Effects of prenatal exposure to glucocorticoids in impulsivity and novelty-seeking behavior

Dissertação de mestrado em Ciências da SaúdeEarly life stress (ELS) or elevated levels of glucocorticoids (GCs) may result in persistent effects in the central nervous system that can lead to maladaptive behavior in adult life and increase the vulnerability to develop psychiatric disorders, such as anxiety, depression or drug addiction. In clinics, synthetic GCs are often prescribed in pregnancies in risk of pre-term labor, to ensure fetal lung maturation. Regardless of its beneficial effect, elevated levels of GCs during this period can lead to deleterious and permanent effects on brain function and development. The mesocorticolimbic dopaminergic circuit, also known as the ‘reward’ system, seems to be a key target of stress/GCs, since it has been shown that animals exposed to GC in utero (iuGC) have structural and molecular alterations in several brain regions of this pathway. Importantly, such changes may underlie the observed addictive-like behavior of iuGC animals. Vulnerability for addictive behavior may be modulated by individual emotional condition and/or specific personality traits. iuGC animals present anxious and depressive-like behavior, but less is known about their novelty-seeking and impulsivity traits, two behavioral dimensions that contribute substantially to drug-seeking behavior. In this perspective, we evaluated iuGC animals in novelty-dependent behavioral tests. iuGC animals did not present major differences in noveltyinduced locomotor activity nor in general exploratory behavior (Novelty Place Preference and Novel Object Recognition). However, iuGC rats explore familiar and novel objects similarly in the 24h retention time test, suggesting long-term memory impairment. In addition, we assessed impulsive action, using the 5-Choice Serial Reaction Time Task (5-CSRTT) and impulsive choice, using the Delay Discounting (DD) test. Whereas no significant differences were found in 5-CSRTT performance, iuGC animals present alterations in the DD task. Since DD task is strongly dependent on the prefrontal cortex (PFC) and also the amygdala, we analyzed the neuronal activation pattern of these brain regions upon task performance. iuGC treatment induced significant changes in c-fos positive cell density in the orbitofrontal cortex, medial PFC and less so in the amygdala, which could potentially explain the observed behavioral differences. Altogether, our results suggest that iuGC treatment does not seem to affect novelty-seeking behavior, but it has an effect in impulsive choice, which may contribute for the observed enhanced drug-seeking behavior.Exposição a stress pré-natal ou a níveis elevados de glucocorticóides (GC) podem resultar em alterações persistentes no sistema nervoso central, aumentando a vulnerabilidade para o desenvolvimento de doenças psiquiátricas tais como a ansiedade, depressão ou dependência de drogas. Na clínica, os GCs sintéticos são vulgarmente prescritos em casos de risco de parto prematuro, para assegurar a maturação pulmonar fetal. Independentemente do seu efeito benéfico, níveis elevados de GCs durante este período podem levar a efeitos nefastos e permanentes na função e desenvolvimento cerebral. O circuito mesocorticolímbico, conhecido como o sistema de recompensa, parece ser um alvo preferencial do stress /GCs, uma vez que foi demonstrado que animais expostos in útero a GCs (iuGC) têm alterações estruturais e moleculares neste circuito. De salientar que tais mudanças podem ser a base do comportamento aditivo observado nestes animais. A vulnerabilidade para o comportamento aditivo pode ser modulada pela condição emocional e/ou características da personalidade do indivíduo. Os animais iuGC são ansiosos e apresentam características do tipo depressivo, mas pouco se sabe sobre o seu efeito em características como a procura de sensação/novidade e impulsividade, duas dimensões comportamentais que contribuem substancialmente para o comportamento aditivo. Nesta perspectiva, estes animais foram avaliados em testes comportamentais baseados na resposta à novidade. Os animais iuGC não apresentam diferenças substanciais na atividade locomotora induzida pela novidade nem no comportamento exploratório geral (Novelty Place Preference e Novel Object Recognition). Contudo, os indivíduos iuGC exploram objectos familiares e novos de forma semelhante no teste com tempo de retenção de 24h. Adicionalmente, avaliámos a acção impulsiva, através do 5-Choice Serial Reaction Time Task (5-CSRTT) e a escolha impulsiva, utilizando o teste Delay Discounting (DD). O grupo iuGC apresenta alterações na tarefa DD, mas não na performance no 5-CSRTT. Como o teste DD é dependente do córtex pré-frontal (PFC) e da amígdala, foi analisado o padrão de activação neuronal destas regiões usando imunohistoquímica para c-fos. O tratamento iuGC induziu alterações na densidade de células cfos positivas no córtex orbito frontal e PFC medial, com menor efeito na amígdala, o que pode ajudar a explicar as diferenças observadas. Em suma, os nossos resultados sugerem que o tratamento iuGC não parece afetar o comportamento exploratório, mas tem um efeito deletério na memória de longo prazo. Em simultâneo, os animais iuGC apresentam maior escolha impulsiva, o que pode contribuir para a maior vulnerabilidade para comportamentos aditivos

