Serotoninergic and dopaminergic modulation of cortico-striatal circuit in executive and attention deficits induced by NMDA receptor hypofunction in the 5-choice serial reaction time task

Executive functions are an emerging propriety of neuronal processing in circuits encompassing frontal cortex and other cortical and subcortical brain regions such as basal ganglia and thalamus. Glutamate serves as the major neurotrasmitter in these circuits where glutamate receptors of NMDA type play key role. Serotonin and dopamine afferents are in position to modulate intrinsic glutamate neurotransmission along these circuits and in turn to optimise circuit performance for specific aspects of executive control over behaviour. In this review, we focus on the 5-choice serial reaction time task which is able to provide various measures of attention and executive control over performance in rodents and the ability of prefrontocortical and striatal serotonin 5-HT1A, 5-HT2A and 5-HT2C as well as dopamine D1- and D2-like receptors to modulate different aspects of executive and attention disturbances induced by NMDA receptor hypofunction in the prefrontal cortex. These behavioural studies are integrated with findings from microdialysis studies. These studies illustrate the control of attention selectivity by serotonin 5-HT1A, 5-HT2A, 5-HT2C and dopamine D1- but not D2-like receptors and a distinct contribution of these cortical and striatal serotonin and dopamine receptors to the control of different aspects of executive control over performance such as impulsivity and compulsivity. An association between NMDA antagonist-induced increase in glutamate release in the prefrontal cortex and attention is suggested. Collectively, this review highlights the functional interaction of serotonin and dopamine with NMDA dependent glutamate neurotransmission in the cortico-striatal circuitry for specific cognitive demands and may shed some light on how dysregulation of neuronal processing in these circuits may be implicated in specific neuropsychiatric disorders

Mechanisms underlying executive function deficits

In our daily life, we come across situations where we meet unanticipated challenges, we must take certain decisions, pay attention, be flexible and inhibit impulsive actions to achieve goal directed behaviour. During these processes, we unknowingly use sets of interdependent cognitive processes collectively called ‘executive function’. Executive function is mainly regulated by the frontal lobe. Impaired executive function is associated with disorders such as schizophrenia, Alzheimer’s disease, autism and attention deficit hyperactivity disorder (ADHD). In this thesis, we investigated neurotransmitters and interactions among them regulating executive function. Further, we investigated mechanisms underlying those interactions mediating executive function in rats using an operant conditioning-based set-shifting task, a common and validated test in animals to assess executive function. In our first study, we identified for the first time that systemic injections of dopamine D1 and glutamate N-methyl-D-aspartate (NMDA) receptor antagonists cause impaired set-shifting and increased the occurrence of perseverative errors only after combined administration at doses that failed to affect set-shifting following separate injections. The discovery of this novel synergistic effect of glutamate and dopamine antagonists on set-shifting prompted us to undertake our second study to determine if such synergy occurs within the medial PFC (mPFC)- an important brain area associated with executive function in rodents. Our results confirmed that mPFC is a site where seemingly mild suppression of glutamate and dopamine activities, similar to that has been reported in schizophrenia brains, may act cooperatively to manifest deficits in executive function via increasing perseverative errors. Our third study was to identify molecular mechanisms underlying such synergy. We found that protein kinase A (PKA) and extracellular signal-regulated kinase (ERK1/2) signaling cascades transduce this effect, with ERK1/2 phosphorylation in mPFC neurons as an obligatory step for set-shifting. The present results have substantially advanced our understanding of the mechanisms underlying executive function. Our results also point to potential novel intracellular targets for therapeutic intervention in cognitive deficits

Disconnection and reconnection: the morphological basis of (mal)adaptation to stress

We would like to thank Antonio Pinheiro, Hugo Almeida, and José Miguel Soares for help with the illustrations. We also thank all past and present members of our laboratories for stimulating discussions.Maladaptive responses to stress and the associated hypersecretion of glucocorticoids cause psychopathologies ranging from hyperemotional states and mood dysfunction to cognitive impairments. Research in both humans and animal models has begun to identify morphological correlates of these functional changes. These include dendritic and synaptic reorganization, glial remodeling, and altered cell fate in cortical and subcortical structures. The emerging view is that stress induces a disconnection syndrome’ whereby the transmission and integration of information that are critical for orchestrating appropriate physiological and behavioral responses are perturbed. High-resolution spatiotemporal mapping of the complete neural circuitry and identification of the cellular processes impacted by stress will help to advance discovery of strategies to reduce or reverse the burden of stress-related neuropsychiatric disorders.Work in our laboratories was supported by the German Academic Exchange Service - Acções Luso-Alemãs, Fundação para a Ciência e Tecnologia (PTDC/SAUNSC/ 111814/2009), and European Union FP7 (SwitchBox Project, Contract 259772; Neuroendocrine Immune Networks in Ageing Scientific Network, Contract 238665)

