We perceive the environment via sensor arrays and interact with it through motor outputs. The work of this thesis concerns how the brain selects actions given the information about the perceived state of the world and how it learns and adapts these selections to changes in this environment. Reinforcement learning theories suggest that an action will be more or less likely to be selected if the outcome has been better or worse than expected. A group of subcortical structures, the basal ganglia (BG), is critically involved in both the selection and the reward prediction. We developed and investigated a computational model of the BG. We implemented a Bayesian-Hebbian learning rule, which computes the weights between two units based on the probability of their activations. We were able test how various configurations of the represented pathways impacted the performance in several reinforcement learning and conditioning tasks. Then, following the development of a more biologically plausible version with spiking neurons, we simulated lesions in the different pathways and assessed how they affected learning and selection. We observed that the evolution of the weights and the performance of the models resembled qualitatively experimental data. The absence of an unique best way to configure the model over all the learning paradigms tested indicates that an agent could dynamically configure its action selection mode, mainly by including or not the reward prediction values in the selection process. We present hypotheses on possible biological substrates for the reward prediction pathway. We base these on the functional requirements for successful learning and on an analysis of the experimental data. We further simulate a loss of dopaminergic neurons similar to that reported in Parkinson’s disease. We suggest that the associated motor symptoms are mostly causedby an impairment of the pathway promoting actions, while the pathway suppressing them seems to remain functional. / <p>At the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 3: Manuscript.</p><p> </p>

abstract: Fibromyalgia (FM) is a chronic musculoskeletal disorder characterized by widespread pain, fatigue, and a variety of other comorbid physiological and psychological characteristics, including a deficit of positive affect. Recently, the focus of research on the pathophysiology of FM has considered the role of a number of genomic variants. In the current manuscript, case-control analyses did not support the hypothesis that FM patients would differ from other chronic pain groups in catechol-O-methyltransferase (COMT) and mu-opioid receptor (OPRM1) genotype. However, evidence is provided in support of the hypothesis that functional single nucleotide polymorphisms on the COMT and OPRM1 genes would be associated with risk and resilience, respectively, in a dual processing model of pain-related positive affective regulation in FM. Forty-six female patients with a physician-confirmed diagnosis of FM completed an electronic diary that included once-daily assessments of positive affect and soft tissue pain. Multilevel modeling yielded a significant gene X environment interaction, such that individuals with met/met genotype on COMT experienced a greater decline in positive affect as daily pain increased than did either val/met or val/val individuals. A gene X environment interaction for OPRM1 also emerged, indicating that individuals with at least one asp allele were more resilient to elevations in daily pain than those homozygous for the asn allele. In sum, the findings offer researchers ample reason to further investigate the contribution of the catecholamine and opioid systems, and their associated genomic variants, to the still poorly understood experience of FM. / Dissertation/Thesis / Ph.D. Psychology 2011

Objectives: This pilot study examined how Methylphenidate (MPH0.5mg/kg) affects appetite sensations, food reinforcement, energy intake (EI), macronutrient consumption, and weight-loss in youth and adults living with obesity, without ADHD. Methods: This study employed a randomized, double-blind, placebo-controlled design. Eleven participants aged 28±6.9 yrs. (4 M, 7 F) were randomized to receive either MPH (n=5) or placebo group (n=6) for 60 days. Participants’ appetite sensations (Visual Analogue Scale), relative-reinforcing value of food (computer task), EI and macronutrient consumption (ad libitum buffet), and anthropometric measurements (DEXA) were measured at baseline and 60 days. Results: Repeated measures ANOVA revealed group x time interactions for appetite sensations [desire to eat (p=0.01), hunger (p=0.002), and prospective food consumption (p=0.006)]; with greater reductions in MPH group compared to placebo. For the sense of fullness, there was an interaction between group and time (p=0.01), with a greater increase for MPH compared to placebo. Body weight significantly decreased in both groups (p=0.01), with a moderate to large effect size favouring the MPH group (-2.66 kg vs. – 1.16 kg, Cohen’s d =0.76). Changes between MPH and placebo did not differ significantly on EI, macronutrient consumption, or food reinforcement. Conclusions: Our data indicate for the first time that MPH suppresses appetite in individuals with obesity resulting in a moderate–sized effect on weight loss in the short-term. These findings warrant a larger trial to more definitively examine the effect that MPH has on weight loss and maintenance of weight loss, thereby evaluating its potential as a novel pharmacological agent in the management of obesity.

