Date of Degree

2-2020

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biology

Advisor

John H. Martin

Committee Members

Andreas Kottmann

Joshua Brumberg

Yutaka Yoshida

George Mentis

Subject Categories

Neuroscience and Neurobiology

Keywords

Cortico-motoneuronal connection, PlexinA1/Semaphorin6d, motoneuron

Abstract

Higher primates, apes, and humans have cortico-motoneuronal (CM) connections between the motor cortical areas and spinal motoneurons. The CM system is thought to confer individuated finger movements and other aspects of skilled movement control; in part, by the selective CM cell they recruit, leading to fractionated patterns of muscle activity. Although CM connections have been examined using several approaches in monkeys, the presence and properties of the CM connection was elucidated in all the species using the technique of stimulus-triggered averaging (StTA). The electrophysiological signature for the CM response is short-latency EMG facilitation (post-stimulus facilitation; PStF) in individual muscles, followed by EMG suppression (post-stimulus suppression; PStS). Intracellular recordings studies in monkeys show that PStF and PStS are associated with monosynaptic motoneuronal depolarization followed by oligosynaptic hyperpolarization, respectively, likely reflect an EPSP-IPSP sequence. Besides the primate, in no other species has the CM connection been studied as extensively. Moreover, CM connections have not been shown to be present in other species.

In the mouse, I show that conditional forebrain deletion of the gene for the guidance molecule PlexinA1 results in increases in CM connections, compared with control mice. The PlexinA1 knock out (KO) mouse thus provides a unique opportunity to study the CM connection in a model where the morphological and electrophysiological characteristics can be examined rigorously. To assay CM connections, I examine EMG multi-unit and single motor-unit facilitation and suppression of responses evoked by motor cortex or corticospinal tract stimulation. KO mice have significantly shorter facilitation latencies, more phasic facilitation, and longer duration EMG suppression than controls. Using high-resolution confocal microscopy, I show for the first time glutamatergic CM contacts on motoneuron cell bodies and proximal dendrites and that these are strongly associated with GAD65+ presynaptic boutons. Although I also show that control mice have a small number of glutamatergic CM contacts, they are less frequently associated with GAD65+ presynaptic boutons; and those that are present, are significantly smaller than those in the KO mice. The presence of large GAD65+ boutons on CM contacts in KO mice may contribute to response suppression through presynaptic inhibition. Direct spinal presynaptic inhibition on CM terminals may mediate sculpting of M1 output (via last-order GABAergic interneuron axo-axonic synapses) by truncating the PStF and lengthening the duration of PStS, similar to lateral inhibition in sensory system.

To summarize and conclude, using a novel mouse model of CM connections my findings demonstrate, for the first time, glutamatergic CM contacts that are consistently paired with GAD65+ presynaptic boutons. These morphological findings parallel electrophysiological findings that motor cortex or CST spinal stimulation evokes short-latency phasic facilitation of single motor units that is followed by robust response suppression. Together, the phasic facilitation-suppression sequence provides novel evidence supporting an important role for CM connections in a motor cortex-to-spinal cord circuit for enhanced muscle response specificity. Short-latency phasic responses in the PlexA1 KO mouse that are tightly linked to robust EMG suppression is a way to ensure the occurrence of temporally fractionated motor unit responses evoked by motor cortex signals. Furthermore, the logical difference between the presence of the CM system in the KO mouse, which also includes corticospinal tract connections with spinal interneurons, and control mice, which do not have a functional CM system, but instead, only CST connections with spinal premotor interneurons, uniquely informs the function of CM connections in primates and humans.

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