Abstract
The first exon of the huntingtin protein (HTTex1) important in Huntington’s disease (HD) can form cross-β fibrils of varying toxicity. We find that the difference between these fibrils is ...the degree of entanglement and dynamics of the C-terminal proline-rich domain (PRD) in a mechanism analogous to polyproline film formation. In contrast to fibril strains found for other cross-β fibrils, these HTTex1 fibril types can be interconverted. This is because the structure of their polyQ fibril core remains unchanged. Further, we find that more toxic fibrils of low entanglement have higher affinities for protein interactors and are more effective seeds for recombinant HTTex1 and HTTex1 in cells. Together these data show how the structure of a framing sequence at the surface of a fibril can modulate seeding, protein-protein interactions, and thereby toxicity in neurodegenerative disease.
Repeated exposure to methamphetamine (MA) in laboratory rodents induces a sensitization of glutamate release within the corticoaccumbens pathway that drives both the rewarding and reinforcing ...properties of this highly addictive drug. Such findings argue the potential for pharmaceutical agents inhibiting glutamate release or its postsynaptic actions at glutamate receptors as treatment strategies for MA use disorder. One compound that may accomplish both of these pharmacological actions is the
-acetylated-alpha-linked-acidic dipeptidase (NAALADase) inhibitor 2-(phosphonomethyl)pentanedioic acid (2-PMPA). 2-PMPA elevates brain levels of the endogenous agonist of glutamate mGluR3 autoreceptors,
-acetyl-aspartatylglutamate (NAAG), while potentially acting as an NMDA glutamate receptor antagonist. Of relevance to treating psychomotor stimulant use disorders, 2-PMPA is reported to reduce indices of both cocaine and synthetic cathinone reward, as well as cocaine reinforcement in preclinical rodent studies.
Herein, we conducted three experiments to pilot the effects of systemic pretreatment with 2-PMPA (0-100 mg/kg, IP) on oral MA self-administration in C57BL/6J mice. The first experiment employed female mice with a prolonged history of MA exposure, while the mice in the second (females) and third (males and females) experiment were MA-naïve prior to study. In all experiments, mice were trained daily to nose-poke for delivery of unadulterated MA solutions until responding stabilized. Then, mice were pretreated with 2-PMPA prior to operant-conditioning sessions in which nose-poking behavior was reinforced by delivery of 120 mg/L or 200 mg/L MA (respectively, in Experiments 1 and 2/3).
Contrary to our expectations, 30 mg/kg 2-PMPA pretreatment altered neither appetitive nor consummatory measures related to MA self-administration. In Experiment 3, 100 mg/kg 2-PMPA reduced responding in the MA-reinforced hole, as well as the number of reinforcers earned, but did not significantly lower drug intake.
These results provide mixed evidenced related to the efficacy of this NAALADase inhibitor for reducing oral MA reinforcement in female mice.
Methamphetamine (MA) is a highly addictive psychomotor stimulant drug. In recent years, MA use has increased exponentially on a global scale, with the number of MA-involved deaths reaching epidemic ...proportions. There is no approved pharmacotherapy for treating MA use disorder, and we know relatively little regarding the neurobiological determinants of vulnerability to this disease. Extracellular signal-regulated kinase (ERK) is an important signaling molecule implicated in the long-lasting neuroadaptations purported to underlie the development of substance use disorders, but the role for this kinase in the propensity to develop addiction, particularly MA use disorder, is uncharacterized. In a previous MA-induced place-conditioning study of C57BL/6J mice, we characterized mice as MA-preferring, -neutral, or -avoiding and collected tissue from the medial prefrontal cortex (mPFC). Using immunoblotting, we determined that elevated phosphorylated ERK expression within the medial prefrontal cortex (mPFC) is a biochemical correlate of the affective valence of MA in a population of C57BL/6J mice. We confirmed the functional relevance for mPFC ERK activation for MA-induced place-preference via site-directed infusion of the MEK inhibitor U0126. By contrast, ERK inhibition did not have any effect upon MA-induced locomotion or its sensitization upon repeated MA treatment. Through studies of transgenic mice with alanine point mutations on T1123/S1126 of mGlu5 that disrupt ERK-dependent phosphorylation of the receptor, we discovered that ERK-dependent mGlu5 phosphorylation normally suppresses MA-induced conditioned place-preference (MA-CPP), but is necessary for this drug's reinforcing properties. If relevant to humans, the present results implicate individual differences in the capacity of MA-associated cues/contexts to hyper-activate ERK signaling within mPFC in MA Use Disorder vulnerability and pose mGlu5 as one ERK-directed target contributing to the propensity to seek out and take MA.
