奈穂子 金子 - Academia.edu (original) (raw)
Papers by 奈穂子 金子
Proceedings for Annual Meeting of The Japanese Pharmacological Society
Ischemic stroke causes massive neuronal loss in the brain, leading to persistent neurological def... more Ischemic stroke causes massive neuronal loss in the brain, leading to persistent neurological deficits. After brain morphogenesis during development, new neurons can be generated only in several areas including the ventricularsubventricular zone (V-SVZ) located at the walls of lateral ventricles. While the newly-generated neurons in the V-SVZ migrate toward the infarct area to replace damaged neurons, the regenerative response is insufficient to induce functional recovery. We are studying the mechanisms of neuronal regeneration using a mouse model for ischemic stroke. Immediately after stroke, local astrocytes a major glial population become hypertrophic and proliferative. We found that the V-SVZ-derived new neurons use a diffusible protein Slit1 to migrate toward the lesion passing through the meshwork of astrocytic processes. Lentivirus-mediated Slit1 overexpression in the new neurons transplanted into the post-stroke brain migrated closer to the lesion than the control neurons, where they mature into multiple types of neurons depending on their positioning 5-10 weeks later. These results suggest that manipulating interactions with astrocytes is critical for fate determination of the new neurons, which will be critical for functional neuronal regeneration in stem/progenitor cell-based therapies for brain injury.
Frontiers in Neuroscience, 2022
Additional file 3: Data S3. Details of statistical analysis for Fig. 4
The SAGE Encyclopedia of Abnormal and Clinical Psychology
IBRO Reports, 2019
hippocampus can drive novelty-associated enhancement of memory retention through non-canonical re... more hippocampus can drive novelty-associated enhancement of memory retention through non-canonical release of dopamine in the hippocampus, in line with the synaptic tagging and capture theory of initial memory consolidation. These studies also raise a possibility that the impact of distinct novel experiences which, by their very nature, bear minimal relationship to past experiences ('distinct novelty') may differ from novel experiences that share some commonality with past experiences ('common novelty') (Yamasaki and Takeuchi, Neural Plasticity, 2017; Duszkiewicz et al., Trends Neurosci, 2019). We now propose that memory of events accompanied by novelty can be selectively retained through two distinct dopaminergic mechanisms, depending on the nature of the novel experience itself.
Advanced Healthcare Materials, 2017
Ischemic brain stroke is caused by blood flow interruption, leading to focal ischemia, neuron dea... more Ischemic brain stroke is caused by blood flow interruption, leading to focal ischemia, neuron death, and motor, sensory, and/or cognitive dysfunctions. Angiogenesis, neovascularization from existing blood vessel, is essential for tissue growth and repair. Proangiogenic therapy for stroke is promising for preventing excess neuron death and improving functional recovery. Vascular endothelial growth factor (VEGF) is a critical factor for angiogenesis by promoting the proliferation, the survival, and the migration of endothelial cells. Here, angiogenic biomaterials to support injured brain regeneration are developed. Porous laminin (LN)‐rich sponge (LN‐sponge), on which histidine‐tagged VEGF (VEGF‐Histag) is immobilized via affinity interaction is developed. In an in vivo mouse stroke model, transplanting VEGF‐Histag‐LN‐sponge produces remarkably stronger angiogenic activity than transplanting LN‐sponge with soluble VEGF. The findings indicate that using affinity interactions to immobil...
Neurogenesis in the Adult Brain I, 2011
ABSTRACT Production of new neurons in the subventricular zone (SVZ) continues into adulthood. Neu... more ABSTRACT Production of new neurons in the subventricular zone (SVZ) continues into adulthood. Neuroblasts generated in the SVZ migrate in chains rostrally toward the olfactory bulb (OB), where they are differentiated into olfactory interneurons. In this paper, we will review our recent studies on production, migration and survival of newly-generated neurons in the adult mouse brain. Although the precise mechanisms controlling the migration of neuroblasts remain unclear, some molecules related to cell adhesion, cytoskeletal regulation or attractive/repulsive cues have been shown to be involved in this process. We have recently demonstrated that neuroblast migration parallels cerebrospinal fluid flow caused by integrated beating of ependymal cilia. While SVZ neuroblasts migrate only toward the OB under physiological conditions, we found that they could reach striatum in a mouse model of focal ischemia using blood vessels as their scaffold. The majority of the newly-generated neurons are known to die before they are integrated into neuronal circuits. However, we found that their survival could be promoted by the long-term administration of donepezil, an acetylcholinesterase inhibitor that is widely used for the treatment of Alzheimer's disease. Understanding more precise and comprehensive mechanisms of adult neurogenesis should lead to future development of regenerative therapies for neuropsychiatric diseases.
