Opportunities for risk-taking during play alters cognitive performance and prefrontal inhibitory signalling in rats of both sexes.

Social play behaviour is a rewarding activity that can entail risks, thus allowing young individuals to test the limits of their capacities and to train their cognitive and emotional adaptability to challenges. Here, we tested in rats how opportunities for risk-taking during play affect the development of cognitive and emotional capacities and medial prefrontal cortex (mPFC) function, a brain structure important for risk-based decision making. Male and female rats were housed socially or social play-deprived (SPD) between postnatal day (P)21 and P42. During this period, half of both groups were daily exposed to a high-risk play environment. Around P85, all rats were tested for cognitive performance and emotional behaviour after which inhibitory currents were recorded in layer 5 pyramidal neurons in mPFC slices. We show that playing in a high-risk environment altered cognitive flexibility in both sexes and improved behavioural inhibition in males. High-risk play altered anxiety-like behaviour in the elevated plus maze in males and in the open field in females, respectively. SPD affected cognitive flexibility in both sexes and decreased anxiety-like behaviour in the elevated plus maze in females. We found that synaptic inhibitory currents in the mPFC were increased in male, but not female, rats after high-risk play, while SPD lowered prefrontal cortex (PFC) synaptic inhibition in both sexes. Together, our data show that exposure to risks during play affects the development of cognition, emotional behaviour and inhibition in the mPFC. Furthermore, our study suggests that the opportunity to take risks during play cannot substitute for social play behaviour.

Animal play and evolution: Seven timely research issues about enigmatic phenomena.

The nature of play in animals has been long debated, but progress is being made in characterizing play and its variants, documenting its distribution across vertebrate and invertebrate taxa, describing its mechanisms and development, and proposing testable theories about its origins, evolution, and adaptive functions. To achieve a deeper understanding of the functions and evolution of play, integrative and conceptual advances are needed in neuroscience, computer modeling, phylogenetics, experimental techniques, behavior development, and inter- and intra-specific variation. The special issue contains papers documenting many of these advances. Here, we describe seven timely areas where further research is needed to understand this still enigmatic class of phenomena more fully. Growing empirical and theoretical evidence reveals that play has been crucial in the evolution of behavior and psychology but has been underestimated, if not ignored, in both empirical and theoretical areas of evolutionary biology and neuroscience. Play research has important ramifications for understanding the evolution of cognition, emotion, and culture, and research on animals can be both informative and transformative.

Neurexin1α knockout in rats causes aberrant social behaviour: relevance for autism and schizophrenia.

RATIONALE: Genetic and environmental factors cause neuropsychiatric disorders through complex interactions that are far from understood. Loss-of-function mutations in synaptic proteins like neurexin1α have been linked to autism spectrum disorders (ASD) and schizophrenia (SCZ), both characterised by problems in social behaviour. Childhood social play behaviour is thought to facilitate social development, and lack of social play may precipitate or exacerbate ASD and SCZ. OBJECTIVE: To test the hypothesis that an environmental insult acts on top of genetic vulnerability to precipitate psychiatric-like phenotypes. To that aim, social behaviour in neurexin1α knockout rats was assessed, with or without deprivation of juvenile social play. We also tested drugs prescribed in ASD or SCZ to assess the relevance of this dual-hit model for these disorders. RESULTS: Neurexin1α knockout rats showed an aberrant social phenotype, with high amounts of social play, increased motivation to play, age-inappropriate sexual mounting, and an increase in general activity. Play deprivation subtly altered later social behaviour, but did not affect the phenotype of neurexin1α knockout rats. Risperidone and methylphenidate decreased play behaviour in both wild-type and knockout rats. Amphetamine-induced hyperactivity was exaggerated in neurexin1α knockout rats. CONCLUSION: Deletion of the neurexin1α gene in rats causes exaggerated social play, which is not modified by social play deprivation. This phenotype therefore resembles disinhibited behaviour rather than the social withdrawal seen in ASD and SCZ. The neurexin1α knockout rat could be a model for inappropriate or disinhibited social behaviour seen in childhood mental disorders.

CaMKIIa+ neurons in the bed nucleus of the stria terminalis modulate pace of natural reward seeking depending on internal state.

