Control of Sensory Axon Conduction by Primary Afferent Depolarization
Creators: Metz, Krista
Publisher: name: University of Alberta Library
Year: 2022

<p>Ia afferents conveying proprioceptive information to the spinal cord, and the regulation of action potential conduction along these afferents, are vital for motor function. After injury to the central nervous system (CNS), hyperexcitability in proprioceptive and other afferent pathways to the motoneuron is partly involved in the development of spasticity and motor dysfunction; however, the mechanisms are poorly understood. In this thesis, we explore how spinal networks involving gamma-aminobutyric acid (GABA) control conduction along Ia afferents before and after spinal cord injury (SCI). Sensory and cortical pathways activate GABAergic interneurons with axo-axonic contacts on Ia afferents that activate GABAA receptors near proximal branch points. Activation of GABAA receptors on Ia afferents results in an efflux of chloride ions and a depolarization of the afferent (primary afferent depolarization, PAD). PAD brings the afferent membrane closer to threshold, facilitating action potential conduction across branch points where failure is likely to occur, ultimately increasing the size of excitatory postsynaptic potentials (EPSPs) in the motoneuron. In chapter 2 we sought evidence of facilitation in the conduction of Ia afferents involved in the human H-reflex by inputs known to activate PAD in animals. Cutaneous afferent and corticospinal tract (CST) inputs produced H-reflex facilitation without direct facilitatory effects on the test motoneurons. The profile of H-reflex facilitation was akin to animal experiments showing GABAA receptor activation on Ia afferents facilitates monosynaptic reflexes (MSR)/EPSPs with a time course similar to PAD recorded from the Ia afferent (100-200 ms). We also observed longer-lasting (10’s of seconds) H-reflex facilitation when trains of cutaneous input were used to condition the H-reflex. The long-lasting H-reflex facilitation was similar to animal experiments showing that trains of cutaneous stimulation produced a long-lasting tonic PAD and facilitation of MSRs/EPSPs, likely via GABA spillover activating extrasynaptic GABAA receptors. After SCI in humans, the same trains of cutaneous stimulation to putatively evoke tonic PAD did not produce long-lasting H-reflex facilitation like it had in controls (chapter 4). <br>
In addition to the facilitatory effects of PAD on Ia afferent conduction and H-reflexes, PAD can also produce inhibition of H-reflexes. PAD evoked in the proximal Ia afferent is often strong enough to reach sodium spiking threshold, producing action potentials that travel orthodromically to the Ia afferent terminal as evidenced by evoking a monosynaptic EPSPs in the motoneuron. Following these PAD-evoked spikes, Ia activation of the motoneuron is inhibited for a long period of time (up to 2500 ms) due to post-activation depression. In light of PAD-evoked spikes causing post-activation depression, in chapter 3 we re-examined experiments showing that extensor H-reflexes are inhibited by a prior activation of flexor afferents that were previously, and likely incorrectly, attributed to PAD-mediated presynaptic inhibition at the Ia afferent terminal. Similar to previous experiments, we found that antagonist flexor afferent conditioning, to putatively evoke PAD, inhibited the soleus H-reflex. The flexor afferent conditioning stimulation also evoked an early excitatory response in the soleus EMG, a response that has been noted in previous studies but largely ignored. A larger early reflex response in the soleus EMG from the flexor afferent conditioning was associated with larger H-reflex inhibition. Moreover, the profile of H-reflex inhibition from flexor afferent conditioning was also similar to the profile of H-reflex suppression from repetitive activations of the same H-reflex, a test of post-activation depression called rate dependent depression (RDD). Therefore, we propose that H-reflex inhibition from flexor afferent conditioning is due to post-activation depression and not PAD-mediated presynaptic inhibition of the Ia afferent terminal as speculated in many previous studies. In participants with SCI, the amount of H-reflex suppression from flexor afferent conditioning and from RDD were similarly reduced compared to controls, likely mediated by a reduced post-activation depression whose mechanism requires further study (chapter 4).</p>