Maladaptive Plasticity following Spinal Cord Injury

Insults to the brain and spinal cord result not only in debilitating motor, sensory and cognitive deficits, but also in chronic, excruciating and relentless pain that is largely resistant to treatment. In most patients, pain starts weeks or months after the original insult, and includes increased pain with noxious stimulation (hyperalgesia), pain in response to previously innocuous stimuli (allodynia), and spontaneous pain. Spinal cord lesions typically produce particularly painful CPS symptoms, with unremitting pain that can be diffuse, bilateral, and may extend, "below-lesion", to locations caudal to the spinal injury. The delayed expression of CPS and the diffuse localization of painful symptoms suggest that the pathophysiology does not reflect only direct effects at the denervated spinal segments. Rather, these features of CPS strongly suggest the occurrence of maladaptive plasticity in supraspinal structures at which inputs from various body parts converge. The ultimate goal of this application is to identify the factors that are causally responsible for this maladaptive plasticity  following spinal cord injury.

To this end, we adapted a rodent spinal cord injury model of CPS. We demonstrated that rats suffering from CPS have abnormally high neuronal activity in the posterior nucleus of the thalamus (PO). We also demonstrated that the activity of PO, and related thalamic nuclei, is tightly regulated by inhibitory inputs from the zona incerta and the anterior pretectal nucleus. These findings suggest that CPS is associated with maladaptive plasticity in the incerto-thalamic pathway. Based on these exciting new findings, we propose that CPS can result from suppressed inhibition to thalamic nuclei from zona incerta and the anterior pretectal nucleus. We use electrophysiological, behavioral and anatomical approached to test the validity of key predictions that emerge from our overarching hypothesis.

Marijuana, brain oscillation and behavior

Marijuana is by far the most widely used illicit drug among adolescents in the USA, with a lifetime prevalence of more that 40% among 12th graders. Although it remains controversial whether cannabis abuse by adults has long-term health risks, it is now established that cognitive and neurological functions are permanently altered in adolescents using marijuana. However, the mechanisms responsible for this susceptibility are unknown. Our goal is to reveal these mechanisms. We test the overarching hypothesis that the adolescent brain is susceptible to cannabis abuse because of the concurrent and rapid development, at this age, of inhibitory cortical circuits, endocannabinoid signaling and cortical oscillations.

Sensory Inputs and Cortical Control of Movements

The motor cortex of all mammalian species, including humans, contains a gross somatotopic representation of the major divisions of the body, such as hindlimb, forelimb, and face. Within each body part, there are multiple, non-contiguous, partially overlapping representations of individual movement patterns. Thus, the motor cortex is comprised of a distributed network in which specific movements emerge from broad patterns of activity. The neural mechanisms that sculpt voluntary movements from these dynamic networks are unknown. Our goal is to narrow this fundamental gap in our knowledge by identifying mechanisms that dynamically regulate the organization of cortical motor networks during voluntary movements. During movement execution, proprioceptive and tactile sensors provide continual inputs that guide the movements. There is compelling evidence that these somatosensory inputs act upon motor cortical networks to dynamically regulate their outputs. Based on our preliminary findings in rats, and on studies in humans, we propose that somatosensory afferents regulate motor cortical activity in a center-surround manner: Somatosensory stimuli from an activated muscle enhance cortical outputs to that muscle (“center-excitation”), whereas cortical outputs to adjacent muscles are suppressed (“surround- inhibition”).

How do somatosensory afferents differentially impact homotypical versus heterotypical cortical modules? We propose that somatosensory afferents exert a net inhibition of motor cortical circuits, such that only ‘strong’ afferent inputs—occurring in response to converging inputs from thalamus and somatosensory cortex—overcome this inhibition to activate homotypical motor cortical neurons. As a result, inputs arising from a limb in motion converge upon and excite cortical modules that activate that limb, while feed-forward inhibition dominates inputs to neighboring modules. We will test this hypothesis in a series of studies.