Hypothalamic Pathways Research Articles

Modulation of neurogenesis and selected neuropeptides expression in the hypothalamus of rats exposed to neuroleptic

Patients treated with neuroleptics suffer from significant weight gain. Hypothalamus consists of neuronal circuits responsible for food intake regulation. Moreover, last finding suggest that adult neurogenesis occurs in the hypothalamus, which could play a role in the energy expenditure control. Considering that neuroleptics affect neural formation in the canonical neurogenic sites, we made a hypothesis that they could modulate hypothalamic neurogenesis and change expression of orexigenic/anorexigenic neuropeptides and their receptors. Experiments were carried out on adult male rats injected intraperitoneally for 1 or 28 days by the neuroleptics: olanzapine, chlorpromazine and haloperidol. Hypothalami were isolated in order to perform RT-PCR reaction and also whole brains were sliced for immunohistochemical assay. We observed that antipsychotics administered chronically supported the origin of newborn cells (Ki67 +) in the hypothalamic regions and affect the number of DCX-positive immature neurons. Furthermore, they have a distinct ability to upregulate preproorexin and orexin A expression and to increase the level of some anorexigenic factors (POMC, α-MSH), at the same time strongly decreasing nesfatin-1 signalling. Our results highlight the role of neuroleptics as potential modulators of the hypothalamic neurogenesis and contribute to better understanding the mechanisms of their side effects. They also underline the complexity of interplay between monoamine receptors, hypothalamic peptidergic pathways and adult neurogenesis which has putative but possible pharmacological applications.

Metabolic syndrome and obesity in childhood and adolescence

This book is the 19th volume in the series ‘Pediatric and Adolescent Medicine’. It presents an exhaustive review of various aspects of obesity and the closely related metabolic syndrome, which are undoubtedly amongst the most rapidly emerging and challenging clinical problems affecting all age groups in the current time. It is well established that childhood and adolescent obesity tracks into adulthood. Since the obesogenic behaviours and lifestyle patterns are established during childhood, it is important to focus on this period, both to enhance our understanding of genesis of obesity, and aid in devising means of preventing it. Also, the seeds for major cardiovascular and metabolic sequelae that are a major cause of morbidity and mortality during adulthood are sowed during this period. The content of the book is categorized under five sections namely, Definitions and Clinical Aspects, Causes, Consequences, Societal Aspects and Prevention, and Obesity Management. The chapter on definition brings out the complexities involved in defining metabolic syndrome in children and gives reference values for individual components. The next chapter on hypothalamic obesity describes the defects in hypothalamic energy regulating pathways in various acquired hypothalamic disorders as well as single gene mutations and genetic syndromes associated with obesity. The first chapter in the section, ‘Causes’ deals with the genetics of obesity and current state of information related to both individual genes as well as genome wide linkage scans. Subsequent chapters in this section are dedicated to the role of nutrition and sedentary lifestyle in the genesis of obesity. The last chapter on the socio-economic aspects brings out elegantly how socio-economic differences in lifestyle, weight and health result from unequal distribution of resources and opportunities within a society. The section, ‘Consequences’ presents updated information about the impact of obesity on its consequences like carbohydrate metabolism, pubertal development and orthopedic complications. In addition, a chapter is devoted to the less frequently recognized and discussed urogenital complications including renal disease, urolithiasis, enuresis and stress urinary incontinence. The next section, ‘Societal Aspects and Prevention’ deals with the less frequently discussed aspects of obesity - environmental conditions promoting obesity and dietary characteristics associated with metabolic syndrome. The chapter on the economic perspective provides an insight into cost of obesity and the cost-effectiveness of interventions to prevent/manage it. The chapter on obesity prevention, discusses the barriers in the management of obesity. It brings out a novel approach to obesity management- shifting the focus of responsibility away from target individuals, to modification of the environment, by development of community-wide health-promoting infrastructure that would promote sustainable implementation of a healthy lifestyle for all community members. The last section, ‘Obesity Management’ has a chapter dedicated to the role and efficacy of comprehensive treatment programmes focussing on diet, exercise and behaviour therapy. Another chapter presents the current information and experience with bariatric surgery during adolescence. Obesity is a global problem affecting both the developed and the developing countries. Thus, including the developing world's perspective would have enriched this book further. Also, there is no mention of the role of drugs (or lack of it) in the management of childhood obesity. It would have been good to include a chapter on the efficacy and safety of various drugs tried for management of adolescent obesity and metabolic syndrome and the current status of their clinical use. Overall this book presents a holistic view of the complex problems of obesity and metabolic syndrome, not just the medical issues. Authors with expertise and personal experience in a wide variety of domains including endocrinology, paediatrics, nutrition, orthopaedics, social sciences, and environmental health have contributed. The content is well organised and presented in a logical sequence, in a lucid and crisp manner. Apart from clinicians and nutritionists dealing with obese children and adolescents, the book would be of interest to, social scientists and economists interested in understanding the phenomenal rise in global prevalence of obesity. It would also help researchers in the above fields in identifying current gaps in our knowledge and developing appropriate research protocols to fill them.

