Immunologic detection of placental lactogen during pregnancy in a mouse model: a preliminary report

PROBLEM: To establish a rapid test differentiating ectopic from failed intrauterine gestation, using placental lactogen (PL) as a marker for placental cells. METHOD OF STUDY: Sixteen Swiss Webster mice had synchronized ovulation and were mated. Eight mice were unmated controls. Study and control mice were sacrificed at 5, 7, 9. and 11 days gestation. Uterine sections were tested for PL by immunofluorescent antibody assay, enzyme-linked immunosorbent assay, and dot blot analysis. Human endometrial samples from a missed abortion and a nonpregnant woman were also tested. RESULTS: Placental lactogen was detectable only in pregnant uterine samples (placental cells only) by all assays and was absent in the endometial glandular cells of nonpregnant uterine samples. CONCLUSION: Three methods detected placental lactogen in the pregnant mouse and human tissue. This is the first step towards developing a reliable clinical test for human endometrial samples from early pregnancy to differentiate early abortion from ectopic pregnancy.     

Uterine endocrinology and paracrinology: insulin-like growth factor binding protein-1 and placental protein 14 revisited

A large number of proteins and peptides have been identifiedin the endometrium where they are likely to exert local biologicaleffects. These substances may be enzymes, their inhibitors,proteinases, proteinase inhibitors, hormones, or bioactive peptideswith diverse functions. Endometrial function and embryo—endometrialinteractions require synchronized actions between endocrineand local factors. As examples of local factors recent studieson the insulin-like growth factor (IGF) system and placentalprotein 14 (PP14) are reviewed. IGF binding protein-1 (IGFBP-1)and PP14 are products of the secretory phase endometrium: IGFBP-1is produced by decidualized stromal cells and PP14 by glandularepithelial cells. IGFBP-1 may inhibit the action of IGFs atthe endometrial-trophoblastic interphase, and it may also havea role in stromal—epithelial interaction. PP14 has immunosuppressiveproperties, and recent findings indicate that it may play apart in the fertilization process by inhibiting binding of spermatozoato the zona.     

The value of serum human placental lactogen and Schwangerschaftsprotein 1 to determine gestation in an ante-natal population

Single assays of Schwangerscbaftsprotein 1 (SP₁) and serum humanplacental lactogen (HPL) were performed in 500 consecutive patientsattending a routine ante-natal clinic for their first visit.All samples were taken before 112 days gestation. Of these 500patients, 233 had a regular menstrual cycle, were certain oflast menstrual period (LMP) and delivered a normal infant afterspontaneous labour. Regression equations were calculated fromthese results to assess their value for correcting gestation.Regression equations from previous publications were also appliedto our data. The gestation and estimated date of delivery werecalculated using SP₁ and HPL and were compared with the actualgestation and date of delivery. The correlation was poor anddid not indicate that SP₁ or HPL could be used to calculatethese values in the normal ante-natal population.     

Growth hormone does not increase the expression of insulin-like growth factors and their receptor genes in the pre-menopausal human ovary

A growing body of information now supports the existence of a complete intraovarian insulin-like growth factor I (IGF-I) system. Although the precise role of IGF-I in the context of ovarian physiology remains to be determined, it is likely that IGF-I may engage in the amplification of gonadotrophin hormonal action. These facts and experiments with animals establishing the ovaries of multiple species as a site of growth hormone (GH) reception and action have led to the use of recombinant GH (rGH) as an adjunctive agent to potentiate ovulation induction by exogenous gonadotrophins. Whether intraovarian IGF-I plays an intermediary role in GH hormonal action at the ovarian level remains uncertain at present. The aim of this study was to evaluate whether rGH administration to pre-menopausal women could modify the expression of the IGF-I gene in the ovary. The expression of the IGF-I gene was examined in a time-dependent manner in normal pre-menopausal ovaries obtained from nine women treated with rGH and nine control women treated with placebo, using solution hybridization/RNase protection assays. Ovarian tissue samples were obtained 24 h (six women) and 7 days (12 women) following rGH/placebo injection. Total RNA (20 microg) from whole pre-menopausal ovaries (with or without rGH treatment) as well as from human granulosa cells was hybridized with a human IGF-I antisense RNA. IGF-I peptide, but not oestradiol, serum concentrations increased significantly 24 h after rGH injection. IGF-I gene, however, was not expressed in the luteinized granulosa cells and whole pre-menopausal ovaries irrespectively of rGH treatment in ovarian samples analysed both 1 and 7 days following rGH injection. On the contrary, IGF-II mRNA transcribed from the fetal or fetal-neonatal IGF-II promoter and IGF-I receptor mRNA (both used as hybridization control) were both found in whole pre-menopausal ovary and luteinized granulosa cells. Nevertheless, no changes in the hybridization patterns were seen in the absence or presence of rGH. These studies demonstrate that rGH administration to normal premenopausal women does not change the expression of insulin-like growth factors and their receptor genes in the pre-menopausal human ovary. Furthermore, these results provide further evidence against locally produced IGF-I as responsible for any ovarian effects seen in systemic rGH administration.     

