Effects of psilocybin on uncertain punishment learning.

Psilocybin may provide a useful treatment for mood disorders including anxiety and depression but its mechanisms of action for these effects are not well understood. While recent preclinical work has begun to assess psilocybin's role in affective behaviors through innate anxiety or fear conditioning, there is scant evidence for its role in conflict between reward and punishment. The current study was designed to determine the impact of psilocybin on the learning of reward-punishment conflict associations, as well as its effects after learning, in male and female rats. We utilized a chained schedule of reinforcement that involved execution of safe and risky reward-guided actions under uncertain punishment. Different patterns of behavioral suppression by psilocybin emerged during learning versus after learning of risky action-reward associations. Psilocybin increased behavioral suppression in female rats as punishment associations were learned. After learning, psilocybin decreased behavioral suppression in both sexes. Thus, psilocybin produces divergent effects on action suppression during approach-avoidance conflict depending on when the conflict is experienced. This observation may have implications for its therapeutic mechanism of action.

Adolescent Dopamine Neurons Represent Reward Differently during Action and State Guided Learning.

Neuronal underpinning of learning cause-and-effect associations in the adolescent brain remains poorly understood. Two fundamental forms of associative learning are Pavlovian (classical) conditioning, where a stimulus is followed by an outcome, and operant (instrumental) conditioning, where outcome is contingent on action execution. Both forms of learning, when associated with a rewarding outcome, rely on midbrain dopamine neurons in the ventral tegmental area (VTA) and substantia nigra (SN). We find that, in adolescent male rats, reward-guided associative learning is encoded differently by midbrain dopamine neurons in each conditioning paradigm. Whereas simultaneously recorded VTA and SN adult neurons have a similar phasic response to reward delivery during both forms of conditioning, adolescent neurons display a muted reward response during operant but a profoundly larger reward response during Pavlovian conditioning. These results suggest that adolescent neurons assign a different value to reward when it is not gated by action. The learning rate of adolescents and adults during both forms of conditioning was similar, supporting the notion that differences in reward response in each paradigm may be because of differences in motivation and independent of state versus action value learning. Static characteristics of dopamine neurons, such as dopamine cell number and size, were similar in the VTA and SN of both ages, but there were age-related differences in stimulated dopamine release and correlated spike activity, suggesting that differences in reward responsiveness by adolescent dopamine neurons are not because of differences in intrinsic properties of these neurons but engagement of different dopaminergic networks.SIGNIFICANCE STATEMENT Reckless behavior and impulsive decision-making by adolescents suggest that motivated behavioral states are encoded differently by the adolescent brain. Motivated behavior, which is dependent on the function of the dopamine system, follows learning of cause-and-effect associations in the environment. We find that dopamine neurons in adolescents encode reward differently depending on the cause-and-effect relationship of the means to receive that reward. Compared with adults, reward contingent on action led to a muted response, whereas reward that followed a cue but was not gated by action produced an augmented phasic response. These data demonstrate an age-related difference in dopamine neuron response to reward that is not uniform and is guided by processes that differentiate between state and action values.

Biochemical defense mechanism associated with host-specific disease resistance pathways against Rhizoctonia solani AG3-PT potatoes canker disease.