Thermoregulatory Instability in Childhood: Linking the Normal Brain to Hypothalamic Storm.

Central core temperature is tightly controlled by hypothalamic centers, a feature that makes sudden changes in body temperature very unusual. A dysfunction of these hypothalamic pathways leads to Shapiro's syndrome, comprising spontaneous hypothermia, hyperhidrosis, and corpus callosum dysgenesis. Although it may affect any age, usually it presents in childhood. Variants to this syndrome with completely normal brain anatomy have been consistently reported, expanding the clinical spectrum of the syndrome. Herein, we report the case of a 4-year-old girl with Shapiro's syndrome and unaffected corpus callosum.

Emerging Hyperprolactinemic Galactorrhea in Obsessive Compulsive Disorder with a Stable Dose of Fluoxetine.

While fluoxetine (FXT) is a frequently prescribed selective serotonin reuptake inhibitor (SSRI), with few major side-effects; altered serotonergic transmissions in hypothalamic pathways might lead to a distressing, and often embarrassing, manifestation of galactorrhea by altering prolactin release in those on FXT. We report here a case of FXT-induced hyperprolactinemic galactorrhea developing late into treatment on a stable regimen, who responded well to subsequent replacement with sertraline. Based on present finding, we suggest that while SSRIs may share similar mechanisms of action, there exist individual differences in their effects on prolactin secretion pathways.

Abstract 11005: Activation of Hypothalamic Mineralocorticoid Receptor-Independent Epithelial Sodium Channels Leads to Salt-Sensitive Hypertension in Mouse Model of Metabolic Syndrome

Introduction and Hypothesis: Metabolic syndrome (MetS) is often associated with salt-sensitive hypertension. In genetic salt-sensitive hypertensive models, activation of the hypothalamic mineralocorticoid receptor (MR)-epithelial sodium channel (ENaC) pathway has been established as a major worsening factor. However, in MetS, contribution of the hypothalamic MR-ENaC pathway to salt-sensitive hypertension remains unknown. Therefore, we determined whether the hypothalamic MR-ENaC pathway activation leads to salt-sensitive hypertension in MetS. Methods and Results: Diet-induced obesity (DIO) was achieved in male C57BL/6 mice by feeding them a high-fat diet from 4 weeks of age. Mice fed a normal diet served as controls (CON). Mice at 12 weeks of age were given tap water with regular salt (RS) or 1% NaCl (high salt; HS) for 8 weeks. HS led to increased systolic blood pressure only in DIO-mice, and not in CON-mice (DIO-HS: 122±3 mmHg vs DIO-RS: 107±2 mmHg, CON-HS: 109±2 mmHg vs CON-RS: 105±1 mmHg, n=6/group, p<0.05). In DIO-mice, 24-h urinary norepinephrine excretion after salt loading was significantly higher than that before salt loading (244±18 ng/day vs 371±29 ng/day, n=6 in each, p<0.05). HS-induced hypertension was significantly prevented by intracerebroventricular infusion of the ENaC blocker benzamil (Ben), but not the MR blocker spironolactone (Spl; DIO-HS-Vehicle 122±1 mmHg, DIO-HS-Ben 108±1 mmHg, DIO-HS-Spl 119±1 mmHg, n=6 in each, p<0.05). Expression of hypothalamic serum and glucocorticoid-regulated kinase (SGK) 1, a marker of MR activity, did not differ between in CON-mice and DIO-mice. However, the SGK1 phosphorylation level was greater in DIO-mice than in CON-mice, suggesting MR-independent SGK1 activation. Water intake and urinary sodium excretion did not differ between in DIO-HS-Vehicle and DIO-HS-Ben. Interestingly, salt loading-induced plasma arginine vasopressin (AVP) secretion was significantly prevented in DIO-HS-Ben. Conclusions: These findings suggest that salt-induced hypertension in DIO-mice results from MR-independent hypothalamic SGK1-ENaC activation with systemic AVP secretion. Hypothalamic ENaC could be a novel therapeutic target in salt-induced hypertension of MetS.

