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1. Single injection of ketamine during mid‐adolescence promotes long‐lasting resilience to activity‐based anorexia of female mice by increasing food intake and attenuating hyperactivity as well as anxiety‐like behavior

   https://doi.org/10.1002/eat.22937  

   Chen, Yi‐Wen ; Sherpa, Ang Doma ; Aoki, Chiye ( August 2018 , International Journal of Eating Disorders)

   This study tested the effects of ketamine on vulnerability of female adolescent mice to activity‐based anorexia (ABA).

   Twenty‐four female C57Bl/6 J mice underwent ABA induction, which involved exposing wheel‐acclimated adolescent mice to two bouts of food restriction (FR)—the first ABA (P41–44, mid‐adolescence) and the second ABA (P55–59, late adolescence), with recovery in between. Ketamine (3 or 30 mg/kg) or vehicle was given once, on the second day of FR of the first ABA (P42). Food consumption, body weight and wheel running activity were measured daily. Anxiety‐like behaviors were accessed by elevated plus maze on P49 and P62, after weight restoration during the recovery phase.

   Ketamine (30 mg/kg) increased food intake during the first ABA (+38%,p = .015) and facilitated weight gain during recovery (+42%,p = .003). During the second ABA, the effect was manifested as increased food intake (+38%,p = .001) and weight gain (+47%,p = .001) while attenuating FR‐induced wheel running activity (−24%,p = .09) and weight loss (−17%,p = .056). Ketamine also reduced anxiety‐like behaviors.

   Thus, single injection of ketamine during mid‐adolescence effectively attenuates vulnerability of female mice to repeated ABA exposures.

    

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2. Individual differences in the positive outcome from adolescent ketamine treatment in a female mouse model of anorexia nervosa involve drebrin A at excitatory synapses of the medial prefrontal cortex

   https://doi.org/10.1002/syn.22253  

   Temizer, Rose ; Chen, Yi‐Wen ; Aoki, Chiye ( October 2022 , Synapse)

   Anorexia nervosa (AN) is a mental illness with the highest rates of mortality and relapse, and no approved pharmacological treatment. Using an animal model of AN, called activity‐based anorexia (ABA), we showed earlier that a single intraperitoneal injection of ketamine at a dose of 30 mg/kg (30mgKET), but not 3 mg/kg (3mgKET), has a long‐lasting effect upon adolescent females of ameliorating anorexia‐like symptoms through the following changes: enhanced food consumption and body weight; reduced running and anxiety‐like behavior. However, there were also individual differences in the drug's efficacy. We hypothesized that individual differences in ketamine's ameliorative effects involve drebrin A, an F‐actin‐binding protein known to be required for the activity‐dependent trafficking of NMDA receptors (NMDARs). We tested this hypothesis by electron microscopic quantifications of drebrin A immunoreactivity at excitatory synapses of pyramidal neurons (PN) and GABAergic interneurons (GABA‐IN) in deep layer 1 of prefrontal cortex (PFC) of these mice. Results reveal that (1) the areal density of excitatory synapses on GABA‐IN is greater for the 30mgKET group than the 3mgKET group; (2) the proportion of drebrin A+ excitatory synapses is greater for both PN and GABA‐IN of 30mgKET than 3mgKET group. Correlation analyses with behavioral measurements revealed that (3) 30mgKET's protection is associated with reduced levels of drebrin A in the cytoplasm of GABA‐IN and higher levels at extrasynaptic membranous sites of PN and GABA‐IN; (5) altogether pointing to 30mgKET‐induced homeostatic plasticity that engages drebrin A at excitatory synapses of both PN and GABA‐IN.

    

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3. Suppression of food restriction‐evoked hyperactivity in activity‐based anorexia animal model through glutamate transporters GLT‐1 at excitatory synapses in the hippocampus

   https://doi.org/10.1002/syn.22197  

   Bilash, Olesia M. ; Actor‐Engel, Hannah S. ; Sherpa, Ang D. ; Chen, Yi‐Wen ; Aoki, Chiye ( March 2021 , Synapse)

   Severe voluntary food restriction is the defining symptom of anorexia nervosa (AN), but anxiety and excessive exercise are maladaptive symptoms that contribute significantly to the severity of AN and which individuals with AN have difficulty suppressing. We hypothesized that the excitability of hippocampal pyramidal neurons, known to contribute to anxiety, leads to the maladaptive behavior of excessive exercise. Conversely, since glutamate transporter GLT‐1 dampens the excitability of hippocampal pyramidal neurons through the uptake of ambient glutamate and suppression of the GluN2B‐subunit containing NMDA receptors (GluN2B‐NMDARs), GLT‐1 may contribute toward dampening excessive exercise. This hypothesis was tested using the mouse model of AN, called activity‐based anorexia (ABA), whereby food restriction evokes the maladaptive behavior of excessive wheel running (food restriction‐evoked running, FRER). We tested whether individual differences in ABA vulnerability of mice, quantified based on FRER, correlated with individual differences in the levels of GLT‐1 at excitatory synapses of the hippocampus. Electron microscopic immunocytochemistry (EM‐ICC) was used to quantify GLT‐1 levels at the excitatory synapses of the hippocampus. The FRER seen in individual mice varied more than 10‐fold, and Pearson correlation analyses revealed a strong negative correlation (p = .02) between FRER and GLT‐1 levels at the axon terminals of excitatory synapses and at the surrounding astrocytic plasma membranes. Moreover, synaptic levels of GluN2B‐NMDARs correlated strongly with GLT‐1 levels at perisynaptic astrocytic plasma membranes. There is at present no accepted pharmacotherapy for AN, and little is known about the etiology of this deadly illness. Current findings suggest that drugs increasing GLT‐1 expression may reduce AN severity through the reduction of GluN2B‐NMDAR activity.

