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Enlargement of the cerebrospinal fluid (CSF)-filled brain ventricles (cerebral ventriculomegaly), the cardinal feature of congenital hydrocephalus (CH), is increasingly recognized among patients with autism spectrum disorders (ASD). KATNAL2, a member of Katanin family microtubule-severing ATPases, is a known ASD risk gene, but its roles in human brain development remain unclear. Here, we show that nonsense truncation of Katnal2 (Katnal2Δ17) in mice results in classic ciliopathy phenotypes, including impaired spermatogenesis and cerebral ventriculomegaly. In both humans and mice, KATNAL2 is highly expressed in ciliated radial glia of the fetal ventricular-subventricular zone as well as in their postnatal ependymal and neuronal progeny. The ventriculomegaly observed in Katnal2Δ17 mice is associated with disrupted primary cilia and ependymal planar cell polarity that results in impaired cilia-generated CSF flow. Further, prefrontal pyramidal neurons in ventriculomegalic Katnal2Δ17 mice exhibit decreased excitatory drive and reduced high-frequency firing. Consistent with these findings in mice, we identified rare, damaging heterozygous germline variants in KATNAL2 in five unrelated patients with neurosurgically treated CH and comorbid ASD or other neurodevelopmental disorders. Mice engineered with the orthologous ASD-associated KATNAL2 F244L missense variant recapitulated the ventriculomegaly found in human patients. Together, these data suggest KATNAL2 pathogenic variants alter intraventricular CSF homeostasis and parenchymal neuronal connectivity by disrupting microtubule dynamics in fetal radial glia and their postnatal ependymal and neuronal descendants. The results identify a molecular mechanism underlying the development of ventriculomegaly in a genetic subset of patients with ASD and may explain persistence of neurodevelopmental phenotypes in some patients with CH despite neurosurgical CSF shunting.
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Cilios , Hidrocefalia , Microtúbulos , Animales , Femenino , Humanos , Masculino , Ratones , ATPasas Asociadas con Actividades Celulares Diversas/genética , ATPasas Asociadas con Actividades Celulares Diversas/metabolismo , Trastorno del Espectro Autista/genética , Trastorno del Espectro Autista/patología , Trastorno del Espectro Autista/metabolismo , Cilios/metabolismo , Cilios/patología , Epéndimo/metabolismo , Epéndimo/patología , Hidrocefalia/genética , Hidrocefalia/patología , Hidrocefalia/metabolismo , Katanina/metabolismo , Katanina/genética , Microtúbulos/metabolismo , Neuronas/metabolismo , Células Piramidales/metabolismo , Células Piramidales/patologíaRESUMEN
The amplitude of low-frequency fluctuations (ALFF) and global functional connectivity density (gFCD) are fMRI (Functional MRI) metrics widely used to assess resting brain function. However, their differential sensitivity to stimulant-induced dopamine (DA) increases, including the rate of DA rise and the relationship between them, have not been investigated. Here we used, simultaneous PET-fMRI to examine the association between dynamic changes in striatal DA and brain activity as assessed by ALFF and gFCD, following placebo, intravenous (IV), or oral methylphenidate (MP) administration, using a within-subject double-blind placebo-controlled design. In putamen, MP significantly reduced D2/3 receptor availability and strongly reduced ALFF and increased gFCD in the brain for IV-MP (Cohen's d > 1.6) but less so for oral-MP (Cohen's d < 0.6). Enhanced gFCD was associated with both the level and the rate of striatal DA increases, whereas decreased ALFF was only associated with the level of DA increases. These findings suggest distinct representations of neurovascular activation with ALFF and gFCD by stimulant-induced DA increases with differential sensitivity to the rate and the level of DA increases. We also observed an inverse association between gFCD and ALFF that was markedly enhanced during IV-MP, which could reflect an increased contribution from MP's vasoactive properties.
