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Abstract Background Eating disorders are multifactorial psychiatric disorders. Chronic stressful experiences and caloric restriction are the most powerful triggers of eating disorders in human and animals. Although compulsive behavior is considered to characterize pathological excessive food intake, to our knowledge, no evidence has been reported of continued food seeking/intake despite its possible harmful consequences, an index of compulsive behavior. Brain monoamine transmission is considered to have a key role in vulnerability to eating disorders, and norepinephrine in medial prefrontal cortex has been shown to be critical for food-related motivated behavior. Here, using a new paradigm of conditioned suppression, we investigated whether the ability of a foot-shock-paired conditioned stimulus to suppress chocolate-seeking behavior was reversed by previous exposure to a food restriction experience, thus modeling food seeking in spite of harmful consequences in mice. Moreover, we assessed the effects of selective norepinephrine inactivation in medial prefrontal cortex on conditioned suppression test in stressed and caloric restricted mice. Results While Control (non food deprived) animals showed a profound conditioned suppression of chocolate seeking during presentation of conditioned stimulus, previously food restricted animals showed food seeking/intake despite its possible harmful consequences. Moreover, food seeking in spite of harmful consequences was prevented by selective norepinephrine inactivation, thus showing that prefrontal cortical norepinephrine is critical also for maladaptive food-related behavior. Conclusions These findings indicate that adaptive food seeking/intake can be transformed into maladaptive behaviors and point to "top-down" influence on eating disturbances and to new targets for therapy of aberrant eating behaviors.

Schizophrenia research has increased in recent decades and focused more on its neural basis. Decision-making and cognitive flexibility are the main cognitive functions that are impaired and considered schizophrenia endophenotypes. Cognitive impairment was recently connected with altered functions of N-methyl-d-aspartate (NMDAR) glutamatergic receptors, which increased cortical activity. Selective NMDAR antagonists, such as MK-801, have been used to model cognitive inflexibility in schizophrenia. Decreased GABAergic inhibitory activity has been shown elsewhere with enhanced cortical activity. This imbalance in the excitatory/inhibitory may reduce the entrainment of prefrontal gamma and hippocampal theta rhythms and result in gamma/theta band de-synchronization. The current study established an acute MK-801 administration model of schizophrenia-like cognitive inflexibility in rats and used the attentional set-shifting task in which rats learned to switch/reverse the relevant rule. During the task, we used in vivo optogenetic stimulations of parvalbumin-positive interneurons at specific light pulses in the prefrontal cortex and ventral hippocampus. The first experiments showed that acute dizocilpine in rats produced schizophrenia-like cognitive inflexibility. The second set of experiments demonstrated that specific optogenetic stimulation at specific frequencies of parvalbumin-positive interneurons in the prefrontal cortex and ventral hippocampus rescued the cognitive flexibility rats that received acute MK-801. These findings advance our knowledge of the pivotal role of parvalbumin interneurons in schizophrenia-like cognitive impairment and may guide further research on this severe psychiatric disorder., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Schizophrenia research arose in the twentieth century and is currently rapidly developing, focusing on many parallel research pathways and evaluating various concepts of disease etiology. Today, we have relatively good knowledge about the generation of positive and negative symptoms in patients with schizophrenia. However, the neural basis and pathophysiology of schizophrenia, especially cognitive symptoms, are still poorly understood. Finding new methods to uncover the physiological basis of the mental inabilities related to schizophrenia is an urgent task for modern neuroscience because of the lack of specific therapies for cognitive deficits in the disease. Researchers have begun investigating functional crosstalk between NMDARs and GABAergic neurons associated with schizophrenia at different resolutions. In another direction, the gut microbiota is getting increasing interest from neuroscientists. Recent findings have highlighted the role of a gut-brain axis, with the gut microbiota playing a crucial role in several psychopathologies, including schizophrenia and autism.There have also been investigations into potential therapies aimed at normalizing altered microbiota signaling to the enteric nervous system (ENS) and the central nervous system (CNS). Probiotics diets and fecal microbiota transplantation (FMT) are currently the most common therapies. Interestingly, in rodent models of binge feeding, optogenetic applications have been shown to affect gut colony sensitivity, thus increasing colonic transit. Here, we review recent findings on the gut microbiota-schizophrenia relationship using in vivo optogenetics. Moreover, we evaluate if manipulating actors in either the brain or the gut might improve potential treatment research. Such research and techniques will increase our knowledge of how the gut microbiota can manipulate GABA production, and therefore accompany changes in CNS GABAergic activity.

