Faculty Bibliography

Photoswitchable lipids are emerging tools for the precise manipulation and study of lipid function. They can modulate many aspects of membrane biophysics, including permeability, fluidity, lipid mobility and domain formation. They are also very useful in lipid physiology and enable optical control of a wide array of lipid receptors, such as ion channels, G protein-coupled receptors, nuclear hormone receptors, and enzymes that translocate to membranes. Enzymes involved in lipid metabolism often process them in a light-dependent fashion. Photoswitchable lipids complement other functionalized lipids widely used in lipid chemical biology, including isotope-labeled lipids (lipidomics), fluorescent lipids (imaging), bifunctional lipids (lipid-protein crosslinking), photocaged lipids (photopharmacology), and other labeled variants.

The reasons why clinical outcomes with auditory brainstem implants (ABIs) are generally poorer than with cochlear implants (CIs) are still somewhat elusive. Prior work has focused on differences in processing of spectral information due to possibly poorer tonotopic representation and higher channel interaction with ABIs than with CIs. In contrast, this study examines the hypothesis that a potential contributing reason for poor speech perception in ABI users may be the relative lack of temporal responsiveness of the primary neurons that are stimulated by the ABI. The cochlear nucleus, the site of ABI stimulation, consists of different neuron types, most of which have much more complex responses than the auditory nerve neurons stimulated by a CI. Temporal responsiveness of primary stimulated neurons was assessed in a group of ABI and CI users by measuring recovery of electrically evoked compound action potentials (ECAPs) from single-pulse forward masking. Slower ECAP recovery tended to be associated with poorer hearing outcomes in both groups. ABI subjects with the longest recovery time had no speech understanding or even no hearing sensation with their ABI device; speech perception for the one CI outlier with long ECAP recovery time was well below average. To the extent that ECAP recovery measures reveal temporal properties of the primary neurons that receive direct stimulation form neural prosthesis devices, they may provide a physiological underpinning for clinical outcomes of auditory implants. ECAP recovery measures may be used to determine which portions of the cochlear nucleus to stimulate, and possibly allow us to enhance the stimulation paradigms.

Consumer valuations are shaped by choice sets, exemplified by patterns of substitution between alternatives as choice sets are varied. Building on recent neuroeconomic evidence that valuations are transformed during the choice process, we incorporate the canonical divisive normalization computation into a discrete choice model and characterize how choice behaviour depends on both size and composition of the choice set. We then examine evidence for such behaviour from two choice experiments that vary the size and composition of the choice set. We find that divisive normalization more accurately captures observed behaviour than alternative models, including an example range normalization model. These results are robust across experimental paradigms. Finally, we demonstrate that Divisive Normalization implements an efficient means for the brain to represent valuations given neurobiological constraints, yielding the fewest choice errors possible given those constraints.

The immune microenvironment of tumors can play a critical role in promoting or inhibiting tumor progression depending on the context. We present evidence that tumor-associated macrophages/microglia (TAMs) can promote tumor progression in the sonic hedgehog subgroup of medulloblastoma (SHH-MB). By combining longitudinal manganese-enhanced magnetic resonance imaging (MEMRI) and immune profiling of a sporadic mouse model of SHH-MB, we found the density of TAMs is higher in the ~50% of tumors that progress to lethal disease. Furthermore, reducing regulatory T cells or eliminating B and T cells in Rag1 mutants does not alter SHH-MB tumor progression. As TAMs are a dominant immune component in tumors and are normally dependent on colony-stimulating factor 1 receptor (CSF1R), we treated mice with a CSF1R inhibitor, PLX5622. Significantly, PLX5622 reduces a subset of TAMs, prolongs mouse survival, and reduces the volume of most tumors within 4 weeks of treatment. Moreover, concomitant with a reduction in TAMs the percentage of infiltrating cytotoxic T cells is increased, indicating a change in the tumor environment. Our studies in an immunocompetent preclinical mouse model demonstrate TAMs can have a functional role in promoting SHH-MB progression. Thus, CSF1R inhibition could have therapeutic potential for a subset of SHH-MB patients.

Ultrasound can be delivered transcranially to ablate brain tissue, open the blood-brain barrier, or affect neural activity. Transcranial focused ultrasound in small rodents is typically done with low-frequency single-element transducers, which results in unspecific targeting and impedes the concurrent use of fast neuroimaging methods. In this article, we devised a wide-angle spherical array bidirectional interface for high-resolution parallelized optoacoustic imaging and transcranial ultrasound (POTUS) delivery in the same target regions. The system operates between 3 and 9 MHz, allowing to generate and steer focal spots with widths down to [Formula: see text] across a field of view covering the entire mouse brain, while the same array is used to capture high-resolution 3-D optoacoustic data in real time. We showcase the system's versatile beam-forming capacities as well as volumetric optoacoustic imaging capabilities and discuss its potential to noninvasively monitor brain activity and various effects of ultrasound emission.