  9. All About Running: Synaptic Plasticity, Growth Factors and Adult Hippocampal Neurogenesis

    PubMed Central

    Vivar, Carmen; Potter, Michelle C.; van Praag, Henriette

    2015-01-01

    Accumulating evidence from animal and human research shows exercise benefits learning and memory, which may reduce the risk of neurodegenerative diseases, and could delay age-related cognitive decline. Exercise-induced improvements in learning and memory are correlated with enhanced adult hippocampal neurogenesis and increased activity-dependent synaptic plasticity. In this present chapter we will highlight the effects of physical activity on cognition in rodents, as well as on dentate gyrus (DG) neurogenesis, synaptic plasticity, spine density, neurotransmission and growth factors, in particular brain-derived nerve growth factor (BDNF). PMID:22847651

  10. Lead decreases cell survival, proliferation, and neuronal differentiation of primary cultured adult neural precursor cells through activation of the JNK and p38 MAP kinases

    PubMed Central

    Engstrom, Anna; Wang, Hao; Xia, Zhengui

    2015-01-01

    Adult hippocampal neurogenesis is the process whereby adult neural precursor cells (aNPCs) in the subgranular zone (SGZ) of the dentate gyrus (DG) generate adult-born, functional neurons in the hippocampus. This process is modulated by various extracellular and intracellular stimuli, and the adult-born neurons have been implicated in hippocampus-dependent learning and memory. However, studies on how neurotoxic agents affect this process and the underlying mechanisms are limited. The goal of this study was to determine whether lead, a heavy metal, directly impairs critical processes in adult neurogenesis and to characterize the underlying signaling pathways using primary cultured SGZ-aNPCs isolated from adult mice. We report here that lead significantly increases apoptosis and inhibits proliferation in SGZ-aNPCs. In addition, lead significantly impairs spontaneous neuronal differentiation and maturation. Furthermore, we found that activation of the c-Jun NH2-terminal kinase (JNK) and p38 mitogen activated protein (MAP) kinase signaling pathways are important for lead cytotoxicity. Our data suggest that lead can directly act on adult neural stem cells and impair critical processes in adult hippocampal neurogenesis, which may contribute to its neurotoxicity and adverse effects on cognition in adults. PMID:25967738

  11. Identifying endogenous neural stem cells in the adult brain in vitro and in vivo: novel approaches.

    PubMed

    Rueger, Maria Adele; Androutsellis-Theotokis, Andreas

    2013-01-01

    In the 1960s, Joseph Altman reported that the adult mammalian brain is capable of generating new neurons. Today it is understood that some of these neurons are derived from uncommitted cells in the subventricular zone lining the lateral ventricles, and the dentate gyrus of the hippocampus. The first area generates new neuroblasts which migrate to the olfactory bulb, whereas hippocampal neurogenesis seems to play roles in particular types of learning and memory. A part of these uncommitted (immature) cells is able to divide and their progeny can generate all three major cell types of the nervous system: neurons, astrocytes, and oligodendrocytes; these properties define such cells as neural stem cells. Although the roles of these cells are not yet clear, it is accepted that they affect functions including olfaction and learning/memory. Experiments with insults to the central nervous system also show that neural stem cells are quickly mobilized due to injury and in various disorders by proliferating, and migrating to injury sites. This suggests a role of endogenous neural stem cells in disease. New pools of stem cells are being discovered, suggesting an even more important role for these cells. To understand these cells and to coax them to contribute to tissue repair it would be very useful to be able to image them in the living organism. Here we discuss advances in imaging approaches as well as new concepts that emerge from stem cell biology with emphasis on the interface between imaging and stem cells.

  12. Green tea compound epigallo-catechin-3-gallate (EGCG) increases neuronal survival in adult hippocampal neurogenesis in vivo and in vitro.

    PubMed

    Ortiz-López, L; Márquez-Valadez, B; Gómez-Sánchez, A; Silva-Lucero, M D C; Torres-Pérez, M; Téllez-Ballesteros, R I; Ichwan, M; Meraz-Ríos, M A; Kempermann, G; Ramírez-Rodríguez, G B

    2016-05-13

    Epigallo-catechin-3-gallate (EGCG), found in the leaves of Camellia sinensis (green tea), has antioxidant- and scavenger-functions and acts neuroprotectively. It has been publicized as anti-aging remedy but data on potential cellular mechanisms are scarce. Recent studies claimed that EGCG specifically promotes neural precursor cell proliferation in the dentate gyrus of C57Bl/6 mice, without changes at the level of immature and mature new neurons. We here analyzed the effects of EGCG on adult hippocampal neurogenesis in male Balb/C mice and saw a different pattern. Two weeks of treatment with EGCG (0, 0.625, 1.25, 2.5, 5 and 10mg/kg) showed a dose-response curve that peaked at 2.5mg/kg of EGCG with significantly increased cell survival without affecting cell proliferation but decreasing apoptotic cells. Also, EGCG increased the population of doublecortin-(DCX)-expressing cells that comprises the late intermediate progenitor cells (type-2b and -3) as well as immature neurons. After EGCG treatment, the young DCX-positive neurons showed more elaborated dendritic trees. EGCG also significantly increased net neurogenesis in the adult hippocampus and increased the hippocampal levels of phospho-Akt. Ex vivo, EGCG exerted a direct effect on survival and neuronal differentiation of adult hippocampal precursor cells, which was absent, when PI3K, a protein upstream of Akt, was blocked. Our results thus support a pro-survival and a pro-neurogenic role of EGCG. In the context of the conflicting published results, however, potential genetic modifiers must be assumed. These might help to explain the overall variability of study results with EGCG. Our data do indicate, however, that natural compounds such as EGCG can in principle modulate brain plasticity.

  13. Modifications of hippocampal circuits and early disruption of adult neurogenesis in the tg2576 mouse model of Alzheimer's disease.

    PubMed

    Krezymon, Alice; Richetin, Kevin; Halley, Hélène; Roybon, Laurent; Lassalle, Jean-Michel; Francès, Bernard; Verret, Laure; Rampon, Claire

    2013-01-01

    At advanced stages of Alzheimer's disease, cognitive dysfunction is accompanied by severe alterations of hippocampal circuits that may largely underlie memory impairments. However, it is likely that anatomical remodeling in the hippocampus may start long before any cognitive alteration is detected. Using the well-described Tg2576 mouse model of Alzheimer's disease that develops progressive age-dependent amyloidosis and cognitive deficits, we examined whether specific stages of the disease were associated with the expression of anatomical markers of hippocampal dysfunction. We found that these mice develop a complex pattern of changes in their dentate gyrus with aging. Those include aberrant expression of neuropeptide Y and reduced levels of calbindin, reflecting a profound remodeling of inhibitory and excitatory circuits in the dentate gyrus. Preceding these changes, we identified severe alterations of adult hippocampal neurogenesis in Tg2576 mice. We gathered converging data in Tg2576 mice at young age, indicating impaired maturation of new neurons that may compromise their functional integration into hippocampal circuits. Thus, disruption of adult hippocampal neurogenesis occurred before network remodeling in this mouse model and therefore may account as an early event in the etiology of Alzheimer's pathology. Ultimately, both events may constitute key components of hippocampal dysfunction and associated cognitive deficits occurring in Alzheimer's disease.

  14. Melatonin synergizes with citalopram to induce antidepressant-like behavior and to promote hippocampal neurogenesis in adult mice.

    PubMed

    Ramírez-Rodríguez, Gerardo; Vega-Rivera, Nelly Maritza; Oikawa-Sala, Julián; Gómez-Sánchez, Ariadna; Ortiz-López, Leonardo; Estrada-Camarena, Erika

    2014-05-01

    Adult hippocampal neurogenesis is affected in some neuropsychiatric disorders such as depression. Numerous evidence indicates that plasma levels of melatonin are decreased in depressed patients. Also, melatonin exerts positive effects on the hippocampal neurogenic process and on depressive-like behavior. In addition, antidepressants revert alterations of hippocampal neurogenesis present in models of depression following a similar time course to the improvement of behavior. In this study, we analyzed the effects of both, citalopram, a widely used antidepressant, and melatonin in the Porsolt forced swim test. In addition, we investigated the potential antidepressant role of the combination of melatonin and citalopram (MLTCITAL), its type of pharmacological interaction on depressive behavior, and its effect on hippocampal neurogenesis. Here, we found decreased immobility behavior in mice treated with melatonin (<14-33%) and citalopram (<17-30%). Additionally, the MLTCITAL combination also decreased immobility (<22-35%) in comparison with control mice, reflecting an antidepressant-like effect after 14 days of treatment. Moreover, MLTCITAL decreased plasma corticosterone levels (≤13%) and increased cell proliferation (>29%), survival (>39%), and the absolute number of -associated new neurons (>53%) in the dentate gyrus of the hippocampus. These results indicate that the MLTCITAL combination exerts synergism to induce an antidepressant-like action that could be related to the modulation of adult hippocampal neurogenesis. This outcome opens the opportunity of using melatonin to promote behavioral benefits and hippocampal neurogenesis in depression and also supports the use of the MLTCITAL combination as an alternative to treat depression.

  15. Hippocampal volumes among older Indian adults: Comparison with Alzheimer's disease and mild cognitive impairment

    PubMed Central

    Dhikav, Vikas; Duraisamy, Sharmila; Anand, Kuljeet Singh; Garga, Umesh Chandra

    2016-01-01

    Background: Hippocampal volume data from India have recently been reported in younger adults. Data in older adults are unknown. The present paper describes hippocampal volume from India among older adults and compares the same with patients having Alzheimer's disease (AD) and mild cognitive impairment (MCI). Materials and Methods: A total of 32 cognitively normal subjects, 20 patients with AD, and 13 patients with MCI were enrolled. Patients were evaluated for the diagnosis of AD/MCI using the National Institute of Neurological and Communicative Disorders and Stroke and the Related Disorders Association criteria and the Clinical Dementia Rating (CDR) Scale (score = 0.5), respectively. Hippocampal volume was measured using magnetic resonance imaging (MRI) machine by manual segmentation (Megnatom Symphony 1.5T scanner) three-dimensional (3D) sequences. Results: Age and duration of illness in the MCI group were 70.6 ± 8.6 years and 1.9 ± 0.9 years, respectively. In the AD group, age and duration of illness were 72 ± 8.1 years and 3.1 ± 2.2 years, respectively. In cognitively normal subjects, the age range was 45-88 years (66.9 ± 10.32) years. Mean mini–mental status examination (MMSE) score of healthy subjects was 28.28 ± 1.33. In the MCI group, MMSE was 27.05 ± 1.79. In the AD group, MMSE was 13.32 ± 5.6. In the healthy group, the hippocampal volume was 2.73 ± 0.53 cm3 on the left side and 2.77 ± 0.6 cm3 on the right side. Likewise, in MCI, the volume on the left side was 2.35 ± 0.42 cm3 and the volume on the right side was 2.36 ± 0.38 cm3. Similarly, in the AD group, the volume on the right side was 1.64 ± 0.55 cm3 and on the left side it was 1.59 ± 0.55 cm3. Post hoc analysis using Tukey's honestly significant difference (HSD) showed, using analysis of variance (ANOVA) that there was a statistically significant difference between healthy and AD (P ≤ 0.01), and between healthy and MCI (P ≤ 0.01) subjects. There was a correlation between MMSE

  16. A role for interleukin-1β in determining the lineage fate of embryonic rat hippocampal neural precursor cells.

    PubMed

    Green, Holly F; Treacy, Eimear; Keohane, Aoife K; Sullivan, Aideen M; O'Keeffe, Gerard W; Nolan, Yvonne M

    2012-03-01

    Neurogenesis occurs in the hippocampus of the developing and adult brain due to the presence of multipotent stem cells and restricted precursor cells at different stages of differentiation. It has been proposed that they may be of potential benefit for use in cell transplantation approaches for neurodegenerative disorders and trauma. Prolonged release of interleukin-1β (IL-1β) from activated microglia has a deleterious effect on hippocampal neurons and is implicated in the impaired neurogenesis and cognitive dysfunction associated with aging, Alzheimer's disease and depression. This study assessed the effect of IL-1β on the proliferation and differentiation of embryonic rat hippocampal NPCs in vitro. We show that IL-1R1 is expressed on proliferating NPCs and that IL-1β treatment decreases cell proliferation and neurosphere growth. When NPCs were differentiated in the presence of IL-1β, a significant reduction in the percentages of newly-born neurons and post-mitotic neurons and a significant increase in the percentage of astrocytes was observed in these cultures. These effects were attenuated by IL-1 receptor antagonist. These data reveal that IL-1β exerts an anti-proliferative, anti-neurogenic and pro-gliogenic effect on embryonic hippocampal NPCs, which is mediated by IL-1R1. The present results emphasise the consequences of an inflammatory environment during NPC development, and indicate that strategies to inhibit IL-1β signalling may be necessary to facilitate effective cell transplantation approaches or in conditions where endogenous hippocampal neurogenesis is impaired.

  17. Habitat-specific shaping of proliferation and neuronal differentiation in adult hippocampal neurogenesis of wild rodents.

    PubMed

    Cavegn, Nicole; van Dijk, R Maarten; Menges, Dominik; Brettschneider, Helene; Phalanndwa, Mashudu; Chimimba, Christian T; Isler, Karin; Lipp, Hans-Peter; Slomianka, Lutz; Amrein, Irmgard

    2013-01-01

    Daily life of wild mammals is characterized by a multitude of attractive and aversive stimuli. The hippocampus processes complex polymodal information associated with such stimuli and mediates adequate behavioral responses. How newly generated hippocampal neurons in wild animals contribute to hippocampal function is still a subject of debate. Here, we test the relationship between adult hippocampal neurogenesis (AHN) and habitat types. To this end, we compare wild Muridae species of southern Africa [Namaqua rock mouse (Micaelamys namaquensis), red veld rat (Aethomys chrysophilus), highveld gerbil (Tatera brantsii), and spiny mouse (Acomys spinosissimus)] with data from wild European Muridae [long-tailed wood mice (Apodemus sylvaticus), pygmy field mice (Apodemus microps), yellow-necked wood mice (Apodemus flavicollis), and house mice (Mus musculus domesticus)] from previous studies. The pattern of neurogenesis, expressed in normalized numbers of Ki67- and Doublecortin(DCX)-positive cells to total granule cells (GCs), is similar for the species from a southern African habitat. However, we found low proliferation, but high neuronal differentiation in rodents from the southern African habitat compared to rodents from the European environment. Within the African rodents, we observe additional regulatory and morphological traits in the hippocampus. Namaqua rock mice with previous pregnancies showed lower AHN compared to males and nulliparous females. The phylogenetically closely related species (Namaqua rock mouse and red veld rat) show a CA4, which is not usually observed in murine rodents. The specific features of the southern environment that may be associated with the high number of young neurons in African rodents still remain to be elucidated. This study provides the first evidence that a habitat can shape adult neurogenesis in rodents across phylogenetic groups.

  18. Habitat-specific shaping of proliferation and neuronal differentiation in adult hippocampal neurogenesis of wild rodents

    PubMed Central

    Cavegn, Nicole; van Dijk, R. Maarten; Menges, Dominik; Brettschneider, Helene; Phalanndwa, Mashudu; Chimimba, Christian T.; Isler, Karin; Lipp, Hans-Peter; Slomianka, Lutz; Amrein, Irmgard

    2013-01-01

    Daily life of wild mammals is characterized by a multitude of attractive and aversive stimuli. The hippocampus processes complex polymodal information associated with such stimuli and mediates adequate behavioral responses. How newly generated hippocampal neurons in wild animals contribute to hippocampal function is still a subject of debate. Here, we test the relationship between adult hippocampal neurogenesis (AHN) and habitat types. To this end, we compare wild Muridae species of southern Africa [Namaqua rock mouse (Micaelamys namaquensis), red veld rat (Aethomys chrysophilus), highveld gerbil (Tatera brantsii), and spiny mouse (Acomys spinosissimus)] with data from wild European Muridae [long-tailed wood mice (Apodemus sylvaticus), pygmy field mice (Apodemus microps), yellow-necked wood mice (Apodemus flavicollis), and house mice (Mus musculus domesticus)] from previous studies. The pattern of neurogenesis, expressed in normalized numbers of Ki67- and Doublecortin(DCX)-positive cells to total granule cells (GCs), is similar for the species from a southern African habitat. However, we found low proliferation, but high neuronal differentiation in rodents from the southern African habitat compared to rodents from the European environment. Within the African rodents, we observe additional regulatory and morphological traits in the hippocampus. Namaqua rock mice with previous pregnancies showed lower AHN compared to males and nulliparous females. The phylogenetically closely related species (Namaqua rock mouse and red veld rat) show a CA4, which is not usually observed in murine rodents. The specific features of the southern environment that may be associated with the high number of young neurons in African rodents still remain to be elucidated. This study provides the first evidence that a habitat can shape adult neurogenesis in rodents across phylogenetic groups. PMID:23616743

  19. Neuronal Splicing Regulator RBFOX3 (NeuN) Regulates Adult Hippocampal Neurogenesis and Synaptogenesis

    PubMed Central

    Lin, Meng-Ying; Chou, Chih-Hsuan; Wu, I-Ju; Huang, Guo-Jen; Gau, Susan Shur-Fen

    2016-01-01

    Dysfunction of RBFOX3 has been identified in neurodevelopmental disorders such as autism spectrum disorder, cognitive impairments and epilepsy and a causal relationship with these diseases has been previously demonstrated with Rbfox3 homozygous knockout mice. Despite the importance of RBFOX3 during neurodevelopment, the function of RBFOX3 regarding neurogenesis and synaptogenesis remains unclear. To address this critical question, we profiled the developmental expression pattern of Rbfox3 in the brain of wild-type mice and analyzed brain volume, disease-relevant behaviors, neurogenesis, synaptic plasticity, and synaptogenesis in Rbfox3 homozygous knockout mice and their corresponding wild-type counterparts. Here we report that expression of Rbfox3 differs developmentally for distinct brain regions. Moreover, Rbfox3 homozygous knockout mice exhibited cold hyperalgesia and impaired cognitive abilities. Focusing on hippocampal phenotypes, we found Rbfox3 homozygous knockout mice displayed deficits in neurogenesis, which was correlated with cognitive impairments. Furthermore, RBFOX3 regulates the exons of genes with synapse-related function. Synaptic plasticity and density, which are related to cognitive behaviors, were altered in the hippocampal dentate gyrus of Rbfox3 homozygous knockout mice; synaptic plasticity decreased and the density of synapses increased. Taken together, our results demonstrate the important role of RBFOX3 during neural development and maturation. In addition, abnormalities in synaptic structure and function occur in Rbfox3 homozygous knockout mice. Our findings may offer mechanistic explanations for human brain diseases associated with dysfunctional RBFOX3. PMID:27701470

  20. Chronic administration of a melatonin membrane receptor antagonist, luzindole, affects hippocampal neurogenesis without changes in hopelessness-like behavior in adult mice.

    PubMed

    Ortiz-López, Leonardo; Pérez-Beltran, Carlos; Ramírez-Rodríguez, Gerardo

    2016-04-01

    Melatonin is involved in the regulation of hippocampal neuronal development during adulthood. Emerging evidence indicates that exogenous melatonin acts during different events of the neurogenic process and exerts antidepressant-like behavior in rodents. Thus, melatonin might act through different mechanism, including acting as an antioxidant, interacting with intracellular proteins and/or activating membrane receptors. The melatonin membrane receptors (MMRs; Mt1/Mt2) are distributed throughout the hippocampus with an interesting localization in the hippocampal neurogenic microenvironment (niche), suggesting the involvement of these receptors in the beneficial effects of melatonin on hippocampal neurogenesis and behavior. In this study, we analyzed the participation of MMRs in the baseline neurogenesis in C57BL/6 mice. To this end, we used a pharmacological approach, administering luzindole (10 mg/kg) for 14 days. We observed a decrease in the absolute number of doublecortin-positive cells (49%) without changes in either the dendrite complexity of mature doublecortin-cells or the number of apoptotic cells (TUNEL). However, after the chronic administration of luzindole, cell proliferation (Ki67) significantly decreased (36%) with increasing (>100%) number of neural stem cells (NSCs; GFAP(+)/Sox2(+)) in the subgranular zone of the dentate gyrus of the hippocampus. In addition, luzindole did not affect hopelessness-like behavior in the forced swim test (FST) or changes in the novelty suppressed feeding test (NST) after 14 days of treatment either neuronal activation in the dentate gyrus after FST. These results suggest that the MMRs are involved in the effects of endogenous melatonin to mediate the transition from NSCs and proliferative cells to the following developmental stages implicated in the hippocampal neurogenic process of adult female C57BL/6 mice.

  1. Effects of combined nicotine and fluoxetine treatment on adult hippocampal neurogenesis and conditioned place preference.

    PubMed

    Faillace, M P; Zwiller, J; Bernabeu, R O

    2015-08-06

    Adult neurogenesis occurs in mammals within the dentate gyrus, a hippocampal subarea. It is known to be induced by antidepressant treatment and reduced in response to nicotine administration. We checked here whether the antidepressant fluoxetine would inverse the decrease in hippocampal neurogenesis caused by nicotine. It is shown that repeated, but not a single injection of rats with fluoxetine was able to abolish the decrease in adult dentate cell proliferation produced by nicotine treatment. We measured the expression of several biochemical parameters known to be associated with neurogenesis in the dentate gyrus. Both drugs increased the expression of p75 neurotrophin receptor, which promotes proliferation and early maturation of dentate gyrus cells. Using the conditioned place preference (CPP) paradigm, we also gave both drugs in a context in which their rewarding properties could be measured. Fluoxetine produced a significant but less robust CPP than nicotine. A single injection of fluoxetine was found to reduce nicotine-induced CPP. Moreover, the rewarding properties of nicotine were completely abolished in response to repeated fluoxetine injections. Expression of nicotine-induced CPP was accompanied by an increase of phospho-CREB (cyclic AMP-responsive element-binding protein) and HDAC2 (histone deacetylase 2) expression in the nucleus accumbens. The data suggest that fluoxetine reward, as opposed to nicotine reward, depends on dentate gyrus neurogenesis. Since fluoxetine was able to disrupt the association between nicotine and the environment, this antidepressant may be tested as a treatment for nicotine addiction using cue exposure therapy.

  2. Cacna1c: Protecting young hippocampal neurons in the adult brain.

    PubMed

    De Jesús-Cortés, Héctor; Rajadhyaksha, Anjali M; Pieper, Andrew A

    2016-01-01

    Neuropsychiatric disease is the leading cause of disability in the United States, and fourth worldwide.(1,2) Not surprisingly, human genetic studies have revealed a common genetic predisposition for many forms of neuropsychiatric disease, potentially explaining why overlapping symptoms are commonly observed across multiple diagnostic categories. For example, the CACNA1C gene was recently identified in the largest human genome-wide association study to date as a risk loci held in common across 5 major forms of neuropsychiatric disease: bipolar disorder, schizophrenia, major depressive disorder (MDD), autism spectrum disorder and attention deficit-hyperactivity disorder.(3) This gene encodes for the Cav1.2 subunit of the L-type voltage-gated calcium channel (LTCC), accounting for 85% of LTCCs in the brain, while the Cav1.3 subunit comprises the remainder.(4) In neurons, LTCCs mediate calcium influx in response to membrane depolarization,(5) thereby regulating neurotransmission and gene expression. Here, we describe our recent finding that Cav1.2 also controls survival of young hippocampal neurons in the adult brain, which has been linked to the etiology and treatment of neuropsychiatric disease. We also describe the effective restoration of young hippocampal neuron survival in adult Cav1.2 forebrain-specific conditional knockout mice using the neuroprotective compound P7C3-A20.

  3. A place for the hippocampus in the cocaine addiction circuit: Potential roles for adult hippocampal neurogenesis.

    PubMed

    Castilla-Ortega, Estela; Serrano, Antonia; Blanco, Eduardo; Araos, Pedro; Suárez, Juan; Pavón, Francisco J; Rodríguez de Fonseca, Fernando; Santín, Luis J

    2016-07-01

    Cocaine addiction is a chronic brain disease in which the drug seeking habits and profound cognitive, emotional and motivational alterations emerge from drug-induced neuroadaptations on a vulnerable brain. Therefore, a 'cocaine addiction brain circuit' has been described to explain this disorder. Studies in both cocaine patients and rodents reveal the hippocampus as a main node in the cocaine addiction circuit. The contribution of the hippocampus to cocaine craving and the associated memories is essential to understand the chronic relapsing nature of addiction, which is the main obstacle for the recovery. Interestingly, the hippocampus holds a particular form of plasticity that is rare in the adult brain: the ability to generate new functional neurons. There is an active scientific debate on the contributions of these new neurons to the addicted brain. This review focuses on the potential role(s) of adult hippocampal neurogenesis (AHN) in cocaine addiction. Although the current evidence primarily originates from animal research, these preclinical studies support AHN as a relevant component for the hippocampal effects of cocaine.

  4. Experience-dependent neural plasticity in the adult damaged brain

    PubMed Central

    Kerr, Abigail L.; Cheng, Shao-Ying; Jones, Theresa A.

    2011-01-01

    Behavioral experience is at work modifying the structure and function of the brain throughout the lifespan, but it has a particularly dramatic influence after brain injury. This review summarizes recent findings on the role of experience in reorganizing the adult damaged brain, with a focus on findings from rodent stroke models of chronic upper extremity (hand and arm) impairments. A prolonged and widespread process of repair and reorganization of surviving neural circuits is instigated by injury to the adult brain. When experience impacts these same neural circuits, it interacts with degenerative and regenerative cascades to shape neural reorganization and functional outcome. This is evident in the cortical plasticity resulting from compensatory reliance on the “good” forelimb in rats with unilateral sensorimotor cortical infarcts. Behavioral interventions (e.g., rehabilitative training) can drive functionally beneficial neural reorganization in the injured hemisphere. However, experience can have both behaviorally beneficial and detrimental effects. The interactions between experience-dependent and injury-induced neural plasticity are complex, time-dependent, and varied with age and other factors. A better understanding of these interactions is needed to understand how to optimize brain remodeling and functional outcome. Learning outcomes Readers will be able to describe (a) experience effects that are maladaptive for behavioral outcome after brain damage, (b) manipulations of experience that drive functionally beneficial neural plasticity, and (c) reasons why rehabilitative training effects can be expected to vary with age, training duration and timing. PMID:21620413

  5. In vivo BDNF modulation of adult functional and morphological synaptic plasticity at hippocampal mossy fibers.

    PubMed

    Gómez-Palacio-Schjetnan, Andrea; Escobar, Martha L

    2008-11-07

    Brain-derived neurotrophic factor (BDNF) has been proposed as a key regulator and mediator of long-term synaptic modifications related to learning and memory maintenance. Our previous studies show that application of high-frequency stimulation (HFS) sufficient to elicit LTP at the dentate gyrus (DG)-CA3 pathway produces mossy fiber structural modifications 7 days after tetanic stimulation. In the present study, we show that acute intrahippocampal microinfusion of BDNF induces a lasting potentiation of synaptic efficacy in the DG-CA3 projection of anesthetized adult rats. Furthermore, we show that BDNF functional modifications in synaptic efficacy are accompanied by a presynaptic structural long-lasting reorganization at the hippocampal mossy fiber pathway. These findings support the idea that BDNF plays an important role as synaptic messenger of activity-dependent synaptic plasticity in the adult mammalian brain, in vivo.

  6. Tumour necrosis factor-alpha impairs neuronal differentiation but not proliferation of hippocampal neural precursor cells: Role of Hes1.

    PubMed

    Keohane, Aoife; Ryan, Sinead; Maloney, Eimer; Sullivan, Aideen M; Nolan, Yvonne M

    2010-01-01

    Tumour necrosis factor-alpha (TNFalpha) is a pro-inflammatory cytokine, which influences neuronal survival and function yet there is limited information available on its effects on hippocampal neural precursor cells (NPCs). We show that TNFalpha treatment during proliferation had no effect on the percentage of proliferating cells prepared from embryonic rat hippocampal neurosphere cultures, nor did it affect cell fate towards either an astrocytic or neuronal lineage when cells were then allowed to differentiate. However, when cells were differentiated in the presence of TNFalpha, significantly reduced percentages of newly born and post-mitotic neurons, significantly increased percentages of astrocytes and increased expression of TNFalpha receptors, TNF-R1 and TNF-R2, as well as expression of the anti-neurogenic Hes1 gene, were observed. These data indicate that exposure of hippocampal NPCs to TNFalpha when they are undergoing differentiation but not proliferation has a detrimental effect on their neuronal lineage fate, which may be mediated through increased expression of Hes1.

  7. Imidacloprid toxicity impairs spatial memory of echolocation bats through neural apoptosis in hippocampal CA1 and medial entorhinal cortex areas.

    PubMed

    Hsiao, Chun-Jen; Lin, Ching-Lung; Lin, Tian-Yu; Wang, Sheue-Er; Wu, Chung-Hsin

    2016-04-13

    It has been reported that the decimation of honey bees was because of pesticides of imidacloprid. The imidacloprid is a wildly used neonicotinoid insecticide. However, whether imidacloprid toxicity interferes with the spatial memory of echolocation bats is still unclear. Thus, we compared the spatial memory of Formosan leaf-nosed bats, Hipposideros terasensis, before and after chronic treatment with a low dose of imidacloprid. We observed that stereotyped flight patterns of echolocation bats that received chronic imidacloprid treatment were quite different from their originally learned paths. We further found that neural apoptosis in hippocampal CA1 and medial entorhinal cortex areas of echolocation bats that received imidacloprid treatment was significantly enhanced in comparison with echolocation bats that received sham treatment. Thus, we suggest that imidacloprid toxicity may interfere with the spatial memory of echolocation bats through neural apoptosis in hippocampal CA1 and medial entorhinal cortex areas. The results provide direct evidence that pesticide toxicity causes a spatial memory disorder in echolocation bats. This implies that agricultural pesticides may pose severe threats to the survival of echolocation bats.

  8. Differential roles of TNFR1 and TNFR2 signaling in adult hippocampal neurogenesis

    PubMed Central

    Chen, Zhiguo; Palmer, Theo D.

    2013-01-01

    Tumor necrosis factor alpha (TNFα) is a potent inhibitor of neurogenesis in vitro but here we show that TNFα signaling has both positive and negative effects on neurogenesis in vivo and is required to moderate the negative impact of cranial irradiation on hippocampal neurogenesis. In vitro, basal levels of TNFα signaling through TNFR2 are required for normal neural progenitor cell proliferation while basal signaling through TNFR1 impairs neural progenitor proliferation. TNFR1 also mediates further reductions in proliferation and elevated cell death following exposure to recombinant TNFα. In vivo, TNFR1−/− and TNFα−/− animals have elevated baseline neurogenesis in the hippocampus, whereas absence of TNFR2 decreases baseline neurogenesis. TNFα is also implicated in defects in neurogenesis that follow radiation injury but we find that loss of TNFR1 has no protective effects on neurogenesis and loss of TNFα or TNFR2 worsened the effects of radiation injury on neurogenesis. We conclude that the immunomodulatory signaling of TNFα mediated by TNFR2 is more significant to radiation injury outcome than the proinflammatory signaling mediated through TNFR1. PMID:23402793

  9. Mice in an enriched environment learn more flexibly because of adult hippocampal neurogenesis.

    PubMed

    Garthe, Alexander; Roeder, Ingo; Kempermann, Gerd

    2016-02-01

    We here show that living in a stimulus-rich environment (ENR) improves water maze learning with respect to specific key indicators that in previous loss-of-function experiments have been shown to rely on adult hippocampal neurogenesis. Analyzing the strategies employed by mice to locate the hidden platform in the water maze revealed that ENR facilitated task acquisition by increasing the probability to use effective search strategies. ENR also enhanced the animals' behavioral flexibility, when the escape platform was moved to a new location. Treatment with temozolomide, which is known to reduce adult neurogenesis, abolished the effects of ENR on both acquisition and flexibility, while leaving other aspects of water maze learning untouched. These characteristic effects and interdependencies were not seen in parallel experiments with voluntary wheel running (RUN), a second pro-neurogenic behavioral stimulus. Since the histological assessment of adult neurogenesis is by necessity an end-point measure, the levels of neurogenesis over the course of the experiment can only be inferred and the present study focused on behavioral parameters as analytical endpoints. Although the correlation of physical activity with precursor cell proliferation and of learning and the survival of new neurons is well established, how the specific functional effects described here relate to dynamic changes in the stem cell niche remains to be addressed. Nevertheless, our findings support the hypothesis that adult neurogenesis is a critical mechanism underlying the beneficial effects of leading an active live, rich in experiences.

  10. Effects of prenatal chronic mild stress exposure on hippocampal cell proliferation, expression of GSK-3α, β and NR2B in adult offspring during fear extinction in rats.

    PubMed

    Li, Min; Li, Xiaobai; Zhang, Xinxin; Ren, Jintao; Jiang, Han; Wang, Yan; Ma, Yuchao; Cheng, Wenwen

    2014-06-01

    Stress during pregnancy has been implicated as a risk factor for the development of many mental disorders; however, the influence of prenatal stress on the fear or anxiety-related behaviors, especially the fear extinction in adult offspring has been little investigated. In order to investigate how prenatal stress affects fear extinction, which is regarded as a form of new learning that counteracts the expression of Pavlovian's conditioned fear, a rat model of prenatal chronic mild stress (PNS) was used to evaluate the effects of PNS on fear extinction in adult offspring. The expression of hippocampal glycogen synthase kinase-3s (GSK-3α, β), N-methyl-d-aspartic acid receptors (NMDARs)-2B and the hippocampal cell proliferation in dentate gyrus in the adult offspring during fear extinction were studied. Our results showed that PNS significantly reduced body weight of pups, indicating PNS might induce growth retardation in offspring. Moreover, PNS significantly enhanced the freezing behavior of offspring at the phase of extinction, suggesting PNS impaired the abilities of fear extinction learning. In addition, PNS significantly increased the levels of GSK-3α, β and NR2B, but reduced hippocampal cell proliferation during fear extinction. Taken together, our findings suggest that maternal stress during pregnancy can impair the fear extinction of adult offspring, probably by affecting the neural plasticity of brain.

  11. Trading new neurons for status: Adult hippocampal neurogenesis in eusocial Damaraland mole-rats.

    PubMed

    Oosthuizen, M K; Amrein, I

    2016-06-02

    Diversity in social structures, from solitary to eusocial, is a prominent feature of subterranean African mole-rat species. Damaraland mole-rats are eusocial, they live in colonies that are characterized by a reproductive division of labor and a subdivision into castes based on physiology and behavior. Damaraland mole-rats are exceptionally long lived and reproductive animals show delayed aging compared to non-reproductive animals. In the present study, we described the hippocampal architecture and the rate of hippocampal neurogenesis of wild-derived, adult Damaraland mole-rats in relation to sex, relative age and social status or caste. Overall, Damaraland mole-rats were found to have a small hippocampus and low rates of neurogenesis. We found no correlation between neurogenesis and sex or relative age. Social status or caste was the most prominent modulator of neurogenesis. An inverse relationship between neurogenesis and social status was apparent, with queens displaying the lowest neurogenesis while the worker mole-rats had the most. As there is no natural progression from one caste to another, social status within a colony was relatively stable and is reflected in the level of neurogenesis. Our results correspond to those found in the naked mole-rat, and may reflect an evolutionary and environmentally conserved trait within social mole-rat species.

  12. Autocrine action of BDNF on dendrite development of adult-born hippocampal neurons.

    PubMed

    Wang, Liang; Chang, Xingya; She, Liang; Xu, Duo; Huang, Wei; Poo, Mu-ming

    2015-06-03

    Dendrite development of newborn granule cells (GCs) in the dentate gyrus of adult hippocampus is critical for their incorporation into existing hippocampal circuits, but the cellular mechanisms regulating their dendrite development remains largely unclear. In this study, we examined the function of brain-derived neurotrophic factor (BDNF), which is expressed in adult-born GCs, in regulating their dendrite morphogenesis. Using retrovirus-mediated gene transfection, we found that deletion and overexpression of BDNF in adult-born GCs resulted in the reduction and elevation of dendrite growth, respectively. This effect was mainly due to the autocrine rather than paracrine action of BDNF, because deletion of BDNF only in the newborn GCs resulted in dendrite abnormality of these neurons to a similar extent as that observed in conditional knockout (cKO) mice with BDNF deleted in the entire forebrain. Furthermore, selective expression of BDNF in adult-born GCs in BDNF cKO mice fully restored normal dendrite development. The BDNF autocrine action was also required for the development of normal density of spines and normal percentage of spines containing the postsynaptic marker PSD-95, suggesting autocrine BDNF regulation of synaptogenesis. Furthermore, increased dendrite growth of adult-born GCs caused by voluntary exercise was abolished by BDNF deletion specifically in these neurons and elevated dendrite growth due to BDNF overexpression in these neurons was prevented by reducing neuronal activity with coexpression of inward rectifier potassium channels, consistent with activity-dependent autocrine BDNF secretion. Therefore, BDNF expressed in adult-born GCs plays a critical role in dendrite development by acting as an autocrine factor.

  13. Surveillance, Phagocytosis, and Inflammation: How Never-Resting Microglia Influence Adult Hippocampal Neurogenesis

    PubMed Central

    Sierra, Amanda; Beccari, Sol; Diaz-Aparicio, Irune; Encinas, Juan M.; Comeau, Samuel; Tremblay, Marie-Ève

    2014-01-01

    Microglia cells are the major orchestrator of the brain inflammatory response. As such, they are traditionally studied in various contexts of trauma, injury, and disease, where they are well-known for regulating a wide range of physiological processes by their release of proinflammatory cytokines, reactive oxygen species, and trophic factors, among other crucial mediators. In the last few years, however, this classical view of microglia was challenged by a series of discoveries showing their active and positive contribution to normal brain functions. In light of these discoveries, surveillant microglia are now emerging as an important effector of cellular plasticity in the healthy brain, alongside astrocytes and other types of inflammatory cells. Here, we will review the roles of microglia in adult hippocampal neurogenesis and their regulation by inflammation during chronic stress, aging, and neurodegenerative diseases, with a particular emphasis on their underlying molecular mechanisms and their functional consequences for learning and memory. PMID:24772353

  14. Gastrin-releasing peptide contributes to the regulation of adult hippocampal neurogenesis and neuronal development.

    PubMed

    Walton, Noah M; de Koning, Anoek; Xie, Xiuyuan; Shin, Rick; Chen, Qian; Miyake, Shinichi; Tajinda, Katsunori; Gross, Adam K; Kogan, Jeffrey H; Heusner, Carrie L; Tamura, Kouichi; Matsumoto, Mitsuyuki

    2014-09-01

    In the postnatal hippocampus, newly generated neurons contribute to learning and memory. Disruptions in neurogenesis and neuronal development have been linked to cognitive impairment and are implicated in a broad variety of neurological and psychiatric disorders. To identify putative factors involved in this process, we examined hippocampal gene expression alterations in mice possessing a heterozygous knockout of the calcium/calmodulin-dependent protein kinase II alpha heterozygous knockout gene (CaMK2α-hKO), an established model of cognitive impairment that also displays altered neurogenesis and neuronal development. Using this approach, we identified gastrin-releasing peptide (GRP) as the most dysregulated gene. In wild-type mice, GRP labels NeuN-positive neurons, the lone exception being GRP-positive, NeuN-negative cells in the subgranular zone, suggesting GRP expression may be relevant to neurogenesis and/or neuronal development. Using a model of in vitro hippocampal neurogenesis, we determined that GRP signaling is essential for the continued survival and development of newborn neurons, both of which are blocked by transient knockdown of GRP's cognate receptor (GRPR). Furthermore, GRP appears to negatively regulate neurogenesis-associated proliferation in neural stem cells both in vitro and in vivo. Intracerebroventricular infusion of GRP resulted in a decrease in immature neuronal markers, increased cAMP response element-binding protein (CREB) phosphorylation, and decreased neurogenesis. Despite increased levels of GRP mRNA, CaMK2α-hKO mutant mice expressed reduced levels of GRP peptide. This lack of GRP may contribute to the elevated neurogenesis and impaired neuronal development, which are reversed following exogenous GRP infusion. Based on these findings, we hypothesize that GRP modulates neurogenesis and neuronal development and may contribute to hippocampus-associated cognitive impairment.

  15. Selection for tameness, a key behavioral trait of domestication, increases adult hippocampal neurogenesis in foxes.

    PubMed

    Huang, Shihhui; Slomianka, Lutz; Farmer, Andrew J; Kharlamova, Anastasiya V; Gulevich, Rimma G; Herbeck, Yury E; Trut, Lyudmila N; Wolfer, David P; Amrein, Irmgard

    2015-08-01

    Work on laboratory and wild rodents suggests that domestication may impact on the extent of adult hippocampal neurogenesis and its responsiveness to regulatory factors. There is, however, no model of laboratory rodents and their nondomesticated conspecifics that would allow a controlled comparison of the effect of domestication. Here, we present a controlled within-species comparison of adult hippocampal neurogenesis in farm-bred foxes (Vulpes vulpes) that differ in their genetically determined degree of tameness. Quantitative comparisons of cell proliferation (Ki67) and differentiating cells of neuronal lineage (doublecortin, DCX) in the hippocampus of foxes were performed as a proxy for neurogenesis. Higher neurogenesis was observed in tameness-selected foxes, notably in an extended subgranular zone of the middle and temporal compartments of the hippocampus. Increased neurogenesis is negatively associated with aggressive behavior. Across all animals, strong septotemporal gradients were found, with higher numbers of proliferating cells and young neurons relative to resident granule cells in the temporal than in the septal hippocampus. The opposite gradient was found for the ratio of DCX/Ki67- positive cells. When tameness-selected and unselected foxes are compared with rodents and primates, proliferation is similar, while the number of young neurons is higher. The difference may be mediated by an extended period of differentiation or higher rate of survival. On the background of this species-specific neurogenic pattern, selection of foxes for a single behavioral trait key to domestication, i.e., genetic tameness, is accompanied by global and region-specific increases in neurogenesis.

  16. Sleep deprivation can inhibit adult hippocampal neurogenesis independent of adrenal stress hormones.

    PubMed

    Mueller, Anka D; Pollock, Michael S; Lieblich, Stephanie E; Epp, Jonathan R; Galea, Liisa A M; Mistlberger, Ralph E

    2008-05-01

    Sleep deprivation (SD) can suppress cell proliferation in the hippocampal dentate gyrus of adult male rodents, suggesting that sleep may contribute to hippocampal functions by promoting neurogenesis. However, suppression of cell proliferation in rats by the platform-over-water SD method has been attributed to elevated corticosterone (Cort), a potent inhibitor of cell proliferation and nonspecific correlate of this procedure. We report here results that do not support this conclusion. Intact and adrenalectomized (ADX) male rats were subjected to a 96-h SD using multiple- and single-platform methods. New cells were identified by immunoreactivity for 5-bromo-2'-deoxyuridine (BrdU) or Ki67 and new neurons by immunoreactivity for BrdU and doublecortin. EEG recordings confirmed a 95% deprivation of rapid eye movement (REM) sleep and a 40% decrease of non-REM sleep. Cell proliferation in the dentate gyrus was suppressed by up to 50% in sleep-deprived rats relative to apparatus control or home cage control rats. This effect was also observed in ADX rats receiving continuous low-dose Cort replacement via subcutaneous minipumps but not in ADX rats receiving Cort replacement via drinking water. In these latter rats, Cort intake via water was reduced by 60% during SD; upregulation of cell proliferation by reduced Cort intake may obscure inhibitory effects of sleep loss on cell proliferation. SD had no effect on the percentage of new cells expressing a neuronal phenotype. These results demonstrate that the Cort replacement method is critical for detecting an effect of SD on cell proliferation and support a significant role for sleep in adult neurogenesis.

  17. Taurine release modified by GABAergic agents in hippocampal slices from adult and developing mice.

    PubMed

    Saransaari, P; Oja, S S

    2000-01-01

    In order to characterize the possible regulation of taurine release by GABAergic terminals, the effects of several agonists and antagonists of GABA receptors on the basal and K+-stimulated release of [3H]taurine were investigated in hippocampal slices from adult (3-month-old) and developing (7-day-old) mice using a superfusion system. Taurine release was concentration-dependently potentiated by GABA, which effect was reduced by phaclofen, saclofen and (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA) at both ages, suggesting regulation by both GABA(B) and GABA(C) receptors. The involvement of GABA(A) receptors could not be excluded since the antagonist bicuculline was able to affect both basal and K+-evoked taurine release. Furthermore, several GABA(B) receptor effectors were able to inhibit K+-stimulated taurine release in the adults, while the GABA(C) receptor agonists trans-4-aminocrotonic acid (TACA) and cis-4-aminocrotonic acid (CACA) potentiated this release. The potentiation of taurine release by agents acting on the three types of GABA receptors in both adult and developing hippocampus further indicates the involvement of transporters operating in an outward direction. This inference is corroborated by the moderate but significant inhibition of taurine uptake by the same compounds.

  18. Hippocampal adult neurogenesis is enhanced by chronic eszopiclone treatment in rats.

    PubMed

    Methippara, Melvi; Bashir, Tariq; Suntsova, Natalia; Szymusiak, Ron; McGinty, Dennis

    2010-09-01

    The adult hippocampal dentate gyrus (DG) exhibits cell proliferation and neurogenesis throughout life. We examined the effects of daily administration of eszopiclone (Esz), a commonly used hypnotic drug and gamma-aminobutyric acid (GABA) agonist, compared with vehicle, on DG cell proliferation and neurogenesis, and on sleep-wake patterns. Esz was administered during the usual sleep period of rats, to mimic typical use in humans. Esz treatment for 7 days did not affect the rate of cell proliferation, as measured by 5-bromo-2'-deoxyuridine (BrdU) immunostaining. However, twice-daily Esz administration for 2 weeks increased survival of newborn cells by 46%. Most surviving cells exhibited a neuronal phenotype, identified as BrdU-neuronal nuclei (NeuN) double-labeling. NeuN is a marker of neurons. Non-rapid eye movement sleep was increased on day 1, but not on days 7 or 14 of Esz administration. Delta electroencephalogram activity was increased on days 1 and 7 of treatment, but not on day 14. There is evidence that enhancement of DG neurogenesis is a critical component of the effects of antidepressant treatments of major depressive disorder (MDD). Adult-born DG cells are responsive to GABAergic stimulation, which promotes cell maturation. The present study suggests that Esz, presumably acting as a GABA agonist, has pro-neurogenic effects in the adult DG. This result is consistent with evidence that Esz enhances the antidepressant treatment response of patients with MDD with insomnia.

  19. Adult-generated hippocampal neurons allow the flexible use of spatially precise learning strategies.

    PubMed

    Garthe, Alexander; Behr, Joachim; Kempermann, Gerd

    2009-01-01

    rather than just a configurational map of the environment. The discovery of highly specific behavioral deficits as consequence of a suppression of adult hippocampal neurogenesis thus allows to link cellular hippocampal plasticity to well-defined hypotheses from theoretical models.

  20. Cross-sectional study of the association of cognitive function and hippocampal volume among healthy elderly adults

    PubMed Central

    Jiang, Lijuan; CHENG, Yan; LI, Qingwei; TANG, Yingying; SHEN, Yuan; LI, Ting; FENG, Wei; CAO, Xinyi; WU, Wenyuan; WANG, Jijun; LI, Chunbo

    2014-01-01

    Background Cognitive impairment and dementia among elderly adults is a pressing public health issue in China but research on biomarkers of cognitive decline has been limited. Aim Explore the relationship between multiple domains of cognitive functioning and the volume of the left and right hippocampus in healthy elderly adults. Methods Structural MRI scanning was performed on 65 community-dwelling healthy participants 65 to 75 years of age using the Siemens 3.0 T Trio Tim with the MPRAGE sequence. The volumes of the left and right hippocampus were determined using Freesurfer software. Cognitive functioning was evaluated using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Both unadjusted and adjusted associations between the hippocampal volumes and cognitive functioning were estimated. Results Within this relatively narrow age range, age was significantly associated with most of the cognitive measures assessed in women but was not significantly associated with any of the cognitive measures in men. In both men and women right hippocampal volume was positively associated with delayed memory and left hippocampal volume was positively associated with both immediate memory and delayed memory (though the relationship with delayed memory in women was only at a trend level). After adjustment for age, gender, and years of formal education (the variable that was most strongly associated with all of the cognitive measures), both left hippocampal volume and right hippocampal volume were positively associated with delayed memory, but not with immediate memory. Interestingly, the difference in the volumes of the left and right hippocampi was negatively associated with the score of the RBANS attention subscale, a relationship that was stronger in women than in men. Conclusions This study confirms previous work about the relationship of hippocampal volume and memory, identifies a possible relationship between attention and the difference in size of

  1. Interneuron precursor transplants in adult hippocampus reverse psychosis-relevant features in a mouse model of hippocampal disinhibition.

    PubMed

    Gilani, Ahmed I; Chohan, Muhammad O; Inan, Melis; Schobel, Scott A; Chaudhury, Nashid H; Paskewitz, Samuel; Chuhma, Nao; Glickstein, Sara; Merker, Robert J; Xu, Qing; Small, Scott A; Anderson, Stewart A; Ross, Margaret Elizabeth; Moore, Holly

    2014-05-20

    GABAergic interneuron hypofunction is hypothesized to underlie hippocampal dysfunction in schizophrenia. Here, we use the cyclin D2 knockout (Ccnd2(-/-)) mouse model to test potential links between hippocampal interneuron deficits and psychosis-relevant neurobehavioral phenotypes. Ccnd2(-/-) mice show cortical PV(+) interneuron reductions, prominently in hippocampus, associated with deficits in synaptic inhibition, increased in vivo spike activity of projection neurons, and increased in vivo basal metabolic activity (assessed with fMRI) in hippocampus. Ccnd2(-/-) mice show several neurophysiological and behavioral phenotypes that would be predicted to be produced by hippocampal disinhibition, including increased ventral tegmental area dopamine neuron population activity, behavioral hyperresponsiveness to amphetamine, and impairments in hippocampus-dependent cognition. Remarkably, transplantation of cells from the embryonic medial ganglionic eminence (the major origin of cerebral cortical interneurons) into the adult Ccnd2(-/-) caudoventral hippocampus reverses these psychosis-relevant phenotypes. Surviving neurons from these transplants are 97% GABAergic and widely distributed within the hippocampus. Up to 6 mo after the transplants, in vivo hippocampal metabolic activity is lowered, context-dependent learning and memory is improved, and dopamine neuron activity and the behavioral response to amphetamine are normalized. These findings establish functional links between hippocampal GABA interneuron deficits and psychosis-relevant dopaminergic and cognitive phenotypes, and support a rationale for targeting limbic cortical interneuron function in the prevention and treatment of schizophrenia.

  2. Serotonin Depletion Hampers Survival and Proliferation in Neurospheres Derived from Adult Neural Stem Cells

    PubMed Central

    Benninghoff, Jens; Gritti, Angela; Rizzi, Matteo; LaMorte, Giuseppe; Schloesser, Robert J; Schmitt, Angelika; Robel, Stefanie; Genius, Just; Moessner, Rainald; Riederer, Peter; Manji, Husseini K; Grunze, Heinz; Rujescu, Dan; Moeller, Hans-Juergen; Lesch, Klaus-Peter; Vescovi, Angelo Luigi

    2010-01-01

    Serotonin (5-HT) and the serotonergic system have recently been indicated as modulators of adult hippocampal neurogenesis. In this study, we evaluated the role of 5-HT on the functional features in neurospheres derived from adult neural stem cells (ANSC). We cultured neurospheres derived from mouse hippocampus in serum-free medium containing epidermal (EGF) and type-2 fibroblast growth factor (FGF2). Under these conditions ANSC expressed both isoforms of tryptophane-hydroxylase (TPH) and produced 5-HT. Blocking TPH function by para-chlorophenylalanine (PCPA) reduced ANSC proliferation, which was rescued by exogenous 5-HT. 5-HT action on ANSC was mediated predominantly by the serotonin receptor subtype 5-HT1A and, to a lesser extent, through the 5-HT2C (receptor) subtype, as shown by selectively antagonizing these receptors. Finally, we documented a 5-HT-induced increase of ANSC migration activity. In summary, we demonstrated a powerful serotonergic impact on ANSC functional features, which was mainly mediated by 5-HT1A receptors. PMID:20010549

  3. Serotonin depletion hampers survival and proliferation in neurospheres derived from adult neural stem cells.

    PubMed

    Benninghoff, Jens; Gritti, Angela; Rizzi, Matteo; Lamorte, Giuseppe; Schloesser, Robert J; Schmitt, Angelika; Robel, Stefanie; Genius, Just; Moessner, Rainald; Riederer, Peter; Manji, Husseini K; Grunze, Heinz; Rujescu, Dan; Moeller, Hans-Juergen; Lesch, Klaus-Peter; Vescovi, Angelo Luigi

    2010-03-01

    Serotonin (5-HT) and the serotonergic system have recently been indicated as modulators of adult hippocampal neurogenesis. In this study, we evaluated the role of 5-HT on the functional features in neurospheres derived from adult neural stem cells (ANSC). We cultured neurospheres derived from mouse hippocampus in serum-free medium containing epidermal (EGF) and type-2 fibroblast growth factor (FGF2). Under these conditions ANSC expressed both isoforms of tryptophane-hydroxylase (TPH) and produced 5-HT. Blocking TPH function by para-chlorophenylalanine (PCPA) reduced ANSC proliferation, which was rescued by exogenous 5-HT. 5-HT action on ANSC was mediated predominantly by the serotonin receptor subtype 5-HT1A and, to a lesser extent, through the 5-HT2C (receptor) subtype, as shown by selectively antagonizing these receptors. Finally, we documented a 5-HT-induced increase of ANSC migration activity. In summary, we demonstrated a powerful serotonergic impact on ANSC functional features, which was mainly mediated by 5-HT1A receptors.

