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121.
Philip E. Chen Michael L. Errington Matthias Kneussel Guiquan Chen Alexander J. Annala York H. Rudhard Georg F. Rast Christian G. Specht Cezar M. Tigaret Mohammed A. Nassar Richard G.M. Morris Timothy V.P. Bliss Ralf Schoepfer 《Learning & memory (Cold Spring Harbor, N.Y.)》2009,16(10):635-644
The NMDA receptor (NMDAR) subunit GluN1 is an obligatory component of NMDARs without a known functional homolog and is expressed in almost every neuronal cell type. The NMDAR system is a coincidence detector with critical roles in spatial learning and synaptic plasticity. Its coincidence detection property is crucial for the induction of hippocampal long-term potentiation (LTP). We have generated a mutant mouse model expressing a hypomorph of the Grin1N598R allele, which leads to a minority (about 10%) of coincidence detection-impaired NMDARs. Surprisingly, these animals revealed specific functional changes in the dentate gyrus (DG) of the hippocampal formation. Early LTP was expressed normally in area CA1 in vivo, but was completely suppressed at perforant path-granule cell synapses in the DG. In addition, there was a pronounced reduction in the amplitude of the evoked population spike in the DG. These specific changes were accompanied by behavioral impairments in spatial recognition, spatial learning, reversal learning, and retention. Our data show that minor changes in GluN1-dependent NMDAR physiology can cause dramatic consequences in synaptic signaling in a subregion-specific fashion despite the nonredundant nature of the GluN1 gene and its global expression.According to Hebb''s postulate, neurons require a molecular mechanism to detect synchronous activity in order to change the strength of synaptic connectivity (Hebb 1949). NMDA receptors (NMDARs) are molecular coincidence detectors, and selective NMDAR antagonists block the induction of long-term potentiation (LTP) in both the dentate gyrus (DG) and CA1 regions of the hippocampus (Bliss and Collingridge 1993; Martin et al. 2000). NMDARs have been long known for their role in spatial learning, but more recently have been implicated in other forms of cognitive function and dysfunction (Gruart et al. 2006; Whitlock et al. 2006; Castner and Williams 2007; Kristiansen et al. 2007; Wilson and Linster 2008).Neuronal NMDARs are hetero-tetrameric ligand-gated ion channels typically comprised of two types of subunits. Two copies of the mandatory GluN1 subunit (or NR1 subunit [Collingridge et al. 2009] encoded by Grin1) are associated with two copies from the GluN2 family, GluN2A–D (or NR2A–D). The GluN1 subunit is expressed ubiquitously both spatially and temporally throughout the developing and adult brain. Global knockout mice models of the GluN1 subunit are postnatally lethal within hours after birth (Forrest et al. 1994; Li et al. 1994), and cell-specific GluN1 mice knockouts (Tsien et al. 1996; Nakazawa et al. 2002; McHugh et al. 2007; Niewoehner et al. 2007) have provided insights on how specific synapses and regional neuronal networks are dependent on NMDAR function.The early postnatal lethality of the global GluN1 knockout is in contrast to the null mutants of the four AMPA receptor genes and other major synaptic proteins, such as αCaMKII (Silva et al. 1992a,b; Jia et al. 1996; Zamanillo et al. 1999; Meng et al. 2003). This can be at least partially explained by the absence of any close GluN1 homologs, which could functionally compensate for the absence of the GluN1 subunit. Recombinant expression studies defined the GluN1 subunit as a mandatory component of NMDARs. This constellation provides a specific opportunity to test whether different local neuronal subnetworks are affected differentially by mutant Grin1 alleles associated with subtle alterations of the functional properties of NMDARs.GluN1 subunits with the N598R point mutation (GluN1R) yield functional NMDARs that are Mg2+ insensitive and Ca2+ impermeable (Burnashev et al. 1992; Mori et al. 1992). The Grin1N598R allele that codes for GluN1R subunits is a gain-of-function mutation that is dominant lethal, even in heterozygous and hemizygous lines (Single et al. 2000; Rudhard et al. 2003). NMDARs with GluN1R subunits do not act as coincidence detectors and, interestingly, mice expressing exclusively the GluN1R allele lack whisker-related pattern formation in the neonate brainstem (Rudhard et al. 2003).To investigate the functional importance of GluN1 subunits with the N598R point mutation, we took advantage of the generation of a variant mutant line of mice (GluN1Rneo/+) expressing a minority (around 10%) of these mutant NMDARs. Even though the majority of the NMDARs are normal, all neurons expressing NMDARs will contain a subset of receptors carrying this mutation.Therefore, this mouse model is an ideal candidate to study the impact of subtle alterations of NMDAR function on different neuronal networks, such as those comprising the hippocampal formation.Studies examining region-specific targeted disruption of GluN1 expression in subregions of the hippocampus have revealed subtle yet important contributions of this NMDAR subunit in synaptic plasticity and spatial learning and memory. CA1-restricted knockout of GluN1 expression in the hippocampus caused impaired spatial learning and memory as well as reduced CA1-LTP (Tsien et al. 1996). In the case of the disruption of GluN1 expression in the DG region of the hippocampus, more subtle behavioral impairments were apparent, including the inability to discriminate between two similar contexts (pattern separation) and deficits in spatial working memory despite normal LTP in the CA1 region (McHugh et al. 2007; Niewoehner et al. 2007).Our GluN1Rneo/+ mice differ from the region-specific GluN1 mutant mice in that they express the mutant hypomorph at the same level in different subregions of the hippocampus. Interestingly, we found that this allele leads to substantial differences in short- and long-term plasticity between area CA1 and the DG of the hippocampus. The specific impairment in the DG was accompanied by impaired spatial recognition, spatial learning, reversal learning, and retention. Our data establish the possibility of a circuit-specific phenotype caused by a mutant variant of a globally expressed major nonredundant synaptic protein. 相似文献
