TY  - JOUR
AB  - At present, many studies support the notion that after stroke, remote regions connected to the infarcted area are also affected and may contribute to functional outcome. In the present study, we have analyzed possible microanatomical alterations in pyramidal neurons from the contralesional hemisphere after induced stroke. We performed intracellular injections of Lucifer yellow in pyramidal neurons from layer III in the somatosensory cortex of the contralesional hemisphere in an ischemic stroke mouse model. A detailed 3-dimensional analysis of the neuronal complexity and morphological alterations of dendritic spines was then performed. Our results demonstrate that pyramidal neurons from layer III in the somatosensory cortex of the contralesional hemisphere show selective changes in their dendritic arbors, namely, less dendritic complexity of the apical dendritic arbor-but no changes in the basal dendritic arbor. In addition, we found differences in spine morphology in both apical and basal dendrites comparing the contralesional hemisphere with the lesional hemisphere. Our results show that pyramidal neurons of remote areas connected to the infarct zone exhibit a series of selective changes in neuronal complexity and morphological distribution of dendritic spines, supporting the hypothesis that remote regions connected to the peri-infarcted area are also affected after stroke.
AU  - Merino-Serrais, P.*
AU  - Plaza-Alonso, S.*
AU  - Hellal, F.
AU  - Valero-Freitag, S.*
AU  - Kastanauskaite, A.*
AU  - Muñoz, A.*
AU  - Plesnila, N.*
AU  - DeFelipe, J.*
C1  - 64822
C2  - 52507
SP  - 1074-1089
TI  - Microanatomical study of pyramidal neurons in the contralesional somatosensory cortex after experimental ischemic stroke.
JO  - Cereb. Cortex
VL  - 33
IS  - 4
PY  - 2022
SN  - 1047-3211
ER  - 

TY  - JOUR
AB  - We have proposed that cortical nNOS/NK1R interneurons have a role in sleep homeostasis. The hypocretins (orexins) are wake-promoting neuropeptides and hypocretin/orexin (Hcrt) neurons project to the cortex. Hcrt peptides affect deep layer cortical neurons, and Hcrt receptor 1 (Hcrtr1; Ox1r) mRNA is expressed in cortical nNOS/NK1R cells. Therefore, we investigated whether Hcrt neuron stimulation affects cingulate cortex nNOS/NK1R neurons. Bath application of HCRT1/orexin-A evoked an inward current and membrane depolarization in most nNOS/NK1R cells which persisted in tetrodotoxin; optogenetic stimulation of Hcrt terminals expressing channelrhodopsin-2 confirmed these results, and pharmacological studies determined that HCRTR1 mediated these responses. Single-cell RT-PCR found Hcrtr1 mRNA in 31% of nNOS/NK1R cells without any Hcrtr2 mRNA expression; immunohistochemical studies of Hcrtr1-EGFP mice confirmed that a minority of nNOS/NK1R cells express HCRTR1. When Hcrt neurons degenerated in orexin-tTA;TetO DTA mice, the increased EEG delta power during NREM sleep produced in response to 4 h sleep deprivation and c-FOS expression in cortical nNOS/NK1R cells during recovery sleep were indistinguishable from that of controls. We conclude that Hcrt excitatory input to these deep layer cells is mediated through HCRTR1 but is unlikely to be involved in the putative role of cortical nNOS/NK1R neurons in sleep homeostasis.
AU  - Williams, R.H.
AU  - Black, S.W.*
AU  - Thomas, A.M.*
AU  - Piquet, J.*
AU  - Cauli, B.*
AU  - Kilduff, T.S.*
C1  - 54995
C2  - 45970
CY  - Journals Dept, 2001 Evans Rd, Cary, Nc 27513 Usa
SP  - 1090-1108
TI  - Excitation of cortical nNOS/NK1R neurons by hypocretin 1 is independent of sleep homeostasis.
JO  - Cereb. Cortex
VL  - 29
IS  - 3
PB  - Oxford Univ Press Inc
PY  - 2019
SN  - 1047-3211
ER  - 