  4. Seipin knockout in mice impairs stem cell proliferation and progenitor cell differentiation in the adult hippocampal dentate gyrus via reduced levels of PPARγ

    PubMed Central

    Li, Guoxi; Zhou, Libin; Zhu, Ying; Wang, Conghui; Sha, Sha; Xian, Xunde; Ji, Yong; Liu, George; Chen, Ling

    2015-01-01

    ABSTRACT The seipin gene (BSCL2) was originally identified in humans as a loss-of-function gene associated with congenital generalized lipodystrophy type 2 (CGL2). Neuronal seipin-knockout (seipin-nKO) mice display a depression-like phenotype with a reduced level of hippocampal peroxisome proliferator-activated receptor gamma (PPARγ). The present study investigated the influence of seipin deficiency on adult neurogenesis in the hippocampal dentate gyrus (DG) and the underlying mechanisms of the effects. We show that the proliferative capability of stem cells in seipin-nKO mice was substantially reduced compared to in wild-type (WT) mice, and that this could be rescued by the PPARγ agonist rosiglitazone (rosi). In seipin-nKO mice, neuronal differentiation of progenitor cells was inhibited, with the enhancement of astrogliogenesis; both of these effects were recovered by rosi treatment during early stages of progenitor cell differentiation. In addition, rosi treatment could correct the decline in hippocampal ERK2 phosphorylation and cyclin A mRNA level in seipin-nKO mice. The MEK inhibitor U0126 abolished the rosi-rescued cell proliferation and cyclin A expression in seipin-nKO mice. In seipin-nKO mice, the hippocampal Wnt3 protein level was less than that in WT mice, and there was a reduction of neurogenin 1 (Neurog1) and neurogenic differentiation 1 (NeuroD1) mRNA, levels of which were corrected by rosi treatment. STAT3 phosphorylation (Tyr705) was enhanced in seipin-nKO mice, and was further elevated by rosi treatment. Finally, rosi treatment for 10 days could alleviate the depression-like phenotype in seipin-nKO mice, and this alleviation was blocked by the MEK inhibitor U0126. The results indicate that, by reducing PPARγ, seipin deficiency impairs proliferation and differentiation of neural stem and progenitor cells, respectively, in the adult DG, which might be responsible for the production of the depression-like phenotype in seipin-nKO mice. PMID

  5. Role of Wnt Signaling in the Control of Adult Hippocampal Functioning in Health and Disease: Therapeutic Implications

    PubMed Central

    Ortiz-Matamoros, Abril; Salcedo-Tello, Pamela; Avila-Muñoz, Evangelina; Zepeda, Angélica; Arias, Clorinda

    2013-01-01

    It is well recognized the role of the Wnt pathway in many developmental processes such as neuronal maturation, migration, neuronal connectivity and synaptic formation. Growing evidence is also demonstrating its function in the mature brain where is associated with modulation of axonal remodeling, dendrite outgrowth, synaptic activity, neurogenesis and behavioral plasticity. Proteins involved in Wnt signaling have been found expressed in the adult hippocampus suggesting that Wnt pathway plays a role in the hippocampal function through life. Indeed, Wnt ligands act locally to regulate neurogenesis, neuronal cell shape and pre- and postsynaptic assembly, events that are thought to underlie changes in synaptic function associated with long-term potentiation and with cognitive tasks such as learning and memory. Recent data have demonstrated the increased expression of the Wnt antagonist Dickkopf-1 (DKK1) in brains of Alzheimer´s disease (AD) patients suggesting that dysfunction of Wnt signaling could also contribute to AD pathology. We review here evidence of Wnt-associated molecules expression linked to physiological and pathological hippocampal functioning in the adult brain. The basic aspects of Wnt related mechanisms underlying hippocampal plasticity as well as evidence of how hippocampal dysfunction may rely on Wnt dysregulation is analyzed. This information would provide some clues about the possible therapeutic targets for developing treatments for neurodegenerative diseases associated with aberrant brain plasticity. PMID:24403870

  6. Potential of adult neural stem cells in stroke therapy.

    PubMed

    Andres, Robert H; Choi, Raymond; Steinberg, Gary K; Guzman, Raphael

    2008-11-01

    Despite state-of-the-art therapy, clinical outcome after stroke remains poor, with many patients left permanently disabled and dependent on care. Stem cell therapy has evolved as a promising new therapeutic avenue for the treatment of stroke in experimental studies, and recent clinical trials have proven its feasibility and safety in patients. Replacement of damaged cells and restoration of function can be accomplished by transplantation of different cell types, such as embryonic, fetal or adult stem cells, human fetal tissue and genetically engineered cell lines. Adult neural stem cells offer the advantage of avoiding the ethical problems associated with embryonic or fetal stem cells and can be harvested as autologous grafts from the individual patients. Furthermore, stimulation of endogenous adult stem cell-mediated repair mechanisms in the brain might offer new avenues for stroke therapy without the necessity of transplantation. However, important scientific issues need to be addressed to advance our understanding of the molecular mechanisms underlying the critical steps in cell-based repair to allow the introduction of these experimental techniques into clinical practice. This review describes up-to-date experimental concepts using adult neural stem cells for the treatment of stroke.

  7. Effect of ketamine on ERK expression in hippocampal neural cell and the ability of learning behavior in minor rats.

    PubMed

    Peng, Sheng; Zhang, Yan; Zhang, Jiannan; Wang, Hua; Ren, Bingxu

    2010-10-01

    To study the effects of ketamine on ERK expression in hippocampal neural cell and the ability of learning behavior in minor rats. Seventy-two Sprague-Dawley rats of 21 days old were randomly divided into nine groups. The Y-maze was used to test the ability of learning and spatial localization. At the end of training, all rats were killed and the expression levels of ERK1, ERK2 and p-ERK1/2 were tested by immunohistochemistry. The learning times and total reaction time (TRT) of group K2a, K2b, K2c and K3 have significant differences compared with T group (P < 0.05). Immunohistochemical staining showed that the level of ERK1, ERK2 and p-ERK1/2 in all rats which received light-electricity integrated training increased remarkably relative to the C group (P < 0.01). The expression levels of ERK1, ERK2 and p-ERK1/2 in hippocampal neural cell of group K2a, K2b and K3 significantly decreased when compared with T group (P < 0.05). Therefore, the results demonstrate that administration of over-anesthetic ketamine may impair learning ability of 21 days old rats within 24 h. ERK signal transduction pathway may be involved in the ability of learning and spatial localization. The inhibition of ERK signal transduction pathway may be one of the mechanisms of the impairment of learning and memory ability by ketamine.

  8. Genetic influences on exercise-induced adult hippocampal neurogenesis across 12 divergent mouse strains

    PubMed Central

    Clark, Peter J.; Kohman, Rachel A.; Miller, Daniel S.; Bhattacharya, Tushar K.; Brzezinska, Weronika J.; Rhodes, Justin S.

    2011-01-01

    New neurons are continuously born in the hippocampus of several mammalian species throughout adulthood. Adult neurogenesis represents a natural model for understanding how to grow and incorporate new nerve cells into pre-existing circuits in the brain. Finding molecules or biological pathways that increase neurogenesis has broad potential for regenerative medicine. One strategy is to identify mouse strains that display large versus small increases in neurogenesis in response to wheel running so the strains can be contrasted to find common genes or biological pathways associated with enhanced neuron formation. Therefore, mice from 12 different isogenic strains were housed with or without running wheels for 43 days to measure the genetic regulation of exercise-induced neurogenesis. The first 10 days mice received daily injections of BrdU to label dividing cells. Neurogenesis was measured as the total number of BrdU cells co-expressing NeuN mature neuronal marker in the hippocampal granule cell layer by immunohistochemistry. Exercise increased neurogenesis in all strains, but the magnitude significantly depended on genotype. Strain means for distance run on wheels, but not distance traveled in cages without wheels, were significantly correlated with strain mean level of neurogenesis. Further, certain strains displayed greater neurogenesis than others for a fixed level of running. Strain means for neurogenesis under sedentary conditions were not correlated with neurogenesis under runner conditions suggesting that different genes influence baseline versus exercise-induced neurogenesis. Genetic contributions to exercise-induced hippocampal neurogenesis suggest that it may be possible to identify genes and pathways associated with enhanced neuroplastic responses to exercise. PMID:21223504

  9. Fetal iron deficiency alters the proteome of adult rat hippocampal synaptosomes

    PubMed Central

    Dakoji, Srikanth; Reise, Kathryn H.; Storey, Kathleen K.; Georgieff, Michael K.

    2013-01-01

    Fetal and neonatal iron deficiency results in cognitive impairments in adulthood despite prompt postnatal iron replenishment. To systematically determine whether abnormal expression and localization of proteins that regulate adult synaptic efficacy are involved, we used a quantitative proteomic approach (isobaric tags for relative and absolute quantitation, iTRAQ) and pathway analysis to identify dysregulated proteins in hippocampal synapses of fetal iron deficiency model. Rat pups were made iron deficient (ID) from gestational day 2 through postnatal day (P) 7 by providing pregnant and nursing dams an ID diet (4 ppm Fe) after which they were rescued with an iron-sufficient diet (200 ppm Fe). This paradigm resulted in a 40% loss of brain iron at P15 with complete recovery by P56. Synaptosomes were prepared from hippocampi of the formerly iron-deficient (FID) and always iron-sufficient controls rats at P65 using a sucrose gradient method. Six replicates per group that underwent iTRAQ labeling and LC-MS/MS analysis for protein identification and comparison elucidated 331 differentially expressed proteins. Western analysis was used to confirm findings for selected proteins in the glutamate receptor signaling pathway, which regulates hippocampal synaptic plasticity, a cellular process critical for learning and memory. Bioinformatics were performed using knowledge-based Interactive Pathway Analysis. FID synaptosomes show altered expression of synaptic proteins-mediated cellular signalings, supporting persistent impacts of fetal iron deficiency on synaptic efficacy, which likely cause the cognitive dysfunction and neurobehavioral abnormalities. Importantly, the findings uncover previously unsuspected pathways, including neuronal nitric oxide synthase signaling, identifying additional mechanisms that may contribute to the long-term biobehavioral deficits. PMID:24089371

  10. Short- and long-term treatment with modafinil differentially affects adult hippocampal neurogenesis.

    PubMed

    Brandt, M D; Ellwardt, E; Storch, A

    2014-10-10

    The generation of new neurons in the dentate gyrus of the adult brain has been demonstrated in many species including humans and is suggested to have functional relevance for learning and memory. The wake promoting drug modafinil has popularly been categorized as a so-called neuroenhancer due to its positive effects on cognition. We here show that short- and long-term treatment with modafinil differentially effects hippocampal neurogenesis. We used different thymidine analogs (5-bromo-2-deoxyuridine (BrdU), chlorodeoxyuridine (CldU), iododeoxyuridine (IdU)) and labeling protocols to investigate distinct regulative events during hippocampal neurogenesis, namely cell proliferation and survival. Eight-week-old mice that were treated with modafinil (64mg/kg, i.p.) every 24h for 4days show increased proliferation in the dentate gyrus indicated by BrdU-labeling and more newborn granule cells 3weeks after treatment. Short-term treatment for 4days also enhanced the number of postmitotic calretinin-expressing progenitor cells that were labeled with BrdU 1week prior to treatment indicating an increased survival of new born immature granule cells. Interestingly, long-term treatment for 14days resulted in an increased number of newborn Prox1(+) granule cells, but we could not detect an additive effect of the prolonged treatment on proliferation and survival of newborn cells. Moreover, daily administration for 14days did not influence the number of proliferating cells in the dentate gyrus. Together, modafinil has an acute impact on precursor cell proliferation as well as survival but loses this ability during longer treatment durations.

  11. Semaphorin 5A inhibits synaptogenesis in early postnatal- and adult-born hippocampal dentate granule cells

    PubMed Central

    Duan, Yuntao; Wang, Shih-Hsiu; Song, Juan; Mironova, Yevgeniya; Ming, Guo-li; Kolodkin, Alex L; Giger, Roman J

    2014-01-01

    Human SEMAPHORIN 5A (SEMA5A) is an autism susceptibility gene; however, its function in brain development is unknown. In this study, we show that mouse Sema5A negatively regulates synaptogenesis in early, developmentally born, hippocampal dentate granule cells (GCs). Sema5A is strongly expressed by GCs and regulates dendritic spine density in a cell-autonomous manner. In the adult mouse brain, newly born Sema5A−/− GCs show an increase in dendritic spine density and increased AMPA-type synaptic responses. Sema5A signals through PlexinA2 co-expressed by GCs, and the PlexinA2-RasGAP activity is necessary to suppress spinogenesis. Like Sema5A−/− mutants, PlexinA2−/− mice show an increase in GC glutamatergic synapses, and we show that Sema5A and PlexinA2 genetically interact with respect to GC spine phenotypes. Sema5A−/− mice display deficits in social interaction, a hallmark of autism-spectrum-disorders. These experiments identify novel intra-dendritic Sema5A/PlexinA2 interactions that inhibit excitatory synapse formation in developmentally born and adult-born GCs, and they provide support for SEMA5A contributions to autism-spectrum-disorders. DOI: http://dx.doi.org/10.7554/eLife.04390.001 PMID:25313870

  12. Altered adult hippocampal neuronal maturation in a rat model of fetal alcohol syndrome.

    PubMed

    Gil-Mohapel, Joana; Boehme, Fanny; Patten, Anna; Cox, Adrian; Kainer, Leah; Giles, Erica; Brocardo, Patricia S; Christie, Brian R

    2011-04-12

    Exposure to ethanol during pregnancy can be devastating to the developing nervous system, leading to significant central nervous system dysfunction. The hippocampus, one of the two brain regions where neurogenesis persists into adulthood, is particularly sensitive to the teratogenic effects of ethanol. In the present study, we tested a rat model of fetal alcohol syndrome (FAS) with ethanol administered via gavage throughout all three trimester equivalents. Subsequently, we assessed cell proliferation, as well as neuronal survival, and differentiation in the dentate gyrus of the hippocampus of adolescent (35 days old), young adult (60 days old) and adult (90 days old) Sprague-Dawley rats. Using both extrinsic (bromodeoxyuridine) and intrinsic (Ki-67) markers, we observed no significant alterations in cell proliferation and survival in ethanol-exposed animals when compared with their pair-fed and ad libitum controls. However, we detected a significant increase in the number of new immature neurons in animals that were exposed to ethanol throughout all three trimester equivalents. This result might reflect a compensatory mechanism to counteract the deleterious effects of prenatal ethanol exposure or an ethanol-induced arrest of the neurogenic process at the early neuronal maturation stages. Taken together these results indicate that exposure to ethanol during the period of brain development causes a long-lasting dysregulation of the neurogenic process, a mechanism that might contribute, at least in part, to the hippocampal deficits that have been reported in rodent models of FAS.

  13. The Nuclear Receptor REV-ERBα Regulates Fabp7 and Modulates Adult Hippocampal Neurogenesis

    PubMed Central

    Schnell, Anna; Chappuis, Sylvie; Schmutz, Isabelle; Brai, Emanuele; Ripperger, Jürgen A.; Schaad, Olivier; Welzl, Hans; Descombes, Patrick; Alberi, Lavinia; Albrecht, Urs

    2014-01-01

    The function of the nuclear receptor Rev-erbα (Nr1d1) in the brain is, apart from its role in the circadian clock mechanism, unknown. Therefore, we compared gene expression profiles in the brain between wild-type and Rev-erbα knock-out (KO) animals. We identified fatty acid binding protein 7 (Fabp7, Blbp) as a direct target of repression by REV-ERBα. Loss of Rev-erbα manifested in memory and mood related behavioral phenotypes and led to overexpression of Fabp7 in various brain areas including the subgranular zone (SGZ) of the hippocampus, where neuronal progenitor cells (NPCs) can initiate adult neurogenesis. We found increased proliferation of hippocampal neurons and loss of its diurnal pattern in Rev-erbα KO mice. In vitro, proliferation and migration of glioblastoma cells were affected by manipulating either Fabp7 expression or REV-ERBα activity. These results suggest an important role of Rev-erbα and Fabp7 in adult neurogenesis, which may open new avenues for treatment of gliomas as well as neurological diseases such as depression and Alzheimer. PMID:24932636

  14. Pharmacological reduction of adult hippocampal neurogenesis modifies functional brain circuits in mice exposed to a cocaine conditioned place preference paradigm.

    PubMed

    Castilla-Ortega, Estela; Blanco, Eduardo; Serrano, Antonia; Ladrón de Guevara-Miranda, David; Pedraz, María; Estivill-Torrús, Guillermo; Pavón, Francisco Javier; Rodríguez de Fonseca, Fernando; Santín, Luis J

    2016-05-01

    We investigated the role of adult hippocampal neurogenesis in cocaine-induced conditioned place preference (CPP) behaviour and the functional brain circuitry involved. Adult hippocampal neurogenesis was pharmacologically reduced with temozolomide (TMZ), and mice were tested for cocaine-induced CPP to study c-Fos expression in the hippocampus and in extrahippocampal addiction-related areas. Correlational and multivariate analysis revealed that, under normal conditions, the hippocampus showed widespread functional connectivity with other brain areas and strongly contributed to the functional brain module associated with CPP expression. However, the neurogenesis-reduced mice showed normal CPP acquisition but engaged an alternate brain circuit where the functional connectivity of the dentate gyrus was notably reduced and other areas (the medial prefrontal cortex, accumbens and paraventricular hypothalamic nucleus) were recruited instead of the hippocampus. A second experiment unveiled that mice acquiring the cocaine-induced CPP under neurogenesis-reduced conditions were delayed in extinguishing their drug-seeking behaviour. But if the inhibited neurons were generated after CPP acquisition, extinction was not affected but an enhanced long-term CPP retention was found, suggesting that some roles of the adult-born neurons may differ depending on whether they are generated before or after drug-contextual associations are established. Importantly, cocaine-induced reinstatement of CPP behaviour was increased in the TMZ mice, regardless of the time of neurogenesis inhibition. The results show that adult hippocampal neurogenesis sculpts the addiction-related functional brain circuits, and reduction of the adult-born hippocampal neurons increases cocaine seeking in the CPP model.

  15. Adult attachment style modulates neural responses in a mentalizing task.

    PubMed

    Schneider-Hassloff, H; Straube, B; Nuscheler, B; Wemken, G; Kircher, T

    2015-09-10

    Adult attachment style (AAS) is a personality trait that affects social cognition. Behavioral data suggest that AAS influences mentalizing proficiency, i.e. the ability to predict and explain people's behavior with reference to mental states, but the neural correlates are unknown. We here tested how the AAS dimensions "avoidance" (AV) and "anxiety" (ANX) modulate neural correlates of mentalizing. We measured brain activation using functional magnetic resonance imaging (fMRI) in 164 healthy subjects during an interactive mentalizing paradigm (Prisoner's Dilemma Game). AAS was assessed with the Relationship Scales Questionnaire, including the subscales AV and ANX. Our task elicited a strong activation of the mentalizing network, including bilateral precuneus, (anterior, middle, and posterior) cingulate cortices, temporal poles, inferior frontal gyri (IFG), temporoparietal junctions, superior medial frontal gyri as well as right medial orbital frontal gyrus, superior temporal gyrus, middle frontal gyrus (MFG), and amygdala. We found that AV is positively and ANX negatively correlated with task-associated neural activity in the right amygdala, MFG, midcingulate cortex, and superior parietal lobule, and in bilateral IFG. These data suggest that avoidantly attached adults activate brain areas implicated in emotion regulation and cognitive control to a larger extent than anxiously attached individuals during mentalizing.

  16. Homeostatic regulation of adult hippocampal neurogenesis in aging rats: long-term effects of early exercise

    PubMed Central

    Merkley, Christina M.; Jian, Charles; Mosa, Adam; Tan, Yao-Fang; Wojtowicz, J. Martin

    2014-01-01

    Adult neurogenesis is highly responsive to environmental and physiological factors. The majority of studies to date have examined short-term consequences of enhancing or blocking neurogenesis but long-term changes remain less well understood. Current evidence for age-related declines in neurogenesis warrant further investigation into these long-term changes. In this report we address the hypothesis that early life experience, such as a period of voluntary running in juvenile rats, can alter properties of adult neurogenesis for the remainder of the animal's life. The results indicate that the number of proliferating and differentiating neuronal precursors is not altered in runners beyond the initial weeks post-running, suggesting homeostatic regulation of these processes. However, the rate of neuronal maturation and survival during a 4 week period after cell division was enhanced up to 11 months of age (the end of the study period). This study is the first to show that a transient period of physical activity at a young age promotes changes in neurogenesis that persist over the long-term, which is important for our understanding of the modulation of neurogenesis by exercise with age. Functional integration of adult-born neurons within the hippocampus that resist homeostatic regulation with aging, rather than the absolute number of adult-born neurons, may be an essential feature of adult neurogenesis that promotes the maintenance of neural plasticity in old age. PMID:25071426

  17. Reward cues in space: commonalities and differences in neural coding by hippocampal and ventral striatal ensembles

    PubMed Central

    Lansink, Carien S.; Jackson, Jadin; Lankelma, Jan V.; Ito, Rutsuko; Robbins, Trevor W.; Everitt, Barry J.; Pennartz, Cyriel M.A.

    2012-01-01

    Forming place-reward associations critically depends on the integrity of the hippocampal-ventral striatal system. The ventral striatum receives a strong hippocampal input conveying spatial-contextual information, but it is unclear how this structure integrates this information to invigorate reward-directed behavior. Neuronal ensembles in rat hippocampus and ventral striatum were simultaneously recorded during a conditioning task in which navigation depended on path integration. In contrast to hippocampus, ventral striatal neurons showed low spatial selectivity, but rather coded behavioral task phases towards reaching goal sites. Outcome-predicting cues induced a remapping of firing patterns in the hippocampus, consistent with its role in episodic memory. Ventral striatum remapped in conjunction with the hippocampus, indicating that remapping can take place in multiple brain regions engaged in the same task. Subsets of ventral striatal neurons showed a “flip” from high activity when cue lights were illuminated to low activity in intertrial intervals, or vice versa. The cues induced an increase in spatial information transmission and sparsity in both structures. These effects were paralleled by an enhanced temporal specificity of ensemble coding and a more accurate reconstruction of the animal’s position from population firing patterns. Altogether, the results reveal strong differences in spatial processing between hippocampal area CA1 and ventral striatum, but indicate similarities in how discrete cues impact on this processing. PMID:22956836

  18. Delayed and transient increase of adult hippocampal neurogenesis by physical exercise in DBA/2 mice.

    PubMed

    Overall, Rupert W; Walker, Tara L; Leiter, Odette; Lenke, Sina; Ruhwald, Susann; Kempermann, Gerd

    2013-01-01

    This study builds on the findings that physical activity, such as wheel running in mice, enhances cell proliferation and neurogenesis in the adult hippocampus of the common mouse strain C57BL/6, and that the baseline level of neurogenesis varies by strain, being considerably lower in DBA/2. Because C57BL/6 and DBA/2 are important as the parental strains of the BXD recombinant inbred cross which allows the detection of genetic loci regulating phenotypes such as adult neurogenesis, we performed the current study to investigate the gene x environment interactions regulating neurogenesis. At equal distances and times run DBA/2J mice lacked the acute increase in precursor cell proliferation known from C57BL/6. In DBA/2J proliferation even negatively correlated with the distance run. This was neither due to a stress response (to running itself or single housing) nor differences in estrous cycle. DBA/2 animals exhibited a delayed and weaker pro-neurogenic response with a significant increase in numbers of proliferating cells first detectable after more than a week of wheel running. The proliferative response to running was transient in both strains, the effect being undetectable by 6 weeks. There was also a small transient increase in the production of new neurons in DBA/2J, although these extra cells did not survive. These findings indicate that the comparison between C57BL/6 and DBA/2, and by extension the BXD genetic reference population derived from these strains, should provide a powerful tool for uncovering the complex network of modifier genes affecting the activity-dependent regulation of adult hippocampal neurogenesis. More generally, our findings also describe how the external physical environment interacts with the internal genetic environment to produce different responses to the same behavioral stimuli.

  19. Large-scale phenotyping links adult hippocampal neurogenesis to the reaction to novelty.

    PubMed

    van Dijk, R Maarten; Lazic, Stanley E; Slomianka, Lutz; Wolfer, David P; Amrein, Irmgard

    2016-05-01

    The discovery of adult-born neurons in the hippocampus has triggered a wide range of studies that link the new neurons to various behavioral functions. However, the role of new neurons in behavior is still equivocal. Conflicting results may be due to the difficulty in manipulating neurogenesis without off-target effects as well as the statistical approach used, which fail to account for neurogenesis-independent effects of experimental manipulations on behavior. In this study, we apply a more comprehensive statistical and conceptual approach. Instead of between-group analyses, we consider the within-group relationships between neurogenesis and behavior (ANCOVA and mediation analysis) in a large-scale experiment, in which distinct age- (3 and 5 months) and strain- (DBA and C57) related differences in basal levels of neurogenesis in mice are compared with a large number (∼1,500) of behavioral read outs. The analysis failed to detect any association between anxiety and motor impulsivity with neurogenesis. However, within-group adult hippocampal neurogenesis is associated with the reaction to novelty. Specifically, more neurogenesis is associated with a longer latency to explore and a lower frequency of exploratory actions, overall indicative of a phenotype where animals with more neurogenesis were slower to explore a novel environment. This effect is observed in 5-months-old, but not in 3-months-old mice of both strains. An association between the reaction to novelty and adult neurogenesis can have a major impact on results from previous studies using classical behavioral experiments, in which animals are tested in a--for the animal--novel experimental set-up. The neurogenesis-novelty association found here is also a necessary link in the relation that has been suggested to exist between neurogenesis and psychiatric disorders marked by a failure to cope with novelty.

  20. Immune Influence on Adult Neural Stem Cell Regulation and Function

    PubMed Central

    Carpentier, Pamela A.; Palmer, Theo D.

    2009-01-01

    Neural stem cells (NSCs) lie at the heart of central nervous system development and repair, and deficiency or dysregulation of NSCs or their progeny can have significant consequences at any stage of life. Immune signaling is emerging as one of the influential variables that define resident NSC behavior. Perturbations in local immune signaling accompany virtually every injury or disease state and signaling cascades that mediate immune activation, resolution, or chronic persistence influence resident stem and progenitor cells. Some aspects of immune signaling are beneficial, promoting intrinsic plasticity and cell replacement, while others appear to inhibit the very type of regenerative response that might restore or replace neural networks lost in injury or disease. Here we review known and speculative roles that immune signaling plays in the postnatal and adult brain, focusing on how environments encountered in disease or injury may influence the activity and fate of endogenous or transplanted NSCs. PMID:19840551

  1. Voluntary Running Prevents Progressive Memory Decline and Increases Adult Hippocampal Neurogenesis and Growth Factor Expression After Whole-Brain Irradiation

    PubMed Central

    Wong-Goodrich, Sarah J.E.; Pfau, Madeline L.; Flores, Catherine T.; Fraser, Jennifer A.; Williams, Christina L.; Jones, Lee W.

    2010-01-01

    Whole-brain irradiation (WBI) therapy produces progressive learning and memory deficits in patients with primary or secondary brain tumors. Exercise enhances memory and adult hippocampal neurogenesis in the intact brain, so we hypothesized that exercise may be an effective treatment to alleviate consequences of WBI. Previous studies using animal models to address this issue have yielded mixed results and have not examined potential molecular mechanisms. We investigated the short- and long-term effects of WBI on spatial learning and memory retention, and determined whether voluntary running after WBI aids recovery of brain and cognitive function. Forty adult female C57Bl/6 mice given a single dose of 5 Gy or sham WBI were trained 2.5 weeks and up to four months after WBI in a Barnes maze. Half of the mice received daily voluntary wheel access starting one month after sham- or WBI. Daily running following WBI prevented the marked decline in spatial memory retention observed months after irradiation. Bromodeoxyuridine (BrdU) immunolabeling and ELISA indicated that this behavioral rescue was accompanied by a partial restoration of newborn BrdU+/NeuN+ neurons in the dentate gyrus and increased hippocampal expression of brain-derived vascular endothelial growth factor and insulin-like growth factor, and occurred despite irradiation-induced elevations in hippocampal pro-inflammatory cytokines. WBI in adult mice produced a progressive memory decline consistent with what has been reported in cancer patients receiving WBI therapy. Our findings show that running can abrogate this memory decline and aid recovery of adult hippocampal plasticity, thus highlighting exercise as a potential therapeutic intervention. PMID:20884629

  2. Maternal postpartum corticosterone and fluoxetine differentially affect adult male and female offspring on anxiety-like behavior, stress reactivity, and hippocampal neurogenesis.

    PubMed

    Gobinath, Aarthi R; Workman, Joanna L; Chow, Carmen; Lieblich, Stephanie E; Galea, Liisa A M

    2016-02-01

    Postpartum depression (PPD) affects approximately 15% of mothers, disrupts maternal care, and can represent a form of early life adversity for the developing offspring. Intriguingly, male and female offspring are differentially vulnerable to the effects of PPD. Antidepressants, such as fluoxetine, are commonly prescribed for treating PPD. However, fluoxetine can reach offspring via breast milk, raising serious concerns regarding the long-term consequences of infant exposure to fluoxetine. The goal of this study was to examine the long-term effects of maternal postpartum corticosterone (CORT, a model of postpartum stress/depression) and concurrent maternal postpartum fluoxetine on behavioral, endocrine, and neural measures in adult male and female offspring. Female Sprague-Dawley dams were treated daily with either CORT or oil and fluoxetine or saline from postnatal days 2-23, and offspring were weaned and left undisturbed until adulthood. Here we show that maternal postpartum fluoxetine increased anxiety-like behavior and impaired hypothalamic-pituitary-adrenal (HPA) axis negative feedback in adult male, but not female, offspring. Furthermore, maternal postpartum fluoxetine increased the density of immature neurons (doublecortin-expressing) in the hippocampus of adult male offspring but decreased the density of immature neurons in adult female offspring. Maternal postpartum CORT blunted HPA axis negative feedback in males and tended to increase density of immature neurons in males but decreased it in females. These results indicate that maternal postpartum CORT and fluoxetine can have long-lasting effects on anxiety-like behavior, HPA axis negative feedback, and adult hippocampal neurogenesis and that adult male and female offspring are differentially affected by these maternal manipulations.

  3. Axonal control of the adult neural stem cell niche.

    PubMed

    Tong, Cheuk Ka; Chen, Jiadong; Cebrián-Silla, Arantxa; Mirzadeh, Zaman; Obernier, Kirsten; Guinto, Cristina D; Tecott, Laurence H; García-Verdugo, Jose Manuel; Kriegstein, Arnold; Alvarez-Buylla, Arturo

    2014-04-03

    The ventricular-subventricular zone (V-SVZ) is an extensive germinal niche containing neural stem cells (NSCs) in the walls of the lateral ventricles of the adult brain. How the adult brain's neural activity influences the behavior of adult NSCs remains largely unknown. We show that serotonergic (5HT) axons originating from a small group of neurons in the raphe form an extensive plexus on most of the ventricular walls. Electron microscopy revealed intimate contacts between 5HT axons and NSCs (B1) or ependymal cells (E1) and these cells were labeled by a transsynaptic viral tracer injected into the raphe. B1 cells express the 5HT receptors 2C and 5A. Electrophysiology showed that activation of these receptors in B1 cells induced small inward currents. Intraventricular infusion of 5HT2C agonist or antagonist increased or decreased V-SVZ proliferation, respectively. These results indicate that supraependymal 5HT axons directly interact with NSCs to regulate neurogenesis via 5HT2C.

  4. Live Imaging of Adult Neural Stem Cells in Rodents

    PubMed Central

    Ortega, Felipe; Costa, Marcos R.

    2016-01-01

    The generation of cells of the neural lineage within the brain is not restricted to early development. New neurons, oligodendrocytes, and astrocytes are produced in the adult brain throughout the entire murine life. However, despite the extensive research performed in the field of adult neurogenesis during the past years, fundamental questions regarding the cell biology of adult neural stem cells (aNSCs) remain to be uncovered. For instance, it is crucial to elucidate whether a single aNSC is capable of differentiating into all three different macroglial cell types in vivo or these distinct progenies constitute entirely separate lineages. Similarly, the cell cycle length, the time and mode of division (symmetric vs. asymmetric) that these cells undergo within their lineage progression are interesting questions under current investigation. In this sense, live imaging constitutes a valuable ally in the search of reliable answers to the previous questions. In spite of the current limitations of technology new approaches are being developed and outstanding amount of knowledge is being piled up providing interesting insights in the behavior of aNSCs. Here, we will review the state of the art of live imaging as well as the alternative models that currently offer new answers to critical questions. PMID:27013941

  5. Axonal Control of the Adult Neural Stem Cell Niche

    PubMed Central

    Tong, Cheuk Ka; Chen, Jiadong; Cebrián-Silla, Arantxa; Mirzadeh, Zaman; Obernier, Kirsten; Guinto, Cristina D.; Tecott, Laurence H.; García-Verdugo, Jose Manuel; Kriegstein, Arnold; Alvarez-Buylla, Arturo

    2014-01-01

    SUMMARY The ventricular-subventricular zone (V-SVZ) is an extensive germinal niche containing neural stem cells (NSC) in the walls of the lateral ventricles of the adult brain. How the adult brain’s neural activity influences the behavior of adult NSCs remains largely unknown. We show that serotonergic (5HT) axons originating from a small group of neurons in the raphe form an extensive plexus on most of the ventricular walls. Electron microscopy revealed intimate contacts between 5HT axons and NSCs (B1) or ependymal cells (E1) and these cells were labeled by a transsynaptic viral tracer injected into the raphe. B1 cells express the 5HT receptors 2C and 5A. Electrophysiology showed that activation of these receptors in B1 cells induced small inward currents. Intraventricular infusion of 5HT2C agonist or antagonist increased or decreased V-SVZ proliferation, respectively. These results indicate that supraependymal 5HT axons directly interact with NSCs to regulate neurogenesis via 5HT2C. PMID:24561083

  6. Stimulation of adult hippocampal neurogenesis by physical exercise and enriched environment is disturbed in a CADASIL mouse model

    PubMed Central

    Klein, C.; Schreyer, S.; Kohrs, F. E.; Elhamoury, P.; Pfeffer, A.; Munder, T.; Steiner, B.

    2017-01-01

    In the course of CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), a dysregulated adult hippocampal neurogenesis has been suggested as a potential mechanism for early cognitive decline. Previous work has shown that mice overexpressing wild type Notch3 and mice overexpressing Notch3 with a CADASIL mutation display impaired cell proliferation and survival of newly born hippocampal neurons prior to vascular abnormalities. Here, we aimed to elucidate how the long-term survival of these newly generated neurons is regulated by Notch3. Knowing that adult neurogenesis can be robustly stimulated by physical exercise and environmental enrichment, we also investigated the influence of such stimuli as potential therapeutic instruments for a dysregulated hippocampal neurogenesis in the CADASIL mouse model. Therefore, young-adult female mice were housed in standard (STD), environmentally enriched (ENR) or running wheel cages (RUN) for either 28 days or 6 months. Mice overexpressing mutated Notch3 and developing CADASIL (TgN3R169C), and mice overexpressing wild type Notch3 (TgN3WT) were used. We found that neurogenic stimulation by RUN and ENR is apparently impaired in both transgenic lines. The finding suggests that a disturbed neurogenic process due to Notch3-dependent micromilieu changes might be one vascular-independent mechanism contributing to cognitive decline observed in CADASIL. PMID:28345617

  7. A Common Language: How Neuroimmunological Cross Talk Regulates Adult Hippocampal Neurogenesis

    PubMed Central

    Leiter, Odette; Kempermann, Gerd; Walker, Tara L.

    2016-01-01

    Immune regulation of the brain is generally studied in the context of injury or disease. Less is known about how the immune system regulates the brain during normal brain function. Recent work has redefined the field of neuroimmunology and, as long as their recruitment and activation are well regulated, immune cells are now known to have protective properties within the central nervous system in maintaining brain health. Adult neurogenesis, the process of new neuron generation in the adult brain, is highly plastic and regulated by diverse extrinsic and intrinsic cues. Emerging research has shown that immune cells and their secreted factors can influence adult neurogenesis, both under baseline conditions and during conditions known to change neurogenesis levels, such as aging and learning in an enriched environment. This review will discuss how, under nonpathological conditions, the immune system can interact with the neural stem cells to regulate adult neurogenesis with particular focus on the hippocampus—a region crucial for learning and memory. PMID:27143977

  8. Hippocampal structure, metabolism, and inflammatory response after a 6-week intense aerobic exercise in healthy young adults: a controlled trial.

    PubMed

    Wagner, Gerd; Herbsleb, Marco; de la Cruz, Feliberto; Schumann, Andy; Brünner, Franziska; Schachtzabel, Claudia; Gussew, Alexander; Puta, Christian; Smesny, Stefan; Gabriel, Holger W; Reichenbach, Jürgen R; Bär, Karl-Jürgen

    2015-10-01

    Interventional studies suggest that changes in physical fitness affect brain function and structure. We studied the influence of high intensity physical exercise on hippocampal volume and metabolism in 17 young healthy male adults during a 6-week exercise program compared with matched controls. We further aimed to relate these changes to hypothesized changes in exercised-induced brain-derived neurotrophic factor (BDNF), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α). We show profound improvement of physical fitness in most subjects and a positive correlation between the degree of fitness improvement and increased BDNF levels. We unexpectedly observed an average volume decrease of about 2%, which was restricted to right hippocampal subfields CA2/3, subiculum, and dentate gyrus and which correlated with fitness improvement and increased BDNF levels negatively. This result indicates that mainly those subjects who did not benefit from the exercise program show decreased hippocampal volume, reduced BDNF levels, and increased TNF-α concentrations. While spectroscopy results do not indicate any neuronal loss (unchanged N-acetylaspartate levels) decreased glutamate-glutamine levels were observed in the right anterior hippocampus in the exercise group only. Responder characteristics need to be studied in more detail. Our results point to an important role of the inflammatory response after exercise on changes in hippocampal structure.

  9. Parvalbumin interneurons mediate neuronal circuitry-neurogenesis coupling in the adult hippocampus.

    PubMed

    Song, Juan; Sun, Jiaqi; Moss, Jonathan; Wen, Zhexing; Sun, Gerald J; Hsu, Derek; Zhong, Chun; Davoudi, Heydar; Christian, Kimberly M; Toni, Nicolas; Ming, Guo-Li; Song, Hongjun

    2013-12-01

    Using immunohistology, electron microscopy, electrophysiology and optogenetics, we found that proliferating adult mouse hippocampal neural precursors received immature GABAergic synaptic inputs from parvalbumin-expressing interneurons. Recently shown to suppress adult quiescent neural stem cell activation, parvalbumin interneuron activation promoted newborn neuronal progeny survival and development. Our results suggest a niche mechanism involving parvalbumin interneurons that couples local circuit activity to the diametric regulation of two critical early phases of adult hippocampal neurogenesis.

  10. Intraoperative Neural Response Telemetry and Neural Recovery Function: a Comparative Study between Adults and Children

    PubMed Central

    Carvalho, Bettina; Hamerschmidt, Rogerio; Wiemes, Gislaine

    2014-01-01

    Introduction Neural response telemetry (NRT) is a method of capturing the action potential of the distal portion of the auditory nerve in cochlear implant (CI) users, using the CI itself to elicit and record the answers. In addition, it can also measure the recovery function of the auditory nerve (REC), that is, the refractory properties of the nerve. It is not clear in the literature whether the responses from adults are the same as those from children. Objective To compare the results of NRT and REC between adults and children undergoing CI surgery. Methods Cross-sectional, descriptive, and retrospective study of the results of NRT and REC for patients undergoing IC at our service. The NRT is assessed by the level of amplitude (microvolts) and REC as a function of three parameters: A (saturation level, in microvolts), t0 (absolute refractory period, in seconds), and tau (curve of the model function), measured in three electrodes (apical, medial, and basal). Results Fifty-two patients were evaluated with intraoperative NRT (26 adults and 26 children), and 24 with REC (12 adults and 12 children). No statistically significant difference was found between intraoperative responses of adults and children for NRT or for REC's three parameters, except for parameter A of the basal electrode. Conclusion The results of intraoperative NRT and REC were not different between adults and children, except for parameter A of the basal electrode. PMID:25992145

  11. 56Fe Particle Exposure Results in a Long-Lasting Increase in a Cellular Index of Genomic Instability and Transiently Suppresses Adult Hippocampal Neurogenesis in Vivo

    PubMed Central

    DeCarolis, Nathan A.; Rivera, Phillip D.; Ahn, Francisca; Amaral, Wellington Z.; LeBlanc, Junie A.; Malhotra, Shveta; Shih, Hung-Ying; Petrik, David; Melvin, Neal; Chen, Benjamin P.C.; Eisch, Amelia J.

    2014-01-01

    The high-LET HZE particles from galactic cosmic radiation pose tremendous health risks to astronauts, as they may incur sub-threshold brain injury or maladaptations that may lead to cognitive impairment. The health effects of HZE particles are difficult to predict and unfeasible to prevent. This underscores the importance of estimating radiation risks to the central nervous system as a whole as well as to specific brain regions like the hippocampus, which is central to learning and memory. Given that neurogenesis in the hippocampus has been linked to learning and memory, we investigated the response and recovery of neurogenesis and neural stem cells in the adult mouse hippocampal dentate gyrus after HZE particle exposure using two nestin transgenic reporter mouse lines to label and track radial glia stem cells (Nestin-GFP and Nestin-CreERT2/R26R:YFP mice, respectively). Mice were subjected to 56Fe particle exposure (0 or 1 Gy, at either 300 or 1000 MeV/n) and brains were harvested at early (24h), intermediate (7d), and/or long time points (2–3mo) post-irradiation. 56Fe particle exposure resulted in a robust increase in 53BP1+ foci at both the intermediate and long time points post-irradiation, suggesting long-term genomic instability in the brain. However, 56Fe particle exposure only produced a transient decrease in immature neuron number at the intermediate time point, with no significant decrease at the long time point post-irradiation. 56Fe particle exposure similarly produced a transient decrease in dividing progenitors, with fewer progenitors labeled at the early time point but equal number labeled at the intermediate time point, suggesting a recovery of neurogenesis. Notably, 56Fe particle exposure did not change the total number of nestin-expressing neural stem cells. These results highlight that despite the persistence of an index of genomic instability, 56Fe particle-induced deficits in adult hippocampal neurogenesis may be transient. These data support

  12. 56Fe particle exposure results in a long-lasting increase in a cellular index of genomic instability and transiently suppresses adult hippocampal neurogenesis in vivo

    NASA Astrophysics Data System (ADS)

    DeCarolis, Nathan A.; Rivera, Phillip D.; Ahn, Francisca; Amaral, Wellington Z.; LeBlanc, Junie A.; Malhotra, Shveta; Shih, Hung-Ying; Petrik, David; Melvin, Neal R.; Chen, Benjamin P. C.; Eisch, Amelia J.

    2014-07-01

    The high-LET HZE particles from galactic cosmic radiation pose tremendous health risks to astronauts, as they may incur sub-threshold brain injury or maladaptations that may lead to cognitive impairment. The health effects of HZE particles are difficult to predict and unfeasible to prevent. This underscores the importance of estimating radiation risks to the central nervous system as a whole as well as to specific brain regions like the hippocampus, which is central to learning and memory. Given that neurogenesis in the hippocampus has been linked to learning and memory, we investigated the response and recovery of neurogenesis and neural stem cells in the adult mouse hippocampal dentate gyrus after HZE particle exposure using two nestin transgenic reporter mouse lines to label and track radial glia stem cells (Nestin-GFP and Nestin-CreERT2/R26R:YFP mice, respectively). Mice were subjected to 56Fe particle exposure (0 or 1 Gy, at either 300 or 1000 MeV/n) and brains were harvested at early (24 h), intermediate (7 d), and/or long time points (2-3 mo) post-irradiation. 56Fe particle exposure resulted in a robust increase in 53BP1+ foci at both the intermediate and long time points post-irradiation, suggesting long-term genomic instability in the brain. However, 56Fe particle exposure only produced a transient decrease in immature neuron number at the intermediate time point, with no significant decrease at the long time point post-irradiation. 56Fe particle exposure similarly produced a transient decrease in dividing progenitors, with fewer progenitors labeled at the early time point but equal number labeled at the intermediate time point, suggesting a recovery of neurogenesis. Notably, 56Fe particle exposure did not change the total number of nestin-expressing neural stem cells. These results highlight that despite the persistence of an index of genomic instability, 56Fe particle-induced deficits in adult hippocampal neurogenesis may be transient. These data support

  13. Gender Differences in the Neurobiology of Anxiety: Focus on Adult Hippocampal Neurogenesis

    PubMed Central

    Marques, Alessandra Aparecida; Bevilaqua, Mário Cesar do Nascimento; da Fonseca, Alberto Morais Pinto; Nardi, Antonio Egidio; Thuret, Sandrine; Dias, Gisele Pereira

    2016-01-01

    Although the literature reports a higher incidence of anxiety disorders in women, the majority of basic research has focused on male rodents, thus resulting in a lack of knowledge on the neurobiology of anxiety in females. Bridging this gap is crucial for the design of effective translational interventions in women. One of the key brain mechanisms likely to regulate anxious behavior is adult hippocampal neurogenesis (AHN). This review paper aims to discuss the evidence on the differences between male and female rodents with regard to anxiety-related behavior and physiology, with a special focus on AHN. The differences between male and female physiologies are greatly influenced by hormonal differences. Gonadal hormones and their fluctuations during the estrous cycle have often been identified as agents responsible for sexual dimorphism in behavior and AHN. During sexual maturity, hormone levels fluctuate cyclically in females more than in males, increasing the stress response and the susceptibility to anxiety. It is therefore of great importance that future research investigates anxiety and other neurophysiological aspects in the female model, so that results can be more accurately applicable to the female population. PMID:26885403

  14. Hippocampal synaptic plasticity: effects of neonatal stress in freely moving adult male rats.

    PubMed

    Petrosino, M; Bronzino, J D; Pizzuti, G P

    1999-01-01

    The present study examines the effects of neonatal isolation on hippocampal LTP in adult male rats. Changes in dentate granule cell population measures, i.e., EPSP slope and population spike amplitude (PSA), evoked by tetanization of the medial perforant pathway were used to assess the effects of neonatal isolation on LTP over a period of 96 h. Following tetanization significant group differences were obtained for input/output (I/O) response measures of EPSP slope and PSA, with isolated males showing consistently higher values than in the other two groups. Comparisons made at 1 h post-tetanization (establishment of LTP) indicated that isolated males showed significantly greater enhancement than any other group. At 96 h (maintenance of LTP), however, neonatally isolated males showed significantly greater enhancement than either non-isolated siblings or unhandled controls. Additionally, isolation resulted in prolonging the duration of enhancement obtained from males. Thus, males show different enhancement profiles with respect to both the magnitude and duration of LTP and neonatal isolation alters these profiles in profound manner.

  15. Effects of postnatal alcohol exposure on hippocampal gene expression and learning in adult mice.

    PubMed

    Lee, Dong Hoon; Moon, Jihye; Ryu, Jinhyun; Jeong, Joo Yeon; Roh, Gu Seob; Kim, Hyun Joon; Cho, Gyeong Jae; Choi, Wan Sung; Kang, Sang Soo

    2016-04-28

    Fetal alcohol syndrome (FAS) is a condition resulting from excessive drinking by pregnant women. Symptoms of FAS include abnormal facial features, stunted growth, intellectual deficits and attentional dysfunction. Many studies have investigated FAS, but its underlying mechanisms remain unknown. This study evaluated the relationship between alcohol exposure during the synaptogenesis period in postnatal mice and subsequent cognitive function in adult mice. We delivered two injections, separated by 2 h, of ethanol (3 g/kg, ethanol/saline, 20% v/v) to ICR mice on postnatal day 7. After 10 weeks, we conducted a behavioral test, sacrificed the animals, harvested brain tissue and analyzed hippocampal gene expression using a microarray. In ethanol-treated mice, there was a reduction in brain size and decreased neuronal cell number in the cortex, and also cognitive impairment. cDNA microarray results indicated that 1,548 genes showed a > 2-fold decrease in expression relative to control, whereas 974 genes showed a > 2-fold increase in expression relative to control. Many of these genes were related to signal transduction, synaptogenesis and cell membrane formation, which are highlighted in our findings.

  16. Stimulus Similarity and Encoding Time Influence Incidental Recognition Memory in Adult Monkeys with Selective Hippocampal Lesions

    ERIC Educational Resources Information Center

    Zeamer, Alyson; Meunier, Martine; Bachevalier, Jocelyne

    2011-01-01

    Recognition memory impairment after selective hippocampal lesions in monkeys is more profound when measured with visual paired-comparison (VPC) than with delayed nonmatching-to-sample (DNMS). To clarify this issue, we assessed the impact of stimuli similarity and encoding duration on the VPC performance in monkeys with hippocampal lesions and…

  17. Low Proliferation and Differentiation Capacities of Adult Hippocampal Stem Cells Correlate with Memory Dysfunction in Humans

    ERIC Educational Resources Information Center

    Coras, Roland; Siebzehnrubl, Florian A.; Pauli, Elisabeth; Huttner, Hagen B.; Njunting, Marleisje; Kobow, Katja; Villmann, Carmen; Hahnen, Eric; Neuhuber, Winfried; Weigel, Daniel; Buchfelder, Michael; Stefan, Hermann; Beck, Heinz; Steindler, Dennis A.; Blumcke, Ingmar

    2010-01-01

    The hippocampal dentate gyrus maintains its capacity to generate new neurons throughout life. In animal models, hippocampal neurogenesis is increased by cognitive tasks, and experimental ablation of neurogenesis disrupts specific modalities of learning and memory. In humans, the impact of neurogenesis on cognition remains unclear. Here, we…

  18. Prospero-related homeobox 1 (Prox1) at the crossroads of diverse pathways during adult neural fate specification.

    PubMed

    Stergiopoulos, Athanasios; Elkouris, Maximilianos; Politis, Panagiotis K

    2014-01-01

    Over the last decades, adult neurogenesis in the central nervous system (CNS) has emerged as a fundamental process underlying physiology and disease. Recent evidence indicates that the homeobox transcription factor Prox1 is a critical intrinsic regulator of neurogenesis in the embryonic CNS and adult dentate gyrus (DG) of the hippocampus, acting in multiple ways and instructed by extrinsic cues and intrinsic factors. In the embryonic CNS, Prox1 is mechanistically involved in the regulation of proliferation vs. differentiation decisions of neural stem cells (NSCs), promoting cell cycle exit and neuronal differentiation, while inhibiting astrogliogenesis. During the complex differentiation events in adult hippocampal neurogenesis, Prox1 is required for maintenance of intermediate progenitors (IPs), differentiation and maturation of glutamatergic interneurons, as well as specification of DG cell identity over CA3 pyramidal fate. The mechanism by which Prox1 exerts multiple functions involves distinct signaling pathways currently not fully highlighted. In this mini-review, we thoroughly discuss the Prox1-dependent phenotypes and molecular pathways in adult neurogenesis in relation to different upstream signaling cues and cell fate determinants. In addition, we discuss the possibility that Prox1 may act as a cross-talk point between diverse signaling cascades to achieve specific outcomes during adult neurogenesis.

