Dissociable and paradoxical roles of rat medial and lateral orbitofrontal cortex in visual serial reversal learning

Much evidence suggests that reversal learning is mediated by cortico-striatal circuitries with the orbitofrontal cortex (OFC) playing a prominent role. The OFC is a functionally heterogeneous region, but potential differential roles of lateral (lOFC) and medial (mOFC) portions in visual reversal learning have yet to be determined. We investigated the effects of pharmacological inactivation of mOFC and lOFC on a deterministic serial visual reversal learning task for rats. For reference, we also targeted other areas previously implicated in reversal learning: prelimbic (PrL) and infralimbic (IL) prefrontal cortex, and basolateral amygdala (BLA). Inactivating mOFC and lOFC produced opposite effects; lOFC impairing, and mOFC improving, performance in the early, perseverative phase specifically. Additionally, mOFC inactivation enhanced negative feedback sensitivity, while lOFC inactivation diminished feedback sensitivity in general. mOFC and lOFC inactivation also affected novel visual discrimination learning differently; lOFC inactivation paradoxically improved learning, and mOFC inactivation had no effect. We also observed dissociable roles of the OFC and the IL/PrL. Whereas the OFC inactivation affected only perseveration, IL/PrL inactivation improved learning overall. BLA inactivation did not affect perseveration, but improved the late phase of reversal learning. These results support opponent roles of the rodent mOFC and lOFC in deterministic visual reversal learning.Wellcome Trus

Adaptive aspects of impulsivity and interactions with effects of catecholaminergic agents in the 5-choice serial reaction time task: implications for ADHD.

BACKGROUND: Work in humans has shown that impulsivity can be advantageous in certain settings. However, evidence for so-called functional impulsivity is lacking in experimental animals. AIMS: This study investigated the contexts in which high impulsive (HI) rats show an advantage in performance compared with mid- (MI) and low impulsive (LI) rats. We also assessed the effects of dopaminergic and noradrenergic agents to investigate underlying neurotransmitter mechanisms. METHODS: We tested rats on a variable inter-trial interval (ITI) version of the 5-choice serial reaction time task (5CSRTT). Rats received systemic injections of methylphenidate (MPH, 1 mg/kg and 3 mg/kg), atomoxetine (ATO, 0.3 mg/kg and 1 mg/kg), amphetamine (AMPH, 0.2 mg/kg), the alpha-2a adrenoceptor antagonist atipamezole (ATI, 0.3 mg/kg) and the alpha-1 adrenoceptor agonist phenylephrine (PHEN, 1 mg/kg) prior to behavioural testing. RESULTS: Unlike LI rats, HI rats exhibited superior performance, earning more reinforcers, on short ITI trials, when the task required rapid responding. MPH, AMPH and ATI improved performance on short ITI trials and increased impulsivity in long ITI trials, recapitulating the behavioural profile of HI. In contrast, ATO and PHEN impaired performance on short ITI trials and decreased impulsivity, thus mimicking the behavioural profile of LI rats. The effects of ATO were greater on MI rats and LI rats. CONCLUSIONS: These findings indicate that impulsivity can be advantageous when rapid focusing and actions are required, an effect that may depend on increased dopamine neurotransmission. Conversely, activation of the noradrenergic system, with ATO and PHEN, led to a general inhibition of responding

Research data supporting "Glutamatergic and Serotonergic Modulation of Rat Medial and Lateral Orbitofrontal Cortex in Visual Serial Reversal Learning"

Much evidence suggests that cognitive flexibility, which can be operationalized in reversal learning tasks, is mediated by cortico-striatal circuitries, with the orbitofrontal cortex (OFC) playing a prominent role. We investigated the effects on reversal learning of pharmacological overactivation of the lateral and medial orbitofrontal cortex (lOFC, mOFC) using a glutamate transporter 1 (GLT-1) inhibitor, dihydrokainate (DHK), which increases extracellular glutamate by blocking its reuptake. We also tested the impact of antagonism of the serotonin 2A receptor (5-HT2AR), which modulates glutamate action, in the mOFC and lOFC on the same task. Each .csv file corresponds to one experiment: reversal learning data from mOFC & lOFC, with rats receiving either the glutamate transporter 1 (GLT-1) inhibitor, dihydrokainate (DHK) or the antagonist of the serotonin 2A receptor (M-100,907).This work was supported by a Wellcome Trust Senior Investigator Grant to TWR (104631/Z/14/Z) and a Lundbeck Foundation Research Fellowship to MEH (R182-2014–2810 and R210-2015–2982)

Theory of visual attention (TVA) applied to rats performing the 5-choice serial reaction time task: differential effects of dopaminergic and noradrenergic manipulations.

