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The Journal of Neuroscience, 1999, 19:RC30:1-5
RAPID COMMUNICATION
Elimination of Aggressive Behavior in Male Mice Lacking
Endothelial Nitric Oxide Synthase
Gregory E.
Demas1, 6,
Lance J.
Kriegsfeld1,
Seth
Blackshaw2,
Paul
Huang5,
Stephen C.
Gammie1,
Randy J.
Nelson1, 2, and
Solomon H.
Snyder2, 3, 4
Department of 1 Psychology, Johns Hopkins University,
and Departments of 2 Neuroscience,
3 Pharmacology and Molecular Sciences, and
4 Psychiatry, Johns Hopkins University School of Medicine,
Baltimore, Maryland 21218, 5 Massachusetts General
Hospital, Division of Cardiology, Boston, Massachusetts 02114, and
6 Georgia State University, Departments of Psychology and
Biology, Atlanta, Georgia 30303
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ABSTRACT |
Male mice with targeted deletion of the gene encoding the neuronal
isoform of nitric oxide synthase (nNOS /) display
increased aggressive behavior compared with wild-type (WT) mice.
Specific pharmacological inhibition of nNOS with 7-nitroindazole also
augments aggressive behavior. We report here that male mice with
targeted deletion of the gene encoding endothelial NOS
(eNOS/) display dramatic reductions in
aggression. The effects are selective, because an extensive battery of
behavioral tests reveals no other deficits. In the resident-intruder
model of aggression, resident eNOS/ males show
virtually no aggression. Latency for aggression onset is 25-30 times
longer in eNOS/ males compared with WT males in
the rare instances of aggressive behaviors. Similarly, a striking lack
of aggression is noted in tests of aggression among groups of four mice
monitored in neutral cages. Although eNOS/ mice
are hypertensive (~14 mmHg blood pressure elevation),
hypertension does not appear responsible for the diminished aggression.
Reduction of hypertension with hydralazine does not change the
prevalence of aggression in eNOS/ mice.
Extensive examination of brains from eNOS/ male
mice reveals no obvious neural damage from chronic hypertension. In situ hybridization in WT animals reveals eNOS mRNA in
the brain associated exclusively with blood vessels and no neuronal
localizations. Accordingly, vascular eNOS in the brain appears capable
of influencing behavior with considerable selectivity.
Key words:
aggression; hypertension; 7-nitroindazole; nitroarginine; nitric oxide synthase; endothelium
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INTRODUCTION |
Nitric
oxide (NO) is formed by three distinct enzymes coded by different
genes, neuronal NO synthase (nNOS), endothelial NOS (eNOS), and
inducible NOS (iNOS) (Jaffrey and Snyder, 1995 ). Although nNOS is the
primary neuronal form of the enzyme, there have been reports of eNOS in
neurons (Dinerman et al., 1994; O'Dell et al., 1994; Doyle and Slater,
1997), and genetic manipulations of eNOS may influence hippocampal
long-term potentiation (Son et al., 1996). Male mice with targeted
deletion of the gene for nNOS (nNOS/)
(Nelson et al., 1995) and mice treated with 7-nitroindazole, an
in vivo selective inhibitor of nNOS (Demas et al., 1997)
display marked increases in aggressive and sexual behavior, The
nNOS/ mice also manifest defects in
nocturnal balance coordination (Kriegsfeld et al., 1999). Initial
studies of eNOS/ mice revealed
hypertension but grossly normal behavior (Huang et al., 1995; Sheseley
et al., 1996).
We now report virtual elimination of aggressive behavior in male
eNOS/ mice, as well as improved fine
motor coordination suggesting reciprocal behavioral roles for eNOS and
nNOS. Our in situ hybridization studies reveal eNOS mRNA in
blood vessels but not in neuronal populations in the brain.
