Influence of Bariatric Surgery on Gut Microbiota Composition and Its Implication on Brain and Peripheral Targets.

Obesity remains a significant global health challenge, with bariatric surgery remaining as one of the most effective treatments for severe obesity and its related comorbidities. This review highlights the multifaceted impact of bariatric surgery beyond mere physical restriction or nutrient malabsorption, underscoring the importance of the gut microbiome and neurohormonal signals in mediating the profound effects on weight loss and behavior modification. The various bariatric surgery procedures, such as Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), act through distinct mechanisms to alter the gut microbiome, subsequently impacting metabolic health, energy balance, and food reward behaviors. Emerging evidence has shown that bariatric surgery induces profound changes in the composition of the gut microbiome, notably altering the Firmicutes/Bacteroidetes ratio and enhancing populations of beneficial bacteria such as Akkermansia. These microbiota shifts have far-reaching effects beyond gut health, influencing dopamine-mediated reward pathways in the brain and modulating the secretion and action of key gut hormones including ghrelin, leptin, GLP-1, PYY, and CCK. The resultant changes in dopamine signaling and hormone levels contribute to reduced hedonic eating, enhanced satiety, and improved metabolic outcomes. Further, post-bariatric surgical effects on satiation targets are in part mediated by metabolic byproducts of gut microbiota like short-chain fatty acids (SCFAs) and bile acids, which play a pivotal role in modulating metabolism and energy expenditure and reducing obesity-associated inflammation, as well as influencing food reward pathways, potentially contributing to the regulation of body weight and reduction in hedonic eating behaviors. Overall, a better understanding of these mechanisms opens the door to developing non-surgical interventions that replicate the beneficial effects of bariatric surgery on the gut microbiome, dopamine signaling, and gut hormone regulation, offering new avenues for obesity treatment.

Vagus nerve damage increases alcohol intake and preference in a nonpreferring rat line: Relationship to vagal regulation of the hypothalamic-pituitary-adrenal axis.

BACKGROUND: Clinical and preclinical research indicates that gastric weight loss surgeries, such as Roux-en-Y gastric bypass surgery, can induce alcohol use disorder (AUD). While numerous mechanisms have been proposed for these effects, one relatively unexplored potential mechanism is physical damage to the gastric branch of the vagus nerve, which can occur during bypass surgery. Therefore, we hypothesized that direct damage to the gastric branch of the vagus nerve, without altering other aspects of gastric anatomy, could result in increased alcohol intake. METHODS: To test this hypothesis, we compared alcohol intake and preference in multiple models in male Sprague-Dawley rats that received selective gastric branch vagotomy (VX) with rats who underwent sham surgery. Because the vagus nerve regulates hypothalamic-pituitary-adrenal (HPA) axis function, and alterations to HPA function are critical to the escalation of non-dependent alcohol intake, we also tested the hypothesis that gastric VX increases HPA function. RESULTS: We found that VX increases alcohol intake and preference in the every-other-day, two-bottle choice test and increases preference for 1 g/kg alcohol in the conditioned place preference test. The effects were selective for alcohol, as sucrose intake and preference were not altered by VX. We also found that VX increases corticotropin releasing factor (CRF) mRNA in the paraventricular nucleus of the hypothalamus (PVN), increases putative PVN CRF neuronal action potential firing, and increases corticosterone levels. CONCLUSIONS: Overall, these findings suggest that the vagus nerve may play a critical role in regulating HPA axis function via modulation of PVN CRF mRNA expression and putative PVN CRF neuronal activity. Furthermore, disruptions to vagal regulation of HPA axis function may increase alcohol intake and preference.

Patients with chronic bipolar disorder show impairments in interpreting literary fiction - A preliminary explorative study with the short story task.

