Yoland Smith

Goal-directed and habitual control in the basal ganglia: implications for Parkinson's disease

Progressive loss of the ascending dopaminergic projection in the basal ganglia is a fundamental pathological feature of Parkinsons disease. Studies in animals and humans have identified spatially segregated functional territories in the basal ganglia for the control of goal-directed and habitual actions. In patients with Parkinsons disease the loss of dopamine is predominantly in the posterior putamen, a region of the basal ganglia associated with the control of habitual behaviour. These patients may therefore be forced into a progressive reliance on the goal-directed mode of action control that is mediated by comparatively preserved processing in the rostromedial striatum. Thus, many of their behavioural difficulties may reflect a loss of normal automatic control owing to distorting output signals from habitual control circuits, which impede the expression of goal-directed action.

The thalamostriatal system: a highly specific network of the basal ganglia circuitry

Although the existence of thalamostriatal projections has long been known, the role(s) of this system in the basal ganglia circuitry remains poorly characterized. The intralaminar and ventral motor nuclei are the main sources of thalamic inputs to the striatum. This review emphasizes the high degree of anatomical and functional specificity of basal ganglia-thalamostriatal projections and discusses various aspects of the synaptic connectivity and neurochemical features that differentiate this glutamate system from the corticostriatal network. It also discusses the importance of thalamostriatal projections from the caudal intralaminar nuclei in the process of attentional orientation. A major task of future studies is to characterize the role(s) of corticostriatal and thalamostriatal pathways in regulating basal ganglia activity in normal and pathological conditions.

CART PEPTIDES IN THE CENTRAL CONTROL OF FEEDING AND INTERACTIONS WITH NEUROPEPTIDE Y

While CART peptides have been implicated as novel, putative peptide neurotransmitters/cotransmitters, behavioral effects of these peptides have not yet been demonstrated. In this study, we show the first behavioral effect of CART peptides. Icv administration of CART peptide fragments inhibits feeding in rats. Moreover, injection of an antibody to CART peptide 82–103 stimulates feeding, suggesting that endogenous CART peptides exert an inhibitory tone on feeding. Injection of CART peptide 82–103 five min before NPY reduces the increase in feeding caused by injection of NPY alone. Also, in light microscopic immunohistochemical studies, NPY‐positive varicosities were observed around CART peptide‐positive cell bodies in the paraventricular nucleus of the hypothalamus. These data suggest functional interactions between CART peptides and NPY. These results indicate that CART peptides play a role in the control of food intake by the brain. Synapse 29:293–298, 1998.

Towards a transgenic model of Huntington’s disease in a non-human primate

Non-human primates are valuable for modelling human disorders and for developing therapeutic strategies; however, little work has been reported in establishing transgenic non-human primate models of human diseases. Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder characterized by motor impairment, cognitive deterioration and psychiatric disturbances followed by death within 10–15 years of the onset of the symptoms. HD is caused by the expansion of cytosine-adenine-guanine (CAG, translated into glutamine) trinucleotide repeats in the first exon of the human huntingtin (HTT) gene. Mutant HTT with expanded polyglutamine (polyQ) is widely expressed in the brain and peripheral tissues, but causes selective neurodegeneration that is most prominent in the striatum and cortex of the brain. Although rodent models of HD have been developed, these models do not satisfactorily parallel the brain changes and behavioural features observed in HD patients. Because of the close physiological, neurological and genetic similarities between humans and higher primates, monkeys can serve as very useful models for understanding human physiology and diseases. Here we report our progress in developing a transgenic model of HD in a rhesus macaque that expresses polyglutamine-expanded HTT. Hallmark features of HD, including nuclear inclusions and neuropil aggregates, were observed in the brains of the HD transgenic monkeys. Additionally, the transgenic monkeys showed important clinical features of HD, including dystonia and chorea. A transgenic HD monkey model may open the way to understanding the underlying biology of HD better, and to the development of potential therapies. Moreover, our data suggest that it will be feasible to generate valuable non-human primate models of HD and possibly other human genetic diseases.

