Basal Ganglia Circuits: What's Now and Next?

The current model of the basal ganglia was introduced two decades ago and has become the basis for most of our current understanding of basal ganglia function and dysfunction. Extensive research efforts have been carried out in recent years leading to unprecedented levels of understanding of the main operational principles underlying the pathophysiology of the basal ganglia. Although somewhat obsolete, the “classical ” basal ganglia model developed in the mid 1980s by the “founding fathers ” (Penney and Young, 1986; Crossman, 1987; Albin et al., 1989; DeLong, 1990) still maintains a remarkable appeal. This model was shaped mainly by the preponderance of anatomical and physiological data available at the time. In the past few years, the development of a whole range of new technical breakthroughs has boosted the availability of data with paramount importance at a breath-taking speed, and thus incorporating these recent advances to further enrich the classical model has becom

Past, Present, and Future of the Pathophysiological Model of the Basal Ganglia

The current model of basal ganglia (BG) was introduced two decades ago and has settled most of our current understanding of BG function and dysfunction. Extensive research efforts have been carried out in recent years leading to further refinement and understanding of the normal and diseased BG. Several questions, however, are yet to be resolved. This short review provides a synopsis of the evolution of thought regarding the pathophysiological model of the BG and summarizes the main recent findings and additions to this field of research. We have also tried to identify major challenges that need to be addressed and resolved in the near future. Detailed accounts and state-of-the-art developments concerning research on the BG are provided in the articles that make up this Special Issue

Notes on the combined use of V-VIP and DAB peroxidase substrates for the detection of colocalising antigens

The purpose of the present report was to investigate to what extent the new peroxidase substrate Vector VIP (V-VIP) can be used in combination with DAB chromogen for the unequivocal and permanent detection of colocalising antigens within a single neurone, according to a two-colour paradigm. With this aim, retrograde tract-tracing with cholera toxin B subunit (CTB) or fluoro-gold (FG) was performed to disclose individual, identified subpopulations of neurones in the primate substantia nigra projecting to the caudate nucleus or to the putamen, respectively. Each tracer was detected by means of a PAP procedure and finally stained brown using DAB as a chromogen. Subsequently, both series of sections were processed for the immunocytochemical detection of tyrosine hydroxylase (TH). TH-immunoreactive neurones were stained purple with the peroxidase substrate V-VIP. As a result of the present procedure, several cell bodies of projection neurones, stained brown, can easily be identified within the primate substantia nigra. Some of these neurones additionally displayed purple TH immunoreaction product located in the neuronal dendrites. By contrast, CTB- or FG-unlabelled neurones only show the typical purple precipitate that belongs to V-VIP substrate, both in the cell body as well as in the dendrites

On the relationships between the caudal intralaminar nuclei of the thalamus and the basal ganglia : implications for the pathophysiology of Parkinson’s disease

Besides corticostriatal projections, the thalamic intralaminar nuclei are a major source of glutamatergic afferents reaching the basal ganglia input nuclei. Although the thalamostriatal system is already well characterized from the anatomical point of view, the role to be played by this pathway within basal ganglia function (both in normal and pathological conditions) remains poorly understood. On one hand, neurode- generation phenomena restricted to the caudal intralaminar nuclei have been described in several neurodegenerative disorders such as Parkinson’s disease, progressive supranuclear palsy and Huntington’s disease. On the other hand, after unilateral dopaminergic depletion in rodents the caudal intralaminar nuclei are highly hyperactive. Indeed, the chemical ablation of the caudal intralaminar nuclei prevents the increase of the activity observed in both the basal ganglia output nuclei and the subthalamic nucleus (STN) after unilateral dopaminergic depletion. These findings suggest that the caudal intralaminar nuclei might be responsible (at least partially) for the changes in activity of the STN and basal ganglia output nuclei typically seen under circumstances of dopamine removal. These results paved the way for the implementation of pioneer clinical experiences focused on targeting the caudal intralaminar nuclei with a deep brain stimulation electrode in patients suffering from advanced Parkinson’s disease. This approach resulted in the alleviation of cardinal symptoms of the disease such as resting tremor, druginduced dyskinesias and chronic pain.peer-reviewe

Divergent and point-to-point connections in the commissural pathway between the inferior colliculi

The commissure of the inferior colliculus interconnects the left and right sides of the auditory midbrain and provides the final opportunity for interaction between the two sides of the auditory pathway at the subcortical level. Although the functional properties of the commissure are beginning to be revealed, the topographical organization of its connections is unknown. A combination of neuroanatomical tracing studies, 3D reconstruction, and neuronal density maps was used to study the commissural connections in rat. The results demonstrate that commissural neurons in the central nucleus of the inferior colliculus send a divergent projection to the equivalent frequency-band laminae in the central nucleus and dorsal and lateral cortices on the opposite side. The density of this projection, however, is weighted toward a point that matches the position of the tracer injection; consistent with a point-to-point emphasis in the wiring pattern. In the dorsal cortex of the inferior colliculus there may be two populations of neurons that project across the commissure, one projecting exclusively to the frequency-band laminae in the central nucleus and the other projecting diffusely to the dorsal cortex. Neurons in the lateral cortex of the inferior colliculus make only a very weak contribution to the commissural pathway. The point-to-point pattern of connections permits interactions between specific regions of corresponding frequency-band laminae, whereas the divergent projection pattern could subserve integration across the lamina. J. Comp. Neurol. 514:226–239, 2009. © 2009 Wiley-Liss, Inc

Glucocerebrosidase mutations and synucleinopathies. Potential role of sterylglucosides and relevance of studying both GBA1 and GBA2 genes.

