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Research paper thumbnail of Requirement for type III (CRD) neuregulin1 in sensorimotor gating and working memory

Neuregulin-1 (Nrg1)/erbB signaling regulates neuronal development, migration, myelination, and sy... more Neuregulin-1 (Nrg1)/erbB signaling regulates neuronal development, migration, myelination, and synaptic maintenance. The Nrg1 gene is a schizophrenia susceptibility gene. To understand the contribution of Nrg1 signaling to adult brain structure and behaviors, we have studied the regulation of Type III Nrg1 expression and evaluated the effect of decreased expression of the Type III Nrg1 isoforms. Type III Nrg1 is transcribed by a promoter distinct from those for other Nrg1 isoforms and, in the adult brain, is expressed in the medial prefrontal cortex, ventral hippocampus and ventral subiculum, regions involved in the regulation of sensorimotor gating and short term memory. Adult heterozygous mutant mice with a targeted disruption for Type III Nrg1 (Nrg1 tm1.1Lwr+/-) have enlarged lateral ventricles and decreased dendritic spine density on subicular pyramidal neurons. MRI imaging of Type III Nrg1 heterozygous mice revealed hypo-function in the medial prefrontal cortex and the hippocampal CA1 and subiculum regions. Type III Nrg1 heterozygous mice also have impaired performance on delayed alternation memory tasks, and deficits in prepulse inhibition (PPI). Chronic nicotine treatment eliminated differences in PPI between Type III Nrg1 heterozygous mice and their wild type littermates. Our findings demonstrate a role of Type III Nrg1-signaling in the maintenance of cortico-striatal components, and in the neural circuits involved in sensorimotor gating and short term memory.

Research paper thumbnail of Cellular Location and Circadian Rhythm of Expression of the Biological Clock GenePeriod 1in the Mouse Retina

The Journal of Neuroscience, 2003

The cellular location and rhythmic expression of Period 1 (Per1) circadian clock gene were examin... more The cellular location and rhythmic expression of Period 1 (Per1) circadian clock gene were examined in the retina of a Per1::GFP transgenic mouse. Mouse Per1 (mPer1) RNA was localized to inner nuclear and ganglion cell layers but was absent in the outer nuclear (photoreceptor) layer. Green fluorescent protein (GFP), which was shown to colocalize with PER1 protein, was found in a few subtypes of amacrine neuron, including those containing tyrosine hydroxylase, calbindin, and calretinin, but not in cholinergic amacrine cells. A small subset of ganglion cells also contained GFP immunoreactivity (GFP-IR), but the melanopsin-containing subtype, which projects to the suprachiasmatic nuclei (SCN), lacked GFP-IR. Although the intensity of GFP-IR varied among the populations of amacrine cells at each time point that was examined, both diurnal and circadian rhythms were found for the fraction of neurons showing strong GFP-IR, with peak expression between Zeitgeber/circadian (ZT/CT) times 10 and 14. In SCNs that were examined in the same mice used for the retinal measures, the peak in GFP-IR also occurred at approximately ZT/CT 10. Our results are the first to demonstrate a circadian rhythm of a biological clock component in identified neurons of a mammalian retina.

Research paper thumbnail of Cell-intrinsic signals that regulate adult neurogenesis in vivo: insights from inducible approaches

Research paper thumbnail of Notch1 Is Required for Maintenance of the Reservoir of Adult Hippocampal Stem Cells

