Purpose: The principal aim of this project was to investigate the influence of clinical indices of injury severity and polymorphism of the apolipoprotein E gene upon the long-term physical, cognitive and emotional sequelae of traumatic brain injury and spontaneous subarachnoid haemorrhage. It was also intended to determine the extent to which changes occur in these sequelae beyond the initial six months post injury. Method: Sixty-two brain injury patients who had previously taken part in a neuropsychological assessment at six months post injury were traced and participated in a follow-up assessmens some 6-9 years subsequent to their injury. Separately, a group of 70 subarachnoid patients drawn from a consecutive series of neurosurgical admissions participated in a neuropsychological assessment at 14 months subsequent to their haemorrhage. In both studies, the assessment comprised a semi-structured interview and a battery of cognitive measures focusing principally upon memory and executive function tasks. A questionnaire including a range of standardised measures of anxiety, depression and quality of life was left with patients to be returned by post. Results: The ApoE e4 allele did not appear to influence recovery amongst these brain injury survivors, though there are suggestions that it may have an influence upon subgroups of patients. Amongst traumatic brain injury survivors, post-traumatic amnesia was a better predictor of functional or emotional outcome than consciousness based measures. However, consciousness based measures were more predictive of cognitive sequelae and low admission Glasgow Coma Scale was associated with continued improvement on information processing tasks. Other than on these tasks, there was little evidence of change between 6 months and 6-9 years post injury. Amongst the subarachnoid haemorrhage patients, Fisher Grade was found to be more predictive of subsequent Glasgow Outcome Scale and cognitive function than WFNS Grade or other clinical indices. Surviving aneurysmal patients had comparable levels of recovery to patients who had a negative angiogram. In both studies emotional sequelae, in particular anxiety-related difficulties, were found to be a principal factor in the functional outcome of some 40% of patients. Conclusions: Greater emphasis should be placed upon measures of post-traumatic amnesia as predictors of functional recovery in surviving patients. The use of an amnesia measure may also be warranted in studies of outcome following subarachnoid haemorrhage or other stroke. The ApoE e4 allele does not appear to have a strong influence upon functional recovery after brain injury across all patients, though it is possible that it interacts with other factors to influence recovery in subgroups. Greater emphasis should be placed upon the prevention and/or detection and treatment of mood disorders following brain injury. In the absence of intensive rehabilitative interventions, survivors of serious brain injury are more likely to deteriorate than to continue to recover beyond six months post injury.

Thesis (Ph. D.)--University of California, San Diego and San Diego State University, 2009. / Title from first page of PDF file (viewed June 16, 2009). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 118-130).

Thesis (Ph.D.)--Kent State University, 2006. / Title from PDF t.p. (viewed Sept. 19, 2006). Advisor: Eric Glasgow. Keywords: oxytocin; isotocin; vasopressin; vasotocin; hypothalamo-neurohypophysial system; hypothalamus; development; autism; Prader-Willi Syndrome; single-minded; orthopedia; arylhydrocarbon nuclear translocator; Brn2; POU; zebrafish; behavior; paraventricular nucleus; supraoptic nucleus; preoptic nucleus; diencephalon; suprachiasmatic nucleus; thyroid transcription factor; sonic hedgehog; NK 2 transcription factor related; distal-less homeobox gene; homeobox; homeodomain; morpholino Includes bibliographical references (p. 230-266).

Thesis (Ph. D.)--University of California, San Diego and San Diego State University, 2007. / Title from first page of PDF file (viewed June 11, 2007). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 171-178).

Serotonin (5HT) is a monoamine neurotransmitter that modulates a wide range of brain functions via the actions at 5HT receptors and 5HT transporters. Dysregulation of 5HT transmission underlies many neurological and psychiatric disorders, such as depression and anxiety disorders. To advance the research in serotonergic neurotransmission and dysfunction, we have focused on two distinct approaches- 1) investigation of basic biology of synaptic function and 2) small molecule drug discovery. We have first developed a novel fluorescent tracer of 5HT, providing a molecular tool to study the serotonergic system in the CNS with subcellular and cellular resolution in vitro and in vivo. Next, we have developed novel small molecules to activate the serotonin 2A receptor (5HT2A agonists). By exploring new scaffolds, we expect to expand the pharmacophore space for 5HT2A agonists to allow exploration of 5HT2A as molecular target for treating neuropsychiatric disorders, and guide structure-based discovery of more selective 5HT2A agonists with desirable pharmacological properties as potential drug candidates.