The role of the medial prefrontal cortex in delay discounting

Indiana University-Purdue University Indianapolis (IUPUI)Increased delay discounting (DD) has been associated with and is theorized to contribute to alcoholism and substance abuse. It is also been associated with numerous other mental disorders and is believed to be a trans-disease process (i.e., a process that occurs in and contributes to multiple different pathologies). Consequently insights gained from studying DD are likely to apply to many different diseases. Studies on the neurobiological underpinnings of DD have two main interpretations. The first interpretation is that two different neurobehavioral systems exist, one favoring delayed rewards (executive system) and one favoring immediate rewards (impulsive system), and the system with the greater relative activation determines choice made by an individual. Alternatively, a single valuation system may exist. This system integrates different information about outcomes and generates a value signal that then guides decision making. Preclinical investigations have steered clear of these two different interpretations and rather focused on the role of individual structures in DD. One such structure, the rat mPFC, may generate an outcome representation of delayed rewards that is critically involved in attributing value to delayed rewards. Moreover, there is evidence indicating the rat mPFC may correspond to the primate dlPFC, an executive system structure. The current body of work set about testing the hypotheses that the mPFC is necessary for attributing value to delayed rewards and that decreasing the activity in an executive system area, and thus the executive system, shifts inter-temporal preference towards immediate rewards. To this end the rat mPFC was inactivated using an hM4Di inhibitory designer receptor exclusively activated by designer drugs (DREADD; experiment 1) or microinjections of tetrodotoxin (TTX; experiment 2) while animals completed an adjusting amount DD task. Activation of the hM4Di inhibitory DREADD receptor caused a decrease in DD, opposite of what was predicted. Electrophysiological recordings revealed a subpopulation of neurons actually increased their firing in response to hM4Di receptor activation, potentially explaining the unpredicted results. Microinjections of TTX to completely silence neural activity in the mPFC failed to produce a change in DD. Together both results indicate that mPFC activity is capable of manipulating but is not necessary for DD and the attribution of value to the delayed reward. Consequently, a secondary role for the rat mPFC in DD is proposed in line with single valuation system accounts of DD. Further investigations determining the primary structures responsible for sustaining delayed reward valuation and how manipulating the mPFC may be a means to decrease DD are warranted, and continued investigation that delineates the neurobiological processes of delayed reward valuation may provide valuable insight to both addiction and psychopathology

Role of nicotinic acetylcholine receptors in the effects of cocaine-paired contextual stimuli on impulsive decision making in rats

Chronic cocaine exposure produces unconditioned enhancement in impulsive decision making; however, little is known about the effects of cocaine-paired conditioned stimuli on this behavior. Thus, this study explored the effects of cocaine-paired contextual stimuli on impulsive decision making and the contribution of nicotinic acetylcholine receptors (nAChRs) to this phenomenon

