Women of child-bearing age are the population group at highest risk for depression. In pregnant w... more Women of child-bearing age are the population group at highest risk for depression. In pregnant women, fluoxetine (Flx) is the most widely prescribed selective serotonin reuptake inhibitor (SSRI) used for the treatment of depression. While maternal stress, depression, and Flx exposure have been shown to effect neurodevelopment of the offspring, separately, combined effects of maternal stress and Flx exposure have not been extensively examined. The present study investigated the effects of prenatal maternal stress and perinatal exposure to the SSRI Flx on the behavior of male mice as adults. C57BL/6 dams exposed to chronic unpredictable stress from embryonic (E) day 4 to E18 and non-stressed dams were administered Flx (25mg/kg/d) in the drinking water from E15 to postnatal day 12. A separate control group consisted of animals that were not exposed to stress or Flx. At 12days of age, brain levels of serotonin were assessed in the male offspring. At two months of age, the male offspring of mothers exposed to prenatal stress (PS), perinatal Flx, PS and Flx, or neither PS or Flx, went through a comprehensive behavioral test battery. At the end of testing brain-derived neurotropic factor (BDNF) levels were assessed in the frontal cortex of the offspring. Maternal behavior was not altered by either stress or Flx treatment. Treatment of the mother with Flx led to detectible Flx and NorFlx levels and lead to a decrease in serotonin levels in pup brains. In the adult male offspring, while perinatal exposure to Flx increased aggressive behavior, prenatal maternal stress decreased aggressive behavior. Interestingly, the combined effects of stress and Flx normalized aggressive behavior. Furthermore, perinatal Flx treatment led to a decrease in anxiety-like behavior in male offspring. PS led to hyperactivity and a decrease in BDNF levels in the frontal cortex regardless of Flx exposure. Neither maternal stress or Flx altered offspring performance in tests of cognitive abilities, memory, sensorimotor information processing, or risk assessment behaviors. These results demonstrate that maternal exposure to stress and Flx have a number of sustained effects on the male offspring.
In the adult mammalian brain, up-regulation of serotonin via the selective serotonin reuptake inh... more In the adult mammalian brain, up-regulation of serotonin via the selective serotonin reuptake inhibitor fluoxetine increases hippocampal neurogenesis. However, research assessing the long-term effects of modulating serotonin during the developmental period on hippocampal neurogenesis, is sparse. Here we evaluated hippocampal neurogenesis early (postnatal day 12), and later in life (postnatal day 60), in the offspring of mouse dams that were administered fluoxetine in their drinking water from embryonic day 15 (E15) through postnatal day 12 (P12). Fluoxetine-exposed mice had significantly higher levels of neuronal proliferation at P12, and P60, despite cessation of fluoxetine on P12. These effects were limited to proliferation, as survival of postnatal-born hippocampal neurons was unaltered. Mice exposed to fluoxetine also showed significantly higher levels of cell death, suggesting that homeostatic mechanisms present within the hippocampus may limit integration of adult-born neurons...
Zinc-containing terminals are found throughout the neocortex, concentrated predominantly in layer... more Zinc-containing terminals are found throughout the neocortex, concentrated predominantly in layers II/III, V, and VI. Synaptic zinc is a potent neurotransmitter/modulator and, therefore, may mediate inter- or intra-cortical integration of sensory information. We have previously shown that levels of synaptic zinc are rapidly modulated in somatosensory (barrel) cortex, in an experience- and activity-dependent manner. Zinc transporter 3 (ZnT3) knockout (KO) mice lack synaptic zinc and provide us with a good model to examine the contribution of synaptic zinc to barrel cortex-dependent behavior. In the present study, we show that ZnT3 KO mice display a marked decrease in acuity for whisker-dependent texture discrimination. ZnT3 KO mice were not able to discriminate between textures having an average particle diameter less than 300 μm while control mice were able to discriminate between textures having particle diameters separated by as little as 25 μm. This loss of texture discrimination...
