Modulation of ventromedial orbitofrontal cortical glutamatergic activity affects the explore-exploit balance and influences value-based decision-making.

The balance between exploration and exploitation is essential for decision-making. The present study investigated the role of ventromedial orbitofrontal cortex (vmOFC) glutamate neurons in mediating value-based decision-making by first using optogenetics to manipulate vmOFC glutamate activity in rats during a probabilistic reversal learning (PRL) task. Rats that received vmOFC activation during informative feedback completed fewer reversals and exhibited reduced reward sensitivity relative to rats. Analysis with a Q-learning computational model revealed that increased vmOFC activity did not affect the learning rate but instead promoted maladaptive exploration. By contrast, vmOFC inhibition increased the number of completed reversals and increased exploitative behavior. In a separate group of animals, calcium activity of vmOFC glutamate neurons was recorded using fiber photometry. Complementing our results above, we found that suppression of vmOFC activity during the latter part of rewarded trials was associated with improved PRL performance, greater win-stay responding and selecting the correct choice on the next trial. These data demonstrate that excessive vmOFC activity during reward feedback disrupted value-based decision-making by increasing the maladaptive exploration of lower-valued options. Our findings support the premise that pharmacological interventions that normalize aberrant vmOFC glutamate activity during reward feedback processing may attenuate deficits in value-based decision-making.

Error-related Alpha Suppression: Scalp Topography and (Lack of) Modulation by Modafinil.

Errors in performance trigger cognitive and neural changes that are implemented to adaptively adjust to fluctuating demands. Error-related alpha suppression (ERAS)-which refers to decreased power in the alpha frequency band after an incorrect response-is thought to reflect cognitive arousal after errors. Much of this work has been correlational, however, and there are no direct investigations into its pharmacological sensitivity. In Study 1 (n = 61), we evaluated the presence and scalp distribution of ERAS in a novel flanker task specifically developed for cross-species assessments. Using this same task in Study 2 (n = 26), which had a placebo-controlled within-subject design, we evaluated the sensitivity of ERAS to placebo (0 mg), low (100 mg), and high (200 mg) doses of modafinil, a wakefulness promoting agent. Consistent with previous work, ERAS was maximal at parieto-occipital recording sites in both studies. In Study 2, modafinil did not have strong effects on ERAS (a significant Accuracy × Dose interaction emerged, but drug-placebo differences did not reach statistical significance after correction for multiple comparisons and was absent after controlling for accuracy rate). ERAS was correlated with accuracy rates in both studies. Thus, modafinil did not impact ERAS as hypothesized, and findings indicate ERAS may reflect an orienting response to infrequent events.

Serotonergic Plasticity in the Dorsal Raphe Nucleus Characterizes Susceptibility and Resilience to Anhedonia.

Chronic stress induces anhedonia in susceptible but not resilient individuals, a phenomenon observed in humans as well as animal models, but the molecular mechanisms underlying susceptibility and resilience are not well understood. We hypothesized that the serotonergic system, which is implicated in stress, reward, and antidepressant therapy, may play a role. We found that plasticity of the serotonergic system contributes to the differential vulnerability to stress displayed by susceptible and resilient animals. Stress-induced anhedonia was assessed in adult male rats using social defeat and intracranial self-stimulation, while changes in serotonergic phenotype were investigated using immunohistochemistry and in situ hybridization. Susceptible, but not resilient, rats displayed an increased number of neurons expressing the biosynthetic enzyme for serotonin, tryptophan-hydroxylase-2 (TPH2), in the ventral subnucleus of the dorsal raphe nucleus (DRv). Further, a decrease in the number of DRv glutamatergic (VGLUT3+) neurons was observed in all stressed rats. This neurotransmitter plasticity is activity-dependent, as was revealed by chemogenetic manipulation of the central amygdala, a stress-sensitive nucleus that forms a major input to the DR. Activation of amygdalar corticotropin-releasing hormone (CRH)+ neurons abolished the increase in DRv TPH2+ neurons and ameliorated stress-induced anhedonia in susceptible rats. These findings show that activation of amygdalar CRH+ neurons induces resilience, and suppresses the gain of serotonergic phenotype in the DRv that is characteristic of susceptible rats. This molecular signature of vulnerability to stress-induced anhedonia and the active nature of resilience could be targeted to develop new treatments for stress-related disorders like depression.SIGNIFICANCE STATEMENT Depression and other mental disorders can be induced by chronic or traumatic stressors. However, some individuals are resilient and do not develop depression in response to chronic stress. A complete picture of the molecular differences between susceptible and resilient individuals is necessary to understand how plasticity of limbic circuits is associated with the pathophysiology of stress-related disorders. Using a rodent model, our study identifies a novel molecular marker of susceptibility to stress-induced anhedonia, a core symptom of depression, and a means to modulate it. These findings will guide further investigation into cellular and circuit mechanisms of resilience, and the development of new treatments for depression.

