Unpredicted human safety events in clinical trials for new drugs are costly in terms of human health and money. The drug discovery industry attempts to minimize those events with diligent preclinical safety testing. Current standard practices are good at preventing toxic compounds from being tested in the clinic; however, false negative preclinical toxicity results are still a reality. Continual improvement must be pursued in the preclinical realm. Higher-quality therapies can be brought forward with more information about potential toxicities and associated mechanisms. The zebrafish model is a bridge between in vitro assays and mammalian in vivo studies. This model is powerful in its breadth of application and tractability for research. In the past two decades, our understanding of disease biology and drug toxicity has grown significantly owing to thousands of studies on this tiny vertebrate. This Review summarizes challenges and strengths of the model, discusses the 3Rs value that it can deliver, highlights translatable and untranslatable biology, and brings together reports from recent studies with zebrafish focusing on new drug discovery toxicology.

Use of Zebrafish in Drug Discovery Toxicology

To continuously process neural activity underlying sensation, movement and cognition, the CNS requires a homeostatic microenvironment that is not only enriched in nutrients to meet its high metabolic demands but that is also devoid of toxins that might harm the sensitive neural tissues. This highly regulated microenvironment is made possible by two unique features of CNS vasculature absent in the peripheral organs. First, the blood-blood barrier, which partitions the circulating blood from the CNS, acts as a gatekeeper to facilitate the selective trafficking of substances between the blood and the parenchyma. Second, neurovascular coupling ensures that, following local neural activation, regional blood flow is increased to quickly supply more nutrients and remove metabolic waste. Here, we review how neural and vascular activity act on one another with regard to these two properties.

Neuronal regulation of the blood–brain barrier and neurovascular coupling

Mammalian studies have shaped our understanding of the endocrine control of appetite and body weight in vertebrates and provided the basic vertebrate model that involves central (brain) and peripheral signaling pathways as well as environmental cues. The hypothalamus has a crucial function in the control of food intake, but other parts of the brain are also involved. The description of a range of key neuropeptides and hormones as well as more details of their specific roles in appetite control continues to be in progress. Endocrine signals are based on hormones that can be divided into two groups: those that induce (orexigenic), and those that inhibit (anorexigenic) appetite and food consumption. Peripheral signals originate in the gastrointestinal (GI) tract, liver, adipose tissue and other tissues and reach the hypothalamus through both endocrine and neuroendocrine actions. While many mammalian-like endocrine appetite-controlling networks and mechanisms have been described for some key model teleosts, mainly zebrafish and goldfish, very little knowledge exists on these systems in fishes as a group. Fishes represent over 30000 species and there is a large variability in their ecological niches and habitats as well as life history adaptations, transitions between life stages and feeding behaviors. In the context of food intake and appetite control, common adaptations to extended periods of starvation or periods of abundant food availability are of particular interest. This review summarizes the recent findings on endocrine appetite controlling systems in fish, highlights their impact on growth and survival, and discusses the perspectives in this research field to shed light on the intriguing adaptations that exist in fish and their underlying mechanisms.

/pdf/appetite-controlling-endocrine-systems-in-teleosts-49977intw0.pdf

Appetite-Controlling Endocrine Systems in Teleosts

Autism is a developmental disorder that starts before age 3, and children with autism has impairment in both social interaction and communication, and has restricted, repetitive and stereotyped patterns of behavior, interests and activities. There is a strong heritable component of autism and autism spectrum disorder as studies have shown that parents who have a child with ASD have a 2-18% chance of having a second child with ASD. Since the prevalence of autism and autism spectrum disorders have been increasing during the last 3 decades, much research has been carried out to understand the etiology, so as to develop novel preventive and treatment strategies. This review aims at summarizing the latest research studies related to autism and autism spectrum disorder, focusing not only on the genetics but also some epigenetic findings of autism/autism spectrum disorder. Some promising areas of research using transgenic/knockout animals and some ideas related to potential novel treatment and prevention strategies will be discussed.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/pcn.12606

Genetics and epigenetics of autism: A Review.

