Palatable Food Reward Research Articles

Transient impact of chronic social stress on effort-based reward motivation in non-food restricted mice: involvement of corticosterone.

Chronic stress has been connected to a reduced effort and motivational deficits. To study effort-based motivation in rodents, operant conditioning is often employed. However, caloric restriction is typically imposed simultaneously. Since caloric restriction is a stressor in its own right, this procedure interferes with data interpretation. Here, we investigate whether chronic social defeat stress (CSD), lasting 10 consecutive days, would alter effort-based reward motivation in mice trained under ad libitum food conditions. Utilizing operant FED3 boxes in home cages, mice were trained within eight days to nose poke for palatable food. After training completion, operant memory was retained for at least 16 days, and mice demonstrated sustained effort, as assessed with a progressive ratio schedule, to obtain reward pellets. Directly after CSD exposure (10th day), mice exhibited reduced effort for palatable food rewards, but also displayed reduced nose poking in general. The effects of CSD on effort were short-lived, with no lasting impact on effort-based reward motivation one week post-stress. As corticosterone (CORT) levels were increased at day 10 of CSD, but not at day 17, we hypothesized that CORT might mediate the acute effects of CSD on effort-based reward motivation. Indeed, CORT administration [100 μg/ml], supplied via the drinking water, mirrored the CSD-induced CORT spike and temporarily reduced reward motivation. Our findings emphasize that CSD does not result in long-term deficits in reward motivation, suggesting a resilient adaptive response in mice under unrestricted feeding conditions. This study underscores the necessity of considering temporal dynamics of stress impacts and highlights the modulating effects of CORT. These insights contribute to a deeper understanding of the resilience mechanisms in motivational impairments and pave the way for further research into factors facilitating this resilience.

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.

Mindfulness and mechanisms of attention in a neutral and palatable food context.

Mindfulness has been associated with benefits on cognitive processes, including attention. However, the exact relationship between mindfulness, components of attention, and the role of reward context has not yet been fully elucidated, which is relevant, especially in the context of addiction. In the current study, we specifically evaluated the relationship between dispositional mindfulness and the balance between voluntary (top-down), and stimulus-driven (bottom-up) attention. In addition, we explored whether the relationship was mediated by asymmetry of frontal brain activity, an index of approach tendencies, and varies as a function of reward context. In total, 95 participants (30 male, 65 female) with a mean age of 25.87 (SD = 7.38) participated. Resting-state electrophysiological activity was recorded using EEG, and participants were assessed on dispositional mindfulness, and performed the visuospatial cueing (VSC) task, which indexed voluntary- and stimulus-driven attention in a neutral and palatable food (reward) context. In the endogenous VSC task, a central cue signals the likely location of a subsequent target. The validity effect represents the benefit of valid cueing relative to the costs of invalid cueing in terms of response time. Dispositional mindfulness was associated with a reduced validity effect, plausibly reflecting a combination of reduced voluntary attention and increased stimulus-driven attention, irrespective of condition. The relationship between dispositional mindfulness and visuospatial attention could not be explained by asymmetry of frontal brain activity.

Spared nerve injury decreases motivation in long-access homecage-based operant tasks in mice.

Neuropathic pain causes both sensory and emotional maladaptation. Preclinical animal studies of neuropathic pain-induced negative affect could result in novel insights into the mechanisms of chronic pain. Modeling pain-induced negative affect, however, is variable across research groups and conditions. The same injury may or may not produce robust negative affective behavioral responses across different species, strains, and laboratories. Here, we sought to identify negative affective consequences of the spared nerve injury model on C57BL/6J male and female mice. We found no significant effect of spared nerve injury across a variety of approach-avoidance conflict, hedonic choice, and coping strategy assays. We hypothesized these inconsistencies may stem in part from the short test duration of these assays. To test this hypothesis, we used the homecage-based Feeding Experimentation Device version 3 to conduct 12-hour, overnight progressive ratio testing to determine whether mice with chronic spared nerve injury had decreased motivation to earn palatable food rewards. Our data demonstrate that despite equivalent task learning, spared nerve injury mice are less motivated to work for a sugar pellet than sham controls. Furthermore, when we normalized behavioral responses across all the behavioral assays we tested, we found that a combined normalized behavioral score is predictive of injury state and significantly correlates with mechanical thresholds. Together, these results suggest that homecage-based operant behaviors provide a useful platform for modeling nerve injury-induced negative affect and that valuable pain-related information can arise from agglomerative data analyses across behavioral assays-even when individual inferential statistics do not demonstrate significant mean differences.

