Faculty Bibliography

Using patch clamp techniques we investigated the characteristics of the spontaneous oscillatory activity displayed by starburst amacrine cells in the mouse retina. At a holding potential of -70 mV, oscillations appeared as spontaneous, rhythmic inward currents with a frequency of ~3.5 Hz and an average maximal amplitude of ~120 pA. Application of TEA, a potassium channel blocker, increased the amplitude of oscillatory currents by more than 70%, but reduced their frequency by about 17%. The TEA effects did not appear to result from direct actions on starburst cells, but rather a modulation of their synaptic inputs. Oscillatory currents were inhibited by CNQX, an antagonist of AMPA/kainate receptors, indicating that they were dependent on a periodic glutamatergic input likely from presynaptic bipolar cells. The oscillations were also inhibited by the calcium channel blockers cadmium and nifedipine, suggesting that the glutamate release was calcium dependent. Application of AP4, an agonist of mGluR6 receptors on on-center bipolar cells, blocked the oscillatory currents in starburst cells. However, subsequent application of TEA overcame the AP4 blockade, suggesting that the periodic glutamate release from bipolar cells is intrinsic to the inner plexiform layer in that, under experimental conditions, it can occur independent of photoreceptor input. The GABA receptor antagonists picrotoxin and bicuculline enhanced the amplitude of oscillations in starburst cells pre-stimulated with TEA. Our results suggest that this enhancement was due to a reduction of a GABAergic feedback inhibition from amacrine cells to bipolar cells and the resultant increased glutamate release. Finally, we found that some ganglion cells and other types of amacrine cell also displayed rhythmic activity, suggesting that oscillatory behavior is expressed by a number of inner retinal neurons

Genetic studies in the mouse have demonstrated that conditional cardiac-resticted loss of connexin43 (Cx43), the major ventricular gap junction protein, is highly arrhythmogenic. However, whether more focal gap junction remodeling, as is commonly seen in acquired cardiomyopathies, influences the propensity for arrhythmogenesis is not known. We examined electrophysiological properties and the frequency of spontaneous and inducible arrhythmias in genetically engineered chimeric mice derived from injection of Cx43-deficient embryonic stem cells into wildtype recipient blastocysts. Chimeric mice had numerous well-circumscribed microscopic Cx43-negative foci in their hearts, comprising ~ 15% of the total surface area as determined by immunohistochemical analysis. Systolic function in the chimeric mice was significantly depressed as measured echocardiographically (19.0% decline in fractional shortening compared with controls, p < 0.05) and by invasive hemodynamics (17.6% reduction in dP/dT, p < 0.01). Chimeras had significantly more spontaneous arrhythmic events than controls (p < 0.01), including frequent runs of non-sustained ventricular tachycardia in some of the chimeric mice. However, in contrast to mice with conditional cardiac-resticted loss of Cx43 in the heart, no sustained ventricular tachyarrhythmias were observed. We conclude that focal areas of uncoupling in the myocardium increase the likelihood of arrhythmic triggers, but more widespread uncoupling is required to support sustained arrhythmias

This review presents an overview of a challenging problem in auditory perception, the cocktail party phenomenon, the delineation of which goes back to a classic paper by Cherry in 1953. In this review, we address the following issues: (1) human auditory scene analysis, which is a general process carried out by the auditory system of a human listener; (2) insight into auditory perception, which is derived from Marr's vision theory; (3) computational auditory scene analysis, which focuses on specific approaches aimed at solving the machine cocktail party problem; (4) active audition, the proposal for which is motivated by analogy with active vision, and (5) discussion of brain theory and independent component analysis, on the one hand, and correlative neural firing, on the other.

Pediatric major depressive disorder (MDD) is a common disease associated with significant morbidity and mortality. Newly available noninvasive neuroimaging techniques provide unique opportunities to illuminate the underlying neurobiological factors of MDD. This article reviews structural and functional neuroimaging data in pediatric MDD. In general, neuroimaging studies in pediatric MDD tend to confirm findings in adult depression implicating the prefrontal cortex, amygdala, and hippocampus. These brain regions are linked and believed to be critical in modulating emotional responses. However, neuroimaging research in pediatric MDD is still in its infancy, and inconsistencies are rife. These inconsistencies are largely due to the small samples and lack of agreement regarding methodology in ascertainment as well as in imaging. Greater focus on careful delineation of clinically and neurobiologically defined subgroups will likely lead to improved understanding of the pathophysiology of MDD. (journal abstract)

Synchronous activity is common in the neocortex, although its significance, mechanisms, and development are poorly understood. Previous work showed that networks of electrically coupled inhibitory interneurons called low-threshold spiking (LTS) cells can fire synchronously when stimulated by metabotropic glutamate receptors. Here we found that the coordinated inhibition emerging from an activated LTS network could induce correlated spiking patterns among neighboring excitatory cells. Synchronous activity among LTS cells was absent at postnatal day 12 (P12) but appeared abruptly over the next few days. The rapid development of the LTS-synchronizing system coincided with the maturation of the inhibitory outputs and intrinsic membrane properties of the neurons. In contrast, the incidence and magnitude of electrical synapses remained constant between P8 and P15. The developmental transformation of LTS interneurons into a synchronous, oscillatory network overlaps with the onset of active somatosensory exploration, suggesting a potential role for this synchronizing system in sensory processing.