For gut microbiota to influence behavior, microorganisms should be able to interfere with specific brain neurochemical circuitries. Understanding these molecular mechanisms is a key task in the new microbiota-gut-brain field. Recent studies have revealed that one major mechanistic link is the modulation of neuropeptide signaling by homologous bacterial proteins acting both directly and indirectly via production of neuropeptide-reactive immunoglobulins.

In the present commentary we expand on two concepts relevant to understanding affliliative bonding. Differences and similarities between the functions and actions of oxytocin and vasopressin are difficult to study but may be critical to an understanding of mechanisms for social bonding. What is termed here a “trait of affiliation” may reflect in part the capacity of these same peptides to program the developing nervous system.

Insect molting is elicited by a class of polyhydroxylated steroids, ecdysteroids, that originate in the prothoracic glands. Ecdysteroid synthesis in the prothoracic glands is controlled in large measure by a peptide hormone from the brain, prothoracicotropic hormone (PTTH), which exists in two forms and is released into the general circulation as a result of environmental and developmental cues. The means by which PTTH activates the prothoracic glands has been examined at the cellular level and the data reveal the involvement of (...) cAMP, calcium, calmodulin, cAMP‐dependent protein kinase and the ultimate phosphorylation of a 34 kDa protein tentatively identified as ribosomal protein S6. (shrink)

Rare copy number variants have a prominent role in the aetiology of schizophrenia and other neuropsychiatric disorders. Substantial risk for schizophrenia is conferred by large CNVs at several loci, including microdeletions at 1q21.1, 3q29, 15q13.3 and 22q11.2 and microduplication at 16p11.2. However, these CNVs collectively account for a small fraction of cases, and the relevant genes and neurobiological mechanisms are not well understood. Here we performed a large two-stage genome-wide scan of rare CNVs and report the significant association of copy (...) number gains at chromosome 7q36.3 with schizophrenia. Microduplications with variable breakpoints occurred within a 362-kilobase region and were detected in 29 of 8,290 patients versus 2 of 7,431 controls in the combined sample. All duplications overlapped or were located within 89 kilobases upstream of the vasoactive intestinal peptide receptor gene VIPR2. VIPR2 transcription and cyclic-AMP signalling were significantly increased in cultured lymphocytes from patients with microduplications of 7q36.3. These findings implicate altered vasoactive intestinal peptide signalling in the pathogenesis of schizophrenia and indicate the VPAC2 receptor as a potential target for the development of new antipsychotic drugs. © 2011 Macmillan Publishers Limited. All rights reserved. (shrink)

Honeybees display a fascinating social behavior. The structural basis for this behavior, which made the bee a model organism for the study of communication, learning and memory formation, is the tiny insect brain. Neurons of the brain communicate via messenger molecules. Among these molecules, neuropeptides represent the structurally most‐diverse group and occupy a high hierarchic position in the modulation of behavior. A recent analysis of the honeybee genome revealed a considerable number of predicted (200) and confirmed (100) neuropeptides (...) in this insect.1 Is this quantity merely the result of advanced mass spectrometric techniques and bioinformatic tools or does it reflect the expression of more of these important messenger molecules, more than known from other insects studied so far? Our analysis of the data suggests that the social behavior is by no means correlated with a specific increase in the number of neuropeptides. Indeed, the honeybee genome is likely to contain fewer neuropeptide genes, neuropeptide paralogues and neuropeptide receptor genes than the solitary fruitfly Drosophila. BioEssays 29:416–421, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Genetic manipulation and purification techniques are facilitating research into the biology of arthropod neuropeptides. The red pigment concentrating hormone (RPCH)/ adipokinetic hormone (AKH) family are a conserved group of peptides which were first recognized for their hormonal activities. Biosynthesis of AKH in the grasshopper seems to proceed via a large protein precursor (12 kDa) in the cell body of the neuron, which implies precise coordination of synthesis and neural activity. Beginning with a 10 amino acid stretch of known precursor (...) protein sequence, an oligonucleotide primer approach is being used to clone a recombinant AKH gene. Once achieved, this will allow fundamental questions on the biochemistry and physiology of neuropeptides to be addressed. Such work in an arthropod system raises the intriguing possibility of studying neuropeptide level and synthetic activity in single, defined neurons. (shrink)

