Faculty Bibliography

Saccades modulate the relationship between visual motion and smooth eye movement. Before a saccade, pursuit eye movements reflect a vector average of motion across the visual field. After a saccade, pursuit primarily reflects the motion of the target closest to the endpoint of the saccade. We tested the hypothesis that the saccade produces a spatial weighting of motion around the endpoint of the saccade. Using a moving pursuit stimulus that stepped to a new spatial location just before a targeting saccade, we controlled the distance between the endpoint of the saccade and the position of the moving target. We demonstrate that the smooth eye velocity following the targeting saccade weights the presaccadic visual motion inputs by the distance from their location in space to the endpoint of the saccade, defining the extent of a spatiotemporal filter for driving the eyes. The center of the filter is located at the endpoint of the saccade in space, not at the position of the fovea. The filter is stable in the face of a distracter target, is present for saccades to stationary and moving targets, and affects both the speed and direction of the postsaccadic eye movement. The spatial filter can explain the target-selecting gain change in postsaccadic pursuit, and has intriguing parallels to the process by which perceptual decisions about a restricted region of space are enhanced by attention. The effect of the spatial saccade plan on the pursuit response to a given retinal motion describes the dynamics of a coordinate transformation.

Response properties of sensory neurons are commonly described using receptive fields. This description may be formalized in a model that operates with a small set of linear filters whose outputs are nonlinearly combined to determine the instantaneous firing rate. Spike-triggered average and covariance analyses can be used to estimate the filters and nonlinear combination rule from extracellular experimental data. We describe this methodology, demonstrating it with simulated model neuron examples that emphasize practical issues that arise in experimental situations

Activating mutations in the epidermal growth factor receptor (EGFR), localized in the activation loop within the kinase domain, have been discovered in non-small cell lung cancers (NSCLC). Most of these mutants are exquisitely sensitive to EGFR tyrosine kinase inhibitors, suggesting that they generate receptor dependence in the cancers that express them. 32D cells stably expressing EGFR-L861Q and EGFR-L858R but not wild-type EGFR exhibited ligand-independent receptor phosphorylation and viability. Ligand-induced receptor down-regulation (LIRD) was impaired in mutant-expressing cells. The EGFR mutants were constitutively associated with the E3 ubiquitin ligase Cbl but did not associate with the adaptor protein CIN85 on the addition of ligand. Inhibition of HSP90 activity with geldanamycin restored Cbl function as indicated by receptor ubiquitination and LIRD. These results suggest that EGFR mutants form defective endocytic complexes. In addition, HSP90 plays a role in maintaining the functional conformation of EGFR mutants and protecting activated receptors from LIRD.

A new strategy to yield information from the maximum number of voxels, each at the optimum signal-to-noise ratio (SNR) per unit time, in MR spectroscopic imaging (MRSI) is introduced. In the past, maximum acquisition duty-cycle was obtained by multiplexing in time several single slices each repetition time (TR), while optimal SNR was achieved by encoding the entire volume of interest (VOI) each TR. We show that optimal SNR and acquisition efficiency can both be achieved simultaneously by multiplexing in space and time several slabs of several slices, each. Since coverage of common VOIs in 3D proton MRSI in the human brain typically requires eight or more slices, at 3 T or higher magnetic fields, two or more slabs can fit into the optimum TR (approximately 1.6 s). Since typically four or less slices would then fit into each slab, Hadamard encoding is favored in that direction for slice profile reasons. It is demonstrated that per fixed examination length, the new method gives, at 3 T, twice as many voxels, each of the same SNR and size, compared with current 3D chemical shift imaging techniques. It is shown that this gain will increase for more extensive spatial coverage or higher fields

Nicotinic acetylcholine receptors (nAChRs) are inhibited by several drugs that are commonly thought to be specific for L-type calcium channels (LTCCs). In neurons, LTCCs are activated by nicotine-induced depolarization to engage downstream signaling events; however, the role of LTCC drug interactions with nAChRs in signaling has not been examined in detail. We investigated the effects of LTCC ligands on nAChR currents and downstream signaling in rat superior cervical ganglion (SCG) neurons. We found that 10microM nicotine and 40mM K(+) both reversibly depolarize SCG neurons to -20mV, sufficient to activate LTCCs and downstream signaling, including induction of nuclear phospho-CREB (pCREB); this induction was blocked by LTCC antagonists. Interestingly, the effects of LTCC antagonists on nicotine-induced signaling to CREB are not mediated by their actions on LTCCs, but rather via inhibition of nAChRs, which prevents nicotine-induced depolarization. We show that this effect is sufficient to block pCREB induction in neurons expressing an antagonist-insensitive LTCC. Taken together, our data show that, at concentrations typically used to block LTCCs, these antagonists inhibit nAChR currents and downstream signaling. These findings serve as a caution in attributing a role for LTCCs when using these drugs experimentally or therapeutically