Challenging the somatic marker hypothesis

Damásio’s Hypothese der Somatischen Marker (SMH) stellt eine plausible neurobiologische Erklärungsmöglichkeit für die in Patienten mit Läsionen im ventromedialen präfrontalen Kortex gefundenen Defizite im Entscheidungsverhalten dar. Diese Beeinträchtigungen betreffen vor allem die Performanz dieser Patienten in der von Bechara entwickelten experimentellen Spielsituation, genannt „Iowa Gambling Task” (IGT). Die SMH besagt, dass Entscheidungsprozesse durch unbewusste emotionale Signale (d.h., Somatische Marker) beeinflusst werden können. Aktuelle Studien belegen, dass ähnliche Mechanismen auch für die Beeinträchtigungen von substanzabhängigen Personen in der IGT verantwortlich sind. Interessanterweise, zeigen Personen mit hohen Neurotizismus Werten vorteilhaftes Entscheidungsverhalten in diesem experimentellen Paradigma. Bechara erklärt sich diese Befunde dadurch, dass es bei Entscheidungsprozessen zu einem Zusammenspiel zwischen reflektiven und impulsiven Prozessen kommt. In Patienten mit Läsionen im ventromedialen präfrontalen Kortex sind die reflektiven Prozesse direkt beeinträchtigt, während bei substanzabhängigen Personen eine Überaktivierung, der für die impulsiven Prozesse relevanten Gehirnstrukturen (insbesondere der Amygdala), die reflektiven Prozesse im ventromedialen präfrontalen Kortex schwächt: Es kommt zu einer Überempfänglichkeit für die belohnenden Effekte von Gewinnen und zu einer indifferenten Haltung gegenüber möglichen künftigen Verlusten in der IGT. Unsere Schlussfolgerungen basieren auf einer überarbeitenden Version des von Busemeyer und Stout vorgeschlagenen „Expectancy-Valence Models“ zur Erklärung des Spielverhaltens in der IGT. Wir behaupten, dass unterschiedliche Sensitivitäten für Gewinne und Verluste die beeinträchtigte Performanz von Patienten mit Läsionen im ventromedialen präfrontalen Kortex und die Variabilität in den Befunden gesunder Probanden in der IGT erklären können. Die folgenden zwei Hypothesen werden durch dieses Model nahe gelegt und in der vorliegenden Arbeit diskutiert: (1) Die gefundenen Performanzunterschiede im Spielverhalten gesunder Versuchspersonen in der IGT lassen sich durch Unterschiede in ihrer Risikowahrnehmung (d.h., durch unterschiedliche Sensitivitäten für Gewinne und Verluste) erklären. (2) Eine verminderte emotionale Wahrnehmung des Risikoaspektes von Spielsituationen in Patienten mit Läsionen im ventromedialen präfrontalen Kortex kann die gefundenen Beeinträchtigungen in der IGT und die gefundene überlegene Spielstrategie in Spielsituationen, die risikoreiches Verhalten belohnen, erklären.Damásio’s Somatic Marker Hypothesis (SMH) provides a plausible neurobiological explanation for the deficits observed in real-life decision-making, and for impairments found in patients with ventromedial prefrontal cortical (VMPFC) lesions in Bechara’s Iowa Gambling Task (IGT). Roughly, the SMH assumes that overt reasoning processes are preceded by covert emotional biases (i.e., somatic markers) that help to decide advantageously under uncertainty and risk. Recent studies suggest that similar mechanisms are responsible for the inferior performance of substance dependent individuals (SDIs) and the superior performance of players with high scores in neuroticism. Bechara proposes an imbalance between reflective and impulsive processes in decision-making as the cause of observed deficits: In VMPFC patients, the reflective processes would be directly affected, whereas hyperactivity in the amygdala in SDIs would lead to an attenuation of reflective processes and thereby to sensitivity to immediate reward, and indifference to possible negative future consequences of decisions. Basing our conclusions on a refined version of the Expectancy-Valence Model (originally developed by Busemeyer and Stout), we argue that distinct sensitivities to punishment and reward might explain the overall performance of VMPFC patients and normal controls in the IGT. The following two hypotheses are endorsed by the model thus derived: (1) Differences in risk aversion can account for the high variability in performance of normal controls. (2) Decreased emotional awareness of risky situations in VMPFC patients can explain their poor performance in the IGT and their superior performance when risk taking is rewarded

Ventral Striatal D2/3 Receptor Availability Is Associated with Impulsive Choice Behavior As Well As Limbic Corticostriatal Connectivity.

