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The Journal of Neuroscience, 2002, 22:RC200:1-6
RAPID COMMUNICATION
The Septohippocampal System Participates in General
Anesthesia
Jingyi
Ma1, 2,
Bixia
Shen1, 2,
Lee S.
Stewart1, 4,
Ian A.
Herrick3, and
L. Stan
Leung1, 2, 4
Departments of 1 Physiology, 2 Clinical
Neurological Sciences, and 3 Anaesthesiology, and
4 Program in Neuroscience, University of Western Ontario,
London, Ontario, Canada N6A 5A5
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ABSTRACT |
How the brain mediates general anesthesia is not known. We report
that two interconnected structures in the forebrain, the medial septum
and the hippocampus, participate in maintaining awareness and movements
during general anesthesia. In the awake, freely behaving rat,
inactivation of the medial septum or the hippocampus by local injection
of a GABAA receptor agonist, muscimol, decreased the
dose of a general anesthetic needed to induce a loss of the tail-pinch
response or a loss of righting reflex. Septohippocampal inactivation
also suppressed the behavioral hyperactivity or the delirium stage
associated with general anesthesia. An increase and decrease of 30-50
Hz (gamma) waves in the hippocampus correlated with an increase
and decrease in behavioral activity, respectively. Similar results were
found for both volatile (halothane and isoflurane) and nonvolatile
(propofol and pentobarbital) anesthetics. We conclude that the
behavioral hyperactivity induced by a general anesthetic is mediated in
part by the septohippocampal system, and that depression of the
septohippocampal system increases the potency of a general anesthetic.
It is suggested that more potent general anesthetics or adjuvants may
be developed by maximizing the pharmacological depression of the
septohippocampal system.
Key words:
delirium; general anesthetic; gamma rhythm; medial
septum; hippocampus; propofol; pentobarbital
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INTRODUCTION |
A
general anesthetic appears to act on lipids and proteins on the
membrane and alter synaptic transmission and intrinsic membrane currents in neurons (Krnjevic, 1991 ; Tanelian et al., 1993; Franks and
Lieb, 1994). However, after >150 years of clinical use, how general
anesthetics act on the brain to mediate general anesthesia is still
unclear. In preference to the early theory of depression of the
brain-stem reticular formation (Moruzzi and Magoun, 1949; Clark and
Rosner, 1973), it is believed that general anesthetics act on different
levels of the brain (Stockard and Bickford, 1975; Krnjevic, 1991). So
far, the data appear to provide more support for a spinal than a
central control of anesthesia (Antognini and Schwartz, 1993; Rampil et
al., 1993; Rampil, 1994). Definitive evidence of the involvement of a
selective part of the forebrain in general anesthesia has been lacking.
One of the earliest demonstrations of a general anesthetic (in 1844)
showed that nitrous oxide induced behavioral excitation or delirium,
termed stage II anesthesia (Guedel, 1951). Based on our preliminary
data (L. S. Leung, unpublished observations) and the recent
literature indicating that the septohippocampal system may induce
behavioral hyperactivity (Ma et al., 1996; Oddie et al., 1996; Ma and
Leung, 1999; 2000), we initially hypothesized that the medial septum
and the hippocampus mediate the delirium stage of general anesthesia.
The initial experiments led to a second hypothesis that the
inactivation of the septohippocampal system enhances the effects of a
general anesthetic.
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MATERIALS AND METHODS |
In male Long-Evans rats under pentobarbital anesthesia, four
23 gauge stainless-steel guide cannulas were implanted above the
hippocampus (two per side) according to the following coordinates: posterior (P) 4, lateral (L) ± 2; P5, L ± 2.5;
relative to bregma (Paxinos and Watson, 1986). A single cannula was
implanted above the medial septum [anterior (A) 0.7, L 0].
