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1.  Divergent neuronal circuitries underlying acute orexigenic effects of peripheral or central ghrelin: critical role of brain accessibility 
Journal of neuroendocrinology  2014;26(8):542-554.
Ghrelin is an octanoylated peptide hormone that potently and rapidly increases food intake. The orexigenic action of ghrelin involves the hypothalamic arcuate nucleus (ARC), which is accessible to plasma ghrelin and expresses high levels of the ghrelin receptor. Local administration of ghrelin in a variety of other brain nuclei also increases food intake. It is currently unclear, however, if these non-ARC ghrelin brain targets are impacted by physiological increases of plasma ghrelin. Thus, the current study was designed to clarify which ghrelin brain targets participate in the short-term orexigenic actions of ghrelin. First, c-Fos induction into mouse brains centrally or peripherally treated with ghrelin was analyzed. It was confirmed that peripherally administered ghrelin dose dependently increases food intake and mainly activates c-Fos in ARC neurons. In contrast, centrally administered ghrelin activates c-Fos in a larger number of brain nuclei. To determine which nuclei are directly accessible to ghrelin, mice were centrally or peripherally injected with a fluorescent ghrelin tracer. It was found that peripherally injected tracer mainly accesses the ARC while centrally injected tracer reaches most brain areas known to express ghrelin receptors. Following that, ghrelin effects in ARC-ablated mice were tested and it was found that these mice failed to increase food intake in response to peripherally administered ghrelin but fully responded to centrally administered ghrelin. ARC-ablated mice showed similar patterns of ghrelin-induced c-Fos expression as seen in control mice with the exception of the ARC, where no c-Fos was found. Thus, peripheral ghrelin mainly accesses the ARC, which is required for the orexigenic effects of the hormone. Central ghrelin accesses a variety of nuclei, which can mediate the orexigenic effects of the hormone even in the absence of an intact ARC.
doi:10.1111/jne.12168
PMCID: PMC4108543  PMID: 24888783
arcuate nucleus; monosodium glutamate; dorsal vagal complex
2.  Neuronal nitric oxide synthase as a substrate for the evolution of pseudosexual behaviour in parthenogenetic whiptail lizard 
Journal of neuroendocrinology  2011;23(3):244-253.
The evolution of neuroendocrine mechanisms governing sex-typical behaviour is poorly understood. An outstanding animal model is the whiptail lizard (Cnemidophorus) as both the ancestral and descendent species still exist. The ancestral little striped whiptail, C. inornatus, consists of males and females, which exhibit sex-specific mating behaviours. The descendent desert grassland whiptail, C. uniparens, consists only of females that alternately exhibit both female-like and male-like pseudosexual behaviour. Castrated male C. inornatus will mount a conspecific in response to exogenous androgen, but some are also sensitive to progesterone. This polymorphism in progesterone sensitivity in the ancestral species may have been involved in evolution of progesterone-mediated male-typical behaviour in the descendant unisexual lizards. We tested if progesterone activates the typically androgenic signalling pathway by investigating hormonal regulation of neuronal nitric oxide synthase (nNOS) using in situ hybridization and NADPH diaphorase histochemistry, a stain for nNOS protein. NADPH diaphorase is widely distributed throughout the brain of both species, but only in the periventricular nucleus of the preoptic area (pvPOA) are there differences between mounting and non-mounting individuals. The number of cells expressing nNOS mRNA and NADPH diaphorase is higher in the pvPOA of individuals that mount in response to progesterone or androgen. Further, the nNOS promoter has both androgen and progesterone response elements, and NADPH diaphorase colocalizes with the progesterone receptor in the pvPOA. These data suggest that a polymorphism in progesterone sensitivity in the sexual ancestor reflects a differential regulation of nNOS and may account for the male-typical behaviour in unisexual whiptail lizards.
doi:10.1111/j.1365-2826.2010.02099.x
PMCID: PMC4509676  PMID: 21126273
progesterone receptor; neuronal nitric oxide synthase; preoptic area; sexual behaviour; parthenogenesis
3.  Galanin-like peptide (GALP) neuron-specific PI3K signaling regulates GALP mRNA levels in the hypothalamus of males and LH levels in both sexes 
Journal of neuroendocrinology  2014;26(7):426-438.
Galanin-like peptide (GALP) neurons participate in the metabolic control of reproduction and are targets of insulin and leptin regulation. Phosphoinositide 3-kinase (PI3K) is common to the signaling pathways utilized by both insulin and leptin. Therefore, we investigated whether PI3K signaling in neurons expressing GALP plays a role in the transcriptional regulation of the GALP gene and in the metabolic control of luteinizing hormone (LH) release. To this end, we deleted PI3K catalytic subunits, p110α and p110β via conditional gene targeting (cKO) in mice (GALP-p110α/β cKO). To monitor PI3K signaling in GALP neurons these animals were also crossed with Cre-dependent FoxO1GFP reporter mice. Compared to insulin-infused control animals, the PI3K-Akt-dependent FoxO1GFP nuclear exclusion in GALP neurons was abolished in GALP-p110α/β cKO mice. We next used food deprivation to investigate if the GALP-neuron specific ablation of PI3K activity affected the susceptibility of the gonadotropic axis to negative energy balance. Treatment did not affect LH levels in either sex. However, a significant genotype effect on LH levels was observed in females. In contrast, no genotype effect on LH levels was observed in males. A sex-specific genotype effect on hypothalamic GALP mRNA was observed, with fed and fasted GALP-p110α/β cKO males having lower GALP mRNA expression compared to WT fed males. Finally, the effects of gonadectomy and steroid hormone replacement on GALP mRNA levels were investigated. Compared to vehicle-treated mice, steroid hormone replacement reduced MBH GALP expression in WT and GALP-p110α/β cKO animals. In addition, within the castrated and vehicle-treated group and compared to WT, LH levels were lower in GALP-p110α/β cKO males. Double immunofluorescence using GALP-Cre/R26-YFP mice showed androgen and estrogen receptor co-localization within GALP neurons. Our data demonstrate that GALP neurons are direct targets of steroid hormones and that PI3K signaling regulates hypothalamic GALP mRNA expression and LH levels in a sex-specific fashion.