BACKGROUND: Low dopamine D2/3 receptor availability in the nucleus accumbens shell is associated with highly impulsive behavior in rats as measured by premature responses in a cued attentional task. However, it is unclear whether dopamine D2/3 receptor availability in the nucleus accumbens is equally linked to intolerance for delayed rewards, a related form of impulsivity. METHODS: We investigated the relationship between D2/3 receptor availability in the nucleus accumbens and impulsivity in a delay-discounting task where animals must choose between immediate, small-magnitude rewards and delayed, larger-magnitude rewards. Corticostriatal D2/3 receptor availability was measured in rats stratified for high and low impulsivity using in vivo [18F]fallypride positron emission tomography and ex vivo [3H]raclopride autoradiography. Resting-state functional connectivity in limbic corticostriatal networks was also assessed using fMRI. RESULTS: Delay-discounting task impulsivity was inversely related to D2/3 receptor availability in the nucleus accumbens core but not the dorsal striatum, with higher D2/3 binding in the nucleus accumbens shell of high-impulsive rats compared with low-impulsive rats. D2/3 receptor availability was associated with stronger connectivity between the cingulate cortex and hippocampus of high- vs low-impulsive rats. CONCLUSIONS: We conclude that delay-discounting task impulsivity is associated with low D2/3 receptor binding in the nucleus accumbens core. Thus, two related forms of waiting impulsivity-premature responding and delay intolerance in a delay-of-reward task-implicate an involvement of D2/3 receptor availability in the nucleus accumbens shell and core, respectively. This dissociation may be causal or consequential to enhanced functional connectivity of limbic brain circuitry and hold relevance for attention-deficit/hyperactivity disorder, drug addiction, and other psychiatric disorders

Functional organisation of behavioural inhibitory control mechanisms in cortico-basal ganglia circuitry: implications for stimulant use disorder.

The neural and psychological mechanisms of inhibitory control processes were investigated, focusing on the cortico-basal ganglia circuits in rats and humans. These included behavioural flexibility, ‘waiting’ and ‘stopping’ impulsivity and involved serial spatial reversal learning task in rodents, and in humans, premature responses in the Monetary Incentive Delay (MID) task and the stop-signal reaction time task. Chapter 2 and Chapter 3 focus on individual differences in behavioural flexibility in rats while Chapter 4, Chapter 5 and Chapter 6 consider how inhibitory control mechanisms are affected by the psychostimulant drug cocaine in both rats and humans. As reported in Chapter 2, systemic modulation of monoaminergic transmission by monoamine oxidase A (MAO-A) inhibitors enhanced reversal learning performance, selectively by decreasing the lose-shift probability, thereby implicating a role for dopamine, serotonin and noradrenaline in facilitating learning from negative feedback. Resting state functional magnetic resonance imaging (fMRI) revealed enhanced functional connectivity of the orbitofrontal and motor cortices as a correlate of flexible reversal learning performance, consistent with elevated levels of monoamines in these region (Chapter 3). Having clarified the mechanisms underlying behavioural flexibility in rats, Chapter 4 reports that escalation of intravenous cocaine self-administration induces behavioural inflexibility in rats even after a relatively short period of cocaine intake. Computational models, including a reinforced and Bayesian learner, revealed a lack of exploitation of the learned response-outcome relationships in cocaine-exposed rats. Chapter 5 focused on impulse control in human volunteers, identifying the striatal and cingulo-opercular networks as substrates of impulsive, premature responding in healthy 4 volunteers, stimulant-dependent individuals and their unaffected siblings. Loss of impulse control was elicited by different incentives for drug-free participants as opposed to drug users. Drug cues elicited striatal activation and increased premature responses in the stimulant-dependent group compared with the control group. In contrast, the ventral striatum was linked to incentive specific activation to reward anticipation. Task-based fMRI demonstrated that interactions between dorsal striatum and cingulo-opercular “cold cognition” networks underlie failures of impulse control in the control, at-risk and stimulant-dependent groups. However, whereas the cingulo-opercular networks were associated with premature responding in all groups, the reward system was activated specifically by the drug incentive cues in the stimulant group, and by monetary incentive cues in the drug-free groups. Chapter 6 presents evidence that corticostriatal functional and effective connectivity in an overlapping network that includes the anterior cingulate and inferior frontal cortices as well as motor cortex, the subthalamic nucleus and dorsal striatum, is critical to stopping impulse control in both control and cocaine individuals. No stopping efficiency impairments were observed in the cocaine-dependent group. Nevertheless, lower structural corticostriatal connectivity measured using diffusion MRI was associated with response execution impairments in cocaine participants performing a stop-signal reaction time task. Further, response execution was rescued by the selective noradrenaline reuptake inhibitor atomoxetine, which also increased corticostriatal effective connectivity. Finally, increased impulsivity and behavioural inflexibility seen in stimulant use disorder in Chapter 5 and Chapter 4, respectively, were not observed in the endophenotype at risk for developing stimulant abuse but were rather a consequence of stimulant abuse. These results further clarify the monoaminergic substrates of behavioural flexibility and specify the neural and computational impairments in inhibitory control induced by stimulant dependence.Pinsent Darwin Studentship from the Dept of Physiology, Development and Neuroscienc

