Faculty Bibliography

We pursue the hypothesis that neuronal placement in animals minimizes wiring costs for given functional constraints, as specified by synaptic connectivity. Using a newly compiled version of the Caenorhabditis elegans wiring diagram, we solve for the optimal layout of 279 nonpharyngeal neurons. In the optimal layout, most neurons are located close to their actual positions, suggesting that wiring minimization is an important factor. Yet some neurons exhibit strong deviations from "optimal" position. We propose that biological factors relating to axonal guidance and command neuron functions contribute to these deviations. We capture these factors by proposing a modified wiring cost function.

We recorded the responses of direction-selective simple and complex cells in the primary visual cortex (V1) of anesthetized, paralyzed macaque monkeys. When studied with sine-wave gratings, almost all simple cells in V1 had responses that were separable for spatial and temporal frequency: the preferred temporal frequency did not change and preferred speed decreased as a function of the spatial frequency of the grating. As in previous recordings from the middle temporal visual area (MT), approximately one-quarter of V1 complex cells had separable responses to spatial and temporal frequency, and one-quarter were 'speed tuned' in the sense that preferred speed did not change as a function of spatial frequency. Half fell between these two extremes. Reducing the contrast of the gratings caused the population of V1 complex cells to become more separable in their tuning for spatial and temporal frequency. Contrast dependence is explained by the contrast gain of the neurons, which was relatively higher for gratings that were either both of high or both of low temporal and spatial frequency. For stimuli that comprised two spatially superimposed sine-wave gratings, the preferred speeds and tuning bandwidths of V1 neurons could be predicted from the sum of the responses to the component gratings presented alone, unlike neurons in MT that showed nonlinear interactions. We conclude that spatiotemporal modulation of contrast gain creates speed tuning from separable inputs in V1 complex cells. Speed tuning in MT could be primarily inherited from V1, but processing that occurs after V1 and possibly within MT computes selective combinations of speed-tuned signals of special relevance for downstream perceptual and motor mechanisms

Drosophila colour vision is achieved by R7 and R8 photoreceptor cells present in every ommatidium. The fly retina contains two types of ommatidia, called 'pale' and 'yellow', defined by different rhodopsin pairs expressed in R7 and R8 cells. Similar to the human cone photoreceptors, these ommatidial subtypes are distributed stochastically in the retina. The choice between pale versus yellow ommatidia is made in R7 cells, which then impose their fate onto R8. Here we report that the Drosophila dioxin receptor Spineless is both necessary and sufficient for the formation of the ommatidial mosaic. A short burst of spineless expression at mid-pupation in a large subset of R7 cells precedes rhodopsin expression. In spineless mutants, all R7 and most R8 cells adopt the pale fate, whereas overexpression of spineless is sufficient to induce the yellow R7 fate. Therefore, this study suggests that the entire retinal mosaic required for colour vision is defined by the stochastic expression of a single transcription factor, Spineless.

The hypothesis that Attention-Deficit/Hyperactivity Disorder (ADHD) reflects a primary inhibitory executive function deficit has spurred a substantial literature. However, empirical findings and methodological issues challenge the etiologic primacy of inhibitory and executive deficits in ADHD. Based on accumulating evidence of increased intra-individual variability in ADHD, we reconsider executive dysfunction in light of distinctions between 'hot' and 'cool' executive function measures. We propose an integrative model that incorporates new neuroanatomical findings and emphasizes the interactions between parallel processing pathways as potential loci for dysfunction. Such a reconceptualization provides a means to transcend the limits of current models of executive dysfunction in ADHD and suggests a plan for future research on cognition grounded in neurophysiological and developmental considerations

We present a detailed theoretical framework for statistical descriptions of neuronal networks and derive (1+1)-dimensional kinetic equations, without introducing any new parameters, directly from conductance-based integrate-and-fire neuronal networks. We describe the details of derivation of our kinetic equation, proceeding from the simplest case of one excitatory neuron, to coupled networks of purely excitatory neurons, to coupled networks consisting of both excitatory and inhibitory neurons. The dimension reduction in our theory is achieved via novel moment closures. We also describe the limiting forms of our kinetic theory in various limits, such as the limit of mean-driven dynamics and the limit of infinitely fast conductances. We establish accuracy of our kinetic theory by comparing its prediction with the full simulations of the original point-neuron networks. We emphasize that our kinetic theory is dynamically accurate, i.e., it captures very well the instantaneous statistical proper-ties of neuronal networks under time-inhomogeneous inputs