doi:10.1111/jne.12163
PMCID: PMC4076824  PMID: 24796383
GALP; LH; PI3K; metabolism; hypothalamus
4.  Hypothalamic Pituitary Adrenal Axis Responses to Low-Intensity Stressors are Reduced After Voluntary Wheel Running in Rats 
Journal of neuroendocrinology  2010;22(8):872-888.
Regular physical exercise is beneficial for both physical and mental health. By contrast, stress is associated with deleterious effects on health and there is growing evidence that regular physical exercise counteracts some of the effects of stress. However, most previous studies have suggested that prior exercise does not alter the acute hypothalamic pituitary adrenal (HPA) axis responses to stress. The present series of studies provides evidence that in rats, 6 weeks (but not 1 or 3 weeks) of voluntary wheel running reduces the HPA axis responses to lower-intensity stressors such as an i.p. saline injection, exposure to a novel environment or exposure to moderate intensity noise, but not to more intense stressors such as predator odour exposure or restraint. Daily exercise does not appear to be necessary for the reduction in HPA axis responses, with intermittent access (24 h out of each 72-h period) to a running wheel for 6 weeks, resulting in similar decrements in adrenocorticotrophic hormone and corticosterone release in response to 85 dBA noise exposure. Data from in situ hybridisation for c-fos mRNA are consistent with the hypothesis that voluntary exercise results in a decrease in HPA axis responsiveness to a low-intensity stressor at a central level, with no changes in primary sensory processing. Together, these data suggest that 6 weeks of daily or intermittent exercise constrains the HPA axis response to mild, but not more intense stressors, and that this regulation may be mediated at a central level beyond the primary sensory input.
doi:10.1111/j.1365-2826.2010.02007.x
PMCID: PMC4469265  PMID: 20406350
stress; HPA axis; exercise; corticosterone; adrenocorticotrophic hormone (ACTH); c-fos
5.  Oestradiol differentially influences feeding behaviour depending on diet composition in female rhesus monkeys 
Journal of neuroendocrinology  2013;25(8):729-741.
In females, cyclical changes in the ovarian hormone oestradiol are known to modulate feeding behaviour. However, what is less clear is how these behavioural effects of oestradiol are modified by the macronutrient content of a diet. Here we present data showing that oestradiol treatment results in both significantly smaller meals and reduced total caloric intake in ovariectomised, socially housed female rhesus macaques when only chow diet is available. Conversely, during a choice dietary condition where both palatable and chow options are available, oestradiol treatment had no observable, attenuating effect on caloric intake. During this choice dietary phase, all animals consumed more of the palatable diet than chow diet; however, oestradiol treatment appeared to further increase preference for the palatable diet. Finally, oestradiol treatment increased snacking behaviour, i.e. consumption of calories outside of empirically defined meals, regardless of diet condition. These findings illustrate how oestradiol differentially influences feeding behaviour depending on the dietary environment and provides a framework in which we can begin to examine the mechanisms underlying these observed changes.
doi:10.1111/jne.12054
PMCID: PMC4427903  PMID: 23714578
6.  Epigenetic Mechanisms may Underlie the Aetiology of Sex Differences in Mental Health Risk and Resilience 
Journal of neuroendocrinology  2013;25(11):1141-1150.
In this review, we propose that experiential and hormonal influences on biological sex during development may produce differences in the epigenome, and that these differences play an important role in gating risk or resilience to a number of neurological and psychiatric disorders. One intriguing hypothesis is that the framework belying sex differences in the brain creates differences in methylation and demethylation patterns, and these in turn confer risk and resilience to mental health disorders. Here, we discuss these concepts with regard to social behaviour in rodent models and briefly discuss their possible relevance to human disease.
doi:10.1111/jne.12074
PMCID: PMC4428578  PMID: 23841484
epigenetics; juvenile; play behaviour; sexual differentiation; methylation; steroid hormones; amygdala
7.  Masculinisation of the Zebra Finch Song System: Roles of Oestradiol and the Z-chromosome Gene Tubulin-Specific Chaperone Protein A 
Journal of neuroendocrinology  2015;27(5):324-334.