The basal ganglia are a set of subcortical nuclei in the forebrain of vertebrates that are highly conserved among mammals. Classically, dysfunction in the basal ganglia has been linked to motor abnormalities. However, it is now widely recognized that in addition to their role in motor behavior, these set of nuclei play a role in reinforcement learning and motivated behavior as well as in many diseases that present with abnormal motivation. In this dissertation, I first provide a review of the literature that describes the current state of research on the basal ganglia and the background for the original studies I later present. I describe the anatomy and physiology of the basal ganglia, including how structures are interconnected to form two parallel pathways, the direct and the indirect pathways. I further review published studies that have investigated how the basal ganglia regulate motor behavior and motivation. And finally, I also summarize findings on how disruption in basal ganglia circuitry function has been linked to a number of neuropsychiatric diseases, with special focus on the symptoms of schizophrenia. I then present original data and discuss the results of three studies investigating basal ganglia function and behavior. In the first study, I investigated the bridging collaterals, axon collaterals of direct-pathway medium spiny neurons (dMSNs) in the striatum that target the external segment of the globus (GPe), the canonical target of indirect-pathway medium spiny neurons (iMSNs). Previous work in the Kellendonk laboratory has linked these collaterals to increased dopamine D2 receptor (D2R) function and increased striatal excitability, as well as to abnormal locomotor response to stimulation of the direct pathway. I expanded on these findings by first demonstrating that bridging collaterals form synaptic contacts with GPe cells. I was also able to generate a viral vector to selectively increase excitability in specific populations of MSNs. I used this virus to show that chronically increasing excitability of the indirect pathway, but not the direct pathway, leads to a circuit-level change in connectivity by inducing the growth of bridging collaterals from dMSNs in the GPe. I also confirmed that increased density of bridging collaterals are associated with an abnormal locomotor response to stimulation of striatal dMSNs and further demonstrated that chronic pharmacologic blockade of D2Rs can rescue this abnormal locomotor phenotype. Furthermore, I found that motor training reverses the enhanced density of bridging collaterals and partially rescue the abnormal locomotor phenotype associated with increased collaterals, thereby establishing a new link between connectivity in the basal ganglia and motor learning. In the second study, I conducted a series of experiments in which I selectively increased excitability of the direct or indirect pathway in specific striatal sub-regions that have been implicated in goal-directed behavior, namely the DMS and NA core. I found that this manipulation was not sufficient to induce significant effects in different behavioral assays of locomotion and motivation, including the progressive ratio and concurrent choice tasks. These findings also suggest that increased bridging collateral density does not have a one-to-one relationship with the motivational deficit of D2R-OEdev mice, as previously hypothesized. In the third and final study, my original aim was to determine whether the motivational deficit of D2R-OEdev mice, induced by upregulation of D2Rs in the striatum, could be reversed by acutely activating Gαi-coupled signaling in the indirect pathway in these animals. I found that this manipulation increased motivation in D2R-OEdev mice but also in control littermates. This effect was due to energized behavioral performance, which, however, came at the cost of goal-directed efficiency. Moreover, selective manipulation of MSNs in either the DMS or NA core showed that both striatal regions contribute to this effect on motivation. Further investigation aimed at understanding how Gαi-coupled signaling affects striatal circuit function revealed that activating a Gαi-coupled receptor did not lead to a significant change in somatic MSN activity in vivo or to a change in neuronal excitability in vitro. In contrast, the GPe, which receives monosynaptic inhibition from the indirect pathway, showed disinhibited activity when Gαi signaling was activated in striatal iMSNs. In addition, as drug therapies for psychiatric diseases are not usually given acutely but involve long-term, continuous administrations, I also studied how chronically decreasing function of iMSNs would affect behavior. I showed that chronically activating a Gαi-coupled receptor in iMSNs does not lead to a measurable effect on locomotion or motivation, a behavioral desensitization response that can be recovered within 48 h and may be due to receptor desensitization to the drug or circuit-level compensation to a chronic decrease in iMSN function. Finally, I conclude this dissertation with a general discussion addressing how the findings from each study can be related to each other to provide a more complete understanding of how basal ganglia function regulate behavior, how disruption in the basal ganglia can underlie neuropsychiatric disease, and how strategies to target basal ganglia function should be employed to treat disorders of motivation. I conclude this dissertation by proposing new avenues of research for further exploring my findings.

No description available.