After at least 7 d of recovery, a rat was habituated in a 30 × 30 × 30 cm clear Plexiglas chamber. Saline or the
GABAA receptor agonist muscimol was injected through a 30 gauge inner cannula into the hippocampal CA1 stratum radiatum (0.5 µg of muscimol in 1 µl of saline at each site; 1 µg
of muscimol is equivalent to 8.76 nmol of muscimol) or the medial septum (1 µg of muscimol in 0.6 µl of saline unless
otherwise noted). Each rat served as its own control in an
order-randomized, counter-balanced design, with experiments separated
by at least 1 d. A general anesthetic was given 15-20 min after
the last injection into the hippocampus and 15 min after a septal
injection. Population spike recordings and dye diffusion indicated that
each muscimol injection affected a volume of ~1 mm radius in <30
min. Therefore, it is estimated that the two-site muscimol injections
into the hippocampus affect ~60% of each hippocampus, primarily
sparing the ventral hippocampus. A single-site injection of muscimol
into the hippocampus of each side gave partial results compared with the two-site injections (data not shown). Some rats had an intravenous catheter inserted into the femoral vein under pentobarbital anesthesia at least 2 d before a propofol experiment. The concentration of halothane and isoflurane (typically 1-3%) in pure oxygen was
determined by specific vaporizers, delivered by a tube into the
observation chamber at a flow rate of 8 l/min, and allowed to leak out
from small holes at the top of the chamber. Propofol (2.5-10 mg/kg, i.v.) was injected into the femoral vein over 30 sec, and pentobarbital (10-60 mg/kg) was injected intraperitoneally. All rats retained spontaneous respiration without apnea for the primary doses of general
anesthetics used.
A positive tail-pinch response was considered to be a movement of the
body or more than one limb in response to a pinch of the tail by
forceps or an alligator clip. The pinch was applied periodically to the
middle part of the tail but not to the same part successively. A
transient pinch induced a normal rat to move but caused no permanent
tissue damage. The righting reflex was considered normal when the rat
could right itself from a prone position. Tail-pinch and righting
responses were tested in room air 10 min after exposure to a gaseous
anesthetic, 5 min after pentobarbital injection, or 1 min after
propofol injection. Horizontal and vertical movements were quantified
by the number of infrared beam interruptions in an observation chamber.
Power-spectral analysis of the EEG was done as described previously
(Leung, 1985).
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RESULTS |
In the first set of experiments, rats were given muscimol or
saline control injections bilaterally into the hippocampus through implanted cannulas, 15-20 min before a general anesthetic. Within 30 sec after introduction of 2% halothane, control rats sniffed, made
head movements, and walked around the observation chamber. By 2 min,
halothane clearly affected the posture of the control rats, which
sometimes showed sudden but small body drops during standing. However,
the rats continued to move vigorously, although their limbs were
increasingly ataxic. Muscimol-injected rats showed significantly fewer
movements than control rats after halothane, as quantified by the
interruptions of infrared light beams (Fig. 1A). Cessation of
voluntary movements occurred at 5-6 min after halothane in control
rats, significantly longer than the 2-3 min in muscimol-injected rats
(p < 0.01; Wilcoxon test). Injection of
muscimol in the hippocampus did not induce an apparent change in
spontaneous behavior or behavioral reactivity. Injection of muscimol in
the parietal cortex (1.5 mm above the hippocampal alvear surface) had
no effect on any behavior induced by the anesthetic.
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Figure 1.
Inactivation of the hippocampus by muscimol
abolished behavioral excitation and enhanced the deep anesthesia
induced by a general anesthetic. Rats were injected, in an
order-randomized design, with saline or muscimol bilaterally into the
hippocampus, and horizontal movements were quantified by the number of
infrared beam interruptions in an observation chamber.
