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Office: W224 Anatomy/Zoology
Phone: 970-491-1672
Fax: 970-491-7907
Email: Stuart.Tobet@colostate.edu 

Stuart Tobet, PhD

​Professor, Department of Biomedical Sciences
Program in Cell and Molecular Biology
Front Range Neuroscience Group
School of Biomedical Engineering
Colorado State University

Education


PhD, Massachusetts Institute of Technology
SM, Massachusetts Institute of Technology
BS, Tulane University 

Overview


Tobet's work advances the understanding of structures in the brain that control neuroendrocrine functions. These structures are important because they regulate fundamental aspects of physiology and behaviors and are susceptible to several diseases and syndromes. Tobet, a professor in the Department of Biomedical Sciences, studies the movements of neuronal cells into groups and what affects their migration. He is particularly focused on following the migratory behavior of cells that might contribute to sex differences in structure or function. He also investigates the differences between the two sexes in the ability to protect and recover from internal and external assaults including brain injuries that occur during development or the harmful influences of environmental toxicants. His laboratory's live video microscopy allowed us to discover the first direct evidence of sex differences in neuronal migration.

Tobet's work is critical to understanding ways to prevent and treat rare genetic conditions that affect structures that impact neuroendocrine function such as Prader-Willi or Kallmann's syndrome. Kallmann's syndrome is related to a small peptide called gonadotropin-releasing hormone called GnRH.The disorder arises when GnRH neurons in a developing fetus fail to migrate from their site of origin in the nose into the basal forebrain. The syndrome is usually inherited and, for some forms, affects more males than females. Migration failure causes a diminished or non-existent sense of smell and although GnRH activity is low during childhood, as young adults, the failure of these neurons to migrate in infancy can lead to unsuccessful reproductive development and function. Other disorders of neuronal migration in the neuroendocrine brain during development may lead to a spectrum of syndromes where function in adulthood may be compromised depending upon events during a persons lifetime. These syndromes may lead to a diverse set of problems ranging from eating disorders to schizophrenia or major depressive disorder.

As science has become more and more interdisciplinary, Tobet's research collaborations at CSU have expanded to fellow faculty in engineering, chemistry, mathematics and computer science.  Collaborations with Drs. Tom Chen in electrical engineering and Chuck Henry in chemistry are leading to the creation of new technologies to visualize and measure molecules that influence migration in tissue slices. Collaboration with Drs. Vakhtang Putkaradze in mathematics and Chuck Anderson in computer science are creating new ways to model and analyze cell motions.

 

Research Interests -- Determination of Cell Positions in the Developing Neuroendocrine Brain


The long-term goal of my research is to determine cellular and molecular events underlying the differentiation of regions of the brain that underlie neuroendocrine function. Neuroendocrine structures are important because they regulate behavior and hoemostasis and are susceptible to a variety of diseases or syndromes such as Kallmann's, Prader-Willi, or Rubenstein-Taybi. I began my career by examining the long-term consequences of early hormone action on sexual behaviors, reproductive physiology, and hypothalamic structure. I proceeded to focus on molecular actions of gonadal steroids during critical periods of hormone action. We are now determining how multiple signals affect migration and cell position in the developing nervous system.

Cellular organization and differentiation may follow several courses leading to primarily layered (e.g., cerebral or cerebellar cortices) or nuclear (cell groupings within the thalamus and hypothalamus) structures. We concentrate on the formation of nuclear structures using the ventromedial and paraventricular nuclei of the hypothalamus (VMH and PVN) as model systems. The VMH and PVN are part of complex neural circuitries that regulate homeostatic, neuroendocrine, and behavioral functions. They migrate to specific positions within the respective nuclei characterized by neurochemical environment, phenotype of neighboring cells, and the pattern of anatomical connections. Our model system allows us to follow the formation of nuclei in vitro (video microscopy) and is easily accessible to manipulation. Our discovery of a unique relationship of the neurotransmitter GABA to the developing VMH, and more recently the PVN, has led to hypotheses that are being tested directly through pharmacological manipulations and selecting transgenic mouse models. In particular, we are taking advantage of two lines of gene-disrupted mice. In one line, a single gene-deletion (the nuclear orphan receptor, steroidogenic factor-1 or SF-1) leads to failure of VMH formation. In the other, the R1 subunit of the GABABreceptor is disrupted and GABABreceptors are functionally impaired. The unique targeting of the SF-1 gene to the VMH also leads to our efforts to examine transgenic mice in which green fluorescent protein (GFP) expression is driven by the SF-1 gene promoter and another line of mice in which GFP expression is driven by the NPY promoter (see images).


