Research Fellow at Monash University
"Nothing tastes as good as skinny feels": How the brain can override the body's pursuit of survival
Anorexia Nervosa (AN) is a complex and debilitating disorder that is characterised by a relentless pursuit of weight loss through extreme food restriction and excessive exercise and has the highest mortality rate of any psychiatric illness. A lack of understanding of how AN develops has hindered the progress of effective treatments, with no clear evidence to support the efficacy of existing pharmaceutical interventions.
How is it possible that individuals suffering AN are able to voluntarily restrict food intake over a number of years when most individuals find it difficult to lose even a few kilos and even harder to maintain that weight loss? At least part of the answer lies in the interplay of brain circuitries that mediate homeostatic, rewarding, cognitive and emotional aspects of food intake.
My research aims to elucidate these circuits and focuses on the view that AN develops from an imbalance between reward and executive control signalling in the brain. The behavioural outcome is that patients become unable or unwilling to experience reward, and through extreme self-discipline, restrict food intake to the point of starvation. This is supported by evidence from functional neuroimaging studies in AN that demonstrate exaggerated neural activity in the prefrontal cortex, which leads to heightened cognitive control, and reduced neural activity in the striatum resulting in depressed reward function. These alterations combine to create a central neural blue print for the poor recognition of homeostatic or “survival” needs that is seen in AN patients.
In order to manipulate these neural circuits to unravel the neurobiology underpinning AN, I have been exploiting a rodent model of AN, known as activity-based anorexia (ABA). The ABA model recapitulates many of the characteristics of the human condition, including reduced food intake, excessive exercise and dramatic weight loss, loss of reproductive cycles, hypothermia and anhedonia. Using this model, I have shown that direct activation of neurons in the mesolimbic reward circuit prevents the body weight “free-fall” that typifies both ABA and AN.
My vision is to build on these results and use them to inform therapeutic strategies for this crippling disorder for which there is currently no effective treatment.
Abstract: Individuals with anorexia nervosa (AN) engage in relentless restrictive eating and often become severely emaciated. Because there are no proven treatments, AN has high rates of relapse, chronicity, and death. Those with AN tend to have childhood temperament and personality traits, such as anxiety, obsessions, and perfectionism, which may reflect neurobiological risk factors for developing AN. Restricted eating may be a means of reducing negative mood caused by skewed interactions between serotonin aversive or inhibitory and dopamine reward systems. Brain imaging studies suggest that altered eating is a consequence of dysregulated reward and/or awareness of homeostatic needs, perhaps related to enhanced executive ability to inhibit incentive motivational drives. An understanding of the neurobiology of this disorder is likely to be important for developing more effective treatments.
Pub.: 22 Jan '13, Pinned: 15 Sep '17
Abstract: Anorexia nervosa (AN) is a psychiatric illness characterized by excessively restricted caloric intake and abnormally high levels of physical activity. A challenging illness to treat, due to the lack of understanding of the underlying neurobiology, AN has the highest mortality rate among psychiatric illnesses. To address this need, neuroscientists are using an animal model to study how neural circuits may contribute toward vulnerability to AN and may be affected by AN. Activity-based anorexia (ABA) is a bio-behavioral phenomenon described in rodents that models the key symptoms of anorexia nervosa. When rodents with free access to voluntary exercise on a running wheel experience food restriction, they become hyperactive - running more than animals with free access to food. Here, we describe the procedures by which ABA is induced in adolescent female C57BL/6 mice. On postnatal day 36 (P36), the animal is housed with access to voluntary exercise on a running wheel. After 4 days of acclimation to the running wheel, on P40, all food is removed from the cage. For the next 3 days, food is returned to the cage (allowing animals free food access) for 2 hr daily. After the fourth day of food restriction, free access to food is returned and the running wheel is removed from the cage to allow the animals to recover. Continuous multi-day analysis of running wheel activity shows that mice become hyperactive within 24 hr following the onset of food restriction. The mice run even during the limited time during which they have access to food. Additionally, the circadian pattern of wheel running becomes disrupted by the experience of food restriction. We have been able to correlate neurobiological changes with various aspects of the animals' wheel running behavior to implicate particular brain regions and neurochemical changes with resilience and vulnerability to food-restriction induced hyperactivity.