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MATERIALS AND METHODS |
Animals and housing conditions. The
eNOS/ mice were derived from animals
originally developed by Huang et al. (1995). Controls included
littermates of the eNOS/ mice as well
as C57/B16 mice that were bred in the same colony. Behavioral measures
for the two groups did not differ so that they were combined for
statistical analyses. All animals were 4-6 months of age (sexually
mature) at the onset of behavioral testing. Animals were individually
housed in polypropylene cages (27 × 17 × 12 cm) in a colony
room with a 24 hr light/dark 16/8 photoperiod (lights on at 7 A.M.
Eastern Standard Time). Ambient temperature was maintained at 20 ± 2°C, and relative humidity was maintained at 50 ± 5%. Food
(Prolab 100; Agway, Syracuse, NY) and tap water were provided ad
libitum throughout the experiment.
Resident-intruder aggression. An adult stimulus male mouse
(i.e., intruder) was introduced into the home cage of either an experimental or control adult male mouse. Intruder mice were selected randomly from a pool of individually housed breeder males. These males
tended not to attack but would respond aggressively if attacked. Intruder mice were marked on the tail with an indelible marker for
purposes of identification. The bedding in the home cages was not
changed for 10 d before behavioral testing. The latency to first
aggressive encounter, the duration of each aggressive encounter, and
the total number of aggressive encounters
initiated by the resident male were recorded. Aggression
tests lasted 5 min and were conducted each day for 3 consecutive days
between 3 and 5 P.M. A novel pairing of animals was made for each
consecutive test, and intruder males were not used more than once per day.
Grouped aggression in neutral arena. Four adult wild-type
(WT) or eNOS/ mice were simultaneously
introduced into a clear glass aquarium (38.5 × 26.5 × 30.7 cm). The floors of the aquarium were covered with 2-3 cm of fresh pine
shavings. The latency to first aggressive encounter, the duration of
each aggressive encounter, and the total number of aggressive
encounters initiated by each male were recorded. Aggression tests
lasted 15 min and were conducted in 1 d between 3 and 5 P.M.
Sensorimotor tests. A battery of sensorimotor tests was used
to assess sensory function and motor coordination and balance (Nelson
et al., 1995; Crawley and Paylor, 1997). A series of standardized tests
to assess anxiety, including tests using an open field and elevated
plus maze, was also conducted. Briefly, to assess open field activity,
a mouse was placed in an open arena (1 m2). An observer recorded the movement of
the mouse during the testing period. The floor was marked off by 16 squares, and the number of squares crossed was counted. Also, the
amount of time spent in the open field (inner squares) was compared
with the time the mouse moved along the walls of the arena. This test
was conducted for 10 min. Incidents of grooming and rearing and number
of fecal boli produced were recorded. Mice were also placed in the
center of an elevated plus maze with two open arms and two closed arms (67 × 5.5 cm). The closed arms contained a 15-cm-high,
black-tinted Plexiglas panel and a 65-cm-long detachable roof.
The maze was mounted 75 cm above the floor on a tripod. Choice behavior
was observed for 5 min, and the number of visits to each arm and the time spent in each arm as well as in the central area were recorded. Incidents of grooming and rearing and number of fecal boli produced were also recorded.
In situ hybridization. In situ hybridization was conducted
as previously described (Blackshaw and Snyder, 1997). The cRNA probe
used corresponded to the region covering 2583-3499 bp of murine eNOS
(Gnanapandithen et al., 1996). This technique uses a digoxigenin label
so that resolution is comparable with immunohistochemistry and
substantially better than with a radiolabeled probe. Control hybridization with sense probes provided negligible signals. Regions selected for analysis were those in which neuronal localizations of
eNOS had been previously reported (Dinerman et al., 1994; O'Dell et
al., 1994; Doyle and Slater, 1997). Sections (20-30) were selected at
random for examination with the experimenter blinded to the identity of
the mice, WT or eNOS/.
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RESULTS |
In routine handling of
eNOS/ mice we note marked docility.
Thus, in contrast to WT mice, the
eNOS/ animals never bite their
handlers and are much gentler in disposition. This contrasts markedly
with nNOS/ animals, which are
extremely aggressive and routinely attack handlers and each other. In
groups of animals, agonistic behavior is extremely rare among
eNOS/ male mice.