Bioactive peptides are a group of diverse intercellular signalling molecules. Almost half a century of research on this topic has resulted in an enormous amount of data. In this essay, a general perspective to interpret all these data will be given. In classical endocrinology, neuropeptides were thought of as simple signalling molecules that each elicit one response. However, the fact that the total bioactive peptide signal is far from simple puts this view under pressure. Cells and tissues express many (...) different bioactive peptides and they are also able to respond to many different bioactive peptides, indicating that multiple receptors and signal transduction pathways are present in a single cell. Therefore, the authors suggest that the bioactive peptide signalling system should be regarded in the context of network and systems biology. Bioactive peptides can best be viewed as an extension of the protein interaction network that allows regulating and fine‐tuning the metabolism of the different cells and tissues in the body. The cell thus responds to the ‘peptidome’ instead of to a single peptide. The intracellular part of this signalling network consists of the various signalling transduction cascades. Recently, new systems biology approaches have emerged for the modelling of cell signalling. The network and systems biology approach is also able to shed new light on the evolution of intercellular signalling. (shrink)

Here we evaluate our current understanding of the function of the nervous system in Hydra, a non‐bilaterian animal which is among the first metazoans that contain neurons. We highlight growing evidence that the nervous system, with its rich repertoire of neuropeptides, is involved in controlling resident beneficial microbes. We also review observations that indicate that microbes affect the animal's behavior by directly interfering with neuronal receptors. These findings provide new insight into the original role of the nervous system, and (...) suggest that it emerged to orchestrate multiple functions including host‐microbiome interactions. The excitement of future research in the Hydra model now relies on uncovering the common rules and principles that govern the interaction between neurons and microbes and the extent to which such laws might apply to other and more complex organisms. (shrink)

Neuropeptides vasopressin and oxytocin regulate a variety of behaviors ranging from maternal and pair bonding to aggression and fear. Their role in modulating fear responses has been widely recognized, but not yet well understood. Animal and human studies indicate the major role of the amygdala in controlling fear and anxiety. The amygdala is involved in detecting threat stimuli and linking them to defensive behaviors. This is accomplished by projections connecting the central nucleus of the amygdala (CeA) to the brain (...) stem and to hypothalamic structures, which organize fear responses. A recent study by Huber et al1 demonstrates that vasopressin and oxytocin modulate the excitatory inputs into the CeA in opposite manners. Therefore this finding elucidates the mechanisms through which these neuropeptides may control the expression of fear. BioEssays 27:869–873, 2005. © 2005 Wiley Periodicals, Inc. (shrink)

Osmoregulation in insects is an essential process whereby changes in hemolymph osmotic pressure induce the release of diuretic or antidiuretic hormones to recruit individual osmoregulatory responses in a manner that optimizes overall homeostasis. However, the mechanisms by which different osmoregulatory circuits interact with other homeostatic networks to implement the correct homeostatic program remain largely unexplored. Surprisingly, recent advances in insect genetics have revealed several important metabolic functions are regulated by classic osmoregulatory pathways, suggesting that internal cues related to osmotic and (...) metabolic perturbations are integrated by the same hormonal networks. Here, we review our current knowledge on the network mechanisms that underpin systemic osmoregulation and discuss the remarkable parallels between the hormonal networks that regulate body fluid balance and those involved in energy homeostasis to provide a framework for understanding the polymodal optimization of homeostasis in insects. (shrink)

Neuronal signalling involves multiple neuropeptides that are diverse in structure and function. Complex patterns of tissue‐specific expression arise from alternate RNA splicing of neuropeptide‐encoding gene transcripts. The pattern of expression and its role in cell signalling is diffecult to study at the level of single neurons in the complex vertebrate brain. However, in the model molluscan system, Lymnaea, it is possible to show that alternate mRNA expression of the FMRFamide gene is specific to single identified neurons. Two different transcripts (...) are expressed in a mutually exclusive manner in different neurons. Post‐translational processing of the two precursor proteins leads to completely distinct sets of neuropeptide transmitters. The function of these transmitter cocktails, resulting from alternate mRNA splicing, was studied physiologically in identified neurons forming part of a behaviourally important network regulating heartbeat. (shrink)

