Neuroendocrine Circuits Research Articles

Radiological evidence to changes in the olfactory bulb volume depending on body mass index in the childhood

ObjectiveEnergy balance is preserved through the exchange between body weight and adipose tissue across the multi-faceted complex network that is composed of the sensorial, metabolic, and neuro-endocrine circuits. The olfactory control of energy homeostasis is maintained through the interplay between the olfactory bulb (OB) and adipose tissue. While extremely studied, most researches still report controversial results and sensorial regulation of obesity is not fully understood. This study aims to investigate the interplay between olfactory bulb volume (OBV) as a radiological clue of sensorial control and obesity in children. Subjects and methodChildren (n = 195) were classified into four groups based on body mass index (BMI) percentiles: normal weight (n = 89), overweight (n = 31), obese (n = 32) and morbidly obese (n = 43). OBV were calculated using MRI. ResultsMean OBV was higher in children with obesity than in those of normal weights. The means of OBV are found higher in the overweight and obese children (43.76 ± 9.50–49.29 ± 8.61 mm3) than in those of morbidly obese (38.23 ± 11.52 mm3) (p < 0.001). In overweight and obese children, a positive correlation were found between the BMI and OBV (roverweigh = 0.275-robese = 0.377), while in the morbidly obese group, there was a negative correlation (rseverelyobese = −0.445). ConclusionThis study reveals that OBV is higher in obese children. Also, it shows that there is a positive correlation between OBV and BMI in overweight and obese children and a negative correlation in the morbidly obese group. These radiological bimodal changes in OBV indicate that olfactory control acts to provide energy balance, mediated by positive in the overweight and obese children, negative feedback in the morbidly obese group.

The regulation of skin pigmentation in response to environmental light by pineal Type II opsins and skin melanophore melatonin receptors

Coupling skin colour with the light/dark cycle helps regulate body temperature in ectotherms. In X. laevis, nocturnal release of melatonin from the pineal complex induces pigment aggregation and skin lightening. This nocturnal blanching is initiated by a sensor (type II opsin) that triggers melatonin release when light intensity falls below a minimum threshold, and an effector (melatonin receptor) in the skin which induces pigment aggregation. The sensor/s and effector/s belong to two families of G-protein coupled receptors that originated from a common ancestor, but diverged with subsequent evolution. The aim of this work was to identify candidate sensor/s and effector/s that regulate melatonin-mediated skin colour variation. In X. laevis, we identified a developmental time (stage 43/44) when skin lightening depends on pineal complex photosensitivity alone. At this stage, the pineal complex comprises the frontal organ and pineal gland. A total of 37 type II opsin (14 duplicated) and 6 melatonin receptor (3 duplicated) genes were identified through a full genome analysis of the allotetraploid, X. laevis. These genes were grouped into subfamilies based on their predicted amino acid sequences and the presence of specific amino acids essential for their function. The pineal complex expresses mainly blue light sensitive opsins [pinopsin, parietopsin, opn3, and melanopsins (opn4 and opn4b)] and UV-light sensitive opsins (opn5 and parapinopsin), while visual opsins and va-ancient opsin are absent, as determined by RT-PCR and in situ hybridization. The photoisomerase retinal G-protein coupled receptor, and an uncharacterized opn6b opsin, are also expressed. The spectral sensitivity that triggers melatonin secretion, and therefore melanophore aggregation, falls in the visible spectrum (470–650 ηm) and peaks in the blue/green range, pointing to the involvement of opsins with sensitivities therein. The effector-melatonin receptors expressed in skin melanophores are mtnr1a and mtnr1c. Our data point to candidate proteins required in the neuroendocrine circuit that underlies the circadian regulation of skin pigmentation, and suggest that multiple initiators and effectors likely participate.

Ultradian Secretion of Growth Hormone in Mice: Linking Physiology With Changes in Synapse Parameters Using Super-Resolution Microscopy.

