73
J. Physiol. (1985), 367, pp. 73-98
With 6 text-ftgurem
Printed in Great Britain
NORADRENALINE AND FUNCTIONAL PLASTICITY IN KITTEN
VISUAL CORTEX: A RE-EXAMINATION
BY J. ADRIENt, G. BLANCt, P. BUISSERET§, Y. FREGNAC*,
E. GARY-BOBOII, M. IMBERTII, J. P. TASSINJ AND Y. TROTTERI
From the Laboratoire de Neurobiologie du De'veloppement, Bat. 440, Paris XI,
Orsay, 91405, t Unite' Inserm U3, 91 Bd. de L'HMpital, 75634, Paris,
I Unite Inserm U114, College de France, 75231, Paris,
§Laboratoire de Neurophysiologie, College de France, 75231, Paris, and
ILaboratoire des Neurosciences de la Vision, Paris VI, 75005, Paris, France
(Received 6 July 1984)
SUMMARY
1. A quantitative re-examination was made of the influence of noradrenergic
depletion on the epigenesis of kitten visual cortex. Two methods were used to deplete
noradrenaline at the cortical level: (1) stereotaxically controlled injection of 6hydroxydopamine (6-OHDA) in the coeruleus complex, from which the noradrenergic
input to visual cortex arises; (2) intraventricular injection of 6-OHDA. The latter
chemical lesion also depleted dopamine levels in the brain.
2. Lesion of the noradrenergic or catecholaminergic systems was performed
neonatally or at an age of 3-4 weeks in kittens submitted to five different rearing
procedures: normal rearing, dark rearing, monocular rearing, monocular exposure
following dark rearing and monocular deprivation following normal rearing.
3. Forty-two kittens between 3 and 12 weeks of age were used for this biochemical
and electrophysiological study. Noradrenaline and dopamine levels were measured
by a radioenzymatic method in the primary visual cortex of twenty-six kittens. A
total of 1263 cells were recorded in area 17 of twenty-six kittens. Combined biochemical and electrophysiological data were obtained in ten 6-OHDA-lesioned
kittens.
4. Whatever the mode of chemical lesion used, cortical noradrenergic depletion
failed to block either maturation or vision-dependent processes which are known to
affect orientation selectivity and/or ocular dominance during the critical period.
However, in some cases, the amplitude of the epigenetic functional modifications was
slightly reduced in 6-OHDA-treated kittens.
5. The cortical effects of monocular deprivation starting from the age of 5 weeks
were studied quantitatively both in lesioned and intact kittens. Disappearance of
noradrenaline in area 17 did not prevent the loss of binocularity in cortical cells.
However, even when monocular occlusion had been maintained for 2 or 3 weeks in
6-OHDA-treated kittens, ocular dominance shifts were limited to a stage equivalent
to that observed in the intact kitten after 5-8 days of monocular occlusion.
*
To whom correspondence should be addressed at the Laboratoire de Neurobiologie du
D6veloppement, Bat. 440, Universite Paris XI, Orsay, 91405, Cedex, France.
74
J. ADRIEN AND OTHERS
6. The amplitude of this partial protective effect was found to be unrelated either
to the delay following the chemical lesion, or to the level of noradrenaline remaining
in lesioned kitten cortex.
7. Although a putative gating role of noradrenaline cannot be excluded in the
development of the intact animal, this report shows that its presence is not required
for functional plasticity to occur in kitten area 17.
INTRODUCTION
Noradrenergic ascending projections have for a long time fascinated theoreticians
of brain mechanisms (Crow, 1968; Kety, 1970; Jouvet, 1974; Gilbert, 1975) by their
rather precise origin and the diffuse pattern of their terminals throughout the
neocortical mantle (Nakamura, 1977). Most cell bodies are grouped in a restricted
region of the brain stem formed by the locus coeruleus and the subcoeruleus complex
(Maeda, Pin, Salvert, Ligier & Jouvet, 1973; Moore & Bloom, 1979). Along its course,
one coeruleo-cortical axon forms several thousand monoamine-containing boutons,
only a limited fraction of which appear to be junctional to surrounding neuronal
elements (Descarries, 1974; Morrisson, Grzanna, Molliver & Coyle, 1978; Itakura,
Kasamatsu & Pettigrew, 1981; review in Foote, Bloom & Aston-Jones, 1983). These
characteristics constitute the ideal morphology sought for a global rewarding or
gating system, which could act as a modulator of the transmission of more specific
information, in particular within the neocortex.
Catecholaminergic endings are already present in 6-8-week-old kittens in regions
as distal as the occipital cortex and are mainly confined to the supragranular layers
(Itakura et al. 1981). Retrograde horseradish peroxidase labelling techniques confirm
that areas 17, 18 and 19 of the adult cat receive afferents from locus coeruleus (T6rk,
Leventhal & Stone, 1979). This cortical noradrenergic input could selectively affect
the signal/noise ratio in the processing of sensory information as described at the
lateral geniculate level (Nakai & Takaori, 1974; Rogawski & Aghajanian, 1980). Such
a filtering action might be critically dependent on the arousal state of the behaving
animal (Livingstone & Hubel, 1981).
A more fundamental role of noradrenaline in cortical function comes from the
proposal that the endogenous level of noradrenaline could locally gate epigenetic
modifications of visual cortical neurones in response to visual manipulation (review
in Kasamatsu, 1983). An impressive series of studies gives strong experimental
support for the implication of catecholamines during a critical post-natal period in
modulating the functional cortical effects of monocular deprivation (Kasamatsu &
Pettigrew, 1976, 1979; Kasamatsu, Pettigrew & Ary, 1979, 1981a; Kasamatsu,
Itakura & Jonsson, 1981b). Closure of one eye in 4-6-week-old normally reared
kittens, even for a few hours, produces a disruption of binocular integration, with
most neurones responding only through the remaining eye as the ultimate result of
the deprivation (Hubel & Wiesel, 1970; Movshon & Dirsteler, 1977; Olson &
Freeman, 1980). Kasamatsu and collaborators showed that this effect of environmental manipulation could be completely prevented if the kitten was submitted to
one of two types of chemical lesions shortly before the start of the visual deprivation
75
NORADRENALINE AND VISUAL CORTICAL PLASTICITY
period: (1) intraventricular injection of 6-hydroxydopamine (6-ODHA) (up to 12 mg
in Kasamatsu & Pettigrew, 1979), (2) intracortical perfusion of the same neurotoxin
at a smaller dose (several hundred micrograms in Kasamatsu et al. 1979).
These authors suggested that both protocols produced the same protective effect
because they both depleted the endogenous cortical catecholamine content to below
a certain level. The implication of the intracortical ,-adrenoreceptor adenosine cyclic
monophosphate (cyclic AMP) system was furthermore suggested by the restoration
of cortical sensitivity to monocular deprivation in 6-OHDA pre-treated kittens,
following local perfusion of exogenous noradrenaline or cyclic AMP in the cortical
tissue itself (Pettigrew & Kasamatsu, 1978; Kasamatsu et al. 1979; Kasamatsu, 1980,
1982).
The starting point of the present study was to know whether this 'gating' effect
is found only for monocular deprivation or if it applies to other kinds of sensory
manipulation; consequently we explored a possible catecholaminergic control of
epigenetic modifications of both ocular dominance and orientation selectivity. The
chosen protocols were normal rearing, dark rearing and retarded visual experience
during the critical period which are known to affect the orientation selectivity level
with quite distinct kinetics (Imbert & Buisseret, 1975; Buisseret & Imbert, 1976;
Fregnac, 1979, 1985).
The second aim of this study was to investigate the noradrenergic nature of the
observed effects. Intraventricular and intracortical injection of 6-OHDA are known
to alter both cortical noradrenergic and dopaminergic contents. Lesion of the coeruleus
complex itself, although technically more difficult to achieve, would produce a more
specific and complete cortical noradrenergic depletion. In addition the use of limited
amounts of 6-OHDA (48 ,ug) in the coeruleus complex avoids major drawbacks of the
protocols initially designed by Kasamatsu & Pettigrew (1979); large doses of the
neurotoxin could severely damage cortical homoeostasis and impair general
behaviour. In most cases we performed bilateral lesions of the coeruleus complex
since ascending fibres of the locus coeruleus project to both sides of the brain (Moore
& Bloom, 1979).
An additional parameter taken into account in this study is the delay between the
start of the chemical lesion and that of the sensory manipulation, or the post-natal
age at which the 6-OHDA injection is performed. Coeruleus complex lesion has
different consequences for paradoxical sleep according to the age at which it is made
(Adrien, 1978, 1981). This in turn could correspond to different levels of spontaneous
activity in the geniculocortical pathway; consequently, we compared the effects of
these lesions on cortical plasticity when performed neonatally and in kittens older
than 3 weeks of age.
Our results show that coeruleus complex lesions appeared ineffective in protecting
cortical neurones from the epigenetic effects of visual experience, although they
produced significant cortical noradrenergic depletion. Since the selective lesion of the
ascending noradrenergic pathway did not block the effects of monocular deprivation,
we reproduced some of the original protocols of Kasamatsu & Pettigrew (1976, 1979),
using intraventricular injection of 6-OHDA. The apparent contradiction between our
data and the original findings of Kasamatsu & Pettigrew, and the very limited effects
76
J. ADRIEN AND OTHERS
produced by lesion of the coeruleus complex, raise some doubt concerning the
importance of the integrity of the ascending noradrenergic system during the
development of kitten visual cortex.
Preliminary results have been presented (Adrien, Buisseret, Fregnac, Gary-Bobo,
Tassin, Trotter & Imbert, 1982a, b; Fregnac, 1982) or reviewed elsewhere (Fregnac
& Imbert, 1984).