MAIN CONCLUSION: Screening for resistance in 40 potato genotypes to Rhizoctonia solani AG-3PT-stem-canker, antioxidant enzymes activity as well as total phenol compounds were documented. Rhizoctonia solani AG-3PT-stem-canker is one of the most devastating diseases that leads to severe economic losses in potatoes, Solanum tuberosum globally. Crop management and eugenic practices, especially the use of resistance can be effective in reducing the disease incidence. However, the information about potato-R. Solani interaction is still limited. This study explored screening for resistance in forty potato genotypes to R. solani, analyzing biomass growth parameters (BGPs), as well as antioxidant enzymes activity of which peroxidase/peroxide-reductases (POXs), superoxide dismutase (SOD), polyphenol oxidase (PPO), catalase (CAT), phenylalanine ammonia-lyase (PAL), ß-1,3-glucanase (GLU) and total phenol compounds (TPCs) were taken into account. In addition, we analyzed up-regulation of two gene markers (PR-1 and Osmotin), using reverse transcription quantitative PCR (RT-qPCR). For which, the resistant 'Savalan', partially resistant 'Agria', partially susceptible 'Sagita' and susceptible 'Pashandi' were selected to explore the trails in their roots and leaves over the time courses of 1, 2 and 3-weeks post inoculation (wpi) following inoculation. Cluster analysis divided potatoes into four distinct groups, based on disease severity scales (0-100%) significance. The BGPs, shoot and root length, fresh and dry weight, and root volume were also significantly higher in infected potatoes compared to non-inoculated controls. Antioxidant enzymes activity also indicated the highest increased levels for POX (fourfold at 3wpi), CAT (1.5-fold at 3wpi), SOD (6.8-fold at 1wpi), and PAL (2.7-fold at 3wpi) in the resistant genotype, 'Savalan', whereas the highest activity was recorded in TPC (twofold at 1 wpi), PPO (threefold at 3wpi), and GLU (2.3-fold at 1wpi) in partially resistant genotypes. Although the defense-related enzymatic activities were sharply elevated in the resistant and partially resistant genotypes following inoculation, no significant correlations were between the activity trends of the related enzymes. The two related gene markers also showed comprehensive transcriptional responses up to 3.4-fold, predominantly in resistant genotypes. Surprisingly, the PR-1 gene marker, basically resistant to Wilting agent Verticillium dahlia was overexpressed in resistant 'Savalan' and 'Agria' against R. solani AG3-PT. Similar results were obtained on Osmotin gene marker resistant to late-blight P. infestans, and early-blight Alternaria solani that similarly modulates immunity against R. solani. Furthermore, there was a significant correlation between resistance, enzyme activity, and gene expression in the aforesaid cultivars. Studying the physiological metabolic pathways of antioxidant enzymes activity appears to be an important direction in research to elucidate resistance to R. solani in potatoes.

The effect of posterior tibial and sural nerve blocks on postoperative pain of patients following open reduction and internal fixation of calcaneal fractures.

INTRODUCTION: Postoperative pain control and achieving opioid-free anesthesia are major issues for surgically treated patients with calcaneal fractures. We evaluated the potential role of posterior tibial and sural nerve blocks as a part of multimodal pain control techniques in patients underwent open reduction and internal fixation (ORIF) of calcaneal fractures via extensile lateral approach. METHODS: Forty-eight patients randomly allocated to receive either posterior tibial and sural nerve blocks with bupivacaine (peripheral nerve block (PNB) group) or normal saline, after induction of general anesthesia. Patients were assessed for pain intensity, Interval from entrance to the recovery room to the first request for analgesic, recovery room and ward morphine consumption, global satisfaction and morphine side effects. RESULTS: PNB group had less pain score compared to sham block (SB) group at each time point measurement during recovery room stay. There was also significant difference between the 2 groups regarding the pain scores after 2, 4 and 6 h of the operation in the ward. Time to the first request for analgesic was significantly prolonged in the PNB group (P < 0.001). The recovery room and ward morphine consumption was significantly lower in the PNB group (P < 0.001). Global satisfaction in PNB group was significantly more than that of SB group. No complication related to the nerve block was detected at the first postoperative visit in the outpatient clinic. CONCLUSION: Peripheral nerve block could result in less postoperative pain especially in the early hours after ORIF of calcaneal fractures and reduce opioid administration within the first 24 h following the surgery.

Prefrontal Cortex Representation of Learning of Punishment Probability During Reward-Motivated Actions.

Actions executed toward obtaining a reward are frequently associated with the probability of harm occurring during action execution. Learning this probability allows for appropriate computation of future harm to guide action selection. Impaired learning of this probability may be critical for the pathogenesis of anxiety or reckless and impulsive behavior. Here we designed a task for punishment probability learning during reward-guided actions to begin to understand the neuronal basis of this form of learning, and the biological or environmental variables that influence action selection after learning. Male and female Long-Evans rats were trained in a seek-take behavioral paradigm where the seek action was associated with varying probability of punishment. The take action remained safe and was followed by reward delivery. Learning was evident as subjects selectively adapted seek action behavior as a function of punishment probability. Recording of neural activity in the mPFC during learning revealed changes in phasic mPFC neuronal activity during risky-seek actions but not during the safe take actions or reward delivery, revealing that this region is involved in learning of probabilistic punishment. After learning, the variables that influenced behavior included reinforcer and punisher value, pretreatment with the anxiolytic diazepam, and biological sex. In particular, females were more sensitive to probabilistic punishment than males. These data demonstrate that flexible encoding of risky actions by mPFC is involved in probabilistic punishment learning and provide a novel behavioral approach for studying the pathogenesis of anxiety and impulsivity with inclusion of sex as a biological variable.SIGNIFICANCE STATEMENT Actions we choose to execute toward obtaining a reward are often associated with the probability of harm occurring. Impaired learning of this probability may be critical for the pathogenesis of anxiety or reckless behavior and impulsivity. We developed a behavioral model to assess this mode of learning. This procedure allowed us to determine biological and environmental factors that influence the resistance of reward seeking to probabilistic punishment and to identify the mPFC as a region that flexibly adapts its response to risky actions as contingencies are learned.

