From autism to eating disorders and more: the role of oxytocin in neuropsychiatric disorders

Oxytocin (oxy) is a pituitary neuropeptide hormone synthesized from the paraventricular and supraoptic nuclei within the hypothalamus. Like other neuropeptides, oxy can modulate a wide range of neurotransmitter and neuromodulator activities. Additionally, through the neurohypophysis, oxy is secreted into the systemic circulation to act as a hormone, thereby influencing several body functions. Oxy plays a pivotal role in parturition, milk let-down and maternal behavior and has been demonstrated to be important in the formation of pair bonding between mother and infants as well as in mating pairs. Furthermore, oxy has been proven to play a key role in the regulation of several behaviors associated with neuropsychiatric disorders, including social interactions, social memory response to social stimuli, decision-making in the context of social interactions, feeding behavior, emotional reactivity, etc. An increasing body of evidence suggests that deregulations of the oxytocinergic system might be involved in the pathophysiology of certain neuropsychiatric disorders such as autism, eating disorders, schizophrenia, mood, and anxiety disorders. The potential use of oxy in these mental health disorders is attracting growing interest since numerous beneficial properties are ascribed to this neuropeptide. The present manuscript will review the existing findings on the role played by oxy in a variety of distinct physiological and behavioral functions (Figure 1) and on its role and impact in different psychiatric disorders. The aim of this review is to highlight the need of further investigations on this target that might contribute to the development of novel more efficacious therapies. Figure 1Oxytocin regulatory control of different and complex processes

Central mechanisms mediating the hypophagic effects of oleoylethanolamide and N-acylphosphatidylethanolamines: different lipid signals?

The spread of "obesity epidemic" and the poor efficacy of many anti-obesity therapies in the long-term highlight the need to develop novel efficacious therapy. This necessity stimulates a large research effort to find novel mechanisms controlling feeding and energy balance. Among these mechanisms a great deal of attention has been attracted by a family of phospholipid-derived signaling molecules that play an important role in the regulation of food-intake. They include N-acylethanolamines (NAEs) and N-acylphosphatidylethanolamines (NAPEs). NAPEs have been considered for a long time simply as phospholipid precursors of the lipid mediator NAEs, but increasing body of evidence suggest a role in many physiological processes including the regulation of feeding behavior. Several observations demonstrated that among NAEs, oleoylethanolamide (OEA) acts as a satiety signal, which is generated in the intestine, upon the ingestion of fat, and signals to the central nervous system. At this level different neuronal pathways, including oxytocinergic, noradrenergic, and histaminergic neurons, seem to mediate its hypophagic action. Similarly to NAEs, NAPE (with particular reference to the N16:0 species) levels were shown to be regulated by the fed state and this finding was initially interpreted as fluctuations of NAE precursors. However, the observation that exogenously administered NAPEs are able to inhibit food intake, not only in normal rats and mice but also in mice lacking the enzyme that converts NAPEs into NAEs, supported the hypothesis of a role of NAPE in the regulation of feeding behavior. Indirect observations suggest that the hypophagic action of NAPEs might involve central mechanisms, although the molecular target remains unknown. The present paper reviews the role that OEA and NAPEs play in the mechanisms that control food intake, further supporting this group of phospholipids as optimal candidate for the development of novel anti-obesity treatments

Chronic Stress, Inflammation, and Colon Cancer: A CRH System-Driven Molecular Crosstalk.

Chronic stress is thought to be involved in the occurrence and progression of multiple diseases, via mechanisms that still remain largely unknown. Interestingly, key regulators of the stress response, such as members of the corticotropin-releasing-hormone (CRH) family of neuropeptides and receptors, are now known to be implicated in the regulation of chronic inflammation, one of the predisposing factors for oncogenesis and disease progression. However, an interrelationship between stress, inflammation, and malignancy, at least at the molecular level, still remains unclear. Here, we attempt to summarize the current knowledge that supports the inseparable link between chronic stress, inflammation, and colorectal cancer (CRC), by modulation of a cascade of molecular signaling pathways, which are under the regulation of CRH-family members expressed in the brain and periphery. The understanding of the molecular basis of the link among these processes may provide a step forward towards personalized medicine in terms of CRC diagnosis, prognosis and therapeutic targeting

AMPK in the central nervous system: physiological roles and pathological implications

5′ AMP-activated protein kinase (AMPK) is considered the master metabolic regulator in all eukaryotes, as it maintains cellular energy homeostasis in a variety of tissues, including the brain. In humans, alterations in AMPK activity can lead to a wide spectrum of metabolic disorders. The relevance of this protein kinase in the pathogenesis of diabetes and metabolic syndrome is now well established. On the contrary, correlations between AMPK and brain physiopathology are still poorly characterized. The aim of this review is to summarize and discuss the current knowledge about the prospective involvement of AMPK in the onset and the progression of different neurological diseases

PACAP and migraine headache: immunomodulation of neural circuits in autonomic ganglia and brain parenchyma.