  19. Long-lasting alterations of hippocampal GABAergic neurotransmission in adult rats following perinatal Δ(9)-THC exposure.

    PubMed

    Beggiato, Sarah; Borelli, Andrea Celeste; Tomasini, Maria Cristina; Morgano, Lucia; Antonelli, Tiziana; Tanganelli, Sergio; Cuomo, Vincenzo; Ferraro, Luca

    2017-03-01

    The long-lasting effects of gestational cannabinoids exposure on the adult brain of the offspring are still controversial. It has already been shown that pre- or perinatal cannabinoids exposure induces learning and memory disruption in rat adult offspring, associated with permanent alterations of cortical glutamatergic neurotransmission and cognitive deficits. In the present study, the risk of long-term consequences induced by perinatal exposure to cannabinoids on rat hippocampal GABAergic system of the offspring, has been explored. To this purpose, pregnant rats were treated daily with Delta(9)-tetrahydrocannabinol (Δ(9)-THC; 5mg/kg) or its vehicle. Perinatal exposure to Δ(9)-THC induced a significant reduction (p<0.05) in basal and K(+)-evoked [(3)H]-GABA outflow of 90-day-old rat hippocampal slices. These effects were associated with a reduction of hippocampal [(3)H]-GABA uptake compared to vehicle exposed group. Perinatal exposure to Δ(9)-THC induced a significant reduction of CB1 receptor binding (Bmax) in the hippocampus of 90-day-old rats. However, a pharmacological challenge with either Δ(9)-THC (0.1μM) or WIN55,212-2 (2μM), similarly reduced K(+)-evoked [(3)H]-GABA outflow in both experimental groups. These reductions were significantly blocked by adding the selective CB1 receptor antagonist SR141716A. These findings suggest that maternal exposure to cannabinoids induces long-term alterations of hippocampal GABAergic system. Interestingly, previous behavioral studies demonstrated that, under the same experimental conditions as in the present study, perinatal cannabinoids exposure induced cognitive impairments in adult rats, thus resembling some effects observed in humans. Although it is difficult and sometimes misleading to extrapolate findings obtained from animal models to humans, the possibility that an alteration of hippocampus aminoacidergic transmission might underlie, at least in part, some of the cognitive deficits affecting the offspring of

  20. Excitability governs neural development in a hippocampal region-specific manner

    PubMed Central

    Johnson-Venkatesh, Erin M.; Khan, Mudassar N.; Murphy, Geoffrey G.; Sutton, Michael A.; Umemori, Hisashi

    2015-01-01

    Neuronal activity, including intrinsic neuronal excitability and synaptic transmission, is an essential regulator of brain development. However, how the intrinsic neuronal excitability of distinct neurons affects their integration into developing circuits remains poorly understood. To investigate this problem, we created several transgenic mouse lines in which intrinsic excitability is suppressed, and the neurons are effectively silenced, in different excitatory neuronal populations of the hippocampus. Here we show that CA1, CA3 and dentate gyrus neurons each have unique responses to suppressed intrinsic excitability during circuit development. Silenced CA1 pyramidal neurons show altered spine development and synaptic transmission after postnatal day 15. By contrast, silenced CA3 pyramidal neurons seem to develop normally. Silenced dentate granule cells develop with input-specific decreases in spine density starting at postnatal day 11; however, a compensatory enhancement of neurotransmitter release onto these neurons maintains normal levels of synaptic activity. The synaptic changes in CA1 and dentate granule neurons are not observed when synaptic transmission, rather than intrinsic excitability, is blocked in these neurons. Thus, our results demonstrate a crucial role for intrinsic neuronal excitability in establishing hippocampal connectivity and reveal that neuronal development in each hippocampal region is distinctly regulated by excitability. PMID:26417041

  1. Neural similarity between encoding and retrieval is related to memory via hippocampal interactions.

    PubMed

    Ritchey, Maureen; Wing, Erik A; LaBar, Kevin S; Cabeza, Roberto

    2013-12-01

    A fundamental principle in memory research is that memory is a function of the similarity between encoding and retrieval operations. Consistent with this principle, many neurobiological models of declarative memory assume that memory traces are stored in cortical regions, and the hippocampus facilitates the reactivation of these traces during retrieval. The present investigation tested the novel prediction that encoding-retrieval similarity can be observed and related to memory at the level of individual items. Multivariate representational similarity analysis was applied to functional magnetic resonance imaging data collected during encoding and retrieval of emotional and neutral scenes. Memory success tracked fluctuations in encoding-retrieval similarity across frontal and posterior cortices. Importantly, memory effects in posterior regions reflected increased similarity between item-specific representations during successful recognition. Mediation analyses revealed that the hippocampus mediated the link between cortical similarity and memory success, providing crucial evidence for hippocampal-cortical interactions during retrieval. Finally, because emotional arousal is known to modulate both perceptual and memory processes, similarity effects were compared for emotional and neutral scenes. Emotional arousal was associated with enhanced similarity between encoding and retrieval patterns. These findings speak to the promise of pattern similarity measures for evaluating memory representations and hippocampal-cortical interactions.

  2. Multifractal analysis of information processing in hippocampal neural ensembles during working memory under Δ9-tetrahydrocannabinol administration

    PubMed Central

    Fetterhoff, Dustin; Opris, Ioan; Simpson, Sean L.; Deadwyler, Sam A.; Hampson, Robert E.; Kraft, Robert A.

    2014-01-01

    Background Multifractal analysis quantifies the time-scale-invariant properties in data by describing the structure of variability over time. By applying this analysis to hippocampal interspike interval sequences recorded during performance of a working memory task, a measure of long-range temporal correlations and multifractal dynamics can reveal single neuron correlates of information processing. New method Wavelet leaders-based multifractal analysis (WLMA) was applied to hippocampal interspike intervals recorded during a working memory task. WLMA can be used to identify neurons likely to exhibit information processing relevant to operation of brain–computer interfaces and nonlinear neuronal models. Results Neurons involved in memory processing (“Functional Cell Types” or FCTs) showed a greater degree of multifractal firing properties than neurons without task-relevant firing characteristics. In addition, previously unidentified FCTs were revealed because multifractal analysis suggested further functional classification. The cannabinoid-type 1 receptor partial agonist, tetrahydrocannabinol (THC), selectively reduced multifractal dynamics in FCT neurons compared to non-FCT neurons. Comparison with existing methods WLMA is an objective tool for quantifying the memory-correlated complexity represented by FCTs that reveals additional information compared to classification of FCTs using traditional z-scores to identify neuronal correlates of behavioral events. Conclusion z-Score-based FCT classification provides limited information about the dynamical range of neuronal activity characterized by WLMA. Increased complexity, as measured with multifractal analysis, may be a marker of functional involvement in memory processing. The level of multifractal attributes can be used to differentially emphasize neural signals to improve computational models and algorithms underlying brain–computer interfaces. PMID:25086297

  3. Postnatal Loss of Hap1 Reduces Hippocampal Neurogenesis and Causes Adult Depressive-Like Behavior in Mice

    PubMed Central

    Xiang, Jianxing; Yan, Sen; Li, Shi-Hua; Li, Xiao-Jiang

    2015-01-01

    Depression is a serious mental disorder that affects a person’s mood, thoughts, behavior, physical health, and life in general. Despite our continuous efforts to understand the disease, the etiology of depressive behavior remains perplexing. Recently, aberrant early life or postnatal neurogenesis has been linked to adult depressive behavior; however, genetic evidence for this is still lacking. Here we genetically depleted the expression of huntingtin-associated protein 1 (Hap1) in mice at various ages or in selective brain regions. Depletion of Hap1 in the early postnatal period, but not later life, led to a depressive-like phenotype when the mice reached adulthood. Deletion of Hap1 in adult mice rendered the mice more susceptible to stress-induced depressive-like behavior. Furthermore, early Hap1 depletion impaired postnatal neurogenesis in the dentate gyrus (DG) of the hippocampus and reduced the level of c-kit, a protein expressed in neuroproliferative zones of the rodent brain and that is stabilized by Hap1. Importantly, stereotaxically injected adeno-associated virus (AAV) that directs the expression of c-kit in the hippocampus promoted postnatal hippocampal neurogenesis and ameliorated the depressive-like phenotype in conditional Hap1 KO mice, indicating a link between postnatal-born hippocampal neurons and adult depression. Our results demonstrate critical roles for Hap1 and c-kit in postnatal neurogenesis and adult depressive behavior, and also suggest that genetic variations affecting postnatal neurogenesis may lead to adult depression. PMID:25875952

  4. Increased extracellular release of hippocampal NE is associated with tetanization of the medial perforant pathway in the freely moving adult male rat.

    PubMed

    Bronzino, J D; Kehoe, P; Mallinson, K; Fortin, D A

    2001-01-01

    The induction of long-term potentiation (LTP) within the dentate gyrus of the hippocampal formation is modulated by many afferent influences from a number of subcortical structures known to be intimately involved in hippocampal-dependent learning and memory. It has been demonstrated in slice and anesthetized preparations that norepinephrine (NE) is one of these major neuromodulators involved in the induction of LTP. However, the majority of these studies have not been conducted in the freely moving animal. Recently, we developed surgical procedures and instrumentation techniques to simultaneously record electrophysiological and neurochemical data from the hippocampal formation. The present study uses these techniques to examine the underlying neurochemical changes in the hippocampus associated with the induction of hippocampal dentate LTP in the freely moving adult rat. These findings establish baseline levels of NE that can be used to evaluate the impact of various tetanization paradigms as well as the effect of a variety of insults on hippocampal plasticity.

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

    PubMed

    Boekhoorn, Karin; van Dis, Vera; Goedknegt, Erika; Sobel, André; Lucassen, Paul J; Hoogenraad, Casper C

    2014-12-01

    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.

  6. A virtual water maze revisited: Two-year changes in navigation performance and their neural correlates in healthy adults.

    PubMed

    Daugherty, Ana M; Raz, Naftali

    2017-02-01

    Age-related declines in spatial navigation are associated with deficits in procedural and episodic memory and deterioration of their neural substrates. For the lack of longitudinal evidence, the pace and magnitude of these declines and their neural mediators remain unclear. Here we examined virtual navigation in healthy adults (N=213, age 18-77 years) tested twice, two years apart, with complementary indices of navigation performance (path length and complexity) measured over six learning trials at each occasion. Slopes of skill acquisition curves and longitudinal change therein were estimated in structural equation modeling, together with change in regional brain volumes and iron content (R2* relaxometry). Although performance on the first trial did not differ between occasions separated by two years, the slope of path length improvement over trials was shallower and end-of-session performance worse at follow-up. Advanced age, higher pulse pressure, smaller cerebellar and caudate volumes, and greater caudate iron content were associated with longer search paths, i.e. poorer navigation performance. In contrast, path complexity diminished faster over trials at follow-up, albeit less so in older adults. Improvement in path complexity after two years was predicted by lower baseline hippocampal iron content and larger parahippocampal volume. Thus, navigation path length behaves as an index of perceptual-motor skill that is vulnerable to age-related decline, whereas path complexity may reflect cognitive mapping in episodic memory that improves with repeated testing, although not enough to overcome age-related deficits.

  7. Comparative aspects of adult neural stem cell activity in vertebrates.

    PubMed

    Grandel, Heiner; Brand, Michael

    2013-03-01

    At birth or after hatching from the egg, vertebrate brains still contain neural stem cells which reside in specialized niches. In some cases, these stem cells are deployed for further postnatal development of parts of the brain until the final structure is reached. In other cases, postnatal neurogenesis continues as constitutive neurogenesis into adulthood leading to a net increase of the number of neurons with age. Yet, in other cases, stem cells fuel neuronal turnover. An example is protracted development of the cerebellar granular layer in mammals and birds, where neurogenesis continues for a few weeks postnatally until the granular layer has reached its definitive size and stem cells are used up. Cerebellar growth also provides an example of continued neurogenesis during adulthood in teleosts. Again, it is the granular layer that grows as neurogenesis continues and no definite adult cerebellar size is reached. Neuronal turnover is most clearly seen in the telencephalon of male canaries, where projection neurons are replaced in nucleus high vocal centre each year before the start of a new mating season--circuitry reconstruction to achieve changes of the song repertoire in these birds? In this review, we describe these and other examples of adult neurogenesis in different vertebrate taxa. We also compare the structure of the stem cell niches to find common themes in their organization despite different functions adult neurogenesis serves in different species. Finally, we report on regeneration of the zebrafish telencephalon after injury to highlight similarities and differences of constitutive neurogenesis and neuronal regeneration.

  8. Running rescues defective adult neurogenesis by shortening the length of the cell cycle of neural stem and progenitor cells.

    PubMed

    Farioli-Vecchioli, Stefano; Mattera, Andrea; Micheli, Laura; Ceccarelli, Manuela; Leonardi, Luca; Saraulli, Daniele; Costanzi, Marco; Cestari, Vincenzo; Rouault, Jean-Pierre; Tirone, Felice

    2014-07-01

    Physical exercise increases the generation of new neurons in adult neurogenesis. However, only few studies have investigated the beneficial effects of physical exercise in paradigms of impaired neurogenesis. Here, we demonstrate that running fully reverses the deficient adult neurogenesis within the hippocampus and subventricular zone of the lateral ventricle, observed in mice lacking the antiproliferative gene Btg1. We also evaluated for the first time how running influences the cell cycle kinetics of stem and precursor subpopulations of wild-type and Btg1-null mice, using a new method to determine the cell cycle length. Our data show that in wild-type mice running leads to a cell cycle shortening only of NeuroD1-positive progenitor cells. In contrast, in Btg1-null mice, physical exercise fully reactivates the defective hippocampal neurogenesis, by shortening the S-phase length and the overall cell cycle duration of both neural stem (glial fibrillary acidic protein(+) and Sox2(+)) and progenitor (NeuroD1(+)) cells. These events are sufficient and necessary to reactivate the hyperproliferation observed in Btg1-null early-postnatal mice and to expand the pool of adult neural stem and progenitor cells. Such a sustained increase of cell proliferation in Btg1-null mice after running provides a long-lasting increment of proliferation, differentiation, and production of newborn neurons, which rescues the impaired pattern separation previously identified in Btg1-null mice. This study shows that running positively affects the cell cycle kinetics of specific subpopulations of newly generated neurons and suggests that the plasticity of neural stem cells without cell cycle inhibitory control is reactivated by running, with implications for the long-term modulation of neurogenesis.

  9. Intra-hippocampal transplantation of neural precursor cells with transgenic over-expression of IL-1 receptor antagonist rescues memory and neurogenesis impairments in an Alzheimer's disease model.

    PubMed

    Ben-Menachem-Zidon, Ofra; Ben Menachem-Zidon, Ofra; Ben-Menahem, Yair; Ben-Hur, Tamir; Yirmiya, Raz

    2014-01-01

    Ample evidence implicates neuroinflammatory processes in the etiology and progression of Alzheimer's disease (AD). To assess the specific role of the pro-inflammatory cytokine interleukin-1 (IL-1) in AD we examined the effects of intra-hippocampal transplantation of neural precursor cells (NPCs) with transgenic over-expression of IL-1 receptor antagonist (IL-1raTG) on memory functioning and neurogenesis in a murine model of AD (Tg2576 mice). WT NPCs- or sham-transplanted Tg2576 mice, as well as naive Tg2576 and WT mice served as controls. To assess the net effect of IL-1 blockade (not in the context of NPCs transplantation), we also examined the effects of chronic (4 weeks) intra-cerebroventricular (i.c.v.) administration of IL-1ra. We report that 12-month-old Tg2576 mice exhibited increased mRNA expression of hippocampal IL-1β, along with severe disturbances in hippocampal-dependent contextual and spatial memory as well as in neurogenesis. Transplantation of IL-1raTG NPCs 1 month before the neurobehavioral testing completely rescued these disturbances and significantly increased the number of endogenous hippocampal cells expressing the plasticity-related molecule BDNF. Similar, but less-robust effects were also produced by transplantation of WT NPCs and by i.c.v. IL-1ra administration. NPCs transplantation produced alterations in hippocampal plaque formation and microglial status, which were not clearly correlated with the cognitive effects of this procedure. The results indicate that elevated levels of hippocampal IL-1 are causally related to some AD-associated memory disturbances, and provide the first example for the potential use of genetically manipulated NPCs with anti-inflammatory properties in the treatment of AD.

  10. Hippocampal abnormalities and age in chronic schizophrenia: morphometric study across the adult lifespan

    PubMed Central

    Pujol, N.; Penadés, R.; Junqué, C.; Dinov, I.; Fu, C. H. Y.; Catalán, R.; Ibarretxe-Bilbao, N.; Bargalló, N.; Bernardo, M.; Toga, A.; Howard, R. J.; Costafreda, S. G.

    2014-01-01

    Background Hippocampal abnormalities have been demonstrated in schizophrenia. It is unclear whether these abnormalities worsen with age, and whether they affect cognition and function. Aims To determine whether hippocampal abnormalities in chronic schizophrenia are associated with age, cognition and socio-occupational function. Method Using 3 T magnetic resonance imaging we scanned 100 persons aged 19-82 years: 51 were out-patients with stable schizophrenia at least 2 years after diagnosis and 49 were healthy volunteers matched for age and gender. Automated analysis was used to determine hippocampal volume and shape. Results There were differential effects of age in the schizophrenia and control samples on total hippocampal volume (group×age interaction: F(1,95) = 6.57, P = 0.012), with steeper age-related reduction in the schizophrenia group. Three-dimensional shape analysis located the age-related deformations predominantly in the mid-body of the hippocampus. In the schizophrenia group similar patterns of morphometric abnormalities were correlated with impaired cognition and poorer socio-occupational function. Conclusions Hippocampal abnormalities are associated with age in people with chronic schizophrenia, with a steeper decline than in healthy individuals. These abnormalities are associated with cognitive and functional deficits, suggesting that hippocampal morphometry may be a biomarker for cognitive decline in older patients with schizophrenia. PMID:25213158

  11. Pannexin 2 Is Expressed by Postnatal Hippocampal Neural Progenitors and Modulates Neuronal Commitment*

    PubMed Central

    Swayne, Leigh Anne; Sorbara, Catherine D.; Bennett, Steffany A. L.

    2010-01-01

    The pannexins (Panx1, -2, and -3) are a mammalian family of putative single membrane channels discovered through homology to invertebrate gap junction-forming proteins, the innexins. Because connexin gap junction proteins are known regulators of neural stem and progenitor cell proliferation, migration, and specification, we asked whether pannexins, specifically Panx2, play a similar role in the postnatal hippocampus. We show that Panx2 protein is differentially expressed by multipotential progenitor cells and mature neurons. Both in vivo and in vitro, Type I and IIa stem-like neural progenitor cells express an S-palmitoylated Panx2 species localizing to Golgi and endoplasmic reticulum membranes. Protein expression is down-regulated during neurogenesis in neuronally committed Type IIb and III progenitor cells and immature neurons. Panx2 is re-expressed by neurons following maturation. Protein expressed by mature neurons is not palmitoylated and localizes to the plasma membrane. To assess the impact of Panx2 on neuronal differentiation, we used short hairpin RNA to suppress Panx2 expression in Neuro2a cells. Knockdown significantly accelerated the rate of neuronal differentiation. Neuritic extension and the expression of antigenic markers of mature neurons occurred earlier in stable lines expressing Panx2 short hairpin RNA than in controls. Together, these findings describe an endogenous post-translational regulation of Panx2, specific to early neural progenitor cells, and demonstrate that this expression plays a role in modulating the timing of their commitment to a neuronal lineage. PMID:20529862

  12. Rit GTPase Signaling Promotes Immature Hippocampal Neuronal Survival

    PubMed Central

    Cai, Weikang; Carlson, Shaun W.; Brelsfoard, Jennifer M.; Mannon, Catherine E.; Moncman, Carole L.; Saatman, Kathryn E.; Andres, Douglas A.

    2012-01-01

    The molecular mechanisms governing the spontaneous recovery seen following brain injury remain elusive, but recent studies indicate that injury-induced stimulation of hippocampal neurogenesis contributes to the repair process. The therapeutic potential of endogenous neurogenesis is tempered by the demonstration that traumatic brain injury (TBI) results in the selective death of adult-born immature neurons, compromising the cell population poised to compensate for trauma-induced neuronal loss. Here, we identify the Ras-related GTPase, Rit, as a critical player in the survival of immature hippocampal neurons following brain injury. While Rit knockout (Rit−/−) did not alter hippocampal development, hippocampal neural cultures derived from Rit−/− mice display increased cell death and blunted MAPK cascade activation in response to oxidative stress, without affecting BDNF-dependent signaling. When compared to wild-type hippocampal cultures, Rit loss rendered immature (Dcx+) neurons susceptible to oxidative damage, without altering the survival of neural progenitor (Nestin+) cells. Oxidative stress is a major contributor to neuronal cell death following brain injury. Consistent with the enhanced vulnerability of cultured Rit−/− immature neurons, Rit−/− mice exhibited a significantly greater loss of adult-born immature neurons within the dentate gyrus after TBI. In addition, post-TBI neuronal remodeling was blunted. Taken together, these data identify a new and unexpected role for Rit in injury-induced neurogenesis, functioning as a selective survival mechanism for immature hippocampal neurons within the subgranular zone of the dentate gyrus following TBI. PMID:22815504

  13. Spike after-depolarization and burst generation in adult rat hippocampal CA1 pyramidal cells.

    PubMed Central

    Jensen, M S; Azouz, R; Yaari, Y

    1996-01-01

    1. Intracellular recordings in adult rat hippocampal slices were used to investigate the properties and origins of intrinsically generated bursts in the somata of CA1 pyramidal cells (PCs). The CA1 PCs were classified as either non-bursters or bursters according to the firing patterns evoked by intrasomatically applied long ( > or = 100 ms) depolarizing current pulses. Non-bursters generated stimulus-graded trains of independent action potentials, whereas bursters generated clusters of three or more closely spaced spikes riding on a distinct depolarizing envelope. 2. In all PCs fast spike repolarization was incomplete and ended at a potential approximately 10 mV more positive than resting potential. Solitary spikes were followed by a distinct after-depolarizing potential (ADP) lasting 20-40 ms. The ADP in most non-bursters declined monotonically to baseline ('passive' ADP), whereas in most bursters it remained steady or even re-depolarized before declining to baseline ('active' ADP). 3. Active, but not passive, ADPs were associated with an apparent increase in input conductance. They were maximal in amplitude when the spike was evoked from resting potential and were reduced by mild depolarization or hyperpolarization (+/- 2 mV). 4. Evoked and spontaneous burst firing was sensitive to small changes in membrane potential. In most cases maximal bursts were generated at resting potential and were curtailed by small depolarizations or hyperpolarizations (+/- 5 mV). 5. Bursts comprising clusters of spikelets ('d-spikes') were observed in 12% of the bursters. Some of the d-spikes attained threshold for triggering full somatic spikes. Gradually hyperpolarizing these neurones blocked somatic spikes before blocking d-spikes, suggesting that the latter are generated at more remote sites. 6. The data suggest that active ADPs and intrinsic bursts in the somata of adult CA1 PCs are generated by a slow, voltage-gated inward current. Bursts arise in neurones in which this current

  14. Auditory Training: Evidence for Neural Plasticity in Older Adults

    PubMed Central

    Anderson, Samira; Kraus, Nina

    2014-01-01

    Improvements in digital amplification, cochlear implants, and other innovations have extended the potential for improving hearing function; yet, there remains a need for further hearing improvement in challenging listening situations, such as when trying to understand speech in noise or when listening to music. Here, we review evidence from animal and human models of plasticity in the brain’s ability to process speech and other meaningful stimuli. We considered studies targeting populations of younger through older adults, emphasizing studies that have employed randomized controlled designs and have made connections between neural and behavioral changes. Overall results indicate that the brain remains malleable through older adulthood, provided that treatment algorithms have been modified to allow for changes in learning with age. Improvements in speech-in-noise perception and cognition function accompany neural changes in auditory processing. The training-related improvements noted across studies support the need to consider auditory training strategies in the management of individuals who express concerns about hearing in difficult listening situations. Given evidence from studies engaging the brain’s reward centers, future research should consider how these centers can be naturally activated during training. PMID:25485037

  15. Resveratrol: A Potential Hippocampal Plasticity Enhancer

    PubMed Central

    Dias, Gisele Pereira; Cocks, Graham; do Nascimento Bevilaqua, Mário Cesar; Nardi, Antonio Egidio

    2016-01-01

    The search for molecules capable of restoring altered hippocampal plasticity in psychiatric and neurological conditions is one of the most important tasks of modern neuroscience. It is well established that neural plasticity, such as the ability of the postnatal hippocampus to continuously generate newly functional neurons throughout life, a process called adult hippocampal neurogenesis (AHN), can be modulated not only by pharmacological agents, physical exercise, and environmental enrichment, but also by “nutraceutical” agents. In this review we focus on resveratrol, a phenol and phytoalexin found in the skin of grapes and red berries, as well as in nuts. Resveratrol has been reported to have antioxidant and antitumor properties, but its effects as a neural plasticity inducer are still debated. The current review examines recent evidence implicating resveratrol in regulating hippocampal neural plasticity and in mitigating the effects of various disorders and diseases on this important brain structure. Overall, findings show that resveratrol can improve cognition and mood and enhance hippocampal plasticity and AHN; however, some studies report opposite effects, with resveratrol inhibiting aspects of AHN. Therefore, further investigation is needed to resolve these controversies before resveratrol can be established as a safe coadjuvant in preventing and treating neuropsychiatric conditions. PMID:27313836

  16. The effects of chronic stress on hippocampal adult neurogenesis and dendritic plasticity are reversed by selective MAO-A inhibition.

    PubMed

    Morais, Mónica; Santos, Paulo A R; Mateus-Pinheiro, António; Patrício, Patrícia; Pinto, Luísa; Sousa, Nuno; Pedroso, Pedro; Almeida, Susana; Filipe, Augusto; Bessa, João M

    2014-12-01

    There is accumulating evidence that adult neurogenesis and dendritic plasticity in the hippocampus are neuroplastic phenomena, highly sensitive to the effects of chronic stress and treatment with most classes of antidepressant drugs, being involved in the onset and recovery from depression. However, the effects of antidepressants that act through the selective inhibition of monoamine oxidase subtype A (MAO-A) in these phenomena are still largely unknown. In the present study, adult neurogenesis and neuronal morphology were examined in the hippocampus of rats exposed to chronic mild stress (CMS) and treated with the selective reversible MAO-A inhibitor (RIMA) drug, pirlindole and the selective serotonin reuptake inhibitor (SSRI), fluoxetine. The results provide the first demonstration that selective MAO-A inhibition with pirlindole is able to revert the behavioural effects of stress exposure while promoting hippocampal adult neurogenesis and rescuing the stress-induced dendritic atrophy of granule neurons.

  17. IL-1 receptor antagonist attenuates neonatal lipopolysaccharide-induced long-lasting learning impairment and hippocampal injury in adult rats

    PubMed Central

    Pang, Yi; Bhatt, Abhay J.; Fan, Lir-Wan

    2015-01-01

    We have previously reported that neonatal lipopolysaccharide (LPS) exposure resulted in an increase in interleukin-1β (IL-1β) content, injury to the hippocampus, and cognitive deficits in juvenile male and female rats, as well as female adult rats. The present study aimed to determine whether an antiinflammatory cytokine, interleukin-1 receptor antagonist (IL-1ra), protects against the neonatal LPS exposure-induced inflammatory responses, hippocampal injury, and long-lasting learning deficits in adult rats. LPS (1 mg/kg) or LPS plus IL-1ra (0.1 mg/kg) was injected intracerebrally to Sprague-Dawley male rat pups at postnatal day 5 (P5). Neurobehavioral tests were carried out on P21, P49, and P70, while neuropathological studies were conducted on P71. Our results showed that neonatal LPS exposure resulted in learning deficits in rats at both developmental and adult ages, as demonstrated by a significantly impaired performance in the passive avoidance task (P21, P49, and P70), reduced hippocampal volume, and reduced number of Nissl+ cells in the CA1 region of the middle dorsal hippocampus of P71 rat brain. Those neuropathological and neurobehavioral alterations by LPS exposure were associated with a sustained inflammatory response in the P71 rat hippocampus, indicated by increased number of activated microglia as well as elevated levels of IL-1β. Neonatal administration of IL-1ra significantly attenuated LPS-induced long-lasting learning deficits, hippocampal injury, and sustained inflammatory responses in P71 rats. Our study demonstrates that neonatal LPS exposure leads to a persistent injury to the hippocampus, resulting in long-lasting learning disabilities related to chronic inflammation in rats, and these effects can be attenuated with an IL-1 receptor antagonist. PMID:25665855

  18. IL-1 receptor antagonist attenuates neonatal lipopolysaccharide-induced long-lasting learning impairment and hippocampal injury in adult rats.

    PubMed

    Lan, Kuo-Mao; Tien, Lu-Tai; Pang, Yi; Bhatt, Abhay J; Fan, Lir-Wan

    2015-04-02

    We have previously reported that neonatal lipopolysaccharide (LPS) exposure resulted in an increase in interleukin-1β (IL-1β) content, injury to the hippocampus, and cognitive deficits in juvenile male and female rats, as well as female adult rats. The present study aimed to determine whether an anti-inflammatory cytokine, interleukin-1 receptor antagonist (IL-1ra), protects against the neonatal LPS exposure-induced inflammatory responses, hippocampal injury, and long-lasting learning deficits in adult rats. LPS (1 mg/kg) or LPS plus IL-1ra (0.1 mg/kg) was injected intracerebrally to Sprague-Dawley male rat pups at postnatal day 5 (P5). Neurobehavioral tests were carried out on P21, P49, and P70, while neuropathological studies were conducted on P71. Our results showed that neonatal LPS exposure resulted in learning deficits in rats at both developmental and adult ages, as demonstrated by a significantly impaired performance in the passive avoidance task (P21, P49, and P70), reduced hippocampal volume, and reduced number of Nissl+ cells in the CA1 region of the middle dorsal hippocampus of P71 rat brain. Those neuropathological and neurobehavioral alterations by LPS exposure were associated with a sustained inflammatory response in the P71 rat hippocampus, indicated by increased number of activated microglia as well as elevated levels of IL-1β. Neonatal administration of IL-1ra significantly attenuated LPS-induced long-lasting learning deficits, hippocampal injury, and sustained inflammatory responses in P71 rats. Our study demonstrates that neonatal LPS exposure leads to a persistent injury to the hippocampus, resulting in long-lasting learning disabilities related to chronic inflammation in rats, and these effects can be attenuated with an IL-1 receptor antagonist.

  19. Brain-specific ablation of Efr3a promotes adult hippocampal neurogenesis via the brain-derived neurotrophic factor pathway.

    PubMed

    Qian, Qi; Liu, Qiuji; Zhou, Dongming; Pan, Hongyu; Liu, Zhiwei; He, Fangping; Ji, Suying; Wang, Dongpi; Bao, Wangxiao; Liu, Xinyi; Liu, Zhaoling; Zhang, Heng; Zhang, Xiaoqin; Zhang, Ling; Wang, Mingkai; Xu, Ying; Huang, Fude; Luo, Benyan; Sun, Binggui

    2017-02-13

    Efr3 is a newly identified plasma membrane protein and plays an important role in the phosphoinositide metabolism on the plasma membrane. However, although it is highly expressed in the brain, the functional significance of Efr3 in the brain is not clear. In the present study, we generated Efr3a(f/f) mice and then crossed them with Nestin-Cre mice to delete Efr3a, one of the Efr3 isoforms, specifically in the brain. We found that brain-specific ablation of Efr3a promoted adult hippocampal neurogenesis by increasing survival and maturation of newborn neurons without affecting their dendritic tree morphology. Moreover, the brain-derived neurotrophic factor (BDNF)-tropomyosin-related kinase B (TrkB) signaling pathway was significantly enhanced in the hippocampus of Efr3a-deficient mice, as reflected by increased expression of BDNF, TrkB, and the downstream molecules, including phospho-MAPK and phospho-Akt. Furthermore, the number of TUNEL(+) cells was decreased in the subgranular zone of dentate gyrus in Efr3a-deficient mice compared with that of control mice. Our data suggest that brain-specific deletion of Efr3a could promote adult hippocampal neurogenesis, presumably by upregulating the expression of BDNF and its receptor, TrkB, and therefore provide new insight into the roles of Efr3 in the brain.-Qian, Q., Liu, Q., Zhou, D., Pan, H., Liu, Z., He, F., Ji, S., Wang, D., Bao, W., Liu, X., Liu, Z., Zhang, H., Zhang, X., Zhang, L., Wang, M., Xu, Y., Huang, F., Luo, B., Sun B. Brain-specific ablation of Efr3a promotes adult hippocampal neurogenesis via the brain-derived neurotrophic factor pathway.

  20. Time-dependent enhancement of hippocampus-dependent memory after treatment with memantine: Implications for enhanced hippocampal adult neurogenesis.

    PubMed

    Ishikawa, Rie; Kim, Ryang; Namba, Takashi; Kohsaka, Shinichi; Uchino, Shigeo; Kida, Satoshi

    2014-07-01

    Adult hippocampal neurogenesis has been suggested to play modulatory roles in learning and memory. Importantly, previous studies have shown that newborn neurons in the adult hippocampus are integrated into the dentate gyrus circuit and are recruited more efficiently into the hippocampal memory trace of mice when they become 3 weeks old. Interestingly, a single high-dose treatment with the N-methyl-d-aspartate receptor antagonist memantine (MEM) has been shown to increase hippocampal neurogenesis dramatically by promoting cell proliferation. In the present study, to understand the impact of increased adult neurogenesis on memory performance, we examined the effects of a single treatment of MEM on hippocampus-dependent memory in mice. Interestingly, mice treated with MEM showed an improvement of hippocampus-dependent spatial and social recognition memories when they were trained and tested at 3-6 weeks, but not at 3 days or 4 months, after treatment with MEM. Importantly, we observed a significant positive correlation between the scores for spatial memory (probe trial in the Morris water maze task) and the number of young mature neurons (3 weeks old) in MEM-treated mice, but not saline-treated mice. We also observed that the young mature neurons generated by treatment with MEM were recruited into the trace of spatial memory similarly to those generated through endogenous neurogenesis. Taken together, our observations suggest that treatment with MEM temporally improves hippocampus-dependent memory formation and that the newborn neurons increased by treatment with MEM contribute to this improvement when they become 3 weeks old.

  1. Resveratrol suppresses calcium-mediated microglial activation and rescues hippocampal neurons of adult rats following acute bacterial meningitis.

    PubMed

    Sheu, Ji-Nan; Liao, Wen-Chieh; Wu, Un-In; Shyu, Ling-Yuh; Mai, Fu-Der; Chen, Li-You; Chen, Mei-Jung; Youn, Su-Chung; Chang, Hung-Ming

    2013-03-01

    Acute bacterial meningitis (ABM) is a serious disease with severe neurological sequelae. The intense calcium-mediated microglial activation and subsequently pro-inflammatory cytokine release plays an important role in eliciting ABM-related oxidative damage. Considering resveratrol possesses significant anti-inflammatory and anti-oxidative properties, the present study aims to determine whether resveratrol would exert beneficial effects on hippocampal neurons following ABM. ABM was induced by inoculating Klebsiella pneumoniae into adult rats intraventricularly. The time-of-flight secondary ion mass spectrometry (TOF-SIMS), Griffonia simplicifolia isolectin-B4 (GSA-IB4) and ionized calcium binding adaptor molecule 1 (Iba1) immunohistochemistry, enzyme-linked immunosorbent assay as well as malondialdehyde (MDA) measurement were used to examine the calcium expression, microglial activation, pro-inflammatory cytokine level, and extent of oxidative stress, respectively. In ABM rats, strong calcium signaling associated with enhanced microglial activation was observed in hippocampus. Increased microglial expression was coincided with intense production of pro-inflammatory cytokines and oxidative damage. However, in rats receiving resveratrol after ABM, the calcium intensity, microglial activation, pro-inflammatory cytokine and MDA levels were all significantly decreased. Quantitative data showed that much more hippocampal neurons were survived in resveratrol-treated rats following ABM. As resveratrol successfully rescues hippocampal neurons from ABM by suppressing the calcium-mediated microglial activation, therapeutic use of resveratrol may act as a promising strategy to counteract the ABM-induced neurological damage.

  2. Increased adult hippocampal brain-derived neurotrophic factor and normal levels of neurogenesis in maternal separation rats.

    PubMed

    Greisen, Mia H; Altar, C Anthony; Bolwig, Tom G; Whitehead, Richard; Wörtwein, Gitta

    2005-03-15

    Repeated maternal separation of rat pups during the early postnatal period may affect brain-derived neurotrophic factor (BDNF) or neurons in brain areas that are compromised by chronic stress. In the present study, a highly significant increase in hippocampal BDNF protein concentration was found in adult rats that as neonates had been subjected to 180 min of daily separation compared with handled rats separated for 15 min daily. BDNF protein was unchanged in the frontal cortex and hypothalamus/paraventricular nucleus. Expression of BDNF mRNA in the CA1, CA3, or dentate gyrus of the hippocampus or in the paraventricular hypothalamic nucleus was not affected by maternal separation. All animals displayed similar behavioral patterns in a forced-swim paradigm, which did not affect BDNF protein concentration in the hippocampus or hypothalamus. Repeated administration of bromodeoxyuridine revealed equal numbers of surviving, newly generated granule cells in the dentate gyrus of adult rats from the 15 min or 180 min groups. The age-dependent decline in neurogenesis from 3 months to 7 months of age did not differ between the groups. Insofar as BDNF can stimulate neurogenesis and repair, we propose that the elevated hippocampal protein concentration found in maternally deprived rats might be a compensatory reaction to separation during the neonatal period, maintaining adult neurogenesis at levels equal to those of the handled rats.

  3. The effect of interburst intervals on measures of hippocampal LTP in the freely moving adult male rat.

    PubMed

    Fortin, D A; Bronzino, J D

    2001-08-01

    An important factor in the induction and maintenance of long-term potentiation (LTP) is the tetanization paradigm. This paper presents the changes associated with the induction and maintenance of hippocampal LTP in the freely moving adult male rat, subjected to three different tetanization paradigms. These results indicate that specific LTP measures including (1) synaptic activation, as measured by the slope of the dentate granule cell population excitatory postsynaptic potential, and (2) cellular response, as measured by the dentate population spike amplitude, evoked by single-pulse stimulation of the medial perforant pathway are dependent on the interburst interval of the bursting paradigm commonly used in LTP studies.

  4. Hippocampal Astrocyte Cultures from Adult and Aged Rats Reproduce Changes in Glial Functionality Observed in the Aging Brain.

    PubMed

    Bellaver, Bruna; Souza, Débora Guerini; Souza, Diogo Onofre; Quincozes-Santos, André

    2016-03-30

    Astrocytes are dynamic cells that maintain brain homeostasis, regulate neurotransmitter systems, and process synaptic information, energy metabolism, antioxidant defenses, and inflammatory response. Aging is a biological process that is closely associated with hippocampal astrocyte dysfunction. In this sense, we demonstrated that hippocampal astrocytes from adult and aged Wistar rats reproduce the glial functionality alterations observed in aging by evaluating several senescence, glutamatergic, oxidative and inflammatory parameters commonly associated with the aging process. Here, we show that the p21 senescence-associated gene and classical astrocyte markers, such as glial fibrillary acidic protein (GFAP), vimentin, and actin, changed their expressions in adult and aged astrocytes. Age-dependent changes were also observed in glutamate transporters (glutamate aspartate transporter (GLAST) and glutamate transporter-1 (GLT-1)) and glutamine synthetase immunolabeling and activity. Additionally, according to in vivo aging, astrocytes from adult and aged rats showed an increase in oxidative/nitrosative stress with mitochondrial dysfunction, an increase in RNA oxidation, NADPH oxidase (NOX) activity, superoxide levels, and inducible nitric oxide synthase (iNOS) expression levels. Changes in antioxidant defenses were also observed. Hippocampal astrocytes also displayed age-dependent inflammatory response with augmentation of proinflammatory cytokine levels, such as TNF-α, IL-1β, IL-6, IL-18, and messenger RNA (mRNA) levels of cyclo-oxygenase 2 (COX-2). Furthermore, these cells secrete neurotrophic factors, including glia-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), S100 calcium-binding protein B (S100B) protein, and transforming growth factor-β (TGF-β), which changed in an age-dependent manner. Classical signaling pathways associated with aging, such as nuclear factor erythroid-derived 2-like 2 (Nrf2), nuclear factor kappa B (NFκ

  5. Brain self-protection: the role of endogenous neural progenitor cells in adult brain after cerebral cortical ischemia.

    PubMed

    Li, Bin; Piao, Chun-Shu; Liu, Xiao-Yun; Guo, Wen-Ping; Xue, Yue-Qiang; Duan, Wei-Ming; Gonzalez-Toledo, Maria E; Zhao, Li-Ru

    2010-04-23

    Convincing evidence has shown that brain ischemia causes the proliferation of neural stem cells/neural progenitor cells (NSCs/NPCs) in both the subventricular zone (SVZ) and the subgranular zone (SGZ) of adult brain. The role of brain ischemia-induced NSC/NPC proliferation, however, has remained unclear. Here we have determined whether brain ischemia-induced amplification of the NSCs/NPCs in adult brain is required for brain self-protection. The approach of intracerebroventricular (ICV) infusion of cytosine arabinoside (Ara-C), an inhibitor for cell proliferation, for the first 7days after brain ischemia was used to block ischemia-induced NSC/NPC proliferation. We observed that ICV infusion of Ara-C caused a complete blockade of NSC/NPC proliferation in the SVZ and a dramatic reduction of NSC/NPC proliferation in the SGZ. Additionally, as a result of the inhibition of ischemia-induced NSC/NPC pool amplification, the number of neurons in the hippocampal CA1 and CA3 was significantly reduced, the infarction size was significantly enlarged, and neurological deficits were significantly worsened after focal brain ischemia. We also found that an NSC/NPC-conditioned medium showed neuroprotective effects in vitro and that adult NSC/NPC-released brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) are required for NSC/NPC-conditioned medium-induced neuroprotection. These data suggest that NSC/NPC-generated trophic factors are neuroprotective and that brain ischemia-triggered NSC/NPC proliferation is crucial for brain protection. This study provides insights into the contribution of endogenous NSCs/NPCs to brain self-protection in adult brain after ischemia injury.

  6. Deep-brain magnetic stimulation promotes adult hippocampal neurogenesis and alleviates stress-related behaviors in mouse models for neuropsychiatric disorders

    PubMed Central

    2014-01-01

    Background Repetitive Transcranial Magnetic Stimulation (rTMS)/ Deep-brain Magnetic Stimulation (DMS) is an effective therapy for various neuropsychiatric disorders including major depression disorder. The molecular and cellular mechanisms underlying the impacts of rTMS/DMS on the brain are not yet fully understood. Results Here we studied the effects of deep-brain magnetic stimulation to brain on the molecular and cellular level. We examined the adult hippocampal neurogenesis and hippocampal synaptic plasticity of rodent under stress conditions with deep-brain magnetic stimulation treatment. We found that DMS promotes adult hippocampal neurogenesis significantly and facilitates the development of adult new-born neurons. Remarkably, DMS exerts anti-depression effects in the learned helplessness mouse model and rescues hippocampal long-term plasticity impaired by restraint stress in rats. Moreover, DMS alleviates the stress response in a mouse model for Rett syndrome and prolongs the life span of these animals dramatically. Conclusions Deep-brain magnetic stimulation greatly facilitates adult hippocampal neurogenesis and maturation, also alleviates depression and stress-related responses in animal models. PMID:24512669

  7. Adherent neural stem (NS) cells from fetal and adult forebrain.

    PubMed

    Pollard, Steven M; Conti, Luciano; Sun, Yirui; Goffredo, Donato; Smith, Austin

    2006-07-01

    Stable in vitro propagation of central nervous system (CNS) stem cells would offer expanded opportunities to dissect basic molecular, cellular, and developmental processes and to model neurodegenerative disease. CNS stem cells could also provide a source of material for drug discovery assays and cell replacement therapies. We have recently reported the generation of adherent, symmetrically expandable, neural stem (NS) cell lines derived both from mouse and human embryonic stem cells and from fetal forebrain (Conti L, Pollard SM, Gorba T, Reitano E, Toselli M, Biella G, Sun Y, Sanzone S, Ying QL, Cattaneo E, Smith A. 2005. Niche-independent symmetrical self-renewal of a mammalian tissue stem cell. PLoS Biol 3(9):e283). These NS cells retain neuronal and glial differentiation potential after prolonged passaging and are transplantable. NS cells are likely to comprise the resident stem cell population within heterogeneous neurosphere cultures. Here we demonstrate that similar NS cell cultures can be established from the adult mouse brain. We also characterize the growth factor requirements for NS cell derivation and self-renewal. We discuss our current understanding of the relationship of NS cell lines to physiological progenitor cells of fetal and adult CNS.

  8. Properties of GABA-mediated synaptic potentials induced by zinc in adult rat hippocampal pyramidal neurones.

    PubMed Central

    Xie, X; Smart, T G

    1993-01-01

    1. Intracellular recording techniques were used to study the actions of the transition ion, zinc, on CA1 and CA3 pyramidal neurones in adult rat hippocampal slices. 2. Zinc (300 microM) hyperpolarized pyramidal neurones, increased the membrane excitability and also induced periodic, spontaneous giant depolarizing potentials associated with a conductance increase mechanism. 3. The occurrence of spontaneous giant depolarizations was dependent on the zinc concentration (10 microM-1 mM) with an apparent dissociation constant of 98 microM. The frequency of zinc-induced depolarizations was unaffected by the membrane potential from -50 to -100 mV. 4. Stimulation of the Schaffer collaterals or mossy fibre pathways evoked an excitatory and inhibitory synaptic potential complex. In the presence of zinc, nerve fibre stimulation evoked, in an all-or-none fashion, a giant depolarizing potential with an increased membrane conductance. Both spontaneous and evoked depolarizations were inhibited by 1 microM tetrodotoxin. 5. Evoked giant depolarizations were labile with too frequent stimulation resulting in a failure of generation. A minimum time of 140 s was required between stimuli to ensure successive giant depolarizations. 6. Spontaneous and evoked zinc-induced depolarizing potentials were inhibited by bicuculline (10 microM) or picrotoxin (40 microM) and enhanced by pentobarbitone (100 microM) or flurazepam (10 microM), suggesting that these potentials are mediated by activation of gamma-aminobutyric acidA (GABAA) receptors. 7. Ionophoretic application of GABA produced biphasic responses at -60 mV membrane potential. The reversal potentials for the depolarizing and hyperpolarizing GABA responses were -56 +/- 5 and -66 +/- 8 mV respectively. The giant depolarizations induced by zinc reversed at -57 +/- 4 mV. This suggests a dendritic location for the generation of these potentials. 8. Excitatory amino acid antagonists, 2-amino-5-phosphonovalerate (APV, 40 microM) or 6-cyano-7

  9. Effects of long-term malnutrition and rehabilitation on the hippocampal formation of the adult rat. A morphometric study.

    PubMed Central

    Andrade, J P; Madeira, M D; Paula-Barbosa, M M

    1995-01-01

    We have previously shown that the numerical density of dentate granule and CA3 pyramidal cells of adult rats is reduced after lengthy periods of low-protein diet. In this study, the total number of these neurons was estimated, together with those for the hilar and CA1 pyramidal cells in order to obtain a complete and unbiased insight into the effects of malnutrition and rehabilitation from malnutrition on the structure of the hippocampal formation. Groups of 2-month-old rats were fed a low protein diet (8% casein) for 6, 12 and 18 months and compared with age-matched control and recovery rats. The recovery group was fed a low protein diet for 6 months and then switched to normal diet during the same period. Total numbers of neurons of each hippocampal region were calculated from their numerical density, estimated with the physical disector, and from the volume of the respective cell layers, after correction for the tissue shrinkage factor. The total number of granule, hilar, CA1 and CA3 pyramidal cells was reduced in all groups of malnourished rats including the recovery group. No differences were found between malnourished and recovery groups. These findings indicate that a prolonged low protein diet, started in adult life, leads to a deficit in neuronal numbers in the hippocampal formation, and that it may also disrupt the normal process of cell acquisition in the dentate gyrus. Moreover, our data support the view that the morphological alterations induced by a low protein intake are irreversible. Images Fig. 1 Fig. 2 Fig. 3 PMID:7592001

  10. Developmental fluoxetine exposure increases behavioral despair and alters epigenetic regulation of the hippocampal BDNF gene in adult female offspring.

    PubMed

    Boulle, Fabien; Pawluski, Jodi L; Homberg, Judith R; Machiels, Barbie; Kroeze, Yvet; Kumar, Neha; Steinbusch, Harry W M; Kenis, Gunter; van den Hove, Daniel L A

    2016-04-01

    A growing number of infants are exposed to selective serotonin reuptake inhibitor (SSRI) medications during the perinatal period. Perinatal exposure to SSRI medications alter neuroplasticity and increase depressive- and anxiety-related behaviors, particularly in male offspring as little work has been done in female offspring to date. The long-term effects of SSRI on development can also differ with previous exposure to prenatal stress, a model of maternal depression. Because of the limited work done on the role of developmental SSRI exposure on neurobehavioral outcomes in female offspring, the aim of the present study was to investigate how developmental fluoxetine exposure affects anxiety and depression-like behavior, as well as the regulation of hippocampal brain-derived neurotrophic factor (BDNF) signaling in the hippocampus of adult female offspring. To do this female Sprague-Dawley rat offspring were exposed to prenatal stress and fluoxetine via the dam, for a total of four groups of female offspring: 1) No Stress+Vehicle, 2) No Stress+Fluoxetine, 3) Prenatal Stress+Vehicle, and 4) Prenatal Stress+Fluoxetine. Primary results show that, in adult female offspring, developmental SSRI exposure significantly increases behavioral despair measures on the forced swim test, decreases hippocampal BDNF exon IV mRNA levels, and increases levels of the repressive histone 3 lysine 27 tri-methylated mark at the corresponding promoter. There was also a significant negative correlation between hippocampal BDNF exon IV mRNA levels and immobility in the forced swim test. No effects of prenatal stress or developmental fluoxetine exposure were seen on tests of anxiety-like behavior. This research provides important evidence for the long-term programming effects of early-life exposure to SSRIs on female offspring, particularily with regard to affect-related behaviors and their underlying molecular mechanisms.

  11. Variability of doublecortin-associated dendrite maturation in adult hippocampal neurogenesis is independent of the regulation of precursor cell proliferation

    PubMed Central

    Plümpe, Tobias; Ehninger, Dan; Steiner, Barbara; Klempin, Friederike; Jessberger, Sebastian; Brandt, Moritz; Römer, Benedikt; Rodriguez, Gerardo Ramirez; Kronenberg, Golo; Kempermann, Gerd

    2006-01-01

    Background In the course of adult hippocampal neurogenesis most regulation takes place during the phase of doublecortin (DCX) expression, either as pro-proliferative effect on precursor cells or as survival-promoting effect on postmitotic cells. We here obtained quantitative data about the proliferative population and the dynamics of postmitotic dendrite development during the period of DCX expression. The question was, whether any indication could be obtained that the initiation of dendrite development is timely bound to the exit from the cell cycle. Alternatively, the temporal course of morphological maturation might be subject to additional regulatory events. Results We found that (1) 20% of the DCX population were precursor cells in cell cycle, whereas more than 70% were postmitotic, (2) the time span until newborn cells had reached the most mature stage associated with DCX expression varied between 3 days and several weeks, (3) positive or negative regulation of precursor cell proliferation did not alter the pattern and dynamics of dendrite development. Dendrite maturation was largely independent of close contacts to astrocytes. Conclusion These data imply that dendrite maturation of immature neurons is initiated at varying times after cell cycle exit, is variable in duration, and is controlled independently of the regulation of precursor cell proliferation. We conclude that in addition to the major regulatory events in cell proliferation and selective survival, additional micro-regulatory events influence the course of adult hippocampal neurogenesis. PMID:17105671

  12. Increased adult hippocampal neurogenesis is not necessary for wheel running to abolish conditioned place preference for cocaine in mice.

