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Molecules & Brains, led by Vincent Rehder (Biology), is concerned with the development and the application of molecular tools and probes to address fundamental questions of the development and function of the nervous system

The Molecules and Brains Research Group have started a series of noon meetings in which faculty members will be giving 10 minute presentations introducing their research and highlight possibilities for future collaborations. All interested faculty, students, and post-docs are invited to participate in this event and share in the science and the opportunities offered by the Molecules and Brains Research Group. Upcoming group meetings

Principle Investigators: Dr. Charles Derby / Dr. Donald Edwards
Title: The role of serotonin in neurogenesis in the crayfish brain

Abstract:
In collaboration with Drs. Deb Baro and Maria Sosa, Ms. Nadia Spitzer in the Edwards lab has identified and obtained antibodies for a 5-HT1-like receptor, 5-HT 1Pro , in the crayfish Procambarus clarkii (Sosa et al., 2004).  Ms. Spitzer has found that in crayfish, 5-HT 1Pro labels most if not all of two populations of olfactory interneurons in clusters 9 and 10 of the crayfish brain, and neuronal processes in each glomerulus of the olfactory and accessory lobes, two major olfactory processing areas of the brain.  Work by Manfred Schmidt (1999) and C.K. Song and Laurel Johnstone has shown that neurogenesis occurs in the brains of postembryonic crayfish among neurons in clusters 9 and 10.  Serotonin modulates neurogenesis in the mammalian brain and in the lobster, where serotonin depletion disturbs the normal growth patterns of olfactory projection neurons from cluster 10 (Benton and Beltz, 2001; Sullivan et al., 2000).

Specific Aims: 

1. To determine the anatomical relationship among neurons in clusters 9 and 10 of the brains of adult crayfish, the subset of those that express BrdU labelling, the subset that express 5-HT 1Pro serotonin receptor labeling, and nearby serotonergic processes.
2. To determine the effect of 5-HT 1Pro serotonin receptor blockage on neurogenesis in clusters 9 and 10 of the adult crayfish brain.

Principle Investigators: Kathry Grant / Dr. Susmita Datta
Title: The Pharmacogenetics of Treatment Resistant Depression

Abstract:
Abnormally low levels of serotonin (5-HT) are found in the majority of non-medicated depressed patients, strongly suggesting a link between 5-HT and the etiology of major depressive disorder. Furthermore, most clinically effective antidepressants exert their therapeutic effects by increasing 5-HT levels. Although antidepressants have proven to be successful in the treatment of major depression, a subset of patients (~33%) displays inadequate response to drug therapy. Because the effect of poor treatment outcome contributes substantially to the morbidity and mortality associated with this disorder, our goal is to identify the best combination of genetic polymorphisms to predict poor response to treatment with commonly used selective serotonin reuptake inhibitors and newer, “atypical” antidepressants. In an ongoing research project, we genotyped the following polymorphic changes in 109 unipolar patients treated with antidepressants: (i) a variable number tandem repeat (VNTR) polymorphism within intron 2 of the serotonin transporter gene; (ii) an insertion/deletion polymorphism in the serotonin transporter promoter region; (iii) an A to G single nucleotide polymorphism (SNP) in intron 13 of monoamine oxidase B; (iv) a VNTR within the monoamine oxidase A promoter; (v) a C to G SNP in the serotonin receptor 1A promoter region. These genes were selected because their encoded proteins either directly or indirectly modulate 5-HT levels. We then conducted Poisson regression analyses to identify the best combination of polymorphic alleles that gave the highest prediction level of poor response to antidepressants. Although 5-HTTLPR l and MAO-B A alleles were of borderline predictive value when examined individually (p = 0.05, in both cases), significance was increased dramatically when they were simultaneously present in individual research subjects. A total of 41% of antidepressant responders, 70% of partial responders, and 93% of non-responders possessed one or more copies of both alleles (p = 0.0004), resulting in a 66% success rate in the prediction of poor response.

Principle Investigators: Dr. Jenny Yang / Dr. Vincent Rehder
Title: Development of Ca2+ Sensors to Monitor Ca2+ Signaling in Mitochondria of Neurons

Abstract:
The goal of this project is to develop a novel class of Ca 2+ sensor proteins that will have wide applicability in studies of human disease and aging. Mitochondria, in addition to functioning as major energy producers in cells, also act as Ca 2+ buffers and stores. As such, this organelle serves multiple functions, which, in part, are even interdependent. For example, Ca 2+ sequestered by mitochondria can affect the rate of oxidative phosphorylation and thereby could affect apoptosis. In its function as a Ca 2+ store, mitochondria can actively transport Ca 2+ into its lumen to decrease the free cytosolic calcium concentration ([Ca 2+ ] i ), and release Ca 2+ through specific channels to increase [Ca 2+ ] i . Thus mitochondria serve to modify the spatial and temporal aspects of cytosolic Ca 2+ signaling. Furthermore, mitochondria have been shown to play an important role in orchestrating cell death mechanisms following hypoxic/ischemic brain damage . While the functioning of mitochondria is dependent on the intramitochondrial free Ca 2+ concentration ([Ca 2+ ] m ), we do not possess tools to dynamically measure this concentration. Thus a major barrier to the understanding of specific spatio-temporal patterns of [Ca 2+ ] i and [Ca 2+ ] m signaling is the lack of targeted sensors that monitor [Ca 2+ ] m , which has been reported to range by up to three orders of magnitude, from low * M to several mM.

Principle Investigators: Michael Weeks / Dr. Vincent Rehder
Title: Neurite Measurement Using Wavelet Image Processing

Abstract:
Biologists who study the development of the nervous system are interested in the morphological changes that nerve cells undergo as they extend specialized processes, termed neurites. Neurites are tipped by motile structures, called growth cones, which are crucial structures for the directed elongation of neurites towards their target area. Neurite advance and growth cone motility are important parameters to score neuronal development, but their quantification relies on a person to manually measure morphological parameters from a digitized phase-contrast images taken through a microscope. This task could certainly be automated, but the problem is more challenging than it appears. While humans are very good at determining the morphological characteristics of a neuron, such as the location of a neurite or the size of its leading growth cone within an image, this is very difficult for a computer. One of the complications is that the image has a variable amount of darkness in the background, so simple segmentation techniques fail. That is, the gray-scale image is made up of very small boxes (called “picture elements”, or pixels) that have a color between black and white, indicated by a number between 0 (black) and 255 (white). A simple segmentation technique would say that every pixel value within a range (say between 50 and 80) belongs to a neurite, but this method fails because there are many background pixels with these values as well. Thus, we need a more complex solution to automatically measure the morphometric parameters of advancing neurites.