Neuroendocrine circuits are orchestrated by the pituitary gland in response to hypothalamic hormone-releasing and inhibiting factors to generate an ultradian and/or circadian rhythm of hormone secretion. However, mechanisms that govern this rhythmicity are not fully understood. It has been shown that synaptic transmission in the rodent hypothalamus undergoes cyclical changes in parallel with rhythmic hormone secretion and a growing body of evidence suggests that rapid rewiring of hypothalamic neurons may be the source of these changes. For decades, structural synaptic studies have been utilizing electron microscopy, which provides the resolution suitable for visualizing synapses. However, the small field of view, limited specificity and manual analysis susceptible to bias fuel the search for a more quantitative approach. Here, we apply the fluorescence super-resolution microscopy approach direct Stochastic Optical Reconstruction Microscopy (dSTORM) to quantify and structurally characterize excitatory and inhibitory synapses that contact growth hormone-releasing-hormone (GHRH) neurons during peak and trough values of growth hormone (GH) concentration in mice. This approach relies on a three-color immunofluorescence staining of GHRH and pre- and post-synaptic markers, and a quantitative analysis with a Density-Based Spatial Clustering of Applications with Noise (DBSCAN) algorithm. With this method we confirm our previous findings, using electron microscopy, of increased excitatory synaptic input to GHRH neurons during peak levels of GH. Additionally, we find a shift in synapse numbers during low GH levels, where more inhibitory synaptic inputs are detected. Lastly, we utilize dSTORM to study novel aspects of synaptic structure. We show that more excitatory (but not inhibitory) pre-synaptic clusters associate with excitatory post-synaptic clusters during peaks of GH secretion and that the numbers of post-synaptic clusters increase during high hormone levels. The results presented here provide an opportunity to highlight dSTORM as a valuable quantitative approach to study synaptic structure in the neuroendocrine circuit. Importantly, our analysis of GH circuitry sheds light on the potential mechanism that drives ultradian changes in synaptic transmission and possibly aids in GH pulse generation in mice.

2040-P: Sex-Dependent Effects of MC4R Genotype on HPA Axis Tone

Neuroendocrine circuits underlying stress integration and systemic fuel homeostasis are substantially intertwined. Accordingly, metabolic diseases such as obesity and diabetes have a high incidence of co-morbidity with stress-associated psychological disorders like anxiety and depression. Importantly, there is a strong female bias in both metabolic and stress-related disorders, making the understanding of sex-specific functions of these pathways critical for treatment. The hypothalamic melanocortin system is a principal regulator of energy balance and also modulates HPA responses to acute stress. Mutations in the melanocortin-4 receptor (MC4R) is the most common monogenic cause of obesity in humans and has been associated with sex-dependent effects, such as more women than men exhibiting ‘emotional’ eating, a behavior that is thought to be stress-induced. Thus, we hypothesized that MC4R deficiency may cause sexually dimorphic metabolic and stress responses. We subjected male and female rats with a MC4R loss-of-function mutation to either chronic variable stress (CVS) or no stress for 31 days. Mid-study, all rats underwent an acute restraint stress challenge. Consistent with previous reports, male and female rats with MC4R deficiency had increased food intake and body weight, which were both decreased by CVS. Contrary to expectation, MC4R genotype did not affect HPA axis or metabolic responses to chronic stress. But importantly, we observed a significant interaction between MC4R genotype and sex in HPA axis tone and acute stress reactivity, such that MC4R deficiency blunted both endpoints in males but exaggerated them in females. Females showed a dramatic 259% and 419% increase in basal corticosterone and HPA reactivity, respectively, compared to males. The heightened stress reactivity of females with MC4R mutations suggests a possible mechanism for the sex-dependent effects associated with this mutation in humans and highlights how stress may differentially regulate metabolism in males and females. Disclosure A.T.B. Chaffin: None. Y. Fang: None. K.R. Larson: None. J. Mul: None. K.K. Ryan: None. Funding National Institutes of Health (R00HL111319)