INTRODUCTION: Theory of mind (ToM) is a crucial skill in navigating and functioning in the social world. Significant ToM impairment was consistently found in bipolar disorder; it can be both a state and trait marker of the disorder. However, most of the ToM tests are not sensitive enough to detect subtle individual differences, which would be necessary for an individualized treatment plan. The Short Story Task (SST) is a new way to sensitively assess individual differences in ToM performance. The aim of the study was to test the feasibility of SST in patients with bipolar disorder. METHOD: 31 persons (11 male, 20 female) with bipolar I disorder and 31 healthy individuals (15 males and 16 females) as a control group were recruited. SST was used to evaluate ToM performance. The SST uses a Hemingway novel, in which the patient is presented with a realistic social situation, where the motivations of the characters and the underlying relationships of events are not explicitly described. RESULTS: In the explicit mental state reasoning questions the CG (M = 8.06) had significantly higher (p < 0.001) scores than the persons with bipolar I disorder (M = 5.03). There was no ceiling effect for explicit ToM scores in either group. Participants in CG (M = 8.03) also significantly outperformed (p = 0.006) the BG participants (M = 6.55) in the comprehension questions. The spontaneous mental state inference question was performed equally (M = 0.23) in both groups. Group assignment (t = -3.503, p < 0.001), comprehension score (t = 2.864, p = 0.006), and spontaneous mentalization (t = 2.846, p = 0.006) significantly predicted the explicit ToM performance. CONCLUSIONS: Overall, we found that the Short Story Task is a promising tool for measuring ToM in patients with bipolar disorder without ceiling effect. Primarily explicit ToM was found to be deficient, which corresponds well with the ToM literature in bipolar disorder. Contrary to our hypothesis we could not detect impairment in spontaneous ToM and found that patients living with bipolar disorder also showed deficits in comprehension. The lack of assessment of neurocognitive skills is a significant limitation of the current study.

Investigation of peripheral inflammatory biomarkers in association with suicide risk in major depressive disorder.

Suicide is the most severe complication of major depressive disorder (MDD). Novel research assumes the role of immunological dysregulation in the background - several studies have reported alterations in the number of inflammatory cells related to both MDD and suicidality. There are currently no objective, routinely measured parameters to indicate suicidal vulnerability. However, altered inflammatory cell numbers and ratios have been proposed as potential biomarkers of suicide risk (SR). The present research aims to examine changes of these values related to increased SR in MDD as an assumed inflammatory state. We investigated laboratory parameters of psychiatric in-patients diagnosed with MDD (n = 101) retrospectively. Individuals with recent suicide attempt (SA) (n = 22) and with past SA (n = 19) represented the high SR group. MDD patients with no history of SA (n = 60) composed the intermediate SR group. We compared the number of neutrophil granulocytes, monocytes, lymphocytes, platelets, white blood cell count (WBC), neutrophil-to-lymphocyte (NLR), monocyte-to-lymphocyte (MLR), platelet-to-lymphocyte ratio (PLR), mean platelet volume (MPV), red blood cell distribution width (RDW) and erythrocyte sedimentation rate (ESR). Furthermore, we evaluated alterations of these parameters related to antidepressant (AD) and antipsychotic (AP) treatment, which have been proved to have anti-inflammatory effects. We found a significant increase in neutrophil granulocyte count, NLR, monocyte count, MLR, WBC and ESR in patients with recent SA compared to patients with no history of SA. Moreover, there was a significant elevation in monocyte count, MLR, ESR and RDW in patients with high SR compared to patients with intermediate SR. AD treatment resulted in a significant decrease in neutrophil granulocyte count and NLR, however, it did not affect monocyte count and MLR. Assuming immunological mechanisms in the background of MDD and suicidality, our findings support the role of NLR as a biomarker of acute SR, though its alterations may be masked by possible anti-inflammatory effects of AD treatment in the long term. However, MLR, a marker exhibiting changes which are not attenuated by pharmacotherapy, may be a possible indicator of both acute and long-term suicidal vulnerability.

Reduced Striatal Dopamine Transporter Availability and Heightened Response to Natural and Pharmacological Stimulation in CCK-1R-Deficient Obese Rats.