Problems associated with the abuse of amphetamine-type stimulants, including methamphetamine (MA), pose serious health and socioeconomic issues world-wide. While it is well-established that MA's ...psychopharmacological effects involve interactions with monoamine neurotransmission, accumulating evidence from animal models implicates dysregulated glutamate in MA addiction vulnerability and use disorder. Recently, we discovered an association between genetic vulnerability to MA-taking and increased expression of the glutamate receptor scaffolding protein Homer2 within both the shell and core subregions of the nucleus accumbens (NAC) and demonstrated a necessary role for Homer2 within the shell subregion in MA reward and reinforcement in mice. This report extends our earlier work by interrogating the functional relevance of Homer2 within the NAC core for the conditioned rewarding and reinforcing properties of MA. C57BL/6J mice with a virus-mediated knockdown of Homer2b expression within the NAC core were first tested for the development and expression of a MA-induced conditioned place-preference/CPP (four pairings of 2 mg/kg MA) and then were trained to self-administer oral MA under operant-conditioning procedures (5-80 mg/L). Homer2b knockdown in the NAC core augmented a MA-CPP and shifted the dose-response function for MA-reinforced responding, above control levels. To determine whether Homer2b within NAC subregions played an active role in regulating MA reward and reinforcement, we characterized the MA phenotype of constitutive
knockout (KO) mice and then assayed the effects of virus-mediated overexpression of Homer2b within the NAC shell and core of wild-type and KO mice. In line with the results of NAC core knockdown,
deletion potentiated MA-induced CPP, MA-reinforced responding and intake, as well as both cue- and MA-primed reinstatement of MA-seeking following extinction. However, there was no effect of Homer2b overexpression within the NAC core or the shell on the KO phenotype. These data provide new evidence indicating a globally suppressive role for Homer2 in MA-seeking and MA-taking but argue against specific NAC subregions as the neural loci through which Homer2 actively regulates MA addiction-related behaviors.
Methamphetamine (MA) and alcohol use disorders exhibit a high degree of co-morbidity and sequential alcohol-MA mixing increases risk for co-abuse. Recently, we reported greater MA-conditioned reward ...in male C57BL/6J mice with a prior history of binge alcohol-drinking (14 days of 2-hour access to 5, 10, 20 and 40% alcohol). As female mice tend to binge-drink more alcohol than males and females tend to be more sensitive than males to the psychomotor-activating properties of MA, we first characterized the effects of binge-drinking upon MA-induced place-conditioning (four pairings of 0.25, 0.5, 1, 2, or 4 mg/kg IP) in females and then incorporated our prior data to analyze for sex differences in MA-conditioned reward. Prior binge-drinking history did not significantly affect locomotor hyperactivity or its sensitization in female mice. However, the dose-response function for place-conditioning was shifted to the left of water-drinking controls, indicating an increase in sensitivity to MA-conditioned reward. The examination of sex differences revealed no sex differences in alcohol intake, although females exhibited greater MA-induced locomotor stimulation than males, irrespective of their prior drinking history. No statistically significant sex difference was apparent for the potentiation of MA-conditioned reward produced by prior binge-drinking history. If relevant to humans, these data argue that both males and females with a prior binge-drinking history are similarly vulnerable to MA abuse and it remains to be determined whether or not the neural substrates underpinning this increased vulnerability reflect common or sex-specific adaptations in reward-related brain regions.
•Prior binge-drinking augmented methamphetamine-conditioned reward in mice.•Prior binge-drinking reduced spontaneous locomotion.•Prior binge-drinking did not influence methamphetamine ...locomotion/sensitization.•Prior binge-drinking increases the reward efficacy of methamphetamine.