Neural Stem Cells, 2008
Neural stem cells (NSCs) have been identified in the mature central nervous system (CNS), and the... more Neural stem cells (NSCs) have been identified in the mature central nervous system (CNS), and they reside in specific areas. Cultures of NSCs can be successfully established in vitro by exploiting the NeuroSphere assay. This methodology relies on the continuous exposure of neural cells to mitogens such as epidermal growth factor and fibroblast growth factor-2. Under these conditions, only NSCs and highly undifferentiated progenitors proliferate, whereas committed precursors and terminally differentiated cells are eliminated from the culture. The proper application of this method to the cells allows the establishment of long-term expanding stable NSC lines, starting from different neural tissues as the adult rodent CNS and human brain tumor specimens.
Neuron, 2020
Highlights d Adult-born neuron (ABN) activity during sleep can be seen using Ca 2+ imaging d ABNs... more Highlights d Adult-born neuron (ABN) activity during sleep can be seen using Ca 2+ imaging d ABNs active after learning reactivate in subsequent rapid eye movement (REM) sleep d Optogenetic manipulation of ABN activity in REM sleep impairs memory consolidation d This effect may be mediated by ABN synaptic plasticity
Neuroscience Research, 2011
Neuroscience Research, 2010
The CREB was phosphorylated at 3-6 h after reoxygenation and then declined toward basal levels af... more The CREB was phosphorylated at 3-6 h after reoxygenation and then declined toward basal levels after 12 h, whereas a significant enhancement of CRE activity was detected after 3 h and continued after 12 h. The activity of the full-length CREB, but not bZIP-less CREB, was enhanced after OGD. TORC1 translocated from the cytoplasm into the nucleus after OGD-reoxygenation. SIK2 levels decreased after OGD. When SIK2 was knocked down using SIK2specific miRNA, CRE activity was enhanced. The knockdown of SIK2 also attenuated neuronal death after OGD. Conclusion: The present study demonstrated that SIK2 plays a crucial role in TORC1-dependent neuronal survival after OGD.
Neuroscience Research, 2009
to neuronal Nogo receptors, thereby triggering signals that can inhibit differentiation, migratio... more to neuronal Nogo receptors, thereby triggering signals that can inhibit differentiation, migration, and neurite outgrowth of neurones. Thus, Nogo signalling is a potent endogenous inhibitor of adult CNS regeneration. Recently, we found that phosphorylation of a particular serine residue on the Nogo receptor NgR inhibits ligand binding, enabling neurite outgrowth even in the presence of the inhibitory myelin-associated proteins. Our work could provide a launching point for developing methods to stimulate neuronal regeneration in the adult mammalian CNS.
The Journal of Neuroscience, 2019
New neurons, referred to as neuroblasts, are continuously generated in the ventricular-subventric... more New neurons, referred to as neuroblasts, are continuously generated in the ventricular-subventricular zone of the brain throughout an animal's life. These neuroblasts are characterized by their unique potential for proliferation, formation of chain-like cell aggregates, and long-distance and high-speed migration through the rostral migratory stream (RMS) toward the olfactory bulb (OB), where they decelerate and differentiate into mature interneurons. The dynamic changes of ultrastructural features in postnatal-born neuroblasts during migration are not yet fully understood. Here we report the presence of a primary cilium, and its ultrastructural morphology and spatiotemporal dynamics, in migrating neuroblasts in the postnatal RMS and OB. The primary cilium was observed in migrating neuroblasts in the postnatal RMS and OB in male and female mice and zebrafish, and a male rhesus monkey. Inhibition of intraflagellar transport molecules in migrating neuroblasts impaired their ciliogenesis and rostral migration toward the OB. Serial section transmission electron microscopy revealed that each migrating neuroblast possesses either a pair of centrioles or a basal body with an immature or mature primary cilium. Using immunohistochemistry, live imaging, and serial block-face scanning electron microscopy, we demonstrate that the localization and orientation of the primary cilium are altered depending on the mitotic state, saltatory migration, and deceleration of neuroblasts. Together, our results highlight a close mutual relationship between spatiotemporal regulation of the primary cilium and efficient chain migration of neuroblasts in the postnatal brain.
