Neural stem/progenitor cells (NSPCs) generate new neurons throughout life in distinct areas of th... more Neural stem/progenitor cells (NSPCs) generate new neurons throughout life in distinct areas of the adult mammalian brain. Besides classical transgenesis-based approaches, retrovirus-mediated genetic manipulation is frequently used to study mechanisms that regulate neurogenesis in the nervous system. Here, we show that fusion of a tamoxifen-regulatable estrogen receptor (ER T2 ) motif to transcription factors (i.e., ASCL1 and NEUROD1) enables temporal control of transgene expression in adult mouse NSPCs in vitro and in vivo. Thus, the approach described here represents a versatile strategy for regulating gene expression to study gene function in dividing cells and their progeny.
Integrins are a major family of heterodimeric surface glycoproteins that act as adhesion molecule... more Integrins are a major family of heterodimeric surface glycoproteins that act as adhesion molecules, have a spectrum of extracellular matrix (ECM) molecules as their ligands, and regulate a variety of cellular functions. Integrins are known to be critical to embryonic brain development, and recent studies have indicated their essential role in adult brain function, although their role in postnatal brain development and function has not been examined. Here, we used the organotypic slice culture system to investigate the role of integrins in postnatal hippocampal development by exposing the tissue to either an integrin competitive antagonist, the peptide GRGDSP containing Arg-Gly-Asp (RGD) attachment site, or to function-blocking b -integrin antibodies to disrupt integrin interactions. These experiments 1 revealed that b -integrin antibodies interfered with spreading of the culture, resulting in a rapid and marked diminution of slice area. 1 b -integrin antibodies and RGD peptide disrupted cell adhesion, causing cell detachment and migration of glial cells from the explant. 1 The majority of the detached cells were of macroglial origin and switched to expression of the intermediate filament proteins vimentin and nestin, suggesting a developmental regression. The organotypic organization of slice cultures was not affected, although exposure to either integrin antagonist or antibody resulted in a statistically significant reduction in the number of synapses measured in the apical dendrites of CA1 pyramidal neurons. The results demonstrate that integrins markedly affect postnatal CNS development, in both ultrastructural construction and organizational processes.
Although new and functional neurons are produced in the adult brain, little is known about how th... more Although new and functional neurons are produced in the adult brain, little is known about how they integrate into mature networks. Here we explored the mechanisms of synaptogenesis on neurons born in the adult mouse hippocampus using confocal microscopy, electron microscopy and live imaging. We report that new neurons, similar to mature granule neurons, were contacted by axosomatic, axodendritic and axospinous synapses. Consistent with their putative role in synaptogenesis, dendritic filopodia were more abundant during the early stages of maturation and, when analyzed in three dimensions, the tips of all filopodia were found within 200 nm of preexisting boutons that already synapsed on other neurons. Furthermore, dendritic spines primarily synapsed on multiple-synapse boutons, suggesting that initial contacts were preferentially made with preexisting boutons already involved in a synapse. The connectivity of new neurons continued to change until at least 2 months, long after the fo...
Adult neurogenesis occurs in the hippocampus and the olfactory bulb of the mammalian CNS. Recent ... more Adult neurogenesis occurs in the hippocampus and the olfactory bulb of the mammalian CNS. Recent studies have demonstrated that newborn granule cells of the adult hippocampus are postsynaptic targets of excitatory and inhibitory neurons, but evidence of synapse formation by the axons of these cells is still lacking. By combining retroviral expression of green fluorescent protein in adult-born neurons of the mouse dentate gyrus with immuno-electron microscopy, we found output synapses that were formed by labeled terminals on appropriate target cells in the CA3 area and the hilus. Furthermore, retroviral expression of channelrhodopsin-2 allowed us to light-stimulate newborn granule cells and identify postsynaptic target neurons by whole-cell recordings in acute slices. Our structural and functional evidence indicates that axons of adult-born granule cells establish synapses with hilar interneurons, mossy cells and CA3 pyramidal cells and release glutamate as their main neurotransmitter.
