Reward-seeking Behavior Research Articles

Sex-Specific Impacts of Early Life Sleep Disruption: Ethanol Seeking, Social Interaction, and Anxiety Are Differentially Altered in Adolescent Prairie Voles.

Early life sleep is important for neuronal development. Using the highly social prairie vole rodent model, we have previously reported that early life sleep disruption (ELSD) during the preweaning period results in interference with social bonding and increases ethanol consumption following a stressor in adulthood. Furthermore, ELSD increases parvalbumin expression and reduces glutamatergic neurotransmission in cortical regions in adult prairie voles. To understand the impact of ELSD on the lifespan, an examination of an earlier time in life is necessary. The aim of the present study was to examine behavioral outcomes of ELSD on adolescent prairie voles. Given the known effects of ELSD on development of neuronal systems involved in mood and social motivation, we hypothesized that anxiety, risk, and reward-related behaviors would be impacted by ELSD in adolescent prairie voles. We report that both male and female adolescent prairie voles that experienced ELSD showed heightened anxiety-like behavior compared to age-matched controls (CONs) as measured by a light-dark box. Additionally, both male and female ELSD voles showed reductions in both ethanol preference and consumption, and affiliative behavior compared to CONs. These results suggest that adolescent prairie voles of both sexes experience heightened anxiety-like behavior and reduced reward-seeking behaviors after ELSD. These results further suggest that early life sleep is critically important for neurotypical behaviors in adolescence.

Temporal dynamics of nucleus accumbens neurons in male mice during reward seeking

The nucleus accumbens (NAc) regulates reward-motivated behavior, but the temporal dynamics of NAc neurons that enable “free-willed” animals to obtain rewards remain elusive. Here, we recorded Ca2+ activity from individual NAc neurons when mice performed self-paced lever-presses for sucrose. NAc neurons exhibited three temporally-sequenced clusters, defined by times at which they exhibited increased Ca2+ activity: approximately 0, −2.5 or −5 sec relative to the lever-pressing. Dopamine D1 receptor (D1)-expressing neurons and D2-neurons formed the majority of the −5-sec versus −2.5-sec clusters, respectively, while both neuronal subtypes were represented in the 0-sec cluster. We found that pre-press activity patterns of D1- or D2-neurons could predict subsequent lever-presses. Inhibiting D1-neurons at −5 sec or D2-neurons at −2.5 sec, but not at other timepoints, reduced sucrose-motivated lever-pressing. We propose that the time-specific activity of D1- and D2-neurons mediate key temporal features of the NAc through which reward motivation initiates reward-seeking behavior.

Resting-state brain activation patterns and network topology distinguish human sign and goal trackers

The “Sign-tracker/Goal-tracker” (ST/GT) is an animal model of individual differences in learning and motivational processes attributable to distinctive conditioned responses to environmental cues. While GT rats value the reward-predictive cue as a mere predictor, ST rats attribute it with incentive salience, engaging in aberrant reward-seeking behaviors that mirror those of impulse control disorders. Given its potential clinical value, the present study aimed to map such model onto humans and investigated resting state functional magnetic resonance imaging correlates of individuals categorized as more disposed to sign-tracking or goal-tracking behavior. To do so, eye-tracking was used during a translationally informed Pavlovian paradigm to classify humans as STs (n = 36) GTs (n = 35) or as Intermediates (n = 33), depending on their eye-gaze towards the reward-predictive cue or the reward location. Using connectivity and network-based approach, measures of resting state functional connectivity and centrality (role of a node as a hub) replicated preclinical findings, suggesting a major involvement of subcortical areas in STs, and dominant cortical involvement in GTs. Overall, the study strengthens the translational value of the ST/GT model, with important implications for the early identification of vulnerable phenotypes for psychopathological conditions such as substance use disorder.

Behavioral changes and transcriptional regulation of mesolimbic dopaminergic genes in a mouse model of binge eating disorder by diet intermittent access.