Sex differences in reward- and punishment-guided actions.

Differences in the prevalence and presentation of psychiatric illnesses in men and women suggest that neurobiological sex differences confer vulnerability or resilience in these disorders. Rodent behavioral models are critical for understanding the mechanisms of these differences. Reward processing and punishment avoidance are fundamental dimensions of the symptoms of psychiatric disorders. Here we explored sex differences along these dimensions using multiple and distinct behavioral paradigms. We found no sex difference in reward-guided associative learning but a faster punishment-avoidance learning in females. After learning, females were more sensitive than males to probabilistic punishment but less sensitive when punishment could be avoided with certainty. No sex differences were found in reward-guided cognitive flexibility. Thus, sex differences in goal-directed behaviors emerged selectively when there was an aversive context. These differences were critically sensitive to whether the punishment was certain or unpredictable. Our findings with these new paradigms provide conceptual and practical tools for investigating brain mechanisms that account for sex differences in susceptibility to anxiety and impulsivity. They may also provide insight for understanding the evolution of sex-specific optimal behavioral strategies in dynamic environments.

Adaptive Encoding of Outcome Prediction by Prefrontal Cortex Ensembles Supports Behavioral Flexibility.

The prefrontal cortex (PFC) is thought to play a critical role in behavioral flexibility by monitoring action-outcome contingencies. How PFC ensembles represent shifts in behavior in response to changes in these contingencies remains unclear. We recorded single-unit activity and local field potentials in the dorsomedial PFC (dmPFC) of male rats during a set-shifting task that required them to update their behavior, among competing options, in response to changes in action-outcome contingencies. As behavior was updated, a subset of PFC ensembles encoded the current trial outcome before the outcome was presented. This novel outcome-prediction encoding was absent in a control task, in which actions were rewarded pseudorandomly, indicating that PFC neurons are not merely providing an expectancy signal. In both control and set-shifting tasks, dmPFC neurons displayed postoutcome discrimination activity, indicating that these neurons also monitor whether a behavior is successful in generating rewards. Gamma-power oscillatory activity increased before the outcome in both tasks but did not differentiate between expected outcomes, suggesting that this measure is not related to set-shifting behavior but reflects expectation of an outcome after action execution. These results demonstrate that PFC neurons support flexible rule-based action selection by predicting outcomes that follow a particular action.SIGNIFICANCE STATEMENT Tracking action-outcome contingencies and modifying behavior when those contingencies change is critical to behavioral flexibility. We find that ensembles of dorsomedial prefrontal cortex neurons differentiate between expected outcomes when action-outcome contingencies change. This predictive mode of signaling may be used to promote a new response strategy at the service of behavioral flexibility.

Anxiety Evokes Hypofrontality and Disrupts Rule-Relevant Encoding by Dorsomedial Prefrontal Cortex Neurons.

