4. Basal Ganglia
Part 2 of 4

James Knierim, Ph.D.
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Basal Ganglia Intrinsic Connections

A number of intrinsic pathways interconnect various basal ganglia structures (Figure 4.4).

Figure 4.4 Basal ganglia intrinsic connections

1. The striatopallidal pathway is a GABAergic, inhibitory connection between the striatum and both segments of the globus pallidus.
2. The striatonigral pathway is a GABAergic, inhibitory connection between the striatum and the SNr.
3. The globus pallidus external segment makes a GABAergic, inhibitory connection to the subthalamic nucleus.
4. The subthalamic nucleus makes glutamatergic, excitatory connections onto both segments of the globus pallidus and the SNr.  This pathway is the only purely excitatory pathway among the intrinsic pathways of the basal ganglia.
5. The nigrostriatal pathway makes a dopaminergic synapse onto striatal neurons.  As we will see below, this is a mixed pathway, with excitatory effects on some striatal neurons and inhibitory effects on others.

Two pathways process signals in the basal ganglia

There are two distinct pathways that process signals through the basal ganglia: the direct pathway and the indirect pathway.  These two pathways have opposite net effects on thalamic target structures.  Excitation of the direct pathway has the net effect of exciting thalamic neurons (which in turn make excitatory connections onto cortical neurons).  Excitation of the indirect pathway has the net effect of inhibiting thalamic neurons (rendering them unable to excite motor cortex neurons).  The normal functioning of the basal ganglia apparently involves a proper balance between the activity of these two pathways.  One hypothesis is that the direct pathway selectively facilitates certain motor (or cognitive) programs in the cerebral cortex that are adaptive for the present task, whereas the indirect pathway simultaneously inhibits the execution of competing motor programs.  An upset of the balance between the direct and indirect pathways results in the motor dysfunctions that characterize the extrapyramidal syndrome (see below).

Direct pathway.  Although the connectivity patterns of the direct and indirect pathways are relatively straightforward, the predominance of inhibitory connections in the system can make an understanding of the functional circuitry complicated and nonintuitive (Figure 4.5). 

The direct pathway starts with cells in the striatum that make inhibitory connections with cells in the GPint.  The GPint cells in turn make inhibitory connections on cells in the thalamus.  Thus, the firing of GPint neurons inhibits the thalamus, making the thalamus less likely to excite the neocortex.  When the direct pathway striatal neurons fire, however, they inhibit the activity of the GPint neurons.  This inhibition releases the thalamic neurons from inhibition (i.e., it disinhibits the thalamic neurons), allowing them to fire to excite the cortex.  Thus, because of the “double negative” in the pathway between the striatum and GPint and the GPint and thalamus, the net result of exciting the direct pathway striatal neurons is to excite motor cortex.

Think of it as a multiplication equation, with an excitatory connection (E) equal to +1 and an inhibitory connection (I) equal to –1:

because the two negative numbers cancel each other out.

Indirect pathway.  The indirect pathway starts with a different set of cells in the striatum.  These neurons make inhibitory connections to the external segment of the globus pallidus (GPext).  The GPext neurons make inhibitory connections to cells in the subthalamic nucleus, which in turn make excitatory connections to cells in the GPint.  (Remember that the subthalamic-GPint pathway is the only purely excitatory pathway within the intrinsic basal ganglia circuitry.)  As we saw before, the GPint neurons make inhibitory connections on the thalamic neurons.  To see the net effects of activation of the indirect pathway, let us work backwards from the GPint.  When the GPint cells are active, they inhibit thalamic neurons, thus 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.  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, the GPint neurons inhibit the thalamus, thereby producing a net inhibition on the motor cortex.

Again, think of a multiplication analogy:

Because there are 3 negative numbers in the equation, the net effect is negative.

Thus, as a result of the complex sequences of excitation, inhibition, and disinhibition, the net effect of the cortex exciting the direct pathway is to further excite the cortex (positive feedback loop), whereas the net effect of cortex exciting the indirect pathway is to inhibit the cortex (negative feedback loop).  Presumably, the function of the basal ganglia is related to a proper balance between these two pathways.  Motor cortex neurons have to excite the proper direct pathway neurons to further increase their own firing, and they have to excite the proper indirect pathways neurons that will inhibit other motor cortex neurons that are not adaptive for the task at hand (see below). 

The nigrostriatal projection

An important pathway in the modulation of the direct and indirect pathways is the dopaminergic, nigrostriatal projection from the substantia nigra pars compacta to the striatum (Figure 4.5).  Direct pathway striatal neurons have D1 dopamine receptors, which depolarize the cell in response to dopamine.  In contrast, indirect pathway striatal neurons have D2 dopamine receptors, which hyperpolarize the cell in response to dopamine.  The nigrostriatal pathway thus has the dual effect of exciting the direct pathway while simultaneously inhibiting the indirect pathway. Because of this dual effect, excitation of the nigrostriatal pathway has the net effect of exciting cortex by two routes, by exciting the direct pathway (which itself has a net excitatory effect on cortex) and inhibiting the indirect pathway (thereby disinhibiting the net inhibitory effect of the indirect pathway on cortex).  The loss of these dopamine neurons in Parkinson’s disease causes the poverty of movement that characterizes this disease, as the balance between direct pathway excitation of cortex and indirect pathway inhibition of cortex is tipped in favor of the indirect pathway, with a subsequent pathological global inhibition of motor cortex areas.

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