Behavioral deficits and subregion-specific suppression of LTP in mice expressing a population of mutant NMDA receptors throughout the hippocampus

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 Grin1^N598R 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 (GluN1^R) yield functional NMDARs that are Mg²⁺ insensitive and Ca²⁺ impermeable (Burnashev et al. 1992; Mori et al. 1992). The Grin1^N598R allele that codes for GluN1^R 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 GluN1^R subunits do not act as coincidence detectors and, interestingly, mice expressing exclusively the GluN1^R 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 (GluN1^Rneo/+) 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 GluN1^Rneo/+ 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.     

Giles’s Game and the Proof Theory of Łukasiewicz Logic

In the 1970s, Robin Giles introduced a game combining Lorenzen-style dialogue rules with a simple scheme for betting on the truth of atomic statements, and showed that the existence of winning strategies for the game corresponds to the validity of formulas in Łukasiewicz logic. In this paper, it is shown that ‘disjunctive strategies’ for Giles’s game, combining ordinary strategies for all instances of the game played on the same formula, may be interpreted as derivations in a corresponding proof system. In particular, such strategies mirror derivations in a hypersequent calculus developed in recent work on the proof theory of Łukasiewicz logic. Presented by Daniele Mundici     

Does attitude certainty beget self-certainty?

This research explores the possibility that changes in attitude certainty can affect general self-certainty and, thus, have consequences that extend beyond the attitude domain. Across two studies, attitude certainty is manipulated using repeated attitude expression and attitude consensus paradigms. The implications of these manipulations are tested for feelings of general self-uncertainty (Study 1) and global self-doubt about one’s abilities (Study 2). In each study, it is demonstrated that participants feel greater self-certainty under conditions of high rather than low attitude certainty, but only when they view aspects of the attitude as central to their self-concept.     

Gibt es perzeptive Phantasie? Als-ob-Bewusstsein,Widerstreit und Neutralität in Husserls Aufzeichnungen zur Bildbetrachtung

Unser Beitrag versucht eine systematische Auslegung des Begriffs der „perzeptiven Phantasie“, den Husserl in einigen Aufzeichnungen zum Bildbewusstsein anwendet. Dabei werden drei der wesentlichen Aspekte, die in der Husserl-Literatur das Thema Bild durchgehend bestimmen, einer gründlichen Analyse unterzogen: der Begriff des „Widerstreitbewusstseins“, die Idee der „Neutralit?t“ und die Scheidung zwischen Impression und Reproduktion. Jedes dieser Themen spielt eine wesentliche Rolle in der husserlschen Auslegung des Bildbewusstseins. Dabei sind aber alle diese Themen, wie wir zeigen wollen, letztlich von einem Einstellungsunterschied bestimmt, der im sp?teren Nachlass Husserls zwischen Erfahrung und Phantasie besteht. Ausgehend von Husserls Unterscheidung zweier Bedeutungsrichtungen des Begriffs „Phantasie“ – als „Reproduktion“ einerseits und als „Modus des Vollzugs“ andererseits – soll bewiesen werden, dass der Ausdruck „perzeptive Phantasie“ keineswegs den Beitrag von reproduktiven Akten zur Konstitution der Bildlichkeit betrifft, sondern eben die Tatsache, dass der Bildbetrachtung eine eigentümliche Einstellung, jene des „Als-ob“, entspricht.     

Cyberethics and Co-operation in the Information Society

The task of this paper is to ground the notion of cyberethics of co-operation. The evolution of modern society has resulted in a shift from industrial society towards informational capitalism. This transformation is a multidimensional shift that affects all aspects of society. Hence also the ethical system of society is penetrated by the emergence of the knowledge society and ethical guidelines for the information age are needed. Ethical issues and conflicts in the knowledge society are connected to topics of ecological and social sustainability. For information ethics and cyberethics, the sustainable design of society, social, and socio-technological systems is important. In this context the notions of sustainability and co-operation are discussed. Based on these categories, the approach of cyberethics of co-operation can be theoretically grounded.     

