The basal ganglia
and cerebellum are major subcortical nuclei that have
long been regarded as critical to the generation and control
of movement. A hierarchical scheme of organization can
be used to describe the internal circuitry in both groups
of nuclei. The "input layer" of basal ganglia
processing is represented by the caudate and putamen.
The functionally analogous level in cerebellar circuits
is represented by specific pontine nuclei which send "mossy
fiber" inputs to cerebellar cortex. The input layers
of both circuits receive signals from diverse regions
of the cerebral cortex, including motor, sensory, posterior
parietal, prefrontal, cingulate and temporal areas. The
"output layer" of basal ganglia processing is
represented by the internal segment of the globus pallidus
and the pars reticulata of the substantia nigra; comparable
structures for the cerebellum are the 3 deep cerebellar
nuclei: dentate, interpositus and fastigial. Neurons in
the output layers of both circuits send their axons to
the thalamus and, by this route, project back onto the
cerebral cortex. Thus, a major structural feature of basal
ganglia and cerebellar circuits is their participation
in multiple loops with the cerebral cortex.
Our understanding
of the organization of basal ganglia and cerebellar loops
with the cerebral cortex has evolved considerably over
the last 20 years. In the past, basal ganglia and cerebellar
output was thought to terminate in a single region of
the thalamus and influence a single cortical area, the
primary motor cortex. According to this view, basal ganglia
and cerebellar loops served to collect signals from motor,
sensory and cognitive areas of the cerebral cortex and
"funnel" this information into the motor system
to generate and control movement.
In recent years,
this "classical" view of basal ganglia and cerebellar
function has been challenged. A number of anatomical studies
has demonstrated that basal ganglia and cerebellar output
terminates in multiple thalamic nuclei, and that these
thalamic nuclei project more widely in the cerebral cortex
than previously suspected. As a consequence, there is
a growing awareness that basal ganglia and cerebellar
output may influence non-motor, as well as motor
areas of the cerebral cortex. For example, we proposed
that the basal ganglia participate in at least five separate
loops with the cerebral cortex (Alexander, DeLong and
Strick, ‘86). These loops were designated the skeletomotor,
oculomotor, dorsolateral prefrontal, lateral orbitofrontal,
and anterior cingulate circuits. Based on this scheme,
basal ganglia output was thought to influence not only
the generation and control of movement, but also the higher
order functions subserved by prefrontal, orbitofrontal
and cingulate cortex.
Similarly,
Leiner et al. (‘86, ‘91, ‘93) have suggested
that cerebellar output is directed to prefrontal, as well
as to motor areas of the cerebral cortex. They noted that,
in the course of hominid evolution, the lateral output
nucleus of the cerebellum - the dentate - undergoes a
marked expansion that parallels the expansion of cerebral
cortex in the frontal lobe. They argued that the increase
in the size of the dentate is accompanied by an increase
in the extent of the cortical areas in the frontal lobe
that are influenced by dentate output. As a consequence,
they proposed that cerebellar function in humans has expanded
to include involvement in certain language and cognitive
tasks.
Until recently,
it has been difficult to evaluate the validity of these
proposals because of the relative paucity of experimental
data on the actual cortical "targets" of basal
ganglia and cerebellar output. To overcome this problem,
we developed a novel neuroanatomical technique for tracing
circuits in the central nervous system of primates (Zemanick
et al., ‘91; Strick and Card, ‘92; Hoover and
Strick, ‘93; Middleton and Strick, ‘94, ‘96;
Kelly and Strick, ‘97). The technique uses retrograde
transneuronal transport of specific strains of neurotrophic
viruses (e.g., herpes simplex virus type 1 and rabies)
to label chains of synaptically linked neurons. For example,
two to three days following injections of HSV1 into the
primary motor cortex, virus is taken up and transported
in the retrograde direction to label the cell bodies of
neurons in the ventrolateral thalamus that innervate the
injection site. After four to five days, virus is then
transported transneuronally in the retrograde
direction and labels neurons at subcortical sites that
project to the ventrolateral thalamus, i.e., output nuclei
in the basal ganglia and cerebellum. Thus, this technique
enables one to map basal ganglia-thalamocortical and cerebello-thalamocortical
pathways of primates.
To date, we
have used trans-neuronal transport of neurotropic viruses
to examine basal ganglia and cerebellar loops with skeletomotor,
oculomotor, prefrontal and inferotemporal areas of the
cerebral cortex. In addition, we have performed physiological
studies to examine the non-motor functions of basal ganglia
and cerebellar output. Overall, our results indicate that
concepts about basal ganglia and cerebellar function should
be expanded to include their participation not only in
motor control, but also in aspects of cognition and even
higher-order visual processing. Our observations indicate
that widespread regions of the prefrontal cortex thought
to be involved in "executive" functioning are
the target of basal ganglia and cerebellar output.
These results
have broad clinical implications. For example, there is
now considerable evidence that a variety of neuropsychiatric
disorders such as schizophrenia, autism, Tourette’s
syndrome, and obsessive-compulsive disorder are associated
with alterations in basal ganglia and/or cerebellar function.
It is possible that alterations in the function of specific
basal ganglia and cerebellar loops lead to an identifiable
set of neuropsychiatric symptoms. Thus, information on
basal ganglia and cerebellar loops with the cerebral cortex
may provide a new anatomical framework for understanding
the contributions of these structures to mental, as well
as motor function.
