14 research outputs found
Post-training depletions of basolateral amygdala serotonin fail to disrupt discrimination, retention, or reversal learning.
In goal-directed pursuits, the basolateral amygdala (BLA) is critical in learning about changes in the value of rewards. BLA-lesioned rats show enhanced reversal learning, a task employed to measure the flexibility of response to changes in reward. Similarly, there is a trend for enhanced discrimination learning, suggesting that BLA may modulate formation of stimulus-reward associations. There is a parallel literature on the importance of serotonin (5HT) in new stimulus-reward and reversal learning. Recent postulations implicate 5HT in learning from punishment. Whereas, dopaminergic involvement is critical in behavioral activation and reinforcement, 5HT may be most critical for aversive processing and behavioral inhibition, complementary cognitive processes. Given these findings, a 5HT-mediated mechanism in BLA may mediate the facilitated learning observed previously. The present study investigated the effects of selective 5HT lesions in BLA using 5,7-dihydroxytryptamine (5,7-DHT) vs. infusions of saline (Sham) on discrimination, retention, and deterministic reversal learning. Rats were required to reach an 85% correct pairwise discrimination and single reversal criterion prior to surgery. Postoperatively, rats were then tested on the (1) retention of the pretreatment discrimination pair, (2) discrimination of a novel pair, and (3) reversal learning performance. We found statistically comparable preoperative learning rates between groups, intact postoperative retention, and unaltered novel discrimination and reversal learning in 5,7-DHT rats. These findings suggest that 5HT in BLA is not required for formation and flexible adjustment of new stimulus-reward associations when the strategy to efficiently solve the task has already been learned. Given the complementary role of orbitofrontal cortex in reward learning and its interconnectivity with BLA, these findings add to the list of dissociable mechanisms for BLA and orbitofrontal cortex in reward learning
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Neurochemical and Neuroanatomical Basis Of Reversal Learning In The Rat
The aim of this thesis was to investigate the neural and neurochemical substrates of cognitive flexibility using a novel touchscreen task involving serial reversal of visual discrimination in rats. Much evidence has implicated frontostriatal circuitry in the mediation of reversal learning and this thesis sought to further delineate the role of these structures. Although dopamine has been implicated in cognitive flexibility in psychopharmacological studies in primates, there are relatively few studies in the rat. Consequently, the behavioural effects of a dopamine D2/D3 receptor antagonist (raclopride) were assessed, both systemically and via intracerebral infusions into different regions of the striatum. Systemic raclopride had no specific effects initially on serial reversal learning, but continued treatment with a low dose did impair retention of a novel visual discrimination, and its subsequent reversal. Intracerebral infusions of raclopride into the dorsomedial and dorsolateral striatum produced a dissociation during separate phases of reversal learning, dorsomedial infusions affecting new learning, and dorsolateral infusions producing perseveration in the early phase. By contrast, raclopride infusions into the anterior dorsomedial striatum produced a general slowing of responding, whereas infusions into the nucleus accumbens core region had no significant effects.
The second part of the thesis investigated the role of prefrontal cortical projections to the striatum in serial reversal learning, focusing on the lateral and medial orbitofrontal cortex, as well as regions of the medial prefrontal cortex. Local temporary inactivation of these structures via infusion of a muscimol/baclofen mixture produced dissociable effects. Inactivation of the infralimbic cortex led to a significant general improvement in reversal learning regardless of phase, while inactivation of the medial orbitofrontal cortex led specifically to a significant reduction in the number of errors during perseveration. By contrast, inactivation of the lateral orbitofrontal cortex caused a significant increase in the number of errors and omissions during perseveration, whereas prelimbic cortex inactivation had no major effects.
The findings of the thesis are discussed in terms of the separate roles for the different phases of reversal learning of different sectors of the frontal lobe and striatum in the rat, and the modulatory role of the striatal D2/D3 receptors. Possible clinical, as well as functional, implications of the results are also considered.BBSR
The role of 5-HT2C receptors in touchscreen visual reversal learning in the rat: a cross-site study.