Binge Eating Disorder (BED) is among the most prevalent eating disorders worldwide. It is characterized by recurrent episodes of excessive consumption of palatable foods in short periods, accompanied by a sense of loss of control and distress around the episode, which tends to worsen over time. The mesolimbic dopaminergic system influences on reinforcement and reward-seeking behaviors is implicated in the disorder's pathogenesis. Animal models that replicate the clinical conditions observed in humans, including the disorder progression, are essential for understanding the underlying physiological mechanisms of BED. This study aimed to evaluate binge eating behavior induced by intermittent High Sugar and Butter (HSB) diet access in mice, their phenotypes, transcriptional regulation of mesolimbic dopaminergic system genes, and behavior. Thus, mice were subdivided into three groups: CHOW (maintenance diet only), HSB-i (maintenance diet with thrice-weekly access to HSB), and HSB (continuous access to HSB). Animals were subjected to marble-burying and light-dark box behavioral tests, and transcriptional regulation was evaluated by RT-qPCR. The results indicated that the HSB-i group established a feeding pattern of significantly more kilocalories on days when HSB was available and reduced intake on non-HSB days similar to human binge eating. Over time, binge episodes intensified, potentially indicating a tolerance effect. Additionally, these animals behave differently towards preferring the HSB diet and exhibited altered transcriptional regulation of the Drd1, Slc6a3, and Lrrk2 genes. Our study provides a mouse model that reflects human BED, showing a progression in binge episodes and mesolimbic dopamine pathway involvement, suggesting targets for future therapeutic interventions.

Olfactory dysfunction decreased local field potential in the reward system and increased EtOH consumption in mice

The relationship between olfactory dysfunction and alcohol intake is unobvious. Chronic alcohol intake results in reduced olfactory acuity and olfactory discrimination and addiction in humans. However, alcohol is a beverage with distinctive odors, which usually works as a cue to induce addictive memories and craving behavior. Whether olfactory impairment increase or decrease alcohol consumption remains an important but unclear issue. In this study, we measured ethanol (EtOH) consumption in the two-bottle choice EtOH drinking test, two bottle choice EtOH/sucrose drinking test and the drinking in the dark (DID) test during the olfactory loss. We also recorded local field potentials (LFPs) from the brain reward system, the ventral tegmental area (VTA), nucleus accumbens (NAc), and piriform cortex (Pir) one and four weeks after the induction of olfactory epithelium lesions using zinc sulfate (ZnSO4) in mice. The results showed that the EtOH consumption and preference were increased during the period of olfactory dysfunction. 1 week after the olfactory injury, LFP powers in the reward system at low- and high-gamma bands decreased significantly, coherence between the Pir and the reward system was also decrease. 4 weeks after the ZnSO4 treatment, LFP powers were reversed, but the coherence between VTA and NAc was decreased, indicating lasting effects post-recovery. This study demonstrates that olfactory dysfunction increased EtOH consumption in mice, which was accompanied by decreased LFP power and coherence in the reward system, which suggest that olfactory deficits changed activities in the reward system and could alter reward-seeking behaviors, which provide insights into the neurobiology of alcohol addiction.

Orbitofrontal Cortex Mediates Sustained Basolateral Amygdala Encoding of Cued Reward-Seeking States.

Basolateral amygdala (BLA) neurons are engaged by emotionally salient stimuli. An area of increasing interest is how BLA dynamics relate to evolving reward-seeking behavior, especially under situations of uncertainty or ambiguity. Here, we recorded the activity of individual BLA neurons in male rats across the acquisition and extinction of conditioned reward seeking. We assessed ongoing neural dynamics in a task where long reward cue presentations preceded an unpredictable, variably time reward delivery. We found that, with training, BLA neurons discriminated the CS+ and CS- cues with sustained cue-evoked activity that correlated with behavior and terminated only after reward receipt. BLA neurons were bidirectionally modulated, with a majority showing prolonged inhibition during cued reward seeking. Strikingly, population-level analyses revealed that neurons showing cue-evoked inhibitions and those showing excitations similarly represented the CS+ and behavioral state. This sustained population code rapidly extinguished in parallel with conditioned behavior. We next assessed the contribution of the orbitofrontal cortex (OFC), a major reciprocal partner to the BLA. Inactivation of the OFC while simultaneously recording in the BLA revealed a blunting of sustained cue-evoked activity in the BLA that accompanied reduced reward seeking. Optogenetic disruption of BLA activity and OFC terminals in the BLA also reduced reward seeking. Our data indicate that the BLA represents reward-seeking states via sustained, bidirectional cue-driven neural encoding. This code is regulated by cortical input and is important for the maintenance of vigilant reward-seeking behavior.

