Our research program includes molecular and cell biology, morphology, and integrative physiology. Our focus is on the inner ear and the central auditory nervous system and to define the mechanisms that cause hearing disorders.
The goal of this research is to understand the neuroendocrine mechanisms that regulate the response of the auditory system to acoustic trauma, with emphasis on the regulation of the hypothalamic-pituitary-adrenal (HPA) axis and steroid receptors.
The ability of the organism to adapt to acute and chronic stress situations is determined by genetic constitution and earlier experiences. We demonstrate how steroid hormones can directly modulate hearing sensitivity in response to a moderate acoustic trauma, and have identified which down-stream pathways are involved in this pathology.
In pursuit of the defining of which transcription factors are responsible for the effects of acoustic trauma, the effects of prior restraint stress on acoustic trauma has been found not only to protect the auditory system from trauma, but also to trigger the nuclear translocation of steroid hormone receptors. Several important advances are also being made on how neurotrophic factors can regulate the sensitivity and survival of neurons of the auditory system.
Sound conditioning is a means of priming the auditory system against subsequent trauma. We are now determining the role of both steroid hormones and neurotrophic factors in protecting the auditory system from trauma by sound conditioning. Overall, these studies are opening a new avenue of research for the auditory field, that of auditory neuroendocrinology.
Our working hypothesis is that distinct patterns of gene expression in glucocorticoid circuits including the transcriptional factors, immediate early genes, protein transduction cascades, together with specific response elements, such as BDNF, and NMDA receptors, including the dopamine transmitter system are playing a crucial role.
The identification of these key participants in the signalling pathways will pinpoint the critical causes underlying individual vulnerability to hearing loss. To address these issues several models have been developed to specifically test and identify key molecules that are regulating these signalling pathways and governing their complex interactions.
Hearing loss induced by acoustic trauma is a common handicap for the human population. According to WHO, hearing-related disabilities will rank 9th in middle-and high-income countries. Strategies are needed to alleviate these hearing and communication problems. Hearing loss triggers a cascade of changes in the cochlea such as damage of sensory hair cells, biochemical disturbances including reactive oxygen and nitrogen species generation, release of pro-inflammatory cytokines and exitotoxicity. Hearing loss can result in transient or permanent hearing loss depending on the physical and temporal characteristics of the type of trauma as well as individual susceptibility. The main focus of the present studies is to elucidate the mechanisms underlying damage to the peripheral and central auditory pathway, and to highlight new strategies to protect against these disorders. The studies involve both experimental animals and human subjects.
The role of glucocorticoid receptors and mitogen-regulated protein kinases in the cochlea
The overall goal of the present studies is to characterize the molecular mechanisms underlying the protective effects of glucocorticoid receptors (GR) and their interactions with the family of mitogen-activated protein kinases (MAPKs) and the otoprotective neurotrophic factor, BDNF. A critical factor for protecting against cochlear trauma includes GR and ERK interactions and the down-stream activation of BDNF. BDNF is up-regulated in the cochlea after acoustic trauma, and the duration of its elevation correlate with the pattern of ERKs activation and the severity of cochlea damage. The knowledge of the glucocorticoids and MAPKs cellular mechanisms is of great importance for clinical audiology, since it opens new avenues for the prevention and treatment of hearing loss. These data will help to understand the nature of individual sensitivity to acoustic trauma since hypothalamic-pituitary adrenal (HPA) axis status is now demonstrated to be a critical factor for determining the overall sensitivity to acoustic trauma.
Mechanisms underlying stress and developing new intervention strategies
New research shows alarming statistics; that about 32 per cent of employed Swedes have some form of hearing problems (hearing loss, tinnitus or both). The findings come from one of the largest studies of hearing problems, psychosocial work and health that we recently completed. Hearing problems are more common in individuals exposed to various forms of stress (eg threat of redundancy / bankruptcy, stress-related symptoms) and those who sleep poorly. Our animal studies also show clear links between chronic stress and hearing damage. Our findings indicate that hearing problems are common in the workplace and these figures are increasing as compared with ten years ago. There is thus a great need for research and development of new diagnostic methods for early identification of individuals at risk, and as well as development of preventive interventions to prevent occurrence of stress-related hearing problems. The aim is to reverse this trend and to reduce the risk of communications problems.
