No description available.

<p>The goal of this dissertation is two-fold: 1) to identify novel biological pathways implicating individual differences in reward and threat processing in the emergence of risk and resilience for psychopathology, 2) to identify novel genetic and epigenetic predictors of the inter-individual variability in these biological pathways. Four specific studies are reported wherein blood oxygen-level dependent functional magnetic resonance imaging (BOLD fMRI) was used to measure individual differences in threat-related amygdala reactivity and reward-related ventral striatum (VS) reactivity; self-report was used to measure of mood and psychopathology as well as the experience of stressful life events. In addition, DNA was derived from peripheral tissues to identify specific genetic and epigenetic markers.</p><p>Results from Study 1 demonstrate that individuals with relatively low reward-related VS reactivity show stress-related reductions in positive affect, while those with high VS reactivity remain resilient to these potentially depressogenic effects. Heightened VS reactivity was, however, associated with stress-related increases in problem drinking in Study 2. Importantly, this effect only occurred in individuals showing concomitantly reduced threat-related amygdala reactivity. Study 3 demonstrates that using a multilocus genetic profile capturing the cumulative impact of five functional polymorphic loci on dopamine signaling increases power to explain variability in reward-related VS reactivity relative to an approach considering each locus independently. Finally, Study 4 provides evidence that methylation in the proximal promoter of the serotonin transporter gene is negatively correlated with gene expression and positively correlated with threat-related amygdala reactivity above and beyond the effects of commonly studied functional DNA-sequence based variation in the same genomic vicinity.</p><p>The results from these studies implicate novel biological pathways, namely reward-related VS reactivity and threat-related amygdala reactivity, as predictors of relative risk or resilience for psychopathology particularly in response to stressful life events. Moreover, the results suggest that genetic and epigenetic markers may serve as easily accessible peripheral tissue proxies for these neural phenotypes and, ultimately, risk and resilience. Such markers may eventually be harnessed to identify vulnerable individuals and facilitate targeted early intervention or prevention efforts.</p> / Dissertation

The goal of this dissertation was two fold: 1) To relate dopamine responses in the ventral striatum to ethanol preference and consumption, and 2) to investigate the role of the mu opioid receptors in this ethanol induced dopamine release in the ventral striatum. First a two bottle choice experiment established that a substrain of C57BL/6 mice (C57BL/6NCrl) had significantly less preference for and consumption of ethanol than a second substrain of mouse based on the same background (C57BL6/J). The C57BL/6 strain has been extensively used in alcohol drinking studies and is well known for it’s propensity to consume alcohol over water. To determine if differences in ventral striatal dopamine response vii could contribute to this variability in drinking behavior, we characterized the dopamine response in both substrains of mice after intraperitoneal injections of 1.0, 2.0 or 3.0 g/kg ethanol or saline. We found that the acute intraperitoneal ethanol injections in naïve mice caused a significant elevation in dopamine in both substrains at all three doses with a significant difference between substrains at the two highest alcohol doses. Therefore, ethanol induced dopamine release in the ventral striatum may contribute to ethanol preference and consumption. Next, we investigated the effect of acute intraperitoneal ethanol injections on naïve mu opioid receptor knockout mice and in mice pretreated with a mu opioid receptor antagonist. The mice used were all established on the C57BL/6J background. We found that ventral striatal dopamine response was similar in these mice after 1.0, 2.0 and 3.0 g/kg intraperitoneal ethanol injections compared to appropriate controls. As both gene deletion and pharmacological blockade of the mu opioid receptor did not affect ethanol stimulated dopamine release, it points to the conclusion that this receptor may not play a significant role in ethanol induced ventral striatal dopamine release. / text

