Sound-seeking before and after hearing loss in mice.

How we move our bodies affects how we perceive sound. For instance, head movements help us to better localize the source of a sound and to compensate for asymmetric hearing loss. However, many auditory experiments are designed to restrict head and body movements. To study the role of movement in hearing, we developed a behavioral task called sound-seeking that rewarded freely moving mice for tracking down an ongoing sound source. Over the course of learning, mice more efficiently navigated to the sound. Next, we asked how sound-seeking was affected by hearing loss induced by surgical removal of the malleus from the middle ear. After bilateral hearing loss sound-seeking performance drastically declined and did not recover. In striking contrast, after unilateral hearing loss mice were only transiently impaired and then recovered their sound-seek ability over about a week. Throughout recovery, unilateral mice increasingly relied on a movement strategy of sequentially checking potential locations for the sound source. In contrast, the startle reflex (an innate auditory behavior) was preserved after unilateral hearing loss and abolished by bilateral hearing loss without recovery over time. In sum, mice compensate with body movement for permanent unilateral damage to the peripheral auditory system. Looking forward, this paradigm provides an opportunity to examine how movement enhances perception and enables resilient adaptation to sensory disorders.

Sound-seeking before and after hearing loss in mice.

How we move our bodies affects how we perceive sound. For instance, we can explore an environment to seek out the source of a sound and we can use head movements to compensate for hearing loss. How we do this is not well understood because many auditory experiments are designed to limit head and body movements. To study the role of movement in hearing, we developed a behavioral task called sound-seeking that rewarded mice for tracking down an ongoing sound source. Over the course of learning, mice more efficiently navigated to the sound. We then asked how auditory behavior was affected by hearing loss induced by surgical removal of the malleus from the middle ear. An innate behavior, the auditory startle response, was abolished by bilateral hearing loss and unaffected by unilateral hearing loss. Similarly, performance on the sound-seeking task drastically declined after bilateral hearing loss and did not recover. In striking contrast, mice with unilateral hearing loss were only transiently impaired on sound-seeking; over a recovery period of about a week, they regained high levels of performance, increasingly reliant on a different spatial sampling strategy. Thus, even in the face of permanent unilateral damage to the peripheral auditory system, mice recover their ability to perform a naturalistic sound-seeking task. This paradigm provides an opportunity to examine how body movement enables better hearing and resilient adaptation to sensory deprivation.

Propagation of scrapie in peripheral nerves after footpad infection in normal and neurotoxin exposed hamsters.

As is known from various animal models, the spread of agents causing transmissible spongiform encephalopathies (TSE) after peripheral infection affects peripheral nerves before reaching the central nervous system (CNS) and leading to a fatal end of the disease. The lack of therapeutic approaches for TSE is partially due to the limited amount of information available on the involvement of host biological compartments and processes in the propagation of the infectious agent. The in vivo model presented here can provide information on the spread of the scrapie agent via the peripheral nerves of hamsters under normal and altered axonal conditions. Syrian hamsters were unilaterally footpad (f.p.) infected with scrapie. The results of the spatiotemporal ultrasensitive immunoblot-detection of scrapie-associated prion protein (PrP(Sc)) in serial nerve segments of both distal sciatic nerves could be interpreted as a centripetal and subsequent centrifugal neural spread of PrP(Sc) for this route of infection. In order to determine whether this propagation is dependent on main components in the axonal cytoskeleton (e.g. neurofilaments, also relevant for the component ;a' of slow axonal transport mechanisms), hamsters were treated -in an additional experiment- with the neurotoxin beta,beta-iminodiproprionitrile (IDPN) around the beginning of the scrapie infection. A comparison of the Western blot signals of PrP(Sc) in the ipsilateral and in the subsequently affected contralateral sciatic nerve segments with the results revealed from IDPN-untreated animals at preclinical and clinical stages of the TSE disease, indicated similar amounts of PrP(Sc). Furthermore, the mean survival time was unchanged in both groups. This in vivo model, therefore, suggests that the propagation of PrP(Sc) along peripheral nerves is not dependent on an intact neurofilament component of the axonal cytoskeleton. Additionally, the model indicates that the spread of PrP(Sc) is not mediated by the slow component ;a' of the axonal transport mechanism.

Preclinical deposition of pathological prion protein PrPSc in muscles of hamsters orally exposed to scrapie.

Recently, pathological prion protein PrP(Sc), the putative key constituent of infectious agents causing transmissible spongiform encephalopathies (TSEs), was found in muscles of rodents experimentally infected with scrapie and in patients with Creutzfeldt-Jakob disease (CJD). For the assessment of risk scenarios originating from these findings (e.g., alimentary transmission of pathogens associated with bovine spongiform encephalopathy [BSE] and chronic wasting disease [CWD] via tainted beef and game or iatrogenic dissemination of CJD agent through contaminated surgical instruments) more detailed information about the time course of PrP(Sc) accumulation in muscles at preclinical and clinical stages of incubation is needed. Here we show that PrP(Sc) in muscles of hamsters fed with scrapie can be detected prior to the onset of clinical symptoms, but that the bulk of PrP(Sc) was deposited late in clinical disease. Additionally, regarding the question of how muscles become invaded, we report on the intramuscular location of PrP(Sc) and substantial indications for centrifugal spread of infection from spinal motor neurons to myofibers. Our findings in a well-established animal model for TSEs contribute to a better assessment of the risks for public health emanating from "Prions in skeletal muscle" and provide new insights into the pathophysiological spread of TSE agents through the body.