International Journal of Developmental Neuroscience, 2012
INSERM U1051, Université Montpellier 2, Institut des Neurosciences de Montpellier, France E-mail ... more INSERM U1051, Université Montpellier 2, Institut des Neurosciences de Montpellier, France E-mail address: [email protected] (J.P. Hugnot). In the brain, specific signalling pathways localized in highly organized regions called niches, allow the persistence of a pool of stem and progenitor cells that generate new neurons and glial cells in adulthood. Much less is known on the spinal cord central canal niche where a sustained adult neurogenesis is not observed. Far from being a simple layer of homogenous cells, we found, both in man and in rodents, that this region is composed of several cell types localized at specific locations, expressing characteristic markers and with different morphologies and functions. Notably the mouse niche contains a subset of Dcx+ Nkx6.1+ neuronal cells sending processes into the lumen and another subpopulation of GFAP+ cells that extends radial processes into the parenchyma. These GFAP+ cells are more frequently observed in the dorsal or ventral central canal parts, either in an ependymal or subependymal position. Using a hGFAP-GFP mouse line, we found that these GFAP+ cells express FoxJ1 and are the main source of adult spinal cord stem cells. Screening of online gene expression databases (notably Allen brain and Gensat atlas) and extensive immunodetections allowed us to identify in the central canal region, the expression of several genes involved in the Notch (Jagged, Hes1), Wnt (Wnt7a, Fzd3), BMP (DAN, BMP6) and Hedgehog (SHH) pathways. We also found that cells in this region, notably the GFAP+ cells, highly expressed Zeb1 (also known as -EF1, TCF8, AREB6), a zinc finger-homeodomain transcription factor which has been described as an important regulator of epithelial-mesenchymal transition. Zeb1 and 2 are expressed by neurosphere cells derived from the adult spinal cord and are required for neurosphere formation and expansion. In depth characterization of the spinal cord niche in man and rodents constitutes an essential framework to understand the role of these cells in spinal cord physiology and damages.
Zinc is released from a subset of cerebral cortical neurons whereupon it exerts a powerful modula... more Zinc is released from a subset of cerebral cortical neurons whereupon it exerts a powerful modulatory influence on excitatory and inhibitory neurotransmission. A number of studies have suggested that alterations in the regulation of zinc may contribute to the genesis of epilepsy. Here, we tested this hypothesis by examining the distribution of zinc-containing axon terminals in rats selectively bred for an innate susceptibility (FAST) or resistance (SLOW) to the development of kindling-induced seizures. Zinc was stained histochemically and levels of staining were quantitatively assessed. We found that the levels of synaptic zinc were significantly lower in the SLOW rats throughout the telencephalon. This relative reduction was most pronounced in limbic cortices where levels were less than 30% of FAST rats. These results suggest that innate differences in the homeostatic regulation of synaptic zinc, particularly in limbic cortices, may underlie differences in epileptogenicity.
In the brain, vesicular zinc, which refers to a subset of zinc that is sequestered into synaptic ... more In the brain, vesicular zinc, which refers to a subset of zinc that is sequestered into synaptic vesicles by zinc transporter 3 (ZnT3), has extensive effects on neuronal signalling and modulation. Vesicular zinc-focused research has mainly been directed to its role in the hippocampus, particularly in adult neurogenesis. However, whether vesicular zinc is involved in modulating neurogenesis during the early postnatal period has been less studied. As a first step to understanding this, we used ZnT3 knockout (KO) mice, which lack ZnT3 and, thus, vesicular zinc, to evaluate cell proliferation at three different age points spanning postnatal development (P6, P14, and P28). The survival and the neuronal phenotype of these cells was also assessed in adulthood. We found that male ZnT3 KO mice exhibited lower rates of cell proliferation at P14, but a greater number of these cells survived to adulthood. Additionally, significantly more cells labelled on P6 survived to adulthood in male and fe...
