Neural Science Lecture 28: Basal Ganglia

Prof. Eidelberg
4.23.03
Transcribed by: Jen Lin (jhl2025@columbia.edu)
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Introduction to the Basal Ganglia

The basal ganglia play a major role in normal voluntary movement (specifically,
“rule-dependent behavior” and “timing”). Unlike most other components of the motor
system, however, they do not have a direct input or output connection with the spinal
cord. The four nuclei of the basal ganglia (striatum, globus pallidus, substantia nigra,
subthalamic nucleus) participate in movement by receiving their primary input from the
cerebral cortex and sending their output to the brainstem and back to the prefrontal,
premotor, and motor cortex (via the ventrolateral thalamus). The motor functions of the
basal ganglia are therefore mediated mostly by motor areas of the frontal cortex. Thus,
the basal ganglia are the principal subcortical components of circuits linking the cortex
and the thalamus.
Parkinson’s disease and Huntington’s disease are both diseases of the basal
ganglia and cause diminished movements (PD) or excessive movements (HD). In
additions to these disorders of movements, damage to the basal ganglia is associated with
complex cognitive and behavioral disturbances, reflecting the wider role of these nuclei
in the diverse functions of the frontal lobe.

Abbreviations:
-GPi = globus pallidus (internal segment) -SNr = substantia nigra (pars reticulata)
-GPe= globus pallidus (external segment) -STN = subthalamic nucleus
-SNc = substantia nigra (pars compacta) -DA = dopamine

Anatomy
The four principal nuclei of the basal ganglia:
General nuclei scheme: The principal input nucleus (striatum) of the basal ganglia
receives input from the cortex, thalamus, and brainstem (and its own regulatory
pathways, i.e. through the substantia nigra pars compacta). The striatum then projects to
the output nuclei of the basal ganglia (internal globus pallidus and substantia nigra pars
reticulata) either directly or indirectly (via intrinsic nuclei- external globus pallidus and
the subthalamic nucleus). The output nuclei then primarily project to thalamic nuclei
(ventrolateral part) which, in turn, projects to different areas of the frontal lobe of the
cortex.

1. Striatum (caudate nucleus, putamen, ventral striatum)

-is the major recipient of input to BG from cortex, thalamus, and brainstem
-caudate: regulates cognitive features
-putamen: regulates locomotion/limb movement
-its neurons project to the Globus Pallidus and Substantia Nigra (output nuclei)
-striatum neurons use GABA as their neurotransmitter.
2. Globus Pallidus (internal and external segments)
-GPi: is a major output nuclei of basal ganglia (inhibitory)

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 -sends projections to thalamus (which in turn, projects to cortex) and
pedunculopontine nucleus (PPN- not that important)
-is a part of the Direct and Indirect Pathways
-functionally related to Substantia Nigra pars reticulata.
-GPi neurons use GABA as neurotransmitter.
-GPe: involved in Indirect Pathway
-sends projections to Subthalamic Nucleus.
-uses GABA.
3. Substantia Nigra (pars reticulata and pars compacta)
-SNr: is a major output nuclei of BG (inhibitory)
-related to GPi
-uses GABA.
-SNc: projects to striatum to regulate BG.
-uses Dopamine
-Parkinson’s Disease affects dopaminergic projections from SN to the
Striatum
4. Subthalamic Nucleus (STN)
-the only excitatory projections of the BG
-part of the Indirect pathway
-receives from GPe, projects to GPi/SNr
-uses Glutamine

Pathways within the Basal Ganglia

(Key figures: PNS Fig 43-3, pg. 856 and Martin Fig 11-4 & Box 11-1, pgs. 330-332)
The striatum projects to the output nuclei via direct and indirect pathways:
The 2 output nuclei of the basal ganglia—the internal Globus Pallidus (GPi) and
Substantia Nigra pars reticulata (SNr)—tonically inhibit their target nuclei in the
ventrolateral thalamus and brainstem. This inhibitory output is modulated by 2 parallel
pathways (direct and indirect pathways) that run from the striatum to the output nuclei.
Overall, activation of the direct pathway excites the thalamus/cortex; the indirect
pathway inhibits the thalamus/cortex.
The two striatal pathways (direct/indirect) are affected differently by the
dopaminergic projection from the Substantia Nigra pars compacta (SNc) to the striatum.
In the striatum region of the direct pathway, striatal neurons have D1 dopamine
receptors that facilitate neuron transmission of the direct pathway (which facilitates
movement); in the indirect pathways, striatal neurons have D2 dopamine receptors
that reduce neuron transmission of the indirect pathway (which normally inhibits
movement, so reducing transmission in this pathway would allow for facilitation of
movement).
THEREFORE: Although their synaptic actions are different, the dopaminergic
inputs to the 2 pathways lead to the same effect—reducing inhibition of the
thalamocortical neurons and thus facilitating movements initiated in the cortex (by
facilitating the direct pathway and inhibiting the indirect pathway). Disease is due to an
imbalance of these pathways.

