Background-Corticotropin-releasing factor (CRF) and gamma-aminobutyric acid (GABA)ergic systems in the central amygdala (CeA) are implicated in the high-anxiety, high-drinking profile associated with ethanol dependence. Ethanol augments CeA GABA release in ethanol-naive rats and mice.

Nicotine, the main psychoactive ingredient of tobacco, induces negative emotional symptoms during abstinence that contribute to a profound craving for nicotine. However, the neurobiological mechanisms underlying how nicotine produces dependence remains poorly understood. We demonstrate one mechanism for both the anxiety-like symptoms of withdrawal and excessive nicotine intake observed after abstinence, through recruitment of the extrahypothalamic stress peptide corticotropin-releasing factor (CRF) system and activation of CRF1 receptors. Overactivation of the CRF-CRF1 system may contribute to nicotine dependence and may represent a prominent target for investigating the vulnerability to tobacco addiction.abstinence ͉ addiction ͉ amygdala ͉ deprivation ͉ stress

SUMMARY Emerging studies suggest a role for tau in regulating the biology of RNA binding proteins (RBPs). We now show that reducing the RBP T-cell intracellular antigen 1 (TIA1) in vivo protects against neurodegeneration and prolongs survival in transgenic P301S tau mice. Biochemical fractionation shows co-enrichment and co-localization of tau oligomers and RBPs in transgenic P301S tau mice. Reducing TIA1 decreases the number and size of granules co-localizing with stress granule markers. Decreasing TIA1 also inhibits the accumulation of tau oligomers at the expense of increasing neurofibrillary tangles (NFTs). Despite the increase in NFTs, TIA1 reduction increases neuronal survival and rescues behavioral deficits and lifespan. These data provide in vivo evidence that TIA1 plays a key role in mediating toxicity, and further suggest that RBPs direct the pathway of tau aggregation and the resulting neurodegeneration. We propose a paradigm in which dysfunction of the translational stress response leads to tau-mediated pathology.

Dieting to control body weight involves cycles of deprivation from palatable food that can promote compulsive eating. The present study shows that rats withdrawn from intermittent access to palatable food exhibit overeating of palatable food upon renewed access and an affective withdrawal-like state characterized by corticotropin-releasing factor-1 (CRF 1) receptor antagonistreversible behaviors, including hypophagia, motivational deficits to obtain less palatable food, and anxiogenic-like behavior. Withdrawal was accompanied by increased CRF expression and CRF 1 electrophysiological responsiveness in the central nucleus of the amygdala. We propose that recruitment of anti-reward extrahypothalamic CRF-CRF 1 systems during withdrawal from palatable food, analogous to abstinence from abused drugs, may promote compulsive selection of palatable food, undereating of healthier alternatives, and a negative emotional state when intake of palatable food is prevented.eating disorders ͉ obesity ͉ palatability ͉ palatable food dependence ͉ withdrawal F orms of obesity and eating disorders, similar to drug addiction, can be conceptualized as chronic relapsing conditions with alternating periods of abstinence (i.e., dieting to avoid ''forbidden'' palatable foods) and relapse (i.e., compulsive, often uncontrollable, eating of high-palatable foods) that continue despite negative consequences (1). Although the positive reinforcing properties of palatable foods are well known (2, 3), less attention has been given to their negative reinforcing properties (4-6), namely the increased probability of a behavioral response produced by removal of an aversive stimulus (e.g., intake of palatable food to relieve negative emotional states). Intermittent cycles of extended use of drugs of abuse can progressively lead to ''affective dependence,'' observed as a need for higher and/or more regular quantities of the drug to maintain a given emotional set point as well as a negative emotional state upon cessation of drug intake (7,8). Such affective withdrawal may maintain use and motivate relapse via the negative reinforcing properties of continuing and resuming drug use, respectively (7,8).Extrahypothalamic corticotropin-releasing factor (CRF) brain stress systems are putatively involved in the transition from drug use to dependence, during which intake of abused drugs becomes increasingly motivated by these negative, rather than positive, reinforcement mechanisms. CRF plays a motivationally relevant role in withdrawal syndromes for every major drug of abuse, including alcohol, nicotine, cocaine, opiates, amphetamines, and tetrahydrocannabinol (7,8). By analogy, repeated cycles of intermittent, extended access to highly palatable food were hypothesized to induce CRF system neuroadaptations similar to those seen in drug dependence models (4, 5, 9). ResultsIntermittent, extended access to palatable food progressively leads to undereating of less preferred diets when palatable food is not available and to overeating of palatable food upon renewed ...

Background and purpose: Pharmacological inhibition of beta-amyloid (Ab) induced reactive gliosis may represent a novel rationale to develop drugs able to blunt neuronal damage and slow the course of Alzheimer's disease (AD). Cannabidiol (CBD), the main non-psychotropic natural cannabinoid, exerts in vitro a combination of neuroprotective effects in different models of Ab neurotoxicity. The present study, performed in a mouse model of AD-related neuroinflammation, was aimed at confirming in vivo the previously reported antiinflammatory properties of CBD. Experimental approach: Mice were inoculated with human Ab (1-42) peptide into the right dorsal hippocampus, and treated daily with vehicle or CBD (2.5 or 10 mg kg À1 , i.p.) for 7 days. mRNA for glial fibrillary acidic protein (GFAP) was assessed by in situ hybridization. Protein expression of GFAP, inducible nitric oxide synthase (iNOS) and IL-1b was determined by immunofluorescence analysis. In addition, ELISA assay of IL-1b level and the measurement of NO were performed in dissected and homogenized ipsilateral hippocampi, derived from vehicle and Ab inoculated mice, in the absence or presence of CBD. Key results: In contrast to vehicle, CBD dose-dependently and significantly inhibited GFAP mRNA and protein expression in Ab injected animals. Moreover, under the same experimental conditions, CBD impaired iNOS and IL-1b protein expression, and the related NO and IL-1b release. Conclusion and implications:The results of the present study confirm in vivo anti-inflammatory actions of CBD, emphasizing the importance of this compound as a novel promising pharmacological tool capable of attenuating Ab evoked neuroinflammatory responses.

