Striatal Activity is Associated with Deficits of Cognitive Control and Aberrant Salience for Patients with Schizophrenia

A recent study has shown that the locus of the largest known dopamine abnormality between patients with schizophrenia and healthy controls is in the associative striatum (Kegeles et al., 2010). This dopamine abnormality in the associative striatum is thought to bring about aberrant salience assignment for patients, which may underlie symptoms of psychosis like delusions and hallucinations (Howes & Kapur, 2009). Interestingly, the associative striatum has segregated, looped, connectivity with cortical regions including the prefrontal and parietal cortices (Draganski et al., 2008; Redgrave, Vautrelle, & Reynolds, 2011) and computational models have suggested that it may function as an information gate during cognitive control (Frank, Loughry, & O\u27Reilly, 2001; Gruber, Dayan, Gutkin, & Solla, 2006), much the way that posterior portions of the striatum gate motor control (Chevalier & Deniau, 1990). The current study sought to explore the relationship between striatal involvement in cognition and aberrant salience symptom expression using a novel task of cognitive control. We examined aberrant salience using a self-report measure (Cicero et al., 2010) and core components of cognitive control (updating, interference control, and simple maintenance), that are critically reliant on intact information gating, in a sample of 22 patients with schizophrenia and 20 healthy controls using a slow event-related fMRI design. We predicted that 1) aberrant salience symptoms would be greater for patients than controls, 2) that patients would demonstrate increased errors during interference controls trials, given that patients may be inappropriately assigning salience to distracters, and 3) that striatal activity during those errors could be positively correlated with aberrant salience symptoms. We found a trend toward significant differences between patients and controls on aberrant salience symptom presence, and a significant difference between groups during updating performance. During interference control trials, although we found no difference between groups when participants were tasked with maintaining targets during distracter presentation, patients were more likely to make errors when probed with those distracters, suggesting inappropriate distracter updating. When examining the brain activity during correct and incorrect updating and interference control trials, for patients update trial activity in the prefrontal cortex and striatum was significantly lower for incorrect updating trials when compared to correct updating trials, and significantly greater when patients inappropriately identified the distracter as correct compared with trials when they correctly rejected the distracter. Activity did not differ between correct and incorrect updating or interference control trials for controls. Further, we found that for patients, as predicted, the increase of activity during incorrect distracter trials was positively correlated with aberrant salience symptoms, but only for the associative striatal region and not the prefrontal region. We found no relationship between aberrant salience and patient brain activity during correct distracter trials, nor did we find significant relationships between aberrant salience and brain activity during either updating or interference control trials for controls. These results demonstrate that cognitive control deficits of patients demonstrate some domain selectivity, given that we found some evidence for preserved simple maintenance and maintenance in the face of task relevant distracter performance, but impaired performance at updating and ignoring distracters. Finally, we found evidence demonstrating a relationship between aberrant salience symptom expression for patients, cognitive deficits, and associative striatal activity. This relationship may have implications for treatments that improve cognitive function and reduce symptom expression

A Neurocomputational Model of the Functional Role of Dopamine in Stimulus-Response Task Learning and Performance

