Synaptic circuitry in the basal

ganglia
LECTURE 3 Part 2
 LEARNING OUTCOMES
• Explain why the overall output of the basal ganglia is
inhibitory
• Describe the normal signalling that occurs in the basal ganglia
and explain how the connections between the nuclei allow
the basal to fulfil its function as a “brake”
• Describe the abnormal signalling that occurs in Parkinson’s
disease
• Describe the abnormal signalling that occurs in Huntington’s
disease
Beginning of a motor movement
A simple movement: is a
coordination marvel
 Symptoms of disordered movement
• Pathologic or pharmacologic disruption to
pathways of the basal ganglia may result in a
variety of disordered movements, though not
frank weakness or paralysis. Defective
movement may be characterized by:
• hypokinesia (reduction in spontaneous
movement)
• akinesia (complete loss of spontaneous
movement)
• bradykinesia (abnormally slow movement)
 Excessive movement may be characterized by:

• tremor
• rigidity
• dyskinesia (unwanted involuntary
movements)
• athetosis (slow involuntary rhythmic
movements of extremities and face)
• ballismus (quick involuntary movements of
face and extremities)
• dystonia
 Basal ganglia circuitry

• Basal ganglia are major components of large cortical-

subcortical re-entrant circuits linking cortex and thalamus
• Part of a loop that begins and ends in the cerebral cortex
• Cerebral cortex projects to striatum then to globus pallidus
and substantia nigra then to thalamus
• Finally back to prefrontal association, premotor and motor
cortex,
• The regions involved in selecting movements and behaviours
 General Pathway
• Information arrives at the caudate nucleus and putamen from
sensory, motor, and integrative areas of the cerebral cortex
• Processing occurs in these nuclei and in the adjacent globus
pallidus
• Most of the output of the basal nuclei leaves the globus
pallidus and synapses in the thalamus
• Nuclei in the thalamus then project the information to the
appropriate areas of the cerebral cortex
 Pathway
• Basal nuclei alter the motor commands issued by the cerebral
cortex through this feedback loop
• For example:
– When you walk, basal nuclei control the cycles of arm and thigh
movements that occur between the time you decide to start walking
and the time you give the stop order
– As you begin a voluntary movement, basal nuclei control and adjust
muscle tone
– Particularly in the appendicular muscles to set your body position
 Basal ganglia circuitry
• Overall function of this loop is to select a particular
movement or sequence of movements or behaviours while
suppressing others
• Two important pathways through which striatal information
reaches globus pallidus (internal)
– Direct pathway
– Indirect pathway

• These two pathways have opposite effects on motor activity

 BG circuitry in normal Conditions
• Excitation of the direct pathway has the net effect of exciting
thalamic neurons
• Excitation of the indirect pathway has the net effect of
inhibiting thalamic neurons
• Normal functioning of the basal ganglia involves a proper
balance between the activity of these two pathways
• In normal brain, parallel neuronal networks of the striatum
connect and integrate functions between the BG nuclei,
various regions of the cerebral cortex and the thalamus
 NOTE!!

• Thalamus stimulate the motor cortex

• GPext – excites the thalamus and motor cortex
• GPint – inhibit the thalamus and motor cortex
• Direct pathway – excites the thalamus and motor cortex
• Indirect pathway – inhibits the thalamus and motor cortex
• Subthalamic nucleus – excites the GPint neurons and
promotes the inhibition of the thalamus and motor cortex
• GPext – inhibits the subthalamic nucleus
 Neurotransmitters

• Glutamate
– Excitatory neurotransmitter

• Gamma Aminobutyric acid (GABA) (Pars reticulata)

– Inhibitory neurotransmitter

• Dopamine (Pars compacta)

– Excite the direct pathway via D1 receptors
– Inhibit the indirect pathway via D2 receptors
 DIRECT PATHWAY
• Start with cells in the striatum that make inhibitory connections
with cells in the globus pallidus (GPint)
– GPint cells in turn make inhibitory connections on cells in the thalamus
– Firing of GPint neurons inhibits the thalamus, making the thalamus less likely
to excite the neocortex