METHODS
A blind procedure was chosen, dissociating the research teams in charge of the drug treatment
(J. A.), of the electrophysiology (P. B., Y. F., E.G. B., M. I., Y. T.) and of the biochemistry (G. B.,
J. P. T.). Thus, when the electrophysiology was performed on kittens, the previous drug treatment
(if any) was unknown at the time of the experiment. In addition two separate teams recorded from
one cortex without communication of each other's results. Samples of cortical tissue were analysed
under a code name unknown to the biochemists.
Drug treatment
Coeruleus complex lesions. Bilateral lesions of the coeruleus complex were performed by
intracerebral infusion of 6-OHDA (6-hydroxydopamine hydrobromide, Sigma) directly into the
lateral pontine tegmentum according to a technique used previously in the rat pup (Lanfumey,
Arluison & Adrien, 1981). The younger kittens (1-4 days of age) were anaesthetized with ether and
the older kittens (23-33 days) were anaesthetized with pentobarbitone. They were maintained in
a stereotaxic apparatus (Kopf) and the needle of a Hamilton syringe was stereotaxically positioned
after craniotomy at three different locations on each side of the pontine tegmentum. Eight
micrograms of 6-OHDA dissolved in 0-8 ,ul of saline containing 0-2 % of ascorbic acid (pH = 3 5),
were slowly infused at each location over 5 min.
The stereotaxic coordinates of the locus coeruleus in both age groups were provided by
histological data from the cat colony and the three infusion sites (S 1, S 2, S 3) calculated from the
ear bars zero were the following: (1) 1st age group (1-4 days): S 1 = (P3 5, L2, V-4); S2 = (P2-5,
L2, V-3); S3 = (P15, L2, V-2). (2) 2nd age group (23-33 days): S1 = (P3, L2-5, V-35);
S2 = (PIP8, L2-7, V-3); S3 = (P0-6, L2-9, V-2-5). After completion of the infusions, the scalp
was sutured and the kittens were returned to the litter. On the next day they could suckle or eat
normally.
Intraventricular injection of 6-OHDA. This procedure was performed according to the original
protocols designed by Kasamatsu & Pettigrew (TJ9 and TJ 13 in Kasamatsu & Pettigrew, p. 145
and 153, 1979). Under pentobarbitone anaesthesia, seven kittens aged from 26 to 33 days underwent
the stereotaxic implantation of a stainless-steel cannula (0-9 mm external diameter, 21 mm long),
whose tip was positioned in the lateral ventricle (A 1, L2-5, V-10 from brain surface) to allow
subsequent injection of 6-OHDA. The cannula was cemented to the skull and a trocar was inserted
to prevent leakage of cerebrospinal fluid. The scalp was then sutured and the kittens were returned
to the litter. Two to five days later the 6-OHDA treatment was started: the neurotoxin was infused
into the ventricle by means of a Hamilton syringe while the experimenter gently held the kitten
in his hands. 6-OHDA was dissolved at a concentration of 16 ,sg//Il in saline containing 0-2 % of
ascorbic acid (pH = 3 8), and was infused at doses which were increased daily: 12-5 ,ul (200 #g) on
the first day of treatment, 25 #1 on the second day, 50 #1s on the third, and 100 #1 on the fourth
day (1-6 mg of 6-OHDA). The latter dose was repeated daily for another 4-8 days in order to reach
a cumulative dose of 10 mg or above.
The treatment induced severe behavioural side effects, which were scored semi-quantitatively
using the following scale: vomiting = 0-25, sham rage = 0.5, epileptic seizure = 1-0. The total
scale for each kitten gave a global estimation of the behavioural side-effects of the neurotoxin.
Rearing conditions and noradrenergic depletion protocols
Forty-four kittens were separated into four experimental groups corresponding to the different
drug treatments and the control condition:
group I: neonatal lesion of the coeruleus complex (seven kittens);
group II: lesion of the coeruleus complex performed during the critical period (twelve kittens,
of which two were used only for biochemical control);
NORADRENALINE AND VISUAL CORTICAL PLASTICITY
77
group III: intraventricular injection of 6-OHDA during the critical period (seven kittens);
group IV: control group (eighteen intact kittens, of which fourteen were used only for biochemical
controls).
The rearing procedure consisted of five types of visual environment: (1) normal rearing (n.r.),
(2) dark rearing (d.r.), (3) monocular rearing with eye-suture performed before eye-opening (m.r.),
(4) delayed monocular visual experience of 6 h following 6 weeks of dark rearing (m.e.), (5)
monocular deprivation with durations ranging from 6 to 25 days following 5 weeks of normal rearing
(m.d.). After delayed visual experience (m.e.), the recording session was begun after a return to
dark of 12 h (Imbert & Buisseret, 1975). Fig. 1 summarizes the rearing and lesion protocols for the
twenty-six kittens in which recordings of visual cortex were carried out.
N. r. -1
_*
N.r.-2
D.r.-2
L _=
D.r.-3
M.d. -1M.d.-2
_
+
MAd.-4
_
A
M.-d. 65 C
11
M.d.-7
M.d.-8
M.d.9
M.d-10
M.d--1 1
M.e. -1
M.e.-2
K.P.-1
K.P.-2
lit
i1 K.PA-3
K.P.-4
KR-3
IV
M.d.-3 *
M.d.-12 ----
-
M.d.-13
M.d.-14
0
--
10
--
50
Post-natal age (days)
Fig. 1. Rearing procedures and lesion protocols. For each kitten used for the electrophysiological recordings the timing and duration of visual experience given to each eye are
represented by open rectangles. Filled rectangles correspond to dark rearing or periods
of unilateral eyelid closure. Lesions of the coeruleus complex are represented by circles
($): bilateral; ®: unilateral). The onset (v) and the duration of the series of daily
intraventricular injection of 6-OHDA (dashed line) are indicated below the appropriate
rectangles. At the bottom, post-natal age scale is expressed in days. K.P.: Kasamatsu &
Pettigrew.
Control electrophysiological recordings in group IV were limited to monocularly reared or
deprived kittens, since control data were obtained at the same time by the same experimenters
in area 17 of 6-week-old kittens, either normally reared or dark reared (five n.r. kittens and three
d.r. kittens in Fregnac, Trotter, Bienenstock, Buisseret, Gary-Bobo & Imbert, 1981) or after
delayed monocular exposure of 6 h (five m.e. kittens in Trotter, Fregnac & Buisseret, 1983). For
the sake of clarity, since they were used in some statistical tests, relevant data taken from these
two latter studies have been included in Table 4.
Recording
Kittens were anaesthetized with an intramuscular injection of Alfatesine (Glaxo: 1-2 ml/kg, i.e.
108 mg alfaxone/kg and 3-6 mg alfadolone acetate/kg) and after intravenous cannulation received
a continuous perfusion ofAlfatesine (0 3 ml/kg. h), and gallamine triiodoethylate (Specia: Flaxedil
78
_~
J. ADRIEN AND OTHERS
N ~P.
';P~~~~t~~~m~~l.,
.-,
4
A
#i7
*
X *.
,
I
\
'I
A\
.~~~
,A
a..
"
N:.,
T
P.c.s.
'\
g
.
%
.,1
Npb'--
S.C.*:,
A_
L% c
i
..Io,
IC_
.
I
.
v
1.
B
.1
I't
%
1.
'O.
;
JFC.1
a
Fig. 2. Lesion of the coeruleus complex produced by in 8itu injection of 6-OHDA.
Fluorescence histochemical photomontages of transverse sections from kitten pons around
level P4. A, control animal. Fluorescent NA neurones are observed in the locus coeruleus
(densely packed cell body zone) and in the subcoeruleus and parabrachialis lateralis nuclei,
dispersed in the dorsolateral tegmentum. A low density of fluorescent CA fibres is present
over the whole section of the pons (reprinted with permission from Arluison et al. 1980).
B, lesioned animal. An 8-week-old kitten, taken from the same breeding colony as the
control animal, was injected bilaterally with 6-OHDA in the coeruleus complex area
according to protocol II. Fluorescent neurones are no longer observed, except for a single
cell body (indicated by a filled arrow) situated in the ventrolateral part of the subcoeruleus
nucleus. Calibration bars indicate 1 mm. L.c., locus coeruleus; n.p.b.l., nucleus parabrachialis lateralis; n.t.m., nucleus tractus mesencephalici nervus trigemini; p.c.s.,
pedunculus cerebellaris superior (brachium conjunctivum); s.c., subcoeruleus nucleus.
NORADRENALINE AND VISUAL CORTICAL PLASTICITY
79
10 mg/kg. h) complemented with glucose and saline. Apart from the anaesthetic, all detailed
procedure concerning the initial surgery, the control of the physiological state of the preparation,
the stereotaxic coordinates of recording in area 17, the use of metallic electrodes and the plotting
of the retinal landmarks have been reported elsewhere (Fr6gnac et al. 1981).
Receptive field classification and data tabulation
The electrode was positioned above the skull opening and inclined at various angles relative to
the frontal plane thus avoiding sampling in the same slab of ocular dominance (Shatz, Lindstrom
& Wiesel, 1977; Tieman & Tumosa, 1983) or of orientation preference (Singer, 1981). Receptive
field analysis was performed at regular intervals (50-100 ,um). In monocularly deprived kittens,
orientated multi-unit activity was taken into account in a few cases, when no single cell could be
isolated over 100 consecutive /sm. This was done to ensure regular sampling throughout the cortical
track. Geniculate fibres were discarded from the analysis.
Three types of cells were classified according to their dynamic and static responses to bars and
spots of light: (1) visually unresponsive cells, (2) non-oriented or 'aspecific' cells activated equally
well by bars and spots of light moving in any direction across the receptive field, (3) orientationsensitive cells, responding better and more selectively to bars than spots. This latter category
includes immature and specific types defined by Imbert & Buisseret (1975). The proportion of
orientation-sensitive cells was calculated relative to the total number of visual cells (see Tables).