TY  - JOUR
AB  - Aging leads to adverse outcomes after traumatic brain injury. The mechanisms underlying these defects, however, are not yet clear. In this study, we found that astrocytes in the aged post-traumatic cerebral cortex develop a significantly reduced proliferative response, resulting in reduced astrocyte numbers in the penumbra. Moreover, experiments of reactive astrocytes in vitro reveal that their diminished proliferation is due to an age-related switch in the division mode with reduced cell-cycle re-entry rather than changes in cell-cycle length. Notably, reactive astrocytes in vivo and in vitro become refractory to stimuli increasing their proliferation during aging, such as Sonic hedgehog signaling. These data demonstrate for the first time that age-dependent, most likely intrinsic changes in the proliferative program of reactive astrocytes result in their severely hampered proliferative response to traumatic injury thereby affecting astrocyte homeostasis.
AU  - Heimann, G.*
AU  - Lange Canhos, L.
AU  - Frik, J.
AU  - Jäger, G.*
AU  - Lepko, T.
AU  - Ninkovic, J.
AU  - Götz, M.
AU  - Sirko, S.
C1  - 51163
C2  - 42674
CY  - Cary
SP  - 1-16
TI  - Changes in the proliferative program limit astrocyte Hhmeostasis in the aged post-traumatic murine cerebral cortex.
JO  - Cereb. Cortex
VL  - 27
IS  - 8
PB  - Oxford Univ Press Inc
PY  - 2017
SN  - 1047-3211
ER  - 

TY  - JOUR
AB  - The neuropeptide S (NPS) system contributes to the pathogenesis of anxiety. The more active T allele of the functional rs324981 variant in the neuropeptide S receptor gene (NPSR1) is associated with panic disorder (PD) and distorted cortico-limbic activity during emotion processing in healthy adults and PD patients. This study investigated the influence of NPSR1 genotype on fronto-limbic effective connectivity within the developing brain. Sixty healthy subjects (8-21 years) were examined using an emotional go-nogo task and fMRI. Fronto-limbic connectivity was determined using Dynamic Causal Modeling. In A allele carriers, connectivity between the right middle frontal gyrus (MFG) and the right amygdala was higher in older (≥14 years) than that in younger (<14 years) probands, whereas TT homozygotes ≥14 years showed a reduction of fronto-limbic connectivity between the MFG and both the amygdala and the insula. Fronto-limbic connectivity varied between NPSR1 genotypes in the developing brain suggesting a risk-increasing effect of the NPSR1T allele for anxiety-related traits via impaired top-down control of limbic structures emerging during adolescence. Provided robust replication in longitudinal studies, these findings may constitute valuable biomarkers for early targeted prevention of anxiety disorders.
AU  - Domschke, K.*
AU  - Akhrif, A.*
AU  - Romanos, M.*
AU  - Bajer, C.*
AU  - Mainusch, M.*
AU  - Winkelmann, J.
AU  - Zimmer, C.*
AU  - Neufang, S.*
C1  - 47234
C2  - 39248
CY  - Cary
SP  - 554-566
TI  - Neuropeptide S receptor gene variation differentially modulates fronto-limbic effective connectivity in childhood and adolescence.
JO  - Cereb. Cortex
VL  - 27
IS  - 1
PB  - Oxford Univ Press Inc
PY  - 2015
SN  - 1047-3211
ER  - 

