Faculty Bibliography

Photochromic ligands have been used to control a variety of biological functions, especially in neural systems. Recently, much effort has been invested in the photocontrol of ion channels and G-protein coupled receptors found in the synapse. Herein, we describe the expansion of our photopharmacological approach toward the remote control of an enzyme. Building on hallmark studies dating from the late 1960s, we evaluated photochromic inhibitors of one of the most important enzymes in synaptic transmission, acetylcholinesterase (AChE). Using structure-based design, we synthesized several azobenzene analogues of the well-known AChE inhibitor tacrine (THA) and determined their effects on enzymatic activity. One of our compounds, AzoTHA, is a reversible photochromic blocker of AChE in vitro and ex vivo with high affinity and fast kinetics. As such, AzoTHA can be used to control synaptic transmission on the neuromuscular endplate based on the light-dependent clearance of a neurotransmitter.

Nitidasin is a pentacyclic sesterterpenoid with a rare 5-8-6-5 carbon skeleton that was isolated from the Peruvian folk medicine "Hercampuri". It belongs to a small class of sesterterpenoids that feature an isopropyl trans-hydrindane moiety fused to a variety of other ring systems. As a first installment of our general approach toward these natural products, we report the total synthesis of the title compound. Our stereoselective, convergent route involves the addition of a complex alkenyl lithium compound to a trans-hydrindanone, followed by chemoselective epoxidation, ring-closing olefin metathesis, and redox adjustment.

Photochromic blockers of voltage gated ion channels are powerful tools for the control of neuronal systems with high spatial and temporal precision. We now introduce fotocaine, a new type of photochromic channel blocker based on the long-lasting anesthetic fomocaine. Fotocaine is readily taken up by neurons in brain slices and enables the optical control of action potential firing by switching between 350 and 450 nm light. It also provides an instructive example for "azologization", that is, the systematic conversion of an established drug into a photoswitchable one.

Amiloride is a widely used diuretic that blocks epithelial sodium channels (ENaCs). These heterotrimeric transmembrane proteins, assembled from beta, gamma and alpha or delta subunits, effectively control water transport across epithelia and sodium influx into non-epithelial cells. The functional role of deltabetagammaENaC in various organs, including the human brain, is still poorly understood and no pharmacological tools are available for the functional differentiation between alpha- and delta-containing ENaCs. Here we report several photoswitchable versions of amiloride. One compound, termed PA1, enables the optical control of ENaC channels, in particular the deltabetagamma isoform, by switching between blue and green light, or by turning on and off blue light. PA1 was used to modify functionally deltabetagammaENaC in amphibian and mammalian cells. We also show that PA1 can be used to differentiate between deltabetagammaENaC and alphabetagammaENaC in a model for the human lung epithelium.

Humans can choose between fundamentally different options, such as watching a movie or going out for dinner. According to the utility concept, put forward by utilitarian philosophers and widely used in economics, this may be accomplished by mapping the value of different options onto a common scale, independent of specific option characteristics (Fehr and Rangel, 2011; Levy and Glimcher, 2012). If this is the case, value-related activity patterns in the brain should allow predictions of individual preferences across fundamentally different reward categories. We analyze fMRI data of the prefrontal cortex while subjects imagine the pleasure they would derive from items belonging to two distinct reward categories: engaging activities (like going out for drinks, daydreaming, or doing sports) and snack foods. Support vector machines trained on brain patterns related to one category reliably predict individual preferences of the other category and vice versa. Further, we predict preferences across participants. These findings demonstrate that prefrontal cortex value signals follow a common scale representation of value that is even comparable across individuals and could, in principle, be used to predict choice.

The goal of neurofeedback training is to provide participants with relevant information on their ongoing brain processes in order to enable them to change these processes in a meaningful way. Under the assumption of an intrinsic brain-behavior link, neurofeedback can be a tool to guide a participant towards a desired behavioral state, such as a healthier state in the case of patients. Current research in clinical neuroscience regarding the most robust indicators of pathological brain processes in psychiatric and neurological disorders indicates that fMRI-based functional connectivity measures may be among the most important biomarkers of disease. The present study therefore investigated the general potential of providing fMRI neurofeedback based on functional correlations, computed from short-window time course data at the level of single task periods. The ability to detect subtle changes in task performance with block-wise functional connectivity measures was evaluated based on imaging data from healthy participants performing a simple motor task, which was systematically varied along two task dimensions representing two different aspects of task difficulty. The results demonstrate that fMRI-based functional connectivity measures may provide a better indicator for an increase in overall (motor) task difficulty than activation level-based measures. Windowed functional correlations thus seem to provide relevant and unique information regarding ongoing brain processes, which is not captured equally well by standard activation level-based neurofeedback measures. Functional connectivity markers, therefore, may indeed provide a valuable tool to enhance and monitor learning within an fMRI neurofeedback setup.