From the stomach to locus coeruleus: new neural substrate for ghrelin's effects on ingestive, motivated and anxiety-like behaviors.

Ghrelin, a stomach-derived orexigenic hormone, has a well-established role in energy homeostasis, food reward, and emotionality. Noradrenergic neurons of the locus coeruleus (LC) are known to play an important role in arousal, emotion, cognition, but recently have also been implicated in control of feeding behavior. Ghrelin receptors (the growth hormone secretagogue receptor, GHSR) may be found in the LC, but the behavioral effects of ghrelin signaling in this area are still unexplored. Here, we first determined whether GHSR are present in the rat LC, and demonstrate that GHSR are expressed on noradrenergic neurons in both sexes. We next investigated whether ghrelin controls ingestive and motivated behaviors as well as anxiety-like behavior by acting in the LC. To pursue this idea, we examined the effects of LC GHSR stimulation and blockade on food intake, operant responding for a palatable food reward and, anxiety-like behavior in the open field (OF) and acoustic startle response (ASR) tests in male and female rats. Our results demonstrate that intra-LC ghrelin administration increases chow intake and motivated behavior for sucrose in both sexes. Additionally, females, but not males, exhibited a potent anxiolytic response in the ASR. In order to determine whether activation of GHSR in the LC was necessary for feeding and anxiety behavior control, we utilized liver-expressed antimicrobial peptide 2 (LEAP2), a newly identified endogenous GHSR antagonist. LEAP2 delivered specifically into the LC was sufficient to reduce fasting-induced chow hyperphagia in both sexes, but food reward only in females. Moreover, blockade of GHSR in the LC increased anxiety-like behavior measured in the ASR test in both sexes. Taken together, these results indicate that ghrelin acts in the LC to alter ingestive, motivated and anxiety-like behaviors, with a degree of sex divergence.

Strain-specific changes in nucleus accumbens transcriptome and motivation for palatable food reward in mice exposed to maternal separation.

In humans, adversity in childhood exerts enduring effects on brain and increases the vulnerability to psychiatric diseases. It also leads to a higher risk of eating disorders and obesity. Maternal separation (MS) in mice has been used as a proxy of stress during infancy. We hypothesized that MS in mice affects motivation to obtain palatable food in adulthood and changes gene expression in reward system. Male and female pups from C57Bl/6J and C3H/HeN mice strains were subjected to a daily MS protocol from postnatal day (PND) 2 to PND14. At adulthood, their motivation for palatable food reward was assessed in operant cages. Compared to control mice, male and female C3H/HeN mice exposed to MS increased their instrumental response for palatable food, especially when the effort required to obtain the reward was high. Importantly, this effect is shown in animals fed ad libitum. Transcriptional analysis revealed 375 genes differentially expressed in the nucleus accumbens of male MS C3H/HeN mice compared to the control group, some of these being associated with the regulation of the reward system (e.g., Gnas, Pnoc). Interestingly, C57Bl/6J mice exposed to MS did not show alterations in their motivation to obtain a palatable reward, nor significant changes in gene expression in the nucleus accumbens. MS produces long-lasting changes in motivation for palatable food in C3H/HeN mice, but has no impact in C57Bl/6J mice. These behavioral alterations are accompanied by drastic changes in gene expression in the nucleus accumbens, a key structure in the regulation of motivational processes.

Lipopolysaccharide-induced changes in effort-related motivational function: Interactions with 2-deoxyglucose

Inflammation is linked to motivational deficits seen in depression and other disorders. Lipopolysaccharide (LPS) induces an inflammatory response and impairs motivated behavior in humans and rodents. It has been suggested that inflammation can shift metabolic needs to functions that warrant more response to the perceived threat (e.g., fighting infection), therefore altering aspects of motivation. Animal models have been developed to assess alterations in motivated behavior by giving the animal the option to work (i.e., lever press) for a highly palatable food reward vs. approaching and consuming a freely available, albeit less preferred, food. This model was used to determine if administration of 2-deoxy-D-glucose (2DG), a substance that inhibits glucose uptake and glycolysis, could reverse the motivational deficits induced by LPS in rats. A food preference/intake task was also conducted to see if LPS affected intake of the highly palatable vs. less palatable foods when both are freely available. It was hypothesized that 2-DG would reverse the motivational deficits caused by LPS and there would be no effect on food preference/intake of the highly palatable food. Results showed that 2-DG significantly reversed LPS effects at the lowest dose, while methylphenidate did not. The food intake/preference tests showed that LPS significantly decreased food intake of both foods but did not alter preference for the highly palatable food compared to vehicle. These results suggest that in addition to having effects on exertion of effort during instrumental behavior, LPS also has direct effects on primary food motivation.