Thesis (Ph.D.) - Indiana University, Psychology, 2009The neuromodulatory neurotransmitter dopamine (DA) plays a complex, but central role in the learning and performance of stimulus-response (S-R) behaviors. Studies have implicated DA's role in reward-driven learning and also its role in setting the overall level of vigor or frequency of response. Here, a neurocomputational model is developed which models DA's influence on a set of brain regions believed to be involved in the learning and execution of S-R tasks, including frontal cortex, basal ganglia, and cingulate cortex. An `actor' component of the model is trained, using `babble' (random behavior selection) and `critic' (rewarding and punishing) components of the model, to perform acceptance/rejection responses upon presentation of color stimuli in the context of recently presented auditory tones. The model behaves like an autonomous organism learning (and relearning) through `trial-and-error'. The focus of the study, the impact of hypo- and hyper-normal DA activity on this model, is investigated by three different dopaminergic pathways--two striatal and one prefrontal cortical--being manipulated independently during the learning and performance of the color response task. Hypo-DA conditions, analogous to Parkinsonism, cause slowing and reduction of frequency of learned responses, and, at extremes, degrade the learning (either initial or reversal) of the task. Hyper-DA conditions, analogous to psychostimulant effects, cause more rapid response times, but also can lead to perseveration of incorrect learning of response on the task. The presence of these effects often depends on which DA-ergic pathway is manipulated, however, which has implications for interpretation of the pharmacological experimental data. The proposed model embodies an integrative theory of dopamine function which suggests that the base rate of DA cell activity encodes the overall `activity-oriented motivation' of the organism, with hunger and/or expectation of reward driving both response vigor and tendency to generate an explorative `babble' response. This more `tonic' feature of DA functionality coexists naturally with the more extensively-studied `phasic' reward-learning features. The model may provide better insights on the role of DA system dysfunction in the cognitive and motivational symptoms of disorders such as Parkinsonism, psychostimulant abuse, ADHD, OCD, and schizophrenia, accounting for deficits in both learning and performance of tasks

The role of dopamine D2 and neuregulin-1 receptors in schizophrenia relevant phenotypes of cognition, attention and memory

Aberrant neurotransmitter function promotes cognitive deficits in schizophrenia. These abnormalities in functioning are seen as disruptions in attentional and information processing, as well as disruptions in the consolidation and retrieval of information. Tasks of attentional salience and memory that are used to model these disruptions include the latent inhibition (LI) task of attentional salience, prepulse inhibition (PPI) task of sensorimotor gating and an Episodic memory (EM) task, which is an index of memory for episodes at a particular point in time. Aberrant functioning of candidate genes that are associated with risk for schizophrenia may be seen as behavioural alterations in these tasks of schizophrenia relevant phenotypes. dopaminergic hyperactivity and hypofunction have been implicated in mediating disruptions on these cognitive tasks. Increased transmission in the dopamine system in the striatal region promotes schizophrenia symptoms, and indirect dopamine (DA) agonist Amphetamine worsens these symptoms in patients, and disrupts schizophrenia relevant behaviours on these cognitive tasks. We investigated the effects of deletion of two genes relevant to schizophrenia on cognitive tasks known to be disrupted in the disorder. The effect of deletion of the dopamine D2 receptor (D2R) and trans membrane (TM) domain Neuregulin-1 (Nrg-1) receptor were investigated in mediating disruptions in cognitive processes in an animal model of schizophrenia. The role of the D2R in an attentional model of sensorimotor gating was assessed. PPI was attenuated in D2R knock out (KO), in a one day sensorimotor gating task. In a one day PPI test protocol, amphetamine disruptions on PPI were spared in D2R WT and KO mice. Following on from previous reports of disrupted LI by a single low dose amphetamine injection, separated by 24h interval, we established a single vs. two low dose PPI protocol in order to facilitate a direct comparison of amphetamine induced disruption in LI with PPI. A one injection (prior to test only) vs. two injection (prior to habituation and prior to test) task was established. In the two day protocol, a single low dose of amphetamine disrupted PPI in D2R KO mice and reduced startle reactivity to the 120 dB pulse alone trials. Two low dose injections of amphetamine however, do not disrupt PPI in D2R KO or their WT littermates, and do not mimic low dose amphetamine disruptions in the LI task. These findings demonstrate that prior conclusions about the requirement of the D2R for amphetamine effects in PPI does not generalise to all dose regimens. Episodic memory was also investigated as a measure of cognitive impairment in schizophrenia. D2R KO mice show sex specific dissociations on an EM task. Male D2R WT and KO animals show equal exploration of old vs. recent objects on the what-when component of the EM task, and female KO animals show enhanced memory for old vs. recent objects. Both D2R WT and KO mice show intact memory for displaced objects. These deficits were also investigated in the TM domain Nrg-1 model. Nrg-1 has been implicated as a candidate gene for schizophrenia, and behavioural phenotypes assessing its role in cognitive impairment in schizophrenia were established. Intact LI is seen in both Nrg-1 WT and Het animals. Nrg-1 TM domain Het mutants also show deficits on the schizophrenia relevant PPI task. Nrg-1 Het mutants show attenuated % PPI compared to their WT littermates, which reflects interrupted sensorimotor gating in schizophrenia. Lastly, we found some evidence that reduced function of TM-domain of the Nrg-1 gene disrupted episodic-like memory (what- where-when recognition) in males and improved it in females