Using immunohistology, electron microscopy, electrophysiology and optogenetics, we found that pro... more 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.
Adult hippocampal neurogenesis results in the formation of new neurons and is a process of brain ... more 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.
Newborn neurons are generated in the adult hippocampus from a pool of self-renewing stem cells lo... more Newborn neurons are generated in the adult hippocampus from a pool of self-renewing stem cells located in the subgranular zone (SGZ) of the dentate gyrus. Their activation, proliferation, and maturation depend on a host of environmental and cellular factors but, until recently, the contribution of local neuronal circuitry to this process was relatively unknown. In their recent publication, Song and colleagues have uncovered a novel circuit-based mechanism by which release of the neurotransmitter, g-aminobutyric acid (GABA), from parvalbumin-expressing (PV) interneurons, can hold radial glia-like (RGL) stem cells of the adult SGZ in a quiescent state. This tonic GABAergic signal, dependent upon the activation of g 2 subunit-containing GABA A receptors of RGL stem cells, can thus prevent their proliferation and subsequent maturation or return them to quiescence if previously activated. PV interneurons are thus capable of suppressing neurogenesis during periods of high network activity and facilitating neurogenesis when network activity is low.
Journal of Alzheimer's Disease xx (20xx) x-xx Abstract. The formation and accumulation of toxic a... more Journal of Alzheimer's Disease xx (20xx) x-xx Abstract. The formation and accumulation of toxic amyloid- peptides (A) in the brain may drive the pathogenesis of Alzheimer's disease. Accordingly, disease-modifying therapies for Alzheimer's disease and related disorders could result from treatments regulating A homeostasis. Examples are the inhibition of production, misfolding, and accumulation of A or the enhancement of its clearance. Here we show that oral treatment with ACI-91 (Pirenzepine) dose-dependently reduced brain A burden in APPPS1, hAPP SL , and APP/PS1 transgenic mice. A possible mechanism of action of ACI-91 may occur through selective inhibition of muscarinic acetylcholine receptors (AChR) on endothelial cells of brain microvessels and enhanced A peptide clearance across the blood-brain barrier. One month treatment with ACI-91 increased the clearance of intrathecallyinjected A in plaque-bearing mice. ACI-91 also accelerated the clearance of brain-injected A in blood and peripheral tissues by favoring its urinal excretion. A single oral dose of ACI-91 reduced the half-life of interstitial A peptide in pre-plaque mhAPP/PS1d mice. By extending our studies to an in vitro model, we showed that muscarinic AChR inhibition by ACI-91 and Darifenacin augmented the capacity of differentiated endothelial monolayers for active transport of A peptide. Finally, ACI-91 16 17 18 19 20 21 22 23 24 25 26 27 1 These authors contributed equally to this work.
Seizure activity within the hippocampal circuitry not only affects pre-existing structures, but a... more Seizure activity within the hippocampal circuitry not only affects pre-existing structures, but also dramatically increases the number of newborn granule cells. A retroviral strategy was used to label dividing cells and their progeny in the adult dentate gyrus and to analyze the impact of epileptic activity on adult-generated cells labeled before or after seizures. We show that epileptic activity led to dramatic changes in the neuronal polarity, migration, and integration pattern of newborn granule cells, depending on the time of birth in relation to the epileptic insult. Aberrant neurons were stably integrated into the dentate circuitry, and the consequences on hippocampal neurogenesis were long lasting. The data presented characterized the consequences of seizure-associated plasticity on adult neurogenesis leading to long-term structural changes in the hippocampal circuitry that might represent a pivotal component of the epileptic disease process.