SUN-478 The Role of Thimet Oligopeptidase (EP24.15) in Regulating Reproduction

For almost six decades, gonadotropin releasing hormone (GnRH) has been examined biochemically and physiologically in the hormonal control of reproduction. More recently, Kisspeptin (Kiss), neurokinin B (NKB) and dynorphin A (DynA) comprising KNDy neurons in the hypothalamus have been demonstrated to regulate gonadotropin releasing hormone (GnRH) release. To add to the complex circuitry of reproduction, and associated physiological processes, we sought to define the role of Phoenixin (Phx), a recently identified neuropeptide produced in the hypothalamus, that increases GnRH peptide, GnRH receptor and Kisspeptin mRNAs, increases GnRH secretion and mediates ovarian cyclicity. EP24.15 (EC 3.4.24.15, thimet oligopeptidase) is a neuropeptide processing metalloenzyme that is expressed throughout the hypothalamus and other brain regions. All neuropeptide hormones have their downstream signaling activity moderated enzymatically in the extracellular space though the specific enzymes remain unknown. EP24.15 is best known for regulating GnRH by degrading the hormone and thus, inactivating binding to the GnRH receptor. Likewise, we have proven that Kiss is likewise degraded by EP24.15 further pointing to a role in regulating reproduction. To validate both physiological and biochemical regulation of DynA and Phx, we determined if these neuropeptides and EP24.15 are co-expressed in the brain, (in addition to our previous studies of GnRH and Kiss) identifying a functional neuroendocrine circuit whereby EP24.15 could regulate reproduction. We have demonstrated Phx immunoreactivity in areas of the brain related to stress (amygdala and bed nucleus of the stria terminalis) and reproduction (hypothalamic arcuate nucleus). Biochemically, we used proteomics to identify new neuropeptide substrates, their binding to the active site and cleavage sites by high resolution 3D structural models, mass spectrometry, and enzyme kinetics. Two cleavage sites are present in Kiss and DynA whereas there is a single cleavage site in GnRH and Phx. Enzyme kinetic variables of DynA and Phx (Km and Vmax) are comparable to published values for GnRH and Kiss. The data demonstrates that EP24.15 cleaves DynA, and Phx in vivo as an additional layer to the elaborate mechanism of reproduction. Though NKB was co-expressed with EP24.1.5, it was not a substrate for the enzyme which allows for finer tuning of the reproductive axis. A better understanding of novel, regulated peptides that integrate stress and reproductive processes will provide insight into brain circuitry for moderating normal and aberrant reproductive function.

Metabolism Disrupting Chemicals and Alteration of Neuroendocrine Circuits Controlling Food Intake and Energy Metabolism.

The metabolism-disrupting chemicals (MDCs) are molecules (largely belonging to the category of endocrine disrupting chemicals, EDCs) that can cause important diseases as the metabolic syndrome, obesity, Type 2 Diabetes Mellitus or fatty liver. MDCs act on fat tissue and liver, may regulate gut functions (influencing absorption), but they may also alter the hypothalamic peptidergic circuits that control food intake and energy metabolism. These circuits are normally regulated by several factors, including estrogens, therefore those EDCs that are able to bind estrogen receptors may promote metabolic changes through their action on the same hypothalamic circuits. Here, we discuss data showing how the exposure to some MDCs can alter the expression of neuropeptides within the hypothalamic circuits involved in food intake and energy metabolism. In particular, in this review we have described the effects at hypothalamic level of three known EDCs: Genistein, an isoflavone (phytoestrogen) abundant in soy-based food (a possible new not-synthetic MDC), Bisphenol A (compound involved in the manufacturing of many consumer plastic products), and Tributyltin chloride (one of the most dangerous and toxic endocrine disruptor, used in antifouling paint for boats).

Epiregulin induces leptin secretion and energy expenditure in high-fat diet-fed mice.

Adipokine leptin regulates neuroendocrine circuits that control energy expenditure, thermogenesis and weight loss. However, canonic regulators of leptin secretion, such as insulin and malonyl CoA, do not support these processes. We hypothesize that epiregulin (EREG), a growth factor that is secreted from fibroblasts under thermogenic and cachexia conditions, induces leptin secretion associated with energy dissipation. The effects of EREG on leptin secretion were studied ex vivo, in the intra-abdominal white adipose tissue (iAb WAT) explants, as well as in vivo, in WT mice with diet-induced obesity (DIO) and in ob/ob mice. These mice were pair fed a high-fat diet and treated with intraperitoneal injections of EREG. EREG increased leptin production and secretion in a dose-dependent manner in iAb fat explants via the EGFR/MAPK pathway. After 2 weeks, the plasma leptin concentration was increased by 215% in the EREG-treated group compared to the control DIO group. EREG-treated DIO mice had an increased metabolic rate and core temperature during the active dark cycle and displayed cold-induced thermogenesis. EREG treatment reduced iAb fat mass, the major site of leptin protein production and secretion, but did not reduce the mass of the other fat depots. In the iAb fat, expression of genes supporting mitochondrial oxidation and thermogenesis was increased in EREG-treated mice vs control DIO mice. All metabolic and gene regulation effects of EREG treatment were abolished in leptin-deficient ob/ob mice. Our data revealed a new role of EREG in induction of leptin secretion leading to the energy expenditure state. EREG could be a potential target protein to regulate hypo- and hyperleptinemia, underlying metabolic and immune diseases.