Pub.: 12 Nov '15, Pinned: 13 Nov '17
Abstract: Anorexia nervosa (AN) is a psychiatric illness with minimal effective treatments and a very high rate of mortality. Understanding the neurobiological underpinnings of the disease is imperative for improving outcomes and can be aided by the study of animal models. The activity-based anorexia rodent model (ABA) is the current best parallel for the study of AN. This review describes the basic neurobiology of feeding and hyperactivity seen in both ABA and AN, and compiles the research on the role that stress-response and reward pathways play in modulating the homeostatic drive to eat and to expend energy, which become dysfunctional in ABA and AN.
Pub.: 09 Nov '16, Pinned: 15 Sep '17
Abstract: The eating disorders anorexia nervosa (AN) and bulimia nervosa (BN) are severe psychiatric disorders with high mortality. Our knowledge about the neurobiology of eating disorders is very limited, and the question remains whether alterations in brain structure or function in eating disorders are state related, remnants of the illness or premorbid traits. The brain reward system is a relatively well-characterized brain circuitry that plays a central role in the drive to eat and individuals with current or past eating disorders showed alterations in those pathways compared to controls. Here we propose that structural and functional alterations in the insula and frontal cortex, including orbitofrontal and cingulate regions, areas that contribute to reward and anxiety processing, could predispose to developing an eating disorder and that adaptive changes in those circuits in response to malnutrition or repeated binge eating and purging could further promote illness behavior, hinder recovery and contribute to relapse.
Pub.: 22 Aug '13, Pinned: 13 Nov '17
Abstract: Activity-based anorexia (ABA) is an animal model of anorexia nervosa that mimics core features of the clinical psychiatric disorder, including severe food restriction, weight loss, and hyperactivity. The ABA model is currently being used to study starvation-induced changes in the brain. Here, we examined hippocampal cell proliferation in animals with ABA (or the appropriate control conditions). Adolescent female Sprague-Dawley rats were assigned to 4 groups: control (24h/day food access), food-restricted (1h/day food access), exercise (24h/day food and wheel access), and ABA (1h/day food access, 24h/day wheel access). After 3 days of ABA, 5-bromo-2'-deoxyuridine (BrdU; 200mg/kg, i.p.) was injected and the rats were perfused 2h later. Brains were removed and subsequently processed for BrdU and Ki67 immunohistochemistry. The acute induction of ABA reduced cell proliferation in the dentate gyrus. This effect was significant in the hilus region of the dentate gyrus, but not in the subgranular zone, where adult neurogenesis occurs. Marked decreases in cell proliferation were also observed in the surrounding dorsal hippocampus and in the corpus callosum. These results indicate a primary effect on gliogenesis rather than neurogenesis following 3 days of ABA. For each brain region studied (except SGZ), there was a strong positive correlation between the level of cell proliferation and body weight/food intake. Future studies should examine whether these changes are maintained following long-term weight restoration and whether alterations in neurogenesis occur following longer exposures to ABA.
Pub.: 18 Sep '12, Pinned: 13 Nov '17
Abstract: Animals housed with running wheels and subjected to daily food restriction show paradoxical reductions in food intake and increases in running wheel activity. This phenomenon, known as activity-based anorexia (ABA), leads to marked reductions in body weight that can ultimately lead to death. Recently, ABA has been proposed as a model of anorexia nervosa (AN). AN affects about 8 per 100,000 females and has the highest mortality rate among all psychiatric illnesses. Given the reductions in quality of life, high mortality rate, and the lack of pharmacological treatments for AN, a better understanding of the mechanisms underlying AN-like behavior is greatly needed. This chapter provides basic guidelines for conducting ABA experiments using mice. The ABA mouse model provides an important tool for investigating the neurobiological underpinnings of AN-like behavior and identifying novel treatments.
