Conte Translational Neuroscience Center on Depression

The Administrative Core is responsible for overseeing all aspects of the Center’s functioning. It coordinates the highly interactive studies across the several Cores and Projects of the Center.
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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. The Core specializes in novel methods of overexpressing or deleting proteins within highly localized regions of adult brain.
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The Behavioral Core provides a broad array of behavioral assays that measure distinct domains of depression- and antidepressant-like responses in rats and mice. A distinguishing feature of the Core is its ongoing efforts to develop depression models in mice with improved etiologic validity.
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The Chromatin and Gene Regulation Core supports gene expression and chromatin profiling, crucial for work in the Center’s Projects. It also assays the effect of chronic stress and antidepressants on chromatin remodeling machinery in the brain’s mood circuits.
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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.
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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 regulates nucleus accumbens neurons to affect complex behavior.
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Project 3 focuses on the ability of feeding peptides, including leptin, ghrelin, melanin concentrating hormine, and orexin (hypocretin), among others, to regulate mood and motivational state. The goal of ongoing studies is to delineate the circuitry of these peptides actions in the hypothalamus and nucleus accumbens and establish the role they play in depression and antidepressant responses.
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Project 4 focuses on the ability of circadian genes in the nucleus accumbens and related brain reward regions to regulate mood. Two particular genes of interest are Clock and NPAS2. Our hypothesis is that these genes act directly within the nucleus accumbens and related brain reward neurons to control circadian variations in mood and motivation.
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Project 5 provides an essential translational component to our Conte Center. It maintains a growing collection of brains obtained from depressed individuals and carefully matched controls. Extensive information is available about these individuals prior to death. Key signaling proteins and genetic regulatory mechanisms, discovered in rodent models in Projects 1-4, are validated in human depression by use of this valuable resource.
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• Krishnan et al., Susceptibility and resistance to social defeat are mediated through molecular adaptations in brain reward regions, Cell 131:391-404, 2007.


• Roybal et al., Mania-like behavior induced by disruption of CLOCK, Proc. Natl. Acad. Sci. USA 104:6406-6411.


• Lutter et al., The orexigenic hormone ghrelin defends against depressive symptoms of chronic stress, Nature Neurosci. 11:752-753, 2008.


• Li et al., TrkB regulates hippocampal neurogenesis and governs sensitivity to antidepressive treatment, Neuron 59:399-412, 2008.


• Krishnan & Nestler, Molecular neurobiology of depression, Nature 455:894-902, 2008.


• Wallace et al., CREB Regulation of nucleus accumbens excitability mediates social isolation-induced behavioral deficits, Nature Neurosci. 12:200-209, 2009.


• Funato et al., Enhanced orexin receptor-2 signaling prevents diet-induced obesity and improves leptin sensitivity, Cell Metab. 9:64-76, 2009.

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.
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