The neurobiological systems that mediate the basic emotions are beginning to be understood. They appear to be constituted of genetically coded, but experientially refined executive circuits situated in subcortical areas of the brain which can coordinate the behavioral, physiological and psychological processes that need to be recruited to cope with a variety of primal survival needs (i.e., they signal evolutionary fitness issues). These birthrights allow newborn organisms to begin navigating the complexities of the world and to learn about the values (...) and contingencies of the environment. Some of these systems have been identified and characterized using modern neuroscientific and psychobiological tools. The fundamental emotional systems can now be defined by the functional psychobiological characteristics of the underlying circuitries ? characteristics which help coordinate behavioral, physiological and psychological aspects of emotionality, including the valenced affective feeling states that provide fundamental values for the guidance of behavior. The various emotional circuits are coordinated by different neuropeptides, and the arousal of each system may generate distinct affective/neurodynamic states and imbalances may lead to various psychiatric disorders. The aim of this essay is to discuss the underlying conceptual issues that must be addressed for additional progress in understanding the nature of primary process affective consciousness. (shrink)

Over many centuries, the homing pigeon has been selectively bred for returning home from a distant location. As a result of this strong selective pressure, homing pigeons have developed an excellent spatial navigation system. This system passes through the hippocampal formation, which shares many striking similarities to the mammalian hippocampus; there are a host of shared neuropeptides, interconnections, and its role in the storage and manipulation of spatial maps. There are some notable differences as well: there are unique connectivity (...) patterns and spatial encoding strategies. This review summarizes the comparisons between the avian and mammalian hippocampal systems, and the responses of single neurons in several general categories: location and place cells responding in specific areas, path and goal cells responding between goal locations, context-dependent cells that respond before or during a task, and pattern, grid, and boundary cells that increase firing at stable intervals. Head-direction cells, responding to a specific compass direction, are found in mammals and other birds but not to date in pigeons. By studying an animal that evolved under significant adaptive pressure to quickly develop a complex and efficient spatial memory system, we may better understand the comparative neurology of neurospatial systems, and plot new and potentially fruitful avenues of comparative research in the future. (shrink)

Ever since it was discovered in hydra, regeneration has remained a stimulating question for developmental biologists. Cellular approaches have revealed that, within the first few hours of apical or basal hydra regeneration, differentiation and determination of nerve cells are the primary cellular events detectable. The head and foot activators (HA, FA), neuropeptides that are released upon injury, are signaling molecules involved in these processes. In conditions where it induces cellular differentiation or determination, HA behaves as an agonist of the (...) cyclic AMP (cAMP) pathway involving the modulation of CREB nuclear transcription factor activity. This cascade would be required for proper regeneration, regardless of whether the polarity involved is apical or basal. Modulations of the protein kinase C pathway, which have been shown to affect apical or basal positional values, might signal to bring about this polarity; however, endogenous ligands responsible for this modulation are as yet unknown. (shrink)

The prevalence of obesity skyrocketed over the past decades to become a significant public health problem. Obesity is recognized as a low-grade inflammatory disease and is linked with several comorbidities such as diabetes, circulatory disease, common neurodegenerative diseases, as well as chronic pain. Adipocytes are a major neuroendocrine organ that continually, and systemically, releases pro-inflammatory factors. While the exact mechanisms driving obesity-induced pain remain poorly defined, nociceptors hypersensitivity may result from the systemic state of inflammation characteristic of obesity as well (...) as weight surplus-induced mechanical stress. Obesity and pain also share various genetic mutations, lifestyle risk factors, and metabolic pathways. For instance, fat pads are often found hyper-innervated and rich in immune cell types of multiple origins. These immunocytes release cytokines, amplifying nociceptor function, which, in turn, via locally-released neuropeptides sustain immunocytes’ function. Here, we posit that along with mechanical stressed stemming from extra weight, the local neuro-immune interplay occurring within the fat pads maintains the state of chronic low-grade inflammation and heightens sensory hypersensitivity. Overall, stopping the harmful neuro-immune crosstalk may constitute a novel pathway to prevent obesity-associated comorbidities, including neuronal hypersensitivity. (shrink)