Journal of Neuroscience, 2010

Notch1 regulates neural stem cell (NSC) number during development, but its role in adult neurogen... more Notch1 regulates neural stem cell (NSC) number during development, but its role in adult neurogenesis is unclear. We generated nestin-CreER T2 /R26R-YFP/Notch1 loxP/loxP [Notch1inducible knockout (iKO)] mice to allow tamoxifen (TAM)-inducible elimination of Notch1 and concomitant expression of yellow fluorescent protein (YFP) in nestin-expressing Type-1 NSCs and their progeny in the adult hippocampal subgranular zone (SGZ). Consistent with previous research, YFPϩ cells in all stages of neurogenesis were evident in the subgranular zone (SGZ) of wild-type (WT) mice (nestin-CreER T2 /R26R-YFP/Notch1 w/w) after tamoxifen (post-TAM), producing adultgenerated YFPϩ dentate gyrus neurons. Compared with WT littermates, Notch1 iKO mice had similar numbers of total SGZ YFPϩ cells 13 and 30 d post-TAM but had significantly fewer SGZ YFPϩ cells 60 and 90 d post-TAM. Significantly fewer YFPϩ Type-1 NSCs and transiently amplifying progenitors (TAPs) resulted in generation of fewer YFPϩ granule neurons in Notch1 iKO mice. Strikingly, 30 d of running rescued this deficit, as the total YFPϩ cell number in Notch iKO mice was equivalent to WT levels. This was even more notable given the persistent deficits in the Type-1 NSC and TAP reservoirs. Our data show that Notch1 signaling is required to maintain a reservoir of undifferentiated cells and ensure continuity of adult hippocampal neurogenesis, but that alternative Notch-and Type-1 NSCindependent pathways compensate in response to physical activity. These data shed light on the complex relationship between Type-1 NSCs, adult neurogenesis, the neurogenic niche, and environmental stimuli.

Research paper thumbnail of Type III Neuregulin-1 Is Required for Normal Sensorimotor Gating, Memory-Related Behaviors, and Corticostriatal Circuit Components

Journal of Neuroscience, 2008

Research paper thumbnail of Regional differences in GABA and GAD

Mammalian horizontal cells are believed to be GABAergic because, in most species, they contain bo... more Mammalian horizontal cells are believed to be GABAergic because, in most species, they contain both GABA and glutamic acid decarboxylase (GAD), and their terminals are presynaptic to GABA receptors. In adult rabbit, however, GABA and GAD immunoreactivity have not been consistently demonstrated in horizontal cells, casting doubts on the assumption that they too are GABAergic. Here we demonstrate that all rabbit horizontal cell terminals---dendritic terminals of type A, and both dendritic and axonal terminals of type B---immunostain for one isoform of GAD, GAD 67 . In addition, we show that type A horizontal cell somas and primary dendrites in the visual streak (identified by their immunoreactivity to calbindin) are immunoreactive for the other GAD isoform, GAD 65 .

Research paper thumbnail of Mapping the mind: A new tool reveals uncharted territories in the brain

Research paper thumbnail of Study Unveils New Method for Universal Extraction and PCR Amplification of Fungal DNA

ANtonio has developed a new method of extraction and amplification for fungal DNA, creating a too... more ANtonio has developed a new method of extraction and amplification for fungal DNA, creating a tool that could be crucial for clinicians treating patients with rare or hard to identify fungal infections. The views, opinions and/or findings contained in this report are those of the author(s) and should not contrued as an official Department of the Army position, policy or decision, unless so designated by other documentation.

Research paper thumbnail of Regional differences in GABA and GAD

Research paper thumbnail of Cellular location and diurnal rhythm of expression of Period 1 in the mouse retina

Research paper thumbnail of Notch1 Is Required for Maintenance of the Reservoir of Adult Hippocampal Stem Cells

Journal of Neuroscience, 2010

Notch1 regulates neural stem cell (NSC) number during development, but its role in adult neurogen... more Notch1 regulates neural stem cell (NSC) number during development, but its role in adult neurogenesis is unclear. We generated nestin-CreER T2 /R26R-YFP/Notch1 loxP/loxP (Notch1 iKO) mice to allow tamoxifen (TAM)-inducible elimination of Notch1 and concomitant expression of yellow fluorescent protein (YFP) in nestin-expressing Type-1 NSCs and their progeny in the adult hippocampal subgranular zone (SGZ). Consistent with previous research, YFP+ cells in all stages of neurogenesis were evident in the subgranular zone (SGZ) of wild type mice (WT; nestin-CreER T2 / R26R-YFP/Notch1 wt/wt ) after tamoxifen (post-TAM), producing adult-generated YFP+ dentate gyrus neurons. Compared to WT littermates, Notch1 iKO mice had similar numbers of total SGZ YFP+ cells 13 and 30 days post-TAM but had significantly fewer SGZ YFP+ cells 60 and 90 days post-TAM. Significantly fewer YFP+ Type-1 NSCs and transiently-amplifying progenitors (TAPs) resulted in generation of fewer YFP+ granule neurons in Notch1 iKO mice. Strikingly, 30 days of running rescued this deficit, as the total YFP+ cell number in Notch iKO mice was equivalent to WT levels. This was even more notable given the persistent deficits in the Type-1 NSC and TAP reservoirs. Our data show that Notch1 signaling is required to maintain a reservoir of undifferentiated cells and ensure continuity of adult hippocampal neurogenesis, but that alternative Notch1-and Type-1 NSC-independent pathways compensate in response to physical activity. These data shed light on the complex relationship between Type-1 NSCs, adult neurogenesis, the neurogenic niche, and environmental stimuli.

