Brain Reward Centers Research Articles

Dietary habits, depression and obesity: an intricate relationship to explore in pediatric preventive strategies.

Obesity and depression represent major health problems due to their high prevalence and morbidity rates. Numerous evidences elucidated the connections between dietary habits and the incidence or severity of depression. This overview aims to investigate the intricate relationship between dietary patterns and depression with the objective of elaborating preventive strategies for childhood obesity. Literature data recognized that there is a link between mood and food choices, with certain foods selected for their impact on the brain's reward centers. This behavior parallels the one observed in substance addiction, suggesting a specific neural mechanism for food addiction that contributes to overeating and obesity. It is important to note the significant correlation between obesity and depression, indicating a shared biological pathway influencing these conditions. Stress substantially affects also eating behaviors, often leading to increased consumption of pleasurable and rewarding foods. This can trigger a cycle of overeating, weight gain, and psychological distress, exacerbating mood disorders and obesity. In addition, consumption of certain types of foods, especially "comfort foods" high in fat and calories, may provide temporary relief from symptoms of depression, but can lead to long-term obesity and further mental health problems. Understanding these complex interactions is critical to developing preventive strategies focusing on dietary, emotional, and environmental factors, thereby reducing the risk of obesity and mood disorders.

Glucose response to sugar challenge moderates the effect of insulin resistance on reinforcing value of sugar-sweetened yogurt

We have shown insulin resistance is associated with the choice of sugar-sweetened over monk fruit sweetened yogurt. This study extends this research by assessing the association between insulin resistance and reinforcing value for sugar versus monk fruit-sweetened yogurt, and testing the hypothesis that this effect is moderated by greater blood glucose response in people with insulin resistance. Eighteen people with overweight/obesity (BMI = 35.8 kg/m2, range 26.2–48.5) with varying degrees of insulin resistance (Homeostatic Model Assessment of Insulin Resistance (HOMA–IR) = 2.6, range of 0.6–8.0) had blood glucose measured for 2 h after a sugar challenge. Over six days, they consumed, in a double-blind fashion, novel flavored-colored sugar or monk fruit-sweetened yogurts, and the reinforcing value of sugar or monk fruit-sweetened yogurts and delay discounting (DD) were measured. HOMA-IR (r = 0.62, p = .006) and insulin (r = 0.51, p = .03) were related to the reinforcing value of sugar-sweetened, but not monk fruit-sweetened yogurt (r = −0.07, −0.10, respectively). The blood glucose area under the curve moderated the relationship between HOMA-IR and the reinforcing value of sugar-sweetened yogurt (p = .02). People with greater HOMA-IR and greater blood glucose excursions responded the most for sugar-sweetened yogurt. These results extend previous research and confirm the hypothesis that individual differences in response to sugar may activate brain reward centers and condition people to prefer high-sugar foods. DD was related to sugar reinforcement (r = −0.46, p = .03), consistent with the idea that those with high sugar reinforcement desire immediate gratification, and DD moderated the relationship between HOMA-IR and the reinforcing value of sugar-sweetened yogurt (p < .001). Research should test whether reducing insulin resistance would permit people with insulin resistance to choose lower-sugar foods.

Leveraging behavioral economics and reinforcement theory in treating heavy episodic drinking among college students.

Heavy Episodic drinking and associated serious adverse impacts is a persistent and often tragic problem among emerging adults including college students that calls out for efficacious clinical interventions and innovative mitigation policies (e.g., Hingson et al., 2017; Hultgren et al., 2021). While heavy drinking has multiple determinants, there is broad recognition that the relative reinforcing effects of alcohol acting at brain reward centers play an essential role in promoting and sustaining that behavior pattern (Martinez-Loredo et al., 2021; MacKillop, 2016).

The Appetite Suppressant D-norpseudoephedrine (Cathine) Acts via D1/D2-Like Dopamine Receptors in the Nucleus Accumbens Shell.