To examine this behavior in greater detail, we investigated intermale
aggression using a resident-intruder model, an experimental model of
territorial aggressive behavior (Thurmond, 1975). We focused our
studies on males, because female mice typically do not display
aggressive behavior in this context. We scored a variety of aggressive
behaviors including wrestling, biting, and tail rattling (Fig.
1). The number
(t(22) = 4.57; p < 0.01) of aggressive encounters and their duration
(t(22) = 4.66; p < 0.01) are profoundly reduced in the
eNOS/ animals, whose values are not
significantly different from zero. The latency to initiate an
aggressive encounter is markedly increased for the very few aggressive
encounters displayed by eNOS/animals
(p < 0.001).
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Figure 1.
Aggressive behavior in WT (n = 12) or eNOS/ (n = 12) mice
in a resident-intruder model. a, Mean ± SEM
number of aggressive encounters; b, mean ± SEM
duration of aggressive encounters. Data were analyzed by
t test. *Statistically significant difference at
p < 0.001.
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To evaluate nonterritorial aggression, we observed groups of WT or
eNOS/ males together in a large cage
(Fig. 2). In this group test, as in the
resident-intruder aggressive model, aggressive behavior is virtually
eliminated in the eNOS/ animals when
monitored in terms of the number
(t(10) =  5.093; p < 0.001) of aggressive encounters and their duration
(t(10) = 0.558; p > 0.05). The latency (t(10) = 5.21;
p < 0.001) for the limited number (3.00 ± 1.3)
of attacks by the eNOS/ mice is 25-30
times greater than for WT (60.5 ± 11) animals.
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Figure 2.
Aggressive behavior in WT or
eNOS/ mice in a grouped aggression model. Six
groups of WT and six groups of eNOS/ mice were
evaluated, with four mice in each group. a, Mean ± SEM number of aggressive encounters; b, mean ± SEM
duration of aggressive encounters; c, mean ± SEM
latency to initial attack. Symbols, conventions, and statistical
analysis are as in Figure 1.
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The eNOS/ mice are derived from two
parent strains, C57 and SV 129 (Huang et al., 1995). The depicted
experiments (Figs. 1, 2) compared the mutant mice with WT C57 animals.
In other experiments in the same paradigms we detect no difference in
aggressive behavior between WT C57 and SV 129 mice or C57-SV 129 hybrid
strains (data not shown), confirming our earlier observations (Nelson
et al., 1995). Thus, the dramatic reduction of aggression in
eNOS/ mice does not merely reflect
strain variations.
Because the blood pressure of eNOS/
animals is ~14 mmHg higher than that of WT controls (Huang et al.,
1995; Sheseley et al., 1996), we speculated that the decreased
aggressive behavior might reflect hypertension. This seems unlikely,
because in models of hypertension that are genetically determined
(Potegal and Myers, 1989) or elicited by long-term treatment with
sodium chloride and corticosterone (Simon and Gandelman, 1978),
aggressive behavior is generally increased; furthermore, there are no
reports of decreased aggression associated with any form of
hypertension in animals. To assess whether the
eNOS/ animals display hypertensive
encephalopathy, we examined sealed sections of all regions of the
brains of the mutant mice with Nissl and DAPI stains and found no
morphological differences compared with WT mice (data not shown),
similar to previous findings (Kantor et al., 1996; Son et al.,
1996).
Although there is no practical way of reversing whatever effects are
elicited by lifelong hypertension, we did make an effort to ascertain
whether reducing blood pressure of the
eNOS/ animals would affect behavior.
We treated the eNOS/ animals with a
regimen of hydralazine administration shown previously to render
eNOS/ animals normotensive (Huang et
al., 1995). For 10 d eNOS/ and WT
mice received hydralazine in the drinking water (250 mg/l, resulting in
~1 mg/d). We examined aggressive behavior in the resident-intruder
neutral arena and group aggression models. No change in aggressive
behavior is evident in the behavioral tests (Fig.