Activation of the medial prefrontal cortex by escapable stress is necessary for protection against subsequent inescapable stress-induced potentiation of morphine conditioned place preference.

Stress can be a predisposing factor in the development of psychiatric disorders. However, not all individuals develop psychiatric disorders following a traumatic event. An attempt to understand these individual differences has led to a focus on factors that produce resistance. Interestingly, in rats, an experience with escapable tailshock (ES) before inescapable tailshock (IS) prevents the typical anxiety-like behavioral outcomes of IS. This type of resistance has been termed 'behavioral immunization', and it depends on activation of the medial prefrontal cortex (mPFC) during ES. However, one outcome of IS that is not anxiety-related is potentiation of morphine conditioned place preference (CPP). The present experiments investigated whether prior ES would block IS-induced potentiation of morphine CPP. Rats received either ES, IS or homecage control treatment on day 1 and then either IS or homecage control treatment on day 2. Twenty-four hours following day 2, rats underwent morphine conditioning, and CPP was subsequently assessed. In a second experiment, rats received ES 3, 14 or 56 days prior to IS to determine the duration of behavioral immunization. In a final experiment, rats were microinjected with the GABA(A) agonist muscimol (50 ng/0.5 µL) or saline in the mPFC before day 1 of stress. Prior ES blocked IS-induced potentiation of morphine CPP. This immunizing effect of ES lasted for at least 56 days. Additionally, intra-mPFC muscimol during ES prevented behavioral immunization. These results suggest that prior experience with ES activates the mPFC and produces long-lasting neural alterations that block subsequent IS-induced potentiation of morphine CPP.

Probabilistic Reinforcement Learning and Anhedonia.

Despite the prominence of anhedonic symptoms associated with diverse neuropsychiatric conditions, there are currently no approved therapeutics designed to attenuate the loss of responsivity to previously rewarding stimuli. However, the search for improved treatment options for anhedonia has been reinvigorated by a recent reconceptualization of the very construct of anhedonia, including within the Research Domain Criteria (RDoC) initiative. This chapter will focus on the RDoC Positive Valence Systems construct of reward learning generally and sub-construct of probabilistic reinforcement learning specifically. The general framework emphasizes objective measurement of a subject's responsivity to reward via reinforcement learning under asymmetrical probabilistic contingencies as a means to quantify reward learning. Indeed, blunted reward responsiveness and reward learning are central features of anhedonia and have been repeatedly described in major depression. Moreover, these probabilistic reinforcement techniques can also reveal neurobiological mechanisms to aid development of innovative treatment approaches. In this chapter, we describe how investigating reward learning can improve our understanding of anhedonia via the four RDoC-recommended tasks that have been used to probe sensitivity to probabilistic reinforcement contingencies and how such task performance is disrupted in various neuropsychiatric conditions. We also illustrate how reverse translational approaches of probabilistic reinforcement assays in laboratory animals can inform understanding of pharmacological and physiological mechanisms. Next, we briefly summarize the neurobiology of probabilistic reinforcement learning, with a focus on the prefrontal cortex, anterior cingulate cortex, striatum, and amygdala. Finally, we discuss treatment implications and future directions in this burgeoning area.

Effects of modafinil on electroencephalographic microstates in healthy adults.