D-norpseudoephedrine (NPE), also known as cathine, is found naturally in the shrub Catha edulis “Khat.” NPE has been widely used as an appetite suppressant for the treatment of obesity. Although it is known that NPE acts on α1-adrenergic receptors, there is little information about the role of dopamine receptors on NPE’s induced anorectic and weight loss effects. Equally untouched is the question of how NPE modulates neuronal activity in the nucleus accumbens shell (NAcSh), a brain reward center, and a pharmacological target for many appetite suppressants. To do this, in rats, we characterized the pharmacological effects induced by NPE on weight loss, food intake, and locomotion. We also determined the involvement of dopamine D1- and D2-like receptors using systemic and intra-NAcSh antagonists, and finally, we recorded single-unit activity in the NAcSh in freely moving rats. We found that NPE decreased 24-h food intake, induced weight loss, and as side effects increased locomotor activity and wakefulness. Also, intraperitoneal and intra-NAcSh administration of D1 and D2 dopamine antagonists partially reversed NPE’s induced weight loss and food intake suppression. Furthermore, the D1 antagonist, SCH-23390, eliminated NPE-induced locomotion, whereas the D2 antagonist, raclopride, only delayed its onset. We also found that NPE evoked a net activation imbalance in NAcSh that propelled the population activity trajectories into a dynamic pharmacological brain state, which correlated with the onset of NPE-induced wakefulness. Together, our data demonstrate that NPE modulates NAcSh spiking activity and that both dopamine D1 and D2 receptors are necessary for NPE’s induced food intake suppression and weight loss.

Oxycodone‐induced Gene adaptations in the brain reward center in a murine Model of Neuropathic pain

The long‐term use of opioids for the treatment of chronic pain can lead to physical dependence and transition to addiction. Recent studies from our group revealed that chronic neuropathic pain promotes several adaptations in the brain reward regions (Descalzi et al., Sci. Signaling, 2017). Here, we are using Next Generation RNA sequencing and upstream pathway analysis to gain insight on gene expression adaptations triggered by persistent exposure to oxycodone in the presence and in the absence of pain. To this extent, we employed the spared nerve injury model (SNI) of neuropathic pain in adult C57Bl/6 mice and assessed peripheral neuropathy symptoms for 9 weeks. We then applied an oxycodone misuse paradigm, where mice were treated daily with oxycodone for two weeks, and gene expression was monitored three weeks after oxycodone withdrawal. Mice were also assessed for emotional and pain‐related behaviors during the three‐week drug withdrawal period. Oxycodone treatment‐induced thermal hyperalgesia regardless of pain states, while withdrawal produced significant mechanical allodynia and deficits in social interaction. Using RNA Sequencing, we monitored changes in gene expression in the medial prefrontal cortex, the nucleus accumbens, and the ventral tegmental area. Although oxycodone treatment promotes mostly unique transcriptome profiles across brain regions, we observed similar downstream effectors and transcription factors to be affected in pain states when compared with non‐pain states. Furthermore, our findings suggest that chronic pain states exacerbate the behavioral and transcriptomic signatures of oxycodone withdrawal. Overall this work will provide new insights on the influence of long term pain in oxycodone‐induced plasticity in the brain reward center.Support or Funding Information5T32DA007135‐34, NIDA, R01 NS086444, R56 NS111351 NINDS, and P01 DA008227, NIDA

Transcriptional mechanisms of drug addiction .

Drugs of abuse can modify gene expression in brain reward and motivation centers, which contribute to the structural and functional remodeling of these circuits that impacts the emergence of a state of addiction. Our understanding of how addictive drugs induce transcriptomic plasticity in addiction-relevant brain regions, particularly in the striatum, has increased dramatically in recent years. Intracellular signaling machineries, transcription factors, chromatin modifications, and regulatory noncoding RNAs have all been implicated in the mechanisms through which addictive drugs act in the brain. Here, we briefly summarize some of the molecular mechanisms through which drugs of abuse can exert their transcriptional effects in the brain region, with an emphasis on the role for microRNAs in this process.

