A4
a4
Pitch and Time Interact in Auditory Perception
Research into pitch perception and time perception has typically treated the two as independent processes. However, previous studies of music and speech perception have suggested that pitch and timing information may be processed in an integrated manner, such that the pitch of an auditory stimulus can influence a person’s perception, expectation, and memory of its duration and tempo. Typically, higher-pitched sounds are perceived as faster and longer in duration than lower-pitched sounds with identical timing. We conducted a series of experiments to better understand the limits of this pitch-time integrality. Across several experiments, we tested whether the higher-equals-faster illusion generalizes across the broader frequency range of human hearing by asking participants to compare the tempo of a repeating tone played in one of six octaves to a metronomic standard. When participants heard tones from all six octaves, we consistently found an inverted U-shaped effect of the tone’s pitch height, such that perceived tempo peaked between A4 (440 Hz) and A5 (880 Hz) and decreased at lower and higher octaves. However, we found that the decrease in perceived tempo at extremely high octaves could be abolished by exposing participants to high-pitched tones only, suggesting that pitch-induced timing biases are context sensitive. We additionally tested how the timing of an auditory stimulus influences the perception of its pitch, using a pitch discrimination task in which probe tones occurred early, late, or on the beat within a rhythmic context. Probe timing strongly biased participants to rate later tones as lower in pitch than earlier tones. Together, these results suggest that pitch and time exert a bidirectional influence on one another, providing evidence for integrated processing of pitch and timing information in auditory perception. Identifying the mechanisms behind this pitch-time interaction will be critical for integrating current models of pitch and tempo processing.
Sleepless in Vienna - how to rescue folding-deficient dopamine transporters by pharmacochaperoning
Diseases that arise from misfolding of an individual protein are rare. However, collectively, these folding diseases represent a large proportion of hereditary and acquired disorders. In fact, the term "Molecular Medicine" was coined by Linus Pauling in conjunction with the study of a folding disease, i.e. sickle cell anemia. In the past decade, we have witnessed an exponential growth in the number of mutations, which have been identified in genes encoding solute carriers (SLC). A sizable faction - presumably the majority - of these mutations result in misfolding of the encoded protein. While studying the export of the GABA transporter (SLC6A1) and of the serotonin transporter (SLC6A4), from the endoplasmic reticulum (ER), we discovered by serendipity that some ligands can correct the folding defect imparted by point mutations. These bind to the inward facing state. The most effective compound is noribogaine, the metabolite of ibogaine (an alkaloid first isolated from the shrub Tabernanthe iboga). There are 13 mutations in the human dopamine transporter (DAT, SLC6A3), which give rise to a syndrome of infantile Parkinsonism and dystonia. We capitalized on our insights to explore, if the disease-relevant mutant proteins were amenable to pharmacological correction. Drosopohila melanogaster, which lack the dopamine transporter, are hyperactive and sleepless (fumin in Japanese). Thus, mutated human DAT variants can be introduced into fumin flies. This allows for examining the effect of pharmacochaperones on delivery of DAT to the axonal territory and on restoring sleep. We explored the chemical space populated by variations of the ibogaine structure to identify an analogue (referred to as compound 9b), which was highly effective: compound 9b also restored folding in DAT variants, which were not amenable to rescue by noribogaine. Deficiencies in the human creatine transporter-1 (CrT1, SLC6A8) give rise to a syndrome of intellectual disability and seizures and accounts for 5% of genetically based intellectual disabilities in boys. Point mutations occur, in part, at positions, which are homologous to those of folding-deficient DAT variants. CrT1 lacks the rich pharmacology of monoamine transporters. Nevertheless, our insights are also applicable to rescuing some disease-related variants of CrT1. Finally, the question arises how one can address the folding problem. We propose a two-pronged approach: (i) analyzing the effect of mutations on the transport cycle by electrophysiological recordings; this allows for extracting information on the rates of conformational transitions. The underlying assumption posits that - even when remedied by pharmacochaperoning - folding-deficient mutants must differ in the conformational transitions associated with the transport cycle. (ii) analyzing the effect of mutations on the two components of protein stability, i.e. thermodynamic and kinetic stability. This is expected to provide a glimpse of the energy landscape, which governs the folding trajectory.
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