Investigation of neuronal structures and networks on the modulation of decision-making and impulse control by temporary inactivation via local microinfusion of the GABAA receptor agonist muscimol in rats

Impulsivity is determined by deficits in decision-making (impulsive choice) and impulse control (impulsive action). Using reversible inactivation via microinfusion of the GABAA receptor agonist muscimol the thesis aimed to elucidate the participation of the ventral medial prefrontal cortex (vmPFC), the nucleus accumbens (NAc) core and shell as well as the connections of the vmPFC and the NAc subregions in both forms of impulsivity in rats. The present results indicate that impulse control is regulated by both structures, while impulsive decision-making is principally modulated by the NAc, and not the vmPFC. The current investigation suggests both functional dissociations and close interactions between the vmPFC and NAc in terms of impulsive action, depending on the involved accumbal subregion. The NAc shell constitutes the critical region mediating both types of impulsivity, whereas the NAc core seems to be implicated in non-specific impairments beyond impulsive choice. Consequently, this work points towards various specific frontostriatal systems differentially contributing to delay-based decision-making and particularly impulse control

Neuropsychology of reinforcement processes in the rat

This thesis investigated the role played by regions of the prefrontal cortex and ventral striatum in the control of rats’ behaviour by Pavlovian conditioned stimuli, and in their capacity to choose delayed reinforcement. First, the function of the anterior cingulate cortex (ACC) in simple Pavlovian conditioning tasks was addressed. The ACC is a subdivision of prefrontal cortex that has previously been suggested to be critical for the formation of stimulus–reward associations. It was found that lesions of the ACC did not prevent rats from learning a simple conditioned approach response to a conditioned stimulus (CS) predictive of food reward, or from utilizing that CS as a conditioned reinforcer subsequently. Additionally, these subjects successfully acquired a conditioned freezing response to a CS predicting footshock. However, the same animals were impaired at the acquisition of autoshaped behaviour, an impairment that has been demonstrated previously. An autoshaping deficit was also observed when lesions were made following training. The phenomenon of Pavlovian–instrumental transfer was intact in these subjects. The hypothesis was developed that the ACC is not critical for the formation of stimulus–reward associations per se, but is critical when multiple stimuli must be discriminated on the basis of their differential association with reward. In support of this hypothesis, animals with lesions of the ACC were impaired on a version of the conditioned approach task in which a second, neutral stimulus, perceptually similar to the CS, was added; the lesioned subjects exhibited reduced discrimination. Second, the role of the nucleus accumbens (Acb) in Pavlovian–instrumental transfer was investigated. The nucleus accumbens core, together with a larger amygdalar–striatal network of which it is a component, has previously been shown to be necessary for the expression of ‘simple’ Pavlovian–instrumental transfer. Rats with lesions of the nucleus accumbens core (AcbC) and shell (AcbSh) were tested on a ‘response-specific’ Pavlovian–instrumental transfer task, in which a Pavlovian CS selectively enhances instrumental responding for the outcome with which the CS was originally paired. AcbC lesions impaired the response specificity of this effect, while AcbSh lesions abolished Pavlovian–instrumental transfer entirely. These results are consistent with some — but not all — previous results in suggesting that the shell provides ‘vigour’ and the core provides ‘direction’ for the potentiation of behaviour by Pavlovian CSs. Third, an attempt was made to train rats on a task for assessing preference for delayed reinforcement, using the ‘adjusting-delay’ paradigm. It was not immediately apparent that the rats reacted to the contingencies operative in this task, and mathematical analysis of their behaviour was conducted to establish whether their behaviour was sensitive to the delay, and what ‘molar’ features of performance on this task could be explained by delay-independent processes. Fourth, a different delayed reinforcement choice task was developed, modifying a previously published task in which the subject is repeatedly offered a choice, in discrete trials, of a small reward delivered immediately, and a large reward delivered after a delay, with the delays systematically varied by the experimenter. Rats were trained on versions of this task in which the large, delayed reinforcer was or was not explicitly signalled by a cue present during the delay. The behavioural basis of performance on this task was examined, and d-amphetamine, chlordiazepoxide, and alpha-flupenthixol were administered systemically. It was found that the effects of d-amphetamine depended on whether the delayed reinforcer was signalled or unsignalled, increasing preference for signalled delayed reinforcement at some doses, but decreasing preference for unsignalled delayed reinforcement. These results may resolve contradictions in the literature, and are suggested to reflect the known effect of amphetamine to potentiate responding for conditioned reinforcers. Fifth, rats that had been trained on this task (with no explicit signals present during the delay) were given lesions of the ACC, AcbC, or medial prefrontal cortex (mPFC). ACC-lesioned rats were no different from sham-operated controls in their ability to choose a large, delayed reinforcer. Lesions of mPFC reduced the tendency of subjects to shift from one lever to the other during the course of a session, but mPFC-lesioned subjects responded normally to removal of the delays, suggesting a loss of stimulus control. However, rats with lesions of the AcbC were severely impaired on this task, preferring the small, immediate reward, even though they discriminated the reinforcers. Additionally, the effects of intra-Acb amphetamine were assessed using a different version of the delayed reinforcement choice task, and found to have slight but inconsistent effects to reduce preference for the delayed reinforcer, though this effect did not depend on whether the delayed reward was signalled or unsignalled. These results suggest that the AcbC contributes significantly to the rat’s ability to choose a delayed reward, a finding that has important implications for the understanding of Acb function. It is suggested that dysfunction of the AcbC may be a key element in the pathology of impulsivity.Supported by a UK Medical Research Council (MRC) research studentship, 1997–2000, and a James Baird award, University of Cambridge School of Clinical Medicine, 1997–2000

