Conte Neuroscience Center
Neural Substrates of Appetitive Behavior in Mood and Motivation
Funded by the National Institute of Mental Health

This new Research Center supports highly integrated and multidisciplinary studies into the molecular and cellular mechanisms of mood regulation. The central hypothesis of this Center is that brain structures that control responses to appetitive stimuli such as food, sex, and drugs of abuse (e.g., nucleus accumbens and hypothalamus) are part of the neural circuitry in the brain that controls mood under normal conditions. A corollary of this hypothesis is that these structures may provide novel targets for antidepressant treatments, and that abnormalities in these structures may even contribute to states of depression.

Administrative Core (Dr. Eric Nestler, Center Director, UT Southwestern)

Transgenic Core (PI, Dr. Eric Nestler, UT Southwestern)
(Includes Subcontract with Dr. Rachael Neve, Harvard University)

The Transgenic Core oversees the generation and efficient use of numerous lines of mutant mice and viral vectors that are required for the Center's Projects. It also supports gene expression profiling, by use of DNA microarray analysis, in the various Projects.

Behavioral Core (PI, Dr. David Self, UT Southwestern)
(Includes Subcontract with Dr. Bill Carlezon, Harvard University)

Project 1 (PI, Dr. Eric Nestler, UT Southwestern)

"Role of CREB in Ventral Striatum in Mood and Motivation"
(Includes Subcontract with Drs. Ronald Duman and Jane Taylor, Yale University)
Project 1 focuses on the role of the transcription factor CREB in the nucleus accumbens in regulating mood and motivational state. The goal of ongoing studies is to characterize the behavioral output of CREB function in the nucleus accumbens and to identify target genes through which CREB produces these effects on mood and motivation.

Project 2 (PI, Dr. Luis Parada, UT Southwestern)

"Role of Neurotrophic Factors in Ventral Striatum in Mood and Motivation"
Project 2 focuses on the ability of neurotrophic factors, particularly BDNF (brain-derived neurotrophic factor), in the nucleus accumbens to regulate mood and motivational state. A related interest is identifying the molecular substrates through which BDNF produces regulates nucleus accumbens neurons to affect complex behavior.

Project 3 (PI, Dr. Masashi Yanagisawa, UT Southwestern)

"Role of Appetitive Peptides in Mood and Motivation"
(Includes Subcontract with Drs. Ronald Duman & Jane Taylor, Yale University)
Project 4 focuses on the ability of particular neuropeptides expressed in the hypothalamus to regulate mood and motivational state. Our work concentrates on three peptides: melanocortin (a-MSH), orexin (hypocretin), and melanin-concentrating hormone (MCH), each of which is known to control feeding behavior. The goal of ongoing studies is to delineate the circuitry of these peptides between the hypothalamus and nucleus accumbens and establish the role they play in the regulation of mood and motivation.

Project 4 (PIs, Drs. Steve McKnight & Joseph Garcia, UT Southwestern)

"Role of Circadian Genes in Appetive Circuits in Mood and Motivation"
Project 4 focuses on the ability of circadian genes in the nucleus accumbens and in hypothalamus to regulate mood. A particular gene of interest is NPAS2. Our hypothesis is that NPAS2-acting within the nucleus accumbens-contributes to circadian variations in mood, psychomotor activity, and affective state, which are often prominently abnormal in depressed patients.

Project 5 (PI, Dr. Tom Wilkie, UT Southwestern)

"Role of RGS Proteins in Appetive Circuits in Mood and Motivation"
Project 5 focuses on the ability of RGS proteins, enriched in nucleus accumbens and hypothalamus, to regulate mood and motivational state. RGS (regulators of G protein signaling) proteins sharpen responses of G protein-coupled receptors. The goal of ongoing studies is to relate understand how these proteins regulate mood and affect.

The neural circuitry of mood. The figure shows a highly simplified summary of a series of neural circuits in the brain that are believed to contribute to the regulation of mood. While most research in the depression field has focused on hippocampus (HP) and cerebral cortex (e.g., prefrontal cortex or PFC), there is the increasing realization that several subcortical structures implicated in reward, fear, and motivation are also critically involved. These include the nucleus accumbens (NAc), amygdala (Amy), and hypothalamus (Hypo). The figure shows only a subset of the many known interconnections among these various brain regions. The figure also shows the innervation of several of these brain regions by monoaminergic neurons. The ventral tegmental area (VTA) provides dopaminergic input to the NAc; inputs to many of the other brain areas are not shown in the figure. Norepinephrine (NE, from the locus coeruleus or LC) and serotonin (5HT from the dorsal raphe and other raphe nuclei) innervate all of the regions shown in the figure. In addition, of particular relevance to this grant, there are strong connections between the hypothalamus and the VTA-NAc pathway.