A, Mean and SEM of beam interruptions before hippocampal
injection and halothane (same 7 rats per group) do not show a
difference between control and muscimol-injected groups. At time 0, 2%
halothane was introduced into the chamber. Control rats showed an
increase in the number of infrared beam interruptions; this increase
was significantly larger than that seen in muscimol-injected rats, and
was also confirmed by videotape analysis. The anesthetic halothane was
replaced by 2% isoflurane (B)
(n = 7) and 5 mg/kg intravenous propofol
(C) (n = 7).
D-F, Duration of loss of the tail-pinch response or
righting reflex (mean plus 1 SEM) was prolonged by muscimol
(mus) compared with control saline
(sal) injection (n = 7).
Tests were done in room air after 10 min in halothane
(D) and isoflurane (E). F,
Pain and righting responses were tested starting 1 min after
administration of 5 mg/kg intravenous propofol. The absence of a
bar for the saline group indicates no mean and SEM or no loss of
the tail pinch or righting responses; muscimol- and
saline-injected groups were compared in A-C using
post hoc t tests after repeated-measures
ANOVAs; groups were compared in D and
E using paired t tests and compared
in F using a paired Wilcoxon test.
*p < 0.05; #p < 0.01; ***p < 0.005.
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Isoflurane (2%) produced similar effects compared with halothane,
except it did not abolish movements in some control rats. In contrast,
all muscimol-injected rats lost the righting reflex and their ability
to move voluntarily after isoflurane. Isoflurane-induced movements were
significantly fewer in muscimol- compared with saline-injected rats
(Fig. 1B). Control rats given a subanesthetic dose of
propofol (5 mg/kg, i.v.) showed an increase in ataxic walking and
circling as well (Fig. 1C), and all control rats retained their righting reflex. In contrast, muscimol-injected rats showed little behavioral hyperactivity after propofol (Fig. 1C),
and five of seven rats lost their ability to move voluntarily 1 min after administration of 5 mg/kg intravenous propofol.
At 10 min after the administration of halothane or isoflurane, rats
were removed from the chamber and periodically tested for pain
responses to tail pinch. Rats with muscimol injected into the
hippocampus showed a prolonged suppression of their response to tail
pinch compared with control rats (Fig. 1D,E). In
addition, muscimol-injected rats took longer than saline-injected rats
to right themselves. After 5 mg/kg intravenous propofol, only
muscimol-injected rats but not saline-injected rats lost their pain and
righting responses (Fig. 1F).
The medial septum controls the electrical activity and functions of the
hippocampus through cholinergic and GABAergic pathways (Stumpf, 1965;
Bland, 1986; Vanderwolf, 1988; Freund and Buzsaki, 1996). After
inactivation of the medial septum by muscimol, a rat was capable of
moving but would remain spontaneously immobile if not disturbed (Ma and
Leung, 1999, 2000). The movements induced by halothane, isoflurane, or
propofol were significantly suppressed in septum-inactivated rats
compared with control rats (Fig.
2A-C). Also, compared
with control rats, septum-inactivated rats showed a prolonged loss of
tail-pinch and righting responses after administration of halothane or
isoflurane (Fig. 2D,E). Propofol (5 mg/kg, i.v.) abolished righting and tail-pinch responses in septum-inactivated rats
but not in control rats (Fig. 2F). Propofol
administered intravenously at 2.5 mg/kg or at a lower dose did not
abolish righting or pain responses in either septum-inactivated or
control rats. When administered intravenously at 10 mg/kg, propofol
suppressed righting and tail-pinch responses longer in
septum-inactivated rats compared with control rats.
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Figure 2.
Inactivation of the medial septum by muscimol
abolished behavioral excitation and enhanced the deep anesthesia
induced by a general anesthetic. Layout and symbols are the same as in
Figure 1. The number of infrared beam interruptions is shown before and
after 2% halothane (A) (n = 6), 2% isoflurane (B) (n = 6), and 5 mg/kg intravenous propofol (C)
(n = 8). Durations of loss of tail-pinch and
righting reflex are shown after 2% halothane (D)
(n = 6), 2% isoflurane (E)
(n = 6), and 5 mg/kg intravenous propofol
(F) (n = 8).