Role of Prefrontal Cortex Dopamine and Noradrenaline Circuitry in Addiction

Understanding the mechanisms of drug dependence has been the goal of a large number of neuroscientists, pharmacologists and clinicians who carried out research with the hope of individuating and proposing an efficacious therapy for this disorder (Sofuoglu, 2010; Kalivas and Volkow, 2011). Unfortunately, although huge efforts, drug dependence is still a relevant health, social and economical problem (Popova et al., 2012; Hiscock et al., 2011; Shorter and Kosten, 2011). Treatments for drug abuse are for the most part ineffective because the molecular and cellular mechanisms through which drugs of abuse alter neuronal circuitry are still unexplained and above all, because drugs of abuse determine a global alteration of cerebral functions that govern behaviour through decision formation, making therefore unfocused the identification of a pharmacological target (Volkow et al., 2011; Schultz 2011). One of the first strategies pursued in drug dependence therapy was directed to removal of pleasure associated with drug taking, but the compliance with the treatment has been always limited, although it could improve when it was supported by psychology based motivational therapy as in alcohol dependence (Krampe and Ehrenreich, 2010; Simkin and Grenoble, 2010). On the other hand it is not infrequent that heavy smokers or heavy drinkers stop suddenly dependence just because their will overcome year-long habits. Decision making is a process based on the interaction between prefrontal cortex (PFC) and subcortical regions involved in reward and motivation, therefore it is likely that failure in self-regulatory behavior, that is common in addicted subjects, could be dependent upon the alteration of interactions between the prefrontal cortex and subcortical regions (Heatherton and Wagner, 2011). In this chapter we will review the role of PFC in addiction with particular attention to dopamine and norepinephrine transmission

The Convergence of Glutamate and GABA Dysregulation in Schizophrenia

Schizophrenia (SCZ) is a heterogeneous neurodevelopmental disorder that afflicts about 1% of the world population, imposing a huge financial and social burden on the community. Schizophrenia is characterized by three core features, positive (e.g., hallucinations, delusions) and negative symptoms (e.g., emotional blunting, reduced motivation), as well as cognitive impairments (i.e., working memory and attention deficits). Current antipsychotic treatments, which primarily target dopamine receptors, are effective at alleviating positive symptoms. However, dopamine‐specific therapies are insufficient to relieve negative symptoms and cognitive impairments, indicating other neuronal systems are involved in SCZ. Evidence for hypofunctioning glutamate and gamma‐aminobutyric acid (GABA) transmission in forebrain tissue has continued to culminate as major contributors to the onset of SCZ. Furthermore, recent genetic studies reveal disrupted mutations in neurodevelopmental proteins at glutamatergic and GABAergic synapses that are potentially responsible for the synaptic abnormalities seen in the disorder. Therefore, schizophrenia symptomatology is influenced by interactions of several neurotransmitter systems. In this chapter, we focus on how glutamatergic and GABAergic hypofunctioning contribute to the variety of symptoms presented in SCZ and its etiology. We also review the current treatment options with respect to their mechanism of action, side effects, and limitations and provide perspective of where research should be directed to move forward with treating this debilitating disease

Role of cholinergic receptors in prefrontal activity of nonhuman primates during an oculomotor rule-based working memory task

