The biochemistry and anatomy of various nuclei of the basal ganglia of the rat were investigated. The head of the striatum was found to project to the anterior globus pallidus (GP) and to the entopeduncular nucleus (EP). A projection from the anterior striatum to the substantia nigra (SN) was confirmed. The tail of the striatum was found to project to the posterior part of the GP. No anatomical evidence was obtained for a projection from the tail of the striatum to the EP. The posterior striatum was found to project to the lateral SN. Biochemically, the presence of glutamic acid decarboxylase (GAD) in the projection from the head of the striatum to the GP has been confirmed. The head and tail of the striatum were found to project GAD-containing fibers to the EP. While the absence of nigral GAD-containing afferents originating in the anterior striatum has been confirmed, it was found that the SN does receive such afferents from more posterior regions of the striatum. The SN was found to be devoid of a GAD-containing input from the GP. The EP efferents to the habenula were found to be GAD-containing. Preliminary evidence was obtained for the presence of cholinergic fibers in the striatal projections to the GP and EP. The cellular localization of various enzyme systems in the SN and of the dopamine (DA) receptor in the SN and striatum was investigated using kainic acid and 6-hydroxydopamine lesion techniques. It was concluded that choline acetyltransferase and DA-sensitive adenylate cyclase are contained in nigral afferents, acetylcholinesterase is contained in both nigral afferents and intrinsic neuronal elements and tyrosine hydroxylase is contained in nigral perikarya. The results concerning nigral GAD were inconclusive. Evidence was obtained for the existence of DA receptors on DA-containing neurons in the SN and their terminals in the striatum. / Medicine, Faculty of / Graduate

Thesis (Ph. D.)--University of Sydney, 2009. / Includes graphs and tables. Includes list of publications. Title from title screen (viewed June 17, 2009) Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy to the School of Physics, Faculty of Science. Degree awarded 2009; thesis submitted 2008. Includes bibliographical references. Also available in print form.

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Diss. (sammanfattning) Stockholm : Karol. inst. / Härtill 7 uppsatser.

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The anatomical organization of the connections of the major components of the basal ganglia was investigated in detail. A sensitive procedure for the simultaneous study of afferents and efferents was carried out on the striatum (CP), globus pallidus (GP), and substantia nigra (SN). Previously well characterized connections of the CP were confirmed, additional evidence for a projection to the CP from the ventromedial nucleus of the thalamus was obtained and a topographically organized projection to the CP from the GP was discovered. A similar study of the SN revealed a nigral projection to the ipsilateral lateral dorsal nucleus of the thalamus and nigral input from the contralateral posterior lateral hypothalamus. The projection of the GP to the SN was found to be linked topographically to the striatonigral and pallidostriatal pathways. A study of the connections of the GP confirmed a massive projection from the CP and provided further evidence of a reciprocal connection. In addition, pallidal innervations of the entopeduncular nucleus and reticular nucleus of the thalamus were indicated. Because of the potential importance of a pallidostriatal projection and the significant number of technical difficulties associated with its demonstration, additional experiments were carried out to confirm the presence of this pathway and to determine its anatomical relationship to other basal ganglia connections. Retrograde labelling of pallidostriatal neurons, studied with electron microscopy and in combination with lesions of the striatum, confirmed that pallidal neurons project either to or through the striatum. Evidence for possibly two groups of pallidal neurons that project to the CP was obtained, and it was observed that both of these cell groups were congruent with the striatopallidal terminal fields. Comparisons of the distribution of cells retrogradely labelled after tracer injections into the cortex and CP in combination with histochemistry for acetylcholinesterase demonstrated that the population of pallidal neurons projecting to the CP was distinct from that of peripallidal cholinergic neurons which may project through the striatum to the cortex. Double retrograde fluorescent tracing experiments indicated that pallidal neurons which project to the CP also have collateral projections to the substantia nigra and perhaps to the subthalamic nucleus. The application of a new technique for studying, efferent projections allowed the confirmation and morphological description of the projection of the globus pallidus to the striatum. The characteristic morphology of this projection was shared by pallidal efferents which project to the entopeduncular nucleus, the reticular nucleus of the thalamus, the subthalamic nucleus and the substantia nigra. The fine morphological detail afforded by this method of anterograde tracing was utilized in combination with a histochemical protocol to show that pallidostriatal terminals end in part on somatostatin-containing neurons in the CP. / Graduate and Postdoctoral Studies / Graduate

Biochemical, anatomical, and histochemical studies were performed in the basal ganglia with an emphasis on the localization of the enzyme acetylcholinesterase (AChE). The existence of the enzyme in dopaminergic nigro-striatal neurons was demonstrated. Descending striato-nigral and pallido-nigral axons did not contain detectable amounts of AChE. A cell group called the nucleus basalis magno-cellularis, intimately associated with the globus pallidus, was found to contain high levels of AChE; furthermore, these neurons were shown to be the source of a cholinergic projection to the neocortex. In the striatum, large neurons containing high levels of AChE were found to be likely candidates as..the cholinergic neuron of the striatum. Cholinergic perikarya were found to be absent in the neocortex; nor were perikarya synthesizing large amounts of AChE found in the neocortex. An empirical hypothesis was formulated on the basis of these and other findings regarding cholinergic neurons: High levels of AChE are a necessary but not sufficient criterion for identifying cholinergic perikarya. / Graduate and Postdoctoral Studies / Graduate

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.

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