Novel insights into the spatial and temporal complexity of hypothalamic organization through precision methods allowing nanoscale resolution.

The mammalian hypothalamus contains an astounding heterogeneity of neurons to achieve its role in coordinating central responses to virtually any environmental stressor over the life-span of an individual. Therefore, while core features of intrahypothalamic neuronal modalities and wiring patterns are stable during vertebrate evolution, integration of the hypothalamus into hierarchical brain-wide networks evolved to coordinate its output with emotionality, cognition and conscious decision-making. The advent of single-cell technologies represents a recent milestone in the study of hypothalamic organization by allowing the dissection of cellular heterogeneity and establishing causality between opto- and chemogenetic activity modulation of molecularly-resolved neuronal contingents and specific behaviours. Thus, organizational rules to accumulate an unprecedented variety of hierarchical neuroendocrine command networks into a minimal brain volume are being unravelled. Here, we review recent understanding at nanoscale resolution on how neuronal heterogeneity in the mammalian hypothalamus underpins the diversification of hormonal and synaptic output and keeps those sufficiently labile for continuous adaptation to meet environmental demands. Particular emphasis is directed towards the dissection of neuronal circuitry for aggression and food intake. Mechanistic data encompass cell identities, synaptic connectivity within and outside the hypothalamus to link vegetative and conscious levels of innate behaviours, and context- and circadian rhythm-dependent rules of synaptic neurophysiology to distinguish hypothalamic foci that either tune the body's metabolic set-point or specify behaviours. Consequently, novel insights emerge to explain the evolutionary advantages of non-laminar organization for neuroendocrine circuits coincidently using fast neurotransmitters and neuropeptides. These are then accrued into novel therapeutic principles that meet therapeutic criteria for human metabolic diseases.

Distinctive stress sensitivity and anxiety-like behavior in female mice: Strain differences matter

Epidemiologic studies have shown that the prevalence of stress-related mood disorders is higher in women, which suggests a different response of neuroendocrine circuits involved in the response to stressful events, as well as a genetic background influence. The aim of this study was to investigate the baseline differences in anxiety-like behaviors of females of two commonly used mice strains. Secondly, we have also aimed to study their behavioral and biochemical alterations following stress. Naïve 3-4 months-old Swiss and C57BL/6 female mice were evaluated in the elevated plus maze (EPM) and in the acoustic startle response (ASR) for anxiety-like behaviors. Besides, an independent group of animals from each strain was exposed to cold-restraint stress (30 min/4 °C, daily) for 21 consecutive days and then evaluated in EPM and in the sucrose consumption tests. Twenty-four hours following behavioral experimentation mice were decapitated and their hippocampi (HP) and cortex (CT) dissected for further Western blotting analysis of glucocorticoid receptor (GR) and glial fibrillary acid protein (GFAP). Subsequent to each behavioral protocol, animal blood samples were collected for further plasma corticosterone analysis. C57BL/6 presented a lower anxiety profile than Swiss female mice in both behavioral tests, EPM and ASR. These phenomena could be correlated with the fact that both strains have distinct corticosterone levels and GR expression in the HP at the baseline level. Moreover, C57BL/6 female mice were more vulnerable to the stress protocol, which was able to induce an anhedonic state characterized by lower preference for a sucrose solution. Behavioral anhedonic-like alterations in these animals coincide with reduced plasma corticosterone accompanied with increased GR and GFAP levels, both in the HP. Our data suggest that in C57BL/6 female mice a dysregulation of the hypothalamus-pituitary-adrenal axis (HPA-axis) occurs, in which corticosterone acting on GRs would possibly exert its pro-inflammatory role, ultimately leading to astrocyte activation in response to stress.

Mild Prenatal Stress Causes Emotional and Brain Structural Modifications in Rats of Both Sexes.