Neuroscience Research, 2009
Subventricular zone (SVZ) in the postnatal brain contains neural stem cells that have the capacit... more Subventricular zone (SVZ) in the postnatal brain contains neural stem cells that have the capacity to regenerate neural tissue after various lesions. Periventricular leukomalacia (PVL), a lesion of white matter around the cerebral ventricles in premature infants, induces long-term neurological deficits including cerebral palsy. Previous studies indicate that hypoxic-ischemic incidents are involved in the development of PVL. However, its precise mechanism remains unclear and currently there is no treatment for PVL. To understand the pathophysiology of PVL and possible molecular/cellular mechanisms for regeneration, we have established a mouse model of PVL using neonatal hypoxia-ischemia. BrdU-labeling and staining for cell-type specific markers revealed that neurogenesis and gliogenesis were activated in the SVZ, suggesting that SVZ-derived progenitors could contribute to the regeneration of damaged neural tissue after PVL.
Neuroscience Research, 2010
e245 strated that Ptf1a and Atoh1 are essential for the generation of cerebellar GABAergic and gl... more e245 strated that Ptf1a and Atoh1 are essential for the generation of cerebellar GABAergic and glutamatergic neurons, respectively. Furthermore, we also showed that Ptf1a and Atoh1 are expressed in distinct neuroepithelial regions throughout the rhombomere 1-8 and required for generation of distinct subtypes of neurons in the cochlear nucleus and precerebellar system, raising the possibility that these TFs determine the spatial identity of the neuroepithelium in the hindbrain. To test this possibility, we generated a novel knock-in mouse line carrying a mutation in which the Atoh1-coding genome sequence is replaced with the Ptf1a cDNA (Ptf1a Atoh1). In the cerebellum and hindbrain of both heterozygotes and homozygotes, Atoh1 was ectopicically expressed in the cerebellar VZ. In the Ptf1a Atoh1 mice, we found that VZ cells ectopically expressed Atoh1 produced glutamatergic neurons, suggesting that Atoh1 can confer the characteristics of the RL even within the VZ. By using an in utero electroporation technique, we introduced Atoh1 into the VZ and found that these cells migrated to the EGL, resembling the migratory behavior of glutamatergic granule cells. In contrast, we introduced Ptf1a into the RL and found these cells migrated radially, resembling the migratory behavior of GABAergic Purkinje cells. These results imply that Atoh1 and Ptf1a might be able to determine the identity of the RL and VZ, respectively. We also found Ptf1a and Atoh1 negatively regulated their expression to each other in the cerebellar neuroepithelium, which may contribute to generating two distinct non-overlapping neuroepithelial domains.
Molecular Brain, 2021
Metabolites underlying brain function and pathology are not as well understood as genes. Here, we... more Metabolites underlying brain function and pathology are not as well understood as genes. Here, we applied a novel metabolomics approach to further understand the mechanisms of memory processing in sleep. As hippocampal dentate gyrus neurons are known to consolidate contextual fear memory, we analyzed real-time changes in metabolites in the dentate gyrus in different sleep–wake states in mice. Throughout the study, we consistently detected more than > 200 metabolites. Metabolite profiles changed dramactically upon sleep–wake state transitions, leading to a clear separation of phenotypes between wakefulness and sleep. By contrast, contextual fear memory consolidation induced less obvious metabolite phenotypes. However, changes in purine metabolites were observed upon both sleep–wake state transitions and contextual fear memory consolidation. Dietary supplementation of certain purine metabolites impaired correlations between conditioned fear responses before and after memory consoli...
