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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.

Anorexia nervosa (AN) has among the highest mortality rates of any psychiatric disorder and is characterised by cognitive inflexibility that persists after weight recovery and contributes to the low rates of recovery. What remains unknown is whether cognitive inflexibility predisposes individuals to AN, a question that is difficult to determine from human studies. Our previous work using the most well-established animal model of AN, known as activity-based anorexia (ABA) identified a neurobiological link between cognitive inflexibility and susceptibility to pathological weight loss in female rats. However, testing flexible learning prior to exposure to ABA in the same animals has been thus far impossible due to the length of training required and the necessity of daily handling, which can itself influence the development of ABA.Here we describe experiments that validate and optimise the first fully-automated and experimenter-free touchscreen cognitive testing system for rats (n=20) and use this novel system to examine the reciprocal links between reversal learning (an assay of cognitive flexibility) and weight loss in the ABA model (n=60). Firstly, we show substantially reduced testing time and increased throughput compared to conventional touchscreen testing methods because animals engage in test sessions at their own direction and can complete multiple sessions per day without experimenter involvement. We also show that, contrary to expectations, cognitive inflexibility does not predispose rats to pathological weight loss in ABA but instead that rats subsequently susceptible to weight loss performed better on the reversal learning task. Intriguingly, we show reciprocal links between ABA exposure and cognitive flexibility, with ABA exposed (but weight recovered) rats performing much worse that ABA naïve rats on the reversal learning task. On the other hand, animals that had been trained on reversal learning were better able to resist weight loss upon subsequent exposure to the ABA model. We also uncovered some stable behavioural differences between ABA susceptible versus resistant rats during touchscreen test sessions using machine learning tools that highlight possible predictors of anorectic phenotypes.These findings shed new light on the relationship between cognitive inflexibility and pathological weight loss and provide a robust target for future studies using the ABA model to investigate potential novel pharmacotherapies for AN.

Anorexia nervosa (AN) has high rates of mortality and low rates of recovery, with outcomes that worsen with illness duration. Improved early intervention strategies are required and identifying risk factors that contribute to the development of AN is critical to their implementation. The development of AN often follows a pre-existing diagnosis of anxiety disorders and obsessive-compulsive disorder and substantial genetic overlap between these conditions suggest common underlying features may predict vulnerability to AN. Moreover, patients with AN have increased levels of circulating proinflammatory cytokines, which may be involved in susceptibility to pathological weight loss considering that children with immune dysfunction have a higher risk of subsequent AN diagnoses.Here, we used the activity-based anorexia (ABA) model to examine whether baseline levels of locomotion, anxiety-like behaviour, compulsive behaviour, and circulating immune markers predict the subsequent development of pathological weight loss in adolescent female rats. While none of these primary features were shown to differentiate rats that went on to be susceptible or resistant to weight loss in ABA, increased locomotion and anxiety-like behaviour were both associated with the extent of weight loss in susceptible but not resistant animals. Intriguingly, behaviour related to poor decision-making in a situation of conflict was shown to predict vulnerability to ABA. Future research using the ABA model to uncover early predictors of AN should focus on translationally relevant assays of decision-making and cognitive behaviour, dysfunction of which may not only predispose animals to ABA but may also represent an endophenotype linking anorectic, anxiety-like and compulsive behaviour.

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.

Patients suffering from anorexia nervosa (AN) become anhedonic; unable or unwilling to derive normal pleasures and avoid rewarding outcomes, most profoundly in food intake. The activity-based anorexia (ABA) model recapitulates many of the characteristics of the human condition, including anhedonia, and allows investigation of the underlying neurobiology of AN. The potential for increased neuronal activity in reward/hedonic circuits to prevent and rescue weight loss is investigated in this model. The mesolimbic pathway extending from the ventral tegmental area (VTA) to the nucleus accumbens (NAc) was activated using a dual viral strategy, involving retrograde transport of Cre (CAV-2-Cre) to the VTA and coincident injection of DREADD receptors (AAV-hSyn-DIO-hM3D(Gq)-mCherry). Systemic clozapine-n-oxide (CNO; 0.3 mg/kg) successfully recruited a large proportion of the VTA-NAc dopaminergic projections, with activity evidenced by colocalization with elevated levels of Fos protein. The effects of reward circuit activation on energy balance and predicted survival was investigated in female Sprague-Dawley rats, where free access to running wheels was paired with time-limited (90 min) access to food, a paradigm (ABA) which will cause anorexia and death if unchecked. Excitation of the reward pathway substantially increased food intake and food anticipatory activity (FAA) to prevent ABA-associated weight loss, while overall locomotor activity was unchanged. Similar activation of reward circuitry, delayed until establishment of the ABA phenotype, rescued rats from their precipitous weight loss. Although these data are consistent with shifts primarily in food intake, the contribution of mechanisms including energy expenditure to survival remains to be determined. These results will inform the neurobiological underpinnings of AN, and provide insight into the mechanisms of reward circuitry relevant to feeding and weight loss.

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, in other words, unable or unwilling to derive normal pleasures and avoid rewarding outcomes, most profoundly in food intake. The neurobiological underpinnings of anhedonia are likely to involve mesolimbic reward circuitry. We propose here that this circuitry and its involvement in AN can be investigated using the activity-based anorexia (ABA) rodent model that recapitulates many of the characteristics of the human condition, most notably rapid weight loss. Preference for sweetened water was used to assay hedonic processing in female Sprague-Dawley rats exposed to the ABA protocol, which involves free access to running wheels paired with time-limited access to food. This protocol uncovered a transient anhedonia in only one quarter of cases; however, exposure to running wheels alone was associated with a rapid aversion to sweetened water (F1.833, 20.17 = 78.29, p < .0001), and time-limited food access alone did not impact preference (F2.205, 24.25 = 0.305, p = .761). High levels of running wheel activity prior to the onset of food restriction increased susceptibility to body weight loss in ABA (F10,196.129 = 2.069, p = .029) and food anticipatory activity predicted subsequent food intake only for rats that were resistant to body weight loss (r = 0.44, p = .001). These data are inconsistent with the hypothesis that anhedonia underscores the precipitous weight loss in ABA, however, they highlight the predictive nature of hyperactivity in susceptibility to the ABA paradigm. These results will help inform the neurobiological framework of ABA and provide insight into the mechanisms of reward relevant to feeding and weight loss.

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.