Pub.: 11 Jan '12, Pinned: 13 Nov '17
Abstract: Patients suffering 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 (CAV2-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 colocalisation 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. While 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.Neuropsychopharmacology accepted article preview online, 21 March 2017. doi:10.1038/npp.2017.63.
Pub.: 23 Mar '17, Pinned: 24 Aug '17
Abstract: Identifying factors associated with risk for eating disorders is important for clarifying etiology and for enhancing early detection of eating disorders in primary care. We hypothesized that autoimmune and autoinflammatory diseases would be associated with eating disorders in children and adolescents and that family history of these illnesses would be associated with eating disorders in probands.In this large, nationwide, population-based cohort study of all children and adolescents born in Denmark between 1989 and 2006 and managed until 2012, Danish medical registers captured all inpatient and outpatient diagnoses of eating disorders and autoimmune and autoinflammatory diseases. The study population included 930 977 individuals (48.7% girls). Cox proportional hazards regression models and logistic regression were applied to evaluate associations.We found significantly higher hazards of eating disorders for children and adolescents with autoimmune or autoinflammatory diseases: 36% higher hazard for anorexia nervosa, 73% for bulimia nervosa, and 72% for an eating disorder not otherwise specified. The association was particularly strong in boys. Parental autoimmune or autoinflammatory disease history was associated with significantly increased odds for anorexia nervosa (odds ratio [OR] = 1.13, confidence interval [CI] = 1.01-1.25), bulimia nervosa (OR = 1.29; CI = 1.08-1.55) and for an eating disorder not otherwise specified (OR = 1.27; CI = 1.13-1.44).Autoimmune and autoinflammatory diseases are associated with increased risk for eating disorders. Ultimately, understanding the role of immune system disturbance for the etiology and pathogenesis of eating disorders could point toward novel treatment targets.
Pub.: 11 Nov '17, Pinned: 14 Nov '17
Abstract: Individuals with anorexia nervosa (AN) and bulimia nervosa (BN) have alterations of measures of serotonin (5-HT) and dopamine (DA) function, which persist after long-term recovery and are associated with elevated harm avoidance (HA), a measure of anxiety and behavioral inhibition. Based on theories that 5-HT is an aversive motivational system that may oppose a DA-related appetitive system, we explored interactions of positron emission tomography (PET) radioligand measures that reflect portions of these systems. Twenty-seven individuals recovered (REC) from eating disorders (EDs) (7 AN-BN, 11 AN, 9 BN) and nine control women (CW) were analyzed for correlations between [(11)C]McN5652 and [(11)C]raclopride binding. There was a significant positive correlation between [(11)C]McN5652 binding potential (BP(non displaceable(ND))) and [(11)C]Raclopride BP(ND) for the dorsal caudate, antero-ventral striatum (AVS), middle caudate, and ventral and dorsal putamen. No significant correlations were found in CW. [(11)C]Raclopride BP(ND), but not [(11)C]McN5652 BP(ND), was significantly related to HA in REC EDs. A linear regression analysis showed that the interaction between [(11)C]McN5652 BP(ND) and [(11)C]raclopride BP(ND) in the dorsal putamen significantly predicted HA. This is the first study using PET and the radioligands [(11)C]McN5652 and [(11)C]raclopride to show a direct relationship between 5-HT transporter and striatal DA D2/D3 receptor binding in humans, supporting the possibility that 5-HT and DA interactions contribute to HA behaviors in EDs.
