Date of Degree

6-2021

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biology

Advisor

John H. Martin

Committee Members

Jonathan Levitt

Marom Bikson

Jason Carmel

Simon Giszter

Subject Categories

Neuroscience and Neurobiology | Other Rehabilitation and Therapy | Systems Neuroscience | Translational Medical Research

Keywords

corticospinal system, intermittent thetaburst stimulation, neural repair, neuromodulation, motor function.

Abstract

The motor cortex and corticospinal tract are necessary for producing skilled movements. I use intermittent theta burst stimulation (iTBS), a high-frequency stimulation protocol known to promote neural plasticity, as a tool to characterize short- and long-term plasticity of the CS system.

Although it is well known that activity-dependent motor cortex (MCX) plasticity produces long-term potentiation (LTP) of local cortical circuits, leading to enhanced motor evoked potentials (MEPs), the effects produced by the corticospinal (CS) projection on spinal cord neurons have not yet been thoroughly studied. In Chapter 2, I determined if the CS tract (CST) is capable of producing LTP in the spinal cord. I used multichannel recording of motor-evoked intraspinal excitatory local field potentials (LFPs) in adult rats after iTBS. I stimulated the wrist area of MCX and recorded at the 6th cervical spinal cord segment. A single 3-minute block of MCX iTBS potentiated the monosynaptic excitatory LFP recorded within the CST termination field in the dorsal horn and intermediate zone, for at least 15 minutes after stimulation. Ventrolaterally in the spinal cord gray matter, iTBS potentiated a late negative LFP that was localized to the wrist muscle motor pool. Response enhancement after a single block of iTBS in MCX thus produces LTP of the evoked monosynaptic and oligosynaptic CST responses. The time course of this LTP has the properties of early-LTP, the first phase of LTP which enables an increase in synaptic strength and is known to play an important role in memory function in the hippocampus, amygdala and other cortical brain structures in mammals. Pharmacological blockade of iTBS-induced LTP in MCX using MK801, an NMDA receptor antagonist, failed to prevent spinal LFP potentiation, showing that spinal plasticity can be induced in an activity-dependent manner without MCX LTP. Pyramidal tract iTBS, which preferentially activates the CST, also produced significant spinal LTP, indicating the capacity for plasticity at the CST-spinal neuron synapse. My findings show CST monosynaptic response plasticity in spinal interneurons and demonstrate that spinal premotor circuits are capable of modifying the way descending MCX signals are processed in an activity-dependent manner. These findings are important for understanding the key structures for motor learning and motor recovery after injury and suggest that spinal circuits, as the implementer of supraspinal muscle control signals, are capable of further modifying the actions of the MCX in an activity-dependent manner.

I next determined if early-LTP can be converted, with repeated and chronic iTBS into the late phase of long-term potentiation (Late- or L-LTP), which allows enduring modification of the structure and function of neuronal connectivity (Chapter 3). I determined if there is day-to-day carryover of MEP augmentation produced by iTBS and elucidated the anatomical and molecular underpinnings of this robust corticospinal system plasticity.

For these experiments, I recorded chronically from the extensor carpi radialis muscle in naïve rats and examined MCX-evoked motor responses (MEPs) as a measure of CS system plasticity. I promoted MEP plasticity by MCX iTBS for varying times daily and for one or more days. I found that one block (3 mins) of iTBS produced strong EMG potentiation lasting for up to 35 min; consistent with early-LTP which is independent of protein synthesis. Five contiguous blocks of iTBS during a single session (27 mins), prolonged EMG potentiation for 24-48 hours and resulted in upregulation of signaling of mammalian target of rapamycin (mTOR), a key regulator of neuronal translational capacity. These changes are a signature of a stable and long-lasting LTP (late-LTP). In addition, iTBS-induced L-LTP was enhanced or blocked bidirectionally by modulating cortical activity chemogenetically using engineered G-protein coupled excitatory and inhibitory receptors (GPCR); Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), respectively. We next assayed CST structural changes that could support the enhanced motor responses. Chronic stimulation promotes a significant increase in CST axon length in the contralateral spinal cord intermediate zone. 3D reconstruction of CST synapses, defined by the co-expression of the pre- and post-synaptic markers VGlut1 and PSD-95 in labeled CST axons, revealed a significant increase in the total number and volume of PSD-95 clusters. Intrinsic presynaptic bouton characteristics did not change; however, the number of presynaptic sites increased in proportion to the increase in CST axon length.

Taken together, my findings show early-LTP of the CST EPSP in the dorsal horn and intermediate zone of the spinal cord that leads to early-LTP of the CST oligosynaptic response in the motor pools and wrist muscle. A prolonged potentiation of MEP, or late-LTP, occurs after repeated blocks of iTBS. The transition from early- to late-LTP is accompanied by upregulation of known L-LTP cortical plasticity markers. Remarkably, delivery of iTBS daily for 10 days leads to the emergence of persistent MEP augmentation. We show that iTBS can be used both to lay the groundwork for a brief to an enduring form of MEP enhancement and CST structural changes underlying the stronger and more effective of synaptic transmission of the CST. The maintained increase in MEP magnitude we observe with L-LTP and CST synaptic structural changes may be viewed as the neurophysiological surrogate for LTP-dependent processes more generally, such as motor learning within the CS motor systems.

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