    

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4. Gut microbiota depletion minimally affects the daily voluntary wheel running activity and food anticipatory activity in female and male C57BL/6J mice

   https://doi.org/10.3389/fphys.2023.1299474  

   Ehichioya, David E. ; Taufique, S. K. ; Magaña, Isabel ; Farah, Sofia ; Obata, Yuuki ; Yamazaki, Shin ( December 2023 , Frontiers in Physiology)

   Emerging evidence has highlighted that the gut microbiota plays a critical role in the regulation of various aspects of mammalian physiology and behavior, including circadian rhythms. Circadian rhythms are fundamental behavioral and physiological processes that are governed by circadian pacemakers in the brain. Since mice are nocturnal, voluntary wheel running activity mostly occurs at night. This nocturnal wheel-running activity is driven by the primary circadian pacemaker located in the suprachiasmatic nucleus (SCN). Food anticipatory activity (FAA) is the increased bout of locomotor activity that precedes the scheduled short duration of a daily meal. FAA is controlled by the food-entrainable oscillator (FEO) located outside of the SCN. Several studies have shown that germ-free mice and mice with gut microbiota depletion altered those circadian behavioral rhythms. Therefore, this study was designed to test if the gut microbiota is involved in voluntary wheel running activity and FAA expression. To deplete gut microbiota, C57BL/6J wildtype mice were administered an antibiotic cocktail via their drinking water throughout the experiment. The effect of antibiotic cocktail treatment on wheel running activity rhythm in both female and male mice was not detectable with the sample size in our current study. Then mice were exposed to timed restricted feeding during the day. Both female and male mice treated with antibiotics exhibited normal FAA which was comparable with the FAA observed in the control group. Those results suggest that gut microbiota depletion has minimum effect on both circadian behavioral rhythms controlled by the SCN and FEO respectively. Our result contradicts recently published studies that reported significantly higher FAA levels in germ-free mice compared to their control counterparts and gut microbiota depletion significantly reduced voluntary activity by 50%.

    

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5. Binge‐eating disorder with and without lifetime anorexia nervosa: A comparison of sociodemographic and clinical features

   https://doi.org/10.1002/eat.23858  

   Pawar, Pratiksha S. ; Thornton, Laura M. ; Flatt, Rachael E. ; Sanzari, Christina M. ; Carrino, Emily A. ; Tregarthen, Jenna P. ; Argue, Stuart ; Bulik, Cynthia M. ; Watson, Hunna J. ( November 2022 , International Journal of Eating Disorders)

   To compare individuals who have experienced binge‐eating disorder (BED) and anorexia nervosa (AN) (BED AN+) to those who have experienced BED and not AN (BED AN–).

   Participants (N = 898) met criteria for lifetime BED and reported current binge eating. Approximately 14% had a lifetime diagnosis of AN. Analyses compared BED AN+ and BED AN– on sociodemographic variables and clinical history.

   The presence of lifetimeANwas associated with more severe eating disorder symptoms, including earlier onset, more frequent, more chronic, and more types of eating disorder behaviors over the lifetime, as well as a higher lifetime prevalence of bulimia nervosa (BN). Participants with lifetimeANreported being more likely to have received treatments forBEDorBN, had significantly lower minimum, current, and maximumBMIs, had more severe general anxiety, and were significantly more likely to be younger and female. In the full sample, the lifetime prevalence of unhealthy weight control behaviors was high and treatment utilization was low, despite an average 15‐year history since symptom onset. Gastrointestinal disorders and comorbid anxiety, depression, and attention‐deficit/hyperactivity disorder symptoms were prevalent.

   Individuals fared poorly on a wide array of domains, yet those with lifetimeANfared considerably more poorly. All patients withBEDshould be screened for mental health and gastrointestinal comorbidities and offered referral and treatment options.

   Individuals experiencing binge‐eating disorder have severe symptomology, but those who have experienced binge‐eating disorder and anorexia nervosa fare even more poorly. Our study emphasizes that patients with binge‐eating disorder would benefit from being screened for mental health and gastrointestinal comorbidities, and clinicians should consider history of unhealthy weight control behaviors to inform treatment and relapse prevention.

    

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