This study aims to investigate the underlying neurobiological mechanisms that regulate natural reward seeking behaviors, specifically in the context of sexual behavior and sucrose self-administration. The role of CaMKIIa+ neurons in the bed nucleus of the stria terminalis (BNST) was explored using chemogenetic silencing and -stimulation. Additionally, the study examined how these effects interacted with the internal state of the animals. Through detailed behavioral analysis, it was demonstrated that CaMKIIa+ neurons in the BNST play a significant role in the regulation of both sexual behavior and sucrose self-administration. Although the behavioral outcome measures differed between the two behaviors, the regulatory role of the CaMKIIa+ neurons in the BNST was found to converge on the modulation of the pacing of engagement in these behaviors in male rats. Moreover, our study confirmed that the internal physiological state of the animal affects how the BNST modulates these behaviors. These findings suggest that different types of natural rewards may recruit a similar brain circuitry to regulate the display of motivated behaviors. Overall, this research provides valuable insights into the neural mechanisms underlying natural reward seeking and sheds light on the interconnected nature of reward-related behaviors in male rats.

The neurobiology of social play behaviour: Past, present and future.

Social play behaviour is a highly energetic and rewarding activity that is of great importance for the development of brain and behaviour. Social play is abundant during the juvenile and early adolescent phases of life, and it occurs in most mammalian species, as well as in certain birds and reptiles. To date, the majority of research into the neural mechanisms of social play behaviour has been performed in male rats. In the present review we summarize studies on the neurobiology of social play behaviour in rats, including work on pharmacological and genetic models for autism spectrum disorders, early life manipulations and environmental factors that influence play in rats. We describe several recent developments that expand the field, and highlight outstanding questions that may guide future studies.

Social play behavior shapes the development of prefrontal inhibition in a region-specific manner.

Experience-dependent organization of neuronal connectivity is critical for brain development. We recently demonstrated the importance of social play behavior for the developmental fine-tuning of inhibitory synapses in the medial prefrontal cortex in rats. When these effects of play experience occur and if this happens uniformly throughout the prefrontal cortex is currently unclear. Here we report important temporal and regional heterogeneity in the impact of social play on the development of excitatory and inhibitory neurotransmission in the medial prefrontal cortex and the orbitofrontal cortex. We recorded in layer 5 pyramidal neurons from juvenile (postnatal day (P)21), adolescent (P42), and adult (P85) rats after social play deprivation (between P21 and P42). The development of these prefrontal cortex subregions followed different trajectories. On P21, inhibitory and excitatory synaptic input was higher in the orbitofrontal cortex than in the medial prefrontal cortex. Social play deprivation did not affect excitatory currents, but reduced inhibitory transmission in both medial prefrontal cortex and orbitofrontal cortex. Intriguingly, the reduction occurred in the medial prefrontal cortex during social play deprivation, whereas the reduction in the orbitofrontal cortex only became manifested after social play deprivation. These data reveal a complex interaction between social play experience and the specific developmental trajectories of prefrontal subregions.

Inhibition of ventral tegmental area projections to the nucleus accumbens shell increases premature responding in the five-choice serial reaction time task in rats.

Exaggerated impulsivity and attentional impairments are hallmarks of certain disorders of behavioural control such as attention-deficit/hyperactivity disorder (ADHD), schizophrenia and addiction. Pharmacological studies have implicated elevated dopamine (DA) levels in the nucleus accumbens shell (NAcbS) in impulsive actions. The NAcbS receives its DA input from the ventral tegmental area (VTA), and we have previously shown that optogenetic activation of VTA-NAcbS projections impaired impulse control and attention in the five-choice serial reaction time task (5-CSRTT) in rats. To better understand the role of VTA-NAcbS projections in impulsivity and attention, the present study sought to inhibit this projection using optogenetics. We demonstrate that inhibiting VTA-NAcbS efferents during the last seconds of the inter-trial interval (i.e. immediately before presentation of the instructive cue) induces exaggerated impulsive action, in the absence of changes in attentional or motivational parameters in the 5-CSRTT. Together with our earlier observations, this suggests that impulse control in the 5-CSRTT is tightly controlled by VTA-NAcbS activity, with deviations in both directions resulting in increased impulsivity.