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Encéfalo , Dopamina , Metilfenidato , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Dopamina/farmacología , Imagen por Resonancia Magnética , Metilfenidato/farmacología , Método Doble CiegoRESUMEN
Congenital hydrocephalus (CH), characterized by cerebral ventriculomegaly, is one of the most common reasons for pediatric brain surgery. Recent studies have implicated lin-41 (lineage variant 41)/TRIM71 (tripartite motif 71) as a candidate CH risk gene, however, TRIM71 variants have not been systematically examined in a large patient cohort or conclusively linked with an OMIM syndrome. Through cross-sectional analysis of the largest assembled cohort of patients with cerebral ventriculomegaly, including neurosurgically-treated CH (totaling 2,697 parent-proband trios and 8,091 total exomes), we identified 13 protein-altering de novo variants (DNVs) in TRIM71 in unrelated children exhibiting variable ventriculomegaly, CH, developmental delay, dysmorphic features, and other structural brain defects including corpus callosum dysgenesis and white matter hypoplasia. Eight unrelated patients were found to harbor arginine variants, including two recurrent missense DNVs, at homologous positions in RPXGV motifs of different NHL domains. Seven additional patients with rare, damaging, unphased or transmitted variants of uncertain significance were also identified. NHL-domain variants of TRIM71 exhibited impaired binding to the canonical TRIM71 target CDKN1A; other variants failed to direct the subcellular localization of TRIM71 to processing bodies. Single-cell transcriptomic analysis of human embryos revealed expression of TRIM71 in early first-trimester neural stem cells of the brain. These data show TRIM71 is essential for human brain morphogenesis and that TRIM71 mutations cause a novel neurodevelopmental syndrome featuring ventriculomegaly and CH.
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Sex differences in the prevalence of dopamine-related neuropsychiatric diseases and in the sensitivity to dopamine-boosting drugs such as stimulants is well recognized. Here we assessed whether there are sex differences in the brain dopamine system in humans that could contribute to these effects. We analyzed data from two independent [11C]raclopride PET brain imaging studies that measured methylphenidate-induced dopamine increases in the striatum using different routes of administration (Cohort A = oral 60 mg; Cohort B = intravenous 0.5 mg/kg; total n = 95; 65 male, 30 female), in blinded placebo-controlled designs. Females when compared to males reported stronger feeling of "drug effects" and showed significantly greater dopamine release in the ventral striatum (where nucleus accumbens is located) to both oral and intravenous methylphenidate. In contrast, there were no significant differences in methylphenidate-induced increases in dorsal striatum for either oral or intravenous administration nor were there differences in levels of methylphenidate in plasma. The greater dopamine increases with methylphenidate in ventral but not dorsal striatum in females compared to males suggests an enhanced sensitivity specific to the dopamine reward system that might underlie sex differences in the vulnerability to substance use disorders and to attention-deficit/hyperactivity disorder (ADHD).
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Trastorno por Déficit de Atención con Hiperactividad , Estimulantes del Sistema Nervioso Central , Metilfenidato , Estriado Ventral , Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Estimulantes del Sistema Nervioso Central/farmacología , Cuerpo Estriado , Dopamina/farmacología , Femenino , Humanos , Masculino , Metilfenidato/farmacología , Metilfenidato/uso terapéutico , Racloprida , Caracteres SexualesRESUMEN
Congenital hydrocephalus (CH), occurring in approximately 1/1,000 live births, represents an important clinical challenge due to the limited knowledge of underlying molecular mechanisms. The discovery of novel CH genes is thus essential to shed light on the intricate processes responsible for ventricular dilatation in CH. Here, we identify FLVCR1 (feline leukemia virus subgroup C receptor 1) as a gene responsible for a severe form of CH in humans and mice. Mechanistically, our data reveal that the full-length isoform encoded by the FLVCR1 gene, FLVCR1a, interacts with the IP3R3-VDAC complex located on mitochondria-associated membranes (MAMs) that controls mitochondrial calcium handling. Loss of Flvcr1a in mouse neural progenitor cells (NPCs) affects mitochondrial calcium levels and energy metabolism, leading to defective cortical neurogenesis and brain ventricle enlargement. These data point to defective NPCs calcium handling and metabolic activity as one of the pathogenetic mechanisms driving CH.
