Neuroscience/Objectives/Lectures 44-45

From PhysioWiki

Contents 1 Basal ganglia and diseases of the basal ganglia 1.1 Define and identify the nuclei composing the basal ganglia. 1.2 Describe the anatomical organization of the basal ganglia. 1.2.1 Afferents to the striatum 1.2.2 Connection within basal ganglia nuclei 1.2.3 Efferents from the striatum 1.3 Illustrate the somatotopic and topographic organization of the basal ganglia and their projections. 1.4 Define the functional role of the direct and indirect pathways. 1.5 List the major cell types and neurotransmitters of the basal ganglia. 1.6 Discuss the major diseases associated with basal ganglia dysfunction. 1.7 Describe the common forms of hyperkinesia. 1.8 Discuss MPTP as a tool to cause experimental Parkinson's syndrome. 1.9 Outline and discuss the basis of Parkinson's therapy.

Basal ganglia and diseases of the basal ganglia

Define and identify the nuclei composing the basal ganglia.

Striatum

Also called the neostriatum, the striatum is composed of the caudate and putamen, which are derived from the same embryonic telencephalic structure. The caudate and putamen are continuous rostrally and ventrally. The ventral striatum includes the nucleus accumbens.

Globus pallidus

Also called the paleostriatum, the globus pallidus (or pallidum) is medial to the putamen and lateral to the internal capsule. It comprises two segments, internal and external, which together with the putamen form the lentiform nucleus.

Substantia nigra

The substantia nigra is composed of a ventral pars reticulata and a dorsal pars compacta. The pars reticulata and medial pallidum are the main outputs of the basal ganglia.

Subthalamic nucleus

The subthalamic nucleus is connected directly to the globus pallidus and substantia nigra. It lies below the thalamus where it joins the midbrain between the substantia nigra and zona incerta.

Describe the anatomical organization of the basal ganglia.

The basal ganglia are subcortical structures with a high degree of connectivity to one another. Most input to the basal ganglia is cortical, although the basal ganglia receive no direct input from sensory ganglia or motor structures.

Output from the basal ganglia is principally from the medial pallidum (GPi) and substantia nigra pars reticulata (SNr). These structures project to the thalamus (principally the ventrolateral [VL] and ventroanterior [VA] nuclei) and selected brainstem structures (chiefly the superior colliculi and reticular formation).

Afferents to the striatum

Corticostriate fibers

All cortical structures except parts of the auditory and visual cortices send glutamatergic fibers to the striatum. These corticostriate fibers synapse on striatal interneurons containing numerous neurotransmitters (e.g. GABA, acetylcholine, enkephalin, and substance P).

Nigrostriatal fibers

The substantia nigra pars compacta (SNc) sends dopaminergic (and possibly cholecystokininergic) fibers to the striatum, where they synapse on cholinergic interneurons and glutamatergic terminals (the latter originating from the cortex). Serotonin from the caudal midbrain raphe and norepinephrine from the locus coeruleus influence nigrostriatal dopamine neurons.

Thalamostriate fibers

The centromedian nucleus of the thalamus (and others) send glutamatergic fibers to the striatum.

Connection within basal ganglia nuclei

Striopallidal fibers

The striatum project to both the medial and lateral pallidum (GPi and GPe, respectively). These fibers contain GABA, enkephalin, substance P, and other neuropeptides.

Strionigral fibers

The bulk of striatal efferents reach the SNr via GABAergic strionigral fibers. The head of the caudate projects to the rostral SNr, while the putamen terminates in the caudal SNr.

Pallidosubthalamic fibers

The GPe sends GABAergic projections to the subthalamic nucleus (STN), which projects glutamatergic subthalamopallidal fibers back to the GPi and GPe. The STN also receives inputs from the substantia nigra and motor cortex, projecting back to the SNr.

Pallidonigral fibers

The GPe also projects to the SNr.

Efferents from the striatum

The net output from the basal ganglia is inhibitory.

Pallidothalamic fibers

The pallidum projects to the VA, VL, and centromedian nuclei of the thalamus. The dorsal GPi gives rise to the lenticular fasciculus, which passes medially through the posterior limb of the internal capsule and through the subthalamus between the subthalamic nucleus and zona incerta. The ansa lenticularis originates in the ventral GPi and loops anterior to the internal capsule. The ansa lenticularis and lenticular fasciculus join as the thalamic fasciculus, traviling chiefly to the VA nucleus of the thalamus, but also to the VL nucleus. From the VA, fibers travel to the premotor and supplementary motor cortices. From the VL nucleus, fibers travel to the primary motor cortex (BA 4). The GPi also projects to the centromedian nucleus of the thalamus.

Nigrothalamic, nigrotectal, and nigrotegmental fibers

Like the GPi, the SNr projects mainly to the VA and VL nuclei of the thalamus via nigrothalamic fibers. The SNr also projects to the superior colliculi via nigrotectal fibers, and to the midbrain tegmentum (including the reticular formation) via nigrotegmental fibers. Nigrothalamic, -tectal, and -tegmental fibers are all GABAergic.

Illustrate the somatotopic and topographic organization of the basal ganglia and their projections.