Thesis (Ph. D.)--University of California, San Diego, and San Diego State University, 2005. / Vita. Includes bibliographical references (leaves 211-233).

Thesis (Ph.D.)--Uppsala Universitet, 2009. / This website links to the complete document in PDF format. Title from title screen (viewed on November 21, 2009). Includes bibliographical references.

Our lives unfold in space and time—we are able to be aware not only of the present instant but also to recollect the past and imagine the future, and our memories tend to be not instantaneous snapshots but rather bear a temporal, sequential dimension. This faculty of time travel allows us to adjust our current actions in light of what we have previously learned and with respect to what we aspire to become. It depends upon faithful records of our personal experiences, termed episodic memory. While over the last century we have learned a great deal about the molecular changes that support this kind of learning, the circuit-level mechanisms with which the brain implements the formation of episodic memory remain to be discovered. Failures of episodic memory can be catastrophic, and unfortunately, such dysfunction is commonplace in a number of human pathologies. In the neuropsychiatric syndrome of schizophrenia, the capacity to form and utilize episodic memory is compromised, a state of affairs that likely contributes to the difficulty people with schizophrenia have adjusting their actions to meet desired goals. Attempts to understand the pathogenesis of schizophrenia’s memory deficits at the molecular level have yielded frustratingly few leads, making circuit-level inquiries a rational next step. Utilizing a genetic mouse model of schizophrenia susceptibility (Df(16)A+/- mice), we have taken a three-pronged approach to the analysis of the circuit mechanisms and missteps of episodic memory. We first developed a behavioral model of episodic memory, a variation on classical ‘trace’ fear conditioning, which involves the formation of an association between an innocuous stimulus (conditioned stimulus, CS) and a temporally separate aversive stimulus (unconditioned stimulus, US). Next, we turned to a region of the brain known to be required for trace fear conditioning and implicated in the pathogenesis of schizophrenia, dorsal CA1 of the hippocampus. Because network coordination and plasticity in dorsal hippocampal CA1 relies heavily on the activity of soma-targeting, parvalbumin-positive interneurons (PV+ INs), we hypothesized that they may be mediators of the associations built during trace fear conditioning. We therefore sought to characterize their activity during temporal association learning in both wild-type (WT) and Df(16)A+/- mice using two-photon calcium imaging. We simultaneously recorded local field potentials in the contralateral dorsal hippocampus to pair the discrete transformations captured through imaging with information about more global states of hippocampal activity. Finally, we manipulated the activity PV+ INs during various epochs of freely-moving trace fear conditioning to test hypotheses regarding their necessity for trace fear conditioning in healthy and schizophrenia-susceptible mice. We found that Df(16)A+/- mice have severe deficits in trace fear conditioning when compared to mice that do not carry their defining mutation. Calcium imaging of PV+, peri-somatic boutons in dorsal CA1 over the course of trace fear conditioning revealed a marked increase in the number of detected boutons that initiate activity during the presentation of the CS and that sustain their activity across the time gap preceding delivery of the US. This shift in activity was notably absent in recordings from Df(16)A+/- mice. Consistent with the observations of others, analysis of local field potentials indicated that successful learning was associated with modulation of amplitude and theta-phase relation in mid- and fast-gamma frequency oscillations. This modulation was compromised in Df(16)A+/- mice. Finally, we found that inhibition of PV+ INs during encoding in Df(16)A+/- mice restores their response to the CS to near-WT levels of fear expression. Our results support the thesis that temporary downregulation of PV+ IN activity during encoding is essential for the formation of complex, hippocampus-dependent associations including temporal association memory. We suggest that this transient disinhibition may serve to allow for the generation of new pyramidal cell ensembles to represent the associated stimuli. The heightened, sustained inhibition observed during post-learning trials in the calcium imaging experiments is consistent with a transition of the PV+ INs into a role of stabilizing the fledgling memory trace during consolidation. Our results also support the hypothesis that in our model of schizophrenia susceptibility, impairments in learning complex associations may be due to the inability of PV+ INs to modulate their activity appropriately over the changing phases of memory formation. We identify PV+ INs as a promising therapeutic target for schizophrenia as we were able to restore behavior of the susceptible mice during our assay of temporal association memory. Further studies combining pharmacogenetic or optogenetic manipulations with calcium imaging and LFP recording could shed light on the mechanisms of these shifts in network plasticity and may help to identify new approaches to the treatment of the debilitating cognitive deficits associated with schizophrenia.