Social Play Behavior Is Critical for the Development of Prefrontal Inhibitory Synapses and Cognitive Flexibility in Rats.

Sensory driven activity during early life is critical for setting up the proper connectivity of the sensory cortices. We ask here whether social play behavior, a particular form of social interaction that is highly abundant during postweaning development, is equally important for setting up connections in the developing prefrontal cortex (PFC). Young male rats were deprived from social play with peers during the period in life when social play behavior normally peaks [postnatal day 21-42] (SPD rats), followed by resocialization until adulthood. We recorded synaptic currents in layer 5 cells in slices from medial PFC of adult SPD and control rats and observed that inhibitory synaptic currents were reduced in SPD slices, while excitatory synaptic currents were unaffected. This was associated with a decrease in perisomatic inhibitory synapses from parvalbumin-positive GABAergic cells. In parallel experiments, adult SPD rats achieved more reversals in a probabilistic reversal learning (PRL) task, which depends on the integrity of the PFC, by using a more simplified cognitive strategy than controls. Interestingly, we observed that one daily hour of play during SPD partially rescued the behavioral performance in the PRL, but did not prevent the decrease in PFC inhibitory synaptic inputs. Our data demonstrate the importance of unrestricted social play for the development of inhibitory synapses in the PFC and cognitive skills in adulthood and show that specific synaptic alterations in the PFC can result in a complex behavioral outcome.SIGNIFICANCE STATEMENT This study addressed the question whether social play behavior in juvenile rats contributes to functional development of the prefrontal cortex (PFC). We found that rats that had been deprived from juvenile social play (social play deprivation - SPD) showed a reduction in inhibitory synapses in the PFC and a simplified strategy to solve a complex behavioral task in adulthood. Providing one daily hour of play during SPD partially rescued the cognitive skills in these rats, but did not prevent the reduction in PFC inhibitory synapses. Our results demonstrate a key role for unrestricted juvenile social play in PFC development and emphasize the complex relation between PFC circuit connectivity and cognitive function.

Increased elasticity of sucrose demand during hyperdopaminergic states in rats.

RATIONALE: Deficits in cost-benefit decision-making are a core feature of several psychiatric disorders, including substance addiction, eating disorders and bipolar disorder. Mesocorticolimbic dopamine signalling has been implicated in various processes related to cognition and reward, but its precise role in reward valuation and cost-benefit trade-off decisions remains incompletely understood. OBJECTIVES: We assessed the role of mesocorticolimbic dopamine signalling in the relationship between price and consumption of sucrose, to better understand its role in cost-benefit decisions. METHODS: Dopamine neurons in the ventral tegmental area (VTA) were chemogenetically activated in rats, and a behavioural economics approach was used to quantify the relationship between price and consumption of sucrose. Motivation for sucrose was also assessed under a progressive ratio (PR) schedule of reinforcement. To further gauge the role of dopamine in cost-benefit trade-offs for sucrose, the effects of treatment with D-amphetamine and the dopamine receptor antagonist alpha-flupentixol were assessed. RESULTS: Chemogenetic activation of VTA dopamine neurons increased demand elasticity, while responding for sucrose under a PR schedule of reinforcement was augmented upon stimulation of VTA dopamine neurons. Treatment with amphetamine partially replicated the effects of chemogenetic dopamine neuron activation, whereas treatment with alpha-flupentixol reduced free consumption of sucrose and had mixed effects on demand elasticity. CONCLUSIONS: Stimulation of mesocorticolimbic dopaminergic neurotransmission altered cost-benefit trade-offs in a complex manner. It reduced the essential value of palatable food, increased incentive motivation and left free consumption unaltered. Together, these findings imply that mesocorticolimbic dopamine signalling differentially influences distinct components of cost expenditure processes aimed at obtaining rewards.

Cognitive performance during adulthood in a rat model of neonatal diffuse white matter injury.