Alterations in dopamine neurotransmission are associated with obesity and food preferences. Otsuka Long-Evans Tokushima Fatty (OLETF) rats that lack functional cholecystokinin receptor type-1 (CCK-1R), due to a natural mutation, exhibit impaired satiation, are hyperphagic, and become obese. In addition, compared to lean control Long-Evans Tokushima (LETO) rats, OLETF rats have pronounced avidity for over-consuming palatable sweet solutions, have greater dopamine release to psychostimulants, reduced dopamine 2 receptor (D2R) binding, and exhibit increased sensitivity to sucrose reward. This supports altered dopamine function in this strain and its general preference for palatable solutions such as sucrose. In this study, we examined the relationship between OLETF's hyperphagic behavior and striatal dopamine signaling by investigating basal and amphetamine stimulated motor activity in prediabetic OLETF rats before and after access to sucrose solution (0.3 M) compared to non-mutant control LETO rats, as well as availability of dopamine transporter (DAT) using autoradiography. In the sucrose tests, one group of OLETF rats received ad libitum access to sucrose while the other group received an amount of sucrose equal to that consumed by the LETO. OLETFs with ad libitum access consumed significantly more sucrose than LETOs. Sucrose exerted a biphasic effect on basal activity in both strains, i.e., reduced activity for 1 week followed by increased activity in weeks 2 and 3. Basal locomotor activity was reduced (-17%) in OLETFs prior to sucrose, compared to LETOs. Withdrawal of sucrose resulted in increased locomotor activity in both strains. The magnitude of this effect was greater in OLETFs and the activity was increased in restricted compared to ad-libitum-access OLETFs. Sucrose access augmented AMPH-responses in both strains with a greater sensitization to AMPH during week 1, an effect that was a function of the amount of sucrose consumed. One week of sucrose withdrawal sensitized AMPH-induced ambulatory activity in both strains. In OLETF with restricted access to sucrose, withdrawal resulted in no further sensitization to AMPH. DAT availability in the nucleus accumbens shell was significantly reduced in OLETF compared with aged-matched LETO. Together, these findings show that OLETF rats have reduced basal DA transmission and a heightened response to natural and pharmacological stimulation.

Severe Anemia in Sprague-Dawley Rats After Roux-en-Y Gastric Bypass Surgery.

Roux-en-Y gastric bypass (RYGB) surgery is one of the most commonly performed bariatric procedures for weight loss in humans. However, this procedure is not risk-free, and patients may experience complications that include small bowel obstruction, gastrointestinal bleeding, chronic diarrhea, ulcers, malnutrition, and anemia. In particular, anemia is a recognized long-term complication and can be severe. Rats have been used as a model to study the effects of gastric bypass surgeries. They can experience similar complications as people, but the development of severe anemia has not previously been reported in rats. We observed 2 cases of severe anemia in female Sprague-Dawley rats after RYGB surgery. These cases prompted us to further investigate the frequency and severity of anemia after RYGB in rats. Blood work and necropsies were performed on 9 additional female Sprague-Dawley rats (5 with RYGB, 4 with sham surgery). In these 9 rats, only one had signs of clinical anemia. These 3 anemic rats displayed moderate to severe pallor of the eyes and ears. Necropsy findings in anemic RYGB rats included pale internal organs and eccentric heart enlargement, which led to a significantly higher heart:body weight ratio in RYGB rats as compared with sham controls. Anemic rats had either a macrocytic normochromic anemia, consistent with vitamin B12 or folate deficiency, or microcytic hypochromic anemia, indicative of iron deficiency. Researchers who perform RYGB surgery in rats should be aware of the potential complication of severe anemia. Plans for the diagnosis and management of this complication and the development of criteria for humane endpoints for severe anemia are recommended as a refinement to these studies.

Calorie restriction, but not Roux-en-Y gastric bypass surgery, increases [3 H] PK11195 binding in a rat model of obesity.

Roux-en-Y gastric bypass surgery (RYGB) remains an effective weight-loss method used to treat obesity. While it is successful in combating obesity, there are many lingering questions related to the changes in the brain following RYGB surgery, one of them being its effects on neuroinflammation. While it is known that chronic high-fat diet (HFD) contributes to obesity and neuroinflammation, it remains to be understood whether bariatric surgery can ameliorate diet-induced inflammatory responses. To examine this, rats were assigned to either a normal diet (ND) or a HFD for 8 weeks. Rats fed a HFD were split into the following groups: sham surgery with ad libitum access to HFD (sham-HF); sham surgery with calorie-restricted HFD (sham-FR); RYGB surgery with ad libitum access to HFD (RYGB). Following sham or RYGB surgeries, rats were maintained on their diets for 9 weeks before being euthanized. [3 H] PK11195 autoradiography was then performed on fresh-frozen brain tissue in order to measure activated microglia. Sham-FR rats showed increased [3 H] PK11195 binding in the amygdala (63%), perirhinal (60%), and ectorhinal cortex (53%) compared with the ND rats. Obese rats who had the RYGB surgery did not show this increased inflammatory effect. Since the sham-FR and RYGB rats were fed the same amount of HFD, the surgery itself seems responsible for this attenuation in [3 H] PK11195 binding. We speculate that calorie restriction following obese conditions may be seen as a stressor and contribute to inflammation in the brain. Further research is needed to verify this mechanism.