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1. Direct Pathway: decreases inhibition of thalamus (excites thalamus) = increases
movement
1. SNc sends its dopaminergic projection to the D1 dopamine receptors of the
striatum (putamen).
2. Putamen neurons (inhibitory) project to the internal Globus Pallidus and SNr.
3. GPi neurons (inhibitory) and SNr project out to the thalamus.

The circuit contains 2 inhibitory projection neurons originating in the Putamen

and GPi (both GABA-ergic). Thus, cortical excitation of the putamen inhibits the GPi.
However, the output of the GPi is also inhibitory. So inhibition from the putamen
decreases the inhibition of the thalamus from the GPi = excites thalamus and cortex.

2. Indirect Pathway: increases inhibition of thalamus (inhibits thalamus) = decreases

movement
This path has the opposite effect on the thalamus/cortex as the direct path. The
key to understanding the indirect path is that the Subthalamic Nucleus (STN) is
excitatory (the only excitatory connection of the basal ganglia).

1. SNc sends its dopaminergic projection to the D2 dopamine receptors of the

striatum (putamen).
2. Putamen neurons (inhibitory) project to the external Globus Pallidus.
3. GPe neurons (inhibitory) project to the Subthalamic Nucleus.
4. Disinhibited STN neurons (excitatory) project to GPi and SNr
5. GPi and SNr (inhibitory) project out to thalamus.

The circuit contains inhibitory neurons and excitatory neurons. The Putamen and
GPe projection neurons (inhibitory) are GABA-ergic. The STN projection neurons
(excitatory) are glutaminergic.
Because the GPe projects to the STN, the putamen disinhibits the STN. This
disinhibition will increase the output of the STN (excitatory) to the GPi and SNr (both
inhibitory), and thereby increase the inhibition of the thalamus from the GPi =
inhibits thalamus and cortex.

Note (not that important): Another output of the GPi (besides its main projection
to the thalamus) briefly mentioned in lecture is a projection to the PPN
(pedunculopontine nucleus), which modifies the cerebellum to regulate gait and balance.

Basal Ganglia’s role in Thalamus-Cortex circuits

The basal ganglia may be viewed as the principal subcortical components of a
family of circuits linking the thalamus and cerebral cortex (i.e. CSTPC motor loop).
These circuits are largely segregated, both structurally and functionally (“closed
loops”). Only in diseased conditions is there “cross-talk” between loops. Each circuit
originates in a specific area of the cerebral cortex and engages different portions of the
BG and thalamus. The thalamic output of each circuit is directed back to the portions of
the frontal lobe from which the circuit originates.

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 Through their interaction with the cerebral cortex, the basal ganglia also
contribute to a variety of behaviors other than voluntary movement, including
skeletomotor, oculomotor, cognitive, and even emotional functions. This occurs through
various circuit loops between the BG, thalamus and cortex:
1. Skeletomotor circuit: [*key loop; somatotopic organization]
-begins and ends in the pre-central motor fields (premotor cortex, motor
cortex, and supplementary motor area)
-the skeletomotor circuit engages specific portions of the cortex, BG, and
thalamus: the putamen receives topographic projections from the cortex,
and projects topographically to GPi/SNr; in turn, these nuclei send
topographic projections to specific thalamic nuclei. The skeletomotor
circuit is then closed by projections from the thalamus to the
supplementary motor area.
2. Oculomotor circuit
-begins and ends in the frontal and supplementary eye fields
3. Prefrontal circuit
-dorsolateral prefrontal cortex: originates in Brodmann’s areas 9,10
-lateral orbitofrontal cortex: originates in lateral prefrontal cortex
4. Limbic circuit
-cingulate area (not well understood)

Physiology
Single cell recording studies suggest serial processing, focusing, and directionally-
selective activity in movement.

Serial processing:
The onset of rapid, stimulus-triggered limb movements is proceeded first by
changes in neuronal firing in motor cortex, and then later in basal ganglia.

Focusing of voluntary movement:

Little is known about how movement-related signals from the direct and indirect
pathways are integrated in the GPi to control basal ganglia output. The direct and
indirect inputs associated with a particular movement could be directed to separate sets of
neurons in the output nuclei of the basal ganglia. The skeletomotor circuit could play a
dual role in focusing the neural activity associated with a desired movement (via direct
pathway) and suppressing conflicting firing patterns associated with unwanted
movements (indirect pathway). This focusing of neural activity that mediates each
voluntary movement is similar to the inhibitory surround described for various sensory
systems.