Cortical area	Target
Frontal association cortex	Head of caudate
Somatosensory cortex	Body of caudate
Occipital/temporal	Tail of caudate
Precentral motor cortex	Putamen

Sensory and motor cortices project to the striatum somatotopically as well. The upper body is mapped onto the lateral aspect of the striatum, while the lower body is represented medially.

Define the functional role of the direct and indirect pathways.

The direct and indirect pathways connect the striatum to the GPi and SNr. Stimulation of the direct pathway inhibits GPi/SNr activity, while stimulation of the indirect pathway increases GPi/SNr activity.

Differential expression of dopamine receptors in the striatum allows nigrostriatal fibers to have differential effects on the direct and indirect pathways. In particular, the SNc stimulates the direct pathway, leading to inhibition of the GPi/SNr. The SNc inhibits the indirect pathway, resulting in the enhancement of GPi/SNr activity. Thus SNc lesions, such as those seen in Parkinson's disease, depress the direct pathway and enhance the indirect pathway, resulting in greater GPi/SNr activity. Elevating the GABAergic output of the GPi and SNr results in akinesia and bradykinesia, among other symptoms of Parkinson's disease.

List the major cell types and neurotransmitters of the basal ganglia.

Nucleus	Neurotransmitter
Cortex (SMA, PMC, MC)	Glutamate
Striatum	Direct pathway → GPi (GABA, substance P) Indirect pathway → GPe (GABA, enkephalins)
GPe	GABA
GPi/SNr	GABA
STN	Glutamate
VL/VA/CM	Glutamate

Discuss the major diseases associated with basal ganglia dysfunction.

Parkinson's syndrome

Insufficient dopamine input to the striatum (e.g. due to a lesion of the SNc) is associated with akinesia, bradykinesia, resting tremor, cogwheel rigidity, and impaired postural reflexes, the constellation of signs seen in Parkinson's syndrome. Impaired nigrostriatal activity results in diminished excitation of the direct pathway and enhanced stimulation of the indirect pathway. Together, these enhance the activity of the GPi and SNr, which inhibit thalamic activity, ultimately depressing the activation of upper motor neurons in the PMC, SMA, and MC. Rigidity results from enhanced alpha motor neuron activity. Their activity is elevated because much of their inhibition—which primarily comes from upper motor neurons—is removed in Parkinson's patients.

Huntington's chorea

Huntington's disease is ssociated with hyperkinesia, hypotonia, dementia, chorea, and dyskinesia. It results from lesions of the striopallidal fibers of the indirect pathway joining the striatum to the GPe. As a result, the activity of the indirect pathway decreases, causing the direct pathway to have a relatively greater inhibitory effect on the GPi/SNr. As a result, the inhibitory activity of the GPi/SNr is reduced, allowing the VA/VL/CM thalamus to become more active.

Ballismus

A form of hyperkinesia, ballismus is characterized by severe involuntary movements often involving the proximal limbs, which fly about in all directions (ballistic pr missile-like motions). Ballismus often results from lesions to the subthalamic nucleus, which sends glutamatergic projections to the GPi/SNr. Impaired subthalamic activity results in decreased activity of the GPi and SNr, decreasing the inhibitory output of the basal ganglia. The net result is that the thalamus receive less inhibition, prompting it to over-excite the motor cortex, leading to hyperkinesia (or hypertonia?). Because ballismus typically affects only the muscles contralateral to the subthalamic lesion, the condition only involves one half of the body and is therefore called hemiballismus.

Describe the common forms of hyperkinesia.

Discuss MPTP as a tool to cause experimental Parkinson's syndrome.

1-Methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) is a neurotoxin that is shuttled into glia, oxidized to MPP⁺, and transported via the dopamine transporter (DAT) into neurons of the substantia nigra. There, MPP⁺ enters nigral mitochondria, where it causes oxidative damage to cells resulting in the death of dopaminergic cells, therefore causing Parkinson's syndrome.

Outline and discuss the basis of Parkinson's therapy.

Treatments for Parkinson's disease focus on enhancing dopaminergic activity in the basal ganglia.

L-Dopa

A precursor in the dopamine biosynthetic pathway, L-dopa is commonly used in treating Parkinson's. Unlike exogenous dopamine, L-dopa can cross the blood-brain barrier where it is converted into dopamine. L-Tyrosine, the amino acid precursor to dopamine, would be a logical treatment for Parkinson's as well, except that tyrosine reduces the activity of tyrosine hydroxylase, the first enzyme in the biosynthesis of dopamine.

Dopaminergic agonists

DAergic agonists such as bromocriptine and apomorphine are also viable treatments for Parkinson's since they mimic the activity of endogenous dopamine.

Anticholinergic agents

The imbalance between indirect and direct pathways can be partly corrected by treating patients with anticholinergic agents.

Transplant

Transplanting dopamine- or neurotrophic factor-producing cells into patients may be a viable treatment for Parkinson's, but few cases are available.

Deep brain stimulation

High-frequency deep brain stimulation (HF-DBS) of the subthalamic nucleus, which is overactive in Parkinson's disease, ameliorates some of the symptoms in many Parkinson's patients. The mechanisms by which HF-DBS helps patients regain normal motor function are not completely understood. Presumably, HF-DBS works by decreasing the activity of the subthalamic nucleus, thereby decreasing the inhibitory output of the GPi and SNr.