Growth hormone (GH), insulin-like growth factors (IGFs), and IGF-binding protein-3 (IGFBP-3) in a child with Proteus syndrome

Proteus syndrome is a congenital hamartomatous disorder characterized by partial overgrowth involving all germ layers. A somatic mutation model has been proposed since familial cases are extremely rare. We report on a 3-year-old girl with typical manifestations of Proteus syndrome, including local, asymmetric hypertrophy of various parts of the body. Total body length was reduced. Serum levels of IGF-I and especially IGF-II and their major growth hormone dependent binding protein (IGFBP-3) were significantly reduced, although growth hormone secretion after a pharmacological stimulus was normal. In vitro studies of fibroblasts derived from hypertrophied tissue showed normal IGF-I production and somewhat reduced IGF-II and IGFBP-3 production as compared to normal human skin fibroblasts. Affinity cross-linking experiments showed that fibroblasts of the affect tissue in Proteus syndrome produced an unusual pattern of IGF bindings proteins containing large amounts of an IGFBP with high affinity to IGF-II. The data suggest that IGF production is generally disturbed in Proteus syndrome with imbalanced levels of specific IGFBP in affected tissue. © 1994 Wiley-Liss, Inc.     

斑马鱼类胰岛素生长因子信号途径及作用机制研究进展

斑马鱼是研究早期发育中类胰岛素生长因子（insulin-like growth factors, IGF）信号途径的模式生物,斑马鱼IGF信号系统主要包括IGF配体、受体、结合蛋白（IGFBPs）。IGF配体包括IGF-1,IGF-2。受体为IGF-1R,该受体有两种全长结构（igf-1ra和igf-1rb）。结合蛋白包括IGFBP-1,IGFBP-2,IGFBP-3,IGFBP-5和 IGFBP-6,它们的结构特征已经阐明,从斑马鱼模式动物中获得的信息不仅可以为斑马鱼胚胎发育生物学提供新的观点,还可以进一步加深我们对一般意义上的脊椎动物的生长和发育的理解。本文就近年来斑马鱼IGF系统的进展作一综述。     

Insulin-like growth factor family in malignant haemangiopericytomas: the expression and role of insulin-like growth factor I receptor

Haemangiopericytoma is a rare soft tissue tumour originating from the contractile pericapillary cells. Relatively little is known about its molecular pathogenesis. To address this issue, the insulin-like growth factor family (IGFs) was analysed in 19 tumours collected from a human tumour bank network. Seven of the tumours were associated with severe hypoglycaemia. Of these, six were retroperitoneal and one was located in the leg. 3 out of the 19 tumours (15·8 per cent) were positive for insulin-like growth factor I (IGF I) mRNA and 11 were positive for IGF II mRNA (57·9 per cent). Almost 90 per cent of haemangiopericytomas expressed IGF I receptor (IGF IR) mRNA (17 out of 19), five (26·3 per cent) expressed IGF binding protein 1 (IGF BP1), three (15·8 per cent) expressed IGF BP2, and four (21 per cent) exhibited IGF BP3 mRNA. All of the 14 haemangiopericytomas examined with regard to specific receptor binding were IGF IR positive, ranging from 1·2 to 16·2 per cent. Binding was much higher in IGF I/IGF IR positive tumours (15·3±0·7) than in IGF I negative/IGF IR positive tumours (5·1±3·3). The potential role of IGF IR as a growth promoting factor in malignant haemangiopericytoma was studied using antisense oligonucleotides and monoclonal antibody αIR3 that specifically inhibit IGF IR synthesis or activity. 10 µM IGF IR antisense oligonucleotides significantly inhibited the growth of haemangiopericytoma cells in culture, by around 50 per cent; monoclonal antibody against IGF IR (αIR3) also significantly inhibited proliferation. The data suggest that IGF IR may play an important role in the genesis and progression of malignant haemangiopericytomas. Copyright © 1999 John Wiley & Sons, Ltd.     

