Spring 2006 Seminar Series in Neuroscience

Thursday Jan 19, 4-5 pm

Sinerik N. Ayrapetyan, UNESCO Chair in the Life Sciences, Life Sciences Inernational Postgraduate Educational Centre, Yerevan, Armenia

TITLE: “Ionic pumps and exchangers as universal and extra-sensitive sensors in neuromembrane”


Abstract: According to the classic “membrane theory” signals can modulate membrane excitability by activation or inactivation of ionic channels, which leads to cell membrane depolarisation or hyperpolarization. In order to activate the potential gating or receptor activating channels in membrane it is necessary to change it by a couple of millivolts or to affect it by agonists’ concentrations at more than 10-8 M, accordingly. However during the last two decades the increasing body of data is accumulated on the modulation effect of extraweak physical and chemical signals on neuronal functional activity, the intensity of which is far from the threshold of potential- and agonist activated ionic channels. On the basis of previous study of our group it was suggested that the currier driving ionic transporting systems like as pumps and cyclic nucleotides-dependent ionic exchangers could be considered as a potential candidates for extrasensitive and universal sensors in neuromembrane through which the biological effects of extra weak physical and chemical signals are realized. These ionic-transporting systems are able to effectively modulate membrane functional activity by various potential-independent pathways, namely by changing both the number of functionally active protein molecules (enzymes, chemoreceptors and ionic channels) in the membrane, as well as by the individual activity of these proteins. From these point the biological effect of electromagnetic fields, mechanical vibration, background radiation, extremely low concentration of biological substances and osmotic stress could be explained.

Thursday Jan 26, 4-5 pm Jeremy Seamans, Medical University of South Carolina

TITLE: "Dopamine modulation of working memory mechanisms in prefrontal cortex"

Abstract: The prefrontal cortex (PFC) is involved in the ability to use previously acquired information to guide forthcoming action. This process, termed working memory is thought to be mediated by recurrently connected assemblies of neurons that actively maintain and manipulate mnemonic information. A description of the detailed biophysical processes that might underlie such active retention mechanisms will be presented. Both working memory and the cellular mechanisms that underlie it, are strongly modulated by a dopamine input originating in the midbrain. Single unit recordings in awake primates suggest that midbrain DA neurons encode fast “prediction errors” about rewards that might serve as a learning signal. However, we have argued that dopamine does not have the properties consistent with fast and accurate transmission of prediction error signals. Rather, we suggest that glutamate is co-released by dopamine neurons and it is this glutamate that transmits temporally precise information about reward to the PFC. In contrast, the co-release of dopamine subtly modulates a variety of intrinsic and synaptic currents to bias network dynamics. This biasing is expressed in different ways at different dopamine concentrations and through different dopamine receptors. Through co-release the ascending dopamine pathway provides both an information rich glutamate signal and an information-poor dopamine signal that alters the dynamics of recurrently active networks encoding working memory in PFC over prolonged periods.
Tuesday Feb14, 4-5 pm

Raz Yirmiya, The Hebrew University of Jerusalem, Israel


TITLE: “The role of proinflammatory cytokines in emotional and cognitive processes”

Abstract: This seminar describe the neurobehavioral implications of immune-to-brain communication, focusing on the role of brain cytokines in mediating illness-associated emotional and cognitive impairments. Studies with human volunteers will be reported, in which cytokine-mediated anorexia, depressed mood, anxiety and memory alterations were demonstrated following vaccination with live-attenuated Rubella virus, endotoxin administration or post-surgery. Parallel studies in rodents showed that cytokines induce depressive-like behavioral and neuroendocrine symptoms, which were attenuated by chronic treatment with various anti-inflammatory or antidepressant drugs. Furthermore, evidence will be presented that brain cytokines play a neuromodulatory role also under normal conditions. In particular, our data suggests that under normal (physiological) conditions, brain cytokines modulate various neurobehavioral processes, such as the responsiveness to stress, pain perception, learning, memory and plasticity within the hippocampus, whereas deviations from the normal balance in brain cytokines, particularly interleukin-1 (i.e., induced by genetic impairment in signaling or over-production during various disease conditions), produce disturbances in these processes.

Tuesday Feb 28, 4-5 pm

Lorraine Ramig & Cynthia Fox, SLHS, CU-Boulder

TITLE: “The Science and Practice of Exercise-based Therapies in Parkinson disease.”

Abstract: Recent advances in neuroscience emphasize the need for human studies of exercise-based interventions in Parkinson disease (PD) that promote activity-dependent neuroplasticity. The potential disease modifying effects of exercise in animal models of PD, and key aspects of exercise that contribute to neuroplasticity, compel the need for well-defined exercise-based behavioral speech and physical treatments in humans with PD. This presentation will (a) present the evidence for disease modifying effects of exercise in animal models of PD (e.g., slowing disease progression), (b) highlight elements of exercise that drive neuroplasticity, and (c) discuss the potential impact of exercise-based speech and physical therapies in humans with PD. In particular, we will focus on a Parkinson-specific intervention (Training Big and Loud) which directly addresses the primary deficit of inadequate muscle activation resulting in slow movement in people with Parkinson disease. This novel approach uses a single motor control parameter – amplitude – to simultaneously treat deficits across different motor systems (speech, reaching, gait).