Pub.: 17 Nov '12, Pinned: 13 Nov '17
Abstract: Serotonin (5-HT) plays an important role in controlling food intake and regulating body weight. In addition, clinical studies suggest a possible role for 5-HT in the etiology of anorexia nervosa. Recently, we have examined the effects of pharmacological manipulation of the 5-HT system in female rats exposed to conditions that promote activity-based anorexia (ABA). In this animal model of anorexia nervosa, rats are food restricted (2 h access/day) while given the opportunity to exercise in running wheels. These conditions promote symptoms of anorexia nervosa including hypophagia, hyperactivity, progressive weight loss, and disruptions of the ovarian reproductive cycle. Previously, we demonstrated that increased 5-HT activity increased the weight loss associated with ABA in female rats. Here, we investigated whether decreased 5-HT activity would attenuate symptoms of ABA. Food-restricted female rats received injections of 8-OH-DPAT, a drug that reduces serotonergic neurotransmission, or saline vehicle 40 min prior to food access. During this restricted-feeding phase, food intake was similar between groups; however, 8-OH-DPAT prevented the hyperactivity observed in saline-treated rats. This resulted in less weight loss in 8-OH-DPAT-treated rats, suggesting that decreased activation of the 5-HT system attenuates the development of ABA.
Pub.: 29 Apr '06, Pinned: 13 Nov '17
Abstract: Resistance to restricted feeding with and without wheel access was tested in rats handled (H) for 20 days since birth. Weight loss produced by 1.5-hr restricted food access was less in H than in non-handled (NH) males when tested aged 41 days. At this age combining food restriction with access to a running wheel (a procedure commonly known as activity-based anorexia, ABA) produced very rapid weight loss and no effect of handling was detected. When 75-day females were tested in the same way, under the ABA procedure H rats took longer than NH controls to reach the removal criterion. Simply restricting food access in these females produced variable weight loss, without detection of any handling effect. No differences in food intake or running were detected between H and NH rats in either males or females. In conclusion, handling seems to have a direct effect on rats' later response to either food deprivation alone or to an ABA procedure.
Pub.: 04 Oct '06, Pinned: 13 Nov '17
Abstract: Anorexia nervosa (AN) is an eating disorder characterized by self-imposed severe starvation and often linked with excessive exercise. Activity-based anorexia (ABA) is an animal model that reproduces some of the behavioral phenotypes of AN, including the paradoxical increase in voluntary exercise following food restriction (FR). Although certain rodents have been used successfully in this animal model, C57BL/6 mice are reported to be less susceptible to ABA. We re-examined the possibility that female C57BL/6 mice might exhibit ABA vulnerability during adolescence, the developmental stage/sex among the human population with particularly high AN vulnerability. After introducing the running wheel to the cage for 3 days, ABA was induced by restricting food access to 1h per day (ABA1, N=13) or 2 h per day (ABA2, N=10). All 23 exhibited increased voluntary wheel running (p<0.005) and perturbed circadian rhythm within 2 days. Only one out of five survived ABA1 for 3 days, while 10 out of 10 survived ABA2 for 3 days and could subsequently restore their body weight and circadian rhythm. Exposure of recovered animals to a second ABA2 induction revealed a large range of vulnerability, even within littermates. To look for the cellular substrate of differences in vulnerability, we began by examining synaptic patterns in the hippocampus, a brain region that regulates anxiety as well as plasticity throughout life. Quantitative EM analysis revealed that CA1 pyramidal cells of animals vulnerable to the second ABA2 exhibit less GABAergic innervation on cell bodies and dendrites, relative to the animals resilient to the second ABA (p<0.001) or controls (p<0.05). These findings reveal that C57BL/6J adolescent females can be used to capture brain changes underlying ABA vulnerability, and that GABAergic innervation of hippocampal pyramidal neurons is one important cellular substrate to consider for understanding the progression of and resilience to AN.
Pub.: 26 Mar '13, Pinned: 13 Nov '17
Abstract: Activity-based anorexia (ABA) is a widely used animal model for identifying the biological basis of excessive exercise and starvation, 2 hallmarks of anorexia nervosa (AN). Anxiety is correlated with exercise in AN. Yet the anxiety level of animals in ABA has not been reported. We asked: Does food restriction as part of ABA induction change the anxiety level of animals? If so, is the degree of anxiety correlated with degree of hyperactivity? We used the open field test before food restriction and the elevated plus maze test (EPM) during food restriction to quantify anxiety among singly housed adolescent female mice and determined whether food restriction alone or combined with exercise (i.e., ABA induction) abates or increases anxiety. We show that food restriction, with or without exercise, reduced anxiety significantly, as measured by the proportion of entries into the open arms of EPM (35.73%, p = .04). Moreover, ABA-induced individuals varied in their open arm time measure of anxiety and this value was highly and negatively correlated to the individual's food restriction-evoked wheel activity during the 24 hr following the anxiety test (R = -.75, p = .004, N = 12). This correlation was absent among the exercise-only controls. In addition, mice with higher increase in anxiety ran more following food restriction. Our data suggest that food restriction-evoked wheel running hyperactivity can be used as a reliable and continuous measure of anxiety in ABA. The parallel relationship between anxiety level and activity in AN and ABA-induced female mice strengthens the animal model.
