Pupillometry as a reliable metric of auditory detection and discrimination across diverse stimulus paradigms in animal models

Estimates of detection and discrimination thresholds are often used to explore broad perceptual similarities between human subjects and animal models. Pupillometry shows great promise as a non-invasive, easily-deployable method of comparing human and animal thresholds. Using pupillometry, previous studies in animal models have obtained threshold estimates to simple stimuli such as pure tones, but have not explored whether similar pupil responses can be evoked by complex stimuli, what other stimulus contingencies might affect stimulus-evoked pupil responses, and if pupil responses can be modulated by experience or short-term training. In this study, we used an auditory oddball paradigm to estimate detection and discrimination thresholds across a wide range of stimuli in guinea pigs. We demonstrate that pupillometry yields reliable detection and discrimination thresholds across a range of simple (tones) and complex (conspecific vocalizations) stimuli; that pupil responses can be robustly evoked using different stimulus contingencies (low-level acoustic changes, or higher level categorical changes); and that pupil responses are modulated by short-term training. These results lay the foundation for using pupillometry as a reliable method of estimating thresholds in large experimental cohorts, and unveil the full potential of using pupillometry to explore broad similarities between humans and animal models.publishersversionpublishe

CACNB4 Overexpression and Dendritic Spine Loss in Schizophrenia

Reduced density of dendritic spines is an intermediate anatomical phenotype for schizophrenia (Sz). This dissertation is a collection of descriptive studies about dendritic spines and the voltage-gated calcium channel protein β4, a study of a Sz-related β4 manipulation, and the impacts of this manipulation on dendritic spine density and morphology. Chapter 2 is a descriptive study of sex differences in dendritic spines in murine sensory cortex over adolescent neurodevelopment. Chapter 3 is an in-depth assessment of the impacts of CACNB4 overexpression (β4OE) on dendritic spines of male and female adult mice. Chapter 4 is a final descriptive study of sex differences in the β4 interactome of adult mice. Sex differences were deliberately assessed at baseline and in the study of the impacts of β4OE on dendritic spines given the importance of sex as a biological factor and known sex differences in the clinical presentation and expression of Sz. In Chapter 2, we identified sex differences in spine density, and in Chapter 3 evidence for volume- as well as sex-specific β4OE-mediated spine loss; small spines were reduced in female β4OE mice only. These findings provide a model for the intermediate phenotype of small spine loss in primary auditory cortex in Sz and support both our group’s previous suggestion to rethink the Feinberg hypothesis, but also the possibility that small mature spines are eliminated excessively in Sz during adolescence, as Feinberg predicted. In Chapter 4 we found that β1b is significantly enriched in the β4 interactome of male mice only, the presence of which may confer protection for males from the effects of β4OE. Moreover, we detail three pathways through which β4OE could reduce small spine density in female mice. These proposed pathways nominate kinases and MAPs in β4-related spine alterations. Overall, the findings described herein underscore the importance of evaluating the biological sex at baseline, over normal neurodevelopment and following a disease-related manipulation, particularly neurodevelopmental disorders, including Sz

Adaptive mechanisms facilitate robust performance in noise and in reverberation in an auditory categorization model

Abstract For robust vocalization perception, the auditory system must generalize over variability in vocalization production as well as variability arising from the listening environment (e.g., noise and reverberation). We previously demonstrated using guinea pig and marmoset vocalizations that a hierarchical model generalized over production variability by detecting sparse intermediate-complexity features that are maximally informative about vocalization category from a dense spectrotemporal input representation. Here, we explore three biologically feasible model extensions to generalize over environmental variability: (1) training in degraded conditions, (2) adaptation to sound statistics in the spectrotemporal stage and (3) sensitivity adjustment at the feature detection stage. All mechanisms improved vocalization categorization performance, but improvement trends varied across degradation type and vocalization type. One or more adaptive mechanisms were required for model performance to approach the behavioral performance of guinea pigs on a vocalization categorization task. These results highlight the contributions of adaptive mechanisms at multiple auditory processing stages to achieve robust auditory categorization

Controlled release of ciprofloxacin and ceftriaxone from a single ototopical administration of antibiotic-loaded polymer microspheres and thermoresponsive gel.

Acute otitis media (AOM) is the main indication for pediatric antibiotic prescriptions, accounting for 25% of prescriptions. While the use of topical drops can minimize the administered dose of antibiotic and adverse systemic effects compared to oral antibiotics, their use has limitations, partially due to low patient compliance, high dosing frequency, and difficulty of administration. Lack of proper treatment can lead to development of chronic OM, which may require invasive interventions. Previous studies have shown that gel-based drug delivery to the ear is possible with intratympanic injection or chemical permeation enhancers (CPEs). However, many patients are reluctant to accept invasive treatments and CPEs have demonstrated toxicity to the tympanic membrane (TM). We developed a novel method of delivering therapeutics to the TM and middle ear using a topical, thermoresponsive gel depot containing antibiotic-loaded poly(lactic-co-glycolic acid) microspheres. Our in vitro and ex vivo results suggest that the sustained presentation can safely allow therapeutically relevant drug concentrations to penetrate the TM to the middle ear for up to 14 days. Animal results indicate sufficient antibiotic released for treatment from topical administration 24h after bacterial inoculation. However, animals treated 72h after inoculation, a more clinically relevant treatment practice, displayed spontaneous clearance of infection as is also often observed in the clinic. Despite this variability in the disease model, data suggest the system can safely treat bacterial infection, with future studies necessary to optimize microsphere formulations for scaled up dosage of antibiotic as well as further investigation of the influence of spontaneous bacterial clearance and of biofilm formation on effectiveness of treatment. To our knowledge, this study represents the first truly topical drug delivery system to the middle ear without the use of CPEs