Photoperiod Regulates vgf-Derived Peptide Processing in Siberian Hamsters.

VGF mRNA is induced in specific hypothalamic areas of the Siberian hamster upon exposure to short photoperiods, which is associated with a seasonal decrease in appetite and weight loss. Processing of VGF generates multiple bioactive peptides, so the objective of this study was to determine the profile of the VGF-derived peptides in the brain, pituitary and plasma from Siberian hamsters, and to establish whether differential processing might occur in the short day lean state versus long day fat. Antisera against short sequences at the C- or N- termini of proVGF, as well as against NERP-1, TPGH and TLQP peptides, were used for analyses of tissues, and both immunohistochemistry and enzyme linked immunosorbent assay (ELISA) coupled with high-performance liquid (HPLC) or gel chromatography were carried out. VGF peptide immunoreactivity was found within cortex cholinergic perikarya, in multiple hypothalamic nuclei, including those containing vasopressin, and in pituitary gonadotrophs. ELISA revealed that exposure to short day photoperiod led to a down-regulation of VGF immunoreactivity in the cortex, and a less pronounced decrease in the hypothalamus and pituitary, while the plasma VGF levels were not affected by the photoperiod. HPLC and gel chromatography both confirmed the presence of multiple VGF-derived peptides in these tissues, while gel chromatography showed the presence of the VGF precursor in all tissues tested except for the cortex. These observations are consistent with the view that VGF-derived peptides have pleiotropic actions related to changing photoperiod, possibly by regulating cholinergic systems in the cortex, vasopressin hypothalamic pathways, and the reproductive axis.

Dissecting the hypothalamic pathways that underlie innate behaviors.

Many complex behaviors that do not require learning are displayed and are termed innate. Although traditionally the subject matter of ethology, innate behaviors offer a unique entry point for neuroscientists to dissect the physiological mechanisms governing complex behaviors. Since the last century, converging evidence has implicated the hypothalamus as the central brain area that controls innate behaviors. Recent studies using cutting-edge tools have revealed that genetically-defined populations of neurons residing in distinct hypothalamic nuclei and their associated neural pathways regulate the initiation and maintenance of diverse behaviors including feeding, sleep, aggression, and parental care. Here, we review the newly-defined hypothalamic pathways that regulate each innate behavior. In addition, emerging general principles of the neural control of complex behaviors are discussed.

Hypothalamic CaMKKβ mediates glucagon anorectic effect and its diet-induced resistance.

ObjectiveGlucagon receptor antagonists and humanized glucagon antibodies are currently studied as promising therapies for obesity and type II diabetes. Among its variety of actions, glucagon reduces food intake, but the molecular mechanisms mediating this effect as well as glucagon resistance are totally unknown.MethodsGlucagon and adenoviral vectors were administered in specific hypothalamic nuclei of lean and diet-induced obese rats. The expression of neuropeptides controlling food intake was performed by in situ hybridization. The regulation of factors of the glucagon signaling pathway was assessed by western blot.ResultsThe central injection of glucagon decreased feeding through a hypothalamic pathway involving protein kinase A (PKA)/Ca2+-calmodulin-dependent protein kinase kinase β (CaMKKβ)/AMP-activated protein kinase (AMPK)-dependent mechanism. More specifically, the central injection of glucagon increases PKA activity and reduces protein levels of CaMKKβ and its downstream target phosphorylated AMPK in the hypothalamic arcuate nucleus (ARC). Consistently, central glucagon significantly decreased AgRP expression. Inhibition of PKA and genetic activation of AMPK in the ARC blocked glucagon-induced anorexia in lean rats. Genetic down-regulation of glucagon receptors in the ARC stimulates fasting-induced hyperphagia. Although glucagon was unable to decrease food intake in DIO rats, glucagon sensitivity was restored after inactivation of CaMKKβ, specifically in the ARC. Thus, glucagon decreases food intake acutely via PKA/CaMKKβ/AMPK dependent pathways in the ARC, and CaMKKβ mediates its obesity-induced hypothalamic resistance.ConclusionsThis work reveals the molecular underpinnings by which glucagon controls feeding that may lead to a better understanding of disease states linked to anorexia and cachexia.