An alcohol use disorder is a major predisposing factor for methamphetamine (MA) abuse. Further, MA-alcohol co-abuse is a risk factor for treatment discontinuation and non-compliance in MA-dependent individuals. No effective treatment exists for MA addiction, let alone treatments directed at those suffering from MA-alcohol addiction co-morbidity. Thus, it is imperative that we develop high-throughput animal models to study the biobehavioral interactions between MA and alcohol of relevance to the etiology and treatment of co-abuse. To this end, we reported that a history of binge alcohol-drinking 5,10, 20 and 40% (v/v); 2 h/day for 10–14 days reduces MA reinforcement and intake, but it augments MA-preference and intake when drug availability is behaviorally non-contingent. To reconcile this apparent discrepancy in findings, we employed a comparable 2-week binge-drinking paradigm as that employed in our previous studies followed by place-conditioning procedures (4 pairings of 0.25, 0.5, 1, 2 or 4 mg/kg MA, i.p.). This was meant to determine how a prior binge-drinking history impacts the affective valence of MA and sensitivity to MA-induced psychomotor-activation/sensitization. Prior binge-drinking history blunted spontaneous locomotor activity and shifted the MA dose-place-preference function upwards of water drinking controls. The potentiation of MA-conditioned reward by prior binge-drinking history was independent of any alcohol effects upon the locomotor-activating or –sensitizing effects of MA. Based on these results we propose that the reduced MA reinforcement reported previously by our group likely reflects a compensatory response to an increased sensitivity to MA’s positive subjective effects rather than increased sensitivity to the drug’s psychomotor-activating effects.
Nutrient-dense foods, which are often low in energy density (ED), are recommended for a healthy diet in infants and children. How ED changes during the transition from a complementary diet in infancy ...to a conventional diet is unknown.
We aimed to describe the ED, the amount of energy (e.g., kcal) per weight (e.g., g), of food or beverage in infants and preschool-age children. It was hypothesized that ED would be higher among older children.
The ED of food (ED-Food Only) and of food and all beverages excluding human milk and infant formula (ED-Food and Beverages) of children's (6 mo–5 y) diets were examined overall and by age subgroups using data from the NHANES (2009–2018). Survey-adjusted linear regression followed by pairwise comparisons were used to compare ED across age subgroups. The percentages of calories consumed from low-, medium-, and high-ED foods across age subgroups were also examined.
Mean ED-Food Only was 1.21 kcal/g (95% CI: 1.13, 1.29 kcal/g) among 6- to 11-mo-olds and 1.62 kcal/g (95% CI: 1.54, 1.69 kcal/g) among 12- to 17-mo-olds (P < 0.05). ED-Food and Beverages was higher across consecutive age subgroups from 0.99 kcal/g (95% CI: 0.96, 1.02 kcal/g) in 12–17 mo through 3 y (1.22 kcal/g; 95% CI: 1.19, 1.26 kcal/g; P < 0.05). Mean percentage of calories consumed from low-ED food (≤1.0 kcal/g) became lower with age from 6- to 11-mo-olds (47.3%; 95% CI: 44.3%, 50.4%) through 18- to 23-mo-olds (16.2%; 95% CI: 14.5%, 17.9%; P < 0.05). A greater percentage of calories was consumed from high-ED food (≥3.0 kcal/g) among 18- to 23-mo-olds (39.0%; 95% CI: 37.1%, 40.9%) than among 12- to 17-mo-olds (34.0%; 95% CI: 32.0%, 35.9%; P < 0.05).
ED increased across age subgroups, driven by a decrease in the percentage of calories consumed from low-ED food and an increase in the percentage of calories consumed from high-ED food.
Feasibility of Implementing a Food Skills Intervention Fultz, Amanda K.; Baker, Sandra; Anderson Steeves, Elizabeth ...
Journal of the Academy of Nutrition and Dietetics,
08/2022, Volume:
122, Issue:
8
Journal Article
Peer reviewed
Food skills are defined as meal planning, preparation, shopping, budgeting, resourcefulness, and label reading/consumer awareness. To date, food skills have not been tested in intervention-based ...studies.
To evaluate the feasibility of implementing a food skills intervention.
This was an 8-week prospective food skills intervention. Study measures were completed through questionnaires provided before the start of the intervention and after the intervention was completed. For questionnaires, the web platform REDCap was used.
Thirty parents (aged 18 years or older) with at least one child (aged 2 to 12 years), attended weekly virtual intervention sessions via Zoom. The intervention took place from August to October 2020 with assessment measures collected within 2 months of the start and end date of the intervention. Participants were from the mid-Atlantic region of the United States
A food skills intervention based on behavior modification strategies from the Social Cognitive Theory was implemented. Intervention goals included meal planning (six of seven dinner meals per week), meal plan implementation (at least four of six planned dinner meals), and always using a grocery list when shopping.