Neurons of the subthalamic nucleus in primates display glutamate but not GABA immunoreactivity

Immunohistochemical studies undertaken with a highly specific antiserum raised against gamma-aminobutyric acid (GABA)-glutaraldehyde-lysyl-protein conjugate showed that cell bodies of the subthalamic nucleus in the squirrel monkey (Saimiri sciureus) were closely surrounded by several GABA-positive terminals but were not themselves immunoreactive. In contrast, after incubation with a monoclonal antibody directed against carbodiimide-fixed glutamate, virtually all cell bodies of the subthalamic nucleus displayed an intense immunoreactivity. They were surrounded by various neuronal processes that also stained for glutamate. These results suggest that the neurons of the subthalamic nucleus in primates utilize the excitatory neurotransmitter glutamate instead of the inhibitory neurotransmitter GABA.

Mitochondrial biogenesis in the anticonvulsant mechanism of the ketogenic diet

The full anticonvulsant effect of the ketogenic diet (KD) can require weeks to develop in rats, suggesting that altered gene expression is involved. The KD typically is used in pediatric epilepsies, but is effective also in adolescents and adults. Our goal was to use microarray and complementary technologies in adolescent rats to understand its anticonvulsant effect.

Glutamate-dependent neuroglial calcium signaling differs between young and adult brain

The Adult Astrocyte Is Different The concept of the tripartite synapse, whereby astrocytes actively modulate the communication between the pre- and postsynaptic site, is widely accepted. The release of gliotransmitters has been linked to release of Ca2÷ from intracellular stores via the activation of astrocytic metabotropic glutamate receptor 5 (mGluR5) by glutamate spillover from synapses. However, nearly all studies on the tripartite synapse have used brain tissue collected from young individuals. Many receptors undergo changes in expression level during development. Sun et al. (p. 197; see the Perspective by Grosche and Reichenbach) applied genomic analysis, electron microscopy, and calcium imaging in slices and in vivo to assess the presence and the functionality of mGluR5 and mGluR3 receptors during postnatal development in human and mouse astrocytes. Astrocytic expression of mGluR5 was lost by the third postnatal week in mice and was not present in human cortical astrocytes, which calls into question the viability of the tripartite synapse model for adult synapses. The expression of metabotropic glutamate receptors in brain astrocytes is down-regulated in early postnatal development. [Also see Perspective by Grosche and Reichenbach] An extensive literature shows that astrocytes exhibit metabotropic glutamate receptor 5 (mGluR5)–dependent increases in cytosolic calcium ions (Ca2+) in response to glutamatergic transmission and, in turn, modulate neuronal activity by their Ca2+-dependent release of gliotransmitters. These findings, based on studies of young rodents, have led to the concept of the tripartite synapse, in which astrocytes actively participate in neurotransmission. Using genomic analysis, immunoelectron microscopy, and two-photon microscopy of astrocytic Ca2+ signaling in vivo, we found that astrocytic expression of mGluR5 is developmentally regulated and is undetectable after postnatal week 3. In contrast, mGluR3, whose activation inhibits adenylate cyclase but not calcium signaling, was expressed in astrocytes at all developmental stages. Neuroglial signaling in the adult brain may therefore occur in a manner fundamentally distinct from that exhibited during development.

Projections of cholinergic and non-cholinergic neurons of the brainstem core to relay and associational thalamic nuclei in the cat and macaque monkey

