However, cells were ERα deficient, which is in accordance with CDK activity Iwanari et al. [22]. Thus, to analyse receptor interaction in detail, the study

was performed in hERα overexpressed HepG2 cells after transient transfection. Though for some less potent AhR agonists such as 3-methylcholanthrene a direct activation of ERα resulted in an estrogenic response, TCDD has been reported to be an indirect ERα inhibitor and exert anti-estrogenic effects. [6], [11], [12], [13] and [14]. Previous studies on the AhR/ER cross-talk mainly focused on investigating these effects in breast cancer cell lines. However, the liver is one of the major target organs of TCDD’s toxic action mediated via AhR. Thus, the focus of this research work was put on the liver since the liver is also one major site of estradiol metabolism and the ERα is highly expressed [28]. In HepG2 cells TCDD led to anti-estrogenic activity by reducing E2-mediated ERα signalling in the ERE-regulated reporter gene activity assay only in the presence of ERα. The complete ER antagonist ZK 191 703 SCH772984 supplier totally blocked the estrogenic response and application of the partial AhR antagonist α-naphthoflavone [29] reversed TCDD’s anti-estrogenic repression of AhR-dependent reporter gene activity in HepG2 cells. Thus, these results support the hypothesis that the ligand-activated AhR interacts with ERα and represses E2-bound ERα-mediated transcription

upon ERE similarly to what is reported in hormone-dependent cell lines [6], [7] and [30]. The activation tuclazepam of AhR by TCDD is supposed to be a crucial step in the interaction of AhR/ER, since various experiments in AHR-deficient cell models have failed to demonstrate the modulation of ERα functional activity. In multiple ER-positive breast and endometrial cancer cells TCDD was shown to be strongly

anti-estrogenic, such as in MCF-7 breast cancer cells, but also in ER-negative Hepa-1 mouse hepatoma cells transfected with an ERα expression vector [3], [10], [30], [31] and [32]. In contrast, in a non-functional AhR mutant Hepa-1 cell line TCDD failed to exert an effect on E2-dependent ER signaling, suggesting an interaction between AhR and ER pathways [30]. Similarly, the expression of E2-responsive genes/proteins and their related activities was decreased in multiple ER-positive breast and endometrial cancer cells after co-treatment of E2 and TCDD and the identification of so-called inhibitory XREs (iXREs) in the critical promoter regions of these E2-responsive genes provided further evidence for the inhibition of E2-dependent target genes via interaction with the activated AhR [3], [31], [32], [33], [34] and [35]. Reciprocally, HepG2 cells transiently transfected with a XRE-luc reporter showed enhanced TCDD-mediated luciferase activity upon E2 treatment only in the presence of constitutively over-expressed ERα⋅ TCDD alone resulted in increased luciferase activity independent of the ERα.

When navigation requires travelling along familiar habitual routes evidence indicates that stimulus–response

associations stored in the dorsal striatum allow an animal to determine in which direction to proceed and when they have travelled far enough to arrive at the goal 1, 2 and 3]. However, when navigation relies on determining self-location in the environment and computing the spatial relationship to the goal, the hippocampus and connected structures of the medial temporal lobe (MTL), such as the entorhinal cortex, are needed for navigation 4, 5, 6, 7 and 8]. MTL and striatum also operate as Selleck PLX4032 part of a wider brain network serving navigation. In summary, it is thought the parahippocampal cortex supports the recognition of specific views and the retrosplenial cortex converts between allocentric (environment-bound) representations in hippocampal–entorhinal regions to egocentric representations in posterior parietal cortex 9•, 10 and 11]. In addition, the prefrontal cortex is thought to aid route planning, decision-making and switching between navigation Olaparib solubility dmso strategies 12 and 13] and the cerebellum is required when navigation involves monitoring self-motion [14]. Here we focus on the role of the hippocampus and entorhinal cortex because of recent discoveries from functional magnetic resonance imaging (fMRI) and single unit recording

studies and the development of new computational models. Electrophysiological investigations have revealed several distinct neural representations of self-location (see Figure 1 and for review [15]). Briefly, place cells found in hippocampal regions CA3 and CA1 signal the animal’s presence in particular regions of space; the cells’ place fields [16] (Figure 1a). Place fields are broadly stable between visits to familiar locations but remap whenever a novel environment is encountered, Mirabegron quickly forming a new and distinct representation 17 and 18]. Grid cells, identified in entorhinal

cortex, and subsequently in the pre-subiculum and para-subiculum, also signal self-location but do so with multiple receptive fields distributed in a striking hexagonal array 19 and 20] (Figure 1b). Head direction cells, found throughout the limbic system, provide a complementary representation, signalling facing direction; with each cell responding only when the animal’s head is within a narrow range of orientations in the horizontal plane (e.g. [21], Figure 1c). Other similar cell types are also known, for example border cells which signal proximity to environmental boundaries [22] and conjunctive grid cells which respond to both position and facing direction [23]. It is likely that these spatial representations are a common feature of the mammalian brain, at the very least grid cells and place cells have been found in animals as diverse as bats, humans, and rodents [15].