RATIONALE: Modafinil has been proposed as a potentially effective clinical treatment for neuropsychiatric disorders characterized by cognitive control deficits. However, the precise effects of modafinil, particularly on brain network functions, are not completely understood. OBJECTIVES: To address this gap, we examined the effects of modafinil on resting-state brain activity in 30 healthy adults using microstate analysis. Electroencephalographic (EEG) microstates are discrete voltage topographies generated from resting-state network activity. METHODS: Using a placebo-controlled, within-subjects design, we examined changes to microstate parameters following placebo (0 mg), low (100 mg), and high (200 mg) modafinil doses. We also examined the functional significance of these microstates via associations between microstate parameters and event-related potential indexes of conflict monitoring and automatic error processing (N2 and error-related negativity) and behavioral responses (accuracy and RT) from a subsequent flanker interference task. RESULTS: Five microstates emerged following each treatment condition, including four canonical microstates (A-D). Modafinil increased microstate C proportion and occurrence regardless of dose, relative to placebo. Modafinil also decreased microstate A proportion and microstate B proportion and occurrence relative to placebo. These modafinil-related changes in microstate parameters were not associated with similar changes in flanker ERPs or behavior. Finally, modafinil made transitions between microstates A and B less likely and transitions from A and B to C more likely. CONCLUSIONS: Previous fMRI work has correlated microstates A and B with auditory and visual networks and microstate C with a salience network. Thus, our results suggest modafinil may deactivate large-scale sensory networks in favor of a higher order functional network during resting-state in healthy adults.

Concordant neurophysiological signatures of cognitive control in humans and rats.

Progress towards understanding neural mechanisms in humans relevant to psychiatric conditions has been hindered by a lack of translationally-relevant cognitive tasks for laboratory animals. Accordingly, there is a critical need to develop parallel neurophysiological assessments of domains of cognition, such as cognitive control, in humans and laboratory animals. To address this, we developed a touchscreen-based cognitive (Eriksen Flanker) task in rats and used its key characteristics to construct a novel human version, with similar testing parameters and endpoints across species. We obtained continuous electroencephalogram (EEG) recordings, including local field potentials in rats, and compared electrophysiological signatures locked to stimulus onset and responses across species. We also assessed whether behavioral or physiological task effects were modulated by modafinil, which enhances aspects of cognitive function in humans. In both species, the task elicited expected flanker interference effects (reduced accuracy) during high-conflict trials. Across homologous neuroanatomical loci, stimulus-locked increases in theta power during high-conflict trials as well as error-related negative potentials were observed. These endpoints were not affected by modafinil in either species. Despite some species-specific patterns, our findings demonstrate the feasibility of a rat Flanker task as well as cross-species behavioral and neurophysiological similarities, which may enable novel insights into the neural correlates of healthy and aberrant behavior and provide mechanistic insights relevant to treatment.

Withdrawal from chronic exposure to amphetamine, but not nicotine, leads to an immediate and enduring deficit in motivated behavior without affecting social interaction in rats.

Psychostimulant withdrawal leads to depressive symptoms, such as anhedonia and social dysfunction. We determined the effects of withdrawal from chronic exposure to nicotine (9 mg/kg/day salt, 28 days) or amphetamine (10 mg/kg/day salt, 7 days) on the motivated response for a sucrose reward and on social interaction in rats. Both nicotine and amphetamine exposure increased the motivated response for sucrose. However, only spontaneous amphetamine withdrawal led to an immediate and persistent decrease in motivated behavior, which was not correlated with body weight loss. Social interaction was not affected during withdrawal from either drug. These results indicate that withdrawal from chronic amphetamine exposure leads to an immediate and enduring anhedonic state.

Assessing the motivational effects of ethanol in mice using a discrete-trial current-intensity intracranial self-stimulation procedure.

BACKGROUND: Alcohol (ethanol) produces both rewarding and aversive effects, and sensitivity to these effects is associated with risk for an alcohol use disorder (AUD). Measurement of these motivational effects in animal models is an important but challenging aspect of preclinical research into the neurobiology of AUD. Here, we evaluated whether a discrete-trial current-intensity intracranial self-stimulation (ICSS) procedure can be used to assess both reward-enhancing and aversive responses to ethanol in mice. METHODS: Male and female C57BL/6J mice were surgically implanted with bipolar stimulating electrodes targeting the medial forebrain bundle and trained on a discrete-trial current-intensity ICSS procedure. Mice were tested for changes in response thresholds after various doses of ethanol (0.5 g/kg-1.75 g/kg; n = 5-7 per dose), using a Latin square design. RESULTS: A 1 g/kg dose of ethanol produced a significant reward-enhancement (i.e., lowered response thresholds), whereas a 1.75 g/kg dose produced an aversive effect (elevated response thresholds). Ethanol doses from 1 to 1.75 g/kg increased response latencies as compared to saline treatment. CONCLUSIONS: The discrete-trial current-intensity ICSS procedure is an effective assay for measuring both reward-enhancing responses to ethanol as well as aversive responses in the same animal. This should prove to be a useful tool for assessing the effects of experimental manipulations on the motivational effects of ethanol in mice.