The hippocampus is involved in declarative memory and produces new neurons throughout adulthood. ... more The hippocampus is involved in declarative memory and produces new neurons throughout adulthood. Numerous experiments have been aimed at testing the possibility that adult neurogenesis is required for learning and memory. However, progress has been encumbered by the fact that abating adult neurogenesis usually affects other biological processes, confounding the interpretation of such experiments. In an effort to circumvent this problem, we used a reverse approach to test the role of neurogenesis in hippocampus-dependent learning, exploiting the low levels of adult neurogenesis in the MRL/MpJ strain of mice compared with other mouse strains. We observed that adult MRL/MpJ mice produce 75% fewer new neurons in the dentate gyrus than age-matched C57BL/6 mice. Learning-induced synaptic remodeling, spatial learning, and visual recognition learning were reduced in MRL/MpJ mice compared with C57BL/6 mice. When MRL/ MpJ mice were allowed unlimited access to running wheels, neurogenesis along with spatial learning and visual recognition learning were increased to levels comparable to those in running C57BL/6 mice. Together, these results suggest that adult neurogenesis is correlated with spatial learning and visual recognition learning, possibly by modulating morphological plasticity in the dentate gyrus. V V C 2009 Wiley-Liss, Inc.
Although new and functional neurons are produced in the adult brain, little is known about how th... more Although new and functional neurons are produced in the adult brain, little is known about how they integrate into mature networks. Here we explored the mechanisms of synaptogenesis on neurons born in the adult mouse hippocampus using confocal microscopy, electron microscopy and live imaging. We report that new neurons, similar to mature granule neurons, were contacted by axosomatic, axodendritic and axospinous synapses. Consistent with their putative role in synaptogenesis, dendritic filopodia were more abundant during the early stages of maturation and, when analyzed in three dimensions, the tips of all filopodia were found within 200 nm of preexisting boutons that already synapsed on other neurons. Furthermore, dendritic spines primarily synapsed on multiple-synapse boutons, suggesting that initial contacts were preferentially made with preexisting boutons already involved in a synapse. The connectivity of new neurons continued to change until at least 2 months, long after the formation of the first dendritic protrusions.
The molecular mechanisms that control how progenitors generate distinct subtypes of neurons, and ... more The molecular mechanisms that control how progenitors generate distinct subtypes of neurons, and how undifferentiated neurons acquire their specific identity during corticogenesis, are increasingly understood. However, whether postmitotic neurons can change their identity at late stages of differentiation remains unknown. To study this question, we developed an electrochemical in vivo gene delivery method to rapidly manipulate gene expression specifically in postmitotic neurons. Using this approach, we found that the molecular identity, morphology, physiology and functional input-output connectivity of layer 4 mouse spiny neurons could be specifically reprogrammed during the first postnatal week by ectopic expression of the layer 5B output neuronspecific transcription factor Fezf2. These findings reveal a high degree of plasticity in the identity of postmitotic neocortical neurons and provide a proof of principle for postnatal re-engineering of specific neural microcircuits in vivo.
Adult neurogenesis is a lifelong feature of brain plasticity; however, the potency of adult neura... more Adult neurogenesis is a lifelong feature of brain plasticity; however, the potency of adult neural stem/ progenitor cells in vivo remains unclear. We found that retrovirus-mediated overexpression of a single gene, the bHLH transcription factor Ascl1, redirected the fate of the proliferating adult hippocampal stem/progenitor (AHP) progeny and lead to the exclusive generation of cells of the oligodendrocytic lineage at the expense of newborn neurons, demonstrating that AHPs in the adult mouse brain are not irrevocably specified in vivo. These data indicate that AHPs have substantial plasticity, which might have important implications for the potential use of endogenous AHPs in neurological disease.
Background: Adult neurogenesis occurs in the hippocampus
of most mammals, including humans, and p... more Background: Adult neurogenesis occurs in the hippocampus of most mammals, including humans, and plays an important role in hippocampal-dependent learning. This process is highly regulated by neuronal activity and might therefore be vulnerable to anesthesia. In this article, the authors investigated this possibility by evaluating the impact of propofol anesthesia on mouse hippocampal neurons generated during adulthood, at two functionally distinct maturational stages of their development. Methods: Adult-born hippocampal neurons were identified using the cell proliferation marker bromodeoxyuridine or a retroviral vector expressing the green fluorescent protein in dividing cells and their progenies. Eleven or 17 days after the labeling procedure, animals (n = 3–5 animals per group) underwent a 6-h-long propofol anesthesia. Twenty-one days after labeling, the authors analyzed the survival, differentiation, and morphologic maturation of adult-born neurons using confocal microscopy. Results: Propofol impaired the survival and maturation of adult-born neurons in an age-dependent manner. Anesthesia induced a significant decrease in the survival of neurons that were 17 days old at the time of anesthesia, but not of neurons that were 11 days old. Similarly, propofol anesthesia significantly reduced the dendritic maturation of neurons generated 17 days before anesthesia, without interfering with the maturation of neurons generated 11 days before anesthesia. Conclusions: These results reveal that propofol impairs the survival and maturation of adult-born hippocampal neurons in a developmental stage-dependent manner in mice.
