Faculty Bibliography

Most of the choices we make have uncertain consequences. In some cases the probabilities for different possible outcomes are precisely known, a condition termed "risky". In other cases when probabilities cannot be estimated, this is a condition described as "ambiguous". While most people are averse to both risk and ambiguity(1,2), the degree of those aversions vary substantially across individuals, such that the subjective value of the same risky or ambiguous option can be very different for different individuals. We combine functional MRI (fMRI) with an experimental economics-based method(3 )to assess the neural representation of the subjective values of risky and ambiguous options(4). This technique can be now used to study these neural representations in different populations, such as different age groups and different patient populations. In our experiment, subjects make consequential choices between two alternatives while their neural activation is tracked using fMRI. On each trial subjects choose between lotteries that vary in their monetary amount and in either the probability of winning that amount or the ambiguity level associated with winning. Our parametric design allows us to use each individual's choice behavior to estimate their attitudes towards risk and ambiguity, and thus to estimate the subjective values that each option held for them. Another important feature of the design is that the outcome of the chosen lottery is not revealed during the experiment, so that no learning can take place, and thus the ambiguous options remain ambiguous and risk attitudes are stable. Instead, at the end of the scanning session one or few trials are randomly selected and played for real money. Since subjects do not know beforehand which trials will be selected, they must treat each and every trial as if it and it alone was the one trial on which they will be paid. This design ensures that we can estimate the true subjective value of each option to each subject. We then look for areas in the brain whose activation is correlated with the subjective value of risky options and for areas whose activation is correlated with the subjective value of ambiguous options.

Dopamine (DA) transporter (DAT) imaging has been studied as a diagnostic tool for degenerative parkinsonism. Our aim was to measure the prognostic value of imaging for motor and nonmotor outcomes in Parkinson's disease (PD). We prospectively evaluated a Parkinson's cohort after enrollment in a de novo clinical trial with a battery of motor (UPDRS), cognitive (Montreal Cognitive Assessment), and behavioral measures. DAT imaging with [(123)I][beta]-CIT and single-photon emission computerized tomography (SPECT) was performed at baseline and after 22 months. In total, 491 (91%) of the 537 subjects had evidence of DA deficiency on their baseline scan, consistent with PD, and were included in the analyses. The cohort was followed for 5.5 (0.8) years, with a mean duration of diagnosis of 6.3 (1.2). Lower striatal binding at baseline was independently associated with higher risk for clinical milestones and measures of disease severity, including motor-related disability, falling and postural instability, cognitive impairment, psychosis, and clinically important depressive symptoms. Subjects in the bottom quartile for striatal binding, compared to the top quartile, had an odds ratio (95% confidence interval) of 3.3 (1.7, 6.7) for cognitive impairment and 12.9 (2.6, 62.4) for psychosis. Change from baseline in imaging after 22 months was also independently associated with motor, cognitive, and behavioral outcomes. DAT imaging with [(123)I][beta]-CIT and SPECT, shortly after the diagnosis of PD, was independently associated with clinically important long-term motor and nonmotor outcomes. These results should be treated as hypothesis generating and require confirmation.

Neurophysiological evidence suggests that a specialized cortical network is involved in the visual perception of biological motion; however, the temporal dynamics underlying this network is largely unexplored. We used magnetoencephalography to determine the spatial distribution and task-related temporal dynamics of the oscillatory activity of random and human motion. We recorded cortical responses in healthy adults while they passively viewed point-light displays of static dots, random, and human motion. By analyzing differences in the time-frequency distributions between pairs of conditions, we found that: (a) the perception of both motion conditions resulted in a significant decrease in the alpha/beta band in the right superior occipital gyrus and a significant decrease in the beta band in the right insula and (b) the human motion condition was associated with specific alterations in alpha, beta, and gamma bands with significant reductions in the alpha band in the right superior temporal gyrus, right precuneus, and left inferior parietal lobule, significant reductions in the beta band in the bilateral superior temporal gyrus, together with a significant increase in the gamma band in the left inferior parietal lobule and superior temporal regions. These data suggest that although the perception of both random and human motion involves desynchronization of oscillatory activity in alpha and beta bands in similar cortical regions, only human motion is associated with a larger network and significant alterations in the alpha/beta band particularly in the right hemisphere.