Interplay between Oxytocin and Sensory Systems in the Orchestration of Socio-Emotional Behaviors

The hypothalamus is a brain region which regulates homeostasis by mediating endocrine, autonomic and behavioral functions. It is comprised of several nuclei containing distinct neuronal populations producing neuropeptides and neurotransmitters that regulate fundamental body functions including temperature and metabolic rate, thirst and hunger, sexual behavior and reproduction, circadian rhythm, and emotional responses. The identity, number and connectivity of these neuronal populations are established during the organism’s development and are of crucial importance for normal hypothalamic function. Studies have suggested that developmental abnormalities in specific hypothalamic circuits can lead to obesity, sleep disorders, anxiety, depression and autism. At the molecular level, the development of the hypothalamus is regulated by transcription factors (TF), secreted growth factors, neuropeptides and their receptors. Recent studies in zebrafish and mouse have demonstrated that some of these molecules maintain their expression in the adult brain and subsequently play a role in the physiological functions that are regulated by hypothalamic neurons. Here, we summarize the involvement of some of the key developmental factors in hypothalamic development and function by focusing on the mouse and zebrafish genetic model organisms.

Role of developmental factors in hypothalamic function.

Proper response to stress and social stimuli depends on orchestrated development of hypothalamic neuronal circuits. Here we address the effects of the developmental transcription factor orthopedia (Otp) on hypothalamic development and function. We show that developmental mutations in the zebrafish paralogous gene otpa but not otpb affect both stress response and social preference. These behavioral phenotypes were associated with developmental alterations in oxytocinergic (OXT) neurons. Thus, otpa and otpb differentially regulate neuropeptide switching in a newly identified subset of OXT neurons that co-express the corticotropin-releasing hormone (CRH). Single-cell analysis revealed that these neurons project mostly to the hindbrain and spinal cord. Ablation of this neuronal subset specifically reduced adult social preference without affecting stress behavior, thereby uncoupling the contribution of a specific OXT cluster to social behavior from the general otpa-/- deficits. Our findings reveal a new role for Otp in controlling developmental neuropeptide balance in a discrete OXT circuit whose disrupted development affects social behavior.

/pdf/homeodomain-protein-otp-affects-developmental-neuropeptide-1nixpsmnp6.pdf

Homeodomain protein Otp affects developmental neuropeptide switching in oxytocin neurons associated with a long-term effect on social behavior

Hormones regulate behavior either through activational effects that facilitate the acute expression of specific behaviors or through organizational effects that shape the development of the nervous system thereby altering adult behavior. Much research has implicated the neuropeptide oxytocin (OXT) in acute modulation of various aspects of social behaviors across vertebrate species, and OXT signaling is associated with the developmental social deficits observed in autism spectrum disorders, however, little is known about the role of OXT in the neurodevelopment of the social brain. We show that perturbation of OXT neurons during early zebrafish development led to a loss of dopaminergic neurons, associated with visual processing and reward, and blunted the neuronal response to social stimuli in the adult brain. Ultimately, adult fish whose OXT neurons were ablated in early life, displayed altered functional connectivity within social decision-making brain nuclei both in naive state and in response to social stimulus and became less social. We propose that OXT neurons have an organizational role, namely to shape forebrain neuroarchitecture during development and to acquire an affiliative response towards conspecifics. SIGNIFICANCE STATEMENT Social behavior is developed over the lifetime of an organism and the neuropeptide oxytocin modulates social behaviors across vertebrate species, and is associated with neuro-developmental social deficits such as autism. However, whether oxytocin plays a role in the developmental maturation of neural systems that are necessary for social behavior remains poorly explored. We show that proper behavioral and neural response to social stimuli depends on a developmental process orchestrated by oxytocin neurons. Animals whose oxytocin system is ablated in early life show blunted neuronal and behavioral responses to social stimuli as well as wide ranging disruptions in the functional connectivity of the social brain. We provide a window into the mechanisms underlying oxytocin-dependent developmental processes that implement adult sociality.

Developmental Effects of Oxytocin Neurons on Social Affiliation and Processing of Social Information.