    PubMed

    Mustroph, M L; Merritt, J R; Holloway, A L; Pinardo, H; Miller, D S; Kilby, C N; Bucko, P; Wyer, A; Rhodes, J S

    2015-01-01

    Recent evidence suggests that wheel running can abolish conditioned place preference (CPP) for cocaine in mice. Running significantly increases the number of new neurons in the hippocampus, and new neurons have been hypothesised to enhance plasticity and behavioral flexibility. Therefore, we tested the hypothesis that increased neurogenesis was necessary for exercise to abolish cocaine CPP. Male nestin-thymidine kinase transgenic mice were conditioned with cocaine, and then housed with or without running wheels for 32 days. Half of the mice were fed chow containing valganciclovir to induce apoptosis in newly divided neurons, and the other half were fed standard chow. For the first 10 days, mice received daily injections of bromodeoxyuridine (BrdU) to label dividing cells. On the last 4 days, mice were tested for CPP, and then euthanized for measurement of adult hippocampal neurogenesis by counting the number of BrdU-positive neurons in the dentate gyrus. Levels of running were similar in mice fed valganciclovir-containing chow and normal chow. Valganciclovir significantly reduced the numbers of neurons (BrdU-positive/NeuN-positive) in the dentate gyrus of both sedentary mice and runner mice. Valganciclovir-fed runner mice showed similar levels of neurogenesis as sedentary, normal-fed controls. However, valganciclovir-fed runner mice showed the same abolishment of CPP as runner mice with intact neurogenesis. The results demonstrate that elevated adult hippocampal neurogenesis resulting from running is not necessary for running to abolish cocaine CPP in mice.

  13. The electrophysiology of the olfactory-hippocampal circuit in the isolated and perfused adult mammalian brain in vitro.

    PubMed

    de Curtis, M; Paré, D; Llinás, R R

    1991-10-01

    The viability and general electrophysiological properties of the limbic system in the adult mammalian brain isolated and maintained in vitro by arterial perfusion are described. The isolated brain preparation combines the advantages of intact synaptic connectivity and accessibility of different areas of the encephalic mass with those of the in vitro approach, i.e., stability and control of the ionic environment. Extracellular field potential as well as intracellular recordings were performed at different levels in the limbic system of isolated adult guinea pig brains. The results demonstrate that in the piriform, entorhinal, and hippocampal cortices, the intrinsic electrical properties of individual cells as well as the spontaneous and evoked electrical activity in the neuronal ensembles they comprise, were virtually identical to those observed in vivo. The properties of the limbic system loop were determined.

  14. Proinflammatory cytokines differentially influence adult hippocampal cell proliferation depending upon the route and chronicity of administration.

    PubMed

    Seguin, Julie Anne; Brennan, Jordan; Mangano, Emily; Hayley, Shawn

    2009-01-01

    Disturbances of hippocampal plasticity, including impaired dendritic branching and reductions of neurogenesis, are provoked by stressful insults and may occur in depression. Although corticoids likely contribute to stressor-induced reductions of neurogenesis, other signaling messengers, including pro-inflammatory cytokines might also be involved. Accordingly, the present investigation assessed whether three proinflammatory cytokines, namely interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha) (associated with depression) influenced cellular proliferation within the hippocampus. In this regard, systemic administration of TNF-alpha reduced 5-bromo-2-deoxyuridine (BrdU) labeling within the hippocampus, whereas IL-1beta and IL-6 had no such effect. However, repeated but not a single intra-hippocampal infusion of IL-6 and IL-1beta actually increased cellular proliferation and IL-6 infusion also enhanced microglial staining within the hippocampus. Yet, no changes in doublecortin expression were apparent, suggesting that the cytokine did not influence the birth of cells destined to become neurons. Essentially, the route of administration and chronicity of cytokine administration had a marked influence upon the nature of hippocampal alterations provoked, suggesting that cytokines may differentially regulate hippocampal plasticity in neuropsychiatric conditions.

  15. Voluntary exercise induces adult hippocampal neurogenesis and BDNF expression in a rodent model of fetal alcohol spectrum disorders.

    PubMed

    Boehme, Fanny; Gil-Mohapel, Joana; Cox, Adrian; Patten, Anna; Giles, Erica; Brocardo, Patricia S; Christie, Brian R

    2011-05-01

    Alcohol consumption during pregnancy can result in a myriad of health problems in the affected offspring ranging from growth deficiencies to central nervous system impairments that result in cognitive deficits. Adult hippocampal neurogenesis is thought to play a role in cognition (i.e. learning and memory) and can be modulated by extrinsic factors such as alcohol consumption and physical exercise. We examined the impact of voluntary physical exercise on adult hippocampal neurogenesis in a rat model of fetal alcohol spectrum disorders (FASD). Intragastric intubation was used to deliver ethanol to rats in a highly controlled fashion through all three trimester equivalents (i.e. throughout gestation and during the first 10 days of postnatal life). Ethanol-exposed animals and their pair-fed and ad libitum controls were left undisturbed until they reached a young adult stage at which point they had free access to a running wheel for 12 days. Prenatal and early postnatal ethanol exposure altered cell proliferation in young adult female rats and increased early neuronal maturation without affecting cell survival in the dentate gyrus (DG) of the hippocampus. Voluntary wheel running increased cell proliferation, neuronal maturation and cell survival as well as levels of brain-derived neurotrophic factor in the DG of both ethanol-exposed female rats and their pair-fed and ad libitum controls. These results indicate that the capacity of the brain to respond to exercise is not impaired in this model of FASD, highlighting the potential therapeutic value of physical exercise for this developmental disorder.

  16. Comparing adult hippocampal neurogenesis in mammalian species and orders: influence of chronological age and life history stage.

    PubMed

    Amrein, Irmgard; Isler, Karin; Lipp, Hans-Peter

    2011-09-01

    Adult hippocampal neurogenesis is a prominent event in rodents. In species with longer life expectancies, newly born cells in the adult dentate gyrus of the hippocampal formation are less abundant or can be completely absent. Several lines of evidence indicate that the regulatory mechanisms of adult neurogenesis differ between short- and long-lived mammals. After a critical appraisal of the factors and problems associated with comparing different species, we provide a quantitative comparison derived from seven laboratory strains of mice (BALB, C57BL/6, CD1, outbred) and rats (F344, Sprague-Dawley, Wistar), six other rodent species of which four are wild-derived (wood mouse, vole, spiny mouse and guinea pig), three non-human primate species (marmoset and two macaque species) and one carnivore (red fox). Normalizing the number of proliferating cells to total granule cell number, we observe an overall exponential decline in proliferation that is chronologically equal between species and orders and independent of early developmental processes and life span. Long- and short-lived mammals differ with regard to major life history stages; at the time points of weaning, age at first reproduction and average life expectancy, long-lived primates and foxes have significantly fewer proliferating cells than rodents. Although the database for neuronal differentiation is limited, we find indications that the extent of neuronal differentiation is subject to species-specific selective adaptations. We conclude that absolute age is the critical factor regulating cell genesis in the adult hippocampus of mammals. Ontogenetic and ecological factors primarily influence the regulation of neuronal differentiation rather than the rate of cell proliferation.

  17. Sex differences in resilience to childhood maltreatment: effects of trauma history on hippocampal volume, general cognition and subclinical psychosis in healthy adults.

    PubMed

    Samplin, Erin; Ikuta, Toshikazu; Malhotra, Anil K; Szeszko, Philip R; Derosse, Pamela

    2013-09-01

    Recent data suggests that a history of childhood maltreatment is associated with reductions in hippocampal volume in healthy adults. Because this association is also evident in adults with psychiatric illness, it has been suggested that reductions in hippocampal volume associated with childhood maltreatment may be a risk factor for psychiatric illness. Such an interpretation suggests that healthy adults with a history of childhood maltreatment are more resilient to the effects of maltreatment. Current models of resilience suggest, however, that resiliency should be measured across multiple domains of functioning. The present study sought to investigate childhood maltreatment in relationship to hippocampal volumes in healthy adults and to address the question of whether the putative resiliency extends to other domains of functioning. Sixty-seven healthy Caucasian adults were assessed for a history of childhood emotional abuse, emotional neglect and physical abuse and received high resolution structural MR imaging scans. Participants with and without histories of abuse or neglect were compared on measures of total hippocampal volume, general cognitive ability and subclinical psychopathology. Our results suggest that childhood emotional abuse is associated with reduced hippocampus volume in males, but not in females. However, emotional abuse was associated with higher levels of subclinical psychopathology in both males and females. These data suggest that while females may be more resilient to the neurological effects of childhood maltreatment, they are not more resilient to the psychiatric symptoms associated with childhood maltreatment. Further research is needed to elucidate the mechanisms involved in these different levels of resilience.

  18. Neural correlates of executive attention in adults born very preterm

    PubMed Central

    Daamen, Marcel; Bäuml, Josef G.; Scheef, Lukas; Meng, Chun; Jurcoane, Alina; Jaekel, Julia; Sorg, Christian; Busch, Barbara; Baumann, Nicole; Bartmann, Peter; Wolke, Dieter; Wohlschläger, Afra; Boecker, Henning

    2015-01-01

    Very preterm birth is associated with an increased prevalence of attention problems and may especially impair executive attention, i.e., top-down control of attentional selection in situations where distracting information interferes with the processing of task-relevant stimuli. While there are initial findings linking structural brain alterations in preterm-born individuals with attention problems, the functional basis of these problems are not well understood. The present study used an fMRI adaptation of the Attentional Network Test to examine the neural correlates of executive attention in a large sample of N = 86 adults born very preterm and/or with very low birth weight (VP/VLBW), and N = 100 term-born controls. Executive attention was measured by comparing task behavior and brain activations associated with the processing of incongruent vs. congruent arrow flanker stimuli. Consistent with subtle impairments of executive attention, the VP/VLBW group showed lower accuracy and a tendency for increased response times during the processing of incongruent stimuli. Both groups showed similar activation patters, especially within expected fronto-cingulo-parietal areas, but no significant between-group differences. Our results argue for a maintained attention-relevant network organization in high-functioning preterm born adults in spite of subtle deficits in executive attention. Gestational age and neonatal treatment variables showed associations with task behavior, and brain activation in the dorsal ACC and lateral occipital areas, suggesting that the degree of prematurity (and related neonatal complications) has subtle modulatory influences on executive attention processing. PMID:26640769

  19. A new perspective on the role of the CREB family of transcription factors in memory consolidation via adult hippocampal neurogenesis

    PubMed Central

    Ortega-Martínez, Sylvia

    2015-01-01

    Adult neurogenesis is the process by which new neurons are generated in the brains of adults. Since its discovery 50 years ago, adult neurogenesis has been widely studied in the mammalian brain and has provided a new perspective on the pathophysiology of many psychiatric and neurodegenerative disorders, some of which affect memory. In this regard, adult hippocampal neurogenesis (AHN), which occurs in the subgranular zone (SGZ) of the dentate gyrus (DG), has been suggested to play a role in the formation and consolidation of new memories. This process involves many transcription factors, of which cyclic AMP (cAMP)-responsive element-binding protein (CREB) is a well-documented one. In the developing brain, CREB regulates crucial cell stages (e.g., proliferation, differentiation, and survival), and in the adult brain, it participates in neuronal plasticity, learning, and memory. In addition, new evidence supports the hypothesis that CREB may also participate in learning and memory through its involvement in AHN. This review examines the CREB family of transcription factors, including the different members and known signaling pathways. It highlights the role of CREB as a modulator of AHN, which could underlie its function in memory consolidation mechanisms. PMID:26379491

  20. Persistent loss of hippocampal neurogenesis and increased cell death following adolescent, but not adult, chronic ethanol exposure.

    PubMed

    Broadwater, Margaret A; Liu, Wen; Crews, Fulton T; Spear, Linda P

    2014-01-01

    Although adolescence is a common age to initiate alcohol consumption, the long-term consequences of exposure to alcohol at this time of considerable brain maturation are largely unknown. In studies utilizing rodents, behavioral evidence is beginning to emerge suggesting that the hippocampus may be persistently affected by repeated ethanol exposure during adolescence, but not by comparable alcohol exposure in adulthood. The purpose of this series of experiments was to explore a potential mechanism of hippocampal dysfunction in adults exposed to ethanol during adolescence. Given that disruption in adult neurogenesis has been reported to impair performance on tasks thought to be hippocampally related, we used immunohistochemistry to assess levels of doublecortin (DCX), an endogenous marker of immature neurons, in the dentate gyrus (DG) of the hippocampus 3-4 weeks after adolescent (postnatal day, PD28-48) or adult (PD70-90) intermittent ethanol exposure to 4 g/kg ethanol administered intragastrically. We also investigated another neurogenic niche, the subventricular zone (SVZ), to determine if the effects of ethanol exposure were region specific. Levels of cell proliferation and cell death were also examined in the DG via assessing Ki67 and cleaved caspase-3 immunoreactivity, respectively. Significantly less DCX was observed in the DG of adolescent (but not adult) ethanol-exposed animals about 4 weeks after exposure when these animals were compared to control age-mates. The effects of adolescent ethanol on DCX immunoreactivity were specific to the hippocampus, with no significant exposure effects emerging in the SVZ. In both the DG and the SVZ there was a significant age-related decline in neurogenesis as indexed by DCX. The persistent effect of adolescent ethanol exposure on reduced DCX in the DG appears to be related to significant increases in cell death, with significantly more cleaved caspase-3-positive immunoreactivity observed in the adolescent ethanol group

  1. Effects of monomethylarsonic and monomethylarsonous acid on evoked synaptic potentials in hippocampal slices of adult and young rats.

    PubMed

    Krüger, Katharina; Straub, Heidrun; Hirner, Alfred V; Hippler, Jörg; Binding, Norbert; Musshoff, Ulrich

    2009-04-01

    Arsenite and its metabolites, dimethylarsinic or dimethylarsinous acid, have previously been shown to disturb synaptic transmission in hippocampal slices of rats (Krüger, K., Gruner, J., Madeja, M., Hartmann, L.M., Hirner, A.V., Binding, N., Mubetahoff, U., 2006a. Blockade and enhancement of glutamate receptor responses in Xenopus oocytes by methylated arsenicals. Arch. Toxicol. 80, 492-501, Krüger, K., Straub, H., Binding, N., Mubetahoff, U., 2006b. Effects of arsenite on long-term potentiation in hippocampal slices from adult and young rats. Toxicol. Lett. 165, 167-173, Krüger, K., Repges, H., Hippler, J., Hartmann, L.M., Hirner, A.V., Straub, H., Binding, N., Mubetahoff, U., 2007. Effects of dimethylarsinic and dimethylarsinous acid on evoked synaptic potentials in hippocampal slices of young and adult rats. Toxicol. Appl. Pharmacol. 225, 40-46). The present experiments investigate, whether the important arsenic metabolites monomethylarsonic acid (MMA(V)) and monomethylarsonous acid (MMA(III)) also influence the synaptic functions of the hippocampus. In hippocampal slices of young (14-21 days-old) and adult (2-4 months-old) rats, evoked synaptic field potentials from the Schaffer collateral-CA1 synapse were measured under control conditions and during and after 30 and 60 min of application of the arsenic compounds. MMA(V) had no effect on the synapse functions neither in slices of adult nor in those from young rats. However, MMA(III) strongly influenced the synaptic transmission: it totally depressed the amplitudes of fEPSPs at concentrations of 50 micromol/l (adult rats) and 25 micromol/l (young rats) and LTP amplitudes at concentrations of 25 micromol/l (adult rats) and 10 micromol/l (young rats), respectively. In contrast, application of 1 micromol/l MMA(III) led to an enhancement of the LTP amplitude in young rats, which is interpretable by an enhancing effect on NMDA receptors and a lack of the blocking effect on AMPA receptors at this concentration (Kr

  2. Effects of monomethylarsonic and monomethylarsonous acid on evoked synaptic potentials in hippocampal slices of adult and young rats

    SciTech Connect

    Krueger, Katharina Straub, Heidrun; Hirner, Alfred V.; Hippler, Joerg; Binding, Norbert; Musshoff, Ulrich

    2009-04-01

    Arsenite and its metabolites, dimethylarsinic or dimethylarsinous acid, have previously been shown to disturb synaptic transmission in hippocampal slices of rats (Krueger, K., Gruner, J., Madeja, M., Hartmann, L.M., Hirner, A.V., Binding, N., Mu{beta}hoff, U., 2006a. Blockade and enhancement of glutamate receptor responses in Xenopus oocytes by methylated arsenicals. Arch. Toxicol. 80, 492-501, Krueger, K., Straub, H., Binding, N., Mu{beta}hoff, U., 2006b. Effects of arsenite on long-term potentiation in hippocampal slices from adult and young rats. Toxicol. Lett. 165, 167-173, Krueger, K., Repges, H., Hippler, J., Hartmann, L.M., Hirner, A.V., Straub, H., Binding, N., Mu{beta}hoff, U., 2007. Effects of dimethylarsinic and dimethylarsinous acid on evoked synaptic potentials in hippocampal slices of young and adult rats. Toxicol. Appl. Pharmacol. 225, 40-46). The present experiments investigate, whether the important arsenic metabolites monomethylarsonic acid (MMA{sup V}) and monomethylarsonous acid (MMA{sup III}) also influence the synaptic functions of the hippocampus. In hippocampal slices of young (14-21 days-old) and adult (2-4 months-old) rats, evoked synaptic field potentials from the Schaffer collateral-CA1 synapse were measured under control conditions and during and after 30 and 60 min of application of the arsenic compounds. MMA{sup V} had no effect on the synapse functions neither in slices of adult nor in those from young rats. However, MMA{sup III} strongly influenced the synaptic transmission: it totally depressed the amplitudes of fEPSPs at concentrations of 50 {mu}mol/l (adult rats) and 25 {mu}mol/l (young rats) and LTP amplitudes at concentrations of 25 {mu}mol/l (adult rats) and 10 {mu}mol/l (young rats), respectively. In contrast, application of 1 {mu}mol/l MMA{sup III} led to an enhancement of the LTP amplitude in young rats, which is interpretable by an enhancing effect on NMDA receptors and a lack of the blocking effect on AMPA receptors at

  3. Roles of neural stem cells and adult neurogenesis in adolescent alcohol use disorders.

    PubMed

    Nixon, Kimberly; Morris, Stephanie A; Liput, Daniel J; Kelso, Matthew L

    2010-02-01

    This review discusses the contributions of a newly considered form of plasticity, the ongoing production of new neurons from neural stem cells, or adult neurogenesis, within the context of neuropathologies that occur with excessive alcohol intake in the adolescents. Neural stem cells and adult neurogenesis are now thought to contribute to the structural integrity of the hippocampus, a limbic system region involved in learning, memory, behavioral control, and mood. In adolescents with alcohol use disorders (AUDs), the hippocampus appears to be particularly vulnerable to the neurodegenerative effects of alcohol, but the role of neural stem cells and adult neurogenesis in alcoholic neuropathology has only recently been considered. This review encompasses a brief overview of neural stem cells and the processes involved in adult neurogenesis, how neural stem cells are affected by alcohol, and possible differences in the neurogenic niche between adults and adolescents. Specifically, what is known about developmental differences in adult neurogenesis between the adult and adolescent is gleaned from the literature, as well as how alcohol affects this process differently among the age groups. Finally, this review suggests differences that may exist in the neurogenic niche between adults and adolescents and how these differences may contribute to the susceptibility of the adolescent hippocampus to damage. However, many more studies are needed to discern whether these developmental differences contribute to the vulnerability of the adolescent to developing an AUD.

  4. Astroglial Plasticity Is Implicated in Hippocampal Remodelling in Adult Rats Exposed to Antenatal Dexamethasone

    PubMed Central

    Shende, Vishvesh H.; McArthur, Simon; Gillies, Glenda E.; Opacka-Juffry, Jolanta

    2015-01-01

    The long-term effects of antenatal dexamethasone treatment on brain remodelling in 3-month-old male Sprague Dawley rats whose mothers had been treated with dexamethasone were investigated in the present study. Dorsal hippocampus, basolateral amygdala and nucleus accumbens volume, cell numbers, and GFAP-immunoreactive astroglial cell morphology were analysed using stereology. Total brain volume as assessed by micro-CT was not affected by the treatment. The relative volume of the dorsal hippocampus (% of total brain volume) showed a moderate, by 8%, but significant reduction in dexamethasone-treated versus control animals. Dexamethasone had no effect on the total and GFAP-positive cell numbers in the hippocampal subregions, basolateral amygdala, and nucleus accumbens. Morphological analysis indicated that numbers of astroglial primary processes were not affected in any of the hippocampal subregions analysed but significant reductions in the total primary process length were observed in CA1 by 32%, CA3 by 50%, and DG by 25%. Mean primary process length values were also significantly decreased in CA1 by 25%, CA3 by 45%, and DG by 25%. No significant astroglial morphological changes were found in basolateral amygdala and nucleus accumbens. We propose that the dexamethasone-dependent impoverishment of hippocampal astroglial morphology is the case of maladaptive glial plasticity induced prenatally. PMID:26345609

  5. Astroglial Plasticity Is Implicated in Hippocampal Remodelling in Adult Rats Exposed to Antenatal Dexamethasone.

    PubMed

    Shende, Vishvesh H; McArthur, Simon; Gillies, Glenda E; Opacka-Juffry, Jolanta

    2015-01-01

    The long-term effects of antenatal dexamethasone treatment on brain remodelling in 3-month-old male Sprague Dawley rats whose mothers had been treated with dexamethasone were investigated in the present study. Dorsal hippocampus, basolateral amygdala and nucleus accumbens volume, cell numbers, and GFAP-immunoreactive astroglial cell morphology were analysed using stereology. Total brain volume as assessed by micro-CT was not affected by the treatment. The relative volume of the dorsal hippocampus (% of total brain volume) showed a moderate, by 8%, but significant reduction in dexamethasone-treated versus control animals. Dexamethasone had no effect on the total and GFAP-positive cell numbers in the hippocampal subregions, basolateral amygdala, and nucleus accumbens. Morphological analysis indicated that numbers of astroglial primary processes were not affected in any of the hippocampal subregions analysed but significant reductions in the total primary process length were observed in CA1 by 32%, CA3 by 50%, and DG by 25%. Mean primary process length values were also significantly decreased in CA1 by 25%, CA3 by 45%, and DG by 25%. No significant astroglial morphological changes were found in basolateral amygdala and nucleus accumbens. We propose that the dexamethasone-dependent impoverishment of hippocampal astroglial morphology is the case of maladaptive glial plasticity induced prenatally.

  6. Epigenetic modification of hippocampal Bdnf DNA in adult rats in an animal model of post-traumatic stress disorder.

    PubMed

    Roth, Tania L; Zoladz, Phillip R; Sweatt, J David; Diamond, David M

    2011-07-01

    Epigenetic alterations of the brain-derived neurotrophic factor (Bdnf) gene have been linked with memory, stress, and neuropsychiatric disorders. Here we examined whether there was a link between an established rat model of post-traumatic stress disorder (PTSD) and Bdnf DNA methylation. Adult male Sprague-Dawley rats were given psychosocial stress composed of two acute cat exposures in conjunction with 31 days of daily social instability. These manipulations have been shown previously to produce physiological and behavioral sequelae in rats that are comparable to symptoms observed in traumatized people with PTSD. We then assessed Bdnf DNA methylation patterns (at exon IV) and gene expression. We have found here that the psychosocial stress regimen significantly increased Bdnf DNA methylation in the dorsal hippocampus, with the most robust hypermethylation detected in the dorsal CA1 subregion. Conversely, the psychosocial stress regimen significantly decreased methylation in the ventral hippocampus (CA3). No changes in Bdnf DNA methylation were detected in the medial prefrontal cortex or basolateral amygdala. In addition, there were decreased levels of Bdnf mRNA in both the dorsal and ventral CA1. These results provide evidence that traumatic stress occurring in adulthood can induce CNS gene methylation, and specifically, support the hypothesis that epigenetic marking of the Bdnf gene may underlie hippocampal dysfunction in response to traumatic stress. Furthermore, this work provides support for the speculative notion that altered hippocampal Bdnf DNA methylation is a cellular mechanism underlying the persistent cognitive deficits which are prominent features of the pathophysiology of PTSD.

  7. Transcriptional profiling of adult neural stem-like cells from the human brain.

    PubMed

    Sandberg, Cecilie Jonsgar; Vik-Mo, Einar O; Behnan, Jinan; Helseth, Eirik; Langmoen, Iver A

    2014-01-01

    There is a great potential for the development of new cell replacement strategies based on adult human neural stem-like cells. However, little is known about the hierarchy of cells and the unique molecular properties of stem- and progenitor cells of the nervous system. Stem cells from the adult human brain can be propagated and expanded in vitro as free floating neurospheres that are capable of self-renewal and differentiation into all three cell types of the central nervous system. Here we report the first global gene expression study of adult human neural stem-like cells originating from five human subventricular zone biopsies (mean age 42, range 33-60). Compared to adult human brain tissue, we identified 1,189 genes that were significantly up- and down-regulated in adult human neural stem-like cells (1% false discovery rate). We found that adult human neural stem-like cells express stem cell markers and have reduced levels of markers that are typical of the mature cells in the nervous system. We report that the genes being highly expressed in adult human neural stem-like cells are associated with developmental processes and the extracellular region of the cell. The calcium signaling pathway and neuroactive ligand-receptor interactions are enriched among the most differentially regulated genes between adult human neural stem-like cells and adult human brain tissue. We confirmed the expression of 10 of the most up-regulated genes in adult human neural stem-like cells in an additional sample set that included adult human neural stem-like cells (n = 6), foetal human neural stem cells (n = 1) and human brain tissues (n = 12). The NGFR, SLITRK6 and KCNS3 receptors were further investigated by immunofluorescence and shown to be heterogeneously expressed in spheres. These receptors could potentially serve as new markers for the identification and characterisation of neural stem- and progenitor cells or as targets for manipulation of cellular fate.

  8. How to make a hippocampal dentate gyrus granule neuron.

    PubMed

    Yu, Diana X; Marchetto, Maria C; Gage, Fred H

    2014-06-01

    Granule neurons in the hippocampal dentate gyrus (DG) receive their primary inputs from the cortex and are known to be continuously generated throughout adult life. Ongoing integration of newborn neurons into the existing hippocampal neural circuitry provides enhanced neuroplasticity, which plays a crucial role in learning and memory; deficits in this process have been associated with cognitive decline under neuropathological conditions. In this Primer, we summarize the developmental principles that regulate the process of DG neurogenesis and discuss recent advances in harnessing these developmental cues to generate DG granule neurons from human pluripotent stem cells.

  9. Hippocampal activation is associated with longitudinal amyloid accumulation and cognitive decline.

    PubMed

    Leal, Stephanie L; Landau, Susan M; Bell, Rachel K; Jagust, William J

    2017-02-08

    The amyloid hypothesis suggests that beta-amyloid (Aβ) deposition leads to alterations in neural function and ultimately to cognitive decline in Alzheimer's disease. However, factors that underlie Aβ deposition are incompletely understood. One proposed model suggests that synaptic activity leads to increased Aβ deposition. More specifically, hyperactivity in the hippocampus may be detrimental and could be one factor that drives Aβ deposition. To test this model, we examined the relationship between hippocampal activity during a memory task using fMRI and subsequent longitudinal change in Aβ using PIB-PET imaging in cognitively normal older adults. We found that greater hippocampal activation at baseline was associated with increased Aβ accumulation. Furthermore, increasing Aβ accumulation mediated the influence of hippocampal activation on declining memory performance, demonstrating a crucial role of Aβ in linking hippocampal activation and memory. These findings support a model linking increased hippocampal activation to subsequent Aβ deposition and cognitive decline.

  10. Oppositional Effects of Serotonin Receptors 5-HT1a, 2, and 2c in the Regulation of Adult Hippocampal Neurogenesis

    PubMed Central

    Klempin, Friederike; Babu, Harish; Tonelli, Davide De Pietri; Alarcon, Edson; Fabel, Klaus; Kempermann, Gerd

    2009-01-01

    Serotonin (5-HT) appears to play a major role in controlling adult hippocampal neurogenesis and thereby it is relevant for theories linking failing adult neurogenesis to the pathogenesis of major depression and the mechanisms of action of antidepressants. Serotonergic drugs lacked acute effects on adult neurogenesis in many studies, which suggested a surprisingly long latency phase. Here we report that the selective serotonin reuptake inhibitor fluoxetine, which has no acute effect on precursor cell proliferation, causes the well-described increase in net neurogenesis upon prolonged treatment partly by promoting the survival and maturation of new postmitotic neurons. We hypothesized that this result is the cumulative effect of several 5-HT-dependent events in the course of adult neurogenesis. Thus, we used specific agonists and antagonists to 5-HT1a, 2, and 2c receptor subtypes to analyze their impact on different developmental stages. We found that 5-HT exerts acute and opposing effects on proliferation and survival or differentiation of precursor cells by activating the diverse receptor subtypes on different stages within the neuronal lineage in vivo. This was confirmed in vitro by demonstrating that 5-HT1a receptors are involved in self-renewal of precursor cells, whereas 5-HT2 receptors effect both proliferation and promote neuronal differentiation. We propose that under acute conditions 5-HT2 effects counteract the positive proliferative effect of 5-HT1a receptor activation. However, prolonged 5-HT2c receptor activation fosters an increase in late-stage progenitor cells and early postmitotic neurons, leading to a net increase in adult neurogenesis. Our data indicate that serotonin does not show effect latency in the adult dentate gyrus. Rather, the delayed response to serotonergic drugs with respect to endpoints downstream of the immediate receptor activity is largely due to the initially antagonistic and un-balanced action of different 5-HT receptors. PMID

  11. Properties of Taurine Release in Glucose-Free Media in Hippocampal Slices from Developing and Adult Mice

    PubMed Central

    Oja, Simo S.; Saransaari, Pirjo

    2015-01-01

    The release of preloaded [3H]taurine from hippocampal slices from developing 7-day-old and young adult 3-month-old mice was studied in a superfusion system in the absence of glucose. These hypoglycemic conditions enhanced the release at both ages, the effect being markedly greater in developing mice. A depolarizing K+ concentration accentuated the release, which indicates that it was partially mediated by exocytosis. The anion channel blockers were inhibitory, witnessing the contribution of ion channels. NO-generating agents fomented the release as a sign of the participation of excitatory amino acid receptors. The other second messenger systems were apparently less efficient. The much greater taurine release could be a reason for the well-known greater tolerance of developing nervous tissue to lack of glucose. PMID:26347028

  12. Differences in Feedback- and Inhibition-Related Neural Activity in Adult ADHD

    ERIC Educational Resources Information Center

    Dibbets, Pauline; Evers, Lisbeth; Hurks, Petra; Marchetta, Natalie; Jolles, Jelle

    2009-01-01

    The objective of this study was to examine response inhibition- and feedback-related neural activity in adults with attention deficit hyperactivity disorder (ADHD) using event-related functional MRI. Sixteen male adults with ADHD and 13 healthy/normal controls participated in this study and performed a modified Go/NoGo task. Behaviourally,…

  13. Genetic Demonstration of a Role for Stathmin in Adult Hippocampal Neurogenesis, Spinogenesis, and NMDA Receptor-Dependent Memory

    PubMed Central

    Martel, Guillaume; Uchida, Shusaku; Hevi, Charles; Chévere-Torres, Itzamarie; Fuentes, Ileana; Park, Young Jin; Hafeez, Hannah; Yamagata, Hirotaka; Watanabe, Yoshifumi

    2016-01-01

    Neurogenesis and memory formation are essential features of the dentate gyrus (DG) area of the hippocampus, but to what extent the mechanisms responsible for both processes overlap remains poorly understood. Stathmin protein, whose tubulin-binding and microtubule-destabilizing activity is negatively regulated by its phosphorylation, is prominently expressed in the DG. We show here that stathmin is involved in neurogenesis, spinogenesis, and memory formation in the DG. tTA/tetO-regulated bitransgenic mice, expressing the unphosphorylatable constitutively active Stathmin4A mutant (Stat4A), exhibit impaired adult hippocampal neurogenesis and reduced spine density in the DG granule neurons. Although Stat4A mice display deficient NMDA receptor-dependent memory in contextual discrimination learning, which is dependent on hippocampal neurogenesis, their NMDA receptor-independent memory is normal. Confirming NMDA receptor involvement in the memory deficits, Stat4A mutant mice have a decrease in the level of synaptic NMDA receptors and a reduction in learning-dependent CREB-mediated gene transcription. The deficits in neurogenesis, spinogenesis, and memory in Stat4A mice are not present in mice in which tTA/tetO-dependent transgene transcription is blocked by doxycycline through their life. The memory deficits are also rescued within 3 d by intrahippocampal infusion of doxycycline, further indicating a role for stathmin expressed in the DG in contextual memory. Our findings therefore point to stathmin and microtubules as a mechanistic link between neurogenesis, spinogenesis, and NMDA receptor-dependent memory formation in the DG. SIGNIFICANCE STATEMENT In the present study, we aimed to clarify the role of stathmin in neuronal and behavioral functions. We characterized the neurogenic, behavioral, and molecular consequences of the gain-of-function stathmin mutation using a bitransgenic mouse expressing a constitutively active form of stathmin. We found that stathmin plays an

  14. Peripheral telomere length and hippocampal volume in adolescents with major depressive disorder.

    PubMed

    Henje Blom, E; Han, L K M; Connolly, C G; Ho, T C; Lin, J; LeWinn, K Z; Simmons, A N; Sacchet, M D; Mobayed, N; Luna, M E; Paulus, M; Epel, E S; Blackburn, E H; Wolkowitz, O M; Yang, T T

    2015-11-10

    Several studies have reported that adults with major depressive disorder have shorter telomere length and reduced hippocampal volumes. Moreover, studies of adult populations without major depressive disorder suggest a relationship between peripheral telomere length and hippocampal volume. However, the relationship of these findings in adolescents with major depressive disorder has yet to be explored. We examined whether adolescent major depressive disorder is associated with altered peripheral telomere length and hippocampal volume, and whether these measures relate to one another. In 54 unmedicated adolescents (13-18 years) with major depressive disorder and 63 well-matched healthy controls, telomere length was assessed from saliva using quantitative polymerase chain reaction methods, and bilateral hippocampal volumes were measured with magnetic resonance imaging. After adjusting for age and sex (and total brain volume in the hippocampal analysis), adolescents with major depressive disorder exhibited significantly shorter telomere length and significantly smaller right, but not left hippocampal volume. When corrected for age, sex, diagnostic group and total brain volume, telomere length was not significantly associated with left or right hippocampal volume, suggesting that these cellular and neural processes may be mechanistically distinct during adolescence. Our findings suggest that shortening of telomere length and reduction of hippocampal volume are already present in early-onset major depressive disorder and thus unlikely to be only a result of accumulated years of exposure to major depressive disorder.

  15. Histological correlates of N40 auditory evoked potentials in adult rats after neonatal ventral hippocampal lesion: animal model of schizophrenia.

    PubMed

    Romero-Pimentel, A L; Vázquez-Roque, R A; Camacho-Abrego, I; Hoffman, K L; Linares, P; Flores, G; Manjarrez, E

    2014-11-01

    The neonatal ventral hippocampal lesion (NVHL) is an established neurodevelopmental rat model of schizophrenia. Rats with NVHL exhibit several behavioral, molecular and physiological abnormalities that are similar to those found in schizophrenics. Schizophrenia is a severe psychiatric illness characterized by profound disturbances of mental functions including neurophysiological deficits in brain information processing. These deficits can be assessed by auditory evoked potentials (AEPs), where schizophrenics exhibit abnormalities in amplitude, duration and latency of such AEPs. The aim of the present study was to compare the density of cells in the temporal cerebral cortex and the N40-AEP of adult NVHL rats versus adult sham rats. We found that rats with NVHL exhibit significant lower amplitude of the N40-AEP and a significant lower number of cells in bilateral regions of the temporal cerebral cortex compared to sham rats. Because the AEP recordings were obtained from anesthetized rats, we suggest that NVHL leads to inappropriate innervation in thalamic-cortical pathways in the adult rat, leading to altered function of cortical networks involved in processing of primary auditory information.

  16. Effects of dimethylarsinic and dimethylarsinous acid on evoked synaptic potentials in hippocampal slices of young and adult rats

    SciTech Connect

    Krueger, Katharina Repges, Hendrik; Hippler, Joerg; Hartmann, Louise M.; Hirner, Alfred V.; Straub, Heidrun; Binding, Norbert; Musshoff, Ulrich

    2007-11-15

    In this study, the effects of pentavalent dimethylarsinic acid ((CH{sub 3}){sub 2}AsO(OH); DMA{sup V}) and trivalent dimethylarsinous acid ((CH{sub 3}){sub 2}As(OH); DMA{sup III}) on synaptic transmission generated by the excitatory Schaffer collateral-CA1 synapse were tested in hippocampal slices of young (14-21 day-old) and adult (2-4 month-old) rats. Both compounds were applied in concentrations of 1 to 100 {mu}mol/l. DMA{sup V} had no effect on the amplitudes of evoked fEPSPs or the induction of LTP recorded from the CA1 dendritic region either in adult or in young rats. However, application of DMA{sup III} significantly reduced the amplitudes of evoked fEPSPs in a concentration-dependent manner with a total depression following application of 100 {mu}mol/l DMA{sup III} in adult and 10 {mu}mol/l DMA{sup III} in young rats. Moreover, DMA{sup III} significantly affected the LTP-induction. Application of 10 {mu}mol/l DMA{sup III} resulted in a complete failure of the postsynaptic potentiation of the fEPSP amplitudes in slices taken both from adult and young rats. The depressant effect was not reversible after a 30-min washout of the DMA{sup III}. In slices of young rats, the depressant effects of DMA{sup III} were more pronounced than in those taken from adult ones. Compared to the (absent) effect of DMA{sup V} on synaptic transmission, the trivalent compound possesses a considerably higher neurotoxic potential.

  17. Hippocampal Dosimetry Predicts Neurocognitive Function Impairment After Fractionated Stereotactic Radiotherapy for Benign or Low-Grade Adult Brain Tumors

    SciTech Connect

    Gondi, Vinai; Hermann, Bruce P.; Mehta, Minesh P.; Tome, Wolfgang A.

    2012-07-15

    Purpose: To prospectively evaluate the association between hippocampal dose and long-term neurocognitive function (NCF) impairment for benign or low-grade adult brain tumors treated with fractionated stereotactic radiotherapy (FSRT). Methods and Materials: Adult patients with benign or low-grade adult brain tumors were treated with FSRT per institutional practice. No attempt was made to spare the hippocampus. NCF testing was conducted at baseline and 18 months follow-up, on a prospective clinical trial. Regression-based standardized z scores were calculated by using similar healthy control individuals evaluated at the same test-retest interval. NCF impairment was defined as a z score {<=}-1.5. After delineation of the bilateral hippocampi according to the Radiation Therapy Oncology Group contouring atlas, dose-volume histograms were generated for the left and right hippocampi and for the composite pair. Biologically equivalent doses in 2-Gy fractions (EQD{sub 2}) assuming an {alpha}/{beta} ratio of 2 Gy were computed. Fisher's exact test and binary logistic regression were used for univariate and multivariate analyses, respectively. Dose-response data were fit to a nonlinear model. Results: Of 29 patients enrolled in this trial, 18 completed both baseline and 18-month NCF testing. An EQD{sub 2} to 40% of the bilateral hippocampi >7.3 Gy was associated with impairment in Wechsler Memory Scale-III Word List (WMS-WL) delayed recall (odds ratio [OR] 19.3; p = 0.043). The association between WMS-WL delayed recall and EQD{sub 2} to 100% of the bilateral hippocampi >0.0 Gy trended to significance (OR 14.8; p = 0.068). Conclusion: EQD{sub 2} to 40% of the bilateral hippocampi greater than 7.3 Gy is associated with long-term impairment in list-learning delayed recall after FSRT for benign or low-grade adult brain tumors. Given that modern intensity-modulated radiotherapy techniques can reduce the dose to the bilateral hippocampi below this dosimetric threshold, patients

  18. Hippocampal Dosimetry Predicts Neurocognitive Function Impairment After Fractionated Stereotactic Radiotherapy for Benign or Low-Grade Adult Brain Tumors

    SciTech Connect

    Gondi, Vinai; Hermann, Bruce P.; Mehta, Minesh P.; Tome, Wolfgang A.

    2013-02-01

    Purpose: To prospectively evaluate the association between hippocampal dose and long-term neurocognitive function (NCF) impairment for benign or low-grade adult brain tumors treated with fractionated stereotactic radiotherapy (FSRT). Methods and Materials: Adult patients with benign or low-grade adult brain tumors were treated with FSRT per institutional practice. No attempt was made to spare the hippocampus. NCF testing was conducted at baseline and 18 months follow-up, on a prospective clinical trial. Regression-based standardized z scores were calculated by using similar healthy control individuals evaluated at the same test-retest interval. NCF impairment was defined as a z score {<=}-1.5. After delineation of the bilateral hippocampi according to the Radiation Therapy Oncology Group contouring atlas, dose-volume histograms were generated for the left and right hippocampi and for the composite pair. Biologically equivalent doses in 2-Gy fractions (EQD{sub 2}) assuming an {alpha}/{beta} ratio of 2 Gy were computed. Fisher's exact test and binary logistic regression were used for univariate and multivariate analyses, respectively. Dose-response data were fit to a nonlinear model. Results: Of 29 patients enrolled in this trial, 18 completed both baseline and 18-month NCF testing. An EQD{sub 2} to 40% of the bilateral hippocampi >7.3 Gy was associated with impairment in Wechsler Memory Scale-III Word List (WMS-WL) delayed recall (odds ratio [OR] 19.3; p = 0.043). The association between WMS-WL delayed recall and EQD{sub 2} to 100% of the bilateral hippocampi >0.0 Gy trended to significance (OR 14.8; p = 0.068). Conclusion: EQD{sub 2} to 40% of the bilateral hippocampi greater than 7.3 Gy is associated with long-term impairment in list-learning delayed recall after FSRT for benign or low-grade adult brain tumors. Given that modern intensity-modulated radiotherapy techniques can reduce the dose to the bilateral hippocampi below this dosimetric threshold, patients

  19. Acute Exercise Improves Prefrontal Cortex but not Hippocampal Function in Healthy Adults.

    PubMed

    Basso, Julia C; Shang, Andrea; Elman, Meredith; Karmouta, Ryan; Suzuki, Wendy A

    2015-11-01

    The effects of acute aerobic exercise on cognitive functions in humans have been the subject of much investigation; however, these studies are limited by several factors, including a lack of randomized controlled designs, focus on only a single cognitive function, and testing during or shortly after exercise. Using a randomized controlled design, the present study asked how a single bout of aerobic exercise affects a range of frontal- and medial temporal lobe-dependent cognitive functions and how long these effects last. We randomly assigned 85 subjects to either a vigorous intensity acute aerobic exercise group or a video watching control group. All subjects completed a battery of cognitive tasks both before and 30, 60, 90, or 120 min after the intervention. This battery included the Hopkins Verbal Learning Test-Revised, the Modified Benton Visual Retention Test, the Stroop Color and Word Test, the Symbol Digit Modalities Test, the Digit Span Test, the Trail Making Test, and the Controlled Oral Word Association Test. Based on these measures, composite scores were formed to independently assess prefrontal cortex- and hippocampal-dependent cognition. A three-way mixed Analysis of Variance was used to determine whether differences existed between groups in the change in cognitive function from pre- to post-intervention testing. Acute exercise improved prefrontal cortex- but not hippocampal-dependent functioning, with no differences found between delay groups. Vigorous acute aerobic exercise has beneficial effects on prefrontal cortex-dependent cognition and these effects can last for up to 2 hr after exercise.

  20. ADULT NEURAL STEM CELLS: RESPONSE TO STROKE INJURY AND POTENTIAL FOR THERAPEUTIC APPLICATIONS

    PubMed Central

    Barkho, Basam Z.; Zhao, Xinyu

    2011-01-01

    The plasticity of neural stem/progenitor cells allows a variety of different responses to many environmental cues. In the past decade, significant research has gone into understanding the regulation of neural stem/progenitor cell properties, because of their promise for cell replacement therapies in adult neurological diseases. Both endogenous and grafted neural stem/progenitor cells are known to have the ability to migrate long distances to lesioned sites after brain injury and differentiate into new neurons. Several chemokines and growth factors, including stromal cell-derived factor-1 and vascular endothelial growth factor, have been shown to stimulate the proliferation, differentiation, and migration of neural stem/progenitor cells, and investigators have now begun to identify the critical downstream effectors and signaling mechanisms that regulate these processes. Both our own lab and others have shown that the extracellular matrix and matrix remodeling factors play a critical role in directing cell differentiation and migration of adult neural stem/progenitor cells within injured sites. Identification of these and other molecular pathways involved in stem cell homing into ischemic areas is vital for the development of new treatments. To ensure the best functional recovery, regenerative therapy may require the application of a combination approach that includes cell replacement, trophic support, and neural protection. Here we review the current state of our knowledge about endogenous adult and exogenous neural stem/progenitor cells as potential therapeutic agents for central nervous system injuries. PMID:21466483

  1. Different Mechanisms Must Be Considered to Explain the Increase in Hippocampal Neural Precursor Cell Proliferation by Physical Activity

    PubMed Central

    Overall, Rupert W.; Walker, Tara L.; Fischer, Tim J.; Brandt, Moritz D.; Kempermann, Gerd

    2016-01-01

    The number of proliferating neural precursor cells in the adult hippocampus is strongly increased by physical activity. The mechanisms through which this behavioral stimulus induces cell proliferation, however, are not yet understood. In fact, even the mode of proliferation of the stem and progenitor cells is not exactly known. Evidence exists for several mechanisms including cell cycle shortening, reduced cell death and stem cell recruitment, but as yet no model can account for all observations. An appreciation of how the cells proliferate, however, is crucial to our ability to model the neurogenic process and predict its behavior in response to pro-neurogenic stimuli. In a recent study, we addressed modulation of the cell cycle length as one possible mode of regulation of precursor cell proliferation in running mice. Our results indicated that the observed increase in number of proliferating cells could not be explained through a shortening of the cell cycle. We must therefore consider other mechanisms by which physical activity leads to enhanced precursor cell proliferation. Here we review the evidence for and against several different hypotheses and discuss the implications for future research in the field. PMID:27536215

  2. Lack of modulation of nicotinic acetylcholine alpha-7 receptor currents by kynurenic acid in adult hippocampal interneurons.

    PubMed

    Dobelis, Peter; Staley, Kevin J; Cooper, Donald C

    2012-01-01

    Kynurenic acid (KYNA), a classical ionotropic glutamate receptor antagonist is also purported to block the α7-subtype nicotinic acetylcholine receptor (α7* nAChR). Although many published studies cite this potential effect, few have studied it directly. In this study, the α7*-selective agonist, choline, was pressure-applied to interneurons in hippocampal subregions, CA1 stratum radiatum and hilus of acute brain hippocampal slices from adolescent to adult mice and adolescent rats. Stable α7* mediated whole-cell currents were measured using voltage-clamp at physiological temperatures. The effects of bath applied KYNA on spontaneous glutamatergic excitatory postsynaptic potentials (sEPSC) as well as choline-evoked α7* currents were determined. In mouse hilar interneurons, KYNA totally blocked sEPSC whole-cell currents in a rapid and reversible manner, but had no effect on choline-evoked α7* whole-cell currents. To determine if this lack of KYNA effect on α7* function was due to regional and/or species differences in α7* nAChRs, the effects of KYNA on choline-evoked α7* whole-cell currents in mouse and rat stratum radiatum interneurons were tested. KYNA had no effect on either mouse or rat stratum radiatum interneuron choline-evoked α7* whole-cell currents. Finally, to test whether the lack of effect of KYNA was due to unlikely slow kinetics of KYNA interactions with α7* nAChRs, recordings of a7*-mediated currents were made from slices that were prepared and stored in the presence of 1 mM KYNA (>90 minutes exposure). Under these conditions, KYNA had no measurable effect on α7* nAChR function. The results show that despite KYNA-mediated blockade of glutamatergic sEPSCs, two types of hippocampal interneurons that express choline-evoked α7* nAChR currents fail to show any degree of modulation by KYNA. Our results indicate that under our experimental conditions, which produced complete KYNA-mediated blockade of sEPSCs, claims of KYNA effects on choline

  3. Long-term deficiency of circulating and hippocampal insulin-like growth factor I induces depressive behavior in adult mice: A potential model of geriatric depression

    PubMed Central

    Mitschelen, Matthew; Yan, Han; Farley, Julie A.; Warrington, Junie P.; Han, Song; Hereñú, Claudia B.; Csiszar, Anna; Ungvari, Zoltan; Bailey-Downs, Lora C.; Bass, Caroline E.; Sonntag, William E.

    2011-01-01

    Numerous studies support the hypothesis that deficiency of insulin-like growth factor I (IGF-1) in adults contributes to depression, but direct evidence is limited. Many psychological and pro-cognitive effects have been attributed to IGF-1, but appropriate animal models of adult-onset IGF-1 deficiency are lacking. In this study, we use a viral-mediated Cre-loxP system to knockout the Igf1 gene in either the liver, neurons of the CA1 region of the hippocampus, or both. Knockout of liver Igf1 reduced serum IGF-1 levels by 40% and hippocampal IGF-1 levels by 26%. Knockout of Igf1 in CA1 reduced hippocampal IGF-1 levels by 13%. The most severe reduction in hippocampal IGF-1 occurred in the group with knockouts in both liver and CA1 (36% reduction), and was associated with a 3.5-fold increase in immobility in the forced swim test. Reduction of either circulating or hippocampal IGF-1 levels did not alter anxiety measured in an open field and elevated plus maze, nor locomotion in the open field. Furthermore, local compensation for deficiencies in circulating IGF-1 did not occur in the hippocampus, nor were serum levels of IGF-1 upregulated in response to the moderate decline of hippocampal IGF-1 caused by the knockouts in CA1. We conclude that adult-onset IGF-1 deficiency alone is sufficient to induce a depressive phenotype in mice. Furthermore, our results suggest that individuals with low brain levels of IGF-1 are at increased risk for depression and these behavioral effects are not ameliorated by increased local IGF-1 production or transport. Our study supports the hypothesis that the natural IGF-1 decline in aging humans may contribute to geriatric depression. PMID:21524689

  4. Adult emotionality and neural plasticity as a function of adolescent nutrient supplementation in male rats

    PubMed Central

    McCall, Nora; Mahadevia, Darshini; Corriveau, Jennifer A.; Glenn, Melissa

    2016-01-01

    The present study explored the effects of supplementing male rats with either choline, omega-3 fatty acids, or phytoestrogens, from weaning into early adulthood, on emotionality and hippocampal plasticity. Because of the neuroprotective properties of these nutrients, we hypothesized that they would positively affect both behavior and hippocampal function when compared to non-supplemented control rats. To test this hypothesis, male Sprague Dawley rats were assigned to one of four nutrient conditions after weaning: 1) control (normal rat chow); 2) choline (supplemented in drinking water); 3) omega 3 fatty acids (daily oral supplements); or 4) phytoestrogens (supplemented in chow). After 4 weeks on their respective diets, a subset of rats began 3 weeks of behavioral testing, while the remaining behaviorally naïve rats were sacrificed after 6 weeks on the diets to assess numbers of adult-born hippocampal neurons using the immature neuron marker, doublecortin. The results revealed that choline supplementation affected emotional functioning; compared to rats in other diet conditions, rats in this group were less anxious in an open field and after exposure to predator odor and showed less behavioral despair after forced swimming. Similar behavioral findings were evident following supplementation with omega-3 fatty acids and phytoestrogens supplementation, though not on all tests and not to the same magnitude. Histological findings followed a pattern consistent with the behavioral findings: choline supplementation, followed by omega-3 fatty acid supplementation, but not phytoestrogen supplementation, significantly increased the numbers of new-born hippocampal neurons. Choline and omega −3 fatty acids have similar biological functions—affecting cell membranes, growth factor levels, and epigenetically altering gene transcription. Thus, the present findings suggest that targeting nutrients with these effects may be a viable strategy to combat adult psychopathologies

  5. Alterations in Brain Inflammation, Synaptic Proteins, and Adult Hippocampal Neurogenesis during Epileptogenesis in Mice Lacking Synapsin2

    PubMed Central

    Chugh, Deepti; Ali, Idrish; Bakochi, Anahita; Bahonjic, Elma; Etholm, Lars; Ekdahl, Christine T.