Abstract 012: Brain Endoplasmic Reticulum (ER) Stress Reduces Appetite and Increases Blood Pressure Independent of the Melanocortin-4 Receptor in Rats

Although there is evidence that chronic endoplasmic reticulum (ER) stress affects hypothalamic pathways that regulate food intake, body weight and blood pressure (BP), the specific mechanisms are unclear. One key pathway for controlling energy balance and BP is the central nervous system (CNS) melanocortin system. However, the importance of this system in mediating the effects of ER stress on metabolic and cardiovascular function is unclear. In this study we examined the role of the melanocortin-4 receptor (MC4R) in controlling blood pressure (BP) and metabolic functions during chronic brain ER stress. MC4R knockout (MC4R -/- , n=5) and control wild-type Wistar Hannover rats (WT, n=5) were implanted with blood pressure (BP) telemetry transmitters and an intracerebroventricular (ICV) cannula was inserted into the third ventricle at 22 weeks of age. After 10 days of recovery, food intake, BP and HR were measured 24-hrs/day. After stable baseline measurements for 4 days, thapsigargin (TG, 5μg/5μl, ICV) was injected daily for 3 consecutive days to induce ER stress. At baseline, MC4R -/- rats ate 23% more food and were 41% heavier than WT rats. MAP was slightly higher (115±3 vs. 109±2 mmHg) and HR was lower (318±10 vs. 363±6 bpm) in MC4R-/- rats. Induction of brain ER stress decreased food intake (26%) while causing no changes in blood glucose levels (WT: 94±4 vs. 98±3 and MC4R-/-: 110±6 vs.116±4 mg/dl) or HR in both groups. Induction of brain ER stress also raised BP in both groups (7 and 5 mmHg, respectively for WT and MC4R -/- rats). These results suggest that chronic brain ER stress-induced reductions in appetite and increases in BP are independent of MC4R signaling. (NHLBI-PO1HL51971, NIGMS- P20GM104357 and AHA SDG5680016)

A talk between fat tissue, gut, pancreas and brain to control body weight

The incidence of obesity and its related disorders are increasing at a rate of pandemic proportions. Understanding the mechanisms behind the maintenance of energy balance is fundamental in developing treatments for clinical syndromes including obesity and diabetes. A neural network located in the nucleus of the solitary tract–area postrema complex in the hindbrain and the hypothalamus in the forebrain has long been implicated in the control of energy balance. In the hypothalamus this central neuronal network consists of small populations of nuclei with distinct functions such as the arcuate nucleus (ARH), the paraventricular nuclei of the hypothalamus (PVH), the dorsomedial (DMH), the ventromedial (VMH) and the lateral hypothalamus (LH). These hypothalamic areas form interconnected neuronal circuits that respond to fluctuations in energy status by altering the expression of neuropeptides, leading to changes in energy intake and expenditure. Regulation of these hypothalamic nuclei involves the actions of orexigenic peptides (ie ghrelin), which act to stimulate energy intake and decrease energy expenditure, and anorexigenic peptides (ie. leptin and insulin), which act to reduce energy intake and stimulate energy expenditure. Here we review the role of the ARH, DMH and PVH in the control of energy homeostasis and how recent advances in research technologies (Cre-loxP technology, optogenetics and pharmacogenetics) have shed light on the role of these hypothalamic nuclei in the control of energy balance. Such novel findings include the implication of ARH POMC and AgRP neurons in the browning of white adipose tissue to regulate energy expenditure as well as the likely existence of divergent hypothalamic pathways in the DMH and PVH in the control of food intake and energy expenditure.

