Citations

Kynurenic acid (KYNA), a glial-derived metabolite of tryptophan metabolism, is an antagonist of the alpha 7 nicotinic acetylcholine receptor and the glycine-binding site of N-methyl-d-aspartate (NMDA) receptors. Kynurenic acid levels are increased in both the brain and cerebrospinal fluid of several psychiatric disorders including bipolar disorder, schizophrenia, and Alzheimer disease. In addition, pro-inflammatory cytokines have been found to be elevated in the blood of schizophrenic patients suggesting inflammation may play a role in psychiatric illness. As both pro-inflammatory cytokines and KYNA can be elevated in the brain by peripheral lipopolysaccharide (LPS) injection, we therefore sought to characterize the role of neuroinflammation on learning and memory using a well-described dual-LPS injection model. Mice were injected with an initial injection (0.25 mg/kg LPS, 0.50 mg/kg, or saline) of LPS and then administrated a second injection 16 hours later. Our results indicate both 0.25 and 0.50 mg/kg dual-LPS treatment increased l-kynurenine and KYNA levels in the medial pre-frontal cortex (mPFC). Mice exhibited impaired acquisition of CS+ (conditioned stimulus) Pavlovian conditioning. Notably, mice showed impairment in reference memory while working memory was normal in an 8-arm maze. Taken together, our findings suggest that neuroinflammation induced by peripheral LPS administration contributes to cognitive dysfunction.

Abstract Waiting impulsivity is a risk factor for many psychiatric disorders including alcohol use disorder (AUD). Highly impulsive individuals are vulnerable to alcohol abuse. However, it is not well understood whether chronic alcohol use increases the propensity for impulsive behavior. Here, we establish a novel experimental paradigm demonstrating that continuous binge‐like ethanol exposure progressively leads to maladaptive impulsive behavior. To test waiting impulsivity, we employed the 5‐choice serial reaction time task (5‐CSRTT) in C57BL/6J male mice. We assessed premature responses in the fixed and variable intertrial interval (ITI) 5‐CSRTT sessions. We further characterized our ethanol‐induced impulsive mice using Open Field, y‐maze, two‐bottle choice, and an action‐outcome task. Our results indicate that continuous binge‐like ethanol exposure significantly increased premature responses when mice were tested in variable ITI sessions even during a prolonged abstinent period. Ethanol‐induced impulsive mice exhibited anxiety‐like behavior during chronic exposures. This behavior was also observed in a separate cohort that was subjected to 20 days of abstinence. Ethanol‐treated mice were less motivated for a sucrose reward compared with air‐exposed control mice, while also demonstrating reduced responding during action‐outcome testing. Overall, ethanol‐treated mice demonstrated increased impulsive behavior, but a reduced motivation for a sucrose reward. Although waiting impulsivity has been hypothesized to be a trait or risk factor for AUD, our findings indicate that maladaptive impulse control can also be potentiated or induced by continuous chronic ethanol exposure in mice.

AbstractWnt signaling is a well‐known molecular pathway in age‐related pathogenesis and therapy of disease. While prior studies have mainly focused on Wnt ligands or Wnt activators, the in vivo functions of naturally secreted Wnt inhibitors are not clear, especially in brain aging. Using BubR1H/H mice as a novel mouse model of accelerated aging, we report that genetic inhibition of sFRP3 restores the reduced body and brain size observed in BubR1H/H mice. Furthermore, sFRP3 inhibition ameliorates hypomyelination in the corpus callosum and rescues neural progenitor proliferation in the hippocampal dentate gyrus of BubR1H/H mice. Taken together, our study identifies sFRP3 as a new molecular factor that cooperates with BubR1 function to regulate brain development, myelination, and hippocampal neurogenesis.

AbstractAcamprosate is an FDA‐approved medication for the treatment of alcoholism that is unfortunately only effective in certain patients. Although acamprosate is known to stabilize the hyper‐glutamatergic state in alcoholism, pharmacological mechanisms of action in brain tissue remains unknown. To investigate the mechanism of acamprosate efficacy, the authors employ a pharmacoproteomics approach using an animal model of alcoholism, type 1 equilibrative nucleoside transporter (ENT1) null mice. The results demonstrate that acamprosate treatment significantly decreased both ethanol drinking and preference in ENT1 null mice compared to that of wild‐type mice. Then, to elucidate acamprosate efficacy mechanism in ENT1 null mice, the authors utilize label‐free quantification proteomics comparing both genotype and acamprosate treatment effects in the nucleus accumbens (NAc). A total of 1040 protein expression changes are identified in the NAc among 3634 total proteins detected. The proteomics and Western blot result demonstrate that acamprosate treatment decreased EAAT expression implicating stabilization of the hyper‐glutamatergic condition in ENT1 null mice. Pathway analysis suggests that acamprosate treatment in ENT1 null mice seems to rescue glutamate toxicity through restoring of RTN4 and NF‐κB medicated neuroimmune signaling compared to wild‐type mice. Overall, pharmacoproteomics approaches suggest that neuroimmune restoration is a potential efficacy mechanism in the acamprosate treatment of certain sub‐populations of alcohol dependent subjects.

SUMMARYPre-pulse inhibition (PPI) of the acoustic startle reflex is deficient in patients with schizophrenia. This deficiency is mimicked in mice by the use of the psychotomimetic drugs d-amphetamine and dizolcipine. Antipsychotic drugs such as clozapine are used to treat schizophrenic patients and are also administered to mice to prevent PPI disruption. Neurotensin (NT) produces antipsychotic-like effects when injected into rodent brain through its effects at NT subtype 1 (NTS1) and 2 (NTS2) receptors. We hypothesized that the NT receptor agonist (NT69L) would prevent PPI disruption in mice challenged with d-amphetamine (10 mg kg–1) and dizocilpine (1 mg kg–1). We investigated the role of NTS1 and NTS2 in PPI using wild-type (WT), NTS1 (NTS1–/–) and NTS2 (NTS2–/–) knockout mice, via its disruption by psychotomimetic drugs, as well as the ability of clozapine and NT69L to block these PPI disruptions. There were no differences in baseline PPI across the three genotypes. d-Amphetamine and dizocilpine disrupted PPI in WT and NTS2–/– mice but not in NTS1–/– mice. In WT mice, clozapine (1 mg kg–1) and NT69L (1 mg kg–1) significantly blocked d-amphetamine-induced disruption of PPI. Similarly, in WT mice, clozapine significantly blocked dizocilpine-induced PPI disruption, but NT69L did not. In NTS2–/– mice clozapine blocked d-amphetamine-but not dizocilpine-induced PPI disruption, while NT69L blocked both d-amphetamine- and dizocilpine-induced PPI disruption. Our results indicate that NTS1 seems essential for d-amphetamine and dizocilpine disruption of PPI. Additionally, this report provides support to the hypothesis that NT analogs could be used as novel antipsychotic drugs.