Anxiety is a debilitating symptom of most psychiatric disorders, including major depression, post-traumatic stress disorder, schizophrenia, and addiction. A detrimental aspect of anxiety is disruption of prefrontal cortex (PFC)-mediated executive functions, such as flexible decision making. Here we sought to understand how anxiety modulates PFC neuronal encoding of flexible shifting between behavioral strategies. We used a clinically substantiated anxiogenic treatment to induce sustained anxiety in rats and recorded from dorsomedial PFC (dmPFC) and orbitofrontal cortex (OFC) neurons while they were freely moving in a home cage and while they performed a PFC-dependent task that required flexible switches between rules in two distinct perceptual dimensions. Anxiety elicited a sustained background "hypofrontality" in dmPFC and OFC by reducing the firing rate of spontaneously active neuronal subpopulations. During task performance, the impact of anxiety was subtle, but, consistent with human data, behavior was selectively impaired when previously correct conditions were presented as conflicting choices. This impairment was associated with reduced recruitment of dmPFC neurons that selectively represented task rules at the time of action. OFC rule representation was not affected by anxiety. These data indicate that a neural substrate of the decision-making deficits in anxiety is diminished dmPFC neuronal encoding of task rules during conflict-related actions. Given the translational relevance of the model used here, the data provide a neuronal encoding mechanism for how anxiety biases decision making when the choice involves overcoming a conflict. They also demonstrate that PFC encoding of actions, as opposed to cues or outcome, is especially vulnerable to anxiety. SIGNIFICANCE STATEMENT: A debilitating aspect of anxiety is its impact on decision making and flexible control of behavior. These cognitive constructs depend on proper functioning of the prefrontal cortex (PFC). Understanding how anxiety affects PFC encoding of cognitive events is of great clinical and evolutionary significance. Using a clinically valid experimental model, we find that, under anxiety, decision making may be skewed by salient and conflicting environmental stimuli at the expense of flexible top-down guided choices. We also find that anxiety suppresses spontaneous activity of PFC neurons, and weakens encoding of task rules by dorsomedial PFC neurons. These data provide a neuronal encoding scheme for how anxiety disengages PFC during decision making.

Action-outcome relationships are represented differently by medial prefrontal and orbitofrontal cortex neurons during action execution.

Internal representations of action-outcome relationships are necessary for flexible adaptation of motivated behavior in dynamic environments. Prefrontal cortex (PFC) is implicated in flexible planning and execution of goal-directed actions, but little is known about how information about action-outcome relationships is represented across functionally distinct regions of PFC. Here, we observe distinct patterns of action-evoked single unit activity in the medial prefrontal cortex (mPFC) and orbitofrontal cortex (OFC) during a task in which the relationship between outcomes and actions was independently manipulated. The mPFC encoded changes in the number of actions required to earn a reward, but not fluctuations in outcome magnitude. In contrast, OFC neurons decreased firing rates as outcome magnitude was increased, but were insensitive to changes in action requirement. A subset of OFC neurons also tracked outcome availability. Pre-outcome anticipatory activity in both mPFC and OFC was altered when reward expectation was reduced, but did not differ with outcome magnitude. These data provide novel evidence that PFC regions encode distinct information about the relationship between actions and impending outcomes during action execution.

Striatum processes reward differently in adolescents versus adults.

Adolescents often respond differently than adults to the same salient motivating contexts, such as peer interactions and pleasurable stimuli. Delineating the neural processing differences of adolescents is critical to understanding this phenomenon, as well as the bases of serious behavioral and psychiatric vulnerabilities, such as drug abuse, mood disorders, and schizophrenia. We believe that age-related changes in the ways salient stimuli are processed in key brain regions could underlie the unique predilections and vulnerabilities of adolescence. Because motivated behavior is the central issue, it is critical that age-related comparisons of brain activity be undertaken during motivational contexts. We compared single-unit activity and local field potentials in the nucleus accumbens (NAc) and dorsal striatum (DS) of adolescent and adult rats during a reward-motivated instrumental task. These regions are involved in motivated learning, reward processing, and action selection. We report adolescent neural processing differences in the DS, a region generally associated more with learning than reward processing in adults. Specifically, adolescents, but not adults, had a large proportion of neurons in the DS that activated in anticipation of reward. More similar response patterns were observed in NAc of the two age groups. DS single-unit activity differences were found despite similar local field potential oscillations. This study demonstrates that in adolescents, a region critically involved in learning and habit formation is highly responsive to reward. It thus suggests a mechanism for how rewards might shape adolescent behavior differently, and for their increased vulnerabilities to affective disorders.

Preparatory attention relies on dynamic interactions between prelimbic cortex and anterior cingulate cortex.

