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The Keio Journal of Medicine 2013Even in the adult brain, new neurons are continuously generated from endogenous neural stem cells that reside in two restricted regions: the subventricular zone (SVZ) of... (Review)
Review
Even in the adult brain, new neurons are continuously generated from endogenous neural stem cells that reside in two restricted regions: the subventricular zone (SVZ) of the lateral ventricle and the dentate gyrus of the hippocampus. These new neurons are integrated into the mature neuronal circuitry and become involved in various functions, thereby contributing to structural and functional plasticity in the adult brain. In this review, we summarize our recent findings on the regulatory mechanisms of SVZ neurogenesis under physiological and pathological conditions in various animal models. Some of these findings were presented in the Kitazato Prize Lecture at Keio University School of Medicine in 2011.
Topics: Adult; Animals; Cell Differentiation; Cell Movement; Cytoskeletal Proteins; Dentate Gyrus; Gene Expression Regulation; Humans; Lateral Ventricles; Neural Stem Cells; Neurogenesis; Neurons; Receptors, Notch; Recovery of Function; Wnt Signaling Pathway
PubMed: 23563788
DOI: 10.2302/kjm.2012-0005-re -
The Journal of Neuroscience : the... Apr 2017Obstructive sleep apnea syndrome (OSAS) is associated with intermittent hypoxia and sleep loss. In children, impairments of cognitive function are important...
Obstructive sleep apnea syndrome (OSAS) is associated with intermittent hypoxia and sleep loss. In children, impairments of cognitive function are important manifestations, but the underlying pathology is unknown. We hypothesized that OSAS would affect the dentate gyrus, a hippocampal subdivision essential to neurogenesis and cognition, and that this impact would further affect cognitive function in children. In children with OSAS ( = 11) and control subjects ( = 12; age and sex matched), we performed diffusion tensor imaging and structural MRI, polysomnography, and neuropsychological assessments. We found that OSAS was associated with decreased mean diffusivity of the left dentate gyrus ( = 0.002; false discovery rate corrected; adjusting for sex, age, and body mass index), showing a large effect size (partial η = 0.491), but not with any other structural measures across the brain. Decreased dentate gyrus mean diffusivity correlated with a higher apnea hypopnea index (Spearman's = -0.50, = 0.008) and a greater arousal index ( = -0.44, = 0.017). OSAS did not significantly affect neuropsychological measures ( values >0.5); however, a lower verbal learning score correlated with lower dentate gyrus mean diffusivity ( = 0.54, = 0.004). Path analysis demonstrated that dentate gyrus mean diffusivity mediates the impact of OSAS on verbal learning capacity. Finally, the diagnostic accuracy of a regression model based on dentate gyrus mean diffusivity reached 85.8% (cross validated). This study demonstrates a likely pathway of effects of OSAS on neurocognitive function in children, as well as potential utility of the dentate gyrus mean diffusivity as an early marker of brain pathology in children with OSAS. In this study we investigate the relationships between dentate gyrus structure, hippocampus-dependent cognition, and obstructive sleep apnea syndrome (OSAS). We demonstrate lower mean diffusivity of the dentate gyrus in children with OSAS, which correlates with a lower verbal learning and memory score. This study provides new evidence of disrupted microstructure of the dentate gyrus in children with OSAS that may help explain some of the neurocognitive deficits described in these children.