Stress or high levels of glucocorticoids (GCs) during developmental periods is known to induce persistent effects in the neuroendocrine circuits that control stress response, which may underlie individuals’ increased risk for developing neuropsychiatric conditions later in life, such as anxiety or depression. We developed a rat model (Wistar han) of mild exposure to unpredictable prenatal stress (PS), which consists in a 4-h stressor administered three times per week on a random basis; stressors include strobe lights, noise and restrain. Pregnant dams subjected to this protocol present disrupted circadian corticosterone secretion and increased corticosterone secretion upon acute stress exposure. Regarding progeny, both young adult (2 months old) male and female rats present increased levels of circulating corticosterone and hyperactivity of the hypothalamus-pituitary-adrenal axis to acute stress exposure. Both sexes present anxious- and depressive-like behaviors, shown by the decreased time spent in the open arms of the elevated plus maze (EPM) and in the light side of the light-dark box (LDB), and by increased immobility time in the forced swim test, respectively. Interestingly, these results were accompanied by structural modifications of the bed nucleus of stria terminalis (BNST) and hippocampus, as well as decreased norepinephrine and dopamine levels in the BNST, and serotonin levels in the hippocampus. In summary, we characterize a new model of mild PS, and show that stressful events during pregnancy can lead to long-lasting structural and neurochemical effects in the offspring, which affect behavior in adulthood.

Brain-gut communications via distinct neuroendocrine signals bidirectionally regulate longevity in C. elegans.

Tissue-tissue communications are integral to organismal aging, orchestrating a body-wide aging process. The brain plays a key role in this process by detecting and processing signals from the environment and then communicating them to distal tissues such as the gut to regulate longevity. How this is achieved, however, is poorly understood. Here, using Caenorhabditis elegans as a model, we identified two distinct neuroendocrine signaling circuits by which the worm nervous system senses cool and warm environmental temperatures through cool- and warm-sensitive neurons and then signals the gut to extend and shorten life span, respectively. The prolongevity "cool" circuit uses the small neurotransmitters glutamate and serotonin, whereas the anti-longevity "warm" circuit is mediated by insulin-like neuropeptides. Both types of neuroendocrine signals converge on the gut through their cognate receptors to differentially regulate the transcription factor DAF-16/FOXO, leading to opposing outcomes in longevity. Our study illustrates how the brain detects and processes environmental signals to bidirectionally regulate longevity by signaling the gut.

Seeing the light to change colour: An evolutionary perspective on the role of melanopsin in neuroendocrine circuits regulating light-mediated skin pigmentation.

Melanopsin photopigments, Opn4x and Opn4m, were evolutionary selected to "see the light" in systems that regulate skin colour change. In this review, we analyse the roles of melanopsins, and how critical evolutionary developments, including the requirement for thermoregulation and ultraviolet protection, the emergence of a background adaptation mechanism in land-dwelling amphibian ancestors and the loss of a photosensitive pineal gland in mammals, may have helped sculpt the mechanisms that regulate light-controlled skin pigmentation. These mechanisms include melanopsin in skin pigment cells directly inducing skin darkening for thermoregulation/ultraviolet protection; melanopsin-expressing eye cells controlling neuroendocrine circuits to mediate background adaptation in amphibians in response to surface-reflected light; and pineal gland secretion of melatonin phased to environmental illuminance to regulate circadian and seasonal variation in skin colour, a process initiated by melanopsin-expressing eye cells in mammals, and by as yet unknown non-visual opsins in the pineal gland of non-mammals.

Hypothalamic Integration of the Endocrine Signaling Related to Food Intake.

Hypothalamic integration of gastrointestinal and adipose tissue-derived hormones serves as a key element of neuroendocrine control of food intake. Leptin, adiponectin, oleoylethanolamide, cholecystokinin, and ghrelin, to name a few, are in a constant "cross talk" with the feeding-related brain circuits that encompass hypothalamic populations synthesizing anorexigens (melanocortins, CART, oxytocin) and orexigens (Agouti-related protein, neuropeptide Y, orexins). While this integrated neuroendocrine circuit successfully ensures that enough energy is acquired, it does not seem to be equally efficient in preventing excessive energy intake, especially in the obesogenic environment in which highly caloric and palatable food is constantly available. The current review presents an overview of intricate mechanisms underlying hypothalamic integration of energy balance-related peripheral endocrine input. We discuss vulnerabilities and maladaptive neuroregulatory processes, including changes in hypothalamic neuronal plasticity that propel overeating despite negative consequences.

The special relationship: glia-neuron interactions in the neuroendocrine hypothalamus.