Repeated dosing with cocaine produces strain-dependent effects on responding for conditioned reinforcement in Collaborative Cross mice.

Cocaine use disorder (CUD) is a highly heritable form of substance use disorder, with genetic variation accounting for a substantial proportion of the risk for transitioning from recreational use to a clinically impairing addiction. With repeated exposures to cocaine, psychomotor and incentive sensitization are observed in rodents. These phenomena are thought to model behavioral changes elicited by the drug that contribute to the progression into addiction, but little is known about how genetic variation may moderate these consequences. Here, we describe the use of two Collaborative Cross (CC) recombinant inbred mouse strains that either exhibit high (CC018/UncJ) or no (CC027/GeniUncJ) psychomotor sensitization in response to cocaine to measure phenotypes related to incentive sensitization after repeated cocaine exposures; given the relationship of incentive motivation to nucleus accumbens core (NAc) dopamine release and reuptake, we also assessed these neurochemical mechanisms. Adult male and female CC018/UncJ and CC027/GeniUncJ mice underwent Pavlovian conditioning to associate a visual cue with presentation of a palatable food reward, then received five, every-other-day injections of cocaine or vehicle. Following Pavlovian re-training, they underwent testing acquisition of a new operant response for the visual cue, now serving as a conditioned reinforcer. Subsequently, electrically evoked dopamine release was assessed using fast-scan cyclic voltammetry from acute brain slices containing the NAc. While both strains acquired the Pavlovian association, only CC018/UncJ mice showed conditioned reinforcement and incentive sensitization in response to cocaine, while CC027/GeniUncJ mice did not. Voltammetry data revealed that CC018/UncJ, compared to CC027/GeniUnc, mice exhibited higher baseline dopamine release and uptake. Moreover, chronic cocaine exposure blunted tonic and phasic dopamine release in CC018/UncJ, but not CC027/GeniUncJ, mice. Genetic background is a moderator of cocaine-induced neuroadaptations in mesolimbic dopamine signaling, which may contribute to both psychomotor and incentive sensitization and indicate a shared biological mechanism of variation.

Examining sex disparities in risk/reward trade-offs in Smith's zokors, Eospalax smithii

Risk taking is imperative for the survival and fitness of animals since they are constantly facing innumerable threats from various sources. Indeed, the ability of the individual to balance the costs and benefits of various options and adopt a wise decision is critical for the animal well-being. We modified several traditionally used anxiety tests [The modified light-dark box (mLDB), the modified open field test (mOFT) and the modified defensive withdrawal apparatus (mDWA)] by adding a palatable food reward within the anxiogenic zone which granted us to assess the sex differences in risk-taking behavior in Smith's zokors (Eospalax smithii), a typical subterranean rodent species endemic to the Qinghai-Tibetan Plateau. Concomitant with our working hypothesis, female zokors showed strong aversion and avoidance behavioral responses when tested in the mOFT and mDWA while there were no apparent sexually dimorphic behavioral changes when they were tested in the mLDB (Except for the percentage of food consumed and the latency till start feeding). Furthermore, comparison between the three behavioral paradigms revealed that both sexes showed different behavioral responses toward the different behavioral tests. Sex differences in repeatable behaviors were more profound in females than males. This might reflect different degrees of risk perception and emotionality that may differ considerably between the different models of anxiety. Our results highlighted the functional significance of a trade-off between risk and incentives in natural environment that both male and female zokors differ in the processing of risk assessment in the presence of a food reward.

One-Night Total Sleep Deprivation Did Not Alter the Effects of Pavlovian Cues on Instrumental Responses for Highly Palatable Food Rewards

One-Night Total Sleep Deprivation Did Not Alter the Effects of Pavlovian Cues on Instrumental Responses for Highly Palatable Food Rewards

"Just not knowing" can make life sweeter (and saltier): Reward uncertainty alters the sensory experience and consumption of palatable food and drinks.