RATIONALE: Infants born prematurely risk developing diffuse white matter injury (WMI), which is associated with impaired cognitive functioning and an increased risk of autism spectrum disorder. Recently, our rat model of preterm diffuse WMI induced by combined fetal inflammation and postnatal hypoxia showed impaired motor performance, anxiety-like behaviour and autism-like behaviour in juvenile rats, especially males. Immunohistochemistry showed delayed myelination in the sensory cortex and impaired oligodendrocyte differentiation. OBJECTIVE: To assess long-term cognitive deficits in this double-hit rat model of diffuse WMI, animals were screened on impulsivity, attention and cognitive flexibility in adulthood using the 5-choice serial reaction time task (5CSRTT) and a probabilistic reversal learning task, tests that require a proper functioning prefrontal cortex. Thereafter, myelination deficits were evaluated by immunofluorescent staining in adulthood. RESULTS: Overall, little effect of WMI or sex was found in the cognitive tasks. WMI animals showed subtle differences in performance in the 5CSRTT. Manipulating 5CSRTT parameters resulted in performance patterns previously seen in the literature. Sex differences were found in perseverative responses and omitted trials: female WMI rats seem to be less flexible in the 5CSRTT but not in the reversal learning task. Males collected rewards faster in the probabilistic reversal learning task. These findings are explained by temporally rather than permanently affected myelination and by the absence of extensive injury to prefrontal cortical subregions, confirmed by immunofluorescent staining in both adolescence and adulthood. CONCLUSION: This rat model of preterm WMI does not lead to long-term cognitive deficits as observed in prematurely born human infants.

On the interrelation between alcohol addiction-like behaviors in rats.

RATIONALE: Alcohol use disorder (AUD) is a complex, heterogeneous disorder that only occurs in a minority of alcohol users. Various behavioral constructs, including excessive intake, habit formation, motivation for alcohol and resistance to punishment have been implicated in AUD, but their interrelatedness is unclear. OBJECTIVE: The aim of this study was therefore to explore the relation between these AUD-associated behavioral constructs in rats. We hypothesised that a subpopulation of animals could be identified that, based on these measures, display consistent AUD-like behavior. METHODS: Lister Hooded rats (n = 47) were characterised for alcohol consumption, habit formation, motivation for alcohol and quinine-adulterated alcohol consumption. The interrelation between these measures was evaluated through correlation and cluster analyses. In addition, addiction severity scores were computed using different combinations of the behavioral measures, to assess the consistency of the AUD-like subpopulation. RESULTS: We found that the data was uniformly distributed, as there was no significant tendency of the behavioral measures to cluster in the dataset. On the basis of multiple ranked addiction severity scores, five animals (~ 11%) were classified as displaying AUD-like behavior. The composition of the remaining subpopulation of animals with the highest addiction severity score (9 rats; ~ 19%) varied, depending on the combination of measures included. CONCLUSION: Consistent AUD-like behavior was detected in a small proportion of alcohol drinking rats. Alcohol consumption, habit formation, motivation for alcohol and punishment resistance contribute in varying degrees to the AUD-like phenotype across the population. These findings emphasise the importance of considering the heterogeneity of AUD-like behavior.

Individual differences in social play behaviour predict alcohol intake and control over alcohol seeking in rats.

RATIONALE: Social play behaviour is a rewarding social activity displayed by young mammals, thought to be important for the development of brain and behaviour. Indeed, disruptions of social play behaviour in rodents have been associated with cognitive deficits and augmented sensitivity to self-administration of substances of abuse, including alcohol, later in life. However, the relation between social development and loss of control over substance use, a key characteristic of substance use disorders including alcohol use disorder (AUD), has not been investigated. Moreover, it remains unknown how inherent differences in playfulness relate to differences in the sensitivity to substance use and AUD. OBJECTIVE: The objective of this study is to determine how individual differences in juvenile social play behaviour predict alcohol intake and loss of control over alcohol seeking. METHODS: Juvenile male Lister hooded rats were characterized for their tendency to engage in social play behaviour. Subsequently, alcohol consumption and conditioned suppression of alcohol seeking were assessed in the tertiles of rats that showed the most and least social play. RESULTS: The rats that engaged most in social play behaviour consumed more alcohol than their less playful counterparts. However, whereas the most playful rats showed intact conditioned suppression of alcohol seeking, the least playful rats showed no such suppression. CONCLUSION: Individual levels of playfulness predict the sensitivity to alcohol-directed behaviour. Highly playful rats are more prone to alcohol intake, yet show greater control over alcohol seeking. These findings increase our understanding of the relationship between social development and vulnerability to AUD.