Adolescent alcohol disrupts development of noradrenergic neurons in the nucleus of the tractus solitarius and enhances stress behaviors in adulthood in mice in a sex specific manner.

Alcohol use disorders (AUDs) are common mental health issues worldwide and can lead to other chronic diseases. Stress is a major factor in the development and continuation of AUDs, and adolescent alcohol exposure can lead to enhanced stress-responsivity and increased risk for AUD development in adulthood. The exact mechanisms behind the interaction between adolescence, stress, and alcohol are not fully understood and require further research. In this regard, the nucleus of the tractus solitarius (NTS) provides dense norepinephrine projections to the extended amygdala, providing a key pathway for stress-related alcohol behaviors. While NTS norepinephrine neurons are known to be alcohol sensitive, whether adolescent alcohol disrupts NTS-norepinephrine neuron development and if this is related to altered stress-sensitivity and alcohol preference in adulthood has not previously been examined. Here, we exposed male and female C57Bl/6J mice to the commonly used adolescent intermittent ethanol (AIE) vapor model during postnatal day 28-42 and examined AIE effects on: 1) tyrosine hydroxylase (TH) mRNA expression in the NTS across various ages (postnatal day 21-90), 2) behavioral responses to acute stress in the light/dark box test in adulthood, 3) NTS TH neuron responses to acute stress and ethanol challenges in adulthood, and 4) ethanol conditioned place preference behavior in adulthood. Overall the findings indicate that AIE alters NTS TH mRNA expression and increases anxiety-like behaviors following acute stress exposure in a sex-dependent manner. These mRNA expression and behavioral changes occur in the absence of AIE-induced changes in NTS TH neuron sensitivity to either acute stress or acute alcohol exposure or changes to ethanol conditioned place preference.

The Neural Code for Taste in the Nucleus of the Solitary Tract of Rats with Obesity Following Roux-En-Y Gastric Bypass Surgery.

Previous work has shown that taste responses in the nucleus tractus solitarius (NTS; the first central relay for gustation) are blunted in rats with diet-induced obesity (DIO). Here, we studied whether these effects could be reversed by Roux-en-Y gastric bypass (RYGB) surgery, an effective treatment for obesity. Rats were fed a high energy diet (60% kcal fat; HED) both before and after undergoing RYGB. Electrophysiological responses from NTS cells in unrestrained rats were recorded as they licked tastants from a lick spout. Sweet, salty, and umami tastes, as well as their naturalistic counterparts, were presented. Results were compared with those of lean rats from a previous study. As with DIO rats, NTS cells in RYGB rats were more narrowly tuned, showed weaker responses, and less lick coherence than those in lean rats. Both DIO and RYGB rats licked at a slower rate than lean rats and paused more often during a lick bout. However, unlike DIO rats, the proportion of taste cells in RYGB rats was similar to that in lean rats. Our data show that, despite being maintained on a HED after surgery, RYGB can induce a partial recovery of the deficits seen in the NTS of DIO rats.

Greater avoidance of a saccharin cue paired with passive delivery of heroin is associated with a select increase in expression of CRFR2 and CRFbp in the hippocampus in rats.