The role of dopamine D2 and neuregulin-1 receptors in schizophrenia relevant phenotypes of cognition, attention and memory

Aberrant neurotransmitter function promotes cognitive deficits in schizophrenia. These abnormalities in functioning are seen as disruptions in attentional and information processing, as well as disruptions in the consolidation and retrieval of information. Tasks of attentional salience and memory that are used to model these disruptions include the latent inhibition (LI) task of attentional salience, prepulse inhibition (PPI) task of sensorimotor gating and an Episodic memory (EM) task, which is an index of memory for episodes at a particular point in time. Aberrant functioning of candidate genes that are associated with risk for schizophrenia may be seen as behavioural alterations in these tasks of schizophrenia relevant phenotypes. dopaminergic hyperactivity and hypofunction have been implicated in mediating disruptions on these cognitive tasks. Increased transmission in the dopamine system in the striatal region promotes schizophrenia symptoms, and indirect dopamine (DA) agonist Amphetamine worsens these symptoms in patients, and disrupts schizophrenia relevant behaviours on these cognitive tasks. We investigated the effects of deletion of two genes relevant to schizophrenia on cognitive tasks known to be disrupted in the disorder. The effect of deletion of the dopamine D2 receptor (D2R) and trans membrane (TM) domain Neuregulin-1 (Nrg-1) receptor were investigated in mediating disruptions in cognitive processes in an animal model of schizophrenia. The role of the D2R in an attentional model of sensorimotor gating was assessed. PPI was attenuated in D2R knock out (KO), in a one day sensorimotor gating task. In a one day PPI test protocol, amphetamine disruptions on PPI were spared in D2R WT and KO mice. Following on from previous reports of disrupted LI by a single low dose amphetamine injection, separated by 24h interval, we established a single vs. two low dose PPI protocol in order to facilitate a direct comparison of amphetamine induced disruption in LI with PPI. A one injection (prior to test only) vs. two injection (prior to habituation and prior to test) task was established. In the two day protocol, a single low dose of amphetamine disrupted PPI in D2R KO mice and reduced startle reactivity to the 120 dB pulse alone trials. Two low dose injections of amphetamine however, do not disrupt PPI in D2R KO or their WT littermates, and do not mimic low dose amphetamine disruptions in the LI task. These findings demonstrate that prior conclusions about the requirement of the D2R for amphetamine effects in PPI does not generalise to all dose regimens. Episodic memory was also investigated as a measure of cognitive impairment in schizophrenia. D2R KO mice show sex specific dissociations on an EM task. Male D2R WT and KO animals show equal exploration of old vs. recent objects on the what-when component of the EM task, and female KO animals show enhanced memory for old vs. recent objects. Both D2R WT and KO mice show intact memory for displaced objects. These deficits were also investigated in the TM domain Nrg-1 model. Nrg-1 has been implicated as a candidate gene for schizophrenia, and behavioural phenotypes assessing its role in cognitive impairment in schizophrenia were established. Intact LI is seen in both Nrg-1 WT and Het animals. Nrg-1 TM domain Het mutants also show deficits on the schizophrenia relevant PPI task. Nrg-1 Het mutants show attenuated % PPI compared to their WT littermates, which reflects interrupted sensorimotor gating in schizophrenia. Lastly, we found some evidence that reduced function of TM-domain of the Nrg-1 gene disrupted episodic-like memory (what- where-when recognition) in males and improved it in females