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Calcio , Hidrocefalia , Proteínas de Transporte de Membrana , Mitocondrias , Células-Madre Neurales , Receptores Virales , Animales , Humanos , Ratones , Calcio/metabolismo , Hidrocefalia/metabolismo , Hidrocefalia/genética , Hidrocefalia/patología , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/genética , Proteínas de Transporte de Membrana/metabolismo , Proteínas de Transporte de Membrana/genética , Mitocondrias/metabolismo , Células-Madre Neurales/metabolismo , Células-Madre Neurales/patología , Neurogénesis/genética , Receptores Virales/metabolismo , Receptores Virales/genéticaRESUMEN
The faster a drug enters the brain, the greater its addictive potential, yet the brain circuits underlying the rate dependency to drug reward remain unresolved. With simultaneous PET-fMRI we linked dynamics of dopamine signaling, brain activity/connectivity, and self-reported 'high' in 20 adults receiving methylphenidate orally (results in slow delivery) and intravenously (results in fast delivery) (trial NCT03326245). We estimated speed of striatal dopamine increases to oral and IV methylphenidate and then tested where brain activity was associated with slow and fast dopamine dynamics (primary endpoint). We then tested whether these brain circuits were temporally associated with individual 'high' ratings to methylphenidate (secondary endpoint). A corticostriatal circuit comprising the dorsal anterior cingulate cortex and insula and their connections with dorsal caudate was activated by fast (but not slow) dopamine increases and paralleled 'high' ratings. These data provide evidence in humans for a link between dACC/insula activation and fast but not slow dopamine increases and document a critical role of the salience network in drug reward.
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Conducta Adictiva , Metilfenidato , Adulto , Humanos , Encéfalo/diagnóstico por imagen , Dopamina , Metilfenidato/farmacología , Recompensa , Ensayos Clínicos como AsuntoRESUMEN
Dopamine facilitates cognition and is implicated in reward processing. Methylphenidate, a dopamine transporter blocker widely used to treat attention-deficit/hyperactivity disorder, can have rewarding and addictive effects if injected. Since methylphenidate's brain uptake is much faster after intravenous than oral intake, we hypothesize that the speed of dopamine increases in the striatum in addition to its amplitude underly drug reward. To test this we use simulations and PET data of [11C]raclopride's binding displacement with oral and intravenous methylphenidate challenges in 20 healthy controls. Simulations suggest that the time-varying difference in standardized uptake value ratios for [11C]raclopride between placebo and methylphenidate conditions is a proxy for the time-varying dopamine increases induced by methylphenidate. Here we show that the dopamine increase induced by intravenous methylphenidate (0.25 mg/kg) in the striatum is significantly faster than that by oral methylphenidate (60 mg), and its time-to-peak is strongly associated with the intensity of the self-report of "high". We show for the first time that the "high" is associated with the fast dopamine increases induced by methylphenidate.
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Trastorno por Déficit de Atención con Hiperactividad , Metilfenidato , Humanos , Metilfenidato/farmacología , Dopamina/metabolismo , Racloprida/metabolismo , Racloprida/farmacología , Racloprida/uso terapéutico , Encéfalo/metabolismo , Antagonistas de Dopamina/metabolismo , Antagonistas de Dopamina/farmacología , Antagonistas de Dopamina/uso terapéuticoRESUMEN
Chiari malformation type 1 (CM1) is the most common structural brain disorder involving the craniocervical junction, characterized by caudal displacement of the cerebellar tonsils below the foramen magnum into the spinal canal. Despite the heterogeneity of CM1, its poorly understood patho-etiology has led to a 'one-size-fits-all' surgical approach, with predictably high rates of morbidity and treatment failure. In this review we present multiplex CM1 families, associated Mendelian syndromes, and candidate genes from recent whole exome sequencing (WES) and other genetic studies that suggest a significant genetic contribution from inherited and de novo germline variants impacting transcription regulation, craniovertebral osteogenesis, and embryonic developmental signaling. We suggest that more extensive WES may identify clinically relevant, genetically defined CM1 subtypes distinguished by unique neuroradiographic and neurophysiological endophenotypes.