3).
eNOS/ mice continue to show
dramatically reduced aggressive behavior relative to WT mice, and
eNOS/ mice rendered normotensive with
hydralazine do not differ from eNOS/
controls.
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Figure 3.
Hydralazine treatment does not alter
aggressive behavior of eNOS/ mice. Mice received
hydralazine in their drinking water (1 mg/d) for 10 d. On the 10th
day aggressive behavior was monitored in resident-intruder area and
group aggression models. Numbers of animals in groups were as indicated
in Figures 1 and 2. Hydralazine does not alter aggressive behavior of
WT or eNOS/ mice as analyzed by omnibus
F test.
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In addition to abnormalities in sexual and aggressive behavior in male
nNOS/ mice, apparent forelimb strength
is decreased, as assessed by the latency to fall from a suspended wire
(Nelson et al., 1995). By contrast, we observe a modest increase in
forelimb strength in eNOS/ animals
(Table 1). Coordinated performance of
eNOS/ animals is also enhanced in
terms of the ability to turn in a blind alley. Apparent alterations in
fine motor coordination, such as the ability to turn in a blind alley,
could conceivably reflect "emotional" disturbances such as anxiety.
However, in anxiety models, such as the elevated plus maze,
eNOS/ animals do not differ from WT
mice (Table 1). The alterations in aggressive behavior, forelimb
strength, and motor coordination do not seem to derive from generalized
behavioral alterations, because most behaviors examined do not
differentiate eNOS/ mice from WT
animals. Thus, we find no differences in the ability to initiate
walking, olfactory ability, visual acuity, tactile behavior, balance,
or body mass.
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Table 1.
Performance of eNOS/ and WT mice in
sensorimotor tasks designed to test motor ability, agility,
balance-coordination, sensory ability, and strength
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The pronounced alterations of aggressive behavior, as well as apparent
forelimb strength and fine motor coordination, in
eNOS/ animals might be associated with
alterations in putative neuronal populations using eNOS. eNOS is
primarily localized to the endothelium of blood vessels throughout the
body, including the brain. However, we (Dinerman et al., 1994; O'Dell
et al., 1994) and others (Doyle and Slater, 1997) have reported
putative eNOS by immunohistochemistry and NADPH diaphorase staining in
some neuronal populations, whereas others have identified eNOS only in
blood vessels in the brain (Seidel et al., 1997; Stanarius et al.,
1997; Topel et al., 1998). Limitations of such immunohistochemical
studies primarily involve the possibility of cross-reactivity of eNOS
antibodies with other forms of NOS or with unrelated antigens. NADPH
diaphorase staining reflects oxidative enzyme activity using NADPH as
an electron donor and so can involve enzymes other than NOS. In
situ hybridization using appropriate probes can be much more
selective. Because aggressive behavior is presumably mediated primarily
through portions of the limbic system, we performed in situ
hybridization focusing on the amygdala, the hypothalamus, and the
septum, as well as the cerebellum (Fig.
4). The probe we used is a cRNA probe,
which, under the high stringency conditions used, is highly specific for eNOS (see Materials and Methods). In all areas of the brain examined, we detect eNOS signal associated with blood vessels but fail
to observe any signal in neurons.
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Figure 4.
In situ hybridization of
endothelial nitric oxide synthase in selected brain regions of WT and
eNOS / mice. Magnification, 100×, except for the
septum, which is 50×. Arrows indicate selected
eNOS-positive blood vessels. A slight background signal, which does not
represent specific hybridization, is seen in white matter of the
cerebellum and septum.
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DISCUSSION |
The most dramatic finding of this study is the virtual elimination
of aggressive behavior in eNOS/
animals. Additionally, the eNOS/ mice
display enhanced forelimb strength and apparent fine motor coordination. It is noteworthy that these results are opposite to those
observed in nNOS/ animals that display
extraordinary augmentation of aggressive behavior and defects in
nocturnal balance coordination and forelimb strength (Nelson et al.,
1995; Kriegsfeld et al., 1999).