There are two views on vertebrate retinogenesis: a deterministic model dependent on fixed lineages and a stochastic model in which choices of division modes and cell fates cannot be predicted. In this issue of Neuron, He et al. (2012) address this question in zebrafish using live imaging and mathematical modeling.

The conventional view of AD (Alzheimer's disease) is that much of the pathology is driven by an increased load of beta-amyloid in the brain of AD patients (the 'Amyloid Hypothesis'). Yet, many therapeutic strategies based on lowering beta-amyloid have so far failed in clinical trials. This failure of beta-amyloid-lowering agents has caused many to question the Amyloid Hypothesis itself. However, AD is likely to be a complex disease driven by multiple factors. In addition, it is increasingly clear that beta-amyloid processing involves many enzymes and signalling pathways that play a role in a diverse array of cellular processes. Thus the clinical failure of beta-amyloid-lowering agents does not mean that the hypothesis itself is incorrect; it may simply mean that manipulating beta-amyloid directly is an unrealistic strategy for therapeutic intervention, given the complex role of beta-amyloid in neuronal physiology. Another possible problem may be that toxic beta-amyloid levels have already caused irreversible damage to downstream cellular pathways by the time dementia sets in. We argue in the present review that a more direct (and possibly simpler) approach to AD therapeutics is to rescue synaptic dysfunction directly, by focusing on the mechanisms by which elevated levels of beta-amyloid disrupt synaptic physiology.

The variecolortides are a family of unusual natural products that combine motifs from a variety of biosynthetic streams. Herein, we present the gradual evolution of a convergent synthetic strategy that ultimately culminated in a reaction cascade featuring a hydrogen shift and a cycloaddition followed by a spontaneous air oxidation. Attempts to link an anthrone building block with an exo-methylene diketopiperazine using radical chemistry were ultimately unsuccessful, but led to interesting observations that shaped our successful strategy. The total synthesis of variecolortide C is presented for the first time.

Changes in neural activity influence synaptic plasticity/scaling, gene expression, and epigenetic modifications. We present the first evidence that short-term and persistent changes in neural activity can alter adenosine-to-inosine (A-to-I) RNA editing, a post-transcriptional site-specific modification found in several neuron-specific transcripts. In rat cortical neuron cultures, activity-dependent changes in A-to-I RNA editing in coding exons are present after 6 hr of high potassium depolarization but not after 1 hr and require calcium entry into neurons. When treatments are extended from hours to days, we observe a negative feedback phenomenon: Chronic depolarization increases editing at many sites and chronic silencing decreases editing. We present several different modulations of neural activity that change the expression of different mRNA isoforms through editing.

There is a substantial body of evidence that spontaneous recurrent seizures occur in a subset of patients with Alzheimer disease (AD), especially the familial forms that have an early onset. In transgenic mice that simulate these genetic forms of AD, seizures or reduced seizure threshold have also been reported. Mechanisms underlying the seizures or reduced seizure threshold in these mice are not yet clear and are likely to be complex, because the synthesis of amyloid beta (Abeta) involves many peptides and proteases that influence excitability. Based on transgenic mouse models of AD where Abeta and its precursor are elevated, it has been suggested that seizures are caused by the downregulation of the Nav1.1 sodium channel in a subset of GABAergic interneurons, leading to a reduction in GABAergic inhibition. Another mechanism of hyperexcitability appears to involve tau, because deletion of tau reduces seizures in some of the same transgenic mouse models of AD. Therefore, altered excitability may be as much a characteristic of AD as plaques and tangles-especially for the familial forms of AD.