Reward uncertainty can prompt exploration and learning, strengthening approach and consummatory behaviors. For humans, these phenomena are exploited in marketing promotions and gambling products, sometimes spurring hedonic consumption. Here, in four experiments, we sought to identify whether reward uncertainty-as a state of "not knowing" that exists between an action and a positively valanced outcome-enhances the in-the-moment consumption and experience of other palatable food and drink rewards. In Experiment 1, we demonstrate that reward uncertainty can increase consumption of commercial alcoholic drinks and energy-dense savory snacks. In Experiment 2, we show that reward uncertainty is unlikely to promote consumption through gross increases in impulsivity (expressed as higher discounting rates) or risk tolerance (expressed as lower probability discounting rates). In Experiment 3, we find that reward uncertainty intensifies the taste of, and hedonic responses to, sucrose solutions in a concentration-dependent manner among individuals with heightened preferences for sweet tastes. Finally, in Experiment 4, we replicate and extend these findings by showing that reward uncertainty intensifies the taste of palatable foods and drinks in ways that are independent of individuals' discounting rates, motor control, reflection impulsivity, and momentary happiness but are strongly moderated by recent depressive symptoms. These data suggest a working hypothesis that (incidental) reward uncertainty, as a state of not knowing, operates as a mood-dependent "taste intensifier" of palatable food and drink rewards, possibly sustaining reward seeking and consumption. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Lifelong enhancement of body mass from adolescent stress in male hamsters

In hamsters, exposure to stress in adulthood causes increased body weight. We addressed how social stress during puberty would impact food intake and body weight. Stressed hamsters started gaining significantly more weight than controls after only two days of stress exposure. Over a two-week period, stressed subjects gained 10% more weight and consumed more food than controls. At the end of the stress period, stressed hamsters collected nearly twice as many palatable sugar pellets from an arena than controls. Stressed subjects presented 15–20% more body fat in mesenteric, inguinal, and retroperitoneal fat pads. In order to assess the duration of these effects, we analyzed data from previous studies keeping hamsters for over two months past the stress period in puberty. Our analysis shows that stressed hamsters stopped gaining more weight after the stress period, but their body weights remained elevated for over two months, consistently weighing 10% more than their non-stressed counterparts. We also analyzed conditioning training data collected after the period of stress in late puberty and early adulthood (P56 to P70) that was part of the original studies. Training consisted of lever pressing for palatable food rewards. At these times, previously stressed hamsters retrieved similar numbers of food pellets from the conditioning chambers, suggesting no difference in appetite after the stress period. These data showing a long-lasting effect of stress on body weight may be relevant to studies on the ontogeny of lifelong obesity.

Economic choice between remifentanil and food in squirrel monkeys

Traditional approaches for evaluating if compounds are reinforcing, and thus a risk for abuse, include preclinical self-administration procedures conducted in the absence of alternative reinforcers. While the track record of this approach for determining abuse potential is good, that for predicting efficacy of addiction treatments is not. An alternate approach would be economic choice between drug and nondrug rewards, with parametrically varied options from trial to trial. This would promote goal-directed decisions between reward modalities and should provide metrics that reflect changes in internal state that influence desirability of a given option. We report herein a high throughput economic choice procedure in which squirrel monkeys choose between a short-lived opiate, remifentanil, and a palatable food reward. Stimuli on touchscreens indicate the amount of each reward type offered by varying the number of reward-specific elements. The rapid clearance of remifentanil avoids accumulation of confounding levels of drug, and permits a large number of trials with a wide range of offers of each reward modality. The use of a single metric encompassing multiple values of each reward type within a session enables estimation of indifference values using logistic regression. This indifference value is sensitive to reward devaluation within each reward domain, and is therefore a useful metric for determining shifts in reward preference, as shown with satiation and pharmacological treatment approaches.

Blockade of Orexin Receptors in the Posterior Paraventricular Nucleus of the Thalamus Prevents Stress-Induced Reinstatement of Reward-Seeking Behavior in Rats With a History of Ethanol Dependence.