Religious Values in Clinical Practice are Here to Stay

Research to date has shown that health professionals often practice according to personal values, including values based on faith, and that these values impact medicine in multiple ways. While some influence of personal values are inevitable, awareness of values is important so as to sustain beneficial practice without conflicting with the values of the patient. Detecting when own personal values, whether based on a theistic or atheistic worldview, are at work, is a daily challenge in clinical practice. Simultaneously ethical guidelines of tone-setting medical associations like American Medical Association, the British General Medical Council and Australian Medical Association have been updated to encompass physicians’ right to practice medicine in accord with deeply held beliefs. Framed by this context, we discuss the concept of value-neutrality and value-based medical practice of physicians from both a cultural and ethical perspective, and reach the conclusion that the concept of a completely value-neutral physician, free from influence of personal values and filtering out value-laden information when talking to patients, is simply an unrealistic ideal in light of existing evidence. Still we have no reason to suspect that personal values, whether religious, spiritual, atheistic or agnostic, should hinder physicians from delivering professional and patient-centered care.

     

How Political Scandals Affect the Electorate. Tracing the Eroding and Spillover Effects of Scandals with a Panel Study

Political scandals are highly relevant for political decision-making and democratic processes more generally. While most prior research employed experimental and cross-sectional survey studies, we tested the effects of a political scandal in the context of the 2017 Austrian Parliamentary Elections using panel data (N = 559, both waves). Importantly, we used a unique data set collected before and just after a major scandal broke in the final election phase. Drawing on a motivated reasoning perspective, attribution theory, and the inclusion/exclusion model, our results revealed a scandal-eroding effect particularly damaging a candidate's own base of supporters and leaving followers in disappointment. The findings also showed a negative scandal-spillover effect for candidate supporters high in scandal knowledge decreasing political trust toward other politicians. Importantly, the results revealed that negative candidate evaluations are not a necessary precondition for negative spillover effects on political trust more generally.     

The Integrated Acculturation Model: Expanding Acculturation to Cultural Identities in Addition to Race and Ethnicity

This article is an attempt to integrate existing conceptual knowledge on acculturation as well as to expand the use of the construct, which has traditionally had race and ethnicity as its focus, to also include cultural identities such as sexual orientation, gender identity, nationality, and disability. The article begins with a review of existing theoretical contributions from both the United States and Europe. We then propose a model to update and expand the use of acculturation. Finally, we provide an assessment framework. Este artículo es un intento de integrar los conocimientos conceptuales existentes sobre la aculturación además de expandir el uso de este constructo, que tradicionalmente se ha enfocado hacia la raza y la etnicidad, para incluir también identidades culturales tales como la orientación sexual, la identidad de sexo, la nacionalidad y la discapacidad. El artículo comienza con una revisión de las contribuciones teóricas existentes tanto de Estados Unidos como de Europa. A continuación, proponemos un modelo para actualizar y expandir el uso de la aculturación. Por último, proporcionamos un marco de evaluación.     

Deception in psychotherapy: Frequency,typology and relationship

Deception in therapy has been documented anecdotally through various narratives of therapists. The investigation of its occurrence within therapy has largely been overlooked. We explored the reported frequency of deception within psychotherapy, the types of deception used within therapy, the likelihood of people lying to a therapist compared to other groups of people, and client perceptions of the types of deception that therapists use. Ninety‐one participants were provided with a series of deception examples, asked questions about the use of these types of deception within therapy, and asked generally about their use of deception in therapy. We found that a majority of the participants had been deceptive in therapy, and a majority were willing to be deceptive in future therapeutic contexts. Participants were more likely to use white lies than other forms of deception in therapy. Lastly, participants were less likely to lie to therapists compared to strangers and acquaintances. Implications for research and practice are discussed.