Altered reward sensitivity to sucrose outcomes prior to drug exposure in alcohol preferring rats.

Addiction involves key impairments in reward sensitivity (RS). The current study explored impaired RS to natural reward as a predisposing factor to addictive-like behavior. Alcohol preferring (P) rats are selectively bred based on significantly greater ethanol consumption and preference and offer the ability to inspect differences in subjects with a positive family history of addictive-like behavior. P rat's RS was compared to RS in the well-used Sprague-Dawley (SD) strain. To assess RS in a novel manner, instrumental incentive contrast, discrimination and consumption of sucrose solution were examined. Animals performed in a free operant situation for different sucrose concentration solutions using a block of 'mixed' trials with alternating outcome concentrations (e.g., 5 and 10 % sucrose) to change outcome value in a predictable manner. Animals also performed for reward in blocks of single outcome trials (5 or 10 or 20 or 40 % sucrose daily exposure) surrounding the mixed block. RS (e.g., reward discrimination and contrast effects between and within-sessions) was measured by changes in trials completed, instrumental response latency and consumption. P rats expressed an altered profile of RS with a greater tendency toward equivalent responding to different outcomes within the same session and an absence of incentive contrast from diverse reward comparisons. In contrast, SD animals expressed within-session reward discrimination and a subset of incentive contrast effects. These effects were moderated by food deprivation more consistently in SD compared to P rats. P rat alterations in processing natural rewards could predispose them to addictive-like behaviors including greater alcohol consumption and preference.

The Human Affectome.

Over the last decades, theoretical perspectives in the interdisciplinary field of the affective sciences have proliferated rather than converged due to differing assumptions about what human affective phenomena are and how they work. These metaphysical and mechanistic assumptions, shaped by academic context and values, have dictated affective constructs and operationalizations. However, an assumption about the purpose of affective phenomena can guide us to a common set of metaphysical and mechanistic assumptions. In this capstone paper, we home in on a nested teleological principle for human affective phenomena in order to synthesize metaphysical and mechanistic assumptions. Under this framework, human affective phenomena can collectively be considered algorithms that either adjust based on the human comfort zone (affective concerns) or monitor those adaptive processes (affective features). This teleologically-grounded framework offers a principled agenda and launchpad for both organizing existing perspectives and generating new ones. Ultimately, we hope the Human Affectome brings us a step closer to not only an integrated understanding of human affective phenomena, but an integrated field for affective research.

The Human Affectome Project: A dedication to Jaak Panksepp.

Mapping the neural basis of the Affectome was certainly the goal of Jaak Panksepp as he extended the work of a long line of thinkers from William James to Paul Maclean. Jaak's contribution was not just an incremental step, but a move to embrace feelings as a key component of affective science. His goal was to develop objective behavioral measures as he identified the neural substrates associated with affective states. He dedicated his career to studying the biological roots of emotional operating systems and his 1998 book "Affective Neuroscience" stands as a seminal accomplishment that provided a foundation for a field of research that has flourished since. His influences can be seen in many of the reviews created for this project and his early references to comfort zones are central to the human affectome. Indeed, Jaak was a tireless investigator who challenged our thinking, and he gave us many insights and gifts. We are immensely grateful for his contributions and this special issue is dedicated to his memory.

Effort-reward balance and work motivation in rats: Effects of context and order of experience.

Being motivated means exerting effort toward a goal. The 'law of least work' emphasizes a preference for exerting relatively less effort. The law crosses boundaries among species and between physical and mental work. Organisms should be highly sensitive to shifts in effort-reward balance (ERB) in order to make optimal choices. We used a free operant-foraging task to investigate changes in ERB on choice between options requiring more or less effort. Results showed a consistent preference for the option with less effort and insensitivity to shifts in ERB. A second aim explored the influence of order of experience on effort choice. Choice for the more effortful option significantly increased after experiencing an equal effort-reward relationship during the initial free operant-foraging session. This relative increase in choice for the effortful option persisted even after effort-reward imbalance. The findings highlight the importance of contextual factors such as order of experience when examining the impact of shifting effort-reward associations. Instead of ignoring or reducing order effects, the sequence of experience (e.g. for shifts in ERB) could be manipulated to enhance or reduce value of outcomes or effort itself.