*p < 0.05; #p < 0.01; ***p < 0.005.
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Sodium pentobarbital was injected intraperitoneally in six rats in
order-randomized experiments after either muscimol (0.4 µg) or
control saline injection in the medial septum. Pentobarbital (20 mg/kg,
i.p.) induced behavioral hyperactivity for a few minutes in control
rats; the rats then became sedated, but with preserved responses to
tail pinch and righting. In contrast, in rats in which muscimol was
injected into the medial septum, pentobarbital only induced a brief
period of behavioral activity; in addition, the amount of movements was
significantly smaller than that seen in control rats (Fig.
3A). Pentobarbital (20 mg/kg,
i.p.) abolished the pain and righting responses in five of six rats in
which muscimol was injected in the medial septum, but in none of the
control rats. As a group, the duration of loss of the tail pinch or the righting response was significantly greater in septum-muscimol-injected rats compared with saline-injected rats (Fig. 3B). After
injection of muscimol (0.4 µg) at 2 mm above the medial septum,
approximately in the genu of the corpus callosum, pentobarbital (20 mg/kg, i.p.) did not induce a loss of pain or righting responses in any
rat (Fig. 3B). In addition, the movements induced by
pentobarbital in the genu-muscimol rats were not significantly
different from those in the genu-saline group (Fig. 3A).
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Figure 3.
Injection of muscimol into the medial
septum, but not 2 mm above the septum, reduced behavioral excitation
and enhanced the general anesthesia induced by pentobarbital.
A, Interruptions of horizontal infrared beams were
measured every minute after administration of 20 mg/kg intraperitoneal
sodium pentobarbital, for four conditions: (1)  , saline (0.4 µl)
injected into the medial septum (Septum-Sal); (2)
 , muscimol (0.4 µg in 0.4 µl of saline) injected into the
medial septum (Septum-Mus); (3)  , saline (0.4 µl)
injected 2 mm above the septum, in the genu of the corpus collosum
(Genu-Sal); and (4)  , muscimol (0.4 µg in
0.4 µl of saline) injected in the genu
(Genu-Mus). The same six rats were tested with saline or
muscimol in a randomized manner, first with septal injections and then
with genu injections. The Septum-Sal,
Genu-Sal, and Genu-Mus groups all show an
initially high amount of movements that declined with time, and none of
these rats lost pain or righting responses. *p < 0.05; #p < 0.01; difference between
Septum-Mus and Septum-Sal groups;
post hoc t tests after repeated-measures
ANOVAs. B, Duration of lost response to tail pinch
(alligator clip) and righting reflex was measured 5 min after
pentobarbital injection; means and SEMs (n = 6)
were zero in all groups except for the Septum-Mus group.
*p < 0.05; difference between the
Septum-Mus and Septum-Sal groups
according to the paired Wilcoxon test.
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Voluntary movements were accompanied by a 7-8 Hz theta rhythm in a
normal rat, which slowed to 4-6 Hz during ataxic walking after a
general anesthetic (Fig.
4A,C). Gamma activity
(30-50 Hz) in the hippocampal EEG (Bragin et al., 1995; Leung, 1998) was increased during the behavioral hyperactivity induced by halothane, compared with walking before halothane (Fig. 4A).
After voluntary movements ceased, theta activity disappeared and gamma
activity decreased (Fig. 4A). No increase in gamma
activity was induced by halothane if muscimol was injected in the
medial septum, but an additional decrease in gamma activity accompanied
deep anesthesia after halothane (Fig. 4B). Similar
results were obtained for isoflurane (data not shown). Hippocampal
gamma activity was also increased during the phase of behavioral
hyperactivity observed after administration of propofol (Fig.
4C) or pentobarbital (Leung, 1985). If the medial septum was
inactivated, no increase in hippocampal gamma activity or behavioral
activity was induced by 5 mg/kg intravenous propofol (Fig.