Neural systems involved in processing natural rewards and drugs of abuse overlap and exposure to drugs of abuse induce neuroadaptations that can cause compulsive-like behavior. For example, the recruitment of the orexin (Orx) system by drugs of abuse has been proposed to induce neuroadaptations that in turn alter its function, reflected by maladaptive, compulsive, and addictive behavior. Orexin neurons project to the paraventricular nucleus of the thalamus (PVT)—particularly the posterior part (pPVT), a structure that plays a key role in stress regulation. This study investigated whether Orx transmission in the pPVT plays a role in stress-induced reinstatement of reward-seeking behavior toward ethanol (EtOH) and a highly palatable food reward [sweetened condensed milk (SCM)] in rats and whether this role changes with EtOH dependence. After being trained to orally self-administer EtOH or SCM, the rats were made dependent (EtOHD and SCMD) by chronic intermittent EtOH vapor exposure. The control nondependent groups (EtOHND and SCMND) were exposed to air. Following extinction, the rats were tested for stress-induced reinstatement of EtOH- and SCM-seeking behavior. Stress reinstated EtOH- and SCM-seeking behavior in all groups (EtOHD/ND and SCMD/ND). Administration of the dual Orx receptor (OrxR) antagonist TCS1102 (15 μg) in the pPVT prevented stress-induced reinstatement only in dependent rats (EtOHD and SCMD). In parallel, the qPCR analysis showed that Orx mRNA expression in the hypothalamus and OrxR1/R2 mRNA expression in the pPVT were increased at the time of testing in the EtOHD and SCMD groups. These results are the first to implicate Orx transmission in the pPVT in the stress-induced reinstatement of reward-seeking behavior in EtOH dependent rats and indicate the maladaptive recruitment of Orx transmission in the pPVT by EtOH dependence.

Chronic Intermittent Ethanol Exposure Increases Ethanol Consumption Following Traumatic Stress Exposure in Mice.

Individuals with post-traumatic stress disorder (PTSD) often use alcohol to cope with their distress. This aberrant use of alcohol often develops into alcohol use disorder (AUD) leading to high rates of PTSD-AUD co-occurrence. Individuals with comorbid PTSD-AUD have more intense alcohol cravings and increased relapse rates during withdrawal than those with AUD alone. Also, individuals with PTSD or AUD alone often show similar psychological behaviors, such as impulsivity and anhedonia. Extensive clinical studies on the behavioral effects of PTSD-AUD comorbidity, namely alcohol use, have been performed. However, these effects have not been well studied or mechanistically explored in animal models. Therefore, the present study evaluated the effects of traumatic stress comorbid with alcohol exposures on ethanol intake, impulsivity, and anhedonia in mice. Adult male C57Bl/6 mice were first exposed to either mouse single-prolonged stress (mSPS), an animal model that has been validated for characteristics akin to PTSD symptoms, or control conditions. Baseline two-bottle choice ethanol consumption and preference tests were conducted after a 7-day isolation period, as part of the mSPS exposure. Next, mice were exposed to air or chronic intermittent ethanol (CIE), a vapor-induced ethanol dependence and withdrawal model, for 4 weeks. Two-bottle choice ethanol drinking was used to measure dependence-induced ethanol consumption and preference during periods intervening CIE cycles. The novelty suppressed feeding (NSF) test was used to evaluate impulsivity and anhedonia behaviors 48 h after mSPS and/or repeated CIE exposure. Results showed that, compared to control conditions, mSPS did not affect baseline ethanol consumption and preference. However, mSPS-CIE mice increased Post-CIE ethanol consumption compared to Control-Air mice. Mice exposed to mSPS had a shorter latency to feed during the NSF, whereas CIE-exposed mice consumed less palatable food reward in their home cage after the NSF. These results demonstrate that mice exposed to both mSPS and CIE are more vulnerable to ethanol withdrawal effects, and those exposed to mSPS have increased impulsivity, while CIE exposure increases anhedonia. Future studies to examine the relationship between behavioral outcomes and the molecular mechanisms in the brain after PTSD-AUD are warranted.