Early life origins of metabolic disease: Developmental programming of hypothalamic pathways controlling energy homeostasis.

A wealth of animal and human studies demonstrate that perinatal exposure to adverse metabolic conditions - be it maternal obesity, diabetes or under-nutrition - results in predisposition of offspring to develop obesity later in life. This mechanism is a contributing factor to the exponential rise in obesity rates. Increased weight gain in offspring exposed to maternal obesity is usually associated with hyperphagia, implicating altered central regulation of energy homeostasis as an underlying cause. Perinatal development of the hypothalamus (a brain region key to metabolic regulation) is plastic and sensitive to metabolic signals during this critical time window. Recent research in non-human primate and rodent models has demonstrated that exposure to adverse maternal environments impairs the development of hypothalamic structure and consequently function, potentially underpinning metabolic phenotypes in later life. This review summarizes our current knowledge of how adverse perinatal environments program hypothalamic development and explores the mechanisms that could mediate these effects.

THE EFFECT OF MASSAGE STIMULATION TO REDUCTION OF TUMOR NECROTIC FACTOR-ALFA (TNF-α) AND INTERLEUKIN-6 (IL-6) IN PRETERM, LOW BIRTH WEIGHT APPROPRIATE WITH GESTATIONAL AGE INFANTS

Preterm condition gives a new stressful environment to infants. This condition needs a good and gradual adaptation. External environmental conditions, treatment, care and good nutrition are needed. Massage stimulation in preterm infants is a method that can prepare preterm infants’ adaptation through the critical post-birth period. A good adaptation of the system will provide better organ homeostasis including the immune system.There are three paths of mechanisms that can explain how massage stimulation can regulate pro-inflammatory cytokines TNF-α and IL-6. The first: the hypothalamus pathway, massage stimulation act as a comfort stimulation that can control (inhibit) the release of pro-inflammatory cytokines TNF-α and IL-6 by macrophages; second: through activation of vagus nerve, massage stimulation act as a tactile stimulation which activates vagal system and the immune system; third: the hypothalamic-pituitary pathway, massage stimulation act as a kinesthetic stimulation that activates the hypothalamic-pituitary to release cortisol, GH (Growth hormone) and IGF-1 (Insulin-like Growth Factor 1). A randomized controlled trial about massage stimulation on preterm infants was performed in Sanglah Hospital Denpasar on 2011. The study revealed a different level of cytokine pro-inflammation TNF-α (p=0.025) and IL-6 (p=0,001) comparing before and after condition massage stimulation. Outcome of body weight were also different at before and after massage stimulation, with p value 0.042.Mechanisms of massage stimulation affect the immune system of preterm infants through regulation of inhibition the release of pro-inflammatory cytokine TNF-α, IL-6 by macrophages, through three main pathways: the hypothalamic; activation of the vagus nerve and the hypothalamic-pituitary-adrenal axis.

FDWI Evaluation of Hypothalamic Appetite Regulation Pathways in Mice Genetically Deficient in Leptin or Neuropeptide Y

We evaluate the contribution of leptin-dependent anorexigenic pathways and neuropeptide Y (NPY)-dependent orexigenic pathways to the changes in hypothalamic water diffusion parameters observed in vivo by functional diffusion weighted MRI (fDWI). Mice genetically deficient in leptin (B6.V-Lep (ob) /J) or NPY (129S-Npy (tm1Rpa) /J) and the corresponding wild-type controls, were subjected to sequential isocaloric feeding, fasting and recovery regimes. Non-invasive fDWI measurements were performed under these conditions, and complemented with parallel determinations of food and water consumption, respiratory exchange ratio (RER), locomotor activity and endocrine profiles. Control mice showed significant increases in hypothalamic water diffusion parameters upon fasting, returning to normal values in the recovery period. Leptin deficient mice depicted permanently increased water diffusion parameters under all feeding conditions as compared to wild type controls, without important changes upon fasting or recovery. These results paralleled sustained increases in food and water intake, significantly augmented body weight, and decreased RER values or locomotor activity, thus configuring an obese phenotype. NPY-deficient mice showed significantly reduced increases (or even slight decreases) in the water diffusion parameters upon fasting as compared to wild type controls, paralleled by decreased food and water intake during the recovery period. In conclusion, leptin deficiency results in sustained orexigenic stimulation, leading to increased water diffusion parameters, while NPY deficiency lead to reduced orexigenic stimulation and water diffusion parameters. Diffusion changes are proposed to reflect net astrocytic volume changes induced by the balance between the orexigenic and anorexigenic firings of AgRP/NPY and POMC/CART neurons, respectively. Together, our results suggest that fDWI provides an adequate tool to investigate hypothalamic appetite disorders.

