Orbitofrontal cortex and amygdalar over-activity is associated with an inability to use the value of expected outcomes to guide behaviour in serotonin transporter knockout rats

Donders Institute for Brain, Cognition, and Behaviour, Centre for Neuroscience, Dept. of Cognitive Neuroscience, Radboud University Nijmegen Medical Centre, Geert Grooteplein 21, 6525 GA Nijmegen, The Netherlands.
Neurobiology of Learning and Memory (Impact Factor: 3.65). 04/2010; 94(1):65-72. DOI: 10.1016/j.nlm.2010.04.002
Source: PubMed


A disturbance in 5-HT signalling can lead to maladaptive and disruptive behavioural changes seen in neuropsychiatric disorders, potentially by 5-HT's role in cognitive control over behaviour. 5-HT levels are tightly controlled by the serotonin transporter (5-HTT). We and others have observed that 5-HTT availability affects reversal learning. Here we investigated the role of 5-HT in another type of cognitive control, which is the ability to use the value of expected outcomes to guide behaviour. 5-HTT knockout (5-HTT(-/-)) rats and wild-type (5-HTT(+/+)) controls were subjected to a Pavlovian reinforcer devaluation paradigm, which assesses the ability of an appetitive conditioned stimulus (CS) to gain access to the motivational properties of an upcoming aversive unconditioned stimulus (US). Neural correlates were evaluated using c-Fos immunohistochemistry, in brains of animals sacrificed 90min following the start of the probe test. Results show that conditioned responding was decreased in 5-HTT(+/+), but not 5-HTT(-/-), rats after US devaluation. In addition, OFC and basolateral amygdala (BLA) c-Fos immunoreactivity was increased in non-devalued 5-HTT(-/-) rats compared to non-devalued 5-HTT(+/+) rats. Whereas US devaluation increased c-Fos immunoreactivity in the OFC and BLA of 5-HTT(+/+) rats, there was no further increase in c-Fos immunoreactivity in the OFC and BLA of 5-HTT(-/-) rats. Taken together, 5-HTT(-/-) rats are unable to use the value of expected outcomes to guide behaviour, potentially due to over-activity of the OFC and BLA. Our findings suggest a new modulatory role of 5-HT in cognitive control over behaviour, which may have important implications for psychopathologies, like anxiety disorders and addiction.

