Rachel E. White

Pyramidal cell selective ablation of N-methyl-D-aspartate receptor 1 causes increase in cellular and network excitability.

BACKGROUND Neuronal activity at gamma frequency is impaired in schizophrenia (SZ) and is considered critical for cognitive performance. Such impairments are thought to be due to reduced N-methyl-D-aspartate receptor (NMDAR)-mediated inhibition from parvalbumin interneurons, rather than a direct role of impaired NMDAR signaling on pyramidal neurons. However, recent studies suggest a direct role of pyramidal neurons in regulating gamma oscillations. In particular, a computational model has been proposed in which phasic currents from pyramidal cells could drive synchronized feedback inhibition from interneurons. As such, impairments in pyramidal neuron activity could lead to abnormal gamma oscillations. However, this computational model has not been tested experimentally and the molecular mechanisms underlying pyramidal neuron dysfunction in SZ remain unclear. METHODS In the present study, we tested the hypothesis that SZ-related phenotypes could arise from reduced NMDAR signaling in pyramidal neurons using forebrain pyramidal neuron specific NMDA receptor 1 knockout mice. RESULTS The mice displayed increased baseline gamma power, as well as sociocognitive impairments. These phenotypes were associated with increased pyramidal cell excitability due to changes in inherent membrane properties. Interestingly, mutant mice showed decreased expression of GIRK2 channels, which has been linked to increased neuronal excitability. CONCLUSIONS Our data demonstrate for the first time that NMDAR hypofunction in pyramidal cells is sufficient to cause electrophysiological, molecular, neuropathological, and behavioral changes related to SZ.

Evidence for a relation between executive function and pretense representation in preschool children

Several theoretical formulations suggest a relation between childrens pretense and executive function (EF) skills. However, there is little empirical evidence for a correlation between these constructs in early development. Preschool children (N = 104; M age = 4-0) were given batteries of EF and pretense representation measures, as well as verbal, memory, and appearance-reality control tasks. Confirmatory factor analysis revealed two separable but overlapping aspects of EF (Conflict and Delay). EF was significantly related to pretense after accounting for all controls. Understanding the pretend-reality distinction was strongly related to Conflict EF, whereas performing pretend actions was more strongly related to Delay EF. These results, although correlational, are consistent with the claim that EF skills are implicated in pretense, such as inhibiting reality and flexibly manipulating dual representations, and offer a potential mechanism by which pretend play interventions may enhance childhood EF.

Spontaneous Self-Distancing and Adaptive Self-Reflection Across Adolescence

Experiments performed primarily with adults show that self-distancing facilitates adaptive self-reflection. However, no research has investigated whether adolescents spontaneously engage in this process or whether doing so is linked to adaptive outcomes. In this study, 226 African American adolescents, aged 11-20, reflected on an anger-related interpersonal experience. As expected, spontaneous self-distancing during reflection predicted lower levels of emotional reactivity by leading adolescents to reconstrue (rather than recount) their experience and blame their partner less. Moreover, the inverse relation between self-distancing and emotional reactivity strengthened with age. These findings highlight the role that self-distancing plays in fostering adaptive self-reflection in adolescence, and begin to elucidate the role that development plays in enhancing the benefits of engaging in this process.

Focusing on the future from afar: Self-distancing from future stressors facilitates adaptive coping.

Prior research indicates that visual self-distancing enhances adaptive self-reflection about negative past events (Kross & Ayduk, 2011). However, whether this process is similarly useful when people reflect on anxiety-provoking future negative experiences, and if so, whether a similar set of mechanisms underlie its benefits in this context, is unknown. Here we addressed these questions using a combination of experimental and individual difference methods with adults and adolescents (total N = 2,344). In Studies 1 and 2, spontaneous self-distancing predicted less anxious emotional reactivity among adults and adolescents. This effect was mediated by differences in how vividly participants imagined a future anxiety-provoking event. Study 3 provided causal evidence in an adult sample: Adopting a self-distanced (vs. self-immersed) perspective when reflecting on a future stressor led to lower levels of anxiety as well as lower imagery vividness. Consistent with Studies 1 and 2, reductions in imagery vividness mediated the emotion regulatory benefits of self-distancing. A meta-analysis of all three studies further confirmed these findings across samples. Thus, the current studies extend previous research on the benefits of self-distancing to future stressors. In addition, they highlight a novel mechanism for this relation: imagery vividness. (PsycINFO Database Record

Hippocampal circuit abnormalities in MeCP2+/- mouse model of Rett syndrome

Rett syndrome (RTT) has a complex developmental course over childhood and adolescence. Patients with RTT often have a pre-symptomatic period with no or little outward signs of the disorder, followed by developmental arrest and regression. Following regression, the individual’s condition is not static, as they often progress into defined stages with unique neurological symptoms. Similarly, the progression of RTT-like symptoms in female mice heterozygous for a null-mutation has a prodromal and symptomatic period. Change in functional local circuit connectivity was studied using hippocampal slices, assaying Schaffer evoked activity in area CA1 using fast voltage sensitive dye imaging. With this technique the local functional interactions between the excitatory and inhibitory components of the circuit can be characterized. The prodromal period was associated with a shift in extent of excitation into the stratum oriens of the hippocampus and reduced sensitivity to changes in divalent cation concentration. These data suggest that hyperexcitability of the hippocampus at the circuit level may contribute to the prodromal reduction in cognitive performance and the onset of developmental regression.