Characterization of a mammalian prosencephalic functional plan.

Hypothalamic organizational concepts have greatly evolved as the primary hypothalamic pathways have been systematically investigated. In the present review, we describe how the hypothalamus arises from a molecularly heterogeneous region of the embryonic neural tube but is first differentiated as a primary neuronal cell cord (earliest mantle layer). This structure defines two axes that align onto two fundamental components: a longitudinal tractus postopticus(tpoc)/retinian component and a transverse supraoptic tract(sot)/olfactory component. We then discuss how these two axonal tracts guide the formation of all major tracts that connect the telencephalon with the hypothalamus/ventral midbrain, highlighting the existence of an early basic plan in the functional organization of the prosencephalic connectome.

Role of the mTOR pathway in the central regulation of energy balance

The pathway of the mammalian (or mechanistic) target of rapamycin kinase (mTOR) responds to different signals such as nutrients and hormones and regulates many cellular functions as the synthesis of proteins and lipids, mitochondrial activity and the organization of the cytoskeleton. At the cellular level, mTOR forms two distinct complexes: mTORC1 and mTORC2. This review intends to summarize the various recent advances on the role of these two protein complexes in the central regulation of energy balance. mTORC1 activity modulates energy balance and metabolic responses by regulating the activity of neuronal populations, such as those located in the arcuate nucleus of the hypothalamus. Recent studies have shown that activity of the hypothalamic mTORC1 pathway varies according to cell and stimulus types, and that this signaling cascade regulates food intake and body weight in response to nutrients, such as leucine, and hormones like leptin, ghrelin and triiodothyronine. On the other hand, mTORC2 seems to be involved in the regulation of neuronal morphology and synaptic activity. However, its function in the central regulation of the energy balance is less known. Dysregulation of mTORC1 and mTORC2 is described in obesity and type 2 diabetes. Therefore, a better understanding of the molecular mechanisms involved in the regulation of energy balance by mTOR may lead to the identification of new therapeutic targets for the treatment of these metabolic pathologies.

Alarming evidence: high fat diet alters brainstem circuits prior to the development of obesity.