Neural stem/progenitor cells (NSPCs) generate new neurons throughout life in distinct areas of th... more Neural stem/progenitor cells (NSPCs) generate new neurons throughout life in distinct areas of the adult mammalian brain. Besides classical transgenesis-based approaches, retrovirus-mediated genetic manipulation is frequently used to study mechanisms that regulate neurogenesis in the nervous system. Here, we show that fusion of a tamoxifen-regulatable estrogen receptor (ER T2 ) motif to transcription factors (i.e., ASCL1 and NEUROD1) enables temporal control of transgene expression in adult mouse NSPCs in vitro and in vivo. Thus, the approach described here represents a versatile strategy for regulating gene expression to study gene function in dividing cells and their progeny.
Integrins are a major family of heterodimeric surface glycoproteins that act as adhesion molecule... more Integrins are a major family of heterodimeric surface glycoproteins that act as adhesion molecules, have a spectrum of extracellular matrix (ECM) molecules as their ligands, and regulate a variety of cellular functions. Integrins are known to be critical to embryonic brain development, and recent studies have indicated their essential role in adult brain function, although their role in postnatal brain development and function has not been examined. Here, we used the organotypic slice culture system to investigate the role of integrins in postnatal hippocampal development by exposing the tissue to either an integrin competitive antagonist, the peptide GRGDSP containing Arg-Gly-Asp (RGD) attachment site, or to function-blocking b -integrin antibodies to disrupt integrin interactions. These experiments 1 revealed that b -integrin antibodies interfered with spreading of the culture, resulting in a rapid and marked diminution of slice area. 1 b -integrin antibodies and RGD peptide disrupted cell adhesion, causing cell detachment and migration of glial cells from the explant. 1 The majority of the detached cells were of macroglial origin and switched to expression of the intermediate filament proteins vimentin and nestin, suggesting a developmental regression. The organotypic organization of slice cultures was not affected, although exposure to either integrin antagonist or antibody resulted in a statistically significant reduction in the number of synapses measured in the apical dendrites of CA1 pyramidal neurons. The results demonstrate that integrins markedly affect postnatal CNS development, in both ultrastructural construction and organizational processes.
Although new and functional neurons are produced in the adult brain, little is known about how th... more Although new and functional neurons are produced in the adult brain, little is known about how they integrate into mature networks. Here we explored the mechanisms of synaptogenesis on neurons born in the adult mouse hippocampus using confocal microscopy, electron microscopy and live imaging. We report that new neurons, similar to mature granule neurons, were contacted by axosomatic, axodendritic and axospinous synapses. Consistent with their putative role in synaptogenesis, dendritic filopodia were more abundant during the early stages of maturation and, when analyzed in three dimensions, the tips of all filopodia were found within 200 nm of preexisting boutons that already synapsed on other neurons. Furthermore, dendritic spines primarily synapsed on multiple-synapse boutons, suggesting that initial contacts were preferentially made with preexisting boutons already involved in a synapse. The connectivity of new neurons continued to change until at least 2 months, long after the fo...