As a drug of abuse tightens its hold on addicted individuals, aspects of life that once brought pleasure lose their appeal while attention and motivation are turned toward acquiring drug. In a rodent model of self-administration and reward devaluation, we previously showed that animals that suppress intake of a drug-paired saccharin cue show greater addiction-like behaviors, as well as increased gene-expression of elements of the corticotropin releasing factor (CRF) pathway in the prefrontal cortex (mPFC), hippocampus (Hipp), and ventral tegmental area (VTA). In the present study, we explored whether the observed differences in components of the CRF signaling pathway were a function of self-administration or devaluation of the cue. Moreover, as an increasing body of work illustrates, functional and molecular hemispheric differences in reward pathway components, we examined whether these CRF pathway components exhibited hemispheric differences in response to heroin administration. Over a period of 7 trials, 30 male rats received brief access to saccharin followed by passive (IP) injection of heroin (n = 20) or saline (n = 10). Saccharin intakes between large saccharin suppressors (LS; 12 animals) and small suppressors (SS; 8 animals) were statistically different after trial 1 and separated further with ensuing trials. We then assessed gene expression for components of the CRF pathway in the mPFC, Hipp, VTA, Amygdala, and nucleus accumbens (NAc). Within the Hipp, LS showed greater expression of CRF binding protein (CRFbp). No differences were observed in the mPFC, VTA, NAc or Amygdala. Several hemisphere differences in CRF signaling pathway genes were detected. These findings indicate that avoidance of the experimenter delivered heroin-paired saccharin cue, do not recapitulate findings observed for avoidance of the iv self-administered heroin-paired saccharin cue, at least in terms of the expression of genes within the CRF pathway, and provide further evidence that consideration should be given to hemisphere differences when exploring molecular phenomena.

Feasibility Study of Bariatric Surgery in a Rat Model of Spinal Cord Injury to Achieve Beneficial Body Weight Outcome.

Approximately two thirds of spinal cord injury (SCI) persons become overweight or obese. Obesity increases the risk of developing type 2 diabetes and limits self-help techniques. Weight-loss surgery (WLS), including vertical sleeve gastrectomy (VSG), is regarded as highly effective in the long-term treatment of obesity and remission of associated type 2 diabetes. Given the increased risk of obesity post-SCI, WLS offers an attractive intervention strategy. Alterations in the physiology of energy homeostasis after SCI necessitate that SCI persons should not be regarded as similar to able-bodied persons. Because of current knowledge gaps, it is unknown whether an obese phenotype with SCI will respond to WLS similarly to the neurally intact obese phenotype. Therefore, this study tested the hypothesis that the VSG procedure is well tolerated and effective in an animal model of high-thoracic (T3) SCI. In Wistar male rats, subsequent to a 2-week recovery period after T3-SCI, but not control laminectomy surgery, daily consumption of a high-fat diet (HFD; 60% kcal from fat) was elevated over 4 weeks preceding VSG. After a 2-week recovery period post-VSG, HFD consumption in T3-SCI rats over a 4-week monitoring period returned to levels comparable to control. Body weight was significantly reduced in T3-SCI rats and remained reduced whereas control rats regained body weight. Further, no adverse complications directly attributable to the VSG procedure were identified. Thus, this rodent model is a viable tool for addressing fundamental questions regarding the mechanisms leading to obesity post-SCI and the development of translational strategies.

Short-term high-fat diet consumption increases body weight and body adiposity and alters brain stem taste information processing in rats.

Diet-induced obesity is known to develop whether exposed to a high-energy diet (HED) or a high-fat diet (HFD). However, it is still not clear whether the elevated energy content or the macronutrient imbalance is the key factor in early disease progression. Therefore, this study compared the short-term effects of 2 widely used rodent obesogenic diets, an HFD with 60 kcal% fat content and a carbohydrate-based HED, on the body weight, body fat content, glucose tolerance, and neuronal taste responses in rats. We found that only HFD induced an early significant body weight increase compared with the control normal diet (ND) group, starting on week 4, and resulting in a significantly elevated body adiposity compared with both the ND and HED groups. Oral glucose tolerance test revealed no difference across groups. Subsequently, we also found that HFD resulted in a significant body weight gain even under energy-restricted (isocaloric to ND) conditions. In vivo electrophysiological recordings revealed that only the ad libitum HFD and not the isocaloric-HFD altered the brain stem gustatory neural responses to oral taste stimulation. In conclusion, this study showed that increased fat intake might result in significant body weight gain even under isocaloric and metabolically healthy conditions and demonstrated changes in central taste processing in an early stage of dietary obesity. A better understanding of these initial physiological changes may offer new drug targets for preventing obesity.

Changes in plasma ghrelin levels following surgical and non-surgical weight-loss in female rats predict alcohol use.