RATIONALE: Attention is compromised in many psychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD). While dopamine and noradrenaline systems have been implicated in ADHD, their exact role in attentional processing is yet unknown. OBJECTIVES: We applied the theory of visual attention (TVA) model, adapted from human research, to the rat 5-choice serial reaction time task (5CSRTT) to investigate catecholaminergic modulation of visual attentional processing in healthy subjects of high- and low-attention phenotypes. METHODS: Rats trained on the standard 5CSRTT and tested with variable stimulus durations were treated systemically with noradrenergic and/or dopaminergic agents (atomoxetine, methylphenidate, amphetamine, phenylephrine and atipamezole). TVA modelling was applied to estimate visual processing speed for correct and incorrect visual perceptual categorisations, independent of motor reaction times, as measures of attentional capacity. RESULTS: Atomoxetine and phenylephrine decreased response frequencies, including premature responses, increased omissions and slowed responding. In contrast, methylphenidate, amphetamine and atipamezole sped up responding and increased premature responses. Visual processing speed was also affected differentially. Atomoxetine and phenylephrine slowed, whereas methylphenidate and atipamezole sped up, visual processing, both for correct and incorrect categorisations. Amphetamine selectively improved visual processing for correct, though not incorrect, responses in high-attention rats only, possibly reflecting improved attention. CONCLUSIONS: These data indicate that the application of TVA to the 5CSRTT provides an enhanced sensitivity to capturing attentional effects. Unexpectedly, we found overall slowing effects, including impaired visual processing, following drugs either increasing extracellular noradrenaline (atomoxetine) or activating the α1-adrenoceptor (phenylephrine), while also ameliorating premature responses (impulsivity). In contrast, amphetamine had potential pro-attentional effects by enhancing visual processing, probably due to central dopamine upregulation

Research data supporting "Dissociable and Paradoxical Roles of Rat Medial and Lateral Orbitofrontal Cortex in Visual Serial Reversal Learning"

We investigated the effects of pharmacological inactivation of mOFC and lOFC on a deterministic serial visual reversal learning task for rats. For reference, we also targeted other areas previously implicated in reversal learning: prelimbic (PrL) and infralimbic (IL) prefrontal cortex, and basolateral amygdala (BLA). We also investigated the effect of lOFC and mOFC inactivatoin on visual discrimination (without a reversal component). Each .csv file corresponds to one experiment: reversal learning data from mOFC, lOFC, IL, PrL, BLA; novel visual discrimination data from mOFC, lOFC.This work was funded by a Wellcome Trust Senior Investigator Grant to TWR (104631/Z/14/Z), a Lundbeck Foundation Research Fellowship (R182-2014-2810 and R210-2015-2982 to MEH) and a BBSRC studentship (to LF)

5-HT 2A and 5-HT 2C receptor antagonism differentially modulate reinforcement learning and cognitive flexibility: behavioural and computational evidence.

RATIONALE: Cognitive flexibility, the ability to adapt behaviour in response to a changing environment, is disrupted in several neuropsychiatric disorders, including obsessive-compulsive disorder and major depressive disorder. Evidence suggests that flexibility, which can be operationalised using reversal learning tasks, is modulated by serotonergic transmission. However, how exactly flexible behaviour and associated reinforcement learning (RL) processes are modulated by 5-HT action on specific receptors is unknown. OBJECTIVES: We investigated the effects of 5-HT2A receptor (5-HT2AR) and 5-HT2C receptor (5-HT2CR) antagonism on flexibility and underlying RL mechanisms. METHODS: Thirty-six male Lister hooded rats were trained on a touchscreen visual discrimination and reversal task. We evaluated the effects of systemic treatments with the 5-HT2AR and 5-HT2CR antagonists M100907 and SB-242084, respectively, on reversal learning and performance on probe trials where correct and incorrect stimuli were presented with a third, probabilistically rewarded, stimulus. Computational models were fitted to task choice data to extract RL parameters, including a novel model designed specifically for this task. RESULTS: 5-HT2AR antagonism impaired reversal learning only after an initial perseverative phase, during a period of random choice and then new learning. 5-HT2CR antagonism, on the other hand, impaired learning from positive feedback. RL models further differentiated these effects. 5-HT2AR antagonism decreased punishment learning rate (i.e. negative feedback) at high and low doses. The low dose also decreased reinforcement sensitivity (beta) and increased stimulus and side stickiness (i.e., the tendency to repeat a choice regardless of outcome). 5-HT2CR antagonism also decreased beta, but reduced side stickiness. CONCLUSIONS: These data indicate that 5-HT2A and 5-HT2CRs both modulate different aspects of flexibility, with 5-HT2ARs modulating learning from negative feedback as measured using RL parameters and 5-HT2CRs for learning from positive feedback assessed through conventional measures