Inhibition of monoacylglycerol lipase reduces nicotine reward in the conditioned place preference test in male mice

Nicotine, the primary psychoactive component in tobacco, plays a major role in the initiation and maintenance of tobacco dependence and addiction, a leading cause of preventable death worldwide. An essential need thus exists for more effective pharmacotherapies for nicotine-use cessation. Previous reports suggest that pharmacological and genetic blockade of CB1 receptors attenuate nicotine reinforcement and reward; while exogenous agonists enhanced these abuse-related behaviors. In this study, we utilized complementary genetic and pharmacologic approaches to test the hypothesis that increasing the levels of the endocannabinoid 2-arachindonoylglycerol (2-AG), will enhance nicotine reward by stimulating neuronal CB1 receptors. Contrary to our hypothesis, we found that inhibition of monoacylglycerol lipase (MAGL), the primary catabolic enzyme of 2-AG, attenuates nicotine conditioned place preference (CPP) in mice, through a non-CB1 receptor-mediated mechanism. MAGL inhibition did not alter palatable food reward or Lithium Chloride (LiCl) aversion. In support of our findings, repeated MAGL inhibition did not induce a reduction in CB1 brain receptor levels or hinder function. To explore the potential mechanism of action, we investigated if MAGL inhibition affected other fatty acid levels in our CPP paradigm. Indeed, MAGL inhibition caused a concomitant decrease in arachidonic acid (AA) levels in various brain regions of interest, suggesting an AA cascade-dependent mechanism. This idea is supported by dose-dependent attenuation of nicotine preference by the selective COX-2 inhibitors valdecoxib and LM-4131. Collectively, these findings, along with our reported studies on nicotine withdrawal, suggest that inhibition of MAGL represents a promising new target for the development of pharmacotherapies to treat nicotine dependence.

ErbB4 Null Mice Display Altered Mesocorticolimbic and Nigrostriatal Dopamine Levels as well as Deficits in Cognitive and Motivational Behaviors.

Natural genetic variants of Neuregulin1 (NRG1) and its cognate receptor ErbB4 are associated with a risk for schizophrenia. Whereas most studies on NRG1-ErbB4 signaling have focused on GABAergic interneurons, ErbB4 is also expressed by midbrain dopaminergic neurons where it modulates extracellular dopamine (DA) levels. Here, we report that extracellular steady-state levels of DA are reduced in the medial prefrontal cortex (mPFC; −65%), hippocampus (−53%) and nucleus accumbens (NAc; −35%), but are elevated in the dorsal striatum (+25%) of ErbB4 knock-out mice (ErbB4 KOs) relative to wild-type controls. This pattern of DA imbalance recapitulates the reported prefrontal cortical reduction and striatal increase of DA levels in schizophrenia patients. Next, we report on a battery of behavioral tasks used to evaluate locomotor, cognitive and motivational behaviors in ErbB4 KOs relative to controls. We found that ErbB4 KOs are hyperactive in a novel open field but not in their familiar home cage, are more sensitive to amphetamine, perform poorly in the T-maze and novel object recognition (NOR) tasks, exhibit reduced spatial learning and memory on the Barnes maze, and perform markedly worse in conditioned place preference (CPP) tasks when associating cued-reward palatable food with location. However, we found that the poor performance of ErbB4 KOs in CPP are likely due to deficits in spatial memory, instead of reward seeking, as ErbB4 KOs are more motivated to work for palatable food rewards. Our findings indicate that ErbB4 signaling affects tonic DA levels and modulates a wide array of behavioral deficits relevant to psychiatric disorders, including schizophrenia.

β4-Nicotinic Receptors Are Critically Involved in Reward-Related Behaviors and Self-Regulation of Nicotine Reinforcement.

