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Project 2: Tobet (Lead Investigator)

Animal Models of Sex-Specific HPA Axis Development

Project 2 focuses on the paraventricular nucleus of the hypothalamus (PVN) as the key final common integration site and output pathway of the hypothalamic-pituitary-adrenal (HPA) axis. The PVN is a key nucleus for regulating homeostatic, neuroendocrine, and behavioral functions. Nuclear development, similar to other brain regions, proceeds through several key developmental phases that can be characterized simply by the generation of neurons, the migration of neurons to proper positions, the choice of life or death for new neurons, the establishment of cell phenotypes, and finally the establishment of functional connections. Our current and proposed research plan tests hypotheses for each of these facets of PVN development as they may contribute as fetal antecedents to adult dysfunction that may include susceptibility to major depressive disorder.

PVN formation and function depends upon the expression of a number of transcription factors on one hand and selected effector molecules on the other. There are two basic hypotheses for mechanisms by which this influence is mediated. One suggests that these transcription factors are critical for the terminal differentiation of PVN neurons that remain in their normal locations. By contrast, we hypothesize that there are alterations in PVN differentiation that are secondary to alterations in the positions of PVN neurons and that a number of factors are critical for determining normal neuronal migration in the region of the PVN. Project 2 studies will test several hypotheses concerning the role of several effector molecules in different stages of PVN development. We will ask what is the pattern of cell migration to the PVN and then how nitric oxide (NO), gamma-aminobutyric acid (GABA), and brain-derived neurotrophic factor (BDNF) may play specific roles in nuclear organization. We will ask these questions in the context of potential differences between males and females to determine how sex differences in the developing HPA axis might contribute to the greater risk of depression in females.

Highlights:

  • The vasculature of the PVN develops in a unique postnatal fashion relative to the rest of the hypothalamus (or the cortex) and this vascular development is influenced significantly by the loss of GABAB receptors
  • Described a new device to examine chemical signaling in live tissue slices by taking advantage of new developments in microfluidics, and a new biosensor to examine chemical signaling in live tissue slices by taking advantage of new developments in electrochemistry
  • Discovered that immunoreactive CRH was increased selectively in newborn female mice that were deficient in GABAB receptors in a pattern that was restricted to the rostral PVN, suggesting a selective tie to the neuroendocrine PVN
  • Pharmacological inhibition of GABAA signaling reduced the number of cells containing immunoreactive estrogen receptor alpha in and around the PVN, but loss of GABAB receptor signaling actually changed their location relative to the PVN selectively in females
  • Loss of GABAB receptors also influenced immunoreactive patterns for neuronal nitric oxide synthase and brain derived neurotrophic factor

Publications:

Goldstein JM, Handa RJ, Tobet SA (2014) Disruption of fetal hormonal programming (prenatal stress) implicates shared risk for sex differences in depression and cardiovascular disease. Front Neuroendocrinol. 2013 Dec 16

Frahm KA, Nash CP, Tobet SA (2013) Endocan immunoreactivity in the mouse brain: method for identifying nonfunctional blood vessels. J Immunol Methods. 398-399:27-32.

Tobet SA, Handa RJ, Goldstein JM (2013) Sex-dependent pathophysiology as predictors of comorbidity of major depressive disorder and cardiovascular disease. Pflugers Arch.  465(5):585-94.

Makris N, Swaab DF, van der Kouwe A, Abbs B, Boriel D, Handa RJ, Tobet S, Goldstein JM (2013) Volumetric parcellation methodology of the human hypothalamus in neuroimaging: normative data and sex differences. Neuroimage.  69:1-10.

Alim Z, Hartshorn C, Mai O, Stitt I, Clay C, Tobet S, Boehm U (2012) Gonadotrope plasticity at cellular and population levels. Endocrinology. 153(10):4729-39

Qian Zhang; Gerrit J Bouma; Kristy McClellan; Stuart Tobet (2012) Hypothalamic Expression of SnoRNA Snord116 is Consistent with a Link to the hyperphagia and obesity symptoms of Prader-Willi Syndrome. Int J Dev Neurosci 30(6):479-85

BM, Tobet SA, Lara HE, Lucion AB, Wilson ME, Recabarren SE, Paredes AH (2012) Hormonal Programming Across the Lifespan. Horm Metab Res. 44(8):577-86

Frahm KA, Schow MJ, Tobet SA (2012) The vasculature within the paraventricular nucleus of the hypothalamus in mice varies as a function of development, subnuclear location, and GABA signaling. Horm Metab Res. 44:1-6

Nugent BM, Tobet SA, Lara HE, Lucion AB, Wilson ME, Recabarren SE, Paredes AH (2012) Hormonal programming across the lifespan. Horm Metab Res. 44:577-86.

Lynn NS, Tobet S, Henry CS, Dandy DS (2012) Mapping spatiotemporal molecular distributions using a microfluidic array. Anal Chem 84:1360-6. PMID: 22126747

Pettine W, Jibson M, Chen T, Tobet S, Nikkel P, Henry CS (2012) Characterization of a Novel Microelectrode Array and Sensor Geometries for Detection of Neurotransmitters. Sensors Journal , IEEE 12(5):1187-1192

Stratton MS, Searcy BT, Tobet SA (2011)GABA regulates corticotropin releasing hormone levels in the paraventricular nucleus of the hypothalamus in newborn mice. Physiol Behav. 104:327-33. PMID: 21236282

McClellan KM, Stratton MS, Tobet SA (2010) Roles for gamma-aminobutyric acid in the development of the paraventricular nucleus of the hypothalamus. J Comp Neurol. 518(14):2710-28. PMCID: PMC2879086

Bonthuis PJ, Cox KH, Searcy BT, Kumar P, Tobet S, Rissman EF (2010) Of mice and rats: key species variations in the sexual differentiation of brain and behavior. Front Neuroendocrinol.  31(3):341-58. PMCID: PMC2910167

Tobet S, Knoll JG, Hartshorn C, Aurand E, Stratton M, Kumar P, Searcy B, McClellan K (2009) Brain sex differences and hormone influences: a moving experience? J Neuroendocrinol.  21:387-92. PMCID: PMC2669491

Bao Y, Hudson QJ, Perera EM, Akan L, Tobet SA, Smith CA, Sinclair AH, Berkovitz GD (2009) Expression and evolutionary conservation of the tescalcin gene during development. Gene Expr Patterns.  9:273-81. PMID: 19345287

Zhao L, Kim KW, Ikeda Y, Anderson KK, Beck L, Chase S, Tobet SA, Parker KL (2008) Central nervous system-specific knockout of steroidogenic factor 1 results in increased anxiety-like behavior. Mol Endocrinol. 22:1403-15. PMCID: PMC2422821

McClellan KM, Calver AR, Tobet SA (2008) GABA receptors role in cell migration and position within the ventromedial nucleus of the hypothalamus. Neuroscience. 151(4):1119-31. PMCID: PMC2292832