Neurotoxic astrocytes express the d-serine synthesizing enzyme, serine racemase, in Alzheimer's disease.

Although ß-amyloid plaques are a well-recognized hallmark of Alzheimer's disease (AD) neuropathology, no drugs reducing amyloid burden have shown efficacy in clinical trials, suggesting that once AD symptoms emerge, disease progression becomes independent of Aß production. Reactive astrocytes are another neuropathological feature of AD, where there is an emergence of neurotoxic (A1) reactive astrocytes. We find that serine racemase (SR), the neuronal enzyme that produces the N-methyl-d-aspartate receptor (NMDAR) co-agonist d-serine, is robustly expressed in A1-reactive neurotoxic astrocytes in the hippocampus and entorhinal cortex of AD subjects and an AD rat model. Furthermore, we observe intracellular signaling changes consistent with increased extra-synaptic NMDAR activation, excitotoxicity and decreased neuronal survival. Thus, reducing neurotoxic d-serine release from A1 inflammatory astrocytes could have therapeutic benefit for mild to advanced AD, when anti-amyloid strategies are ineffective.

Chemogenetic locus coeruleus activation restores reversal learning in a rat model of Alzheimer's disease.

See Grinberg and Heinsen (doi:10.1093/brain/awx261) for a scientific commentary on this article. Clinical evidence suggests that aberrant tau accumulation in the locus coeruleus and noradrenergic dysfunction may be a critical early step in Alzheimer's disease progression. Yet, an accurate preclinical model of these phenotypes that includes early pretangle tau accrual in the locus coeruleus, loss of locus coeruleus innervation and deficits locus coeruleus/norepinephrine modulated behaviours, does not exist, hampering the identification of underlying mechanisms and the development of locus coeruleus-based therapies. Here, a transgenic rat (TgF344-AD) expressing disease-causing mutant amyloid precursor protein (APPsw) and presenilin-1 (PS1ΔE9) was characterized for histological and behavioural signs of locus coeruleus dysfunction reminiscent of mild cognitive impairment/early Alzheimer's disease. In TgF344-AD rats, hyperphosphorylated tau was detected in the locus coeruleus prior to accrual in the medial entorhinal cortex or hippocampus, and tau pathology in the locus coeruleus was negatively correlated with noradrenergic innervation in the medial entorhinal cortex. Likewise, TgF344-AD rats displayed progressive loss of hippocampal norepinephrine levels and locus coeruleus fibres in the medial entorhinal cortex and dentate gyrus, with no frank noradrenergic cell body loss. Cultured mouse locus coeruleus neurons expressing hyperphosphorylation-prone mutant human tau had shorter neurites than control neurons, but similar cell viability, suggesting a causal link between pretangle tau accrual and altered locus coeruleus fibre morphology. TgF344-AD rats had impaired reversal learning in the Morris water maze compared to their wild-type littermates, which was rescued by chemogenetic locus coeruleus activation via designer receptors exclusively activated by designer drugs (DREADDs). Our results indicate that TgF344-AD rats uniquely meet several key criteria for a suitable model of locus coeruleus pathology and dysfunction early in Alzheimer's disease progression, and suggest that a substantial window of opportunity for locus coeruleus/ norepinephrine-based therapeutics exists.

Differentiating neural sensitivity and bias during face-emotion processing in youth: a computational approach.

The ability to interpret face-emotion displays is critical for the development of adaptive social interactions. Using a novel variant of a computational model and fMRI data, we examined behavioral and neural associations between two metrics of face-emotion labeling (sensitivity and bias) and age in youth. Youth and adults (n = 44, M age = 20.02, s.d. = 7.44, range = 8-36) completed an explicit face-emotion labeling fMRI task including happy to angry morphed face emotions. A drift-diffusion model was applied to choice and reaction time distributions to examine sensitivity and bias in interpreting face emotions. Model fit and reliability of parameters were assessed on adult data (n = 42). Linear and quadratic slopes modeled brain activity associated with dimensions of face-emotion valence and ambiguity during interpretation. Behaviorally, age was associated with sensitivity. The bilateral anterior insula exhibited a more pronounced neural response to ambiguity with older age. Associations between sensitivity and bias metrics and activation patterns indicated that systems encoding face-emotion valence and ambiguity both contribute to the ability to discriminate face emotions. The current study provides evidence for age-related improvement in perceptual sensitivity to facial affect across adolescence and young adulthood.

Persistent Frustration-Induced Reconfigurations of Brain Networks Predict Individual Differences in Irritability.

OBJECTIVE: Aberrant responses to frustration are central mechanisms of pediatric irritability, which is a common reason for psychiatric consultation and a risk factor for affective disorders and suicidality. This pilot study aimed to characterize brain network configuration during and after frustration and test whether characteristics of networks formed during or after frustration relate to irritability. METHOD: During functional magnetic resonance imaging, a transdiagnostic sample enriched for irritability (N = 66, mean age = 14.0 years, 50% female participants) completed a frustration-induction task flanked by pretask and posttask resting-state scans. We first tested whether and how the organization of brain regions (ie, nodes) into networks (ie, modules) changes during and after frustration. Then, using a train/test/held-out procedure, we aimed to predict past-week irritability from global efficiency (Eglob) (ie, capacity for parallel information processing) of these modules. RESULTS: Two modules present in the baseline pretask resting-state scan (one encompassing anterior default mode and temporolimbic regions and one consisting of frontoparietal regions) contributed most to brain circuit reorganization during and after frustration. Only Eglob of modules in the posttask resting-state scans (ie, after frustration) predicted irritability symptoms. Self-reported irritability was predicted by Eglob of a frontotemporal-limbic module. Parent-reported irritability was predicted by Eglob of ventral-prefrontal-subcortical and somatomotor-parietal modules. CONCLUSION: These pilot results suggest the importance of the postfrustration recovery period in the pathophysiology of irritability. Eglob in 3 specific posttask modules, involved in emotion processing, reward processing, or motor function, predicted irritability. These findings, if replicated, could represent specific intervention targets for irritability.