Orientation preference was established using a back projector and directly drawn on the
projection screen. In a restricted number of cases (twenty), orientation tuning curves were plotted
using an automatized exploration of the receptive field to periodically control the good fit between
the computed value (Fregnac et al. 1981) and that found with the back projector. Orientation
preference distributions were established with a 22-5 deg bin width and Chi-square tests with Yates'
correction were carried out to reject the hypothesis of a uniform polar distribution.
Ocular dominance was assessed on a 5-class scale, ranging from monocular activation through
one eye to monocular activation through the other eye via three groups of binocular activation.
By convention, class 1 represents monocular activation through the eye controlateral to the
recording site in binocularly experienced or deprived kittens (n.r. and d.r.) or monocular activation
through the open eye in monocularly experienced kittens (m.r., m.e. and m.d.). From the ocular
dominance distributions, two parameters were calculated similarly to those defined by Kasamatsu
et al. (1981 a). Binocularity (B) is the proportion of visually responding cells which are driven
through both eyes. Weighted binocularity (A) is given by eqn. (1), assuming that binocular
convergence fluctuates linearly between 0 (classes 1 and 5) and 1 (class 3). Capture index from the
open eye (S) is the proportion of all visually responsive cells receiving an excitatory influence from
this eye. Weighted shift (8) is given by eqn. (2) with a weighting factor fluctuating linearly between
0 (closed eye) and 1 (open eye).
(c3(c2+c)/2)
+ (C2 + C4)/2).B.()
B=~ (C3
B,
(1)
Cl + C2 + C3 + C4+ C5
=
(
h
with
43 +
+2
-
+ 41+12 C3
-
C4..S,
(2)
ci being the number of visual cells in the ith class of the ocular dominance histogram.
Histology
Coeruleus complex lesion. Brain stems in groups I and II were processed according to the Glenner
enzymatic technique (Glenner, Burkner & Brown, 1957) in order to visualize the monoamine
oxidase activity in the coeruleus complex. Fresh tissue was immediately frozen at -20 °C and
sectioned in the frontal plane at 40 ,um. Alternate sections were processed with the Glenner and
the Nissl methods. This histological procedure allowed a precise estimation of the extent of the lesion
at the level of the coerulean cell bodies (Lanfumey et al. 1981). However, in order to verify the
actual destruction of the noradrenergic neurones in the kitten, fluorescence histochemistry was
performed in one lesioned and one control animal (see Biochemistry, last paragraph). A modified
Falck-Hillarp method was used, employing a perfusion with glyoxylic acid (Arluison, de la
Manche, Adrien, Hamon, Laguzzi & Bourgoin, 1980).
Intraventricular injection of 6-OHDA. Because previous reports described no profound histo-
80
J. ADRIEN AND OTHERS
logical modifications in the locus coeruleus of the cat after such treatment (Bourgoin, Adrien,
Laguzzi, Dolphin, Bockaert, Hery & Hamon, 1979; Arluison et al. 1980), the hind brains of kittens
in group III were not used for histological analysis. However, careful examination of the forebrain
was performed, especially on the side of the cannula: in most cases there was a small enlargement
of the ventricle around the tip of the cannula, and necrosis was observed all along its track. This
phenomenon was probably due to repeated injections of large doses of 6-OHDA because it did not
appear in previous experiments in which, with the same technique of infusion, only small doses
of the neurotoxin were used (Arluison et al. 1980).
Biochemistry
Dopamine and noradrenaline levels were measured using a radioenzymatic method initially
described by Gauchy, Tassin, Glowinski & Cheramy (1976). Samples taken from the occipital cortex
(10-20 mg of fresh tissue) were removed rapidly and immersed in 110 1 of a 0-1 N-perchloric acid,
0-01 N-thioglycollic acid solution to be kept frozen at -20 'C. They were then homogenized by
sonication (10 s). After centrifugation (20000 g, 20 min at 4 0C) the catecholamines (CA) contained
in the supernatants were isolated by adsorption on alumina microcolumns and eluted by 200 ,sl
of a 0-1 M-acetic acid, 0-005'N-oxalic acid solution. Eluates were then evaporated to dryness and
CA were simultaneously transformed into their radioactive methylated derivatives by catechol0-methyl transferase using a [3H]S-adenosyl methionine (10-2 Ci/mmol, Amersham) as the methyl
donor. Radioactive 3-methoxy-4-hydroxyphenylethylamine and 3-methoxy-4-hydroxyphenylethanolamine were separated by organic extraction and isolated by silica-gel chromatography
(Herv6, Blanc, Glowinski & Tassin, 1982). Blank values ranged between 50 and 100 pg, both for
noradrenaline (NA) and dopamine (DA), depending on the biochemical series.
In order to reduce intrinsic variability in the estimates of catecholaminergic depletion when
comparing CA levels in 6-OHDA-treated and intact kitten cortices, the following precautions were
taken. (1) Identical measurement sensitivity and blank values were ensured by comparing
experimental assays only with the control ones which had been processed through the same series
of biochemical treatments. (2) In addition to the kitten group used for the electrophysiology, we
sacrificed thirteen normally reared kittens (included in group IV) under the same anaesthesia
conditions coming from four separate litters, at ages varying from 3 to 12 weeks. NA and DA levels
were shown to be significantly linearly correlated with age (see Results, first section). Since control
and experimental kittens were not always the same age, age correction factors (established from
samples taken from kittens of the same litter at 3 and 7 weeks of age) were given by the mean
relative increases with age of NA and DA contents. We assumed that these factors would be the
same for all the other series of biochemical measurements. According to these conventions,
noradrenergic levels in 6-OHDA-treated kitten cortex were expressed in Tables and Fig. 3B as a
percentage of control value found in the same biochemical treatment series, after correction for
age. Absolute levels of NA and DA are also indicated in the Tables.
Finally, CA levels were measured at 31 days in area 17 of three normally reared kittens of the
same litter: one was intact (included in group IV) and the two others had a lesion (either bilateral
or unilateral) of the coeruleus complex performed at 23 days of age (included in group II). The delay
between the coeruleus complex lesion and the sacrifice date was the same as the shortest interval
between the lesion and the onset of monocular occlusion in kittens which were subsequently used
for electrophysiology (see Table 2). These biochemical controls were made to assess the level of NA
depletion at the start of the monocular deprivation period and compare the relative effects of
unilateral and bilateral lesions of the coeruleus complex on area 17 NA content in each hemisphere.
RESULTS
Lesion protocols and noradrenergic depletion
Our control data in n.r. kittens indicated a significant linear dependence of the area
17 CA contents (average value of four samples) on age during the first 10 weeks of
post-natal life (NA: r = +0-74; F test: F = 21-8, d.f. = 1,18; DA: r = +0-90; F
test: F = 76, d.f. = 1,18). The NA level was 40 ng/g of wet tissue at 6 weeks of age
NORADRENALINE AND VISUAL CORTICAL PLASTICITY
A
a
50.
I
81
NA
AO
,
+
C
0
4/7
8
,,
TX
,,I
I
10
DA
-
As
v i
0
U-W
10
50
<i
B
1 00
?/
Age (days)
A-V
50-
0D
z
I
v
10
v
0
10
-V-
20
Delay (days)
30
Fig. 3. NA levels in normal (A) and lesioned (B) kitten visual cortex. A, dependence of
NA and DA levels (ng/g) on age (days) under 8 weeks of age. All kittens belonged to the
same litter. Two samples of fresh grey matter were taken from the medial bank of each
visual cortex around P0 and P4. Assays taken from a given kitten are represented by
identical symbols. A significant increase of NA (r= +0 77; F = 26-6; d.f. = 1, 18) and DA
(r = +0-94; F = 125-4; d.f. = 1, 18) is found between 3 and 7 weeks of age. The age
correction factors are given by the relative slopes of the regression lines which have been
plotted both for NA (dashed line) and DA (half-dashed line). B, noradrenergic depletion
in kitten visual cortex after injection of 6-OHDA in the right ventricle (V) or in the
coeruleus complex. (@). The injection onset ranged from 24 up to 35 days. Abscissa: delay
from the injection onset expressed in days. Ordinates: NA levels in each sample taken
from lesioned animals (whatever the extent of the lesion) given as a percentage of the value
in intact control animals of the same age (see Methods, Biochemistry section). The lower
levels (25%) obtained for the younger kittens where lesion was complete, i.e. for the
shortest delays from the lesion, were found in the range of their associated blank values.
and increased to 80 ng/g 6 weeks later. At a given age, variability between litters
appeared larger than between kittens of the same litter and intrinsic variability
between the four measurements made in one kitten increased with age. The NA level
was systematically 2-3 times higher than the DA level. For kittens less than 8 weeks
old, corresponding to the period when most recordings were made, the age correction
factor (estimated from animals belonging to the same litter) was found to be around
1 ng/g per day for NA and 0.5 ng/g per day for DA (Fig. 3A).
82
J. ADRIEN AND OTHERS
The injections ofmicrodoses of 6-OHDA at three different locations in the coeruleus
complex resulted in the disappearance of monoamine oxidase enzymatic activity
revealed by the Glenner reaction. Fig. 2 exemplifies the difference in fluorescence
produced by CA neurones in the pons in lesioned and control kittens coming from
the same rearing colony. Two observations can be drawn from the comparison at 31
days of age of NA levels in each hemisphere of a bilaterally lesioned, a unilaterally
lesioned and an intact kitten from the same normally reared litter. (1) Eight days
after the complex coeruleus lesion, the unilateral lesion produced a noradrenergic
depletion in the ipsilateral cortex comparable to that observed in each cortex of the
bilaterally lesioned kitten. The NA values found were indistinguishable from the
blank level (which in this case was as high as 25 % of the control value). (2) The NA
level in the cortex contralateral to the lesion was comparable to the value found in
both cortices of the intact kitten. In summary, a unilateral lesion protocol seems to
affect the cortical NA level only on the ipsilateral side; a delay as short as 8 days
appears to be sufficient to observe a significant noradrenergic depletion, at least in
the visual cortex.