Neurochemical modulation of affective and behavioural control: Models and applications for psychiatry

Impairments in emotional reactivity and behavioural flexibility are pervasive across disparate psychiatric conditions as traditionally defined. Here, I provide new evidence on how these processes are altered by neuromodulators in humans, with a primary focus on serotonin (5- HT; 5-hydroxytryptamine). Emotional reactions prepare the body for action. Some emotion is primitive, implicit, and critical for surviving threats, yet can inappropriately persist in times of safety. Other emotions are more complex, self-conscious and important in maintaining harmonious interpersonal relationships. At the same time, learned behaviours that are adaptive in the first instance, may become irrelevant or even disadvantageous as circumstances change. In Chapters 3 through 6, I report on experiments in healthy human volunteers that employed the dietary technique acute tryptophan depletion (ATD). ATD temporarily lowers serotonin synthesis and release by depleting its biosynthetic precursor tryptophan. Chapter 3 is a study of self-reported social emotion. ATD enhanced emotion in response to social injustice non-specifically; however, consideration of personality traits revealed that highly empathic participants reported more guilt under ATD, whereas individuals high in trait psychopathy demonstrated more annoyance. Chapter 4, in contrast, considers evolutionarily ancient automatic emotional reactions to threats. This was assayed instead by an objective measure, the skin conductance response (SCR). Here, ATD conversely attenuated the retention of Pavlovian conditioned emotional memory to threat. Traits again influenced this response: individuals more intolerant of uncertainty displayed the greatest attenuation of emotional reactions. Chapter 5 both extends the studies on emotion and bridges to the remaining empirical work by investigating reversal learning, an index of cognitive flexibility, in two experiments. Individuals again underwent Pavlovian (stimulus-outcome) threat conditioning, whereby one stimulus predicted threat, and another was safe. These contingencies then swapped (reversed). In a separate experiment, participants underwent instrumental (stimulus-response-outcome) conditioning on a deterministic schedule (the correct option was always correct), followed by reversal of the contingencies. ATD impaired both Pavlovian and instrumental reversal learning. Chapters 6 through 8 instead examine instrumental reversal learning that was probabilistic (the correct option was correct most but not all of the time), rather than deterministic. Chapter 6 expands on previous ATD studies of probabilistic reversal learning (PRL) in the literature, which had not found effects on choice behaviour. Despite nearly tripling the sample size, behaviour here assessed by conventional methods was unaffected, replicating previously published null results. Applying reinforcement learning (RL) models, however, revealed ATD elevated a basic perseverative tendency, referred to as “stimulus stickiness”; behaviour was more stimulus-bound and insensitive to the outcome of actions, consistent with the deterministic instrumental reversal impairment following ATD. Chapters 7 and 8 apply RL models as well, to existing datasets on PRL for comparison. Chapter 7 shows that healthy volunteers under lysergic acid diethylamide (LSD), which acts both at serotonin but also dopamine receptors, showed enhanced learning from positive feedback in particular, which was related to perseveration. Chapter 8 applies computational methods to PRL in clinical populations. RL modelling revealed a computational signature that dissociated PRL in stimulant use disorder (SUD) and obsessive-compulsive disorder (OCD): Individuals with SUD showed heightened stimulus stickiness, as occurred following ATD in healthy volunteers, whereas the OCD group (under serotonergic medication) demonstrated lower stimulus stickiness than healthy controls. Dopaminergic agents remediated a reward learning deficit in SUD, among other measures. The general discussion considers these various findings in terms of theories of central serotonin function, in relation to the animal literature, and its relevance to mental disorder. These results, collectively, advance knowledge of neurochemical and computational mechanisms underlying psychiatric conditions trans-diagnostically, with implications for revised psychiatric classifications in line with the Research Domain Criteria (RDoC).Gates Cambridge Trust Wellcome Trus

