6514 • The Journal of Neuroscience, May 20, 2009 • 29(20):6514 – 6525

Development/Plasticity/Repair

Equalization of Ocular Dominance Columns Induced by an
Activity-Dependent Learning Rule and the Maturation of
Inhibition
Taro Toyoizumi and Kenneth D. Miller
Department of Neuroscience and Center for Theoretical Neuroscience, College of Physicians and Surgeons, Columbia University, New York, New York 10032

Early in development, the cat primary visual cortex (V1) is dominated by inputs driven by the contralateral eye. The pattern thenreorganizes into ocular dominance columns that are roughly equally distributed between inputs serving the two eyes. This reorganization
does not occur if the eyes are kept closed. The mechanism of this equalization is unknown. It has been argued that it is unlikely to involve
Hebbian activity-dependent learning rules, on the assumption that these would favor an initially dominant eye. The reorganization
occurs at the onset of the critical period (CP) for monocular deprivation (MD), the period when MD can cause a shift of corticalinnervation in favor of the nondeprived eye. In mice, the CP is opened by the maturation of cortical inhibition, which does not occur if theeyes are kept closed. Here we show how these observations can be united: under Hebbian rules of activity-dependent synaptic modification, strengthening of intracortical inhibition can lead to equalization of the two eyes’ inputs. Furthermore, when the effects of homeostatic synaptic plasticity or certain other mechanisms are incorporated, activity-dependent learning can also explain how MD causes ashift toward the open eye during the CP despite the drive by inhibition toward equalization of the two eyes’ inputs. Thus, assuming similar
mechanisms underlie the onset of the CP in cats as in mice, this and activity-dependent learning rules can explain the interocularequalization observed in cat V1 and its failure to occur without visual experience.

Introduction
The question of the relative roles of genetic specification vsactivity-dependent self-organization in the development of cerebral cortex remains an important and controversial one. A key
system for studying these roles is the development of ocular dominance columns in primary visual cortex (V1) (Crair et al., 2001;
Crowley and Katz, 2002; Huberman, 2007).
In cat V1, responses early in development are dominated by
the contralateral eye (Crair et al., 1998). Both physiologically andanatomically (Crair et al., 1998, 2001), inputs from the ipsilateraleye are restricted to patches within a continuous sea ofcontralateral-eye inputs. Then, beginning at the end of the third
postnatal week, coincident with the onset of the critical period forplasticity in response to monocular deprivation, the inputs fromthe two eyes become roughly equalized and segregate into alternating ocular dominance columns (Crair et al., 1998). This equalization and segregation does not occur if the animal is deprived ofnormal visual experience by binocular lid suture (Crair et al.,1998). Nonetheless, it was repeatedly argued (Crair et al., 1998;
Crowley and Katz, 1999; Katz and Crowley, 2002) that this equalReceived Feb. 3, 2008; revised Feb. 5, 2009; accepted April 6, 2009.
This work was supported by the Japan Society for the Promotion of Science (JSPS), Grant-in-Aid 1806772 for JSPS
fellows (T.T.), The Robert Leet and Clara Guthrie Patterson Trust Postdoctoral Fellowship, Bank of America, Trustee(T.T.), National Institutes of Health Grant R01 EY 11001 (K.D.M.), and Research Grant RGP63/2003 from the Human
Frontiers Science Organization (K.D.M.).
Correspondence should be addressed to Kenneth D. Miller, Department of Neuroscience, Columbia University,
1051 Riverside Drive, Unit 87, New York, NY 10032. E-mail: ken@neurotheory.columbia.edu.
DOI:10.1523/JNEUROSCI.0492-08.2009
Copyright © 2009 Society for Neuroscience 0270-6474/09/296514-12$15.00/0

ization was unlikely to arise simply from Hebbian rules of synaptic plasticity, which are typically thought to play a major role inactivity-dependent self-organization (Katz and Shatz, 1996;
Miller, 1996; Swindale, 1996; Katz and Crowley, 2002; MrsicFlogel et al., 2007). This was presumably based on the intuition
that, in a Hebbian competition between two inputs with similar
activities, the initially dominant input could not lose innervation
to the initially weak input. To our knowledge, no model has beenshown to explain this activity-dependent equalization of OD
columns.
In mouse V1, the onset of the critical period for monoculardeprivation plasticity coincides with, and depends on, a sufficientmaturation of intracortical inhibition (Hensch et al., 1998; Fagiolini and Hensch, 2000; Morales, 2002). The maturation of inhibition and the associated onset of the critical period does notoccur if the eyes are not opened.
Here we show how these observations can be united: sufficiently strong inhibition can force equalization of the two eyes
under a Hebbian rule. If recurrent intracortical connections are
inhibition-dominated, then activation of some cortical cells by
one eyes’ inputs evokes net inhibition that suppresses the simultaneous activation of other cortical cells. This suppresses patterns
in which a majority of cortex is driven by a single eye, leaving only
those in which the two eyes equally share cortex. If cortical activation tends to occur in periodic patterns, as has been shown indeveloping V1 (Chiu and Weliky, 2002) and as will occur inmodels using a “Mexican hat’’ pattern of excitation and inhibition, then a periodically alternating ocular dominance pattern
results. For this solution to be viable biologically, it must also beToyoizumi and Miller • Equalization of Ocular Dominance Columns

J. Neurosci., May 20, 2009 • 29(20):6514 – 6525 • 6515

generalizes directly to the two-dimensional case
(Miller et al., 1989; Miller and MacKay, 1994;
Miller, 1996; Erwin and Miller, 1998). Periodic
boundary conditions simply remove boundary
effects as an issue; since most of V1 is far from aboundary as measured in units of the oculardominance spatial period, boundary conditions are unlikely to play a critical role in theprocesses we are studying. We consider only
two input lines, whereas in reality there aremany types of cells projecting to cortex (e.g.,
ON and OFF cells, and cells representing many
retinotopic positions). These multiple inputs
are important for studies of the organization of
structured receptive fields and multifeature
Figure 1. A schematic figure of the model. N cortical neurons are lined up on a one-dimensional axis x. Each neuron receives maps in visual cortex. However, when correlafeedforward input from both ipsilateral and contralateral eyes, and those synapses are modified according to activity-dependent tions among these inputs are such that individplasticity rules. The intracortical connectivity, M, is a function of the distance between two cortical positions and changes its profile ual receptive fields show ocular dominance segat the onset of the critical period when cortical inhibition matures.
regation, then the arrangement of oculardominance across the cortex is determined byintracortical interactions and the internal structhe case that imbalances of the two eyes induced by monocularture of receptive fields beyond the eye of dominance is irrelevant to thisdeprivation can lead to inequalities of the territories of the twoprocess (Miller et al., 1989; Miller, 1996; Erwin and Miller, 1998). Thus,eyes, despite the drive of inhibition to equalize these territories.
a model in which inputs simply represent the two eyes is sufficient to
We show that, in the simplest purely Hebbian models of plasticunderstand the arrangement of ocular dominance across the cortex,
ity, this solution can work but is fragile, working only in fairly
which we are studying here.
restricted parameter regimes because synapses that do not drive
At each time step, unrectified input firing rates ĥC and ĥI are drawn
postsynaptic neurons stay weak under Hebbian plasticity. The
␯Cfrom a two-dimensional Gaussian distribution with mean ␯ and coproblem is that the simplest rules do not have robust means forI␯C /␶ c/␶
synapses that have approached zero strength to regain strengthvariance matrix c/␶ ␯ /␶ with ␯C ⫽ ␯I ⫽ 10 Hz and ␶ ⫽ 0.5 s, whereI
after maturation of inhibition or MD. More complex plasticity
the variable c ⫽ 5 Hz parameterizes the strength of the covariance. The
rules that deal with this problem can allow both inhibitionvariances, of the form ␯/␶, are the variances of the average rate over a time
mediated equalization of equally active eyes and monocular de␶ of a Poisson process with mean rate ␯. Thus, this form of covarianceprivation effects to robustly occur. To illustrate this, we study aarises from imagining that the input firing rates averaged over a time
simple modification of the model that incorporates homeostaticcomparable to ␶ are the relevant variables for the plasticity process [e.g.,plasticity, which forces the average activity level of the postsynsee Stryker (1986) and Butts et al. (2007) for evidence of long timescales
aptic cell to remain roughly constant (Turrigiano et al., 1998;
in early visual system plasticity], although similar covariance structure
Maffei et al., 2004; Turrigiano and Nelson, 2004; Mrsic-Flogel etmight arise in other ways. The LGN input firing rates from the contralateral and ipsilateral eyes in that time step are then given by hC ⫽ [ĥC]⫹ andal., 2007; Kaneko et al., 2008), as well as correlation-based plashI ⫽ [ĥI]⫹. Here, [ 䡠 ]⫹ is the half rectification function [x]⫹ ⫽ x, x ⱖ 0;
ticity, and show that under it the entire developmental sequence⫽ 0, otherwise.
is more robustly replicated. An initial condition of synaptic
The firing rate, r, of a V1 neuron at position xi and at time step t isweights consisting of ipsilateral-eye-dominated patches in a condetermined by self-consistently solving (see below)

