Emerging evidence suggests that hippocampal memory processing is modulated by midbrain regions under conditions of reward, resulting in enhanced encoding of episodic information—long-term memory for events. Current theories further suggest that hippocampal subregions may have distinct roles in episodic memory formation, and may be differentially influenced by dopaminergic midbrain inputs. Using high-resolution functional magnetic resonance imaging (fMRI), the present study investigated hippocampal subregional function as well as activation in surrounding medial temporal lobe (MTL) cortex, midbrain, and nucleus accumbens during associative encoding and cued recall under varying conditions of reward. A high-value or low-value monetary cue preceded a pair of objects indicating potential reward for successful retrieval of the association. At test, participants performed cued recall followed by match (correct association) or mismatch (incorrect association) probe decisions and received feedback on their performance. Behaviorally, cued recall performance was superior for pairs preceded by high reward cues at encoding relative to pairs preceded by low reward cues. FMRI analysis revealed regions within hippocampus, parahippocampal cortex, nucleus accumbens, and midbrain showing subsequent memory effects (greater encoding activation for remembered, compared to forgotten associations) and reward effects (greater activation for high-value, compared to low-value associations) during stimulus encoding. Within several of these regions, individual differences in reward-related encoding activation were correlated with the degree of the behavioral reward effect (better memory for high-value compared to low-value object pairs). At retrieval, regions in midbrain and subiculum predicted successful associative recall, and regions within hippocampus, parahippocampal cortex, nucleus accumbens, and midbrain showed reward effects in the absence of explicit reward cues. Within several MTL regions, activation was greater for match than mismatch probes. These findings are consistent with theories suggesting that reward-based motivation influences memory formation through interactions between dopaminergic midbrain and hippocampus. / text

This study tested two key assumptions in developing regional biocriteria: (1) the accuracy of the ecoregion classification framework and (2) the accuracy of standardized qualitative sampling. Except for the Central Appalachians ecoregion, there was little or no correspondence of benthic macroinvertebrate distribution with the ecoregions or subregions of western Virginia. I found that it was more accurate to rearrange the subregions into three larger regions called bioregions: the forested hills and mountains (subregion 69a), valleys and plateaus (subregions 66c, 67a, and 67b), and the mountains (subregions 66a, 66b, 67c, and 67d). As an alternative to the ecoregion classification scheme, I classified my reference sites in biotic groups and then assessed the effect of several environmental variables on discriminating between the groups. There was a 69.8% correct classification rate using 14 environmental variables. Stepwise multiple discriminant analysis and graphical analysis showed that sampling date, slope, pH, habitat assessment score and distance to source were the best predictors of community structure. These environmental variables correctly classified 52.8% of the reference sites. These classification rates are comparable to rates published in similar studies. My study demonstrated that aggregations of subregions into bioregions and a biotic approach are more accurate classification schemes than ecoregions or subregions for biocriteria based on benthic macroinvertebrates. A second study evaluated the accuracy of a standardized qualitative sampling approach, commonly used in rapid bioassessments, in assessing the biological condition of lotic systems. I compared a typical standardized qualitative sampling method with subsampling with a typical quantitative sampling method on a stream with varying degrees of impairment. Although some metrics did respond to differences in sample abundance, overall the two methods made similar estimates of community composition. The two sampling methods made the same assessment an average 89% of the time using multimetric index developed for the Mid-Atlantic Region. I found no pattern showing one method was more accurate in making assessments of biological condition than the other. Given the greater time and costs associated with quantitative sampling methods, I conclude that standardized qualitative methods, are preferable for rapid bioassessment approaches to environmental assessment. / Ph. D.

Dopamine increases in the nucleus accumbens after contingent and noncontingent ethanol administration in rats, but the contributions of the core, coreshell border, and shell subregions to this response are unclear. Also, it is not fully understood if increases in dopamine under these circumstances are due to the pharmacological effects of ethanol, stimuli associated with administration, or both. The studies presented in this dissertation were conducted to investigate dopamine’s role in each of these accumbal regions during ethanol administration and presentation of associated stimuli. Using microdialysis, ethanol and dopamine concentrations in accumbal subregions were measured every five minutes before, during, and after either experimenter-delivered intravenous ethanol or operant ethanol self-administration. After intravenous ethanol infusions, the increase in dopamine in the shell of the accumbens was significantly higher than that observed in the core. During operant ethanol self-administration, the core, core-shell border, and shell, all exhibited significant increases in dopamine during transfer of the animal into the operant chamber, with animals trained to drink sucrose + ethanol showing significantly higher increases when compared to those trained to drink sucrose alone. Dopamine increased significantly only in the core-shell border during ethanol consumption, and dopamine levels in the core and shell responded in a similar manner during all phases of the experiment. Together, these results suggest that dopamine responses to intravenous ethanol infusions and operant ethanol self-administration are subregion specific. Also, while increases in dopamine resulting from intravenous ethanol infusions in naïve animals appear to be due to the pharmacological effects of the drug, increases in ethanol-experienced animals during transfer into the operant chamber, and during ethanol consumption, may also be due to stimuli associated with ethanol administration. / text

The placebo effect, a beneficial effect attributable to a treatment containing no specific properties for the condition being treated, has been demonstrated in a variety of medical conditions. This thesis includes four studies aimed at increasing our knowledge on the neurobiology of placebo. Study I, a review of the placebo neuroimaging literature, suggested that the anterior cingulate cortex (ACC) may be a common site of action for placebo responses. However, because placebo neuroimaging studies in clinical disorders are largely lacking, the clinical relevance of this needs further clarification. The subsequent three empirical studies were thus designed from a clinical perspective. Using positron emission tomography (PET) these studies investigated the underlying neurobiology of sustained placebo responses in patients with social anxiety disorder (SAD), a disabling psychiatric condition that nonetheless may be mitigated by placebo interventions. Study II demonstrated that serotonergic gene polymorphisms affect anxiety-induced neural activity and the resultant placebo phenotype. In particular, anxiety reduction resulting from placebo treatment was tied to the attenuating effects of the TPH2 G-703T polymorphism on amygdala activity. Study III further compared the neural response profile of placebo with selective serotonin reuptake inhibitors (SSRIs), i.e the first-line pharmacological treatment for SAD. A similar anxiety reduction was noted in responders of both treatments. PET-data further revealed that placebo and SSRI responders had similar decreases of the neural response in amygdala subregions including the left basomedial/basolateral (BM/BLA) and the right ventrolateral (VLA) sections. To clarify whether successful placebo and SSRI treatments operate via similar or distinct neuromodulatory pathways, study IV focused on the connectivity patterns between the amygdala and prefrontal cortex that may be crucial for normal emotion regulation. In responders of both treatment modalities, the left amygdala (BM/BLA) exhibited negative coupling with the dorsolateral prefrontal cortex and the rostral ACC as well as a shared positive coupling with the dorsal ACC. This may represent shared treatment mechanisms involving improved emotion regulation and decreased rumination. This thesis constitutes a first step towards better understanding of the neurobiology of placebo in the treatment of anxiety, including the neural mechanisms that unite and segregate placebo and SSRI treatment.