The weight-loss surgery Roux-en Y gastric bypass (RYGB) is a relatively effective, long-term treatment option for patients with morbid obesity. However, accumulating clinical evidence suggests that patients receiving RYGB may be at increased risk of developing alcohol use disorder. This observation has been repeatedly supported by preclinical studies showing rodents increase intake of ethanol (EtOH) after RYGB, and has been further confirmed by human studies. A promising alternative to RYGB is sleeve gastrectomy (SG), which has resulted in decreased EtOH consumption in some rodent studies. The exact mechanism underlying the differential alcohol outcomes after RYGB versus SG has yet to be elucidated. However, the gut hormone ghrelin has emerged as a potential candidate from previous preclinical studies specific to RYGB surgeries and due to its action to stimulate food and alcohol intake and cravings. To directly assess changes in plasma ghrelin levels following weigh loss surgeries in the context of alcohol intake, 24 female rats were separated into three surgical groups receiving RYGB, SG, or Sham surgery followed by caloric restriction to produce adiposity matched controls (Sham-AM). Blood was drawn for fasted and fed plasma ghrelin (acyl and des-acyl) assays at multiple time points: while on a normal diet (ND), after 5-week exposure to a high fat diet (HFD), following surgery, and after a series of two-bottle alcohol choice test with increasing concentrations (2%, 4%, 6%, 8%) of EtOH. Consistent with previous observations, RYGB rats drank more EtOH than SG rats across all concentrations. As expected, fasted ghrelin levels were blunted after HFD feeding, compared to normal diet baseline. After RYGB, fasted ghrelin levels returned to higher levels while remained blunted after SG and Sham-AM. Fed acyl ghrelin levels were significantly increased to above "normal" levels after RYGB, but remain low after SG and Sham-AM. Given that post-RYGB acyl ghrelin levels are raised to a fasted state regardless of actual prandial status, we conclude that RYGB may results in a hormonal state reminiscence of a fasted state with the inability of feeding to inhibit ghrelin production, an effect which could potentially contribute to increased EtOH intake following the surgery. In contrast, following SG, ghrelin levels in rats remain consistent with the fed state regardless of prandial status, potentially explaining lower alcohol intake and lower risk of developing AUD.

Impact of Nutrition, Microbiota Transplant and Weight Loss Surgery on Dopaminergic Alterations in Parkinson's Disease and Obesity.

Parkinson's disease (PD), the second most common neurodegenerative disorder worldwide, is characterized by dopaminergic neuron degeneration and α-synuclein aggregation in the substantia nigra pars compacta of the midbrain. Emerging evidence has shown that dietary intake affects the microbial composition in the gut, which in turn contributes to, or protects against, the degeneration of dopaminergic neurons in affected regions of the brain. More specifically, the Mediterranean diet and Western diet, composed of varying amounts of proteins, carbohydrates, and fats, exert contrasting effects on PD pathophysiology via alterations in the gut microbiota and dopamine levels. Interestingly, the negative changes in the gut microbiota of patients with PD parallel changes that are seen in individuals that consume a Western diet, and are opposite to those that adhere to a Mediterranean diet. In this review, we first examine the role of prominent food groups on dopamine bioavailability, how they modulate the composition and function of the gut microbiota and the subsequent effects on PD and obesity pathophysiology. We then highlight evidence on how microbiota transplant and weight loss surgery can be used as therapeutic tools to restore dopaminergic deficits through optimizing gut microbial composition. In the process, we revisit dietary metabolites and their role in therapeutic approaches involving dopaminergic pathways. Overall, understanding the role of nutrition on dopamine bioavailability and gut microbiota in dopamine-related pathologies such as PD will help develop more precise therapeutic targets to rescue dopaminergic deficits in neurologic and metabolic disorders.

Involvement of the Dorsal Vagal Complex in Alcohol-Related Behaviors.