Certain eating behaviors are characterized by a trend of elevated food consumption. However, neural mechanisms mediating the motivation for food consumption are not fully understood. Food impacts the brain-rewarding-system via both oral-sensory and post-ingestive information. Recent studies have reported an important role of visceral gut information in mediating dopamine (DA) release in the brain rewarding system. This is independent of oral sensation, suggesting a role of the gut-brain-DA-axis in feeding behavior. In this study, we investigated the effects of intra-gastric (IG) self-administration of glucose on neuronal firings in the nucleus accumbens (NA) of water-deprived rats. Rats were trained in an operant-licking paradigm. During training, when the light was on for 2 min (light-period), rats were required to lick a spout to acquire the water oral-intake learning, and either an IG self-infusion of 0.4 M glucose (GLU group) or water (H 2 O group). Rats rested in the dark-period (3 min) following the light-period. Four cycles of the operant-licking paradigm consisting of the light-dark periods were performed per day, for 4 consecutive days. In the test session, the same rats licked the same spout to acquire the IG self-administration of the corresponding solutions, without oral water ingestion (dry licking). Behavioral results indicated IG self-administration of glucose elicits more dry-licking behavior than that of water. Neurophysiological results indicated in the dark period, coefficient of variance (CV) measuring the inter-spike interval variability of putative medial spiny neurons (pMSNs) in the NA was reduced in the H 2 O group compared to the GLU group, while there was no significant difference in physical behaviors in the dark period between the two groups. Since previous studies reported that DA release increases CV of MSNs, the present results suggest that greater CV of pMSNs in the GLU group reflects greater DA release in the NA and elevated motivation in the GLU group, which might increase lickings in the test session in the GLU group compared to the H 2 O group.

Addiction is a chronic compulsion and relapsing disorder. It involves several brain areas and circuits, which encode vary functions such as reward, motivation, and memory. Drug addiction is defined as a "pathological pattern of use of a substance", characterized by the loss of control on drug-taking-related behaviors, the pursuance of those behaviors even in the presence of negative consequences, and a strong motivated activity to assume substances. Three different theories guide experimental research on drug addiction. Each of these theories consider singles features, such as an aberrant motivation, a hedonic dysregulation, and an aberrant habit learning as the main actor to explain the entire process of the addictive behaviors. The major goal of this study is to present a new hypotheses of transitionality from a controlled use to abuse of addictive substances trough the overview of the three different theories, considering all the single features of each single theory together on the same "temporal continuum" from use to abuse of addictive substances. Recently, it has been suggested that common neural systems may be activated by natural and pharmacological stimuli, raising the hypotheses that binge-eating disorders could be considered as addictive behaviors. The second goal of this study is to present evidences in order to highlight a possible psycho-bio-physiological superimposition between drug and "food addiction". Finally, interesting questions are brought up starting from last findings about a theoretical/psycho-bio-physiological superimposition between drug and "food addiction" and their possibly same transitionality along the same "temporal continuum" from use to abuse of addictive substances in order to investigate new therapeutic strategies based on new therapeutic strategies based on the individual moments characterizing the transition from the voluntary intake of substances to the maladaptive addictive behavior., (Copyright © 2016. Published by Elsevier Ltd.)

Previous behavioral studies have suggested that l-glutamate, an umami substance, is detected in the gut, and that this information regarding glutamate is conveyed from the gut to the amygdala and the lateral hypothalamus (LH) through the vagus nerve to establish glutamate preference. In this study, we investigated the roles of the amygdala and LH in the information processing of gut glutamate. We recorded the activity of amygdalar and LH neurons during the intragastric administration of five test solutions (monosodium l-glutamate [MSG, 60 mmol/L]; inosine monophosphate [IMP, 60 mmol/L]; a mixture of MSG and IMP; NaCl [60 mmol/L]; or physiological saline) in intact and subdiaphragmatic vagotomized awake rats. In intact rats, 349 and 189 neurons were recorded from the amygdala and LH, respectively, while in vagotomized rats, 104 and 90 neurons were recorded from the amygdala and LH, respectively. In intact rats, similar percentages of neurons (30-60%) in the amygdala and LH responded to the intragastric infusion of the solutions. Vagotomy significantly altered responses to the MSG and NaCl solutions. In particular, vagotomy suppressed the inhibitory responses to the NaCl solution. Furthermore, vagotomy increased the response similarity between the MSG and NaCl solutions, suggesting that vagotomy impaired the coding of the postingestive consequences of the MSG solution in the amygdala and LH, which are unique for glutamate. The present results provide the first neurophysiological evidence that amygdalar and LH neurons process glutamate signals from the gut., (© 2015 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.)