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Malformación de Arnold-Chiari , Encefalopatías , Humanos , Malformación de Arnold-Chiari/genética , Malformación de Arnold-Chiari/complicaciones , Malformación de Arnold-Chiari/cirugía , Foramen Magno , Genética Humana , Imagen por Resonancia MagnéticaRESUMEN
To elucidate the pathogenesis of vein of Galen malformations (VOGMs), the most common and most severe of congenital brain arteriovenous malformations, we performed an integrated analysis of 310 VOGM proband-family exomes and 336,326 human cerebrovasculature single-cell transcriptomes. We found the Ras suppressor p120 RasGAP (RASA1) harbored a genome-wide significant burden of loss-of-function de novo variants (2042.5-fold, p = 4.79 x 10-7). Rare, damaging transmitted variants were enriched in Ephrin receptor-B4 (EPHB4) (17.5-fold, p = 1.22 x 10-5), which cooperates with p120 RasGAP to regulate vascular development. Additional probands had damaging variants in ACVRL1, NOTCH1, ITGB1, and PTPN11. ACVRL1 variants were also identified in a multi-generational VOGM pedigree. Integrative genomic analysis defined developing endothelial cells as a likely spatio-temporal locus of VOGM pathophysiology. Mice expressing a VOGM-specific EPHB4 kinase-domain missense variant (Phe867Leu) exhibited disrupted developmental angiogenesis and impaired hierarchical development of arterial-capillary-venous networks, but only in the presence of a "second-hit" allele. These results illuminate human arterio-venous development and VOGM pathobiology and have implications for patients and their families.
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Enfermedades Vasculares , Malformaciones de la Vena de Galeno , Humanos , Animales , Ratones , Malformaciones de la Vena de Galeno/genética , Malformaciones de la Vena de Galeno/patología , Células Endoteliales/patología , Mutación , Transducción de Señal/genética , Mutación Missense , Proteínas Activadoras de GTPasa/genética , Receptores de Activinas Tipo II/genética , Proteína Activadora de GTPasa p120/genéticaRESUMEN
Low socioeconomic status (SES) in childhood is associated with deficits in executive function and changes in cortical morphology. Furthermore, rates of childhood obesity are greater among low SES children and childhood obesity is also associated with cortical alterations and impaired neurocognition, specifically in the domain of executive function. To investigate the influence of BMI on the relationships between SES and both neurocognition and brain morphology, we used data from the Adolescent Brain Cognitive Development (ABCD) study to construct multiple linear regression models and conduct mediation analyses. Overall, SES as measured by household income, highest level of parental education, and area deprivation, was associated with lower BMI, greater total and prefrontal cortical volume, and better performance on assessments of executive function. Mediation analysis indicated that BMI had a significant indirect effect on associations between area deprivation and both total and prefrontal cortical volumes. BMI also played a mediating role in the associations between area deprivation and composite neurocognitive scores, which were driven by performance on tasks of working memory and cognitive flexibility, but not cognitive control. These findings suggest that BMI should be considered in future studies investigating the relationship between low SES and poor neurodevelopmental outcomes.
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Obesidad Infantil , Adolescente , Índice de Masa Corporal , Encéfalo , Niño , Función Ejecutiva , Humanos , Obesidad Infantil/epidemiología , Clase SocialRESUMEN
Ketamine, a noncompetitive NMDA receptor antagonist, has been exclusively used as an anesthetic in medicine and has led to new insights into the pathophysiology of neuropsychiatric disorders. Clinical studies have shown that low subanesthetic doses of ketamine produce antidepressant effects for individuals with depression. However, its use as a treatment for psychiatric disorders has been limited due to its reinforcing effects and high potential for diversion and misuse. Preclinical studies have focused on understanding the molecular mechanisms underlying ketamine's antidepressant effects, but a precise mechanism had yet to be elucidated. Here we review different hypotheses for ketamine's mechanism of action including the direct inhibition and disinhibition of NMDA receptors, AMPAR activation, and heightened activation of monoaminergic systems. The proposed mechanisms are not mutually exclusive, and their combined influence may exert the observed structural and functional neural impairments. Long term use of ketamine induces brain structural, functional impairments, and neurodevelopmental effects in both rodents and humans. Its misuse has increased rapidly in the past 20 years and is one of the most common addictive drugs used in Asia. The proposed mechanisms of action and supporting neuroimaging data allow for the development of tools to identify 'biotypes' of ketamine use disorder (KUD) using machine learning approaches, which could inform intervention and treatment.
