Department of Neuroscience and Graduate Program in Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455
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ABSTRACT |
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Zhang, X., H. N. Wenk, A. P. Gokin, C. N. Honda, and G. J. Giesler Jr.. Physiological Studies of Spinohypothalamic Tract Neurons in the Lumbar Enlargement of Monkeys. J. Neurophysiol. 82: 1054-1058, 1999. Recent anatomic results indicate that a large direct projection from the spinal cord to the hypothalamus exists in monkeys. The aim of this study was to determine whether the existence of this projection could be confirmed unambiguously using electrophysiological methods and, if so, to determine the response characteristics of primate spinohypothalamic tract (SHT) neurons. Fifteen neurons in the lumbar enlargement of macaque monkeys were antidromically activated using low-amplitude current pulses in the contralateral hypothalamus. The points at which antidromic activation thresholds were lowest were found in the supraoptic decussation (n = 13) or in the medial hypothalamus (n = 2). Recording points were located in the superficial dorsal horn (n = 1), deep dorsal horn (n = 10), and intermediate zone (n = 4). Each of the 12 examined neurons had cutaneous receptive fields on the ipsilateral hindlimb. All neurons responded exclusively or preferentially to noxious stimuli, suggesting that the transmission of nociceptive information is an important role of primate SHT axons. Twelve SHT neurons were also antidromically activated from the thalamus. In all cases, the antidromic latency from the thalamus was shorter than that from the hypothalamus, suggesting that the axons pass through the thalamus then enter the hypothalamus. These results confirm the existence of a SHT in primates and suggest that this projection may contribute to the production of autonomic, neuroendocrine, and emotional responses to noxious stimuli in primates, possibly including humans.
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INTRODUCTION |
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The hypothalamus is involved in the production of
autonomic, neuroendocrine, and motivational/emotional responses to
somatosensory and visceral stimuli (reviewed in Giesler et al.
1994). Several lines of evidence indicate that the
spinohypothalamic tract (SHT) carries somatosensory and visceral
information directly from the spinal cord to the hypothalamus in rats
(Burstein et al. 1990
; Dado et al.
1994a
,b
; Katter et al. 1996
; Malick and
Burstein 1998
; Zhang et al. 1995
). Anatomic
studies indicate that an SHT exists in primates and that its
organization is similar to that in rats (Chang and Ruch
1949
; Morin et al. 1951
; Newman et al.
1996
). Recently, we found that injections of wheat germ
agglutinin-horseradish peroxidase (WGA-HRP) into the hypothalamus of
monkeys labeled large numbers of neurons throughout the length of the
spinal cord (Zhang et al. 1997
). These findings suggest
that nociceptive information may reach the hypothalamus of primates in
part through a direct projection from the spinal cord. In this study,
we have 1) attempted to confirm unequivocally the existence
of this projection in primates and 2) tested the idea that
primate SHT neurons are capable of conveying nociceptive information.
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METHODS |
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All procedures followed the guidelines of the International Association for the Study Pain and were approved by the institutional animal care and use committee.
Monkeys (Macaca fascicularis or mulatta)
were anaesthetized initially with ketamine (100 mg/kg im), followed by
-chloralose (60 mg/kg iv) and maintained with a continuous infusion
of nembutal (2-4 mg · kg
1 · h
1 iv). Animals were placed in a stereotaxic
frame, paralyzed, and artificially ventilated. Body temperature,
end-tidal CO2, and blood pressure were monitored
and kept within physiological limits. Pneumothoraces were performed to
improve mechanical stability. Laminectomies and large craniotomies were
made. Multiunit recordings of somatosensory responses in the thalamus
were made to locate the ventral posterior lateral nucleus (VPL). The
initial placement of the stimulating electrode (stainless steel) in the
hypothalamus was made using the location of VPL as a reference point.
The search stimulus consisted of cathodal pulses (200 µs, 750 µA)
delivered within the contralateral hypothalamus. Single-unit recordings were made in the lumbosacral spinal cord using stainless steel microelectrodes (5-10 M
). After isolating an antidromically
activated action potential (criteria in Fig.