Binge eating and an increased role for palatability in determining food intake are abnormal adaptations in feeding behavior linked to eating disorders and body weight dysregulation. The present study tested the hypothesis that rats with limited access to highly preferred food would develop analogous opioid-dependent learned adaptations in feeding behavior, with associated changes in metabolism and anxiety-like behavior. For this purpose, adolescent female Wistar rats were daily food deprived (2 h) and then offered 10-min access to a feeder containing chow followed sequentially by 10-min access to a different feeder containing either chow (chow/chow; n ¼ 7) or a highly preferred, but macronutrient-comparable, sucrose-rich diet (chow/preferred; n ¼ 8). Chow/preferred-fed rats developed binge-like hyperphagia of preferred diet from the second feeder and anticipatory chow hypophagia from the first feeder with a time course suggesting associative learning. The feeding adaptations were dissociable in onset, across individuals, and in their dose-response to the opioid-receptor antagonist nalmefene, suggesting that they represent distinct palatability-motivated processes. Chow/preferred-fed rats showed increased anxiety-like behavior in relation to their propensity to binge as well as increased feed efficiency, body weight, and visceral adiposity. Chow/preferred-fed rats also had increased circulating leptin levels and decreased growth hormone and 'active' ghrelin levels. Thus, the short-term control of food intake in rats with restricted access to highly preferred foods comes to rely more on hedonic, rather than nutritional, properties of food, through associative learning mechanisms. Such rats show changes in ingestive, metabolic, endocrine, and anxiety-related measures, which resemble features of binge eating disorders or obesity.

Background Eating disorders are lethal and heritable; however, the underlying genetic factors are unknown. Binge eating is a highly heritable trait associated with eating disorders that is comorbid with mood and substance use disorders. Therefore, understanding its genetic basis will inform therapeutic development that could improve several comorbid neuropsychiatric conditions. Methods We assessed binge eating in closely related C57BL/6 mouse substrains and in an F2 cross to identify quantitative trait loci (QTL) associated with binge eating. We used gene targeting to validated candidate genetic factors. Finally, we used transcriptome analysis of the striatum via mRNA sequencing (RNA-seq) to identify the premorbid transcriptome and the binge-induced transcriptome to inform molecular mechanisms mediating binge eating susceptibility and establishment. Results C57BL/6NJ but not C57BL/6J mice showed rapid and robust escalation in palatable food consumption. We mapped a single genome-wide significant QTL on chromosome 11 (LOD=7.4) to a missense mutation in cytoplasmic FMR1-interacting protein 2 (Cyfip2). We validated Cyfip2 as a major genetic factor underlying binge eating in heterozygous knockout mice on a C57BL/6N background that showed reduced binge eating toward a wild-type C57BL/6J-like level. Transcriptome analysis of premorbid genetic risk identified the enrichment terms “morphine addiction” and “retrograde endocannabinoid signaling” whereas binge eating resulted in the downregulation of a gene set enriched for decreased myelination, oligodendrocyte differentiation, and expression. Conclusions We identified Cyfip2 as a major significant genetic factor underlying binge eating and provide a behavioral paradigm for future genome-wide association studies in populations with increased genetic complexity.

Impulsivity is a behavioral trait frequently seen not only in drug-addicted individuals but also in individuals who pathologically overeat. However, whether impulsivity predates the development of uncontrollable feeding is unknown. In this study, we hypothesized that a high impulsivity trait precedes and confers vulnerability for food addiction-like behavior. For this purpose, we trained ad libitum-fed male Wistar rats in a differential reinforcement of low rates of responding (DRL) task to select Low- and High-impulsive rats. Then, we allowed Low- and High-impulsive rats to self-administer a highly palatable diet (Palatable group) or a regular chow diet (Chow group) in 1-h daily sessions, under fixed ratio (FR) 1, FR3, FR5, and under a progressive ratio (PR) schedules of reinforcement. In addition, we tested the compulsiveness for food in Low- and High-impulsive rats by measuring the food eaten in the aversive, open compartment of a light/dark conflict test. Finally, we measured the expression of the transcription factor ΔFosB in the shell and the core of the nucleus accumbens, which is a marker for neuroadaptive changes following addictive drug exposure. The data we obtained demonstrate that impulsivity is a trait that predicts the development of food addiction-like behaviors, including: (i) excessive intake, (ii) heightened motivation for food, and (iii) compulsive-like eating, when rats are given access to highly palatable food. In addition, we show that the food addiction phenotype in high impulsive subjects is characterized by an increased expression of the transcription factor ΔFosB in the nucleus accumbens shell. These results reveal that impulsivity confers an increased propensity to develop uncontrollable overeating of palatable food.