El enamoramiento implica procesos bioquímicos en los que sustancias como neurotransmisores, neuromoduladores y hormonas  interaccionan con células nerviosas u otros órganos. Al estar enamorados, los niveles de dopamina aumentan generando atención, deseo y motivación en todo lo relacionado al ser amado. La serotonina, por el contrario, se presenta en concentraciones bajas en este estado. La oxitocina, por su parte, entra en juego cuando la demanda de dopamina no se logra suplir y es crucial al entablar relaciones de largo plazo. El entendimiento del mecanismo de la oxitocina en el ser humano es crucial no solo para el conocimiento académico sino también porque brinda luces para el tratamiento de algunos desórdenes psicológicos. / Romantic love involves biochemical processes in which substances such as neurotransmitters, neuromodulators and hormones interact with other nerve cells or organs. When being in love, dopamine levels increases, generating attention, desire and motivation in everything related to the beloved person. Serotonin, however, is present in low levels in this state. When the body does not supply the necessary amount of dopamine, oxytocin is released. Oxytocin is vital in long term relationships. Understanding the mechanism of oxytocin in humans is crucial not only for academic knowledge of the chemistry of love but also because it provides new lights for the treatment of some psychological disorders.

Many human pharmaceuticals have limited biodegradability and can end up in the aquatic environment. The effects of these pharmaceuticals on aquatic organisms is not fully understood. Ropinirole is a drug used to treat Parkinson’s disease. Ropinirole is a dopamine agonist that targets the dopaminergic system that many diverse organisms share. In this study, threespined sticklebacks (Gasterosteus aculeatus) were used to investigate the effect of ropinirole on wild animals. Wild captured sticklebacks were exposed to ropinirole, ropinirole and fluoxetine, or untreated control. The fish were sacrificed at two different time points to study the effects on gene expression after long and short- time exposure of the drug. Gene expression of two dopamine receptor genes (drd2 and drd1b) and one adrenergic receptor gene (adrd2a) is studied in this project. The fish brains were dissected, total mRNA isolated and translated to cDNA, and finally qPCR was done. The expression of drd2 and adrd2a genes did not differ across the treatment groups or time. Drd1b showed higher expression at long term of exposure relative to short time exposure to ropinirole, but no other differences were observed between treatment groups. Collectively, my results show that ropinirole, or ropinirole together with fluoxetine did not interact with the adrenergic receptor or the dopamine 2-receptor. Exposure to ropinirole longer time can upregulate genes, as seem for the gene drd1b.  Overall, these results show that pharmaceuticals in the environment can affect gene expression on other animals than the targeted humans.

Dopaminergic systems regulate many brain functions and dysfunction of dopaminergic neurotransmission is thought to underlie numerous disorders, including schizophrenia, attention deficit hyperactivity disorder (ADHD), depression and Alzheimer’s disease. In the hippocampus, a dopaminergic projection from the ventral tegmental area (VTA) is proposed to be essential for controlling entry of sensory information into long-term memory through novelty and salience detection. However, the effects of the VTA-dopamine system on hippocampal synaptic transmission are largely under-explored and the underlying mechanisms are unclear. The goal of this project was to investigate mechanisms involved in dopaminergic modulation of hippocampal neurophysiology. Specifically, I (1) examined if dopamine modulates hippocampal synaptic transmission in a region- and input-specific manner, and (2) studied the signaling mechanisms underlying such modulation. In the first aim for the study, I tested whether SKF38393, a dopamine D1-like receptor agonist, differentially affects excitatory synaptic transmission in perforant path synapses onto dentate gyrus granule cells and whether such effects differ from those at area CA1 synapses. I found that SKF38393 produced a concentration-dependent increase in field excitatory postsynaptic potential (fEPSP) in both subregions, but that higher concentrations were needed in the dentate gyrus to produce comparable effects. This synaptic enhancement was long-lasting and largely irreversible which suggests it may be a form of long term enhancement (LTP). Also, the increase in synaptic transmission at medial perforant path synapses was larger than in the lateral perforant path. Importantly, effects in the dentate gyrus, unlike those in CA1, differed substantially along the dorsoventral axis, with effects being significantly larger at the dorsal compared to the ventral pole. In the second aim, various combinations of D1 and D2-like receptor agonists and antagonists as well as inhibitors of second messenger systems, demonstrated that differential mechanisms were required for initiation and maintenance of SKF38393-mediated early and late-phase enhancement and that a novel non-canonical phospholipase-C (PLC) dependent signaling pathway may be involved. Based on recent discoveries in other brain regions, we hypothesized that multiple subcellular signaling pathways may contribute to PLC activation which may include but are not limited to D1(5)-D2 heteromers and Gβγ complex. In conclusion, this work uncovers novel dopaminergic signaling pathways regulating hippocampal physiology, which will lead to development of better (functionally selective) therapeutic agents.

