Jozsef Vigh - US grants

DESCRIPTION (provided by applicant): Retinal inhibitory inputs shape the kinetics of graded, sustained photoreceptor signals as they pass through the retina. At the network level, retinal inhibition mediates the antagonistic center-surround organization of the bipolar cell's receptive field, and in turn, that of the ganglion cell. This retinal circuit underlies contrast detection, a fundamental feature of signal processing by the retina. The goal of the proposed research is to study the distribution, functional characteristics and regulation of inhibitory inputs targeting an identified retinal bipolar cell. I will take advantage of a unique preparation made from the goldfish retina, in which patch-clamp recordings of light evoked membrane currents can be made either from the soma or the axon terminal of an ON-type, Mb bipolar cell in a slice preparation. Stable recordings from these compartments is possible even after axon severing, thus outer or inner retinal inhibitory inputs can be separately studied. Using this preparation I will revisit fundamental questions of visual information processing in the vertebrate retina. My preliminary data show that light evokes different responses at the bipolar cell soma compared to the axon terminal, due to differences in their respective synaptic inputs and voltage-gated channels. The first specific aim will characterize the light-evoked responses of the axon terminal in intact Mb bipolar cells and will study with high time-resolution capacitance measurements how these physiological responses trigger glutamate release. The second specific aim will focus on separating outer and inner retinal inhibition targeting Mb bipolar cells. I will determine how each influence the glutamate output, and separate their contributions to the antagonistic surround response. I recorded light-evoked inhibitory synaptic currents from bipolar axon terminals with severed axons, which represents pure lateral inhibition. I will characterize electrophysiologically and pharmacologically these synaptic inputs at various light adaptation levels, and determine their underlying synaptic circuitry. I have preliminary evidence that NMDA receptors provide enough calcium to trigger GABA release from amacrine cells directly and locally, bypassing voltage-gated calcium channels. The last specific aim will test the hypothesis that NMDA receptor regulation in amacrine cells influences synaptically triggered GABA release and in turn, bipolar cell output. Overall, these experiments will use a combination of capacitance, membrane potential/ current measurements and pharmacological manipulations to determine how the excitatory visual information reaching the ganglion cells is regulated by progressive levels of inhibition as the signal passes through the retinal network. PUBLIC HEALTH RELEVANCE: Images of the environment are translated into neural codes by all vertebrate retinas, including that of humans, in a very similar manner: the retina codes for contours, colors and motion. The proposed research investigates the natural mechanisms underlying contour detection. The results can be used to guide the design of prosthetic vision devices to restore some sight to blind people.

Abstract Chronic pain (CP) is a cardinal feature of a diverse spectrum of diseases including arthritis, migraine, cancer, metabolic disorders, and neuropathies; it afflicts at least 20? 30% of Americans. Opioids remain the pharmacological cornerstone of CP therapy, despite potentially harmful side effects. In addition to the high propensity for developing opioid addiction, insomnia-type sleep problems associated with daytime sleepiness and depression occur in approximately 90% of those receiving long-term opioid treatment to reduce suffering from CP. Importantly, sleep disorder is a serious risk factor for suicidal ideation in CP patients receiving opioid therapy. Therefore, understanding the cellular mechanisms and neuronal circuits contributing to sleep disturbances associated with long-term opioid therapy in those suffering from chronic pain is absolutely critical for determining whether sleep disruption is a modifiable risk factor for suicidal ideation. Melanopsin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs) projecting to the suprachiasmatic nucleus and other sleep-promoting brain centers are the principal conduits responsible for photoentrainment of sleep/wake cycle. We found that ipRGCs express µ-opioid receptors (MORs) and our preliminary data shows that MOR specific agonists strongly attenuate light-evoked firing of ipRGCs. Strong evidence suggests that systemically applied opioids cross the tight blood/retina barrier and reach ipRGCs. The objectives of the current proposal are to analyze how opioids alter light-evoked activity of ipRGCs and to study the behavioral consequences of opioid modulation of ipRGC-mediated photoentrainment of circadian sleep/wake cycles. The results of this project will provide a mechanistic description of a novel neural pathway by which systemically administered opioids alter light-driven behavior, including sleep/wake cycle. Additionally, the data will predict the feasibility of using MOR selective antagonists for focal targeting of MORs expressed by ipRGCs to reduce the severity and inherent comorbidities of sleep disorders in patients receiving long-term opioid therapies.