Insulin is a member of a family of hormones, growth factors and neuropeptides which are found in both vertebrates and invertebrates. A common ‘insulin fold’ is probably adopted by all family members. Although the specificities of receptor binding are different, there is possibility of co‐evolution of polypeptides and their receptors.

Spirituality and religiosity have a significant impact on one's well-being. Although previous studies have indicated that the neuropeptide hormone oxytocin is associated with spirituality/religiosity, existing findings remain inconsistent. Some studies have reported a positive relationship between oxytocin and spirituality/religiosity, while other studies have reported a negative association. Herein, we examined the association between endogenous oxytocin and spirituality/religiosity in 200 non-Abrahamic Japanese individuals by measuring the level of salivary oxytocin and spiritual/religious faith. We found that the level of salivary oxytocin was (...) negatively associated with spiritual/religious faith. Individuals with higher levels of salivary oxytocin tend to have more negative spiritual/religious faith compared with those with low oxytocin levels. Moreover, this tendency was only significant in individuals who were not interested in a specific religion. The uniqueness of spirituality/religiosity in Japan could help interpret the current findings. (shrink)

Recently a number of complex electrophysiological responses to neurotransmitters have been observed that cannot be described as simple excitation or inhibition. These responses are often characterized as modulatory, although there is no consensus on what defines modulation. Morphological studies reveal certain neurotransmitters stored in what might be release sites without synaptic contact. There is no direct evidence for nonsynaptic release from CNS sites, although such release does occur in the periphery and in invertebrates. Nonsynaptic release might provide a basis for (...) diffuse one-cell-to-many communication, but it might also simply be a means of sending the transmitter to a broader area of a single neuron than occurs in typical synapses. Several kinds of macromolecules have been found to be transported in a retrograde direction – and in some cases transsynaptically. There have been suggestions that some neurons may release more than one type of transmitter. Particularly intriguing is the possibility of release of substances that modulate actions of a primary transmitter. Taken together this range of evidence suggests that neurons may use a variety of forms of molecular communication in addition to traditionally described synaptic transmission.Several authors have suggested modes of communication distinct from classical synaptic transmission and have classified released substances using terms such as neurohumor, neurohormone, neuroregulator, and modulator. These suggestions have the heuristic value of drawing together diverse kinds of data, but it remains to be established that the pieces fit together in that fashion – for example, that complex electrophysiological effects are associated with substances released nonsynaptically. In order to reduce confusion, a flexible, generic approach to nomenclature for substances released from neurons and for hypothetical modes of communication is recommended. Some behavioral implications of nonconventional transmission are considered. (shrink)

Social acceptance is assumed to have widespread positive effects on the recipient; however, ethnic/racial minorities often react negatively to social acceptance by White individuals. One possibility for such reactions might be their lack of trust in the genuineness of White individuals’ positive evaluations. Here, we examined the role that oxytocin—a neuropeptide putatively linked to social processes—plays in modulating reactions to acceptance or rejection during interracial interactions. Black participants received intranasal oxytocin or placebo and interacted with a White, same-sex stranger who (...) provided positive or negative social feedback. After positive feedback, participants given oxytocin tended to display approach-oriented cardiovascular responses of challenge, exhibited more cooperative behavior, and perceived the partner to have more favorable attitudes toward them after the interaction. Following negative feedback, oxytocin reduced anger suppression. Oxytocin did not modulate testosterone reactivity directly, but our exploratory analysis showed that the less participants suppressed anger during the interaction with their partner, the greater testosterone reactivity they displayed after the interaction. These results survived the correction for multiple testing with a false discovery rate of 20%, but not with a rate of 10 or 5%. Discussion centers on the interplay between oxytocin and social context in shaping interracial interactions. (shrink)