1A), the stimulating electrode was moved systematically through the hypothalamus until a point was
located at which the antidromic threshold was
30 µA (Fig. 1A) (Dado et al. 1994a
). We determined
whether each of the examined SHT neurons could also be antidromically
activated from the contralateral thalamus using search pulses of
500-750 µA. If a neuron was activated, the thalamic stimulating
electrode was moved until a low-threshold point (
30 µA) was
located. Collision of action potentials evoked from the electrodes in
the hypothalamus and thalamus was demonstrated (Dado et al.
1994a
) to ensure that the same neuron was activated from both
locations. Cutaneous receptive fields and response characteristics of
recorded cells were determined using innocuous and noxious mechanical
stimuli (Dado et al. 1994b
). At the end of each
experiment, electrolytic lesions were made at each low-threshold
stimulation point and at the recording site. Monkeys were perfused with
0.9% saline followed by 10% Formalin containing 1% potassium
ferrocyanide (Prussian blue reaction). The areas of the brain and
spinal cord containing lesions were removed, cut transversely, and
stained with neutral red. The locations of lesions were reconstructed with a microscope equipped with a camera lucida drawing attachment.
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RESULTS |
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Fifteen SHT neurons were antidromically activated using current
pulses 30 µA delivered in the contralateral hypothalamus. Two
examples of such neurons are illustrated in Figs. 1 and
2. In Fig. 1, an SHT neuron in the
lateral reticulated area of L4 (Fig.
1C) was antidromically activated from the supraoptic
decussation (SoD) of the contralateral hypothalamus (Fig.
1A) at a latency of 4.2 ms (Fig. 1, a1-a3). The
axon was also activated in the contralateral thalamus at a latency of
4.0 ms. Spikes elicited from the hypothalamus and thalamus collided
within a critical period (Fig. 1, a4 and a5),
indicating that action potentials from both locations traveled in the
same axon. This axon was also activated from the SoD of the
hypothalamus ipsilateral to the recording site at a latency of 5.0 ms
(Fig. 1B), and spikes elicited from this location also
collided with spikes elicited in the contralateral thalamus (Fig. 1,
b2 and b3). The antidromic latencies at these three points indicate that the SHT axon ascended through the
contralateral thalamus to the hypothalamus and crossed the midline from
the contralateral to the ipsilateral hypothalamus, as frequently occurs in rats (Dado et al. 1994a
). Figure 2 illustrates an SHT
neuron in the marginal zone that was activated antidromically from a low-threshold point in the contralateral medial hypothalamus (Fig. 2,
A and C). This axon was also activated using
small-amplitude current pulses in contralateral VPL at a shorter
latency (Fig. 2B). Action potentials elicited from these two
points collided (Fig. 2, b2 and b3). This cell
had a receptive field on the ipsilateral hind limb (Fig.
2D), and it responded preferentially to noxious stimuli
(wide dynamic range, WDR, Fig. 2E).
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The points at which antidromic activation thresholds were lowest for
the examined neurons (Fig. 3, A,
b1, and b2) were located in the SoD (n = 13) and medial hypothalamus (n = 2), areas in which
many SHT axons were seen in anterograde tracing experiments in monkeys
(Chang and Ruch 1949; Morin et al.
1951
; Newman et al. 1996
). Recording points
(Fig. 3, C and D) were located in the marginal
zone (n = 1), deep dorsal horn (n = 10), and lateral intermediate zone (n = 4), areas in
which the majority of labeled SHT neurons were found in our retrograde
tracing experiments (Zhang et al. 1997
). The mean
antidromic conduction velocity was 45 m/s (range, 17-75 m/s),
indicating that information is carried rapidly in SHT axons.
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Spike amplitudes were sufficient to determine cutaneous receptive fields (RF) for 12 of the 15 antidromically identified SHT neurons. Each RF was restricted to the ipsilateral hind limb (Fig. 3E). The smallest RF covered one toe, and the largest covered the entire hind limb. Each of the tested neurons was nociceptive (Figs. 2E and 3F); nine were WDR neurons and three responded specifically to noxious stimuli (high-threshold neurons, HT). Responses of two additional SHT neurons to cutaneous mechanical stimuli are illustrated in Fig. 3F. One was classified WDR (Fig. 3F1), the other HT (Fig. 3F2).