    2015-01-01

    Synapsins are pre-synaptic vesicle-associated proteins linked to the pathogenesis of epilepsy through genetic association studies in humans. Deletion of synapsins causes an excitatory/inhibitory imbalance, exemplified by the epileptic phenotype of synapsin knockout mice. These mice develop handling-induced tonic-clonic seizures starting at the age of about 3 months. Hence, they provide an opportunity to study epileptogenic alterations in a temporally controlled manner. Here, we evaluated brain inflammation, synaptic protein expression, and adult hippocampal neurogenesis in the epileptogenic (1 and 2 months of age) and tonic-clonic (3.5-4 months) phase of synapsin 2 knockout mice using immunohistochemical and biochemical assays. In the epileptogenic phase, region-specific microglial activation was evident, accompanied by an increase in the chemokine receptor CX3CR1, interleukin-6, and tumor necrosis factor-α, and a decrease in chemokine keratinocyte chemoattractant/ growth-related oncogene. Both post-synaptic density-95 and gephyrin, scaffolding proteins at excitatory and inhibitory synapses, respectively, showed a significant up-regulation primarily in the cortex. Furthermore, we observed an increase in the inhibitory adhesion molecules neuroligin-2 and neurofascin and potassium chloride co-transporter KCC2. Decreased expression of γ-aminobutyric acid receptor-δ subunit and cholecystokinin was also evident. Surprisingly, hippocampal neurogenesis was reduced in the epileptogenic phase. Taken together, we report molecular alterations in brain inflammation and excitatory/inhibitory balance that could serve as potential targets for therapeutics and diagnostic biomarkers. In addition, the regional differences in brain inflammation and synaptic protein expression indicate an epileptogenic zone from where the generalized seizures in synapsin 2 knockout mice may be initiated or spread. PMID:26177381

  6. Beneficial effect of a CNTF tetrapeptide on adult hippocampal neurogenesis, neuronal plasticity, and spatial memory in mice.

    PubMed

    Blanchard, Julie; Chohan, Muhammad Omar; Li, Bin; Liu, Fei; Iqbal, Khalid; Grundke-Iqbal, Inge

    2010-01-01

    A therapeutic strategy against cognitive disorders like Alzheimer's disease is to take advantage of the regenerative ability of the brain and the properties of neurotrophic factors to shift the balance from neurodegeneration to neurogenesis and neuronal plasticity. Although the ciliary neurotrophic factor (CNTF) has some of the required neuroprotective characteristics, its clinical use, due to its side effects, i.e., anorexia, skeletal muscle loss, hyperalgesia, cramps, and muscle pain, has not materialized. In the present study, we report that Peptide 6c (GDDL) that corresponds to CNTF amino acid residues 147-150, enhances the dentate gyrus neurogenesis and neuronal plasticity, and improves cognition without weight loss or any other apparent side effects in mice. Normal adult C57Bl6 mice received subcutaneous implants of extended release depot pellets containing vehicle or Peptide 6c for 30 days of continuous dosing. Dentate gyrus neurogenesis was assessed by stereological analysis of cells expressing neuronal markers, doublecortin and NeuN, and BrdU uptake. We found that Peptide 6c significantly increased early neuronal commitment, differentiation, and survival of newborn progenitor cells. These newborn neurons were functionally integrated into the hippocampal network, since basal expression of c-fos was enhanced and neuronal plasticity was increased, as reflected by higher expression of MAP2a,b and synaptophysin. Consequently, Peptide 6c treatment improved encoding of hippocampal-dependent information in a spatial reference memory task in mice. Overall, these findings demonstrated the therapeutic potential of Peptide 6c for regeneration of the brain and improvement of cognition.

  7. Effects of social isolation and enriched environment on behavior of adult Swiss mice do not require hippocampal neurogenesis.

    PubMed

    Silva, Cristiane Felisbino; Duarte, Filipe Silveira; Lima, Thereza Christina Monteiro De; de Oliveira, Cilene Lino

    2011-11-20

    Housing conditions are important determinants of animal behavior. Their impact on behavioral output depends on the behavior of interest, species, strain, and age of the animal evaluated. In the present study, male Swiss mice reared from weaning up to 8 weeks in social isolation (SI8), in enriched environment (EE8) or in standard environment (SE8) were evaluated in the elevated plus-maze (EPM), open-field (OFT) and tail-suspension (TST) tests. The effect of housing for 6 weeks in EE followed by 2 weeks in SI (EE6SI2) and the opposite condition (SI6EE2) was also studied. Housing conditions are reported to affect hippocampal neurogenesis; therefore, the expression of doublecortin (DCX) in the dentate gyrus of the hippocampus (DG) of these mice was monitored. Data showed that SI8, EE8 and EE6SI2 reduced the stretching-attend postures in the EPM and explored more the center of the apparatus when compared to SE8. The time and the number of entries in the closed arms of the EPM was not affected indicating that effects of housing conditions in the EPM were not consequence of motor activity alteration. Accordingly, EE8 mice exploration of the OFT was similar to SE8. However, the SI8 mice explored the OFT more than the EE8 mice, suggesting hyperactivity induced by isolation. Behavior of Swiss mice in the TST was not altered, indicating that this test was not sensitive to the environmental changes in this mice strain. Compared to SE8, EE8 did not affect the number of DCX cells, whereas SI8, EE6SI2, and SI6EE2 decreased it. Taken together, our data suggest that the behavior of adult Swiss mice in the EPM and OFT was affected by environmental changes but that these changes seem to be independent of hippocampal neurogenesis.

  8. Differential dendritic targeting of AMPA receptor subunit mRNAs in adult rat hippocampal principal neurons and interneurons.

    PubMed

    Cox, David J; Racca, Claudia

    2013-06-15

    In hippocampal neurons, AMPA receptors (AMPARs) mediate fast excitatory postsynaptic responses at glutamatergic synapses, and are involved in various forms of synaptic plasticity. Dendritic local protein synthesis of selected AMPAR subunit mRNAs is considered an additional mechanism to independently and rapidly control the strength of individual synapses. We have used fluorescent in situ hybridization and immunocytochemistry to analyze the localization of AMPAR subunit (GluA1-4) mRNAs and their relationship with the translation machinery in principal cells and interneurons of the adult rat hippocampus. The mRNAs encoding all four AMPAR subunits were detected in the somata and dendrites of CA3 and CA1 pyramidal cells and those of six classes of CA1 γ-aminobutyric acid (GABA)ergic interneurons. GluA1-4 subunit mRNAs were highly localized to the apical dendrites of pyramidal cells, whereas in interneurons they were present in multiple dendrites. In contrast, in the dentate gyrus, GluA1-4 subunit mRNAs were virtually restricted to the somata and were absent from the dendrites of granule cells. These different regional and cell type-specific labeling patterns also correlated with the localization of markers for components of the protein synthesis machinery. Our results support the local translation of GluA1-4 mRNAs in dendrites of hippocampal pyramidal cells and CA1 interneurons but not in granule cells of the dentate gyrus. Furthermore, the regional and cell type-specific differences we observed suggest that each cell type uses distinct ways of regulating the local translation of AMPAR subunits.

  9. Zif268/egr1 gene controls the selection, maturation and functional integration of adult hippocampal newborn neurons by learning.

    PubMed

    Veyrac, Alexandra; Gros, Alexandra; Bruel-Jungerman, Elodie; Rochefort, Christelle; Kleine Borgmann, Felix B; Jessberger, Sebastian; Laroche, Serge

    2013-04-23

    New neurons are continuously added to the dentate gyrus of the adult mammalian brain. During the critical period of a few weeks after birth when newborn neurons progressively mature, a restricted fraction is competitively selected to survive in an experience-dependent manner, a condition for their contribution to memory processes. The mechanisms that control critical stages of experience-dependent functional incorporation of adult newborn neurons remain largely unknown. Here, we identify a unique transcriptional regulator of the functional integration of newborn neurons, the inducible immediate early gene zif268/egr1. We show that newborn neurons in zif268-KO mice undergo accelerated death during the critical period of 2-3 wk around their birth and exhibit deficient neurochemical and morphological maturation, including reduced GluR1 expression, increased NKCC1/KCC2b chloride cotransporter ratio, altered dendritic development, and marked spine growth defect. Investigating responsiveness of newborn neurons to activity-dependent expression of zif268 in learning, we demonstrate that in the absence of zif268, training in a spatial learning task during this critical period fails to recruit newborn neurons and promote their survival, leading to impaired long-term memory. This study reveals a previously unknown mechanism for the control of the selection, functional maturation, and experience-dependent recruitment of dentate gyrus newborn neurons that depends on the inducible immediate early gene zif268, processes that are critical for their contribution to hippocampal-dependent long-term memory.

  10. BDNF-induced LTP is associated with rapid Arc/Arg3.1-dependent enhancement in adult hippocampal neurogenesis

    PubMed Central

    Kuipers, Sjoukje D.; Trentani, Andrea; Tiron, Adrian; Mao, Xiaosong; Kuhl, Dietmar; Bramham, Clive R.

    2016-01-01

    Adult neurogenesis in the hippocampus is a remarkable phenomenon involved in various aspects of learning and memory as well as disease pathophysiology. Brain-derived neurotrophic factor (BDNF) represents a major player in the regulation of this unique form of neuroplasticity, yet the mechanisms underlying its pro-neurogenic actions remain unclear. Here, we examined the effects associated with brief (25 min), unilateral infusion of BDNF in the rat dentate gyrus. Acute BDNF infusion induced long-term potentiation (LTP) of medial perforant path-evoked synaptic transmission and, concomitantly, enhanced hippocampal neurogenesis bilaterally, reflected by increased dentate gyrus BrdU + cell numbers. Importantly, inhibition of activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) translation through local, unilateral infusion of anti-sense oligodeoxynucleotides (ArcAS) prior to BDNF infusion blocked both BDNF-LTP induction and the associated pro-neurogenic effects. Notably, basal rates of proliferation and newborn cell survival were unaltered in homozygous Arc/Arg3.1 knockout mice. Taken together these findings link the pro-neurogenic effects of acute BDNF infusion to induction of Arc/Arg3.1-dependent LTP in the adult rodent dentate gyrus. PMID:26888068

  11. Neural Correlates Associated with Successful Working Memory Performance in Older Adults as Revealed by Spatial ICA

    PubMed Central

    Saliasi, Emi; Geerligs, Linda; Lorist, Monicque M.; Maurits, Natasha M.

    2014-01-01

    To investigate which neural correlates are associated with successful working memory performance, fMRI was recorded in healthy younger and older adults during performance on an n-back task with varying task demands. To identify functional networks supporting working memory processes, we used independent component analysis (ICA) decomposition of the fMRI data. Compared to younger adults, older adults showed a larger neural (BOLD) response in the more complex (2-back) than in the baseline (0-back) task condition, in the ventral lateral prefrontal cortex (VLPFC) and in the right fronto-parietal network (FPN). Our results indicated that a higher BOLD response in the VLPFC was associated with increased performance accuracy in older adults, in both the baseline and the more complex task condition. This ‘BOLD-performance’ relationship suggests that the neural correlates linked with successful performance in the older adults are not uniquely related to specific working memory processes present in the complex but not in the baseline task condition. Furthermore, the selective presence of this relationship in older but not in younger adults suggests that increased neural activity in the VLPFC serves a compensatory role in the aging brain which benefits task performance in the elderly. PMID:24911016

  12. Effects of deprivation of oxygen or glucose on the neural activity in the guinea pig hippocampal slice--intracellular recording study of pyramidal neurons.

    PubMed

    Takata, T; Okada, Y

    1995-06-12

    The block of synaptic transmission and neural activity during deprivation of oxygen or glucose has been simply attributed to the lack of energy due to the disorder of energy production. To clarify the interrelation between neural activity and energy metabolism during hypoxia or glucose deprivation, we studied the changes in ATP levels and electrical events of pyramidal neurons in the CA3 region and [Ca2+]i mobilization of the dendritic and cellular region of CA3 area, using guinea pig hippocampal slices. The studies of field potentials and intracellular recording from the pyramidal cell of CA3 area during hypoxia or glucose deprivation revealed that the cessation of synaptic activity and the depolarization of resting potential occurred earlier than during glucose deprivation while the increase of [Ca2+]i was slow during hypoxia but rapid during glucose deprivation although the ATP level of CA3 area was maintained at its original level for 20 min during both conditions. When glucose was replaced by lactate, ATP concentration was not reduced but the electrical activity decayed and [Ca2+]i increased with the similar time course as observed during lack of glucose, only. These results suggest that different mechanisms underlie the block of synaptic transmission in the CA3 pyramidal neurons during hypoxia and glucose deprivation and that lactate cannot substitute for glucose in the maintenance of neural activity.

  13. Bumetanide promotes neural precursor cell regeneration and dendritic development in the hippocampal dentate gyrus in the chronic stage of cerebral ischemia

    PubMed Central

    Xu, Wang-shu; Sun, Xuan; Song, Cheng-guang; Mu, Xiao-peng; Ma, Wen-ping; Zhang, Xing-hu; Zhao, Chuan-sheng

    2016-01-01

    Bumetanide has been shown to lessen cerebral edema and reduce the infarct area in the acute stage of cerebral ischemia. Few studies focus on the effects of bumetanide on neuroprotection and neurogenesis in the chronic stage of cerebral ischemia. We established a rat model of cerebral ischemia by injecting endothelin-1 in the left cortical motor area and left corpus striatum. Seven days later, bumetanide 200 µg/kg/day was injected into the lateral ventricle for 21 consecutive days with a mini-osmotic pump. Results demonstrated that the number of neuroblasts cells and the total length of dendrites increased, escape latency reduced, and the number of platform crossings increased in the rat hippocampal dentate gyrus in the chronic stage of cerebral ischemia. These findings suggest that bumetanide promoted neural precursor cell regeneration, dendritic development and the recovery of cognitive function, and protected brain tissue in the chronic stage of ischemia. PMID:27335557

  14. Sonic Hedgehog Signaling and Hippocampal Neuroplasticity.

    PubMed

    Yao, Pamela J; Petralia, Ronald S; Mattson, Mark P

    2016-12-01

    Sonic hedgehog (Shh) is a secreted protein that controls the patterning of neural progenitor cells, and their neuronal and glial progeny, during development. Emerging findings suggest that Shh also has important roles in the formation and plasticity of neuronal circuits in the hippocampus, a brain region of fundamental importance in learning and memory. Shh mediates activity-dependent and injury-induced hippocampal neurogenesis. Activation of Shh receptors in the dendrites of hippocampal neurons engages a trans-neuronal signaling pathway that accelerates axon outgrowth and enhances glutamate release from presynaptic terminals. Impaired Shh signaling may contribute to the pathogenesis of several developmental and adult-onset neurological disorders that affect the hippocampus, suggesting a potential for therapeutic interventions that target Shh pathways.

  15. When are new hippocampal neurons, born in the adult brain, integrated into the network that processes spatial information?

    PubMed

    Sandoval, C Jimena; Martínez-Claros, Marisela; Bello-Medina, Paola C; Pérez, Oswaldo; Ramírez-Amaya, Víctor

    2011-03-09

    Adult-born neurons in the dentate gyrus (DG) functionally integrate into the behaviorally relevant hippocampal networks, showing a specific Arc-expression response to spatial exploration when mature. However, it is not clear when, during the 4- to 6-week interval that is critical for survival and maturation of these neurons, this specific response develops. Therefore, we characterized Arc expression after spatial exploration or cage control conditions in adult-born neurons from rats that were injected with BrdU on one day and were sacrificed 1, 7, 15, 30, and 45 days post-BrdU injection (PBI). Triple immunostaining for NeuN, Arc, and BrdU was analyzed through the different DG layers. Arc protein expression in BrdU-positive cells was observed from day 1 to day 15 PBI but was not related to behavioral stimulation. The specific Arc-expression response to spatial exploration was observed from day 30 and 45 in about 5% of the BrdU-positive cell population. Most of the BrdU-positive neurons expressing Arc in response to spatial exploration (∼90%) were located in DG layer 1, and no Arc expression was observed in cells located in the subgranular zone (SGZ). Using the current data and that obtained previously, we propose a mathematical model suggesting that new neurons are unlikely to respond to exploration by expressing Arc after they are 301 days old, and also that in a 7-month-old rat the majority (60%) of the neurons that respond to exploration must have been born during adulthood; thus, suggesting that adult neurogenesis in the DG is highly relevant for spatial information processing.

  16. When Are New Hippocampal Neurons, Born in the Adult Brain, Integrated into the Network That Processes Spatial Information?

    PubMed Central

    Sandoval, C. Jimena; Pérez, Oswaldo; Ramírez-Amaya, Víctor

    2011-01-01

    Adult-born neurons in the dentate gyrus (DG) functionally integrate into the behaviorally relevant hippocampal networks, showing a specific Arc-expression response to spatial exploration when mature. However, it is not clear when, during the 4- to 6-week interval that is critical for survival and maturation of these neurons, this specific response develops. Therefore, we characterized Arc expression after spatial exploration or cage control conditions in adult-born neurons from rats that were injected with BrdU on one day and were sacrificed 1, 7, 15, 30, and 45 days post-BrdU injection (PBI). Triple immunostaining for NeuN, Arc, and BrdU was analyzed through the different DG layers. Arc protein expression in BrdU-positive cells was observed from day 1 to day 15 PBI but was not related to behavioral stimulation. The specific Arc-expression response to spatial exploration was observed from day 30 and 45 in about 5% of the BrdU-positive cell population. Most of the BrdU-positive neurons expressing Arc in response to spatial exploration (∼90%) were located in DG layer 1, and no Arc expression was observed in cells located in the subgranular zone (SGZ). Using the current data and that obtained previously, we propose a mathematical model suggesting that new neurons are unlikely to respond to exploration by expressing Arc after they are 301 days old, and also that in a 7-month-old rat the majority (60%) of the neurons that respond to exploration must have been born during adulthood; thus, suggesting that adult neurogenesis in the DG is highly relevant for spatial information processing. PMID:21408012

  17. Influence of mild traumatic brain injury during pediatric stage on short-term memory and hippocampal apoptosis in adult rats

    PubMed Central

    Park, Mi-Sook; Oh, Hyean-Ae; Ko, Il-Gyu; Kim, Sung-Eun; Kim, Sang-Hoon; Kim, Chang-Ju; Kim, Hyun-Bae; Kim, Hong

    2014-01-01

    Traumatic brain injury (TBI) is a leading cause of neurological deficit in the brain, which induces short- and long-term brain damage, cognitive impairment with/without structural alteration, motor deficits, emotional problems, and death both in children and adults. In the present study, we evaluated whether mild TBI in childhood causes persisting memory impairment until adulthood. Moreover, we investigated the influence of mild TBI on memory impairment in relation with hippocampal apoptosis. For this, step-down avoidance task, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay, and immunohistochemistry for caspase-3 were performed. Male Sprague-Dawley rats were used in the experiments. The animals were randomly divided into two groups: sham-operation group and TBI-induction group. The mild TBI model was created with an electromagnetic contusion device activated at a velocity of 3.0 m/sec. The results showed that mild TBI during the pediatric stage significantly decreased memory retention. The numbers of TUNEL-positive and caspase-3-positive cells were increased in the TBI-induction group compared to those in the sham-operation group. Defective memory retention and apoptosis sustained up to the adult stage. The present results shows that mild TBI induces long-lasting cognitive impairment from pediatric to adult stages in rats through the high level of apoptosis. The finding of this study suggests that children with mild TBI may need intensive treatments for the reduction of long-lasting cognitive impairment by secondary neuronal damage. PMID:25061593

  18. Influence of mild traumatic brain injury during pediatric stage on short-term memory and hippocampal apoptosis in adult rats.

    PubMed

    Park, Mi-Sook; Oh, Hyean-Ae; Ko, Il-Gyu; Kim, Sung-Eun; Kim, Sang-Hoon; Kim, Chang-Ju; Kim, Hyun-Bae; Kim, Hong

    2014-06-01

    Traumatic brain injury (TBI) is a leading cause of neurological deficit in the brain, which induces short- and long-term brain damage, cognitive impairment with/without structural alteration, motor deficits, emotional problems, and death both in children and adults. In the present study, we evaluated whether mild TBI in childhood causes persisting memory impairment until adulthood. Moreover, we investigated the influence of mild TBI on memory impairment in relation with hippocampal apoptosis. For this, step-down avoidance task, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay, and immunohistochemistry for caspase-3 were performed. Male Sprague-Dawley rats were used in the experiments. The animals were randomly divided into two groups: sham-operation group and TBI-induction group. The mild TBI model was created with an electromagnetic contusion device activated at a velocity of 3.0 m/sec. The results showed that mild TBI during the pediatric stage significantly decreased memory retention. The numbers of TUNEL-positive and caspase-3-positive cells were increased in the TBI-induction group compared to those in the sham-operation group. Defective memory retention and apoptosis sustained up to the adult stage. The present results shows that mild TBI induces long-lasting cognitive impairment from pediatric to adult stages in rats through the high level of apoptosis. The finding of this study suggests that children with mild TBI may need intensive treatments for the reduction of long-lasting cognitive impairment by secondary neuronal damage.

  19. The effects of glucose, mannose, fructose and lactate on the preservation of neural activity in the hippocampal slices from the guinea pig.

    PubMed

    Wada, H; Okada, Y; Uzuo, T; Nakamura, H

    1998-03-30

    Using hippocampal slices from guinea pigs, we investigated the effect of different concentrations of glucose and replacement of glucose with mannose, fructose and lactate on neural activity. As an index of neural activity, the population spikes (PS) were recorded in the granule cell layer of the dentate gyrus (DG) and the pyramidal cell layer of the CA3 area in the hippocampal slices. Lowering the concentration of glucose from 10 mM to 5, 3, 2, 1 and 0 mM caused a reduction in the PS amplitude. There were differences in the decay times of the PS evoked in these two regions. PS evoked in CA3 region decayed faster even at a concentration of 3 mM glucose at which PS in granule cell layer was well maintained. The decay time of the PS in the CA3 region in the presence of glucose up to a concentration of 3 mM was shorter than that evoked in the DG. After the replacement of glucose with mannose, fructose or lactate, the PS disappeared within 35 min and there were no significant differences between the decay times in the two regions of slices incubated in the same medium. ATP, creatine phosphate (CrP) and lactate levels in each slice were determined. To investigate whether mannose and fructose could be metabolized or not in the tissue slice, anaerobic production of lactate from glucose, mannose and fructose were measured during oxygen and glucose deprivation. Under anaerobic conditions for 60 min, the levels of high-energy phosphates decreased to 50% of the initial level and lactate was produced from glucose, mannose or fructose. However, there were significant differences in the rate of lactate production between the DG and CA3 areas during application of 3 mM glucose, 10 mM mannose and 10 mM fructose. These results indicate that mannose, fructose and lactate can be metabolized and are available for maintaining the levels of high-energy phosphates but not for neural activity in the tissue slices and that the presence of glucose is indispensable for the maintenance of

  20. Neural correlates of single word reading in bilingual children and adults.

    PubMed

    Hernandez, Arturo E; Woods, Elizabeth A; Bradley, Kailyn A L

    2015-04-01

    The present study compared the neural correlates of language processing in children and adult Spanish-English bilinguals. Participants were asked to perform a visual lexical processing task in both Spanish and English while being scanned with fMRI. Both children and adults recruited a similar network of left hemisphere "language" areas and showed similar proficiency profiles in Spanish. In terms of behavior, adults showed better language proficiency in English relative to children. Furthermore, neural activity in adults was observed in the bilateral MTG. Age-related differences were observed in Spanish in the right MTG. The current results confirm the presence of neural activity in a set of left hemisphere areas in both adult and child bilinguals when reading words in each language. They also reveal that differences in neural activity are not entirely driven by changes in language proficiency during visual word processing. This indicates that both skill development and age can play a role in brain activity seen across development.

  1. Impacts of thyroxine combined with donepezil on hippocampal ultrastructures and expressions of synaptotagmin-1 and SNAP-25 in adult rats with hypothyroidism

    PubMed Central

    Yang, Hao; Zha, Xiaoxue; Cai, Yaojun; Wang, Fen; Wu, Zhangbi; Wu, Bo; Jia, Xuemei; Zhu, Defa

    2015-01-01

    The study aims to observe the impacts of thyroxine (T4) combined with donepezil (DON) on hippocampal ultrastructures and expressions of synaptotagmin-1 and SNAP-25 in adult rats with hypothyroidism. All rats were randomly divided into five groups: the normal control group (CON), the hypothyroidism group (Hypo), the T4 treatment group (T4), the DON treatment group (DON) and the T4+DON combined treatment group (T4+DON). Technique of Electron Microscope (TEM) was used to observe the hippocampal ultrastructures of each group, Western blot and real-time RT-PCR were performed to analyze the protein and mRNA expressions of syt-1 and SNAP-25 in the hippocampus of each group. TEM revealed that the Hypo group exhibited the significant vacuolar degeneration of mitochondria in the hippocampal neurons, the free ribosomes were sparse, the synaptic structures were damaged, and the number of synaptic vesicles was reduced, the above injuries in the T4 or DON group were improved, and the performance of the T4+DON group was the most close to the CON group. From the protein and mRNA levels, the dorsal hippocampal syt-1 expression of the Hypo group was significantly reduced, while SNAP-25 was significantly increased, the expressions were partially recovered after the T4 treatment, and the T4+DON combined treatment made the expression return to normal. The adult hypothyroid rats exhibited pathological damages in the hippocampal ultrastructures, the expression of syt-1 was downregulated, while that of SNAP-25 was upregulated, the T4+DON combined therapy could repair the above injuries, and the roles were better than the single drug treatment. PMID:26770386

  2. Exercise-Induced Fitness Changes Correlate with Changes in Neural Specificity in Older Adults.

    PubMed

    Kleemeyer, Maike M; Polk, Thad A; Schaefer, Sabine; Bodammer, Nils C; Brechtel, Lars; Lindenberger, Ulman

    2017-01-01

    Neural specificity refers to the degree to which neural representations of different stimuli can be distinguished. Evidence suggests that neural specificity, operationally defined as stimulus-related differences in functional magnetic resonance imaging (fMRI) activation patterns, declines with advancing adult age, and that individual differences in neural specificity are associated with individual differences in fluid intelligence. A growing body of literature also suggests that regular physical activity may help preserve cognitive abilities in old age. Based on this literature, we hypothesized that exercise-induced improvements in fitness would be associated with greater neural specificity among older adults. A total of 52 adults aged 59-74 years were randomly assigned to one of two aerobic-fitness training regimens, which differed in intensity. Participants in both groups trained three times a week on stationary bicycles. In the low-intensity (LI) group, the resistance was kept constant at a low level (10 Watts). In the high-intensity (HI) group, the resistance depended on participants' heart rate and therefore typically increased with increasing fitness. Before and after the 6-month training phase, participants took part in a functional MRI experiment in which they viewed pictures of faces and buildings. We used multivariate pattern analysis (MVPA) to estimate the distinctiveness of neural activation patterns in ventral visual cortex (VVC) evoked by face or building stimuli. Fitness was also assessed before and after training. In line with our hypothesis, training-induced changes in fitness were positively associated with changes in neural specificity. We conclude that physical activity may protect against age-related declines in neural specificity.

  3. Exercise-Induced Fitness Changes Correlate with Changes in Neural Specificity in Older Adults

    PubMed Central

    Kleemeyer, Maike M.; Polk, Thad A.; Schaefer, Sabine; Bodammer, Nils C.; Brechtel, Lars; Lindenberger, Ulman

    2017-01-01

    Neural specificity refers to the degree to which neural representations of different stimuli can be distinguished. Evidence suggests that neural specificity, operationally defined as stimulus-related differences in functional magnetic resonance imaging (fMRI) activation patterns, declines with advancing adult age, and that individual differences in neural specificity are associated with individual differences in fluid intelligence. A growing body of literature also suggests that regular physical activity may help preserve cognitive abilities in old age. Based on this literature, we hypothesized that exercise-induced improvements in fitness would be associated with greater neural specificity among older adults. A total of 52 adults aged 59–74 years were randomly assigned to one of two aerobic-fitness training regimens, which differed in intensity. Participants in both groups trained three times a week on stationary bicycles. In the low-intensity (LI) group, the resistance was kept constant at a low level (10 Watts). In the high-intensity (HI) group, the resistance depended on participants’ heart rate and therefore typically increased with increasing fitness. Before and after the 6-month training phase, participants took part in a functional MRI experiment in which they viewed pictures of faces and buildings. We used multivariate pattern analysis (MVPA) to estimate the distinctiveness of neural activation patterns in ventral visual cortex (VVC) evoked by face or building stimuli. Fitness was also assessed before and after training. In line with our hypothesis, training-induced changes in fitness were positively associated with changes in neural specificity. We conclude that physical activity may protect against age-related declines in neural specificity. PMID:28360850

  4. Neural Mechanisms Underlying Action Observation in Adults with Down Syndrome

    ERIC Educational Resources Information Center

    Virji-Babul, Naznin; Moiseev, Alexander; Cheung, Teresa; Weeks, Daniel J.; Cheyne, Douglas; Ribary, Urs

    2010-01-01

    Results of a magnetoencephalography (MEG) brain imaging study conducted to examine the cortical responses during action execution and action observation in 10 healthy adults and 8 age-matched adults with Down syndrome are reported. During execution, the motor responses were strongly lateralized on the ipsilateral rather than the contralateral side…

  5. Increased Amygdalar and Hippocampal Volumes in Young Adults with Social Anxiety

    PubMed Central

    Machado-de-Sousa, João Paulo; Osório, Flávia de Lima; Jackowski, Andrea P.; Bressan, Rodrigo A.; Chagas, Marcos H. N.; Torro-Alves, Nelson; DePaula, André L. D.; Crippa, José A. S.; Hallak, Jaime E. C.

    2014-01-01

    Background Functional neuroimaging studies have consistently shown abnormal limbic activation patterns in socially anxious individuals, but structural data on the amygdala and hippocampus of these patients are scarce. This study explored the existence of structural differences in the whole brain, amygdala, and hippocampus of subjects with clinical and subthreshold social anxiety compared to healthy controls. We hypothesized that there would be volumetric differences across groups, without predicting their direction (i.e. enlargement or reduction). Methods Subjects classified as having social anxiety disorder (n = 12), subthreshold social anxiety (n = 12) and healthy controls (n = 14) underwent structural magnetic resonance imaging scans. The amygdala and hippocampus were defined a priori as regions of interest and volumes were calculated by manual tracing. Whole brain volume was calculated using voxel-based morphometry. Results The bilateral amygdala and left hippocampus were enlarged in socially anxious individuals relative to controls. The volume of the right hippocampus was enlarged in subthreshold social anxiety participants relative to controls. No differences were found across groups in respect to total brain volume. Conclusions Our results show amygdalar and hippocampal volume alterations in social anxiety, possibly associated with symptom severity. The time course of such alterations and the cellular and molecular bases of limbic plasticity in social anxiety should be further investigated. PMID:24523911

  6. Alcohol and pregnancy: Effects on maternal care, HPA axis function, and hippocampal neurogenesis in adult females.

    PubMed

    Workman, Joanna L; Raineki, Charlis; Weinberg, Joanne; Galea, Liisa A M

    2015-07-01

    Chronic alcohol consumption negatively affects health, and has additional consequences if consumption occurs during pregnancy as prenatal alcohol exposure adversely affects offspring development. While much is known on the effects of prenatal alcohol exposure in offspring less is known about effects of alcohol in dams. Here, we examine whether chronic alcohol consumption during gestation alters maternal behavior, hippocampal neurogenesis and HPA axis activity in late postpartum female rats compared with nulliparous rats. Rats were assigned to alcohol, pair-fed or ad libitum control treatment groups for 21 days (for pregnant rats, this occurred gestation days 1-21). Maternal behavior was assessed throughout the postpartum period. Twenty-one days after alcohol exposure, we assessed doublecortin (DCX) (an endogenous protein expressed in immature neurons) expression in the dorsal and ventral hippocampus and HPA axis activity. Alcohol consumption during pregnancy reduced nursing and increased self-directed and negative behaviors, but spared licking and grooming behavior. Alcohol consumption increased corticosterone and adrenal mass only in nulliparous females. Surprisingly, alcohol consumption did not alter DCX-expressing cell density. However, postpartum females had fewer DCX-expressing cells (and of these cells more immature proliferating cells but fewer postmitotic cells) than nulliparous females. Collectively, these data suggest that alcohol consumption during pregnancy disrupts maternal care without affecting HPA function or neurogenesis in dams. Conversely, alcohol altered HPA function in nulliparous females only, suggesting that reproductive experience buffers the long-term effects of alcohol on the HPA axis.

  7. Alcohol and pregnancy: effects on maternal care, HPA axis function, and hippocampal neurogenesis in adult females

    PubMed Central

    2015-01-01

    Chronic alcohol consumption negatively affects health, and has additional consequences if consumption occurs during pregnancy as prenatal alcohol exposure adversely affects offspring development. While much is known on the effects of prenatal alcohol exposure in offspring less is known about effects of alcohol in dams. Here, we examine whether chronic alcohol consumption during gestation alters maternal behavior, hippocampal neurogenesis and HPA axis activity in late postpartum female rats compared with nulliparous females. Rats were assigned to alcohol, pair-fed or ad libitum control treatment groups for 21 days (for pregnant rats, this occurred gestation days 1 – 21). Maternal behavior was assessed throughout the postpartum period. Twenty-one days after alcohol exposure, we assessed doublecortin (DCX) (an endogenous protein expressed in immature neurons) expression in the dorsal and ventral hippocampus and HPA axis activity. Alcohol consumption during pregnancy reduced nursing and increased self-directed and negative behaviors, but spared licking and grooming behavior. Alcohol consumption increased corticosterone and adrenal mass only in nulliparous females. Surprisingly, alcohol consumption did not alter DCX-expressing cell density. However, postpartum females had fewer DCX-expressing cells (and of these cells more immature proliferating cells but fewer postmitotic cells) than nulliparous females. Collectively, these data suggest that alcohol consumption during pregnancy disrupts maternal care without affecting HPA function or neurogenesis in dams. Conversely, alcohol altered HPA function in nulliparous females only, suggesting that reproductive experience buffers the long-term effects of alcohol on the HPA axis. PMID:25900594

  8. Cannabinoid Receptor Activation Modifies NMDA Receptor Mediated Release of Intracellular Calcium: Implications for Endocannabinoid Control of Hippocampal Neural Plasticity

    PubMed Central

    Hampson, Robert E.; Miller, Frances; Palchik, Guillermo; Deadwyler, Sam A.

    2011-01-01

    Chronic activation or inhibition of cannabinoid receptors (CB1) leads to continuous suppression of neuronal plasticity in hippocampus and other brain regions, suggesting that endocannabinoids may have a functional role in synaptic processes that produce state-dependent transient modulation of hippocampal cell activity. In support of this, it has previously been shown in vitro that cannabinoid CB1 receptors modulate second messenger systems in hippocampal neurons that can modulate intracellular ion channels, including channels which release calcium from intracellular stores. Here we demonstrate in hippocampal slices a similar endocannabinoid action on excitatory glutamatergic synapses via modulation of NMDA-receptor mediated intracellular calcium levels in confocal imaged neurons. Calcium entry through glutamatergic NMDA-mediated ion channels increases intracellular calcium concentrations via modulation of release from ryanodine-sensitive channels in endoplasmic reticulum. The studies reported here show that NMDA-elicited increases in Calcium Green fluorescence are enhanced by CB1 receptor antagonists (i.e. rimonabant), and inhibited by CB1 agonists (i.e. WIN 55,212-2). Suppression of endocannabinoid breakdown by either reuptake inhibition (AM404) or fatty-acid amide hydrolase inhibition (URB597) produced suppression of NMDA elicited calcium increases comparable to WIN 55,212-2, while enhancement of calcium release provoked by endocannabinoid receptor antagonists (Rimonabant) was shown to depend on the blockade of CB1 receptor mediated de-phosphorylation of Ryanodine receptors. Such CB1 receptor modulation of NMDA elicited increases in intracellular calcium may account for the respective disruption and enhancement by CB1 agents of trial-specific hippocampal neuron ensemble firing patterns during performance of a short-term memory task, reported previously from this laboratory. PMID:21288475

  9. Defining a developmental path to neural fate by global expression profiling of mouse embryonic stem cells and adult neural stem/progenitor cells.

    PubMed

    Aiba, Kazuhiro; Sharov, Alexei A; Carter, Mark G; Foroni, Chiara; Vescovi, Angelo L; Ko, Minoru S H

    2006-04-01

    To understand global features of gene expression changes during in vitro neural differentiation, we carried out the microarray analysis of embryonic stem cells (ESCs), embryonal carcinoma cells, and adult neural stem/progenitor (NS) cells. Expression profiling of ESCs during differentiation in monolayer culture revealed three distinct phases: undifferentiated ESCs, primitive ectoderm-like cells, and neural progenitor cells. Principal component (PC) analysis revealed that these cells were aligned on PC1 over the course of 6 days. This PC1 represents approximately 4,000 genes, the expression of which increased with neural commitment/differentiation. Furthermore, NS cells derived from adult brain and their differentiated cells were positioned along this PC axis further away from undifferentiated ESCs than embryonic stem-derived neural progenitors. We suggest that this PC1 defines a path to neural fate, providing a scale for the degree of commitment/differentiation.

  10. Effects of selective neonatal hippocampal lesions on tests of object and spatial recognition memory in monkeys.

    PubMed

    Heuer, Eric; Bachevalier, Jocelyne

    2011-04-01

    Earlier studies in monkeys have reported mild impairment in recognition memory after nonselective neonatal hippocampal lesions. To assess whether the memory impairment could have resulted from damage to cortical areas adjacent to the hippocampus, we tested adult monkeys with neonatal focal hippocampal lesions and sham-operated controls in three recognition tasks: delayed nonmatching-to-sample, object memory span, and spatial memory span. Further, to rule out that normal performance on these tasks may relate to functional sparing following neonatal hippocampal lesions, we tested adult monkeys that had received the same focal hippocampal lesions in adulthood and their controls in the same three memory tasks. Both early and late onset focal hippocampal damage did not alter performance on any of the three tasks, suggesting that damage to cortical areas adjacent to the hippocampus was likely responsible for the recognition impairment reported by the earlier studies. In addition, given that animals with early and late onset hippocampal lesions showed object and spatial recognition impairment when tested in a visual paired comparison task, the data suggest that not all object and spatial recognition tasks are solved by hippocampal-dependent memory processes. The current data may not only help explain the neural substrate for the partial recognition memory impairment reported in cases of developmental amnesia, but they are also clinically relevant given that the object and spatial memory tasks used in monkeys are often translated to investigate memory functions in several populations of human infants and children in which dysfunction of the hippocampus is suspected.

  11. Highest trkB mRNA expression in the entorhinal cortex among hippocampal subregions in the adult rat: contrasting pattern with BDNF mRNA expression.

    PubMed

    Tokuyama, W; Hashimoto, T; Li, Y X; Okuno, H; Miyashita, Y

    1998-11-20

    Brain-derived neurotrophic factor (BDNF) and its receptor, TrkB, regulate synaptic functions in the hippocampus of the adult rodent. In previous studies, in situ hybridization methods have been used to evaluate regional differences in BDNF and trkB mRNA expression levels in hippocampal subregions. However, these studies have failed to reach consensus regarding the regional differences in the mRNA expression levels. In the present study, we quantitated mRNA expression levels using two different methods, ribonuclease protection assays and a quantitative reverse-transcription polymerase chain reaction technique, in four hippocampal subregions: the entorhinal cortex, dentate gyrus (DG), CA3 and CA1. These two methods yielded the same results. We found that BDNF and trkB mRNA expression levels did not covary in the four subregions. BDNF and full length trkB (trkB FL) mRNA in the entorhinal cortex and the DG show contrasting expression patterns. The expression level of BDNF mRNA was highest in the DG among the hippocampal subregions and low in the entorhinal cortex and the CA1, whereas the trkB FL mRNA expression level was highest in the entorhinal cortex, low in the DG and lowest in the CA3. These results suggest regional differences in BDNF/TrkB signaling for maintenance and modifiability of neuronal connections in the hippocampal formation.

  12. Gene-environment interaction in programming hippocampal plasticity: focus on adult neurogenesis

    PubMed Central

    Koehl, Muriel

    2015-01-01

    Interactions between genes and environment are a critical feature of development and both contribute to shape individuality. They are at the core of vulnerability resiliency for mental illnesses. During the early postnatal period, several brain structures involved in cognitive and emotional processing, such as the hippocampus, still develop and it is likely that interferences with this neuronal development, which is genetically determined, might lead to long-lasting structural and functional consequences and increase the risk of developing psychopathology. One particular target is adult neurogenesis, which is involved in the regulation of cognitive and emotional processes. Insights into the dynamic interplay between genes and environmental factors in setting up individual rates of neurogenesis have come from laboratory studies exploring experience-dependent changes in adult neurogenesis as a function of individual’s genetic makeup. These studies have implications for our understanding of the mechanisms regulating adult neurogenesis, which could constitute a link between environmental challenges and psychopathology. PMID:26300723

  13. Comprehensive neural networks for guilty feelings in young adults.

    PubMed

    Nakagawa, Seishu; Takeuchi, Hikaru; Taki, Yasuyuki; Nouchi, Rui; Sekiguchi, Atsushi; Kotozaki, Yuka; Miyauchi, Carlos Makoto; Iizuka, Kunio; Yokoyama, Ryoichi; Shinada, Takamitsu; Yamamoto, Yuki; Hanawa, Sugiko; Araki, Tsuyoshi; Hashizume, Hiroshi; Kunitoki, Keiko; Sassa, Yuko; Kawashima, Ryuta

    2015-01-15

    Feelings of guilt are associated with widespread self and social cognitions, e.g., empathy, moral reasoning, and punishment. Neural correlates directly related to the degree of feelings of guilt have not been detected, probably due to the small numbers of subjects, whereas there are growing numbers of neuroimaging studies of feelings of guilt. We hypothesized that the neural networks for guilty feelings are widespread and include the insula, inferior parietal lobule (IPL), amygdala, subgenual cingulate cortex (SCC), and ventromedial prefrontal cortex (vmPFC), which are essential for cognitions of guilt. We investigated the association between regional gray matter density (rGMD) and feelings of guilt in 764 healthy young students (422 males, 342 females; 20.7 ± 1.8 years) using magnetic resonance imaging and the guilty feeling scale (GFS) for the younger generation which comprises interpersonal situation (IPS) and rule-breaking situation (RBS) scores. Both the IPS and RBS were negatively related to the rGMD in the right posterior insula (PI). The IPS scores were negatively correlated with rGMD in the left anterior insula (AI), right IPL, and vmPFC using small volume correction. A post hoc analysis performed on the significant clusters identified through these analyses revealed that rGMD activity in the right IPL showed a significant negative association with the empathy quotient. These findings at the whole-brain level are the widespread comprehensive neural network regions for guilty feelings. Interestingly, the novel finding in this study is that the PI was implicated as a common region for feelings of guilt with interaction between the IPS and RBS. Additionally, the neural networks including the IPL were associated with empathy and with regions implicated in moral reasoning (AI and vmPFC), and punishment (AI).

  14. High-frequency stimulation induces gradual immediate early gene expression in maturing adult-generated hippocampal granule cells.

    PubMed

    Jungenitz, Tassilo; Radic, Tijana; Jedlicka, Peter; Schwarzacher, Stephan W

    2014-07-01

    Increasing evidence shows that adult neurogenesis of hippocampal granule cells is advantageous for learning and memory. We examined at which stage of structural maturation and age new granule cells can be activated by strong synaptic stimulation. High-frequency stimulation of the perforant pathway in urethane-anesthetized rats elicited expression of the immediate early genes c-fos, Arc, zif268 and pCREB133 in almost 100% of mature, calbindin-positive granule cells. In contrast, it failed to induce immediate early gene expression in immature doublecortin-positive granule cells. Furthermore, doublecortin-positive neurons did not react with c-fos or Arc expression to mild theta-burst stimulation or novel environment exposure. Endogenous expression of pCREB133 was increasingly present in young cells with more elaborated dendrites, revealing a close correlation to structural maturation. Labeling with bromodeoxyuridine revealed cell age dependence of stimulation-induced c-fos, Arc and zif268 expression, with only a few cells reacting at 21 days, but with up to 75% of cells activated at 35-77 days of cell age. Our results indicate an increasing synaptic integration of maturing granule cells, starting at 21 days of cell age, but suggest a lack of ability to respond to activation with synaptic potentiation on the transcriptional level as long as immature cells express doublecortin.

  15. Startle response memory and hippocampal changes in adult zebrafish pharmacologically-induced to exhibit anxiety/depression-like behaviors.

    PubMed

    Pittman, Julian T; Lott, Chad S

    2014-01-17

    Zebrafish (Danio rerio) are rapidly becoming a popular animal model for neurobehavioral and psychopharmacological research. While startle testing is a well-established assay to investigate anxiety-like behaviors in different species, screening of the startle response and its habituation in zebrafish is a new direction of translational biomedical research. This study focuses on a novel behavioral protocol to assess a tapping-induced startle response and its habituation in adult zebrafish that have been pharmacologically-induced to exhibit anxiety/depression-like behaviors. We demonstrated that zebrafish exhibit robust learning performance in a task adapted from the mammalian literature, a modified plus maze, and showed that ethanol and fluoxetine impair memory performance in this maze when administered after training at a dose that does not impair motor function, however, leads to significant upregulation of hippocampal serotoninergic neurons. These results suggest that the maze associative learning paradigm has face and construct validity and that zebrafish may become a translationally relevant study species for the analysis of the mechanisms of learning and memory changes associated with psychopharmacological treatment of anxiety/depression.

  16. The longitudinal study of rat hippocampus influenced by stress: early adverse experience enhances hippocampal vulnerability and working memory deficit in adult rats.

    PubMed

    Jin, Fengkui; Li, Lei; Shi, Mei; Li, Zhenzi; Zhou, Jinghua; Chen, Li

    2013-06-01

    Epidemiologic studies indicate that early adverse experience is related to learning disabilities in adults, but the neurobiological mechanisms have not yet been identified. We used longitudinal animal experiments to test the hypothesis that early life stress enhances hippocampal vulnerability and working memory deficit in adult rats. The expression of Synaptophysin (SYN) and apoptosis (Apo) in hippocampal CA3 and dentate gyrus (DG) regions were examined to evaluate the effects of environmental factors on the hippocampus. The working memory errors via radial 8-arm maze were studied to evaluate the long-term effect of early stress on rats' spatial learning ability. Our results indicated that chronic restraint stress in early life and forced cold water swimming stress in adulthood reduced SYN expression and increased Apo levels in rat hippocampus, but the hippocampal damage tended to recover when rats returned to a non-stress environment. In addition, when the rats were exposed to forced cold water swimming stress during adulthood, SYN expression (CA3 and DG regions) and Apo levels (CA3 region) in rat hippocampus showed statistical difference between early restraint stress group and non-early restraint stress group (rats exposed to stress in adulthood only). One month after the two groups of rats returned to non-stress environment, this difference of SYN expression (CA3 and DG regions) and working memory deficit between the two groups was still statistically significant. Our study findings suggested that early adverse experience enhances hippocampal vulnerability and working memory deficit in adult rats, and reduces structural plasticity of hippocampus.

  17. The Neural Representation of Consonant-Vowel Transitions in Adults Who Wear Hearing Aids

    PubMed Central

    Tremblay, Kelly L.; Kalstein, Laura; Billings, Cuttis J.; Souza, Pamela E.

    2006-01-01

    Hearing aids help compensate for disorders of the ear by amplifying sound; however, their effectiveness also depends on the central auditory system's ability to represent and integrate spectral and temporal information delivered by the hearing aid. The authors report that the neural detection of time-varying acoustic cues contained in speech can be recorded in adult hearing aid users using the acoustic change complex (ACC). Seven adults (50–76 years) with mild to severe sensorineural hearing participated in the study. When presented with 2 identifiable consonant-vowel (CV) syllables (“shee” and “see”), the neural detection of CV transitions (as indicated by the presence of a P1-N1-P2 response) was different for each speech sound. More specifically, the latency of the evoked neural response coincided in time with the onset of the vowel, similar to the latency patterns the authors previously reported in normal-hearing listeners. PMID:16959736

  18. Sustained increase in adult neurogenesis in the rat hippocampal dentate gyrus after transient brain ischemia.

    PubMed

    Wang, Congmin; Zhang, Mingguang; Sun, Chifei; Cai, Yuqun; You, Yan; Huang, Liping; Liu, Fang

    2011-01-13

    It is known that the number of newly generated neurons is increased in the young and adult rodent subventricular zone (SVZ) and dentate gyrus (DG) after transient brain ischemia. However, it remains unclear whether increase in neurogenesis in the adult DG induced by ischemic stroke is transient or sustained. We here reported that from 2 weeks to 6 months after transient middle cerebral artery occlusion (MCAO), there were more doublecortin positive (DCX+) cells in the ipsilateral compared to the sham-control and contralateral DG of the adult rat. After the S-phase marker 5-bromo-2'-deoxyuridine (BrdU) was injected 2 days after MCAO to label newly generated cells, a large number of BrdU-labeled neuroblasts differentiated into mature granular neurons. These BrdU-labeled neurons survived for at least 6 months. When BrdU was injected 6 weeks after injury, there were still more newly generated neuroblasts differentiated into mature neurons in the ipsilateral DG. Altogether, our data indicate that transient brain ischemia initiates a prolonged increase in neurogenesis and promotes the normal development of the newly generated neurons in the adult DG.

  19. Neural Correlates of Working Memory Performance in Adolescents and Young Adults with Dyslexia

    ERIC Educational Resources Information Center

    Vasic, Nenad; Lohr, Christina; Steinbrink, Claudia; Martin, Claudia; Wolf, Robert Christian

    2008-01-01

    Behavioral studies indicate deficits in phonological working memory (WM) and executive functioning in dyslexics. However, little is known about the underlying functional neuroanatomy. In the present study, neural correlates of WM in adolescents and young adults with dyslexia were investigated using event-related functional magnetic resonance…

  20. The Neural Basis of Sustained and Transient Attentional Control in Young Adults with ADHD

    ERIC Educational Resources Information Center

    Banich, Marie T.; Burgess, Gregory C.; Depue, Brendan E.; Ruzic, Luka; Bidwell, L. Cinnamon; Hitt-Laustsen, Sena; Du, Yiping P.; Willcutt, Erik G.

    2009-01-01

    Differences in neural activation during performance on an attentionally demanding Stroop task were examined between 23 young adults with ADHD carefully selected to not be co-morbid for other psychiatric disorders and 23 matched controls. A hybrid blocked/single-trial design allowed for examination of more sustained vs. more transient aspects of…

  1. Neural Signatures of Semantic and Phonemic Fluency in Young and Old Adults

    ERIC Educational Resources Information Center

    Meinzer, Marcus; Flaisch, Tobias; Wilser, Lotte; Eulitz, Carsten; Rockstroh, Brigitte; Conway, Tim; Gonzalez-Rothi, Leslie; Crosson, Bruce

    2009-01-01

    As we age, our ability to select and to produce words changes, yet we know little about the underlying neural substrate of word-finding difficulties in old adults. This study was designed to elucidate changes in specific frontally mediated retrieval processes involved in word-finding difficulties associated with advanced age. We implemented two…

  2. No effect of running and laboratory housing on adult hippocampal neurogenesis in wild caught long-tailed wood mouse

    PubMed Central

    Hauser, Thomas; Klaus, Fabienne; Lipp, Hans-Peter; Amrein, Irmgard

    2009-01-01

    Background Studies of adult hippocampal neurogenesis (AHN) in laboratory rodents have raised hopes for therapeutic interventions in neurodegenerative diseases and mood disorders, as AHN can be modulated by physical exercise, stress and environmental changes in these animals. Since it is not known whether cell proliferation and neurogenesis in wild living mice can be experimentally changed, this study investigates the responsiveness of AHN to voluntary running and to environmental change in wild caught long-tailed wood mice (Apodemus sylvaticus). Results Statistical analyses show that running had no impact on cell proliferation (p = 0.44), neurogenesis (p = 0.94) or survival of newly born neurons (p = 0.58). Likewise, housing in the laboratory has no effect on AHN. In addition, interindividual differences in the level of neurogenesis are not related to interindividual differences of running wheel performance (rs = -0.09, p = 0.79). There is a correlation between the number of proliferating cells and the number of cells of neuronal lineage (rs = 0.63, p < 0.001) and the number of pyknotic cells (rs = 0.5, p = 0.009), respectively. Conclusion Plasticity of adult neurogenesis is an established feature in strains of house mice and brown rats. Here, we demonstrate that voluntary running and environmental changes which are effective in house mice and brown rats cannot influence AHN in long-tailed wood mice. This indicates that in wild long-tailed wood mice different regulatory mechanisms act on cell proliferation and neurogenesis. If this difference reflects a species-specific adaptation or a broader adaptive strategy to a natural vs. domestic environment is unknown. PMID:19419549

  3. Relationship between brain accumulation of manganese and aberration of hippocampal adult neurogenesis after oral exposure to manganese chloride in mice.