Micro-Electrocorticography (muECoG) offers a minimally invasive, high resolution interface with large areas of cortex. However, large arrays of electrodes with many contacts that are individually wired to external recording systems are cumbersome and make chronic recording in freely behaving small animals challenging. Multiplexed headstages overcome this limitation by combining the signals from many electrodes to a smaller number of connections directly on the animal's head. Commercially available multiplexed headstages provide high performance integrated amplification, multiplexing and analog to digital conversion. However, the cost of these systems can be prohibitive for small labs or for experiments that require a large number of animals to be continuously recorded at the same time. Here we have developed a multiplexed 60-channel headstage amplifier optimized to chronically record electrophysiological signals from high-density muECoG electrode arrays. A single, ultraflexible (2 mm thickness) microHDMI cable provided the data interface. Using low cost components, we have reduced the cost of the multiplexed headstage to ~$125. Paired with a custom interface printed circuit board (PCB) and a general purpose data acquisition system (M-series DAQ, National Instruments), an inexpensive and customizable electrophysiology system is assembled. Open source LabVIEW software that we have previously released controlled the system. It can also be used with other open source neural data acquisition packages. Combined, we have presented a scalable, low-cost platform for high-channel count electrophysiology.

Interacting with the mother during the daily nursing, newborn rabbits experience her body odor cues. In particular, the mammary pheromone (MP) contained in rabbit milk triggers the typical behavior which helps to localize and seize the nipples. It also promotes the very rapid appetitive learning of simple or complex stimuli (odorants or mixtures) through associative conditioning. We previously showed that 24 h after MP-induced conditioning to odorants A (ethyl isobutyrate) or B (ethyl maltol), newborn rabbits perceive the AB mixture in a weak configural way, i.e., they perceive the odor of the AB configuration in addition to the odors of the elements. Moreover, after conditioning to the mixture, elimination of the memories of A and B does not affect the memory of AB, suggesting independent elemental and configural memories of the mixture. Here, we evaluated whether configural memory persistence differs from elemental one. First, whereas 1 or 3-day-old pups conditioned to A or B maintained their responsiveness to the conditioned odorant for 4 days, those conditioned to AB did not respond to the mixture after the same retention period. Second, the pups conditioned to AB still responded to A and B 4 days after conditioning, which indicates stronger retention of the elements than of the configuration when all information are learned together. Third, we determined whether the memory of the elements competes with the memory of the configuration: after conditioning to AB, when the memories of A and B were erased using pharmacological treatment, the memory of the mixture was extended to day 5. Thus, newborn rabbits have access to both elemental and configural information in certain odor mixtures, and competition between these distinct representations of the mixture influences the persistence of their memories. Such effects certainly occur in the natural context of mother-pup interactions and may contribute to early acquisition of knowledge about the surroundings.

Nearly one-third of patients with calcium stones have hyperuricosuria. In vitro studies and clinical trials have investigated the relationship between uric acid and calcium stones, but the association between hyperuricosuria and calcium stone formation in patients is still being debated. Uric acid appears to cause salting out of calcium oxalate in human urine. However, the importance of this in vitro phenomenon to the proposed association is not supported in cross-sectional observational studies. A small placebo-controlled randomized clinical trial showed that allopurinol decreased the rate of recurrent calcium oxalate calculi in patients with hyperuricosuria and normocalciuria. An assessment of the effect of combination therapy of allopurinol with indapamide showed no additive effect. Allopurinol may have antioxidant effects that are responsible for its reducing calcium stone formation, which are independent of xanthine oxidase inhibition. In addition, a newer xanthine oxidoreductase inhibitor, febuxostat, may also be effective in the prevention of calcium stones, as it reduces urinary uric acid excretion.