Faculty Bibliography

A unified approach toward the taiwaniaquinoids that has yielded four natural products is described. A new variant of the Nazarov reaction with concomitant formation of an enol triflate serves as one of the key steps, considerably shortening the synthetic scheme and providing a general entry into this class of bioactive natural products.

The neuronal ubiquitin/proteasomal pathway has been implicated in the pathogenesis of Alzheimer's disease (AD). We now show that a component of the pathway, ubiquitin C-terminal hydrolase L1 (Uch-L1), is required for normal synaptic and cognitive function. Transduction of Uch-L1 protein fused to the transduction domain of HIV-transactivator protein (TAT) restores normal enzymatic activity and synaptic function both in hippocampal slices treated with oligomeric Abeta and in the APP/PS1 mouse model of AD. Moreover, intraperitoneal injections with the fusion protein improve the retention of contextual learning in APP/PS1 mice over time. The beneficial effect of the Uch-L1 fusion protein is associated with restoration of normal levels of the PKA-regulatory subunit IIalpha, PKA activity, and CREB phosphorylation.

Responses of mitral cells represent the results of the first stage of odor processing in the olfactory bulb. Most of our knowledge about mitral cell activity has been obtained from recordings in anesthetized animals. We compared odor-elicited changes in firing rate of mitral cells in awake behaving mice and in anesthetized mice. We show that odor-elicited changes in mitral cell firing rate were larger and more frequently observed in the anesthetized than in the awake condition. Only 27% of mitral cells that showed a response to odors in the anesthetized state were also odor responsive in the awake state. The amplitude of their response in the awake state was smaller, and some of the responses changed sign compared with their responses in the anesthetized state. The odor representation in the olfactory bulb is therefore sparser in awake behaving mice than in anesthetized preparations. A qualitative explanation of the mechanism responsible for this phenomenon is proposed.

Within a large-scale neuronal network model of macaque primary visual cortex, we examined how intrinsic dynamic fluctuations in synaptic currents modify the effect of strong recurrent excitation on orientation selectivity. Previously, we showed that, using a strong network inhibition countered by feedforward and recurrent excitation, the cortical model reproduced many observed properties of simple and complex cells. However, that network's complex cells were poorly selective for orientation, and increasing cortical self-excitation led to network instabilities and unrealistically high firing rates. Here, we show that a sparsity of connections in the network produces large, intrinsic fluctuations in the cortico-cortical conductances that can stabilize the network and that there is a critical level of fluctuations (controllable by sparsity) that allows strong cortical gain and the emergence of orientation-selective complex cells. The resultant sparse network also shows near contrast invariance in its selectivity and, in agreement with recent experiments, has extracellular tuning properties that are similar in pinwheel center and iso-orientation regions, whereas intracellular conductances show positional dependencies. Varying the strength of synaptic fluctuations by adjusting the sparsity of network connectivity, we identified a transition between the dynamics of bistability and without bistability. In a network with strong recurrent excitation, this transition is characterized by a near hysteretic behavior and a rapid rise of network firing rates as the synaptic drive or stimulus input is increased. We discuss the connection between this transition and orientation selectivity in our model of primary visual cortex

This study explores subtle defects in the myelin of proteolipid protein (PLP)-null mice that could potentially underlie the functional losses and axon damage known to occur in this mutant and in myelin diseases including multiple sclerosis. We have compared PLP-null central nervous system (CNS) myelin with normal myelin using ultrastructural methods designed to emphasize fine differences. In the PLP-null CNS, axons large enough to be myelinated often lack myelin entirely or are surrounded by abnormally thin sheaths. Short stretches of cytoplasm persist in many myelin lamellae. Most strikingly, compaction is incomplete in this mutant as shown by the widespread presence of patent interlamellar spaces of variable width that can be labeled with ferricyanide, acting as an aqueous extracellular tracer. In thinly myelinated fibers, interlamellar spaces are filled across the full width of the sheaths. In thick myelin sheaths, they appear filled irregularly but diffusely. These patent spaces constitute a spiral pathway through which ions and other extracellular agents may penetrate gradually, possibly contributing to the axon damage known to occur in this mutant, especially in thinly myelinated fibers, where the spiral path length is shortest and most consistently labeled. We show also that the 'radial component' of myelin is distorted in the mutant ('diagonal component'), extending across the sheaths at 45 degrees instead of 90 degrees. These observations indicate a direct or indirect role for PLP in maintaining myelin compaction along the external surfaces of the lamellae and to a limited extent, along the cytoplasmic surfaces as well and also in maintaining the normal alignment of the radial component