The projections of brainstem core neurons to relay and associational thalamic nuclei were studied in the cat and macaque monkey by combining the retrograde transport of wheat germ agglutinin conjugated with horseradish peroxidase with choline acetyltransferase immunohistochemistry. All major sensory (medial geniculate, lateral geniculate, ventrobasal), motor (ventroanterior, ventrolateral, ventromedial), associational (mediodorsal, pulvinar, lateral posterior) and limbic (anteromedial, anteroventral) thalamic nuclei of the cat were found to receive projections from cholinergic neurons located in the peribrachial area of the pedunculopontine nucleus and in the laterodorsal tegmental nucleus as well as from non-cholinergic neurons in the rostral (perirubral) part of the central tegmental mesencephalic field. Specific relay nuclei receive less than 10% of their brainstem afferents from non-cholinergic neurons located at rostral midbrain levels and receive 85-96% of their brainstem innervation from a region at midbrain-pontine junction where the cholinergic peribrachial area and laterodorsal tegmental nucleus are maximally developed. Of the total number of horseradish peroxidase-positive brainstem neurons seen after injections in various specific relay nuclei, the double-labeled (horseradish peroxidase + choline acetyltransferase) neurons represent approximately 70-85%. Three to eight times more numerous horseradish peroxidase-labeled brainstem cells were found after injections in associational (mediodorsal and pulvinar-lateral posterior complex) and diffusely cortically-projecting (ventromedial) thalamic nuclei of cat than after injections in specific relay nuclei. The striking retrograde cell labeling observed after injections in nuclei with associative functions and widespread cortical projections was due to massive afferentation from non-cholinergic parts of the midbrain and pontine reticular formation, on both ipsi- and contralateral sides. After wheat germ agglutinin-horseradish peroxidase injections in the associative pulvinar-lateral posterior complex and mediodorsal nucleus of Macaca sylvana, 45-50% of horseradish peroxidase-positive brainstem peribrachial neurons were also choline acetyltransferase-positive. While cells in the medial part of the cholinergic peribrachial area were found to project especially towards the pulvinar-lateral posterior nuclear complex in monkey, the retrograde cell labeling seen after the mediodorsal injection was mostly confined to the lateral part of both dorsal and ventral aspects of the peribrachial area.(ABSTRACT TRUNCATED AT 400 WORDS)

The striatopallidal and striatonigral projections: two distinct fiber systems in primate

The use of the fluorescence retrograde double-labeling method has revealed that striatal neurons projecting to the globus pallidus in the squirrel monkey are mainly confined to the putamen whereas those projecting to the substantia nigra occur mostly in the caudate nucleus. Only about 10% of the striatal neurons were found to be double-labeled after injections into the globus pallidus and substantia nigra. The segregation of the putaminofugal and caudatofugal projections was further confirmed by the anterograde tracing of WGA-HRP. These findings do not fit in the current unitary concept of the striatofugal fiber system. Instead, they suggest that the striatopallidal and striatonigral projections exist largely as two distinct subsystems in the primate.

THE SUBTHALAMIC NUCLEUS AND THE EXTERNAL PALLIDUM: TWO TIGHTLY INTERCONNECTED STRUCTURES THAT CONTROL THE OUTPUT OF THE BASAL GANGLIA IN THE MONKEY

The aim of the present study was to elucidate the organization of the interconnections between the subthalamic nucleus and the two segments of the globus pallidus in squirrel monkeys. By making small deposits of tracers in the two segments of the globus pallidus, we demonstrate that interconnected neurons of the subthalamic nucleus and the external pallidum innervate, via axon collaterals, the same population of neurons in the internal pallidum. Furthermore, this organizational principle holds true for different functional regions of the pallidum and the subthalamic nucleus. Injections of biotinylated dextran amine were made in the dorsal (associative), ventrolateral (sensorimotor) and rostromedial (limbic) regions of the internal pallidum. Following these injections, there were rich clusters of labelled terminals in register with retrogradely labelled perikarya in related functional regions of the subthalamic nucleus and the external pallidum. At the electron microscopic level, the majority of labelled terminals in the external pallidum displayed the ultrastructural features of boutons from the subthalamic nucleus and were non-immunoreactive for GABA, whereas those in the subthalamic nucleus resembled terminals from the external pallidum and displayed GABA immunoreactivity. In both cases, the synaptic targets of the labelled terminals included labelled neurons. These observations suggest that the biotinylated dextran amine injected in the internal globus pallidus was transported retrogradely to perikarya in the external pallidum and the subthalamic nucleus and then anterogradely, via axon collaterals, to the subthalamic nucleus and the external pallidum respectively. This suggestion was supported by injections of biotinylated dextran amine or Phaseolus vulgaris-leucoagglutinin in regions of the external pallidum that corresponded to those containing retrogradely labelled cells following injections in the internal pallidum. The clusters of labelled cells and varicosities that resulted from these injections were found in regions of the subthalamic nucleus similar to those labelled following injections in the internal globus pallidus. Furthermore, terminals from the external pallidum and the subthalamic nucleus converged on the same regions in the internal globus pallidus. The results of the present tracing study define the basic network underlying the interconnections between the external segment of the globus pallidus and the subthalamic nucleus, and their connections with the output neurons of the basal ganglia in primates.