The prevalence of obesity and its associated diseases, including type 2 diabetes mellitus, has substantially increased worldwide, placing a significant burden both on individuals and society as a whole. This healthcare crisis requires the development of novel interventions and effective obesity prevention strategies. Alarmingly, numerous recent studies have emphasized the importance of gestational and perinatal periods, which have a critical influence on the offspring's weight and metabolism in the development of obesity (Kubo et al. 2014; Sullivan & Grove 2010; Sullivan et al. 2011). Considering the high incidence of obesity in the general population, including women of child-bearing age, studies investigating the effect of overnutrition and a high fat diet (HFD) during gestational and perinatal periods on the health of offspring have particular relevance and importance for global health and economy. It has been demonstrated that maternal hyperglycaemia or gestational diabetes is associated with a higher risk of childhood obesity and this risk increases if the mother is overweight or obese (Kubo et al. 2014). Studies using rodent models showed that maternal HFD consumption or overnutrition contributes to the development of hyperphagia (Sullivan et al. 2011). Upregulation of orexigenic peptides, decreased sensitivity to leptin, and abnormalities of the central melanocortin, serotonin and dopamine systems have also been reported and associated with maternal HFD consumption (Chang et al. 2008; Sullivan & Grove, 2010; Sullivan et al. 2011). These findings have been linked to changes in hypothalamic pathways controlling feeding circuits and disruption of these circuits contributes to the development of obesity. The hypothalamus works in concert with brainstem autonomic centres to maintain homeostatic functions. A variety of studies have demonstrated that diet-induced obesity causes multiple changes in vagal neural circuits, which compromise the function of both the vagal afferents and efferents; however, in these studies it is difficult to differentiate the effect of diet and/or obesity. Therefore, the following question arises: does HFD alone modulate vagal neural circuits and if it does, when do the changes occur? Previous studies demonstrated the vulnerability of the brainstem autonomic neural circuits to exposure to HFD and postulated that HFD dysregulates the vagal reflex control independently of obesity (Covasa & Ritter, 2000; Swartz et al. 2010; Browning et al. 2013); however, direct evidence demonstrating the effect of perinatal HFD on neuronal excitability remained unknown. Bhagat and his coworkers have designed an elegant study, reported in this issue of The Journal of Physiology (Bhagat et al. 2015), to investigate the consequences of perinatal HFD consumption on vagal motor neurons using electrophysiological, pharmacological and morphological approaches. Their study focuses on gastric-related motor neurons and demonstrates that perinatal HFD consumption dysregulates neurotransmitter release from synaptic inputs and reduces the excitability of gastric-projecting neurons in the dorsal motor nucleus of the vagus. These changes were accompanied by increased size and dendritic arborization of gastric-projecting vagal motor neurons, and were observed prior to the development of obesity. The observation that the changes occur before the development of obesity gives a particular importance to these novel findings, because it points out that the attenuation of the vago-vagal reflex signalling exists before the development of obesity. In agreement with previous findings that show the vulnerability of autonomic circuits, the authors’ data demonstrate that the perinatal period is a critical time, which may determine the weight and/or metabolism of the offspring. On the other hand, further studies are needed to establish the particular time frame (e.g. in utero or pre-weaning phrases) responsible for these changes to answer the question: are these changes in vagal neural circuits caused by perinatal HFD exposure reversible or not, and what are the underlying mechanisms? Taken together, increasing evidence, including the current study by Bhagat et al., demonstrates that maternal and perinatal diet has a significant effect on the central nervous system, including the autonomic pathways that regulate homeostatic functions. Furthermore, these changes in vagal circuitry may define the susceptibility to obesity and metabolic disorders; however, further detailed studies are needed to delineate the underlying mechanisms.

Hypothalamic pathways for energy intake and expenditure including recent insights into circadian cycles

Hypothalamic pathways for energy intake and expenditure including recent insights into circadian cycles

Abstract 20343: Leptin and the Developmental Origins of Hypertension

Introduction: Individuals with growth restriction through 2 years of age are relatively protected from adult obesity, but they are at increased risk of adult hypertension. Modeling this in mice, neonatal growth restriction (GR) leads to neonatal leptin deficiency, impaired neurodevelopment, adult growth restriction and adult hypertension. Hypothesis: We hypothesized that neonatal leptin deficiency during a window of developmental plasticity permanently increases central leptin sensitivity with subsequent renal sympathetic over-activation and hypertension. Methods: From day 4 to 14, C57BL/6 mice were randomized to vehicle (0.9% NaCl) or leptin at a dose shown to normalize the plasma levels of GR mice without impacting neonatal growth (1 mg/kg/d, intraperitoneal). GR mice were identified by weanling weights below the 10th percentile. Beginning at 4 months, adult phenotypes were assessed. Results: Compared to normal weight controls, adult GR mice had significantly increased leptin receptor mRNA expression within the arcuate nucleus of the hypothalamus (ARC), decreased adult food intake (0.09±0.01 vs. 0.13±0.02g/g/d; p<0.05), decreased adult body weight, and exaggerated leptin-triggered increases in both renal sympathetic nerve activity (29+/-11 vs. -9+/-6% change from baseline, p<0.01 for GR versus control) and systolic blood pressure (8+/-3 vs. -1+/-6% change from baseline, p<0.05 for icv leptin versus icv saline in GR mice). Leptin supplementation normalized the hypothalamic gene expression and leptin responsiveness of GR adult mice in association with a programmed suppression in leptin-triggered activation of signal transducer and activator of transcription 3 (STAT3). Conclusions: Neonatal GR-related leptin deficiency is associated with a sustained increase in ARC leptin receptor expression and enhanced adult leptin responsiveness. This heightened central leptin responsiveness may contribute to the increased risk of hypertension seen patients with a history of perinatal growth restriction. We are currently assessing the effects of neonatal GR and neonatal leptin administration on cell-specific leptin-mediated hypothalamic signaling pathways.

