Darryl B. Neill - US grants

The long-term objective of this project is to contribute to an understanding of the neurobiological bases of the affective disorders of depression and mania. The central idea behind the experiments proposed is that these disorders have behaviorally-described subcomponents, and that these components reflect the activity of anatomically and perhaps chemically distinct parts of the brain. Rather than attempting to create an "animal model" of depression or mania, these experiments are designed to examine brain mechanisms which, in animal tests, appear to reflect processes which in humans are described by terms such as pleasure appreciation, motivation, and cognition. The dysfunctions of these mechanisms in depression are described as anhedonia, psychomotor retardation, and "thinking disorder." These animal experiments rely upon a conceptual scheme developed by the author to assess changes in intracranial self-stimulation following brain manipulations. Specifically brain areas have been identified using the autotitration self-stimulation procedure which seem to control pleasure appreciation and motivation. These studies will further investigate the neural bases of these phenomena and test the ideas developed with the conventional rewards of food and water.

9412703 Justice Much of our understanding of how the brain controls behavior depends upon our ability to accurately describe how cells within the brain communicate with one another. Some general information on this process has been obtained by removing brain tissue and analyzing it chemically, but this provides no information on the dynamics of chemical signalling that actually takes place during episodes of behavior. With this grant, Dr. Justice will refine techniques for measuring the flux of chemical neurotransmitters within the brain during bouts of natural behavior. Dr. Justice's group will concentrate upon the dynamics of the neurotransmitter dopamine. This work will make it possible to describe the chemical dynamics of the dopamine system (and also, to some extent, serotonin and acetylcholine) in a precise way that is directly correlated with organismic behavior. It should greatly stimulate our understanding of normal brain function, the action of several classes of drugs on the brain, and the processes associated with abnormal function of neurotransmitter systems. ***

IBN-9808865 LAY ABSTRACT The idea of a "reward system" in the brain has become popular in neuroscience in the past decade. The most common idea is of a single reward system; the favorite candidate for such a system is the mesoaccurnbens dopamine system, originating in the ventral tegmental area of the midbrain and terminating in the nucleus accumbens of the forebrain. The experiments in the proposal are designed to test the idea of two separate reward systems. One centered in the nucleus accumbens, receives a glutamatergic input from the subiculum and a dopaminergic input from the ventral tegmental area. It is involved in activating the motor programs of "appetitive" behaviors, such as exploration and locomotion. The second, centered in the ventrolateral striatum, receives a glutamatergic input from the sulcal prefrontal cortex and and dopaminergic input from the substantia nigra. It is involved in activating the motor programs of "consummatory" behaviors, particularly feeding. The experiments are largely devoted to behaviorally examining hypothesized roles of glutamatergic, dopaminergic, and GABAergic neurotransmission at the accumbens and ventrolateral striatal nodes of these functionally distinct systems. This will be done by intracerebral microinjections of drugs, which affect specific receptor subtypes of the glutamatergic, dopaminergic, and GABAergic systems. The injections are proposed to modify responding of rats for electrical self-stimulation of ventral subiculum or sulcal prefrontal cortex in ways consistent with known electrophysiological effects of these drugs. These experiments also emphasize the idea that these "reward systems" are actually "behavior systems," wherein dopamine modulates activity in hierarchically organized neural systems of cortical origin. Self-stimulation of subiculum and sulcal prefrontal cortex develops very slowly; the development seems dependent upon the number of stimulations, not the number of responses. Thus it appears more like neural activity- dependent plasticity than response-dependent learning. To examine this phenomenon, the investigators will test the idea that the development of this brain stimulation reward depends on activity at glutamate receptors of the NMDA subtype.