Molecular Brain, 2020
In many mammalian species, the production of new neurons in the hippocampal dentate gyrus continu... more In many mammalian species, the production of new neurons in the hippocampal dentate gyrus continues throughout life. Previous studies using rodents suggest that adult-born neurons are involved in memory and cognition tasks and mood regulation. Interferon-alpha (IFNα), a proinflammatory cytokine used for the treatment of chronic viral hepatitis and malignancies, frequently causes depressive symptoms in patients and animals, including non-human primates. We have previously demonstrated that chronic IFNα treatment decreases hippocampal neurogenesis in mice. Here, we investigated the effects of four-week human pegylated IFNα treatment on hippocampal neurogenesis and behavior in common marmosets. Continuous monitoring of voluntary activity levels using an actigraphy device suggested that adaptive ability is impaired in IFNα-treated animals. Analyses of BrdU-labeled cells expressing a marker for immature or mature neurons revealed a significant reduction in the number of new neurons in th...
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 9, 2018
In the rodent olfactory system, neuroblasts produced in the ventricular-subventricular zone of th... more In the rodent olfactory system, neuroblasts produced in the ventricular-subventricular zone of the postnatal brain migrate tangentially in chain-like cell aggregates toward the olfactory bulb (OB) through the rostral migratory stream (RMS). After reaching the OB, the chains are dissociated and the neuroblasts migrate individually and radially toward their final destination. The cellular and molecular mechanisms controlling cell-cell adhesion during this detachment remain unclear. Here we report that Fyn, a nonreceptor tyrosine kinase, regulates the detachment of neuroblasts from chains in the male and female mouse OB. By performing chemical screening and loss-of-function and gain-of-function experiments, we found that Fyn promotes somal disengagement from the chains and is involved in neuronal migration from the RMS into the granule cell layer of the OB. Fyn knockdown or Dab1 (disabled-1) deficiency caused p120-catenin to accumulate and adherens junction-like structures to be sustai...
Proceedings for Annual Meeting of The Japanese Pharmacological Society
Ischemic stroke causes massive neuronal loss in the brain, leading to persistent neurological def... more Ischemic stroke causes massive neuronal loss in the brain, leading to persistent neurological deficits. After brain morphogenesis during development, new neurons can be generated only in several areas including the ventricularsubventricular zone (V-SVZ) located at the walls of lateral ventricles. While the newly-generated neurons in the V-SVZ migrate toward the infarct area to replace damaged neurons, the regenerative response is insufficient to induce functional recovery. We are studying the mechanisms of neuronal regeneration using a mouse model for ischemic stroke. Immediately after stroke, local astrocytes a major glial population become hypertrophic and proliferative. We found that the V-SVZ-derived new neurons use a diffusible protein Slit1 to migrate toward the lesion passing through the meshwork of astrocytic processes. Lentivirus-mediated Slit1 overexpression in the new neurons transplanted into the post-stroke brain migrated closer to the lesion than the control neurons, where they mature into multiple types of neurons depending on their positioning 5-10 weeks later. These results suggest that manipulating interactions with astrocytes is critical for fate determination of the new neurons, which will be critical for functional neuronal regeneration in stem/progenitor cell-based therapies for brain injury.
Frontiers in Neuroscience, 2022
Additional file 3: Data S3. Details of statistical analysis for Fig. 4
The SAGE Encyclopedia of Abnormal and Clinical Psychology
IBRO Reports, 2019
hippocampus can drive novelty-associated enhancement of memory retention through non-canonical re... more hippocampus can drive novelty-associated enhancement of memory retention through non-canonical release of dopamine in the hippocampus, in line with the synaptic tagging and capture theory of initial memory consolidation. These studies also raise a possibility that the impact of distinct novel experiences which, by their very nature, bear minimal relationship to past experiences ('distinct novelty') may differ from novel experiences that share some commonality with past experiences ('common novelty') (Yamasaki and Takeuchi, Neural Plasticity, 2017; Duszkiewicz et al., Trends Neurosci, 2019). We now propose that memory of events accompanied by novelty can be selectively retained through two distinct dopaminergic mechanisms, depending on the nature of the novel experience itself.