Natural fluctuations in physiological conditions require adaptive responses involving rapid and reversible structural and functional changes in the hypothalamic neuroendocrine circuits that control homeostasis. Here, we discuss the data that implicate hypothalamic glia in the control of hypothalamic neuroendocrine circuits, specifically neuron-glia interactions in the regulation of neurosecretion as well as neuronal excitability. Mechanistically, the morphological plasticity displayed by distal processes of astrocytes, pituicytes and tanycytes modifies the geometry and diffusion properties of the extracellular space. These changes alter the relationship between glial cells of the hypothalamus and adjacent neuronal elements, especially at specialized intersections such as synapses and neurohaemal junctions. The structural alterations in turn lead to functional plasticity that alters the release and spread of neurotransmitters, neuromodulators and gliotransmitters, as well as the activity of discrete glial signalling pathways that mediate feedback by peripheral signals to the hypothalamus. An understanding of the contributions of these and other non-neuronal cell types to hypothalamic neuroendocrine function is thus critical both to understand physiological processes such as puberty, the maintenance of bodily homeostasis and ageing and to develop novel therapeutic strategies for dysfunctions of these processes, such as infertility and metabolic disorders.

Sex differences in avoidance behavior after perceiving potential risk in mice

BackgroundSex has been considered as a potential factor regulating individual behaviors in different contexts. Recently, findings on sex differences in the neuroendocrine circuit have expanded due to exact measurements and control of neuronal activity, while findings on sex differences in behavioral phenotypes are limited. One efficient way to determine the miscellaneous aspects of a sexually different behavior is to segment it into a set of simpler responses induced by discrete scenes.MethodsIn the present study, we conducted a battery of behavioral tests within a variety of unique risky scenes, to determine where and how sex differences arise in responses under those scenes.ResultsA significant sex difference was observed in the avoidance responses measured in the two-way active and the passive avoidance tests. The phenotype observed was higher mobility in male mice and reduced mobility in female mice, and required associative learning between an escapable risk and its predictive cue. This was limited in other scenes where escapable risk or predictive cue or both were missing.ConclusionsTaken together, the present study found that the primary sex difference occurs in mobility in the avoidance response after perceiving escapable risks.

AgRP to Kiss1 neuron signaling links nutritional state and fertility

Mammalian reproductive function depends upon a neuroendocrine circuit that evokes the pulsatile release of gonadotropin hormones (luteinizing hormone and follicle-stimulating hormone) from the pituitary. This reproductive circuit is sensitive to metabolic perturbations. When challenged with starvation, insufficient energy reserves attenuate gonadotropin release, leading to infertility. The reproductive neuroendocrine circuit is well established, composed of two populations of kisspeptin-expressing neurons (located in the anteroventral periventricular hypothalamus, Kiss1AVPV, and arcuate hypothalamus, Kiss1ARH), which drive the pulsatile activity of gonadotropin-releasing hormone (GnRH) neurons. The reproductive axis is primarily regulated by gonadal steroid and circadian cues, but the starvation-sensitive input that inhibits this circuit during negative energy balance remains controversial. Agouti-related peptide (AgRP)-expressing neurons are activated during starvation and have been implicated in leptin-associated infertility. To test whether these neurons relay information to the reproductive circuit, we used AgRP-neuron ablation and optogenetics to explore connectivity in acute slice preparations. Stimulation of AgRP fibers revealed direct, inhibitory synaptic connections with Kiss1ARH and Kiss1AVPV neurons. In agreement with this finding, Kiss1ARH neurons received less presynaptic inhibition in the absence of AgRP neurons (neonatal toxin-induced ablation). To determine whether enhancing the activity of AgRP neurons is sufficient to attenuate fertility in vivo, we artificially activated them over a sustained period and monitored fertility. Chemogenetic activation with clozapine N-oxide resulted in delayed estrous cycles and decreased fertility. These findings are consistent with the idea that, during metabolic deficiency, AgRP signaling contributes to infertility by inhibiting Kiss1 neurons.

Genetic control of encoding strategy in a food-sensing neural circuit.