Exercise influences the impact of polychlorinated biphenyl exposure on immune function.

Polychlorinated biphenyls (PCBs) are environmental pollutants and endocrine disruptors, harmfully affecting reproductive, endocrine, neurological and immunological systems. This broad influence has implications for processes such as wound healing, which is modulated by the immunological response of the body. Conversely, while PCBs can be linked to diminished wound healing, outside of PCB pollution systems, exercise has been shown to accelerate wound healing. However, the potential for moderate intensity exercise to modulate or offset the harmful effects of a toxin like PCB are yet unknown. A key aim of the present study was to examine how PCB exposure at different doses (0, 100, 500, 1000 ppm i.p.) altered wound healing in exercised versus non-exercised subgroups of mice. We examined PCB effects on immune function in more depth by analyzing the concentrations of cytokines, interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), Interleukin-6 (IL-6) and granulocyte macrophage colony stimulating factor (GM-CSF) in these wounds inflicted by punch biopsy. Mice were euthanized at Day 3 or Day 5 after PCB injection (n = 3-6) and skin excised from the wound area was homogenized and analyzed for cytokine content. Results revealed that wound healing was not signficantly impacted by either PCB exposure or exercise, but there were patterns of delays in healing that depended on PCB dose. Changes in cytokines were also observed and depended on PCB dose and exercise experience. For example, IL-1ß concentrations in Day 5 mice without PCB administration were 33% less in exercised mice than mice not exercised. However, IL-1ß concentrations in Day 3 mice administered 100 ppm were 130% greater in exercised mice than not exercisedmice. Changes in the other measured cytokines varied with mainly depressions at lesser PCB doses and elevations at higher doses. Exercise had diverse effects on cytokine levels, but increased cytokine levels in the two greater doses. Explanations for these diverse effects include the use of young animals with more rapid wound healing rates less affected by toxin exposure, as well as PCB-mediated compensatory effects at specific doses which could actually enhance immune function. Future work should examine these interactions in more detail across a developmental time span. Understanding how manipulating the effects of exposure to environemntal contaminants using behavioral modification could be very useful in certain high risk populations or exposed individuals.

Mapping the interconnected neural systems underlying motivation and emotion: A key step toward understanding the human affectome.

As a part of a larger Affectome Project (http://neuroqualia.org/background.php) with an overarching goal of mapping and redefining biological substrates of feelings and emotions, we explored the neural underpinnings for the functions of motivation and emotion. Historically emotion and motivation have been placed into distinct neural circuits and examined separately. We propose a novel view of significant neural convergence of emotion and motivation, in contrast to conventional neural-based frameworks emphasizing segregation. Evidence from diverse research areas in emotion and motivation was reviewed, pinpointing key neural regions of overlap. The findings support important neural sharing between emotion and motivation, suggesting that these two functions are tightly intertwined with one another in the brain. Neural overlap does not necessarily imply continuous functional overlap. Even if identical brain regions/systems are activated for motivation and emotion, this activation may involve distinct and unique patterns of connection and information flow as the network shifts functionality. This review highlights the crucial importance of further research to explicate the patterns and modes of responding of these overlapping systems.

An investigation of variety effects during operant responding in the rat utilizing different reward flavors.

Humans and nonhuman animals respond to food diversity by increasing intake and appetitive behaviors, reflecting enhanced valuation for items presented in the context of variety. Previous work on food variety effects has posited two main explanatory mechanisms. Variety could slow habituation processes by decreasing exposure to a single food item or could elicit contrast effects in which comparisons between items impact relative valuation. This study used three flavors of sucrose rewards to investigate rats' responses to qualitative reward variety in different variety contexts: low (2 flavors) and high (3 flavors) conditions. Control sessions used only a single flavored pellet (no variety). Animals were tested in low (10 trials), moderate (20 trials) and high consumption (30 trials) sessions. A trial within each session was defined as completion of the operant response and acquisition of the reward pellet. Cues associated with flavors were used to examine predictability and between-trial ('micro') variety. Indicators of a variety effect were found including faster responding for rewards during the variety context compared to an initial control (no variety) context. This decrease in response latency continued to be observed for some measures in post-variety control contexts. The most robust statistical finding of variety effects was found using trial-by-trial analysis, with shorter response latencies obtained for trials with outcomes differing from the preceding trial compared to successive trials with identical outcomes. These results have implications for understanding how a general reward context like variety impacts behavior, and for informing clinical approaches focusing on motivation and eating disorders.