Adult neurogenesis occurs in the hippocampus and the olfactory bulb of the mammalian CNS. Recent ... more Adult neurogenesis occurs in the hippocampus and the olfactory bulb of the mammalian CNS. Recent studies have demonstrated that newborn granule cells of the adult hippocampus are postsynaptic targets of excitatory and inhibitory neurons, but evidence of synapse formation by the axons of these cells is still lacking. By combining retroviral expression of green fluorescent protein in adult-born neurons of the mouse dentate gyrus with immuno-electron microscopy, we found output synapses that were formed by labeled terminals on appropriate target cells in the CA3 area and the hilus. Furthermore, retroviral expression of channelrhodopsin-2 allowed us to light-stimulate newborn granule cells and identify postsynaptic target neurons by whole-cell recordings in acute slices. Our structural and functional evidence indicates that axons of adult-born granule cells establish synapses with hilar interneurons, mossy cells and CA3 pyramidal cells and release glutamate as their main neurotransmitter.
Using immunohistology, electron microscopy, electrophysiology and optogenetics, we found that pro... more 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.
Adult hippocampal neurogenesis results in the formation of new neurons and is a process of brain ... more 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.
Newborn neurons are generated in the adult hippocampus from a pool of self-renewing stem cells lo... more Newborn neurons are generated in the adult hippocampus from a pool of self-renewing stem cells located in the subgranular zone (SGZ) of the dentate gyrus. Their activation, proliferation, and maturation depend on a host of environmental and cellular factors but, until recently, the contribution of local neuronal circuitry to this process was relatively unknown. In their recent publication, Song and colleagues have uncovered a novel circuit-based mechanism by which release of the neurotransmitter, g-aminobutyric acid (GABA), from parvalbumin-expressing (PV) interneurons, can hold radial glia-like (RGL) stem cells of the adult SGZ in a quiescent state. This tonic GABAergic signal, dependent upon the activation of g 2 subunit-containing GABA A receptors of RGL stem cells, can thus prevent their proliferation and subsequent maturation or return them to quiescence if previously activated. PV interneurons are thus capable of suppressing neurogenesis during periods of high network activity and facilitating neurogenesis when network activity is low.
Journal of Alzheimer's Disease xx (20xx) x-xx Abstract. The formation and accumulation of toxic a... more Journal of Alzheimer's Disease xx (20xx) x-xx Abstract. The formation and accumulation of toxic amyloid- peptides (A) in the brain may drive the pathogenesis of Alzheimer's disease. Accordingly, disease-modifying therapies for Alzheimer's disease and related disorders could result from treatments regulating A homeostasis. Examples are the inhibition of production, misfolding, and accumulation of A or the enhancement of its clearance. Here we show that oral treatment with ACI-91 (Pirenzepine) dose-dependently reduced brain A burden in APPPS1, hAPP SL , and APP/PS1 transgenic mice. A possible mechanism of action of ACI-91 may occur through selective inhibition of muscarinic acetylcholine receptors (AChR) on endothelial cells of brain microvessels and enhanced A peptide clearance across the blood-brain barrier. One month treatment with ACI-91 increased the clearance of intrathecallyinjected A in plaque-bearing mice. ACI-91 also accelerated the clearance of brain-injected A in blood and peripheral tissues by favoring its urinal excretion. A single oral dose of ACI-91 reduced the half-life of interstitial A peptide in pre-plaque mhAPP/PS1d mice. By extending our studies to an in vitro model, we showed that muscarinic AChR inhibition by ACI-91 and Darifenacin augmented the capacity of differentiated endothelial monolayers for active transport of A peptide. Finally, ACI-91 16 17 18 19 20 21 22 23 24 25 26 27 1 These authors contributed equally to this work.
Seizure activity within the hippocampal circuitry not only affects pre-existing structures, but a... more Seizure activity within the hippocampal circuitry not only affects pre-existing structures, but also dramatically increases the number of newborn granule cells. A retroviral strategy was used to label dividing cells and their progeny in the adult dentate gyrus and to analyze the impact of epileptic activity on adult-generated cells labeled before or after seizures. We show that epileptic activity led to dramatic changes in the neuronal polarity, migration, and integration pattern of newborn granule cells, depending on the time of birth in relation to the epileptic insult. Aberrant neurons were stably integrated into the dentate circuitry, and the consequences on hippocampal neurogenesis were long lasting. The data presented characterized the consequences of seizure-associated plasticity on adult neurogenesis leading to long-term structural changes in the hippocampal circuitry that might represent a pivotal component of the epileptic disease process.
