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Burkitt lymphoma cells (BL) exploit antigen-independent tonic signals transduced by the B-cell antigen receptor (BCR) for their survival, but the molecular details of the rewired BL-specific BCR signal network remain unclear. A loss of function screen revealed the SH2 domain-containing 5`-inositol phosphatase 2 (SHIP2) as a potential modulator of BL fitness. We characterized the role of SHIP2 in BL survival in several BL cell models and show that perturbing SHIP2 function renders cells more susceptible to apoptosis, while attenuating proliferation in a BCR-dependent manner. Unexpectedly, SHIP2 deficiency did neither affect PI3K survival signals nor MAPK activity, but attenuated ATP production. We found that an efficient energy metabolism in BL cells requires phosphatidylinositol-3,4-bisphosphate (PI(3,4)P2), which is the enzymatic product of SHIP proteins. Consistently, interference with the function of SHIP1 and SHIP2 augments BL cell susceptibility to PI3K inhibition. Notably, we provide here a molecular basis of how tonic BCR signals are connected to energy supply, which is particularly important for such an aggressively growing neoplasia. These findings may help to improve therapies for the treatment of BL by limiting energy metabolism through the inhibition of SHIP proteins, which renders BL cells more susceptible to the targeting of survival signals.

The mechanisms underlying striatal cholinergic interneurons (ChINs) synchronization and its interaction with dopamine release are unclear. Here, the authors showed that polysynaptic inhibition between ChINs shapes their network activity and is mediated by dopaminergic input.

Huntington's disease (HD) is a progressive, fatal neurodegenerative disorder characterized by motor, cognitive, and psychiatric disturbances. There is no known cure for HD, but its progressive nature allows for early therapeutic intervention. Currently, much of the research has focused on the striatum, however, there is evidence suggesting that disruption of thalamocortical circuits could underlie some of the early symptoms of HD. Loss of both cortical pyramidal neurons (CPNs) and thalamic neurons occurs in HD patients, and cognitive, somatosensory, and attention deficits precede motor abnormalities. However, the role of thalamocortical pathways in HD progression has been understudied. Here, we measured single unit activity and local field potentials (LFPs) from electrode arrays implanted in the thalamus and primary motor cortex of 4–5 month-old male and female Q175 mice. We assessed neuronal activity under baseline conditions as well as during presentation of rewards delivered via actuation of an audible solenoid valve. HD mice showed a significantly delayed licking response to the reward stimulus. At the same time, neuronal activation to the reward was delayed in thalamic neurons, CPNs and fast-spiking cortical interneurons (FSIs) of HD mice. In addition, thalamocortical coherence increased at lower frequencies in HD relative to wildtype mice. Together, these data provide evidence that impaired cortical and thalamic responses to reward stimuli, and impaired thalamocortical coherence, may play an important early role in motor, cognitive, and learning deficits in HD patients.

Summary: The cortex and thalamus send excitatory projections to the striatum, but little is known about how these inputs, either individually or collectively, regulate striatal dynamics during behavior. The lateral striatum receives overlapping input from the secondary motor cortex (M2), an area involved in licking, and the parafascicular thalamic nucleus (PF). Using neural recordings, together with optogenetic terminal inhibition, we examine the contribution of M2 and PF projections on medium spiny projection neuron (MSN) activity as mice performed an anticipatory licking task. Each input has a similar contribution to striatal activity. By comparing how suppressing single or multiple projections altered striatal activity, we find that cortical and thalamic input signals modulate MSN gain and that this effect is more pronounced in a temporally specific period of the task following the cue presentation. These results demonstrate that cortical and thalamic inputs synergistically regulate striatal output during reward-conditioned behavior. : Lee et al. show that excitatory corticostriatal and thalamostriatal projections regulate striatal activity and gain in mice performing a Pavlovian reward conditioning task. They find that gain modulation by these projections is more evident in the period between cue and reward presentation. Keywords: Corticostriatal, thalamostriatal, secondary motor cortex, parafasicular thalamus, integration, multiplication, summation

This nationwide study examined the relationships among gender, ethnicity, and poverty with fifth graders' (n = 8,741) science performance. Extant fifth grade data files (2003-2004), from the Early Childhood Longitudinal Study, Kindergarten Class of 1998-99 (ECLS-K), were used. An ANOVA test revealed that males performed significantly better than females on science assessments, and this difference was maintained across ethnic groups. The science scores, in order of ethnicity from the highest to lowest scores, were White, Asian, Hispanic, and African American. Asian fifth graders showed the largest ethnic discrepancy between students above and below poverty. The unique features of this study were the depth of the disaggregation of the data and statistical analyses. Disaggregation of data by all three variables revealed compounding consequences for students at the extremes. White "at/above poverty" males had the highest mean science IRT scale score, while African American "below poverty" females had the lowest mean score. (Contains 5 tables and 1 figure.)