Research paper thumbnail of Type III Neuregulin-1 Is Required for Normal Sensorimotor Gating, Memory-Related Behaviors, and Corticostriatal Circuit Components

Journal of Neuroscience, 2008

Neuregulin-1 (Nrg1)/erbB signaling regulates neuronal development, migration, myelination, and sy... more Neuregulin-1 (Nrg1)/erbB signaling regulates neuronal development, migration, myelination, and synaptic maintenance. The Nrg1 gene is a schizophrenia susceptibility gene. To understand the contribution of Nrg1 signaling to adult brain structure and behaviors, we studied the regulation of type III Nrg1 expression and evaluated the effect of decreased expression of the type III Nrg1 isoforms. Type III Nrg1 is transcribed by a promoter distinct from those for other Nrg1 isoforms and, in the adult brain, is expressed in the medial prefrontal cortex, ventral hippocampus, and ventral subiculum, regions involved in the regulation of sensorimotor gating and short-term memory. Adult heterozygous mutant mice with a targeted disruption for type III Nrg1 (Nrg1 tm1.1Lwrϩ/Ϫ ) have enlarged lateral ventricles and decreased dendritic spine density on subicular pyramidal neurons. Magnetic resonance imaging of type III Nrg1 heterozygous mice revealed hypofunction in the medial prefrontal cortex and the hippocampal CA1 and subiculum regions. Type III Nrg1 heterozygous mice also have impaired performance on delayed alternation memory tasks, and deficits in prepulse inhibition (PPI). Chronic nicotine treatment eliminated differences in PPI between type III Nrg1 heterozygous mice and their wild-type littermates. Our findings demonstrate a role of type III Nrg1 signaling in the maintenance of corticostriatal components and in the neural circuits involved in sensorimotor gating and short-term memory.

Research paper thumbnail of Requirement for type III (CRD) neuregulin1 in sensorimotor gating and working memory

Neuregulin-1 (Nrg1)/erbB signaling regulates neuronal development, migration, myelination, and sy... more Neuregulin-1 (Nrg1)/erbB signaling regulates neuronal development, migration, myelination, and synaptic maintenance. The Nrg1 gene is a schizophrenia susceptibility gene. To understand the contribution of Nrg1 signaling to adult brain structure and behaviors, we have studied the regulation of Type III Nrg1 expression and evaluated the effect of decreased expression of the Type III Nrg1 isoforms. Type III Nrg1 is transcribed by a promoter distinct from those for other Nrg1 isoforms and, in the adult brain, is expressed in the medial prefrontal cortex, ventral hippocampus and ventral subiculum, regions involved in the regulation of sensorimotor gating and short term memory. Adult heterozygous mutant mice with a targeted disruption for Type III Nrg1 (Nrg1 tm1.1Lwr+/-) have enlarged lateral ventricles and decreased dendritic spine density on subicular pyramidal neurons. MRI imaging of Type III Nrg1 heterozygous mice revealed hypo-function in the medial prefrontal cortex and the hippocampal CA1 and subiculum regions. Type III Nrg1 heterozygous mice also have impaired performance on delayed alternation memory tasks, and deficits in prepulse inhibition (PPI). Chronic nicotine treatment eliminated differences in PPI between Type III Nrg1 heterozygous mice and their wild type littermates. Our findings demonstrate a role of Type III Nrg1-signaling in the maintenance of cortico-striatal components, and in the neural circuits involved in sensorimotor gating and short term memory.