冉tinuous sea of contralateral-eye input is stable when inhibition is
weak. After maturation of inhibition, an equalized, periodicallyalternating ocular dominance pattern emerges, but monoculardeprivation still causes an ocular dominance shift. In summary,assuming that the onset of the critical period in cats coincides
with a maturation of inhibition that depends on the eyes being
open, as in mice, this and activity-dependent learning rules cansuffice to explain the interocular equalization observed at theonset of the critical period in cats and its failure to occur underbinocular deprivation (Crair et al., 1998).

Materials and Methods
Model. We model N ⫽ 100 pyramidal neurons in primary visual cortex
receiving input from LGN (see Fig. 1). These neurons are uniformly
distributed on a one-dimensional axis x (⫺1 ⬍ xⱕ 1). The ends of thisone-dimensional axis are connected, i.e., we use periodic boundary conditions. The model has only two inputs, one representing the contralateral eye ( C) and one the ipsilateral eye ( I). Each V1 neuron receives aconnection from each of these two inputs.
We use this very simplified model because it contains the key ingredients needed to understand the problems of ocular dominance map formation, and in particular of ocular equalization and the role of inhibitionin this process, while simplifying analysis and simulation-based parameter exploration. Our analysis of the 1-D system in terms of eigenmodes
and constraints (supplemental material, available at www.jneurosci.org)

r 共 x i兲 ⫽

冋冘

a⫽C,I

冉冊

冊

w a 共 x i 兲 h a ⫹ ␴␰ 共 x i 兲 ⫹

2
N

冘
j

M 共 x i ⫺ x j兲 r 共 x j兲 ⫺ T

册

.
⫹

(1)
Here, wC and wI are the synaptic weights of the contralateral and ipsilateral input, and M(xi ⫺ xj) represents the strength and sign of intracortical
input between the cells at positions xi and xj (described in more detailbelow). The noise variance is ␴ 2 and ␰ is a Gaussian random variable withmean 0 and variance 1. As we explain in the Results, noise is required toinduce an OD shift after MD given lateral interactions with strong
enough inhibition to cause equalization. The noise level, ␴, is varied in
Results and its effects discussed. The factor 2/N represents the interval
between adjacent neurons (N neurons over a cortex of length 2), and ischosen so that the total strength of intracortical input stays roughly fixed
as N changes. T ⫽ 1 Hz is a fixed threshold.
Equation 1 is solved by iteration, as follows. Let r(t) represent thesolution for the vector of firing rates across all spatial positions at time t,
and let r(t, n) represent the nth iteration toward the solution r(t). For t ⫽0, the first iteration, r(t, 1), is set to 0; for t ⬎ 0, it is set to the solution of
the previous time step. Then, for each n ⫽ 2, 3, . . . , r(t, n ⫺ 1) is used forthe right side of Eq. 1, and the resulting left side is r(t, n). Iterations
continue until the criterion 兩ri(t, n) ⫺ ri(t, n ⫺ 1)兩 ⬍ 10 ⫺3([1/N]⌺iri(t,n ⫺ 1)) is met for all i at n ' nc. At this point the solution is taken to be

Toyoizumi and Miller • Equalization of Ocular Dominance Columns

6516 • J. Neurosci., May 20, 2009 • 29(20):6514 – 6525

r(t)⫽ r(t, nc). We used two parameter sets in the main text, described
below: for parameter set 1, convergence typically requires 20 –50 iterations and never ⬎70; for parameter set 2, convergence typically requires
10 –20 iterations and never ⬎30. Our iteration criterion is very conservative: simply running 20 iterations without an explicit convergence criterion gave indistinguishable results with both parameter sets. The random variables—the input from the two eyes and the noise ␰—are fixed
throughout the iterations for a given time step, but vary from time step totime step.
The strength of the intracortical connection is only a function of thedifference of two neurons’ cortical positions and is set to a difference ofGaussians (DOG):

M 共 ⌬x 兲 ⫽ M A

冋冑

1

冉 冊 冑

exp ⫺
2

2 ␲␴ ⫹

冉 冊册

⌬x2
R
⌬x2
⫺
exp
⫺
2
2
2
2␴⫹
2␴⫺
2␲␴⫺

(2)

with ␴⫹ ⫽ 0.05 and ␴⫺ ⫽ 0.20. Here, MA parameterizes the strength ofrecurrent versus feedforward contributions to r, while R is the ratio of theintegral of the inhibitory part of the DOG to the integral of the excitatory
part of the DOG. Thus, for R ⫽ 1, each cell receives equal strengths oftotal inhibitory and total excitatory input. The specific choices of ␴⫹ and␴⫺ are not important to the results; all that is important is that, when
inhibition is strong enough to yield equalization (see Results), the DOG
select a nonzero spatial frequency whose cycle length spans a reasonable
number of cells (so that effects of the discrete grid of cells do not become
crucial) but spans only a fraction of the total grid (so that there can be atmultiple cycles of each eye’s dominance within the grid). The ranges ofMA and R that give appropriate outcomes are described in Results. For
the Hebbian model of synaptic plasticity with subtractive constraints,
described below, for which only a narrow range of MA gives appropriate
outcomes, the range of MA that works varies as the ratio of ␴⫹/␴⫺ varies.
The DOG function is not meant to be a realistic model of corticalconnectivity, which is three-dimensional and cell specific and develops
along with the geniculocortical weights. However, it should be noted thata DOG can be achieved with short-range inhibitory connections andlonger-range excitatory connections, as is observed in cortex, if feedback
inhibition (the product of E3I and I3E weights) is sufficiently strong,and either E3E connections fall off more quickly with distance than E3I
connections, or the two have the same distance dependence but inhibition is fast relative to excitation (the latter scenario is discussed in Kang etal., 2003; Pinto and Ermentrout, 2001).
More generally, the model requires only that the patterns of corticalactivity have appropriate relative strengths of periodic activity and of
spatially uniform (or low-spatial-frequency) activity, with the latter being suppressed relative to the former by inhibition. The DOG is a simple
way to achieve this, but any circuitry that achieves this will yield the samemodel behavior. Given that ocular dominance segregation occurs andthat low-spatial-frequency activity is relatively suppressed, ocular dominance will then tend to develop with a spatial period across cortex
matching the spatial period of the cortical activity. Consistent with thesemore general ideas, periodic patterns of activity exist in V1 relatively earlyin development; these patterns are found in monocular as well as binocular cortex, so that they are not simply a consequence of ocular dominance segregation; and the early and weak physiological segregation ofocular dominance occurs with a spatial period that appears to match thespatial period of this activity (Chiu and Weliky, 2002).
We model the onset of the critical period (CP) as an increase in R. For
simplicity, this increase occurs abruptly in the model, but this is notnecessary for the results. During the CP, we model monocular deprivation (MD) to the contralateral eye as reductions in ␯C and in c by acommon factor fMD ⫽ 1/10 unless otherwise stated. The between-eye
correlation, c, is set to a nonzero value even during MD here, but setting
this to zero did not change the results (data not shown). Nonzero interocular correlations during MD could arise due to residual visual signals
thorough an eyelid and/or due to correlations induced by cortical feedback to LGN, as has been observed in pre-CP ferret LGN (Weliky andKatz, 1999).
We focused on two sets of parameters in this paper. The values of thoseparameters at different developmental phases (each phase, before CP,

Table 1. The values of parameters before the CP, during the CP, and during MD
Parameter set 1
Parameter set 2

