John A. Dani, Ph.D.
Neuroscience
Nicotinic cholinergic mechanisms underlying disease and tobacco addiction
Dr. Dani's laboratory studies the fundamental mechanisms for processing information
in the brain. The same receptors, neurotransmitters, and synapses that normally
govern all of our moods and behaviors can be misdirected by disease or commandeered
by drugs to bring about addiction. An understanding of basic synaptic mechanisms,
therefore, offers points of entry for methods aimed at relieving or preventing diseases
and drug addiction.
Successful synaptic transmission is a low probability event, but Dr. Dani's research
showed that nicotinic cholinergic activity ensures that important events can emerge
out of the electrical noise of the brain. For example, early in the development
of Alzheimer's dementia cholinergic projections degeneration and the number of nicotinic
receptors decreases. Dr. Dani's work indicated that the diminished capacity of Alzheimer's
patients can arise, in part, from the loss of synaptic fidelity caused by loss of
nicotinic cholinergic functions.
Related work also explained aspects of the addictive power of nicotine obtained
from tobacco. Midbrain dopamine neurons normally help to shape behavior by reinforcing
biologically rewarding actions. Dr. Dani proved that these midbrain dopamine neurons
initially respond vigorously to nicotine before falling quiet and less responsive.
In simple terms, the initial rapid firing of the neurons reinforces the addiction
to nicotine by providing the perception of pleasure, but their later unresponsiveness
causes short-term tolerance to the drug. The research led to a new model for nicotine
addiction that accounts for behavioral effects in terms of the underlying molecular
and cellular events, and suggested a common route for other drugs of addiction.
Dr. Dani's nomination was based on the following publications:
Gray R, Rajan AS, Radcliffe KA, Yakehiro M, Dani JA."
Hippocampal synaptic transmission enhanced by low concentrations of nicotine.
". Nature. 1996 Oct 24;383(6602):713-6.
Pidoplichko VI, DeBiasi M, Williams JT, Dani JA. "
Nicotine activates and desensitizes midbrain dopamine neurons. ". Nature.
1997 Nov 27;390(6658):401-4.