Oxycodone‐induced gene expression adaptations in the brain reward center in a murine model of neuropathic pain

Chronic neuropathic pain is a complex condition with complications beyond physical symptoms that include depression, anxiety, and cognitive issues. One in five patients suffering from chronic pain is prescribed an opiate drug such as oxycodone for pain relief. Long‐term use of oxycodone and other opiates for the treatment of chronic pain can lead to physical dependence and addiction. Recent studies from our group revealed that chronic neuropathic pain promotes several adaptations in the brain reward regions responsible for both the sensory and affective components associated with chronic pain (Descalzi et al., 2017, Sci. Signaling). Here, we are using Next Generation RNA‐sequencing to gain insight on the gene expression adaptations triggered by persistent exposure to oxycodone and to determine the impact of neuropathic pain in maladaptive plasticity to oxycodone. We employed the spared nerve injury model (SNI) of neuropathic pain in adult C57Bl/6 mice and assessed peripheral neuropathy symptoms (thermal hyperalgesia, mechanical allodynia) for ~9 weeks. Mice were then treated daily with oxycodone, for two weeks and gene expression was monitored three weeks after oxycodone withdrawal. Oxycodone treatment induced thermal hyperalgesia regardless of pain states, while withdrawal produced significant mechanical allodynia. We next monitored changes in gene expression for three brain regions implicated in the symptoms of chronic neuropathic pain: medial prefrontal cortex (mPFC), nucleus accumbens (NAc) and the ventral tegmental area (VTA). Although oxycodone treatment promotes mostly unique transcriptome profile across brain regions, we observed similar downstream effectors and transcription factors to be affected in pain states when compared with non‐pain states. We are currently validating these genes using transgenic mouse lines to investigate their roles in potentiating oxycodone induced analgesia as well as physical dependence and addiction‐like behaviors. Understanding the gene adaptions in the brain after oxycodone treatment provides novel insight into the cellular machinery involved in maladaptive responses to drugs of abuse in the presence and absence of pain.Support or Funding Information5T32DA007135‐34, NIDA, R01 NS086444‐01, NINDS, and P01 DA008227, NIDAThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The Endogenous Opioid System: Role and Dysfunction Caused by Opioid Therapy.

The endogenous opioid system is comprised of a wide array of receptors and ligands that are present throughout the central and peripheral nervous system, the gastrointestinal tract, and the immune system. This explains the multitude of physiological functions it is responsible for including analgesia, mood regulation, and modulation of the stress response. It also plays a pivotal role in modulating the brain's reward center with behavioral and social implications on mood disorders and addiction. Exogenous opioid therapy hijacks the endogenous system and alters its functions contributing to an imbalance that is responsible for the pathogenesis of several disease states.

Teenagers and Cannabis Use: Why It's a Problem and What Can Be Done About It.

Teenagers' use of cannabis is a significant problem due to the known detrimental effects it has on the developing brain. Cannabis use in the teenage years is associated with a disruption to the brain's reward system, impaired memory and cognition, and the potential for structural brain changes. Smoking cannabis can have a negative impact on the pulmonary system because it is a respiratory irritant. Teenagers are increasingly using electronic cigarettes, or vaping, to administer cannabis, which delivers a higher concentration of its psychoactive properties. Teenagers are not recognizing the health or other risks of using cannabis, such as motor vehicle accidents. All teenagers should be screened for cannabis use, and education about cannabis use should be age-specific and start in elementary education and continue through high school. Nurses are in a prime position to provide up-to-date, evidence-based education to teenagers, parents, and other health care professionals about teenagers' use of cannabis. Additional measures that can affect cannabis use in teenagers are screening for other underlying mental health disorders; improving quality of life, self-efficacy, and spirituality; and providing teenagers with opportunities to naturally stimulate the brain's reward center. [Journal of Psychosocial Nursing and Mental Health Services, 57(3), 11-15.].

The cerebellum and reward-driven behavior

Neuroscience Damage to the cerebellum manifests itself in various forms of cognitive impairment and abnormal social behavior. However, the exact role the cerebellum plays in these conditions is far from clear. Working in mice, Carta et al. found direct projections from the deep cerebellar nuclei to the brain's reward center, a region called the ventral tegmental area (see the Perspective by D'Angelo). These direct projections allowed the cerebellum to play a role in showing a social preference. Intriguingly, this pathway was not prosocial on its own. Cerebellar inputs into the ventral tegmental area were more active during social exploration. Depolarization of ventral tegmental area neurons thus represents a similar reward stimulus as social interaction for mice. Science , this issue p. [eaav0581][1]; see also p. [229][2] [1]: /lookup/doi/10.1126/science.aav0581 [2]: /lookup/doi/10.1126/science.aaw2571

Cerebellar modulation of the reward circuitry and social behavior.