MAR␴

Before CP

CP/MD

Before CP

CP/MD

1.1
0.3
10 Hz/␶

1.1
1.2
10 Hz/␶

0.8
0.3
1 Hz/␶

0.8
1.0
1 Hz/␶

during CP, and during MD, has 1.0 ⫻ 10 5 time steps) are summarized inTable 1. The reasons for these values are established in the Results.
Learning rule. The initial condition for synaptic weights is “islands” ofipsilateral inputs in a “sea” of contralateral inputs, illustrated in Figure
2b. The synaptic strengths between the V1 neurons and LGN inputs are
updated at each time step by one of two activity-dependent synaptic
update rules. The first learning rule is a simple Hebbian learning rule witha subtractive normalization constraint, which forces the total synaptic
strength received by a postsynaptic cell to remain constant (Miller et al.,
1989; Miller and MacKay, 1994; Erwin and Miller, 1998). In the unconstrained Hebbian learning rule, the change dwa(xi) in the synaptic
strength wa(xi) in one time step (where a ⫽ C, I is the index describing
either the contralateral or the ipsilateral eye) is described by

dw a 共 x i 兲 ⫽ ␣ h a 关 r 共 x i 兲 ⫺ ␳ r៮ 共 x i 兲兴 ,(3)

where ␳ is a constant coefficient for the LTP/LTD threshold (see below
for explanation), r៮ is the running average of the output firing rate, updated at each time step by⌬r៮ 共 x i ,t 兲 ⫽ ␤ 共 r 共 x i ,t 兲 ⫺ r៮ 共 x i ,t ⫺ 1 兲兲

(4)with ␤ ⫽ 0.02. This means that the average is a discrete version of an
exponential average across previous time steps with time constant 50
time steps. This is a long enough averaging time to obtain a reasonable(not too noisy) estimate of the average firing rates under the input ensemble for fixed weights, and short enough that it can track changes inaverage firing rates due to changes in weights. The learning rate is set to␣ ⫽ 2.0 ⫻ 10 ⫺5/Hz 2. This number is fairly arbitrary. This rate should besmall enough that learning is shaped by the average input statistics (thatis, a reasonable sample of the input ensemble is seen over a time in whichweight change is negligible), rather than having large changes in weights
induced by individual input instantiations (“one-shot learning”). It
should also be small enough that the discrete-time dynamics we use wellapproximates continuous-time dynamics. Both will be true if the time
constant is small enough that making it smaller, while making the number of time steps proportionately larger, does not appreciably change theresults. The value used is far below this threshold. Otherwise the number
is simply chosen to make the outcome for a given condition (pre-CP,
post-CP, post-CP-with-MD) equilibrate in the 10 5 time steps we used foreach condition.
One interpretation of the plasticity rule of Equation 6 is that theamount of postsynaptic activity needed to cause potentiation varies depending on the mean postsynaptic rate r៮. However, it can also be interpreted as a statistical model of the relative rate of individual potentiationand depression events that themselves have fixed requirements for presynaptic and postsynaptic activities. Under simple models of spiketiming-dependent plasticity (STDP) (Song et al., 2000; Gerstner andKistler, 2002) [but e.g., see critique in Lisman and Spruston (2005)],
potentiation occurs when postsynaptic spike follows presynaptic spikewithin a fixed window, the rate of which depends on pre–post correlation(the product of the mean presynaptic and postsynaptic spike rates plus
the covariance between them), while depression occurs when postsynaptic spike occurs within a fixed window before the presynaptic spike, therate of which only depends on the product of mean presynaptic andpostsynaptic spike rates. (Input temporal correlations may lead the depression rate also to have some dependence on pre–post covariance, but
we neglect that here.) After averaging over the input ensemble for a given
value of weights, Equation 3 says that the weight change depends on the
difference between the pre–post correlation, represented in our rate
model by the term har, and the product of the presynaptic and postsyn-

Toyoizumi and Miller • Equalization of Ocular Dominance Columns

B 2.5

x

C 2.5

2

2

1.5

1.5

w

contralateralw

A

J. Neurosci., May 20, 2009 • 29(20):6514 – 6525 • 6517

1

0.5

0.5
0
−1

0
−1

−0.5

ipsilateral

0

x

0.5

2

2

1.5

1.5

w

w

E 2.5

1

x

0

0.5

1

−0.5

x

0

0.5

1

1

0.5

0.5
0
−1

−0.5

1

D 2.5
x

step

1

−0.5

0

x

0.5

1

0
−1

Figure 2. The evolution of synaptic weights using a Hebbian learning rule with subtractive weight normalization (Eq. 6). A, The evolution of synapses carrying information from the contralateral(top) and ipsilateral (bottom) eye. Synaptic strengths are shown as color, ranging from zero (blue) to maximal (dark red). Vertical axis is position along the one-dimensional cortical grid. Horizontal
axis is time: the CP starts at time 1 (10 5 iterations), and MD of the contralateral eye is initiated at time 2 (2 ⫻ 10 5 iterations). B–E, Snapshots of the synaptic strengths from the contralateral eye(red) and from the ipsilateral eye (blue) at different times: initial state, time 0 (B); before CP, time 1 (C); during CP but before MD, time 2 (D); and after MD, time 3 (E). Vertical axis, Synaptic strength;
horizontal axis, position along the cortical grid.
aptic mean rates, represented here by the term har៮. The parameter ␳ in
Equation 6, which determines the relative size of the two terms, corresponds to the ratio of the absolute value of the integral of the negative or
depressing part of the temporal function describing STDP (this function
tells the weight change for a given time interval between presynaptic andpostsynaptic spikes) to the integral of the positive or potentiating part[e.g., see Song et al. (2000), where the depressing part is assumed to havethe larger integral].
We use ␳ ⫽ 0.3 for the simulations in the main text. This corresponds
to the assumption that, when inputs and outputs are uncorrelated, potentiation strongly dominates over depression. This assumption appears
to be true for plasticity based on spike bursts in early development in the
LGN (Butts et al., 2007), and more generally the potentiating part of the
STDP temporal function may have larger integral than the depressing
part in some cortical systems [Abbott and Nelson (2000), their Fig. 2a].
As we will show, this assumption is important for monocular deprivation
effects to arise along with equalization under the Hebbian learning rulewith subtractive normalization. The second learning rule we will study
gives a more robust solution to this problem with a more firmly established biological basis.
The normalization constraint is imposed by setting the total change⌬wa(xi) in the synaptic strength per time step to1⌬w a 共 x i 兲 ⫽ dw a 共 x i 兲 ⫺ 关 dw C 共 x i 兲 ⫹ dw I 共 x i 兲兴 .
2

(5)This ensures that ⌬wC(xi) ⫹ ⌬wI(xi) ⫽ 0, and thus that the sum ofipsilateral- and contralateral-synaptic strengths at each location xi,
wC(xi) ⫹ ⌬wI(xi), is constant. Equation 5 can be rewritten␣⌬w a 共 x i 兲 ⫽ 共 h a ⫺ h b 兲关 r 共 x i 兲 ⫺ ␳ r៮ 共 x i 兲兴 ,2

(6)

where b is the opposite eye to a. For this learning rule, synapses change
their values within limits that keep synapses excitatory and bounded: theminimum and the maximum values are wmin ⫽ 0 and wmax ⫽ 2, respectively. If a change in a synaptic weight under the above rules would exceed
these limits, the weight is instead set to the limit. This can cause thesubtractive weight normalization constraint to be violated. The lower
weight limit enforces the biological fact that geniculocortical synapses are
excitatory. Without an upper weight limit, the weights can grow arbitrarily large (because weights hitting the lower limit violate the normalization constraint), so the upper limit is imposed to prevent this, but the
precise value of this limit does not affect results.
Another learning rule is described by a Hebbian learning rule with ahomeostatic constraint, which forces the average activity level of thepostsynaptic cell to remain roughly constant (Turrigiano et al., 1998;
Maffei et al., 2004; Turrigiano and Nelson, 2004; Mrsic-Flogel et al., 2007;
Kaneko et al., 2008). In this case, the changes in synaptic strength are
given by⌬w a 共 x i 兲 ⫽ ␣ 兵 h a 关 r 共 x i 兲 ⫺ ␪ 共 x i 兲兴 ⫺ ␥ 共 w a 共 x i 兲兲 2 其(7)with a sliding threshold ␪ ⫽ r៮ 2/r0. The learning rate is set to ␣ ⫽ 5.0 ⫻10 ⫺6/Hz 2 (a quarter the size used for the previous rule to keep the rates
of monocular deprivation effects approximately equal in the two rules),the reference firing rate is r0 ⫽ 10 Hz, and the synaptic decay coefficientis ␥ ⫽ 10 Hz 2 for ha ⬎ 1 Hz and ␥ ⫽ 0 otherwise. The dependency of ␥ onpresynaptic activity makes the learning rule consistent with observations
that LTD does not occur when there is no presynaptic activity (Rittenhouse, 1999; Frenkel and Bear, 2004; Heynen, 2003). Setting ␥ to a constant does not change the results of this paper except for the fMD ⬇ 0behavior in Figure 7. The nonzero value of ␥ sets the speed of effects of
MD on the deprived eye and also determines the maximum synaptic
weight. [After this work was completed, Linden et al. (2009) suggested adifferent interpretation of the monocular inactivation experiment.]
Other factors are as in the previous rule.
The learning rule of Equation 7 is a combination of Hebbian plasticity
and homeostatic regulation because the postsynaptic threshold separating LTP from LTD changes faster than linearly with the recent mean
postsynaptic firing rate (whereas in Eq. 3, this dependence is linear). The
activity-dependent threshold ␪ with a faster-than-linear dependence on r៮
is a key feature of the BCM learning rule (Bienenstock et al., 1982; Cooper
et al., 2004). It has the effect of causing a nonspecific increase in synaptic
weights if r៮ ⬍⬍ r0 and a nonspecific decrease in synaptic weights if r៮ ⬎⬎ r0,