Gaucher's disease (GD) is the most prevalent lysosomal storage disorder. GD is caused by homozygous mutations of the GBA1 gene, which codes for beta-glucocerebrosidase (GCase). Although GD primarily affects peripheral tissues, the presence of neurological symptoms has been reported in several GD subtypes. GBA1 mutations have recently deserved increased attention upon the demonstration that both homo- and heterozygous GBA1 mutations represent the most important genetic risk factor for the appearance of synucleinopathies like Parkinson's disease (PD) and dementia with Lewy bodies (LBD). Although reduced GCase activity leads to alpha-synuclein aggregation, the mechanisms sustaining a role for GCase in alpha-synuclein homeostasis still remain largely unknown. Furthermore, the role to be played by impairment in the physiological function of endoplasmic reticulum, mitochondria and other subcellular membranous components is currently under investigation. Here we focus on the impact of GCase loss-of-function that impact on the levels of sterylglucosides, molecules that are known to trigger a PD-related synucleinopathy upon administration in rats. Moreover, the concurrence of another gene also coding for an enzyme with GCase activity (GBA2 gene) should also be taken into consideration, bearing in mind that in addition to a hydrolytic function, both GCases also share transglycosylation as a second catalytic activity. Accordingly, sterylglycoside levels should also be considered to further assess their impact on the neurodegenerative process. In this regard¿and besides GBA1 genotyping¿we suggest that screening for GBA2 mutations should be considered, together with analytical measurements of cholesterol glycosides in body fluids, as biomarkers for both PD risk and disease progression

Relationships between thalamostriatal neurons and pedunculopontine projections to the thalamus: a neuroanatomical tract-tracing study in the rat

The present study aimed to investigate whether the pedunculopontine projection to the thalamus overlaps with identified thalamostriatal neurons. These projections were studied using a dual tract-tracing procedure combining anterogradely transported biotinylated dextran amine (pedunculopontine projections) and retrogradely transported Fluoro-Gold (thalamostriatal projections). Overlapping thalamic territories between thalamostriatal neurons and the axon terminals arising from the pedunculopontine tegmental nucleus were observed in the midline (paraventricular) and in the intralaminar (centrolateral, central medial, paracentral and parafascicular) thalamic nuclei. Other thalamic nuclei, such as the ethmoid, intermediodorsal, mediodorsal, paratenial, posteromedian, ventromedian, ventrolateral and rhomboid thalamic nuclei, displayed a lesser degree of overlap. These observations suggest the existence of presumptive contacts between thalamostriatal neurons and axons emerging from the pedunculopontine tegmental nucleus, therefore supporting the possible existence of feedback circuits in the rat basal ganglia in which the tegmento-thalamic projection would play a major role

Re-examination of the thalamostriatal projections in the rat with retrograde tracers

Topographical arrangements of thalamostriatal projection neurons was examined in the rat by the retrograde tract-tracing method. After injecting Fluoro-Gold (FG) and/or cholera toxin beta-subunit (CTB) in different regions of the caudate-putamen (CPu), distribution of retrogradely labeled neurons was observed in the thalamus. The main findings were as follows: (1) Retrogradely labeled neurons were seen in the midline-intralaminar thalamic nuclei in all rats examined in the present study. Neurons in the ventral lateral and posterior thalamic nuclear groups were also labeled in the rats which were injected with the tracer into the dorsal part of Cpu, but not in the rats which were injected with the tracer into the nucleus accumbens (Acb) and its adjavent regions in the ventromedial part of the Cpu. (2) Topographical organization was observed in the projections from the midline-intralaminar thalamic nuclei to the CPu. After the tracer injection into the dorsal part of the CPu or the ventral part of the CPu (including the Acb), labeled neurons in the midline-intralaminar thalamic nuclei were distributed predominantly in the lateral part of the intralaminar nuclei or the midline nuclei, respectively. On the other hand, after the tracer injection into the medial or the lateral part of the CPu, labeled neurons in the midline-intralaminar nuclei were distributed mainly in the dorsal or the ventral part of these nuclei, respectively. (3) Topographical organization was also observed in the thalamostriatal projections from the ventral and Pos. After the tracer injection into the rostral part of the CPu, labeled neurons were distributed mainly in the rostral part of the ventral nuclear group. On the other hand, after the tracer injection into the caudal part of the CPu, labeled neurons were distributed mainly in the caudal part of the ventral nuclear group, as well as in the posterior nuclear group