Water drinking improves OT (orthostatic tolerance) in healthy volunteers; however, responses to water in patients with PRS (posturally related syncope) are unknown. Therefore the aim of the present study was to examine whether water would improve OT in patients with PRS. In a randomized controlled cross-over fashion, nine patients with PRS ingested 500 ml and 50 ml (control) of water 15 min before tilting on two separate days. OT was determined using a combined test of head-up tilting and lower body suction and expressed as the time required to induce presyncope. We measured blood pressure and heart rate (using Portapres) and middle cerebral artery velocity (using transcranial Doppler). SV (stroke volume) and TPR (total peripheral resistance) were calculated using the Modelflow method. OT was significantly (P<0.02) greater after drinking 500 ml of water than after 50 ml (25.4+/-1.5 compared with 19.8+/-2.3 min respectively). After ingestion of 500 ml of water, blood pressure during tilting was higher, the tiltinduced reduction in SV was smaller and the increase in TPR was greater (all P<0.05). The correlation coefficient of the relationship between cerebral blood flow velocity and pressure was lower after 500 ml of water (0.43+/-0.1 compared with 0.73+/-0.1; P<0.05), indicating better autoregulation. In conclusion, drinking 500 ml of water increased OT and improved cardiovascular and cerebrovascular control during orthostasis. Patients with PRS should be encouraged to drink water before situations likely to precipitate a syncopal attack.

We studied ocular asymmetries and orienting responses induced by angular rotation in rabbits with binocular video recordings. Slow phase velocities were significantly larger in the eye moving temporonasally than nasotemporally. The eyes also converged and pitched down during rotation, which increased and refocused binocular overlap in the visual fields. Eye position also shifted into the slow phase direction. Vergence and pitch outlasted the induced nystagmus, suggesting that they were generated by a separate vestibulo-oculomotor subsystem(s). Thus, mechanisms in the rabbit increase compensatory eye velocity in the eye that leads into the direction of rotation and enhance binocular vision

Huntington's disease (HD) is a fatal neurodegenerative disorder of genetic origin with no known therapeutic intervention that can slow or halt disease progression. Transgenic murine models of HD have significantly improved the ability to assess potential therapeutic strategies. The R6/2 murine model of HD, which recapitulates many aspects of human HD, has been used extensively in pre-clinical HD therapeutic treatment trials. Of several potential therapeutic candidates, both minocycline and coenzyme Q10 (CoQ10) have been demonstrated to provide significant improvement in the R6/2 mouse. Given the specific cellular targets of each compound, and the broad array of abnormalities thought to underlie HD, we sought to assess the effects of combined minocycline and CoQ10 treatment in the R6/2 mouse. Combined minocycline and CoQ10 therapy provided an enhanced beneficial effect, ameliorating behavioral and neuropathological alterations in the R6/2 mouse. Minocycline and CoQ10 treatment significantly extended survival and improved rotarod performance to a greater degree than either minocycline or CoQ10 alone. In addition, combined minocycline and CoQ10 treatment attenuated gross brain atrophy, striatal neuron atrophy, and huntingtin aggregation in the R6/2 mice relative to individual treatment. These data suggest that combined minocycline and CoQ10 treatment may offer therapeutic benefit to patients suffering from HD.

The treatment of cystinuria is hampered by methods used to measure urinary lithogenicity. Most cystine assays cannot reliably distinguish cystine from soluble thiol drug-cysteine complexes. We used a solid-phase assay of urinary cystine capacity in a large sample of patients with cystinuria. A known amount of solid-phase cystine is added to urine. In supersaturated urine, cystine precipitates onto added crystals, so the solid phase recovered after incubation will be greater than that added. We studied the effect of cystine-binding thiol drugs (CBTD) to solubilize cystine and determined correlates of cystine capacity in patients who were and were not taking CBTD. Increasing concentrations of D-penicillamine, tiopronin and captopril dissolved cystine in urine with similar efficacy. A general linear model in which 24 h cystine excretion was the dependent variable showed that creatinine, urea nitrogen, and sodium excretions were associated with cystine excretion (P<0.02, all three). Urine volume, pH, and cystine excretion strongly correlated with cystine capacity (P<0.001). Tiopronin had no effect on supersaturation in a cross-sectional analysis. A subset of supersaturated samples, with negative cystine capacity, occurred mainly among women not taking CBTD. For this subset, capacity differed significantly between CBTD users and non-users; use of CBTD avoided extremes of supersaturation. Female enrichment in the supersaturated group was accounted for in part by underprescription of CBTD to women. This assay of cystine capacity was reliable in the presence of CBTD. It should be useful in monitoring patients' response to dietary interventions and administration of fluid, citrate, and CBTD.