6518 • J. Neurosci., May 20, 2009 • 29(20):6514 – 6525

thus forcing the average activity to approach r៮ ⬇ r0. Thus, it provides asimple mathematical implementation of a homeostatic constraint. Thisparticular, sliding-threshold form of the homeostatic rule is not criticalto the results; we have obtained similar results with a rule in which thehomeostatic constraint was enforced by a term separate from the LTP/
LTD term (see Discussion). The decay term ⫺␥(wa(xi)) 2 ensures thatsynapses with small but nonzero presynaptic activity (ha ⬎ 1 Hz) decay
back to zero in the absence of sufficiently strong pre/post correlations.
This ensures that, under monocular deprivation, the deprived-eye synapses weaken before the open-eye synapses strengthen. Again, this canalternatively be addressed by using separate homeostatic and LTP/LTD
terms (see Discussion). For this learning rule we only enforced a minimum value of synaptic strength, wmin ⫽ 0. Again, if a change in a synaptic
weight under the above rule would exceed this limit, the weight is instead
set to wmin. We set no explicit maximum value because the weight decay
term keeps synaptic weights from growing too large.

Results
We begin by describing the basic intuition and mathematics behind our results, then demonstrate the results in simulations.
To understand how sufficiently strong inhibition can force
equalization, we rely on the following basic intuition about Hebbian rules (Miller, 1990, 1996). If activation of cortical location A
tends to cause excitation of cortical location B, then inputs to A
tend to promote development of coactive inputs to B. This isbecause the inputs to A tend to activate the A cells, hence to cause
excitation at B, and hence to assist coactive inputs at B in becoming strengthened by a Hebbian mechanism. Conversely, if activation of cortical location A tends to cause inhibition of corticallocation B, then inputs to A tend to suppress development ofcoactive inputs to B. Now suppose recurrently driven inhibition
becomes strong enough that the integrated effect on any one
cortical location of activating all of cortex is inhibition. Assuminginteractions are sufficiently localized, this means that a large
enough region dominated by one eye will tend to suppress development of that eye’s inputs at the center of the region, which inmost competitive scenarios will lead to development of the othereye’s inputs there. Thus, any large region dominated by one eye
must break up and allow emergence of the other eye’s inputs.
Mathematically, this can be seen from the analysis of simple
models of ocular dominance development involving a Hebbianlearning rule and conservation of total postsynaptic strength(Miller et al., 1989; Miller, 1990; Erwin and Miller, 1998) [see also
Swindale (1980), their Appendix, and supplemental material,
available at www.jneurosci.org]. It was shown that, if input correlations are such as to lead to the development of ocular dominance segregation, the overall period of this segregation is determined by an intracortical interaction function K(x) describing
the influence of activity at one cortical location on activity at
another location a distance x away. In particular, the growth of aperiodic pattern of ocular dominance with period 2␲/k occurs at
a rate K̃(k) ⫽ (1 ⫺ M̃(k)) ⫺1, where M(x) describes the strengthand sign of connection between two neurons separated by distance 兩x兩 and M̃(k) is the Fourier transform of M(x) at frequency
k. In this picture, all patterns with nonzero k involve a periodic
oscillation between the eyes (the “AC’’ patterns) and thus involve
overall equality of the two eyes. Inequality can arise only if thepattern with k ⫽ 0 (the “DC” pattern—the pattern in which one
eye dominates everywhere) can grow. The growth rate of the DC
pattern is K̃(0) ⫽ (1 ⫺ M̃(0)) ⫺1, where M̃(0) is proportional tothe integral over space of the intracortical connectivity: M̃(0) ⬀兰dxM(x). Thus, for dominant inhibition, M̃(0) ⬍ 0, and as thedominance of inhibition increases, M̃(0) becomes increasingly
negative and the corresponding growth rate K̃(0) becomes in-

Toyoizumi and Miller • Equalization of Ocular Dominance Columns

creasingly small. If the growth rate of the DC pattern K̃(0) is
sufficiently small relative to those of the fastest-growing AC patterns K̃(k) with k ⫽ 0, then, given reasonable nonlinearities (forexample, limiting the synaptic strengths to remain positive andsmaller than some maximum), the pattern with k ⫽ 0 will be
suppressed in favor of patterns with nonzero k. This causes any
inequality between the eyes to be eliminated (for further analysis,
see supplemental material, available at www.jneurosci.org). The
basic intuition behind this analysis—that if a given location receives strong enough net inhibition from all other locations, thisprevents overall domination by a single eye—is likely to be robust
across a variety of proposed ocular dominance models.
An additional requirement for a realistic model is that, although the strong inhibition enforces overall equality of the twoeyes when they have equal activities, it still allows the development of inequality in response to monocular deprivation (MD).
Let us refer to the two eyes as the open and the closed eye, even
before MD is initiated. Once inhibition matures and the two eyes
equalize, activation of the open eye elicits net inhibition in columns dominated by the closed eye. This is due both to inhibition
from columns dominated by the open eye and to the fact that
open-eye inputs to the closed-eye columns have become very
weak. After MD is initiated, it remains true that activation of theopen eye leads to inhibition of cells that were dominated by theclosed eye, even if MD leads to loss of strength of the closed-eye
inputs. Thus, for an OD shift to occur under MD, something
must strengthen open-eye inputs to closed-eye columns evenwhen they cannot drive the postsynaptic cell, as has been observed in experiments (Mioche and Singer, 1989). These inputs
must be strengthened to the point that they can drive the cellwhen the open eye is activated despite the inhibition from openeye-dominated columns. We show that noise in postsynaptic firing can contribute to this, and more generally, homeostatic plasticity can accomplish this. Since this work was largely completed,it has indeed been shown that homeostatic plasticity is the mechanism causing strengthening of the open eye after MD (Kaneko etal., 2008). (Homeostatic weakening of inhibition onto these cells
could be part of this process, but for simplicity we do not model
inhibitory plasticity here.)
We demonstrate the effectiveness of these ideas in simulationsof a one-dimensional grid of cortical cells each receiving two
inputs, one representing each eye, where the weights of the input
synapses develop under simple learning rules (see Fig. 1). We
model N ⫽ 100 excitatory layer 4 neurons in primary visual cortex, which are uniformly distributed on a one-dimensional axis x(⫺1 ⬍ x ⱕ 1), where each neuron is labeled by its cortical position x. Each V1 neuron receives input from both the contralateral( C) and the ipsilateral ( I) eye, from other V1 neurons throughintracortical connections, and additional noisy input modeled as
Gaussian random noise with mean 0 and variance ␴ 2. For simplicity we consider the feedforward connections from a given eye
to a cortical cell to be described by one effective input, which has
been shown to be adequate to understand the development ofpatterning across cortex of ocular dominance when input correlations are appropriate to yield ocular dominance segregation(Miller et al., 1989; Miller, 1990, 1996). These feedforward synaptic strengths from the contralateral and ipsilateral eyes to aneuron at position x are described by wC(x) and wI(x), respectively, and they are subject to activity-dependent plasticity (seeMaterials and Methods). The strength of the intracortical connection between two neurons is modeled as a function of thedifference of their positions and is set to a difference of Gaussians(DOG). As discussed in Materials and Methods, the key require-Toyoizumi and Miller • Equalization of Ocular Dominance Columns