The role of estrogen receptors in the auditory system
Our recent studies on estrogen receptors (ER) showed, for the first time, their presence in the peripheral auditory system of young males and females and that the ER beta protected against noise-induced hearing loss (Meltser et al, J Clinical Investigation, April 2008). In the present proposal we will extend our findings to elucidate whether protection of auditory function by either ER alpha or ER beta decreases with aging as well as to determine the signaling mechanisms underlying ER beta protection and how the signaling may change with aging in the peripheral and central auditory system.
Effects of acute and chronic stress on the auditory system
Both acute and chronic stress significantly elevates serum corticosterone concentrations. However, only acute stress provides protection against acoustic trauma. A decreased sensitivity of the auditory system to corticosterone over time could explain why acute stress protects against acoustic trauma, but chronic stress does not. Different acute stressors have been shown to alter susceptibility to hearing loss. Restraint stress and sound conditioning are two acute stressors that correlate to changes in the hypothalamic-pituitary-adrenal (HPA) axis. These changes subsequently affect glucocorticoid receptor pathways in the auditory system and protect against noise induced hearing loss. Today, little is known about chronic stress and hearing. These effects cannot be explained by differences in the HPA-axis respones (hormonal levels in the blood). Thus the effects mediated by stress must be further down the glucocorticoid signalling pathways. The main aim of this project is to find a pharmacological target for protection against noise induced hearing loss.
Characterizing how stress modulates hearing problems in the human population
A unique clinical investigation is underway where the effects of stress on hearing are being directly tested. The main objective is to identify individuals who have an increased susceptibility to hearing problems (e.g. an increased noise sensitivity, tinnitus and hearing loss), and to reduce the risk of adverse health and safety implications and long-term illness. Our study involves an in-depth characterization of individuals from the SLOSH-cohort who have hearing problems. Their hearing thresholds and speech in noise abilities will be monitored before and after a stress test. To explore physiological measurements the function of the autonomic nervous system function will be assessed (e.g. heart rate variability). Preliminary results show that individuals with hearing problems have lower heart rate variability, while those who do not have hearing problems have significantly higher heart rate variability. In addition, it is important to develop tests for the early identification of individuals at risk. Finally, future studies will develop preventive interventions to prevent the occurrence of stress-related hearing problems.
Development of ion pump drug delivery to the inner ear for long-term use
Pharmacotherapy for inner ear disorders is hampered by the difficulties in local application. During the past two years, together with other researchers from the Department of Neuroscience and Linköping University, a novel technology using organic bio-electronics has been developed to create an interface between electronics and the inner ear. Organic conducting polymers were used as programmable delivery electrodes, in which an electronic in-put signal translates into release of bio-signals (ions, neurotransmitters, antioxidants, neurotrophic factors). Using the peripheral auditory system, we show that the device can selectively stimulate nerve cells responding to glutamate. This technology has great potential as a therapeutic platform, where malfunctioning signal transduction pathways can be modulated by programmable, dose-controlled delivery of signal substances from an implanted bio-electronic device. This new method of communication between electronics and the inner ear will help accelerate the development of therapeutic strategies for hearing disorders. These studies are published in Nature Materials (Simon et al., 2009).
Audiogenic seizures and the role of the inferior colliculus
Audiogenic seizure (AGS) models manifest generalized seizures such as wild running, clonus and tonus. The initiation and propagation of AGS activity relies upon hyperexcitability in the auditory system, particularly the inferior colliculus. The inferior colliculus (IC) is critical in AGS initiation as extensive firing increases in this region and is observed prior to seizure initiation. The deep layers of superior colliculus, the pontine reticular nucleus and the periaqueductal gray are critical to the clonic phase, and the firing patterns appear in these neurons just prior to this phase. Analyses of the temporal relationships and the neurotransmitter mechanisms between these nuclei suggest that each one plays a specific role in different convulsive behaviors. In this context it is important to note that alterations in hormonal profiles are known to influence the occurrence and severity of epilepsy.
Stereological analysis of the peripheral and central auditory system
A major goal of biology is to integrate structural and functional studies, and to understand the correlation between the two. Over the past few years we have used morphometric techniques which allow structural data to be quantified and thus facilitate comparison with functional studies. Stereology, the study of three-dimensional objects through the interpretation of two-dimensional images, provides a means of correlating structure and function.
Inna Meltser 2009