4D). Instead, rats appeared to be in deep anesthesia
and showed reduced gamma activity compared with baseline walking (Fig. 4D). In conclusion, the behavioral excitation and
depression induced by a general anesthetic were correlated with an
increase and decrease in hippocampal gamma activity, respectively.
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Figure 4.
Hippocampal gamma waves increased with
behavioral excitation in control rats and decreased with deep
anesthesia in control and septum-inactivated rats. A,
Top, Raw EEG traces recorded in the CA1 stratum radiatum
of a representative rat during three time periods: baseline walking
(before any injection), 5 min after halothane (behavioral excitation
phase), and 10 min after halothane (deep anesthesia).
Bottom, Power spectra of the hippocampal EEG in the
control rat, showing the slowing of theta activity and the increase in
gamma activity at 5 min (anesthesia-induced behavioral excitation) and
the abolition of both theta and gamma activity at 10 min (deep
anesthesia). B, EEGs and power spectra before and after
halothane in the same rat after muscimol injection in the medial
septum. Theta activity was abolished in muscimol-injected rats, and
halothane induced slow (<1 Hz) waves but no increase in gamma or
behavioral activity. C, Power spectra of the hippocampal
EEG in a control rat before and 3 min (behavioral excitatory phase)
after 5 mg/kg intravenous propofol. Deep anesthesia was not induced in
the control rat. D, Power spectra before and 3 min after
propofol in a rat that had muscimol injected into the medial septum.
Deep anesthesia was induced at 3 min, and no gamma increase or
behavioral hyperactivity was found at any time after propofol.
Calibration of power spectrum: 6.3 log units = 1 mV peak-to-peak
sine wave.
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DISCUSSION |
This study provides direct evidence that the hippocampus or the
medial septum is necessary for the behavioral hyperactivity or delirium
induced by a general anesthetic. Stage II (delirium stage) of general
anesthesia was accompanied by an increase in 30-50 Hz gamma waves in
the hippocampus, whereas deeper anesthesia (stage III) was accompanied
by diminished gamma activity. A hippocampal theta rhythm was present in
stage II anesthesia and could still be induced by strong sensory
stimulation during stage III anesthesia (Stumpf, 1965; Bland, 1986;
Vanderwolf, 1988; Khanna and Zheng, 1999). Diminished gamma activity
after a general anesthetic has been reported in other preparations
(Whittington et al., 1996; Uchida et al., 2000). Medial septal
inactivation or lesion is known to suppress theta waves and behavior
(Bland et al., 1996; Oddie et al., 1996) and gamma waves (Leung, 1987;
Ma and Leung, 1999, 2000).
Medial septal lesion is known to affect various behaviors of a rat,
including increased reactivity to handling and loss of response
inhibition (Grossman, 1978; O'Keefe and Nadel, 1978). Exaggerated
response to handling was more apparent after a high (1 µg) than a low
(<0.5 µg) dose of muscimol administered to the medial septum, and
this response was not apparent after muscimol injections into
the hippocampus. All movements induced by a general anesthetic were
strongly attenuated in rats with septohippocampal inactivation compared
with control rats. However, septohippocampal inactivation by itself did
not induce any sign of anesthesia, and after inactivation, a rat was
responsive to touch, sound, and light, and was capable of righting
itself. Latency of paw withdrawal on a hot plate was not different
between septum- or hippocampus-inactivated rats and controls (data not
shown), suggesting that the pain threshold was not critically altered
by septohippocampal inactivation.
