A Pilot Study on Early-Onset Schizophrenia Reveals the Implication of Wnt, Cadherin and Cholecystokinin Receptor Signaling in Its Pathophysiology

Early-Onset Schizophrenia (EOS) is a very rare mental disorder that is a form of schizophrenia occurring before the age of 18. EOS is a brain disease marked by an early onset of positive and negative symptoms of psychosis that impact development and cognitive functioning. Clinical manifestations commonly include premorbid features of Autism Spectrum Disorder (ASD), attention deficits, Intellectual Disability (ID), neurodevelopmental delay, and behavioral disturbances. After the onset of psychotic symptoms, other neuropsychiatric comorbidities are also common, including obsessive-compulsive disorder, major depressive disorder, expressive and receptive language disorders, auditory processing, and executive functioning deficits. With the purpose to better gain insight into the genetic bases of this disorder, we developed a pilot project performing whole exome sequencing of nine trios affected by EOS, ASD, and mild ID. We carried out gene prioritization by combining multiple bioinformatic tools allowing us to identify the main pathways that could underpin the neurodevelopmental phenotypes of these patients. We identified the presence of variants in genes belonging to the Wnt, cadherin and cholecystokinin receptor signaling pathways.

Escape Steering by Cholecystokinin Peptidergic Signaling

Escape is an evolutionarily conserved and essential avoidance response. Considered to be innate, most studies on escape responses focused on hard-wired circuits. We report here that peptidergic signaling is an integral and necessary component of the Caenorhabditis elegans escape circuit. Combining genetic screening, electrophysiology, and calcium imaging, we reveal that a neuropeptide NLP-18 and its cholecystokinin receptor CKR-1 enable the escape circuit to execute a full omega turn, the last motor step where the animal robustly steers away from its original trajectory. We demonstrate in vivo and in vitro that CKR-1 is a Gq protein-coupled receptor for NLP-18. in vivo, NLP-18 is mainly secreted by the gustatory sensory neuron (ASI) to activate CKR-1 in the head motor neuron (SMD) and the turn-initiating interneuron (AIB). Removal of NLP-18, removal of CKR-1, or specific knockdown of CKR-1 in SMD or AIB neurons lead to shallower turns hence less robust escape steering. Consistently, the Ca2+ transients elevation of head motor neuron SMD during escape steering is attenuated upon the removal of NLP-18 or CKR-1. in vitro, synthetic NLP-18 directly evokes CKR-1-dependent currents in oocytes and CKR-1-dependent Ca2+ transients in SMD. Thus, cholecystokinin signaling modulates an escape circuit to generate robust escape steering.

The Characteristic of Critical Genes in Neuroendocrine System and Their Regulation on Food Habit Transition and Metamorphosis of Veined Rapa Whelk Rapana venosa (Valenciennes, 1846)

Metamorphosis is a critical developmental event in mollusks, and neuroendocrine system plays an essential role in this process. Rapana venosa is an economically important shellfish in China, but the artificial technology of R. venosa aquaculture is limited by metamorphosis. As a carnivorous gastropod, food habit transition makes the mechanism of R. venosa metamorphosis more complex. To investigate the changes in the neuroendocrine system and to reveal its role in regulating the food habit transition and metamorphosis of R. venosa, we cloned the cDNA sequences encoding 5-hydroxytryptamine receptor (Rv-5HTR), nitric oxide synthetase (Rv-NOS) and cholecystokinin receptor (Rv-CCKR), and investigated their expression by quantitative real-time PCR analysis, and explore the spatio-temporal changes of 5-HT protein expression using Immunohistochemical (IHC) analysis. The expression of the three geens was significantly increased in the early intramembrane veliger stage, which indicates that the three genes are related to the development of digestive system. Additionally, expression of the three genes was decreased after metamorphosis, while Rv-NOS and Rv-CCKR were increasingly expressed in competent larvae, which may help the larvae find suitable environments and promote digestive system development for metamorphosis, and the result of 5-HT IHC analysis also reflects the development of neuroendocrine system. Furthermore, results show that CCK can effect the expression of digestive enzyme, NOS and 5-HT receptor. Finally, based on the present results, we hypothesized that CCK and CCK receptor may be critical regulatory factors of food habit transition and metamorphosis. These results might provide information on the development of neuroendocrine system of R. venosa, and new insight into the regulation of the food habit transition and metamorphosis of gastropods.