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    • "For example, knocking out SERT reduces mouse reward-seeking behaviors (Sanders et al. 2007) but improves reversal learning (Brigman et al. 2010). SERT knockout rats are unable to change behaviors based on expected reward values in a Pavlovian reinforcer devaluation paradigm (Nonkes et al. 2010), and respond excessively to the conditioned stimuli in an operant conditioning task (Nonkes and Homberg 2013). Knocking out Tph2 results in impulsivity, hyper-aggression, and abnormal sociosexual behaviors (Savelieva et al. 2008; Liu et al. 2011; Angoa-Perez et al. 2012; Kane et al. 2012; Zhang et al. 2013; Gutknecht et al. 2015). "
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    ABSTRACT: The dorsal raphe nucleus (DRN) represents one of the most sensitive reward sites in the brain. However, the exact relationship between DRN neuronal activity and reward signaling has been elusive. In this review, we will summarize anatomical, pharmacological, optogenetics, and electrophysiological studies on the functions and circuit mechanisms of DRN neurons in reward processing. The DRN is commonly associated with serotonin (5-hydroxytryptamine; 5-HT), but this nucleus also contains neurons of the neurotransmitter phenotypes of glutamate, GABA and dopamine. Pharmacological studies indicate that 5-HT might be involved in modulating reward- or punishment-related behaviors. Recent optogenetic stimulations demonstrate that transient activation of DRN neurons produces strong reinforcement signals that are carried out primarily by glutamate. Moreover, activation of DRN 5-HT neurons enhances reward waiting. Electrophysiological recordings reveal that the activity of DRN neurons exhibits diverse behavioral correlates in reward-related tasks. Studies so far thus demonstrate the strong power of DRN neurons in reward signaling and at the same time invite additional efforts to dissect the roles and mechanisms of different DRN neuron types in various processes of reward-related behaviors. © 2015 Luo et al.; Published by Cold Spring Harbor Laboratory Press.
    Full-text · Article · Sep 2015 · Learning & memory (Cold Spring Harbor, N.Y.)
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    • "Increased brain serotonergic tone, due to deletion of the serotonin transporter or chronic 5-HT reuptake blockade, has been shown to decrease motivation for natural rewards in mice (Sanders et al., 2007). Particularly intriguing, increased serotonergic tone in the orbitofrontal areas of the PFC has been specifically associated with impaired ability to use the value of expected outcomes to guide behavior (Nonkes et al., 2010). This suggests that the motivational deficit in Nogo-A KD rats could indeed be a consequence of the observed alterations of 5-HT levels in the PFC. "
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    ABSTRACT: Nogo-A is an important neurite growth-regulatory protein in the adult and developing nervous system. Mice lacking Nogo-A, or rats with neuronal Nogo-A deficiency, exhibit behavioral abnormalities such as impaired short-term memory, decreased pre-pulse inhibition, and behavioral inflexibility. In the current study, we extended the behavioral profile of the Nogo-A deficient rat line with respect to reward sensitivity and motivation, and determined the concentrations of the monoamines dopamine and serotonin in the prefrontal cortex (PFC), dorsal striatum (dSTR), and nucleus accumbens (NAcc). Using a limited access consumption task, we found similar intake of a sweet condensed milk solution following ad libitum or restricted feeding in wild-type and Nogo-A deficient rats, indicating normal reward sensitivity and translation of hunger into feeding behavior. When tested for motivation in a spontaneous progressive ratio task, Nogo-A deficient rats exhibited lower break points and tended to have lower "highest completed ratios." Further, under extinction conditions responding ceased substantially earlier in these rats. Finally, in the PFC we found increased tissue levels of serotonin, while dopamine was unaltered. Dopamine and serotonin levels were also unaltered in the dSTR and the NAcc. In summary, these results suggest a role for Nogo-A regulated processes in motivated behavior and related neurochemistry. The behavioral pattern observed resembles aspects of the negative symptomatology of schizophrenia.
    Full-text · Article · Jan 2014 · Frontiers in Behavioral Neuroscience
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    • "These have recently been shown to have highly specific effects on the maintenance of information in working or scratchpad memory in prefrontal cortex (Castner et al. 2011; Wang et al. 2011). Similarly, serotonergic tone has been shown to be necessary for reversal learning and devaluation (Clarke et al. 2004; Nonkes et al. 2010; Schilman et al. 2010). Our results suggest that approaches that combine these agents with typical psychotherapeutic interventions that appropriately target individuals who show abnormal processing in orbital or other prefrontal areas might prove especially beneficial. "
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    ABSTRACT: Addiction is characterized by maladaptive decision-making, in which individuals seem unable to use adverse outcomes to modify their behavior. Adverse outcomes are often infrequent, delayed, and even rare events, especially when compared to the reliable rewarding drug-associated outcomes. As a result, recognizing and using information about their occurrence put a premium on the operation of so-called model-based systems of behavioral control, which allow one to mentally simulate outcomes of different courses of action based on knowledge of the underlying associative structure of the environment. This suggests that addiction may reflect, in part, drug-induced dysfunction in these systems. Here, we tested this hypothesis. This study aimed to test whether cocaine causes deficits in model-based behavior and learning independent of requirements for response inhibition or perception of costs or punishment. We trained rats to self-administer sucrose or cocaine for 2 weeks. Four weeks later, the rats began training on a sensory preconditioning and inferred value blocking task. Like devaluation, normal performance on this task requires representations of the underlying task structure; however, unlike devaluation, it does not require either response inhibition or adapting behavior to reflect aversive outcomes. Rats trained to self-administer cocaine failed to show conditioned responding or blocking to the preconditioned cue. These deficits were not observed in sucrose-trained rats nor did they reflect any changes in responding to cues paired directly with reward. These results imply that cocaine disrupts the operation of neural circuits that mediate model-based behavioral control.
    Full-text · Article · Aug 2013 · Psychopharmacology
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