Neuroendocrine circuits encode environmental information via changes in gene expression and other biochemical activities to regulate physiological responses. Previously, we showed that daf-7 TGFβ and tph-1 tryptophan hydroxylase expression in specific neurons encode food abundance to modulate lifespan in Caenorhabditis elegans, and uncovered cross- and self-regulation among these genes (Entchev et al., 2015). Here, we now extend these findings by showing that these interactions between daf-7 and tph-1 regulate redundancy and synergy among neurons in food encoding through coordinated control of circuit-level signal and noise properties. Our analysis further shows that daf-7 and tph-1 contribute to most of the food-responsiveness in the modulation of lifespan. We applied a computational model to capture the general coding features of this system. This model agrees with our previous genetic analysis and highlights the consequences of redundancy and synergy during information transmission, suggesting a rationale for the regulation of these information processing features.

Two light-activated neuroendocrine circuits arising in the eye trigger physiological and morphological pigmentation.

Two biological processes regulate light-induced skin colour change. A fast 'physiological pigmentation change' (i.e. circadian variations or camouflage) involves alterations in the distribution of pigment containing granules in the cytoplasm of chromatophores, while a slower 'morphological pigmentation change' (i.e. seasonal variations) entails changes in the number of pigment cells or pigment type. Although linked processes, the neuroendocrine coordination triggering each response remains largely obscure. By evaluating both events in Xenopus laevis embryos, we show that morphological pigmentation initiates by inhibiting the activity of the classical retinal ganglion cells. Morphological pigmentation is always accompanied by physiological pigmentation, and a melatonin receptor antagonist prevents both responses. Physiological pigmentation also initiates in the eye, but with repression of melanopsin-expressing retinal ganglion cell activity that leads to secretion of alpha-melanocyte-stimulating hormone (α-MSH). Our findings suggest a model in which eye photoperception links physiological and morphological pigmentation by altering α-MSH and melatonin production, respectively.

Blockage of neonatal leptin signaling induces changes in the hypothalamus associated with delayed pubertal onset and modifications in neuropeptide expression during adulthood in male rats

The neonatal leptin surge, occurring from postnatal day (PND) 5 to 13 and peaking at PND9 in rodents, is important for the development of neuroendocrine circuits involved in metabolic control and reproductive function. We previously demonstrated that treatment with a leptin antagonist from PND 5 to 9, coincident with peak leptin levels in the neonatal surge, modified trophic factors and markers of cell turnover and neuronal maturation in the hypothalamus of peri-pubertal rats. The kisspeptin system and metabolic neuropeptide and hormone levels were also modified. Here our aim was to investigate if the timing of pubertal onset is altered by neonatal leptin antagonism and if the previously observed peripubertal modifications in hormones and neuropeptides persist into adulthood and affect male sexual behavior. To this end, male Wistar rats were treated with a pegylated super leptin antagonist (5mg/kg, s.c.) from PND 5 to 9 and killed at PND102–103. The appearance of external signs of pubertal onset was delayed. Hypothalamic kiss1 mRNA levels were decreased in adult animals, but sexual behavior was not significantly modified. Although there was no effect on body weight or food intake, circulating leptin, insulin and triglyceride levels were increased, while hypothalamic leptin receptor, POMC and AgRP mRNA levels were decreased. In conclusion, alteration of the neonatal leptin surge can modify the timing of pubertal onset and have long-term effects on hypothalamic expression of reproductive and metabolic neuropeptides.

Blood pressure regulation by CD4+ lymphocytes expressing choline acetyltransferase.

Blood pressure regulation is known to be maintained by a neuro-endocrine circuit, but whether immune cells contribute to blood pressure homeostasis has not been defined. We previously described that CD4+ T lymphocytes that express choline acetyltransferase (ChAT), which catalyzes the synthesis of the vasorelaxant acetylcholine, relay neural signals1. Here we show that these CD4+ CD44high CD62Llow T helper cells by gene expression are a distinct T cell population defined by ChAT (CD4 TChAT). Mice lacking ChAT expression in CD4+ cells have elevated arterial blood pressure and echocardiographic assessment consistent with increased vascular resistance as compared to littermate controls. Jurkat T cells overexpressing ChAT (JTChAT) decreased blood pressure when infused into mice. Co-incubation of JTChAT increased endothelial cell levels of phosphorylated eNOS, and of nitrates and nitrites in conditioned media, indicating increased release of the potent vasodilator nitric oxide. The isolation and characterization of CD4 TChAT cells will enable analysis of the role of these cells in hypotension and hypertension, and may suggest novel therapeutic strategies by targeting cell-mediated vasorelaxation.