• When the direct pathway striatal neurons fire, they inhibit the
activity of the GPint neurons
• This inhibition releases the thalamic neurons from inhibition
allowing them to fire to excite the cortex
• GPext neurons inhibits the subthalamic nucleus which excite GPint
• Net results of exciting the direct pathway striatal neurons is to
excite motor cortex
x x
x x
 INDIRECT PATHWAY
• Starts with different set of cells in the striatum
– Neurons make inhibitory connections to the external segment of the globus
pallidus (GPext)
– GPext neurons make inhibitory connections to cells in the subthalamic nucleus

• Subthalamic neurons
– Which in turn make excitatory connections to cells in the GPint
– When the GPint neurons are active, they inhibit thalamic neurons, making
cortex less active
– When the subthalamic neurons are firing, they increase the firing rate of GPint
neurons
– Thus increasing the net inhibition on cortex
 INDIRECT PATHWAY

• Firing of the GPext neurons inhibits the subthalamic neurons

• Thus making the GPint neurons less active and disinhibiting the thalamus
• However, when the indirect pathway striatal neurons are active, they
inhibit the GPext neurons
• Thus disinhibiting the subthalamic neurons
• With the subthalamic neurons free to fire, GPint neurons inhibit the
thalamus
• Producing a net inhibition on the motor cortex
 x

x
x

x
x
 Net effects

• Net effect of the cortex exciting the direct pathway is to

further excite the cortex (positive feedback loop)
• Net effect of cortex exciting the indirect pathway is to inhibit
the cortex (negative feedback loop)
 Regulation of Basal nuclei
activities
• Activity of the basal nuclei is inhibited by neurons in the
substantia nigra of the midbrain
• Substantia nigra releases neurotransmitter dopamine
• If substantia nigra is damaged or the neurons secrete less
dopamine, basal nuclei become more active
 Modulation

• An important pathway in the modulation of the direct and

indirect pathways is the dopaminergic
• Nigrostriatal pathway from the substantia nigra pars
compacta to the striatum
• Direct pathway striatal neurons have D1 dopamine receptors,
which depolarize the cell in response to dopamine
 Modulation
• Indirect pathway striatal neurons have D2 dopamine
receptors, which hyperpolarize the cell in response to
dopamine
• Nigrostriatal pathway thus has the dual effect of exciting the
direct pathway while simultaneously inhibiting the indirect
pathway
 Modulation

• Because of this dual effect, excitation of the nigrostriatal

pathway has the net effect of exciting cortex by two routes:
– Exciting the direct pathway (has a net excitatory effect on
cortex)
– Inhibiting the indirect pathway (thereby disinhibiting the net
inhibitory effect of the indirect pathway on cortex).
NIGROSTRIATAL PATHWAY
 Modulation
• The loss of dopamine neurons in Parkinson’s disease causes
the poor of movement that characterizes this disease,
• As the balance between direct pathway excitation of cortex
and indirect pathway inhibition of cortex is tipped in favour of
the indirect pathway,
• With a subsequent pathological global inhibition of motor
cortex areas
 Parkinson’s disease
• Characterized by slowness or absence of movement
(bradykinesia or akinesia), rigidity, and a resting tremor
(especially in the hands and fingers)
• Patients have difficulty initiating movements, and
• Once initiated the movements are abnormally slow
• The cause of Parkinson’s disease is the loss of the
dopaminergic neurons in the substantia nigra pars compacta
 Parkinson’s disease

• Because the nigrostriatal pathway excites the direct pathway

• Inhibits the indirect pathway, the loss of this input tips the
balance in favor of activity in the indirect pathway
• The GPint neurons are abnormally active, keeping the
thalamic neurons inhibited
• Without the thalamic input, the motor cortex neurons are not
as excited, and therefore the motor system is less able to
execute the motor plans in response to the patient’s volition
 Huntington’s disease
• Symptoms of Huntington’s disease are in many respects the
opposite of the symptoms of Parkinson’s disease
• Huntington’s disease is characterized by choreiform
movements:
– Involuntary, continuous movement of the body, especially of the
extremities and face.

• Often these movements resemble pieces of adaptive

movements, but they occur involuntarily and without
behavioural significance
 Huntington’s disease
• Results from the selective loss of striatal neurons in the
indirect pathway
• Thus, the balance between the direct and indirect pathways
becomes tipped in favour of the direct pathway
• Without the normal inhibitory influence on the thalamus that
is provided by the indirect pathway
• Thalamic neurons can fire randomly and inappropriately,
causing the motor cortex to execute motor programs with no
control by the patient
 SUMMARY
• The functional histology and basic circuitry of the basal
ganglia.