    PubMed

    Kikuchihara, Yoh; Abe, Hajime; Tanaka, Takeshi; Kato, Mizuho; Wang, Liyun; Ikarashi, Yoshiaki; Yoshida, Toshinori; Shibutani, Makoto

    2015-05-04

    We previously found persistent aberration of hippocampal adult neurogenesis, along with brain manganese (Mn) accumulation, in mouse offspring after developmental exposure to 800-ppm dietary Mn. Reduction of parvalbumin (Pvalb)(+) γ-aminobutyric acid (GABA)-ergic interneurons in the hilus of the dentate gyrus along with promoter region hypermethylation are thought to be responsible for this aberrant neurogenesis. The present study was conducted to examine the relationship between the induction of aberrant neurogenesis and brain Mn accumulation after oral Mn exposure as well as the responsible mechanism in young adult animals. We used two groups of mice with 28- or 56-day exposure periods to oral MnCl2·xH2O at 800 ppm as Mn, a dose sufficient to lead to aberrant neurogenesis after developmental exposure. A third group of mice received intravenous injections of Mn at 5-mg/kg body weight once weekly for 28 days. The 28-day oral Mn exposure did not cause aberrations in neurogenesis. In contrast, 56-day oral exposure caused aberrations in neurogenesis suggestive of reductions in type 2b and type 3 progenitor cells and immature granule cells in the dentate subgranular zone. Brain Mn accumulation in 56-day exposed cases, as well as in directly Mn-injected cases occurred in parallel with reduction of Pvalb(+) GABAergic interneurons in the dentate hilus, suggesting that this may be responsible for aberrant neurogenesis. For reduction of Pvalb(+) interneurons, suppression of brain-derived neurotrophic factor-mediated signaling of mature granule cells may occur via suppression of c-Fos-mediated neuronal plasticity due to direct Mn-toxicity rather than promoter region hypermethylation of Pvalb.

  4. Curcumin Alters Neural Plasticity and Viability of Intact Hippocampal Circuits and Attenuates Behavioral Despair and COX-2 Expression in Chronically Stressed Rats

    PubMed Central

    Choi, Ga-Young; Kim, Hyun-Bum; Hwang, Eun-Sang; Lee, Seok; Kim, Min-Ji; Choi, Ji-Young; Lee, Sung-Ok

    2017-01-01

    Curcumin is a major diarylheptanoid component of Curcuma longa with traditional usage for anxiety and depression. It has been known for the anti-inflammatory, antistress, and neurotropic effects. Here we examined curcumin effect in neural plasticity and cell viability. 60-channel multielectrode array was applied on organotypic hippocampal slice cultures (OHSCs) to monitor the effect of 10 μM curcumin in long-term depression (LTD) through low-frequency stimulation (LFS) to the Schaffer collaterals and commissural pathways. Cell viability was assayed by propidium iodide uptake test in OHSCs. In addition, the influence of oral curcumin administration on rat behavior was assessed with the forced swim test (FST). Finally, protein expression levels of brain-derived neurotrophic factor (BDNF) and cyclooxygenase-2 (COX-2) were measured by Western blot in chronically stressed rats. Our results demonstrated that 10 μM curcumin attenuated LTD and reduced cell death. It also recovered the behavior immobility of FST, rescued the attenuated BDNF expression, and inhibited the enhancement of COX-2 expression in stressed animals. These findings indicate that curcumin can enhance postsynaptic electrical reactivity and cell viability in intact neural circuits with antidepressant-like effects, possibly through the upregulation of BDNF and reduction of inflammatory factors in the brain. PMID:28167853

  5. Adult-generated hippocampal and neocortical neurons in macaques have a transient existence

    PubMed Central

    Gould, E.; Vail, N.; Wagers, M.; Gross, C. G.

    2001-01-01

    Previously we reported that new neurons are added to the hippocampus and neocortex of adult macaque monkeys. Here we compare the production and survival of adult-generated neurons and glia in the dentate gyrus, prefrontal cortex, and inferior temporal cortex. Twelve adult macaques were injected with the thymidine analogue BrdUrd, and the phenotypes of labeled cells were examined after 2 h, 24 h, 2 wk, 5 wk, 9 wk, and 12 wk by using the following immunocytochemical markers: for immature and mature neurons, class III β-tubulin (TuJ1); for mature neurons, neuronal nuclei; for astrocytes, glial fibrillary acidic protein; and for oligodendrocytes, 2′,3′-cyclic nucleotide 3′ phosphodiesterase. We found that the dentate gyrus had many more BrdUrd-labeled cells than either neocortical area. Furthermore, a greater percentage of BrdUrd-labeled cells expressed a neuronal marker in the dentate gyrus than in either neocortical area. The number of new cells in all three areas declined by 9 wk after BrdUrd labeling, suggesting that some of the new cells have a transient existence. BrdUrd-labeled cells also were found in the subventricular zone and in the white matter between the lateral ventricle and neocortex; some of the latter cells were double-labeled for BrdUrd and TuJ1. Adult neocortical neurogenesis is not restricted to primates. Five adult rats were injected with BrdUrd, and after a 3-wk survival time, there were cells double-labeled for BrdUrd and either TuJ1 or neuronal nuclei in the anterior neocortex as well as the dentate gyrus. PMID:11526209

  6. Sox2-mediated regulation of adult neural crest precursors and skin repair.

    PubMed

    Johnston, Adam P W; Naska, Sibel; Jones, Karen; Jinno, Hiroyuki; Kaplan, David R; Miller, Freda D

    2013-01-01

    Nerve-derived neural crest cells are essential for regeneration in certain animals, such as newts. Here, we asked whether they play a similar role during mammalian tissue repair, focusing on Sox2-positive neural crest precursors in skin. In adult skin, Sox2 was expressed in nerve-terminal-associated neural crest precursor cells (NCPCs) around the hair follicle bulge, and following injury was induced in nerve-derived cells, likely dedifferentiated Schwann cell precursors. At later times postinjury, Sox2-positive cells were scattered throughout the regenerating dermis, and lineage tracing showed that these were all neural-crest-derived NCPCs. These Sox2-positive NCPCs were functionally important, since acute deletion of Sox2 prior to injury caused a decrease of NCPCs in the wound and aberrant skin repair. These data demonstrate that Sox2 regulates skin repair, likely by controlling NCPCs, and raise the possibility that nerve-derived NCPCs may play a general role in mammalian tissue repair.

  7. The novel steroidal alkaloids dendrogenin A and B promote proliferation of adult neural stem cells

    SciTech Connect

    Khalifa, Shaden A.M.; Medina, Philippe de; Erlandsson, Anna; El-Seedi, Hesham R.; Silvente-Poirot, Sandrine; Poirot, Marc

    2014-04-11

    Highlights: • Dendrogenin A and B are new aminoalkyl oxysterols. • Dendrogenins stimulated neural stem cells proliferation. • Dendrogenins induce neuronal outgrowth from neurospheres. • Dendrogenins provide new therapeutic options for neurodegenerative disorders. - Abstract: Dendrogenin A (DDA) and dendrogenin B (DDB) are new aminoalkyl oxysterols which display re-differentiation of tumor cells of neuronal origin at nanomolar concentrations. We analyzed the influence of dendrogenins on adult mice neural stem cell proliferation, sphere formation and differentiation. DDA and DDB were found to have potent proliferative effects in neural stem cells. Additionally, they induce neuronal outgrowth from neurospheres during in vitro cultivation. Taken together, our results demonstrate a novel role for dendrogenins A and B in neural stem cell proliferation and differentiation which further increases their likely importance to compensate for neuronal cell loss in the brain.

  8. Design and implementation of in vivo imaging of neural injury responses in the adult Drosophila wing.

    PubMed

    Fang, Yanshan; Soares, Lorena; Bonini, Nancy M

    2013-04-01

    Live-imaging technology has markedly advanced in the field of neural injury and axon degeneration; however, studies are still predominantly performed in in vitro settings such as cultured neuronal cells or in model organisms such as Caenorhabditis elegans in which axons lack glial wrappings. We recently developed a new in vivo model for adult-stage neural injury in Drosophila melanogaster, using the highly accessible wing of the animal. Because the Drosophila wing is translucent and dispensable for survival, it allows clear and direct visualization of injury-induced progressive responses of axons and glia highlighted by fluorescent protein (FP) markers in live animals over time. Moreover, unlike previous Drosophila models of neural injury, this procedure does not require dissection of the CNS. Thus, the key preparation steps for in vivo imaging of the neural injury response described in this protocol can be completed within 30 min.

  9. Stroke Increases Neural Stem Cells and Angiogenesis in the Neurogenic Niche of the Adult Mouse

    PubMed Central

    Zhang, Rui Lan; Chopp, Michael; Roberts, Cynthia; Liu, Xianshuang; Wei, Min; Nejad-Davarani, Siamak P.; Wang, Xinli; Zhang, Zheng Gang

    2014-01-01

    The unique cellular and vascular architecture of the adult ventricular-subventricular zone (V/SVZ) neurogenic niche plays an important role in regulating neural stem cell function. However, the in vivo identification of neural stem cells and their relationship to blood vessels within this niche in response to stroke remain largely unknown. Using whole-mount preparation of the lateral ventricle wall, we examined the architecture of neural stem cells and blood vessels in the V/SVZ of adult mouse over the course of 3 months after onset of focal cerebral ischemia. Stroke substantially increased the number of glial fibrillary acidic protein (GFAP) positive neural stem cells that are in contact with the cerebrospinal fluid (CSF) via their apical processes at the center of pinwheel structures formed by ependymal cells residing in the lateral ventricle. Long basal processes of these cells extended to blood vessels beneath the ependymal layer. Moreover, stroke increased V/SVZ endothelial cell proliferation from 2% in non-ischemic mice to 12 and 15% at 7 and 14 days after stroke, respectively. Vascular volume in the V/SVZ was augmented from 3% of the total volume prior to stroke to 6% at 90 days after stroke. Stroke-increased angiogenesis was closely associated with neuroblasts that expanded to nearly encompass the entire lateral ventricular wall in the V/SVZ. These data indicate that stroke induces long-term alterations of the neural stem cell and vascular architecture of the adult V/SVZ neurogenic niche. These post-stroke structural changes may provide insight into neural stem cell mediation of stroke-induced neurogenesis through the interaction of neural stem cells with proteins in the CSF and their sub-ependymal neurovascular interaction. PMID:25437857

  10. Presenilin-1 regulates neural progenitor cell differentiation in the adult brain

    PubMed Central

    Gadadhar, Archana; Marr, Robert; Lazarov, Orly

    2011-01-01

    Presenilin-1 (PS1) is the catalytic core of the aspartyl protease γ-secretase. Previous genetic studies using germ-line deletion of PS1 and conditional knockout mice demonstrated that PS1 plays an essential role in neuronal differentiation during neural development, but it remained unclear whether PS1 plays a similar role in neurogenesis in the adult brain. Here we show that neural progenitor cells infected with lentiviral vectors expressing short interfering RNA (siRNA) for the exclusive knockdown of PS1 in the neurogenic microenvironments, exhibit a dramatic enhancement of cell differentiation. Infected cells differentiated into neurons, astrocytes and oligodendrocytes, suggesting that multipotentiality of neural progenitor cells is not affected by reduced levels of PS1. Neurosphere cultures treated with γ-secretase inhibitors exhibit a similar phenotype of enhanced cell differentiation, suggesting that PS1 function in neural progenitor cells is γ-secretase-dependent. Neurospheres infected with lentiviral vectors expressing siRNA for the targeting of PS1 differentiated even in the presence of the proliferation factors epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF), suggesting that PS1 dominates EFG and bFGF signaling pathways. Reduction of PS1 expression in neural progenitor cells was accompanied by a decrease in epidermal growth factor receptor (EGFR) and β-catenin expression level, suggesting that they are downstream essential transducers of PS1 signaling in adult neural progenitor cells. These findings suggest a physiological role for PS1 in adult neurogenesis, and a potential target for the manipulation of neural progenitor cell differentiation. PMID:21325529

  11. Long-term fate of neural precursor cells following transplantation into developing and adult CNS.

    PubMed

    Lepore, A C; Neuhuber, B; Connors, T M; Han, S S W; Liu, Y; Daniels, M P; Rao, M S; Fischer, I

    2006-05-12

    Successful strategies for transplantation of neural precursor cells for replacement of lost or dysfunctional CNS cells require long-term survival of grafted cells and integration with the host system, potentially for the life of the recipient. It is also important to demonstrate that transplants do not result in adverse outcomes. Few studies have examined the long-term properties of transplanted neural precursor cells in the CNS, particularly in non-neurogenic regions of the adult. The aim of the present study was to extensively characterize the fate of defined populations of neural precursor cells following transplantation into the developing and adult CNS (brain and spinal cord) for up to 15 months, including integration of graft-derived neurons with the host. Specifically, we employed neuronal-restricted precursors and glial-restricted precursors, which represent neural precursor cells with lineage restrictions for neuronal and glial fate, respectively. Transplanted cells were prepared from embryonic day-13.5 fetal spinal cord of transgenic donor rats that express the marker gene human placental alkaline phosphatase to achieve stable and reliable graft tracking. We found that in both developing and adult CNS grafted cells showed long-term survival, morphological maturation, extensive distribution and differentiation into all mature CNS cell types (neurons, astrocytes and oligodendrocytes). Graft-derived neurons also formed synapses, as identified by electron microscopy, suggesting that transplanted neural precursor cells integrated with adult CNS. Furthermore, grafts did not result in any apparent deleterious outcomes. We did not detect tumor formation, cells did not localize to unwanted locations and no pronounced immune response was present at the graft sites. The long-term stability of neuronal-restricted precursors and glial-restricted precursors and the lack of adverse effects suggest that transplantation of lineage-restricted neural precursor cells can

  12. Neural correlates of letter reversal in children and adults.

    PubMed

    Blackburne, Liwei King; Eddy, Marianna D; Kalra, Priya; Yee, Debbie; Sinha, Pawan; Gabrieli, John D E

    2014-01-01

    Children often make letter reversal errors when first learning to read and write, even for letters whose reversed forms do not appear in normal print. However, the brain basis of such letter reversal in children learning to read is unknown. The present study compared the neuroanatomical correlates (via functional magnetic resonance imaging) and the electrophysiological correlates (via event-related potentials or ERPs) of this phenomenon in children, ages 5-12, relative to young adults. When viewing reversed letters relative to typically oriented letters, adults exhibited widespread occipital, parietal, and temporal lobe activations, including activation in the functionally localized visual word form area (VWFA) in left occipito-temporal cortex. Adults exhibited significantly greater activation than children in all of these regions; children only exhibited such activation in a limited frontal region. Similarly, on the P1 and N170 ERP components, adults exhibited significantly greater differences between typical and reversed letters than children, who failed to exhibit significant differences between typical and reversed letters. These findings indicate that adults distinguish typical and reversed letters in the early stages of specialized brain processing of print, but that children do not recognize this distinction during the early stages of processing. Specialized brain processes responsible for early stages of letter perception that distinguish between typical and reversed letters may develop slowly and remain immature even in older children who no longer produce letter reversals in their writing.

  13. SEXUAL INTERACTIONS WITH UNFAMILIAR FEMALES REDUCE HIPPOCAMPAL NEUROGENESIS AMONG ADULT MALE RATS

    PubMed Central

    Spritzer, Mark D.; Curtis, Molly G.; DeLoach, Julia P.; Maher, Jack; Shulman, Leanne M.

    2016-01-01

    Recent experiments have shown that sexual interactions prior to cell proliferation cause an increase in neurogenesis in adult male rats. Because adult neurogenesis is critical for some forms of memory, we hypothesized that sexually induced changes in neurogenesis may be involved in mate recognition. Sexually naive adult male rats were either exposed repeatedly to the same sexual partner (familiar group) or to a series of novel sexual partners (unfamiliar group), while control males never engaged in sexual interactions. Ovariectomized female rats were induced into estrus every four days. Males were given two injections of BrdU (200 mg/kg) to label proliferating cells, and the first sexual interactions occurred three days later. Males in the familiar and unfamiliar groups engaged in four, 30 min sexual interactions at four-day intervals, and brain tissue was collected the day after the last sexual interaction. Immunohisotchemistry followed by microscopy was used to quantify BrdU-labeled cells. Sexual interactions with unfamiliar females caused a significant reduction in neurogenesis in the dentate gyrus compared to males that interacted with familiar females and compared to the control group. The familiar group showed no difference in neurogenesis compared to the control group. There were no differences in the amount of sexual behavior (mounts, intromissions, ejaculations, or contact time) that the familiar and unfamiliar groups engaged in, indicating that the differences in neurogenesis were not due to the relative amounts of sexual activity. In a second experiment, we tested whether this effect was unique to sexual interactions by replicating the entire procedure using anestrus females. We found that interactions with unfamiliar anestrus females reduced neurogenesis relative to the other groups, but this effect was not statistically significant. In combination, these results indicate that interactions with unfamiliar females reduce adult neurogenesis and the effect

  14. Sexual interactions with unfamiliar females reduce hippocampal neurogenesis among adult male rats.

    PubMed

    Spritzer, M D; Curtis, M G; DeLoach, J P; Maher, J; Shulman, L M

    2016-03-24

    Recent experiments have shown that sexual interactions prior to cell proliferation cause an increase in neurogenesis in adult male rats. Because adult neurogenesis is critical for some forms of memory, we hypothesized that sexually induced changes in neurogenesis may be involved in mate recognition. Sexually naive adult male rats were either exposed repeatedly to the same sexual partner (familiar group) or to a series of novel sexual partners (unfamiliar group), while control males never engaged in sexual interactions. Ovariectomized female rats were induced into estrus every four days. Males were given two injections of 5-bromo-2'-deoxyuridine (BrdU) (200mg/kg) to label proliferating cells, and the first sexual interactions occurred three days later. Males in the familiar and unfamiliar groups engaged in four, 30-min sexual interactions at four-day intervals, and brain tissue was collected the day after the last sexual interaction. Immunohistochemistry followed by microscopy was used to quantify BrdU-labeled cells. Sexual interactions with unfamiliar females caused a significant reduction in neurogenesis in the dentate gyrus compared to males that interacted with familiar females and compared to the control group. The familiar group showed no difference in neurogenesis compared to the control group. Males in the familiar group engaged in significantly more sexual behavior (ejaculations and intromissions) than did males in the unfamiliar group, suggesting that level of sexual activity may influence neurogenesis levels. In a second experiment, we tested whether this effect was unique to sexual interactions by replicating the entire procedure using anestrus females. We found that interactions with unfamiliar anestrus females reduced neurogenesis relative to the other groups, but this effect was not statistically significant. In combination, these results indicate that interactions with unfamiliar females reduce adult neurogenesis and the effect is stronger for sexual

  15. Large-scale live imaging of adult neural stem cells in their endogenous niche.

    PubMed

    Dray, Nicolas; Bedu, Sébastien; Vuillemin, Nelly; Alunni, Alessandro; Coolen, Marion; Krecsmarik, Monika; Supatto, Willy; Beaurepaire, Emmanuel; Bally-Cuif, Laure

    2015-10-15

    Live imaging of adult neural stem cells (aNSCs) in vivo is a technical challenge in the vertebrate brain. Here, we achieve long-term imaging of the adult zebrafish telencephalic neurogenic niche and track a population of >1000 aNSCs over weeks, by taking advantage of fish transparency at near-infrared wavelengths and of intrinsic multiphoton landmarks. This methodology enables us to describe the frequency, distribution and modes of aNSCs divisions across the entire germinal zone of the adult pallium, and to highlight regional differences in these parameters.

  16. Experience-Dependent Neural Plasticity in the Adult Damaged Brain

    ERIC Educational Resources Information Center

    Kerr, Abigail L.; Cheng, Shao-Ying; Jones, Theresa A.

    2011-01-01

    Behavioral experience is at work modifying the structure and function of the brain throughout the lifespan, but it has a particularly dramatic influence after brain injury. This review summarizes recent findings on the role of experience in reorganizing the adult damaged brain, with a focus on findings from rodent stroke models of chronic upper…

  17. The effects of high-frequency oscillations in hippocampal electrical activities on the classification of epileptiform events using artificial neural networks

    NASA Astrophysics Data System (ADS)

    Chiu, Alan W. L.; Jahromi, Shokrollah S.; Khosravani, Houman; Carlen, Peter L.; Bardakjian, Berj L.

    2006-03-01

    The existence of hippocampal high-frequency electrical activities (greater than 100 Hz) during the progression of seizure episodes in both human and animal experimental models of epilepsy has been well documented (Bragin A, Engel J, Wilson C L, Fried I and Buzsáki G 1999 Hippocampus 9 137-42 Khosravani H, Pinnegar C R, Mitchell J R, Bardakjian B L, Federico P and Carlen P L 2005 Epilepsia 46 1-10). However, this information has not been studied between successive seizure episodes or utilized in the application of seizure classification. In this study, we examine the dynamical changes of an in vitro low Mg2+ rat hippocampal slice model of epilepsy at different frequency bands using wavelet transforms and artificial neural networks. By dividing the time-frequency spectrum of each seizure-like event (SLE) into frequency bins, we can analyze their burst-to-burst variations within individual SLEs as well as between successive SLE episodes. Wavelet energy and wavelet entropy are estimated for intracellular and extracellular electrical recordings using sufficiently high sampling rates (10 kHz). We demonstrate that the activities of high-frequency oscillations in the 100-400 Hz range increase as the slice approaches SLE onsets and in later episodes of SLEs. Utilizing the time-dependent relationship between different frequency bands, we can achieve frequency-dependent state classification. We demonstrate that activities in the frequency range 100-400 Hz are critical for the accurate classification of the different states of electrographic seizure-like episodes (containing interictal, preictal and ictal states) in brain slices undergoing recurrent spontaneous SLEs. While preictal activities can be classified with an average accuracy of 77.4 ± 6.7% utilizing the frequency spectrum in the range 0-400 Hz, we can also achieve a similar level of accuracy by using a nonlinear relationship between 100-400 Hz and <4 Hz frequency bands only.

  18. Low intensity, long term exposure to tobacco smoke inhibits hippocampal neurogenesis in adult mice.

    PubMed

    Csabai, Dávid; Csekő, Kata; Szaiff, Lilla; Varga, Zsófia; Miseta, Attila; Helyes, Zsuzsanna; Czéh, Boldizsár

    2016-04-01

    Previous data have shown that high dose of nicotine administration or tobacco smoke exposure can reduce cell formation and the survival rate of adult-born neurons in the dentate gyrus. Here, we subjected adult mice to low intensity cigarette smoke exposure over long time periods. We did a 2×30min/day smoke exposure with two cigarettes per occasion over 1- or 2-months. Subsequently, we carried out a systematic quantitative histopathological analysis to assess the number of newborn neurons in the dentate gyrus. To investigate cell proliferation, the exogenous marker 5-bromo-2'-deoxyuridine (BrdU) was administered on the last experimental day and animals were sacrificed 2h later. To investigate the effect of tobacco smoke on the population of immature neurons, we quantified the number of doublecortin-positive (DCX+) neurons in the same animals. We found that exposing animals to cigarette smoke for 1- or 2-months had no influence on cell proliferation rate, but significantly reduced the number of DCX-positive immature neurons. Our tobacco smoke exposure regimen caused no substantial changes in respiratory functions, but histopathological analysis of the pulmonary tissue revealed a marked perivascular/peribronchial edema formation after 1-month and signs of chronic pulmonary inflammation after 2-months of cigarette smoke exposure. These data demonstrate that even mild exposure to cigarette smoke, without significantly affecting respiratory functions, can have a negative effect on adult-born neurons in the dentate gyrus, when applied over longer time periods. Our data indicate that besides nicotine other factors, such as inflammatory mediators, may also contribute to this effect.

  19. Perinatal exposure to methoxychlor enhances adult cognitive responses and hippocampal neurogenesis in mice

    PubMed Central

    Martini, Mariangela; Calandreau, Ludovic; Jouhanneau, Mélanie; Mhaouty-Kodja, Sakina; Keller, Matthieu

    2014-01-01

    During perinatal life, sex steroids, such as estradiol, have marked effects on the development and function of the nervous system. Environmental estrogens or xenoestrogens are man-made chemicals, which animal and human population encounter in the environment and which are able to disrupt the functioning of the endocrine system. Scientific interest in the effects of exposure to xenoestrogens has focused more on fertility and reproductive behaviors, while the effects on cognitive behaviors have received less attention. Therefore, the present study explored whether the organochlorine insecticide Methoxychlor (MXC), with known xenoestrogens properties, administered during the perinatal period (from gestational day 11 to postnatal day 8) to pregnant-lactating females, at an environmentally relevant dose (20 µg/kg (body weight)/day), would also affect learning and memory functions depending on the hippocampus of male and female offspring mice in adulthood. When tested in adulthood, MXC perinatal exposure led to an increase in anxiety-like behavior and in short-term spatial working memory in both sexes. Emotional learning was also assessed using a contextual fear paradigm and MXC treated male and female mice showed an enhanced freezing behavior compared to controls. These results were correlated with an increased survival of adult generated cells in the adult hippocampus. In conclusion, our results show that perinatal exposure to an environmentally relevant dose of MXC has an organizational effect on hippocampus-dependent memory and emotional behaviors. PMID:24982620

  20. Now you see it, now you don't: Testing environments modulate the association between hippocampal volume and cortisol levels in young and older adults.

    PubMed

    Sindi, Shireen; Fiocco, Alexandra J; Juster, Robert-Paul; Lord, Catherine; Pruessner, Jens; Lupien, Sonia J

    2014-12-01

    The hypothalamic pituitary adrenal axis production of the stress hormone cortisol interacts with the hippocampal formation and impacts memory function. A growing interest is to determine whether hippocampal volume (HV) predicts basal and/or reactive cortisol levels in young and older adults. Recent evidence shows that contextual features in testing environments might be stressful and inadvertently induce a stress response in young and/or older populations. This latter result suggests that variations in testing environments might influence associations between HV and cortisol levels in young and older adults. To this end, we investigated 28 healthy young adults (ages 18-35) and 32 healthy older adults (ages 60-75) in two different environments constructed to be more or less stressful for each age group (Favoring-Young versus Favoring-Old conditions). Cortisol levels were repeatedly assessed in each environment, and young and older participants underwent an anatomical magnetic resonance imaging scan for subsequent assessment of HV. Results in both age groups showed that HV was significantly associated with cortisol levels only in the unfavorable stressful testing conditions specific for each age group. This association was absent when testing environments were designed to decrease stress for each age group. These findings are fundamental in showing that unless the nature of the testing environment is taken into consideration, detected associations between HV and cortisol levels in both young and older populations might be confounded by environmental stress.

  1. Embryonic requirements for ErbB signaling in neural crest development and adult pigment pattern formation

    PubMed Central

    Budi, Erine H.; Patterson, Larissa B.; Parichy, David M.

    2009-01-01

    SUMMARY Vertebrate pigment cells are derived from neural crest cells and are a useful system for studying neural crest-derived traits during post-embryonic development. In zebrafish, neural crest-derived melanophores differentiate during embryogenesis to produce stripes in the early larva. Dramatic changes to the pigment pattern occur subsequently during the larva-to-adult transformation, or metamorphosis. At this time, embryonic melanophores are replaced by newly differentiating metamorphic melanophores that form the adult stripes. Mutants with normal embryonic/early larval pigment patterns but defective adult patterns identify factors required uniquely to establish, maintain, or recruit the latent precursors to metamorphic melanophores. We show that one such mutant, picasso, lacks most metamorphic melanophores and results from mutations in the ErbB gene erbb3b, encoding an EGFR-like receptor tyrosine kinase. To identify critical periods for ErbB activities, we treated fish with pharmacological ErbB inhibitors and also knocked-down erbb3b by morpholino injection. These analyses reveal an embryonic critical period for ErbB signaling in promoting later pigment pattern metamorphosis, despite the normal patterning of embryonic/early larval melanophores. We further demonstrate a peak requirement during neural crest migration that correlates with early defects in neural crest pathfinding and peripheral ganglion formation. Finally, we show that erbb3b activities are both autonomous and non-autonomous to the metamorphic melanophore lineage. These data identify a very early, embryonic, requirement for erbb3b in the development of much later metamorphic melanophores, and suggest complex modes by which ErbB signals promote adult pigment pattern development. PMID:18508863

  2. Neural correlates of conceptual object priming in young and older adults: An event-related fMRI study

    PubMed Central

    Ballesteros, Soledad; Bischof, Gérard N.; Goh, Joshua O.; Park, Denise C.

    2012-01-01

    In this event-related fMRI study, we investigated age-related differences in brain activity associated with conceptual repetition priming in young and older adults. Participants performed a speeded “living/non-living” classification task with three repetitions of familiar objects. Both young and older adults showed a similar magnitude of behavioral priming to repeated objects and evidencing repetition-related activation reductions in fusiform gyrus, superior occipital, middle and inferior temporal cortex, as well as inferior frontal and insula regions. The neural priming effect in young adults was extensive and continued through both the second and third stimulus repetitions, whereas neural priming in older adults was markedly attenuated and reached floor at the second repetition. In young adults, greater neural priming in multiple brain regions correlated with greater behavioral facilitation whereas in older adults, only activation reduction in the left inferior frontal correlated with faster behavioral responses. These findings provide evidence for altered neural priming in older adults despite preserved behavioral priming, and suggest the possibility that age-invariant behavioral priming is observed as a result of more sustained neural processing of stimuli in older adults which may be a form of compensatory neural activity. PMID:23102512

  3. Neural correlates of conceptual object priming in young and older adults: an event-related functional magnetic resonance imaging study.

    PubMed

    Ballesteros, Soledad; Bischof, Gérard N; Goh, Joshua O; Park, Denise C

    2013-04-01

    In this event-related functional magnetic resonance imaging study, we investigated age-related differences in brain activity associated with conceptual repetition priming in young and older adults. Participants performed a speeded "living/nonliving" classification task with 3 repetitions of familiar objects. Both young and older adults showed a similar magnitude of behavioral priming to repeated objects and evidenced repetition-related activation reductions in fusiform gyrus, superior occipital, middle, and inferior temporal cortex, and inferior frontal and insula regions. The neural priming effect in young adults was extensive and continued through both the second and third stimulus repetitions, and neural priming in older adults was markedly attenuated and reached floor at the second repetition. In young adults, greater neural priming in multiple brain regions correlated with greater behavioral facilitation and in older adults, only activation reduction in the left inferior frontal correlated with faster behavioral responses. These findings provide evidence for altered neural priming in older adults despite preserved behavioral priming, and suggest the possibility that age-invariant behavioral priming is observed as a result of more sustained neural processing of stimuli in older adults which might be a form of compensatory neural activity.

  4. Different regulation of adult hippocampal neurogenesis in Western house mice (Mus musculus domesticus) and C57BL/6 mice.

    PubMed

    Klaus, Fabienne; Hauser, Thomas; Lindholm, Anna K; Cameron, Heather A; Slomianka, Lutz; Lipp, Hans-Peter; Amrein, Irmgard

    2012-02-14

    Adult hippocampal neurogenesis (AHN) of laboratory rodents is enhanced by physical exercise in a running wheel. However, little is known about modulation of AHN in wild-living rodent species. The finding that AHN cannot be modulated by voluntary exercise in wild wood mice suggests that AHN may be regulated differently under natural conditions than in laboratory adapted animals. In order to minimize genetic influences, we aimed to investigate the genetically closest wild-living relatives of laboratory mice. Here, C57BL/6 mice and F1 offspring of wild house mice (Mus musculus domesticus) were tested in two different running paradigms: voluntary running and running-for-food--a condition in which mice had to run for their daily allowance of food. In house mice, we found a non-significant trend towards increased numbers of proliferating cells and doublecortin-positive immature neurons in both voluntary runners and runners-for-food. Voluntary running in C57BL/6 mice resulted in a 30% increase in cell proliferation and a pronounced 70% increase in doublecortin-positive cells. C57BL/6 runners-for-food ran as much as voluntary runners, but they showed no enhancement of cell proliferation, a small increase in the number of doublecortin-positive cells and more pyknotic cells compared to controls. Taken together, these findings suggest that motivational aspects of running are critical determinants of the increased cell proliferation in C57BL/6 mice. In contrast, running has smaller and context-independent effects in house mice. The findings imply a difference in the regulation of AHN in C57BL/6 mice and their wild-derived conspecifics.

  5. Opioid Receptor-Dependent Sex Differences in Synaptic Plasticity in the Hippocampal Mossy Fiber Pathway of the Adult Rat

    PubMed Central

    Harte-Hargrove, Lauren C.; Varga-Wesson, Ada; Duffy, Aine M.; Milner, Teresa A.

    2015-01-01

    The mossy fiber (MF) pathway is critical to hippocampal function and influenced by gonadal hormones. Physiological data are limited, so we asked whether basal transmission and long-term potentiation (LTP) differed in slices of adult male and female rats. The results showed small sex differences in basal transmission but striking sex differences in opioid receptor sensitivity and LTP. When slices were made from females on proestrous morning, when serum levels of 17β-estradiol peak, the nonspecific opioid receptor antagonist naloxone (1 μm) enhanced MF transmission but there was no effect in males, suggesting preferential opioid receptor-dependent inhibition in females when 17β-estradiol levels are elevated. The μ-opioid receptor (MOR) antagonist Cys2,Tyr3,Orn5,Pen7-amide (CTOP; 300 nm) had a similar effect but the δ-opioid receptor (DOR) antagonist naltrindole (NTI; 1 μm) did not, implicating MORs in female MF transmission. The GABAB receptor antagonist saclofen (200 μm) occluded effects of CTOP but the GABAA receptor antagonist bicuculline (10 μm) did not. For LTP, a low-frequency (LF) protocol was used because higher frequencies elicited hyperexcitability in females. Proestrous females exhibited LF-LTP but males did not, suggesting a lower threshold for synaptic plasticity when 17β-estradiol is elevated. NTI blocked LF-LTP in proestrous females, but CTOP did not. Electron microscopy revealed more DOR-labeled spines of pyramidal cells in proestrous females than males. Therefore, we suggest that increased postsynaptic DORs mediate LF-LTP in proestrous females. The results show strong MOR regulation of MF transmission only in females and identify a novel DOR-dependent form of MF LTP specific to proestrus. PMID:25632146

  6. Impact of cocaine on adult hippocampal neurogenesis in an animal model of differential propensity to drug abuse

    PubMed Central

    García-Fuster, M. Julia; Perez, Javier A.; Clinton, Sarah M.; Watson, Stanley J; Akil, Huda

    2014-01-01

    Hippocampal plasticity (e.g., neurogenesis) likely plays an important role in maintaining addictive behavior and/or relapse. This study assessed whether rats with differential propensity to drug-seeking behavior, bred Low-Responders (bLR) and bred High-Responders (bHR) to novelty, show differential neurogenesis regulation after cocaine exposure. Using specific immunological markers, we labeled distinct populations of adult stem cells in the dentate gyrus at different time-points of the cocaine sensitization process; Ki-67 for newly born cells, NeuroD for cells born partway, and BrdU for older cells born prior to sensitization. Results show that: (1) bHRs exhibited greater psychomotor response to cocaine than bLRs. (2) Acute cocaine did not alter cell proliferation in bLR/bHR rats. (3) Chronic cocaine decreased cell proliferation in bLRs only, which became amplified through the course of abstinence. (4) Neither chronic cocaine nor cocaine abstinence affected the survival of immature neurons in either phenotype. (5) Cocaine abstinence decreased survival of mature neurons in bHRs only, an effect that paralleled the greater psychomotor response to cocaine. (6) Cocaine treatment did not affect the ratio of neurons to glia in bLR/bHR rats as most cells differentiated into neurons in both lines. Thus, cocaine exerts distinct effects on neurogenesis in bLR versus bHR rats, with a decrease in the birth of new progenitor cells in bLRs and a suppression of the survival of new neurons in bHRs which likely leads to an earlier decrease in formation of new connections. This latter effect in bHRs could contribute to their enhanced degree of cocaine-induced psychomotor behavioral sensitization. PMID:20104651

  7. Lithium-induced effects on adult hippocampal neurogenesis are topographically segregated along the dorso-ventral axis of stressed mice.

    PubMed

    O'Leary, Olivia F; O'Connor, Richard M; Cryan, John F

    2012-01-01

    Adult hippocampal neurogenesis is an important process in the regulation of cognition, stress responsivity, and sensitivity to antidepressant and mood stabiliser drugs. Increasing evidence suggests that the hippocampus is functionally divided along its axis with the ventral hippocampus (vHi) playing a preferential role in stress- and anxiety-related processes, while the dorsal hippocampus (dHi) is crucial for spatial learning and memory. However, it is currently unclear whether stress or the medications used to treat stress-related disorders, preferentially affect neurogenesis in the vHi rather than dHi. The aim of this study was to determine whether the mood stabiliser, lithium, preferentially affects cell proliferation and survival in the vHi rather than dHi under stress conditions. To this end, mice of the stress-sensitive strain, BALB/c, underwent chronic exposure to immobilisation stress plus lithium treatment (0.2% lithium-supplemented diet), and the rates of cell proliferation and survival were compared in the dHi and vHi. Lithium preferentially increased cell proliferation in the vHi under stress conditions only. This increase in cell proliferation was secondary to reductions in the survival of newly-born cells. Moreover, lithium-induced decreases in cell survival in the vHi were only observed under stress conditions. Taken together, the data suggest that the turnover of newly-born cells in response to chronic stress and lithium treatment occurs predominantly in the vHi rather than the dHi. This article is part of a Special Issue entitled 'Anxiety and Depression'.

  8. Chronic unpredictable mild stress alters an anxiety-related defensive response, Fos immunoreactivity and hippocampal adult neurogenesis.

    PubMed

    de Andrade, J S; Céspedes, I C; Abrão, R O; Dos Santos, T B; Diniz, L; Britto, L R G; Spadari-Bratfisch, R C; Ortolani, D; Melo-Thomas, L; da Silva, R C B; Viana, M B

    2013-08-01

    Previous results show that elevated T-maze (ETM) avoidance responses are facilitated by acute restraint. Escape, on the other hand, was unaltered. To examine if the magnitude of the stressor is an important factor influencing these results, we investigated the effects of unpredictable chronic mild stress (UCMS) on ETM avoidance and escape measurements. Analysis of Fos protein immunoreactivity (Fos-ir) was used to map areas activated by stress exposure in response to ETM avoidance and escape performance. Additionally, the effects of the UCMS protocol on the number of cells expressing the marker of migrating neuroblasts doublecortin (DCX) in the hippocampus were investigated. Corticosterone serum levels were also measured. Results showed that UCMS facilitates ETM avoidance, not altering escape. In unstressed animals, avoidance performance increases Fos-ir in the cingulate cortex, hippocampus (dentate gyrus) and basomedial amygdala, and escape increases Fos-ir in the dorsolateral periaqueductal gray and locus ceruleus. In stressed animals submitted to ETM avoidance, increases in Fos-ir were observed in the cingulate cortex, ventrolateral septum, hippocampus, hypothalamus, amygdala, dorsal and median raphe nuclei. In stressed animals submitted to ETM escape, increases in Fos-ir were observed in the cingulate cortex, periaqueductal gray and locus ceruleus. Also, UCMS exposure decreased the number of DCX-positive cells in the dorsal and ventral hippocampus and increased corticosterone serum levels. These data suggest that the anxiogenic effects of UCMS are related to the activation of specific neurobiological circuits that modulate anxiety and confirm that this stress protocol activates the hypothalamus-pituitary-adrenal axis and decreases hippocampal adult neurogenesis.

  9. Nonspecific effects of the gap junction blocker mefloquine on fast hippocampal network oscillations in the adult rat in vitro.

    PubMed

    Behrens, C J; Ul Haq, R; Liotta, A; Anderson, M L; Heinemann, U

    2011-09-29

    It has been suggested that gap junctions are involved in the synchronization during high frequency oscillations as observed during sharp wave-ripple complexes (SPW-Rs) and during recurrent epileptiform discharges (REDs). Ripple oscillations during SPW-Rs, possibly involved in memory replay and memory consolidation, reach frequencies of up to 200 Hz while ripple oscillations during REDs display frequencies up to 500 Hz. These fast oscillations may be synchronized by intercellular interactions through gap junctions. In area CA3, connexin 36 (Cx36) proteins are present and potentially sensitive to mefloquine. Here, we used hippocampal slices of adult rats to investigate the effects of mefloquine, which blocks Cx36, Cx43 and Cx50 gap junctions on both SPW-Rs and REDs. SPW-Rs were induced by high frequency stimulation in the CA3 region while REDs were recorded in the presence of the GABA(A) receptor blocker bicuculline (5 μM). Both, SPW-Rs and REDs were blocked by the gap junction blocker carbenoxolone. Mefloquine (50 μM), which did not affect stimulus-induced responses in area CA3, neither changed SPW-Rs nor superimposed ripple oscillations. During REDs, 25 and 50 μM mefloquine exerted only minor effects on the expression of REDs but significantly reduced the amplitude of superimposed ripples by ∼17 and ∼54%, respectively. Intracellular recordings of CA3 pyramidal cells revealed that mefloquine did not change their resting membrane potential and input resistance but significantly increased the afterhyperpolarization following evoked action potentials (APs) resulting in reduced probability of AP firing during depolarizing current injection. Similarly, mefloquine caused a reduction in AP generation during REDs. Together, our data suggest that mefloquine depressed RED-related ripple oscillations by reducing high frequency discharges and not necessarily by blocking electrical coupling.

  10. Adult Hippocampal Neurogenesis, Aging and Neurodegenerative Diseases: Possible Strategies to Prevent Cognitive Impairment.

    PubMed

    Vivar, Carmen

    2015-01-01

    The adult brain of humans and other mammals continuously generates new neurons throughout life. However, this neurogenic capacity is limited to two brain areas, the dentate gyrus (DG of the hippocampus and the subventricular zone (SVZ of the lateral ventricle. Although the DG generates new neurons, its neurogenic capacity declines with age and neurodegenerative diseases such as Alzheimer's disease (AD and Huntington's disease (HD. This review focuses on the role of newly-born neurons in cognitive processes, and discusses some of the strategies proposed in humans and animals to enhance neurogenesis and counteract age-related cognitive deficits, such as physical exercise and intake of natural products like omega-3 fatty acids, curcumin and flavanols.

  11. Is silence golden? Effects of auditory stimuli and their absence on adult hippocampal neurogenesis.

    PubMed

    Kirste, Imke; Nicola, Zeina; Kronenberg, Golo; Walker, Tara L; Liu, Robert C; Kempermann, Gerd

    2015-03-01

    We have previously hypothesized that the reason why physical activity increases precursor cell proliferation in adult neurogenesis is that movement serves as non-specific signal to evoke the alertness required to meet cognitive demands. Thereby a pool of immature neurons is generated that are potentially recruitable by subsequent cognitive stimuli. Along these lines, we here tested whether auditory stimuli might exert a similar non-specific effect on adult neurogenesis in mice. We used the standard noise level in the animal facility as baseline and compared this condition to white noise, pup calls, and silence. In addition, as patterned auditory stimulus without ethological relevance to mice we used piano music by Mozart (KV 448). All stimuli were transposed to the frequency range of C57BL/6 and hearing was objectified with acoustic evoked potentials. We found that except for white noise all stimuli, including silence, increased precursor cell proliferation (assessed 24 h after labeling with bromodeoxyuridine, BrdU). This could be explained by significant increases in BrdU-labeled Sox2-positive cells (type-1/2a). But after 7 days, only silence remained associated with increased numbers of BrdU-labeled cells. Compared to controls at this stage, exposure to silence had generated significantly increased numbers of BrdU/NeuN-labeled neurons. Our results indicate that the unnatural absence of auditory input as well as spectrotemporally rich albeit ethological irrelevant stimuli activate precursor cells-in the case of silence also leading to greater numbers of newborn immature neurons-whereas ambient and unstructured background auditory stimuli do not.

  12. Adult Olfactory Bulb Interneuron Phenotypes Identified by Targeting Embryonic and Postnatal Neural Progenitors

    PubMed Central

    Figueres-Oñate, Maria; López-Mascaraque, Laura

    2016-01-01

    Neurons are generated during embryonic development and in adulthood, although adult neurogenesis is restricted to two main brain regions, the hippocampus and olfactory bulb. The subventricular zone (SVZ) of the lateral ventricles generates neural stem/progenitor cells that continually provide the olfactory bulb (OB) with new granule or periglomerular neurons, cells that arrive from the SVZ via the rostral migratory stream. The continued neurogenesis and the adequate integration of these newly generated interneurons is essential to maintain homeostasis in the olfactory bulb, where the differentiation of these cells into specific neural cell types is strongly influenced by temporal cues. Therefore, identifying the critical features that control the generation of adult OB interneurons at either pre- or post-natal stages is important to understand the dynamic contribution of neural stem cells. Here, we used in utero and neonatal SVZ electroporation along with a transposase-mediated stable integration plasmid, in order to track interneurons and glial lineages in the OB. These plasmids are valuable tools to study the development of OB interneurons from embryonic and post-natal SVZ progenitors. Accordingly, we examined the location and identity of the adult progeny of embryonic and post-natally transfected progenitors by examining neurochemical markers in the adult OB. These data reveal the different cell types in the olfactory bulb that are generated in function of age and different electroporation conditions. PMID:27242400

  13. Neural processing during older adults' comprehension of spoken sentences: age differences in resource allocation and connectivity.

    PubMed

    Peelle, Jonathan E; Troiani, Vanessa; Wingfield, Arthur; Grossman, Murray

    2010-04-01

    Speech comprehension remains largely preserved in older adults despite significant age-related neurophysiological change. However, older adults' performance declines more rapidly than that of young adults when listening conditions are challenging. We investigated the cortical network underlying speech comprehension in healthy aging using short sentences differing in syntactic complexity, with processing demands further manipulated through speech rate. Neural activity was monitored using blood oxygen level-dependent functional magnetic resonance imaging. Comprehension of syntactically complex sentences activated components of a core sentence-processing network in both young and older adults, including the left inferior and middle frontal gyri, left inferior parietal cortex, and left middle temporal gyrus. However, older adults showed reduced recruitment of inferior frontal regions relative to young adults; the individual degree of recruitment predicted accuracy at the more difficult fast speech rate. Older adults also showed increased activity in frontal regions outside the core sentence-processing network, which may have played a compensatory role. Finally, a functional connectivity analysis demonstrated reduced coherence between activated regions in older adults. We conclude that decreased activation of specialized processing regions, and limited ability to coordinate activity between regions, contribute to older adults' difficulty with sentence comprehension under difficult listening conditions.

  14. Stimulation of dendrogenesis and neural maturation in adult mammals.

    PubMed

    Soto-Vázquez, Ramón; Labastida-López, Carlos; Romero-Castello, Samuel; Benítez-King, Gloria; Parra-Cervantes, Patricia

    2016-05-01

    This work is the result of a technical research patent on dendritogenesis and neuronal maturation, in which the existence was determined of patent documents involving the use of melatonin for the treatment of anxiety, obesity and related diseases of the peripheral and CNS. In this study, an analysis of the state of the art in order to collect technical and scientific elements for the drafting of a new patent on the use of the melatonin molecule in stimulating neuronal maturation in dendritogenesis and mammals was conducted in adults. This study is based on an invention related with this novel use of melatonin.

  15. The Neuropsychiatric Disease-Associated Gene cacna1c Mediates Survival of Young Hippocampal Neurons123

    PubMed Central

    Lee, Anni S.; Kabir, Zeeba D.; Knobbe, Whitney; Orr, Madeline; Burgdorf, Caitlin; Huntington, Paula; McDaniel, Latisha; Britt, Jeremiah K.; Hoffmann, Franz; Brat, Daniel J.; Rajadhyaksha, Anjali M.

    2016-01-01

    Genetic variations in CACNA1C, which encodes the Cav1.2 subunit of L-type calcium channels (LTCCs), are associated with multiple forms of neuropsychiatric disease that manifest high anxiety in patients. In parallel, mice harboring forebrain-specific conditional knockout of cacna1c (forebrain-Cav1.2 cKO) display unusually high anxiety-like behavior. LTCCs in general, including the Cav1.3 subunit, have been shown to mediate differentiation of neural precursor cells (NPCs). However, it has not previously been determined whether Cav1.2 affects postnatal hippocampal neurogenesis in vivo. Here, we show that forebrain-Cav1.2 cKO mice exhibit enhanced cell death of young hippocampal neurons, with no change in NPC proliferation, hippocampal size, dentate gyrus thickness, or corticosterone levels compared with wild-type littermates. These mice also exhibit deficits in brain levels of brain-derived neurotrophic factor (BDNF), and Cre recombinase-mediated knockdown of adult hippocampal Cav1.2 recapitulates the deficit in young hippocampal neurons survival. Treatment of forebrain-Cav1.2 cKO mice with the neuroprotective agent P7C3-A20 restored the net magnitude of postnatal hippocampal neurogenesis to wild-type levels without ameliorating their deficit in BDNF expression. The role of Cav1.2 in young hippocampal neurons survival may provide new approaches for understanding and treating neuropsychiatric disease associated with aberrations in CACNA1C. Visual Abstract PMID:27066530

  16. The Neuropsychiatric Disease-Associated Gene cacna1c Mediates Survival of Young Hippocampal Neurons.

    PubMed

    Lee, Anni S; De Jesús-Cortés, Héctor; Kabir, Zeeba D; Knobbe, Whitney; Orr, Madeline; Burgdorf, Caitlin; Huntington, Paula; McDaniel, Latisha; Britt, Jeremiah K; Hoffmann, Franz; Brat, Daniel J; Rajadhyaksha, Anjali M; Pieper, Andrew A

    2016-01-01

    Genetic variations in CACNA1C, which encodes the Cav1.2 subunit of L-type calcium channels (LTCCs), are associated with multiple forms of neuropsychiatric disease that manifest high anxiety in patients. In parallel, mice harboring forebrain-specific conditional knockout of cacna1c (forebrain-Cav1.2 cKO) display unusually high anxiety-like behavior. LTCCs in general, including the Cav1.3 subunit, have been shown to mediate differentiation of neural precursor cells (NPCs). However, it has not previously been determined whether Cav1.2 affects postnatal hippocampal neurogenesis in vivo. Here, we show that forebrain-Cav1.2 cKO mice exhibit enhanced cell death of young hippocampal neurons, with no change in NPC proliferation, hippocampal size, dentate gyrus thickness, or corticosterone levels compared with wild-type littermates. These mice also exhibit deficits in brain levels of brain-derived neurotrophic factor (BDNF), and Cre recombinase-mediated knockdown of adult hippocampal Cav1.2 recapitulates the deficit in young hippocampal neurons survival. Treatment of forebrain-Cav1.2 cKO mice with the neuroprotective agent P7C3-A20 restored the net magnitude of postnatal hippocampal neurogenesis to wild-type levels without ameliorating their deficit in BDNF expression. The role of Cav1.2 in young hippocampal neurons survival may provide new approaches for understanding and treating neuropsychiatric disease associated with aberrations in CACNA1C. Visual Abstract.

  17. Effects of chronic oestradiol, progesterone and medroxyprogesterone acetate on hippocampal neurogenesis and adrenal mass in adult female rats.