Chronic maternal stress during pregnancy can have long-term, detrimental consequences for the off... more Chronic maternal stress during pregnancy can have long-term, detrimental consequences for the offspring. An understanding of the mechanisms responsible for mediating these effects is essential for devising therapeutic interventions. Here, we examined whether serotonin 1A receptor (5-HTR) mediates the effects of maternal stress on the behavioral outcomes of the offspring as adults. Heterozygous (HET) mouse dams were bred with HET males and were randomly assigned to stress or control groups. Pregnant dams in the stress group were exposed to a regime of chronic unpredictable stress from embryonic day 7 to 18. At two months of age, groups of male and female wildtype (WT), HET, and knockout (KO) offspring underwent a comprehensive behavioral test battery that included tests of social behavior, memory, aggression, anxiety, sensorimotor information processing, and exploratory and risk assessment behaviors. Independent of genotype, prenatal stress resulted in a change in locomotor activity ...
Journal of Cerebral Blood Flow & Metabolism, 2008
We hypothesized that magnetic resonance magnetization transfer (MT) imaging would be sensitive fo... more We hypothesized that magnetic resonance magnetization transfer (MT) imaging would be sensitive for detecting cerebral ischemic injury in white matter of neonatal brain. We compared the progression of changes in T2 and the MT ratio (MTR) after cerebral hypoxic-ischemic insults of differing severity in neonatal rats. Magnetization transfer imaging parameters were first optimized, and then MTR and T2 maps were acquired at various times after a mild (rather selective white matter) or substantial insult produced by unilateral cerebral hypoxia—ischemia. Depending on insult severity, time after insult, and region (e.g., subcortical white matter or cortex), cerebral hypoxia—ischemia produced reductions in MTR and an increase in T2. The exception was acutely at 1 to 5 h at which time points MTR was reduced ipsilaterally in white matter, whereas T2 was not affected significantly. Progression of imaging changes differed in rats grouped according to whether gross damage was present after chroni...
Zinc is highly concentrated in synaptic vesicles throughout the mammalian telencephalon and, in p... more Zinc is highly concentrated in synaptic vesicles throughout the mammalian telencephalon and, in particular, the hippocampal dentate gyrus. A role for zinc in modulating synaptic plasticity has been inferred, but whether zinc has a particular role in experience-dependent plasticity has yet to be determined. The aim of the current study was to determine whether vesicular zinc is important for modulating adult hippocampal neurogenesis in an experience-dependent manner and, consequently, hippocampal-dependent behaviour. We assessed the role of vesicular zinc in modulating hippocampal neurogenesis and behaviour by comparing ZnT3 knockout (KO) mice, which lack vesicular zinc, to wild-type (WT) littermates exposed to either standard housing conditions (SH) or an enriched environment (EE). We found that vesicular zinc is necessary for a cascade of changes in hippocampal plasticity following EE, such as increases in hippocampal neurogenesis and elevations in mature brain-derived neurotrophic...
Zinc is an important neuromodulatory transmitter that is co-released with glutamate at many centr... more Zinc is an important neuromodulatory transmitter that is co-released with glutamate at many central excitatory synapses. Growing evidence suggests that zinc is a key mediator and modulator of ischemic cell death in neurons. Vesicular release of zinc from presynaptic nerve terminals following ischemia is thought to be a key step in the excitotoxic injury of postsynaptic neurons. As a first step in determining the role of zinc in post-ischemic neuronal injury we have assessed the distribution of synaptic zinc in the motor cortex of adult mice at various intervals following induction of a photothrombotic stroke.
Zinc is important in neural and synaptic development and neuronal transmission. Within the brain,... more Zinc is important in neural and synaptic development and neuronal transmission. Within the brain, zinc transporter 3 (ZnT3) is essential for zinc uptake into vesicles. Loss of vesicular zinc has been shown to produce neurodevelopmental disorder (NDD)-like behavior, such as decreased social interaction and increased anxiety- and repetitive-like behavior. Maternal immune activation (MIA) has been identified as an environmental factor for NDDs, such as autism spectrum disorders (ASDs) and schizophrenia (SZ), in offspring, which occurs during pregnancy when the mother’s immune system reacts to the exposure to viruses or infectious diseases. In this study, we investigated the interaction effect of a genetic factor [ZnT3 knockout (KO) mice] and an environmental factor (MIA). We induced MIA in pregnant female (dams) mice during mid-gestation, using polyinosinic:polycytidylic acid (polyI:C), which mimics a viral infection. Male and female ZnT3 KO and wild-type (WT) offspring were tested in ...
