Seven problems on the basal ganglia

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Our knowledge on the functions of the basal ganglia has increased enormously during the last two decades. However, we still do not completely understand the primary function of the basal ganglia. In this article, I review fundamental problems on the basal ganglia that have emerged from recent findings, and propose their solutions in the following seven topics: first, organization of the cortico–basal ganglia loop, second, limitations of the ‘direct and indirect pathways model’, third, feedforward inhibition in the striatum, fourth, contribution of the basal ganglia to cortical activity through the thalamus, fifth, focused selection of movements and learning, sixth, firing rate model versus firing pattern model for the pathophysiology of movement disorders, and lastly mechanisms of stereotaxic surgery.

Introduction

Since 1990, our understanding on the basal ganglia has changed substantially. The basal ganglia circuitry was simplified as represented by the direct and indirect pathways, and the pathophysiology of movement disorders was explained by firing rate changes through these two pathways. During the last two decades since then, our knowledge on the functions of the basal ganglia has increased tremendously. However, we still do not have a straight answer to the simple question, ‘What is the primary function of the basal ganglia?’. This article will discuss the current problems on the basal ganglia that have emerged from recent findings. Trying to solve these problems will lead us to better understanding of their functions and better treatment for movement disorders.

Section snippets

Problem 1: how is the cortico–basal ganglia loop organized?

The basal ganglia receive inputs from wide areas of the cerebral cortex. The information processed in the basal ganglia returns primarily to the cerebral cortex, in particular the frontal lobe, via the thalamus, to form a cortico–basal ganglia loop [1, 2]. Additional output from the basal ganglia descends to the brain stem. The cortico–basal ganglia loops are composed of several parallel, segregated, and functionally distinct, but homologous loops (Figure 1) [1, 3]. The motor loop, which

Problem 2: is the ‘direct and indirect pathways model’ still reasonable?

The basal ganglia circuitry is considered to be composed of two major projection systems: the ‘direct’ and ‘indirect’ pathways (Figure 1) [2]. The direct pathway arises from GABAergic striatal neurons containing substance P and dynorphin, and projects monosynaptically to the GPi/SNr. The indirect pathway arises from GABAergic striatal neurons containing enkephalin, and projects polysynaptically to the GPi/SNr by way of sequential connections with the GPe and subthalamic nucleus (STN). In

Problem 3: what kind of computation does the striatum perform?

The striatum, one of the input nuclei of the basal ganglia, is composed primarily of projection neurons (80–95%) as well as a small population of interneurons [34]. The projection neurons are GABAergic medium spiny neurons that receive glutamatergic excitatory inputs from the cortex and thalamus, and dopaminergic inputs from the SNc. They send their axons to the GPe, GPi, and SNr. In addition, they have extensive local axon collaterals that form synapses with other neighboring projection

Problem 4: how do the basal ganglia contribute to the cortical and thalamic activity?

The classical and widely accepted ‘disinhibition theory’ [42] states that inhibitory GABAergic neurons in the output nuclei of the basal ganglia fire spontaneously at high frequency, continuously inhibiting neurons in target structures, such as the thalamus (Figure 2). When striatal neurons are activated by cortical inputs, the striatal neurons inhibit GPi/SNr activity through the striato–GPi/SNr direct pathway. The continuous inhibition from the output nuclei to the target structures is

Focused selection of movements

Disinhibition via the striato–GPi/SNr direct pathway releases a selected motor program. On the other hand, signals through the hyperdirect and indirect pathways have excitatory effects on the GPi/SNr, and therefore, have inhibitory effects on thalamic and cortical neurons (Figure 2) [15, 16••, 56]. Considering the onset timing and conduction velocity of cortical neurons (Figure 1), signals through the hyperdirect pathway first actively inhibit thalamic neurons, then those through the direct

Firing rate model

Malfunctions of the basal ganglia cause movement disorders, such as Parkinson's disease, Huntington's disease, hemiballism, and dystonia, which are characterized by disturbances in the execution of voluntary movements (hyperkinetic–hypokinetic) and in muscle tone (hypertonic–hypotonic). DeLong [64] has proposed that activity imbalance between the direct and indirect pathways changes the mean firing rate of the output nuclei of the basal ganglia and induces hypokinetic or hyperkinetic disorders.

Problem 7: how does stereotaxic surgery work?

Recent developments in stereotaxic surgery have shown that lesions or high frequency stimulation, that is, deep brain stimulation (DBS), in the basal ganglia, ameliorates the motor disabilities of movement disorders. Nuclei that fire abnormally, such as with abnormally high or low frequency discharges or abnormal oscillatory firings, are the targets for surgery. Both small lesions and high frequency stimulation show similar clinical results. In Parkinson's disease, the GPi and STN exhibit

Conclusions

This article has discussed current problems regarding the basal ganglia. To solve these problems, we should focus on the information flow through the basal ganglia rather than the information representation. The following experiments will be important.

  • (1)

    Neuronal activity should be recorded from behaving animals, especially from monkeys. In addition to well-established chronic experiments, we should combine electrical stimulation and/or local drug injection into the vicinity of recording neurons

References and recommended reading

Papers of particular interest, published within two years, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgments

Our work was supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and the Uehara Memorial Foundation.

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