This section reviews the basic anatomical interconnections between neurons that make up the basal ganglia-thalamic-cortical circuits. The anatomy is discussed only to a level of detail necessary for conceptual understanding of current models of function and dysfunction and for possible futures theories. This section will neither cover a fine-grained analysis of interconnections nor the histology [for reviews see Refs. (8-12)].
Traditional approaches to the anatomy of the basal ganglia have been divided into input, output, and intermediary stages. This approach belies the key fundamental assumptions of current theories, because demarcation of input and output structures necessarily suggests a sequential and hierarchical organization (13), which are misleading from a physiological perspective (7). Rather, the anatomy can be reconsidered and viewed as a re-entrant circuit or closed loop. Just as it is hard to say where a circle starts and an arbitrary starting point must be selected, this description will begin with the striatum that is made up of the caudate nucleus and the putamen.
The major sources of input to the striatum are glutaminergic projections from the cerebral cortex and thalamus. Virtually, the entire cortex projects to the striatum in a topographic fashion. The frontal cortex projects to the head of the caudate and anterior putamen, the motor and somatosensory cortices project to the postcommissural putamen, and the temporal cortex projects to the tail of the caudate. The cortex also projects directly to the STN. Inputs from the thalamus include projections from the centromedian, parafascicular, and VL thalamus. The substantia nigra pars compacta (SNpc) sends dopaminergic projections to the striatum.
The striatum projects to the globus pallidus external segment (GPe), Gpi, and substantia nigra pars reticulata (SNr). There appears to be two separate groups of striatal neurons based on projection targets and neurotransmitters. All outputs from the striatum utilize gamma amino butyric acid (GABA) but differ in the polypeptide cotransmitter. Striatal neurons projecting to the GPe express enkephalin and have predominantly D2 receptors. Whereas striatal neurons projecting to GPi express substance P and dynorphin and have predominantly Dt receptors (14).
The GPe has inhibitory GABAergic projections to the STN and GPi. The STN has excitatory glutamatergic projections to the GPi and SNr and back to GPe. The GPi has GABAergic outputs to the VL and ventroanterior (VA) nuclei of the thalamus, which then have extensive glutaminergic projections back to the cerebral cortex. In addition, the GPi projects to the pedunculopontine nucleus (PPN) in the brainstem. The PPN has received considerable attention, particularly as it relates to gait and balance. Injections of bicucullin, a GABA antagonist, into the PPN alleviates symptoms of experimental parkinsonism induced by administration of n-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) in nonhuman primates (15). There are case reports suggesting that DBS of the PPN may be helpful in PD, particularly for gait and postural abnormalities (16). The SNr has GABAergic projections to the superior colliculi and are thought to be involved in eye movements.
The basic architecture is replicated for a number of different functional systems. For example, a network involving projections from the limbic cortex through the basal ganglia and back to the limbic cortex may serve emotional functions. Networks involving the orbital frontal cortex and the basal ganglia may involve cognitive functions. These different networks may be important for nonmotor symptoms of PD. As the motor symptoms increasingly are improved with current therapies, attention is shifting to the nonmotor symptoms.
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