Effects of expressive writing and self-distancing on electrodermal activity during writing

Writing about traumas can influence mood and bodily changes. In three studies we researched the influence of writing on affective and physiological changes by measuring electrodermal activity (EDA) during expressive writing sessions and manipulating self-distancing. In Study 1, we randomly assigned 57 participants to write about control or expressive topics using a first-person perspective (I). In Study 2, we assigned 55 participants to write about control or expressive topics using a third-person perspective (She/He). And in Study 3, we compared the effects of perspective (first or third-person) in the data collected in the preceding studies. Across Study 1 and 2 results showed that EDA consistently rose at the beginning of the writing session, reached a plateau, and then rose again upon completing the writing task, irrespective of the writing topic or perspective. While the initial EDA increase seems related to the start of a demanding task, the post-writing increase might signal reward-seeking behavior upon task completion. Results of Study 3 confirmed that EDA increases in the beginning and upon writing completion are magnified by adopting a third-person perspective. These results show that expressive writing and self-distancing have measurable impacts on writers’ electrodermal activity.

The neural circuit of Superior colliculus to ventral tegmental area modulates visual cue associated with rewarding behavior in optical intracranial Self-Stimulation in mice

Visual system is the most important system of animal to cognize the information in outside world, and reward-related visual cues are the key factors in the consolidation and retrieval of reward memory. However, the neural circuit mechanism is still unclear. Superior Colliculus (SC) receive direct input from the retina and belong to the earliest stages of visual processing. Recent studies identified a specific pathway from SC to ventral tegmental area (VTA) that underlie specific innate behaviors, eg. flight or freezing, approach behaviors and so on. In present research, we investigated that inhibition of SC to VTA circuit with chemogenetics suppressed light cue-associated reward-seeking behaviors, while activation of the SC-VTA circuit with chemogenetic technology triggered the reward-seeking behaviors in optical intracranial self-stimulation for VTA DA neurons (oICSS) in mice. These findings suggest that neural circuit of SC-VTA mediates the retrieval of reward memory associated with visual cues, which will provide a new field for revealing the neural mechanism of pathological memory such as addiction.

Divergent reward cue representations in prefrontal cortex underlie differences in reward motivation between adolescents and adults.

A prevailing view on postnatal brain development is that brain regions gradually acquire adult functions as they mature. The medial prefrontal cortex (mPFC) regulates reward learning, motivation, and behavioral inhibition, and undergoes a protracted postnatal maturation. During adolescence, reward-seeking behavior is heightened compared to adulthood - a developmental difference that may be driven by a hypoactive mPFC, with decreased top-down control of impulsive reward-seeking. However, this hypothesis has been difficult to test directly, due in part to technical challenges of recording neuronal activity in vivo across this developmental period. Here, using a novel 2-photon imaging-compatible platform for recording mPFC activity during an operant reward conditioning task beginning early in life, we show that the adolescent mPFC is hyper-responsive to reward cues. Distinct populations of mPFC neurons encode reward-predictive cues across development, but representations of no-reward cues and unrewarded outcomes are relatively muted in adolescence. Chemogenetic inhibition of GABAergic neurons decreased motivation in adolescence but not in adulthood. Together, our findings indicate that reward-related activity in the adolescent mPFC does not gradually increase across development. On the contrary, adolescent mPFC neurons are hyper-responsive to reward-related stimuli and encode reward-predictive cues and outcomes through qualitatively different mechanisms relative to the adult mPFC, opening avenues to developing distinct, developmentally informed strategies for modulating reward-seeking behavior in adolescence and adulthood.

Sex differences in neural representations of social and nonsocial reward in the medial prefrontal cortex

The reinforcing nature of social interactions is necessary for the maintenance of appropriate social behavior. However, the neural substrates underlying social reward processing and how they might differ based on the sex and internal state of the animal remains unknown. It is also unclear whether these neural substrates are shared with those involved in nonsocial rewarding processing. We developed a fully automated, two choice (social-sucrose) operant assay in which mice choose between social and nonsocial rewards to directly compare the reward-related behaviors associated with two competing stimuli. We performed cellular resolution calcium imaging of medial prefrontal cortex (mPFC) neurons in male and female mice across varying states of water restriction and social isolation. We found that mPFC neurons maintain largely non-overlapping, flexible representations of social and nonsocial reward that vary with internal state in a sex-dependent manner. Additionally, optogenetic manipulation of mPFC activity during the reward period of the assay disrupted reward-seeking behavior across male and female mice. Thus, using a two choice operant assay, we have identified sex-dependent, non-overlapping neural representations of social and nonsocial reward in the mPFC that vary with internal state and that are essential for appropriate reward-seeking behavior.

