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DIR Papers of the Month

By Eddy Ball
February 2007

Nicotinic Acetylcholine Receptors in Amygdala Section of the Brain

Two Laboratory of Neurobiology investigators have demonstrated for the first time the presence of functional α7-containing nicotinic acetylcholine receptors (nAChRs) in the rat basolateral (BLA) amygdala complex, which is located within the limbic system. In their NIEHS-funded study published in the Journal of Physiology, Rebecca Klein, Ph.D., and Jerrel Yakel, Ph.D., postulate that these receptors are likely to have an important role in the emotionally mediated aspects of nicotine addiction and working memory performance.

The researchers performed their experiments on acute amygdala slices from 14- to 21-day-old-rats within six hours of preparation. They performed whole-cell patch-clamp electrophysiological recordings on neurons in acute slices to identify the presence of functional nAChRs in BLA. Pressure application of acetycholine and laser-induced photolysis of caged-carbachol indicated that functional somato-dendritic nAChRs are present within the lateral and BLA nuclei. Using an α7-selective antagonist, Klein and Yakel also confirmed that the nAChRs in BLA complex are predominantly α7-containing.

The researchers concluded that "this information is critical as it might provide insight into the basic mechanism involved in various human disorders, such as anxiety, schizophrenia, epilepsy, addiction and autism." In addition, it offers insight into the effects of nicotine on behavior and contributes to the search for effective therapeutics for treating these devastating conditions.

Citation: Klein RC, Yakel JL. 2006. Functional somato-dendritic α7-containing nicotinic acetylcholine receptors in the rat basolateral amygdala complex. J Physiol 576(Pt 3):865-872.

NAG-1 Over-expression Protects against Intestinal Tumors

In an NIEHS-funded study published in the journal Gastroenterology, a team of intramural investigators report on the anti-tumorigenic effects of over-expression of nonsteroidal anti-inflammatory drug-activated gene NAG-1) in transgenic mice.

The investigators developed a transgenic mouse (NAG-Tg+) expressing the human form of a protein called NAG-1 to analyze the effect of the gene's expression in preventing intestinal tumor development in vivo.

They evaluated two colorectal carcinogenesis models in NAG-Tg+ mice to determine the efficacy of NAG-1 over-expression.

The team used a known intestinal carcinogen, azoxymethane, to induce tumors chemically and an intestinal tumor-specific genetic mutation (ApcMin+) to induce cancer genetically in NAG-Tg+ mice and controls. Both groups of NAG-Tg+ mice showed a greater than 50% reduction in intestinal cancer, confirming the tumor suppression activity of NAG-1. In addition, they demonstrated the efficacy of overexpression in genetically induced tumorigenesis and reported that there were no apparent side effects associated with the intervention.

By elucidating the specific role of NAG-1 gene over-expression, the study's findings may have important consequences in the clinical setting. Colorectal cancer is one of the most common cancers and is responsible for the deaths of over 50,000 Americans each year.

Citation: Baek SJ, Okazaki R, Lee SH, Martinez J, Kim JS, Yamaguchi K, Mishina Y, Martin DW, Shoieb A, McEntee MF, Eling TE. 2006. Nonsteroidal anti-inflammatory drug activated gene-1 over expression in transgenic mice suppresses intestinal neoplasia, Gastroenterology 131(5):1553-60.

Role of Estrogen Receptor-α in Gonadotropin Regulation

In a study published in the Journal of Endocrinology, a team of Laboratory of Reproductive and Developmental Toxicology investigators collaborated with a Lock Haven University researcher supported by the NIEHS Summers of Discovery Research Program to elucidate the effects of estrogen receptor-α (ERα) on gonadotropin synthesis and secretion. The authors of the NIEHS-funded study demonstrated that estradiol (E2)-mediated negative feedback on the hypothalamic-pituitary (HP) axis is an ERα specific action.

The team of researchers conducted three experiments on groups of adult wild-type (WT) and ERα-null (αERKO) mice. All subjects were also genotyped by PCR on DNA extracted from tail biopsies. Experiment 1 involved determining basal levels of hypothalamic gonadotropin-releasing hormone, pituitary gonadotropin, plasma gonadotropin, and serum and plasma inhibin-A levels in intact animals. In Experiment 2, the team injected ovariectomized adult female WT and αERKO mice with vehicle or E2 to determine effects on plasma gonadotropin and pituitary gonadotropin gene expression in vivo. The final experiment examined the effects of E2 on lutenizing hormone secretion in dispersed pituitary cell cultures.

This study contributed significantly to the understanding of the mechanisms and precise sites of action by which estrogens exert both negative and positive effects on the HP axis, processes which are critical to reproductive function in mammals.

Citation: Lindzey J, Jayes FL, Yates MM, Couse JF, Korach KS. 2006. The bi-modal effects of estradiol on gonadotropin synthesis and secretion in female mice are dependent on estrogen receptor-alpha. J Endocrinol 191(1):309-317.

Novel Pathway for Glucocorticoid Regulation of TNFα

A recent study by Laboratory of Signal Transduction Investigators Kathleen Smoak, Ph.D., and John Cidlowski, Ph.D., presented evidence for the first time of a new anti-inflammatory pathway for glucocorticoids by means of induction of tristetraprolin (TTP) mRNA and protein synthesis, which differs from classical anti-inflammatory pathways. The NIEHS-funded research appeared in the December issue of the journal Molecular and Cellular Biology.

To demonstrate this new pathway, Smoak and Cidlowski used the glucocorticoid dexamethasone to induce the synthesis of TTP mRNA and protein in human A549 lung epithelial cells and in lung, thymus, liver and spleen tissue of one-month-old male Sprague-Dawley rats. They verified the role of glucocorticoids by then treating with the glutocorticoid receptor antagonist mifepristone, which abrogated dexamethasone induction of TTP. Analyzing TTP gene transcription by dexamethasone, the researchers were able to determine that the effect of dexamethasone on TTP occurred at a primarily transcriptional level. They also showed that induction of TTP was critical for dexamethasone inhibition of the inflammatory cytokine tumor necrosis factor alpha (TNFα) mRNA expression post-transcriptionally.

Clinicians commonly prescribe glucocorticoids to treat immune and inflammatory diseases. Understanding this novel pathway may have wide-ranging clinical implications in the design of new glucocorticoids with a focus on transrepression-selective compounds.

Citation: Smoak K, Cidlowski JA. Glucocorticoids regulate tristetraprolin synthesis and posttranscriptionally regulate tumor necrosis factor alpha inflammatory signaling. Mol Cell Biol 26(23):9126-9135.

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