The two modes of lesion of the NA ascending system, 6-OHDA injection in the
coeruleus complex or in the right ventricle, were found to be equally effective in
producing a cortical NA depletion. The ratio of NA content found in individual
samples of visual cortex of lesioned kittens to that found in intact kittens decreased
significantly with increasing delay separating the sacrifice from the lesion or the first
day of 6-OHDA injection (Fig. 3B). The only experimental point whose level seemed
unaffected by the lesion was taken from one cortex of an incompletely lesioned kitten
(m.e.-2). Note that values given in the Tables are the mean calculated from all samples
taken in both cortices. This decrease was independent of the mode of lesion chosen
to deplete NA. No compensatory noradrenergic reappearance seemed to occur for
longer delays (2 or 3 weeks).
The two 6-OHDA treatments also affected the cortical DA content but not in the
same way. DA was completely (see kitten K.P.-3 in Fig. 1 and Table 3) or partially
depleted in 6-OHDA intraventricularly treated kittens (see Table 3); after coeruleus
complex lesion, the DA level showed very large variance around normal values for a
delay of 8-10 days, before definitely increasing above normal levels for longer delays
(see Table 2).
Electrophysiological recordings in area 17
A total of 1263 cells, among which 1136 were visual neurones, were recorded in both
hemispheres of twenty-two 6-OHDA-treated kittens and four intact monocularly
deprived kittens. 403 cells, among which 348 were visual neurones, recorded at the
same time in thirteen intact kittens and which have been published elsewhere
(Fregnac et al. 1981; Trotter et al. 1983) constituted an additional control group.
Because NA depletion level and coeruleus copnplex lesion extent might vary between
subjects submitted to the same environmental manipulation, individual data are
presented in Tables (Tables 1-4) and Figures represent pooled data from kittens
submitted to the same lesion and rearing protocols.
Neonatal lesion of the coeruleus complex. Both unilateral and bilateral lesions were
used. Since, except for one case (n.r.-2), electrophysiological results obtained in
83
NORADRENALINE AND VISUAL CORTICAL PLASTICITY
unilaterally lesioned animals were similar for each hemisphere, data were pooled from
both cortices. Table 1 and Fig. 4 show clearly that manipulations of visual input
during the critical period induce functional changes in lesioned kittens comparable
to those observed in control intact kittens (Fregnac et al. 1981; Trotter et al. 1983).
Most cells were orientation sensitive at 6 weeks of age in n.r. lesioned kittens
although the proportion of orientated neurones was significantly smaller than found
in intact ones (compare n.r.-1 and n.r.-2 in Table 1 and control data from Fregnac
TABLE 1. Neonatal lesion of the coeruleus complex and cortical effects of visual experience
Monocular
Dark
Normal
Visual
Total
rearing
rearing
rearing
experience
8
N.r.-1 N.r.-2 D.r.-1 D.r.-2 D.r.-3 M.d.-i M.d.-2
Code name
323
69
97
40
30
15
28
36
No. of cells
301
34
69
95
10
28
25
32
No. of visual cells
0.88
0.91
0.15
0 00
Proportion of oriented 0.55* 0.59* 0 00
cells
0 10** 0.15**
0-85
0 74
0-67
0 74
0 75
Proportion of
binocular cells
B.
B.
B.
U.
U.
U.
B.
Extent of the lesion
Lesion of the coeruleus complex: bilateral (B.), unilateral (U.). Bilateral lesions which were found
to be incomplete after histological control (see Methods) are referred as 'partial' (P. on both sides,
P .U on one side). Electrophysiological indices which are significantly different from values obtained
in control kittens (Table 4) are indicated by one (a = 0 05) or two (a = 0 005) asterisks. NA levels
were averaged over four assays in both cortices and expressed as a percentage of the value found
in the control kitten used in the same biochemical series, after correction for the age (see Methods).
Average absolute values of NA and DA found at 6-7 weeks of age in control kittens were respectively
40 ng/g and 15 ng/g.
et al. 1981 in Table 4). Neurones were mainly binocularly activated. All orientation
preferences were equally represented. However, in the unilaterally lesioned n.r.-2
kitten, more orientation-selective cells were found in the contralateral cortex than
in the cortex ipsilateral to the lesion, but this difference was not statistically
significant. In dark-reared lesioned kittens, most cells were binocularly activated and
non-selective to orientation as reported in intact control kittens (Fregnac et al. 1981).
In the two lesioned kittens who experienced vision through only one eye (m.r.: m.d.-1
and m.d.-2), most cells were found to be orientation sensitive and strongly dominated
by the open eye. The level of orientation selectivity in these 6-OHDA-treated kittens
was indistinguishable from that found in control kittens (control data from Trotter
et al. 1983 in Table 4).
In conclusion, neonatal lesion of the coeruleus complex does not protect visual
cortical neurones from the epigenetic functional changes produced by environmental
manipulation during the critical period.
Late lesion of the coeruleus complex. All attempted lesions were bilateral and half
of them were complete. Two rearing protocols were used: monocular deprivation
(m.d.-4-m.d.-1 1) and delayed monocular experience of short duration following dark
rearing (m.e.). In all cases a clear dominance of the open eye was found, and levels
of orientation selectivity were indistinguishable from those observed in control
J. ADRIEN AND OTHERS
84
D.r.
N- 3
n- 83
N.r.
N-2
n- 62
L.c.
IIM
C.
N -5
n= 102
N-3
n= 95
M r.
N= 2
n- 166
M .e.
N=2
n - 96
L.c.
.
C.
N =1
n 79
=
N
=
17
-
5
206
Fig. 4. Lesion of the coeruleus complex and cortical effects of visual experience. Ocular
dominance histograms on a 5-class scale (1: contralateral; 5: ipsilateral eye; 0: open eye;
*: closed eye) are normalized relative to the total number of visual cells. The vertical
filled bars indicate the 25% level. Visual cells are classified either non-oriented (open
columns) or orientation sensitive (filled columns). Non-visual cells are represented by a
shaded column beside each histogram. n: total number of cells. N: number of kittens.
Normal histograms represent data from coeruleus complex lesioned kittens (l.c.). Pooled
results are given for kittens with a neonatal lesion (group I) followed by normal rearing
(n.r., code names: n.r.-1 +n.r.-2), dark rearing (d.r., code names: d.r.-1 +d.r.-2+d.r.-3),
or monocular rearing (m.r., code names: m.d.-I +m.d.-2). The bottom right histogram
refers to group II deprived kittens, monocularly exposed for 6 h after a late lesion of the
coeruleus complex (m.e., code names: m.e.-1 + m.e., 2). Inverted histograms represent data
from control kittens (C.) submitted to identical rearing procedures (see Table 4).
NORADRENALINE AND VISUAL CORTICAL PLASTICITY
0
4-
-C
= aq
8
C)
o
S
X
X X
>~C
*
_
o
_*
~ ~~.
~
C)
=
Nb ab
0c
o
0~
0~ ~
~~0
79~~~~c
0~
~
~~~0
X0 "t
.
4CbIo
C;
X~~~~~~X
C ° S X
X
betoo
.=~~~
0Ue
b
E
i
~~~~~~~~~~~I
o
,0
;e
-S oX>X
0~~~~~~~~~~~
=
~~~~~~~~*
0
0~~~~
0u
O a
0~~~~
*
0~~~~~
o
X
"t .p t o
be ¢
° b¢¢
0
r
C
I
v
85
86
J. ADRIEN AND OTHERS
kittens (Table 4: group JV for m.d. and data from Trotter et al. 1983 for m.e.). In
kittens monocularly exposed for 6 h (m.e.), orientated cells were more monocular
(74 % in lesioned kittens; 79 0 in intact kittens) than non-orientated ones (50 % in
lesioned kittens; 52 % in intact kittens). This covariation between the degree of
monocularity and that of orientation selectivity is in fact a general feature of the
effects of delayed monocular exposure in the intact animal (Cynader, Timney &
Mitchell, 1980; Trotter et al. 1983). All orientation preferences were equally
represented.
However, several results observed in the 6-OHDA-treated group of monocularly
deprived kittens (Table 2: m.d.-4-m.d.-1 1) depart from our control group (Table 4)
and stand in contrast with the well documented effects of monocular vision in intact
animals (Blakemore & Pettigrew, 1970; Movshon & Dfirsteler, 1977; Van Sluyters,
1978). The proportion of binocular neurones did not decrease significantly with the
actual duration of deprivation, although in all cases the eyelid closure began at the
same age (5-6 weeks). In addition, comparison of individual histograms between
Tables 2 and 4 for similar periods of monocular deprivation indicates that in half of
the lesioned kittens the proportion of binocular neurones appeared significantly
higher than in intact kittens (see asterisks in Table 2). However, the proportion of
binocular neurones was found uncorrelated either with the amplitude of the
noradrenergic depletion or the extent of the coeruleus complex lesion. It may be noted
that the delay between the lesion and the onset of the monocular deprivation period
was not critical since the effects of monocular vision were identical whether its onset
was fixed 1 week or 2 weeks after the coeruleus complex lesion. The latter observation fits with the biochemical results described in the second paragraph of Results,
first section, which states that a noradrenergic depletion is already achieved at the
cortical level 8 days after the lesion.
At this point, a qualitative conclusion can be drawn: neonatal or late lesions of
the coeruleus complex do not fully protect visual cortex from the effects of monocular
deprivation. However, a higher proportion of binocular neurones was found in some
lesioned kittens than in intact animals.