The neurobiological mechanisms that regulate the development and maintenance of alcohol use disorder (AUD) are complex and involve a wide variety of within and between systems neuroadaptations. While classic reward, preoccupation, and withdrawal neurocircuits have been heavily studied in terms of AUD, viable treatment targets from this established literature have not proven clinically effective as of yet. Therefore, examination of additional neurocircuitries not classically studied in the context of AUD may provide novel therapeutic targets. Recent studies demonstrate that various neuropeptides systems are important modulators of alcohol reward, seeking, and intake behaviors. This includes neurocircuitry within the dorsal vagal complex (DVC), which is involved in the control of the autonomic nervous system, control of intake of natural rewards like food, and acts as a relay of interoceptive sensory information via interactions of numerous gut-brain peptides and neurotransmitter systems with DVC projections to central and peripheral targets. DVC neuron subtypes produce a variety of neuropeptides and transmitters and project to target brain regions critical for reward such as the mesolimbic dopamine system as well as other limbic areas important for the negative reinforcing and aversive properties of alcohol withdrawal such as the extended amygdala. This suggests the DVC may play a role in the modulation of various aspects of AUD. This review summarizes the current literature on neurotransmitters and neuropeptides systems in the DVC (e.g., norepinephrine, glucagon-like peptide 1, neurotensin, cholecystokinin, thyrotropin-releasing hormone), and their potential relevance to alcohol-related behaviors in humans and rodent models for AUD research. A better understanding of the role of the DVC in modulating alcohol related behaviors may lead to the elucidation of novel therapeutic targets for drug development in AUD.

Implicit Mentalizing in Patients With Schizophrenia: A Systematic Review and Meta-Analysis.

INTRODUCTION: Mentalizing is a key aspect of social cognition. Several researchers assume that mentalization has two systems, an explicit one (conscious, relatively slow, flexible, verbal, inferential) and an implicit one (unconscious, automatic, fast, non-verbal, intuitive). In schizophrenia, several studies have confirmed the deficit of explicit mentalizing, but little data are available on non-explicit mentalizing. However, increasing research activity can be detected recently in implicit mentalizing. The aim of this systematic review and meta-analysis is to summarize the existing results of implicit mentalizing in schizophrenia. METHODS: A systematic search was performed in four major databases: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science. Eleven publications were selected. Five studies were found to be eligible for quantitative synthesis, and 9 studies were included in qualitative synthesis. RESULTS: The meta-analysis revealed significantly lower accuracy, slower reaction time during implicit mentalizing in patients with schizophrenia. The systematic review found different brain activation pattern, further alterations in visual scanning, cue fixation, face looking time, and difficulties in perspective taking. DISCUSSION: Overall, in addition to the deficit of explicit mentalization, implicit mentalization performance is also affected in schizophrenia, if not to the same extent. It seems likely that some elements of implicit mentalization might be relatively unaffected (e.g., detection of intentionality), but the effectiveness is limited by certain neurocognitive deficits. These alterations in implicit mentalizing can also have potential therapeutic consequences.Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier: CRD42021231312.

Role of Microbiota-Gut-Brain Axis in Regulating Dopaminergic Signaling.

Dopamine is a neurotransmitter that plays a critical role both peripherally and centrally in vital functions such as cognition, reward, satiety, voluntary motor movements, pleasure, and motivation. Optimal dopamine bioavailability is essential for normal brain functioning and protection against the development of neurological diseases. Emerging evidence shows that gut microbiota have significant roles in maintaining adequate concentrations of dopamine via intricate, bidirectional communication known as the microbiota-gut-brain axis. The vagus nerve, immune system, hypothalamus-pituitary-adrenal axis, and microbial metabolites serve as important mediators of the reciprocal microbiota-gut-brain signaling. Furthermore, gut microbiota contain intrinsic enzymatic activity that is highly involved in dopamine metabolism, facilitating dopamine synthesis as well as its metabolite breakdown. This review examines the relationship between key genera of gut microbiota such as Prevotella, Bacteroides, Lactobacillus, Bifidobacterium, Clostridium,Enterococcus, and Ruminococcus and their effects on dopamine. The effects of gut dysbiosis on dopamine bioavailability and the subsequent impact on dopamine-related pathological conditions such as Parkinson's disease are also discussed. Understanding the role of gut microbiota in modulating dopamine activity and bioavailability both in the periphery and in the central nervous system can help identify new therapeutic targets as well as optimize available methods to prevent, delay, or restore dopaminergic deficits in neurologic and metabolic disorders.

Glucagon-like peptide-1 receptor agonist, liraglutide, reduces heroin self-administration and drug-induced reinstatement of heroin-seeking behaviour in rats.