TY  - JOUR
AB  - In order to adequately explore the neurobiological basis of eating behavior of humans and their changes with body weight, interactions between brain areas or networks need to be investigated. In the current functional magnetic resonance imaging study, we examined the modulating effects of stimulus category (food vs. nonfood), caloric content of food, and body weight on the time course and functional connectivity of 5 brain networks by means of independent component analysis in healthy lean and overweight/obese adults. These functional networks included motor sensory, default-mode, extrastriate visual, temporal visual association, and salience networks. We found an extensive modulation elicited by food stimuli in the 2 visual and salience networks, with a dissociable pattern in the time course and functional connectivity between lean and overweight/obese subjects. Specifically, only in lean subjects, the temporal visual association network was modulated by the stimulus category and the salience network by caloric content, whereas overweight and obese subjects showed a generalized augmented response in the salience network. Furthermore, overweight/obese subjects showed changes in functional connectivity in networks important for object recognition, motivational salience, and executive control. These alterations could potentially lead to top-down deficiencies driving the overconsumption of food in the obese population.
AU  - Kullmann, S.
AU  - Pape, A.-A.*
AU  - Heni, M.*
AU  - Ketterer, C.*
AU  - Schick, F.*
AU  - Häring, H.-U.
AU  - Fritsche, A.
AU  - Preissl, H.
AU  - Veit, R.*
C1  - 11045
C2  - 30476
SP  - 1247-1256
TI  - Functional network connectivity underlying food processing: Disturbed salience and visual processing in overweight and obese adults.
JO  - Cereb. Cortex
VL  - 23
IS  - 5
PB  - Oxford Univ. Press
PY  - 2013
SN  - 1047-3211
ER  - 

TY  - JOUR
AB  - Regional patterning of the cerebral cortex is initiated by morphogens secreted by patterning centers that establish graded expression of transcription factors within cortical progenitors. Here, we show that Dmrt5 is expressed in cortical progenitors in a high-caudomedial to low-rostrolateral gradient. In its absence, the cortex is strongly reduced and exhibits severe abnormalities, including agenesis of the hippocampus and choroid plexus and defects in commissural and thalamocortical tracts. Loss of Dmrt5 results in decreased Wnt and Bmp in one of the major telencephalic patterning centers, the dorsomedial telencephalon, and in a reduction of Cajal-Retzius cells. Expression of the dorsal midline signaling center-dependent transcription factors is downregulated, including Emx2, which promotes caudomedial fates, while the rostral determinant Pax6, which is inhibited by midline signals, is upregulated. Consistently, Dmrt5(-/-) brains exhibit patterning defects with a dramatic reduction of the caudomedial cortex. Dmrt5 is increased upon the activation of Wnt signaling and downregulated in Gli3(xt/xt) mutants. We conclude that Dmrt5 is a novel Wnt-dependent transcription factor required for early cortical development and that it may regulate initial cortical patterning by promoting dorsal midline signaling center formation and thereby helping to establish the graded expression of the other transcription regulators of cortical identity.
AU  - Saulnier, A.*
AU  - Keruzore, M.*
AU  - de Clercq, S.*
AU  - Bar, I.*
AU  - Moers, V.*
AU  - Magnani, D.*
AU  - Walcher, T.
AU  - Filippis, C.*
AU  - Kricha, S.*
AU  - Parlier, D.*
AU  - Viviani, L.*
AU  - Matson, C.K.*
AU  - Nakagawa, Y.*
AU  - Theil, T.*
AU  - Götz, M.
AU  - Mallamaci, A.*
AU  - Marine, J.-C.*
AU  - Zarkower, D.*
AU  - Bellefroid, E.J.*
C1  - 10525
C2  - 30306
SP  - 2552-2567
TI  - The doublesex homolog Dmrt5 is required for the development of the caudomedial cerebral cortex in mammals.
JO  - Cereb. Cortex
VL  - 23
IS  - 11
PB  - Oxford Univ. Press
PY  - 2013
SN  - 1047-3211
ER  - 