Intraventricular injection of 6-OHDA. Two groups of kittens received intraventricular injections of 6-OHDA during the critical period and were later
monocularly deprived according to protocols originally designed by Kasamatsu &
Pettigrew (1979). When the cumulative doses of 6-OHDA reached a certain level
(4-5 mg), behavioural side-effects appeared and generally peaked between the 7th
and the 9th day following the injection onset. The most dramatic effects were
epileptic seizures, which led to death in two cases. For the remaining kittens electrophysiological results failed to reproduce the complete protection of binocularity
observed by Kasamatsu & Pettigrew. Binocularity levels found in our lesioned
kittens (group III, Table 3) are below 350 (in contrast to 790 in TJ9 in Kasamatsu
& Pettigrew, 1979) and are comparable to those observed in kittens injected only
with the vehicle solution (saline and ascorbic acid: 23 % in TJ 11 and 14 % in TJ 15 D
in Kasamatsu & Pettigrew, 1979). These latter kittens were referred to as 'control'
in Kasamatsu & Pettigrew's original study. Moreover, in our data, no correlation was
found between the proportion of binocular cells and the amplitude of the noradrenergic depletion. One may even note the case of a complete depletion (K.P.-3) where
only 9 % of neurones remained binocularly activated. No significant correlation was
NORADRENALINE AND VISUAL CORTICAL PLASTICITY
87
found either between the degree of binocularity and the amplitude of the behavioural
side-effects (see Table 3).
In summary, intraventricular injection of 6-OHDA failed to protect visual cortex
from the loss of binocular interaction produced by monocular occlusion and these
findings contradict the previous results of Kasamatsu & Pettigrew (Pettigrew &
Kasamatsu, 1978; Kasamatsu & Pettigrew, 1979).
TABLE 3. Intraventricular injection of 6-OHDA and cortical effects of monocular vision
Original protocol:
TJ 13 B
Total
TJ9
Kasamatsu & Pettigrew
(1979)
Code name
Delay between 1st 6-OHDA
injection and monocular
vision onset (days)
Duration of monocular
vision (days)
No. of cells
No. of visual cells
Proportion of oriented
cells
Proportion of binocular
cells
NA (% control)
NA (ng/g)
DA (ng/g)
Behavioural side-effects
Visual experience
Code name
Duration of monocular
vision (days)
No. of cells
No. of visual cells
Proportion of
oriented cells
Proportion of
binocular cells
K.P?.-3
6
K.P.-4
7
K.P.-5
6
6
8
9
55
37
0-94
53
38
1*00
34
33
1.00
0-14
0 09
0.30
K.P.-1
3
K.P.-2
3
25
24
48
44
0.95
64
58
0-25
08
3
2
0
0
For explanation see Table 1 legend.
9
TABLE 4. Control kittens
Monocular occlusion
Monocular
following normal
rearing
rearing
M.d.-3
32
254
210
0'88
0-34
38
15
20
5
10
4
22
2-5
Total
M.d.-12 M.d.-13 M.d.-14
7
22
17
5
(+)
(++)
4
N.r.
0
D.r.
0
M.e.
0-25
79
78
0-95
67
65
0.95
55
51
0-92
25
20
0.95
226
214
102
99
0-94
95
72
000
206
177
0-73
0 00
0-27
0-18
0.10
-
0.69
0-82
0-29
(+): from Fregnac et al. (1981).
(+ +): from Trotter et al. (1983).
For explanation see Table 1 legend.
Noradrenergic depletion and the cortical effects of monocular deprivation
From the results presented above it can be concluded that: (1) similar levels of NA
depletion at the cortical level could be achieved by coeruleus complex lesion and
88
J. ADRIEN AND OTHERS
L.c.
C.
n
67
n
OOm
-.
I.V
83
n
-142
1.
n- 165
n
55
a)
n = 132
ND
O
0
U_
n
25
ILX
n=
)~~~~~~~~~~~~~~
1 12
Lu
0
0
Fig. 5. Noradrenergic depletion and cortical effects of monocular experience: ocular
dominance histograms. Histogram conventions are detailed in Fig. 4. Rows from top to
bottom correspond respectively to 1 week, 2 weeks and 3 weeks of monocular occlusion
starting in all cases from 5 weeks of age. The left column represents intact control kittens
(c.: code names from top to bottom: m.d.-12, m.d.-13, m.d.-14), the middle column
represents group II coeruleus complex lesioned kittens (I.c.: code names: m.d.-4 + m.d.-5,
m.d.-6+m.d.-7+m.d.-8, m.d.-9+m.d.-10+m.d.-11), and the right column represents
results from group III intraventricularly 6-OHDA injected kittens (i.v.: code names:
k.P.-3+k.P.-4+k.P.-5, k.P.-1+k.P.-2). The second and third lower histograms in the
second column correspond respectively to delays of 8 and 15 days between the coeruleus
complex lesion and the onset of the monocular occlusion period.
intraventricular injection of 6-OHDA; (2) no blockade of plasticity was observed
whatever the mode of destruction of the NA system (Fig. 5); (3) the level of
binocularity found in coeruleus complex lesioned kittens appeared unrelated to the
delay between the lesion and the onset of the monocular occlusion period (Fig. 5).
In order to assess more quantitatively the significance of the differences observed
between lesioned and intact kittens, we developed an 'iso-effect' analysis. For each
kitten two parameters were extracted from the ocular dominance histogram, one
NORADRENALINE AND VISUAL CORTICAL PLASTICITY
89
C
A
-
V
20
-
,
/@0
0-5
1~~~~~~~~~~~~1
.1~ ~~1
0 /
00
I.
2
D
10
20
10
t
20
t
D
B
1.0
---~~~~0
V~~~~~~~~~~~~~V
Fig. 6. Noradrenergic depletion and cortical effects of monocular experience: iso-effect
analysis. A and B, evolution of weighted binocularity (A) and weighted shift of ocular
dominance (S) function of the duration of monocular occlusion (t) expressed in days. These
parameters calculated from individual kitten ocular dominance histograms are defined in
Methods, fourth section. The dashed curves give the standard monotonous relationships
10
observed in intact kittens established from group IV results or calculated from data
published by Hubel & Wiesel (1962), Blakemore & Pettigrew (1970), Movshon & Dfirsteler
(1977), Fregnac & Imbert (1978) and Van Sluyters (1978). The arrows in A and B indicate
how the theoretical -durations of occlusion are obtained, which in intact kittens would
correspond to the electrophysiological index values (A and I) observed in lesioned animals
((D for coeruleus complex and V for intraventricular injections). These values are termed
'iso-effect' durations. C and D, the iso-effect duration (iso-t), given in days, is plotted with
the actual duration of monocular occlusion in lesioned kittens for each index (C for index
A; D for index I). Each point situated on the right side of the bisecting dashed line
indicates a smaller amplitude cortical effect of monocular deprivation in lesioned kittens
than in intact ones.
characterizing binocular convergence (B), and the other the open eye dominance (S).
A standard evolution of these parameters as a function of the occlusion time can be
established in the intact kitten, on condition that eyelid closure begins at the same
age (in this study, at 5-6 weeks). The decrease in A and the increase in 4 shown by
the dashed curves in Fig. 6A and B, correspond to the progressive transition from
a bell-shaped ocular dominance histogram to the classical L shape (all cells being
activated monocularly by the open eye after a few weeks of deprivation). These
reference or standard curves are smoothed functions fitting data from group IV
and from the literature (Fig. 6). It may be noted from Fig. 6A and B that most
experimental points correspond to lower A and higher S values than would normally
be expected.
90
J. ADRIEN AND OTHERS
For each experimental point (lesion of the coeruleus complex or intraventricular
injection of 6-OHDA) one additional parameter was extracted to define its distance
from the standard curves: the iso-duration time is the theoretical duration of
monocular occlusion which, in intact kittens, would correspond to the same electrophysiological index (iso-A or iso-S) as that observed in the lesioned kittens. The
calculation of iso-effect duration (iso-t) is given in the legend of Fig. 6. If no effect
on cortical sensitivity to monocular vision were introduced by the lesion, all
experimental points in graphs C and D of Fig. 6 would lie centred on the main
bisecting line: on average, iso-time should equal the real duration of monocular
deprivation. Apart from one kitten (K.P.-3, Table 3), which was more monocularly
activated by the open eye than expected in an intact kitten, all points for both indices
A and 8 lie on the same side of the iso-effect bisecting line (Fig. 6C and D). Iso-effect
durations also appear to be non-significantly correlated with the actual duration of
deprivation. One can note that lesion protected more cortical cells from capture by
the remaining eye than from breakdown in binocularity. The average imposed time
of monocular deprivation was 14-2 days in lesioned kittens; this corresponds to an
iso-A time of 8X6 days and to an iso-il time of 5-2 days of occlusion in intact kittens.
This analysis indicates that the effects of monocular deprivation appear to be limited
in lesioned animals to the level of those observed in 5-8 day monocularly deprived
intact kittens, although the actual deprivation period might be extended over more
than 3 weeks. In this sense only can we describe a protective effect induced by NA
system lesion on the visual cortex sensitivity to environmental manipulation.
DISCUSSION
This report shows that noradrenergic projections are not essential in the expression
of epigenetic modifications of visual cortical receptive fields. In kittens submitted
neonatally or at 3 weeks of age to lesion of the coeruleus complex, cortical NA
depletion failed to block functional plasticity of cortical neurones. Similar negative
results were observed when area 17 depletion was achieved by intraventricular
injection of massive doses of 6-OHDA. These findings strongly moderate the
importance attributed to NA during cortical development by Kasamatsu & Pettigrew
(1976, 1979): these authors proposed that the disappearance of NA at the cortical
level would freeze the susceptibility of visual cortical integration to incoming retinal
signals during the critical period. The only agreement which remains qualitative is
on the limitation of the deleterious cortical effects of monocular deprivation following
noradrenergic depletion. Whatever its putative importance in the development of the
intact kitten cortex, the role of NA in relation to visual cortical plasticity should no
longer appear as 'unique' and, as proposed in recent reviews (Sillito, 1983; Fregnac
& Imbert, 1984), its gating action must stand open to re-examination.