RATIONALE: Reversal learning requires associative learning and executive functioning to suppress non-adaptive responding. Reversal-learning deficits are observed in e.g. schizophrenia and obsessive-compulsive disorder and implicate neural circuitry including the orbitofrontal cortex (OFC). Serotonergic function has been strongly linked to visual reversal learning in humans and experimental animals but less is known about which receptor subtypes are involved. OBJECTIVES: The objectives of the study were to test the effects of systemic and intra-OFC 5-HT2C-receptor antagonism on visual reversal learning in rats and assess the psychological mechanisms underlying these effects within novel touchscreen paradigms. METHODS: In experiments 1-2, we used a novel 3-stimulus task to investigate the effects of 5-HT2C-receptor antagonism through SB 242084 (0.1, 0.5 and 1.0 mg/kg i.p.) cross-site. Experiment 3 assessed the effects of SB 242084 in 2-choice reversal learning. In experiment 4, we validated a novel touchscreen serial visual reversal task suitable for neuropharmacological microinfusions by baclofen-/muscimol-induced OFC inactivation. In experiment 5, we tested the effect of intra-OFC SB 242084 (1.0 or 3.0 μg/side) on performance in this task. RESULTS: In experiments 1-3, SB 242084 reduced early errors but increased late errors to criterion. In experiment 5, intra-OFC SB 242084 reduced early errors without increasing late errors in a reversal paradigm validated as OFC dependent (experiment 4). CONCLUSION: Intra-OFC 5-HT2C-receptor antagonism decreases perseveration in novel touchscreen reversal-learning paradigms for the rat. Systemic 5-HT2C-receptor antagonism additionally impairs late learning-a robust effect observed cross-site and potentially linked to impulsivity. These conclusions are discussed in terms of neural mechanisms underlying reversal learning and their relevance to psychiatric disorders.The research leading to these results has received support from the Innovative Medicine Initiative Joint Undertaking under grant agreement no. 115008 of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union’s Seventh Framework Programme (FP7/2007-2013). The study was also supported by a Wellcome Trust Grant (089589/z/09/z) to T.W.R., B.J. Everitt, B.J. Sahakian, A.C. Roberts and J.W. Dalley, and by a Wellcome Trust Senior Investigator Award to T.W.R. (104631/Z/14/Z). The Behavioural and Clinical Neuroscience Institute is co-funded by the Medical Research Council and the Wellcome Trust. J.A. was supported by the Swedish Pharmaceutical Society and the Swedish Research Council (350-2012-230). S.R.O.N was supported by BBSRC and Eli Lilly through CASE studentship (BB/F529054/1).This is the final version of the article. It first appeared from Springer via http://dx.doi.org/10.1007/s00213-015-3963-
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The role of ventrolateral prefrontal cortex in performance of spatial self-ordered response sequences in the marmoset
The ventrolateral prefrontal cortex (vlPFC) in primates plays an important role in cognitive control and working memory, but as argued in the Introduction its contribution to those aspects of goal-directed behaviour such as planning and executing spatial response sequences requires further analysis, using more refined methods than have been employed hitherto.
These studies investigated the role of vlPFC in performance of self-ordered response sequences using intra-cerebral microinfusions of specific pharmacologic agents in the common marmoset. Following a description of the necessary methodology, including behavioural training and surgical details (Chapter 2), a causal role for vlPFC in performance of spatial-self ordered sequences was confirmed in Chapter 3 by demonstrating that local inactivation of vlPFC using muscimol/baclofen infusions impairs sequencing. This effect was shown to be selective to performance of sequences that varied spatially from trial to trial; thus, no effects of vlPFC inactivation were observed for performance of a fixed response sequence. Once animals could learn a heuristical strategy for a self-ordered fixed sequence, vlPFC inactivation no longer impaired performance. Chapter 4 investigated the effects of the chemical neuromodulation of vlPFC on self-ordered sequencing using microinfusions of dopamine receptor D2 antagonist, sulpiride, and 5HT2A receptor antagonist, M100907 on performance of variable sequences. These drugs produced contrasting, dose-dependent impairments. M100907 impaired accuracy, while sulpiride impaired error correction. Chapter 5 studied effects of blocking glutamatergic receptors in a region of the caudate nucleus to which the vlPFC projects, but no significant effects on sequencing accuracy were observed, although there were large effects on perseverative errors in 2 out of 3 animals.
