Zugl.: Bremen, Univ., Diss., 2007

Thesis advisor: Michael A. McDannald / Thesis advisor: John P. Christianson / The ability to accurately evaluate and respond to threats is vital to survival. Disruptions in neural circuits of fear give rise to maladaptive threat responding, and have clinical implications in fear and anxiety disorders. To better inform therapeutic interventions, it is imperative that roles for regions classically associated with fear continue to be refined, and that novel nodes are incorporated into what is most certainly a larger fear circuit. In the canonical view, threat estimates are generated at the level of the amygdala and sent to the ventrolateral periaqueductal gray (vlPAG), which organizes an appropriate behavioral response, most notably freezing. Despite a multitude of studies successfully linking the vlPAG and Pavlovian fear behavior, evidence of a direct neural correlate for fear expression in the vlPAG is lacking. By contrast, a role for the caudal substantia nigra (cSN) in fear, stands apart from its canonical associations with movement and reward processes. Although there is new interest in examining a role for the nigra in fear modulation, this is essentially an uncharted area of discovery. The goals of this dissertation are three-fold. First, to propose a role for vlPAG activity in threat estimation, a function previously restricted to the upstream amygdala. Second, to scrutinize vlPAG neural activity using a novel multi-cue Pavlovian procedure and identify the long-anticipated, direct neural correlate for fear expression. Third, to present causal evidence supporting the cSN as a potential node in a circuit that most certainly extends beyond regions canonically associated with fear. / Thesis (PhD) — Boston College, 2021. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Psychology.

Thesis (Ph.D.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / The overall goal of this dissertation was to determine the role of the subthalamic nucleus (STN) in regulating the release of dopamine in the substantia nigra (SN). Experiments first established the existence of a direct connection between subthalamic neurons and SN dopaminergic cells. Further experiments showed that this connection triggers the dopamine release in the SN, and the mechanisms involved in this release were determined. Whole-cell current clamp recordings were performed in parasagittal brain slices obtained from 10 to 16 day-old rat pups. Electrical stimulations of the STN reliably triggered excitatory post-synaptic potentials (EPSPs) in dopaminergic neurons of the SN pars compacta (SNc). Pharmacological experiments with specific receptor antagonists indicated that this EPSP was mediated by NMDA, non-NMDA and metabotropic glutamate receptors. Stimulations of the subthalamic input triggered the release of dopamine. In a subset of neurons in the SN pars reticulata (SNr), repetitive stimulations of the STN produced a summating EPSP that was followed by an inhibitory postsynaptic potential (IPSP). A D2 receptor antagonist blocked this IPSP suggesting that it represents the D2 receptor-mediated response of the recorded cell to dopamine released upon stimulation of the STN. Pharmacological experiments using this assay indicated that NMDA, non-NMDA or metabotropic glutamate receptors were individually not required for dendritic release of dopamine; however, each contributed to this release. In dopaminergic neurons located in the SN pars compacta, the inhibitory effect of dopamine was revealed following block of L-type Ca channels, NMDA and non-NMDA glutamate receptors. These results indicated that dopaminergic neurons located both in the SNc and SNr respond to the dendritic release of dopamine triggered upon stimulations of the STN. Finally, a specific blocker of the dopamine transporter (GBR12935) blocked the IPSP reversibly in both SNr and SNc dopaminergic neurons. If release occurred by exocytosis, block of the transporter should increase extracellular levels of dopamine and produce an increase in the size of the recorded IPSP. Therefore, these results suggest that dopamine dendritic release triggered by activation of the subthalamic input was mediated by reversed transport of dopamine rather than by exocytosis. / 2031-01-01

Thesis (M. Phil.)--University of Hong Kong, 2002. / Includes bibliographical references (leaves 91-116).

published_or_final_version / Psychology / Master / Master of Philosophy

Brain tissue samples were collected from individuals with histologically and biochemically confirmed Alzheimer's Disease (AD), as well as from a group of individuals without any signs of neurological disease (NNC). Ribonucleic acid (RNA) was extracted from these tissues, characterized by several chemical methods, and the yields were compared between AD and NNC groups. High molecular weight RNA could be effectively extracted from frozen postmortem human brain. In comparison to the NNC group, tissue RNA levels were reduced in the AD hippocampus, but not in the temporal cortex or substantia innominata (SI). No difference in the physical integrity of the RNA was apparent between AD and NNC groups. A high complexity complementary deoxyribonucleic acid (cDNA) library was prepared using RNA extracted from the NNC SI. Differential hybridization screening using a variety of cDNA probes was employed to identify mRNAs expressed differentially between AD and NNC tissue, and between SI and other human tissues. Many selected mRNAs were examined for specificity of expression in brain tissue and brain regions. The cDNA clone pSI3a-24 identified an mRNA, which, on Northern blot hybridization, was expressed in brain tissue but not in the other human tissues examined. The identified mRNA was unusually large, with a chain length estimated at 15,500 bases. Quantification of the brain tissue levels of this mRNA was carried out using a ribonuclease protection assay. Tissue levels were higher in the SI (40 pg/μg RNA) than in the temporal cortex (28.6 pg/μg), and were lowest in the cerebellum (11.2 pg/μ9). Levels of the mRNA in temporal cortex samples were increased 29% in the AD group, relative to NNC. No significant difference in the SI tissue levels was observed between AD and NNC groups. Hybridization analysis of human genomic DNA indicated that the mRNA was encoded by a single copy gene. Sequence analysis of the full 3 kilobases of cloned cDNA was completed. Computer database searches failed to identify any known nucleic acid sequence with homology to the cDNA. Examination of the cDNA sequence for potential polypeptide coding regions suggested that the corresponding mRNA has a 3' untranslated region of at least 3 kilobases. / Medicine, Faculty of / Graduate