We are also studying GABAergic mechanisms in the development of neurons that synthesize gonadotropin-releasing hormone (GnRH). During embryonic development, neurons containing GnRH migrate from the
nasal compartment, across the cribriform plate, into the brain to reside in the basal forebrain. Over their early migration, we have found GABA either in neighboring cells or within GnRH neurons in mice, rats, humans and lamprey. Using pharmacology and a unique in vitro slice paradigm that keeps the relationship of the head and brain intact, we are testing mechanisms of migration directly. Here again, we are taking advantage of lines of transgenic and gene-disrupted mice. In particular, we are examining GnRH neuron migration in mice deficient in the netrin-1 receptor, deleted in colon cancer (DCC). In addition, we are using live video microscopy to examine the migration of GnRH neurons that are revealed by GFP expression driven by the GnRH gene promoter. We are characterizing intracellular, extracellular, and cell surface molecules as they relate to this instance of neuronal migration from the periphery into the CNS, a unique event.

Finally, we were led to examine the role of gonadal steroids in cell migration when a monoclonal antibody we generated revealed sex differences in antigen expression in radial glia in the hypothalamus of perinatal rats. We further discovered a transient radial glial scaffold that reaches from the lateral ventricles across the anterior commissure through the sexually dimorphic preoptic/anterior hypothalamus (POAA/AH) to the pial surface at its base. We are exploring which cells might utilize this unique radial glial pathway using im

munocytochemical and live video microscopy techniques. We are particularly focused on following the migratory behavior of cells that might contribute to sex differences in structure or function. Our live video microscopy allowed us to discover the first evidence of sex differences in neuronal mi

gration. Now, it is providing for our examination of hypotheses of the mechanism(s) of sex differences. By focusing our efforts primarily in murine models, we combine the utility of in vitro work and pharmacology with the power of mouse genetics. Thus we are taking advantage of different transgenic mice or mice in which selected genes have been disrupted (e.g., SF-1 mentioned above, and others) to explore the importance of specific steroid hormone systems in the POA/AH.

Representative Publications


For a complete list of publications, please visit: Tobet S PubMed

 
An organotypic slice model for ex vivo study of neural, immune, and microbial interactions of mouse intestine. Schwerdtfeger LA, Ryan EP, Tobet SA. Am J Physiol Gastrointest Liver Physiol. 2016 Feb 15;310(4):G240-8. doi: 10.1152/ajpgi.00299.2015. 
 
Spatiotemporal norepinephrine mapping using a high-density CMOS microelectrode array. Wydallis JB, Feeny RM, Wilson W, Kern T, Chen T, Tobet S, Reynolds MM, Henry CS.
Lab Chip. 2015 Oct 21;15(20):4075-82. doi: 10.1039/c5lc00778j. 
 
Development of the blood-brain barrier within the paraventricular nucleus of the hypothalamus: influence of fetal glucocorticoid excess. Frahm KA, Tobet SA. Brain Struct Funct. 2015 Jul;220(4):2225-34. doi: 10.1007/s00429-014-0787-8. 
 
Fetal hormonal programming of sex differences in depression: linking women's mental health with sex differences in the brain across the lifespan. Goldstein JM, Holsen L, Handa R, Tobet S. Front Neurosci. 2014 Sep 8;8:247. doi: 10.3389/fnins.2014.00247.
 
Disruption of fetal hormonal programming (prenatal stress) implicates shared risk for sex differences in depression and cardiovascular disease. Goldstein JM, Handa RJ, Tobet SA. Front Neuroendocrinol. 2014 Jan;35(1):140-58. doi: 10.1016/j.yfrne.2013.12.001.
 
The vasculature within the paraventricular nucleus of the hypothalamus in mice varies as a function of development, subnuclear location, and GABA signaling. Frahm KA, Schow MJ, Tobet SA. Horm Metab Res. 2012 Jul;44(8):619-24. doi: 10.1055/s-0032-1304624.
 
Mapping spatiotemporal molecular distributions using a microfluidic array. Lynn NS, Tobet S, Henry CS, Dandy DS. Anal Chem. 2012 Feb 7;84(3):1360-6. doi: 10.1021/ac202314n.
 
"Characterization of Novel Microelectrode Geometries for Detection of Neurotransmitters," Pettine, W.; Jibson, M.; Chen, T.; Tobet, S.; Nikkel, P.; Henry, C.S., Sensors Journal, IEEE , vol.12, no.5, pp.1187,1192, May 2012 doi: 10.1109/JSEN.2011.2163708