The findings are discussed in Chapter 6 in terms of the functioning of the vlPFC and its possible role in controlling flexible response sequencing and working memory. The findings are shown to be of relevance for psychiatric disorders such as obsessive compulsive disorder (OCD) and schizophrenia, which show functional dysconnectivity of the vlPFC in association with response sequencing impairments
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The role of 5-HT2CR modulation in a reversal learning model of cognitive flexibility in mice
Previous research employing modulation of 5-HT2C receptors (5-HT2CRs) in rodents has identified a potential role in mediating cognitive flexibility. The work presented in this thesis explores the effects of systemic administration of the selective 5-HT2CR antagonist SB242084 on a range of Pavlovian and operant learning paradigms used to model cognitive flexibility and reward-based learning in mice.
Based on a key design difference in previous research reporting discrepant outcomes, trial initiation requirements were manipulated. However the effect of SB242084 administration relative to vehicle-treatment was consistent with prior reports of impaired reversal performance following reductions in 5-HT2CR activity, regardless of whether trials were automatically or self-initiated. In contrast, performance on a probabilistic reversal learning task was enhanced by drug-treatment, raising the possibility that task difficulty mediates the effect of this manipulation on performance. A drug-related enhancement in the ability to overcome learned non-reward at the previously incorrect location was additionally demonstrated under probabilistic reversal conditions, with no effect on perseverance at the previously correct location. However, performance of drug-treated animals in two closely related tasks demonstrated impaired extinction learning but intact development of latent inhibition to a pre-exposed stimulus. The effect of SB242084 on incentive motivation was additionally explored, but did not impact upon the acquisition of a sign-tracking response to a conditioned stimulus, or a subsequent reversal; suggesting that 5-HT2CRs may be more critically involved in instrumental than Pavlovian learning.
These experiments reveal a complex picture for the involvement of 5-HT2CRs in flexible cognition, however, systemic manipulations may not be optimal for dissecting their role. Therefore, a final study explored the expression of c-Fos immunoreactivity in response to reversal learning. A broad network was activated by elements of the reversal task, including regions of the prefrontal cortex and amygdala, providing a basis for future studies targeting components of this circuitry
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Modelling the Neuropsychopharmacology of Obsessive-Compulsive Disorder in the Common Marmoset (Callithrix jacchus)
This thesis extends the understanding of the neural and neurochemical contributions to two forms of behavioural adaptation, reversal learning and contingency degradation, in which stimulus/action–reward contingencies are altered. The results are interpreted within the psychological framework of the compulsivity construct, and their implications for the pathological behaviour of obsessive-compulsive-disorder (OCD) are considered.
The orbitofrontal cortex (OFC) and striatum are key brain structures involved in reversal learning, as are the neurotransmitters serotonin (5-hydroxytryptamine, 5-HT) and dopamine (DA) within those respective regions. However, there has been little empirical evidence of how these two structures and neurochemical systems interact, especially in the functional context of reversal learning. In Chapter Three, the impact of experimentally-induced reductions of 5-HT in the anterior OFC on monoamine levels in subcortical structures such as the striatum and amygdala was determined, DA being found to be significantly up-regulated in the amygdala. Functionally, 5-HT depletion of the OFC has previously been shown to induce deficits in reversal learning. To determine the possible causal significance of amygdala dopamine up-regulation for said reversal learning deficit, the effects of blocking the upregulation with the infusion of intra amygdala DA receptor antagonists following bilateral OFC 5-HT depletion were investigated in a reversal learning paradigm.
In Chapter Four, the differential roles of regions of striatum were examined in visual reversal learning. Two recent investigations in non-human primates highlighted the role of the striatum in reversal learning,but pinpointed the critical region to be either the ventromedial caudate or the putamen. Marmosets were
trained on a serial reversal task that allowed multiple acute neural manipulations, and the ventromedial caudate and putamen were then reversibly inactivated using the GABAA agonist muscimol. Results indicated dose-related impairments specifically in reversal learning within the putamen, with sparing of discrimination retention. By contrast, similar reversible inactivation of the caudate nucleus produced marked deficits in visual discrimination performance (retention).
