Download Cortical and subcortical afferents to the nucleus reticularis tegmenti

Visual Neuroscience (2001), 18, 725–740. Printed in the USA.
Copyright © 2001 Cambridge University Press 0952-5238001 $12.50
DOI: 10.1017.S0952523801185068
Cortical and subcortical afferents to the nucleus reticularis
tegmenti pontis and basal pontine nuclei
in the macaque monkey
ROLAND A. GIOLLI,1 KENNETH M. GREGORY,2 DAVID A. SUZUKI,3 ROBERT H. I. BLANKS,1
FAUSTA LUI,4 and KATHLEEN F. BETELAK 3
1
Department
Department
3
Department
4
Department
2
of Anatomy and Neurobiology, College of Medicine, University of California, Irvine
of Biological Sciences, California State University, Long Beach
of Ophthalmology, Indiana University School of Medicine
of Biomedical Sciences, University of Modena and Reggio Emilia, Via Campi 287, 41100 Modena, Italia
(Received February 6, 2001; Accepted July 25, 2001)
Abstract
Anatomical findings are presented that identify cortical and subcortical sources of afferents to the nucleus reticularis
tegmenti pontis (NRTP) and basal pontine nuclei. Projections from the middle temporal visual area (MT), medial
superior temporal visual area (MST), lateral intraparietal area (LIP), and areas 7a and 7b to the basal pontine nuclei
were studied using 3 H-leucine autoradiography. The results complemented a parallel study of retrograde neuronal
labeling attributable to injecting WGA-HRP into NRTP and neighboring pontine nuclei. Small 3 H-leucine injections
confined to MT, MST, LIP, area 7a, or area 7b, produced multiple patches of pontine terminal label distributed as
follows: (1) An injection within MT produced terminal label limited to the dorsolateral and lateral pontine nuclei.
(2) Injections restricted to MST or LIP showed patches of terminal label in the dorsal, dorsolateral, lateral, and
peduncular pontine nuclei. (3) Area 7a targets the dorsal, dorsolateral, lateral, peduncular, and ventral pontine
nuclei, whereas area 7b projects, additionally, to the dorsomedial and paramedian pontine nuclei. Notably, no
projections were seen to NRTP from any of these cortical areas. In contrast, injections made by other investigators
into cortical areas anterior to the central sulcus revealed cerebrocortical afferents to NRTP, in addition to nuclei of
the basal pontine gray. With our pontine WGA-HRP injections, retrograde neuronal labeling was observed over a
large extent of the frontal cortex continuing onto the medial surface which included the lining of the cingulate
sulcus and cingulate gyrus. Significant subcortical sources for afferents to the NRTP and basal pontine nuclei were
the zona incerta, ventral mesencephalic tegmentum, dorsomedial hypothalamic area, rostral interstitial nucleus of the
medial longitudinal fasciculus, red nucleus, and subthalamic nucleus. The combined anterograde and retrograde
labeling data indicated that visuo-motor cortico-pontine pathways arising from parietal cortices target only the basal
pontine gray, whereas the NRTP, together with select pontine nuclei, is a recipient of afferents from frontal cortical
areas. The present findings implicate the existence of parallel direct and indirect cortico-pontine pathways from
frontal motor-related cortices to NRTP and neighboring pontine nuclei.
Keywords: Corticopontine projections, Visual cortical areas, Frontal cortical areas, Parietal cortical areas, Nucleus
reticularis tegmenti pontis, Basal pontine nuclei, Autoradiography, WGA-HRP, Anterograde & retrograde neuronal
labeling
agents into the cortex (i.e. cortico-centric studies) and cerebellocentric studies where lesions or anatomic tracers were placed
within regions of cerebellum. The possibility that tracers injected
into the internuncial regions of the pons would yield further
insights and a more detailed and complete anatomic view has not
been thoroughly pursued.