Pub.: 03 Mar '15, Pinned: 13 Nov '17
Abstract: Activity-based anorexia (ABA) occurs when there is limited access to food and an opportunity to engage in high levels of physical activity. While the ABA effect is well established, the distinct functions of exercise and food restriction in maintaining ABA have not been determined. The current study examined the effect of pre-exposure to a restricted feeding schedule and pre-exposure to a running wheel on the incidence of ABA in 36 rats. Access to food and the running wheel was also varied in the recovery phase of the study in order to establish the effect of these variables on recovery from ABA. Three adaptation conditions (pre-exposed to food restriction, pre-exposed to wheel access and non-exposed) and two recovery conditions (wheel access and food restriction recovery) defined the six groups in the current study. Pre-exposure to food restriction was found to ameliorate the ABA effect during the anorexia phase while pre-exposure to wheel access exacerbated ABA. It was also found that subjects in the wheel access recovery condition gained more weight than the subjects in the food restriction recovery. In food restriction recovery, there was an interaction between the adaptation and recovery condition, with subjects that were pre-exposed to food restriction gaining the most weight. The results of the current study aid in understanding the distinct functions of food restriction and exercise in maintaining and recovering from ABA and have possible implications for the treatment of people diagnosed with some types of anorexia nervosa.
Pub.: 02 Feb '11, Pinned: 13 Nov '17
Abstract: Several lines of evidence support the possibility that disturbances of dopamine (DA) function could contribute to alterations of weight, feeding, motor activity, and reward in anorexia nervosa (AN).To assess possibly trait-related disturbances but avoid confounding effects of malnutrition, 10 women who were recovered from AN (REC AN) were compared with 12 healthy control women (CW). Positron emission tomography with [(11)C]raclopride was used to assess DA D2/D3 receptor binding.The women who were recovered from AN had significantly higher [(11)C]raclopride binding potential in the antero-ventral striatum than CW. For REC AN, [(11)C]raclopride binding potential was positively related to harm avoidance in the dorsal caudate and dorsal putamen.These data lend support for the possibility that decreased intrasynaptic DA concentration or increased D2/D3 receptor density or affinity is associated with AN and might contribute to the characteristic harm avoidance or increased physical activity found in AN. Most intriguing is the possibility that individuals with AN might have a DA related disturbance of reward mechanisms contributing to altered hedonics of feeding behavior and their ascetic, anhedonic temperament.
Pub.: 05 Jul '05, Pinned: 13 Nov '17
Abstract: Anorexia nervosa (AN) is an eating disorder characterized by severe hypophagia and weight loss, and an intense fear of weight gain. Activity-based anorexia (ABA) refers to the weight loss, hypophagia and paradoxical hyperactivity that develops in rodents exposed to running wheels and restricted food access, and provides a model for aspects of AN. The atypical antipsychotic olanzapine was recently shown to reduce both AN symptoms and ABA. We examined which component of the complex pharmacological profile of olanzapine reduces ABA. Mice received 5-HT(2A/2C), 5-HT3, dopamine D1-like, D2, D3 or D2/3 antagonist treatment, and were assessed for food intake, body weight, wheel running and survival in ABA. D2/3 receptor antagonists eticlopride and amisulpride reduced weight loss and hypophagia, and increased survival during ABA. Furthermore, amisulpride produced larger reductions in weight loss and hypophagia than olanzapine. Treatment with either D3 receptor antagonist SB277011A or D2 receptor antagonist L-741,626 also increased survival. All the other treatments either had no effect or worsened ABA. Overall, selective antagonism of D2 and/or D3 receptors robustly reduces ABA. Studies investigating the mechanisms by which D2 and/or D3 receptors regulate ABA, and the efficacy for D2/3 and/or D3 antagonists to treat AN, are warranted.