A great variety of medical conditions are subject to the placebo effect. Although there is mounting evidence to suggest that the placebo effect is related to the expectation of clinical benefit, little is still known about the biochemical bases underlying placebo responses. Positron emission tomography studies have recently shown that the placebo effect in Parkinson’s disease, pain, and depression is related to the activation of the limbic circuitry. The observation that placebo administration induces the release of dopamine in the ventral (...) striatum of patients with Parkinson’s disease suggests a link between the placebo effect and reward mechanisms. In addition to Parkinson’s disease, the placebo-reward model may also apply to other disorders. However, the relative contribution of the different neurotransmitters and neuropeptides that are known to be involved in modulating the activity of the limbic system may be disease-specific. Thus, while the placebo-induced clinical benefit observed in Parkinson’s disease would mostly reflect the release of dopamine in the dorsal striatum, the activation of opioid and serotonin pathways could be particularly implicated in mediating placebo responses encountered in pain and depression, respectively. (shrink)

A great variety of medical conditions are subject to the placebo effect. Although there is mounting evidence to suggest that the placebo effect is related to the expectation of clinical benefit, little is still known about the biochemical bases underlying placebo responses. Positron emission tomography studies have recently shown that the placebo effect in Parkinson’s disease, pain, and depression is related to the activation of the limbic circuitry. The observation that placebo administration induces the release of dopamine in the ventral (...) striatum of patients with Parkinson’s disease suggests a link between the placebo effect and reward mechanisms. In addition to Parkinson’s disease, the placebo-reward model may also apply to other disorders. However, the relative contribution of the different neurotransmitters and neuropeptides that are known to be involved in modulating the activity of the limbic system may be disease-specific. Thus, while the placebo-induced clinical benefit observed in Parkinson’s disease would mostly reflect the release of dopamine in the dorsal striatum, the activation of opioid and serotonin pathways could be particularly implicated in mediating placebo responses encountered in pain and depression, respectively. (shrink)

The co-occurrence of stress-induced posttraumatic stress disorder and obesity is common, particularly among military personnel but the link between these conditions is unclear. Individuals with comorbid PTSD and obesity manifest other physical and psychological problems, which significantly diminish their quality of life. Current understanding of the pathways connecting stress to PTSD and obesity is focused largely on behavioral mediators alone with little consideration of the biological regulatory mechanisms that underlie their co-occurrence. In this work, we leverage prior knowledge to systematically (...) highlight such bio-behavioral mechanisms and inform on the design of confirmatory pilot studies. We use natural language processing to extract documented regulatory interactions involved in the metabolic response to stress and its impact on obesity and PTSD from over 8 million peer-reviewed papers. The resulting network describes the propagation of stress to PTSD and obesity through 34 metabolic mediators using 302 documented regulatory interactions supported by over 10,000 citations. Stress jointly affected both conditions through 21 distinct pathways involving only two intermediate metabolic mediators out of a total of 76 available paths through this network. Moreover, oxytocin, Neuropeptide-Y, and cortisol supported an almost direct propagation of stress to PTSD and obesity with different net effects. Although stress upregulated both NPY and cortisol, the downstream effects of both markers are reported to relieve PTSD severity but exacerbate obesity. The stress-mediated release of oxytocin, however, was found to concurrently downregulate the severity of both conditions. These findings highlight how a network-informed approach that leverages prior knowledge might be used effectively in identifying key mediators like OXT though experimental verification of signal transmission dynamics through each path will be needed to determine the actual likelihood and extent of each marker’s participation. (shrink)

In recent decades, scientists have begun to identify the brain processes and neurochemicals associated with the different stages of love, including the all-important stage of attachment. Experimental findings—readily seized upon by those bioethicists who want to urge that we sometimes have good reason pharmaceutically to enhance flagging relationships—are presented as demonstrating that attachment is regulated and strengthened by the neuropeptides oxytocin and vasopressin. I shall argue, however, that often what the experimental data in fact show is only that exogenous (...) administration of such chemicals can control and intensify the trappings of attachment, not attachment itself. That this is sometimes overlooked by both scientists and ethicists, is due to attachment being miscategorised as a set of feelings or a drive, rather than as a disposition to think about, feel toward, and behave toward its object in certain distinctive ways. (shrink)