Roles of Cholecystokinin in the Nutritional Continuum. Physiology and Potential Therapeutics

Cholecystokinin is a gastrointestinal peptide hormone with important roles in metabolic physiology and the maintenance of normal nutritional status, as well as potential roles in the prevention and management of obesity, currently one of the dominant causes of direct or indirect morbidity and mortality. In this review, we discuss the roles of this hormone and its receptors in maintaining nutritional homeostasis, with a particular focus on appetite control. Targeting this action led to the development of full agonists of the type 1 cholecystokinin receptor that have so far failed in clinical trials for obesity. The possible reasons for clinical failure are discussed, along with alternative pharmacologic strategies to target this receptor for prevention and management of obesity, including development of biased agonists and allosteric modulators. Cellular cholesterol is a natural modulator of the type 1 cholecystokinin receptor, with elevated levels disrupting normal stimulus-activity coupling. The molecular basis for this is discussed, along with strategies to overcome this challenge with a corrective positive allosteric modulator. There remains substantial scope for development of drugs to target the type 1 cholecystokinin receptor with these new pharmacologic strategies and such drugs may provide new approaches for treatment of obesity.

Pain, Pathophysiological Mechanisms, and New Therapeutic Options for Alternative Analgesic Agents in Sheep: A Review and Investigation

Relief from suffering is the guiding principle of medical and veterinary ethics. Medical care for animals should be carried out to meet all welfare conditions. The need for pain management is demonstrated by recent monographs devoting attention to this urgent ethical need. Little data, however, are available on the prevention and attenuation of pain in sheep. After administration of narcotic analgesics used for severe visceral pain, sheep react with a state of excitement. Therefore, it was decided to experimentally investigate the usefulness of potential non-narcotic drugs to relieve pain in sheep with intestinal colic caused by 10 min of mechanical distension of their duodenal and/or descending colonic wall. The results indicate the potential usefulness of VGCCIs (diltiazem, nifedipine, verapamil), cholecystokinin receptor antagonists (PD, proglumide), and metabotropic glutaminergic receptor antagonists (mGluRAs), such as L-AP3, DL-AP3. As a premedication, these substances prevented the occurrence of symptoms of acute intestinal pain including atony of reticulo-rumen, tachycardia, hyperventilation, moaning, gnashing of teeth, hypercortisolemia, and catecholaminemia; hence, these substances are considered potential agents in the treatment of sheep visceral pain.

417 Citrus aurantium flavonoid extract modifies the gene expression in the rumen of genes related to inflammation and behavior in Holstein bulls fed high-concentrate diets

One hundred forty-four bulls (164.8 ± 5.91 kg BW and 135 ± 7.2 d of age) were randomly allocated to one of 8 pens and assigned to control (C) or Citrus aurantium (BF, 0.4 kg of Bioflavex® CA per ton of concentrate). Each pen had one drinker, one separate straw feeder, and one three-space feeder where mash concentrate rich in corn, barley, DDG and wheat was offered. Concentrate intake was recorded daily, and BW and animal behavior by visual scan fortnightly. Animals were slaughtered after 168 d of study (12 periods of 14 d), HCW and carcass quality were recorded. Rumen wall samples were collected from 18 animals per treatment to analyze the expression of 15 genes associated with inflammation and behavior. Data were analyzed with ANOVA. In the rumen, the expression of free fatty acid receptor 2 (stimulates PPY and serotonin secretion), pancreatic polypeptide receptor 1 (acts asNPY and PYY receptor), cholecystokinin receptor 4 (is a CCK and gastrin receptor), Toll-like receptor-4 (pattern recognition receptor), IL-25 (proinflammatory cytokine) and β-defensin1 (antimicrobial peptide) were greater (P < 0.05) in C compared with BF bulls (P < 0.05). Moreover, the expression of all bitter taste receptors (TAS2R, member 7, 16, 38 and 39) which are related with eating modulation and immune function were lesser (P < 0.05) expressed in BF compared with C bulls (P < 0.05). The supplementation with citrus flavonoids in these bulls fed high-concentrate diets tended (P < 0.10) to improve concentrate efficiency, reduced oral non-nutritive behaviors, agonistic interactions and sexual behaviors. The reduction on TAS2R expression is indicative of an inhibition of bitter taste receptor function by BF and the expression increase in the other genes could explain the changes observed on animal behavior within the gut-brain axis paradigm.