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L-glutamate (Glu) is the predominant excitatory neurotransmitter inthe mammalian central nervous system (CNS) and is associated with a widevariety of functions including motor behavior and sensory perception. Whilemicrodialysis methods have been used to record tonic levels of Glu, little isknown about the more rapid changes in Glu signals that may occur in awakeanimals. We have previously reported acute recording methods using anenzyme-based microelectrode array (MEA) with fast temporal resolution (800msec), that is minimally invasive and is capable of detecting low levels of Glu (andlt;0.2 ??M) in anesthetized animals with little interference from other analytes. Wehave made a series of modifications to the MEA design to allow for reliablemeasures in the brain of awake behaving rats. In these studies, wecharacterized the effects of chronic implantation of the MEA into the striatum andprefrontal cortex (PFC) of Fischer 344 and Long Evans rats. We measuredresting levels of Glu and local application of Glu for 7 days without a significantloss of sensitivity and determined that Glu measures due to exogenous Gluvaried between rat strain and brain region. In addition, we determined theviability of the recordings in the brains of awake animals. We performed studiesof tail-pinch induced stress which caused an increase in Glu in the striatum andPFC of Long Evans and Fischer 344 rats. Histological data show that chronicimplantation of our MEAs caused minimal injury to the CNS. Taken together, ourdata support that chronic recordings of tonic and phasic Glu can be carried out inawake rats reliably for 7 days in vivo allowing for longer term studies of Gluregulation in behaving rats.

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.

Hyperthermia worsens outcome after ischemia. While it seems reasonable that hyperthermia would also worsen outcome after intracerebral hemorrhage (ICH), clinical studies attempting to find a causative relationship between hyperthermia and outcome have been inconclusive. We induced ICH with an injection of autologous whole blood (100 l) immediately followed by 3 hours of hyperthermia (HYPER; 39C) or normothermia (NORMO; 37C). Surprisingly, hyperthermia reduced edema at 72 hours, and improved outcome on day 3 post-ICH. There were no behavioural differences at later time points (day 11 and 32 post-ICH) and no difference in lesion volume (NORMO 14.0 mm3, HYPER: 14.5 mm3). Overall, this study does not support the hypothesis that mild, transient hyperthermia worsens outcome after ICH. Further research is needed to determine if more severe or prolonged hyperthermia worsens outcome, or if the cause of hyperthermia (e.g. infection) is important.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 4 uppsatser.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 4 uppsatser.

Thesis (M. Phil.)--University of Hong Kong, 1997. / Includes bibliographical references (leaf 79-98).

Thesis (Ph.D.)--University of Florida, 2004. / Title from title page of source document. Document formatted into pages; contains 96 pages. Includes Vita. Includes bibliographical references.

