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.     

Child Delinquents: Examining the Market for Criminal Futures

This article investigates child delinquency (offenders younger than 13 years of age). The population of child delinquents under various dispositions in the state of Louisiana, at one point in time, is described. Eighty youth are examined using the following characteristics: Race, Gender, Age, Offense Type (violent, nonviolent) Crime Category (felony, status offense, misdemeanor, and felony or misdemeanor) and Disposition (supervision, secure custody, and non-secure custody). Child delinquency is an important topic because the younger the age of first offense the greater the probability of a delinquent and criminal career. Findings reveal very few youth in secure custody and black males account for over half of the population of child delinquents. Over 75% of the population was 12 years of age.     

Effort denial in self-deception

We propose a mixed belief model of self-deception. According to the theory, people distribute belief over two possible causal paths to an action, one where the action is freely chosen and one where it is due to factors outside of conscious control. Self-deceivers take advantage of uncertainty about the influence of each path on their behavior, and shift weight between them in a self-serving way. This allows them to change their behavior to provide positive evidence and deny doing so, enabling diagnostic inference to a desired trait. In Experiment 1, women changed their pain tolerance to provide positive evidence about the future quality of their skin, but judgments of effort claimed the opposite. This “effort denial” suggests that participants’ mental representation of their behavior was dissociated from their actual behavior, facilitating self-deception. Experiment 2 replicated the pattern in a hidden picture task where search performance was purportedly linked to self-control.     

The tight coupling between category and causal learning

The main goal of the present research was to demonstrate the interaction between category and causal induction in causal model learning. We used a two-phase learning procedure in which learners were presented with learning input referring to two interconnected causal relations forming a causal chain (Experiment 1) or a common-cause model (Experiments 2a, b). One of the three events (i.e., the intermediate event of the chain, or the common cause) was presented as a set of uncategorized exemplars. Although participants were not provided with any feedback about category labels, they tended to induce categories in the first phase that maximized the predictability of their causes or effects. In the second causal learning phase, participants had the choice between transferring the newly learned categories from the first phase at the cost of suboptimal predictions, or they could induce a new set of optimally predictive categories for the second causal relation, but at the cost of proliferating different category schemes for the same set of events. It turned out that in all three experiments learners tended to transfer the categories entailed by the first causal relation to the second causal relation.     

Using video and role‐play to introduce medical students to family therapy: is watching better than appearing?

Family therapists emphasize introducing members of the caring professions to systemic ideas. Doctors in training usually gain some experience of systemic therapy. In this study two participatory styles of learning were used with medical students. Six groups of forty students were randomly allocated to learn about family therapy either by watching a video of a family or through role-play. The two mediums used are feasible, scored similarly on students' level of satisfaction, and result in gains in the students' knowledge of systemic principles.     

Effects of worry and somatic anxiety induction on thoughts, emotion and physiological activity

Thirty-six Ss received Velten (1968) emotion inductions designed to produce either worrisome, somatically anxious, or neutral states. A breathing-focus task assessed the frequency of negative thought intrusions before and after the emotion induction. Worry induction produced the greatest increase in negative intrusions, significantly greater than the neutral condition. Somatic anxiety induction produced some increase in intrusions, nonsignificantly between worry and neutral inductions. Both worry and somatic anxiety inductions generated significant increases in cardiovascular activity relative to the neutral condition, while no effect was observed on gastric myoelectric activity. Worry was characterized by emotions on the Multiple Affect Adjective Checklist that overlap with those of depression and somatic anxiety.     

Effects of age and sex on reciprocal tapping performance

Using a reciprocal tapping task (Fitts's task), the speed and accuracy of small-amplitude motor movements of the hand were measured for 62 men and 84 women, 20 to 89 yr. of age. Men and women in their 20s and 30s performed similarly, although men in their 20s displayed a tendency to trade accuracy in favor of speed. Movement time increased noticeably for both men and women beginning with the 40s decade and continued to increase through the 80s decade. Error rates were lower for women than men and were relatively uniform for both men and women across all age decades past 30 yr. Older subjects of both sexes appeared to sacrifice speed (slowed down) to maintain accuracy on the task. The slope of the linear regression relating movement time to task difficulty was steeper for men than for women and increased more for men than women with advancing age, indicating that older men slowed down relatively more than older women on more difficult tasks.     

The role of the hemispheres in closed loop movements

The purpose of these experiments was to determine if the two hemispheres play different roles in controlling closed loop movements. Subjects were asked to move to a narrow or wide target in the left or right hemispace. Reaction time (RT) was faster for the left arm of normals, only in the right hemispace, but there were no differences between arms in movement execution. Right but not left hemisphere stroke (CVA) patients showed longer RTs for the contralateral but not ipsilateral arm. The right CVA group's ipsilateral movement, especially to narrow targets was less accurate. The left CVA group's RT did not benefit from advanced information, but ipsilateral movement execution was normal. These results were discussed in terms of inter- as well as intrahemispheric control of programming and execution of closed loop movements.     

Adult reflection in a graduate-level online distance education course

This study examined adult learners’ ability to engage in critical reflection concerning their own learning in a graduate-level online instructional technology course. The online course was facilitated through asynchronous discussions, and the course topic was about the design and delivery of distance education. The data for this study consisted of four critical reflection papers about students’ perception of their learning. The Periodic Reflection Tool, based on activity systems analysis, was introduced to participants as a guide for engaging in in-depth reflection about their learning process and completing their course assignment. After course completion and during data analysis, we applied instrumental learning and communicative learning theories to evaluate how participants used the tool to reflect on their personal learning in the course. At the conclusion of an analysis of their reflection statements, it was found that purposeful reflections guided by the Periodic Reflection Tool could help guide adult learners to reflect on many aspects of their learning and we suggest that the tool could be used to examine adults’ transition from traditional to online settings.