Research paper thumbnail of Cellular Location and Circadian Rhythm of Expression of the Biological Clock GenePeriod 1in the Mouse Retina

The Journal of Neuroscience, 2003

The cellular location and rhythmic expression of Period 1 (Per1) circadian clock gene were examin... more The cellular location and rhythmic expression of Period 1 (Per1) circadian clock gene were examined in the retina of a Per1::GFP transgenic mouse. Mouse Per1 (mPer1) RNA was localized to inner nuclear and ganglion cell layers but was absent in the outer nuclear (photoreceptor) layer. Green fluorescent protein (GFP), which was shown to colocalize with PER1 protein, was found in a few subtypes of amacrine neuron, including those containing tyrosine hydroxylase, calbindin, and calretinin, but not in cholinergic amacrine cells. A small subset of ganglion cells also contained GFP immunoreactivity (GFP-IR), but the melanopsin-containing subtype, which projects to the suprachiasmatic nuclei (SCN), lacked GFP-IR. Although the intensity of GFP-IR varied among the populations of amacrine cells at each time point that was examined, both diurnal and circadian rhythms were found for the fraction of neurons showing strong GFP-IR, with peak expression between Zeitgeber/circadian (ZT/CT) times 10 and 14. In SCNs that were examined in the same mice used for the retinal measures, the peak in GFP-IR also occurred at approximately ZT/CT 10. Our results are the first to demonstrate a circadian rhythm of a biological clock component in identified neurons of a mammalian retina.

Research paper thumbnail of Cell-intrinsic signals that regulate adult neurogenesis in vivo: insights from inducible approaches

Research paper thumbnail of Notch1 Is Required for Maintenance of the Reservoir of Adult Hippocampal Stem Cells

Journal of Neuroscience, 2010

Notch1 regulates neural stem cell (NSC) number during development, but its role in adult neurogen... more Notch1 regulates neural stem cell (NSC) number during development, but its role in adult neurogenesis is unclear. We generated nestin-CreER T2 /R26R-YFP/Notch1 loxP/loxP [Notch1inducible knockout (iKO)] mice to allow tamoxifen (TAM)-inducible elimination of Notch1 and concomitant expression of yellow fluorescent protein (YFP) in nestin-expressing Type-1 NSCs and their progeny in the adult hippocampal subgranular zone (SGZ). Consistent with previous research, YFPϩ cells in all stages of neurogenesis were evident in the subgranular zone (SGZ) of wild-type (WT) mice (nestin-CreER T2 /R26R-YFP/Notch1 w/w) after tamoxifen (post-TAM), producing adultgenerated YFPϩ dentate gyrus neurons. Compared with WT littermates, Notch1 iKO mice had similar numbers of total SGZ YFPϩ cells 13 and 30 d post-TAM but had significantly fewer SGZ YFPϩ cells 60 and 90 d post-TAM. Significantly fewer YFPϩ Type-1 NSCs and transiently amplifying progenitors (TAPs) resulted in generation of fewer YFPϩ granule neurons in Notch1 iKO mice. Strikingly, 30 d of running rescued this deficit, as the total YFPϩ cell number in Notch iKO mice was equivalent to WT levels. This was even more notable given the persistent deficits in the Type-1 NSC and TAP reservoirs. Our data show that Notch1 signaling is required to maintain a reservoir of undifferentiated cells and ensure continuity of adult hippocampal neurogenesis, but that alternative Notch-and Type-1 NSCindependent pathways compensate in response to physical activity. These data shed light on the complex relationship between Type-1 NSCs, adult neurogenesis, the neurogenic niche, and environmental stimuli.

Research paper thumbnail of Type III Neuregulin-1 Is Required for Normal Sensorimotor Gating, Memory-Related Behaviors, and Corticostriatal Circuit Components

Journal of Neuroscience, 2008

Research paper thumbnail of Regional differences in GABA and GAD

Mammalian horizontal cells are believed to be GABAergic because, in most species, they contain bo... more Mammalian horizontal cells are believed to be GABAergic because, in most species, they contain both GABA and glutamic acid decarboxylase (GAD), and their terminals are presynaptic to GABA receptors. In adult rabbit, however, GABA and GAD immunoreactivity have not been consistently demonstrated in horizontal cells, casting doubts on the assumption that they too are GABAergic. Here we demonstrate that all rabbit horizontal cell terminals---dendritic terminals of type A, and both dendritic and axonal terminals of type B---immunostain for one isoform of GAD, GAD 67 . In addition, we show that type A horizontal cell somas and primary dendrites in the visual streak (identified by their immunoreactivity to calbindin) are immunoreactive for the other GAD isoform, GAD 65 .