The discovery that intravenous (IV) infusions of the neuropeptide PACAP-38 (pituitary adenylyl cyclase activating peptide-38) induced delayed migraine-like headaches in a large majority of migraine patients has resulted in considerable excitement in headache research. In addition to suggesting potential therapeutic targets for migraine, the finding provides an opportunity to better understand the pathological events from early events (aura) to the headache itself. Although PACAP-38 and the closely related peptide VIP (vasoactive intestinal peptide) are well-known as vasoactive molecules, the dilation of cranial blood vessels per se is no longer felt to underlie migraine headaches. Thus, more recent research has focused on other possible PACAP-mediated mechanisms, and has raised some important questions. For example, (1) are endogenous sources of PACAP (or VIP) involved in the triggering and/or propagation of migraine headaches?; (2) which receptor subtypes are involved in migraine pathophysiology?; (3) can we identify specific anatomical circuit(s) where PACAP signaling is involved in the features of migraine? The purpose of this review is to discuss the possibility, and supportive evidence, that PACAP acts to induce migraine-like symptoms not only by directly modulating nociceptive neural circuits, but also by indirectly regulating the production of inflammatory mediators. We focus here primarily on postulated extra-dural sites because potential mechanisms of PACAP action in the dura are discussed in detail elsewhere (see X, this edition)

Identification and characterization of neuroendocrine pathways involved in the regulation of seasonal body weight cycles

Die vorliegende Dissertation beschreibt die Identifizierung und Charakterisierung von neuroendokrinen Signalwegen, die in die saisonale Körpergewichtsregulation involviert sind. Die vorliegenden Untersuchungen liefern neue Befunde über die Bedeutung des zentralen hypothalamischen Signalweges, der die Interaktion von Photoperiode und Leptin auf die saisonale Anpassung des Dsungarischen Hamsters vermittelt. Die erste Studie (Kapitel 2) konzentriert sich auf die Verteilung und Charakterisierung von ausgewählten Neuropeptiden (CART, MCH, OXB), die in der Regulation der Energiebalance eine Rolle spielen. Es scheint eine neuroanatomische Grundlage für ein neuronales CART-MCH-OXB System zu geben, das indirekt die Erzeugung der ciradianen Rhythmik beeinflusst. Die zweite Studie (Kapitel 3) beschäftigte sich mit einer möglichen Interaktion zwischen den neuropeptidhaltigen Neuronen (OXB) und dem Hauptsignalweg, dem geniculohypothalamischen Tractus. Dieser Hauptsignalweg gesteht aus NPY-enthaltenen Neuronen im IGL. OXB-ir Fasern innervieren dort die NPY Neuronen. Dies deutet auf die Existenz eines Rückkopplungsmechanismus von Neuropeptiden auf das circadiane Zeitgebersystem hin. In Kaptitel IV wurde der Effekt der saisonalen Anpassung auf die Expression von CART untersucht. Die Ergebnisse dieser Studie offenbarten eine erhöhte Anzahl von CART ir Zellen innerhalb des rostralen und ventromedialen ARC. Diese Region spielt bei Tierarten wie Ratte und Maus eine wichtige Rolle bei der Vermittlung eines inhibitorischen Effektes von Leptin auf die Nahrungsaufnahme. Deshalb haben wir uns im Kapitel V auf die Identifizierung der hypothalamischen Strukturen konzentriert, die den Effekt von Leptin im Dsungarischen Hamster vermitteln. Diese Studie ergab, dass Leptin die zelluläre Antwort (Induktion von fos) in mehreren hypothalmischen Strukturen induziert. Hierzu gehören auch die Strukturen der rostralen und ventrolateralen Region des ARC (peri-ARC). Insgesamt deuten diese Befunde darauf hin, dass der ARC als zentrales anatomisches Integrationszentrum für Körperfett und photoperiodische Information, die Energiebilanz im Dsungarischen Hamster reguliert. Der Schlussteil der Arbeit umfasst eine generelle Disksussion der Ergebnisse und einen Ausblick auf zukünftige mögliche Studien

Hypothalamic Integration of Metabolic, Endocrine, and Circadian Signals in Fish: Involvement in the Control of Food Intake

The regulation of food intake in fish is a complex process carried out through several different mechanisms in the central nervous system (CNS) with hypothalamus being the main regulatory center. As in mammals, a complex hypothalamic circuit including two populations of neurons: one co-expressing neuropeptide Y (NPY) and Agouti-related peptide (AgRP) and the second one population co-expressing pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART) is involved in the integration of information relating to food intake control. The production and release of these peptides control food intake, and the production results from the integration of information of different nature such as levels of nutrients and hormones as well as circadian signals. The present review summarizes the knowledge and recent findings about the presence and functioning of these mechanisms in fish and their differences vs. the known mammalian model

A GABAergic cell type in the lateral habenula links hypothalamic homeostatic and midbrain motivation circuits with sex steroid signaling

Abstract The lateral habenula (LHb) has a key role in integrating a variety of neural circuits associated with reward and aversive behaviors. There is limited information about how the different cell types and neuronal circuits within the LHb coordinate physiological and motivational states. Here, we report a cell type in the medial division of the LHb (LHbM) in male rats that is distinguished by: (1) a molecular signature for GABAergic neurotransmission (Slc32a1/VGAT) and estrogen receptor (Esr1/ERα) expression, at both mRNA and protein levels, as well as the mRNA for vesicular glutamate transporter Slc17a6/VGLUT2, which we term the GABAergic estrogen-receptive neuron (GERN); (2) its axonal projection patterns, identified by in vivo juxtacellular labeling, to both local LHb and to midbrain modulatory systems; and (3) its somatic expression of receptors for vasopressin, serotonin and dopamine, and mRNA for orexin receptor 2. This cell type is anatomically located to receive afferents from midbrain reward (dopamine and serotonin) and hypothalamic water and energy homeostasis (vasopressin and orexin) circuits. These afferents shared the expression of estrogen synthase (aromatase) and VGLUT2, both in their somata and axon terminals. We demonstrate dynamic changes in LHbM VGAT+ cell density, dependent upon gonadal functional status, that closely correlate with motivational behavior in response to predator and forced swim stressors. The findings suggest that the homeostasis and reward-related glutamatergic convergent projecting pathways to LHbMC employ a localized neurosteroid signaling mechanism via axonal expression of aromatase, to act as a switch for GERN excitation/inhibition output prevalence, influencing depressive or motivated behavior