Pub.: 05 Aug '15, Pinned: 13 Nov '17
Abstract: Activity-based anorexia (ABA) is considered an animal model for anorexia nervosa (AN). By scheduled feeding and voluntary wheel running, it mimics severe body weight loss and increased physical activity in AN. Pharmacological, genetic and imaging studies implicate dopamine and serotonin in the regulation of feeding behavior, food-anticipatory activity, and food reward. Previous studies propose that the nucleus accumbens (NAc) plays an important role in these food-related processes. Here we determined dopamine and serotonin levels in the NAc upon exposure to the ABA model. Surprisingly, the release of dopamine and serotonin in the NAc were not increased during the initiation of food-anticipatory behavior in ABA rats. Dopamine release in the NAc was increased during feeding behavior in ABA rats. During ABA, levels of serotonin were low and circadian activity is blunted. We conclude that during the early stages of development of food-anticipatory activity, increased dopamine does not trigger hyperactivity.
Pub.: 03 Feb '09, Pinned: 13 Nov '17
Abstract: Anorexia nervosa (AN) includes the restricting (AN-r) and binge-eating/purging (AN-bp) subtypes, which have been reported to differ regarding their underlying pathophysiologies as well as their behavioral patterns. However, the differences in neural mechanisms of reward systems between AN subtypes remain unclear. The aim of the present study was to explore differences in the neural processing of reward and punishment between AN subtypes.Twenty-three female patients with AN (11 AN-r and 12 AN-bp) and 20 healthy women underwent functional magnetic resonance imaging while performing a monetary incentive delay task. Whole-brain one-way analysis of variance was conducted to test between-group differences.There were significant group differences in brain activation in the rostral anterior cingulate cortex and right posterior insula during loss anticipation, with increased brain activation in the AN-bp group relative to the AN-r and healthy women groups. No significant differences were found during gain anticipation.AN-bp patients showed altered neural responses to punishment in brain regions implicated in emotional arousal. Our findings suggest that individuals with AN-bp are more sensitive to potential punishment than individuals with AN-r and healthy individuals at the neural level. The present study provides preliminary evidence that there are neurobiological differences between AN subtypes with regard to the reward system, especially punishment processing.
Pub.: 02 May '17, Pinned: 15 Sep '17
Abstract: Objective: Individuals with anorexia nervosa (AN) have anxious and inhibited temperaments with high concern for consequences. Studies using either positron emission tomography (PET) or functional magnetic resonance imaging (fMRI) suggest involvement of the middle and dorsal caudate (DC) in individuals recovered (REC) from AN. For example, dopamine (DA) D2/D3 receptor binding in the middle caudate and DC was associated with anxiety and harm avoidance, and blood-oxygen-level-dependent (BOLD) response in the DC was positively related to trait anxiety. It has not been shown yet whether BOLD response in individuals REC from AN was related to DA function.Methods: Post-hoc correlation analyses between the PET and fMRI studies by correlating D2/D3 binding in striatal regions and BOLD signal in the anteroventral striatum (AVS) and DC for wins and losses respectively in 12 individuals REC from AN.Results: Individuals REC from AN with the greatest BOLD response in the DC in a monetary choice task had higher middle caudate D2/D3 binding, and greater anxiety and/or harm avoidance.Discussion: Though preliminary, these findings suggest that increased dorsal striatal D2/D3 binding is associated with enhanced cognitive response to feedback, potentially related to anxious anticipation of consequences. © 2016 Wiley Periodicals, Inc.(Int J Eat Disord 2016)
Pub.: 18 Oct '16, Pinned: 15 Sep '17
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