The cerebellum has been implicated in a number of nonmotor mental disorders such as autism spectrum disorder, schizophrenia, and addiction. However, its contribution to these disorders is not well understood. In mice, we found that the cerebellum sends direct excitatory projections to the ventral tegmental area (VTA), one of the brain regions that processes and encodes reward. Optogenetic activation of the cerebello-VTA projections was rewarding and, in a three-chamber social task, these projections were more active when the animal explored the social chamber. Intriguingly, activity in the cerebello-VTA pathway was required for the mice to show social preference in this task. Our data delineate a major, previously unappreciated role for the cerebellum in controlling the reward circuitry and social behavior.

A Novel Spatiotemporal Longitudinal Methodology for Predicting Obesity Using Near Infrared Spectroscopy (NIRS) Cerebral Functional Activity Data

Globally, there has been a dramatic increase in obesity, with prevalence in males and females expected to increase to 18 and 21%, respectively (NCD Risk Factor Collaboration, Lancet 387(10026):1377–96, 2016). However, there are hardly any data-analytic calorie-based cognitive studies, especially using non-invasive near infrared spectroscopy (NIRS) data that predict obesity using predictive data mining. Obesity is linked with neurodegenerative diseases, diabetes, and cardiovascular diseases. Thus, understanding, predicting, preventing, and managing obesity have the potential to save the lives of millions. Behavioral studies suggest that overeating in obese individuals is triggered by exaggerated brain reward center (BRC) activity to high-calorie food stimuli (Shefer et al., Neurosci Biobehav Rev 37(10):2489–503, 2013). In this paper, details of a novel research methodology are presented for a 24-month longitudinal study using a 44-channel NIRS device with the subjects in a natural environment. The proposed methodology consists of using visual stimuli of low/high calorie food items under fasting and satiated conditions for three types of subjects. The experiments consist of block design, longitudinal plan, data smoothing, BRC activation mapping, stereotactic normalization, generating paired t-test maps under fasting and non-fasting conditions and subsequently using Naive Bayes modeling to generate obesity prediction maps for the control subjects. The simulated results consist of generation of Bayesian prediction maps using layers of paired t-test cerebral activity maps for the four BRC functional regions considered for three types of subjects, i.e., obese, control, and control subjects fed high calorie diet. We have demonstrated how cerebral functional activity data in response to visual food stimuli can be used to predict obesity in the non-obese, thus offering a non-invasive preventive measure.

Effects of alkaloid-rich extract from Mitragyna speciosa (Korth.) Havil. on naloxone-precipitated morphine withdrawal symptoms and local field potential in the nucleus accumbens of mice

Ethnopharmacological relevanceMitragyna speciosa (Korth.) Havil. (M. speciosa) is among the most well-known plants used in ethnic practice of Southeast Asia. It has gained increasing attention as a plant with potential to substitute morphine in addiction treatment program. However, its action on the central nervous system is controversial. Aim of the studyThis study investigated the effects of M. speciosa alkaloid extract on naloxone-precipitated morphine withdrawal and neural signaling in the nucleus accumbens (NAc, brain reward center) of mice. Materials and methodsThe effects of M. speciosa alkaloid extract and mitragynine, a pure major constituent, on naloxone-precipitated morphine withdrawal were examined. Male Swiss Albino (ICR) mice were rendered dependent on morphine before injection with naloxone, a nonspecific opioid antagonist, to induce morphine withdrawal symptoms. The intensity of naloxone-precipitated morphine withdrawal was assessed from jumping behavior and diarrhea induced during a period of morphine withdrawal. To test possible addictive effect of M. speciosa alkaloid extract, mice were implanted with intracranial electrode into the NAc for local field potential (LFP) recording. Following M. speciosa alkaloid extract (80mg/kg) and morphine (15mg/kg) treatment, LFP power spectra and spontaneous motor activity were analyzed in comparison to control levels. ResultsOne-way ANOVA and multiple comparisons revealed that M. speciosa alkaloid extract (80 and 100mg/kg) significantly decreased the number of jumping behavior induced by morphine withdrawal whereas mitragynine did not. Additionally, M. speciosa alkaloid extract significantly decreased dry and wet fecal excretions induced by morphine withdrawal. LFP analysis revealed that morphine significantly decreased alpha (9.7–12Hz) and increased low gamma (30.3–44.9Hz) and high gamma (60.5–95.7Hz) powers in the NAc whereas M. speciosa alkaloid extract did not. Spontaneous motor activity was significantly increased by morphine but not M. speciosa alkaloid extract. ConclusionsTaken together, M. speciosa alkaloid extract, but not mitragynine, attenuated the severity of naloxone-precipitated morphine withdrawal symptoms. Neural signaling in the NAc and spontaneous motor activity were sensitive to morphine but not M. speciosa alkaloid extract. Therefore, treatment with the M. speciosa alkaloid extract may be useful for opiate addiction treatment program.