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BACKGROUND: Side effects of medications for opioid use disorder (MOUD) such as weight gain contribute to their stigma. Substantial evidence suggests that women have a more severe side effect profile to MOUD than men, and concerns about weight gain during treatment are prevalent. However, the few studies reporting sex differences in weight gain during treatment show conflicting results and are restricted to methadone. In addition, little is known about possible sex differences in weight gain to buprenorphine, which is the most commonly prescribed MOUD in the United States. METHODS: To address these issues, we performed a systematic review and meta-analysis on the few studies reporting longitudinal data on sex differences in body mass index (BMI) gain during methadone treatment (Study 1). In a separate study, we also re-analyzed data from trial CTN-0030 of the National Institute on Drug Abuse Clinical Trial Network (NIDA CTN), which involved a 12-week buprenorphine treatment regimen (Study 2; n = 360; 209 Male, 151 Female). RESULTS: For Study 1, across all papers reporting longitudinal data (k = 4, n = 362 OUD patients), there were BMI increases that ranged from 2.2 to 5.4 BMI after at least one year of methadone treatment, but there were no significant sex differences in BMI increases (Standardized Mean Difference, Female > Male = 0.352, SE =0.270; 95 % CI = [-0.18 0.88]; p = .193). Study 2 showed no significant differences in weight before and after 12 weeks of buprenorphine treatment nor did it show sex differences in weight change with treatment (ß = 2.34, p = .511). CONCLUSION: These analyses corroborate evidence of weight gain with methadone treatment but did not observe a sex-based disparity in weight gain with methadone or buprenorphine treatment for OUD.
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Buprenorfina , Trastornos Relacionados con Opioides , Analgésicos Opioides/efectos adversos , Buprenorfina/uso terapéutico , Femenino , Humanos , Masculino , Metadona/uso terapéutico , Tratamiento de Sustitución de Opiáceos/métodos , Trastornos Relacionados con Opioides/tratamiento farmacológico , Estudios Retrospectivos , Caracteres Sexuales , Estados Unidos , Aumento de PesoRESUMEN
Chronic exposure to addictive drugs in substance use disorders and stressors in mood disorders render the brain more vulnerable to inflammation. Inflammation in the brain, or neuroinflammation, is characterized by gliosis, microglial activation, and sustained release of cytokines, chemokines, and pro-inflammatory factors compromising the permeability of the blood-brain barrier. There is increased curiosity in understanding how substance misuse and/or repeated stress exposure affect inflammation and contribute to abnormal neuronal activity, altered neuroplasticity, and impaired cognitive control, which eventually promote compulsive drug-use behaviors and worsen mood disorders. This review will emphasize human imaging studies to explore the link between brain function and peripheral markers of inflammation in substance use disorders and mood disorders.
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Eye-blink rate has been proposed as a biomarker of the brain dopamine system, however, findings have not been consistent. This study assessed the relationship between blink rates, measured after oral placebo) (PL) and after a challenge with oral methylphenidate (MP; 60 mg) and striatal D1 receptor (D1R) (measured at baseline) and D2 receptor (D2R) availability (measured after PL and after MP) in healthy participants. PET measures of baseline D1R ([11C]NNC112) (BL-D1R) and D2R availability ([11C]raclopride) after PL (PL-D2R) and after MP (MP-D2R) were quantified in the striatum as non-displaceable binding potential. MP reduced the number of blinks and increased the time participants kept their eyes open. Correlations with dopamine receptors were only significant for the eye blink measures obtained after MP; being positive for BL-D1R in putamen and MP-D2R in caudate (PL-D2R were not significant). MP-induced changes in blink rates (PL minus MP) were negatively correlated with BL-D1R in caudate and putamen. Our findings suggest that eye blink measures obtained while stressing the dopamine system might provide a more sensitive behavioral biomarker of striatal D1R or D2R in healthy volunteers than that obtained at baseline or after placebo.