Synergistic effects of 1,25-Dihydroxyvitamin D3 and TGF-beta1 on the production of insulin-like growth factor binding protein 3 in human bone marrow stromal cell cultures

1,25-Dihydroxyvitamin D3 (calcitriol), transforming growth factor-beta (TGF-beta), and insulin-like growth factors (IGFs) are all important bone regulatory factors known to affect proliferation and differentiation of human bone-forming cells (osteoblasts). We have previously shown that TGF-beta1 increased IGF-I and IGF-binding protein (IGFBP)-3 production in human bone marrow stromal (hMS) osteoblast progenitors and calcitriol stimulated IGFBP-3 and IGFBP-4 production. As interaction between signaling pathways of these factors has been reported, the present study aimed at examining the concerted actions on components of the IGF-system. We report that co-treatment with TGF-beta1 and calcitriol resulted in a synergistic increase in IGFBP-3 production, thereby suggesting that the effects of these factors on hMS osteoblast differentiation may involve the observed increase in IGFBP-3.     

Expression of insulin-like growth factor in the placenta of intrauterine growth-retarded human fetuses

Many cases of intrauterine growth retardation (IUGR) are the result of placental and fetal tissue insufficiency. Insulin-like growth factor-I (IGF-I) is known to play a role in placental and fetal growth. An immunocytochemical study was performed to localize IGF-I peptides in human placenta and umbilical cords of normal (n = 3) and IUGR (n = 3) fetuses. The peripartum fetal conditions were evaluated as well. Immunoreactive IGF-I was detected in the cytotrophoblast, syncytiotrophoblast, amnion, endothelial cells of fetal capillaries and in the decidua in both normal and IUGR placental tissue. A more robust immunostaining and increased numbers of positively stained cells were found in the decidua of IUGR placenta (p < 0.001). Intense immunostaining was also found in endothelial cells, smooth muscle cells and fibroblasts of the umbilical vein. IGF-I immunoreactivity was also present in stroma (Hofbauer cells and/or fibroblasts) of IUGR villi. Our results indicate that expression of IGF-I is high in specific sites in placenta and umbilical cords, which indicates a paracrine and/or endocrine function. The increased expression of IGF-I in placenta of IUGR fetuses indicates its involvement in restoring normal growth by means of a positive feed-back mechanism.     

腺病毒介导hIGF-1基因转染对软骨细胞增殖的影响

目的：探讨腺病毒介导人胰岛素样生长因子(human insulin—like growth factor，hIGF-1)基因转染对软骨细胞增殖的影响。方法：构建携带hIGF—1基因的重组腺病毒并进行PCR、Western blot鉴定。体外培养人胚胎软骨细胞，用处于对数增长期的第3代软骨细胞进行实验?分别转染1、10、100及500不同感染复数单位(multiplicity of infection，MOI)的Ad／hIGF-1，用PBS做阴性对照，hIGF-1生长因子(100μg/L)做阳性对照，采用四氮甲基唑蓝(methyl thiazolyl tetmzolium，MTT)法检测不同时间、不同组别软骨细胞吸光度。结果：第2代重组腺病毒上清液中PCR鉴定含有hIGF-1基因，Westem blot，证实Ad／hIGF-1表达成熟的hIGF-1生长因子。不同病毒滴度转染对软骨细胞增殖的影响存在量效依赖关系，100MO1软骨细胞吸光度约为对照组3倍，1MOI与10MOI、500MOI对软骨细胞增殖的影响近似；PBS组随着细胞体外培养时间延长，细胞增殖下降，hlGF-1生长因子、hIGF-1基因对软骨细胞增殖的影响存在时效关系，72h达到峰值。结论：Ad／hlGF-1基因转染对软骨细胞增殖的影响存在量效、时效依赖关系。     

Progesterone production by human granulosa cells cultured in serum free medium: effects of gonadotrophins and insulin-like growth factor I (IGF-I).