Topics: Adolescent; Case-Control Studies; Dentate Gyrus; Female; Humans; Magnetic Resonance Imaging; Male; Memory; Sleep Apnea, Obstructive; Verbal Learning
PubMed: 28320844
DOI: 10.1523/JNEUROSCI.3583-16.2017 -
Cold Spring Harbor Perspectives in... Dec 2015The adult hippocampus generates functional dentate granule cells (GCs) that release glutamate onto target cells in the hilus and cornus ammonis (CA)3 region, and receive... (Review)
Review
The adult hippocampus generates functional dentate granule cells (GCs) that release glutamate onto target cells in the hilus and cornus ammonis (CA)3 region, and receive glutamatergic and γ-aminobutyric acid (GABA)ergic inputs that tightly control their spiking activity. The slow and sequential development of their excitatory and inhibitory inputs makes them particularly relevant for information processing. Although they are still immature, new neurons are recruited by afferent activity and display increased excitability, enhanced activity-dependent plasticity of their input and output connections, and a high rate of synaptogenesis. Once fully mature, new GCs show all the hallmarks of neurons generated during development. In this review, we focus on how developing neurons remodel the adult dentate gyrus and discuss key aspects that illustrate the potential of neurogenesis as a mechanism for circuit plasticity and function.
Topics: Dentate Gyrus; Hippocampus; Models, Biological; Nerve Net; Neurogenesis; Neuronal Plasticity; Neurons; Synapses
PubMed: 26637288
DOI: 10.1101/cshperspect.a018903 -
Frontiers in Neural Circuits 2013Dentate gyrus granule cells (GCs) have been suggested to synthesize both GABA and glutamate immediately after birth and under pathological conditions in the adult....
Dentate gyrus granule cells (GCs) have been suggested to synthesize both GABA and glutamate immediately after birth and under pathological conditions in the adult. Expression of the GABA synthesizing enzyme GAD67 by GCs during the first few weeks of postnatal development may then allow for transient GABA synthesis and synaptic release from these cells. Here, using the GAD67-EGFP transgenic strain G42, we explored the phenotype of GAD67-expressing GCs in the mouse dentate gyrus. We report a transient, GAD67-driven EGFP expression in differentiating GCs throughout ontogenesis. EGFP expression correlates with the expression of GAD and molecular markers of GABA release and uptake in 2-4 weeks post-mitotic GCs. These rather immature cells are able to fire action potentials (APs) and are synaptically integrated in the hippocampal network. Yet they show physiological properties that differentiate them from mature GCs. Finally, GAD67-expressing GCs express a specific complement of GABAA receptor subunits as well as distinctive features of synaptic and tonic GABA signaling. Our results reveal that GAD67 expression in dentate gyrus GCs is a transient marker of late differentiation that persists throughout life and the G42 strain may be used to visualize newborn GCs at a specific, well-defined differentiation stage.
Topics: Animals; Animals, Newborn; Cell Differentiation; Dentate Gyrus; Gene Expression Regulation, Enzymologic; Glutamate Decarboxylase; Hippocampus; Mice; Mice, Inbred C57BL; Mice, Transgenic; Organ Culture Techniques
PubMed: 23565079
DOI: 10.3389/fncir.2013.00060 -
The Journal of Comparative Neurology Dec 2002The rat dentate gyrus is usually described as relatively homogeneous. Here, we present anatomic and physiological data which demonstrate that there are striking...
The rat dentate gyrus is usually described as relatively homogeneous. Here, we present anatomic and physiological data which demonstrate that there are striking differences between the supra- and infrapyramidal blades after status epilepticus and recurrent seizures. These differences appear to be an accentuation of a subtle asymmetry present in normal rats. In both pilocarpine and kainic acid models, there was greater mossy fiber sprouting in the infrapyramidal blade. This occurred primarily in the middle third of the hippocampus. Asymmetric sprouting was evident both with Timm stain as well as antisera to brain-derived neurotrophic factor (BDNF) or neuropeptide Y (NPY). In addition, surviving NPY-immunoreactive hilar neurons were distributed preferentially in the suprapyramidal region of the hilus. Extracellular recordings from infrapyramidal sites in hippocampal slices of pilocarpine-treated rats showed larger population spikes and weaker paired-pulse inhibition in response to perforant path stimulation relative to suprapyramidal recordings. A single stimulus could evoke burst discharges in infrapyramidal granule cells but not suprapyramidal blade neurons. BDNF exposure led to spontaneous epileptiform discharges that were larger in amplitude and longer lasting in the infrapyramidal blade. Stimulation of the infrapyramidal molecular layer evoked larger responses in area CA3 than suprapyramidal stimulation. In slices from the temporal pole, in which anatomic evidence of asymmetry waned, there was little evidence of physiological asymmetry either. Of interest, some normal rats also showed signs of greater evoked responses in the infrapyramidal blade, and this could be detected with both microelectrode recording and optical imaging techniques. Although there were no signs of hyperexcitability in normal rats, the data suggest that there is some asymmetry in the normal dentate gyrus and this asymmetry is enhanced by seizures. Taken together, the results suggest that supra- and infrapyramidal blades of the dentate gyrus could have different circuit functions and that the infrapyramidal blade may play a greater role in activating the hippocampus.
