Modulation of mGlu5 Improves Sensorimotor Gating Deficits in Rats Neonatally Treated With Quinpirole Through Changes in Dopamine D2 Signaling

This study analyzed whether the positive allosteric modulator of metabotropic glutamate receptor type 5 (mGlu5) 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) benzamide (CDPPB) would alleviate deficits in prepulse inhibition (PPI) and affect dopamine (DA) D2 signaling in the dorsal striatum and prefrontal cortex (PFC) in the neonatal quinpirole (NQ) model of schizophrenia (SZ). Male and female Sprague-Dawley rats were neonatally treated with either saline (NS) or quinpirole HCL (1 mg/kg; NQ), a DAD2 receptor agonist, from postnatal days (P) 1–21. Rats were raised to P44 and behaviorally tested on PPI from P44-P48. Before each trial, rats were subcutaneous (sc) administered saline or CDPPB (10 mg/kg or 30 mg/kg). On P50, rats were given a spontaneous locomotor activity test after CDPPB or saline administration. On P51, the dorsal striatum and PFC were evaluated for both arrestin-2 (βA-2) and phospho-AKT protein levels. NQ-treated rats demonstrated a significant deficit in PPI, which was alleviated to control levels by the 30 mg/kg dose of CDPPB. There were no significant effects of CDPPB on locomotor activity. NQ treatment increased βA-2 and decreased phospho-AKT in both the dorsal striatum and PFC, consistent with an increase DAD2 signaling. The 30 mg/kg dose of CDPPB significantly reversed changes in βA-2 in the dorsal striatum and PFC and phospho-AKT in the PFC equivalent to controls. Both doses of CDPPB produced a decrease of phospho-AKT in the PFC compared to controls. This study revealed that a mGlu5 positive allosteric modulator was effective to alleviate PPI deficits and striatal DAD2 signaling in the NQ model of SZ

Metabotropic Glutamate Receptor Type 5 (Mglu5) as a Therapeutic Target Towards the Enhanced Rewarding Effects of Nicotine and Deficits in Sensorimotor Gating in a Heritable Model of Drug Abuse Vulnerability in Psychosis

Heritable and environmental factors contribute to an individual’s risk of substance abuse and psychosis. Individuals diagnosed with a mental disorder have greater vulnerability for substance abuse. Our laboratory established that neonatal treatment of rats with quinpirole (NQ), a dopamine (DA) D2-like agonist, results in a significant increase of DAD2 receptor sensitivity throughout the animal’s lifetime. An increase of DAD2 receptor sensitivity is relevant to a model of schizophrenia (SZ), although increases of DAD2 receptor activity also occur in a number of clinical disorders, including bipolar disorder, obsessive-compulsive disorder, panic disorder, and major depression. Common amongst these clinical conditions is a dramatic increase in cigarette smoking compared to the general population. We bred NQ-treated male and female rats with their NQ-treated or neonatal saline (NS)-treated counterparts once they reached adulthood to determine whether increases in DAD2 sensitivity were passed to the next generation. Offspring of these animals, regardless of whether one or both founders received NQ-treatment, also demonstrated increases of DAD2 receptor sensitivity both behaviorally and neurobiologically. RNASeq preliminary data revealed an increase in cortisol synthesis and release in F1 generation animals, demonstrating an enhanced response to stress, consistent with a model of drug abuse vulnerability. Consistent with this finding, F1 generation rats demonstrated enhanced nicotine conditioned place preference (CPP) and had an enhanced brain derived neurotrophic factor (BDNF) response to nicotine in the nucleus accumbens (NAcc), a brain area critical to drug reward. The DAD2 receptor forms a triple heteromer with the adenosine A(2A) and metabotropic glutamate type 5 (mGlu5) receptor, such that stimulation of either receptor results in a decrease of DAD2 activity. Therefore, we analyzed whether use of a positive allosteric modulator (PAM) of mGlu5 in the F1 generation would block nicotine CPP and improve sensorimotor gating deficits, which is a hallmark of psychosis. In both experiments, the mGlu5 PAM effectively blocked the enhanced rewarding effects of nicotine and also alleviated sensorimotor gating deficits in this model. In essence, we demonstrate in results reported here that there may be a common therapeutic target for the dual treatment of substance abuse and psychosis

Insights into the accuracy of social scientists' forecasts of societal change

How well can social scientists predict societal change, and what processes underlie their predictions? To answer these questions, we ran two forecasting tournaments testing the accuracy of predictions of societal change in domains commonly studied in the social sciences: ideological preferences, political polarization, life satisfaction, sentiment on social media, and gender-career and racial bias. After we provided them with historical trend data on the relevant domain, social scientists submitted pre-registered monthly forecasts for a year (Tournament 1; N = 86 teams and 359 forecasts), with an opportunity to update forecasts on the basis of new data six months later (Tournament 2; N = 120 teams and 546 forecasts). Benchmarking forecasting accuracy revealed that social scientists' forecasts were on average no more accurate than those of simple statistical models (historical means, random walks or linear regressions) or the aggregate forecasts of a sample from the general public (N = 802). However, scientists were more accurate if they had scientific expertise in a prediction domain, were interdisciplinary, used simpler models and based predictions on prior data. How accurate are social scientists in predicting societal change, and what processes underlie their predictions? Grossmann et al. report the findings of two forecasting tournaments. Social scientists' forecasts were on average no more accurate than those of simple statistical models

Insights into accuracy of social scientists' forecasts of societal change

How well can social scientists predict societal change, and what processes underlie their predictions? To answer these questions, we ran two forecasting tournaments testing accuracy of predictions of societal change in domains commonly studied in the social sciences: ideological preferences, political polarization, life satisfaction, sentiment on social media, and gender-career and racial bias. Following provision of historical trend data on the domain, social scientists submitted pre-registered monthly forecasts for a year (Tournament 1; N=86 teams/359 forecasts), with an opportunity to update forecasts based on new data six months later (Tournament 2; N=120 teams/546 forecasts). Benchmarking forecasting accuracy revealed that social scientists’ forecasts were on average no more accurate than simple statistical models (historical means, random walk, or linear regressions) or the aggregate forecasts of a sample from the general public (N=802). However, scientists were more accurate if they had scientific expertise in a prediction domain, were interdisciplinary, used simpler models, and based predictions on prior data

Tug of war in the haematopoietic stem cell niche: do myeloma plasma cells compete for the HSC niche?

Extent: 10p.In the adult mammal, normal haematopoiesis occurs predominantly in the bone marrow, where primitive haematopoietic stem cells (HSC) and their progeny reside in specialised microenvironments. The bone marrow microenvironment contains specific anatomical areas (termed niches) that are highly specialised for the development of certain blood cell types, for example HSCs. The HSC niche provides important cell–cell interactions and signalling molecules that regulate HSC self-renewal and differentiation processes. These same signals and interactions are also important in the progression of haematological malignancies, such as multiple myeloma (MM). This review provides an overview of the bone marrow microenvironment and its involvement in normal, physiological HSC maintenance and plasma cell growth throughout MM disease progression.JE Noll, SA Williams, LE Purton and ACW Zannettin