There is evidence that insulin-like growth factor I (IGF-I) is a potent regulator of oestradiol synthesis by human granulosa and luteal cells; however, the question of whether IGF-I regulates progesterone synthesis by these cell types has yet to be answered. As a first step towards this goal, we have compared the effects of IGF-I, follicle stimulating hormone (FSH), and human chorionic gonadotrophin (HCG) on progesterone production by human granulosa cells obtained from individual dominant and cohort follicles, and granulosa luteal cells from preovulatory follicles of patients undergoing in-vitro fertilization (IVF). Granulosa cells from normal, unstimulated follicles cultured in serum-free medium as controls (no additions) produced some progesterone spontaneously. In all cases, FSH stimulated basal progesterone levels (10-fold average increase) and the effect was dose-dependent (ED50 of FSH = 9.1 +/- 3.9 ng/ml). Similar effects were observed when granulosa cells from large follicles were incubated with HCG (ED50 of HCG = 6.9 +/- 2.8 ng/ml). By comparison, the effects of IGF-I on progesterone production were not marked, being absent in 80% of the follicles tested. However, granulosa cells from healthy follicles co-incubated with IGF-I and FSH or HCG produced more progesterone compared with cells treated with the gonadotrophins alone; this effect of IGF-I was dose dependent (ED50 of IGF-I = 10 ng/ml). When the effect of each agonist was tested on IVF granulosa luteal cells, HCG but not FSH or IGF-I stimulated basal progesterone levels but the HCG effect required a two-day lag phase.(ABSTRACT TRUNCATED AT 250 WORDS)     

Spontaneous pregnancies in two women with Laron-type dwarfism: are growth hormone and circulating insulin-like growth factor mandatory for induction of ovulation?

It has recently been claimed that growth hormone (GH) and insulin-like growth factors have a role in follicular development; different mechanisms of action have been proposed. Of late, many investigators have been led by these findings to use GH and growth hormone-releasing hormone (GHRH) for induction of ovulation, in combination with human menopausal gonadotrophins. It is, however, still doubtful whether or not growth hormones and/or insulin-like growth factors are mandatory for follicular development and fertility. In this study we describe two women with Laron-type dwarfism who lacked insulin-like growth factors and who had spontaneous pregnancies. We also discuss different natural defects in the production and metabolism of growth hormone and insulin-like growth factors in humans, and the fertility performance of the affected females. It is our assumption that GH and systemic insulin-like growth factors may modulate follicular development, but that they are not necessarily mandatory for ovarian follicular development.     

Distribution of insulin-like growth factors in condylar hyperplasia

Condylar hyperplasia (CH) is a local overgrowth of the condylar process of the temporomandibular joint (TMJ) of unknown etiology. Probably, growth factors like the insulin-like growth factors (IGFs) are involved in its pathogenesis. Specimens from 12 patients were investigated histologically and immunohistochemically to obtain the distribution of the IGFs-I and -II and the IGF1 receptor. The results revealed juvenile and adult subtypes. While generally IGF-II could only be detected weakly, in the juvenile cases strong immunostaining for IGF-I in cartilage and bone supposes an influence on pathological growth processes.     

胰岛素样生长因子-1对雪旺细胞氧化损伤的保护作用

目的:探讨胰岛素样生长因子-1(IGF-1)对雪旺细胞氧化损伤的保护作用。方法:用体外纯化培养的雪旺细胞建立氧化损伤模型,将培养细胞分成氧化损伤组、IGF-1保护组和正常对照组。四甲基偶氮唑蓝比色法(MTT)检测细胞的活性,生化技术检测细胞内超氧化物歧化酶(SOD)的含量,免疫印迹法检测凋亡蛋白Bcl-2的表达水平。结果:与对照组相比,H2O2处理组细胞胞体积缩小、空泡化,细胞活性降低,SOD含量明显减少,Bcl-2表达减弱;而IGF-1保护组细胞存活率明显升高,SOD含量较损伤组高,Bcl-2表达明显上调。结论:IGF-1对氧化损伤的雪旺细胞有保护作用。     

Expression and distribution of insulin-like growth factor-1 receptor in human carcinomas