The recent discovery of the medullary circuit driving “hunger responses” – reduced thermogenesis and promoted feeding – has greatly expanded our knowledge on the central neural networks for energy homeostasis. However, how hypothalamic hunger and satiety signals generated under fasted and fed conditions, respectively, control the medullary autonomic and somatic motor mechanisms remains unknown. Here, in reviewing this field, we propose two hypothalamomedullary neural pathways for hunger and satiety signaling. To trigger hunger signaling, neuropeptide Y activates a group of neurons (...) in the paraventricular hypothalamic nucleus (PVH), which then stimulate an excitatory pathway to the medullary circuit to drive the hunger responses. In contrast, melanocortin‐mediated satiety signaling activates a distinct group of PVH neurons, which then stimulate a putatively inhibitory pathway to the medullary circuit to counteract the hunger signaling. The medullary circuit likely contains inhibitory and excitatory premotor neurons whose alternate phasic activation generates the coordinated masticatory motor rhythms to promote feeding. (shrink)

Oxytocin (OT) is one of the most intensively researched neuropeptides during the three past decades. In benign social contexts, OT exerts a range of desirable socioemotional, stress-reducing, and immunoregulatory effects in mammals and humans and influences mammalian parenting. Consequentially, research in potential pharmacological applications of OT toward human social deficits/disorders and physical illness has increased substantially. Regrettably, the results from the administration of exogenous OT are still relatively inconclusive. Research in rodent maternal developmental programming has demonstrated the susceptibility of (...) offspring endogenous OT systems to maternal somatosensory stimulation, with consequences for behavioral, epigenetic, cognitive, and neurological outcomes. A translation of this animal research into practically feasible human parenting recommendations has yet to happen, despite the significant prevention potential implied by the maternal developmental programming research. Extended physical contact with full-term healthy infants in the months following birth (infant carrying) might constitute the human equivalent of those specific rodent maternal behaviors, found to positively influence emerging OT systems. Findings from both OT and maternal programming research parallel those found for infants exposed to such extended parental physical contact, whether through skin-to-skin contact or infant carrying. Clinical support of parents to engage in extended physical contact represents a feasible intervention to create optimum conditions for the development of infant OT systems, with potential beneficial long-term health effects. (shrink)

This commentary on coderre & katz, wiesenfeld-hallin et al., and dickenson focuses on: (a) the brain as an under-recognized contributor to pain facilitation at the spinal cord; (b) these brain-to-spinal pathways being activated by learning or by body infection/inflammation; and (c) the resultant spinal release of anti-analgesic neuropeptides, activators of the NMDA-NO cascade, and activators of glia.

The discovery of a novel polypeptide (Islet Amyloid Polypeptide: IAPP) isolated from human and cat islet amyloid and from amyloid of a human insulinoma is reviewed. Structurally, IAPP from the human and cat resembles calcitonin gene‐related peptide (CGRP). The structural similarities between the neuropeptide CGRP and IAPP support the premise that IAPP is hormonal in nature. Our immunohistochemical studies also indicate that normal islet B‐cells of several mammalian species (including man and cat) give strong immunoreactivity with antiserum directed to a (...) synthetic peptide segment of IAPP. The fact that IAPP is deposited as amyloid in the pancreatic islets of type 2 (noninsulin‐dependent) diabetics strongly supports an important but yet unknown link between IAPP and the development of this disease. (shrink)

