Faculty Bibliography

Recently, we had the opportunity to review the progress that has been made in the field of cardiovascular disease over the past century in The FASEB Journal and, based on those thoughts, in this article we predict what may transpire inthis 'century of biology'. Although it is true that 'the best way to predict the future is to invent it', we gaze through the prism of modern biomolecular science for a vision of a possible future and see cardiology practice that is transformed. In the second half of the 20th century, we developed a more fundamental understanding of atherosclerotic vascular disorders and invented life-saving therapeutics. We saw a similar development of mechanism-based pharmacotherapy to address heart failure, primarily through agents that antagonize the excessive concentration of circulating neurohumoral agents. Now we are in the midst of the device era, from stents to cardiac resynchronization therapy to transcatheter valves.The next wave of treatments will build on an increasingly sophisticated understanding of the molecular determinants of cardiovascular disorders and engineering feats that are barely perceptible now. Genomic profiling, molecular prescriptions for prevention and personalized therapeutics, regenerative medicine and the new field of cardiovascular tissue bioengineering will transform cardiovascular medicine. If the human species can survive threats of our own doing, such as the related epidemics of obesity and diabetes, by the turn of the next century, treatment of cardiovascular disease will not resemble the present in almost any way. Touch Medical Media 2012

Dopamine transmission is critical for exploratory motor behaviour. A key regulator is acetylcholine; forebrain acetylcholine regulates striatal dopamine release, whereas brainstem cholinergic inputs regulate the transition of dopamine neurons from tonic to burst firing modes. How these sources of cholinergic activity combine to control dopamine efflux and exploratory motor behaviour is unclear. Here we show that mice lacking total forebrain acetylcholine exhibit enhanced frequency-dependent striatal dopamine release and are hyperactive in a novel environment, whereas mice lacking rostral brainstem acetylcholine are hypoactive. Exploratory motor behaviour is normalized by the removal of both cholinergic sources. Involvement of dopamine in the exploratory motor phenotypes observed in these mutants is indicated by their altered sensitivity to the dopamine D2 receptor antagonist raclopride. These results support a model in which forebrain and brainstem cholinergic systems act in tandem to regulate striatal dopamine signalling for proper control of motor activity.