Cortical biochemical effects produced by 6-OHDA injections
Assessment of the absolute level of CA depletion is somewhat obscured by the
difficulty of measuring CA levels in area 17 of kittens which have undergone several
hours of anaesthesia and paralysis. We report here intrinsic low levels of NA
(40-80 ng/g) in 6-10-week-old intact kittens. DA stands at about half the NA level
during development. These values are in agreement with recent reports (Jonsson &
NORADRENALINE AND VISUAL CORTICAL PLASTICITY
91
Kasamatsu, 1983; Daw, Robertson, Rader, Videen & Coscia, 1984) using techniques
of comparable sensitivity (high pressure liquid chromatography with electrochemical
detection). It may be noted from other studies that low levels corresponded to a
refinement in sensitivity: for the same team of experimenters, absolute NA levels in
n.r. kitten cortex tended to decrease with more recent work (compare Kasamatsu &
Pettigrew, 1979; Kasamatsu et al. 1981 b and Jonsson & Kasamatsu, 1983 or compare
Paradiso, Bear & Daniels, 1983 and Bear, Paradiso, Schwartz, Nelson, Carnes &
Daniels, 1983).
The second observation from our control data is that, in spite of large intrinsic
variability between litters, a strong dependency of CA levels on age was observed.
A linear increase with age was also found by Jonsson & Kasamatsu (1983) up to 9
weeks of age but these findings contradict data from Daniels and colleagues (Paradiso
et al. 1983; Bear & Daniels, 1983; Bear et al. 1983) in whose study intrinsic variance
seemed to mask age dependency. In addition the average age-dependent slope is
higher in our data (1 ng/g per day) than in Jonsson & Kasamatsu's study
(0 3 ng/g per day).
We have attempted two different types of chemical lesion of the noradrenergic
system:
(1) injection of more than 10 mg of 6-OHDA in the lateral ventricle produced
cortical noradrenergic depletion levels (70-90 %) comparable to those obtained by
other authors (Kasamatsu & Pettigrew, 1976, 1979; Daw, Videen, Rader, Robertson
& Coscia, 1985; Allen, Trombley, Soyke & Gordon, 1984).
(2) Stereotaxic injection of 48 ug 6-OHDA restricted to the coeruleus complex
produced cortical NA depletion levels as severe as 98 % which were on average, of
the same order as those reported after lesion of the ascending noradrenergic forebrain
bundle (Daw et at. 1984). However, injection of the neurotoxin at the cell body level
ensured a better chance of destroying the majority of noradrenergic neurones since
monoaminergic neurones are known to survive severe axotomy. NA levels were
indistinguishable from blank values as early as 8 days after the lesion. Similar findings
have been obtained in the rat pup (Lanfumey et al. 1981). Our observation of a
correlated increase of DA 3 weeks after coeruleus complex lesion is in agreement with
biochemical studies in the rat which suggested that selective NA depletion produced
by destruction of the ascending noradrenergic bundle or lesion of the coeruleus
complex is later followed by a compensatory DA collateral sprouting (Tassin,
Lavielle, Herve, Blanc, Thierry, Alvarez, Berger & Glowinski, 1979; Harik, 1984).
Cortical electrophysiological effects of visual experience following noradrenergic
depletion
Orientation selectivity changes
Our results do not confirm the suggestion that early CA depletion might freeze
development of orientation selectivity (Pettigrew, 1978). Uncontrolled factors other
than the lesion itself (for instance weight loss) might explain the intermediate level
of orientation-sensitive neurones in n.r. kittens after neonatal lesion of the coeruleus
complex, since most cells were found to be orientation selective in the m.r. lesioned
kitten cortex (see m.d.-l and m.d.-2 in Table 1).
92
J. ADRIEN AND OTHERS
Ocular dominance shifts
Ocular dominance shiftfollowing intraventricular injection of6-OHDA. We replicated
two original protocols designed by Kasamatsu & Pettigrew (1979), but we were
unable to reproduce a complete protection of binocularity following 1 to 2 weeks of
monocular deprivation in spite of severe NA depletion. Similar negative findings
have been very recently reported by Daw et al. (1985) and Allen et al. (1984), which
raise further doubt concerning the efficiency of intraventricular injection of 6-OHDA
in producing significant blockade of cortical plasticity.
Ocular dominance shift following late lesion of the NA ascending projection system.
Injection of 6-OHDA limited to the coeruleus complex area and performed 1 or 2
weeks before closure of one eye did not prevent the loss of binocularity of cortical
cells. This conclusion appears in agreement with that reported in studies of the effects
of lesion of the ascending NA forebrain bundle (Daw et al. 1984) or of systemic
injection of drugs (DSP-4(N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine) which
silence locus coeruleus activity (Daw, Rader, Robertson & Videen, 1983 b). However,
the ocular dominance shifts we observed following monocular deprivation appeared
to be significantly less pronounced in some coeruleus complex lesioned kittens than in
intact ones, which indicates the existence of a very limited protective effect.
Ocular dominance shifts following neonatal lesion of the NA system. Visual cortical
plasticity survives neonatal destruction of the coeruleus complex although cortical
NA depletion found at 6 weeks of age is comparable to that produced by later lesions
performed during the cortical period. These results are compatible with a recent study
of the cortical effects produced by systemic injection of 6-OHDA before blood-brain
barrier formation (Bear et al. 1983; Bear & Daniels, 1983). From both reports, it can
be concluded that no complete protection of ocular dominance shift was observed
whatever the mode of NA lesion attempted neonatally.
Re-examination of the 'NA hypothesis'
Apart from earlier findings of Kasamatsu & Pettigrew (1976, 1979) concerning
6-OHDA intraventricular injections, most studies producing lesions or disfunction
of the NA or CA ascending pathways have failed to describe a protection of loss of
binocularity of cortical neurones in response to monocular deprivation (Adrien et al.
1982a, b and this study; Bear & Daniels, 1983; Bear et al. 1983; Daw et al. 1983b,
1984, 1985; Allen et al. 1984).
The observed effects are quite different if 6-OHDA is directly perfused in the
cortical tissue. In this situation, blockade of cortical plasticity appears to apply to
ocular dominance (Pettigrew & Kasamatsu, 1978; Daw, Rader, Robertson & Ariel,
1983 a; Paradiso et al. 1983), to orientation selectivity (Daniels, Ellis, Bianco, Garrett,
Nelson & Schwartz, 1981) and to direction selectivity (Daw et al. 1983a).
Several factors have been evoked to explain this experimental controversy such
as the timing between the neurotoxin injection and the onset of environmental
manipulation (Bear et al. 1983; Bear & Daniels, 1983) or the relative importance of
NA depletion produced by each protocol (Kasamatsu, Itakura, Jonsson, Heggelund,
Pettigrew, Nakai, Watabe, Kuppermann & Ary, 1985).
NORADRENALINE AND VISUAL CORTICAL PLASTICITY
93
Influence of the timing of the 6-OHDA injections
Our results raise doubts as to the importance of the age at which the lesion is
performed or of the delay between the lesion and the environmental manipulation.
The hypothesis of chronic versus acute differences in the protective virtues of CA
depletion was in fact introduced by Bear and colleagues when comparing results
obtained in neonatally intraperitoneally injected kittens with those obtained following
intracortical 6-OHDA injection (Bear et al. 1983; Bear & Daniels, 1983). In view of
the data presented here, the importance of these differences might be ignored if one
restricts the comparison between systemic and intraventricular or coeruleus complex
injection paradigms.
Influence of the level of NA depletion
The second important claim by proponents of the 'NA hypothesis' is the existence
of a correlation between the amplitude of the plasticity blockade and the depletion
of NA in visual cortex (Kasamatsu & Pettigrew, 1979; Paradiso et al. 1983). The
original observation was that for comparable monocular deprivation periods the
proportion of binocular cells was roughly proportional to the quantity of intraventricularly injected 6-OHDA. By extension, although NA levels were not systematically
measured, Kasamatsu & Pettigrew proposed that this correlation reflected a control
of the cortical effects of visual experience monotonously dependent on the endogenous
NA level (Kasamatsu & Pettigrew, 1979). In contrast our own results show no
significant correlation between the level of binocularity or the open eye dominance
index and the relative noradrenergic depletion in lesioned kittens. An additional
negative argument comes from comparison of electrophysiological results from both
cortices of kittens in which the coeruleus complex lesions were unilateral or
incomplete: although NA levels might differ in each cortex, in all but one case (n.r.-2)
electrophysiological properties appeared indistinguishable. We conclude that after
coeruleus complex lesion or intraventricular 6-OHDA injection no significant correlation is found between the protection in ocular dominance shift and the NA depletion
level in visual cortex.
The only remaining convincing argument in favour of a noradrenergic gating of
cortical plasticity is the demonstration of the restoration of plasticity by NA intracortical injection following previous 6-OHDA intracortical treatment (Kasamatsu
et al. 1981 a) and the preliminary report of blockade of cortical plasticity following
injection of propranolol (Kasamatsu, 1983, p. 61). However, blockade of plasticity
following 6-OHDA intracortical injection is not a proof in itself: indeed intracortical
injections of glutamate (Shaw & Cynader, 1984) or of scopolamine (W. Singer, personal communication) as well as electrical stimulations of the visual cortex (Shaw &
Cynader, 1984) are all procedures producing qualitatively similar blockades in the
expression of cortical plasticity.
Three hypotheses may be put forward.
