Toward a Prefrontal Model of Short-term Synaptic Plasticity:
Network Architecture and Working Memory Deficits
1Centerfor Complex Systems Studies, Kalamazoo College, Kalamazoo, Michigan, USA,
2Department of Biophysics, KFKI Research Institute of Particle and Nuclear Physics of the
3Department of Computer Science Western Michigan University, Kalamazoo, Michigan, USA
Abstract
Working memory (WM) is an important cognitive function that refers
to the maintenance and online manipulation of information for a short
period of time. It has been suggested that short-term synaptic
facilitation in recurrent connections of neocortical networks can
sustain WM (Mongillo, Barak, &Tsodyks, 2008). We propose a
prefrontal network model for relating short-term synaptic plasticity
and network architecture to WM tasks such as the n-back task and a
version of the Sternberg task that manipulates WM load. Our overall
purpose is to model WM as realistically as possible in order to
measure the effects of synaptic facilitation/depression and network
architecture on WM performance.
Introduction
Working memory (WM) is an important cognitive function that refers
to the maintenance and online manipulation of information for a short
period of time. WM is mediated by activity in recurrent networks in
the prefrontal cortex (PFC). During WM tasks, a stimulus that is
briefly presented to an animal often has to be remembered during a
delay period that takes place between the presentation of a stimulus
and the execution of a task. For instance, in computerized versions of
Sternberg WM tasks, which are commonly used in research, a
sequence of capitalized consonant letters (e.g., BGZXF) is presented
on the screen and is followed by a delay period lasting 1-3 s during
which the screen is blank. After the delay period, a letter-position
probe (e.g., z=3) is presented and the subject is required to specify
whether the probe is true or false. In versions of another commonly
used WM task, the n-back task, a sequence of letters is presented one
letter at a time and the subject is asked to hit a target key each time
the letter on the screen matches the letter presented 1-, 2-, or 3-back
(i.e., 1-, 2-, or 3-letters earlier) in the sequence or matches a pre-
determined target letter (0-back). Thus, every letter serves as a probe
and the delay depends on the condition (0-, 1-, 2-, or 3-back).
Early theories suggested that enhanced spiking activity in the form of
persistent reverberations among neurons that code for a stimulus
allow for the stimulus to be remembered during a delay period
(Hempel et al., 2000). However, electrophysiological studies have
shown that spiking activity may disappear during a delay period
(Mongillo, Barak, &Tsodyks, 2008). ST facilitation reflects an
increase in the probability of neurotransmitter release that can last up
to 1 s (Abbot &Regehr, 2004). ST depression reflects a decrease in
the probability of neurotransmitter release that last up to several
seconds. A more recent synaptic theory of WM (Mongillo et al.)
suggests that ST synaptic facilitation mediated by residual calcium
levels at presynaptic terminals of pyramidal glutamatergic neurons in
the PFC that code for a stimulus, allows a stimulus to be remembered
for about 1 s without enhanced spiking activity (Altamura et al.,
2007). In this case, a probe can act as a weak non-specific excitatory
input that can reactivate the network and thus, the memory of the
stimulus. ST depression is also taking place and plays a role. It should
be noted that PFC activation has been shown to increase directly with
WM load (e.g., the number of letters in a stimulus sequence) but not
length of delay (Altamura et al., 2004). A possible explanation is that
a larger network of neurons in the PFC is involved with a larger WM
load.
WM deficits are a core cognitive deficit in schizophrenic patients.
Altered connectivity is the proposed mechanism. In the present
research, we propose a prefrontal network model for relating ST
synaptic plasticity and network architecture to WM tasks such as the
n-back task and a version of the Sternberg task that manipulate WM
load. Our overall purpose is to model WM as realistically as possible
in order to measure the effects of synaptic facilitation/depression and
network architecture on WM performance and in the process, to
elucidate possible explanations for WM deficits in schizophrenic
patients.
Chris D. 1,3
Gore , Phillip J.