Injury to the central or peripheral nervous system is often associated with persistent pain. After ischemic injury to the spinal cord, rats develop severe mechanical allodynia-like symptoms, expressed as a pain-like response to innocuous stimuli. In its short-lasting phase the allodynia can be relieved with the [gamma]-aminobutyric acid (GABA)-B receptor agonist baclofen, which also reverses the hyperexcitability of dorsal horn interneurons to mechanical stimuli. Furthermore, there is a reduction in GABA immunoreactivity in the dorsal horn of allodynic rats. Clinical neuropathic (...) pain of peripheral and central origin often cannot be relieved by opiates at doses that do not cause side effects. The loss of sensitivity to opiates may be associated with the up-regulation of endogenous antiopioid substances, such as the neuropeptide cholecystokinin (CCK). CCK and its receptor (CCK-R) protein is normally not detectable in rat dorsal root ganglion cells. After peripheral nerve section, both CCK and CCK-R are up-regulated in the dorsal root ganglia. Furthermore, CI 988, an antagonist of the CCK-B receptor, chronically coadministered with morphine, reduces autotomy, a behavior that may be a sign of neuropathic pain following peripheral nerve section. Thus, opiate insensitivity may be due to the release of CCK from injured primary afferents. Similarly, in the chronic phase of the spinal ischemic model of central pain, the allodynia-like symptom is not relieved by systemic morphine, but is significantly reversed by the CCK-B antagonist. Consequently, up-regulation of CCK and CCK-R in the CNS may also underlie opiate drug insensitivity following CNS injury. Thus, dysfunction of central inhibition involving GABA and endogenous opioids may be a factor underlying the development of sensory abnormalities and/or pain following injury to neural tissue. (shrink)

Powerful ultrastructural tools are providing new insights into neuronal circuits, revealing a wealth of anatomically‐defined synaptic connections. These wiring diagrams are incomplete, however, because functional connectivity is actively shaped by neuromodulators that modify neuronal dynamics, excitability, and synaptic function. Studies of defined neural circuits in crustaceans, C. elegans, Drosophila, and the vertebrate retina have revealed the ability of modulators and sensory context to reconfigure information processing by changing the composition and activity of functional circuits. Each ultrastructural connectivity map encodes multiple (...) circuits, some of which are active and some of which are latent at any given time. (shrink)

Peptides serve as important signalling molecules in development and differentiation in the simple metazoan Hydra. A systematic approach (The Hydra Peptide Project) has revealed that Hydra contains several hundreds of peptide signalling molecules, some of which are neuropeptides and others emanate from epithelial cells. These peptides control biological processes as diverse as muscle contraction, neuron differentiation, and the positional value gradient. Signal peptides cause changes in cell behaviour by controlling target genes such as matrix metalloproteases. The abundance of peptides (...) in Hydra raises the question of whether, in early metazoan evolution, cell–cell communication was based mainly on these small molecules rather than on the growth‐factor‐like cytokines that control differentiation and development in higher animals. BioEssays 23:420–427, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Neurons are now known to produce a variety of types of chemical transmitters. Classical transmitters are stored within synaptic vesicles which undergo synaptic exocytosis in association with presynaptic thickenings. The larger, dense‐cored secretory granules present in most neurons contain neuropeptides and mainly discharge their contents at morphologically undifferentiated (i.e.nonsynaptic) sites. The synaptic character of vesicle discharge enables transmitters to exercise a highly focal action, whereas nonsynaptic release probably relates to the slow rate of degradation of many neuropeptides and (...) their consequent widespread diffusion and sphere of action. However, one variant of the basic pattern, involving the restriction of granule discharge to areas of the terminal plasmalemma situated adjacent to the postsynaptic cells (i.e. a parasynaptic configuration), enables a degree of targeted peptide discharge to be achieved. The diversity of patterns of neural exocytosis adds a further dimension to the complexity of nervous function. (shrink)

Both the sensory and the motivational-affective component of pain must be taken into account in studies on sex differences as well as on neuropathic, postoperative, sympathetic, and visceral pain. In all these cases, therapeutic strategies should be aimed at controlling the peripheral, central, and psychological mechanisms underlying the global pain experience. Similarly, it should be recalled that some neuropeptides act on both sensory and affective pain mechanisms. [berkley; mcmahon; dickenson; coderre & katz; wiesenfeld-hallin et al.; blumberg et al.].