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Hippocampal Activations during Repetitive Learning and Recall of Geometric Patterns 总被引:4,自引:0,他引:4
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Georg Grn Daniel Bittner Bernd Schmitz Arthur P. Wunderlich Reinhard Tomczak Matthias W. Riepe 《Learning & memory (Cold Spring Harbor, N.Y.)》2001,8(6):336-345
Hippocampal activation is required for episodic memory. Encoding and retrieval of novel and memorable items have been related to different locations in the hippocampus; however, the data remain ambiguous. The application of a newly designed keyboard allowed investigation of brain activation during encoding and free immediate and delayed recall with functional magnetic resonance imaging (fMRI) in young healthy controls (n=12). Because of the repetitive learning and recall conditions, an individual learning gradient was used to contrast neural activity at different individual levels of novelty. During learning, subjects were asked to memorize 10 geometric patterns requiring the establishment of intra-item associations for memorization. After learning, subjects were asked to recall the items actively via the keyboard. Learning and recall were alternated five times. Delayed recall was scanned about 15 min after the fifth immediate recall condition without subjects having seen the items again. Left-sided anterior hippocampal activity was observed during conditions of initial learning as well as maximum recall. Neural activity during delayed recall did not reveal hippocampal responses and was characterized by a transition of neural activity from occipitoparietal regions to bilateral temporal cortices. We conclude that both lateralization and segregation depend on the specific relational characteristics of the stimuli requiring establishment of intra-item associations for encoding as well as retrieval. The absence of hippocampal activation during delayed recall together with the increase of lateral temporal involvement possibly corresponds with an emerging transition from episodic to long-term memory. 相似文献
124.
Georg Katona 《Psychological research》1926,7(1):226-256
Zusammenfassung
A. Lehmann hat in seiner Psychophysiologie ein allgemeines Gesetz aufgestellt, wonach gleichzeitige Erregungen sich hemmen, sukzessive
dagegen sich bahnen. Die Schwelle für einen Schallreiz ist z. B. h?her, wenn gleichzeitig ein elektrischer Reiz einwirkt,
wogegen, im allgemeinen von zwei einander folgenden gleich starken Reizen der zweite für st?rker gehalten wird. Wir führen
hier diesen Satz an, um die Vermutung ausdrücklich abzuweisen, als ob unsere Prinzipien diesen oder einen ?hnlichen Sachverhalt
ausdrückten. Wir sprachen nicht von einwirkenden Reizen oder physiologischen Erregungen, sondern von psychischen Inhalten,
bzw. von deren gleichzeitigem oder sukzessivem Gegebensein. Und es war das Ergebnis unserer Versuche nicht, da? gleichzeitig
erscheinende psychische Inhalte sich hemmen bzw. sukzessive sich bahnen, sondern es ergab sich nur,da? stückhafte Teile in einer einheitlichen simultanen Wahrnehmung in minderwertigerer Weise zur Geltung kommen als in zwei
sukzessiven Wahrnehmungen, wo sie eben keine stückhaften Teile mehr sind, sondern selbst?ndige Gegebenheiten. Die Umkehrung dieses Satzes trifft aber auch zu und ist z. B. ableitbar aus unseren Versuchen über den Entfernungsvergleich
der Diagonalen eines Quadrates. In jeder simultanen Wahrnehmung ergibt sich ein einheitlicher Gesamteindruck, und die diesem
entsprechende Wahrnehmungsart ist eben die simultane, in welcher er auch besser verwirklicht wird, als wenn er aus einigen
sukzessiven Wahrnehmungen zu entstehen h?tte.
Mit 10 Figuren im Text.
über einen Teil der nachfolgenden Experimente hat der Verf. schon auf dem Münchener Psychologenkongre? (April 1925) berichtet. 相似文献
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Zan Strabac Ola Listhaug Tor Georg Jakobsen 《Journal of International Migration and Integration》2012,13(4):459-479
This paper examines the patterns of ethnic intolerance in European societies based on data from the 1999/2000 wave of the European Values Survey. We analyze the differences in intolerance targeted toward Muslims, Jews, immigrants, Gypsies, and persons of different race, using modernisation theory and ??competition for scarce resource?? theories as our point of departure. Furthermore, we focus on the differences in the levels of intolerance in Western Europe, Eastern Europe, and Turkey. The present paper builds on previous empirical research, especially findings of recent multilevel analyses. Our larger and more extensive data material enables us to introduce two important improvements in this line of research. Theoretically, we are able to test if there are differences in the patterns of intolerance targeted toward specific minority groups. Methodologically, the number of countries in our data material is much larger, allowing us to apply multilevel models in a more statistically appropriate setting. Our results show that Gypsies stand out as an ethnic group particularly exposed to intolerance. The level of intolerance is lowest in Western Europe and highest in Turkey. In addition, the level of intolerance against Jews is particularly high in Turkey. 相似文献
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