Important physiological changes occur during lactation to allow for nourishment of the offspring. Specific neuronal groups within the arcuate nucleus of the hypothalamus influence prolactin (PRL) secretion, metabolism and fertility during lactation. Our overall goal was to identify gene expression changes in the arcuate nucleus during lactation and examine the roles of PRL and ovarian hormones in regulating expression of select genes. We evaluated transcriptome changes in the arcuate nucleus during lactation using RNA-sequencing. Thirty-seven differentially expressed genes, including neuropeptides, signaling molecules, receptors and enzymes, were identified between suckled and pup-deprived groups. Selected genes were evaluated by qRT-PCR in ovary-intact and ovariectomized lactating models, which included non-lactating, suckled and 24hr pup-deprived lactating groups. The mRNA expression of tyrosine hydroxylase (Th), kisspeptin (Kiss1), and neurokinin B (Tac3) was decreased, whereas mRNA expression of proenkephalin (Penk), parathyroid hormone 2 receptor (Pth2r), insulin-like growth factor binding protein 3 (Igfbp3), membrane progesterone receptor beta (Paqr8), suppressor of cytokine signaling 2 (Socs2) and cytokine-inducible SH2 domain-containing protein (Cish) was increased in suckled lactating rats. In 24hr pup-deprived dams, mRNA expression of Pth2r, Igfbp3, Paqr8, Socs2 and Cish was decreased and Th was increased, as compared to suckled rats. The mRNA expression of Kiss1 and Tac3 was increased and Penk was decreased after 72hr, but not 24hr, pup deprivation suggesting gene expression of these neuropeptides is slow to return to non-lactating levels after removing the suckling stimulus. Tyrosine hydroxylase (TH) protein and enkephalin (ENK) peptide expression was examined by immunohistochemistry. Lactating rats had increased ENK in the median eminence and decreased TH in the median eminence and arcuate nucleus as compared to virgin ovariectomized rats. ENK co-localization with TH in the arcuate nucleus was more predominant in lactating rats. Penk, Igfbp3, Pth2r, Cish, and Socs2 mRNA expression was decreased after 72hr bromocriptine treatment in suckled rats, suggesting that these genes are PRL-regulated. In contrast, gene expression of Th, Tac3 and Kiss1 were increased and Paqr8 was decreased with 72hr pup-deprivation, but expression of these genes, were not altered with bromocriptine treatment, indicating that these genes are regulated by a non-PRL component of the suckling stimulus. The mRNA expression of Kiss1, Socs2 and Igfbp3 was increased and Penk was decreased in ovariectomized as compared to ovary intact lactating rats, suggesting that ovarian hormones influence the expression of these genes during lactation. Our data show gene expression changes in the arcuate nucleus that may contribute to increased PRL secretion (Th, Penk and Pth2r), decreased PRL receptor signaling (Cis and Socs2), reduced fertility (Kiss1 and Tac3), increased metabolism (Igfbp3) and support a role for progesterone membrane actions (Paqr8). The expression of some genes appeared to be selectively regulated by ovarian hormone input and/or PRL feedback.

