scholarly journals Astrocyte-derived neurons provide excitatory input to the adult striatal circuitry

2021 ◽  
Vol 118 (33) ◽  
pp. e2104119118
Author(s):  
Matthijs C. Dorst ◽  
María Díaz-Moreno ◽  
David O. Dias ◽  
Eduardo L. Guimarães ◽  
Daniel Holl ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Neuronal Loss ◽  
Excitatory Input ◽  
Mammalian Brain ◽  
Striatal Neurons ◽  
Intact Mouse ◽  
Neuronal Markers ◽  
Electrophysiological Properties ◽  
Striatal Interneurons ◽  
Adult Mammalian Brain

Astrocytes have emerged as a potential source for new neurons in the adult mammalian brain. In mice, adult striatal neurogenesis can be stimulated by local damage, which recruits striatal astrocytes into a neurogenic program by suppression of active Notch signaling (J. P. Magnusson et al., Science 346, 237–241 [2014]). Here, we induced adult striatal neurogenesis in the intact mouse brain by the inhibition of Notch signaling in astrocytes. We show that most striatal astrocyte-derived neurons are confined to the anterior medial striatum, do not express established striatal neuronal markers, and exhibit dendritic spines, which are atypical for striatal interneurons. In contrast to striatal neurons generated during development, which are GABAergic or cholinergic, most adult astrocyte-derived striatal neurons possess distinct electrophysiological properties, constituting the only glutamatergic striatal population. Astrocyte-derived neurons integrate into the adult striatal microcircuitry, both receiving and providing synaptic input. The glutamatergic nature of these neurons has the potential to provide excitatory input to the striatal circuitry and may represent an efficient strategy to compensate for reduced neuronal activity caused by aging or lesion-induced neuronal loss.

scholarly journals Regenerative capacity of neural precursors in the adult mammalian brain is under the control of p53

2009 ◽  
Vol 30 (3) ◽  
pp. 483-497 ◽  
Author(s):  
Silvia Medrano ◽  
Melissa Burns-Cusato ◽  
Marybless B. Atienza ◽  
Donya Rahimi ◽  
Heidi Scrable
Keyword(s):  
Mammalian Brain ◽  
Regenerative Capacity ◽  
Neural Precursors ◽  
Adult Mammalian Brain

Applying Basic Neuroscience to Aphasia Therapy

1995 ◽  
Vol 4 (4) ◽  
pp. 88-93 ◽  
Author(s):  
Kristen A. Keefe
Keyword(s):  
Learning And Memory ◽  
Neural Plasticity ◽  
Behavioral Interventions ◽  
Cortical Reorganization ◽  
Mammalian Brain ◽  
Cortical Injury ◽  
Aphasia Therapy ◽  
Neural Processes ◽  
Adult Mammalian Brain ◽  
Environmental Demands

Advances in basic neuroscience have increased our knowledge about the neural processes underlying learning and memory and the cortical reorganization that occurs in response to environmental demands and cortical injury. This article provides a selective review of published studies conducted in animals that examine functional and structural substrates of neural plasticity in the adult mammalian brain, and discusses the implications of this knowledge for aphasia therapy. The processes and constraints identified in the studies reviewed can be used to refine and justify current aphasia therapies, as well as to design additional behavioral interventions.

scholarly journals Transcriptomic analysis of frontotemporal lobar degeneration with TDP-43 pathology reveals cellular alterations across multiple brain regions

2021 ◽  
Author(s):  
Rahat Hasan ◽  
Jack Humphrey ◽  
Conceicao Bettencourt ◽  
Tammaryn Lashley ◽  
Pietro Fratta ◽  
...  
Keyword(s):  
Gene Expression ◽  
Frontotemporal Lobar Degeneration ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Temporal Cortex ◽  
Neuronal Loss ◽  
Underlying Disease ◽  
Brain Regions ◽  
Neuronal Markers ◽  
The Brain

Frontotemporal lobar degeneration (FTLD) is a group of heterogeneous neurodegenerative disorders affecting the frontal and temporal lobes of the brain. Nuclear loss and cytoplasmic aggregation of the RNA-binding protein TDP-43 represents the major FTLD pathology, known as FTLD-TDP. To date, there is no effective treatment for FTLD-TDP due to an incomplete understanding of the molecular mechanisms underlying disease development. Here we compared post-mortem tissue RNA-seq transcriptomes from the frontal cortex, temporal cortex and cerebellum between 28 controls and 30 FTLD-TDP patients to profile changes in cell-type composition, gene expression and transcript usage. We observed downregulation of neuronal markers in all three regions of the brain, accompanied by upregulation of microglia, astrocytes, and oligodendrocytes, as well as endothelial cells and pericytes, suggesting shifts in both immune activation and within the vasculature. We validate our estimates of neuronal loss using neuropathological atrophy scores and show that neuronal loss in the cortex can be mainly attributed to excitatory neurons, and that increases in microglial and endothelial cell expression are highly correlated with neuronal loss. All our analyses identified a strong involvement of the cerebellum in the neurodegenerative process of FTLD-TDP. Altogether, our data provides a detailed landscape of gene expression alterations to help unravel relevant disease mechanisms in FTLD.

