Lorna W. Role, PhD

Research Summary
Central cholinergic systems, which provide important modulatory control of synaptic excitability, have been strongly implicated in neuropsychiatric diseases including attentional disorders, schizophrenia, depression and Alzheimer's dementia. The Role laboratory studies the generation, plasticity and maintenance of cholinergic and cholinoceptive synapses in the mammalian brain. Recent work tests the hypothesis that a novel class of signaling molecules (products of the neuregulin1 gene) are important in the susceptibility to such diseases because neuregulin1-signaling is essential to the maintenance of normal cholinergic circuits. Recent studies in the Role lab demonstrated that neuregulin1-signaling is bi-directional and that neuregulin1 expressing neurons require such signaling to survive. Current work employs molecular and biochemical approaches to further examine the signaling cascades and target genes activated by NRG1-erb B interactions in both the pre and postsynaptic neurons. The role of neuregulin1 signaling in synaptic function is also being studied with electrophysiological and behavioral analyses of mice genetically altered to express reduced levels of functional neuregulin1 protein. As the neuregulin1 gene has recently been identified as a potential susceptibility locus for schizophrenia, current work should provide important insight as to the role of NRG1 at identifiable synapses and circuits whose function and dysfunction may underlie this and other neuropsychiatric disorders.

1. Bao J, Wolpowitz D, Role LW, Talmage DA. Back signaling by the Nrg-1 intracellular domain. J Cell Biol. 2003 Jun 23;161(6):1133-41.

2. Girod R, Jareb M, Moss J, Role L. Mapping of presynaptic nicotinic acetylcholine receptors using fluorescence imaging of neuritic calcium. J Neurosci Methods. 2003 Jan 30;122(2):109-22.

3. Jo YH, Talmage DA, Role LW. Nicotinic receptor-mediated effects on appetite and food intake. J Neurobiol. 2002 Dec;53(4):618-32.

4. Jo YH, Role LW. Cholinergic modulation of purinergic and GABAergic co-transmission at in vitro hypothalamic synapses. J Neurophysiol. 2002 Nov;88(5):2501-8.

5. Jo YH, Role LW. Coordinate release of ATP and GABA at in vitro synapses of lateral hypothalamic neurons. J Neurosci. 2002 Jun 15;22(12):4794-804.

6. Girod R, Role LW. Long-lasting enhancement of glutamatergic synaptic transmission by acetylcholine contrasts with response adaptation after exposure to low-level nicotine. J Neurosci. 2001 Jul 15;21(14):5182-90.

1. Expression of Neuronal Nicotinic Acetylcholine Receptors
We propose to test the hypothesis that alterations in nAChR-expression and targeting, due to inherited deficits in CRD-Nrg1, disrupt the function of specific limbic synapses. In view of the essential role of such limbic relays in the memory and reinforcement of motivated and goal-directed behaviors, the proposed cellular and molecular analyses would be an important first foray into understanding how Nrg1 deficits and consequent alterations in nAChR signaling could contribute to neuro-psychiatric diseases.
National Institute of Neurological Disorders and Stroke
1/1/1991-6/30/2008

2. Modulation of neuronal acetylcholine receptors
The goal of proposed studies is to ascertain how nicotinic acetylcholine receptors (nAChR) influence synaptic activity at specific CNS relays involved in nociception, attention and arousal. The current proposal: (1) determines the role of specific nAChR subtypes in tuning glutamatergic and GABA-ergic transmission at selected cholinoceptive relays and (2) probes the mechanisms by which the activation and inactivation of native nAChRs may be modulated at intracellular and extracellular sites.
National Institute of Neurological Disorders and Stroke
7/01/1985-12/31/2005

Society for Neuroscience
American College of Neuropsychopharmacology
Associate Editor, Journal of Neurophysiology
Society for Nicotine and Tobacco Research (Associate Editor for Nicotine & Tobacco Research)
MDCN5 Review Committee, NIH

developmental neurobiology, neuregulin, nicotinic receptor, receptor expression, synapse, biological signal transduction, brain electrical activity, central nervous system, cytoskeletal protein, goal oriented behavior, memory, protein signal sequence, electrophysiology, immunocytochemistry, in situ hybridization, laboratory mouse, mixed tissue /cell culture, polymerase chain reaction, transgenic animal, voltage /patch clamp