Basal pontine afferents from visual cortical areas, including
primary visual cortex (area 17), areas 18 and 19, superior temporal
cortex, and posterior parietal cortex, have been studied in nonhuman primates employing a variety of tract-tracing techniques
(Spatz & Tigges, 1973; Künzle & Akert, 1977; Brodal, 1978;
Introduction
A major proportion of the primate motor repertoire is comprised of
visually guided behaviors. The neural substrate underlying some of
these behaviors includes parallel cortico-ponto-cerebellar pathways which have been deduced primarily from neuroanatomical
tract-tracing studies following injections of anterograde transport
Address correspondence and reprint requests to: Roland A. Giolli,
Department of Anatomy and Neurobiology, College of Medicine, University of California, Irvine, CA 92697-1275, USA. E-mail: [email protected]
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Wiesendanger et al., 1979; Glickstein et al., 1980; Galletti et al.,
1982; Maunsell & Van Essen, 1983a,b; Leichnetz et al., 1984;
Leichnetz, 1989; Ungerleider et al., 1984; Weber & Yin, 1984;
Huerta et al., 1986; May & Andersen, 1986; Stanton et al., 1988;
Schmahmann & Pandya, 1989, 1991, 1993; Fries, 1990; Boussaoud et al., 1992; Baizer et al., 1993). The cortico-pontine projections from these cortical areas terminate in a variety of nuclei in
the basal pontine gray. The nucleus reticularis tegmenti pontis
(NRTP) appears to be excluded from the collection of termination
sites (May & Andersen, 1986; present results). Cortical projections
that do include terminations in NRTP arise from frontal areas such
as the frontal (FEF) and supplementary (SEF) eye fields as well as
the premotor and motor cortices (e.g. Shook et al., 1990). Within
basal pontine nuclei, the frontal cortical projections overlap inputs
from the parietal cortical areas.
Given the growing body of knowledge concerning the functions of certain pontine structures receiving cortical inputs, the
design of future physiological studies would benefit greatly from a
better understanding of the anatomic details. What are needed are
injections of tract tracers into the pons to show possible cortical
and subcortical afferent sources that previously have not been
apparent in “top–down”, cortico-centric anatomical investigations
as enumerated above. In the macaque, Glickstein et al. (1985) were
the first to address this need with relatively massive injections of
HRP that incorporated large portions of the pons. The intent of the
present study was to extend these studies with injections of WGAHRP that involved fewer pontine structures. By utilizing a “bottom–
up” approach, we could compare the results of WGA-HRP injections
into NRTP and neighboring pontine gray with the findings obtained with radioactive tracer injected into cerebral cortical areas.
Brief reports of these findings have been presented (Giolli et al.,
1995; Suzuki et al., 1998).
Methods
Autoradiography
The projections of cerebrocortical areas onto basal pontine nuclei
were analyzed in six adult monkeys (Macaca mulatta) after injections of 3 H-leucine and light-field autoradiography. Different cytoarchitecturally defined cerebral cortical areas were injected
individually (viz., areas 17, PGa, OAa, POa, and 7a, 7b). All
surgeries were performed in an AAALAC accredited surgical
facility under aseptic conditions. Each monkey was preanesthetized with ketamine (10 mg0kg) plus acepromazine (0.5 mg0kg)
and anesthetized through inhalation of 1.5–2.0% isofluorane. A
portion of calvarium was removed with a dental drill and the dura
mater transected carefully to expose the cerebral cortex. The
monkeys were placed on a heating pad in order to maintain normal
body temperature.
The isotope, 3 H-leucine, was dissolved in physiological saline
to a concentration of 33 mCi0ml. Two or three closely spaced
injections (0.5 ml each, 0.5-mm separation) were made with finely
drawn glass microelectrodes (Blanks et al., 1982). Injections were
placed on the right and left sides of the cortex to optimally utilize
these animals. Thus, bilateral 3 H-leucine injections were produced
in cerebral cortical areas given the entirely ipsilateral or uncrossed
nature of the corticopontine projections (e.g. Spatz et al., 1970;
Spatz & Tigges, 1973; Tigges et al., 1973; Brodal, 1978; Wiesendanger et al., 1979; Maunsell & Van Essen, 1983a; Leichnetz
et al., 1984; May & Andersen, 1986; Fries, 1990; Leichnetz, 1990).
Each side was considered as a separate case and designated
R.A. Giolli et al.