The frontostriatal dopamine system modulates brain function and is affected by both genetic and environmental factors. Dysfunction of this system is associated with many pathological states, including schizophrenia. The enzyme catechol-O- methyltransferase (COMT) metabolises dopamine and its gene contains a polymorphism (Val¹⁵⁸Met) that affects enzyme activity. Delta-9- tetrahydrocannabinol (THC), the main psychoactive component of cannabis, has been suggested to interact with this polymorphism to increase the risk for psychosis and cognitive impairments. Dopaminergic mechanisms are a plausible candidate for mediating this interaction. I used microdialysis coupled with high performance liquid chromatography (HPLC) to examine the effects of THC on extracellular dopamine and its metabolites in the nucleus accumbens, dorsal striatum and medial prefrontal cortex (mPFC) in freely moving mice. Following acute COMT inhibition with tolcapone, THC increased extracellular dopamine levels in the nucleus accumbens in tolcapone-, but not in vehicle-, treated mice. The introduction of the low activity Met allele into the COMT gene produced a highly specific, novel mouse model of the Val158Met polymorphism. In contrast to the effects of acute COMT inhibition, the Met allele protected against THC-induced changes in accumbal dopamine. No interactive neurochemical effects were observed in the dorsal striatum (pharmacological and genetic study) or in a preliminary study of the mPFC (genetic study only). On a progressive ratio task measuring motivational salience, the direction of the interactive effect between COMT genotype and THC differed between 2 independent cohorts and provided tentative leads that stress/arousal-dependent effects on COMT may have a confounding effect. My data provide evidence that COMT activity modulates the effect of THC on accumbal dopamine function, and suggest the mechanism through which this interaction is mediated differs between acute and lifelong reduction in COMT activity. Through the interactive effect on the dopaminergic system, the data provide a potential mechanism for the reported interaction between COMT and cannabis/THC in determining psychosis risk and cognitive impairments.

abstract: The thrill of a live performance can enhance endorphin, serotonin, dopamine, and adrenaline levels in the body. This mixture of heightened chemical levels is a result of "performance adrenaline." This phenomenon can positively and/or negatively affect a performing singer. A singer's body is her instrument, and therefore, any bodily change can alter the singing voice. The uptake of these chemicals can especially influence a central aspect of singing: breath. "Performance adrenaline" can induce shallow or clavicular breathing, alter phonation, and affect vibrato. To optimize the positive effects and counteract the negative, diaphragmatic breathing, yoga, and beta-blockers are explored as viable management tools. When managed properly, the boost offered by "performance adrenaline" can aid the singer in performing and singing. After a review of medical and psychological studies that reveal the physiological and emotional effects of endorphins, serotonin, dopamine, and adrenaline, this paper will explore the biological changes specific to vocalists and methods to optimize these effects in performance. / Dissertation/Thesis / Doctoral Dissertation Music 2015

Cocaine is known for its severe addictive properties and still, there is no effective treatment for cocaine addiction. Cocaine is a powerful chemical substance. It enters the brain rapidly and cause abnormal high levels of dopamine. Dopamine is found to be the neural correlate for reward. Addictive drugs such as cocaine are reported to be rewarding and initially generate many dimensions of positive effects. However, repeated cocaine use are associated with both structural and functional abnormalities in several brain regions, especially in areas responsible for voluntary control. Loss of control gives way to compulsive consumption and craving for more cocaine stimulation. These neuronal changes and negative symptoms tend to occur gradually, while the tolerance increases. The addicted individual has to enhance the dose in order to obtain the desired effect, which is; becoming physically dependent of a substance. Also, dysregulation of reward circuitries causes decreased sensitivity to natural rewards leading to increased interest in cocaine-related reward stimulation. The abstinence usually last for long time, even years, after self-administration, which makes addicts highly sensitive to relapse. Up to date, effective therapeutic interventions and pharmacological treatments are limited. Neurostimulation techniques such as DBS have shown positive results in regulation of dopaminergic excitability. Though, more research in the complexity of dopamine and mesolimbic areas is well needed, in order to better understand the neural basis of cocaine addiction and be able to offer evidence-based treatments. This thesis will provide an overview of the neuronal impact of cocaine on the dopaminergic reward circuitries in the brain.