    PubMed

    Chan, M; Chow, C; Hamson, D K; Lieblich, S E; Galea, L A M

    2014-06-01

    Both natural oestrogens and progesterone influence synaptic plasticity and neurogenesis within the female hippocampus. However, less is known of the impact of synthetic hormones on hippocampal structure and function. There is some evidence that the administration of the synthetic progestin, medroxyprogesterone acetate (MPA) is not as beneficial as natural progesterone and can attenuate oestrogen-induced neuroprotection. Although the effects of oestradiol have been well studied, little is known about the effects of natural and synthetic progestins alone and in combination with oestradiol on adult neurogenesis in females. In the present study, we investigated the effects of chronic oestradiol, progesterone, MPA and the co-administration of each progestin with oestradiol on neurogenesis within the dentate gyrus of adult ovariectomised female rats. Twenty-four hours after a bromodeoxyuridine (BrdU; 200 mg/kg) injection, female rats were repeatedly administered either progesterone (1 or 4 mg), MPA (1 or 4 mg), oestradiol benzoate (EB), progesterone or MPA in combination with EB (10 μg), or vehicle for 21 days. Rats were perfused on day 22 and brain tissue was analysed for the number of BrdU-labelled and Ki67 (an endogenous marker of cell proliferation)-expressing cells. EB alone and MPA + EB significantly decreased neurogenesis and the number of surviving BrdU-labelled cells in the dorsal region of the dentate gyrus, independent of any effects on cell proliferation. Furthermore, MPA (1 and 4 mg) and MPA + EB treated animals had significantly lower adrenal/body mass ratios and reduced serum corticosterone (CORT) levels. By contrast, progesterone + EB treated animals had significantly higher adrenal/body mass ratios and 1 mg of progesterone, progesterone + EB, and EB significantly increased CORT levels. The results of the present study demonstrate that different progestins alone and in combination with oestradiol can differentially affect neurogenesis (via cell survival

  18. Impaired adult hippocampal neurogenesis and cognitive ability in a mouse model of intrastriatal hemorrhage.

    PubMed

    Yang, Yuan; Zhang, Meikui; Kang, Xiaoni; Jiang, Chen; Zhang, Huan; Wang, Pei; Li, Jingjing

    2015-07-10

    Thrombin released by hematoma is an important mediator of the secondary injury of intracerebral hemorrhage (ICH), however, the effect of thrombin on adult neurogenesis and cognitive ability remains elusive. In this study, intrastriatal injection of 0.05 U thrombin didn't affect the neurogenesis at the subgranular zone (SGZ), which was distal to the injection site. 0.1 U thrombin increased the 5-bromo-2-deoxyuridine(+) (BrdU(+), S-phase proliferating cells)/doublecortin(+) (DCX(+), immature neurons) double labelled neurons, but decreased BrdU(+)/NeuN(+) double labelled mature neurons. Higher doses of thrombin (1 U, 2 U, and 5 U) significantly decreased the BrdU(+)/DCX(+) and BrdU(+)/NeuN(+) double labelled cells. After 1 U thrombin injection, cell apoptosis was found at the dentate gyrus of hippocampus at 3-24 h, but not 5 d post-injury. Thrombin infusion (1 U) induced spatial memory deficits in Morris water maze test; whereas, hirudin, the thrombin antagonist, significantly reversed both neurogenesis loss and spatial learning and memory impairment. In conclusion, at least at short term (5 days) after striatum ICH, the effect of high dose of thrombin on neurogenesis of SGZ, and the spatial learning and memory ability, is detrimental.

  19. Mouse genetic differences in voluntary wheel running, adult hippocampal neurogenesis and learning on the multi-strain-adapted plus water maze

    PubMed Central

    Merritt, Jennifer; Rhodes, Justin S.

    2014-01-01

    Moderate levels of aerobic exercise broadly enhance cognition throughout the lifespan. One hypothesized contributing mechanism is increased adult hippocampal neurogenesis. Recently, we measured the effects of voluntary wheel running on adult hippocampal neurogenesis in 12 different mouse strains, and found increased neurogenesis in all strains, ranging from 2 to 5 fold depending on the strain. The purpose of this study was to determine the extent to which increased neurogenesis from wheel running is associated with enhanced performance on the water maze for 5 of the 12 strains, chosen based on their levels of neurogenesis observed in the previous study (C57BL/6J, 129S1/SvImJ, B6129SF1/J, DBA/2J, and B6D2F1/J). Mice were housed with or without a running wheels for 30 days then tested for learning and memory on the plus water maze, adapted for multiple strains, and rotarod test of motor performance. The first 10 days, animals were injected with BrdU to label dividing cells. After behavioral testing animals were euthanized to measure adult hippocampal neurogenesis using standard methods. Levels of neurogenesis depended on strain but all mice had a similar increase in neurogenesis in response to exercise. All mice acquired the water maze but performance depended on strain. Exercise improved water maze performance in all strains to a similar degree. Rotarod performance depended on strain. Exercise improved rotarod performance only in DBA/2J and B6D2F1/J mice. Taken together, results demonstrate that despite different levels of neurogenesis, memory performance and motor coordination in these mouse strains, all strains have the capacity to increase neurogenesis and improve learning on the water maze through voluntary wheel running. PMID:25435316

  20. Mouse genetic differences in voluntary wheel running, adult hippocampal neurogenesis and learning on the multi-strain-adapted plus water maze.

    PubMed

    Merritt, Jennifer R; Rhodes, Justin S

    2015-03-01

    Moderate levels of aerobic exercise broadly enhance cognition throughout the lifespan. One hypothesized contributing mechanism is increased adult hippocampal neurogenesis. Recently, we measured the effects of voluntary wheel running on adult hippocampal neurogenesis in 12 different mouse strains, and found increased neurogenesis in all strains, ranging from 2- to 5-fold depending on the strain. The purpose of this study was to determine the extent to which increased neurogenesis from wheel running is associated with enhanced performance on the water maze for 5 of the 12 strains, chosen based on their levels of neurogenesis observed in the previous study (C57BL/6 J, 129S1/SvImJ, B6129SF1/J, DBA/2 J, and B6D2F1/J). Mice were housed with or without a running wheels for 30 days then tested for learning and memory on the plus water maze, adapted for multiple strains, and rotarod test of motor performance. The first 10 days, animals were injected with BrdU to label dividing cells. After behavioral testing animals were euthanized to measure adult hippocampal neurogenesis using standard methods. Levels of neurogenesis depended on strain but all mice had a similar increase in neurogenesis in response to exercise. All mice acquired the water maze but performance depended on strain. Exercise improved water maze performance in all strains to a similar degree. Rotarod performance depended on strain. Exercise improved rotarod performance only in DBA/2 J and B6D2F1/J mice. Taken together, results demonstrate that despite different levels of neurogenesis, memory performance and motor coordination in these mouse strains, all strains have the capacity to increase neurogenesis and improve learning on the water maze through voluntary wheel running.

  1. Adult retinal pigment epithelium cells express neural progenitor properties and the neuronal precursor protein doublecortin.

    PubMed

    Engelhardt, Maren; Bogdahn, Ulrich; Aigner, Ludwig

    2005-04-08

    The adult mammalian retina is devoid of any detectable neurogenesis. However, different cell types have been suggested to potentially act as neural progenitors in the adult mammalian retina in vitro, such as ciliary body (CB), Muller glia, and retinal pigment epithelium (RPE) cells. In rodents and humans, strong evidence for neural stem or progenitor properties exists only for CB-derived cells, but not for other retinal cell types. Here, we provide a comparative analysis of adult rat CB- and RPE-derived cells suggesting that the two cell types share certain neural progenitor properties in vitro. CB and RPE cells expressed neural progenitor markers such as Nestin, Flk-1, Hes1, and Musashi. They proliferated under adherent and neurosphere conditions and showed limited self-renewal. Moreover, they differentiated into neuronal and glial cells based on the expression of differentiation markers such as the young neuronal marker beta-III tubulin and the glial and progenitor markers GFAP and NG2. Expression of beta-III tubulin was found in cells with neuronal and non-neuronal morphology. A subpopulation of RPE- and CB-derived progenitor cells expressed the neurogenesis-specific protein doublecortin (DCX). Interestingly, DCX expression defined a beta-III tubulin-positive CB and RPE fraction with a distinct neuronal morphology. In summary, the data suggest that RPE cells share with CB cells the potential to de-differentiate into a cell type with neural progenitor-like identity. In addition, DCX expression might define the neuronal-differentiating RPE- and CB-derived progenitor population.

  2. 12-Deoxyphorbols Promote Adult Neurogenesis by Inducing Neural Progenitor Cell Proliferation via PKC Activation

    PubMed Central

    Geribaldi-Doldán, Noelia; Flores-Giubi, Eugenia; Murillo-Carretero, Maribel; García-Bernal, Francisco; Carrasco, Manuel; Macías-Sánchez, Antonio J.; Domínguez-Riscart, Jesús; Verástegui, Cristina; Hernández-Galán, Rosario

    2016-01-01

    Background: Neuropsychiatric and neurological disorders frequently occur after brain insults associated with neuronal loss. Strategies aimed to facilitate neuronal renewal by promoting neurogenesis constitute a promising therapeutic option to treat neuronal death-associated disorders. In the adult brain, generation of new neurons occurs physiologically throughout the entire life controlled by extracellular molecules coupled to intracellular signaling cascades. Proteins participating in these cascades within neurogenic regions constitute potential pharmacological targets to promote neuronal regeneration of injured areas of the central nervous system. Methodology: We have performed in vitro and in vivo approaches to determine neural progenitor cell proliferation to understand whether activation of kinases of the protein kinase C family facilitates neurogenesis in the adult brain. Results: We have demonstrated that protein kinase C activation by phorbol-12-myristate-13-acetate induces neural progenitor cell proliferation in vitro. We also show that the nontumorogenic protein kinase C activator prostratin exerts a proliferative effect on neural progenitor cells in vitro. This effect can be reverted by addition of the protein kinase C inhibitor G06850, demonstrating that the effect of prostratin is mediated by protein kinase C activation. Additionally, we show that prostratin treatment in vivo induces proliferation of neural progenitor cells within the dentate gyrus of the hippocampus and the subventricular zone. Finally, we describe a library of diterpenes with a 12-deoxyphorbol structure similar to that of prostratin that induces a stronger effect than prostratin on neural progenitor cell proliferation both in vitro and in vivo. Conclusions: This work suggests that protein kinase C activation is a promising strategy to expand the endogenous neural progenitor cell population to promote neurogenesis and highlights the potential of 12-deoxyphorbols as pharmaceutical

  3. Olfactory and cortical projections to bulbar and hippocampal adult-born neurons

    PubMed Central

    De La Rosa-Prieto, Carlos; De Moya-Pinilla, Miguel; Saiz-Sanchez, Daniel; Ubeda-banon, Isabel; Arzate, Dulce M.; Flores-Cuadrado, Alicia; Liberia, Teresa; Crespo, Carlos; Martinez-Marcos, Alino

    2015-01-01

    New neurons are continually generated in the subependymal layer of the lateral ventricles and the subgranular zone of dentate gyrus during adulthood. In the subventricular zone, neuroblasts migrate a long distance to the olfactory bulb where they differentiate into granule or periglomerular interneurons. In the hippocampus, neuroblasts migrate a short distance from the subgranular zone to the granule cell layer of the dentate gyrus to become granule neurons. In addition to the short-distance inputs, bulbar interneurons receive long-distance centrifugal afferents from olfactory-recipient structures. Similarly, dentate granule cells receive differential inputs from the medial and lateral entorhinal cortices through the perforant pathway. Little is known concerning these new inputs on the adult-born cells. In this work, we have characterized afferent inputs to 21-day old newly-born neurons. Mice were intraperitoneally injected with bromodeoxyuridine. Two weeks later, rhodamine-labeled dextran-amine was injected into the anterior olfactory nucleus, olfactory tubercle, piriform cortex and lateral and medial entorhinal cortices. One week later, animals were perfused and immunofluorescences were carried out. The data show that projection neurons from the mentioned structures, establish putative synaptic contacts onto 21-day-old neurons in the olfactory bulb and dentate gyrus, in some cases even before they start to express specific subpopulation proteins. Long-distance afferents reach middle and outer one-third portions of the molecular layer of the dentate gyrus and granule and, interestingly, periglomerular layers of the olfactory bulb. In the olfactory bulb, these fibers appear to establish presumptive axo-somatic contacts onto newly-born granule and periglomerular cells. PMID:25698936

  4. Impaired contextual fear extinction and hippocampal synaptic plasticity in adult rats induced by prenatal morphine exposure.

    PubMed

    Tan, Ji-Wei; Duan, Ting-Ting; Zhou, Qi-Xin; Ding, Ze-Yang; Jing, Liang; Cao, Jun; Wang, Li-Ping; Mao, Rong-Rong; Xu, Lin

    2015-07-01

    Prenatal opiate exposure causes a series of neurobehavioral disturbances by affecting brain development. However, the question of whether prenatal opiate exposure increases vulnerability to memory-related neuropsychiatric disorders in adult offspring remains largely unknown. Here, we found that rats prenatally exposed to morphine (PM) showed impaired acquisition but enhanced maintenance of contextual fear memory compared with control animals that were prenatally exposed to saline (PS). The impairment of acquisition was rescued by increasing the intensity of footshocks (1.2 mA rather than 0.8 mA). Meanwhile, we also found that PM rats exhibited impaired extinction of contextual fear, which is associated with enhanced maintenance of fear memory. The impaired extinction lasted for 1 week following extinction training. Furthermore, PM rats exhibited reduced anxiety-like behavior in the elevated plus-maze and light/dark box test without differences in locomotor activity. These alterations in PM rats were mirrored by abnormalities in synaptic plasticity in the Schaffer collateral-CA1 synapses of the hippocampus in vivo. PS rats showed blocked long-term potentiation and enabled long-term depression in CA1 synapses following contextual fear conditioning, while prenatal morphine exposure restricted synaptic plasticity in CA1 synapses. The smaller long-term potentiation in PM rats was not further blocked by contextual fear conditioning, and the long-term depression enabled by contextual fear conditioning was abolished. Taken together, our results provide the first evidence suggesting that prenatal morphine exposure may increase vulnerability to fear memory-related neuropsychiatric disorders in adulthood.

  5. Neural-competent cells of adult human dermis belong to the Schwann lineage.

    PubMed

    Etxaniz, Usue; Pérez-San Vicente, Adrián; Gago-López, Nuria; García-Dominguez, Mario; Iribar, Haizea; Aduriz, Ariane; Pérez-López, Virginia; Burgoa, Izaskun; Irizar, Haritz; Muñoz-Culla, Maider; Vallejo-Illarramendi, Ainara; Leis, Olatz; Matheu, Ander; Martín, Angel G; Otaegui, David; López-Mato, María Paz; Gutiérrez-Rivera, Araika; MacLellan, Robb; Izeta, Ander

    2014-11-11

    Resident neural precursor cells (NPCs) have been reported for a number of adult tissues. Understanding their physiological function or, alternatively, their activation after tissue damage or in vitro manipulation remains an unsolved issue. Here, we investigated the source of human dermal NPCs in adult tissue. By following an unbiased, comprehensive approach employing cell-surface marker screening, cell separation, transcriptomic characterization, and in vivo fate analyses, we found that p75NTR(+) precursors of human foreskin can be ascribed to the Schwann (CD56(+)) and perivascular (CD56(-)) cell lineages. Moreover, neural differentiation potential was restricted to the p75NTR(+)CD56(+) Schwann cells and mediated by SOX2 expression levels. Double-positive NPCs were similarly obtained from human cardiospheres, indicating that this phenomenon might be widespread.

  6. Neural-Competent Cells of Adult Human Dermis Belong to the Schwann Lineage

    PubMed Central

    Etxaniz, Usue; Pérez-San Vicente, Adrián; Gago-López, Nuria; García-Dominguez, Mario; Iribar, Haizea; Aduriz, Ariane; Pérez-López, Virginia; Burgoa, Izaskun; Irizar, Haritz; Muñoz-Culla, Maider; Vallejo-Illarramendi, Ainara; Leis, Olatz; Matheu, Ander; Martín, Angel G.; Otaegui, David; López-Mato, María Paz; Gutiérrez-Rivera, Araika; MacLellan, Robb; Izeta, Ander

    2014-01-01

    Summary Resident neural precursor cells (NPCs) have been reported for a number of adult tissues. Understanding their physiological function or, alternatively, their activation after tissue damage or in vitro manipulation remains an unsolved issue. Here, we investigated the source of human dermal NPCs in adult tissue. By following an unbiased, comprehensive approach employing cell-surface marker screening, cell separation, transcriptomic characterization, and in vivo fate analyses, we found that p75NTR+ precursors of human foreskin can be ascribed to the Schwann (CD56+) and perivascular (CD56−) cell lineages. Moreover, neural differentiation potential was restricted to the p75NTR+CD56+ Schwann cells and mediated by SOX2 expression levels. Double-positive NPCs were similarly obtained from human cardiospheres, indicating that this phenomenon might be widespread. PMID:25418723

  7. Phase matters: responding to and learning about peripheral stimuli depends on hippocampal θ phase at stimulus onset.

    PubMed

    Nokia, Miriam S; Waselius, Tomi; Mikkonen, Jarno E; Wikgren, Jan; Penttonen, Markku

    2015-06-01

    Hippocampal θ (3-12 Hz) oscillations are implicated in learning and memory, but their functional role remains unclear. We studied the effect of the phase of local θ oscillation on hippocampal responses to a neutral conditioned stimulus (CS) and subsequent learning of classical trace eyeblink conditioning in adult rabbits. High-amplitude, regular hippocampal θ-band responses (that predict good learning) were elicited by the CS when it was timed to commence at the fissure θ trough (Trough group). Regardless, learning in this group was not enhanced compared with a yoked control group, possibly due to a ceiling effect. However, when the CS was consistently presented to the peak of θ (Peak group), hippocampal θ-band responding was less organized and learning was retarded. In well-trained animals, the hippocampal θ phase at CS onset no longer affected performance of the learned response, suggesting a time-limited role for hippocampal processing in learning. To our knowledge, this is the first study to demonstrate that timing a peripheral stimulus to a specific phase of the hippocampal θ cycle produces robust effects on the synchronization of neural responses and affects learning at the behavioral level. Our results support the notion that the phase of spontaneous hippocampal θ oscillation is a means of regulating the processing of information in the brain to a behaviorally relevant degree.

  8. Anomaly in neural phase coherence accompanies reduced sensorimotor integration in adults who stutter.

    PubMed

    Sengupta, Ranit; Shah, Shalin; Gore, Katie; Loucks, Torrey; Nasir, Sazzad M

    2016-12-01

    Despite advances in our understanding of the human speech system, the neurophysiological basis of stuttering remains largely unknown. Here, it is hypothesized that the speech of adults who stutter (AWS) is susceptible to disruptions in sensorimotor integration caused by neural miscommunication within the speech motor system. Human speech unfolds over rapid timescales and relies on a distributed system of brain regions working in a parallel and synchronized manner, and a breakdown in neural communication between the putative brain regions could increase susceptibility to dysfluency. Using a speech motor adaptation paradigm under altered auditory feedback with simultaneous recording of EEG, the oscillatory cortical dynamics was investigated in stuttering and fluent adults (FA). Auditory feedback perturbation involved the shifting of the formant frequencies of the target vowel sound. Reduced adaptation in response to the feedback error was observed in AWS and was accompanied by differences in EEG spectral powers and anomalies in phase coherence evolving over the course of speech motor training. It is understood that phase coherence possibly captures neural communication within speech motor networks. Thus, the phase coherence network of the two groups exhibited differences involving the EEG frequency bands. These findings in anomalous neural synchrony provide novel evidence for compromised neuronal communication at short time scales within the speech motor network of AWS.

  9. Isolation of neural crest derived chromaffin progenitors from adult adrenal medulla.

    PubMed

    Chung, Kuei-Fang; Sicard, Flavie; Vukicevic, Vladimir; Hermann, Andreas; Storch, Alexander; Huttner, Wieland B; Bornstein, Stefan R; Ehrhart-Bornstein, Monika

    2009-10-01

    Chromaffin cells of the adrenal medulla are neural crest-derived cells of the sympathoadrenal lineage. Unlike the closely-related sympathetic neurons, a subpopulation of proliferation-competent cells exists even in the adult. Here, we describe the isolation, expansion, and in vitro characterization of proliferation-competent progenitor cells from the bovine adrenal medulla. Similar to neurospheres, these cells, when prevented from adherence to the culture dish, grew in spheres, which we named chromospheres. These chromospheres were devoid of mRNA specific for smooth muscle cells (MYH11) or endothelial cells (PECAM1). During sphere formation, markers for differentiated chromaffin cells, such as phenylethanolamine-N-methyl transferase, were downregulated while neural progenitor markers nestin, vimentin, musashi 1, and nerve growth factor receptor, as well as markers of neural crest progenitor cells such as Sox1 and Sox9, were upregulated. Clonal analysis and bromo-2'-deoxyuridine-incorporation analysis demonstrated the self-renewing capacity of chromosphere cells. Differentiation protocols using NGF and BMP4 or dexamethasone induced neuronal or endocrine differentiation, respectively. Electrophysiological analyses of neural cells derived from chromospheres revealed functional properties of mature nerve cells, such as tetrodotoxin-sensitive sodium channels and action potentials. Our study provides evidence that proliferation and differentiation competent chromaffin progenitor cells can be isolated from adult adrenal medulla and that these cells might harbor the potential for the treatment of neurodegenerative diseases, such as Parkinson's disease.

  10. Effects of addictive drugs on adult neural stem/progenitor cells

    PubMed Central

    Xu, Chi; Loh, Horace H.; Law, Ping-Yee

    2015-01-01

    Neural stem/progenitor cells (NSPCs) undergo a series of developmental processes before giving rise to newborn neurons, astrocytes and oligodendrocytes in adult neurogenesis. During the past decade, the role of NSPCs has been highlighted by studies on adult neurogenesis modulated by addictive drugs. It has been proven that these drugs regulate the proliferation, differentiation and survival of adult NSPCs in different manners, which results in the varying consequences of adult neurogenesis. The effects of addictive drugs on NSPCs are exerted via a variety of different mechanisms and pathways, which interact with one another and contribute to the complexity of NSPC regulation. Here, we review the effects of different addictive drugs on NSPCs, and the related experimental methods and paradigms. We also discuss the current understanding of major signaling molecules, especially the putative common mechanisms, underlying such effects. Finally, we review the future directions of research in this area. PMID:26468052

  11. Induction of c-fos mRNA expression in an in vitro hippocampal slice model of adult rats after kainate but not gamma-aminobutyric acid or bicuculline treatment.

    PubMed

    Massamiri, T; Khrestchatisky, M; Ben-Ari, Y

    1994-01-17

    Levels of gene expression following in vitro treatment of rat hippocampal slices with kainate, gamma-aminobutyric acid (GABA), or bicuculline were measured by the reverse transcription-coupled polymerase chain reaction method. Following a short-term exposure to kainate, c-fos gene expression was induced by 12-fold in the adult, but not the newborn, hippocampus. Under the same experimental conditions, zifl268 and brain-derived neurotrophic factor (BDNF) gene expression were unchanged. Our results also demonstrate a lack of induction of c-fos, zifl268 and BDNF after short-time treatment of either adult or newborn hippocampal slices with GABA or bicuculline. The relevance of the differential induction of gene expression in the adult and newborn in an in vitro hippocampal slice model as compared to previously described in vivo models is discussed.

  12. Radial glia and neural progenitors in the adult zebrafish central nervous system.

    PubMed

    Than-Trong, Emmanuel; Bally-Cuif, Laure

    2015-08-01

    The adult central nervous system (CNS) of the zebrafish, owing to its enrichment in constitutive neurogenic niches, is becoming an increasingly used model to address fundamental questions pertaining to adult neural stem cell (NSC) biology, adult neurogenesis and neuronal repair. Studies conducted in several CNS territories (notably the telencephalon, retina, midbrain, cerebellum and spinal cord) highlighted the presence, in these niches, of progenitor cells displaying NSC-like characters. While pointing to radial glial cells (RG) as major long-lasting, constitutively active and/or activatable progenitors in most domains, these studies also revealed a high heterogeneity in the progenitor subtypes used at the top of neurogenic hierarchies, including the persistence of neuroepithelial (NE) progenitors in some areas. Likewise, dissecting the molecular pathways underlying RG maintenance and recruitment under physiological conditions and upon repair in the zebrafish model revealed shared processes but also specific cascades triggering or sustaining reparative NSC recruitment. Together, the zebrafish adult brain reveals an extensive complexity of adult NSC niches, properties and control pathways, which extends existing understanding of adult NSC biology and gives access to novel mechanisms of efficient NSC maintenance and recruitment in an adult vertebrate brain.

  13. c-jun is differentially expressed in embryonic and adult neural precursor cells.

    PubMed

    Kawashima, Fumiaki; Saito, Kengo; Kurata, Hirofumi; Maegaki, Yoshihiro; Mori, Tetsuji

    2017-01-16

    c-jun, a major component of AP-1 transcription factor, has a wide variety of functions. In the embryonic brain, c-jun mRNA is abundantly expressed in germinal layers around the ventricles. Although the subventricular zone (SVZ) of the adult brain is a derivative of embryonic germinal layers and contains neural precursor cells (NPCs), the c-jun expression pattern is not clear. To study the function of c-jun in adult neurogenesis, we analyzed c-jun expression in the adult SVZ by immunohistochemistry and compared it with that of the embryonic brain. We found that almost all proliferating embryonic NPCs expressed c-jun, but the number of c-jun immunopositive cells among proliferating adult NPCs was about half. In addition, c-jun was hardly expressed in post-mitotic migrating neurons in the embryonic brain, but the majority of c-jun immunopositive cells were tangentially migrating neuroblasts heading toward the olfactory bulb in the adult brain. In addition, status epilepticus is known to enhance the transient proliferation of adult NPCs, but the c-jun expression pattern was not significantly affected. These expression patterns suggest that c-jun has a pivotal role in the proliferation of embryonic NPCs, but it has also other roles in adult neurogenesis.

  14. Sex-dependent effects of early life inflammatory pain on sucrose intake and sucrose-associated hippocampal Arc expression in adult rats.

    PubMed

    Henderson, Yoko O; Nalloor, Rebecca; Vazdarjanova, Almira; Murphy, Anne Z; Parent, Marise B

    2017-05-01

    We hypothesize that dorsal hippocampal (dHC) neurons, which are critical for episodic memory, form a memory of a meal and inhibit the initiation of the next meal and the amount ingested during that meal. In support, we showed previously that (1) consuming a sucrose meal induces expression of the synaptic plasticity marker activity-regulated cytoskeleton-associated protein (Arc) in dHC neurons and (2) reversible inactivation of these neurons immediately following a sucrose meal accelerates the onset of the next meal and increases the size of that meal. These data suggest that hippocampal-dependent memory inhibits intake; therefore, the following experiments were conducted to determine whether hippocampal-dependent memory impairments are associated with increased intake. We reported recently that one episode of early life inflammatory pain impairs dHC-dependent memory in adult rats. The present study determined whether neonatal inflammatory pain also increases sucrose intake and attenuates sucrose-associated Arc expression. Male and female Sprague-Dawley rats were given an intraplantar injection of the inflammatory agent carrageenan (1%) on the day of birth and sucrose intake and sucrose-associated dHC Arc expression were measured in adulthood. Neonatal inflammatory pain increased sucrose intake in adult female and male rats, decreased sucrose-associated dHC Arc expression in female rats, and tended to have a similar effect on Arc expression in male rats. Neonatal inflammatory pain significantly decreased the interval between two sucrose meals in female but not in male rats. Morphine administration at the time of insult attenuated the effects of injury on sucrose intake. Collectively, these findings indicate that one brief episode of inflammatory pain on the day of birth has a long long-lasting, sex-dependent impact on intake of a palatable food in adulthood.

  15. Age effects on the regulation of adult hippocampal neurogenesis by physical activity and environmental enrichment in the APP23 mouse model of Alzheimer disease.

    PubMed

    Mirochnic, Sebastian; Wolf, Susanne; Staufenbiel, Matthias; Kempermann, Gerd

    2009-10-01

    An active lifestyle is to some degree protective against Alzheimer's disease (AD), but the biological basis for this benefit is still far from clear. We hypothesize that physical and cognitive activity increase a reserve for plasticity by increasing adult neurogenesis in the hippocampal dentate gyrus (DG). We thus assessed how age affects the response to activity in the murine APP23 model of AD compared with wild type (WT) controls and studied the effects of physical exercise (RUN) and environmental enrichment (ENR) in comparison with standard housing (CTR) at two different ages (6 months and 18 months) and in both genotypes. At 18 months, both activity paradigms reduced the hippocampal human Abeta1-42/Abeta1-40 ratio when compared with CTR, despite a stable plaque load in the hippocampus. At this age, both RUN and ENR increased the number of newborn granule cells in the DG of APP23 mice when compared with CTR, whereas the levels of regulation were equivalent to those in WT mice under the same housing conditions. At 6 months, however, neurogenesis in ENR but not RUN mice responded like the WT. Quantifying the number of cells at the doublecortin-positive stage in relation to the number of cells on postmitotic stages we found that ENR overproportionally increased the number of the DCX-positive "late" progenitor cells, indicative of an increased potential to recruit even more new neurons. In summary, the biological substrates for activity-dependent regulation of adult hippocampal neurogenesis were preserved in the APP23 mice. We thus propose that in this model, ENR even more than RUN might contribute to a "neurogenic reserve" despite a stable plaque load and that age affects the outcome of an interaction based on "activity."

  16. Augmenting saturated LTP by broadly spaced episodes of theta-burst stimulation in hippocampal area CA1 of adult rats and mice

    PubMed Central

    Cao, Guan

    2014-01-01

    Hippocampal long-term potentiation (LTP) is a model system for studying cellular mechanisms of learning and memory. Recent interest in mechanisms underlying the advantage of spaced over massed learning has prompted investigation into the effects of distributed episodes of LTP induction. The amount of LTP induced in hippocampal area CA1 by one train (1T) of theta-burst stimulation (TBS) in young Sprague-Dawley rats was further enhanced by additional bouts of 1T given at 1-h intervals. However, in young Long-Evans (LE) rats, 1T did not initially saturate LTP. Instead, a stronger LTP induction paradigm using eight trains of TBS (8T) induced saturated LTP in hippocampal slices from both young and adult LE rats as well as adult mice. The saturated LTP induced by 8T could be augmented by another episode of 8T following an interval of at least 90 min. The success rate across animals and slices in augmenting LTP by an additional episode of 8T increased significantly with longer intervals between the first and last episodes, ranging from 0% at 30- and 60-min intervals to 13–66% at 90- to 180-min intervals to 90–100% at 240-min intervals. Augmentation above initially saturated LTP was blocked by the N-methyl-d-aspartate (NMDA) glutamate receptor antagonist d-2-amino-5-phosphonovaleric acid (d-APV). These findings suggest that the strength of induction and interval between episodes of TBS, as well as the strain and age of the animal, are important components in the augmentation of LTP. PMID:25057146

  17. Quiescent adult neural stem cells are exceptionally sensitive to cosmic radiation

    PubMed Central

    Encinas, Juan M.; Vazquez, Marcelo E.; Switzer, Robert C.; Chamberland, Dennis W.; Nick, Harry; Levine, Howard G.; Scarpa, Philip J.; Enikolopov, Grigori; Steindler, Dennis A.

    2012-01-01

    Generation of new neurons in the adult brain, a process that is likely to be essential for learning, memory, and mood regulation, is impaired by radiation. Therefore, radiation exposure might have not only such previously expected consequences as increased probability of developing cancer, but might also impair cognitive function and emotional stability. Radiation exposure is encountered in settings ranging from cancer therapy to space travel; evaluating the neurogenic risks of radiation requires identifying the at-risk populations of stem and progenitor cells in the adult brain. Here we have used a novel reporter mouse line to find that early neural progenitors are selectively affected by conditions simulating the space radiation environment. This is reflected both in a decrease in the number of these progenitors in the neurogenic regions and in an increase in the number of dying cells in these regions. Unexpectedly, we found that quiescent neural stem cells, rather than their rapidly dividing progeny, are most sensitive to radiation. Since these stem cells are responsible for adult neurogenesis, their death would have a profound impact on the production of new neurons in the irradiated adult brain. Our finding raises an important concern about cognitive and emotional risks associated with radiation exposure. PMID:18076878

  18. Resting state neural networks for visual Chinese word processing in Chinese adults and children.

    PubMed

    Li, Ling; Liu, Jiangang; Chen, Feiyan; Feng, Lu; Li, Hong; Tian, Jie; Lee, Kang

    2013-07-01

    This study examined the resting state neural networks for visual Chinese word processing in Chinese children and adults. Both the functional connectivity (FC) and amplitude of low frequency fluctuation (ALFF) approaches were used to analyze the fMRI data collected when Chinese participants were not engaged in any specific explicit tasks. We correlated time series extracted from the visual word form area (VWFA) with those in other regions in the brain. We also performed ALFF analysis in the resting state FC networks. The FC results revealed that, regarding the functionally connected brain regions, there exist similar intrinsically organized resting state networks for visual Chinese word processing in adults and children, suggesting that such networks may already be functional after 3-4 years of informal exposure to reading plus 3-4 years formal schooling. The ALFF results revealed that children appear to recruit more neural resources than adults in generally reading-irrelevant brain regions. Differences between child and adult ALFF results suggest that children's intrinsic word processing network during the resting state, though similar in functional connectivity, is still undergoing development. Further exposure to visual words and experience with reading are needed for children to develop a mature intrinsic network for word processing. The developmental course of the intrinsically organized word processing network may parallel that of the explicit word processing network.

  19. Adult hippocampal neurogenesis along the dorsoventral axis contributes differentially to environmental enrichment combined with voluntary exercise in alleviating chronic inflammatory pain in mice.

    PubMed

    Zheng, Jie; Jiang, Ying-Ying; Xu, Ling-Chi; Ma, Long-Yu; Liu, Feng-Yu; Cui, Shuang; Cai, Jie; Liao, Fei-Fei; Wan, You; Yi, Ming

    2017-03-14

    Cognitive behavioral therapy, such as environmental enrichment combined with voluntary exercise (EE-VEx), is under active investigation as an adjunct to pharmaceutical treatment for chronic pain. However, the effectiveness and underlying mechanisms of EE-VEx remain unclear. In mice with intra-plantar injection of complete Freund's adjuvant (CFA), our results revealed that EE-VEx alleviated perceptual, affective and cognitive dimensions of chronic inflammatory pain. These effects of EE-VEx on chronic pain were contingent on the occurrence of adult neurogenesis in the dentate gyrus in a functionally dissociated manner along the dorsoventral axis: neurogenesis in the ventral dentate gyrus participated in alleviating perceptual and affective components of chronic pain by EE-VEx, whereas neurogenesis in the dorsal dentate gyrus was involved in EE-VEx's cognitive-enhancing effects. Chronic inflammatory pain was accompanied by decreased levels of brain-derived neurotrophic factor (BDNF) in the dentate gyrus, which were reversed by EE-VEx. Over-expression of BDNF in the dentate mimicked the effects of EE-VEx. Our results demonstrate distinct contribution of adult hippocampal neurogenesis along the dorsoventral axis to EE-VEx's beneficial effects on different dimensions of chronic pain.SIGNIFICANCE STATEMENTEnvironmental enrichment combined with voluntary exercise (EE-VEx) is under active investigation as an adjunct to pharmaceutical treatment for chronic pain, but its effectiveness and underlying mechanisms remain unclear. In a mouse model of inflammatory pain, the present study demonstrates that the beneficial effects of EE-VEx on chronic pain depend on adult neurogenesis with a dorsoventral dissociation along the hippocampal axis. Adult neurogenesis in the ventral dentate gyrus participates in alleviating perceptual and affective components of chronic pain by EE-VEx, whereas that in the dorsal pole is involved in EE-VEx's cognitive-enhancing effects in chronic pain.

  20. Mitochondria modify exercise-induced development of stem cell-derived neurons in the adult brain.

    PubMed

    Steib, Kathrin; Schäffner, Iris; Jagasia, Ravi; Ebert, Birgit; Lie, D Chichung

    2014-05-07

    Neural stem cells in the adult mammalian hippocampus continuously generate new functional neurons, which modify the hippocampal network and significantly contribute to cognitive processes and mood regulation. Here, we show that the development of new neurons from stem cells in adult mice is paralleled by extensive changes to mitochondrial mass, distribution, and shape. Moreover, exercise-a strong modifier of adult hippocampal neurogenesis-accelerates neuronal maturation and induces a profound increase in mitochondrial content and the presence of mitochondria in dendritic segments. Genetic inhibition of the activity of the mitochondrial fission factor dynamin-related protein 1 (Drp1) inhibits neurogenesis under basal and exercise conditions. Conversely, enhanced Drp1 activity furthers exercise-induced acceleration of neuronal maturation. Collectively, these results indicate that adult hippocampal neurogenesis requires adaptation of the mitochondrial compartment and suggest that mitochondria are targets for enhancing neurogenesis-dependent hippocampal plasticity.

  1. Catalog of gene expression in adult neural stem cells and their in vivo microenvironment

    SciTech Connect

    Williams, Cecilia; Wirta, Valtteri; Meletis, Konstantinos; Wikstroem, Lilian; Carlsson, Leif; Frisen, Jonas; Lundeberg, Joakim . E-mail: joakim.lundeberg@biotech.kth.se

    2006-06-10

    Stem cells generally reside in a stem cell microenvironment, where cues for self-renewal and differentiation are present. However, the genetic program underlying stem cell proliferation and multipotency is poorly understood. Transcriptome analysis of stem cells and their in vivo microenvironment is one way of uncovering the unique stemness properties and provides a framework for the elucidation of stem cell function. Here, we characterize the gene expression profile of the in vivo neural stem cell microenvironment in the lateral ventricle wall of adult mouse brain and of in vitro proliferating neural stem cells. We have also analyzed an Lhx2-expressing hematopoietic-stem-cell-like cell line in order to define the transcriptome of a well-characterized and pure cell population with stem cell characteristics. We report the generation, assembly and annotation of 50,792 high-quality 5'-end expressed sequence tag sequences. We further describe a shared expression of 1065 transcripts by all three stem cell libraries and a large overlap with previously published gene expression signatures for neural stem/progenitor cells and other multipotent stem cells. The sequences and cDNA clones obtained within this framework provide a comprehensive resource for the analysis of genes in adult stem cells that can accelerate future stem cell research.

  2. Hearing loss in older adults affects neural systems supporting speech comprehension.

    PubMed

    Peelle, Jonathan E; Troiani, Vanessa; Grossman, Murray; Wingfield, Arthur

    2011-08-31

    Hearing loss is one of the most common complaints in adults over the age of 60 and a major contributor to difficulties in speech comprehension. To examine the effects of hearing ability on the neural processes supporting spoken language processing in humans, we used functional magnetic resonance imaging to monitor brain activity while older adults with age-normal hearing listened to sentences that varied in their linguistic demands. Individual differences in hearing ability predicted the degree of language-driven neural recruitment during auditory sentence comprehension in bilateral superior temporal gyri (including primary auditory cortex), thalamus, and brainstem. In a second experiment, we examined the relationship of hearing ability to cortical structural integrity using voxel-based morphometry, demonstrating a significant linear relationship between hearing ability and gray matter volume in primary auditory cortex. Together, these results suggest that even moderate declines in peripheral auditory acuity lead to a systematic downregulation of neural activity during the processing of higher-level aspects of speech, and may also contribute to loss of gray matter volume in primary auditory cortex. More generally, these findings support a resource-allocation framework in which individual differences in sensory ability help define the degree to which brain regions are recruited in service of a particular task.

  3. Residual Neural Processing of Musical Sound Features in Adult Cochlear Implant Users

    PubMed Central

    Timm, Lydia; Vuust, Peter; Brattico, Elvira; Agrawal, Deepashri; Debener, Stefan; Büchner, Andreas; Dengler, Reinhard; Wittfoth, Matthias

    2014-01-01

    Auditory processing in general and music perception in particular are hampered in adult cochlear implant (CI) users. To examine the residual music perception skills and their underlying neural correlates in CI users implanted in adolescence or adulthood, we conducted an electrophysiological and behavioral study comparing adult CI users with normal-hearing age-matched controls (NH controls). We used a newly developed musical multi-feature paradigm, which makes it possible to test automatic auditory discrimination of six different types of sound feature changes inserted within a musical enriched setting lasting only 20 min. The presentation of stimuli did not require the participants’ attention, allowing the study of the early automatic stage of feature processing in the auditory cortex. For the CI users, we obtained mismatch negativity (MMN) brain responses to five feature changes but not to changes of rhythm, whereas we obtained MMNs for all the feature changes in the NH controls. Furthermore, the MMNs to deviants of pitch of CI users were reduced in amplitude and later than those of NH controls for changes of pitch and guitar timber. No other group differences in MMN parameters were found to changes in intensity and saxophone timber. Furthermore, the MMNs in CI users reflected the behavioral scores from a respective discrimination task and were correlated with patients’ age and speech intelligibility. Our results suggest that even though CI users are not performing at the same level as NH controls in neural discrimination of pitch-based features, they do possess potential neural abilities for music processing. However, CI users showed a disrupted ability to automatically discriminate rhythmic changes compared with controls. The current behavioral and MMN findings highlight the residual neural skills for music processing even in CI users who have been implanted in adolescence or adulthood. Highlights: -Automatic brain responses to musical feature changes

  4. GABAA receptor-mediated feedforward and feedback inhibition differentially modulate the gain and the neural code transformation in hippocampal CA1 pyramidal cells.

    PubMed

    Jang, Hyun Jae; Park, Kyerl; Lee, Jaedong; Kim, Hyuncheol; Han, Kyu Hun; Kwag, Jeehyun

    2015-12-01

    Diverse variety of hippocampal interneurons exists in the CA1 area, which provides either feedforward (FF) or feedback (FB) inhibition to CA1 pyramidal cell (PC). However, how the two different inhibitory network architectures modulate the computational mode of CA1 PC is unknown. By investigating the CA3 PC rate-driven input-output function of CA1 PC using in vitro electrophysiology, in vitro-simulation of inhibitory network, and in silico computational modeling, we demonstrated for the first time that GABAA receptor-mediated FF and FB inhibition differentially modulate the gain, the spike precision, the neural code transformation and the information capacity of CA1 PC. Recruitment of FF inhibition buffered the CA1 PC spikes to theta-frequency regardless of the input frequency, abolishing the gain and making CA1 PC insensitive to its inputs. Instead, temporal variability of the CA1 PC spikes was increased, promoting the rate-to-temporal code transformation to enhance the information capacity of CA1 PC. In contrast, the recruitment of FB inhibition sub-linearly transformed the input rate to spike output rate with high gain and low spike temporal variability, promoting the rate-to-rate code transformation. These results suggest that GABAA receptor-mediated FF and FB inhibitory circuits could serve as network mechanisms for differentially modulating the gain of CA1 PC, allowing CA1 PC to switch between different computational modes using rate and temporal codes ad hoc. Such switch will allow CA1 PC to efficiently respond to spatio-temporally dynamic inputs and expand its computational capacity during different behavioral and neuromodulatory states in vivo.

  5. Adult neurogenesis, neural stem cells and Alzheimer's disease: developments, limitations, problems and promises.

    PubMed

    Taupin, Philippe

    2009-12-01

    Alzheimer's disease (AD) is an irreversible progressive neurodegenerative disease, leading to severe incapacity and death. It is the most common form of dementia among older people. AD is characterized in the brain by amyloid plaques, neurofibrillary tangles, neuronal degeneration, aneuploidy and enhanced neurogenesis and by cognitive, behavioral and physical impairments. Inherited mutations in several genes and genetic, acquired and environmental risk factors have been reported as causes for developing the disease, for which there is currently no cure. Current treatments for AD involve drugs and occupational therapies, and future developments involve early diagnosis and stem cell therapy. In this manuscript, we will review and discuss the recent developments, limitations, problems and promises on AD, particularly related to aneuploidy, adult neurogenesis, neural stem cells (NSCs) and cellular therapy. Though adult neurogenesis may be beneficial for regeneration of the nervous system, it may underly the pathogenesis of AD. Cellular therapy is a promising strategy for AD. Limitations in protocols to establish homogeneous populations of neural progenitor and stem cells and niches for neurogenesis need to be resolved and unlocked, for the full potential of adult NSCs to be realized for therapy.

  6. Noggin and BMP4 co-modulate adult hippocampal neurogenesis in the APP(swe)/PS1(DeltaE9) transgenic mouse model of Alzheimer's disease.

    PubMed

    Tang, Jun; Song, Min; Wang, Yanyan; Fan, Xiaotang; Xu, Haiwei; Bai, Yun

    2009-07-31

    In addition to the subventricular zone, the dentate gyrus of the hippocampus is one of the few brain regions in which neurogenesis continues into adulthood. Perturbation of neurogenesis can alter hippocampal function, and previous studies have shown that neurogenesis is dysregulated in Alzheimer disease (AD) brain. Bone morphogenetic protein-4 (BMP4) and its antagonist Noggin have been shown to play important roles both in embryonic development and in the adult nervous system, and may regulate hippocampal neurogenesis. Previous data indicated that increased expression of BMP4 mRNA within the dentate gyrus might contribute to decreased hippocampal cell proliferation in the APP(swe)/PS1(DeltaE9) mouse AD model. However, it is not known whether the BMP antagonist Noggin contributes to the regulation of neurogenesis. We therefore studied the relative expression levels and localization of BMP4 and its antagonist Noggin in the dentate gyrus and whether these correlated with changes in neurogenesis in 6-12 mo old APP(swe)/PS1(DeltaE9) transgenic mice. Bromodeoxyuridine (BrdU) was used to label proliferative cells. We report that decreased neurogenesis in the APP/PS1 transgenic mice was accompanied by increased expression of BMP4 and decreased expression of Noggin at both the mRNA and protein levels; statistical analysis showed that the number of proliferative cells at different ages correlated positively with Noggin expression and negatively with BMP4 expression. Intraventricular administration of a chimeric Noggin/Fc protein was used to block the action of endogenous BMP4; this resulted in a significant increase in the number of BrdU-labeled cells in dentate gyrus subgranular zone and hilus in APP/PS1 mice. These results suggest that BMP4 and Noggin co-modulate neurogenesis.

  7. Adult Neurogenesis Leads to the Functional Reconstruction of a Telencephalic Neural Circuit

    PubMed Central

    Macedo-Lima, Matheus; Miller, Kimberly E.; Brenowitz, Eliot A.

    2016-01-01

    Seasonally breeding songbirds exhibit pronounced annual changes in song behavior, and in the morphology and physiology of the telencephalic neural circuit underlying production of learned song. Each breeding season, new adult-born neurons are added to the pallial nucleus HVC in response to seasonal changes in steroid hormone levels, and send long axonal projections to their target nucleus, the robust nucleus of the arcopallium (RA). We investigated the role that adult neurogenesis plays in the seasonal reconstruction of this circuit. We labeled newborn HVC neurons with BrdU, and RA-projecting HVC neurons (HVCRA) with retrograde tracer injected in RA of adult male white-crowned sparrows (Zonotrichia leucophrys gambelii) in breeding or nonbreeding conditions. We found that there were many more HVCRA neurons in breeding than nonbreeding birds. Furthermore, we observed that more newborn HVC neurons were back-filled by the tracer in breeding animals. Behaviorally, song structure degraded as the HVC-RA circuit degenerated, and recovered as the circuit regenerated, in close correlation with the number of new HVCRA neurons. These results support the hypothesis that the HVC-RA circuit degenerates in nonbreeding birds, and that newborn neurons reconstruct the circuit in breeding birds, leading to functional recovery of song behavior. SIGNIFICANCE STATEMENT We investigated the role that adult neurogenesis plays in the seasonal reconstruction of a telencephalic neural circuit that controls song behavior in white-crowned sparrows. We showed that nonbreeding birds had a 36%–49% reduction in the number of projection neurons compared with breeding birds, and the regeneration of the circuit in the breeding season is due to the integration of adult-born projection neurons. Additionally, song structure degraded as the circuit degenerated and recovered as the circuit regenerated, in close correlation with new projection neuron number. This study demonstrates that steroid hormones

  8. Lithium increases proliferation of hippocampal neural stem/progenitor cells and rescues irradiation-induced cell cycle arrest in vitro.

    PubMed

    Zanni, Giulia; Di Martino, Elena; Omelyanenko, Anna; Andäng, Michael; Delle, Ulla; Elmroth, Kecke; Blomgren, Klas

    2015-11-10

    Radiotherapy in children causes debilitating cognitive decline, partly linked to impaired neurogenesis. Irradiation targets primarily cancer cells but also endogenous neural stem/progenitor cells (NSPCs) leading to cell death or cell cycle arrest. Here we evaluated the effects of lithium on proliferation, cell cycle and DNA damage after irradiation of young NSPCs in vitro.NSPCs were treated with 1 or 3 mM LiCl and we investigated proliferation capacity (neurosphere volume and bromodeoxyuridine (BrdU) incorporation). Using flow cytometry, we analysed apoptosis (annexin V), cell cycle (propidium iodide) and DNA damage (γH2AX) after irradiation (3.5 Gy) of lithium-treated NSPCs.Lithium increased BrdU incorporation and, dose-dependently, the number of cells in replicative phase as well as neurosphere growth. Irradiation induced cell cycle arrest in G1 and G2/M phases. Treatment with 3 mM LiCl was sufficient to increase NSPCs in S phase, boost neurosphere growth and reduce DNA damage. Lithium did not affect the levels of apoptosis, suggesting that it does not rescue NSPCs committed to apoptosis due to accumulated DNA damage.Lithium is a very promising candidate for protection of the juvenile brain from radiotherapy and for its potential to thereby improve the quality of life for those children who survive their cancer.

  9. Plasmid-Based Generation of Induced Neural Stem Cells from Adult Human Fibroblasts

    PubMed Central

    Capetian, Philipp; Azmitia, Luis; Pauly, Martje G.; Krajka, Victor; Stengel, Felix; Bernhardi, Eva-Maria; Klett, Mariana; Meier, Britta; Seibler, Philip; Stanslowsky, Nancy; Moser, Andreas; Knopp, Andreas; Gillessen-Kaesbach, Gabriele; Nikkhah, Guido; Wegner, Florian; Döbrössy, Máté; Klein, Christine

    2016-01-01

    Direct reprogramming from somatic to neural cell types has become an alternative to induced pluripotent stem cells. Most protocols employ viral expression systems, posing the risk of random genomic integration. Recent developments led to plasmid-based protocols, lowering this risk. However, these protocols either relied on continuous presence of a variety of small molecules or were only able to reprogram murine cells. We therefore established a reprogramming protocol based on vectors containing the Epstein-Barr virus (EBV)-derived oriP/EBNA1 as well as the defined expression factors Oct3/4, Sox2, Klf4, L-myc, Lin28, and a small hairpin directed against p53. We employed a defined neural medium in combination with the neurotrophins bFGF, EGF and FGF4 for cultivation without the addition of small molecules. After reprogramming, cells demonstrated a temporary increase in the expression of endogenous Oct3/4. We obtained induced neural stem cells (iNSC) 30 days after transfection. In contrast to previous results, plasmid vectors as well as a residual expression of reprogramming factors remained detectable in all cell lines. Cells showed a robust differentiation into neuronal (72%) and glial cells (9% astrocytes, 6% oligodendrocytes). Despite the temporary increase of pluripotency-associated Oct3/4 expression during reprogramming, we did not detect pluripotent stem cells or non-neural cells in culture (except occasional residual fibroblasts). Neurons showed electrical activity and functional glutamatergic synapses. Our results demonstrate that reprogramming adult human fibroblasts to iNSC by plasmid vectors and basic neural medium without small molecules is possible and feasible. However, a full set of pluripotency-associated transcription factors may indeed result in the acquisition of a transient (at least partial) pluripotent intermediate during reprogramming. In contrast to previous reports, the EBV-based plasmid system remained present and active inside the cells at

  10. Neural patterns underlying the effect of negative distractors on working memory in older adults.

    PubMed

    Oren, Noga; Ash, Elissa L; Tarrasch, Ricardo; Hendler, Talma; Giladi, Nir; Shapira-Lichter, Irit

    2017-02-03

    Working memory (WM) declines with age. Older adults, however, perform similar to younger adults in WM tasks with negative distractors at low WM load. To clarify the neural basis of this phenomenon, older (n = 28) and younger (n = 24) adults performed an emotional n-back task during an fMRI scan, and activity in task-related regions was examined. Comparing negative with neutral distraction at low WM load, older adults demonstrated shorter reaction times (RT) and reduced activation in frontoparietal regions: bilateral middle frontal gyrus (MFG) and left parietal cortex. They also had greater coherence within the frontoparietal network, as well as greater deactivation of the ventromedial prefrontal cortex and the amygdala. These patterns probably contributed to the older adults' diminished distractibility by negative task-irrelevant stimuli. Since recruitment of control mechanisms was less required, the frontoparietal network was less activated and performance was improved. Faster RT during the negative condition was related to lesser activation of the MFG in both age groups, corroborating the functional significance of this region to WM across the lifespan.