Translational Assessments of Reward and Anhedonia: A Tribute to Athina Markou.

Loss of pleasure (clinically referred to as anhedonia), impairments in other reward-related processes such as reward learning, motivation, and reward valuation, and blunted affect characterize several mood and other psychiatric disorders. Despite the availability of many therapeutic options for these disorders, reward-related impairments remain challenging to treat and often persist despite alleviation of other symptoms. Lack of animal models of reward-related impairments and affect that have high construct and predictive validity is a key obstacle to developing novel treatments. This review highlights 1) guidelines to consider when developing translatable animal models; and 2) recent efforts to develop new reward-related assessments in humans and nonhuman animals that have been translated or back-translated from one species to another. The procedures described in this review are used to assess aspects of reward learning, motivated behavior, reward valuation, and affect. In several cases, researchers have attempted to implement task parameters that are as identical as possible to the parallel parameters used in existing cross-species tasks, with the goal of improving the translation of preclinical drug discovery findings to the clinic. In this regard, Dr. Athina Markou, who worked tirelessly throughout her career to understand and treat reward-related impairments across several psychiatric disorders, had great influence on conceptualizing the development and use of translational animal models of reward-related processes.

Current Status of Animal Models of Posttraumatic Stress Disorder: Behavioral and Biological Phenotypes, and Future Challenges in Improving Translation.

Increasing predictability of animal models of posttraumatic stress disorder (PTSD) has required active collaboration between clinical and preclinical scientists. Modeling PTSD is challenging, as it is a heterogeneous disorder with ≥20 symptoms. Clinical research increasingly utilizes objective biological measures (e.g., imaging, peripheral biomarkers) or nonverbal behaviors and/or physiological responses to complement verbally reported symptoms. This shift toward more-objectively measurable phenotypes enables refinement of current animal models of PTSD, and it supports the incorporation of homologous measures across species. We reviewed >600 articles to examine the ability of current rodent models to probe biological phenotypes of PTSD (e.g., sleep disturbances, hippocampal and fear-circuit dysfunction, inflammation, glucocorticoid receptor hypersensitivity) in addition to behavioral phenotypes. Most models reliably produced enduring generalized anxiety-like or depression-like behaviors, as well as hyperactive fear circuits, glucocorticoid receptor hypersensitivity, and response to long-term selective serotonin reuptake inhibitors. Although a few paradigms probed fear conditioning/extinction or utilized peripheral immune, sleep, and noninvasive imaging measures, we argue that these should be incorporated more to enhance translation. Data on female subjects, on subjects at different ages across the life span, or on temporal trajectories of phenotypes after stress that can inform model validity and treatment study design are needed. Overall, preclinical (and clinical) PTSD researchers are increasingly incorporating homologous biological measures to assess markers of risk, response, and treatment outcome. This shift is exciting, as we and many others hope it not only will support translation of drug efficacy from animal models to clinical trials but also will potentially improve predictability of stage II for stage III clinical trials.

Effects of adolescent alcohol exposure on stress-induced reward deficits, brain CRF, monoamines and glutamate in adult rats.

BACKGROUND: Adolescent alcohol exposure may increase depression vulnerability in adulthood by increasing the anhedonic response to stress. METHODS: Male Wistar rats (postnatal days 28-53) were exposed to binge-like adolescent intermittent ethanol (AIE) or water. In adulthood, rats were exposed to social defeat, consisting of daily confrontations with an aggressive conspecific, followed by testing of brain reward function in a discrete-trial current-intensity intracranial self-stimulation procedure for 10 consecutive days. Neurochemistry and corticotropin-releasing factor (CRF) and CRF receptor 1 (CRFR1) mRNA levels were assessed in corticolimbic brain areas on day 11 of social defeat stress. RESULTS: Social defeat elevated reward thresholds in both AIE- and water-exposed rats indicating stress-induced anhedonia. However, AIE-exposed rats were more likely to show threshold elevations after repeated stress compared to water-exposed rats. AIE exposure decreased CRF mRNA levels in the nucleus accumbens and increased CRFR1 mRNA levels in the prefrontal cortex, while stress increased CRF mRNA levels in the central amygdala. In the caudate putamen, AIE exposure decreased dopamine turnover, while stress increased glutamate and serotonin metabolism and turnover. CONCLUSIONS: These results demonstrate increased risk of repeated stress-induced anhedonia after AIE exposure, an effect that may be due to alterations in brain CRF and dopamine systems. These results suggest that the increased rates of depression reported in people with a history of adolescent alcohol exposure may be related to alterations in brain reward and stress systems that may contribute to increased stress-induced anhedonia.