In Chapter Five, the neural basis of action–outcome contingency knowledge was investigated by inactivating distinct regions of the PFC, the perigenual ACC (pgACC; area 32) and the anterior OFC, and
determining response sensitivity to the degradation of action–outcome contingencies. In previous work, excitotoxic lesions of either the pgACC or the OFC had been found to induce insensitivity to contingency degradation in marmosets. However, the design of that experiment did not allow specification of whether stimulus– or action–outcome associations were disrupted, and a precise neural locus could not be determined for the behavioural effects as the OFC lesions included parts of the lateral and medial OFC. I therefore developed a novel contingency degradation paradigm that distinguished between stimulus– and action–outcome associations to enable the study of acute pharmacological manipulations in both brain regions. The pgACC and OFC were reversibly inactivated using GABAA–GABAB agonists (muscimol–baclofen). Whereas the pgACC inactivation produced selective deficits in sensitivity to action–outcome contingency degradation, OFC inactivation reduced the suppressive effect of noncontingent reward on
responding more generally but left intact sensitivity to degradation of the contingencies.
These results are discussed in terms of different theories of the functions of the pgACC and OFC. In the final discussion the findings on the neural substrates of reversal learning and contingency degradation are drawn together in terms of their significance for theories of PFC involvement in cognitive control, and
for the understanding of OCD and other neuropsychiatric disorders.Research that formed the thesis was supported by a Programme Grant (G0901884) from the Medical Research Council UK (MRC) to Professor Angela Roberts and a Wellcome Trust Senior Investigator Award (104631/Z/14/Z) to Professor Trevor Robbins. I was personally supported by a BCNI-MRC studentship. The research was conducted at the Behavioural and Clinical Neuroscience Institute, which was supported by a joint award from the MRC and Wellcome Trust (G00001354)
The neuropsychopharmacology of reversal learning
Reversal learning deficits are a feature of many neuropsychiatric disorders, most
notably schizophrenia. These deficits could be due, in part, to altered ability to dissipate
either or both associations of previous positive (perseverance) and negative (learned
non-reward) valence. Studies reported in this thesis developed an egocentric maze task
and a visuospatial operant task for separate assessments of spatial reversal learning,
perseverance and learned non-reward in mice. These tasks were subsequently used to
assess the cognitive causes for altered performance after manipulations to brain systems
recognised to be involved in reversal learning and relevant for human psychopathology,
with a specific focus on schizophrenia.
NMDA receptor (NMDAr) antagonism through acute phencyclidine did not
affect reversal learning in the operant task, but caused general impairments in the maze
task. Orbitofrontal (OFC) lesioned mice showed perseverative impairments in the
operant task. Mice treated with the 5-HT2C receptor (5-HT2CR) antagonist SB242084
and 5-HT2CR KO mice showed facilitated reversal learning and decreased learned nonreward in the operant task. In the maze task, SB242084 decreased perseverance but increased learned non-reward, while 5-HT2CR KO mice showed perseverance and
discrimination learning deficits. The final experimental chapter investigated the effect of SB242084 on touch-screen visual reversal learning in the rat. SB242084 retarded
learning in this task.
These studies demonstrate that previously non-reinforced associations can be of
considerable importance in tasks of cognitive flexibility. The studies also show that the
NMDAr, the 5-HT2CR, and the OFC, are involved in reversal learning and can modulate
mechanisms related to both perseverance and learned non-reward. Moreover, in reversal
learning, few effects of manipulations affecting PFC-functioning, or activity at the
NMDAr and 5-HT2CR, generalise across the procedures in the visuospatial, egocentric
spatial, and visual domains
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Serotonergic modulation of attentional processes in the rat prefrontal cortex.
