Theoretical Framework - Principles of Cortical Self-Organization
The mammalian brain is a highly sophisticated self-organizing
system, which learns by transforming its experience into changes in circuitry
that improve the animal’s chances of survival. The same principles
that guide day to day learning also allow the cortex to compensate for
damage either to peripheral sensory structures or within the central nervous
system. Although studies of long-term potentiation and depression
have demonstrated that plasticity mechanisms are dependent on correlation-based
rules, we still do not understand the principles that govern how sensory
experience alters the distributed responses of thousands of cortical neurons
in a behaviorally useful manner.
The anatomy of cortical connections strongly suggests
that both bottom-up and top-down information shape perception and guide
cortical plasticity. The sensory saltation illusion provides a robust
example of the degree to which our experiences are shaped by attention
and expectation (Nature, 1995). Other experiments from Merzenich
and colleagues have established that attention is required for sensory
input to drive reorganization of cortical maps. These results suggest
that attention gates cortical plasticity mechanisms, allowing correlation-based
rules to operate preferentially on stimuli which are relevant to the animal.
It has been proposed that the brain uses ascending neuromodulatory
projections, such as the central cholinergic system, to differentiate important
stimuli from among the tens of thousands of behaviorally irrelevant stimuli
encountered each day. I have developed a simple and robust plasticity
paradigm using electrical activation of the cholinergic nucleus basalis
and confirmed that release of acetylcholine paired with sensory stimuli
is sufficient to generate enduring reorganizations of cortical circuitry.
This powerful new paradigm will serve as the basis
for a series of experiments exploring the basic principles of plasticity
that shape the cortical representation of stimulus features with the explicit
goal of assembling these principles into a functional general theory of
cortical self-organization.
Experimental Approach
Nucleus basalis (NB) neurons located in the basal
forebrain provide almost all of the cholinergic input to the cortex.
In my experiments, activation of NB, via a chronic stimulating electrode,
is repeatedly paired with the presentation of an auditory stimulus to adult
rats that are awake and unrestrained. After four weeks of such pairing,
a detailed map of the response properties of primary auditory cortex neurons
is reconstructed from up to one hundred microelectrode penetrations.
The reorganizations that result are among the largest ever recorded in
primary sensory cortex. Importantly, the plasticity observed is specific
to the stimulus paired with NB stimulation. For example, when 9 kHz
tones are paired, the region of the A1 map representing this frequency
is expanded as neurons that previously responded to other frequencies shift
their responses toward 9 kHz (Science, 1998). In contrast, stimuli
presented without NB activation do not result in cortical reorganization.
These results confirm the hypothesis that the NB functions to demark significant
stimuli allowing cortical plasticity mechanisms to operate specifically
on important events.
My goal is to use NB activation to investigate the
principles of self-organization that specify how connection strengths and
network dynamics are modified to result in plasticity that is behaviorally
useful. Stimulation of NB provides a means of enabling cortical
plasticity, and the auditory system allows a freedom of stimulus generation
that will facilitate the investigation of the rules that guide plasticity
in response to stimuli located within a continuous multi-dimensional feature
space.
The first principle I investigated relates changes
in receptive field size to specific qualities of the stimulus paired with
acetylcholine release. Recanzone and colleagues showed that in monkeys
cortical receptive field size decreases after practicing a task requiring
discrimination of location on the receptor surface (cochlea or skin), and
increases following training on a task requiring detection of changes in
stimulus modulation rate. In my simplified preparation, this differential
plasticity can be mimicked, without behavioral training, by changing the
statistics of the sensory input paired with NB stimulation. Receptive
field sizes are increased when amplitude modulated stimuli are paired with
acetylcholine release and decreased when different tone frequencies are
paired. By pairing six different types of stimuli, I have shown that
receptive fields are altered as a continuous function of spatial variability
and temporal modulation of stimuli. These results demonstrate that
simple rules operate in the cortex to generate useful changes in circuitry
based on the statistics of sensory stimuli marked by NB activity.
