TRH and TRH receptor system in the basolateral amygdala mediate stress-induced depression-like behaviors Juli Choi a, 1 , Ji-eun Kim a, 1 , Tae-Kyung Kim a, 1 , Jin-Young Park a , Jung-Eun Lee a , Hannah Kim a , Eun-Hwa Lee a , Pyung-Lim Han a, b, c, * a Departments of Brain and Cognitive Sciences, Ewha Womans University, Seoul, Republic of Korea b Chemistry and Nano Science, Ewha Womans University, Seoul, Republic of Korea c Brain Disease Research Institute, Ewha Womans University, Seoul, Republic of Korea article info Article history: Received 31 January 2015 Accepted 25 March 2015 Available online 21 June 2015 Keywords: Depression Sociability TRH TRH receptor Amygdala abstract Chronic stress is a potent risk factor for depression, but the mechanism by which stress causes depression is not fully understood. To investigate the molecular mechanism underlying stress-induced depression, C57BL/6 inbred mice were treated with repeated restraint to induce lasting depressive behavioral changes. Behavioral states of individual animals were evaluated using the forced swim test, which measures psychomotor withdrawals, and the U-field test, which measures sociability. From these behavioral analyses, individual mice that showed depression-like behaviors in both psychomotor withdrawal and sociability tests, and individuals that showed a resiliency to stress-induced depression in both tests were selected. Among the neuropeptides expressed in the amygdala, thyrotropin-releasing hormone (TRH) was identified as being persistently up-regulated in the basolateral amygdala (BLA) in individuals exhibiting severe depressive behaviors in the two behavior tests, but not in individuals displaying a stress resiliency. Activation of TRH receptors by local injection of TRH in the BLA in normal mice produced depressive behaviors, mimicking chronic stress effects, whereas siRNA-mediated sup- pression of either TRH or TRHR1 in the BLA completely blocked stress-induced depressive symptoms. The TRHR1 agonist, taltirelin, injection in the BLA increased the level of p-ERK, which mimicked the increased p-ERK level in the BLA that was induced by treatment with repeated stress. Stereotaxic injection of U0126, a potent inhibitor of the ERK pathway, within the BLA blocked stress-induced behavioral depression. These results suggest that repeated stress produces lasting depression-like behaviors via the up-regulation of TRH and TRH receptors in the BLA. © 2015 Elsevier Ltd. All rights reserved. 1. Introduction A growing body of evidence suggests that the thyrotropin- releasing hormone (TRH) system plays a role in depression (Joffe and Marriott, 2000). TRH was initially identified as a hypothalamic tripeptide hormone (pGlu-His-Pro-NH2) that stimulates the ante- rior pituitary to release thyroid-stimulating hormone (TSH), which in turn stimulates the thyroid gland to synthesize and secrete thy- roid hormones, forming the hypothalamicepituitaryethyroid (HPT) neuroendocrine axis (Segerson et al., 1987; Patel et al., 2011; Gilbert et al., 2012; Costa-e-Sousa and Hollenberg, 2012). TRH acts through TRH receptor-1 and -2 (TRHR1 and TRHR2), which are coupled to phospholipase C via Gq (Sun et al., 2003; Bagriacik et al., 2012). TRH receptors are heavily expressed in the cortico-limbic regions including the hippocampus and amygdala (Heuer et al., 2000; Gary, 2003; Guti errez-Mariscal et al., 2012). Important sources of TRH that stimulate TRH receptors in the cortico-limbic regions are the hy- pothalamic TRH neurons (Chiamolera and Wondisford, 2009; Fliers et al., 2014). TRH is also expressed in the cortico-limbic regions including the hippocampus and amygdala (Heuer et al., 2000). It has been proposed that the local TRH in the cortico-limbic regions has cognitive and emotional functions (Joffe, 2011). However, the functional significance of the local TRH system in cortico-limbic regions has not been studied in detail. TRH-R1 KO mice and TRH-R2 KO mice exhibit depression-like and anxiety-like behaviors (Zeng et al., 2007; Sun et al., 2008). * Corresponding author. Department of Brain and Cognitive Sciences, Ewha Womans University, 11-1 Daehyun-Dong, Seodaemoon-Gu, Seoul, 120-750, Re- public of Korea. E-mail address: plhan@ewha.ac.kr (P.-L. Han). 1 These authors contributed equally to this work. Contents lists available at ScienceDirect Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm http://dx.doi.org/10.1016/j.neuropharm.2015.03.030 0028-3908/© 2015 Elsevier Ltd. All rights reserved. Neuropharmacology 97 (2015) 346e356