The ability to flexibly react to our dynamic environment is a cardinal component of cognition and our human identity. Millions across the globe are affected by disorders of cognition, affecting their ability to live independently. Prefrontal cortex is required for optimal cognitive functioning, but its circuitry is often disrupted in conditions of impaired cognition. In addition, the cholinergic system is vital to optimal executive function, but this is disrupted in a number of conditions, including Alzheimer’s disease and schizophrenia. The actions of cholinergic receptors were explored in this project with local application of cholinergic compounds onto prefrontal neurons as rhesus monkeys performed a rule-based saccadic task that requires working memory maintenance. The antisaccade task is a useful probe of prefrontal cortex function that elicits errors in neuropsychiatric conditions. Some prefrontal neurons respond to different task aspects of the antisaccade task, e.g., discharging preferentially for one task rule over the other (pro- or antisaccades), and are thought to be involved in the circuitry for correct behavioural responses. Chapter 2 explored the effect of general stimulation of cholinergic receptors on rhesus PFC neuronal activity during antisaccade performance. In Chapter 3, newly developed cholinergic receptor subtype-specific compounds were utilized to examine the actions of muscarinic M1 receptor stimulation on prefrontal activity. Cortical oscillations are emerging as an important aspect of cognitive circuitry, such as during working memory maintenance. Chapter 4 examined the influence of local cholinergic receptor stimulation and blockade on the power of local field potential in different frequency bands. This project characterized the role of cholinergic receptors in prefrontal cortical neurons that were actively involved in cognitive circuitry. This and future work on the cholinergic influence on prefrontal cortex will provide insights into the altered cognitive functioning in Alzheimer’s disease and schizophrenia, which are also affected by disrupted cholinergic systems

The medial prefrontal cortex and the dorsomedial striatum are necessary for working memory in rats: role of NMDA receptors

Working memory is a form of short-term memory involved in the storage (maintenance) of information over time and reorganization (manipulation) of a memory set necessary for complex cognition. The human frontal cortex and striatum are involved with working memory; however, the mechanisms through which these structures contribute to working memory are incompletely understood. Given the similarities between cortical and striatal areas in the human and rodent brain, I used rats to elucidate the contrbutions of N-methyl-D-aspartate (NMDA) receptors in medial prefrontal cortex (mPFC) and dorsomedial striatum (dmSTR) using two working memory tasks. The trial unique non-match to location (TUNL) task is a delayed-non-match-to-sample visual working memory task performed in touchscreen equipped operant conditioning chambers. TUNL enables the concurrent assessment of delay-dependent and “pattern separation” effects that were not possible with previous delayed-non-match-to-sample-tasks. The odour span task (OST) measures working memory capacity using an incremental delayed-non-match-to-sample paradigm that involves the addition of stimuli (scented bowls) after each correct response. Results obtained following systemic treatment of rats with a broad spectrum NMDA receptor antagonist showed that NMDA receptors contribute to performance of both tasks. Given the contribution of cortical GluN2B-containing NMDA receptors to working memory in primates, we tested the role of these receptors in the TUNL task and OST. Systemic injections of the GluN2B-containing NMDA receptor antagonist Ro 25-6981 impaired OST but not TUNL accuracy. Additional experiments with intracranial infusions showed NMDA receptors in mPFC or dmSTR contribute to TUNL task accuracy. Ro 25-6981 infusions into dmSTR, but not mPFC impaired OST. These experiments contribute to our understanding of the role NMDA receptors perform in mPFC and dmSTR in working memory

The subchronic phencyclidine rat model: relevance for the assessment of novel therapeutics for cognitive impairment associated with schizophrenia

Rationale: Current treatments for schizophrenia have modest, if any, efficacy on cognitive dysfunction, creating a need for novel therapies. Their development requires predictive animal models. The N-methyl-D-aspartate (NMDA) hypothesis of schizophrenia indicates the use of NMDA antagonists, like subchronic phencyclidine (scPCP) to model cognitive dysfunction in adult animals. Objectives: The objective of this study was to assess the scPCP model by (1) reviewing published findings of scPCP-induced neurochemical changes and effects on cognitive tasks in adult rats and (2) comparing findings from a multi-site study to determine scPCP effects on standard and touchscreen cognitive tasks. Methods: Across four research sites, the effects of scPCP (typically 5 mg/kg twice daily for 7 days, followed by at least 7-day washout) in adult male Lister Hooded rats were studied on novel object recognition (NOR) with 1-h delay, acquisition and reversal learning in Morris water maze and touchscreen-based visual discrimination. Results: Literature findings showed that scPCP impaired attentional set-shifting (ASST) and NOR in several labs and induced a variety of neurochemical changes across different labs. In the multi-site study, scPCP impaired NOR, but not acquisition or reversal learning in touchscreen or water maze. Yet, this treatment regimen induced locomotor hypersensitivity to acute PCP until 13-week post-cessation. Conclusions: The multi-site study confirmed that scPCP impaired NOR and ASST only and demonstrated the reproducibility and usefulness of the touchscreen approach. Our recommendation, prior to testing novel therapeutics in the scPCP model, is to be aware that further work is required to understand the neurochemical changes and specificity of the cognitive deficits

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