My second class of experiments examined representational
plasticity of time-varying stimulus features. The maximum following
rate of cortical neurons can be significantly increased after repeated
pairing of NB activation with stimuli modulated at 15 Hz, and significantly
decreased after pairing with 5 Hz stimuli. Interestingly, my first
attempt to generate temporal plasticity, by pairing 9 kHz tones modulated
at 15 Hz, failed. Although this procedure resulted in a large reorganization
of the cortical map of frequency, the maximum following rate was unaltered.
In contrast, when the tone frequency was randomized while maintaining the
15 Hz modulation rate, dramatic plasticity of A1 temporal responses occurred
without any map reorganization. Thus, variability of one feature
can profoundly impact plasticity of another.
Determining which features of a stimulus are behaviorally
important is a difficult problem that has been largely ignored in the plasticity
literature. In tasks involving simple tonal stimuli, it seems obvious
that experience with 9 kHz should increase the 9 kHz region of the map,
but how does the cortex know that tone frequency is important and not duration,
intensity, modulation rate, bandwidth, or any other stimulus feature?
It would not only be inefficient to simultaneously adjust the cortical
tuning for every stimulus feature, it would create representations that
did not generalize well. There is no evidence that primary sensory
cortex has specific information about task goals, so the cortex probably
uses information contained in the input itself to make an educated guess
about how to improve performance.
Variability shapes behavioral generalization functions in humans and
animals. My results demonstrate that input variability can serve
as an important cue for the cortex about which feature(s) of the stimulus
contain information. This result further substantiates the hypothesis
that NB activity marks important stimuli and allows simple cortical rules
to improve the representation of features likely to be useful based on
the statistics of input.
Research Objectives
These studies represent my initial investigations
of the principles of cortical self-organization using NB stimulation.
I have three major goals for my continuing research. The first is
to develop a general theory of cortical plasticity by extending my investigations
of the plasticity rules that operate in relation to simple features for
which auditory cortex neurons are tuned. These features include duration,
intensity, bandwidth, FM direction and rate. I will also examine
how plasticity rules operate on conjunctions of these features, such as
harmonic relationships and sequenced stimuli. Finally, I will determine
how well the principles investigated with simple stimuli apply to complex
spatiotemporal stimuli, such as human speech. I believe that this
incremental approach, exploiting both the power of cholinergic modulation
and the flexibility of auditory stimuli, will yield a more complete understanding
of cortical plasticity.
My second goal is to relate cortical plasticity
to changes in behavior. To date it has not been possible to demonstrate
that cortical plasticity is sufficient to improve performance. Previous
studies have correlated cortical plasticity with behavior, but could not
establish causality. An important advantage of my model is
that plasticity can be generated independently of behavior. I will
use NB stimulation to generate cortical reorganizations and quantify the
consequences on behavioral performance. Initial experiments will
focus on improving behavior by exaggerating the distinction between the
internal representations of features required for task performance (e.g.
15 vs. 30 Hz AM discrimination). Such preparation may speed learning
by facilitating relevant distinctions. Subsequently, I will use NB
stimulation to degrade the distinction between representations and explore
how inappropriate plasticity can affect performance. These studies
should clarify the functional principles relating cortical plasticity to
behavioral performance.
The third goal of my experiments will be to use
these principles to develop models to study the role of plasticity
in the genesis and remeditation of CNS pathology. Determining how
plasticity contributes to the stability and instability of cortical representations
will provide insight into a number of disorders in which aberrant plasticity
processes have been implicated, such as tinnitus, epilepsy, Alzheimer’s
disease, and dyslexia. I will also develop animal models to test
the feasibility of using cholinergic modulation to accelerate functional
recovery from head-trauma and stroke. Studies of cortical plasticity
have already proven useful in designing treatment strategies for a number
of neurological disorders, and a more complete understanding will facilitate
the application of neuroscience principles in clinical settings.