Neural encoding of choice during a delayed response task in primate striatum and orbitofrontal cortex.

Reward outcomes are available in many diverse situations and all involve choice. If there are multiple outcomes each rewarding, then decisions regarding relative value lead to choosing one over another. Important factors related to choice context should be encoded and utilized for this form of adaptive choosing. These factors can include the number of alternatives, the pacing of choice behavior and the possibility to reverse one's choice. An essential step in understanding if the context of choice is encoded is to directly compare choice with a context in which choice is absent. Neural activity in orbitofrontal cortex and striatum encodes potential value parameters related to reward quality and quantity as well as relative preference. We examined how neural activations in these brain regions are sensitive to choice situations and potentially involved in a prediction for the upcoming outcome selection. Neural activity was recorded and compared between a two-choice spatial delayed response task and an imperative 'one-option' task. Neural activity was obtained that extended from the instruction cue to the movement similar to previous work utilizing the identical imperative task. Orbitofrontal and striatal neural responses depended upon the decision about the choice of which reward to collect. Moreover, signals to predictive instruction cues that precede choice were selective for the choice situation. These neural responses could reflect chosen value with greater information on relative value of individual options as well as encode choice context itself embedded in the task as a part of the post-decision variable.

The effects of ethanol on diverse components of choice in the rat: reward discrimination, preference and relative valuation.

Alcohol consumption impairs judgment and choice. How alcohol alters these crucial processes is primarily unknown. Choice can be fractionated into different components including reward discrimination, preference and relative valuation that can function together or in isolation depending upon diverse factors including choice context. We examined the diverse components and contextual effects by analyzing the effects of alcohol drinking on choice behavior in a task with a reduced level of temporal and spatial constraints. Rats were trained to drink 10% ethanol during 6 weeks of behavior testing using a combined sucrose-fade and two-bottle free-choice procedure. Two different sucrose pellet outcomes (e.g., constant vs. variable) were presented each week to examine the impact of voluntary drinking on reward-based decision-making. Behavioral contexts of single option, free choice and extinction were examined for each outcome set. Comparisons were made between alcohol and control groups and within the alcohol group over time to inspect choice profiles. Between-group results showed alcohol drinking animals expressed altered place preference and modified sucrose reward approach latencies. The within-group profile showed that alcohol drinking animals can express adequate reward discrimination, preference and incentive contrast during free choice. All of these components were significantly reduced during the context of extinction. Control animals were also impacted by extinction but not as severely. The findings point to a need for a greater focus on the context and the diverse components of choice when examining external and internal factors influencing decision-making during alcohol or other substance of abuse exposure.

Effects of anandamide administration on components of reward processing during free choice.

Previous research has implicated the positive modulation of anandamide, an endocannabinoid neurotransmitter, on feeding behavior. Anandamide is particularly noteworthy as it acts as an endogenous ligand of the CB1 receptor, the same receptor that is activated by tetrahydrocannabinol, the primary psychoactive component in Cannabis sativa. Cannabis legalization in North America has presented with a need to study endocannabinoid agonists and their effects on behavior. Much has yet to be determined in terms of the role of the endocannabinoid system in decision-making scenarios. The research presented here tested the hypothesis that anandamide would augment motivation and reward processing via appetitive and consummatory measures during an operant, foraging task. A three-box design was used in order to provide the animals with a free choice, exploratory foraging environment. Discrimination, preference, and incentive contrast were analyzed as discrete measures of decision-making in the three-box paradigm. Anandamide administration (1mg/kg) was found to significantly increase motivation for the optimal foraging outcome and alter basic processing of reward information involved in discrimination and relative valuation. The positive effects of anandamide on eating behavior and motivation have implications toward possible treatment modalities for patient populations presenting with disorders of motivation. These findings suggest the need for continued investigation of the endocannabinoid system as a central component of motivated behavior.

Striatal Activity and Reward Relativity: Neural Signals Encoding Dynamic Outcome Valuation.