The hippocampus is involved in declarative memory and produces new neurons throughout adulthood. ... more The hippocampus is involved in declarative memory and produces new neurons throughout adulthood. Numerous experiments have been aimed at testing the possibility that adult neurogenesis is required for learning and memory. However, progress has been encumbered by the fact that abating adult neurogenesis usually affects other biological processes, confounding the interpretation of such experiments. In an effort to circumvent this problem, we used a reverse approach to test the role of neurogenesis in hippocampus-dependent learning, exploiting the low levels of adult neurogenesis in the MRL/MpJ strain of mice compared with other mouse strains. We observed that adult MRL/MpJ mice produce 75% fewer new neurons in the dentate gyrus than age-matched C57BL/6 mice. Learning-induced synaptic remodeling, spatial learning, and visual recognition learning were reduced in MRL/MpJ mice compared with C57BL/6 mice. When MRL/ MpJ mice were allowed unlimited access to running wheels, neurogenesis along with spatial learning and visual recognition learning were increased to levels comparable to those in running C57BL/6 mice. Together, these results suggest that adult neurogenesis is correlated with spatial learning and visual recognition learning, possibly by modulating morphological plasticity in the dentate gyrus. V V C 2009 Wiley-Liss, Inc.
Although new and functional neurons are produced in the adult brain, little is known about how th... more Although new and functional neurons are produced in the adult brain, little is known about how they integrate into mature networks. Here we explored the mechanisms of synaptogenesis on neurons born in the adult mouse hippocampus using confocal microscopy, electron microscopy and live imaging. We report that new neurons, similar to mature granule neurons, were contacted by axosomatic, axodendritic and axospinous synapses. Consistent with their putative role in synaptogenesis, dendritic filopodia were more abundant during the early stages of maturation and, when analyzed in three dimensions, the tips of all filopodia were found within 200 nm of preexisting boutons that already synapsed on other neurons. Furthermore, dendritic spines primarily synapsed on multiple-synapse boutons, suggesting that initial contacts were preferentially made with preexisting boutons already involved in a synapse. The connectivity of new neurons continued to change until at least 2 months, long after the formation of the first dendritic protrusions.
The molecular mechanisms that control how progenitors generate distinct subtypes of neurons, and ... more The molecular mechanisms that control how progenitors generate distinct subtypes of neurons, and how undifferentiated neurons acquire their specific identity during corticogenesis, are increasingly understood. However, whether postmitotic neurons can change their identity at late stages of differentiation remains unknown. To study this question, we developed an electrochemical in vivo gene delivery method to rapidly manipulate gene expression specifically in postmitotic neurons. Using this approach, we found that the molecular identity, morphology, physiology and functional input-output connectivity of layer 4 mouse spiny neurons could be specifically reprogrammed during the first postnatal week by ectopic expression of the layer 5B output neuronspecific transcription factor Fezf2. These findings reveal a high degree of plasticity in the identity of postmitotic neocortical neurons and provide a proof of principle for postnatal re-engineering of specific neural microcircuits in vivo.
Adult neurogenesis is a lifelong feature of brain plasticity; however, the potency of adult neura... more Adult neurogenesis is a lifelong feature of brain plasticity; however, the potency of adult neural stem/ progenitor cells in vivo remains unclear. We found that retrovirus-mediated overexpression of a single gene, the bHLH transcription factor Ascl1, redirected the fate of the proliferating adult hippocampal stem/progenitor (AHP) progeny and lead to the exclusive generation of cells of the oligodendrocytic lineage at the expense of newborn neurons, demonstrating that AHPs in the adult mouse brain are not irrevocably specified in vivo. These data indicate that AHPs have substantial plasticity, which might have important implications for the potential use of endogenous AHPs in neurological disease.