Stress-induced glucocorticoids suppress the antisense molecular regulation of FGF-2 expression.

Psychological stress can upregulate basic fibroblast growth factor (FGF-2) expression. Because glucocorticoids can also upregulate FGF-2 expression, the present studies investigated whether stress-induced glucocorticoids mediate the effects of stress on FGF-2. FGF-2 is regulated by an FGF-2 antisense (AS) molecular mechanism and so the present experiments also, for the first time, assessed the effects of stress on FGF-2-AS mRNA, as well as the mediating role of glucocorticoids. The effects of either escapable shock (ES) or yoked-inescapable tail shock (IS) on FGF-2 and FGF-2-AS were determined. To test whether glucocorticoids mediate the effect of stress on FGF-2 and FGF-2-AS, animals were pretreated with temporary corticosterone (CORT) synthesis inhibitors and exposed to IS. To test whether glucocorticoids are sufficient to modulate FGF-2 and FGF-2-AS mRNA, animals were injected with CORT and mRNA measured. ES and IS similarly downregulated FGF-2-AS mRNA at 0 h post-stress and upregulated FGF-2 mRNA 2 h post-stress. Inhibition of CORT synthesis abrogated the effect of IS on both FGF-2-AS and FGF-2 mRNA. Exogenous CORT mimicked the effects of ES and IS on FGF-2, but not FGF-2-AS mRNA. The present study demonstrates that glucocorticoids mediate the effects of stress on FGF-2 and FGF-2-AS.

The effects of a single session of inescapable tailshock on the subsequent locomotor response to brief footshock and cocaine administration in rats.

RATIONALE: We have previously shown that exposure to a single session of inescapable (IS), but not escapable (ES), tailshock can sensitize the subsequent conditioned place preference and locomotor responses to opioids, but not other drug classes. However, prior work suggests that IS might sensitize nonopioid drug responding if the drug were to be preceded by a mild stressor. OBJECTIVES: In the following experiments, we examined the effects of IS and ES on the subsequent locomotor response to brief footshock and/or cocaine administration. METHODS: First, we measured the locomotor response to cocaine (0, 1, 5, 10 mg/kg, intraperitoneally) 48 h after a single session of IS in adult, male Sprague-Dawley rats. Then, this procedure was repeated with 10 mg/kg cocaine, except that half of the rats received two footshocks immediately before drug administration. Finally, we manipulated the escapability of the initial stressor, as rats received either ES or yoked IS 48 h prior to footshock and cocaine administration. RESULTS: IS did not affect the subsequent locomotor response to cocaine, but did enhance this response when cocaine administration was immediately preceded by two footshocks. The footshocks alone were without effect. This sensitizing effect was dependent on the escapability of the initial stressor, as ES did not alter the locomotor response to footshock and cocaine administration. CONCLUSIONS: These results indicate that acute exposure to IS, but not ES, can sensitize the locomotor response to cocaine 48 h later, but only when cocaine administration is immediately preceded by a brief stressor.

The effects of a single exposure to uncontrollable stress on the subsequent conditioned place preference responses to oxycodone, cocaine, and ethanol in rats.

