Regulatory Mechanisms of the Posterior Nucleus of Thalamus and Their Contributions to Pain After Spinal Cord Injury

Abstract

For patients suffering from spinal cord injury (SCI), chronic pain is one of the most debilitating aspect of the disorder. As many as 80% of patients with SCI eventually develop chronic pain, typically described as burning, stabbing, and shooting (SCI-Pain). Such pain occurs spontaneously, and diffusely across the body, and are typically combined with enhanced pain responses to both noxious, and normally innocuous, stimuli. While the precise mechanisms underlying such pain has remained elusive, accumulating evidence implicates pathologically disinhibited thalamus. The posterior nucleus of thalamus (PO) is a higher-order somatosensory nucleus thought to be specialized in processing nociceptive information, and prior work from our laboratory has shown that activity in PO is dramatically increased in SCI-Pain. This hyperactivity, in turn, was found to be mediated by pathological suppression of inhibition from the zona incerta (ZI; this forms the incerto-thalamic circuit), an inhibitory nucleus that sends powerful GABAergic afferents to PO and mediates both tonic and feed-forward inhibition. Notably, inactivation of ZI results in immediate and profound hyperalgesia in naive rats, along with a concomitant increased activity of thalamic neurons while direct stimulation of ZI in SCI animals results in immediate reversal of behavioral signs of pain. Direct stimulation of ZI, however, is a highly undesirable clinical solution; instead, we endeavor to discover molecular targets for interventions, and to this end, examine synaptic mechanisms regulating PO activity. In Chapter 1, we develop a biophysically realistic in silico model of the incerto-thalamic circuit, generating several critical predictions. Among them, the most insightful predictions were 1) that spontaneous PO activity is preferentially regulated by GABABR-mediated mechanisms, while evoked activity is preferentially regulated by GABAAR, and 2) that modulation of presynaptic GABA release an effective means to regulate the incerto-thalamic circuit. In Chapter 2, we experimentally test the second prediction that modulation of presynaptic release is an effective regulatory mechanism in PO, and demonstrate several potential mechanisms by which presynaptic regulation occurs. In Chapter 3, we test whether regulatory mechanisms of presynaptic release are altered in SCI-Pain, and show evidence of pathological alterations in regulatory mechanisms of presynaptic release mediated by GABAB receptors.