The discovery that hypocretins are involved in narcolepsy, a disorder associated with excessive daytime sleepiness, cataplexy and unusually rapid transitions to rapid‐eye‐movement sleep, opens a new field of investigation in the area of sleep control physiology. Hypocretin‐1 and ‐2 (also called orexin‐A and ‐B) are newly discovered neuropeptides processed from a common precursor, preprohypocretin. Hypocretin‐containing cells are located exclusively in the lateral hypothalamus, with widespread projections to the entire neuroaxis. Two known receptors, Hcrtr1 and Hcrtr2, have been reported. The (...) functional significance of the hypocretin system is rapidly emerging in both animals and humans. Hypocretin abnormalities cause narcolepsy in dogs, human and mice. The role of the hypocretin system in normal sleep regulation is more uncertain. We believe hypocretin cells drive cholinergic and monoaminergic activity across the sleep cycle. Input from the suprachiasmatic nucleus to hypocretin‐containing neurons may explain the occurrence of clock‐dependent alertness. Other functions are suggested by pharmacological and neurochemical experiments. These include regulation of food intake, neuroendocrine function, autonomic nervous system activity and energy balance. BioEssays 23:397–408, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Current psychological perspectives emphasize “attack” and “defense” as the behavioral mechanisms underlying conflict. Here, we extend this view by highlighting the relevance of pathological altruism and the neuroendocrine pathways associated with hostile behaviors. Specifically, we elucidate the modulatory role of the neuropeptide hormone oxytocin in motivating extraordinary levels of in-group commitment that can promote extreme behaviors and endure conflict with out-groups.

Healthcare workers are at a high risk of psychological morbidity in the face of the COVID-19 pandemic. However, there is significant variability in the impact of this crisis on individual healthcare workers, which can be best explained through an appreciation of the construct of resilience. Broadly speaking, resilience refers to the ability to successfully adapt to stressful or traumatic events, and thus plays a key role in determining mental health outcomes following exposure to such events. A proper understanding of resilience (...) is vital in enabling a shift from a reactive to a proactive approach for protecting and promoting the mental well-being of healthcare workers. Research in the past decade has identified six areas that provide promising leads in understanding the biological basis of individual variations in resilience. These are: the key role played by the monoamines noradrenaline and serotonin, the centrality of the hypothalamic-pituitary-adrenal axis in influencing stress vulnerability and resilience, the intimate links between the immune system and stress sensitivity, the role of epigenetic modulation of gene expression in influencing the stress response, the role played by certain neuropeptides as a natural “brake” mechanism in the face of stress, and the neurobiological mechanisms by which environmental factors, such as exercise, diet, and social support, influence resilience to subsequent life events. Though much of this research is still in its early stages, it has already provided valuable information on which strategies – including dietary changes, lifestyle modification, environmental modification, psychosocial interventions, and even pharmacological treatments – may prove to be useful in fostering resilience in individuals and groups. This paper examines the above evidence more closely, with a specific focus on the challenges faced by healthcare workers during the COVID-19 pandemic, and provides suggestions regarding how it may be translated into real-world interventions, as well as how the more tentative hypotheses advanced in this field may be tested during this critical period. (shrink)

Human skin produces numerous neurohormones and neuropeptides. Recent evidence has shown that the neuroendocrine regulation of human skin biology also extends to keratins, the major structural components of epithelial cells. For example, thyrotropin‐releasing hormone, thyrotropin, opioids, prolactin, and cannabinoid receptor 1‐ligands profoundly modulate human keratin gene and protein expression in human epidermis and/or hair follicle epithelium in situ. Since selected keratins are now understood to exert important regulatory functions beyond mechanical stability, we argue that neuroendocrine pathways of keratin regulation (...) are important for maintaining skin and hair follicle homeostasis. This invites innovative neuroendocrine therapeutic interventions for skin disorders characterized by abnormal keratin expression, ranging from psoriasis to genodermatoses, and for promoting skin wound healing and hair growth. This strategy can be probed in simple, but instructive and readily available human skin and hair follicle organ culture assays as ideal models for exploring this new neuroendocrine frontier in translational epithelial biology. (shrink)