LY-2183240 enhances reward-seeking behavior with inducing neuronal excitation and early apoptosis in mouse

LY-2183240 enhances reward-seeking behavior with inducing neuronal excitation and early apoptosis in mouse

Anhedonia is associated with higher functional connectivity between the nucleus accumbens and paraventricular nucleus of thalamus

BackgroundAnhedonia stands as a life-threatening transdiagnostic feature of many mental illnesses, most notably major depression and involves neural circuits for processing reward information. The paraventricular nucleus of the thalamus (PVT) is associated with reward-seeking behavior, however, links between the PVT circuit and anhedonia have not been investigated in humans. MethodsIn a sample of adults with and without psychiatric symptoms (n = 75, 18–41 years, 55 female), we generated an anhedonia factor score for each participant using a latent factor analysis, utilizing data from depression and anxiety assessments. Functional connectivity between the PVT and the nucleus accumbens (NAc) was calculated from high-resolution (1.5 mm) resting state fMRI. ResultsAnhedonia factor scores showed a positive relationship with functional connectivity between the PVT and the NAc, principally in males and in those with psychiatric symptoms. In males, connectivity between other midline thalamic nuclei and the NAc did not show these relationships, suggesting that this link may be specific to PVT. LimitationsThis cohort was originally recruited to study depression and not anhedonia per se. The distribution of male and female participants in our cohort was not equal. Partial acquisition in high-resolution fMRI scans restricted regions of interest outside of the thalamus and reward networks. ConclusionsWe report evidence that anhedonia is associated with enhanced functional connectivity between the PVT and the NAc, regions that are relevant to reward processing. These results offer clues as to the potential prevention and prevention and treatment of anhedonia.

Dynorphin modulates motivation through a pallido-amygdala cholinergic circuit.

The endogenous opioid peptide dynorphin and its receptor κ-opioid receptor (KOR) have been implicated in divergent behaviors, but the underlying mechanisms remain elusive. Here we show that dynorphin released from nucleus accumbens dynorphinergic neurons exerts powerful modulation over a ventral pallidum (VP) disinhibitory circuit, thereby controlling cholinergic transmission to the amygdala and motivational drive in mice. On one hand, dynorphin acts postsynaptically via KORs on local GABAergic neurons in the VP to promote disinhibition of cholinergic neurons, which release acetylcholine into the amygdala to invigorate reward-seeking behaviors. On the other hand, dynorphin also acts presynaptically via KORs on dynorphinergic terminals to limit its own release. Such autoinhibition keeps cholinergic neurons from prolonged activation and release of acetylcholine, and prevents perseverant reward seeking. Our study reveals how dynorphin exquisitely modulate motivation through cholinergic system, and provides an explanation for why these neuromodulators are involved in motivational disorders, including depression and addiction.

Late Positive Potential Elicited by Monetary Reward Feedback Predicts Changes of Disordered Eating From Age 11 to Age 12 in Community-Dwelling Girls.

Early adolescence is marked by elevated psychopathology, including disrupted eating attitudes and behaviors. Reward processing is an identified mechanism in portending eating pathology, that is, aberrant reward responsivity may contribute to disrupted reward-seeking behaviors (e.g., food consuming). This literature has focused on adults or mid-to-late adolescents, with little work done on early adolescence. We examined the linkages between reward feedback processing, indexed by event-related potentials (ERPs), and changes of emerging disordered eating in community-dwelling early adolescents. At T1, 115 youths (66 girls, mean/SD age = 11.00/1.16 years) completed an EEG monetary reward Doors task. Youths completed the Eating Disorder Examination-Questionnaire Short at T1 and ~6 months (T2) and ~12 months (T3) after T1. In the ERP data, we isolated a reward positivity (RewP) and a late positive potential (LPP) via principal component analysis. We applied multilevel modeling to examine whether baseline ERPs interacted with Time in predicting disordered eating and whether these interactions varied by sex. We found a significant Time × LPP interaction in girls but not boys. Among girls, only those with a smaller LPP toward the losses (versus wins), which might reflect suboptimal evaluation and regulatory processes in undesired situations, showed increases in disordered eating from T1 to T3. We provided preliminary yet novel evidence concerning the prospective associations between reward processing and changes of disordered eating in early adolescents. Future studies along this line will be critical for understanding the early mechanisms of eating pathology, identifying youths at risk, and developing prevention strategies.