Effects of Acute Aerobic Exercise and Protein Intake on Appetite and the Neural Response to Visual Food Cues

Functional magnetic resonance imaging (fMRI) studies reveal altered food cue processing in brain reward centers [e.g. insula (INS), amygdala (AMY), orbitofrontal cortex (OFC), caudate (CAU), putamen (PUT)] of obese vs. normal weight individuals. We assessed the effects of acute aerobic exercise (Ex) and protein intake [normal (NP) or high (HP)] on appetite and the neural response to visual food cues (NRVFC) in 7 women (BMI 35.5 ± 1.0 kg/m2, 29 ± 3 y). All meals for 24h were provided, dinner was NP or HP (15 vs. 30% of energy), and subjects rested (R) or Ex for 30min before dinner, resulting in 4 testing days (NPR, NPEx, HPR, HPEx) with 4 fMRI per day (pre, 1, 2.5, and 4h after dinner). Regions of interest were defined by activation clusters (threshold p< 0.001) from the first fMRI scan and where activation peaks fell within left/right INS, AMY, OFC, CAU, and PUT. Appetite was assessed before and after fMRI, Ex/R, and dinner. Hunger and desire to eat decreased and fullness increased at all postprandial time points vs. pre-dinner with no difference among testing days. NRVFC was not different among time points or testing days. Data from this pilot study do not support an effect of acute exercise and protein intake on neural food cue processing in obese women, but interpretations should be made with caution due to the small sample size. Support: NIH UL1 TR001108, USDA 2011-38420-20038

Long-Term Reduction of Cocaine Self-Administration in Rats Treated with Adenoviral Vector-Delivered Cocaine Hydrolase: Evidence for Enzymatic Activity

A new pharmacokinetic approach treating cocaine addiction involves rapidly metabolizing cocaine before it reaches brain reward centers using mutated human butyrylcholinesterase (BChE) or cocaine hydrolase (CocH). Recent work has shown that helper-dependent adenoviral (hdAD) vector-mediated plasma CocH reduced the locomotor-activating effects of cocaine and prevented reinstatement of cocaine-seeking behavior up to 6 months in rats. The present study investigated whether hdAD-CocH could decrease ongoing intravenous cocaine (0.4 mg/kg) self-administration. The hdAD-CocH vector was injected into self-administering rats, and after accumulation of plasma CocH, there was a dramatic reduction in cocaine infusions earned under a fixed ratio 1 schedule of reinforcement that lasted for the length of the study (>2 months). Pretreatment with the selective BChE and CocH inhibitor iso-OMPA (1.5 mg/kg) restored cocaine intake; therefore, the decline in self-administration was likely due to rapid CocH-mediated cocaine metabolism. Direct measurements of cocaine levels in plasma and brain samples taken after the conclusion of behavioral studies provided strong support for this conclusion. Further, rats injected with hdAD-CocH did not experience a deficit in operant responding for drug reinforcement and self-administered methamphetamine (0.05 mg/kg) at control levels. Overall, these outcomes suggest that viral gene transfer can yield plasma CocH levels that effectively diminish long-term cocaine intake and may have potential treatment implications for cocaine-dependent individuals seeking to become and remain abstinent.

