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Identifying risk factors that contribute to the development of anorexia nervosa (AN) is critical for the implementation of early intervention strategies. Anxiety, obsessive-compulsive behavior, and immune dysfunction may be involved in the development of AN; however, their direct influence on susceptibility to the condition remains unclear. Here, we used the activity-based anorexia (ABA) model to examine whether activity, anxiety-like behavior, compulsive behavior, and circulating immune markers predict the subsequent development of pathological weight loss.Female Sprague-Dawley rats (n = 44) underwent behavioral testing before exposure to ABA conditions after which they were separated into susceptible and resistant subpopulations. Blood was sampled before behavioral testing and after recovery from ABA to screen for proinflammatory cytokines.Rats that were vulnerable to pathological weight loss differed significantly from resistant rats on all key ABA parameters. While the primary measures of anxiety-like or compulsive behavior were not shown to predict vulnerability to ABA, increased locomotion and anxiety-like behavior were both associated with the extent of weight loss in susceptible but not resistant animals. Moreover, the change in expression of proinflammatory markers IL-4 and IL-6 evoked by ABA was associated with discrete vulnerability factors. Intriguingly, behavior related to risk assessment was shown to predict vulnerability to ABA.We did not find undisputable behavioral or immune predictors of susceptibility to pathological weight loss in the ABA rat model. Future research should examine the role of cognition in the development of ABA, dysfunction of which may represent an endophenotype linking anorectic, anxiety-like and compulsive behavior.Anorexia nervosa (AN) has among the highest mortality rates of all psychiatric disorders and treatment options remain limited in their efficacy. Understanding what types of risk factors contribute to the development of AN is essential for implementing early intervention strategies. This study describes how some of the most common psychological features of AN could be used to predict susceptibility to pathological weight loss in a well-established animal model.

RationaleThe blood-brain barrier (BBB) is a major impediment to therapeutic intracranial drug delivery for the treatment of neurodegenerative diseases, including Alzheimer’s disease (AD). Focused ultrasound applied together with microbubbles (FUS+MB) is a novel technique to transiently open the BBB and increase drug delivery. Evidence suggests that FUS+MBis safe, however the effects of FUS+MBon human BBB cells, especially in the context of AD, remain sparsely investigated.MethodsHere we generated BBB cells (induced brain endothelial cells (iBECs) and astrocytes (iAstrocytes)) from apolipoprotein E gene allele E4 (APOE4, high AD risk) and allele E3 (APOE3, lower AD risk) carrying patient-derived induced pluripotent stem cells (iPSCs). We then developed a human sporadic AD BBB cell platform to investigate the effects of FUS+MBon BBB cells and screen for the delivery of two potentially therapeutic AD antibodies.ResultsWe utilized this robust and reproducible human BBB model to demonstrate increased delivery of therapeutic AD antibodies across the BBB following FUS+MBtreatment, including an analogue of Aducanumab (AduhelmTM; anti-amyloid-β) and a novel anti-Tau antibody RNF5. Our results also demonstrate the safety of FUS+MBindicated by minimal changes in the cell transcriptome as well as little or no changes in cell viability and inflammatory responses within the first 24 h post FUS+MB. Finally, we report a more physiologically relevant hydrogel-based 2.5D BBB model as a key development for FUS+MB-mediated drug delivery screening, with potentially higher translational utility.ConclusionOur results demonstrate an important translatable patient BBB cell model for identifying FUS+MB-deliverable drugs and screening for cell- and patient-specific effects of FUS+MB, accelerating the use of FUS+MBas a therapeutic modality in AD.One Sentence SummaryFocused ultrasound increases thein vitrodelivery of therapeutic antibodies Aducanumab and anti-Tau in a sporadic Alzheimer’s disease patient-derived blood-brain barrier cell model.

BackgroundThe ability to adapt behavior to changing environmental circumstances, orcognitive flexibility, is impaired in multiple psychiatric conditions, including anorexia nervosa (AN). Exaggerated prefrontal cortical activity likely underpins the inflexible thinking and rigid behaviors exhibited by patients with AN. A better understanding of the neural basis of cognitive flexibility is necessary to enable treatment approaches that may target impaired executive control.MethodsUtilizing the activity-based anorexia (ABA) rat model and touchscreen operant learning paradigms, we investigated the neurobiological link between pathological weight loss and cognitive flexibility. We used pathway-specific chemogenetics to selectively modulate activity in neurons of the medial prefrontal cortex (mPFC) projecting to the nucleus accumbens shell (AcbSh) in female Sprague-Dawley rats.ResultsDREADD-based inhibition of the mPFC-AcbSh pathway prevented weight loss in ABA and improved flexibility during early reversal learning by reducing perseverative responding. Modulation of activity within the mPFC-AcbSh pathway had no effect on running, locomotor activity or feeding under ad libitum conditions, indicating the specific involvement of this circuit in conditions of dysregulated reward.ConclusionsBoth attenuation of weight loss in ABA and improved cognitive flexibility following suppression of mPFC-AcbSh activity aligns with the relationship between disrupted prefrontal function and cognitive rigidity in AN patients. The identification of a neurobiological correlate between cognitive flexibility and pathological weight loss provides a unique insight into the executive control of feeding behavior. It also highlights the utility of the ABA model for understanding the biological bases of cognitive deficits in AN and provides context for new treatment strategies.

Smoke from bushfires (also known as wildfires or forest fires) has blanketed large regions of Australia during the southern hemisphere summer of 2019/2020, potentially endangering residents who breathe the polluted air. While such air pollution is known to cause respiratory irritation and damage, its effect on the brain is not well described. In this review, we aim to outline the potentially damaging effects of bushfire smoke on brain health. We also describe the composition of air pollution, including ambient particulate matter (PM) and bushfire PM, before covering the general health effects of each. The investigated entry routes for ambient PM and postulated entry routes for bushfire PM are discussed, along with epidemiological and experimental evidence of the effect of both PMs in the brain. It appears that bushfire PM may be more toxic than ambient PM, and that it may enter the brain through extrapulmonary or olfactory routes to cause inflammation and oxidative stress. Ultimately, this review highlights the desperate requirement of greater research into the effects of bushfire PM on brain health.

Patients suffering anorexia nervosa (AN) become anhedonic, unable or unwilling to derive normal pleasures and tend to avoid rewarding outcomes, most profoundly in food intake. The activity-based anorexia (ABA) model recapitulates many of the pathophysiological and behavioural hallmarks of the human condition, including a reduction in food intake, excessive exercise, dramatic weight loss, loss of reproductive cycles, hypothermia and anhedonia, and therefore allows investigation of the underlying neurobiology of AN. The use of this model has directed attention to disruptions in central reward neurocircuitry, which may contribute to disease susceptibility. The purpose of this review is to demonstrate the utility of this unique model to provide insight into the mechanisms of reward relevant to feeding and weight loss, which may ultimately help to unravel the neurobiology of anorexia and, in a broader sense, the foundation of reward-based feeding. This article is protected by copyright. All rights reserved.