Robust sex differences in brain and behaviour exist in zebra finches. Only males sing, and forebrain song control regions are more developed in males. The factors driving these differences are not clear, although numerous experiments have shown that oestradiol (E2) administered to female hatchlings partially masculinises brain and behaviour. Recent studies suggest that an increased expression of Z-chromosome genes in males (ZZ; females: ZW) might also play a role. The Z-gene tubulin-specific chaperone A (TBCA) exhibits increased expression in the lateral magnocellular nucleus of the anterior nidopallium (LMAN) of juvenile males compared to females; TBCA+ cells project to the robust nucleus of the arcopallium (RA). In the present study, we investigated the role of TBCA and tested hypotheses with respect to the interactive or additive effects of E2 and TBCA. We first examined whether E2 in hatchling zebra finches modulates TBCA expression in the LMAN. It affected neither the mRNA, nor protein in either sex. We then unilaterally delivered TBCA small interfering (si)RNA to the LMAN of developing females treated with E2 or vehicle and males treated with the aromatase inhibitor, fadrozole, or its control. In both sexes, decreasing TBCA in LMAN reduced RA cell number, cell size and volume. It also decreased LMAN volume in females. Fadrozole in males increased LMAN volume and RA cell size. TBCA siRNA delivered to the LMAN also decreased the projection from this brain region to the RA, as indicated by anterograde tract tracing. The results suggest that TBCA is involved in masculinising the song system. However, because no interactions between the siRNA and hormone manipulations were detected, TBCA does not appear to modulate effects of E2 in the zebra finch song circuit.
doi:10.1111/jne.12267
PMCID: PMC4422980  PMID: 25702708
sex difference; song system; neural development; sex chromosome
8.  Hypothalamic KISS1 Expression, GnRH, and Neurotransmitter Innervation Vary with Stress and Sensitivity in Macaques 
Journal of neuroendocrinology  2014;26(5):267-281.
This study examined the effect of short-term psychosocial and metabolic stress in a monkey model of Stress-Induced Amenorrhea on the HPG axis. KISS1 expression was determined with ISH in the infundibular arcuate nucleus (INF ARC). Downstream of KISS1, GnRH axons in lateral areas rostral to the infundibular recess, serum LH and serum oestrogen (E) were measured with IHC and RIA. Upstream of KISS1, norepinephrine (NE) axons in the rostral ARC and serotonin axons in the anterior hypothalamus and periaqueductal gray (PAG) were measured with IHC. Female cynomolgus macaques (Macaca fascicularis) characterized as highly stress resilient (HSR) or stress sensitive (SS) were examined. After characterization of stress sensitivity, monkeys were either not stressed, or mildly stressed for 5 days prior to euthanasia in the early follicular phase. Stress consisted of 5 days of 20% food reduction in a novel room with unfamiliar conspecifics. There was a significant increase in KISS1 expression in HSR and SS animals in the presence versus absence of stress (p=0.005). GnRH axon density increased with stress in HSR and SS animals (p=0.015), while LH showed a gradual, but non-significant increase with stress. E trended higher in the HSR animals and there was no effect of stress (p=0.83). NE axon density (marked with dopamine β-hydroxylase, DBH) increased with stress in both HSR and SS groups (p≤0.002), whereas serotonin axon density was higher in HSR compared to SS animals and there was no effect of stress (p=0.03). The ratio of DBH/E correlated with KISS1 (p=0.052), and GnRH correlated with serum LH (p=0.039). In conclusion, E inhibited KISS1 in the absence of stress, but stress increased NE, which may override E inhibition of KISS1 expression. We speculate that neural pathways transduce stress to KISS1 neurones, which changes their sensitivity to E.
doi:10.1111/jne.12146
PMCID: PMC4012296  PMID: 24617839
Stress; resilience; KISS1; GnRH; norepinephrine; serotonin; LH; oestrogen; amenorrhea; macaques
9.  Oestradiol modulation of cognition in adult female marmosets (Callithrix jacchus) 
Journal of neuroendocrinology  2014;26(5):296-309.
The common marmoset (Callithrix jacchus) provides many advantages over traditional rodent and macaque species as a model for human aging and may be very valuable to study the effects of sex steroids on cognitive and brain aging. We present the first study examining the effects of oestrogens on cognitive function in female marmosets. Adult monkeys (3-5 years of age) were trained to a specific learning criterion on a battery of cognitive tasks preoperatively (object discrimination, delayed response with increasing delays and detour reaching with opaque box) and tested on different versions of these tasks (object reversals, delayed response with randomised delays and detour reaching with clear box) following ovariectomy and simultaneous implantation with 17β-oestradiol (E2, n=6) or blank (n=6) Silastic capsules. Acquisition of a delayed matching-to-position task with a 1s delay was also administered following completion of these tests. E2-treated monkeys were significantly impaired on the second Reversal and showed an increase in perseverative responding from Reversals 1 to 3. Their performance also tended to be worse than that of control monkeys on the Delayed Response task. Performance acquisition on the DMP tended to be better in E2-treated relative to control monkeys, but the group difference did not reach statistical significance. No effect of treatment was detected for Detour Reaching or affiliative behaviours. Overall, the findings indicate that E2 compromises performance on prefrontally-mediated tasks. The suggestion that E2 may improve acquisition on tasks dependent on the hippocampus will require further validation. These results are discussed in the context of dopaminergic and serotonergic signaling. We conclude that the marmoset is a useful new primate model to examine the effects of oestrogens on cognitive function.
doi:10.1111/jne.12147
PMCID: PMC4040528  PMID: 24617856
Aging; menopause; learning and memory; ovariectomy; oestrogens
10.  Sex Differences in Expression of Estrogen Receptor Alpha but not Androgen Receptor mRNAs in the Fetal Lamb Brain 
Journal of neuroendocrinology  2014;26(5):321-328.