Objective: Substantia nigra hyperechogenicity is found in children with attention- deficit hyperactivity disorder (ADHD). Research with transcranial sonography (TCS) in adults suggests that echogenic alterations are linked to subclinical behavioral deficits and that brain iron homeostasis is involved in the signal genesis. The purpose of this study was to explore substantia nigra echogenicity in healthy children, to assess age-related changes and to investigate whether echogenic signals relate to subclinical alterations in behavior. Furthermore, associations of central nigral neuromelanin measures and peripheral serum iron parameters to echogenic signals of the substantia nigra were evaluated. Methods: In a multimodal study design, neuroimaging of the substantia nigra was conducted with TCS and neuromelanin-sensitive magnetic resonance imaging (MRI) in 28 healthy children (8 − 12 years). Correlations and multiple regression analyses determined associations between the neuroimaging methods, behavioral data from Strength and Difficulties Questionnaire (SDQ) and serum iron-related parameters. Results: Substantia nigra echogenicity correlated inversely with hyperactivity ratings in healthy, non-ADHD children (r = −.602, p = .001). Echogenic sizes did not change as a function of age. Neuromelanin-sensitive MRI measures of the substantia nigra and peripheral serum iron parameters were not associated with nigral TCS signals. Conclusion: In healthy children behavioral differences in hyperactive tendencies are associated with differences in substantia nigra echogenicity. This could help to identify those children who are at risk of subclinical ADHD. / Ziele: Bei Kindern mit AHDS findet sich eine hyperechogene Substantia nigra in der transkraniellen Sonographie (TCS). Bei gesunden Erwachsenen gibt es Hinweise darauf, dass Substantia nigra Hyperechogenität mit subklinischen Verhaltensdefiziten korreliert und dass ein aberranter Eisenstoffwechsel in die Genese des Signals involviert ist. Ziel der Studie war die Substantia nigra Echogenität bei gesunden Kindern zu explorieren, potentielle altersabhängige Veränderungen darzustellen und Zusammenhänge mit subklinischen Verhaltensabnormitäten zu untersuchen. Außerdem wurden Zusammenhänge mit peripheren Serum Eisen Parametern und zentralen Neuromelanin Maßen evaluiert. Methoden: In einem multimodalen Studiendesign wurde die Substantia nigra bei 28 Kindern (8-12 Jahre) mittels TCS und Neuromelanin-sensitiver MRT dargestellt. Korrelationen und Regressionsanalysen wurden angewandt, um die beiden neuroimaging Methoden, Verhaltensdaten aus dem Strength and Difficulties Questionnaire (SDQ) und Serum Eisen Parametern zu relatieren. Resultate: Substantia nigra Echogenität korrelierte invers mit Hyperaktivität bei gesunden Kindern ohne ADHS (r = -.602, p = .001). Es zeigte sich kein Zusammenhang mit Alter, peripheren Serum Eisen Parametern oder Messungen der Substantia nigra mittels Neuromelanin-sensitiver MRT. Schlussfolgerung: Bei gesunden Kindern sind Unterschiede in hyperaktiven Tendenzen assoziiert mit unterschiedlichen Signalen der Substantia Nigra mittels TCS.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 4 uppsatser.

Vom Deletionssyndrom 22q11.2 Betroffene sind einem überdurchschnittlich hohen Risiko ausgesetzt im Entwicklungsverlauf psychisch zu erkranken. Häufige Störungsbilder sind unter anderem ADHS, Angsterkrankungen, affektive Störungen, Erkrankungen aus dem schizophrenen Formenkreis und Morbus Parkinson. Ziel der Studie war es, phänotypische Auffälligkeiten beim DS22q11 zu identifizieren, die dabei helfen könnten, Hochrisikogruppen innerhalb des Syndroms frühzeitig identifizieren zu können und in Form von Biomarkern messbar sind. Hierzu wurden die bereits in Forschung und teilweise auch in der Klinik etablierten Verfahren der transkraniellen Sonographie und der standardisierten Riechtestung eingesetzt. / Individuals affected with 22q11.2 Deletion Syndrome (22q11.2DS) are at an above average risk to develop neuropsychiatric disorders (such as attention-deficit/hyperactivity disorder, anxiety disorders, affective disorders, schizophrenia and Parkinson's disease). The aim of this study is to identify phenotypical characteristics in 22q11.2DS to help point out high-risk groups within the syndrome and then be measured as biomarkers. To achieve this, we performed transcranial sonography and olfactory testing which are known to be established clinical and research methods.

Zugl.: Hannover, Tierärztliche Hochsch., Diss., 2009