Genes associated with cortical thickness alterations in behavioral addiction.

Behavioral addiction (BA) is a conceptually new addictive phenotype characterized by compulsive reward-seeking behaviors despite adverse consequences. Currently, its underlying neurogenetic mechanism remains unclear. Here, this study aimed to investigate the association between cortical thickness (CTh) and genetic phenotypes in BA. We conducted a systematic search in five databases and extracted gene expression data from the Allen Human Brain Atlas. Meta-analysis of 10 studies (343 addicted individuals and 355 controls) revealed that the BA group showed thinner CTh in the precuneus, postcentral gyrus, orbital-frontal cortex, and dorsolateral prefrontal cortex (P < 0.005). Meta-regression showed that the CTh in the precuneus and postcentral gyrus were negatively associated with the addiction severity (P < 0.0005). More importantly, the CTh phenotype of BA was spatially correlated with the expression of 12 genes (false discovery rate [FDR] < 0.05), and the dopamine D2 receptor had the highest correlation (rho = 0.55). Gene enrichment analysis further revealed that the 12 genes were involved in the biological processes of behavior regulation and response to stimulus (FDR < 0.05). In conclusion, our findings demonstrated the thinner CTh in cognitive control-related brain areas in BA, which could be associated with the expression of genes involving dopamine metabolism and behavior regulation.

Pivotal role of orexin signaling in the posterior paraventricular nucleus of the thalamus during the stress-induced reinstatement of oxycodone-seeking behavior.

The orexin (OX) system has received increasing interest as a potential target for treating substance use disorder. OX transmission in the posterior paraventricular nucleus of the thalamus (pPVT), an area activated by highly salient stimuli that are both reinforcing and aversive, mediates cue- and stress-induced reinstatement of reward-seeking behavior. Oral administration of suvorexant (SUV), a dual OX receptor (OXR) antagonist (DORA), selectively reduced conditioned reinstatement of oxycodone-seeking behavior and stress-induced reinstatement of alcohol-seeking behavior in dependent rats. This study tested whether OXR blockade in the pPVT with SUV reduces oxycodone or sweetened condensed milk (SCM) seeking elicited by conditioned cues or stress. Male Wistar rats were trained to self-administer oxycodone (0.15 mg/kg, i.v., 8 h/day) or SCM (0.1 ml, 2:1 dilution [v/v], 30 min/day). After extinction, we tested the ability of intra-pPVT SUV (15 µg/0.5 µl) to prevent reinstatement of oxycodone or SCM seeking elicited by conditioned cues or footshock stress. The rats acquired oxycodone and SCM self-administration, and oxycodone intake correlated with signs of physical opioid withdrawal, confirming dependence. Following extinction, the presentation of conditioned cues or footshock elicited reinstatement of oxycodone- and SCM-seeking behavior. Intra-pPVT SUV blocked stress-induced reinstatement of oxycodone seeking but not conditioned reinstatement of oxycodone or SCM seeking or stress-induced reinstatement of SCM seeking. The results indicate that OXR signaling in the pPVT is critical for stress-induced reinstatement of oxycodone seeking, further corroborating OXRs as treatment targets for opioid use disorder.

Medial prefrontal cortex suppresses reward-seeking behavior with risk of punishment by reducing sensitivity to reward.

Reward-seeking behavior is frequently associated with risk of punishment. There are two types of punishment: positive punishment, which is defined as addition of an aversive stimulus, and negative punishment, involves the omission of a rewarding outcome. Although the medial prefrontal cortex (mPFC) is important in avoiding punishment, whether it is important for avoiding both positive and negative punishment and how it contributes to such avoidance are not clear. In this study, we trained male mice to perform decision-making tasks under the risks of positive (air-puff stimulus) and negative (reward omission) punishment, and modeled their behavior with reinforcement learning. Following the training, we pharmacologically inhibited the mPFC. We found that pharmacological inactivation of mPFC enhanced the reward-seeking choice under the risk of positive, but not negative, punishment. In reinforcement learning models, this behavioral change was well-explained as an increase in sensitivity to reward, rather than a decrease in the strength of aversion to punishment. Our results suggest that mPFC suppresses reward-seeking behavior by reducing sensitivity to reward under the risk of positive punishment.

Differential effects of acute and prolonged morphine withdrawal on motivational and goal-directed control over reward-seeking behaviour.