The striatum is a key brain region involved in reward processing. Striatal activity has been linked to encoding reward magnitude and integrating diverse reward outcome information. Recent work has supported the involvement of striatum in the valuation of outcomes. The present work extends this idea by examining striatal activity during dynamic shifts in value that include different levels and directions of magnitude disparity. A novel task was used to produce diverse relative reward effects on a chain of instrumental action. Rats (Rattus norvegicus) were trained to respond to cues associated with specific outcomes varying by food pellet magnitude. Animals were exposed to single-outcome sessions followed by mixed-outcome sessions, and neural activity was compared among identical outcome trials from the different behavioral contexts. Results recording striatal activity show that neural responses to different task elements reflect incentive contrast as well as other relative effects that involve generalization between outcomes or possible influences of outcome variety. The activity that was most prevalent was linked to food consumption and post-food consumption periods. Relative encoding was sensitive to magnitude disparity. A within-session analysis showed strong contrast effects that were dependent upon the outcome received in the immediately preceding trial. Significantly higher numbers of responses were found in ventral striatum linked to relative outcome effects. Our results support the idea that relative value can incorporate diverse relationships, including comparisons from specific individual outcomes to general behavioral contexts. The striatum contains these diverse relative processes, possibly enabling both a higher information yield concerning value shifts and a greater behavioral flexibility.

Effects of striatal lesions on components of choice: Reward discrimination, preference, and relative valuation.

The striatum is a key structure involved in reward processing and choice. Recently, we have developed a paradigm to explore how components of reward processing work together or independently during choice behavior. These components include reward discrimination, preference and relative valuation, and the goal of the present study was to determine how the striatum is involved in these dissociable components during this novel free choice paradigm. We tested choice utilizing two different outcome series with one being a more straightforward single-option discrimination anchored by a 0 reward outcome, and the other as a multi-option outcome discrimination of greater difficulty. We compared the free choice reward task to a sequential reward task and an extinction task. Striatal lesions impaired responding only in the free choice version with alterations in both appetitive and consummatory measures. Ventral striatal lesions had greater impact altering discrimination, preference and relative valuation in both the single and multi-option week studies. A major factor involved in these deficits was a significant aversion to the multi-option that contained a larger outcome option but with a longer delay to reward. Dorsal striatal lesions caused less impairment even leading to enhanced choice behavior compared to control animals during the more difficult multi-option free choice series. Overall, the results suggest that the context of action is crucial when linking striatal function to choice behavior and its diverse components. The implications include the idea that striatal involvement in decision-making is increased when responses are self-paced and diverse in a more naturalistic environment.

Influence of emotional states on inhibitory gating: animals models to clinical neurophysiology.

Integrating research efforts using a cross-domain approach could redefine traditional constructs used in behavioral and clinical neuroscience by demonstrating that behavior and mental processes arise not from functional isolation but from integration. Our research group has been examining the interface between cognitive and emotional processes by studying inhibitory gating. Inhibitory gating can be measured via changes in behavior or neural signal processing. Sensorimotor gating of the startle response is a well-used measure. To study how emotion and cognition interact during startle modulation in the animal model, we examined ultrasonic vocalization (USV) emissions during acoustic startle and prepulse inhibition. We found high rates of USV emission during the sensorimotor gating paradigm and revealed links between prepulse inhibition (PPI) and USV emission that could reflect emotional and cognitive influences. Measuring inhibitory gating as P50 event-related potential suppression has also revealed possible connections between emotional states and cognitive processes. We have examined the single unit responses during the traditional gating paradigm and found that acute and chronic stress can alter gating of neural signals in regions such as amygdala, striatum and medial prefrontal cortex. Our findings point to the need for more cross-domain research on how shifting states of emotion can impact basic mechanisms of information processing. Results could inform clinical work with the development of tools that depend upon cross-domain communication, and enable a better understanding and evaluation of psychological impairment.

Ultrasonic vocalizations, predictability and sensorimotor gating in the rat.