(1) A conservative view is to propose that an early sign of breakdown in cortical
homoeostasis in response to in situ exogenous perturbation is a loss of plasticity: this
would occur before a more profound disorganization of cortical connexions, affecting
in particular the 'static' receptive field properties (Mountcastle, 1979), takes place;
94
94
J. ADRIEN AND OTHERS
such impairment of the sole 'dynamic' functioning of the cortical network and of its
ability to modify neuronal connexions should be observed mainly in the case of
intracortical injection. Non-specific side-effects of this lesion technique should indeed
be investigated carefully: data from Bear et al. (1983) suggest that the injection of
the vehicle solution itself might produce protective effects. In addition, as pointed
out by Daw et al. (1984, 1985) no control study has been made on the
effects of 6-OHDA injection following administration of a NA (and 6-OHDA) uptake
blocker.
(2) A more speculative proposal holds as follows: on one hand, all procedures which
increase the temporal correlation between the afferent geniculate message and the
cortical response would improve the transmission efficiency in the activated synapses
(Hebb, 1949): the presence of NA in the cortical tissue might suppress spontaneous
activity, facilitate visual response and thus increase signal/noise ratio. However,
ionophoretic experimental evidence concerning a selective enhancement of visual
information transmission by exogenous NA remains contradictory (Kasamatsu &
Heggelund, 1982; Videen, Daw & Rader, 1984). On the other hand, all procedures
which decrease correlation between pre- and post-synaptic activities would damp the
epigenetic influence of incoming signals on cortical function. This could be the
case when post-synaptic activity is driven to an abnormally low level (following
anaesthesia, paralysis or intracortical scopolamine injection) or an abnormally high
level (following intracortical glutamate or 6-OHDA injection or electrical intracortical stimulations). In this respect it would be crucial to record the chronic effects
of 6-OHDA injection on cortical single unit activity.
(3) A more simple hypothesis might be proposed from the observation of a
fundamental distinction among procedures used to lesion the NA terminals: in most
lesions) the
protocols (systemic, intraventricular or coeruleus complex
the
brain;
in one
neurones
is
affected
of
the
NA
throughout
morphological integrity
terminal
a
remote
to
confined
the
NA
lesion
is
case (intracortical
injection)
the
region (occipital cortex). We propose that all lesion procedures which affect
of
action
modulatory
neurones
into
the
of
coeruleus
NA
play
put
complex
integrity
predominant
compensatory systems thus masking in lesioned kittens the otherwise
gating role of NA during cortical development. In this respect it cannot be excluded
that injection of 6-OHDA localized in the visual cortex might be the only situation
in which a very limited NA terminal deafferentation does not trigger lesion-induced
compensatory phenomena.
The authors are indebted to Michel Arluison for the fluorescence histochemical controls. They
thank Michele Gautier for assistance with the Figures, Pierre Godement for helpful comments and
Inserm U 3
Kirsty Grant for correcting the English. The chemical lesions were performed at
non-specific
6-OHDA
6-OHDA
Unite
de France
(1), the electrophysiological recordings at the Laboratoire de Neurophysiologie du College
from
by
grants
supported
was
at
Inserm
This
research
and
the
U
(2).
14
biochemistry Unite
(3)
CNRS and DGRST.
REFERENCES
ADRIEN, J. (1978). Ontogenesis of some sleep regulations: early postnatal impairment of the
monoaminergic systems. Progress in Brain Research 48, 393-403.
ADRIEN, J. (1981). Monoaminergic regulations of sleep: development and plasticity. In Physiological
and Biochemical Basis for Perinatal Medicine, ed.
296-307. Basel: S. Karger.
MONSET-COUCHARD, M. & MINKOWSKI, A., pp.
NORADRENALINE AND VISUAL CORTICAL PLASTICITY
95
ADRIEN, J., BUISSERET, P., FREGNAC, Y., GARY-BOBo E., TASSIN, J. P., TROTTER, Y. & IMBERT,
M. (1982a). Catecholamines et plasticity du cortex visuel du chaton: un reexamen. Journal de
physiologie 78, 1 B.
ADRIEN, J., BUISSERET, P., FREGNAC, Y., GARY-BOBO, E., TASSIN, J. P., TROTTER, Y. & IMBERT,
M. (1982 b). Noradrenaline et plasticity du cortex visuel du chaton. Comptes rendus de l'Academie
des sciences III, 295, 745-750.
ALLEN, E. E., TROMBLEY, P., SOYKE, J. & GORDON, B. (1984). Norepinephrine depletion; relation
to visual cortical plasticity. Neuroscience Abstracts 10, 1079.
ARLUISON, M., DE LA MANCHE, I., ADRIEN, J., HAMON, M., LAGUZZI, R. & BOURGOIN, S. (1980).
Effects of intraventricular injection of 6-hydroxydopamine in the developing kitten. III.
Histochemical fluorescence and radioautographic studies of the noradrenaline hyperinnervation
in the pons. Brain Research 198, 285-305.
BEAR, M. F. & DANIELS, J. D. (1983). The plastic response to monocular deprivation persists in
kitten cortex after chronic depletion of norepinephrine. Journal of Neuroscience 3, 407-416.
BEAR, M. F., PARADISO, M. A., SCHWARTZ, M., NELSON, S. B., CARNES, K. M. & DANIELS, J. D.
(1983). Two methods of catecholamine depletion in kitten visual cortex yield different effects on
plasticity. Nature 302, 245-247.
BLAKEMORE, C. & PETTIGREW, J. D. (1970). Eye dominance and visual cortex. Nature 225, 426-429.
BoURGOIN, S., ADRIEN, J., LAGUZZI, R. F., DOLPHIN, A., BOCKAERT, J., HERY F. & HAMON, M.
(1979). Effects of intraventricular injection of 6-hydroxydopamine in the developing kitten. II.
On central monoaminergic innervation. Brain Research 160, 461-478.
BUISSERET, P. & IMBERT, M. (1976). Visual cortical cells: their developmental properties in normal
and dark reared kittens. Journal of Physiology 255, 511-525.
CROW, T. J. (1968). Cortical synapses and reinforcement: a hypothesis. Nature 219, 736-737.
CYNADER, M., TIMNEY, B. N. & MITCHELL, D. E. (1980). Period of susceptibility of kitten visual
cortex to the effects of monocular deprivation extends beyond six months of age. Brain Research
191, 545-550.
DANIELS, J. D., ELLIS, M. K., BIANCO, S. A., GARRETT, M., NELSON, S. B. & SCHWARTZ, M. (1981).
Catecholamine depletion, ocular dominance shift and direction selectivity in kitten visual cortex.
Neuroscience Abstracts 7, 673.
DAW, N. W., RADER, R. K., ROBERTSON, T. W. & ARIEL, M. (1983a). Effects of 6-hydroxydopamine
on visual deprivation in the kitten striate cortex. Journal of Neuroscience 3, 907-914.
DAW, N. W., RADER, R. K., ROBERTSON, T. W. & VIDEEN, T. 0. (1983b). Do short term and long
term depletion of noradrenaline have different effects of visual deprivation in the kitten visual
cortex? Neuroscience Abstracts 9, 1217.
DAW, N. W., ROBERTSON, T. W., RADER, R. K., VIDEEN, T. O. & COSCIA, C. J. (1984). Substantial
reduction of noradrenaline by lesions of adrenergic pathway does not prevent effects of
monocular deprivation. Journal of Neuroscience 4, 1354-1360.
DAW, N. W., VIDEEN, T. O., RADER, R. K., ROBERTSON, T. W. & COSCIA, C. J. (1985) Substantial reduction of noradrenaline in kitten visual cortex by intraventricular injections of
6-hydroxydopamine does not always prevent ocular dominance shifts after monocular deprivation. Experimental Brain Research (in the Press).
DESCARRIES, L. (1974). High resolution radioautography of noradrenergic axon terminals in the
neocortex. In Vision in Fishes, ed. ALI, M. A., pp. 211-232. New York: Plenum.
FOOTE, S. L., BLOOM, F. E. & ASTON-JONES, G. (1983). Nucleus locus coeruleus: new evidence of
anatomical and physiological specificity. Physiological Reviews 63, 844-914.
FRtGNAC, Y. (1979). Development of orientation selectivity in the primary visual cortex of
normally and dark reared kittens. I. Kinetics. Biological Cybernetics 34, 187-193.
FREIGNAC, Y. (1982). D6veloppement de la selectivit6 neuronale dans le cortex visuel primaire du
chat. These d'Etat es-Sciences, 296 pp. Paris, VI.
FREGNAC, Y. (1985). Functional multicompartment models: a kinetic study of the development
of orientation selectivity. In Models of the Visual Cortex, ed. ROSE, D. & DOBSON, V., pp. 172-181.
New York: John Wiley and Sons.
FREaGNAC, Y. & IMBERT, M. (1978). Early development of visual cortical cells in normal and dark
reared kittens: relationship between orientation selectivity and ocular dominance. Journal of
Physiology 278, 37-44.
FRIaNAC, Y. & IMBERT, M. (1984). Development of neuronal selectivity in the primary visual cortex
of the cat. Physiological Reviews 64, 325-434.
96
J. ADRIEN AND OTHERS
FREGNAC, Y., TROTTER, Y., BIENENSTOCK, E. L., BUISSERET, P., GARY-BOBO, E. & IMBERT, M.
(1981). Effect of neonatal unilateral enucleation on the development of orientation selectivity
in the primary visual cortex of normally and dark reared kittens. Experimental Brain Research
42, 453-466.
GAUCHY, C., TASSIN, J. P., GLOWINSKI, J. & CHERAMY, A. (1976). Isolation and radioenzymatic
estimation of picogram quantities of DA and NE in biological samples. Journal of Neurochemistry
26, 471-480.
GILBERT, P. (1975). How the cerebellum could memorise movements. Nature 254, 688-689.
GLENNER, G. G., BURTNER, H. J. & BROWN, G. W. (1957). The histochemical demonstration of
monoamine oxidase activity by tetrazolium salts. Journal of Histochemistry and Cytochemistry
5, 591-400.