An emerging view of prefrontal cortex (PFC) function is that multiple PFC areas process information in parallel, rather than as distinct modules. Two key functions assigned to the PFC are the regulation of top-down attention and stimulus-guided action. Electrophysiology and lesion studies indicate the involvement of both the anterior cingulate cortex (ACC) and prelimbic cortex (PL) in these functions. Little is known, however, about how these cortical regions interact. We recorded single unit spiking and local field potentials (LFPs) simultaneously in rodents during a sustained attention task and assessed interactions between the ACC and PL by measuring spike-LFP phase synchrony and LFP-LFP phase synchrony between these areas. We demonstrate that the magnitude of synchrony between the ACC and PL, before stimulus onset, predicts the subjects' behavioral choice after the stimulus. Furthermore, neurons switched from a state of beta synchrony during attention to a state of delta synchrony before the instrumental action. Our results indicate that multiple PFC areas interact during attention and that the same neurons may participate in segregated assemblies that support both attention and action.

Reward and punishment contingency shifting reveals distinct roles for VTA dopamine and GABA neurons in behavioral flexibility.

In dynamic environments where stimuli predicting rewarding or aversive outcomes unexpectedly change, it is critical to flexibly update behavior while preserving recollection of previous associations. Dopamine and GABA neurons in the ventral tegmental area (VTA) are implicated in reward and punishment learning, yet little is known about how each population adapts when the predicted outcome valence changes. We measured VTA dopamine and GABA population activity while male and female rats learned to associate three discrete auditory cues to three distinct outcomes: reward, punishment, or no outcome within the same session. After learning, the reward and punishment cue-outcome contingencies were reversed, and subsequently re-reversed. As expected, the dopamine population rapidly adapted to learning and contingency reversals by increasing the response to appetitive stimuli and decreasing the response to aversive stimuli. In contrast, the GABA population increased activity to all sensory events regardless of valence, including the neutral cue. Reversing learned contingencies selectively influenced GABA responses to the reward-predictive cue, prolonging increased activity within and across sessions. The observed valence-specific dissociations in the directionality and temporal progression of VTA dopamine and GABA calcium activity indicates that these populations are independently recruited and serve distinct roles during appetitive and aversive associative learning and contingency reversal.

Orbitofrontal and Prelimbic Cortices Serve Complementary Roles in Adapting Reward Seeking to Learned Anxiety.

BACKGROUND: Anxiety is a common symptom of several mental health disorders and adversely affects motivated behaviors. Anxiety can emerge from associating risk of future harm while engaged in goal-guided actions. Using a recently developed behavioral paradigm to model this aspect of anxiety, we investigated the role of 2 cortical subregions, the prelimbic medial frontal cortex (PL) and lateral orbitofrontal cortex (lOFC), which have been implicated in anxiety and outcome expectation, in flexible representation of actions associated with harm risk. METHODS: A seek-take reward-guided instrumental task design was used to train animals (N = 8) to associate the seek action with a variable risk of punishment. After learning, animals underwent extinction training for this association. Fiber photometry was used to measure and compare neuronal activity in the PL and lOFC during learning and extinction. RESULTS: Animals increased action suppression in response to punishment contingencies. This increase dissipated after extinction training. These behavioral changes were associated with region-specific changes in neuronal activity. PL neuronal activity preferentially adapted to the threat of punishment, whereas lOFC activity adapted to safe aspects of the task. Moreover, correlated activity between these regions was suppressed during actions associated with harm risk, suggesting that these regions may guide behavior independently under anxiety. CONCLUSIONS: These findings suggest that the PL and lOFC serve distinct but complementary roles in the representation of learned anxiety. This dissociation may provide a mechanism to explain how overlapping cortical systems are implicated in reward-guided action execution during anxiety.

Impact of supplementation with omega-3 fatty acids after maternal dietary deficiency on adolescent anxiety and microglial morphology.