Abbreviations
Aq
ai
as
AV
Br.p
Br. SC
ce
CG
cg
ca
CL
CM
CP
D
dBC
DL
DM
DMH
ec
FEF
H1-H2
INC
IC
ip
la
L
LG
LH
LIP
LP
lu
mc
MD
MG
MIP
ML
MLF
MN
MST
MT
NOT
NRTP, Rt
n.3
OAa
oi
p
P
Ped
PGa
PM
Po,
POa
PP
Pul.i
Pul.l
Pul.m
Pul.o
R
RN
riMLF
R
Rt, NRTP
SEF
Sg.Li,
SNc
SNr
cerebral aqueduct
arcuate sulcus, inferior branch
arcuate sulcus, superior branch
anterior ventral nucleus, thalamus
brachium pontis
brachium, superior colliculus
central sulcus
cingulate gyrus
cingulate sulcus
calcarine fissure
nucleus centralis lateralis
nucleus centromedian
cerebral peduncle
dorsal pontine gray
decussation, brachium conjuntivum
dorsolateral pontine gray
dorsomedial pontine gray
dorsomedial hypothalamic area
external calcarine fissure
frontal eye field
H1 and H2 fields
interstitial nucleus, Cajal
internal capsule
intraparietal sulcus
lateral fissure
lateral pontine gray
lateral geniculate nucleus, pars dorsalis
lateral hypothalamus
lateral intraparietal area
nucleus lateralis posterior
lunate sulcus
pars magnocellularis, medial geniculate nucleus
nucleus medialis dorsalis
medial geniculate nucleus
medial intraparietal area
medial lemniscus
medial longitudinal fasciculus
mammillary nuclear complex
medial superior temporal visual area
middle temporal visual area
nucleus of the optic tract
nucleus reticularis tegmenti pontis
nucleus, oculomotor nerve
cytoarchitectonic area OAa
inferior occipital sulcus
principal sulcus
peduncular pontine gray
peduncle, corticobulbar & corticospinal tracts
cytoarchitectonic area PGa
paramedian pontine gray
posterior nucleus, thalamus
cytoarchitectonic area POa
posterior pretectal nucleus
pulvinar, inferior division
pulvinar, lateral division
pulvinar, medial division
pulvinar, oral division
thalamic reticular nucleus
red nucleus
rostral interstitial nucleus, medial longitudinal fasciculus
thalamic reticular nucleus
nucleus reticularis tegmenti pontis
supplemental eye field
nucleus suprageniculatus0nucleus limitans
substantia nigra, pars compacta
substantia nigra, pars reticulata
Afferents to basal pons
St
sts
V
VA,
VIP
VL,
VMT
VP
VPI
VPL
VPLc
VPM
ZI
3N
4
6
7a, 7b
9
44
47
III
subthalamic nucleus
superior temporal sulcus
ventral pontine gray
ventral anterior nucleus, thalamus
ventral intraparietal area
central lateral nucleus, thalamus
ventral mesencephalic tegmentum
nucleus ventralis posterior
nucleus ventralis posterior intermedialis
nucleus ventralis posterior lateralis
nucleus centralis lateralis, pars caudalis
nucleus ventralis posterior medialis
zona incerta
oculomotor nerve
area 4
area 6
areas 7a, 7b
area 9
area 44
area 47
third ventricle
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Wheat-germ agglutinin-horseradish peroxidase
(WGA-HRP)
The goal was to make an injection in NRTP. The location of NRTP
was determined from stereotaxic coordinates taking into account
the functionally and histologically determined locations in six
previous monkeys. In two monkeys, one Macaca nemestrina
(NEM1) and one Macaca fascicularis (FAS1), 0.1 ml (0.1 mg0ml)
of WGA-HRP (Sigma L7017, St. Louis, MO) was injected with a
Hamilton syringe over a 10-min period. The injection needles were
left in place for more than 15 min before being slowly removed.
Perfusions were performed 48 h postinjection using a sequence of
isotonic saline, buffered paraformaldehyde plus glutaraldehyde,
and buffered 10%, 20%, and 30% sucrose. After removal, each
brain was placed in phosphate-buffered 30% sucrose for 24–36 h.