The striatum is the largest nucleus of the basal ganglia, and acts as a point of convergence for thalamic, cortical and midbrain inputs. It is involved in both motor and associative forms of learning, and is composed of spiny projection neurons (SPNs) whose output along the so-called "direct pathway" and "indirect pathway" is modified by the activity of diverse sets of interneurons. Four "classical" or major classes of striatal interneuron can be identified according to the selective expression of the molecular markers parvalbumin (PV), calretinin (CR), nitric oxide synthase (NOS) or choline acetyltransferase (ChAT). Although the interneurons within a class are generally considered to be homogeneous in form and function, there is emerging evidence that some classes encompass multiple types of neuron, and that the heterogeneity in striatal interneurons extends beyond these four classes. Defining the extent of interneuron heterogeneity is important for understanding how the striatum processes distinct, topographically-organized inputs from the cortex and thalamus in order to govern a wide range of behaviors. To address these issues, a combination of immunofluorescence microscopy and stereological cell counting approaches was used in striatal tissue from rat, mouse and non-human primate. This was supplemented by in vivo recording and juxtacellular labelling of single neurons in rat. A first set of experiments showed that secretagogin (Scgn), a calcium-binding protein, is expressed by a large number of interneurons in the dorsal striatum of rat and primate, but not in the mouse. In all species tested, secretagogin was expressed by a subset of PV+ interneurons and a subset of CR+ interneurons in the dorsal striatum, but also labelled a group of interneurons that did not express any of the classical markers of striatal interneurons. A second set of experiments in the rat demonstrated that the selective co-expression of Scgn by PV+ interneurons delineates two topographically-, physiologically- and morphologically-distinct cell populations. These topographical differences in distribution were largely conserved in the primate caudate/putamen. In rats, PV+/Scgn+ and PV+/Scgn- interneurons differed significantly in their firing rates, firing patterns and phase-locking to cortical oscillations. The axons of PV+/Scgn+ interneurons were more likely to form appositions with the somata of direct pathway SPNs than indirect pathway SPNs, whereas the opposite was true for the axons of PV+/Scgn- interneurons. These two populations of GABAergic interneurons provide a potential substrate through which either of the striatal output pathways can be rapidly and selectively inhibited, and in turn mediate the expression of behavioral routines. A third set of experiments showed that CR+ interneurons of the dorsal striatum can be separated into three populations based on their molecular, topographical and morphological properties. Small-sized ("Type 3") CR+ interneurons co-expressed Scgn and were restricted in their distribution towards the rostro-medial poles of the striatum in both rats and primates. In rats, these neurons also expressed the transcription factor SP8, suggesting that they may be newly generated throughout adulthood. Large-sized, ("Type 1") CR+ interneurons did not express Scgn, but could be further distinguished by their expression of the transcription factor Lhx7. Medium-sized ("Type 2") CR+ interneurons did not express Scgn or Lhx7, and had heterogeneous electrophysiological properties in vivo. The expression of Scgn, but not other classical interneuron markers, identified a group of interneurons that were restricted in their distribution towards the ventro-medial aspects of the dorsal striatum. A fourth set of experiments showed that these neurons are also present in the core and the shell of the nucleus accumbens. Unlike the case of dorsal striatum, however, PV+ interneurons and CR+ interneurons of the nucleus accumbens did not co-express Scgn. Moreover, many of the interneuron populations studied had greater densities in the ventral striatum compared to the dorsal striatum, and had quantifiably strong biases in their distribution towards a variety of axes within both the core and the shell of the nucleus accumbens. These data thus highlight some major differences in the constituent elements of the microcircuits of dorsal striatum and nucleus accumbens. In conclusion, these studies have revealed a great deal of molecular, topographical, electrophysiological and structural heterogeneity within the interneuron populations of the striatum. As several of these interneuron populations were not evenly distributed throughout the striatum, this ultimately suggests that the microcircuit of the striatum is specialized according to regions that differ in their cortical, thalamic and dopaminergic inputs.

Parkinson's disease (PD) is a neurodegenerative disease that causes degeneration of nigral dopaminergic terminals in the caudate and the putamen regions of the striatum in the basal ganglia. According to current practice, when an unequivocal clinical diagnosis of PD cannot be made, a single-photon emission computed tomography scan using the DaTscan radionuclide (SPECT DaT scan) is ordered. However, the assessment of SPECT DaT scans in the diagnosis of PD depends on the subjective judgment of a radiologist, which can pose problems for the accuracy of the diagnosis. Furthermore, as research studies generally do not quantify SPECT DaT scans when using them, their conclusions are not based on standardized data. The aim of this paper is to propose a method of quantification for SPECT DaT scans, to be employed in diagnostic and research environments. The methodology proposed in this thesis project will eventually be used for a much larger multimodal imaging project investigating the connectivity changes in the brain related to cognitive and affective symptoms in PD patients. Each of the 4 subjects in this project underwent a SPECT DaT scan and an MPRAGE scan (Magnetization Prepared Rapid Gradient Echo), an anatomical MRI (magnetic resonance image). The SPECT DaT scans and the MPRAGEs were coregistered, and then a voxel-based quantification of the caudate and the putamen in the left and the right hemispheres was performed in every subject. First, the percentages of voxels with intensities exceeding various pericalcarine baselines were calculated. A pericalcarine baseline was used because the pericalcarine gyrus in the occipital lobe has been shown to have little to no dopaminergic activity, particularly on SPECT DaT scans. Next, asymmetry indices (AI) were calculated for two of the thresholds whereby the ratio of the percentage of voxels in the right to the left hemispheric region was taken. Wilcoxon Signed-Rank tests and bootstrapping analyses were performed on both the caudate and the putamen in all four subjects to determine the significance of any detected asymmetry. The quantification of the data and the AI values revealed asymmetries in the voxel intensities between the left and right hemispheres. This asymmetry was consistent with each subject's side of physical symptom onset. According to the bootstrapping analyses, this asymmetry was significant in five of the eight comparisons. In summary, this methodology has potential to bring greater objectivity to the use of SPECT DaT scans in the diagnosis of PD and in research through its anatomically accurate, voxel-based quantification.