Nicotine addiction, through smoking, is the principal cause of preventable mortality worldwide. Human genome-wide association studies have linked polymorphisms in the CHRNA5-CHRNA3-CHRNB4 gene cluster, coding for the α5, α3, and β4 nicotinic acetylcholine receptor (nAChR) subunits, to nicotine addiction. β4*nAChRs have been implicated in nicotine withdrawal, aversion, and reinforcement. Here we show that β4*nAChRs also are involved in non-nicotine-mediated responses that may predispose to addiction-related behaviors. β4 knock-out (KO) male mice show increased novelty-induced locomotor activity, lower baseline anxiety, and motivational deficits in operant conditioning for palatable food rewards and in reward-based Go/No-go tasks. To further explore reward deficits we used intracranial self-administration (ICSA) by directly injecting nicotine into the ventral tegmental area (VTA) in mice. We found that, at low nicotine doses, β4KO self-administer less than wild-type (WT) mice. Conversely, at high nicotine doses, this was reversed and β4KO self-administered more than WT mice, whereas β4-overexpressing mice avoided nicotine injections. Viral expression of β4 subunits in medial habenula (MHb), interpeduncular nucleus (IPN), and VTA of β4KO mice revealed dose- and region-dependent differences: β4*nAChRs in the VTA potentiated nicotine-mediated rewarding effects at all doses, whereas β4*nAChRs in the MHb-IPN pathway, limited VTA-ICSA at high nicotine doses. Together, our findings indicate that the lack of functional β4*nAChRs result in deficits in reward sensitivity including increased ICSA at high doses of nicotine that is restored by re-expression of β4*nAChRs in the MHb-IPN. These data indicate that β4 is a critical modulator of reward-related behaviors.SIGNIFICANCE STATEMENT Human genetic studies have provided strong evidence for a relationship between variants in the CHRNA5-CHRNA3-CHRNB4 gene cluster and nicotine addiction. Yet, little is known about the role of β4 nicotinic acetylcholine receptor (nAChR) subunit encoded by this cluster. We investigated the implication of β4*nAChRs in anxiety-, food reward- and nicotine reward-related behaviors. Deletion of the β4 subunit gene resulted in an addiction-related phenotype characterized by low anxiety, high novelty-induced response, lack of sensitivity to palatable food rewards and increased intracranial nicotine self-administration at high doses. Lentiviral vector-induced re-expression of the β4 subunit into either the MHb or IPN restored a "stop" signal on nicotine self-administration. These results suggest that β4*nAChRs provide a promising novel drug target for smoking cessation.

Ovarian Hormones Mediate Changes in Adaptive Choice and Motivation in Female Rats.

In female rodents, sexual receptivity is coordinated with cyclic changes in the release of gonadal hormones. Increases in estradiol (E) and progesterone (P) during proestrus and estrus not only induce ovulation but also modulate behaviors that increase the likelihood that the female will find a mate and reproduce. This includes changes in receptive behaviors, such as lordosis, as well as changes in appetitive or proceptive behaviors, including motivation. Interestingly, the direction of these changes in motivation is dependent on the type of reward that is being pursued. While induction of sexual receptivity by E and P increases motivation for access to a male, motivation for a palatable food reward is decreased. These concurrent changes may facilitate adaptive choice across the estrous cycle; females bias their choice for sex when fertilization is most likely to occur, but for food when copulation is unlikely to result in impregnation. In order to test this hypothesis, we developed a novel paradigm to measure the motivated choice between a palatable food reward and access to a male conspecific. Ovariectomized, hormone primed females were trained to operantly respond for both food and sex on a fixed interval (FI) schedule. After training, unprimed and primed females were tested in a chamber that allows them to choose between food and sex while still requiring responding on the FI schedule for reach reward. From this we can not only determine the impact of hormone priming on female choice for food or sex, but also how this is reflected by changes in motivation for each specific reward, as measured by the average number of responses made during each fixed interval. Induction of sexual receptivity by hormone priming biases choice toward sex over food and this change is accompanied by an increase in motivation for sex but a decrease in motivation for food. This work provides evidence in support of a novel framework for understanding how the release of ovarian hormones over the course of the estrous cycle modulates adaptive behavioral choice in females by directly assessing motivation via operant responding when multiple rewards are available.

Distinct cortical-amygdala projections drive reward value encoding and retrieval.

The value of an anticipated rewarding event is a crucial component of the decision to engage in its pursuit. But little is known of the networks responsible for encoding and retrieving this value. Using biosensors and pharmacological manipulations, we found that basolateral amygdala (BLA) glutamatergic activity tracks and mediates the encoding and retrieval of the state-dependent incentive value of a palatable food reward. Projection-specific, bidirectional chemogenetic and optogenetic manipulations revealed the orbitofrontal cortex (OFC) supports the BLA in these processes. Critically, the function of ventrolateral (lOFC) and medial (mOFC) OFC→BLA projections is doubly dissociable. Whereas lOFC→BLA projections are necessary and sufficient for encoding of the positive value of a reward, mOFC→BLA projections are necessary and sufficient for retrieving this value from memory. These data reveal a new circuit for adaptive reward valuation and pursuit and provide insight into the dysfunction in these processes that characterizes myriad psychiatric diseases.