The behavioral alterations we observe do not appear to reflect any type
of nonspecific, general behavioral disruption. We evaluated an
extensive sensorimotor repertoire and find no notable abnormalities in
eNOS/ animals. By direct observation,
the gross appearance and overall behavior of the
eNOS/ animals do not differ from those
of WT mice (Huang et al., 1995; Sheseley et al., 1996). The absence of
any gross behavioral abnormalities is consistent with our failure to
observe any neuroanatomical defect despite careful examination of
multiple sections from many brain regions, similar to findings of
others (Huang et al., 1995; Sheseley et al., 1996).
To ascertain the cellular substrate for any behavior associated with
eNOS, we conducted in situ hybridization with a highly specific probe and observe label in blood vessels but not in neurons. In earlier studies using an antibody directed against eNOS peptide, we
observed neuronal localizations (Dinerman et al., 1994; O'Dell, 1994).
As controls, the earlier studies observed elimination of staining with
preabsorption using the peptide and the absence of staining with
preimmune serum. However, these types of controls do not rule out
cross-reactivity with other proteins. Recent immunohistochemical studies using a number of selective eNOS antibodies reveal staining confined to blood vessels (Seidel et al., 1997; Stanarius et al., 1997;
Topel et al., 1998). In our own recent studies we also observed immunoreactivity for eNOS restricted to blood vessels in the brain (S. Blackshaw, M. Eliasson, and S. H. Snyder, unpublished observations).
How might eNOS in blood vessels exert such selective influences on
behavior? eNOS does not occur uniformly in all vessels. It tends to be
most enriched in large and medium-size blood vessels, although there is
some eNOS in small arterioles and veins, which lack smooth muscle
(Catalan et al., 1996; Seidel et al., 1997; Stanarius et al., 1997;
Topel et al., 1998). The selective regulation of behavior by NO derived
from blood vessels is highlighted by the absence of observable
morphological alterations in the brain, as well as the selectivity of
the behavioral changes. Furthermore, the observation that behavior is
improved in measures such as general motor coordination and forelimb
strength argues against hypertensive encephalopathy as an explanation
of the altered behaviors.
The apparent reciprocal regulation of behavior by nNOS and eNOS in the
brain is puzzling, especially because one of the enzymes is neuronal
and the other is associated with blood vessels. However, the fact that
cerebral blood vessels of all sizes show extensive innervation
(Kobayashi et al., 1985; MacKenzie and Scatton, 1987; Iadecola et
al., 1993; Ruat et al., 1995) raises the possibility that NO derived
from eNOS located in endothelial cells of the brain may diffuse to
nearby neurons and influence their activity. This notion is supported
by data demonstrating the importance of NO derived from eNOS in the
control of inhibitory neurotransmitter release in mouse cerebral cortex
(Kano et al., 1998).
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FOOTNOTES |
Received March 1, 1999; revised July 15, 1999; accepted July 30, 1999.
This work was supported by US Public Health Service Grants MH-57535
(R.J.N.), MH-57760 (R.J.N.), MH-18501 (S.H.S.), DA-00266 (S.H.S.), and
HL-57818 (P.H.) and Research Scientist Award DA-00074 (S.H.S.).
Correspondence should be addressed to Dr. Solomon H. Snyder, Department
Neuroscience, Johns Hopkins University School of Medicine, 725 North
Wolfe Street, Baltimore, MD 21218.
This article is published in
The Journal of Neuroscience, Rapid Communications Section,
which publishes brief, peer-reviewed papers online, not in print. Rapid
Communications are posted online approximately one month earlier than
they would appear if printed. They are listed in the Table of Contents
of the next open issue of JNeurosci. Cite this article as:
JNeurosci, 1999, 19:RC30 (1-5). The
publication date is the date of posting online at
www.jneurosci.org.
| |
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TOP
ABSTRACT
INTRODUCTION