Advanced Healthcare Materials, 2017
Ischemic brain stroke is caused by blood flow interruption, leading to focal ischemia, neuron dea... more Ischemic brain stroke is caused by blood flow interruption, leading to focal ischemia, neuron death, and motor, sensory, and/or cognitive dysfunctions. Angiogenesis, neovascularization from existing blood vessel, is essential for tissue growth and repair. Proangiogenic therapy for stroke is promising for preventing excess neuron death and improving functional recovery. Vascular endothelial growth factor (VEGF) is a critical factor for angiogenesis by promoting the proliferation, the survival, and the migration of endothelial cells. Here, angiogenic biomaterials to support injured brain regeneration are developed. Porous laminin (LN)‐rich sponge (LN‐sponge), on which histidine‐tagged VEGF (VEGF‐Histag) is immobilized via affinity interaction is developed. In an in vivo mouse stroke model, transplanting VEGF‐Histag‐LN‐sponge produces remarkably stronger angiogenic activity than transplanting LN‐sponge with soluble VEGF. The findings indicate that using affinity interactions to immobil...
Neurogenesis in the Adult Brain I, 2011
ABSTRACT Production of new neurons in the subventricular zone (SVZ) continues into adulthood. Neu... more ABSTRACT Production of new neurons in the subventricular zone (SVZ) continues into adulthood. Neuroblasts generated in the SVZ migrate in chains rostrally toward the olfactory bulb (OB), where they are differentiated into olfactory interneurons. In this paper, we will review our recent studies on production, migration and survival of newly-generated neurons in the adult mouse brain. Although the precise mechanisms controlling the migration of neuroblasts remain unclear, some molecules related to cell adhesion, cytoskeletal regulation or attractive/repulsive cues have been shown to be involved in this process. We have recently demonstrated that neuroblast migration parallels cerebrospinal fluid flow caused by integrated beating of ependymal cilia. While SVZ neuroblasts migrate only toward the OB under physiological conditions, we found that they could reach striatum in a mouse model of focal ischemia using blood vessels as their scaffold. The majority of the newly-generated neurons are known to die before they are integrated into neuronal circuits. However, we found that their survival could be promoted by the long-term administration of donepezil, an acetylcholinesterase inhibitor that is widely used for the treatment of Alzheimer's disease. Understanding more precise and comprehensive mechanisms of adult neurogenesis should lead to future development of regenerative therapies for neuropsychiatric diseases.
Neural Stem Cells, 2008
Neural stem cells (NSCs) have been identified in the mature central nervous system (CNS), and the... more Neural stem cells (NSCs) have been identified in the mature central nervous system (CNS), and they reside in specific areas. Cultures of NSCs can be successfully established in vitro by exploiting the NeuroSphere assay. This methodology relies on the continuous exposure of neural cells to mitogens such as epidermal growth factor and fibroblast growth factor-2. Under these conditions, only NSCs and highly undifferentiated progenitors proliferate, whereas committed precursors and terminally differentiated cells are eliminated from the culture. The proper application of this method to the cells allows the establishment of long-term expanding stable NSC lines, starting from different neural tissues as the adult rodent CNS and human brain tumor specimens.
Neuron, 2020
Highlights d Adult-born neuron (ABN) activity during sleep can be seen using Ca 2+ imaging d ABNs... more Highlights d Adult-born neuron (ABN) activity during sleep can be seen using Ca 2+ imaging d ABNs active after learning reactivate in subsequent rapid eye movement (REM) sleep d Optogenetic manipulation of ABN activity in REM sleep impairs memory consolidation d This effect may be mediated by ABN synaptic plasticity
Neuroscience Research, 2011
Neuroscience Research, 2010
The CREB was phosphorylated at 3-6 h after reoxygenation and then declined toward basal levels af... more The CREB was phosphorylated at 3-6 h after reoxygenation and then declined toward basal levels after 12 h, whereas a significant enhancement of CRE activity was detected after 3 h and continued after 12 h. The activity of the full-length CREB, but not bZIP-less CREB, was enhanced after OGD. TORC1 translocated from the cytoplasm into the nucleus after OGD-reoxygenation. SIK2 levels decreased after OGD. When SIK2 was knocked down using SIK2specific miRNA, CRE activity was enhanced. The knockdown of SIK2 also attenuated neuronal death after OGD. Conclusion: The present study demonstrated that SIK2 plays a crucial role in TORC1-dependent neuronal survival after OGD.