Gonadal steroid hormones play important roles during critical periods of development to organize brain structures that control sexually dimorphic neuroendocrine responses and behaviors. Specific receptors for androgens and estrogens must be expressed at appropriate times during development in order to mediate these processes. The present study was performed to test for sex differences in the relative expression of estrogen receptor-α (ERα) and androgen receptor (AR) mRNA during the window of time in gestation that is critical for behavioral masculinization and differentiation of the ovine sexually dimorphic nucleus (oSDN) in the sheep. In addition, we examined whether ERα and AR mRNA expression is localized within the nascent oSDN and could be involved in its development. Using quantitative RT-PCR, we found that females expressed more ERα mRNA than males in medial preoptic area and medial basal hypothalamus during the mid-gestational critical period for brain sexual differentiation. No sex differences were found for AR mRNA in any tissue examined or for ERα in amygdala and frontal cortex. Using radioactive in situ hybridization, we found that the distributions of ERα and AR mRNA overlapped with aromatase mRNA, which delineates the boundaries of the developing oSDN and identifies this nucleus as a target for both androgens and estrogens These data demonstrate that the transcriptional machinery for synthesizing gonadal steroid receptors is functional in the fetal lamb brain during the critical period for sexual differentiation and suggest possible mechanisms for establishing dimorphisms controlled by gonadal steroids may exist at the level of steroid hormone receptor expression.
doi:10.1111/jne.12152
PMCID: PMC4071168  PMID: 24730418
estrogen receptor-alpha; androgen receptor; medial preoptic area; medial basal hypothalamus; amygdala; sheep; fetus
11.  Prenatal Testosterone Excess Decreases Neurokinin 3 Receptor Immunoreactivity within the Arcuate Nucleus KNDy cell population 
Journal of neuroendocrinology  2015;27(2):100-110.
Prenatal exposure of the ovine fetus to excess testosterone (T) leads to neuroendocrine disruptions in adulthood, evidenced by defects in responsiveness to the ability of gonadal steroids to regulate GnRH secretion. In the ewe, neurones of the arcuate nucleus (ARC), which co-expresses kisspeptin, neurokinin B (NKB) and dynorphin (termed KNDy cells), play a key role in steroid feedback control of GnRH and show altered peptide expression after prenatal T-treatment. KNDy cells also colocalise NKB receptors (NK3R), and it has been proposed that NKB may act as an autoregulatory transmitter in KNDy cells where it participates in the mechanisms underlying steroid negative feedback. In addition, recent evidence suggests that NKB/NK3R signaling may be involved in the positive feedback actions of oestradiol leading to the GnRH/LH surge in the ewe. Thus we hypothesise that decreased expression of NK3R in KNDy cells may be present in the brains of prenatal T-treated animals, potentially contributing to reproductive defects. Using single- and dual-label immunocytochemistry we found that NK3R-positive cells in diverse areas of the hypothalamus; however, after prenatal T-treatment, decreased numbers of NK3R immunoreactive (IR) cells were seen only in the ARC. Moreover, dual-label confocal analyses revealed a significant decrease in the percentage of KNDy cells (using kisspeptin as a marker) that colocalised NK3R. To investigate how NKB ultimately affects GnRH secretion in the ewe, we examined GnRH neurones in the POA and mediobasal hypothalamus (MBH) for the presence of NK3R. Although, consistent with earlier findings, we found no instances of NK3R colocalization in GnRH neurones in either the POA or MBH, >70% GnRH neurones in both areas were contacted by NK3R-IR presynaptic terminals suggesting that, in addition to its role at KNDy cell bodies, NKB may regulate GnRH neurones by presynaptic actions. In summary, decreased NK3R within KNDy cells in prenatal T-treated sheep complement previous observations of decreased NKB and dynorphin in the same population, and may contribute to deficits in the feedback control of GnRH/LH secretion in this animal model. The possibility that NKB agonists may be able to ameliorate the severity of neuroendocrine deficits in prenatal T-treated animals remains to be explored.
doi:10.1111/jne.12244
PMCID: PMC4412353  PMID: 25496429
Neuroendocrine; Developmental programming; Reproduction; Neurokinin B; Kisspeptin; GnRH
12.  Photoperiodic Effects on Seasonal Physiology, Reproductive Status and Hypothalamic Gene Expression in Young Male F344 Rats 
Journal of Neuroendocrinology  2015;27(2):79-87.
Seasonal or photoperiodically sensitive animals respond to altered day length with changes in physiology (growth, food intake and reproductive status) and behaviour to adapt to predictable yearly changes in the climate. Typically, different species of hamsters, voles and sheep are the most studied animal models of photoperiodism. Although laboratory rats are generally considered nonphotoperiodic, one rat strain, the inbred Fischer 344 (F344) rat, has been shown to be sensitive to the length of daylight exposure by changing its physiological phenotype and reproductive status according to the season. The present study aimed to better understand the nature of the photoperiodic response in the F344 rat. We examined the effects of five different photoperiods on the physiological and neuroendocrine responses. Young male F344 rats were held under light schedules ranging from 8 h of light/day to 16 h of light/day, and then body weight, including fat and lean mass, food intake, testes weights and hypothalamic gene expression were compared. We found that rats held under photoperiods of ≥ 12 h of light/day showed increased growth and food intake relative to rats held under photoperiods of ≤ 10 h of light/day. Magnetic resonance imaging analysis confirmed that these changes were mainly the result of a change in lean body mass. The same pattern was evident for reproductive status, with higher paired testes weight in photoperiods of ≥ 12 h of light/day. Accompanying the changes in physiological status were major changes in hypothalamic thyroid hormone (Dio2 and Dio3), retinoic acid (Crabp1 and Stra6) and Wnt/β-Catenin signalling genes (sFrp2 and Mfrp). Our data demonstrate that a photoperiod schedule of 12 h of light/day is interpreted as a stimulatory photoperiod by the neuroendocrine system of young male F344 rats.
doi:10.1111/jne.12241
PMCID: PMC4329330  PMID: 25443173
photoperiod; F344 rat; body weight; reproduction; hypothalamic gene expression
13.  A Role for Nonapeptides and Dopamine in Nest-Building Behaviour 
Journal of Neuroendocrinology  2015;27(2):158-165.