Temporally Specific Roles of Ventral Tegmental Area Projections to the Nucleus Accumbens and Prefrontal Cortex in Attention and Impulse Control.

Deficits in impulse control and attention are prominent in the symptomatology of mental disorders such as attention deficit hyperactivity disorder (ADHD), substance addiction, schizophrenia, and bipolar disorder, yet the underlying mechanisms are incompletely understood. Frontostriatal structures, such as the nucleus accumbens (NAcb), the medial prefrontal cortex (mPFC), and their dopaminergic innervation from the ventral tegmental area (VTA) have been implicated in impulse control and attention. What remains unclear is how the temporal pattern of activity of these VTA projections contributes to these processes. Here, we optogenetically stimulated VTA dopamine (DA) cells, as well as VTA projections to the NAcb core (NAcbC), NAcb shell (NAcbS), and the mPFC in male rats performing the 5-choice serial reaction time task (5-CSRTT). Our data show that stimulation of VTA DA neurons, and VTA projections to the NAcbC and the mPFC immediately before presentation of the stimulus cue, impaired attention but spared impulse control. Importantly, in addition to reducing attention, activation of VTA-NAcbS also increased impulsivity when tested under a longer intertrial interval (ITI), to provoke impulsive behavior. Optogenetic stimulation at the beginning of the ITI only partially replicated these effects. In sum, our data show how attention and impulsivity are modulated by neuronal activity in distinct ascending output pathways from the VTA in a temporally specific manner. These findings increase our understanding of the intricate mechanisms by which mesocorticolimbic circuits contribute to cognition.SIGNIFICANCE STATEMENT Deficits in impulse control and attention are prominent in the symptomatology of several mental disorders, yet the brain mechanisms involved are incompletely understood. Since frontostriatal circuits have been implicated in impulse control and attention, we here examined the role of ascending projections from the midbrain ventral tegmental area (VTA) to the nucleus accumbens (NAcb) and prefrontal cortex (PFC). Using optogenetics to individually stimulate these projections with time-locked precision, we distinguished the role that each of these projections plays, in both impulse control and attention. As such, our study enhances our understanding of the neuronal circuitry that drives impulsive and attentive behavior.

Addiction as a brain disease revised: why it still matters, and the need for consilience.

The view that substance addiction is a brain disease, although widely accepted in the neuroscience community, has become subject to acerbic criticism in recent years. These criticisms state that the brain disease view is deterministic, fails to account for heterogeneity in remission and recovery, places too much emphasis on a compulsive dimension of addiction, and that a specific neural signature of addiction has not been identified. We acknowledge that some of these criticisms have merit, but assert that the foundational premise that addiction has a neurobiological basis is fundamentally sound. We also emphasize that denying that addiction is a brain disease is a harmful standpoint since it contributes to reducing access to healthcare and treatment, the consequences of which are catastrophic. Here, we therefore address these criticisms, and in doing so provide a contemporary update of the brain disease view of addiction. We provide arguments to support this view, discuss why apparently spontaneous remission does not negate it, and how seemingly compulsive behaviors can co-exist with the sensitivity to alternative reinforcement in addiction. Most importantly, we argue that the brain is the biological substrate from which both addiction and the capacity for behavior change arise, arguing for an intensified neuroscientific study of recovery. More broadly, we propose that these disagreements reveal the need for multidisciplinary research that integrates neuroscientific, behavioral, clinical, and sociocultural perspectives.

The Persistent Challenge of Developing Addiction Pharmacotherapies.