Topics: Animals; Brain-Derived Neurotrophic Factor; Dentate Gyrus; Electrophysiology; Excitatory Amino Acid Agonists; Immunohistochemistry; Kainic Acid; Male; Mossy Fibers, Hippocampal; Muscarinic Agonists; Neuropeptide Y; Pilocarpine; Rats; Rats, Sprague-Dawley; Seizures; Status Epilepticus; Synapses
PubMed: 12455007
DOI: 10.1002/cne.10449 -
Frontiers in Neural Circuits 2013The hippocampus is crucial for memory formation. New neurons are added throughout life to the hippocampal dentate gyrus (DG), a brain area considered important for... (Review)
Review
The hippocampus is crucial for memory formation. New neurons are added throughout life to the hippocampal dentate gyrus (DG), a brain area considered important for differential storage of similar experiences and contexts. To better understand the functional contribution of adult neurogenesis to pattern separation processes, we recently used a novel synapse specific trans-neuronal tracing approach to identify the (sub) cortical inputs to new dentate granule cells (GCs). It was observed that newly born neurons receive sequential innervation from structures important for memory function. Initially, septal-hippocampal cells provide input to new neurons, including transient innervation from mature GCs as well as direct feedback from area CA3 pyramidal neurons. After about 1 month perirhinal (PRH) and lateral entorhinal cortex (LEC), brain areas deemed relevant to integration of novel sensory and environmental information, become substantial input to new GCs. Here, we review the developmental time-course and proposed functional relevance of new neurons, within the context of their unique neural circuitry.
Topics: Animals; Dentate Gyrus; Humans; Nerve Net; Neurogenesis; Neurons; Synapses; Time Factors
PubMed: 23443839
DOI: 10.3389/fncir.2013.00015 -
Neuron May 2011Recently, investigation of new neurons in memory formation has focused on a specific function-pattern separation. However, it has been difficult to reconcile the form of... (Review)
Review
Recently, investigation of new neurons in memory formation has focused on a specific function-pattern separation. However, it has been difficult to reconcile the form of separation tested in behavioral tasks with how it is conceptualized according to computational and electrophysiology perspectives. Here, we propose a memory resolution hypothesis that considers the unique information contributions of broadly tuned young neurons and highly specific mature neurons and describe how the fidelity of memories can relate to spatial and contextual discrimination. See the related Perspective from Sahay, Wilson, and Hen, "Pattern Separation: A Common Function for New Neurons in Hippocampus and Olfactory Bulb," in this issue of Neuron.
Topics: Adult; Age Factors; Animals; Dentate Gyrus; Humans; Memory; Neurogenesis
PubMed: 21609818
DOI: 10.1016/j.neuron.2011.05.010 -
Cell Reports Dec 2018The supramammillary nucleus (SuM) of the hypothalamus projects to the dentate gyrus (DG) and the CA2 region of the hippocampus. Although the SuM-to-hippocampus circuits...