Twelve of the 15 tested SHT neurons were also antidromically activated
from the thalamus using 500- to 750-µA pulses. In each case,
antidromic activity elicited from the thalamus and hypothalamus collided, and the antidromic latency from the thalamus was less than
that from the hypothalamus. In seven cases, the stimulating electrode
was moved dorsal-ventrally and medial-laterally within the thalamus
until the threshold for antidromic activation was 30 µA (Figs.
2B and 3B3). Four SHT neurons were antidromically activated from such low-threshold points in VPL and one from the white
matter dorsomedial to the lateral geniculate nucleus (Fig. 3B3). In the other two cases, SHT neurons were
antidromically activated at multiple low-threshold points (each at a
different antidromic latency, Fig. 3B3).
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DISCUSSION |
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The 15 examined SHT neurons were antidromically activated by
stimulus pulses 30 µA delivered within the hypothalamus. These small-amplitude pulses have an effective spread of
400 µm
(Dado et al. 1994a
; Ranck 1975
). Each of
the low-threshold points was located in the ventral half of the
hypothalamus, at a considerable distance from areas such as the
thalamus, zona incerta, or midbrain that are known to receive a direct
input from spinal cord neurons (Apkarian and Hodge 1989
;
Cliffer et al. 1991
). Indeed, with the exception of one
low-threshold point that was ~4 mm from the thalamus, low-threshold
points in the hypothalamus were at least 6 mm from these areas.
Therefore the axons of the examined neurons were activated within the
hypothalamus and not as a result of current that spread into the zona
incerta, thalamus, or midbrain. Thus the present findings strongly
confirm the existence of SHT in primates.
All tested SHT neurons responded preferentially or exclusively to
noxious mechanical stimulation, indicating that conveying nociceptive
information is an important function of primate SHT neurons. The
physiological characteristics of SHT neurons, including conduction
velocities, sizes of cutaneous receptive fields, and responses to
mechanical stimuli, were similar to those of spinothalamic tract (STT)
neurons in monkeys (Willis 1985; Willis et al.
1974
).
In this study, 12 of the 15 examined SHT neurons could also be
antidromically activated from thalamus. In each case, the antidromic latency from the thalamus was less than that from the hypothalamus, demonstrating that the current had not spread from the electrode in the
thalamus to the axon in the hypothalamus. These findings suggest that a
significant number of SHT axons either pass through the thalamus before
reaching the hypothalamus or give rise to collateral branches that
enter thalamus. In four cases, SHT neurons were activated using 30
µA from points within VPL. VPL is generally thought to play an
important role in localization of somatosensory stimuli (Willis
1985
). The present results suggest that, through collateral
projections to VPL, SHT axons may also contribute to the localization
of noxious stimuli.
In many previous studies, either antidromic activation or retrograde labeling from injections of tracer into thalamus was used to identify "STT" cells. The present findings suggest that some of these neurons may have had axons that continued rostrally and medially into the hypothalamus.
The present findings demonstrate that primate SHT neurons are
nociceptive. Previous anterograde tracing experiments in rats and
monkeys (Cliffer et al. 1991; Newman et al.
1996
) indicate that SHT axons terminate densely and widely
throughout many regions of the hypothalamus. Our preliminary retrograde
tracing experiments also indicate that large numbers of SHT neurons
located throughout the length of the spinal cord of monkeys project
directly to the hypothalamus (Zhang et al. 1997
). The
previous and present results suggest that the SHT is an important
source of sensory information to neurons in the hypothalamus that
underlie the production or modification of neuroendocrine, autonomic,
and affective responses to painful stimuli in primates, including humans.
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ACKNOWLEDGMENTS |
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We thank H. Truong for valuable technical assistance, and we are grateful to Dr. Martin Wessendorf for critically reading an early version of this manuscript.
This work was supported by National Institutes of Health Grants NS-25932 to G. J. Giesler, DA-09641 to C. N. Honda, and by NIH Training Grant DE-07288 to H. N. Wenk.
Present address of A. P. Gokin: Dept. of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St., Boston, MA 02115.
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FOOTNOTES |
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Address for reprint requests: G. J. Giesler, Dept. of Cell Biology and Neuroanatomy, 4-102 Owre Hall, University of Minnesota, Minneapolis, MN 55455.
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 15 September 1998; accepted in final form 1 April 1999.
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REFERENCES |
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