Feasibility was evaluated based on parent attendance, number of self-monitoring booklets completed, adherence to goals, implementation fidelity, and qualitative responses to interviews. Change in food skills confidence and nutrition knowledge were also assessed.
Descriptive statistics and qualitative responses were used to describe feasibility. Paired t tests were used to evaluate change in food skills confidence and nutrition knowledge from baseline to 8 weeks.
Parents attended a mean of 7.6 ± 1.0 (out of eight) sessions and completed a mean of 6.2 ± 1.7 (out of seven) self-monitoring booklets. Parents planned a mean of 6.1 ± 1.5 dinners per week and implemented a mean of 4.7 ± 1.6 of the six planned dinners, achieving the intervention goals. Of the mean 1.2 ± 0.6 trips/week to the grocery store reported, grocery lists were used a mean of 1.1 ± 0.6 times. Mean food skills confidence score increased significantly from baseline to 8 weeks (baseline = 86.5 ± 18.0; 8 weeks = 101.4 ± 15.3; P < 0.001). Mean nutrition knowledge score also significantly increased (baseline = 64.1 ± 7.2; 8 weeks = 69.1 ± 6.6; P < 0.001). Parents reported on a scale of zero (“easy”) to 10 (“difficult”) a mean difficulty rating of 2.4 ± 2.4 for meal planning, a mean of 2.1 ± 2.1 for meal plan implementation, and a mean of 1.0 ± 1.7 for always using a grocery shopping list indicating acceptability of goals.
Feasibility of a food skills intervention was demonstrated by high session attendance, high numbers of self-monitoring booklets turned in, high achievement of intervention goals, parent acceptability, and high ratings of implementation fidelity. There was an increase in food skill confidence and nutrition knowledge. Future research should examine the efficacy of changing food skill behaviors on dietary intake.
The Nutrition Environment Measurement Survey (NEMS) measures were developed to assess the consumer food environment in stores and restaurants. NEMS tools have been widely used in research and adapted ...for diverse settings and populations in the 15 years since they were created. This systematic review examines the use and adaptations of these measures and what can be learned from published studies using NEMS tools.
A comprehensive search of bibliographic databases was conducted from 2007 to September 2021, supplemented by backward searches and communications with authors, to identify research articles using NEMS tools. Data on purpose, key findings, sample characteristics, NEMS characteristics, and modifications were abstracted. Articles were categorized on the basis of study goals, NEMS tool(s) used, variables measured, and common themes.
A total of 190 articles from 18 countries were identified. Most studies (69.5%, n=123) used a modified version of NEMS tools. There were 23 intervention studies that used measures from NEMS tools or adaptations as outcomes, moderators, or process assessments. A total of 41% (n=78) of the articles evaluated inter-rater reliability, and 17% (n=33) evaluated test–retest reliability.
NEMS measures have played an important role in the growth of research on food environments and have helped researchers to explore the relationships among healthy food availability, demographic variables, eating behaviors, health outcomes, and intervention-driven changes in food environments. The food environment is constantly changing, so NEMS measures should continue to evolve. Researchers should document data quality of modifications and use in new settings.
Food shopping frequency may be an important modifiable factor related to increasing fruit and vegetable (FV) intake. Because of mixed findings of individual studies of shopping frequency, a ...systematic review is needed to examine findings across studies and store types.
To conduct a systematic review of articles examining the relationship between frequency of food shopping and FV intake including examination of participation in federal nutrition assistance programs on FV intake, if reported.
A search, guided by the Preferred Reported Items for Systematic Reviews and Metanalyses, using terms related to FV consumption and food shopping across 4 online databases, was conducted. Studies conducted in the US and published through October, 2020, included adults, and had a cross-sectional, longitudinal, cohort, or randomized study design were eligible for inclusion.
Twenty-four articles were included. The majority of studies found at least 1 positive finding between the frequency of food shopping and FV intake, indicating that as the frequency of food shopping increased, FV intake increased. In studies with 100% participation in government/federal nutrition assistance programs, participation was associated with FV intake. Studies that included participation as a subset found participation not associated with FV intake.
The frequency of shopping may be modifiable to increase FV intake. Experimental research is needed to test the directionality and causality of the relationship. Federal nutrition assistance programs may be a logical place to test the relationship through the adjustment of fund disbursements.
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