Opioid addiction is a relapsing disorder marked by uncontrolled drug use and reduced interest in normally rewarding activities. The current study investigated the impact of spontaneous withdrawal from chronic morphine exposure on emotional, motivational and cognitive processes involved in regulating the pursuit and consumption of food rewards in male rats. In Experiment 1, rats experiencing acute morphine withdrawal lost weight and displayed somatic signs of drug dependence. However, hedonically driven sucrose consumption was significantly elevated, suggesting intact and potentially heightened reward processing. In Experiment 2, rats undergoing acute morphine withdrawal displayed reduced motivation when performing an effortful response for palatable food reward. Subsequent reward devaluation testing revealed that acute withdrawal disrupted their ability to exert flexible goal-directed control over reward seeking. Specifically, morphine-withdrawn rats were impaired in using current reward value to select actions both when relying on prior action-outcome learning and when given direct feedback about the consequences of their actions. In Experiment 3, rats tested after prolonged morphine withdrawal displayed heightened rather than diminished motivation for food rewards and retained their ability to engage in flexible goal-directed action selection. However, brief re-exposure to morphine was sufficient to impair motivation and disrupt goal-directed action selection, though in this case, rats were only impaired in using reward value to select actions in the presence of morphine-paired context cues and in the absence of response-contingent feedback. We suggest that these opioid-withdrawal induced deficits in motivation and goal-directed control may contribute to addiction by interfering with the pursuit of adaptive alternatives to drug use.

NMDA receptor within nucleus accumbens shell regulates propofol self-administration through D1R/ERK/CREB signalling pathway.

Addictive properties of propofol have been demonstrated in both humans and animals. The nucleus accumbens (NAc) shell (NAsh) in the brain, along with the interactions between N-methyl-D-aspartate receptor (NMDAR) and the dopamine D1 receptor (D1R), as well as their downstream ERK/CREB signalling pathway in the NAc, are integral in regulating reward-seeking behaviour. Nevertheless, it remains unclear whether NMDARs and the NMDAR-D1R/ERK/CREB signalling pathway in the NAsh are involved in mediating propofol addiction. To investigate it, we conducted experiments with adult male Sprague-Dawley rats to establish a model of propofol self-administration behaviour. Subsequently, we microinjected D-AP5 (a competitive antagonist of NMDARs, 1.0-4.0μg/0.3μL/site) or vehicle into bilateral NAsh in rats that had previously self-administered propofol to examine the impact of NMDARs within the NAsh on propofol self-administration behaviour. Additionally, we examined the protein expressions of NR2A and NR2B subunits, and the D1R/ERK/CREB signalling pathways within the NAc. The results revealed that propofol administration behaviour was enhanced by D-AP5 pretreatment in NAsh, accompanied by elevated expressions of phosphorylation of NR2A (Tyr1246) and NR2B (Tyr1472) subunits. There were statistically significant increases in the expressions of D1Rs, as well as in the phosphorylated ERK1/2 (p-ERK1/2) and CREB (p-CREB). This evidence substantiates a pivotal role of NMDARs in the NAsh, with a particular emphasis on the NR2A and NR2B subunits, in mediating propofol self-administration behaviour. Furthermore, it suggests that this central reward processing mechanism may operate through the NMDAR-D1R/ERK/CREB signal transduction pathway.

Orexins in apoptosis: a dual regulatory role.

The orexins, also referred to as hypocretins, are neuropeptides that originate from the lateral hypothalamus (LH) region of the brain. They are composed of two small peptides, orexin-A, and orexin-B, which are broadly distributed throughout the central and peripheral nervous systems. Orexins are recognized to regulate diverse functions, involving energy homeostasis, the sleep-wake cycle, stress responses, and reward-seeking behaviors. Additionally, it is suggested that orexin-A deficiency is linked to sleepiness and narcolepsy. The orexins bind to their respective receptors, the orexin receptor type 1 (OX1R) and type 2 (OX2R), and activate different signaling pathways, which results in the mediation of various physiological functions. Orexin receptors are widely expressed in different parts of the body, including the skin, muscles, lungs, and bone marrow. The expression levels of orexins and their receptors play a crucial role in apoptosis, which makes them a potential target for clinical treatment of various disorders. This article delves into the significance of orexins and orexin receptors in the process of apoptosis, highlighting their expression levels and their potential contributions to different diseases. The article offers an overview of the existing understanding of the orexin/receptor system and how it influences the regulation of apoptosis.