A

J. Neurosci., May 20, 2009 • 29(20):6514 – 6525 • 6519

B

x
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tic firing rates, subject to a constraint thatthe total synaptic strength to each cell isheld constant, which forces a competition
between the eyes (Miller et al., 1989;
Miller, 1990; Erwin and Miller, 1998) (seeMaterials and Methods). Each synapse ispotentiated or depressed until it saturates
to the upper or lower bound of synaptic
strength (wmax ⫽ 2 and wmin ⫽ 0, respecipsilateral
ipsilateral
tively). We take as our initial condition thestrong bias observed in pre-critical-periodcats (Crair et al., 1998): ipsilateral “islands” in a “sea” of contralateral inputs(Fig. 2 B). Development before the critical
period, modeled as a period in which intracortical inhibition is relatively weak
step
step
(the integral of intracortical inhibition isCDcontralateralcontralateral
3/10 of that of intracortical excitation, that
is, R ⫽ 0.3), leads synapses to go to the
maximum or minimum allowed values
with no change in the overall,
contralateral-dominated pattern (Fig.
2C). Initiation of the critical period, modeled as an increase of the strength of intracortical inhibition (the integral of intraipsilateral
ipsilateral
cortical inhibition becomes 1.2 times thatof intracortical excitation, R ⫽ 1.2), slowly
leads to an equalization of the two eyes
(Fig. 2 D). Although inhibition drives thetwo eyes to have equal innervation, monocular deprivation (MD) of the contralateral eye causes a shift in favor of the open,
step
step
ipsilateral eye (Fig. 2 E). Here, MD of the
Figure 3. Parameter dependence of the development of OD columns using a Hebbian learning rule with subtractive weight contralateral eye is modeled as a reduction
normalization (Eq. 6). Panels plot synaptic strengths in color as a function of cortical position, x, and simulated time steps as in in its activity (mean, variance, and covariFigure 2 A. Explicitly mentioned parameters are changed, whereas the other parameters are as in the parameter set 1. The learning ance with the open eye) by a factor fMD ⫽rule of Equation 6 is sensitive to parameter choices: with intracortical connections that are too weak, MA ⫽ 1.0, the two eyes do 1/10 (see Materials and Methods).
not equalize even after the maturation of inhibition (A); with inhibition during the CP that is too weak, R ⫽ 1.0, the two eyes do
The outcomes under this rule are sennot equalize (B); with too little noise, ␴ 2 ⫽ 3 Hz/␶, almost no OD shift is observed during the simulated MD (C). D, For balanced sitive to parameter choices in at least two
LTP and LTD, ␳ ⫽ 1.0, no OD shift is observed after MD.
ways. First, they are very sensitive to theparameters describing intracortical interment is not that cortical circuitry be described by a DOG, but that
actions. If MA, the strength of recurrent connections relative tofeedforward, is too weak after the CP (such as MA ⫽ 1.0; we usedthe cortical circuitry produce periodic patterns of activity, as has
MA ⫽ 1.1 in Fig. 2), then equalization of the eyes does not occur
been observed (Chiueliky and Weliky, 2002), with the balance
after the onset of the CP (Fig. 3A). Much stronger inhibition
between periodic and spatially uniform patterns of activity varyduring the CP is required in this case for the equalization of OD
ing appropriately with inhibition. The DOG is a simple circuitry
columns (R ⫽ 1.8 equalizes but R ⫽ 1.6 does not: data notthat achieves this. Two important parameters characterize thisshown). On the other hand, if MA is too strong (such as MA ⫽DOG: MA represents the strength of recurrent versus feedforward
contributions to postsynaptic activities, whereas R is the ratio of
1.2), then given weak initial inhibition (R ⫽ 0.3), the system
the integral of the inhibitory part of the DOG to the integral of the
becomes unstable. Strong MA together with stronger inhibition at
the beginning to prevent instability (e.g., MA ⫽ 1.2 and R ⫽ 0.5
excitatory part of the DOG. We model the onset of the criticalduring pre-CP) tends to equalize the OD columns from the beperiod (CP) as a threefold to fourfold increase of cortical inhibiginning of the simulation even before further maturation of intion (Morales et al., 2002). Hence, R changes from an excitationhibition (data not shown). Only a narrow band of MA yields
dominated profile (R ⬍ 1) to a balanced or inhibition-dominatedocular dominance equalization only upon the maturation of inone (R ⱖ 1).
hibition. Moreover, with this model and these parameters, theinhibitory strength does not merely need to equal excitation in
Hebbian learning rule with a subtractive
the intracortical connections, but actually needs to exceed it (wenormalization constraint
use R ⫽ 1.2); R ⫽ 1.0, which represents equality of total excitatory
We first simulate development under a Hebbian learning ruleand total inhibitory strength, does not lead to equalization (seewith subtractive normalization of the total postsynaptic weightFig. 3B).
on a cell (Fig. 2), using the parameter set 1 (see Materials andNote that equalization can occur even with relatively weak
Methods). The modification of synapses at each time step deinhibition when recurrence is strong enough that the system ispends on the covariance between the postsynaptic and presynapcontralateralcontralateral6520 • J. Neurosci., May 20, 2009 • 29(20):6514 – 6525

close to instability, for the following reason. With weak inhibition, the fastest-growing pattern is an “AC’’ pattern with period2␲/kmax for kmax ⫽ 0, but the Fourier transform of the intracortical connection function at this frequency, M̃(kmax), is only
slightly larger than that of the “DC” pattern, M̃(0). With weakerrecurrence, this difference is not sufficient to cause equalization.
However, moving the system close to instability means thatM̃(kmax) becomes close to 1 so that the largest growth rate (1 ⫺M̃(kmax)) ⫺1 becomes both arbitrarily large and arbitrarily larger
than the growth rate (1 ⫺ M̃(0)) ⫺1 of the DC mode, leading toequalization.
Second, for MD to lead to an OD shift despite inhibition
strong enough to cause equalization, active synapses need to havea strong advantage over less active synapses. To achieve this (Fig.
2 E), we needed to use a learning rule in which LTP strongly
dominates over LTD (␳ ⫽ 0.3: see Materials and Methods) alongwith noise in postsynaptic neuronal response. Without these twoelements, equality of the two eyes is maintained even after one
eye’s activity is strongly reduced (see Fig. 3). This is because,
during MD, neurons in the patches dominated by the closed eye
receive more lateral inhibition than excitation as a result of open
eye input. Therefore, the activity levels of these neurons duringopen-eye input are lower than their threshold level, leading todepression of the open-eye synapses onto them. This prevents
any MD shift toward the open eye. Larger noise along with anonlinear input– output relation enables those neurons to besometimes active in the presence of lateral inhibition. If LTP
dominates over LTD, even random presynaptic and postsynaptic
activity leads more active inputs to show relatively greater potentiation than less active inputs. When this is combined with aconstraint preserving total synaptic strength, the result is that
relatively more active synapses are potentiated while less active
synapses are depressed. This allows MD shifts to occur (Fig. 2 E).
These considerations explain why we used parameter set 1 (seeMaterials and Methods) for this model, which included highnoise and a large critical period R and MA. Using parameter set 2(see Materials and Methods) with this model does not yield
equalization of the two eyes (see supplemental material, availableat www.jneurosci.org).
The biological relevance of the dominance of LTP over LTD
assumed here is certainly questionable, but some systems have
temporal windows for spike-timing-dependent plasticity (STDP)
in which integrated potentiation appears larger than integrated
depression [Abbott and Nelson (2000), their Fig. 2a; Butts et al.
(2007)]. More generally, there must be some additional mechanism that leads open-eye synapses to strengthen during MD evenwhen they cannot drive the postsynaptic cell, as observed in experiments (Mioche and Singer, 1989). A more plausible mechanism, and one that in fact seems to drive potentiation of the
open-eye during MD (Kaneko et al., 2008), is homeostatic plasticity, to which we now turn.
Hebbian learning with a homeostatic constraint andweight decay
We reasoned that the fragility of the result presented in the lastsection is likely to be induced by the simplicity of the learning rulestudied, and that more complex biological learning rules may be
more robust. One simple mechanism, though probably not the
only one, that can be added to a Hebbian rule to support suchrobustness is activity homeostasis (Turrigiano et al., 1998; Maffei
et al., 2004; Turrigiano and Nelson, 2004; Mrsic-Flogel et al.,2007; Kaneko et al., 2008): the requirement that cortical cells
adjust their weights to maintain roughly constant overall levels of