Acher, R. and Chauvet, J. (1953) The structure of bovine vasopressin. Biochimica et Biophysica Acta, 12(3), 487. Acher, R., Chauvet, J., and Chauvet, M.T. (1972) Phylogeny of the Neurohypophysial Hormones Two New Active Peptides Isolated from a Cartilaginous Fish, Squalus acanthias Eur. J. Biochem. 29, 12–19. Acher, R., Chauvet, J., Chauvet, M.T. and Crepy, D. (1962). Isolation of a new neurohypophysial hormone, isotocin, present in bony fish. Biochimica et biophysica acta, 58, 624–625. Acher, R., Chauvet, J., Chauvet, M.T. and Crepy, D. (1965). Phylogeny of neurophyophyseal peptides: isolation of a new hormone, glumitocin (Ser 4-Gln 8-ocytocin) present in a cartilaginous fish, the ray (Raia clavata). Biochimica et biophysica acta, 107(2), 393–396. Acher, R., Chauvet, J., Chauvet, M.T. and Crepy, D. (1967). Amphibian neurohypophyseal hormones: isolation and characterization of mesotocin and vasotocin from the toad (Bufo bufo). General and comparative endocrinology, 8(2), 337. Acher, R., Chauvet, J. and Rouille, Y. (1997) Adaptive evolution of water homeostasis regulation in amphibians, vasotocin and hydrins. Biology of the Cell, 89(5–6), 283–291. Ahrens, M.B. and Keller, P. (2013) Whole‐brain functional imaging at cellular resolution using light‐sheet microscopy. Nature Methods, 10, 413–420. Almeida, O., Gozdowska, M., Kulczykowska, E. and Oliveira, R. (2012) Brain levels of arginine‐vasotocin and isotocin in dominant and subordinate males of a cichlid fish. Hormones and Behavior, 61(2), 212–217. Ansai, S., Sakuma, T., Yamamoto, T., et al. (2013) Efficient targeted mutagenesis in medaka using custom‐ designed transcription activator‐like effector nucleases. Genetics, 193(3), 739–749. Atasoy, D., Betley, J., Su, H. and Sternson, S. (2012) Deconstruction of a neural circuit for hunger. Nature, 488(7410), 172–177. Atkins, N., Jones, S. and Guillette, L. Jr (2006) Timing of parturition in two species of viviparous lizard, influences of beta‐adrenergic stimulation and temperature upon uterine responses to arginine vasotocin (AVT). Journal of Comparative Physiology B, 176(8), 783–792. Ayers, L.W., Missig, G., Schulkin, J. and Rosen, J. (2011) Oxytocin reduces background anxiety in a fear‐ potentiated startle paradigm, peripheral vs central administration. Neuropsychopharmacology, 36(12), 2488–2497. Ballesteros, J.A. and Weinstein, H. (1995) Integrated methods for the construction of three‐dimensional models and comptuational probing of structure–function relations in G protein‐coupled receptors. Methods in Neuroscience, 25, 366–428. Bannister, S., Antonova, O., Polo, A., et al. (2014) TALENs mediate efficient and heritable mutation of endogenous genes in the marine Annelid Platynereis dumerilii. Genetics, 197, 77–89. Barberis, C., Mouillac, B. and Durroux, T. (1998) Structural bases of vasopressin/oxytocin receptor function. Journal of Endocrinology, 156(2), 223–229. Barth, S.W., Bathgate, R., Mess, A., Parry, L., Ivell, R. and Grossmann, R. (1997) Mesotocin gene expression in the diencephalon of domestic fowl, cloning and sequencing of the MT cDNA and distribution of MT gene expressing neurons in the chicken hypothalamus. Journal of Neuroendocrinology, 9(10), 777–787. Bedell, V.M., Wang, Y., Campbell, J., et al. (2012) In vivo genome editing using a high‐efficiency TALEN system. Nature, 491(7422), 114–118.

Non‐Mammalian Models for Neurohypophysial Peptides

Development and Function of the Zebrafish Neuroendocrine System

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