HARIK, S. I. (1984). Locus ceruleus lesion by local 6-hydroxydopamine infusion causes marked and
specific destruction of noradrenergic neurons, long-term depletion of norepinephrine and the
enzymes that synthesize it, and enhanced dopaminergic mechanisms in the ipsilateral cerebral
cortex. Journal of Neuroscience 4, 699-707.
HEBB, D. 0. (1949). The Organization of Behavior. New York: Wiley.
HERVE, D., BLANC, G., GLOWINSKI, J. & TASSIN, J. P. (1982). Reduction of dopamine utilization
in the prefrontal cortex but not in the nucleus accumbens after selective destruction by
noradrenergic fibers innervating the ventral tegmental area in the rat. Brain Research 237,
510-516.
HUBEL, D. H. & WIESEL, T. N. (1962). Receptive fields, binocular interaction and functional
architecture in the cat's visual cortex. Journal of Physiology 160, 106-154.
HUBEL, D. H. & WIESEL, T. N. (1970). The period of susceptibility to the physiological effects of
unilateral eye closure in kittens. Journal of Physiology 206, 419-436.
IMBERT, M. & BUISsERET, P. (1975). Receptive field characteristics and plastic properties of visual
cortical cells in kittens reared with or without visual experience. Experimental Brain Research
22, 25-36.
ITAKURA, T., KASAMATSU, T. & PETTIGREW, J. D. (1981). Norepinephrine-containing terminals in
kitten visual cortex: laminar distribution and ultrastructure. Neuroscience 6, 159-175.
JONSSON, G. & KASAMATSU, T. (1983). Maturation of monoamine neurotransmitters and receptors
in cat occipital cortex during postnatal critical period. Experimental Brain Research 50, 449-458.
JOUVET, M. (1974). Monoaminergic regulation of the sleep waking cycle in the cat. In The
Neurosciences: Third Study Program, ed. SCHMITT, F. 0. & WORDEN, F. G., pp. 499-508.
Cambridge, Mass.: M.I.T. Press.
KASAMATSU, T. (1980). A possible role for cyclic nucleotides in plasticity of visual cortex.
Neuroscience Abstracts 6, 494.
KASAMATSU, T. (1982). A role of the central norepinephrine system in regulation of neuronal
plasticity in cat visual cortex. In Biomedical Research Supplement, Neurotransmitters in the Retina
and the Visual Centers, ed. KANEKO, A., TSUKAHARA, N. & UCHIZONO, K., pp. 88-93. Tokyo:
Biomedical Research Foundation.
KASAMATSU, T. (1983). Neuronal plasticity maintained by the central norepinephrine system in the
cat visual cortex. In Progress in Psychobiology and Physiological Psychology, vol. 10, ed. SPRAGUE,
J. M. & EPSTEIN, A. N., pp. 1-112. London: Academic Press.
KASAMATSU, T. & HEGGELUND, P. (1982). Single cell responses in cat visual cortex to visual
stimulation during the iontophoresis of noradrenaline. Experimental Brain Research 45, 317-327.
KASAMATSU, T., ITAKURA, T. & JONSSON, G. (1981 b). Intracortical spread of exogenous catecholamines: effective concentration for modifying cortical plasticity. Journal of Pharmacology and
Experimental Therapeutics 217, 841-850.
KASAMATSU, T., ITAKURA, T., JONSSON, G., HEGGELUND, P., PETTIGREW, J. D., NAKAI, K.,
WATABE, K., KUPPERMANN, B. D. & ARY, M. (1985). Neuronal plasticity in cat visual cortex:
a proposed role for the central norepinephrine system. In Monoamine Innervation of Cerebral
Cortex, ed. DESCARRIES, L., READER, T. A. & JASPER, H. H. New York: Alan Liss Inc. (in the
Press).
KASAMATSU, T. & PETTIGREW, J. D. (1976). Depletion of brain catecholamines: failure of ocular
dominance shift after monocular occlusion in kittens. Science 194, 206-209.
KASAMATSU, T. & PETTIGREW, J. D. (1979). Preservation of binocularity after monocular deprivation in the striate cortex of kittens treated with 6-hydroxydopamine. Journal of Comparative
Neurology 185, 139-161.
NORADRENALINE AND VISUAL CORTICAL PLASTICITY
97
KASAMATSU, T., PETTIGREW, J. D. & ARY, M. (1979). Restoration of visual cortical plasticity by
local microperfusion of norepinephrine. Journal of Comparative Neurology 185, 163-182.
KASAMATSU, T., PETTIGREW, J. D. & ARY, M. (1981 a). Cortical recovery from effects of monocular
deprivation: acceleration with norepinephrine and suppression with 6-hydroxydopamine.
Journal of Neurophysiology 45, 254-266.
KETY, S. S. (1970). The biogenic amines in the central nervous system: their possible roles in
arousal, emotion and learning. In The Neurosciences: Second Study Program, ed. SCHMITT, F. O.,
pp. 324-336. New York: Rockefeller University Press.
LANFUMEY, L., ARLUISON, M. & ADRIEN, J. (1981). Destruction of noradrenergic cell bodies by
intracerebral 6-hydroxydopamine in the newborn rat. Brain Research 214, 445-450.
LIVINGSTONE, M. S. & HUBEL, D. H. (1981). Effects of sleep and arousal on the processing of visual
information in the cat. Nature 291, 554-561.
MAEDA, T., PIN, C., SALVERT, D., LIGIER, M. & JOUVET, M. (1973). Les neurones contenant des
catecholamines du tegmentum pontique et leurs voies de projection chez le chat. Brain Research
57, 119-152.
MOORE, R. Y. & BLOOM, F. E. (1979). Central catecholamine neuron systems: anatomy and
physiology of the norepinephrine and epinephrine systems. Annual Review of Neuroscience 2,
113-168.
MORRISON, J. H., GRZANNA, R., MOLLIVER, M. E. & COYLE, J. T. (1978). The distribution and
orientation of noradrenergic fibers in neocortex of the rat: an immuno-fluorescence study. Journal
of Comparative Neurology 181, 17-40.
MOUNTCASTLE, V. B. (1979). An organizing principle for cerebral function: the unit module and
the distributed system. In The Neurosciences: Fourth Study Program, ed. SCHMITT, F. 0. &
WORDEN, F. G., pp. 21-42. Cambridge, Mass.: M.I.T. Press.
MOVSHON, J. A. & DtRSTELER, M. R. (1977). Effects of brief periods of unilateral eye closure on
the kitten's visual system. Journal of Neurophysiology 40, 1255-1265.
NAKAI, Y. & TAKAORI, S. (1974). Influence of norepinephrine-containing neurons derived from the
locus coeruleus on lateral geniculate activities in cats. Brain Research 71, 47-60.
NAKAMURA, S. (1977). Some electrophysiological properties of neurones of rat locus coeruleus.
Journal of Physiology 267, 641-658.
OLSON, C. R. & FREEMAN, R. D. (1980). Profile of the sensitive period for monocular deprivation
in kittens. Experimental Brain Research 39, 17-21.
PARADISO, M. A., BEAR, M. F. & DANIELS, J. D. (1983). Effects of intracortical infusion of
6-hydroxydopamine on the response of kitten visual cortex to monocular deprivation. Experimental Brain Research 51, 413-422.
PETTIGREW, J. D. (1978). The paradox of the critical period for striate cortex. In Neuronal
Plasticity, ed. COTMAN, C. W., pp. 311-330. New York: Raven Press.
PETTIGREw, J. D. & KASAMATSU, T. (1978). Local perfusion of noradrenaline maintains visual
cortical plasticity. Nature 271, 761-763.
ROGAWSKI, M. A. & AGHAJANIAN, G. K. (1980). Modulation of lateral geniculate neurone excitability
by noradrenaline microiontophoresis of locus coeruleus stimulation. Nature 287, 731-734.
SHATZ, C. J., LINDSTROM, S. & WIESEL, T. N. (1977). The distribution of afferents representing the
right and left eyes in the cat's visual cortex. Brain Research 131, 103-116.
SHAW, C. & CYNADER, M. (1984). Disruption of cortical activity prevents ocular dominance changes
in monocularly deprived kittens. Nature 308, 731-734.
SILLITO, A. M. (1983). Plasticity in the visual cortex. Nature 303, 477-478.
SINGER, W. (1981). Topographic organization of orientation columns in cat visual cortex. A
deoxyglucose study. Experimental Brain Research 44, 431-436.
TASSIN, J. P., LAVIELLE, S., HERVE', D., BLANC, G., THIERRY, A. M., ALVAREZ, C., BERGER, B. &
GLOWINSKI, J. (1979). Collateral sprouting and reduced activity of the rat mesocortical
dopaminergic neurons after selective destruction of ascending noradrenergic bundles. Neuroscience
4, 1569-1582.
TIEMAN, S. B. & TUMOSA, N. (1983). ('4C)-2-deoxyglucose demonstration of the organization of
ocular dominance in areas 17 and 18 of the normal cat. Brain Research 267, 35-46.
TORK, I., LEVENTHAL, A. G. & STONE, J. (1979). Brain stem afferents to visual cortical areas 17,
18, and 19 in the cat, demonstrated by horseradish peroxidase. Neuroscience Letters 11, 247-252.
TROTTER, Y., FRAGNAC, Y. & BUISSERET, P. (1983). Synergie de la vision et de la proprioception
4
PRHY 367
98
J. ADRIEN AND OTHERS
extraoculaire dans les mecanismes de plasticity fonctionnelle du cortex visuel primaire du chaton.
Compte8 rendu8 de l'Academie de8 Sciences D 296, 665-668.
VAN SLUYTERS, R. C. (1978). Reversal of the physiological effects of brief periods of monocular
deprivation in the kitten. Journal of Phy8iology 284, 1-7.
VIDEEN, T. O., DAW, N. W. & RADER, R. K. (1984). The effect of norepinephrine on visual cortical
neurons in kittens and adult cats. Journal of Neuro8cience 4, 1607-1617.