BRAIN Publication Roundup – March 2019

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Contributions of the basal ganglia to speech production … High-speed volumetric microscopy of freely-moving Drosophila larvae … Identifying functional neuron subclasses with specificity …

Differences in timing and direction of basal ganglia firing accompany speech production

Translating thought into spoken words is one of the most complicated human motor behaviors, and the basal ganglia in the brain play a role in control of most complex movements. Impairments in speech production due to neurodegenerative disorders (e.g., Parkinson’s disease) and speech disorders, such as stuttering, have been linked to malfunctioning of the basal ganglia. However, no studies have yet explored in detail how the basal ganglia, which include the subthalamic nucleus (STN) neurons, contribute to human speech. To identify how the basal ganglia regulate speech, Dr. R. Mark Richardson and colleagues at the University of Pittsburgh established a protocol to record from STN neurons while patients performed a speech task. Twelve patients undergoing deep brain stimulation surgery for Parkinson’s disease read aloud word cues presented on a computer screen. A high percentage of the STN neurons in these patients changed activity during the speech production process. Some neurons decreased activity, mostly during early cognitive stages of speech, which involved processing the word cue. In contrast, other neurons strongly increased activity, often during the later stages, when the vocal cords are activated to produce speech output. These findings are the first to define a role for STN neurons in speech production, suggesting that separate STN populations with distinct functions act at different stages of speech. This elegant, pioneering work done by Dr. Richardson’s team establishes a foundation for advancing studies of basal ganglia function in human speech.

STN neuronal firing rate varies in timing and direction during the experimental task. These plots show increases (top, in red), decreases (middle, in blue), or mixed responses (bottom) in STN neuronal firing relative to the onset of the task cue presentation (indicated by “c”) or end of speech output (indicated by “e”) during the task. Decreases in STN firing were more closely associated with cue presentation, whereas increases in STN firing were more closely associated with motor speech output.
High-speed volumetric microscopy shows movement dynamics of Drosophila larvae

Careful coordination and awareness of body position is required in order to move and act in the world, and proprioceptors provide feedback about body position that is essential for this coordinated movement. Learning how body position is dynamically encoded is key to understanding how sensory activity is transformed into action, but studying proprioceptors dynamics in freely moving animals has been very difficult. Here, Dr. Elizabeth Hillman and colleagues at Columbia University utilized their previously-developed multispectral, high-speed, volumetric swept confocally aligned planar excitation (SCAPE) microscope to characterize proprioceptor system dynamics in live, freely moving Drosophila larvae. This approach allowed the group to examine real-time spatiotemporal and functional dynamics in Drosophila proprioceptors as the larvae contracted and extended segments during crawling, as well as during exploratory head movements. Most proprioceptive neurons increased activity during segment contraction, with different proprioceptors exhibiting sequential activity to create a continuum of feedback during forward crawling. Timing of activity was associated with distinct dendrite morphologies and movement dynamics, suggesting that proprioceptors monitor different features of segment deformation. This research suggests that there is a set of proprioceptors that provides sensory feedback to the diverse movements of the larval body. By investigating how a range of proprioceptive neurons can encode forward locomotion and exploration behavior during naturalistic movement, this finding holds important implications for models of sensory feedback, including understanding the neural mechanisms underlying movement in freely behaving animals.

High-speed, volumetric SCAPE microscopy was used to capture the activity of proprioceptive neurons inside freely moving Drosophila larvae. The high-resolution imaging approach allowed researchers to view a continuum of sensory feedback from proprioceptive neurons during forward crawling and exploratory head movements. Central structure (in pink) is the larva’s ventral nerve cord.
Selective targeting of functional circuits in rodent and primate hippocampus using viral vectors

Multiple approaches have been taken to link the neurons in circuits to behavior. Research with transgenic model organisms allows precision in interrogating specific cell populations, but these models are costly and time-consuming to produce. Viral vectors are simpler to generate and easy to deploy, but often broadly affect cells in the brain. Here, Dr. Boris Zemelman and colleagues achieved specificity with viral vector approaches. They developed combinatorial strategies using viral promoters for accessing specific neuronal subclasses in mouse and primate hippocampus. Their novel method leveraged broad access, before using interdependent viruses to target specific cell subpopulations. The group first used an intersectional approach, using viral vectors to label two promoters for subclasses of GABAergic neurons. After identifying these populations, they then used viruses to restrict access to specific excitatory and inhibitory subpopulations, by effectively subtracting the expression patterns of one promoter from the other. By replicating this result across multiple species, the researchers found that when the regions demonstrating the same pattern of gene expression were conserved across species, functional circuit specificity was conserved as well. This result carries important potential for future investigations. By using combinatorial methods to refine genetic targeting, a method for brain-wide study of functionally significant cell populations – without dependence on transgenic models – may be possible.

Hippocampal excitatory neurons (bottom) were targeted and isolated using a set difference strategy – subtracting inhibitory interneurons from all other neurons.