The impact of stress in the risk-based decision-making processes : insights from the lab and the clinics

Tese de Doutoramento em MedicinaDecision-making is a routine in our daily life, constituting one of the most prominent differential features of each human being. Several psychiatric disorders, including obsessive compulsive spectrum disorders, schizophrenia and depression, present significant impairments of decisionmaking abilities. Decision-making requires complex cognitive processes, modulated by a variety of intrinsic and environmental elements, including stress. Indeed, the brain networks involved in decision-making, have been found to be targeted by chronic stress exposure. In the present series of studies, we have thoroughly characterized how decision-making processes, namely pavlovian-to-instrumental transfer (PIT) processes and risk-based decisionmaking, can be influenced by chronic stress, detailing some neurochemical, neuroanatomical and neurophysiologic mechanisms underlying these changes and proposing therapeutic interventions to revert stress-induced impairments. We also explored the relationship between stress and features of obsessive compulsive disorder and analyzed risk-based decision-making in a cohort of patients with this psychiatric pathology. We show that chronic stress transiently impairs PIT, reducing the ability of environmental cues to influence instrumental actions, and induces a risk-aversive behavior in a novel decision making task. Using c-fos labeling techniques we found that stress-induced risk-aversion was related with an overactivation of the orbitofrontal and insula cortices. Chronic stress also induced an hypertrophy of apical dendritic trees of layer II/III pyramidal neurons of the orbitofrontal cortex, an effect that was also observed in neurons activated during the decision-making task. Finally, we reveal that stress induces a hypodompaminergic status in the orbitofrontal cortex, characterized not only by decreased dopamine levels, but also by an increased expression of the D2 receptor, and show that stress-induced changes in risk-based behavior can be reverted by systemic administration of the D2/D3 agonist quinpirole. In a separate set of experiments, we found that obsessive compulsive patients displayed higher levels of perceived stress and cortisol, when compared with age and sex-matched healthy controls, and had difficulties in risk-based decisionmaking that correlated with decreased activity in the dorsal striatum when deciding, hypoactivation of the amygdala before making high-risk choices and increased activity in several areas of the (orbito)fronto-striato-thalamic circuit implicated in decision upon loosing. In this thesis we show that chronic stress profoundly influences decisions, biasing behavior to risk-aversion, and impairing PIT. We further revealed that stress is also associated with symptoms in obsessive compulsive disorder patients, who present impairments in risk-based decision-making. We conclude by suggesting that decision-making deficits are key in obsessive compulsive disorders clinical presentation and might be used as diagnosis and/or prognosis markers and finally hypothesize that the neurochemical mechanisms and therapeutic approaches identified in the study of chronic stress effects can be translated to obsessive-compulsive spectrum disorders and challenge our current knowledge, paving the way for new treatments.A forma como tomamos decisões é uma das características mais diferenciadoras dos indivíduos. Alterações dos processos de tomada de decisão são frequentes em várias doenças psiquiátricas, incluindo as doenças do espectro obsessivo-compulsivo, a esquizofrenia e a depressão. A tomada de decisão envolve processos cognitivos complexos que são modulados por uma panóplia de elementos internos e