The main objectives of this study are to identify the hormones, peptides and neurotransmitters that regulate biosynthesis of TRH in the paraventricular nucleus (PVN) of the hypothalamus, the principal source of neurons that regulate anterior pituitary TSH secretion, and to elucidate their mechanisms of action. The factors responsible for the cell-specific feedback effects of thyroid hormone (TH) on proTRH mRNA in the PVN will be investigated by nuclear run-off assays to determine whether TH regulates the rate of transcription and/or stability of proTRH mRNA; quantitating the amount of (125I)T3 produced from (125I)T4 in the PVN to determine whether TH effects are dependent upon local 5'- monodeiodination of T4 or exerted directly by circulating levels of T3; and in situ hybridization and immunocytochemistry using c- erbA probes as markers of the TH receptor to determine if TH has direct or indirect effects on TRH-synthesizing neurons. The origin and identification of peptides and neurotransmitter substances which make synaptic contacts on TH-responsive PVN neurons will be determined by double immunolabeling techniques including anterograde tracing with PHA-L and immunocytochemistry at light and ultrastructural levels. The role of each of these factors (agonists and/or antagonists) in regulating TRH gene expression will be demonstrated in vivo after stereotaxic implantation unilaterally into the hypothalamus using semiquantitative in situ hybridization, immunocytochemistry and computer image analysis. Similar techniques will be used to determine whether the nyctohemeral variation of TSH secretion and changes in TH levels associated with glucocorticoids, cold exposure and caloric deprivation are mediated through effects on proTRH mRNA and whether TH establishes the permanent set point for TRH secretion at a critical time during development. The significance and functional regulation of another group of TRH-synthesizing. TH-unresponsive PVN neurons will also be determined by retrograde and anterograde tracing studies and immunocytochemistry to demonstrate the topography of innervation of the median eminence, its afferent input and neurotransmitter/neuropeptide mediators.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK037021-05
Application #
3235685
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1986-02-01
Project End
1994-01-31
Budget Start
1990-02-01
Budget End
1991-01-31
Support Year
5
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Tufts University
Department
Type
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02111
Wittmann, Gábor; Szabon, Judit; Mohácsik, Petra et al. (2015) Parallel regulation of thyroid hormone transporters OATP1c1 and MCT8 during and after endotoxemia at the blood-brain barrier of male rodents. Endocrinology 156:1552-64
Wittmann, Gábor; Harney, John W; Singru, Praful S et al. (2014) Inflammation-inducible type 2 deiodinase expression in the leptomeninges, choroid plexus, and at brain blood vessels in male rodents. Endocrinology 155:2009-19
Fekete, Csaba; Lechan, Ronald M (2014) Central regulation of hypothalamic-pituitary-thyroid axis under physiological and pathophysiological conditions. Endocr Rev 35:159-94
Wittmann, Gabor; Hrabovszky, Erik; Lechan, Ronald M (2013) Distinct glutamatergic and GABAergic subsets of hypothalamic pro-opiomelanocortin neurons revealed by in situ hybridization in male rats and mice. J Comp Neurol 521:3287-302
Fekete, C; Zseli, G; Singru, P S et al. (2012) Activation of anorexigenic pro-opiomelanocortin neurones during refeeding is independent of vagal and brainstem inputs. J Neuroendocrinol 24:1423-31
Singru, Praful S; Wittmann, Gabor; Farkas, Erzsebet et al. (2012) Refeeding-activated glutamatergic neurons in the hypothalamic paraventricular nucleus (PVN) mediate effects of melanocortin signaling in the nucleus tractus solitarius (NTS). Endocrinology 153:3804-14
Marsili, Alessandro; Sanchez, Edith; Singru, Praful et al. (2011) Thyroxine-induced expression of pyroglutamyl peptidase II and inhibition of TSH release precedes suppression of TRH mRNA and requires type 2 deiodinase. J Endocrinol 211:73-8
Rosene, Matthew L; Wittmann, Gabor; Arrojo e Drigo, Rafael et al. (2010) Inhibition of the type 2 iodothyronine deiodinase underlies the elevated plasma TSH associated with amiodarone treatment. Endocrinology 151:5961-70
Sanchez, Edith; Singru, Praful S; Wittmann, Gabor et al. (2010) Contribution of TNF-alpha and nuclear factor-kappaB signaling to type 2 iodothyronine deiodinase activation in the mediobasal hypothalamus after lipopolysaccharide administration. Endocrinology 151:3827-35
Freitas, Beatriz C G; Gereben, Balazs; Castillo, Melany et al. (2010) Paracrine signaling by glial cell-derived triiodothyronine activates neuronal gene expression in the rodent brain and human cells. J Clin Invest 120:2206-17

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