Dietary maternal deficiency in omega-3 polyunsaturated fatty acids (n-3 PUFA) is a potential risk factor for the development of anxiety and other mood disorders in children and adolescents. Here, we used a previously characterized maternal n-3 PUFA dietary deficiency model in rats to determine the impact of postweaning supplementation on adolescent anxiety-like behaviors. We focused on two models of anxiety: innate anxiety tested by the elevated plus maze and a novel operant model of learned anxiety where animals learn that actions may be associated with a variable probability of harm. Given that recent basic and clinical studies have associated anxiety and other adverse effects of n-3 PUFA deficiency on inflammatory processes and microglial structure and function, we also assessed the impact of our dietary deficiency model and supplementation on adolescent microglial morphology in multiple brain regions. We found that the male and female adolescent n-3 PUFA-deficient groups exhibit increased innate anxiety, but only females showed enhanced learned anxiety. Supplementation after weaning did not significantly affect innate anxiety but ameliorated learned anxiety in females. Thus, the beneficial effects of supplementation on adolescent anxiety may be sex-specific and depend on the type of anxiety. We also found that n-3 PUFA deficiency influences microglia function in adolescents in the amygdala and nigrostriatal, but not mesolimbic, brain regions. Collectively, these data suggest that while n-3 PUFA dietary supplementation may be effective in reducing adolescent anxiety, this effect is context-, sex-, and brain network-specific. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Adolescents rats engage the orbitofrontal-striatal pathway differently than adults during impulsive actions.

Adolescence is characterized by increased impulsive and risk-taking behaviors. To better understand the neural networks that subserves impulsivity in adolescents, we used a reward-guided behavioral model that quantifies age differences in impulsive actions in adult and adolescent rats of both sexes. Using chemogenetics, we identified orbitofrontal cortex (OFC) projections to the dorsomedial striatum (DMS) as a critical pathway for age-related execution of impulsive actions. Simultaneous recording of single units and local field potentials in the OFC and DMS during task performance revealed an overall muted response in adolescents during impulsive actions as well as age-specific differences in theta power and OFC-DMS functional connectivity. Collectively, these data reveal that the OFC-DMS pathway is critical for age-differences in reward-guided impulsive actions and provide a network mechanism to enhance our understanding of how adolescent and adult brains coordinate behavioral inhibition.

Disruption of prefrontal cortex large scale neuronal activity by different classes of psychotomimetic drugs.

In the absence of overt cellular pathology but profound perceptual disorganization and cognitive deficits, schizophrenia is increasingly considered a disorder of neural coordination. Thus, different causal factors can similarly interrupt the dynamic function of neuronal ensembles and networks, in particular in the prefrontal cortex (PFC), leading to behavioral disorganization. The importance of establishing preclinical biomarkers for this aberrant function has prompted investigations into the nature of psychotomimetic drug effects on PFC neuronal activity. The drugs used in this context include serotonergic hallucinogens, amphetamine, and NMDA receptor antagonists. A prominent line of thinking is that these drugs create psychotomimetic states by similarly disinhibiting the activity of PFC pyramidal neurons. In the present study we did not find evidence in support of this mechanism in PFC subregions of freely moving rats. Whereas the NMDA receptor antagonist MK801 increased PFC population activity, the serotonergic hallucinogen DOI dose-dependently decreased population activity. Amphetamine did not strongly affect this measure. Despite different effects on the direction of change in activity, all three drugs caused similar net disruptions of population activity and modulated gamma oscillations. We also observed reduced correlations between spike-rate and local field potential power selectively in the gamma band suggesting that these drugs disconnect spike-discharge from PFC gamma oscillators. Gamma band oscillations support cognitive functions affected in schizophrenia. These findings provide insight into mechanisms that may lead to cortical processing deficits in schizophrenia and provide a novel electrophysiological approach for phenotypic characterization of animal models of this disease.

Distinct prestimulus and poststimulus activation of VTA neurons correlates with stimulus detection.

Dopamine neurons of the ventral tegmental area (VTA) signal the occurrence of a reward-predicting conditioned stimulus (CS) with a subsecond duration increase in post-CS firing rate. Important theories about reward-prediction error and reward expectancy have been informed by the substantial number of studies that have examined post-CS phasic VTA neuron activity. On the other hand, the role of VTA neurons in anticipation of a reward-predicting CS and analysis of prestimulus spike rate rarely has been studied. We recorded from the VTA in rats during the 3-choice reaction time task, which has a fixed-duration prestimulus period and a difficult-to-detect stimulus. Use of a stimulus that was difficult to detect led to behavioral errors, which allowed us to compare VTA activity between trials with correct and incorrect stimulus-guided choices. We found a sustained increase in firing rate of both putative dopamine and GABA neurons during the pre-CS period of correct and incorrect trials. The poststimulus phasic response, however, was absent on incorrect trials, suggesting that the stimulus-evoked phasic response of dopamine neurons may relate to stimulus detection. The prestimulus activation of VTA neurons may modulate cortical systems that represent internal states of stimulus expectation and provide a mechanism for dopamine neurotransmission to influence preparatory attention to an expected stimulus.