externos dos indivíduos, incluindo o stresse. Sabe ainda que este último, sobretudo em situações de exposição prolongada, modula as áreas e as redes cerebrais que se sabe estarem implicadas nos processos de tomada de decisão. Nos estudos apresentados nesta tese, caracterizamos a forma como os processos de tomada de decisão, nomeadamente os processos de transferência pavloviano-instrumental (PIT) e a decisão baseada no risco, podem ser influenciados pelo stresse crónico. Adicionalmente, detalhamos alguns dos mecanismos neuroquímicos, neuroanatómicos e neurofisiológicos subjacentes às alterações encontradas e propomos intervenções terapêuticas capazes de reverter as consequências negativas induzidas pelo stresse crónico nos processos de tomada de decisão. As relações entre o stresse e a doença obsessivo compulsiva foram também exploradas e analisámos os processos de tomada de decisão de risco num grupo de doentes com esta patologia. Os nossos resultados demonstraram que o stresse crónico provoca alterações reversíveis no PIT, prejudicando a forma como as pistas ambientais influenciam as acções instrumentais. Verificámos também, numa nova tarefa de tomada de decisão de risco em roedores, que o stresse crónico induz um padrão de comportamento aversivo ao risco. A utilização de técnicas de marcação com c-fos permitiu demonstrar que a aversão ao risco está relacionada com uma hiperactivação dos córtices orbitofrontal e insular. Verificámos também que o stresse crónico induz uma hipertrofia das dendrites apicais dos neurónios piramidais das camadas II e III do córtex orbitofrontal, um efeito que também foi observado em neurónios activados durante a tarefa de tomada de decisão descrita. Concomitantemente, demonstrámos que o stresse crónico induz um estado hipodopaminérgico no córtex orbitofrontal, caracterizado tanto pela diminuição dos níveis de dopamina como pelo aumento da expressão do mRNA dos receptores de dopamina D2. Por último, demonstrámos que as alterações induzidas pelo stresse podem ser revertidas pela administração sistémica do agonista selectivo dos receptores da dopamina D2/D3, quinpirole. No contexto dos nossos trabalhos clínicos, demonstrámos que os doentes com perturbação obsessivo compulsiva apresentam níveis mais elevados de stresse percebido e de cortisol, quando comparados com voluntários saudáveis, emparelhados para sexo, idade e nível educacional. Verificámos também que apresentam dificuldades nos processos de tomada de decisão de risco que estão relacionadas com uma diminuição da actividade do estriado dorsal no momento da decisão, uma activação paradoxal da amígdala antes da tomada de decisões de risco e um aumento da actividade em várias áreas cerebrais do circuito (orbito)fronto-estriatotalâmico nas decisões que implicam perdas. Em síntese, ao longo desta tese demonstrámos que o stresse crónico influencia profundamente os processos de tomada de decisão, prejudicando o PIT e induzindo comportamentos de aversão ao risco. Adicionalmente demonstrámos que o stresse está associado com sintomas da doença obsessivo-compulsiva, cujos pacientes apresentam défices nos mecanismos de tomada de decisão. No seu conjunto, estes dados permitem afirmar que os défices da tomada de decisão são fundamentais no fenótipo das doenças do espectro obsessivo-compulsivo e podem ser utilizados como ferramentas diagnósticas e/ou como marcadores do prognóstico. Por último, propomos que os mecanismos neuroquímicos e as estratégias terapêuticas identificados no estudo dos efeitos do stresse crónico podem ser extrapolados para as doenças do espectro obsessivo, desafiando o conhecimento actual acerca da doença e suportando novas abordagens para o desenvolvimento de tratamentos mais efectivos.This work was supported by a grant from Fundação para a Ciência e Tecnologia: SFRH/SINTD/60129/2009