Women of child-bearing age are the population group at highest risk for depression. In pregnant w... more Women of child-bearing age are the population group at highest risk for depression. In pregnant women, fluoxetine (Flx) is the most widely prescribed selective serotonin reuptake inhibitor (SSRI) used for the treatment of depression. While maternal stress, depression, and Flx exposure have been shown to effect neurodevelopment of the offspring, separately, combined effects of maternal stress and Flx exposure have not been extensively examined. The present study investigated the effects of prenatal maternal stress and perinatal exposure to the SSRI Flx on the behavior of male mice as adults. C57BL/6 dams exposed to chronic unpredictable stress from embryonic (E) day 4 to E18 and non-stressed dams were administered Flx (25mg/kg/d) in the drinking water from E15 to postnatal day 12. A separate control group consisted of animals that were not exposed to stress or Flx. At 12days of age, brain levels of serotonin were assessed in the male offspring. At two months of age, the male offspring of mothers exposed to prenatal stress (PS), perinatal Flx, PS and Flx, or neither PS or Flx, went through a comprehensive behavioral test battery. At the end of testing brain-derived neurotropic factor (BDNF) levels were assessed in the frontal cortex of the offspring. Maternal behavior was not altered by either stress or Flx treatment. Treatment of the mother with Flx led to detectible Flx and NorFlx levels and lead to a decrease in serotonin levels in pup brains. In the adult male offspring, while perinatal exposure to Flx increased aggressive behavior, prenatal maternal stress decreased aggressive behavior. Interestingly, the combined effects of stress and Flx normalized aggressive behavior. Furthermore, perinatal Flx treatment led to a decrease in anxiety-like behavior in male offspring. PS led to hyperactivity and a decrease in BDNF levels in the frontal cortex regardless of Flx exposure. Neither maternal stress or Flx altered offspring performance in tests of cognitive abilities, memory, sensorimotor information processing, or risk assessment behaviors. These results demonstrate that maternal exposure to stress and Flx have a number of sustained effects on the male offspring.
In the adult mammalian brain, up-regulation of serotonin via the selective serotonin reuptake inh... more In the adult mammalian brain, up-regulation of serotonin via the selective serotonin reuptake inhibitor fluoxetine increases hippocampal neurogenesis. However, research assessing the long-term effects of modulating serotonin during the developmental period on hippocampal neurogenesis, is sparse. Here we evaluated hippocampal neurogenesis early (postnatal day 12), and later in life (postnatal day 60), in the offspring of mouse dams that were administered fluoxetine in their drinking water from embryonic day 15 (E15) through postnatal day 12 (P12). Fluoxetine-exposed mice had significantly higher levels of neuronal proliferation at P12, and P60, despite cessation of fluoxetine on P12. These effects were limited to proliferation, as survival of postnatal-born hippocampal neurons was unaltered. Mice exposed to fluoxetine also showed significantly higher levels of cell death, suggesting that homeostatic mechanisms present within the hippocampus may limit integration of adult-born neurons...
Zinc-containing terminals are found throughout the neocortex, concentrated predominantly in layer... more Zinc-containing terminals are found throughout the neocortex, concentrated predominantly in layers II/III, V, and VI. Synaptic zinc is a potent neurotransmitter/modulator and, therefore, may mediate inter- or intra-cortical integration of sensory information. We have previously shown that levels of synaptic zinc are rapidly modulated in somatosensory (barrel) cortex, in an experience- and activity-dependent manner. Zinc transporter 3 (ZnT3) knockout (KO) mice lack synaptic zinc and provide us with a good model to examine the contribution of synaptic zinc to barrel cortex-dependent behavior. In the present study, we show that ZnT3 KO mice display a marked decrease in acuity for whisker-dependent texture discrimination. ZnT3 KO mice were not able to discriminate between textures having an average particle diameter less than 300 μm while control mice were able to discriminate between textures having particle diameters separated by as little as 25 μm. This loss of texture discrimination...