There are currently effective Food and Drug Administration (FDA)-approved therapies for alcohol, nicotine, and opioid use disorders. This article will review the development of eight compounds used in the treatment of drug addiction with an emphasis on pharmacological mechanisms and the utility of preclinical animal models of addiction in therapeutic development. In contrast to these successes, animal research has identified a number of promising medications for the treatment of psychostimulant use disorder, none of which have proven to be clinically effective. A specific example of an apparently promising pharmacotherapeutic for cocaine that failed clinically will be examined to determine whether this truly represents a challenge to the predictive validity of current models of cocaine addiction. In addition, the development of promising cocaine use disorder therapeutics derived from animal research will be reviewed, with some discussion regarding how preclinical studies might be modified to better inform clinical outcomes.

Animal Models of the Behavioral Symptoms of Substance Use Disorders.

To more effectively manage substance use disorders, it is imperative to understand the neural, genetic, and psychological underpinnings of addictive behavior. To contribute to this understanding, considerable efforts have been made to develop translational animal models that capture key behavioral characteristics of addiction on the basis of DSM5 criteria of substance use disorders. In this review, we summarize empirical evidence for the occurrence of addiction-like behavior in animals. These symptoms include escalation of drug use, neurocognitive deficits, resistance to extinction, exaggerated motivation for drugs, increased reinstatement of drug seeking after extinction, preference for drugs over nondrug rewards, and resistance to punishment. The occurrence of addiction-like behavior in laboratory animals has opened the opportunity to investigate the neural, genetic, and psychological background of key aspects of addiction, which may ultimately contribute to the prevention and treatment of substance use disorders.

Baclofen and naltrexone, but not N-acetylcysteine, affect voluntary alcohol drinking in rats regardless of individual levels of alcohol intake.

In humans, there is profound individual variation in the risk of alcohol use disorder (AUD). Because GABA, opioid and glutamate neurotransmission have been implicated in AUD, functional differences in these neural systems may underlie the individual vulnerability to AUD. We therefore determined the effects of drugs affecting GABA, opioid and glutamatergic neurotransmission on alcohol consumption in rats that differed in baseline alcohol intake. Subgroups of low-, medium- and high-alcohol-drinking rats were selected on the basis of alcohol consumption using an intermittent alcohol access procedure. The subgroups were treated with the GABAB receptor agonist baclofen, the opioid receptor antagonist naltrexone and the cysteine precursor N-acetylcysteine, and the effects on alcohol intake and preference were determined. Both baclofen and naltrexone reduced alcohol consumption, but N-acetylcysteine did not. These effects were comparable for low-, medium- and high-alcohol-drinking rats. However, there was a substantial degree of individual variation in the responsivity to baclofen and naltrexone, across the subgroups. Taken together, these results suggest that variation in alcohol consumption does not predict the responsivity to baclofen and naltrexone. This implies that individual variability in alcohol consumption on the one hand and sensitivity to treatment with these drugs on the other hand represent separate processes that likely involve distinct biological mechanisms.

Detrimental effects of the 'bath salt' methylenedioxypyrovalerone on social play behavior in male rats.

Methylenedioxypyrovalerone (MDPV) is the most popular synthetic cathinone found in products marketed as 'bath salts', widely abused among teenagers and young adults. Synthetic cathinones have pharmacological effects resembling those of psychostimulants, which are known to disrupt a variety of social behaviors. However, despite the popular use of MDPV by young people in social contexts, information about its effects on social behavior is scarce. To investigate the impact of MDPV on social behavior at young age, and the underlying neurobehavioral mechanisms, we focused on social play behavior. Social play behavior is the most characteristic social behavior displayed by young mammals and it is crucial for neurobehavioral development. Treatment with MDPV reduced social play behavior in both juvenile and young adult male rats, and its play-suppressant effect was subject to tolerance but not sensitization. As the behavioral effects of MDPV have been ascribed to dopaminergic and noradrenergic neurotransmission, and given the role of these neurotransmitters in social play, we investigated the involvement of dopamine and noradrenaline in the play-suppressant effects of MDPV. The effects of MDPV on social play were blocked by either the α2 adrenoceptor antagonist RX821002 or the dopamine receptor antagonist flupenthixol, given alone or together at sub-effective doses. In sum, MDPV selectively suppresses the most vigorous social behavior of developing rats through both noradrenergic and dopaminergic mechanisms. This study provides important preclinical evidence of the deleterious effects of MDPV on social behavior, and as such increases our understanding of the neurobehavioral effects of this popular cathinone.