Toyoizumi and Miller • Equalization of Ocular Dominance Columns

average activity. Both maturation of inhibition and MD will induce a reduction in the activity level of either all cells or closedeye columns, respectively, and the homeostasis will oppose thisby potentiating unsaturated synapses. This strengthens the initially weak ipsilateral-eye synapses and the weak open-eye synapses in closed-eye columns, allowing them to more robustly
recover from their weakness and compete. Thus, given homeostasis, even relatively weak cortical connections that are sufficiently inhibition-dominated can equalize the two eyes’ innervations in cortex, and a pattern in which the innervations of thetwo eyes are equal can be destabilized by monocular deprivationeven with low noise, as we now show.
In Figure 4 we show the same set of simulations as in Figure 2
but now using a learning rule (Eq. 7) with a homeostatic constraint rather than a weight-conservation constraint. The homeostatic constraint keeps the mean activity level of each postsynaptic
cell roughly constant. For fixed input activities, this behaves similarly to the weight-conservation constraint, but if input activities
are decreased by maturation of inhibition or by MD, the homeostatic constraint increases the total weight received by the cell tobring the postsynaptic activity back to the set point. As an implementation of a homeostatic rule, we used an LTP/LTD thresholdthat slides faster than linearly with the mean postsynaptic activity,
as in the BCM learning rule (see Materials and Methods), but thisparticular implementation is not critical to the results (see Discussion). We also add a weight-decay term to the learning rule for
inputs with nonzero activity, which causes synaptic weights ofthese inputs to decay in the absence of Hebbian or homeostatic
strengthening. This term causes closed-eye synapses to shrink
after MD before open-eye synapses grow, as observed experimentally (Mioche and Singer, 1989; Frenkel and Bear, 2004; MrsicFlogel et al., 2007; Kaneko et al., 2008). This rule is far morerobust than the previous, so we now use parameter set 2 (seeMaterials and Methods), in which noise levels are low, total excitatory and inhibitory strength are equal (R ⫽ 1) during the critical
period, and the parameter controlling the overall strength of recurrent connections, MA, is slightly smaller than before, for reasonsdescribed below. This learning rule also works with parameter set 1(see supplemental material, available at www.jneurosci.org).
The simulation proceeds much as in the previous case (Fig. 4).
Before the critical period, the initial condition of ipsilateral islands in a contralateral sea (Fig. 4 B) is stable (Fig. 4C). Initiationof the CP, modeled as a strengthening of inhibition, leads to theequalization of contralateral- and ipsilateral-eye columns (Fig.
4 D). Application of MD leads to the expansion of the open-eye
territory and the gradual shrinking of the closed-eye territory(Fig. 4 E).
With this learning rule, the equalization of ocular dominancecolumns occurs more robustly. Fine tuning of the strength of theintracortical connections, MA, is not required (Fig. 5A), and inhibition that is balanced with excitation (R ⫽ 1.0, used in Fig. 4)
or even somewhat weaker than excitation (Fig. 5B) is now sufficient to drive equalization. It has been suggested that cortex
shows a rough balance of excitation and inhibition (vanVreeswijk and Sompolinsky, 1998; Shu et al., 2003; Wehr andZador, 2003; Haider et al., 2006; Higley and Contreras, 2006). We
use an approximately threefold increase of inhibitory strength atthe onset of the critical period, consistent with the literature (Morales et al., 2002).
The difference in robustness is due to the different constraints
imposed on the two learning rules. The subtractive constraint
always forces the sum of contralateral- and ipsilateral-synapses tobe constant at each neuron (except when synapses take the max-

Toyoizumi and Miller • Equalization of Ocular Dominance Columns

J. Neurosci., May 20, 2009 • 29(20):6514 – 6525 • 6521

B
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step

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0
−1

Figure 4. The evolution of synaptic weights using a combination of Hebbian and homeostatic learning (Eq. 7); conventions as in Figure 2. A, The evolution of synapses carrying information fromthe contralateral (top) and ipsilateral (bottom) eye, shown as color, versus time (horizontal) and position (vertical). B–E, Snapshots of synaptic strengths from the contralateral eye (red) and fromthe ipsilateral eye (blue) at the initial state (B), before the CP (C), during the CP but before MD (D), and after MD (E).

A

B

Eq. 7 becomes small for these less active
synapses relative to the second, decay
term. The open-eye synapses also shrink
by a small amount due to the loss of
between-eye correlation after MD but are
mostly unchanged because of the intact input from the open-eye. On a slower timescale, the homeostatic learning rule along
ipsilateral
ipsilateralwith a small amount of noise leads the
open-eye synapses to grow. The homeostatic rule drives the mean postsynaptic activity, r៮, estimated as an exponentiallyweighted average of past rates with a time
constant of 50 iterations, to be comparable
to some set point activity level r0. After the
step
step
closure of the contralateral eye, a patch ofcortex that was previously driven by the
Figure 5. Parameter dependence of the development of OD columns under the Hebbian-plus-homeostatic plasticity rule.
closed-eye mainly receives lateral inhibiPanels plot synaptic strengths in color as a function of cortical position, x, and simulated steps as in Figure 2 A or Figure 4 A.
Parameters are from parameter set 2 except where other values are explicitly noted. The homeostatic plasticity rule is more robust tion from the surrounding cortical area
therefore its LTP/LTD threshold, ␪ ⬃to parameter choices: the two eyes equalize after the maturation of inhibition with weak intracortical interactions (A) (MA ⫽ 0.5) andr៮ 2, is close to zero. In the presence of small
or with relatively weak inhibition (B) (R ⫽ 0.8).
noise, those neurons near the border between the two eyes’ columns will be active
imum or minimum value), so where the ipsilateral eye is initiallyoccasionallybecausethey receive relatively weaker inhibition
weak, it can be difficult for it to recover under Hebbian plasticity.
than
at
the
centeroftheclosed-eye dominated column. Hence,
In contrast, the homeostatic constraint lets the summed synaptic
open-eyesynapsesattheborder are slowly potentiated at a rate
strength increase to compensate for the reduction in cortical acproportional to the activation of those neurons with coincident
tivity caused by the sudden maturation of inhibition, so that the
open-eye input until the output firing rate again approaches r0
ipsilateral eye can gain a foothold everywhere. The correlation(Fig. 4 E). On the other hand, around the center of the closed-eye
based competition can then more robustly select the pattern of
dominated column, open-eye synapses cannot grow because latinnervation in which contralateral and ipsilateral synaptic
eral inhibition from the surrounding columns is much stronger
strengths alternate across cortex.
than the noise level. The growth rate of open-eye synapses deWith this learning rule, even a small amount of noise ispends on the noise level, the threshold of the input– output nonenough to see the MD effect (the simulations of Fig. 4 use 1/10 the
linearity and the strength of inhibition during the CP. Smaller
noise of those of Fig. 2). In the absence of strong input from LGN,
noise, larger threshold or stronger lateral inhibition reduces thethe closed-eye synapses shrink after MD because the first term of

x

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x

contralateralcontralateralToyoizumi and Miller • Equalization of Ocular Dominance Columns