TY  - JOUR
AB  - In the subependymal zone and the dentate gyrus of the adult brain of rodents, neural stem cells with glial properties generate new neurons in a life-long process. The identification of glial progenitors outside the neurogenic niches, oligodendrocyte precursors in the healthy brain, and reactive astrocytes after cortical injury led to the idea of using these cells as endogenous cell source for neural repair in the cerebral cortex. Recently, our group showed that proliferating astroglia from the cerebral cortex can be reprogrammed into neurons capable of action potential firing by forced expression of neurogenic fate determinants but failed to develop synapses. Here, we describe a maturation profile of cultured reprogrammed NG2+ and glial fibrillary acidic protein+ glia cells of the postnatal rat cortex that ends with the establishment of a glutamatergic neuronal network. Within 3 weeks after viral expression of the transcription factor neurogenin 2 (Ngn2), glia-derived neurons exhibit network-driven, glutamate receptor-dependent oscillations in Ca(2+) and exhibit functional pre- and postsynaptic specialization. Interestingly, the Ngn2-instructed glutamatergic network also supports the maturation of a gamma-aminobutyric acid (GABA)ergic input via GABA(A) receptors in a non-cell autonomous manner. The "proof-of-principle" results imply that a single transcription factor may be sufficient to instruct a neuronal network from a glia-like cell source.
AU  - Blum, R.*
AU  - Heinrich, C.*
AU  - Sánchez, R.*
AU  - Lepier, A.*
AU  - Gundelfinger, E.D.*
AU  - Berninger, B.*
AU  - Götz, M.
C1  - 1650
C2  - 27360
SP  - 413-424
TI  - Neuronal network formation from reprogrammed early postnatal rat cortical glial cells.
JO  - Cereb. Cortex
VL  - 21
IS  - 2
PB  - Oxford Univ. Press
PY  - 2011
SN  - 1047-3211
ER  - 

TY  - JOUR
AB  - In order to unravel the molecular determinants of cell fate, it is important to understand when fate restriction occurs during brain development. Lineage analysis suggested that bi- or multipotent progenitors persist into late developmental stages in some central nervous system regions, whereas most progenitor cells in the cerebral cortex appeared to be restrained to generate only a single cell type already at early stages. Here we discuss this previous work and present new data demonstrating that cortical progenitors generating exclusively glial cells appear late in development. In utero transduction of cortical progenitors at early and mid-neurogenesis using a combination of replication-defective retroviral vectors encoding different fluorescent proteins indicated that the early developing cortex is devoid of glia-restricted progenitors, although these are frequent during mid- and late neurogenesis. Clonal analyses in vitro using retroviral vectors and live cell tracking by video time-lapse microscopy confirmed these findings, revealing that the early developing cortex harbors 2 main progenitor types: neuron-restricted and bipotent (neuron-glial) progenitors. The latter are responsible for the generation of glial-restricted progenitors at mid- and late neurogenesis.
AU  - Costa, M.R.
AU  - Bucholz, O.
AU  - Schroeder, T.
AU  - Götz, M.
C1  - 1419
C2  - 26438
SP  - i35-i143
TI  - Late origin of glia-restricted progenitors in the developing mouse cerebral cortex.
JO  - Cereb. Cortex
VL  - 19
IS  - SUPPL. 1
PB  - Oxford Univ Press
PY  - 2009
SN  - 1047-3211
ER  - 

TY  - JOUR
AB  - Asymmetric cell divisions are correlated to neurogenesis in the mammalian cortex and occur often with a horizontal orientation of cell division. However, the molecular mechanisms of spindle orientation or asymmetric cell divisions are not well understood in the developing mammalian central nervous system. Here we show a new molecular marker for horizontally dividing precursors in the mammalian telencephalon. The antibody 2G12 directed against phosphorylated serine of growth associated protein 43 (GAP-43) labels postmitotic neurons and a subset of cells in mitoses in the developing rat telencephalon. 2G12 immunoreactivity was found at a high frequency in mitotic cells dividing parallel to the ventricular surface throughout neurogenesis (embryonic day 13-17) in the cerebral cortex and ganglionic eminence. Interestingly, we detected the same predominance of 2G12 immunoreactivity in horizontally dividing cells in the subventricular zone, the second proliferative layer that has recently been involved in the generation of neurons. Moreover, 2G12 immunostaining is no longer detectable in mitotic cells of the ventricular zones at E21, the onset of gliogenesis in rat telencephalon. These data imply GAP-43 phosphorylation in the phase of neuronal commitment during M-phase and present to our knowledge the first molecular correlate to horizontally dividing precursors in mammalian neurogenesis.
AU  - Stricker, S.*
AU  - Meiri, K.*
AU  - Götz, M.
C1  - 4970
C2  - 24132
SP  - 121-131
TI  - P-GAP-43 is enriched in horizontal cell divisions throughout rat cortical development.
JO  - Cereb. Cortex
PY  - 2006
SN  - 1047-3211
ER  -