  11. Distinct neural correlates of emotional and cognitive empathy in older adults.

    PubMed

    Moore, Raeanne C; Dev, Sheena I; Jeste, Dilip V; Dziobek, Isabel; Eyler, Lisa T

    2015-04-30

    Empathy is thought to be a mechanism underlying prosocial behavior across the lifespan, yet little is known about how levels of empathy relate to individual differences in brain functioning among older adults. In this exploratory study, we examined the neural correlates of affective and cognitive empathy in older adults. Thirty older adults (M=79 years) underwent fMRI scanning and neuropsychological testing and completed a test of affective and cognitive empathy. Brain response during processing of cognitive and emotional stimuli was measured by fMRI in a priori and task-related regions and was correlated with levels of empathy. Older adults with higher levels of affective empathy showed more deactivation in the amygdala and insula during a working memory task, whereas those with higher cognitive empathy showed greater insula activation during a response inhibition task. Our preliminary findings suggest that brain systems linked to emotional and social processing respond differently among older adults with more or less affective and cognitive empathy. That these relationships can be seen both during affective and non-emotional tasks of "cold" cognitive abilities suggests that empathy may impact social behavior through both emotional and cognitive mechanisms.

  12. Fragile x mental retardation protein regulates proliferation and differentiation of adult neural stem/progenitor cells.

    PubMed

    Luo, Yuping; Shan, Ge; Guo, Weixiang; Smrt, Richard D; Johnson, Eric B; Li, Xuekun; Pfeiffer, Rebecca L; Szulwach, Keith E; Duan, Ranhui; Barkho, Basam Z; Li, Wendi; Liu, Changmei; Jin, Peng; Zhao, Xinyu

    2010-04-08

    Fragile X syndrome (FXS), the most common form of inherited mental retardation, is caused by the loss of functional fragile X mental retardation protein (FMRP). FMRP is an RNA-binding protein that can regulate the translation of specific mRNAs. Adult neurogenesis, a process considered important for neuroplasticity and memory, is regulated at multiple molecular levels. In this study, we investigated whether Fmrp deficiency affects adult neurogenesis. We show that in a mouse model of fragile X syndrome, adult neurogenesis is indeed altered. The loss of Fmrp increases the proliferation and alters the fate specification of adult neural progenitor/stem cells (aNPCs). We demonstrate that Fmrp regulates the protein expression of several components critical for aNPC function, including CDK4 and GSK3beta. Dysregulation of GSK3beta led to reduced Wnt signaling pathway activity, which altered the expression of neurogenin1 and the fate specification of aNPCs. These data unveil a novel regulatory role for Fmrp and translational regulation in adult neurogenesis.

  13. Tianeptine reverses stress-induced asymmetrical hippocampal volume and N-acetylaspartate loss in rats: an in vivo study.

    PubMed

    Liu, Wei; Shu, Xi-Ji; Chen, Fu-Yin; Zhu, Cheng; Sun, Xiao-Hai; Liu, Li-Jiang; Ai, Yong-Xun; Li, Yu-Guang; Zhao, Hu

    2011-12-30

    Stress-induced hippocampal volume loss and decrease in N-acetylaspartate (NAA) level have been reported to be associated with impaired neural plasticity and neuronal damage in adults. Accordingly, reversing structural and metabolite damage in the hippocampus may be a desirable goal for antidepressant therapy. The present study investigated the effects of tianeptine on chronic stress-induced hippocampal volume loss and metabolite alterations in vivo in 24 Sprague-Dawley rats. Rats were subjected to a consecutive 28-day forced swimming test stress. Tianeptine (50mg/kg) or saline was administered intragastrically 4h after swimming each day. Spontaneous behaviors, serum corticosterone concentration, hippocampal volume and NAA level were evaluated after stress. Chronic tianeptine treatment counteracted the chronic stress-induced suppression of spontaneous behaviors, elevated serum corticosterone concentration, reduced hippocampal volume and decreased NAA level. Moreover, we found asymmetrical right-left hippocampal volume loss in stressed rats, with the left hippocampus more sensitive to chronic stress than the right hippocampus. In addition, stressed rats showed a decreased level of hippocampal metabolites, without significant loss of hippocampal volume. These findings provide experimental evidence for impaired structural plasticity of the brain being an important feature of depressive illness and suggest that prophylactic tianeptine treatments could reverse structural changes in brain. The structural and neurochemical alterations in the hippocampus may be valuable indexes for evaluating the prophylactic and curative effect of antidepressant treatments in depressive and stress-related disorders.

  14. The effects of stress during early postnatal periods on behavior and hippocampal neuroplasticity markers in adult male mice.

    PubMed

    van der Kooij, M A; Grosse, J; Zanoletti, O; Papilloud, A; Sandi, C

    2015-12-17

    Infancy is a critical period for brain development. Emerging evidence indicates that stress experienced during that period can have long-term programming effects on the brain and behavior. However, whether different time periods represent different vulnerabilities to the programming of different neurobehavioral domains is not yet known. Disrupted maternal care is known to interfere with neurodevelopmental processes and may lead to the manifestation of behavioral abnormalities in adulthood. Mouse dams confronted with insufficient bedding/nesting material have been shown to provide fragmented maternal care to their offspring. Here, we compared the impact of this model of early-life stress (ELS) during different developmental periods comprising either postnatal days (PNDs) 2-9 (ELS-early) or PND 10-17 (ELS-late) on behavior and hippocampal cell adhesion molecules in male mice in adulthood. ELS-early treatment caused a permanent reduction in bodyweight, whereas this reduction only occurred transiently during juvenility in ELS-late mice. Anxiety was only affected in ELS-late mice, while cognition and sociability were equally impaired in both ELS-treated groups. We analyzed hippocampal gene expression of the γ2 subunit of the GABAa receptor (Gabrg2) and of genes encoding cell adhesion molecules. Gabrg2 expression was increased in the ventral hippocampus in ELS-late-treated animals and was correlated with anxiety-like behavior in the open-field (OF) test. ELS-early-treated animals exhibited an increase in nectin-1 expression in the dorsal hippocampus, and this increase was associated with the social deficits seen in these animals. Our findings highlight the relevance of developmental age on stress-induced long-term behavioral alterations. They also suggest potential links between early stress-induced alterations in hippocampal Gabrg2 expression and the developmental programming of anxiety and between changes in hippocampal nectin-1 expression and stress-induced social

  15. Buttressing a balanced brain: Target-derived FGF signaling regulates excitatory/inhibitory tone and adult neurogenesis within the maturating hippocampal network.

    PubMed

    Dabrowski, Ania; Umemori, Hisashi

    2016-01-01

    Brain development involves multiple levels of molecular coordination in forming a functional nervous system. The hippocampus is a brain area that is important for memory formation and spatial reasoning. During early postnatal development of the hippocampal circuit, Fibroblast growth factor 22 (FGF22) and FGF7 act to establish a balance of excitatory and inhibitory tone. Both FGFs are secreted from CA3 dendrites, acting on excitatory or inhibitory axon terminals formed onto CA3 dendrites, respectively. Mechanistically, FGF22 utilizes FGFR2b and FGFR1b to induce synaptic vesicle recruitment within axons of dentate granule cells (DGCs), and FGF7 utilizes FGFR2b to induce synaptic vesicle recruitment within interneuron axons. FGF signaling eventually induces gene expression in the presynaptic neurons; however, the effects of FGF22-induced gene expression within DGCs and FGF7-induced gene expression within interneurons in the context of a developing hippocampal circuit have yet to be explored. Here, we propose one hypothetical mechanism of FGF22-induced gene expression in controlling adult neurogenesis.

  16. Neurodevelopment. Live imaging of adult neural stem cell behavior in the intact and injured zebrafish brain.

    PubMed

    Barbosa, Joana S; Sanchez-Gonzalez, Rosario; Di Giaimo, Rossella; Baumgart, Emily Violette; Theis, Fabian J; Götz, Magdalena; Ninkovic, Jovica

    2015-05-15

    Adult neural stem cells are the source for restoring injured brain tissue. We used repetitive imaging to follow single stem cells in the intact and injured adult zebrafish telencephalon in vivo and found that neurons are generated by both direct conversions of stem cells into postmitotic neurons and via intermediate progenitors amplifying the neuronal output. We observed an imbalance of direct conversion consuming the stem cells and asymmetric and symmetric self-renewing divisions, leading to depletion of stem cells over time. After brain injury, neuronal progenitors are recruited to the injury site. These progenitors are generated by symmetric divisions that deplete the pool of stem cells, a mode of neurogenesis absent in the intact telencephalon. Our analysis revealed changes in the behavior of stem cells underlying generation of additional neurons during regeneration.

  17. Neural Correlates of Dual-Task Walking: Effects of Cognitive versus Motor Interference in Young Adults.

    PubMed

    Beurskens, Rainer; Steinberg, Fabian; Antoniewicz, Franziska; Wolff, Wanja; Granacher, Urs

    2016-01-01

    Walking while concurrently performing cognitive and/or motor interference tasks is the norm rather than the exception during everyday life and there is evidence from behavioral studies that it negatively affects human locomotion. However, there is hardly any information available regarding the underlying neural correlates of single- and dual-task walking. We had 12 young adults (23.8 ± 2.8 years) walk while concurrently performing a cognitive interference (CI) or a motor interference (MI) task. Simultaneously, neural activation in frontal, central, and parietal brain areas was registered using a mobile EEG system. Results showed that the MI task but not the CI task affected walking performance in terms of significantly decreased gait velocity and stride length and significantly increased stride time and tempo-spatial variability. Average activity in alpha and beta frequencies was significantly modulated during both CI and MI walking conditions in frontal and central brain regions, indicating an increased cognitive load during dual-task walking. Our results suggest that impaired motor performance during dual-task walking is mirrored in neural activation patterns of the brain. This finding is in line with established cognitive theories arguing that dual-task situations overstrain cognitive capabilities resulting in motor performance decrements.

  18. Both synaptic and intrinsic mechanisms underlie the different properties of population bursts in the hippocampal CA3 area of immature versus adult rats

    PubMed Central

    Shao, Li-Rong; Dudek, F Edward

    2009-01-01

    Pharmacological blockade of GABAA receptors on CA3 pyramidal cells in hippocampal slices from immature rats (i.e. second to third postnatal weeks), compared to CA3 slices from adult rats, is known to cause prolonged burst discharges (i.e. several seconds vs. tens of milliseconds). Synaptic and intrinsic mechanisms responsible for this developmental difference in burst duration were analysed in isolated minislices of the CA3 area. The frequency and amplitude of spontaneous EPSCs in CA3 pyramidal cells were greater in slices from immature than mature rats. In the presence of GABAA- and GABAB-receptor antagonists, the burst discharges of immature CA3 pyramidal cells were still prolonged in thinner slices (350 μm, vs. 450 μm in adults, to compensate for developmental differences in neuronal density) and in NMDA- and mGlu1-receptor antagonists. The AMPA receptor antagonist DNQX blocked the remaining burst discharges, suggesting that differences in recurrent excitatory circuits contributed to the prolonged bursts of immature CA3 pyramidal cells. In slices from immature versus adult rats, the CA3 recurrent synaptic responses showed potentiation to repetitive stimulation, suggestive of a lower transmitter release probability. The intrinsic firing ability was greater in CA3 pyramidal neurons from immature than adult rats, and the medium-duration afterhyperpolarization was smaller. These data suggest that, compared to adults, the CA3 area of immature rats contains a more robust recurrent excitatory synaptic network, greater intrinsic membrane excitability, and an increased capacity for sustained transmitter release, which together may account for the more prolonged network bursts in immature versus adult CA3. PMID:19884320

  19. Hippocampal protein expression is differentially affected by chronic paroxetine treatment in adolescent and adult rats: a possible mechanism of “paradoxical” antidepressant responses in young persons

    PubMed Central

    Karanges, Emily A.; Kashem, Mohammed A.; Sarker, Ranjana; Ahmed, Eakhlas U.; Ahmed, Selina; Van Nieuwenhuijzen, Petra S.; Kemp, Andrew H.; McGregor, Iain S.

    2013-01-01

    Selective serotonin reuptake inhibitors (SSRIs) are commonly recognized as the pharmacological treatment of choice for patients with depressive disorders, yet their use in adolescent populations has come under scrutiny following reports of minimal efficacy and an increased risk of suicidal ideation and behavior in this age group. The biological mechanisms underlying these effects are largely unknown. Accordingly, the current study examined changes in hippocampal protein expression following chronic administration of paroxetine in drinking water (target dose = 10 mg/kg for 22 days) to adult and adolescent rats. Results indicated age-specific changes in protein expression, with paroxetine significantly altering expression of 8 proteins in adolescents only and 10 proteins solely in adults. A further 12 proteins were significantly altered in both adolescents and adults. In adults, protein changes were generally suggestive of a neurotrophic and neuroprotective effect of paroxetine, with significant downregulation of apoptotic proteins Galectin 7 and Cathepsin B, and upregulation of the neurotrophic factor Neurogenin 1 and the antioxidant proteins Aldose reductase and Carbonyl reductase 3. Phosphodiesterase 10A, a signaling protein associated with major depressive disorder, was also downregulated (-6.5-fold) in adult rats. Adolescent rats failed to show the neurotrophic and neuroprotective effects observed in adults, instead displaying upregulation of the proapoptotic protein BH3-interacting domain death agonist (4.3-fold). Adolescent protein expression profiles also suggested impaired phosphoinositide signaling (Protein kinase C: -3.1-fold) and altered neurotransmitter transport and release (Syntaxin 7: 5.7-fold; Dynamin 1: -6.9-fold). The results of the present study provide clues as to possible mechanisms underlying the atypical response of human adolescents to paroxetine treatment. PMID:23847536

  20. Ly6C(hi) Monocytes Provide a Link between Antibiotic-Induced Changes in Gut Microbiota and Adult Hippocampal Neurogenesis.

    PubMed

    Möhle, Luisa; Mattei, Daniele; Heimesaat, Markus M; Bereswill, Stefan; Fischer, André; Alutis, Marie; French, Timothy; Hambardzumyan, Dolores; Matzinger, Polly; Dunay, Ildiko R; Wolf, Susanne A

    2016-05-31

    Antibiotics, though remarkably useful, can also cause certain adverse effects. We detected that treatment of adult mice with antibiotics decreases hippocampal neurogenesis and memory retention. Reconstitution with normal gut flora (SPF) did not completely reverse the deficits in neurogenesis unless the mice also had access to a running wheel or received probiotics. In parallel to an increase in neurogenesis and memory retention, both SPF-reconstituted mice that ran and mice supplemented with probiotics exhibited higher numbers of Ly6C(hi) monocytes in the brain than antibiotic-treated mice. Elimination of Ly6C(hi) monocytes by antibody depletion or the use of knockout mice resulted in decreased neurogenesis, whereas adoptive transfer of Ly6C(hi) monocytes rescued neurogenesis after antibiotic treatment. We propose that the rescue of neurogenesis and behavior deficits in antibiotic-treated mice by exercise and probiotics is partially mediated by Ly6C(hi) monocytes.

  1. Characterization of Proliferating Neural Progenitors after Spinal Cord Injury in Adult Zebrafish

    PubMed Central

    Hui, Subhra Prakash; Nag, Tapas Chandra; Ghosh, Sukla

    2015-01-01

    Zebrafish can repair their injured brain and spinal cord after injury unlike adult mammalian central nervous system. Any injury to zebrafish spinal cord would lead to increased proliferation and neurogenesis. There are presences of proliferating progenitors from which both neuronal and glial loss can be reversed by appropriately generating new neurons and glia. We have demonstrated the presence of multiple progenitors, which are different types of proliferating populations like Sox2+ neural progenitor, A2B5+ astrocyte/ glial progenitor, NG2+ oligodendrocyte progenitor, radial glia and Schwann cell like progenitor. We analyzed the expression levels of two common markers of dedifferentiation like msx-b and vimentin during regeneration along with some of the pluripotency associated factors to explore the possible role of these two processes. Among the several key factors related to pluripotency, pou5f1 and sox2 are upregulated during regeneration and associated with activation of neural progenitor cells. Uncovering the molecular mechanism for endogenous regeneration of adult zebrafish spinal cord would give us more clues on important targets for future therapeutic approach in mammalian spinal cord repair and regeneration. PMID:26630262

  2. Altered Neural Processing to Social Exclusion in Young Adult Marijuana Users

    PubMed Central

    Gilman, Jodi M.; Curran, Max T.; Calderon, Vanessa; Schuster, Randi M.; Evins, A. Eden

    2015-01-01

    Previous studies have reported that peer groups are one of the most important predictors of adolescent and young adult marijuana use, and yet the neural correlates of social processing in marijuana users have not yet been studied. In the current study, marijuana-using young adults (n = 20) and non-using controls (n = 22) participated in a neuroimaging social exclusion task called Cyberball, a computerized ball-tossing game in which the participant is excluded from the game after a pre-determined number of ball tosses. Controls, but not marijuana users, demonstrated significant activation in the insula, a region associated with negative emotion, when being excluded from the game. Both groups demonstrated activation of the ventral anterior cingulate cortex (vACC), a region associated with affective monitoring, during peer exclusion. Only the marijuana group showed a correlation between vACC activation and scores on a self-report measure of peer conformity. This study indicates that marijuana users show atypical neural processing of social exclusion, which may be either caused by, or the result of, regular marijuana use. PMID:26977454

  3. Inducible expression of noggin selectively expands neural progenitors in the adult SVZ.

    PubMed

    Morell, M; Tsan, Yao-chang; O'Shea, K Sue

    2015-01-01

    Multipotent, self-renewing stem cells are present throughout the developing nervous system remaining in discrete regions of the adult brain. In the subventricular zone (SVZ) signaling molecules, including the bone morphogenetic proteins and their secreted inhibitor, noggin appear to play a critical role in controlling neural stem cell (NSC) behavior. To examine the function of this signaling pathway in the intact nervous system, we developed a transgenic mouse model in which noggin expression can be induced specifically in NSC via a nestin-driven reverse tetracycline-controlled transactivator (rtTA). In adult animals, the induction of noggin expression promotes the proliferation of neural progenitors in the SVZ, and shifts the differentiation of B cells (NSC) from mature astrocytes to transit amplifying C cells and oligodendrocyte precursor cells without depleting the NSC population. Noggin expression significantly increases neuronal and oligodendrocyte differentiation both in vivo and in vitro when NSCs are grown as neurospheres. These results demonstrate that noggin/BMP interactions tightly control cell fate in the SVZ.

  4. Neural stem cells in the adult ciliary epithelium express GFAP and are regulated by Wnt signaling

    SciTech Connect

    Das, Ani V.; Zhao Xing; James, Jackson; Kim, Min; Cowan, Kenneth H.; Ahmad, Iqbal . E-mail: iahmad@unmc.edu

    2006-01-13

    The identification of neural stem cells with retinal potential in the ciliary epithelium (CE) of the adult mammals is of considerable interest because of their potential for replacing or rescuing degenerating retinal neurons in disease or injury. The evaluation of such a potential requires characterization of these cells with regard to their phenotypic properties, potential, and regulatory mechanisms. Here, we demonstrate that rat CE stem cells/progenitors in neurosphere culture display astrocytic nature in terms of expressing glial intermediate neurofilament protein, GFAP. The GFAP-expressing CE stem cells/progenitors form neurospheres in proliferating conditions and generate neurons when shifted to differentiating conditions. These cells express components of the canonical Wnt pathway and its activation promotes their proliferation. Furthermore, we demonstrate that the activation of the canonical Wnt pathway influences neuronal differentiation of CE stem cells/progenitors in a context dependent manner. Our observations suggest that CE stem cells/progenitors share phenotypic properties and regulatory mechanism(s) with neural stem cells elsewhere in the adult CNS.

  5. Inhibition of glycogen synthase kinase-3 enhances the differentiation and reduces the proliferation of adult human olfactory epithelium neural precursors

    SciTech Connect

    Manceur, Aziza P.; Tseng, Michael; Holowacz, Tamara; Witterick, Ian; Weksberg, Rosanna; McCurdy, Richard D.; Warsh, Jerry J.; Audet, Julie

    2011-09-10

    The olfactory epithelium (OE) contains neural precursor cells which can be easily harvested from a minimally invasive nasal biopsy, making them a valuable cell source to study human neural cell lineages in health and disease. Glycogen synthase kinase-3 (GSK-3) has been implicated in the etiology and treatment of neuropsychiatric disorders and also in the regulation of murine neural precursor cell fate in vitro and in vivo. In this study, we examined the impact of decreased GSK-3 activity on the fate of adult human OE neural precursors in vitro. GSK-3 inhibition was achieved using ATP-competitive (6-bromoindirubin-3'-oxime and CHIR99021) or substrate-competitive (TAT-eIF2B) inhibitors to eliminate potential confounding effects on cell fate due to off-target kinase inhibition. GSK-3 inhibitors decreased the number of neural precursor cells in OE cell cultures through a reduction in proliferation. Decreased proliferation was not associated with a reduction in cell survival but was accompanied by a reduction in nestin expression and a substantial increase in the expression of the neuronal differentiation markers MAP1B and neurofilament (NF-M) after 10 days in culture. Taken together, these results suggest that GSK-3 inhibition promotes the early stages of neuronal differentiation in cultures of adult human neural precursors and provide insights into the mechanisms by which alterations in GSK-3 signaling affect adult human neurogenesis, a cellular process strongly suspected to play a role in the etiology of neuropsychiatric disorders.

  6. Estrogen receptor-beta colocalizes extensively with parvalbumin-labeled inhibitory neurons in the cortex, amygdala, basal forebrain, and hippocampal formation of intact and ovariectomized adult rats.

    PubMed

    Blurton-Jones, Mathew; Tuszynski, Mark H

    2002-10-21

    Estrogen has been reported to regulate the activity of gamma-aminobutyric acid (GABA)ergic interneurons within the hippocampus, basal forebrain, and hypothalamus of adult rodents. Although estrogen receptor-alpha bearing GABAergic interneurons have been identified previously, the neurotransmitter phenotype of cells that express the more recently characterized estrogen receptor-beta (ER-beta) has not been examined in vivo. We, therefore, have used fluorescent immunohistochemistry to further characterize the phenotype of ER-beta-bearing cells by double labeling for the GABAergic-associated calcium-binding protein, parvalbumin (PV). We find that a large proportion of ER-beta-immunoreactive cells within the cortex, amygdala, basal forebrain, and hippocampal formation of intact and ovariectomized (ovx) adult rats are PV-immunoreactive. Within the infralimbic, agranular insular, primary motor, parietal association, perirhinal, and lateral entorhinal cortices, an average of 95.6% +/- 0.8% (intact) and 94.5% +/- 1.4% (ovx) of all ER-beta-immunoreactive cells coexpress parvalbumin, and this proportion is strikingly similar across these diverse cortical regions. ER-beta/PV double-labeled cells represent 23.3% +/- 1.6% (intact) and 25.8% +/- 2.0% (ovx) of all PV-labeled cells within these regions. ER-beta/PV double-labeled cells are also observed within the lateral, accessory basal, and posterior cortical nuclei of the amygdala, and periamygdaloid cortex. Within the basal forebrain, 31.0% +/- 3.1% (intact) and 26.0% +/- 5.2 % (ovx) of ER-beta-immunoreactive cells coexpress PV. Almost all ER-beta-immunoreactive cells within the subiculum, a major output region of the hippocampal formation, double label for PV (intact = 97.2% +/- 2.8%; ovx = 100% +/- 0.0%). Thus, ER-beta exhibits extensive colocalization with a subclass of inhibitory neurons, suggesting a potential mechanism whereby estrogen can regulate neuronal excitability in diverse and broad brain regions by modulating

  7. The common and distinct neural bases of affect labeling and reappraisal in healthy adults

    PubMed Central

    Burklund, Lisa J.; Creswell, J. David; Irwin, Michael R.; Lieberman, Matthew D.

    2014-01-01

    Emotion regulation is commonly characterized as involving conscious and intentional attempts to change felt emotions, such as, for example, through reappraisal whereby one intentionally decreases the intensity of one's emotional response to a particular stimulus or situation by reinterpreting it in a less threatening way. However, there is growing evidence and appreciation that some types of emotion regulation are unintentional or incidental, meaning that affective modulation is a consequence but not an explicit goal. For example, affect labeling involves simply verbally labeling the emotional content of an external stimulus or one's own affective responses without an intentional goal of altering emotional responses, yet has been associated with reduced affective responses at the neural and experiential levels. Although both intentional and incidental emotional regulation strategies have been associated with diminished limbic responses and self-reported distress, little previous research has directly compared their underlying neural mechanisms. In this study, we examined the extent to which incidental and intentional emotion regulation, namely, affect labeling and reappraisal, produced common and divergent neural and self-report responses to aversive images relative to an observe-only control condition in a sample of healthy older adults (N = 39). Affect labeling and reappraisal produced common activations in several prefrontal regulatory regions, with affect labeling producing stronger responses in direct comparisons. Affect labeling and reappraisal were also associated with similar decreases in amygdala activity. Finally, affect labeling and reappraisal were associated with correlated reductions in self-reported distress. Together these results point to common neurocognitive mechanisms involved in affect labeling and reappraisal, supporting the idea that intentional and incidental emotion regulation may utilize overlapping neural processes. PMID:24715880

  8. Ketamine Affects the Neurogenesis of the Hippocampal Dentate Gyrus in 7-Day-Old Rats.

    PubMed

    Huang, He; Liu, Cun-Ming; Sun, Jie; Hao, Ting; Xu, Chun-Mei; Wang, Dan; Wu, Yu-Qing

    2016-08-01

    Ketamine has been reported to cause neonatal neurotoxicity via a neuronal apoptosis mechanism; however, no in vivo research has reported whether ketamine could affect postnatal neurogenesis in the hippocampal dentate gyrus (DG). A growing number of experiments suggest that postnatal hippocampal neurogenesis is the foundation of maintaining normal hippocampus function into adulthood. Therefore, this study investigated the effect of ketamine on hippocampal neurogenesis. Male Sprague-Dawley rats were divided into two groups: the control group (equal volume of normal saline), and the ketamine-anesthesia group (40 mg/kg ketamine in four injections at 1 h intervals). The S-phase marker 5-bromodeoxyuridine (BrdU) was administered after ketamine exposure to postnatal day 7 (PND-7) rats, and the neurogenesis in the hippocampal DG was assessed using single- or double-immunofluorescence staining. The expression of GFAP in the hippocampal DG was measured by western blot analysis. Spatial reference memory was tested by Morris water maze at 2 months after PND-7 rats exposed to ketamine treatment. The present results showed that neonatal ketamine exposure significantly inhibited neural stem cell (NSC) proliferation, decreased astrocytic differentiation, and markedly enhanced neuronal differentiation. The disruptive effect of ketamine on the proliferation and differentiation of NSCs lasted at least 1 week and disappeared by 2 weeks after ketamine exposure. Moreover, the migration of newborn neurons in the granule cell layer and the growth of astrocytes in the hippocampal DG were inhibited by ketamine on PND-37 and PND-44. Finally, ketamine caused a deficit in hippocampal-dependent spatial reference memory tasks at 2 months old. Our results suggested that ketamine may interfere with hippocampal neurogenesis and long-term neurocognitive function in PND-7 rats. These findings may provide a new perspective to explain the adult neurocognitive dysfunction induced by neonatal

  9. Effects of selective neonatal hippocampal lesions on tests of object and spatial recognition memory in monkeys

    PubMed Central

    Heuer, Eric; Bachevalier, Jocelyne

    2011-01-01

    Earlier studies in monkeys have reported mild impairment in recognition memory following nonselective neonatal hippocampal lesions (Bachevalier, Beauregard, & Alvarado, 1999; Rehbein, Killiany, & Mahut, 2005). To assess whether the memory impairment could have resulted from damage to cortical areas adjacent to the hippocampus, we tested adult monkeys with neonatal focal hippocampal lesions and sham-operated controls in three recognition tasks: delayed nonmatching-to-sample, object memory span, and spatial memory span. Further, to rule out that normal performance on these tasks may relate to functional sparing following neonatal hippocampal lesions, we tested adult monkeys that had received the same focal hippocampal lesions in adulthood and their controls in the same three memory tasks. Both early and late onset focal hippocampal damage did not alter performance on any of the three tasks, suggesting that damage to cortical areas adjacent to the hippocampus was likely responsible for the recognition impairment reported by the earlier studies. In addition, given that animals with early and late onset hippocampal lesions showed object and spatial recognition impairment when tested in a visual paired comparison task (Zeamer, Meunier, & Bachevalier, Submitted; Zeamer, Heuer & Bachevalier, 2010), the data suggest that not all object and spatial recognition tasks are solved by hippocampal-dependent memory processes. The current data may not only help explain the neural substrate for the partial recognition memory impairment reported in cases of developmental amnesia (Adlam, Malloy, Mishkin, & Vargha-Khadem, 2009), but they are also clinically relevant given that the object and spatial memory tasks used in monkeys are often translated to investigate memory functions in several populations of human infants and children in which dysfunction of the hippocampus is suspected. PMID:21341885

  10. Lifestyle Shapes the Dialogue between Environment, Microglia, and Adult Neurogenesis.

    PubMed

    Valero, Jorge; Paris, Iñaki; Sierra, Amanda

    2016-04-20

    Lifestyle modulates brain function. Diet, stress levels, and physical exercise among other factors influence the "brain cognitive reserve", that is, the capacity of the brain to maintain a normal function when confronting neurodegenerative diseases, injury, and/or aging. This cognitive reserve relays on several cellular and molecular elements that contribute to brain plasticity allowing adaptive responses to cognitive demands, and one of its key components is the hippocampal neurogenic reserve. Hippocampal neural stem cells give rise to new neurons that integrate into the local circuitry and contribute to hippocampal functions such as memory and learning. Importantly, adult hippocampal neurogenesis is well-known to be modulated by the demands of the environment and lifestyle factors. Diet, stress, and physical exercise directly act on neural stem cells and/or their progeny, but, in addition, they may also indirectly affect neurogenesis by acting on microglia. Microglia, the guardians of the brain, rapidly sense changes in the brain milieu, and it has been recently shown that their function is affected by lifestyle factors. However, few studies have analyzed the modulatory effect of microglia on adult neurogenesis in these conditions. Here, we review the current knowledge about the dialogue maintained between microglia and the hippocampal neurogenic cascade. Understanding how the communication between microglia and hippocampal neurogenesis is affected by lifestyle choices is crucial to maintain the brain cognitive reserve and prevent the maladaptive responses that emerge during disease or injury through adulthood and aging.

  11. A comparison of epithelial and neural properties in progenitor cells derived from the adult human ciliary body and brain.

    PubMed

    Moe, Morten C; Kolberg, Rebecca S; Sandberg, Cecilie; Vik-Mo, Einar; Olstorn, Havard; Varghese, Mercy; Langmoen, Iver A; Nicolaissen, Bjørn

    2009-01-01

    Cells isolated from the ciliary body (CB) of the adult human eye possess properties of retinal stem/progenitor cells and can be propagated as spheres in culture. As these cells are isolated from a non-neural epithelium which has neuroepithelial origin, they may have both epithelial and neural lineages. Since it is the properties of neural progenitor cells that are sought after in a future scenario of autotransplantation, we wanted to directly compare human CB spheres with neurospheres derived from the human subventricular zone (SVZ), which is the best characterized neural stem cell niche in the CNS of adults. The CB epithelium was dissected from donor eyes (n = 8). Biopsies from the ventricular wall were harvested during neurosurgery due to epilepsy (n = 7). CB and SVZ tissue were also isolated from Brown Norwegian rats. Dissociated single cells were cultivated in a sphere-promoting medium and passaged every 10-30 days. Fixed spheres were studied by immunohistochemistry, quantitative RT-PCR and scanning/transmission electron microscopy. We found that both CB and SVZ spheres contained a mixed population of cells embedded in extracellular matrix. CB spheres, in contrast to SVZ neurospheres, contained pigmented cells with epithelial morphology that stained for cytokeratins (3/12 + 19), were connected through desmosomes and tight-junctions and produced PEDF. Markers of neural progenitors (nestin, Sox-2, GFAP) were significantly lower expressed in human CB compared to SVZ spheres, and nestin positive cells in the CB spheres also contained pigment. There was higher expression of EGF and TGF-beta receptors in human CB spheres, and a comparative greater activation of the canonical Wnt pathway. These results indicate that adult human CB spheres contain progenitor cells with epithelial properties and limited expression of neural progenitor markers compared to CNS neurospheres. Further studies mapping the regulation between epithelial and neural properties in the adult human

  12. Prolonged protein deprivation differentially affects calretinin- and parvalbumin-containing interneurons in the hippocampal dentate gyrus of adult rats.

    PubMed

    Hipólito-Reis, José; Pereira, Pedro Alberto; Andrade, José Paulo; Cardoso, Armando

    2013-10-25

    Protein deprivation is a detrimental nutritional state that induces several deleterious changes in the rat hippocampal formation. In this study, we compared the effects of protein deprivation in the number of parvalbumin (PV)-immunoreactive and calretinin (CR)-immunoreactive interneurons of the dentate gyrus, which are involved in the control of calcium homeostasis and fine tuning of the hippocampal circuits. Two month-old rats were randomly assigned to control and low-protein diet groups. The rats of the latter group were fed with a low-protein diet (8% casein) for 6 months. All animals were perfused at 8 months of age. The number of neurons expressing CR in the molecular layer and in the hilus of dentate gyrus was reduced in protein-deprived rats. Conversely, protein deprivation increased the number of PV-containing interneurons in the dentate granule cell layer and hilus. These results support the view that protein deprivation may disturb calcium homeostasis, leading to neuronal death including GABAergic interneurons expressing CR. In the other hand, the up-regulation of PV cells may reflect a protective mechanism to counteract the calcium overload and protect the remaining neurons of the dentate gyrus.

  13. The interplay of early-life stress, nutrition, and immune activation programs adult hippocampal structure and function

    PubMed Central

    Hoeijmakers, Lianne; Lucassen, Paul J.; Korosi, Aniko

    2015-01-01

    Early-life adversity increases the vulnerability to develop psychopathologies and cognitive decline later in life. This association is supported by clinical and preclinical studies. Remarkably, experiences of stress during this sensitive period, in the form of abuse or neglect but also early malnutrition or an early immune challenge elicit very similar long-term effects on brain structure and function. During early-life, both exogenous factors like nutrition and maternal care, as well as endogenous modulators, including stress hormones and mediator of immunological activity affect brain development. The interplay of these key elements and their underlying molecular mechanisms are not fully understood. We discuss here the hypothesis that exposure to early-life adversity (specifically stress, under/malnutrition and infection) leads to life-long alterations in hippocampal-related cognitive functions, at least partly via changes in hippocampal neurogenesis. We further discuss how these different key elements of the early-life environment interact and affect one another and suggest that it is a synergistic action of these elements that shapes cognition throughout life. Finally, we consider different intervention studies aiming to prevent these early-life adversity induced consequences. The emerging evidence for the intriguing interplay of stress, nutrition, and immune activity in the early-life programming calls for a more in depth understanding of the interaction of these elements and the underlying mechanisms. This knowledge will help to develop intervention strategies that will converge on a more complete set of changes induced by early-life adversity. PMID:25620909

  14. Neural Underpinnings of Working Memory in Adult Survivors of Childhood Brain Tumors.

    PubMed

    King, Tricia Z; Na, Sabrina; Mao, Hui

    2015-08-01

    Adult survivors of childhood brain tumors are at risk for cognitive performance deficits that require the core cognitive skill of working memory. Our goal was to examine the neural mechanisms underlying working memory performance in survivors. We studied the working memory of adult survivors of pediatric posterior fossa brain tumors using a letter n-back paradigm with varying cognitive workload (0-, 1-, 2-, and 3-back) and functional magnetic resonance imaging as well as neuropsychological measures. Survivors of childhood brain tumors evidenced lower working memory performance than demographically matched healthy controls. Whole-brain analyses revealed significantly greater blood-oxygen level dependent (BOLD) activation in the left superior / middle frontal gyri and left parietal lobe during working memory (2-back versus 0-back contrast) in survivors. Left frontal BOLD response negatively correlated with 2- and 3-back working memory performance, Auditory Consonant Trigrams (ACT), and Digit Span Backwards. In contrast, parietal lobe BOLD response negatively correlated with 0-back (vigilance task) and ACT. The results revealed that adult survivors of childhood posterior fossa brain tumors recruited additional cognitive control resources in the prefrontal lobe during increased working memory demands. This increased prefrontal activation is associated with lower working memory performance and is consistent with the allocation of latent resources theory.

  15. Age-Associated Increase in BMP Signaling Inhibits Hippocampal Neurogenesis.

    PubMed

    Yousef, Hanadie; Morgenthaler, Adam; Schlesinger, Christina; Bugaj, Lukasz; Conboy, Irina M; Schaffer, David V

    2015-05-01

    Hippocampal neurogenesis, the product of resident neural stem cell proliferation and differentiation, persists into adulthood but decreases with organismal aging, which may contribute to the age-related decline in cognitive function. The mechanisms that underlie this decrease in neurogenesis are not well understood, although evidence in general indicates that extrinsic changes in an aged stem cell niche can contribute to functional decline in old stem cells. Bone morphogenetic protein (BMP) family members are intercellular signaling proteins that regulate stem and progenitor cell quiescence, proliferation, and differentiation in various tissues and are likewise critical regulators of neurogenesis in young adults. Here, we establish that BMP signaling increases significantly in old murine hippocampi and inhibits neural progenitor cell proliferation. Furthermore, direct in vivo attenuation of BMP signaling via genetic and transgenic perturbations in aged mice led to elevated neural stem cell proliferation, and subsequent neurogenesis, in old hippocampi. Such advances in our understanding of mechanisms underlying decreased hippocampal neurogenesis with age may offer targets for the treatment of age-related cognitive decline.

  16. Gestational Chronodisruption Impairs Hippocampal Expression of NMDA Receptor Subunits Grin1b/Grin3a and Spatial Memory in the Adult Offspring

    PubMed Central

    Vilches, Nelson; Spichiger, Carlos; Mendez, Natalia; Abarzua-Catalan, Lorena; Galdames, Hugo A.; Hazlerigg, David G.; Richter, Hans G.; Torres-Farfan, Claudia

    2014-01-01

    Epidemiological and experimental evidence correlates adverse intrauterine conditions with the onset of disease later in life. For a fetus to achieve a successful transition to extrauterine life, a myriad of temporally integrated humoral/biophysical signals must be accurately provided by the mother. We and others have shown the existence of daily rhythms in the fetus, with peripheral clocks being entrained by maternal cues, such as transplacental melatonin signaling. Among developing tissues, the fetal hippocampus is a key structure for learning and memory processing that may be anticipated as a sensitive target of gestational chronodisruption. Here, we used pregnant rats exposed to constant light treated with or without melatonin as a model of gestational chronodisruption, to investigate effects on the putative fetal hippocampus clock, as well as on adult offspring’s rhythms, endocrine and spatial memory outcomes. The hippocampus of fetuses gestated under light:dark photoperiod (12:12 LD) displayed daily oscillatory expression of the clock genes Bmal1 and Per2, clock-controlled genes Mtnr1b, Slc2a4, Nr3c1 and NMDA receptor subunits 1B-3A-3B. In contrast, in the hippocampus of fetuses gestated under constant light (LL), these oscillations were suppressed. In the adult LL offspring (reared in LD during postpartum), we observed complete lack of day/night differences in plasma melatonin and decreased day/night differences in plasma corticosterone. In the adult LL offspring, overall hippocampal day/night difference of gene expression was decreased, which was accompanied by a significant deficit of spatial memory. Notably, maternal melatonin replacement to dams subjected to gestational chronodisruption prevented the effects observed in both, LL fetuses and adult LL offspring. Collectively, the present data point to adverse effects of gestational chronodisruption on long-term cognitive function; raising challenging questions about the consequences of shift work during

  17. Altered neural activity of magnitude estimation processing in adults with the fragile X premutation.

    PubMed

    Kim, So-Yeon; Hashimoto, Ryu-ichiro; Tassone, Flora; Simon, Tony J; Rivera, Susan M

    2013-12-01

    Mutations of the fragile X mental retardation 1 (FMR1) gene are the genetic cause of fragile X syndrome (FXS). Expanded CGG trinucleotide repeat (>200 repeats) result in transcriptional silencing of the FMR1 gene and deficiency/absence of the FMR1 protein (FMRP). Carriers with a premutation allele (55-200 CGG repeats) are often associated with mildly reduced levels of FMRP and/or elevated levels of FMR1 mRNA, and are associated with the risk of developing a neurodegenerative disorder known as fragile X-associated tremor/ataxia syndrome (FXTAS). While impairments in numerical processing have been well documented in FXS, recent behavioral research suggests that premutation carriers also present with subtle but significant impairments in numerical processing. Using fMRI, the current study examined whether asymptomatic adults with the premutation would show aberrant neural correlates of magnitude estimation processing in the fronto-parietal area. Using a magnitude estimation task, we demonstrated that activity in the intraparietal sulcus and inferior frontal gyrus, associated with magnitude estimation processing, was significantly attenuated in premutation carriers compared to their neurotypical counterparts despite their comparable behavioral performance. Further, multiple regression analysis using CGG repeat size and FMR1 mRNA indicated that increased CGG repeat size is a primary factor for the decreased fronto-parietal activity, suggesting that reduced FMRP, rather than a toxic gain-of-function effect from elevated mRNA, contributes to altered neural activity of magnitude estimation processing in premutation carriers. In conclusion, we provide the first evidence on the aberrant neural correlates of magnitude estimation processing in premutation carriers accounted for by their FMR1 gene expression.

  18. Attenuated Neural Processing of Risk in Young Adults at Risk for Stimulant Dependence

    PubMed Central

    Reske, Martina; Stewart, Jennifer L.; Flagan, Taru M.; Paulus, Martin P.

    2015-01-01

    Objective Approximately 10% of young adults report non-medical use of stimulants (cocaine, amphetamine, methylphenidate), which puts them at risk for the development of dependence. This fMRI study investigates whether subjects at early stages of stimulant use show altered decision making processing. Methods 158 occasional stimulants users (OSU) and 50 comparison subjects (CS) performed a “risky gains” decision making task during which they could select safe options (cash in 20 cents) or gamble them for double or nothing in two consecutive gambles (win or lose 40 or 80 cents, “risky decisions”). The primary analysis focused on risky versus safe decisions. Three secondary analyses were conducted: First, a robust regression examined the effect of lifetime exposure to stimulants and marijuana; second, subgroups of OSU with >1000 (n = 42), or <50 lifetime marijuana uses (n = 32), were compared to CS with <50 lifetime uses (n = 46) to examine potential marijuana effects; third, brain activation associated with behavioral adjustment following monetary losses was probed. Results There were no behavioral differences between groups. OSU showed attenuated activation across risky and safe decisions in prefrontal cortex, insula, and dorsal striatum, exhibited lower anterior cingulate cortex (ACC) and dorsal striatum activation for risky decisions and greater inferior frontal gyrus activation for safe decisions. Those OSU with relatively more stimulant use showed greater dorsal ACC and posterior insula attenuation. In comparison, greater lifetime marijuana use was associated with less neural differentiation between risky and safe decisions. OSU who chose more safe responses after losses exhibited similarities with CS relative to those preferring risky options. Discussion Individuals at risk for the development of stimulant use disorders presented less differentiated neural processing of risky and safe options. Specifically, OSU show attenuated brain response in regions

  19. Designer Self-Assembling Peptide Nanofiber Scaffolds for Adult Mouse Neural Stem Cell 3-Dimensional Cultures

    PubMed Central

    Gelain, Fabrizio; Bottai, Daniele; Vescovi, Angleo; Zhang, Shuguang

    2006-01-01

    Biomedical researchers have become increasingly aware of the limitations of conventional 2-dimensional tissue cell culture systems, including coated Petri dishes, multi-well plates and slides, to fully address many critical issues in cell biology, cancer biology and neurobiology, such as the 3-D microenvironment, 3-D gradient diffusion, 3-D cell migration and 3-D cell-cell contact interactions. In order to fully understand how cells behave in the 3-D body, it is important to develop a well-controlled 3-D cell culture system where every single ingredient is known. Here we report the development of a 3-D cell culture system using a designer peptide nanofiber scaffold with mouse adult neural stem cells. We attached several functional motifs, including cell adhesion, differentiation and bone marrow homing motifs, to a self-assembling peptide RADA16 (Ac-RADARADARADARADA-COHN2). These functionalized peptides undergo self-assembly into a nanofiber structure similar to Matrigel. During cell culture, the cells were fully embedded in the 3-D environment of the scaffold. Two of the peptide scaffolds containing bone marrow homing motifs significantly enhanced the neural cell survival without extra soluble growth and neurotrophic factors to the routine cell culture media. In these designer scaffolds, the cell populations with β-Tubulin+, GFAP+ and Nestin+ markers are similar to those found in cell populations cultured on Matrigel. The gene expression profiling array experiments showed selective gene expression, possibly involved in neural stem cell adhesion and differentiation. Because the synthetic peptides are intrinsically pure and a number of desired function cellular motifs are easy to incorporate, these designer peptide nanofiber scaffolds provide a promising controlled 3-D culture system for diverse tissue cells, and are useful as well for general molecular and cell biology. PMID:17205123

  20. Electrical coupling can prevent expression of adult-like properties in an embryonic neural circuit.

    PubMed

    Bem, Tiaza; Le Feuvre, Yves; Simmers, John; Meyrand, Pierre

    2002-01-01

    Electrical coupling is widespread in developing nervous systems and plays a major role in circuit formation and patterning of activity. In most reported cases, such coupling between rhythmogenic neurons tends to synchronize and enhance their oscillatory behavior, thereby producing monophasic rhythmic output. However, in many adult networks, such as those responsible for rhythmic motor behavior, oscillatory neurons are linked by synaptic inhibition to produce rhythmic output with multiple phases. The question then arises whether such networks are still able to generate multiphasic output in the early stage of development when electrical coupling is abundant. A suitable model for addressing this issue is the lobster stomatogastric nervous system (STNS). In the adult animal, the STNS consists of three discrete neural networks that are comprised of oscillatory neurons interconnected by reciprocal inhibition. These networks generate three distinct rhythmic motor patterns with large amplitude neuronal oscillations. By contrast, in the embryo the same neuronal population expresses a single multiphasic rhythm with small-amplitude oscillations. Recent findings have revealed that adult-like network properties are already present early in the embryonic system but are masked by an as yet unknown mechanism. Here we use computer simulation to test whether extensive electrical coupling may be involved in masking adult-like properties in the embryonic STNS. Our basic model consists of three different adult-like STNS networks that are built of relaxation oscillators interconnected by reciprocal synaptic inhibition. Individual model cells generate slow membrane potential oscillations without action potentials. The introduction of widespread electrical coupling between members of these networks dampens oscillation amplitudes and, at moderate coupling strengths, may coordinate neuronal activity into a single rhythm with different phases, which is strongly reminiscent of embryonic STNS

  1. Anxiety and neural responses to infant and adult faces during pregnancy.

    PubMed

    Rutherford, Helena J V; Byrne, Simon P; Austin, Grace M; Lee, Jonathan D; Crowley, Michael J; Mayes, Linda C

    2017-03-06

    Women are vulnerable to anxiety during pregnancy and postpartum. However, little is known about antenatal anxiety and neural processing of infant-relevant information. In this experiment, the N170, P300, and LPP (late positive potential) event-related potentials were measured from 43 pregnant women as they viewed infant and adult faces, which were either neutral or distressed in expression. Mother's self-reported anxiety levels were also assessed. The N170 was comparable across face conditions and was not associated with anxiety. However, our central finding was that greater levels of antenatal anxiety were associated with a larger LPP, but only for neutral infant faces. Results suggest that antenatal anxiety may result in deeper processing of neutral, emotionally ambiguous, infant faces during pregnancy. These findings are discussed in light of other work indicating an interpretive bias toward threat in response to neutral stimuli in anxiety.

  2. Long-lasting memory deficits in mice withdrawn from cocaine are concomitant with neuroadaptations in hippocampal basal activity, GABAergic interneurons and adult neurogenesis

    PubMed Central

    Ladrón de Guevara-Miranda, David; Millón, Carmelo; Rosell-Valle, Cristina; Pérez-Fernández, Mercedes; Missiroli, Michele; Serrano, Antonia; Pavón, Francisco J.; Rodríguez de Fonseca, Fernando; Martínez-Losa, Magdalena; Álvarez-Dolado, Manuel; Santín, Luis J.

    2017-01-01

    ABSTRACT Cocaine addiction disorder is notably aggravated by concomitant cognitive and emotional pathology that impedes recovery. We studied whether a persistent cognitive/emotional dysregulation in mice withdrawn from cocaine holds a neurobiological correlate within the hippocampus, a limbic region with a key role in anxiety and memory but that has been scarcely investigated in cocaine addiction research. Mice were submitted to a chronic cocaine (20 mg/kg/day for 12 days) or vehicle treatment followed by 44 drug-free days. Some mice were then assessed on a battery of emotional (elevated plus-maze, light/dark box, open field, forced swimming) and cognitive (object and place recognition memory, cocaine-induced conditioned place preference, continuous spontaneous alternation) behavioral tests, while other mice remained in their home cage. Relevant hippocampal features [basal c-Fos activity, GABA+, parvalbumin (PV)+ and neuropeptide Y (NPY)+ interneurons and adult neurogenesis (cell proliferation and immature neurons)] were immunohistochemically assessed 73 days after the chronic cocaine or vehicle protocol. The cocaine-withdrawn mice showed no remarkable exploratory or emotional alterations but were consistently impaired in all the cognitive tasks. All the cocaine-withdrawn groups, independent of whether they were submitted to behavioral assessment or not, showed enhanced basal c-Fos expression and an increased number of GABA+ cells in the dentate gyrus. Moreover, the cocaine-withdrawn mice previously submitted to behavioral training displayed a blunted experience-dependent regulation of PV+ and NPY+ neurons in the dentate gyrus, and neurogenesis in the hippocampus. Results highlight the importance of hippocampal neuroplasticity for the ingrained cognitive deficits present during chronic cocaine withdrawal. PMID:28138095

  3. Long-lasting memory deficits in mice withdrawn from cocaine are concomitant with neuroadaptations in hippocampal basal activity, GABAergic interneurons and adult neurogenesis.

    PubMed

    Ladrón de Guevara-Miranda, David; Millón, Carmelo; Rosell-Valle, Cristina; Pérez-Fernández, Mercedes; Missiroli, Michele; Serrano, Antonia; Pavón, Francisco J; Rodríguez de Fonseca, Fernando; Martínez-Losa, Magdalena; Álvarez-Dolado, Manuel; Santín, Luis J; Castilla-Ortega, Estela

    2017-03-01

    Cocaine addiction disorder is notably aggravated by concomitant cognitive and emotional pathology that impedes recovery. We studied whether a persistent cognitive/emotional dysregulation in mice withdrawn from cocaine holds a neurobiological correlate within the hippocampus, a limbic region with a key role in anxiety and memory but that has been scarcely investigated in cocaine addiction research. Mice were submitted to a chronic cocaine (20 mg/kg/day for 12 days) or vehicle treatment followed by 44 drug-free days. Some mice were then assessed on a battery of emotional (elevated plus-maze, light/dark box, open field, forced swimming) and cognitive (object and place recognition memory, cocaine-induced conditioned place preference, continuous spontaneous alternation) behavioral tests, while other mice remained in their home cage. Relevant hippocampal features [basal c-Fos activity, GABA(+), parvalbumin (PV)(+) and neuropeptide Y (NPY)(+) interneurons and adult neurogenesis (cell proliferation and immature neurons)] were immunohistochemically assessed 73 days after the chronic cocaine or vehicle protocol. The cocaine-withdrawn mice showed no remarkable exploratory or emotional alterations but were consistently impaired in all the cognitive tasks. All the cocaine-withdrawn groups, independent of whether they were submitted to behavioral assessment or not, showed enhanced basal c-Fos expression and an increased number of GABA(+) cells in the dentate gyrus. Moreover, the cocaine-withdrawn mice previously submitted to behavioral training displayed a blunted experience-dependent regulation of PV(+) and NPY(+) neurons in the dentate gyrus, and neurogenesis in the hippocampus. Results highlight the importance of hi