scholarly journals Simultaneous high-speed imaging and optogenetic inhibition in the intact mouse brain

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Serena Bovetti ◽  
Claudio Moretti ◽  
Stefano Zucca ◽  
Marco Dal Maschio ◽  
Paolo Bonifazi ◽  
...  
Keyword(s):  
Mouse Brain ◽  
High Speed ◽  
Pyramidal Neurons ◽  
Functional Organization ◽  
Single Photon ◽  
Electrophysiological Recording ◽  
Mammalian Brain ◽  
Cellular Mechanisms ◽  
High Speed Imaging ◽  
Intact Mouse

Abstract Genetically encoded calcium indicators and optogenetic actuators can report and manipulate the activity of specific neuronal populations. However, applying imaging and optogenetics simultaneously has been difficult to establish in the mammalian brain, even though combining the techniques would provide a powerful approach to reveal the functional organization of neural circuits. Here, we developed a technique based on patterned two-photon illumination to allow fast scanless imaging of GCaMP6 signals in the intact mouse brain at the same time as single-photon optogenetic inhibition with Archaerhodopsin. Using combined imaging and electrophysiological recording, we demonstrate that single and short bursts of action potentials in pyramidal neurons can be detected in the scanless modality at acquisition frequencies up to 1 kHz. Moreover, we demonstrate that our system strongly reduces the artifacts in the fluorescence detection that are induced by single-photon optogenetic illumination. Finally, we validated our technique investigating the role of parvalbumin-positive (PV) interneurons in the control of spontaneous cortical dynamics. Monitoring the activity of cellular populations on a precise spatiotemporal scale while manipulating neuronal activity with optogenetics provides a powerful tool to causally elucidate the cellular mechanisms underlying circuit function in the intact mammalian brain.

Abstract 386: Notch1 Signaling Negatively Modulates Repolarizing Kv Currents in Cardiomyocytes

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Giulia Borghetti ◽  
Sergio Signore ◽  
Andrea Sorrentino ◽  
Polina Goichberg ◽  
Marcello Rota
Keyword(s):  
Patch Clamp ◽  
Notch Signaling ◽  
Splice Variants ◽  
Postnatal Life ◽  
Wild Type ◽  
Early Postnatal Development ◽  
Electrophysiological Properties ◽  
Notch1 Signaling ◽  
Developing Heart

Notch1 is a critical signaling pathway during embryonic and early postnatal development and activity of this transduction system gradually declines after birth. Conversely, outward K + Kv currents are progressively increased in myocytes during postnatal life leading to shortening of the action potential (AP) duration and acquisition of the mature electrical phenotype. Thus, we tested the possibility that Notch1 signaling modulates the electrophysiological properties of developing cells by interfering with Kv current densities. For this purpose, molecular and physiological studies were conducted in vitro using mouse neonatal myocytes (NMs). These assays were complemented with tests in adult cells obtained from a conditional mouse model of Notch1 intracellular domain (NICD) overexpression. NMs were treated with a γ-secretase inhibitor (DAPT) to prevent the cleavage of Notch1 receptor and subsequent translocation of the active NICD to the nucleus. By RT-PCR, Notch1 targets Hes1 and Hey1 were reduced with DAPT-treatment, confirming the effective perturbation of Notch1 signaling. Importantly, inhibition of Notch signaling led to upregulation of the three splice variants of the Kv channel-interacting proteins 2 (KChIP2) gene, which controls the appearance of outward Kv currents in myocytes. By patch-clamp, Kv currents were identified in only 15% of NMs (n=20) cultured for 1-2 days in in control condition, whereas this fraction increased to 50% (n=18) in cells treated with DAPT. Thus, Notch inhibition promotes the expression of KChIP2 and appearance of Kv currents. To clarify these in vitro findings, the consequences of ectopic activation of Notch1 signaling on the electrical behavior of adult myocytes were established. By patch-clamp, NICD-overexpressing myocytes presented a >2-fold longer duration of the early repolarization phase of the AP, with respect to cells from wild type hearts. This alteration was coupled with a >50% reduction of Kv currents I to and I Kslow1 in NICD-overexpressing cells, with respect to wild-type myocytes. Thus, Notch signaling represses KChIP2 and Kv currents in cardiomyocytes representing an important modulator of the electrical phenotype of the developing heart.

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