Directionally-selective neurons:
At all stages of the motor circuit, the activity of substantial proportions of
movement-related neurons depends upon the direction of limb movement (independent of
the pattern of muscle activity). Directionally-selective activity before movement also
occurs within the Putamen and GPi. Individual neurons tend to exhibit either set-related

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or phasic movement-related responses, suggesting that the preparation and execution of
motor action are mediated by separate subchannels in the skeletomotor circuit.
In the GPi, neurons that receive input from the supplementary motor area (via
striatum) show set-related activity; GPi neurons that receive input from the primary
motor cortex (via striatum) show phasic movement-related activity.

Movement Disorders (Key fig: PNS fig 43-6, pg. 860)

Hypokinetic disorders (i.e. Parkinson’s disease) are characterized by impaired
initiation of movement (akinesia) and by slowed voluntary movement (bradykinesia).
They are usually accompanied by muscular rigidity and tremor.
Hyperkinetic disorders (i.e. Huntington’s disease and hemiballism) are
characterized by excessive motor activity, decreased muscle tone (hypotonia), and
involuntary movements (dyskinesia). Types of dyskinesia include: slow writhing
movements of extremities (athetosis); jerky, random movements of limbs/orofacial
structures (chorea); violent, large limb movements (ballism).

As stated before, the dopaminergic inputs to the two pathways lead to the same
effect—disinhibition of the thalamocortical neurons and thus facilitating movements
initiated in the cortex. The two pathways are always occurring simultaneously; it is only
when there is an imbalance between them that a disease will occur. Basically,
overactivity in the indirect pathway results in hypokinetic disorders; underactivity
in the indirect pathway results in hyperkinetic disorders.

HYPOKINETIC DISORDERS:
• Parkinson’s Disease
This disease is characterized by the degeneration of dopaminergic neurons in the
Substantia Nigra pars compacta. Without the dopamine projection to the striatum,
activity in the output nuclei increase (via diminished excitatory effects of the direct path
on cortical motor areas and enhanced inhibitory effects of the indirect path), thereby
increasing inhibition on the thalamocortical neurons that otherwise facilitate initiation of
movement. Parkinson’s signs are caused by overactivity in the indirect pathway.

Results of PD Studies
-Treatment:
Intravenous administration of L-DOPA causes dramatic but transient
reversal of symptoms. However, the benefits of drug therapy usually begin to
wane after about five years; troublesome side effects include motor response
fluctuations and drug-related dyskinesias.
-PD Pathophysiology:
MPTP (drug) studies provided a working model of the pathophys. of PD:
Loss of dopamine input from SNc to striatum leads to increased activity in
the indirect pathway and decreased activity in the direct pathway because of
the different actions of dopamine on the 2 pathways (via D1 and D2 receptors
respectively). Both changes lead to increased activity in the GPi, which results in
increased inhibition of movement.

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 Single cell recordings: PD patients show increased activity in STN and
GPi. Lesions of STN or GPi will ameliorate symptoms of PD.
PET findings: PD shows progressive loss of nigro-striatal dopamine
function; abnormal expression of metabolic brain networks in PD can be reversed
by treatment.

HYPERKINETIC DISORDERS:
• Hemiballism
The symptoms of this disease (violent involuntary throwing movements of the
limb from a lesion in the contralateral STN) occur because the output of the GPi is
reduced. Reduced inhibitory output to the ventrolateral thalamus may lead to excessive
thalamocortical activity. Hemiballism signs are caused by underactivity in the indirect
pathway.

• Huntington’s Disease
HD is an autosomal dominant hyperkinetic disorder characterized by chorea,
dementia, and behavioral disturbance. Early death of striatal spiny neurons (specifically,
in the caudate nucleus) that give rise to the indirect pathway cause functional
inactivation of the STN. (How: the striatal inhibition of the GPe is reduced, causing
excessive discharge of these neurons and inhibition of the STN). Inactivation of the STN
= reduced inhibitory output of GPi = excessive thalamocortical activity. Huntington’s
signs are caused by underactivity in the indirect pathway.

Results of HD Studies
-HD genetics:
The disease is a highly penetrant, autosomal dominant disorder w/a gene
defect on chromosome 4 (encodes a cytoplasmic protein called Huntingtin). The
first exon of the gene contains CAG repeats which encode glutamine. Whereas
normal subjects have less than 40 repeats, HD patients have more than 40. Once
expanded beyond 40, the repeats become unstable and tend to increase from
generation to generation, a phenomenon which accounts for “genetic
anticipation”: the earlier onset of the disease in the offspring than in the parent.
-HD Pathophysiology:
Rat studies: show that the HD pattern of cell loss closely resembles the
cell death caused by glutamate exitotoxicity (i.e. after acute brain injury such as
stroke or convulsions; excessive glutamate on NMDA receptors cause an
excessive toxic influx of calcium). Thus, it is possible that the altered gene on
chromosome 4 produces an abnormality that leads to excessive activation of
NMDA receptors or release of glutamate.
PET studies: HD patients have a loss of D2 receptors and glucose
metabolism in the striatum. This reflects the specific loss of D2 bearing
projection neurons from the striatum to the GPe via the indirect pathway (typical
of HD).