Research paper thumbnail of Mapping the mind: A new tool reveals uncharted territories in the brain

Research paper thumbnail of Study Unveils New Method for Universal Extraction and PCR Amplification of Fungal DNA

ANtonio has developed a new method of extraction and amplification for fungal DNA, creating a too... more ANtonio has developed a new method of extraction and amplification for fungal DNA, creating a tool that could be crucial for clinicians treating patients with rare or hard to identify fungal infections. The views, opinions and/or findings contained in this report are those of the author(s) and should not contrued as an official Department of the Army position, policy or decision, unless so designated by other documentation.

Research paper thumbnail of Regional differences in GABA and GAD

Research paper thumbnail of Cellular location and diurnal rhythm of expression of Period 1 in the mouse retina

Research paper thumbnail of Notch1 Is Required for Maintenance of the Reservoir of Adult Hippocampal Stem Cells

Journal of Neuroscience, 2010

Notch1 regulates neural stem cell (NSC) number during development, but its role in adult neurogen... more Notch1 regulates neural stem cell (NSC) number during development, but its role in adult neurogenesis is unclear. We generated nestin-CreER T2 /R26R-YFP/Notch1 loxP/loxP (Notch1 iKO) mice to allow tamoxifen (TAM)-inducible elimination of Notch1 and concomitant expression of yellow fluorescent protein (YFP) in nestin-expressing Type-1 NSCs and their progeny in the adult hippocampal subgranular zone (SGZ). Consistent with previous research, YFP+ cells in all stages of neurogenesis were evident in the subgranular zone (SGZ) of wild type mice (WT; nestin-CreER T2 / R26R-YFP/Notch1 wt/wt ) after tamoxifen (post-TAM), producing adult-generated YFP+ dentate gyrus neurons. Compared to WT littermates, Notch1 iKO mice had similar numbers of total SGZ YFP+ cells 13 and 30 days post-TAM but had significantly fewer SGZ YFP+ cells 60 and 90 days post-TAM. Significantly fewer YFP+ Type-1 NSCs and transiently-amplifying progenitors (TAPs) resulted in generation of fewer YFP+ granule neurons in Notch1 iKO mice. Strikingly, 30 days of running rescued this deficit, as the total YFP+ cell number in Notch iKO mice was equivalent to WT levels. This was even more notable given the persistent deficits in the Type-1 NSC and TAP reservoirs. Our data show that Notch1 signaling is required to maintain a reservoir of undifferentiated cells and ensure continuity of adult hippocampal neurogenesis, but that alternative Notch1-and Type-1 NSC-independent pathways compensate in response to physical activity. These data shed light on the complex relationship between Type-1 NSCs, adult neurogenesis, the neurogenic niche, and environmental stimuli.

Research paper thumbnail of Type III Neuregulin-1 Is Required for Normal Sensorimotor Gating, Memory-Related Behaviors, and Corticostriatal Circuit Components

Journal of Neuroscience, 2008

Neuregulin-1 (Nrg1)/erbB signaling regulates neuronal development, migration, myelination, and sy... more Neuregulin-1 (Nrg1)/erbB signaling regulates neuronal development, migration, myelination, and synaptic maintenance. The Nrg1 gene is a schizophrenia susceptibility gene. To understand the contribution of Nrg1 signaling to adult brain structure and behaviors, we studied the regulation of type III Nrg1 expression and evaluated the effect of decreased expression of the type III Nrg1 isoforms. Type III Nrg1 is transcribed by a promoter distinct from those for other Nrg1 isoforms and, in the adult brain, is expressed in the medial prefrontal cortex, ventral hippocampus, and ventral subiculum, regions involved in the regulation of sensorimotor gating and short-term memory. Adult heterozygous mutant mice with a targeted disruption for type III Nrg1 (Nrg1 tm1.1Lwrϩ/Ϫ ) have enlarged lateral ventricles and decreased dendritic spine density on subicular pyramidal neurons. Magnetic resonance imaging of type III Nrg1 heterozygous mice revealed hypofunction in the medial prefrontal cortex and the hippocampal CA1 and subiculum regions. Type III Nrg1 heterozygous mice also have impaired performance on delayed alternation memory tasks, and deficits in prepulse inhibition (PPI). Chronic nicotine treatment eliminated differences in PPI between type III Nrg1 heterozygous mice and their wild-type littermates. Our findings demonstrate a role of type III Nrg1 signaling in the maintenance of corticostriatal components and in the neural circuits involved in sensorimotor gating and short-term memory.