Visualization of oxytocin release that mediates paired pulse facilitation in hypothalamic pathways to brainstem autonomic neurons.

Recent work has shown that oxytocin is involved in more than lactation and uterine contraction. The paraventricular nucleus of the hypothalamus (PVN) contains neuroendocrine neurons that control the release of hormones, including vasopressin and oxytocin. Other populations of PVN neurons do not release hormones, but rather project to and release neurotransmitters onto other neurons in the CNS involved in fluid retention, thermoregulation, sexual behavior and responses to stress. Activation of oxytocin receptors can be cardioprotective and reduces the adverse cardiovascular consequences of anxiety and stress, yet how oxytocin can affect heart rate and cardiac function is unknown. While anatomical work has shown the presence of peptides, including oxytocin, in the projections from the PVN to parasympathetic nuclei, electrophysiological studies to date have only demonstrated release of glutamate and activation of fast ligand gated receptors in these pathways. In this study, using rats, we directly show, using sniffer CHO cells that express oxytocin receptors and the Ca2+ indicator R-GECO, that optogenetic activation of channelrhodopsin-2 (ChR2) expressing PVN fibers in the brainstem activates oxytocin receptors in the dorsomotor nucleus of the vagus (DMNV). We also demonstrate that while a single photoactivation of PVN terminals only activates glutamatergic receptors in brainstem cardiac vagal neurons (CVNs), neurons that dominate the neural control of heart rate, both the paired pulse facilitation, and sustained enhancement of glutamate release in this pathway is mediated by activation of oxytocin receptors. Our results provide direct evidence that a pathway from the PVN likely releases oxytocin and enhances short-term plasticity of this critical autonomic connection.

30.: Quantifying abnormal eating behavior and metabolic changes in frontotemporal dementia and motor neuron disease

Abnormal eating behavior is a core diagnostic feature for behavioral frontotemporal dementia (bvFTD). We aimed to define the patterns of eating behavior and intake in bvFTD and semantic dementia (SD) compared to Alzheimer’s disease (AD) and controls. We hypothesized that these changes are not the result of increased hunger/decreased satiety, but may relate to disinhibition and dysfunction of hypothalamic pathways that control appetite. We examined the association between eating behaviors and metabolic health of FTD compared with motor neuron disease (MND), which shares a common pathology with FTD, and where the metabolic profile has been hypothesized to affect disease progression. Carers of 75 dementia patients (21 bvFTD, 26 SD, 28 AD) and 18 healthy control subjects completed validated questionnaires on appetite and eating behavior. All participants completed surveys on their hunger and satiety. Body mass index (BMI), and blood samples measuring cholesterol and insulin levels were prospectively collected. BMI measurements were compared to a cohort of 100 MND (bulbar and limb) and FTD/ MND patients. bvFTD patients displayed significant abnormalities in all domains of eating compared to AD patients. bvFTD patients had significantly increased carbohydrate intake and SD patients significantly increased sugar intake. Despite increased intake in the FTD groups, their hunger/satiety scores did not differ from the control group. BMI measurements were significantly higher in the FTD and FTD/MND groups than in the MND (bulbar and limb) and control groups. Increased BMI in the bvFTD and SD groups was also significantly associated with abnormal eating behavior. BvFTD patients had significantly increased insulin levels, triglyceride, cholesterol ratios, and lower high-density lipoprotein cholesterol levels compared to controls. Abnormal eating behavior is prominent in bvFTD and SD patients, and is associated with increased sugar and carbohydrate intake, and is not the result of increased hunger and lower satiety. Similar findings have been shown in obese patients, attributed to disinhibition, orbitofrontal pathology and dysfunction of hypothalamic pathways that control appetite, suggesting similar pathways may be affected in FTD. Abnormal eating behavior in FTD is associated with changes in BMI, and a blood metabolic profile similar to that seen in MND. Despite similar pathology however, BMI in all forms of MND appears lower than in FTD.