A Randomized Controlled Trial of Computerized Interpretation Bias Training for Disruptive Mood Dysregulation Disorder: A Fast-Fail Study.

OBJECTIVE: To examine targeted, mechanism-based interventions is the next generation of treatment innovation. Biased threat labeling of ambiguous face emotions (interpretation bias) is a potential behavioral treatment target for anger, aggression, and irritability. Changing biases in face-emotion labeling may improve irritability-related outcomes. Here, we report the first randomized, double-blind, placebo-controlled targeted trial of interpretation bias training (IBT) in youths with chronic, severe irritability. METHOD: Patients with current disruptive mood dysregulation disorder (DMDD; N = 44) were randomly assigned to complete 4 sessions of active (n = 22) or sham (n = 22) computerized IBT training within a 1-week period. The first and last trainings were completed onsite, and 2 trainings were completed at home. We examined the effects of active IBT on labeling bias, primary outcome measures of irritability, and secondary outcome measures of anxiety, depression, and functional impairment. Follow-up assessments were completed immediately after the intervention as well as 1 and 2 weeks later. RESULTS: We found that active IBT engaged the behavioral target in the active relative to the sham condition, as shown by a significant shift toward labeling ambiguous faces as happy. However, there was no consistent clinical improvement in active IBT relative to the sham condition either immediately after or 2 weeks after training in either the primary or secondary outcome measures. CONCLUSION: Although this randomized controlled trial of IBT in youths with DMDD engaged the proposed behavioral target, there was no statistically significant improvement on clinical outcome. Identifying and changing behavioral targets is a first step in novel treatment development; these results have broader implications for target-based intervention development. CLINICAL TRIAL REGISTRATION INFORMATION: Psychological Treatments for Youth With Severe Irritability; https://clinicaltrials.gov/; NCT02531893.

Rationale and validation of a novel mobile application probing motor inhibition: Proof of concept of CALM-IT.

Identification of behavioral mechanisms underlying psychopathology is essential for the development of novel targeted therapeutics. However, this work relies on rigorous, time-intensive, clinic-based laboratory research, making it difficult to translate research paradigms into tools that can be used by clinicians in the community. The broad adoption of smartphone technology provides a promising opportunity to bridge the gap between the mechanisms identified in the laboratory and the clinical interventions targeting them in the community. The goal of the current study is to develop a developmentally appropriate, engaging, novel mobile application called CALM-IT that probes a narrow biologically informed process, inhibitory control. We aim to leverage the rigorous and robust methods traditionally used in laboratory settings to validate this novel mechanism-driven but easily disseminatable tool that can be used by clinicians to probe inhibitory control in the community. The development of CALM-IT has significant implications for the ability to screen for inhibitory control deficits in the community by both clinicians and researchers. By facilitating assessment of inhibitory control outside of the laboratory setting, researchers could have access to larger and more diverse samples. Additionally, in the clinical setting, CALM-IT represents a novel clinical screening measure that could be used to determine personalized courses of treatment based on the presence of inhibitory control deficits.

Effects of the selective dopamine D3 receptor antagonist PG01037 on morphine-induced hyperactivity and antinociception in mice.

Recent preclinical studies have reported that pretreatment with the novel and highly-selective dopamine D3 receptor (D3R) antagonists R-VK4-40 or VK4-116 attenuates the abuse-related behavioral effects of oxycodone while enhancing its analgesic properties. However, whether these observed effects are generalizable to the broad class of D3R antagonists and/or extend to opioids other than oxycodone has not been extensively explored. The present study sought to assess the impact of pretreatment with another selective D3R antagonist, PG01037, on several behavioral effects of morphine in mice. C57Bl/6 J mice were pretreated with PG01037 (0-10 mg/kg) and tested for 1) hyperlocomotion induced by acute morphine (5.6-56 mg/kg), 2) locomotor sensitization following repeated morphine (56 mg/kg), 3) antinociception following acute morphine (18 mg/kg), and 4) catalepsy following administration of PG01037 alone or in combination with morphine (56 mg/kg). PG01037 dose-dependently attenuated morphine-induced hyperlocomotion and morphine-induced antinociception at doses that did not alter basal locomotion or nociception alone, but did not prevent the induction of locomotor sensitization following repeated morphine administration. Moreover, PG01037 did not induce catalepsy either alone or in combination with morphine. These results suggest that attenuation of acute opioid-induced hyperactivity may be a behavioral effect shared among D3R-selective antagonists, thus supporting continued investigations into their use as potential treatments for opioid use disorder. However, PG01037 is unlike newer, highly-selective D3R antagonists in its capacity to reduce opioid-induced antinociception, indicating that modulation of opioid analgesia may vary across different D3R antagonists.