The insulin-like growth factor-1 receptor (IGF1-R) is a cellular receptor overexpressed in many tumor cell lines and in some human tumors that seems to play a critical role in transformation, tumorigenicity, and metastasis. To date, a comprehensive evaluation of tissue distribution of IGF1-R in human carcinomas from different anatomical sites has been lacking. Using stage-oriented human cancer tissue microarrays, we studied IGF1-R expression and distribution in a group of 152 human carcinomas from a variety of anatomical sites and from 63 normal tissues through immunohistochemistry. The tumors included carcinomas from breast (8), ovary (9), endometrium (7), esophagus (5), stomach (7), pancreas (7), liver (4), colon (10), kidney (14), bladder (17), prostate (11), head and neck (31), salivary glands (8), lung (13), and skin (1). Formalin-fixed, paraffin embedded tissues of each case were immuno-stained using the avidin-biotin peroxidase method and an anti-IGF1-R rabbit polyclonal antibody. High-membranous IGF1-R staining was observed in 7 of 8 (87.5%) breast carcinomas, in 9 of 9 (100%) ovarian carcinomas, in 7 of 7 (100%) endometrial carcinomas, in 5 of 7 (71.1%) gastric carcinomas, in 4 of 7 (57.1%) pancreatic carcinomas, in 9 of 10 (90%) colon adenocarcinomas, in 11 of 13 (84.6%) lung carcinomas, in 6 of 11 (54.5%) prostatic adenocarcinomas, and in 17 of 17 (100%) transitional cell carcinomas of the bladder. Only a minority of squamous cell carcinomas of the head and neck and esophagus (34), salivary gland tumors (5), and renal cell carcinomas (14) were IGF1-R positive. This study demonstrates the overexpression of IGF1-R across a wide variety of human carcinomas of glandular or transitional cell origin.     

转染hIGF-1基因增强兔退变椎间盘蛋白多糖的表达

目的 探讨人胰岛素样生长因子(hlGF-1)基因在退变椎间盘中的表达及对椎间盘中蛋白多糖(agglecan)的影响.方法 制备新西兰大白兔腰椎间盘退变(IDD)模型24只,随机分为Ad/CMV.hlGF-1、hlGF.1生长因子及PBS组,每组8只.IA-5、L5-6椎间盘中分别注射第2代Ad/CMV-hlGF-1(8×108PFU)、hlGF-1生长因子(100μg/L)、PBS均25μL.注射后1、2.4和8周,Western blot检测hlGF-1蛋白表达;RT-PCR检测aggrecan mRNA的表达.结果 hlGF-1蛋白带出现在7.6×103ku.Ad/CMV-hlGF-1组hIGF-I蛋白表达持续达4周以上,hIGF-1组表达持续约2周;PBS注射组无hIGF-1蛋白表达.aggrecan电泳条带出现在200～300 bp;在注射后1～4周,Ad/CMV-hlGF-I组内aggrecan mRNA相对表达量进行性增加,8周轻度下降,4个时期总的比较(F=8.51,P<0.05),注射后1～8周,hlGF-1组、PBS组aggrecan mRNA相对表达量进行性下降.结论 hlGF-1能够增强椎间盘aggrecan的表达.     

Serum levels of insulin-like growth factor-1, IGF binding protein-1 and insulin and the response to human menopausal gonadotrophins in women with polycystic ovary syndrome

In order to determine which factors influence the large variationsin sensitivity to gonadotrophins witnessed in women with polycysticovary syndrome (PCOS), a prospective study was conducted ofthe correlation between basal clinical and endocrinologicalfeatures and gonadotrophin requirements of 20 women with clomiphene-resistantPCOS undergoing ovulation induction. Baseline evaluation ofserum concentrations of luteinizing hormone (LH), follicle stimulatinghormone (FSH), testosterone, fasting insulin, insulin-like growthfactor-1 (IGF-1), IGF binding protein-1 (IGFBP-1) and sex hormone-bindingglobulin (SHBG) were performed before administering gonadotrophin-releasinghormone agonist (GnRHa). Two weeks later, human menopausal gonadotrophin(HMG) was given in a standard individualized protocol accordingto ovarian response, until human chorionic gonadotrophin (HCG)was given. Serum concentrations of insulin, IGF-1, and IGFBP-1were unaffected by GnRHa. The BMI correlated positively withinsulin and inversely with IGFBP-1 serum concentrations andinsulin and IGFBP-1 were inversely correlated. The amount ofHMG required correlated positively with BMI and insulin concentrationsand inversely with IGFBP-1 in the whole group and these correlationswere maintained in the sub-group of lean women. No correlationwas observed between HMG requirements and IGF-1 or other hormones.Womenwith hyperinsulinaemia and low IGFBP-1 concentrations requiredsignificantly more HMG. Multiple regression analysis revealedthat insulin concentration is the most significant determinantof HMG requirement even when dissociated from BMI. We concludedthat requirement of HMG in PCOS is not merely determined byobesity but by a cardinal role of insulin concentrations which,when high, induce, hypothetically, a hyperandrogenic intrafollicularmilieu.     