5-HT 2A and 5-HT 2C receptor antagonism differentially modulate reinforcement learning and cognitive flexibility:behavioural and computational evidence

Rationale: Cognitive flexibility, the ability to adapt behaviour in response to a changing environment, is disrupted in several neuropsychiatric disorders, including obsessive–compulsive disorder and major depressive disorder. Evidence suggests that flexibility, which can be operationalised using reversal learning tasks, is modulated by serotonergic transmission. However, how exactly flexible behaviour and associated reinforcement learning (RL) processes are modulated by 5-HT action on specific receptors is unknown. Objectives: We investigated the effects of 5-HT2A receptor (5-HT2AR) and 5-HT2C receptor (5-HT2CR) antagonism on flexibility and underlying RL mechanisms. Methods: Thirty-six male Lister hooded rats were trained on a touchscreen visual discrimination and reversal task. We evaluated the effects of systemic treatments with the 5-HT2AR and 5-HT2CR antagonists M100907 and SB-242084, respectively, on reversal learning and performance on probe trials where correct and incorrect stimuli were presented with a third, probabilistically rewarded, stimulus. Computational models were fitted to task choice data to extract RL parameters, including a novel model designed specifically for this task. Results: 5-HT2AR antagonism impaired reversal learning only after an initial perseverative phase, during a period of random choice and then new learning. 5-HT2CR antagonism, on the other hand, impaired learning from positive feedback. RL models further differentiated these effects. 5-HT2AR antagonism decreased punishment learning rate (i.e. negative feedback) at high and low doses. The low dose also decreased reinforcement sensitivity (beta) and increased stimulus and side stickiness (i.e., the tendency to repeat a choice regardless of outcome). 5-HT2CR antagonism also decreased beta, but reduced side stickiness. Conclusions: These data indicate that 5-HT2A and 5-HT2CRs both modulate different aspects of flexibility, with 5-HT2ARs modulating learning from negative feedback as measured using RL parameters and 5-HT2CRs for learning from positive feedback assessed through conventional measures.</p

Dissociating reward sensitivity and negative urgency effects on impulsivity in the five-choice serial reaction time task.

Negative urgency describes the tendency for rash and impulsive behaviour during negative emotional states and has been linked to a number of psychiatric disorders. However, there has been limited research on negative urgency as an explanatory mechanism for impulsivity in experimental animals. Such research has important implications for elucidating the neurobiology of negative urgency and thereby the development of future therapeutic interventions. In this study, we investigated the effects of negative urgency using a partial reinforcement schedule to increase the frequency of non-rewarded (i.e. frustrative) trials in the five-choice serial reaction time task, a widely used task to assess visual attention and impulsivity. Using a Markov chain model to analyse trial-by-trial outcomes we found that premature (i.e. impulsive) responses in the five-choice serial reaction time task were more likely to occur after a non-rewarded trial, and mostly after a previous premature trial. However, contrary to the frustration hypothesis of negative urgency, increasing the probability of reinforcement (p(R)) from p(R) = 0.5 to p(R) = 1 increased the number of premature responses in each session. Micro and macro levels of analyses revealed that impulsivity in the five-choice serial reaction time task is governed by at least two processes, one dependent on the overall level of reinforcement hypothesised to determine the state of behavioural activation, the second dependent on trial-by-trial outcomes consistent with negative urgency effects. These processes may depend on distinct neurobiological mechanisms and have relevance for neuropsychiatric disorders that implicate impulsive behaviours dependent on positive and negative affective states