During nest building in zebra finches (Taeniopygia guttata), several regions in the social behaviour network and the dopaminergic reward system, which are two neural circuits involved in social behaviour, appear to be active in male and female nest-building finches. Because the nonapeptides, mesotocin and vasotocin and the neurotransmitter, dopamine, play important roles in avian social behaviour, we tested the hypothesis that mesotocinergic-vasotocinergic and dopaminergic neuronal populations in the social behaviour network and dopaminergic reward system, respectively, are active during nest building. We combined immunohistochemistry for Fos (an indirect marker of neuronal activity) and vasotocin, mesotocin or tyrosine hydroxylase on brain tissue from nest-building and non-nest-building male and female zebra finches and compared Fos immunoreactivity in these neuronal populations with the variation in nest-building behaviour. Fos immunoreactivity in all three types of neuronal populations increased with some aspect of nest building: (i) higher immunoreactivity in a mesotocinergic neuronal population of nest-building finches compared to controls; (ii) increased immunoreactivity in the vasotocinergic neuronal populations in relation to the amount of material picked up by nest-building males and the length of time that a male spent in the nest with his mate; and (iii) increased immunoreactivity in a dopaminergic neuronal population in relation to the length of time that a male nest-building finch spent in the nest with his mate. Taken together, these findings provide evidence for a role of the mesotocinergic-vasotocinergic and dopaminergic systems in avian nest building.
doi:10.1111/jne.12250
PMCID: PMC4329408  PMID: 25514990
vasotocin; mesotocin; tyrosine hydroxylase; dopamine; nest building
14.  Neuroendocrinology of Parental Response to Baby-Cry 
Journal of neuroendocrinology  2011;23(11):1036-1041.
This overview attempts to synthesise current understandings of the neuroendocrine basis of parenting. The parent–infant bond is central to the human condition, contributes to risks for mood and anxiety disorders, and provides the potential for resiliency and protection against the development of psychopathology. Animal models of parenting provide compelling evidence that biological mechanisms may be studied in humans. This has led to brain imaging and endocrine system studies of human parents using baby stimuli and concerted psychological and behavioural measures. Certain brain circuits and related hormonal systems, including subcortical regions for motivation (striatum, amygdala, hypothalamus and hippocampus) and cortical regions for social cognition (anterior cingulate, insula, medial frontal and orbitofrontal cortices), appear to be involved. These brain circuits work with a range of endocrine systems to manage stress and motivate appropriate parental caring behaviour with a flexibility appropriate to the environment. Work in this field promises to link evolving models of parental brain performance with resilience, risk and treatment toward mother–infant mental health.
doi:10.1111/j.1365-2826.2011.02212.x
PMCID: PMC4319977  PMID: 21848646
parent–child relationships; brain imaging; functional magnetic resonance imaging; attachment; parenting; caregiving; cortisol; dopamine; opioids
15.  Oestradiol alters central 5HT1A receptor binding potential differences related to psychosocial stress but not differences related to 5HTTLPR genotype in female rhesus monkeys 
Journal of neuroendocrinology  2014;26(2):80-88.
Social subordination in female macaques represents a well-described model of chronic psychosocial stress. Additionally, a length polymorphism (5HTTLPR) in the regulatory region of the serotonin (5HT) transporter (5HTT) gene (SLC6A4) is present in rhesus macaques, which has been linked to adverse outcomes similar to what has been described in humans with an analogous 5HTTLPR polymorphism. The present study determined the effects of social status and the 5HTTLPR genotype on 5HT1A receptor binding potential (5HT1A BPND) in brain regions implicated in emotional regulation and stress reactivity in ovariectomised female monkeys, and then assessed how these effects were altered by 17β-oestradiol (E2) treatment. Areas analyzed included the prefrontal cortex [anterior cingulate (ACC); medial prefrontal cortex (mPFC); dorsolateral prefrontal cortex; orbitofrontal prefrontal cortex], amygdala, hippocampus, hypothalamus and raphe nucleui. Positron emission tomography (PET) using p-[18F]MPPF was performed to determine the levels of 5HT1A BPND under a non-E2 and a 3-wk E2 treatment condition. The short variant (s-variant) 5HTTLPR genotype produced a significant reduction in 5HT1A BPND in the mPFC regardless of social status, and subordinate s-variant females showed a reduction in 5HT1A BPND within the ACC. Both these effects of 5HTTLPR were unaffected by E2. Additionally, E2 reduced 5HT1A BPND in the dorsal raphe of all females irrespective of psychosocial stress or 5HTTLPR genotype. Hippocampal 5HT1A BPND was attenuated in subordinate females regardless of 5HTTLPR genotype during the non-E2 condition, an effect that was normalised with E2. Similarly, 5HT1A BPND in the hypothalamus was significantly lower in subordinate females regardless of 5HTTLPR genotype, an effect reversed with E2. Together, the data indicate that the effect of E2 on modulation of central 5HT1A BPND may only occur in brain regions that show no 5HTTLPR genotype-linked control of 5HT1A binding.
doi:10.1111/jne.12129
PMCID: PMC3962807  PMID: 24382202
oestradiol; social subordination; psychosocial stress; 5HT1A receptor; 5HTTLPR; monkeys
16.  [No title available] 
PMCID: PMC4108483  PMID: 24219627
17.  The Response of Glucose-Excited Neurones in the Ventromedial Hypothalamus to Decreased Glucose is Enhanced in a Murine Model of Type 2 Diabetes Mellitus 
Journal of neuroendocrinology  2009;22(2):65-74.