The experimental evidence for the 5-HT system involvement in cognitive processes sensitive to dysfunction of the prefrontal cortex is sparse. The aim of this project was to examine serotonergic modulation of attentional performance deficits in the 5-
choice serial reaction time (5-CSRT) task induced by blockade of NMDA receptors in the medial prefrontal cortex (mPFC) of rats. Using in-vivo microdialysis techniques attempts have been made to relate the behavioural effects of 5-HT receptors agonists and antagonists to changes in glutamate and 5-HT efflux induced by blockade of NMDA receptors in the mPFC. The data clearly demonstrate that glutamate transmission in the mPFC is involved in the control of attentional performance on the 5-CSRT task. The data also show for the first time that enhanced glutamate and 5-HT release induced by blockade of NMDA receptors in the mPFC are not causally related to aspects of inhibitory response control as indexed by impulsive anticipatory and compulsive perseverative responses. The important suggestion emerging from this study is that of distinct neuromodulation in the control of impulsive responding by 5-HT 2A/5-HT2C receptors and in compulsive behaviours by 5-HT1A and DA D 2 receptors in the prefrontal cortex. Intriguingly deficits in attentional accuracy might be associated with increased glutamate release in the mPFC. Thus behavioural evidence obtained in animals with dysfunctional glutamate transmission performing the 5-CSRT task, as well as a series of pharmacological manipulations of 5-HT, DA and mGlu2/3 receptor mechanisms have been presented that are consistent with the hypothesis that serotonergic mechanisms in the prefrontal cortex play specific roles in attention and response selection particularly when these have a possible function in the strategic control of behaviour. These behavioural and neurochemical studies provide new information on the physiological mechanisms involved in the control of various aspects of attentional performance as well as in cognitive deficits associated with some neuropsychiatric disorders
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Serotonin and Threat: from Gene to Behaviour
Anxiety and fear are emotions provoked by threatening situations and shape adaptive behaviours, but excessive and uncontrollable anxiety and fear form core symptoms of anxiety disorders. High trait anxiety, an individual’s disposition to feel anxious, is associated with greater risk of developing depression and anxiety disorders. This raises the question: why are some more vulnerable to experiencing negative emotions associated with threat than others? As serotonin has been implicated as a key neuromodulator of emotion, the thesis addresses this question by adopting a multi-systems approach to investigate the link between serotonin and both threat-driven behaviour and trait anxiety with the common marmoset as a model.
Firstly, factors underlying threat-related behaviour modelled with an exploratory factor analysis revealed a relationship between a predominantly avoidant fear coping style and an increased propensity for anxiety, establishing a link between specific fear-driven behavioural patterns and anxiety.
After characterising anxiety and fear-driven behaviours, mRNA quantification of brain regions implicated in anxiety revealed serotonergic gene expressions corresponding to anxiety and fear-driven behaviours. Most notably, amygdala serotonin transporter expression was positively associated with anxious behaviour and was differentiated by the serotonin transporter polymorphism. Based on this association, the hypothesis that increased amygdala serotonin transporter expression may contribute to the high trait anxious phenotype was tested. Consistent with this hypothesis, blockade of amygdala serotonin transporters via local infusions of a selective serotonin reuptake inhibitor (SSRI), citalopram reduced key characteristics of the high trait anxious phenotype: high state anxiety, and both the behavioural and physiological expression of conditioned fear.
Anatomically, high anxious animals showed reduced basolateral amygdala (BLA) volume in adulthood. Moreover, BLA volume in adulthood was differentiated by the serotonin transporter polymorphism. During development, high anxious animals showed a delayed BLA growth trajectory. These findings demonstrate morphological changes in the BLA across different developmental timepoints predictive of high anxiety in adulthood.
Taken together, findings here provide evidence of amygdala serotonin’s role in trait anxious expression, and propose behavioural, genetic, molecular and anatomical factors that may contribute to an individual’s vulnerability to anxiety.Work here was supported by an MRC Programme grant (ACR: MR/M023990/1) and performed within the Behavioural and Clinical Neuroscience Institute, University of Cambridge, funded jointly by the Wellcome Trust and MRC. SKLQ was supported by a scholarship by the Malaysian Public Service Department
Inhibition of prandial and waterspray-induced rat grooming by 8-OH-DPAT
The effects of 8-OH-DPAT treatment on rat grooming behaviour, elicited either prandially or in response to spraying with water were investigated. Dose (≤0.1 mg/kg s.c.) response studies employed momentary time sampling over 30 or 60 min with behaviour being scored in one of 6 or 7 (depending on food availability) mutually exclusive categories (feeding, active, scratching, face-grooming, body grooming, genital-grooming and resting) at 15 s intervals. In non-deprived rats, tested with wet mash available, feeding and activity frequencies were increased, but resting and total grooming were inhibited by 8-OH-DPAT. Face-, body- and genital-grooming occurred at higher levels than scratching, but all categories were reduced with reductions in scratching occurring at a lower dose (0.01 mg/kg). Misting rats with a fine water spray selectively increased body grooming and decreased activity without altering feeding, while 8-OH-DPAT increased feeding and reduced face-, body- and genital-grooming, without affecting already low levels of scratching. In misted rats, tested without food, 8-OH-DPAT reduced face-, body- and genital-grooming and increased resting. These results confirm i) that the water spray technique is a useful method for increasing grooming and ii) that 8-OH-DPAT has a suppressant effect on grooming independent of response competition from enhanced feeding