The basic psychophysical principle of speed-accuracy tradeoff (SAT) has been used to understand key aspects of neuronal information processing in vision and audition, but the principle of SAT is still debated in olfaction. In this study we present the direct observation of SAT in olfaction. We developed a behavioral paradigm for mice in which both the duration of odorant sampling and the difficulty of the odor discrimination task were controlled by the experimenter. We observed that the accuracy of odor discrimination increases with the duration of imposed odorant sampling, and that the rate of this increase is slower for harder tasks. We also present a unifying picture of two previous, seemingly disparate experiments on timing of odorant sampling in odor discrimination tasks. The presence of SAT in olfaction provides strong evidence for temporal integration in olfaction and puts a constraint on models of olfactory processing.

Dorsal dermis and epaxial muscle have been shown to arise from the central dermomyotome in the chick. En1 is a homeobox transcription factor gene expressed in the central dermomyotome. We show by genetic fate mapping in the mouse that En1-expressing cells of the central dermomyotome give rise to dorsal dermis and epaxial muscle and, unexpectedly, to interscapular brown fat. Thus, the En1-expressing central dermomyotome normally gives rise to three distinct fates in mice. Wnt signals are important in early stages of dermomyotome development, but the signal that acts to specify the dermal fate has not been identified. Using a reporter transgene for Wnt signal transduction, we show that the En1-expressing cells directly underneath the surface ectoderm transduce Wnt signals. When the essential Wnt transducer beta-catenin is mutated in En1 cells, it results in the loss of Dermo1-expressing dorsal dermal progenitors and dermis. Conversely, when beta-catenin was activated in En1 cells, it induces Dermo1 expression in all cells of the En1 domain and disrupts muscle gene expression. Our results indicate that the mouse central dermomyotome gives rise to dermis, muscle, and brown fat, and that Wnt signalling normally instructs cells to select the dorsal dermal fate

Converging evidence from human and animal studies suggests that decision-making relies upon a distributed neural network based in the frontal lobes. In particular, models of decision-making emphasize the involvement of orbitofrontal cortices (OFC) and the medial wall. While decision-making has been studied broadly as a class of executive function, recent models have suggested the differentiation between risky and ambiguous decision-making. Given recent emphasis on the role of OFC in affectively laden 'hot' executive function and dorsolateral prefrontal cortex (DLPFC) in more purely cognitive 'cool' executive function, we hypothesize that the neural substrates of decision-making may differ depending on the nature of the decision required. To test this hypothesis, we used recently developed meta-analytic techniques to examine the existent functional neuroimaging literature. An initial meta-analysis of decision-making, both risky and ambiguous, found significantly elevated probabilities of activation in frontal and parietal regions, thalamus, and caudate. Ambiguous decision-making was associated with activity in DLPFC, regions of dorsal and subcallosal anterior cingulate cortex (ACC), and parietal cortex. Risky decision-making was associated with activity in OFC, rostral portions of the ACC, and parietal cortex. Direct statistical comparisons revealed significant differences between risky and ambiguous decision-making in frontal regions, including OFC, DLPFC, and ACC, that were consistent with study hypotheses. These findings provide evidence for the dissociation of neural circuits underlying risky and ambiguous decision-making, reflecting differential involvement of affective 'hot' and cognitive 'cool' processes

ABCA1 promotes cholesterol efflux from cells and is required for maintaining plasma cholesterol levels. Cholesterol homeostasis is important in the production of beta-amyloid (Abeta), a peptide that is overproduced in Alzheimer's disease (AD). Overexpression of ABCA1 can be achieved by stimulating Liver X Receptors (LXR), and changes in Abeta have been reported after LXR stimulation in vitro. To determine whether ABCA1 could alter endogenous Abeta levels, we used two different in vivo systems. We first examined the effects of an LXR agonist (TO-901317) on wild-type mice and found an increase in brain ABCA1 and apoE levels, which caused an increase in plasma cholesterol. This was accompanied by a decrease in brain Abeta levels. We then examined endogenous Abeta levels in ABCA1 knockout mice and found that, despite having no ABCA1, lowered brain apoE levels, and lowered plasma cholesterol, there was no change in Abeta levels. To assess these in vivo models in an in vitro system, we designed a model in which cholesterol transport via ABCA1 (or related transporters) was prevented. Switching off cholesterol efflux, even in the presence of TO-901317, caused no change in Abeta levels. However, when efflux capability was restored, TO-901317 reduced Abeta levels. These data show that promoting cholesterol efflux is a viable target for Abeta reducing strategies; however, knockout of cholesterol transporters is not sufficient to alter Abeta in vitro or in vivo