RATIONALE: Acute stress has been shown to facilitate the rewarding effects of a number of commonly abused drugs, although the stressor typically must be administered either immediately before or during drug administration and often in the same environment. We have previously reported that a single session of an uncontrollable (inescapable tailshock, IS), but not controllable (escapable tailshock, ES), stressor can enhance the conditioned place preference (CPP) response to morphine, even when stressor and drug administration are separated temporally and spatially. However, this persistent, trans-situational enhancement did not occur to amphetamine CPP. OBJECTIVES: The following experiments were conducted to determine whether the long-term effects of IS on drug reward are specific to opioids. MATERIALS AND METHODS: Adult, male Sprague-Dawley rats were exposed to a single session of IS or remained in their home cages (HC). Twenty-four hours later, using an unbiased procedure, CPP conditioning was conducted with either oxycodone (0, 2, or 5 mg/kg, sc), cocaine (0, 1, 5, or 10 mg/kg, ip), or ethanol (0.3, 1, or 2 g/kg, ip). Another group of rats were exposed to IS, ES, or HC treatment and conditioned with oxycodone (5 mg/kg, sc) 24 h later. RESULTS: IS enhanced the subsequent CPP response to oxycodone, but not cocaine or ethanol. This enhancement was dependent on the controllability of the stressor, as ES did not affect oxycodone CPP. CONCLUSIONS: These results indicate that the long-term, trans-situational enhancing effect of uncontrollable stress on drug reward is specific to opioids.

Effects of early life stress and adolescent ethanol exposure on adult cognitive performance in the 5-choice serial reaction time task in Wistar male rats.

RATIONALE: Early life stress combined with heavy adolescent alcohol use predicts impaired neuropsychological functioning in adulthood. We investigated whether adolescent intermittent ethanol (AIE) exposure combined with neonatal maternal separation in rats altered attentional processes and impulsivity in adulthood. METHODS: Male Wistar rat pups were exposed to maternal separation (postnatal days (PNDs) 1-14) and moderate AIE exposure (PNDs 28-57). Adult rats were tested in the five-choice serial reaction time task, which provides separate measures of attention, motor impulsivity, and compulsivity. Rats were tested under baseline conditions and in response to task manipulations that increased attentional load and impulsive behaviors, and after acute ethanol administration. RESULTS: Short stimulus and short intertrial interval (ITI) durations disrupted attention while long ITI durations impaired impulsivity in all rats. Moderate- and high-dose ethanol challenges impaired attention in all rats. Rats exposed to maternal separation and/or AIE exposure had significantly decreased omissions than non-handled water-exposed rats at baseline and tended to retain this effect in response to task challenges (i.e., the shorter stimulus and ITI durations, longer test session) and ethanol challenges, indicating moderate improvement of attentional performance. Maternal separation significantly increased perseverative responses at baseline and in response to decreased stimulus duration challenge, suggesting increased compulsivity. CONCLUSIONS: Separate or combined exposure to early life stress and AIE exposure moderately disrupts some aspects of adult executive control functions (e.g., increased compulsivity) but improves others (e.g., increased attention). The relative intensity of either manipulation during neonatal and adolescent periods may influence the direction in which cognitive behaviors are affected in adulthood.

Social defeat disrupts reward learning and potentiates striatal nociceptin/orphanin FQ mRNA in rats.

RATIONALE: Mood disorders can be triggered by stress and are characterized by deficits in reward processing, including disrupted reward learning (the ability to modulate behavior according to past rewards). Reward learning is regulated by the anterior cingulate cortex (ACC) and striatal circuits, both of which are implicated in the pathophysiology of mood disorders. OBJECTIVES: Here, we assessed in rats the effects of a potent stressor (social defeat) on reward learning and gene expression in the ACC, ventral tegmental area (VTA), and striatum. METHODS: Adult male Wistar rats were trained on an operant probabilistic reward task (PRT) and then exposed to 3 days of social defeat before assessment of reward learning. After testing, the ACC, VTA, and striatum were dissected, and expression of genes previously implicated in stress was assessed. RESULT: Social defeat blunted reward learning (manifested as reduced response bias toward a more frequently rewarded stimulus) and was associated with increased nociceptin/orphanin FQ (N/OFQ) peptide mRNA levels in the striatum and decreased Fos mRNA levels in the VTA. Moreover, N/OFQ peptide and nociceptin receptor mRNA levels in the ACC, VTA and striatum were inversely related to reward learning. CONCLUSIONS: The behavioral findings parallel previous data in humans, suggesting that stress similarly disrupts reward learning in both species. Increased striatal N/OFQ mRNA in stressed rats characterized by impaired reward learning is consistent with accumulating evidence that antagonism of nociceptin receptors, which bind N/OFQ, has antidepressant-like effects. These results raise the possibility that nociceptin systems represent a molecular substrate through which stress produces reward learning deficits in mood disorders.