Obesity and type 2 diabetes mellitus (T2DM) are associated with dysfunctional insulin signalling and impaired central glucose sensing. Glucose sensing neurones reside in key areas of the brain involved in glucose and energy homeostasis (e.g. ventromedial hypothalamus; VMH). We have recently shown that insulin attenuates the ability of glucose-excited (GE) neurones to sense decreased glucose. We hypothesise that this effect of insulin on VMH GE neurones is impaired during T2DM when insulin signalling is dysfunctional. To test our hypotheses, we used whole cell patch clamp recording techniques to evaluate the effects of insulin on VMH GE neurones in brain slices from wild-type and diabetic (db/db) mice. The effects of decreasing glucose from 2.5 to 0.1 mm on VMH GE neurones were similar in wild-type and db/db mice. However, decreasing glucose from 2.5 to 0.5 mm decreased the action potential frequency, membrane potential and input resistance of VMH GE neurones to a significantly greater extent in db/db versus wild-type mice. Furthermore, insulin (5 nm) blunted the effects of decreased glucose in wild-type, but not db/db mice. These differences in both glucose and insulin sensitivity between wild-type and db/db mice were completely ameliorated by the insulin sensitiser, Compound 2 (300 nm). These data are consistent with our hypothesis that impaired insulin signalling in T2DM sensitises VMH GE neurones to decreased glucose.
doi:10.1111/j.1365-2826.2009.01938.x
PMCID: PMC4270105  PMID: 20002964
phosphatidylinositol-3-kinase; db/db mice; insulin; compound 2; electrophysiology
18.  Reproductive Experience Alters Neural and Behavioural Responses to Acute Oestrogen Receptor α Activation 
Journal of neuroendocrinology  2013;25(12):1280-1289.
Reproductive experience (i.e. parturition and lactation) leads to persistent alterations in anxietylike behaviour that are influenced by the oestrous cycle. We recently found that repeated administration of the selective oestrogen receptors (ER)α agonist propyl-pyrazole triol (PPT) results in anxiolytic-like behaviours on the elevated plus maze (EPM) in primiparous (but not nulliparous) female rats. The present study examined the effects of the acute administration of PPT on EPM behaviour in primiparous and aged-matched, nulliparous female rats. In addition, corticosterone secretion, corticotrophin-releasing hormone (CRH) gene expression and expression of the immediate early gene product Fos in the paraventricular nucleus (PVN) and amygdala were measured either after EPM testing or in home cage controls. Acute PPT administration significantly modified EPM behaviour as a function of reproductive experience, with nulliparous females tending toward increased anxiety-like behaviours and primiparous females tending toward decreased anxiety-like behaviours. In home cage controls, PPT increased corticosterone secretion in all females; however, both vehicle- and PPT-treated, primiparous females had reduced corticosterone levels compared to their nulliparous counterparts. Significant effects of PPT on CRH mRNA within the PVN were observed after the administration of PPT but only in primiparous females tested on the EPM. PPT also increased Fos expression within the PVN of EPM-exposed females; however, both vehicle- and PPT-treated primiparous females had reduced Fos expression compared to nulliparous females. In the amygdala, PPT increased Fos immunore-activity in the central but not the medial or basolateral amygdala, although these effects were only observed in home cage females. Additionally, both vehicle- and PPT-treated home cage, primiparous females had increased Fos in the central nucleus of the amygdala compared to nullip-arous controls. Overall, these data demonstrate that reproductive experience alters the behavioural response to acute ERα activation. Moreover, the findings suggest that central regulation of the hypothalamic-adrenal-pituitary axis is modified as a consequence of reproductive experience.
doi:10.1111/jne.12113
PMCID: PMC4269101  PMID: 24118285
Corticotrophin-releasing hormone; anxiety; stress; Fos; PVN; amygdala
19.  Oestrogen-independent circadian clock gene expression in the anteroventral periventricular nucleus in female rats: Possible role as an integrator for circadian and ovarian signals timing the LH surge 
Journal of neuroendocrinology  2013;25(12):1273-1279.