International Journal of Developmental Neuroscience, 2012
INSERM U1051, Université Montpellier 2, Institut des Neurosciences de Montpellier, France E-mail ... more INSERM U1051, Université Montpellier 2, Institut des Neurosciences de Montpellier, France E-mail address: [email protected] (J.P. Hugnot). In the brain, specific signalling pathways localized in highly organized regions called niches, allow the persistence of a pool of stem and progenitor cells that generate new neurons and glial cells in adulthood. Much less is known on the spinal cord central canal niche where a sustained adult neurogenesis is not observed. Far from being a simple layer of homogenous cells, we found, both in man and in rodents, that this region is composed of several cell types localized at specific locations, expressing characteristic markers and with different morphologies and functions. Notably the mouse niche contains a subset of Dcx+ Nkx6.1+ neuronal cells sending processes into the lumen and another subpopulation of GFAP+ cells that extends radial processes into the parenchyma. These GFAP+ cells are more frequently observed in the dorsal or ventral central canal parts, either in an ependymal or subependymal position. Using a hGFAP-GFP mouse line, we found that these GFAP+ cells express FoxJ1 and are the main source of adult spinal cord stem cells. Screening of online gene expression databases (notably Allen brain and Gensat atlas) and extensive immunodetections allowed us to identify in the central canal region, the expression of several genes involved in the Notch (Jagged, Hes1), Wnt (Wnt7a, Fzd3), BMP (DAN, BMP6) and Hedgehog (SHH) pathways. We also found that cells in this region, notably the GFAP+ cells, highly expressed Zeb1 (also known as -EF1, TCF8, AREB6), a zinc finger-homeodomain transcription factor which has been described as an important regulator of epithelial-mesenchymal transition. Zeb1 and 2 are expressed by neurosphere cells derived from the adult spinal cord and are required for neurosphere formation and expansion. In depth characterization of the spinal cord niche in man and rodents constitutes an essential framework to understand the role of these cells in spinal cord physiology and damages.
Zinc is released from a subset of cerebral cortical neurons whereupon it exerts a powerful modula... more Zinc is released from a subset of cerebral cortical neurons whereupon it exerts a powerful modulatory influence on excitatory and inhibitory neurotransmission. A number of studies have suggested that alterations in the regulation of zinc may contribute to the genesis of epilepsy. Here, we tested this hypothesis by examining the distribution of zinc-containing axon terminals in rats selectively bred for an innate susceptibility (FAST) or resistance (SLOW) to the development of kindling-induced seizures. Zinc was stained histochemically and levels of staining were quantitatively assessed. We found that the levels of synaptic zinc were significantly lower in the SLOW rats throughout the telencephalon. This relative reduction was most pronounced in limbic cortices where levels were less than 30% of FAST rats. These results suggest that innate differences in the homeostatic regulation of synaptic zinc, particularly in limbic cortices, may underlie differences in epileptogenicity.
In the brain, vesicular zinc, which refers to a subset of zinc that is sequestered into synaptic ... more In the brain, vesicular zinc, which refers to a subset of zinc that is sequestered into synaptic vesicles by zinc transporter 3 (ZnT3), has extensive effects on neuronal signalling and modulation. Vesicular zinc-focused research has mainly been directed to its role in the hippocampus, particularly in adult neurogenesis. However, whether vesicular zinc is involved in modulating neurogenesis during the early postnatal period has been less studied. As a first step to understanding this, we used ZnT3 knockout (KO) mice, which lack ZnT3 and, thus, vesicular zinc, to evaluate cell proliferation at three different age points spanning postnatal development (P6, P14, and P28). The survival and the neuronal phenotype of these cells was also assessed in adulthood. We found that male ZnT3 KO mice exhibited lower rates of cell proliferation at P14, but a greater number of these cells survived to adulthood. Additionally, significantly more cells labelled on P6 survived to adulthood in male and fe...
Chronic maternal stress during pregnancy can have long-term, detrimental consequences for the off... more Chronic maternal stress during pregnancy can have long-term, detrimental consequences for the offspring. An understanding of the mechanisms responsible for mediating these effects is essential for devising therapeutic interventions. Here, we examined whether serotonin 1A receptor (5-HTR) mediates the effects of maternal stress on the behavioral outcomes of the offspring as adults. Heterozygous (HET) mouse dams were bred with HET males and were randomly assigned to stress or control groups. Pregnant dams in the stress group were exposed to a regime of chronic unpredictable stress from embryonic day 7 to 18. At two months of age, groups of male and female wildtype (WT), HET, and knockout (KO) offspring underwent a comprehensive behavioral test battery that included tests of social behavior, memory, aggression, anxiety, sensorimotor information processing, and exploratory and risk assessment behaviors. Independent of genotype, prenatal stress resulted in a change in locomotor activity ...