Drug addiction is a chronic brain disease characterized by the uncontrolled use of a substance. Due to its relapsing nature, addiction is difficult to treat, as individuals can relapse following even long periods of abstinence and, it is during this time, that they are most vulnerable to overdose. In America, opioid overdose has been increasing for decades, making finding new treatments to help patients remain abstinent and prevent overdose deaths imperative. Recently, glucagon-like peptide-1 (GLP-1) receptor agonists have shown promise in reducing motivated behaviours for drugs of abuse. In this study, we test the effectiveness of the GLP-1 analogue, liraglutide (LIR), in reducing heroin addiction-like behaviour, and the potential side effects associated with the treatment. We show that daily treatment with LIR (0.1 mg/kg sc) increases the latency to take heroin, reduces heroin self-administration, prevents escalation of heroin self-administration and reduces drug-induced reinstatement of heroin-seeking behaviour in rats. A 1-h pretreatment time, however, was too short to reduce cue-induced seeking in our study. Moreover, we showed that, while LIR (0.1, 0.3, 0.6 and 1.0 mg/kg sc) supported conditioned taste avoidance of a LIR-paired saccharin cue, it did not elicit intake of the antiemetic kaolin in heroin-naïve or heroin-experienced rats. Further, 0.1 mg/kg LIR did not produce great disruptions in food intake or body weight. Overall, the data show that LIR is effective in reducing heroin taking and heroin seeking at doses that do not cause malaise and have a modest effect on food intake and body weight gain.

Sprague Dawley Rats Gaining Weight on a High Energy Diet Exhibit Damage to Taste Tissue Even after Return to a Healthy Diet.

Many reports detail taste dysfunction in humans and animals with obesity. For example, mice consuming an obesogenic diet for a short period have fewer taste buds than their lean littermates. Further, rats with diet-induced obesity (DIO) show blunted electrophysiological responses to taste in the brainstem. Here, we studied the effects of high energy diet (HED)-induced peripheral taste damage in rats, and whether this deficiency could be reversed by returning to a regular chow diet. Separate groups of rats consumed a standard chow diet (Chow), a HED for 10 weeks followed by a return to chow (HED/chow), or a HED for 10 weeks followed by a restricted HED that was isocaloric with consumption by the HED/chow group (HED/isocal). Fungiform taste papilla (FP) and circumvallate taste bud abundance were quantified several months after HED groups switched diets. Results showed that both HED/chow and HED/isocal rats had significantly fewer FP and lower CV taste bud abundance than control rats fed only chow. Neutrophil infiltration into taste tissues was also quantified, but did not vary with treatment on this timeline. Finally, the number of cells undergoing programmed cell death, measured with caspase-3 staining, inversely correlated with taste bud counts, suggesting taste buds may be lost to apoptosis as a potential mechanism for the taste dysfunction observed in obesity. Collectively, these data show that DIO has lasting deleterious effects on the peripheral taste system, despite a change from a HED to a healthy diet, underscoring the idea that obesity rather than diet predicts damage to the taste system.

Differential Response in Ethanol Behaviors of Female Rats Given Various Weight Loss Surgeries.

AIMS: Currently, the only effective treatment for morbid obesity and its comorbidities is weight loss surgery (WLS). Growing evidence suggests that different types of WLS, such as Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG), have differential effects on alcohol consumption in humans and rats. Thus, we aimed to directly compare the effects of these two surgical procedures, for the first time in female rats, and to determine whether presence or absence of the ghrelin-producing stomach tissue has critical influence on postoperative alcohol intake. METHODS: We performed two experiments using an identical behavioral protocol, a continuous-access two-bottle choice protocol for various concentrations of ethanol (EtOH). In Experiment 1, 23 high fat diet (HFD) obese, female rats were randomized to three groups: RYGB, SG or sham-operated food-restricted (Sham) controls. In Experiment 2, HFD obese female rats received either sham (n = 11) or a modified RYGB surgery where the remnant stomach was removed (RYGB-X; n = 12). RESULTS: SG rats drank significantly less than RYGB for 4, 6 and 8% and significantly less than Sham for 6, 8 and 8% reinstatement. RYGB-X consumed significantly less EtOH than Sham across all concentrations, reaching significance for 6 and 8% reinstatement. CONCLUSION: These findings confirm reduced EtOH consumption by female SG rats as opposed to increased intake following RYGB, and provide the first experimental evidence that the remnant stomach in the RYGB procedure is contributory. Future studies in rats and humans are warranted to confirm that ghrelin plays a critical role in susceptibility to AUD development following WLS.