Decisions, such as choosing between different rewards, are known to be influenced by a number of variables such as value, uncertainty and delay associated with a rewarding outcome. Various structures in the brain are responsible for handling different aspects of reward related decision making. To understand how such decisions are made, we can attempt to reverse engineer the brain. This involves understanding how brain activity is related to the representation and processing of rewards and also to subsequent behavior in response to rewarding events. One of the central elements of the reward circuitry of the brain is the ventral striatum. It has traditionally been known as the limbic-motor interface and thought to act as a link between various structures in the brain that are responsible for processing reward and reward related behavior. To study the neural processes that underlie processing rewards, I recorded from the ventral striatum of rats as they performed a cue-reward task. The aim of my project was twofold: First, to examine how rats behave in response to changes in value and uncertainty associated with a particular rewarding outcome and second, to investigate how rewards and cues that predict rewards are represented in the neural activity of the ventral striatum. Rats (n=6) were trained on a cue-reward task, where cues indicated the mean or variance of associated outcome distributions. Behavioral responses to the reward predictive cues demonstrated that the rats learned the value and risk associated with subsequent reward outcomes. Ventral striatal gamma oscillations are known to align to rewards in a variety of reward motivated tasks. However, it is not clear if these oscillations are associated with anticipation of obtaining the reward or the reward itself. In previous studies, reward delivery has been correlated with the anticipation of reward. In the current work, a delay is used to distinguish between anticipation of reward and the reward delivery itself. This is achieved by making the rats nose poke for a fixed time interval before the arrival of reward. The analysis presented in this thesis reveals that ventral striatal gamma oscillations occur both during the anticipation and delivery of reward, opening up the possibility of formal tests. They also align to arrival of cues that predict rewarding outcomes. This suggests that gamma oscillations might be essential for modulating behavior in response to cues and rewards both before and after reward delivery. Ventral striatum is ideally situated to modulate behavior in response to rewarding events. Past studies show that ventral striatal neural activity is associated with reward and reward motivated actions. However, as suggested by the research presented in this thesis, it is not clear what specific aspects of the decision making process can be attributed to the ventral striatum once learning in complete. Studying the ventral striatum is important because its malfunctioning is implicated in brain disorders such as drug addiction.

Projection neurons of nucleus accumbens (NAC) of the rat were identified by either antidromic activation from stimulation of midbrain ventral tegmental area-substantia nigra (VTA-SN) regions, or by tracing axons of intracellularly labeled NAC neurons into the ventral pallidum. The morphology of these NAC projection neurons were determined to be medium spiny neurons similar to those identified in the caudate-putamen.

No description available.

<p>Sexual risk behavior among young adults is a serious public health concern; 50% will contract a sexually transmitted infection (STI) before the age of 25. The current study collected self-report personality and sexual history data, as well as neuroimaging, experimental behavioral (e.g., real-time hypothetical sexual decision making data), and self-report sexual arousal data from 120 heterosexual young adults ages 18-26. In addition, longitudinal changes in self-reported sexual behavior were collected from a subset (n = 70) of the participants. The primary aims of the study were (1) to predict differences in self-report sexual behavior and hypothetical sexual decision-making (in response to sexually explicit audio-visual cues) as a function of ventral striatum (VS) and amygdala activity, (2) test whether the association between sexual behavior/decision-making and brain function is moderated by gender, self-reported sexual arousal, and/or trait-level personality factors (i.e., self-control, impulsivity, and sensation seeking) and (3) to examine how the main effects of neural function and interaction effects predict sexual risk behavior over time. Our hypotheses were mostly supported across the sexual behavior and decision-making outcome variables, such that neural risk phenotypes (heightened reward-related ventral striatum activity coupled with decreased threat-related amygdala activity) were associated with greater lifetime sexual partners at baseline measured and over time (longitudinal analyses). Impulsivity moderated the relationship between neural function and self-reported number of sexual partners at baseline and follow up measures, as well as experimental condom use decision-making. Sexual arousal and sensation seeking moderated the relationship between neural function and baseline and follow up self-reports of number of sexual partners. Finally, unique gender differences were observed in the relationship between threat and reward-related neural reactivity and self-reported sexual risk behavior. The results of this study provide initial evidence for the potential role for neurobiological approaches to understanding sexual decision-making and risk behavior. With continued research, establishing biomarkers for sexual risk behavior could help inform the development of novel and more effective individually tailored sexual health prevention and intervention efforts.</p> / Dissertation

Normal aging is associated with a decline in different cognitive domains and local structural atrophy as well as decreases in dopamine concentration and receptor density. To date, it is largely unknown how these reductions in dopaminergic neurotransmission affect human brain regions responsible for reward-based decision making in older adults. Using a learning criterion in a probabilistic object reversal task, we found a learning stage by age interaction in the dorsolateral prefrontal cortex (dIPFC) during decision making. While young adults recruited the dlPFC in an early stage of learning reward associations, older adults recruited the dlPFC when reward associations had already been learned. Furthermore, we found a reduced change in ventral striatal BOLD signal in older as compared to younger adults in response to high probability rewards. Our data are in line with behavioral evidence that older adults show altered stimulus-reward learning and support the view of an altered fronto-striatal interaction during reward-based decision making in old age, which contributes to prolonged learning of reward associations.