Background: Eating disorders appear to be caused by a complex interaction between environmental and genetic factors, and compulsive eating in response to adverse circumstances characterizes many eating disorders., Materials and Methods: We compared compulsion-like eating in the form of conditioned suppression of palatable food-seeking in adverse situations in stressed C57BL/6J and DBA/2J mice, two well-characterized inbred strains, to determine the influence of gene-environment interplay on this behavioral phenotype. Moreover, we tested the hypothesis that low accumbal D2 receptor (R) availability is a genetic risk factor of food compulsion-like behavior and that environmental conditions that induce compulsive eating alter D2R expression in the striatum. To this end, we measured D1R and D2R expression in the striatum and D1R, D2R and α1R levels in the medial prefrontal cortex, respectively, by western blot., Results: Exposure to environmental conditions induces compulsion-like eating behavior, depending on genetic background. This behavioral pattern is linked to decreased availability of accumbal D2R. Moreover, exposure to certain environmental conditions upregulates D2R and downregulates α1R in the striatum and medial prefrontal cortex, respectively, of compulsive animals. These findings confirm the function of gene-environment interplay in the manifestation of compulsive eating and support the hypothesis that low accumbal D2R availability is a "constitutive" genetic risk factor for compulsion-like eating behavior. Finally, D2R upregulation and α1R downregulation in the striatum and medial prefrontal cortex, respectively, are potential neuroadaptive responses that parallel the shift from motivated to compulsive eating.

Eating disorders are multifactorial conditions that can involve a combination of genetic, metabolic, environmental, and behavioral factors. Studies in humans and laboratory animals show that eating can also be regulated by factors unrelated to metabolic control. Several studies suggest a link between stress, access to highly palatable food, and eating disorders. Eating "comfort foods" in response to a negative emotional state, for example, suggests that some individuals overeat to self-medicate. Clinical data suggest that some individuals may develop addiction-like behaviors from consuming palatable foods. Based on this observation, "food addiction" has emerged as an area of intense scientific research. A growing body of evidence suggests that some aspects of food addiction, such as compulsive eating behavior, can be modeled in animals. Moreover, several areas of the brain, including various neurotransmitter systems, are involved in the reinforcement effects of both food and drugs, suggesting that natural and pharmacological stimuli activate similar neural systems. In addition, several recent studies have identified a putative connection between neural circuits activated in the seeking and intake of both palatable food and drugs. The development of well-characterized animal models will increase our understanding of the etiological factors of food addiction and will help identify the neural substrates involved in eating disorders such as compulsive overeating. Such models will facilitate the development and validation of targeted pharmacological therapies.

Background: Eating disorders are multifactorial psychiatric disorders. Chronic stressful experiences and caloric restriction are the most powerful triggers of eating disorders in human and animals. Although compulsive behavior is considered to characterize pathological excessive food intake, to our knowledge, no evidence has been reported of continued food seeking/intake despite its possible harmful consequences, an index of compulsive behavior. Brain monoamine transmission is considered to have a key role in vulnerability to eating disorders, and norepinephrine in medial prefrontal cortex has been shown to be critical for food-related motivated behavior.Here, using a new paradigm of conditioned suppression, we investigated whether the ability of a foot-shock-paired conditioned stimulus to suppress chocolate-seeking behavior was reversed by previous exposure to a food restriction experience, thus modeling food seeking in spite of harmful consequences in mice. Moreover, we assessed the effects of selective norepinephrine inactivation in medial prefrontal cortex on conditioned suppression test in stressed and caloric restricted mice., Results: While Control (non food deprived) animals showed a profound conditioned suppression of chocolate seeking during presentation of conditioned stimulus, previously food restricted animals showed food seeking/intake despite its possible harmful consequences. Moreover, food seeking in spite of harmful consequences was prevented by selective norepinephrine inactivation, thus showing that prefrontal cortical norepinephrine is critical also for maladaptive food-related behavior., Conclusions: These findings indicate that adaptive food seeking/intake can be transformed into maladaptive behaviors and point to "top-down" influence on eating disturbances and to new targets for therapy of aberrant eating behaviors.

A major problem in the dietary treatment of disorders associated with excessive eating, such as obesity, is the high rate of relapse into maladaptive eating habits after withdrawal from consumption of palatable, energy-dense food. As olfaction has a major role in appetite and eating behavior, in this study we used a reinstatement model based on conditioned place preference to investigate the ability of olfactory priming to reinstate extinguished chocolate-induced conditioned place preference in sated mice. We found that olfactory priming, which was ineffective in inducing conditioned place preference in the control group, reactivated place preference following the extinction procedure in the experimental group. These results extend previous reports of the reinstatement of food seeking induced by pellet priming and, for the first time, show the possibility of using olfactory priming in an animal model of relapse. In light of the major role of olfactory inputs in appetite and of cues in relapse, the present results indicate that smell is an important factor to consider in the treatment of eating disorders., (2009 Elsevier Ltd. All rights reserved.)