Neonatal infection-induced memory impairment after lipopolysaccharide in adulthood is prevented via caspase-1 inhibition.

We have reported that neonatal infection leads to memory impairment after an immune challenge in adulthood. Here we explored whether events occurring as a result of early infection alter the response to a subsequent immune challenge in adult rats, which may then impair memory. In experiment 1, peripheral infection with Escherichia coli on postnatal day 4 increased cytokines and corticosterone in the periphery, and cytokine and microglial cell marker gene expression in the hippocampus of neonate pups. Next, rats treated neonatally with E. coli or PBS were injected in adulthood with lipopolysaccharide (LPS) or saline and killed 1-24 h later. Microglial cell marker mRNA was elevated in hippocampus in saline controls infected as neonates. Furthermore, LPS induced a greater increase in glial cell marker mRNA in hippocampus of neonatally infected rats, and this increase remained elevated at 24 h versus controls. After LPS, neonatally infected rats exhibited faster increases in interleukin-1beta (IL-1beta) within the hippocampus and cortex and a prolonged response within the cortex. There were no group differences in peripheral cytokines or corticosterone. In experiment 2, rats treated neonatally with E. coli or PBS received as adults either saline or a centrally administered caspase-1 inhibitor, which specifically prevents the synthesis of IL-1beta, 1 h before a learning event and subsequent LPS challenge. Caspase-1 inhibition completely prevented LPS-induced memory impairment in neonatally infected rats. These data implicate IL-1beta in the set of immune/inflammatory events that occur in the brain as a result of neonatal infection, which likely contribute to cognitive alterations in adulthood.

The role of glucocorticoids in the uncontrollable stress-induced potentiation of nucleus accumbens shell dopamine and conditioned place preference responses to morphine.

Exposure to stressors can impact on the responsiveness to drugs of abuse, and glucocorticoid hormones (CORT) may interact with dopamine (DA) within the nucleus accumbens shell (NAcs) to mediate these responses. We have previously shown that the CORT response to morphine, but not to a previous uncontrollable stressor, is necessary for the stress-induced potentiation of morphine's rewarding effects. Here, we test (1) the necessity of CORT during inescapable stress (IS) and/or morphine for IS potentiation of morphine-induced NAcs DA and (2) the sufficiency of enhanced CORT, in the absence of prior IS, to potentiate morphine-induced NAcs DA as well as morphine conditioned place preference (CPP) in male Sprague-Dawley rats. In the first experiment, we administered the CORT synthesis inhibitors metyrapone and aminoglutethimide (100mg/kg each, sc) to suppress the CORT response to either IS (100 1 mA tailshocks) or subsequent morphine (3 mg/kg, sc) treatment. Twenty-four hour after IS, microdialysis was performed and morphine was administered. In the next experiments, CORT (1 mg/kg, sc) was injected 20 or 30 min before morphine during either microdialysis or CPP testing, respectively, in non-stressed rats. We found that IS potentiated subsequent morphine-induced NAcs DA and this was completely blocked by CORT suppression before morphine, but not before IS. However, elevated levels of CORT concurrent with morphine, but in the absence of a stressor, failed to potentiate NAcs DA or CPP. These results suggest that the CORT response to morphine is necessary, but not sufficient in the absence of prior IS, for sensitized NAcs DA and CPP responding to morphine, and provide further evidence that CORT is involved in the expression, but not the induction, of this sensitization.

Translational Assessment of Reward and Motivational Deficits in Psychiatric Disorders.

Deficits in reward and motivation are common symptoms characterizing several psychiatric and neurological disorders. Such deficits may include anhedonia, defined as loss of pleasure, as well as impairments in anticipatory pleasure, reward valuation, motivation/effort, and reward learning. This chapter describes recent advances in the development of behavioral tasks used to assess different aspects of reward processing in both humans and non-human animals. While earlier tasks were generally developed independently with limited cross-species correspondence, a newer generation of translational tasks has emerged that are theoretically and procedurally analogous across species and allow parallel testing, data analyses, and interpretation between human and rodent behaviors. Such enhanced conformity between cross-species tasks will facilitate investigation of the neurobiological mechanisms underlying discrete reward and motivated behaviors and is expected to improve our understanding and treatment of neuropsychiatric disorders characterized by reward and motivation deficits.