MATERNAL SEPARATION PERSISTENTLY ALTERS THE EXPRESSION OF KEY ELEMENTS OF THE NEUROENDOCRINE TRH SYSTEM

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 414-436-HPT Axis Biology & Action
Basic/Translational
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-428
Lorraine Jaimes-Hoy*1, Carmen Espinosa-Ayala1, Jean-Louis Charli2 and Patricia Ileana Joseph-Bravo2
1Instituto de Biotecnología, UNAM, Cuernavaca, Mexico, 2UNAM, Cuernavaca MOR, Mexico
In rodents, maternal care takes the form of arched-back nursing and licking/grooming. These maternal demeanors influence the offspring's behavior and shape their HPA responsiveness to stress by altering expression levels of key genes through epigenetic marking1,2 . As the activity of the HPT axis is susceptible to various forms of stress3,4, we hypothesized that maternal separation during the lactation period alters the HPT axis function and its response to a metabolic cue such as fasting or cold exposure in the adult rat.

We studied the effect of maternal separation on adult rats exposed to fasting or cold, stimuli that inhibit or stimulate the activity of the HPT axis5,6,7. Wistar dams were divided into a naïve (N) group and a maternal separation (MS) group. From PD 2 -21, pups in the MS group underwent maternal separation for 3h daily. From PD 22, rats were housed 4/cage and fed ad libitum until adulthood. At PD60, rats were housed 2/cage, and half of the N and MS female rats were fasted for 48h; half of the N or MS male rats were exposed 1-4 h to 4°C. Coronal brain sections were cut through the rostrocaudal extent of the PVN and mediobasal hypothalamus (MBH) for quantitative in situ hybridization of levels of proTRH mRNA, and of pyroglutamyl peptidase II (PPII) mRNA, the ectoenzyme which inactivates TRH and controls the amount of TRH reaching the pituitary8,9. Hormones were analyzed in serum by radioimmunoanalysis.

ProTRH mRNA expression was higher in the MS than in the N group, in the anterior and medial PVN (mPVN) in female rats. On the other hand, in male rats PPII mRNA expression was increased in response to maternal separation.  Female naïve rats presented the reported changes after 48h of fasting: reduced proTRH expression in the mPVN, and increased PPII expression in MBH; in contrast, in fasted MS rats proTRH mRNA levels decreased to a lesser extent than in N rats, and PPII expression was not modified. These results suggest that maternal separation alters hypothalamic TRH and PPII expression in response to fasting, which could lead to higher levels of TRH reaching the pituitary in MS than in N adults, suggesting altered adaptive responses to conserve energy. 

Cold exposure increased proTRH mRNA levels in anterior, medial and caudal PVN of N male rats as reported7; levels were similarly increased in the MS group pointing for a lack of effect of maternal separation on the hypothalamic response to an acute insult. However, only N animals showed an increase in serum concentration of TSH and T4, suggesting a blunted response of the axis at pituitary-thyroid level in animals submitted to maternal separation.

In conclusion, maternal separation can alter the expression of genes that control TRH levels in the neuroendocrine axis, and may additionally interfere with peripheral aspects of thyroid hormones turnover.

(1) Weaver IC, Cervoni N, Champagne FA, D'Alessio AC, Sharma S, Seckl JR, Dymov S, Szyf M, Meaney MJ. Epigenetic programming by maternal behavior. Nat Neurosci. 2004; 7(8):847-54. (2) Fish EW, Shahrokh D, Bagot R, Caldji C, Bredy T, Szyf M, Meaney MJ. Epigenetic programming of stress responses through variations in maternal care. Ann N Y Acad Sci. 2004; 1036:167-80. (3) Kakucska I, Qi Y, Lechan RM. Changes in adrenal status affect hypothalamic thyrotropin-releasing hormone gene expression in parallel with corticotropin-releasing hormone. Endocrinology. 199; 136(7):2795-802. (4) Gutiérrez-Mariscal M, Sánchez E, García-Vázquez A, Rebolledo-Solleiro D, Charli JL, Joseph-Bravo P. Acute response of hypophysiotropic thyrotropin releasing hormone neurons and thyrotropin release to behavioral paradigms producing varying intensities of stress and physical activity. Regul Pept 2012; 179(1-3):61-70. (5) van Haasteren GA, Linkels E, Klootwijk W, van Toor H, Rondeel JM, Themmen AP, de Jong FH, Valentijn K, Vaudry H, Bauer K, et al. Starvation-induced changes in the hypothalamic content of prothyrotrophin-releasing hormone (proTRH) mRNA and the hypothalamic release of proTRH-derived peptides: role of the adrenal gland. J Endocrinol. 1995; 145(1):143-53. (6) Uribe RM, Redondo JL, Charli JL, Joseph-Bravo P. Suckling and cold stress rapidly and transiently increase TRH mRNA in the paraventricular nucleus. Neuroendocrinology. 1993; 58(1):140-5. (7) Sánchez E, Uribe RM, Corkidi G, Zoeller RT, Cisneros M, Zacarias M, Morales-Chapa C, Charli JL, Joseph-Bravo P. Differential responses of thyrotropin-releasing hormone (TRH) neurons to cold exposure or suckling indicate functional heterogeneity of the TRH system in the paraventricular nucleus of the rat hypothalamus. Neuroendocrinology 2001; 74(6):407-22. (8) Charli JL, Vargas MA, Cisneros M, de Gortari P, Baeza MA, Jasso P, Bourdais J, Peréz L, Uribe RM, Joseph-Bravo P. TRH inactivation in the extracellular compartment: role of pyroglutamyl peptidase II. Neurobiology 1998; 6(1):45-57. (9) Sánchez E, Vargas MA, Singru PS, Pascual I, Romero F, Fekete C, Charli JL, Lechan RM. Tanycyte pyroglutamyl peptidase II contributes to regulation of the hypothalamic-pituitary-thyroid axis through glial-axonal associations in the median eminence. Endocrinology. 2009; 150(5):2283-91. (10) Lazcano-Iván, Jean-Louis C, Joseph-Bravo P, Linares G, Sánchez E. Fasting induces a delayed increase of thyrotropin-releasing hormone degrading ectoenzyme activity in the tanycytes of the median eminence of the rat hypothalamus. Endocrines Society´s 94th Annual Meeting 2012. SAT-392.

Nothing to Disclose: LJ, CE, JLC, PIJ

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: CONACyT 180009