OBJECTIVE: Obese patients without clinically apparent heart disease may have a high output state and elevated total and central blood volumes. Central circulatory congestion should result in elevated pulmonary diffusing capacity (DLCO) and capillary blood volume (Vc) reflecting pulmonary capillary recruitment; however, the effect on membrane diffusion (Dm) is uncertain. We examined DLCO and its partition into Vc and Dm in 13 severely obese subjects (BMI = 51 +/- 14 kg/m2) without manifest cardiopulmonary disease before and after surgically induced weight loss. RESEARCH METHODS AND PROCEDURES: DLCO and its partition into Vc and Dm [referenced to alveolar volume (VA)] as described by Roughton and Forster, total body water by tritiated water, and fat distribution by waist-to-hip ratio were performed. RESULTS: Despite normal DLCO (mean 98 +/- 16% predicted), Vc/VA was increased (mean 118 +/- 30% predicted), and Dm/VA was reduced (mean 77 +/- 34% predicted). Nine of 13 subjects were restudied after weight loss (mean 52 +/- 43 kg); Vc/VA decreased to 89 +/- 18% predicted (p = 0.01), and Dm/VA increased to 139 +/- 30% predicted (p < 0.01). Increasing total body water was associated with both increasing Vc (r = 0.74, p = 0.01) and increasing waist-to-hip ratio (r = 0.65, p = 0.02), indicating that circulatory congestion increases with increasing central obesity. DISCUSSION: Severely obese subjects without manifest cardiopulmonary disease may have increased Vc indicating central circulatory congestion and reduced Dm suggesting associated alveolar capillary leak, despite normal DLCO. Reversibility with weight loss is in accord with reversibility of the hemodynamic abnormalities of obesity.

Pax6 and Gli3 are dorsally expressed genes that are known to antagonize sonic hedgehog (Shh) activity. We have previously shown that dorsoventral patterning defects seen in Shh(-/-) mutants are rescued in Shh(-/-);Gli3(-/-) compound mutants. Here we investigate if the loss of Pax6 can also ameliorate defects seen in Shh(-/-) mutants. In support of this notion, we observe that the fusion of the cerebral vesicles seen in Shh(-/-) mutants is partially corrected in E12.5 Shh(-/-);Pax6(-/-) compound mutants. Investigation of pan-ventral markers such as Dlx2 also shows that, unlike Shh(-/-), a broad domain of expression of this gene is observed in Shh(-/-);Pax6(-/-) mice. Interestingly, we observe that while the expression of ER81 in the ventral telencephalon is expanded, the expression of Ebf1 is lost. This suggests that the rescued ventral domain observed in Shh(-/-);Pax6(-/-) mice is the dorsal lateral ganglionic eminence region. With regard to dorsal telencephalic patterning, we also observe rescue of the pallial-subpallial boundary, as well as a partial rescue of the dorsal midline. Together, our findings are consistent with Pax6 function being required for aspects of Gli3-mediated telencephalic patterning

Blood-cerebrospinal fluid (CSF) barrier function and expansion of the ventricular system were investigated in embryonic rats (E12-18). Permeability markers (sucrose and inulin) were injected intraperitoneally and concentrations measured in plasma and CSF at two sites (lateral and 4th ventricles) after 1 h. Total protein concentrations were also measured. CSF/plasma concentration ratios for endogenous protein were stable at approximately 20% at E14-18 and subsequently declined. In contrast, ratios for sucrose (100%) and inulin (40%) were highest at the earliest ages studied (E13-14) and then decreased substantially. Between E13 and E16 the volume of the lateral ventricles increased over three-fold. Decreasing CSF/plasma concentration ratios for small, passively diffusing molecules during embryonic development may not reflect changes in permeability. Instead, increasing volume of distribution appears to be important in this decline. The intracellular presence of a small marker (3000 Da biotin-dextranamine) in plexus epithelial cells following intraperitoneal injection indicates a transcellular route of transfer. Ultrastructural evidence confirmed that choroid plexus tight junctions are impermeable to small molecules at least as early as E15, indicating the blood-CSF barrier is morphologically and functionally mature early in embryonic development. Comparison of two albumins (human and bovine) showed that transfer of human albumin (surrogate for endogenous protein) was 4-5 times greater than bovine, indicating selective blood-to-CSF transfer. The number of plexus epithelial cells immunopositive for endogenous plasma protein increased in parallel with increases in total protein content of the expanding ventricular system. Results suggest that different transcellular mechanisms for protein and small molecule transfer are operating across the embryonic blood-CSF interface.