Gray ,
Hungarian Academy of Sciences, Budapest, Hungary
Methods
The complexity of the brain, as a system of feedback loops and recurrent
connections, and the number of neurons comprising it make it difficult to
understand the totality of the processes relevant for schizophrenia and
working memory solely by imagination. The methods of system science
may be useful tools in understanding the physiology and dynamics of
relevant neural systems. A computational approach to schizophrenia and
short-term plasticity fosters an understanding of the nature and limits of
the strategies neural systems employ in processing and transmitting
information. One of the major problems in biological memory is how it is
maintained and changed through multiple time scales. Computational
tools can contribute greatly to our understanding of how synapses
function and change in relation to external stimulus. By emphasizing
descriptions of functionally and biologically realistic neural systems, a
formal computational model captures the essential features of this
prefrontal system at multiple spatial-temporal scales. Such a model can
be used to test hypotheses—like the synaptic theory of working memory
—that can be directly verified by current or future biological
experiments. Models can help in understanding the loci of abnormal
plasticity processes, and the consequences involved. It is generally
accepted that schizophrenia is related to excessive pruning of cortical
connections, and simple network studies have shown that this cortical
pruning may lead to the formation of “pathological attractors". In our
study we are developing a prefrontal network model of short-term
plasticity giving consideration to differences in network architecture
observed in healthy and schizophrenic brains.
Initial Analysis of Synaptic Theory of
Working Memory
For our initial study in working memory, we took some steps with
Synaptic Theory of Working Memory (Mongillo et al. Science 2008):
§Exploration of model’s parameter space for facilitation and depression
§Test simulations with/without network connections
§Test simulations with/without read out signal
After exploring this model for working memory, we found that we were
unable to evaluate its effectiveness due to its focus on realistic biology
rather than neural computation. Thus, we decided to temporarily leave
this model to build our own with a real-world task. The task we chose is
a well-known psychological test known as the Sternberg delay.
1
Julia 1
Kane , Mihály Bányai 1,2
Network Architecture Experiments
We simulated the Sternberg delay by storing sets of 3, 5, and 8 consonants in networks of 15, 25,
Artificial Neural Networks and 40 neurons respectively. Each letter is represented in binary; for example:
A biological CMPLX 3 13 16 12 24 00011 01101 10000 01100 11000
neuron, like those
found in the brain. In a recurrent network, all the synapses fire simultaneously, each time bringing the values closer to
a known pattern. To queue the network to remember the pattern, we give it one of the letters and
positions. For the above example, we could ask it if it recognizes the M with the queue 00000
01101 00000 00000 00000. We ran 100 simulations for each set size with all patterns chosen at
random. It was able to closely replicate actual results from human subjects. Results from the
traditional Sternberg delay are on the left, while our simulation results are on the right.
A simple artificial
neuron that fires a
synapse if the sum
of its incoming
synapses is above a
4 threshold.
Here we can see a scale-free Barabasi-Albert (BA) network along
side a Highly Diluted Hopfield Network (HDHN). These were
two of the networks used to store 8 letters (40 neurons because
each letter requires 5 neurons). Although they have the same
number of neurons and connections, the scale-free network is much
more effective and much closer to a biological neural network.
Discussion Selected References
From the simulation data it is evident that as network connectivity decreases, Abbot, L.F., &Regehr, W.G. (2004). Synaptic computation. Nature, 431, 796-803.
network performance also decreases. The random graph network was slower
and much less accurate than the scale free graph network in task performance. Altamura, M., Elvevag, B., Blasi, G., Bertolino, A., Callicot, J.H., Wienberger, D.R.,
Mattay, V.S., & Goldberg, T.E. (2007). Dissociating the effects of Sternberg working
This is consistent with previous findings and highlights the importance of memory demands in prefrontal cortex. Psychiatry Research, 154, 103-114.
network architecture in working memory performance. Schizophrenia has been
characterized by excessive pruning of cortical connections and the loss of Basset, D.S., Bullmore, E., Verchinski, B.A., Mattay, V.S., Weinberger, D.R., & Meyer-
frontal network hubs. These abnormalities in network connectivity may indeed Lindenberg, A. (2008). Hierarchical organization of human cortical networks in health and
be what leads to such prevalent working memory deficits observed in schizophrenia. Journal of Neuroscience, 28, 9239-9248.
schizophrenia.
Hempel, C.M., Hartman, K.H., Wang, X.-J., Turrigiano, G.G., & Nelson, S.B. (2000).
Multiple forms of short-term plasticity at excitatory synapses in rat medial prefrontal
cortex. Neurophysiology, 83, 3031-3041.
Future Directions Henneg, M.H., Postlethwaite, M., Forsythe, I.D., & Graham, B.P. (2007). A biophysical
model of short-term plasticity at the calyx of Held. Neurocomputing, 70, 1626-1629.
We would like to convert our model to a more biophysically accurate network
model of short-term plasticity in the PFC by considering the parameters Mongillo, G., Barak, O., &Tsodyks, M. (2008). Synaptic theory of working memory.
present in biophysically realistic single-synapse models such as the model Science, 319, 1543-1546.
proposed by Hennig, Postlethwaite, Forsythe, and Graham (2006).
Project Supervisor: Dr. Péter Érdi1,2