Evaluation of weight, caloric intake, and behavior of rats after bilateral ablation of the nucleus accumbens shell

Introduction: Deep brain stimulation and ablation of certain regions of the brain are being widely used in research aiming to link some region of the cortex with certain psychiatric disorders. The nucleus accumbens, for example, belonging to the basal ganglia, responsible for modulating the reward system and limbic-motor integration, according to studies, is related to the pathophysiology of alterations in neurotransmitters and neuronal connections in anorexia nervosa. Research in animals and humans reinforces this theory. Objective: To evaluate whether even in healthy rats, it is possible to observe changes in eating patterns and behavior that would justify such relationship. Materials and methods: A total of 24 female Wistar rats were randomly divided into experimental group (n=20) and control group (n=4). The rats in the experimental group underwent surgery with bilateral ablation of the nucleus accumbens shell using a stereotactic-guided radiofrequency needle. After surgery, the rats had their weights and caloric intake measured daily. Their behavior was empirically observed and then compared with that exhibited by the control group. Results: Regarding behavioral changes, it was observed an exaggerated increase in grooming, sniffing, searching/exploration, and avoidance/escape. Aggressiveness was present in only one animal of the experimental group. Regarding weight gain and caloric intake, a statistically significant relationship was found between them in relation to the time after the surgical intervention, when comparing the experimental and control groups. Discussion/Conclusion: In this study we investigated whether even in healthy rats, performing an inhibition – ablation of the Nucleus Accumbens – would cause an increase in caloric intake and consequently weight of the rats, and whether the procedure would cause changes in their behavior. From the results obtained we can infer that such assumption is true. Moreover, other research, both in humans and animals, support the data and the connection of the Nucleus Accumbens given by the reward system, to psychiatric disorders, in this case, anorexia nervosa. More investigations are necessary to further elucidate such interactions and consequences.

Stress-impaired reward pathway promotes distinct feeding behavior patterns

Psychosocial stress can impact feeding behavior outcomes. Although many studies have examined alterations to food intake, little is known about how stress affects feeding behavior patterns. To determine the impact of psychological stress on feeding behavior patterns, mice were subjected to various psychosocial stressors (social isolation, intermittent high-fat-diet, or physical restraint) prior to timed observations in a feeding arena that incorporated multiple bait loci. In addition, in vivo microdialysis was used to assess the effects of stressors on the reward system by measuring dopamine levels in the nucleus accumbens (NAcc) shell. Impaired feeding behavior patterns characterized by significant deviations in bait selection (i.e. fixated feeding) and prolonged periods of eating (i.e. protracted feeding) were observed in stressed mice relative to non-stressed controls. In addition to clear behavioral effects, the stressors also negatively impacted dopamine levels at the nucleus accumbens shell. Normalization of dopamine reversed the fixated feeding behavior, whereas specifically inhibiting neuronal activity in the dopaminergic neurons of the ventral tegmental area that project to the nucleus accumbens shell caused similar impairments in feeding. Given that the deviations were not consistently accompanied by changes in the amount of bait consumed, body weight, or metabolic factors, the qualitative effects of psychosocial stressors on feeding behavior likely reflect perturbations to a critical pathway in the mesolimbic dopamine system. These findings provide compelling evidence that aberrations in feeding behavior patterns can be developed as sensitive biomarkers of psychosocial stress and possibly a prodromal state of neuropsychiatric diseases.

Viral-Mediated Knockdown of Nucleus Accumbens Shell PAC1 Receptor Promotes Excessive Alcohol Drinking in Alcohol-Preferring Rats