Prepulse inhibition (PPI) is a measure of sensorimotor gating in diverse groups of animals including humans. Emotional states can influence PPI in humans both in typical subjects and in individuals with mental illness. Little is known about emotional regulation during PPI in rodents. We used ultrasonic vocalization recording to monitor emotional states in rats during PPI testing. We altered the predictability of the PPI trials to examine any alterations in gating and emotional regulation. We also examined PPI in animals selectively bred for high or low levels of 50kHz USV emission. Rats emitted high levels of 22kHz calls consistently throughout the PPI session. USVs were sensitive to prepulses during the PPI session similar to startle. USV rate was sensitive to predictability among the different levels tested and across repeated experiences. Startle and inhibition of startle were not affected by predictability in a similar manner. No significant differences for PPI or startle were found related to the different levels of predictability; however, there was a reduction in USV signals and an enhancement of PPI after repeated exposure. Animals selectively bred to emit high levels of USVs emitted significantly higher levels of USVs during the PPI session and a reduced ASR compared to the low and random selective lines. Overall, the results support the idea that PPI tests in rodents induce high levels of negative affect and that manipulating emotional styles of the animals alters the negative impact of the gating session as well as the intensity of the startle response.

Perinatal exposure to polychlorinated biphenyls alters social behaviors in rats.

Perinatal exposure to polychlorinated biphenyls (PCBs) leads to significant alterations of neural and hormonal systems. These alterations have been shown to impair motor and sensory development. Less is known about the influence of PCB exposure on developing emotional and motivational systems involved in social interactions and social learning. The present study examined the impact of perinatal PCB exposure (mixture of congeners 47 and 77) on social recognition in juvenile animals, conspecific-directed investigation in adults and on neural and hormonal systems involved in social functions. We used a standard habituation-dishabituation paradigm to evaluate juvenile recognition and a social port paradigm to monitor adult social investigation. Areal measures of the periventricular nucleus (PVN) of the hypothalamus were obtained to provide correlations with related hormone and brain systems. PCB exposed rats were significantly impaired in social recognition as indicated by persistent conspecific-directed exploration by juvenile animals regardless of social experience. As adults, PCB exposure led to a dampening of the isolation-induced enhancement of social investigation. There was not a concomitant alteration of social investigation in pair-housed PCB exposed animals at this stage of development. Interestingly, PVN area was significantly decreased in juvenile animals exposed to PCB during the perinatal period. Shifts in hypothalamic regulation of hormones involved in social behavior and stress could be involved in the behavioral changes observed. Overall, the results suggest that PCB exposure impairs context or experience-dependent modulation of social approach and investigation. These types of social-context deficits are similar to behavioral deficits observed in social disorders such as autism and other pervasive developmental disorders.

Reduction of prelimbic inhibitory gating of auditory evoked potentials after fear conditioning.

Inhibitory gating (IG) is a basic central nervous system process for filtering repetitive sensory information. Although IG deficits coincide with cognitive and emotional dysfunction in a variety of neuropsychiatric disorders, limited research has been completed on the basic, functional nature of IG. Persistent IG occurs in rat prelimbic medial prefrontal cortex (mPFC), a crucial site for modulating emotional learning. To investigate the interaction of affect and IG, we recorded local field potentials (LFP) directly from prelimbic mPFC and examined the influence of tone-shock fear conditioning (FC) on IG. Behavioral reactions during IG were observed before and after FC, and increase of orienting response after FC indicated induction of tone-shock association. After FC, some components of LFP response exhibited short-term weakening of IG. On a subsequent day of recording, IG strengthened for all LFP components, but individual components differed in their particular changes. Affective regulation of IG represents an important factor influencing within-subject IG variability, and these results have implications for understanding the role of rapid, implicit neural coding involved in emotional learning and affective disruption in psychiatric disease.

The effects of selective breeding for differential rates of 50-kHz ultrasonic vocalizations on emotional behavior in rats.

Fifty-kHz ultrasonic vocalizations have previously been shown to be positively correlated with reward and appetitive social behavior in rats, and to reflect a positive affective state. In this study, rats selectively bred for high and low rates of 50-kHz vocalizations as juveniles were tested as adults in a battery of behavioral tests for social/emotional behaviors. We found that animals selectively bred for high rates of 50-kHz vocalizations exhibited more crosses into the center area of the open field apparatus, were more likely to show a preference for a dilute sucrose solution (.8%) compared to tap water, and were less aggressive than randomly bred animals. Conversely, animals bred for low rates of 50-kHz calls produced more fecal boli during both open field testing and "tickling" stimulation, and made less contact with conspecifics in a social interaction test compared to randomly bred animals. We also observed that low line rats have elevated brain levels of cholecystokinin (CCK) in the cortex, which is consistent with literature showing that CCK content in the cortex is positively correlated with rates of aversive 22-kHz USVs. Conversely, high line animals had elevated levels of met-enkephalin in several brain regions, which is consistent with the role of endogenous-opioids in the generation 50-kHz USVs and positive affect. These results suggest that animals bred for high rates of 50-kHz may show a stress resilient phenotype, whereas low line rats may show a stress prone phenotype. As such these animals could provide novel insights into the neurobiology of emotion.