Acute psilocybin enhances cognitive flexibility in rats.

Psilocybin has been shown to improve symptoms of depression and anxiety when combined with psychotherapy or other clinician-guided interventions. To understand the neural basis for this pattern of clinical efficacy, experimental and conceptual approaches that are different than traditional laboratory models of anxiety and depression are needed. A potential novel mechanism is that acute psilocybin improves cognitive flexibility, which then enhances the impact of clinician-assisted interventions. Consistent with this idea, we find that acute psilocybin robustly improves cognitive flexibility in male and female rats using a task where animals switched between previously learned strategies in response to uncued changes in the environment. Psilocybin did not influence Pavlovian reversal learning, suggesting that its cognitive effects are selective to enhanced switching between previously learned behavioral strategies. The serotonin (5HT) 2A receptor antagonist ketanserin blocked psilocybin's effect on set-shifting, while a 5HT2C-selective antagonist did not. Ketanserin alone also improved set-shifting performance, suggesting a complex relationship between psilocybin's pharmacology and its impact on flexibility. Further, the psychedelic drug 2,5-Dimethoxy-4-iodoamphetamine (DOI) impaired cognitive flexibility in the same task, suggesting that this effect of psilocybin does not generalize to all other serotonergic psychedelics. We conclude that the acute impact of psilocybin on cognitive flexibility provides a useful behavioral model to investigate its neuronal effects relevant to its positive clinical outcome.

Acute psilocybin enhances cognitive flexibility in rats.

Psilocybin has been shown to improve symptoms of depression and anxiety when combined with psychotherapy or other clinician-guided interventions. To understand the neural basis for this pattern of clinical efficacy, experimental and conceptual approaches that are different than traditional laboratory models of anxiety and depression are needed. A potential novel mechanism is that acute psilocybin improves cognitive flexibility, which then enhances the impact of clinician-assisted interventions. Consistent with this idea, we find that acute psilocybin robustly improves cognitive flexibility in male and female rats using a task where animals switched between previously learned strategies in response to uncued changes in the environment. Psilocybin did not influence Pavlovian reversal learning, suggesting that its cognitive effects are selective to enhanced switching between previously learned behavioral strategies. The serotonin (5HT) 2 A receptor antagonist ketanserin blocked psilocybin's effect on set-shifting, while a 5HT2C-selective antagonist did not. Ketanserin alone also improved set-shifting performance, suggesting a complex relationship between psilocybin's pharmacology and its impact on flexibility. Further, the psychedelic drug 2,5-Dimethoxy-4-iodoamphetamine (DOI) impaired cognitive flexibility in the same task, suggesting that this effect of psilocybin does not generalize to all other serotonergic psychedelics. We conclude that the acute impact of psilocybin on cognitive flexibility provides a useful behavioral model to investigate its neuronal effects relevant to its positive clinical outcome.

Reduced neuronal inhibition and coordination of adolescent prefrontal cortex during motivated behavior.

Adolescence is a time of both cognitive maturation and vulnerability to several major psychiatric illnesses and drug dependence. There is increasing awareness that behavioral or pharmacological intervention during this period may be critical for disease prevention in susceptible individuals. Therefore, we must attain a deeper understanding of how the adolescent brain processes salient events relevant to motivated behavior. To do this, we recorded single-unit and local field potential activity in the orbitofrontal cortex of rats as they performed a simple reward-driven operant task. Adolescents encoded basic elements of the task differently than adults, indicating that neuronal processing of salient events differs in the two age groups. Entrainment of local field potential oscillations, variance in spike timing, and relative proportions of inhibitory and excitatory responses differed in an event-specific manner. Overall adolescent phasic neural activity was less inhibited and more variable through much of the task. Cortical inhibition is essential for efficient communication between neuronal groups, and reduced inhibitory control of cortical activity has been implicated in schizophrenia and other disorders. Thus, these results suggest that reduced inhibitory responses of adolescent cortical neurons to salient events could be a critical mechanism for some of the increased vulnerabilities of this period.