Alcohol use disorder (AUD) is a chronic, relapsing disorder whose genetic and environmental susceptibility components are not fully understood. Neuropeptidergic signaling has been repeatedly implicated in modulating excessive alcohol drinking, especially within sub-regions of the striatum. Here, we investigated the potential involvement of the selective receptor for pituitary adenylate cyclase-activating polypeptide (PACAP), PAC1R, in the nucleus accumbens shell (NAcc Shell) in excessive alcohol drinking in alcohol-preferring rats, an established animal model of the genetic propensity for alcoholism. Scr:sP alcohol-preferring rats were trained to operantly self-administer alcohol and then either an AAV virus short-hairpin RNA (shRNA) targeted to knockdown PAC1R, or an AAV control virus were microinfused into the NAcc Shell. NAcc Shell PAC1R shRNA knockdown virus was confirmed to significantly decrease PAC1R levels in the NAcc Shell. The effects of NAcc Shell PAC1R shRNA knockdown on ethanol self-administration were investigated using a Fixed Ratio (FR) 1 and a Progressive Ratio (PR) schedule of reinforcement. The effect of PAC1R knockdown on self-administration of an alternative reinforcer, saccharin, was also assessed. The results showed that the reduction in PAC1R in the NAcc Shell led to excessive ethanol drinking, increased preference for ethanol, and higher motivation to drink. NAcc Shell PAC1R shRNA knockdown did not comparably increase saccharin self-administration, suggesting selectivity of action. These data suggest that NAcc Shell PAC1R may serves as a “brake” on alcohol drinking, and thereby the loss of function of PAC1R leads to excessive alcohol consumption. Therefore, the PACAP/PAC1R system may represent a novel target for the treatment of AUD.

Adolescent Intermittent Ethanol (AIE) Enhances the Dopaminergic Response to Ethanol within the Mesolimbic Pathway during Adulthood: Alterations in Cholinergic/Dopaminergic Genes Expression in the Nucleus Accumbens Shell

A consistent preclinical finding is that exposure to alcohol during adolescence produces a persistent hyperdopaminergic state during adulthood. The current experiments determine that effects of Adolescent Intermittent Ethanol (AIE) on the adult neurochemical response to EtOH administered directly into the mesolimbic dopamine system, alterations in dendritic spine and gene expression within the nucleus accumbens shell (AcbSh), and if treatment with the HDACII inhibitor TSA could normalize the consequences of AIE. Rats were exposed to the AIE (4 g/kg ig; 3 days a week) or water (CON) during adolescence, and all testing occurred during adulthood. CON and AIE rats were microinjected with EtOH directly into the posterior VTA and dopamine and glutamate levels were recorded in the AcbSh. Separate groups of AIE and CON rats were sacrificed during adulthood and Taqman arrays and dendritic spine morphology assessments were performed. The data indicated that exposure to AIE resulted in a significant leftward and upward shift in the dose-response curve for an increase in dopamine in the AcbSh following EtOH microinjection into the posterior VTA. Taqman array indicated that AIE exposure affected the expression of target genes (Chrna7, Impact, Chrna5). The data indicated no alterations in dendritic spine morphology in the AcbSh or any alteration in AIE effects by TSA administration. Binge-like EtOH exposure during adolescence enhances the response to acute ethanol challenge in adulthood, demonstrating that AIE produces a hyperdopaminergic mesolimbic system in both male and female Wistar rats. The neuroadaptations induced by AIE in the AcbSh could be part of the biological basis of the observed negative consequences of adolescent binge-like alcohol exposure on adult drug self-administration behaviors.

Anterior Insular-Nucleus Accumbens Pathway Controls Refeeding-Induced Analgesia Under Chronic Inflammatory Pain Condition

Feeding behaviors are closely associated with chronic pain in adult rodents. Our recent study revealed that 2 hr refeeding after 24hr fasting (i.e. refeeding) attenuates pain behavior under chronic inflammatory pain conditions. However, while brain circuits mediating fasting-induced analgesia have been identified, the underlying mechanism of refeeding-induced analgesia is still elusive. Herein, we demonstrate that the neural activities in the nucleus accumbens shell (NAcS) and anterior insular cortex (aIC) were increased in a modified Complete Freund’s Adjuvant (CFA)-induced chronic inflammatory pain condition, which was reversed by refeeding. We also found that refeeding reduced the enhanced excitability of aICCamKII–NAcSD2R projecting neurons in this CFA model. Besides, chemogenetic inhibition of aICCamKII–NAcSD2R neural circuit suppressed chronic pain behavior while activation of this circuit reversed refeeding-induced analgesia. Thus, the present study suggests that aICCamKII – NacSD2R neural circuit mediates refeeding-induced analgesia, thereby serving as a potential therapeutic target to manage chronic pain.