Periodic ovulation in rats, mice and hamsters is the result of a surge in LH that depends on circadian gating signals emerging from the master circadian clock within the suprachiasmatic nucleus (SCN) and rising ovarian oestrogen levels. These two signals converge into the anteroventral periventricular nucleus (AVPV) and lead to the release of kisspeptin, which is responsible for surges of GnRH and, in turn, of LH release. How the AVPV integrates circadian and reproductive signals remains unclear. Here we show that the female rat AVPV itself shows circadian oscillations in the expression of the clock genes PER1 and BMAL1, which lie at the core circadian clockwork of mammals. In ovariectomized (OVX) females treated with estradiol (E2) these oscillations are in synchrony with the AVPV rhythmic expression of the KISS1 gene and the gene that codes for the arginine-vasopressin (AVP) receptor AVPr1a. Whereas clock gene oscillations are independent of oestrogen levels, circadian expression of Kiss1 and Avpr1a (also referred to as V1a) mRNA are respectively blunted and absent in ovariectomized animals without E2 replacement. Because AVP is believed to be a critical SCN transmitter to gate the LH surge, our data suggest that a there is a circadian oscillator located in the AVPV, and that such a putative oscillator could time, in an oestrogen dependent manner, the sensitivity to circadian signals emerging from the SCN and the release of kisspeptin.
doi:10.1111/jne.12104
PMCID: PMC3954464  PMID: 24028332
kisspeptin; vasopressin; circadian oscillators; ovulation
20.  Compromise of Endogenous Neuropeptide W Production Abrogates the Dipsogenic and Pressor Effects of Angiotensin II in Adult, Male Rats 
Journal of neuroendocrinology  2013;25(12):1290-1297.
Neuropeptide W (NPW), an endogenous ligand for the G-Protein coupled receptor GPR7 (NPBWR1), is produced in neurones in the rat hypothalamus and brain stem known to be important in the control of food intake and the neuroendocrine response to stress. In previous studies, central administration of NPW during the light phase increased food and water intake and elevated prolactin and corticosterone levels in conscious, unrestrained male rats. In the present studies, central administration of siRNA reduced NPW levels in hypothalamus and resulted in a failure of angiotensin II to stimulate water drinking or increase mean arterial pressure. In addition siRNA treated animals failed to mount a significant prolactin response to immobilisation stress, while maintaining a normal corticosterone response. These results suggest that endogenous NPW may be a physiologically relevant, downstream mediator of the central actions of angiotensin II to stimulate thirst and increase arterial pressure. In addition, NPW-producing neurones appear to participate in the hypothalamic mechanisms controlling prolactin, but not corticosterone, secretion.
doi:10.1111/jne.12102
PMCID: PMC3954465  PMID: 24028220
Angiotensin II; Neuropeptide W; Water Drinking; Blood Pressure; Stress Hormones
21.  Annexin A1 Complex Mediates Oxytocin Vesicle Transport 
Journal of neuroendocrinology  2013;25(12):1241-1254.
Oxytocin is a major neuropeptide that modulates the brain functions involved in social behavior and interaction. Despite of the importance of oxytocin for neural control of social behavior, little is known about the molecular mechanism(s) by which oxytocin secretion in the brain is regulated. Pro-oxytocin is synthesized in the cell bodies of hypothalamic neurons in the supraoptic and paraventricular nuclei and processed to a 9-amino-acid mature form during post-Golgi transport to the secretion sites at the axon terminals and somatodendritic regions. Oxytocin secreted from the somatodendritic regions diffuses throughout the hypothalamus and its neighboring brain regions. Some oxytocin-positive axons innervate and secrete oxytocin to the brain regions distal to the hypothalamus. Brain oxytocin binds to its receptors in the brain regions involved in social behavior. Oxytocin is also secreted from the axon terminal at the posterior pituitary gland into the blood circulation. We have discovered a new molecular complex consisting of annexin A1 (ANXA1), A-kinase anchor protein 150 (AKAP150), and microtubule motor, that controls the distribution of oxytocin vesicles between the axon and the cell body in a protein kinase A (PKA)- and protein kinase C (PKC)-sensitive manner. ANXA1 showed significant co-localization with oxytocin vesicles. Activation of PKA enhanced the association of kinesin-2 with ANXA1, thus increasing the axon-localization of oxytocin vesicles. Conversely, activation of PKC decreased the binding of kinesin-2 to ANXA1, thus attenuating the axon-localization of oxytocin vesicles. Our study suggests that ANXA1 complex coordinates the actions of PKA and PKC to control the distribution of oxytocin vesicles between the axon and the cell body.
doi:10.1111/jne.12112
PMCID: PMC3975805  PMID: 24118254
Oxytocin; Annexin A1; Kinesin-2; AKAP150; PKA; PKC
22.  Cyp19a1 (Aromatase) Expression in the Xenopus Brain at Different Developmental Stages 
Journal of Neuroendocrinology  2014;26(4):226-236.
Cytochrome P450 aromatase (P450arom; aromatase) is a microsomal enzyme involved in the production of endogeneous sex steroids by converting testosterone into oestradiol. Aromatase is the product of the cyp19a1 gene and plays a crucial role in the sexual differentiation of the brain and in the regulation of reproductive functions. In the brain of mammals and birds, expression of cyp19a1 has been demonstrated in neuronal populations of the telencephalon and diencephalon. By contrast, a wealth of evidence established that, in teleost fishes, aromatase expression in the brain is restricted to radial glial cells. The present study investigated the precise neuroanatomical distribution of cyp19a1 mRNA during brain development in Xenopus laevis (late embryonic to juvenile stages). For this purpose, we used in situ hybridisation alone or combined with the detection of a proliferative (proliferating cell nuclear antigen), glial (brain lipid binding protein, Vimentin) or neuronal (acetylated tubulin; HuC/D; NeuroβTubulin) markers. We provide evidence that cyp19a1 expression in the brain is initiated from the very early larval stage and remains strongly detected until the juvenile and adult stages. At all stages analysed, we found the highest expression of cyp19a1 in the preoptic area and the hypothalamus compared to the rest of the brain. In these two brain regions, cyp19a1-positive cells were never detected in the ventricular layers. Indeed, no co-labelling could be observed with radial glial (brain lipid binding protein, Vimentin) or dividing progenitors (proliferating cell nuclear antigen) markers. By contrast, cyp19a1-positive cells perfectly matched with the distribution of post-mitotic neurones as shown by the use of specific markers (HuC/D, acetylated tubulin and NeuroβTubulin). These data suggest that, similar to that found in other tetrapods, aromatase in the brain of amphibians is found in post-mitotic neurones and not in radial glia as reported in teleosts.
doi:10.1111/jne-12142
PMCID: PMC4238815  PMID: 24612124
Aromatase; Cyp19a1; radial glia; Xenopus; Brain
23.  Nuclear receptor coactivators: Regulators of steroid action in brain and behavior 
Journal of neuroendocrinology  2013;25(11):1209-1218.