The effects of prenatal stress on motivation in the rat pup.

Exposure to prenatal stress (PNS) has been shown to induce a set of psychological and behavioral changes in developing offspring. We used the rodent model to investigate whether PNS produces changes in the ability of the pup to express social motivation. We used a set of behavioral tasks including monitoring ultrasonic vocalizations after isolation, a conditioned place preference, and a novel and familiar odor approach test. Pregnant Long-Evans rats were exposed to an unpredictable, variable stressor twice daily during the third week of gestation. Isolation vocalizations were assessed on postnatal day (PND) 10. Pup affinity for the dam was evaluated on PND 15. Typically, pups display a selective preference for an odor-paired environment only after the odor has been associated with the dam. This previous association produces a positive conditioned stimulus (CS). Normally, pups exposed to a neutral CS (odor paired with cotton balls) do not form this place preference. Results indicate that PNS exposed pups had significantly increased distress vocalizations and an equal preference for the positive and neutral conditioned stimuli. This type of alteration in forming early preferences could be detrimental because of decreases in the specificity of social learning and an impaired responsiveness in social relationships.

Sensory gating: a translational effort from basic to clinical science.

Sensory gating (SG) is a prevalent physiological process important for information filtering in complex systems. SG is evaluated by presenting repetitious stimuli and measuring the degree of neural inhibition that occurs. SG has been found to be impaired in several psychiatric disorders. Recent animal and human research has made great progress in the study of SG, and in this review we provide an overview of recent research on SG using different methods. Animal research has uncovered findings that suggest (1) SG is displayed by single neurons and can be similar to SG observed from scalp recordings in humans, (2) SG is found in numerous brain structures located in sensory, motor and limbic subregions, (3) SG can be significantly influenced by state changes of the organism, and (4) SG has a diverse pharmacological profile accented by a strong influence from nicotine receptor activation. Human research has addressed similar issues using deep electrode recordings of brain structures. These experiments have revealed that (1) SG can be found in cortical regions surrounding hippocampus, (2) the order of neural processing places hippocampal involvement during a later stage of sensory processing than originally thought, and (3) multiple subtypes of gating exist that could be dependent on different brain circuits and more or less influenced by alterations in organismal state. Animal and human research both have limitations. We emphasize the need for integrative approaches to understand the process and combine information between basic and clinical fields so that a more complete picture of SG will emerge.

Effects of polychlorinated biphenyls on maternal odor conditioning in rat pups.

Polychlorinated biphenyls (PCBs) are pervasive environmental contaminants that can have damaging effects on physiologic, motoric and cognitive function. Results from studies on PCBs and behavior have shown that exposure can alter learning and memory processes and that these shifts in cognitive abilities can be related to changes in hormonal and neural function. Little experimentation has been done on the impact of exposure to PCBs on social and emotional development. Previous work has shown that exposure to PCBs in children can alter play behavior. Importantly, exposure to PCBs has been found to change aspects of maternal-offspring interactions in rodents. The present study examined the impact of PCBs on maternal odor conditioning in rat pups 12-14 days of age. A modified version of the conditioned place preference paradigm was used that incorporated a maternal-associated odor cue (lemon scent) as the conditioned stimulus. PCBs significantly depressed the preference for the maternal-associated cue but did not impair discrimination for a novel odor. These effects could arise due to changes in the social dynamics between the dam and offspring after co-exposure to PCBs. For example, dams exposed to PCBs during gestation have been found to show elevated grooming directed towards pups exposed to PCBs. This change in maternal care can have dramatic effects on behavioral and hormonal systems in the developing rat pup. In conclusion, perinatal PCBs alter important social behaviors of both the mother and pup, and these alterations could have long-lasting effects on behavioral, cognitive and emotional development.