The supramammillary nucleus (SuM) of the hypothalamus projects to the dentate gyrus (DG) and the CA2 region of the hippocampus. Although the SuM-to-hippocampus circuits have been implicated in spatial and emotional memory formation, little is known about precise neural connections between the SuM and hippocampus. Here, we report that axons of SuM neurons make monosynaptic connections to granule cells (GCs) and GABAergic interneurons, but not to hilar mossy cells, in the DG and co-release glutamate and γ-aminobutyric acid (GABA) at these synapses. Although inputs from the SuM can excite some interneurons, the inputs alone fail to generate spikes in GCs. However, despite the insufficient excitatory drive and GABAergic co-transmission, SuM inputs have net excitatory effects on GCs and can potentiate GC firing when temporally associated with perforant path inputs. Our results indicate that the SuM influences DG information processing by modulating GC outputs.
Topics: Action Potentials; Afferent Pathways; Animals; Dentate Gyrus; Glutamic Acid; Hypothalamus, Posterior; Interneurons; Mice, Inbred C57BL; Mossy Fibers, Hippocampal; Optogenetics; Perforant Pathway; Synapses; gamma-Aminobutyric Acid
PubMed: 30517859
DOI: 10.1016/j.celrep.2018.11.016 -
Physiological Reviews Oct 2014Adult neurogenesis in the hippocampus is a notable process due not only to its uniqueness and potential impact on cognition but also to its localized vertical... (Review)
Review
Adult neurogenesis in the hippocampus is a notable process due not only to its uniqueness and potential impact on cognition but also to its localized vertical integration of different scales of neuroscience, ranging from molecular and cellular biology to behavior. This review summarizes the recent research regarding the process of adult neurogenesis from these different perspectives, with particular emphasis on the differentiation and development of new neurons, the regulation of the process by extrinsic and intrinsic factors, and their ultimate function in the hippocampus circuit. Arising from a local neural stem cell population, new neurons progress through several stages of maturation, ultimately integrating into the adult dentate gyrus network. The increased appreciation of the full neurogenesis process, from genes and cells to behavior and cognition, makes neurogenesis both a unique case study for how scales in neuroscience can link together and suggests neurogenesis as a potential target for therapeutic intervention for a number of disorders.
Topics: Animals; Brain; Dentate Gyrus; Gene Expression Regulation; Humans; Neural Stem Cells; Neurogenesis
PubMed: 25287858
DOI: 10.1152/physrev.00004.2014 -
BMB Reports Feb 2010Homozygous staggerer (RORa(sg/sg)) mice showed a severe ataxia caused by cerebellum degeneration. Decreased and dysfunctional Rora is a main cause of this neurologic...
Homozygous staggerer (RORa(sg/sg)) mice showed a severe ataxia caused by cerebellum degeneration. Decreased and dysfunctional Rora is a main cause of this neurologic phenotype. The phenotype of staggerer mice has been well known in cerebellum. However, there has been rarely reported about cerebrum even though of staggerer is expressed in merely cerebellum but hippocampus, thalamus, cortex, and olfactory bulb. The expressions of Ki67, doublecortin (DCX), and NeuN, which are cell proliferation, neuronal differentiation and mature neuron markers, respectively, were measured with immunohistochemistry in dentate gyrus in staggerer mice in order to uncover whether staggerer can affect the change in dentate gyrus. The immunoreactivities of DCX and NeuN were significantly reduced in the dentate gyrus of staggerer mice than normal control, while Ki67 were rarely unchanged in staggerer mice. These results suggest that staggerer mutation has an influence on the neuronal differentiation and development not only in cerebellum but also in dentate gyrus.
Topics: Animals; Cell Differentiation; Cell Proliferation; DNA-Binding Proteins; Dentate Gyrus; Doublecortin Domain Proteins; Doublecortin Protein; Genotype; Homozygote; Ki-67 Antigen; Male; Mice; Mice, Neurologic Mutants; Microtubule-Associated Proteins; Nerve Tissue Proteins; Neurons; Neuropeptides; Nuclear Proteins
PubMed: 20193131
DOI: 10.5483/bmbrep.2010.43.2.122