Our most important finding is that inactivation of the septohippocampal
system increases the potency of a general anesthetic. Control rats
required ~10 mg/kg intravenous propofol and >45 mg/kg intraperitoneal pentobarbital to abolish the tail-pinch response, compared with 5 mg/kg intravenous propofol and 20 mg/kg intraperitoneal pentobarbital in hippocampal- or septal-inactivated rats. Thus, the
potency of propofol or pentobarbital was enhanced by  100% after
septohippocampal inactivation. Septohippocampal inactivation also
enhanced the potency of halothane or isoflurane, because normally
subanesthetic doses of halothane or isoflurane induced deep anesthesia
with concomitant septohippocampal inactivation. How inactivation of the
septohippocampal system potentiates general anesthesia is not known.
Mediation through the thalamocortical system, normally regarded as
important for arousal, is not ruled out, but more immediate neural
pathways are as follows: First, the hippocampus mediates movements in
part by a direct projection to the nucleus accumbens, which in turn
projects to the ventral pallidum, midbrain locomotor areas,
hypothalamus, and frontal cortex (Vanderwolf, 1988; Mogenson et al.,
1993; Skinner and Garcia-Rill, 1993; Pennartz et al., 1994; Ma et al.,
1996). Second, the septohippocampal system is normally activated by
pain (Khanna and Zheng, 1999), and the nucleus accumbens has been shown
to be involved in forebrain-mediated suppression of pain (Ma and Han,
1991; Gear et al., 1999). Third, connections of the medial septum with
the mesopontine cholinergic neurons (Semba and Fibiger, 1992) may help
to maintain overall vigilance and influence the sleep-wake states
(Steriade et al., 1991; Jones, 1993). A decrease in the central
acetylcholine level has been shown to increase general anesthetic
potency (Zucker, 1991), and cholinergic stimulation can induce EEG and
behavioral arousal (Vanderwolf, 1988; Meuret et al., 2000). Through the
above pathways, a general anesthetic may initially induce movements and
subsequently suppress pain, awareness (consciousness), and movement
control. Complete inactivation of the septohippocampal outputs may
facilitate all of the desirable clinical effects of a general
anesthetic, including the loss of consciousness, pain, voluntary
movements, and memory (Squire, 1992).
To our knowledge, this is the first study that reports a
septohippocampal influence on the effects of general anesthesia. The
results are not at odds with previous reports indicating that general
anesthetics suppress pain-induced behaviors at the spinal level. The
findings that spinal cord transection and precollicular decerebration
did not alter the anesthetic potency in acute preparations (Rampil et
al., 1993; Rampil, 1994) do not exclude the possible selective
facilitatory and inhibitory effects that the brain may exert on the
spinal cord in a behaving animal. Specific nociceptive and
anti-nociceptive pathways are known in the spinal cord (Fields and
Basbaum, 1994). An increase in anesthetic (halothane) requirement when
only the brain was preferentially perfused with anesthetic-loaded blood
(Antognini and Schwartz, 1993) may suggest that halothane did not
inactivate the septohippocampal system effectively. Although general
anesthetics depressed hippocampal neural activity (Kendig et al., 1991;
Krnjevic, 1991; Tanelian et al., 1993; Tanner et al., 2000), it appears
that muscimol suppresses local neural activity more completely than any
general anesthetic used alone. Thus, we suggest that more potent
general anesthetics or adjuvants may be developed to maximize the
pharmacological depression of the septohippocampal system.
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FOOTNOTES |
Received Aug. 10, 2001; revised Oct. 29, 2001; accepted Nov. 2, 2001.
This research was supported by the Natural Sciences and Engineering
Research Council, by Canadian Institutes of Health Research Grant MT-15685, and by an Ontario Mental Health Foundation
postdoctoral fellowship (J.M.). We thank B. MacIver, B. Bland, and C. Vanderwolf for comments on this manuscript.
Correspondence should be addressed to Dr. L. Stan Leung, Department of
Clinical Neurological Sciences, University Hospital, University of
Western Ontario, London, Ontario, Canada N6A 5A5. E-mail:
sleung{at}uwo.ca.
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, 2002, 22:RC200 (1-6). The
publication date is the date of posting online at
www.jneurosci.org.
| |
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