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Metilfenidato , Cuerpo Estriado/diagnóstico por imagen , Cuerpo Estriado/metabolismo , Dopamina/metabolismo , Humanos , Metilfenidato/metabolismo , Metilfenidato/farmacología , Racloprida/metabolismo , Racloprida/farmacología , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/metabolismoRESUMEN
Dopamine signaling plays a critical role in shaping brain functional network organization and behavior. Prominent theories suggest the relative expression of D1- to D2-like dopamine receptors shapes excitatory versus inhibitory signaling, with broad consequences for cognition. Yet it remains unknown how the balance between cortical D1R versus D2R signaling coordinates the activity and connectivity of functional networks in the human brain. To address this, we collected three PET scans and two fMRI scans in 36 healthy adults (13 female/23 male; average age 43 ± 12 years), including a baseline D1R PET scan and two sets of D2R PET scans and fMRI scans following administration of either 60 mg oral methylphenidate or placebo (two separate days, blinded, order counterbalanced). The drug challenge allowed us to assess how pharmacologically boosting dopamine levels alters network organization and behavior in association with D1R-D2R ratios across the brain. We found that the relative D1R-D2R ratio was significantly greater in high-level association cortices than in sensorimotor cortices. After stimulation with methylphenidate compared to placebo, brain activity (as indexed by the fractional amplitude of low frequency fluctuations) increased in association cortices and decreased in sensorimotor cortices. Further, within-network resting state functional connectivity strength decreased more in sensorimotor than association cortices following methylphenidate. Finally, in association but not sensorimotor cortices, the relative D1R-D2R ratio (but not the relative availability of D1R or D2R alone) was positively correlated with spatial working memory performance, and negatively correlated with age. Together, these data provide a framework for how dopamine-boosting drugs like methylphenidate alter brain function, whereby regions with relatively higher inhibitory D2R (i.e., sensorimotor cortices) tend to have greater decreases in brain activity and connectivity compared to regions with relatively higher excitatory D1R (i.e., association cortices). They also support the importance of a balanced interaction between D1R and D2R in association cortices for cognitive function and its degradation with aging.
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Metilfenidato , Receptores de Dopamina D1 , Adulto , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/metabolismo , Dopamina/metabolismo , Femenino , Humanos , Masculino , Metilfenidato/efectos adversos , Persona de Mediana Edad , Receptores de Dopamina D1/metabolismoRESUMEN
From humans to vinegar flies, exposure to diets rich in sugar and fat lowers taste sensation, changes food choices, and promotes feeding. However, how these peripheral alterations influence eating is unknown. Here we used the genetically tractable organism D. melanogaster to define the neural mechanisms through which this occurs. We characterized a population of protocerebral anterior medial dopaminergic neurons (PAM DANs) that innervates the ß'2 compartment of the mushroom body and responds to sweet taste. In animals fed a high sugar diet, the response of PAM-ß'2 to sweet stimuli was reduced and delayed, and sensitive to the strength of the signal transmission out of the sensory neurons. We found that PAM-ß'2 DANs activity controls feeding rate and satiation: closed-loop optogenetic activation of ß'2 DANs restored normal eating in animals fed high sucrose. These data argue that diet-dependent alterations in taste weaken satiation by impairing the central processing of sensory signals.
Obesity is a major health problem affecting over 650 million adults worldwide. It is typically caused by overeating high-energy foods, which often contain a lot of sugar. Consuming sugary foods triggers the production of a reward signal called dopamine in the brains of insects and mammals, which reinforces sugar-consuming behavior. The brain balances this with a process called 'sensory-enhanced satiety', which makes foods that provide a stronger sensation of sweetness better at reducing hunger and further eating. High-energy food was scarce for most of human evolution, but over the past century sugar has become readily available in our diet leading to an increase in obesity. Last year, a study in fruit flies reported that a sugary diet reduces the sensitivity to sweet flavors, which leads to overeating and weight gain. It appears that this sensitivity is linked to the effectiveness of sensory-enhanced satiety. However, the mechanism linking diets high in sugar and overeating is still poorly understood. One hypothesis is that fruit flies estimate the energy content of food based on the degree of dopamine released in response to the sugar. May et al. compared the responses of neurons in fruit flies fed a normal diet to those in flies fed a diet high in sugar. As expected, both groups activated the neurons involved in the dopamine reward response when they tasted sugar. However, when the flies were on a sugar-heavy diet, these neurons were less active. This was because the neurons responsible for tasting sweetness were activated less in flies fed a high-sugar diet, leading to a lowered response by the neurons that produce dopamine. The flies in these experiments were genetically engineered so that the dopamine-producing neurons could be artificially activated in response to light, a technique called optogenetics. When May et al. applied this technique to the flies on a sugar-heavy diet, they were able to stop these flies from overeating. These findings provide further evidence to support the idea that a sugary diet reduces the brain's sensitivity to overeating. Given the significant healthcare cost of obesity to society, this improved understanding could help public health initiatives focusing on manufacturing food that is lower in sugar.