Due to abnormal functioning of the brain’s reward and prediction system patients with schizophrenia spectrum disorders are thought to assign salience to non-relevant objects and events and to form context-inappropriate associations. The brain’s ventral striatum is critical in the formation of associations, and aberrant associations are believed to create delusional content during psychosis. The study wanted to examine the neural response, particularly in the ventral striatum, combined with subjective reports as patients learn associations in an aversive Pavlovian conditioning paradigm. The stimuli were randomized and involved circles of different colors. The conditioned stimuli (CS+) was followed by an unconditioned stimuli (US), consisting of an unpleasant sound, in 50% of events. The unconditioned (CS-) stimuli was followed by a low, not unpleasant sound in 50% of events. The degree of striatal activation was thought to be associated with the severity of patient’s illness. Functional magnetic resonance imaging (fMRI) blood-oxygen-level dependent (BOLD) responses were examined in eleven unmedicated non-institutionalized patients with schizophrenia spectrum disorders and 15 matched healthy controls. No significant within group differences in neural or subjective response to the [CS+ &gt; CS-] contrast were found. No significant associations between severity of illness and degree of striatal activation in response to CS+ or CS- were found. Significant differences in neural activation for the [CS+ &gt; CS-] contrast were found in the ventral striatum, the right inferor frontal gyrus, and the right angular gyrus, with patients exhibiting stronger activation compared to controls. The results and implications are discussed along with suggestions for future research.

Numerous social and educational psychologists propose that intrinsic motivation generated by personal interests and spontaneous satisfactions is qualitatively different from extrinsic types of motivation generated by external compensations and also that intrinsic motivation is more beneficial to learning than extrinsic types of motivation. However, in the field of neuroscience, intrinsic motivation has been little studied while extrinsic types of motivation (e.g., incentive motivation) have been thoroughly studied. The purpose of the present studies was to expand the neural understanding of motivation to include intrinsic motivational processes. To do so, a series of three event-related functional magnetic resonance imaging (fMRI) studies were conducted. Study 1 and Study 2 compared the neural activities when participants decided to act for intrinsic reasons (i.e., self-determined volitional and agentic behavior) versus when they decided to act for extrinsic reasons (i.e., non-self-determined volitional and agentic behavior). Both studies showed that the anterior insular cortex, known to be related to a sense of agency, was more activated during self-determined behavior associated with intrinsic reasons for acting while the posterior parietal regions (e.g., posterior cingulate cortex, angular gyrus), known to be related to a sense of a loss of agency, were more activated during non-self-determined behavior associated with extrinsic reasons for acting. These findings confirm the existence of neural-based intrinsic motivational processes, differentiate intrinsic motivation from incentive motivation, and document the important neural activities which function for generating self-determined agentic action. Study 3 examined these same neural activities as participants engaged in interesting and uninteresting versions of two experimental tasks. Results confirmed the results of the earlier two studies, as the anterior insular cortex was more recruited when participants performed the interesting, but not the uninteresting, version of the tasks. Results also extended the findings from Studies 1 and 2 in an important way in that the ventral striatum, a well-known brain region for reward processing, was more activated when participants performed the interesting, but not the uninteresting, version of the experimental tasks. These findings suggest that intrinsic motivation is generated based on the feeling of intrinsic need satisfaction (from anterior insular cortex activations) and the feeling of reward (from ventral striatum activations). Overall, the present research established three new findings: (1) the neural bases of intrinsic motivation lies largely in increased anterior insular cortical activities; (2) when people made decisions about self-determined intrinsically-motivated behavior, they show enhanced insular cortical activities and suppressed posterior parietal cortical activities; and (3) when people engaged in actual self-determined intrinsically-motivated behavior, they show enhanced insular cortical and ventral striatal activities. In establishing these new findings, the paper introduces a new area of study for motivational neuroscience--namely, intrinsic motivation.