Neuroscience Research, 2009
to neuronal Nogo receptors, thereby triggering signals that can inhibit differentiation, migratio... more to neuronal Nogo receptors, thereby triggering signals that can inhibit differentiation, migration, and neurite outgrowth of neurones. Thus, Nogo signalling is a potent endogenous inhibitor of adult CNS regeneration. Recently, we found that phosphorylation of a particular serine residue on the Nogo receptor NgR inhibits ligand binding, enabling neurite outgrowth even in the presence of the inhibitory myelin-associated proteins. Our work could provide a launching point for developing methods to stimulate neuronal regeneration in the adult mammalian CNS.
The Journal of Neuroscience, 2019
New neurons, referred to as neuroblasts, are continuously generated in the ventricular-subventric... more New neurons, referred to as neuroblasts, are continuously generated in the ventricular-subventricular zone of the brain throughout an animal's life. These neuroblasts are characterized by their unique potential for proliferation, formation of chain-like cell aggregates, and long-distance and high-speed migration through the rostral migratory stream (RMS) toward the olfactory bulb (OB), where they decelerate and differentiate into mature interneurons. The dynamic changes of ultrastructural features in postnatal-born neuroblasts during migration are not yet fully understood. Here we report the presence of a primary cilium, and its ultrastructural morphology and spatiotemporal dynamics, in migrating neuroblasts in the postnatal RMS and OB. The primary cilium was observed in migrating neuroblasts in the postnatal RMS and OB in male and female mice and zebrafish, and a male rhesus monkey. Inhibition of intraflagellar transport molecules in migrating neuroblasts impaired their ciliogenesis and rostral migration toward the OB. Serial section transmission electron microscopy revealed that each migrating neuroblast possesses either a pair of centrioles or a basal body with an immature or mature primary cilium. Using immunohistochemistry, live imaging, and serial block-face scanning electron microscopy, we demonstrate that the localization and orientation of the primary cilium are altered depending on the mitotic state, saltatory migration, and deceleration of neuroblasts. Together, our results highlight a close mutual relationship between spatiotemporal regulation of the primary cilium and efficient chain migration of neuroblasts in the postnatal brain.
Neuroscience Research, 2009
Subventricular zone (SVZ) in the postnatal brain contains neural stem cells that have the capacit... more Subventricular zone (SVZ) in the postnatal brain contains neural stem cells that have the capacity to regenerate neural tissue after various lesions. Periventricular leukomalacia (PVL), a lesion of white matter around the cerebral ventricles in premature infants, induces long-term neurological deficits including cerebral palsy. Previous studies indicate that hypoxic-ischemic incidents are involved in the development of PVL. However, its precise mechanism remains unclear and currently there is no treatment for PVL. To understand the pathophysiology of PVL and possible molecular/cellular mechanisms for regeneration, we have established a mouse model of PVL using neonatal hypoxia-ischemia. BrdU-labeling and staining for cell-type specific markers revealed that neurogenesis and gliogenesis were activated in the SVZ, suggesting that SVZ-derived progenitors could contribute to the regeneration of damaged neural tissue after PVL.
