Neural correlates for cortical and subcortical control of vocalization

National Institute Of Neurological Disorders And Stroke

Investigators

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Abstract

The Neuron-Glia Signaling and Circuits Unit (NGSC), established in 2019, focuses on understanding how voluntary and involuntary motor behaviors are generated and controlled in the mammalian CNS at cellular, circuit, and system levels, emphasizing glia and neuron interactions. Our research uses genetic, electrophysiological, imaging, and behavioral methods applied to rodent nervous systems in both in vitro and in vivo models. The main goal is to explore neural mechanisms in cortical and subcortical regions involved in producing vocalizations, both voluntary and involuntary. Specifically, our planned studies aim to investigate synchronized activity between cortical areas that control vocalization and breathing in rodents. A key focus is on stuttering disorder (SD), a neurodevelopmental condition affecting more than 1% of adults across various cultural, racial, ethnic, and economic groups. It is now widely recognized that SD is highly heritable, with genetic factors contributing over 80% of cases. To this end, we have developed expertise and set up experiments using a recently created mouse model of stuttering. We have established pipelines for analyzing animal behavior and vocalizations, as well as histology experiments and analysis. Our planned studies will employ viral vector-based circuit mapping to identify cortical regions involved in vocalization, along with simultaneous recordings of cortical activity and vocal output in freely moving rodents to study the synchronized activity of these regions. Ultimately, we aim to introduce a functional copy of the mutated gene into a subset of cells via viral vectors to rescue abnormal vocalization in mutant animals. Since recent discoveries link most genes associated with familial stuttering to glial cell expression, we are exploring a novel hypothesis that dysfunction of myelinating oligodendrocytes may underlie SD development. Although the role of glial cells in developmental stuttering has not been previously considered, white-matter abnormalities have been reported in people who stutter. Long-term, we aim to develop new tools to investigate how glial cells influence vocalization and complex motor behaviors. Over the past year, our efforts to elucidate the mechanism of iron accumulation in the brains of mutant animals have continued. Based on these preclinical investigations, we proposed employing an iron chelator as a potential treatment for stuttering. Additionally, we started a new line of experiments to study sleep homeostasis in mutant versus control animals. Moreover, we identified developmental white matter abnormalities in the brains of the mutant animals. Finally, we started an important project: performing a preclinical gene therapy experiment. Although most of these experiments are in early phases, as we plan to continue them in my new lab at Stony Brook University, collectively, our findings strongly suggest that stuttering has a biological basis, with glial cells potentially playing a crucial role in the disorder's pathophysiology.