Faculty Bibliography

In summary, NPY is clearly an important peptide in the adult rat dentate gyrus because it has the potential to influence synaptic transmission and neurogenesis. It may even have other functions, as yet undiscovered, mediated by glia or vasculature. The remarkable plasticity of NPY puts it in a position to allow dentate gyrus function to be modified in a changing environment. The importance of this plasticity in the context of epilepsy cannot be emphasized enough. It could help explain a range of observations about epilepsy that currently is poorly understood. For example, rapid increases in NPY could mediate postictal depression, the period of depression that can last for several hours after generalized seizures. It may mediate the 'priming effect,' which is a reduction in seizure threshold following an initial period of seizures. Finally, it could contribute to the resistance of dentate granule cells to degeneration after seizures. However, despite the focus in this review on seizure-induced changes, the changes described here also appear to occur after other types of manipulations, which considerably broadens the scope of NPY's role in the brain

The wasp Nasonia vitripennis is emerging as a useful model organism in which to address a variety of biological questions, due, in part, to its ease of laboratory use, unique aspects of its biology and the sequencing of its genome. In order to take full advantage of the potential of this organism, methods for manipulating gene function are needed. To this end, a protocol for parental RNA interference (pRNAi) in N. vitripennis is described. pRNAi entails injecting pupae with double-stranded RNA, allowing the injected wasps to eclose and examining the progeny for developmental defects. This basic protocol is described in the context of the life cycle of N. vitripennis. This technique has been useful in elucidating the function of most, although not all, genes tested to date, and has potential applications beyond embryonic patterning. pRNAi experiments in Nasonia can be completed in as little as 2 weeks.

There are now a number of studies that suggest that cholesterol might regulate the processing of the amyloid precursor protein to form the neurotoxic peptide Abeta. This research has opened the possibility that cholesterol-lowering drugs might be efficacious as anti-Abeta drugs for use in Alzheimer's disease. The use of HMG-CoA reductase inhibitors (commonly called statins) in vitro and in vivo has proven them to be Abeta-lowering agents, however, the mechanism of action of these drugs is not yet known. One possible mechanism is that they reduce Abeta levels indirectly by reducing cholesterol in the central nervous system (CNS). In this study, we administered three different statins (simvastatin, lovastatin, and atorvastatin) to nontransgenic mice. We found that all three compounds had similar effects on Abeta, reducing both Abeta40 and Abeta42. The statins decreased beta-cleaved C-terminal fragment (CTF) although having no effect on alpha-CTF levels. However, the drugs did not have a similar effect on cholesterol in the CNS. Only lovastatin significantly reduced total cholesterol in isolated plasma membranes. As cholesterol is not distributed evenly in the plasma membrane, we examined bilayer distribution of cholesterol and found that all three statins caused CNS cholesterol to translocate from the cytofacial leaflet to the exofacial leaflet. This data suggests that cholesterol distribution and not total cholesterol levels may be important to Abeta production in the CNS

Attention deficit hyperactivity disorder (ADHD) is highly heritable but is likely a complex disorder involving multiple genes of moderate effect (Smalley [1997: Am J Hum Genet 60:1276-1282]). Over 100 studies have examined the genetics of ADHD by linkage or association, though no article has presented a comprehensive overview of all published reports. We reviewed all ADHD studies, including 3 genome-wide linkage studies, and association studies of 94 polymorphisms in 33 candidate genes. To simplify comparisons across heterogeneous articles, demographics and comorbidity were ignored; analyses of subtype and haplotypes were excluded; and only the most positive finding for each polymorphism in a study was reported. Thirty-six percent of all findings were positive (P < 0.05), 17% were trends (0.05 < P < 0.15), and 47% were negative (P > 0.15). Studies utilizing dimensional measures of ADHD tended to result in higher rates of positive findings than those using categorical diagnoses (chi2 = 5.6, P = 0.018), and case-control studies tended to result in higher rates of positive findings than family-based studies (chi2 = 18.8, P < 0.001). However, for either dichotomy, no significant difference remained when analyzing only studies using both methods within the same population and polymorphism. Evidence for association exists for four genes in ADHD: the dopamine D4 and D5 receptors, and the dopamine and serotonin transporters; others are promising but need further replication, including the dopamine D2 and serotonin 2A receptors. All candidate gene approaches continue to face the problem of relatively low power, given modest odds ratios for even the best replicated genes.

Many cells in the mammalian brain undergo apoptosis as a normal and critical part of development but the signals that regulate the survival and death of neural progenitor cells and the neurons they produce are not well understood. The Notch signaling pathway is involved in multiple decision points during development and has been proposed to regulate the survival and apoptosis of neural progenitor cells in the developing brain; however, previous experiments have not resolved whether Notch activity is pro- or anti-apoptotic. To elucidate the function of Notch signaling in the survival and death of cells in the nervous system, we have produced single and compound Notch conditional mutants in which Notch1 and Notch3 are removed at different times during brain development and in different populations of cells. We show here that a large number of neural progenitor cells, as well as differentiating neurons, undergo apoptosis in the absence of Notch1 and Notch3, suggesting that Notch activity promotes the survival of both progenitors and newly differentiating cells in the developing nervous system. Finally, we show that postmitotic neurons do not require Notch activity indefinitely to regulate their survival since elevated levels of cell death are observed only during embryogenesis in the Notch mutants and are not detected in neonates

Our large-scale computational model of the primary visual cortex that incorporates orientation-specific, long-range couplings with slow NMDA conductances operates in a fluctuating dynamic state of intermittent desuppression (IDS), which captures the behavior of coherent spontaneous cortical activity, as revealed by in vivo optical imaging based on voltage-sensitive dyes. Here, we address the functional significance of the IDS cortical operating points by investigating our model cortex response to the Hikosaka line-motion illusion (LMI) stimulus-a cue of a quickly flashed stationary square followed a few milliseconds later by a stationary bar. As revealed by voltage-sensitive dye imaging, there is an intriguing similarity between the cortical spatiotemporal activity in response to (i) the Hikosaka LMI stimulus and (ii) a small moving square. This similarity is believed to be associated with the preattentive illusory motion perception. Our numerical cortex produces similar spatiotemporal patterns in response to the two stimuli above, which are both in very good agreement with experimental results. The essential network mechanisms underpinning the LMI phenomenon in our model are (i) the spatiotemporal structure of the LMI input as sculpted by the lateral geniculate nucleus, (ii) a priming effect of the long-range NMDA-type cortical coupling, and (iii) the NMDA conductance-voltage correlation manifested in the IDS state. This mechanism in our model cortex, in turn, suggests a physiological underpinning for the LMI-associated patterns in the visual cortex of anaesthetized cat