Neuroscience Research, 2010
e245 strated that Ptf1a and Atoh1 are essential for the generation of cerebellar GABAergic and gl... more e245 strated that Ptf1a and Atoh1 are essential for the generation of cerebellar GABAergic and glutamatergic neurons, respectively. Furthermore, we also showed that Ptf1a and Atoh1 are expressed in distinct neuroepithelial regions throughout the rhombomere 1-8 and required for generation of distinct subtypes of neurons in the cochlear nucleus and precerebellar system, raising the possibility that these TFs determine the spatial identity of the neuroepithelium in the hindbrain. To test this possibility, we generated a novel knock-in mouse line carrying a mutation in which the Atoh1-coding genome sequence is replaced with the Ptf1a cDNA (Ptf1a Atoh1). In the cerebellum and hindbrain of both heterozygotes and homozygotes, Atoh1 was ectopicically expressed in the cerebellar VZ. In the Ptf1a Atoh1 mice, we found that VZ cells ectopically expressed Atoh1 produced glutamatergic neurons, suggesting that Atoh1 can confer the characteristics of the RL even within the VZ. By using an in utero electroporation technique, we introduced Atoh1 into the VZ and found that these cells migrated to the EGL, resembling the migratory behavior of glutamatergic granule cells. In contrast, we introduced Ptf1a into the RL and found these cells migrated radially, resembling the migratory behavior of GABAergic Purkinje cells. These results imply that Atoh1 and Ptf1a might be able to determine the identity of the RL and VZ, respectively. We also found Ptf1a and Atoh1 negatively regulated their expression to each other in the cerebellar neuroepithelium, which may contribute to generating two distinct non-overlapping neuroepithelial domains.
Molecular Brain, 2021
Metabolites underlying brain function and pathology are not as well understood as genes. Here, we... more Metabolites underlying brain function and pathology are not as well understood as genes. Here, we applied a novel metabolomics approach to further understand the mechanisms of memory processing in sleep. As hippocampal dentate gyrus neurons are known to consolidate contextual fear memory, we analyzed real-time changes in metabolites in the dentate gyrus in different sleep–wake states in mice. Throughout the study, we consistently detected more than > 200 metabolites. Metabolite profiles changed dramactically upon sleep–wake state transitions, leading to a clear separation of phenotypes between wakefulness and sleep. By contrast, contextual fear memory consolidation induced less obvious metabolite phenotypes. However, changes in purine metabolites were observed upon both sleep–wake state transitions and contextual fear memory consolidation. Dietary supplementation of certain purine metabolites impaired correlations between conditioned fear responses before and after memory consoli...
Molecular Brain, 2020
In many mammalian species, the production of new neurons in the hippocampal dentate gyrus continu... more In many mammalian species, the production of new neurons in the hippocampal dentate gyrus continues throughout life. Previous studies using rodents suggest that adult-born neurons are involved in memory and cognition tasks and mood regulation. Interferon-alpha (IFNα), a proinflammatory cytokine used for the treatment of chronic viral hepatitis and malignancies, frequently causes depressive symptoms in patients and animals, including non-human primates. We have previously demonstrated that chronic IFNα treatment decreases hippocampal neurogenesis in mice. Here, we investigated the effects of four-week human pegylated IFNα treatment on hippocampal neurogenesis and behavior in common marmosets. Continuous monitoring of voluntary activity levels using an actigraphy device suggested that adaptive ability is impaired in IFNα-treated animals. Analyses of BrdU-labeled cells expressing a marker for immature or mature neurons revealed a significant reduction in the number of new neurons in th...
The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 9, 2018
In the rodent olfactory system, neuroblasts produced in the ventricular-subventricular zone of th... more In the rodent olfactory system, neuroblasts produced in the ventricular-subventricular zone of the postnatal brain migrate tangentially in chain-like cell aggregates toward the olfactory bulb (OB) through the rostral migratory stream (RMS). After reaching the OB, the chains are dissociated and the neuroblasts migrate individually and radially toward their final destination. The cellular and molecular mechanisms controlling cell-cell adhesion during this detachment remain unclear. Here we report that Fyn, a nonreceptor tyrosine kinase, regulates the detachment of neuroblasts from chains in the male and female mouse OB. By performing chemical screening and loss-of-function and gain-of-function experiments, we found that Fyn promotes somal disengagement from the chains and is involved in neuronal migration from the RMS into the granule cell layer of the OB. Fyn knockdown or Dab1 (disabled-1) deficiency caused p120-catenin to accumulate and adherens junction-like structures to be sustai...