Background: Adult neurogenesis occurs in the hippocampus
of most mammals, including humans, and p... more Background: Adult neurogenesis occurs in the hippocampus of most mammals, including humans, and plays an important role in hippocampal-dependent learning. This process is highly regulated by neuronal activity and might therefore be vulnerable to anesthesia. In this article, the authors investigated this possibility by evaluating the impact of propofol anesthesia on mouse hippocampal neurons generated during adulthood, at two functionally distinct maturational stages of their development. Methods: Adult-born hippocampal neurons were identified using the cell proliferation marker bromodeoxyuridine or a retroviral vector expressing the green fluorescent protein in dividing cells and their progenies. Eleven or 17 days after the labeling procedure, animals (n = 3–5 animals per group) underwent a 6-h-long propofol anesthesia. Twenty-one days after labeling, the authors analyzed the survival, differentiation, and morphologic maturation of adult-born neurons using confocal microscopy. Results: Propofol impaired the survival and maturation of adult-born neurons in an age-dependent manner. Anesthesia induced a significant decrease in the survival of neurons that were 17 days old at the time of anesthesia, but not of neurons that were 11 days old. Similarly, propofol anesthesia significantly reduced the dendritic maturation of neurons generated 17 days before anesthesia, without interfering with the maturation of neurons generated 11 days before anesthesia. Conclusions: These results reveal that propofol impairs the survival and maturation of adult-born hippocampal neurons in a developmental stage-dependent manner in mice.
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Papers by Nicolas Toni
of most mammals, including humans, and plays an important
role in hippocampal-dependent learning. This process
is highly regulated by neuronal activity and might therefore
be vulnerable to anesthesia. In this article, the authors investigated
this possibility by evaluating the impact of propofol
anesthesia on mouse hippocampal neurons generated during
adulthood, at two functionally distinct maturational stages
of their development.
Methods: Adult-born hippocampal neurons were identified
using the cell proliferation marker bromodeoxyuridine or a
retroviral vector expressing the green fluorescent protein in
dividing cells and their progenies. Eleven or 17 days after
the labeling procedure, animals (n = 3–5 animals per group)
underwent a 6-h-long propofol anesthesia. Twenty-one days
after labeling, the authors analyzed the survival, differentiation,
and morphologic maturation of adult-born neurons
using confocal microscopy.
Results: Propofol impaired the survival and maturation of
adult-born neurons in an age-dependent manner. Anesthesia
induced a significant decrease in the survival of neurons
that were 17 days old at the time of anesthesia, but
not of neurons that were 11 days old. Similarly, propofol
anesthesia significantly reduced the dendritic maturation
of neurons generated 17 days before anesthesia, without
interfering with the maturation of neurons generated 11
days before anesthesia.
Conclusions: These results reveal that propofol impairs the
survival and maturation of adult-born hippocampal neurons
in a developmental stage-dependent manner in mice.
of most mammals, including humans, and plays an important
role in hippocampal-dependent learning. This process
is highly regulated by neuronal activity and might therefore
be vulnerable to anesthesia. In this article, the authors investigated
this possibility by evaluating the impact of propofol
anesthesia on mouse hippocampal neurons generated during
adulthood, at two functionally distinct maturational stages
of their development.
Methods: Adult-born hippocampal neurons were identified
using the cell proliferation marker bromodeoxyuridine or a
retroviral vector expressing the green fluorescent protein in
dividing cells and their progenies. Eleven or 17 days after
the labeling procedure, animals (n = 3–5 animals per group)
underwent a 6-h-long propofol anesthesia. Twenty-one days
after labeling, the authors analyzed the survival, differentiation,
and morphologic maturation of adult-born neurons
using confocal microscopy.
Results: Propofol impaired the survival and maturation of
adult-born neurons in an age-dependent manner. Anesthesia
induced a significant decrease in the survival of neurons
that were 17 days old at the time of anesthesia, but
not of neurons that were 11 days old. Similarly, propofol
anesthesia significantly reduced the dendritic maturation
of neurons generated 17 days before anesthesia, without
interfering with the maturation of neurons generated 11
days before anesthesia.
Conclusions: These results reveal that propofol impairs the
survival and maturation of adult-born hippocampal neurons
in a developmental stage-dependent manner in mice.