• Drug induced dyskinesias: due to DOPA therapy for PD c.f. chorea in HD: excessive
dopaminergic inhibition of indirect pathway striatal projection to GPe, leading to

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 inhibition of STN, leading to decreased inhibitory output from GPi = excessive
movements, i.e. chorea (jerky, random limb movements)

Cognitive Roles of the Basal Ganglia

As mentioned before, the basal ganglia are also involved in other closed circuits
other than the skeletomotor loop. These circuits originate in the prefrontal and limbic
regions of the cortex and play roles in motivation, emotional arousal, and executive
function. In general, the disorders associated with dysfunction of the prefrontal cortex
and corticobasalganglia-thalamocortical circuits involve action rather than
perception/sensation. Other circuit examples:
Prefrontal Circuits:
-Dorsolateral Prefrontal Circuit: involved in executive functions and
working memory. Frontal dysfunction may indirectly impair memory
(verbal/nonverbal) and visuospatial performance, and some attentional
functions. Language is generally intact.

-Lateral Orbitofrontal Circuit: mediates empathetic and socially

appropriate responses. Damage to this area is associated with impulsivity,
Obsessive-Compulsive Disorder, and Tourette’s Syndrome.

Limbic Circuit:
-Anterior Cingulate Circuit: involved in motivation, procedural learning.
Damage can cause apathy and akinetic mutism (profound impairment of
movement initiation)

Important stuff from the lecture not on the Lecture Notes:

Parkinson’s Disease: (most treatable)
- In PD, you lose the enzymatic activities to package and make dopamine (in SN)
- In early PD patients, there is an asymmetric loss of dopaminergic neurons of the
Putamen. This can be shown by imaging cocaine receptors.
- Glucose metabolism is another way to image the brain. More glucose metabolism =
more dopamine loss. So PD patients have abnormally overactive pattern of brain
metabolism.
- Treatment studies:
-Fetal dopamine cell transplants: the patients with the implants did not have
progressive loss of neurons like the sham surgery patients did.
-Acute intervention: L-DOPA
-Corrective Lesioning: go to hyperactive inhibitory areas and lesion (remember
that PD is caused by an overactive indirect pathway)
-ablate GPi (main exit source) or STN (modulator of the exit source)
-“if someone were to ask you this on a test…”: the STN is a place
that you can also lesion/stimulate because it is “more proximal,
it’s the regulator of the GPi.”
-lesioning the GPi proper does not have any neg consequences

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 -BUT, lesioning the STN may result in serious consequences (i.e.
hemiballism), as seen by strokes at STN.
-stroke at STN of normal person: reduced STN projection to GPi =
marked reduction of GPi activity = get a hyperkinetic motor
disease, hemiballism.
-Pallidotomy methods:
-old days: used a cannula w/ electrodes in PD patients to locate and
burn a hole in GPi
-nowadays: use PET scans to help locate areas for lesion surgery

Huntington’s Disease (least treatable)

- From degeneration of neurons of indirect pathway
- STN liberated thru genetic problem due to too many CAG repeats. This results in
massive inhibition of STN, which leads to chorea.
- May develop dementia after initial hyperkinetic symptoms
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THINGS TO DEFINITELY KNOW:

• Skelemotor circuit has a somatotopic organization
• Direct pathway: decreases inhibition on thalamus = increases movement; striatal
neurons in this pathway have D1 receptors
• Indirect pathway: increases inhibition on thalamus = decreases movement; striatal
neurons in this pathway have D2 receptors
-the STN is (a positive) regulator of the GPi
-therefore: in PD lesioning surgery, one can lesion either the STN or the GPi to
get the desired results of suppressing the overinhibition.
• Parkinson’s Disease (hypokinetic disorder) is caused by “loss of dopaminergic
projection neurons of the SNc” and is a result of overactivity in the indirect pathway,
and decreased activity in the direct pathway (by virtue of the different actions of
dopamine on D2 and D1 receptors)
• Huntington’s Disease (hyperkinetic disorder) is caused by underactivity in the
indirect pathway.

Sorry there are no jokes and that this transcript isn’t as fun to read as the ‘02
magical walking decerebrate cat one. The basal ganglia just isn’t that exciting.
Anyways, be sure to check out the figure in Martin’s Neuroanatomy (Fig11-4 and Box
11-1, pgs 330-333)--it makes things a hell of a lot easier.