Steroid hormones act in specific regions of the brain to alter behavior and physiology. While it has been well established that the bioavailability of the steroid and the expression of its receptor is critical to understanding steroid action in brain, the importance of nuclear receptor coactivators in brain is becoming more apparent. This review will focus on the function of the p160 family of coactivators, which includes steroid receptor coactivator-1 (SRC-1), SRC-2 and SRC-3, in steroid receptor action in brain. The expression, regulation and function of these coactivators in steroid-dependent gene expression in brain and behavior will be discussed.
doi:10.1111/jne.12065
PMCID: PMC3830605  PMID: 23795583
steroid receptor coactivator-1 (SRC-1/NcoA-1); SRC-2 (GRIP1/TIF2/NCoA-2); androgen receptor; estrogen receptor; progestin receptor; sex behavior; hypothalamus; steroid hormones
24.  The implication of neuroactive steroids in Tourette syndrome pathogenesis: a role for 5α-reductase? 
Journal of neuroendocrinology  2013;25(11):1196-1208.
Tourette syndrome (TS) is a neurodevelopmental disorder characterized by recurring motor and phonic tics. The pathogenesis of TS is thought to reflect dysregulations in the signaling of dopamine (DA) and other neurotransmitters, which lead to excitation/inhibition imbalances in cortico-striato-thalamocortical circuits. The causes of these deficits may reflect complex gene × environment × sex (G×E×S) interactions; indeed, the disorder is markedly predominant in males, with a male-to-female prevalence ratio of ~4:1. Converging lines of evidence point to neuroactive steroids as likely molecular candidates to account for GxExS interactions in TS. Building on these premises, our group has begun examining the possibility that alterations in the steroid biosynthetic process may be directly implicated in TS pathophysiology; in particular, our research has focused on 5α-reductase (5αR), the enzyme catalyzing the key rate-limiting step in the synthesis of pregnane and androstane neurosteroids. In clinical and preclinical studies, we found that 5αR inhibitors exerted marked anti-DAergic and tic-suppressing properties, suggesting a central role for this enzyme in TS pathogenesis. Based on these data, we hypothesize that enhancements in 5αR activity in early developmental stages may lead to an inappropriate activation of the “backdoor” pathway for androgen synthesis from adrenarche until the end of puberty. We predict that the ensuing imbalances in steroid homeostasis may impair the signaling of DA and other neurotransmitters, ultimately resulting in the facilitation of tics and other behavioral abnormalities in TS.
doi:10.1111/jne.12066
PMCID: PMC3849218  PMID: 23795653
25.  Prenatal corticosteroids modify glutamatergic and GABAergic synapse genomic fabric: Insights from a novel animal model of infantile spasms 
Journal of neuroendocrinology  2013;25(11):964-979.
Summary
Prenatal exposure to corticosteroids has long-term postnatal somatic and neurodevelopmental consequences. Animal studies indicate that corticosteroid exposure-associated alterations in the nervous system include hypothalamic function. Infants with infantile spasms, a devastating epileptic syndrome of infancy with characteristic spastic seizures, chaotic irregular waves on interictal electroencephalogram (EEG; hypsarhythmia) and mental deterioration, have decreased concentrations of adrenocorticotropic hormone (ACTH) and cortisol in cerebrospinal fluid strongly suggesting hypothalamic dysfunction. We have exploited this feature to develop a model of human infantile spasms by using repeated prenatal exposure to betamethasone and postnatal trigger of developmentally relevant spasms with N-methyl-D-aspartic acid (NMDA). The spasms triggered in prenatally primed rats are more severe compared to prenatally saline-injected ones and respond to ACTH, a treatment of choice for infantile spasms in humans. Using autoradiography and immunohistochemistry, we have identified a link between the spasms in our model and hypothalamus, especially the arcuate nucleus. Transcriptomic analysis of the arcuate nucleus after prenatal priming with betamethasone but before trigger of spasms indicates that prenatal betamethasone exposure down-regulates genes encoding several important proteins participating in glutamatergic and GABAergic transmission. Interestingly, there were significant sex-specific alterations after prenatal betamethasone in synapse-related gene expression but no such sex differences were found in prenatally saline-injected controls. A pair-wise relevance analysis revealed that, although the synapse gene expression in controls was independent of sex, these genes form topologically distinct gene fabrics in males and females and these fabrics are altered by betamethasone in a sex-specific manner. These findings may explain the sex differences in both normal behaviour and occurrence and severity of infantile spasms. Changes in transcript expression and their coordination may contribute to a molecular substrate of permanent neurodevelopmental changes (including infantile spasms) found after prenatal exposure to corticosteroids.
doi:10.1111/jne.12061
PMCID: PMC3855178  PMID: 23763471

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