Journal of Cerebral Blood Flow & Metabolism, 2008
We hypothesized that magnetic resonance magnetization transfer (MT) imaging would be sensitive fo... more We hypothesized that magnetic resonance magnetization transfer (MT) imaging would be sensitive for detecting cerebral ischemic injury in white matter of neonatal brain. We compared the progression of changes in T2 and the MT ratio (MTR) after cerebral hypoxic-ischemic insults of differing severity in neonatal rats. Magnetization transfer imaging parameters were first optimized, and then MTR and T2 maps were acquired at various times after a mild (rather selective white matter) or substantial insult produced by unilateral cerebral hypoxia—ischemia. Depending on insult severity, time after insult, and region (e.g., subcortical white matter or cortex), cerebral hypoxia—ischemia produced reductions in MTR and an increase in T2. The exception was acutely at 1 to 5 h at which time points MTR was reduced ipsilaterally in white matter, whereas T2 was not affected significantly. Progression of imaging changes differed in rats grouped according to whether gross damage was present after chroni...
Zinc is highly concentrated in synaptic vesicles throughout the mammalian telencephalon and, in p... more Zinc is highly concentrated in synaptic vesicles throughout the mammalian telencephalon and, in particular, the hippocampal dentate gyrus. A role for zinc in modulating synaptic plasticity has been inferred, but whether zinc has a particular role in experience-dependent plasticity has yet to be determined. The aim of the current study was to determine whether vesicular zinc is important for modulating adult hippocampal neurogenesis in an experience-dependent manner and, consequently, hippocampal-dependent behaviour. We assessed the role of vesicular zinc in modulating hippocampal neurogenesis and behaviour by comparing ZnT3 knockout (KO) mice, which lack vesicular zinc, to wild-type (WT) littermates exposed to either standard housing conditions (SH) or an enriched environment (EE). We found that vesicular zinc is necessary for a cascade of changes in hippocampal plasticity following EE, such as increases in hippocampal neurogenesis and elevations in mature brain-derived neurotrophic...
Zinc is an important neuromodulatory transmitter that is co-released with glutamate at many centr... more Zinc is an important neuromodulatory transmitter that is co-released with glutamate at many central excitatory synapses. Growing evidence suggests that zinc is a key mediator and modulator of ischemic cell death in neurons. Vesicular release of zinc from presynaptic nerve terminals following ischemia is thought to be a key step in the excitotoxic injury of postsynaptic neurons. As a first step in determining the role of zinc in post-ischemic neuronal injury we have assessed the distribution of synaptic zinc in the motor cortex of adult mice at various intervals following induction of a photothrombotic stroke.
Zinc is important in neural and synaptic development and neuronal transmission. Within the brain,... more Zinc is important in neural and synaptic development and neuronal transmission. Within the brain, zinc transporter 3 (ZnT3) is essential for zinc uptake into vesicles. Loss of vesicular zinc has been shown to produce neurodevelopmental disorder (NDD)-like behavior, such as decreased social interaction and increased anxiety- and repetitive-like behavior. Maternal immune activation (MIA) has been identified as an environmental factor for NDDs, such as autism spectrum disorders (ASDs) and schizophrenia (SZ), in offspring, which occurs during pregnancy when the mother’s immune system reacts to the exposure to viruses or infectious diseases. In this study, we investigated the interaction effect of a genetic factor [ZnT3 knockout (KO) mice] and an environmental factor (MIA). We induced MIA in pregnant female (dams) mice during mid-gestation, using polyinosinic:polycytidylic acid (polyI:C), which mimics a viral infection. Male and female ZnT3 KO and wild-type (WT) offspring were tested in ...
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Papers by Richard Dyck