Oxytocin enhances attractiveness of unfamiliar female faces independent of the dopamine reward system

Evidence from animal studies suggests that the social attraction and bonding effects of the neuropeptide oxytocin (OXT) are mediated by its modulation of dopamine (DA) release in brain reward centers, but this has not yet been demonstrated in humans. DA release can be measured by positron emission tomography (PET) using the radioligand [11C]raclopride. Its binding to DA D2 receptors (D2R) is sensitive and reciprocally related to endogenous DA, especially in the striatum. In a randomized double-blind placebo-controlled within-subjects trial on 18 adult male volunteers we combined [11C]raclopride PET and a facial attractiveness rating task to establish whether intranasal OXT (24 IU) increased both the perceived attractiveness of unfamiliar female faces and striatal DA release compared with placebo administration. While our behavioral data confirmed that subjects rated unfamiliar female faces as more attractive following OXT treatment, and this correlated with an increased perfusion rate in the striatum, there was no evidence for altered [11C]raclopride binding in the striatum or pallidum. Instead under OXT we rather observed an increased [11C]raclopride binding and reduced perfusion rate in subregions of the right dorsomedial prefrontal gyrus and superior parietal gyrus. The absence of OXT effects on dopamine release and D2 receptors in brain reward centers, despite increased striatal activity, implies that the peptide may facilitate perceived attraction via non-dopaminergic actions.

Sleep restriction increases the neuronal response to unhealthy food in normal-weight individuals

Sleep restriction alters responses to food. However, the underlying neural mechanisms for this effect are not well understood. The purpose of this study was to determine whether there is a neural system that is preferentially activated in response to unhealthy compared with healthy foods. Twenty-five normal-weight individuals, who normally slept 7-9 h per night, completed both phases of this randomized controlled study. Each participant was tested after a period of five nights of either 4 or 9 h in bed. Functional magnetic resonance imaging (fMRI) was performed in the fasted state, presenting healthy and unhealthy food stimuli and objects in a block design. Neuronal responses to unhealthy, relative to healthy food stimuli after each sleep period were assessed and compared. After a period of restricted sleep, viewing unhealthy foods led to greater activation in the superior and middle temporal gyri, middle and superior frontal gyri, left inferior parietal lobule, orbitofrontal cortex, and right insula compared with healthy foods. These same stimuli presented after a period of habitual sleep did not produce marked activity patterns specific to unhealthy foods. Further, food intake during restricted sleep increased in association with a relative decrease in brain oxygenation level-dependent (BOLD) activity observed in the right insula. This inverse relationship between insula activity and food intake and enhanced activation in brain reward and food-sensitive centers in response to unhealthy foods provides a model of neuronal mechanisms relating short sleep duration to obesity.

Auditory Training: Evidence for Neural Plasticity in Older Adults.

Improvements in digital amplification, cochlear implants, and other innovations have extended the potential for improving hearing function; yet, there remains a need for further hearing improvement in challenging listening situations, such as when trying to understand speech in noise or when listening to music. Here, we review evidence from animal and human models of plasticity in the brain's ability to process speech and other meaningful stimuli. We considered studies targeting populations of younger through older adults, emphasizing studies that have employed randomized controlled designs and have made connections between neural and behavioral changes. Overall results indicate that the brain remains malleable through older adulthood, provided that treatment algorithms have been modified to allow for changes in learning with age. Improvements in speech-in-noise perception and cognition function accompany neural changes in auditory processing. The training-related improvements noted across studies support the need to consider auditory training strategies in the management of individuals who express concerns about hearing in difficult listening situations. Given evidence from studies engaging the brain's reward centers, future research should consider how these centers can be naturally activated during training.

Control of protein and energy intake - brain mechanisms

The protein content of the diet has long been investigated for its influence on food behavior. High-protein diets promote satiety and reduce calorie intake, whereas results for low-protein diets are more contradictory and less established. Protein sensing might take place in the oral cavity or in the post-oral gastrointestinal tract, where specific receptors have been found. Protein signaling to the brain may act through the vagal nerve and involve gastric hormones, such as cholecystokinin and peptide YY. Other pathways are post-absorptive signaling and the direct influence of brain levels of amino acids. High-protein diet enhances the activity of brain satiety centers, mainly the nucleus of the solitary tract and arcuate nucleus, although the activity of brain reward centers might also be modified. A better understanding of the role of both homeostatic and hedonic systems is needed to fully describe the influence of protein on food intake.

Losing the Lust for Life: A New Role for an Old Feeding Peptide?

A recent paper in Nature (Lim etal., 2012) describes the effects of melanocortin receptors in the nucleus accumbens. The studies connect a hypothalamic peptide system with brain reward centers and show effects on specific neuronal populations and behavioral components of mood.