6522 • J. Neurosci., May 20, 2009 • 29(20):6514 – 6525

4

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x

firing rates of neurons in previouslyA
contralateralclosed-eye-dominated patches and hence
slows the growth of open-eye synapses
Cthere (compare Figs. 4 A, 5B).
In the simulations presented thus far,
ipsilateral
the equalization of the two eyes is achievedby adding columns for the ipsilateral eye,so that the overall spatial wavelength of the
OD columns is reduced. This issue has notbeen studied quantitatively, and maps
step
were not followed across time in single anB
contralateralimals in Crair et al. (1998, 2001). However,the data in those papers are suggestive thatthe wavelength does not greatly change.
This can be achieved in the model for apipsilateral
propriate parameters. To show this, wefirst start the simulation from a contralaterally dominated initial condition with asmaller wavelength than previously. Wheninhibition matures, the two eyes are equalstep
ized, as in previous simulations, but the
wavelength of OD columns is not altered Figure 6. The spacing of ocular dominance columns is determined also by the initial condition: the evolution of synaptic(Fig. 6 A). Starting from an even smaller weights with the Hebbian-plus-homeostatic learning rule of Equation 7, starting from an intermediate (4 cycles; A) or high (6wavelength without altering the intracor- cycles; B) spatial frequency pattern of initial synaptic strengths. The evolution of synapses carrying information from the contical connections, the equalized OD col- tralateral (top) and ipsilateral (bottom) eye, shown as color, versus time (horizontal) and position (vertical). C, The final spatialumns still preserve the wavelength of the frequency (in cycles) of the ocular dominance columns, shown in color, as a function of the spatial frequency of the initial condition
initial condition (Fig. 6 B). In general, the and the strength of the intracortical connections, MA. The peak of the power spectrum of the function M, which describes
intracortical connections, peaked at ⬃4 cycles. The spatial frequency of the final OD column was close to the spatial frequency of
final spatial wavelength of the OD col- the initial weight pattern when M was not too large and when the spatial frequency of the initial weight pattern was three to sixAumns is determined both by the amplitude cycles close to the four-cycle spectrum
peak of M; otherwise the frequency of the final OD columns was set by the spectrum peakof each wavelength in the initial condition of M. (For better spatial resolution, N ⫽ 400 neurons were simulated instead of N ⫽ 100 in this panel.) The cortex did not equalize
and the growth rates of the different wave- (the synaptic strength from one eye exceeded 60% of the total) within the simulation time when MA was too small (shown as
lengths (as noted previously, the growth white color). The cortex equalized before the maturation of inhibition when MA was too big (shown as black).
rates are proportional to (1 ⫺ M̃(k)) ⫺1,
where the wavelength is 2␲/k and M̃(k) isABthe Fourier transform at that wavelengthof the function describing intracorticalE
connections). The wavelength with thefastest growth rate will tend to dominate,
but if other wavelengths have a strong adx
xvantage in the initial condition and are notCD
too disadvantaged in terms of growth rate,they may dominate instead (Fig. 6C).
Weakening the intracortical connections,as we have done in parameter set 2 by def MD
creasing MA from 1.1 to 0.8, lessens thedifferences between growth rates, and soxx
allows bias in the initial condition toward agiven wavelength to control the final out- Figure 7. The synaptic strengths from the contralateral eye (red) and the ipsilateral eye (blue) after MD using the Hebbiancome over a wider range of wavelengths. plus-homosynaptic plasticity rule. The figure shows the results for different values of fMD: 0 (A), 0.2 (B), 0.8 (C), and 1 (D). E, The
Thus, for different parameters, the final mean strength of the open-eye (ipsi) and closed-eye (contra) synapses after MD for differing values of fMD during MD.
wavelength may be determined either by
the intracortical connections or by the initial condition (or both).
strengths and an increase of open-eye synapses as discussed above
Regardless of the choice of parameters controlling this feature,(Fig. 7 A, B) (as fMD approaches zero, the MD effect almost disaphowever, it seems to be a robust phenomenon that maturation ofpears, because the rate of firing of the closed-eye inputs falls
inhibition equalizes the two eyes’ innervations in cortex.
below the threshold for the LTD induced by weight decay, see
The MD effect in this scenario depends on the degree of weakMaterials and Methods). However, if fMD is larger than 0.7, weening of the closed-eye activity. To investigate this effect, we sysobserve an increase of closed-eye synaptic strengths (see Fig. 7C).
tematically varied the strength of the closed-eye activity (mean,
In this case, the homeostatic rule leads to an increase in closedvariance, and covariance with the open-eye) by a factor fMD thateye synapses rather than in open-eye synapses to compensate forwas varied from zero to one. Figure 7 shows the mean strength ofthe decreased postsynaptic activity. Although, the precise fMD
both the closed-eye and open-eye synapses after MD. If fMD isvalue for this switching behavior depends on parameters such as
smaller than 0.6, we see a decrease of closed-eye synaptic
the weight decay coefficient ␥ [making ␥ smaller makes the
1

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Toyoizumi and Miller • Equalization of Ocular Dominance Columns

closed-eye-potentiating domain larger (see supplemental material, available at www.jneurosci.org)], the qualitative feature
seems to be robust. That is, if it were possible experimentally to
induce a weak decrease in one eye’s firing, one should see a homeostatic increase in that eye’s synaptic strength, rather than the
deprivation effect that occurs with a strong decrease in the eye’s
firing. This kind of partial decrease of the LGN activity corresponding to one eye might be achievable with a weakly blurring
contact lens that reduces the effective contrast of stimuli seen
through one eye. Finally, if fMD ⫽ 1, as a control case, we see nosignificant changes in synaptic weights (see Fig. 7D).

Discussion
We have shown that the equalization of the input serving the twoeyes that occurs at the onset of the critical period (CP) in cat V1,
its failure to occur in the absence of visual experience (Crair et al.,1998), and the ability of monocular deprivation to drive oculardominance shifts despite the tendency of cortex to equalize thetwo eyes’ innervations, can all be understood from activitydependent rules of synaptic plasticity along with an experiencedependent maturation of inhibition at the onset of the CP like thatobserved in mice (Hensch et al., 1998; Fagiolini and Hensch, 2000).
While the models used to demonstrate this are simple and imperfect,
the underlying principles they expose are general and robust:(1) Inhibition that is sufficiently strong will drive the innervations of the two eyes to equalize if they have comparable activities.
(2) To nonetheless obtain ocular dominance shifts in response
to monocular deprivation, some mechanism must enable excitatory synapses driven by the open eye to grow under MD in closedeye-dominated regions, even when they cannot activate thepostsynaptic cell, as is known to occur in vivo (Mioche andSinger, 1989). These synapses cannot activate the postsynaptic
cell both because they are weak and because inhibition fromopen-eye-dominated regions is strong. Some combination of
weakening of open-eye-driven inhibition and strengthening of
open-eye-driven excitation must occur that brings the open eye
to the point that it can successfully activate the postsynaptic cell.
We have shown that homeostatic plasticity of excitatory synapses, which in fact is implicated in the strengthening of open-eye
synapses after MD (Kaneko et al., 2008b), along with a minimal
amount of noise, is sufficient to achieve this. Alternatively, an
LTP/LTD rule that favors LTP, along with strong noise and a rulesuch as weight normalization to force some synapses to shrink
when others grow, can also achieve this.
Our model makes two clear predictions. First, just as in mice,a maturation of inhibition should occur in cat V1 to initiate theCP, and visual deprivation (which prevents the equalization of
the two eyes) should prevent this maturation. Second, just as
early strengthening of inhibition, induced by infusion of benzodiazepine agonists (Fagiolini and Hensch, 2000; Iwai et al., 2003;
Fagiolini et al., 2004) or excess brain-derived neurotrophic factor
expression (Hanover et al., 1999; Huang et al., 1999), can cause an
early initiation of the CP in mice, such treatment should cause
early equalization of ocular dominance in cat V1. Given the slow
onset of the effects of these treatments, this might most easily beobserved by showing that the treatment rescues the delayed
equalization of ocular dominance caused by visual deprivation.
The simplest rules of correlation-based plasticity with subtractive weight normalization can show equalization of oculardominance in visual cortex, but the results are somewhat fragile:some parameter tuning is needed, and after inhibition leads toequalization, sufficient noise and a learning rule that is biased
toward potentiation are needed for monocular deprivation to