Tuesday Mar 14, 4-5 pm Zhigang He, Harvard, Children's Hospital Boston, Dept Neurology
TITLE: “Mechanisms of axon degeneration and regeneration”

Abstract: We are interested in understanding the cellular and molecular mechanisms involved in axon regeneration and degeneration, in a hope to provide insights into designing strategies for promoting axon regeneration after brain and spinal cord injury and protecting axon degeneration in neurodegenerative diseases.
AXON DEGENERATION: Axon degeneration occurs frequently in physiological neuronal remodeling and pathological neurodegeneration. By using Wallerian degeneration as a model, we found that intracellular NAD levels represent a critical determinant for maintaining neuronal integrity. Our current studies include to define the mechanisms that control neuronal NAD levels and to utilize these principals to design strategies for axon protection in the models of neurodegenerative diseases, such as multiple sclerosis, and Amyotrophic Lateral Sclerosis.
AXON REGENERATION: It has been proposed that failure of successful axon regeneration in the CNS may be attributed to the intrinsic regenerative incompetence of mature neurons and the environment encountered by injured axons. However, it is unclear how and to what extent these different mechanisms act in restricting axon regeneration in vivo. To address these questions, we have been focused on elucidating the mechanisms of environmental inhibitory influences. Previous studies indicate that the inhibitory activity is principally associated with components of CNS myelin and molecules in the glial scar at the lesion site. Recent studies from our laboratory and others suggested that three myelin proteins, myelin-associated glycoprotein (MAG), Nogo-A and oligodendrocyte myelin glycoprotein (OMgp), collectively account for the majority of the inhibitory activity in CNS myelin. The inhibitory activity of MAG, OMgp and the extracellular domain of Nogo-A might be mediated by receptor complexes with Nogo receptor or its functional homologues and at least two co-receptors, p75/TROY and Lingo-1. Our systematic small molecule screen also results in identification of several intracellular molecules required for the inhibitory activities of both myelin inhibitors and glial scar components. Our current studies are aimed to examine the effects of blocking these inhibitory activities on promoting axon regeneration and synaptic reconnection in different injury models. We are also actively studying the cellular and molecular mechanisms underlying the intrinsic regenerative capacity of mature neurons.
Tuesday April 11, 4-5 pm Michael Browning, UCHSC, Fitzsimmons campus

TITLE: "Aging, Alcohol, Memory & Molecules"

Abstract: The past decade has seen an explosive growth in our understanding of the molecular mechanisms that underlie brain function. Dr. Browning will discuss this progress. He will focus on his and other group’s studies of a remarkable protein that acts as a coincidence detector in the brain. This protein is able to detect the coincidence of two neuronal events in a manner somewhat homologous to Pavlov’s dog who detected the coincidence of meat powder and a bell. Once this protein detects a coincidence, it turns on a mechanism thought to be a basic building block of memory. Dr. Browning will discuss how this protein works and how it is inhibited by alcohol and impaired during normal aging.
Tuesday April 25, 4-5 pm

Melissa Mahoney, Chem Engineering, CU Boulder

TITLE: “Polymer Materials for Regeneration in the Central Nervous System”

Abstract:Transplantation of neural progenitor cells is a powerful approach towards restoring neural cell function following injury and during disease. Grafted cell survival, differentiation, and synaptic integration are factors that determine the overall success of transplantation therapies. Administration of neurotrophic proteins can enhance these cell functions; however, targeted delivery of proteins to transplanted cells is difficult to achieve. Most proteins do not efficiently permeate the blood brain barrier, they have a short half-life and a limited penetration distance in tissue, and undesirable side-effects when delivered to non-targeted regions of tissue. Polymer-based protein and cell delivery systems can be designed to selectively target therapeutic proteins to transplanted cells. The effectiveness of localized neurotrophin delivery via polymeric controlled release devices was tested in the CNS of adult rats by implanting small neurotrophin (nerve growth factor, NGF) releasing polymer pellets (~ 1 mm in diameter) at controlled distances from a target site containing transplanted nervous tissue. NGF-releasing implants placed within 1-2 mm of the treatment site enhanced the biological activity of cellular targets whereas identical implants placed ~3 mm from the target site produced no beneficial effect. Effectiveness of NGF therapy required millimeter-scale positioning of the neurotrophin source and correlated with the spatial pattern of NGF concentration in the tissue. Since NGF penetration through tissue is restricted to a localized region that is considerably smaller than a typical anatomical structure in the human brain (~1 cm), drug delivery technologies facilitating the precise spatial positioning of multiple sources of therapeutic agents throughout tissue structures must be developed. One approach is to assemble protein releasing poly-lactic-glycolic-acid microspheres (~1 µm in diameter) throughout transplantable aggregates of cells (~150 µm in diameter). When assembled in this manner, NGF released from distributed microparticles increased the biological activity of nervous tissue over the course of 3 weeks in vivo. Alternately, cells and sources of protein can be assembled locally together within three-dimensional degradable polymer hydrogels. When encapsulated within photopolymerizable polyethylene glycol based hydrogels neural cells survive, proliferate, and differentiate over the course of 15-30 days. By changing the degradation rate of the polymer network, the time-scale over which neural cells extend processes throughout the hydrogel could be tuned. Results from these studies indicate that polymer-based protein and cell delivery systems can be designed to selectively target therapeutic proteins to transplanted cells and support neural cell function. These strategies may be useful clinically, for the treatment of diseases of the CNS including Alzheimer’s Disease, Huntington’s Disease and Parkinson’s Disease, and in the treatment of chronic pain.