Allometric studies on growth and development of the human placenta: growth of tissue compartments and diffusive conductances in relation to placental volume and fetal mass

Correlations between placental size and fetal mass during gestation fail to account for changes in composition that accompany placental growth and maturation. This study uses stereological data on the sizes of different tissue compartments in human placentas from 10 weeks of gestation to term and relates them to placental volume and to fetal mass by means of allometric analysis. In addition, tissue dimensions are used to calculate a physiological transport measure (diffusive conductance) for the villous membrane. Histological sections randomly sampled from placentas and analysed stereologically provided estimates of structural quantities (volumes, exchange surface areas, lengths, numbers of nuclei, diffusion distances). These data were combined with a physicochemical quantity (Krogh's diffusion coefficient) in order to estimate oxygen diffusive conductances for the villous membrane and its two components (trophoblast and stroma). Allometric relationships between these quantities and placental volume or fetal mass were obtained by linear regression analyses after log-transformation. Placental tissues had different growth trajectories: most grew more rapidly than placental volume and all grew more slowly than fetal mass. Diffusion distances were inversely related to placental and fetal size. Differential growth impacted on diffusive conductances, which, again, did not improve commensurately with placental volume but did match exactly growth of the fetus. Findings show that successful integration between supply and demand can be achieved by differential tissue growth. Allometric analysis of results from recent studies on the murine placenta suggest further that diffusive conductances may also be matched to fetal mass during gestation and to fetal mass at term across species.     

Endoplasmic reticulum stress disrupts placental morphogenesis: implications for human intrauterine growth restriction

We recently reported the first evidence of placental endoplasmic reticulum (ER) stress in the pathophysiology of human intrauterine growth restriction. Here, we used a mouse model to investigate potential underlying mechanisms. Eif2s1^tm1RjK mice, in which Ser51 of eukaryotic initiation factor 2 subunit alpha (eIF2α) is mutated, display a 30% increase in basal translation. In Eif2s1^tm1RjK placentas, we observed increased ER stress and anomalous accumulation of glycoproteins in the endocrine junctional zone (Jz), but not in the labyrinthine zone where physiological exchange occurs. Placental and fetal weights were reduced by 15% (97 mg to 82 mg, p < 0.001) and 20% (1009 mg to 798 mg, p < 0.001), respectively. To investigate whether ER stress affects bioactivity of secreted proteins, mouse embryonic fibroblasts (MEFs) were derived from Eif2s1^tm1RjK mutants. These MEFs exhibited ER stress, grew 50% slower, and showed reduced Akt–mTOR signalling compared to wild‐type cells. Conditioned medium (CM) derived from Eif2s1^tm1RjK MEFs failed to maintain trophoblast stem cells in a progenitor state, but the effect could be rescued by exogenous application of FGF4 and heparin. In addition, ER stress promoted accumulation of pro‐Igf2 with altered glycosylation in the CM without affecting cellular levels, indicating that the protein failed to be processed after release. Igf2 is the major growth factor for placental development; indeed, activity in the Pdk1–Akt–mTOR pathways was decreased in Eif2s1^tm1RjK placentas, indicating loss of Igf2 signalling. Furthermore, we observed premature differentiation of trophoblast progenitors at E9.5 in mutant placentas, consistent with the in vitro results and with the disproportionate development of the labyrinth and Jz seen in placentas at E18.5. Similar disproportion has been reported in the Igf2‐null mouse. These results demonstrate that ER stress adversely affects placental development, and that modulation of post‐translational processing, and hence bioactivity, of secreted growth factors contributes to this effect. Placental dysmorphogenesis potentially affects fetal growth through reduced exchange capacity. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Uncovering the molecular basis of positive affect using rough-and-tumble play in rats: a role for insulin-like growth factor I

Positive emotional states have been shown to confer resilience to depression and anxiety in humans, but the molecular mechanisms underlying these effects have not yet been elucidated. In laboratory rats, positive emotional states can be measured by 50-kHz ultrasonic vocalizations (hedonic USVs), which are maximally elicited by juvenile rough-and-tumble play behavior. Using a focused microarray platform, insulin-like growth factor I (IGFI) extracellular signaling genes were found to be upregulated by hedonic rough-and-tumble play but not depressogenic social defeat. Administration of IGFI into the lateral ventricle increased rates of hedonic USVs in an IGFI receptor (IGFIR)-dependent manner. Lateral ventricle infusions of an siRNA specific to the IGFIR decreased rates of hedonic 50-kHz USVs. These results show that IGFI plays a functional role in the generation of positive affective states and that IGFI-dependent signaling is a potential therapeutic target for the treatment of depression and anxiety.