J. Neurosci., May 20, 2009 • 29(20):6514 – 6525 • 6523

induce a loss of equalization. The fundamental problem withthese simple rules is that they tend to push synaptic weights either
to zero or to their maximal allowed values (Miller and MacKay,1994), and they have no robust means by which weights that havebeen pushed to zero can recover after a change in input activity or
in intracortical inhibition, although such recovery may occur forparticular parameter choices. In reality, biology seems to haverobust mechanisms by which even weights that have been driven
to or near zero can bounce back under appropriate conditions(Mioche and Singer, 1989). The simplest learning rules do a reasonable job of modeling the emergence of a pattern from an
initially unpatterned set of synapses, but do not have any robust
mechanism for “unlearning’’ a pattern in which many synapses
have zero or near-zero weights.
We have shown that one simple fix for these problems is foundby adding a homeostatic learning mechanism (Turrigiano et al.,
1998; Maffei et al., 2004; Turrigiano and Nelson, 2004; MrsicFlogel et al., 2007; Kaneko et al., 2008). While under stationary
and homogeneous input, this homeostatic constraint is similar to
the weight normalization of the total synaptic weight on a cell, it
enables weights that are pushed to zero to recover strength if thepostsynaptic cell is not well driven. We used a BCM-like rule
(Bienenstock et al., 1982; Cooper et al., 2004) as a simple mechanism to instantiate this homeostasis, but this mechanism is notcritical. In this rule, homeostasis arises because the thresholdseparating LTP from LTD changes faster than linearly with themean postsynaptic activity. We have obtained similar results(data not shown) using a rule in which one term describes
correlation-based LTP and LTD, without such a faster-thanlinear change in threshold, and a separate term causes synapses tobe multiplicatively scaled in proportion to the deviation of average postsynaptic activity from a desired set point, as suggested byresults on homeostatic synaptic scaling (Turrigiano et al., 1998;
Maffei et al., 2004; Turrigiano and Nelson, 2004; Mrsic-Flogel etal., 2007; Kaneko et al., 2008). Indeed, an empirical problem with
the BCM-like mechanism is that it enforces homeostasis througha subtractive rather than multiplicative change in synaptic
strengths [note, however, homeostatic plasticity in developing
visual cortex can also cause an additive change in neuronal responses by additively modifying the curve of firing rate vs input
current (Maffei and Turrigiano, 2008)]. Multiplicative scalingshows all the same behaviors as the subtractive rule studied here
(data not shown), so long as the minimal weight is above zero (sothat synapses do not reach zero, from which they cannot recoverunder multiplicative scaling) and the LTP/LTD rule produces
LTD of closed-eye synapses under MD.
We modified the BCM-like rule by adding a weight decay term
(Eq. 7). This was necessary to explain the observation that, afterMD, deprived-eye synapses weaken before open-eye synapses
strengthen (Mioche and Singer, 1989; Frenkel and Bear, 2004;
Mrsic-Flogel et al., 2007; Kaneko et al., 2008). This cannot be
captured by the BCM-like rule alone, because the homeostatic
weight regulation and the correlation-based LTP/LTD are in thesame term. The LTP induced by the homeostatic response to theloss of postsynaptic activity thus prevents LTD due todeprivation-induced reduction of presynaptic activity (this problem might be fixed by making the LTP/LTD threshold change
slowly, but then the BCM rule loses stability, leading to weightoscillations). This problem can also alternatively be solved (datanot shown) using a model with separate LTP/LTD and homeostasis terms, as described above, a model we will more systematically study elsewhere.
Mice do not show equalization of the two eyes’ innervations:Toyoizumi and Miller • Equalization of Ocular Dominance Columns

6524 • J. Neurosci., May 20, 2009 • 29(20):6514 – 6525

the binocular segment of mouse V1 remains dominated by thecontralateral eye after the opening of the CP (Gordon andStryker, 1996). Why does the maturation of inhibition not cause
equalization in the mouse? Mice, like other rodents (Van Hooser
et al., 2005), do not have OD columns. We suspect the explanation for the lack of equalization is closely tied to the explanation
for the lack of OD columns. In mathematical and computationalmodels, OD columns arise through a combination of two factors:
cooperative interactions between nearby V1 cells that lead themto tend to receive correlated inputs, and more widespread competitive interactions that ensure that not all cells become dominated by the same inputs (Miller, 1990, 1996). In Hebbian models, the cooperative interactions typically involve excitatory
connections between nearby cells. In this framework, the most
likely explanation for the lack of columnar organization in rodents is that the effective connectivity between nearby neurons
during development is either too weak to organize columns, or isof the wrong sign—net inhibitory rather than excitatory. As wehave seen, strong net inhibition between cells can act as a competitive factor leading to equalization of inputs, so the lack ofequalization may indicate that overall interactions are relatively
weak during development. Note that inhibition onto each cell
can be strong, as presumably occurs after the maturation of inhibition that initiates the CP, without necessarily involving strong
inhibitory effective interactions between excitatory cells, for example if inhibition is predominantly driven by feedforward
rather than recurrent projections.
Mitchell et al. (1977) pointed out a similar problem of equalization: if a transition from MD to normal binocular experience
was made sufficiently early, the originally deprived eye showed asignificant, though not full, recovery both physiologically andbehaviorally. That is, the weaker eye gained while both eyes had
equal activity. They suggested that this might involve an advantage of the deprived eye in competing to reinnervate territory it
lost during MD. This recovery process is now known to require
BDNF (brain-derived neurotrophic factor) signaling, whereas
the processes of MD do not (Kaneko et al., 2008). The equalization we are studying may involve a different mechanism, one testof which would be to determine whether it also requires BDNF.
Swindale (1980) modeled the data of Mitchell et al. (1977) as
dynamic equalization under linear dynamics. He assumed a phenomenological interaction between synapses that depended on theireyes of origin and was a DOG function of their separation in cortex.
The integral of the DOG determined the growth rate of the “DC’’pattern, in which one eye dominates everywhere. He assumed theintegral was negative, so that the DC pattern decayed to zero, yielding ocular equalization. MD added a “source” term to the dynamics
of the DC pattern, causing the more active eye to dominate.
Our explanations of equalization and the ability to achieve
MD effects despite equalization, although similar in spirit to
Swindale’s, differ from his in four respects, as discussed in moredetail in supplemental material (available at www.jneurosci.org):(1) the spatial dependence of Swindale’s phenomenological interaction has been identified, in the limit of spatially broad correlations, with the intracortical interaction function (Miller et al.,1989); (2) with this identification, the growth rate of the DC
pattern is always positive (the growth rate is K̃(0) ⫽ (1 ⫺M̃(0)) ⫺1, where M̃(0) ⬍ 1 and is proportional to the integral of
the DOG describing intracortical connectivity); (3) nonlinear effects, whereby the faster growth of periodic patterns leads to suppression of the DC pattern, therefore are essential to equalization;and (4) to attain MD along with equalization becomes problematic in this scenario, and so requires specific solutions such as

homeostatic plasticity to allow weak synapses to recover andcompete, as we address here.
The idea that intracortical connectivity can create a periodic
organization of receptive field properties and determine its period is an old one (van der Malsburg, 1973; Amari, 1977; Swindale, 1980; Kohonen, 1982; Miller et al., 1989; Castellani et al.,
1999; Ernst et al., 2001; Koulakov and Chklovskii, 2001) Consistent with this idea, genetic factors, which might act by influencing
the structure of intracortical connectivity, contribute to the spacing of cortical orientation and ocular dominance maps (Kaschube et al., 2002, 2003). A recent experiment on cats also demonstrated that a chronic increase in the strength of intracorticalinhibition from large basket cells, which project horizontal axons
at longer distances than other inhibitory cell types, widens the
spacing of ocular dominance columns (Hensch and Stryker,
2004). As those authors noted, this is the expected result from
simple models like those studied here if homeostatic mechanisms
preserved the overall strength of inhibition after its maturation at
the onset of the CP, so that the overall effect of the chronic change
was to relatively increase the strength of longer-range inhibition
versus shorter-range inhibition. In contrast, the overall increasein the strength of inhibition that occurs at the onset of the CP
would not be expected to widen column width.
The question of whether ocular dominance columns are genetically specified or arise through activity-dependent selforganization has been a controversial one in recent years (Crair etal., 2001; Crowley and Katz, 2002; Kaschube et al., 2002, 2003;
Huberman, 2007) (see also Miller et al., 1999 on the same question with respect to orientation columns). In cats, activityindependent genetic factors alone could at most account for thecondition of ipsilateral “islands’’ in a “sea” of contralateral inputs
observed both physiologically and anatomically in the third postnatal week (Crair et al., 1998, 2001), because the subsequentequalization of inputs serving the two eyes and their organization
into ocular dominance columns does not occur without visual experience (Crair et al., 1998). There has been no proposal as to how
this experience-dependent equalization and reorganization could
occur, and it has been repeatedly been argued that it could not be
explained by activity-dependent self-organization (Crair et al., 1998;
Crowley and Katz, 1999; Katz and Crowley, 2002). Here, we haveshown that activity-dependent learning rules, together with a pattern of intracortical interactions that yields ocular dominance columns, provide a simple, robust, and testable explanation.
In summary, we argue that the observation in cat V1 that
ocular dominance equalizes at the onset of the critical period may
simply be a different window on the observation, made in mouse
V1, that the critical period is initiated by the maturation of intracortical inhibition.

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