Neural correlates for cortical and subcortical control of vocalization

National Institute Of Neurological Disorders And Stroke

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Abstract

The Neuron-Glia Signaling and Circuits Unit (NGSC) was established in 2019, and its research is directed toward understanding mechanisms underlying the generation and control of voluntary and involuntary motor behaviors in the mammalian CNS at the cellular, circuit, and systems levels of glia and neurons interactions. Our research involves genetic, electrophysiological, imaging, and behavioral approaches applied to rodent nervous systems using both in vitro and in vivo models. The unit's main focus is on neural correlates of cortical and subcortical mechanisms underlying the production of volitional and non-volitional vocalizations. Specifically, the aim of our planned studies is to investigate the synchronous activities of cortical regions controlling vocalization and breathing in rodents. A particular focus in the unit is on stuttering disorder (SD). SD is a neurodevelopmental disorder present in most cultural, racial, ethnic, and economic groups, and it is estimated that more than 1% of the adult population is affected by this disorder. It is now accepted that SD is a highly heritable disorder and that genetic factors can contribute to more than 80% of the cases. Therefore, we have developed the necessary skills and established the experimental setup to use a recently developed mouse model of stuttering. We generated pipelines to analyze animal behavior and vocalization. In addition, we also established a pipeline for histology experiments and analysis. In our planned studies, viral vector-based circuit mapping techniques will identify the cortical regions involved in vocalization. Simultaneous recordings of regional cortical activity and vocalization in freely behaving rodents will be used to investigate the synchronous activity of cortical regions controlling vocalization. Ultimately, a functional copy of the mutated gene will be introduced to a subgroup of cells via viral vectors in mutant animals to rescue the abnormal vocalization. Because all the recently discovered genes linked to familial stuttering are mainly expressed in glial cells, in the short term, we are pursuing a novel hypothesis that the dysfunction of myelinating oligodendrocytes underlies the development of the SD. The involvement of glial cells in developmental stuttering has not been considered previously despite white-matter defects being reported in people who stutter. Over the long term, we will incorporate developing new tools into the research program to investigate the little-understood mechanism of how glial cells control vocalization and other complex motor behaviors. Our research will not only significantly advance our understanding of the neural basis of voluntary movement and human speech, but just as importantly, with the thorough investigation of brain circuit mechanisms controlling vocal production in transgenic animals, will provide opportunities for identifying cell-specific therapeutic agents for motor control disorders, especially stuttering disorder. Over the last year, we have discovered that iron accumulates in the brain of our mutant, stuttering animal. We also found white-matter abnormalities in the brains of the mutant animal. These data strongly suggested that stuttering has a biological underlying mechanism, and glial cells may play a key role in the pathophysiology of this disorder. We also continued our collaborative research with clinicians.