Recent advances in integrative and cognitive neuroscience
now allow penetration into the neural circuits and cellular
processes that underlie human cognition and provide insights
into the pathophysiology of diseases like schizophrenia.
Nonhuman primates share with humans the capacity for working
memory, the ability to hold items of information transiently
in mind in order to meld together separate events and
ideas into coherent lines of thought and communications.
Metaphors for working memory include "blackboard of the
mind," "mental sketch-pad" (Baddeley, 1989), and "on-line
memory" (GoIdman-Rakic, 1987). When we listen to human
speech, we are using working memory to hold the segments
of sentences "on-line" millisecond by millisecond. We
employ working memory to carry forward, in real time,
the subject of a sentence and associate it with verbs
and objects in order to comprehend the sense and meaning
of sentences. When we perform a mental arithmetic problem,
recall a phone number, plan a hand of bridge or chess
move, or follow a verbal instruction, we use working memory.
In fact it is difficult to think of a cognitive function
that does not engage the working memory systems of the
brain.
Working memory differs from the traditional idea of short-term
memory, which was thought of as a passageway for information
to enter long-term memory. The modem concept is more dynamic
and active-an information processing mechanism rather
than a transitory but static state of information before
it is permanently stored. In testimony to the conservation
of mental processes in nonhuman primates and humans, behavioral
tasks used in human imaging and in neuropsychological
testing in patients are formally similar to those employed
in nonhuman primate research. The cortical areas of the
cerebral cortex, upon which working memory capacity depends,
are well developed in the nonhuman primate (and poorly
or not at all represented in lower mammals). These considerations
make the macaque monkey unexcelled as an animal model
of human mentation and human neurological and psychiatric
disease.
Physiological and behavioral studies in the nonhuman
primate are providing high resolution maps of the functional
architecture of the prefrontal areas. These studies have
revealed a striking modularity of function at the areal,
cellular, and subcellular levels of neural organization.
At the level of areal parcellation, different informational
processing domains have been mapped to distinct anatomical
subdivisions in prefrontal cortex such that spatial representations
are processed in dorsolateral regions of the prefrontal
cortex while object representations are processed in inferior
regions of prefrontal cortex. These localizations have
provided a framework for analysis of homologous working
memory systems in the human brain by positron emission
tomography and functional magnetic resonance imaging.
The areal modularity observed through physiological and
behavioral analyses are supported by findings from anatomical
tracing studies. These studies have revealed the intercortical
networks that link distant sensory, motor, and limbic
areas into domain constrained networks. Again such studies
are critical to the interpretation of the landscape of
cortical activations observed in noninvasive studies of
human cognition.
At the cellular level, different neurons have been found
to encode and process different items of information,
indicating that information processing is carried out
by neurons of remarkable specificity. Indeed, neurons
that code only the identity of faces or only the location
of an object and no other item of information have been
observed in circumscribed areas of the prefrontal cortex.
Some of these neurons, once triggered by a preferred stimulus,
are specialized for maintaining their activity for many
seconds after the stimulus has disappeared. This selective
capacity is referred to as the "memory field" of the neuron,
in analogy with receptive fields of sensory and motor
neurons. Recent studies in this laboratory employing both
single and dual unit recording reveal that neurons with
shared memory fields, i.e., encode the same location of
objects, are organized into microcolumns, as are neurons
which encode the features of objects or identity of faces.
These studies suggest that the local organization of neurons
in prefrontal cortex is similar to that in sensory systems,
i.e., neurons coding the same item of information appear
to be clustered and confined to a distinct location within
the columnar structure of the cortex.
Electronmicroscopic, electrophysiological, and biochemical
studies on the localization of specific neurotransmitter
receptors are establishing that modularity exists at the
subcellular level, as they show that receptors of different
subtype specificities are sequestered in different compartments
of the same cell. For example, the dopamine D1 receptor
is prominent in the distal portions of certain cortical
neurons while the serotonergic 5-HT2 receptor is associated
with more proximal elements of the same cell. Basic information
on receptor localization and function is essential for
understanding the signaling pathways and molecular mechanisms
that are critical to optimal neurotransmission in prefrontal
circuits. Thus, the study of neurotransmitters and neurotransmitter
receptors in nonhuman primates are establishing a rational
basis for development of drug therapies for the treatment
of depression, age-related memory decline, Parkinson's
disease, and schizophrenia, all of which exhibit some
form of monoamine dysfunction.
Finally, as prefrontal areas are among those that have
often been implicated in schizophrenia by imaging and
postmortem neuropathological studies, experimental study
of these areas in nonhuman primates provides a powerful
approach to understanding the cellular mechanisms of psychopathology.
