Sanchez Lab Research Projects
The long-term goal of my research program is to elucidate mechanisms regulating neural coding in the developing auditory system. The pursuit of understanding the maturation of neural coding (i.e., how brain cells process sound) is important because deficits in neural coding result in numerous auditory pathologies. These include, but are not limited to, auditory neuropathy and temporal processing disorders. Six active lines of research are currently being pursued to address this research goal.
(1) Neurotrophin signaling in the auditory brainstem
The purpose of this research is to determine molecular mechanisms of normal and irregular neurotrophin function in the auditory system. Neurotrophins are growth factor proteins critical for numerous brain-related tasks. They are abundantly expressed in the nervous systems of all vertebrates. In the auditory system, neurotrophins are important for normal inner ear development and maintenance. Despite their abundance in the brain and established role in the auditory periphery, neurotrophin function in the central auditory pathway remains elusive. The goal of this research is to fill this gap in knowledge. Specifically, we will (1) characterize neurotrophin function in the auditory brainstem, (2) determine the molecular mechanism by which they operate, (3) identify their role in establishing normal structure and function, and (4) delineate functional consequences by genetic modification of their biological properties. The research proposed is essential and timely. A better understanding of neurotrophin function provides a foundation for developing stem cell-based therapies that target novel therapeutic pathways for auditory-related disorders.
(2) Short-term synaptic plasticity in the auditory brainstem
Synapses are the primary point of contact between neurons in the brain. When operating under optimal conditions, they provide the appropriate signaling for neurons to create circuits within the central nervous system. Neural circuits allow the brain to encode the surrounding world and are responsible for the biological mechanisms underlying sensation, perception, and thought. Appropriately, synapses are capable of exhibiting several forms of plasticity, playing important computational roles in neural function, from learning and memory to sensory information processing. Short-term synaptic depression is one form of neural plasticity in the auditory system. Defined as reduced neural responses during high rates of repetitive stimulation, short-term synaptic depression is an excellent example of temporal filtering critical for encoding acoustic cues of sound. Although mechanisms contributing to neural plasticity are well known elsewhere in the brain, this line of research seeks to determine if similar factors give rise to short-term synaptic depression in the developing auditory brainstem.
(3) Glutamate clearance in the auditory brainstem
Glutamate transmission is tightly regulated at mature synapses throughout the brain. Features regulating glutamate transmission include (1) transmitter release at presynaptic terminals, (2) transmitter action on postsynaptic receptors, and (3) transmitter clearance from the synaptic cleft by transporters. Neural and glial transporters clear glutamate from mature auditory synapses, which increases synaptic efficiency, the recycling of transmitter, and the prevention of excitotoxic damage. Less clear is the relationship between glutamate transporters and synaptic response properties in the developing auditory system. The purpose of this line of research is to characterize the developmental profile of glutamate clearance from the synaptic cleft in the auditory brainstem.
(4) Voltage-dependent ion channel function in the auditory brainstem
Auditory brainstem neurons fire synchronized action potentials by “locking” to a specific phase of incoming afferent inputs. This form of neural synchrony depends on specialized time-coding properties found in brainstem neurons and is important for normal auditory temporal processing. Numerous studies have shown that specific ion channels contribute to temporal processing abilities in the mature brainstem but how they regulate such properties in the developing circuit is lacking. This line of research investigates the development of voltage-dependent ion channel function in the regulation of time-coding properties in the auditory brainstem.
(5) Regulation of synaptic glutamate receptors in the auditory brainstem
It is generally believed that events mediated by glutamate receptors are critical for basic neural structure and function in the developing brain. It is not clear how glutamate receptors develop in the auditory brainstem and more importantly, the role they play in the establishment, refinement and maturation of hearing. Experiments aimed at addressing these issues are critical for understanding the ontogeny of events that define auditory neural circuits, and are the focus of my future research direction. Utilizing the “auditory brainstem fate map” as a guide, my future research plan will take advantage of recently developed plasmid systems allowing temporal and spatial control of glutamate receptors’ genetic expression. The goal is to determine the specific role of glutamate receptors in the emergence of physiological specializations, testing the fundamental hypothesis that glutamate receptors are required for the normal maturation of a brainstem circuit responsible for hearing. The objective is to determine how glutamate receptors regulate the development of cellular specialization required for normal hearing, focusing on developmental time periods when synapses form, specializations are established and hearing emerges. As molecular medicine emerges, the translational importance of this type of research is becoming increasingly evident and necessary. Understanding how mechanisms at the molecular-level influence the development of auditory neurons at the cellular, synaptic and network levels will ultimately contribute to the improvement of therapies for individuals deprived of auditory information early in life.
(6) Towards development of clinical procedures to identify hidden hearing loss in humans
Surprisingly, numerous adults who have normal hearing complain of difficulties understanding speech in noisy environments, such as crowed restaurants. Recent animal work has identified the possible source of the problem and researchers have termed the phenomenon “hidden hearing loss”. Standard clinical procedures however are not sensitive enough to detect such problems in humans and the current research project will address this issue by developing tools to identify hidden hearing loss in adults. The research project utilizes perceptual and performance measures of speech in noise difficulties. The Speech, Spatial, and Qualities of Hearing Scale questionnaire (SSQ) is used to measure individuals’ perceptual speech in noise abilities. The modified Quick Speech-in-Noise (mQuickSIN) test is used to measure individuals’ speech in noise performance. The neurodiagnostic auditory brainstem response is conducted to determine if the early component of the response is sensitive enough to objectively measure cochlear synaptopathy in humans. Developing a framework to assess these abilities will be essential for diagnosis, treatment, education, and prevention of the hearing condition.