All 50-mm sections were reacted with tetramethylbenzidine (Mesulam, 1978) and subsequently counterstained with neutral red.
The experimental and surgical protocols employed for the autoradiography and WGA-HRP studies complied with the policies of
the United States Public Health Service concerning the care and
use of laboratory animals.
Results
Injection sites
accordingly as M-1R, M-IL, M-2R, and so forth. All injections
were placed stereotaxically in relationship to the topography of the
visual cortical areas (Hoffmann et al., 1991), aided by direct
stereomicroscopic examination of relevant gyri, sulci, and vascular
landmarks of the cerebrum. The locations of the injection sites
were subsequently confirmed using certain cytoarchitectural features and the patterns of corticothalamic projections from each
area studied (see Results).
Each delivery of tracer lasted 10–15 min, followed by a 10-min
period prior to the removal of the micropipette. Postinjection, the
dura mater and skin were sutured. Each monkey received an
intramuscular injection of Ampicillin (12 mg0kg) to prevent infection and an intramuscular injection of Torbutrol (Butophanol
tartrate) (0.1 ml of a 0.5 mg0ml solution IM) every 6 h for pain.
Monkeys were then transferred to a recovery room and monitored
continuously until they had recovered completely, that is, until the
animals were ambulatory.
After postoperative survival periods of 5–7 days, animals were
again deeply anesthetized with Ketamine0Isofluorane and perfused transcardially with physiological saline followed by 10%
formalin. Brains were blocked stereotaxically in the coronal plane
and removed. Tissue blocks were embedded in paraffin, serially
sectioned at 15 mm, and every fourth section mounted onto
histologic slides. Mounted sections were coated in Kodak NTB-2
nuclear track emulsion, exposed in the dark at 48 C for 6–10
weeks, developed in Kodak D-19, fixed with Kodak Polimax T
fixer, counterstained with thionin and coverslipped using the protocol of Cowan et al. (1972). The sections were examined under
bright- and dark-field illumination. Microprojector drawings were
made of sections through the injection site of each case to show the
extent of the 3 H-leucine injections in relation to cortical cytoarchitecture. Microprojector drawings were also made of every other
mounted section through the pons in order to study the organization of fields of terminal label in the basal pons. Drawings of the
cortico-thalamic projections were used to provide validation for
the location of the cortical injections.
Autoradiography
Labeled tracer was injected into several cortical areas. In two
cases (M-1R and M-2R, not shown), injections were limited to
area 17 located dorsomedial to the external calcarine fissure, and
caudal to the lunate sulcus, that is, within area 17 representing
central vision (Talbot & Marshall, 1941, their Fig. 5; Myers, 1965;
Zeki, 1969, see his Fig. 10). The column of terminal label in the
dorsal lateral geniculate nucleus in each case was restricted to the
central region of the caudal half of this nucleus (Brouwer &
Zeeman, 1926; Malpeli & Baker, 1975). However, neither of these
area 17 cases showed terminal axonal labeling in the NRTP and
basal pontine complex. The remaining anterograde cases produced
terminal labeling in the basal pons and these are described below.
Injections were made in MT and MST in superior temporal
cortex (Fig. 1). The 3 H-leucine injection in case M-7L was restricted to area MT as shown in Figs. 1A and 1B, cytoarchitecturally equivalent to area OAa of Seltzer and Pandya (1978, 1989).
This injection was small and limited to the caudal region of MT. It
involved primarily the infragranular laminae with extension into
the underlying white matter. The injection in M-8R was restricted
to the caudal region of MST (Figs. 1D and 1E), corresponding
cytoarchitecturally to area PGa of Seltzer and Pandya (1978,
1989).
Cases M-8L and M-9R (Fig. 2) involve injections restricted to
the lateral convexity of the inferior parietal lobule, originally
designated cytoarchitecturally as area 7 (subdivided into 7a and 7b
by Vogt & Vogt, 1919) and subsequently so defined by Weber and
Yin (1984) and Andersen et al. (1990). Areas 7a and 7b correspond, respectively, to areas PG and PGF of von Bonin and Bailey
(1947), Pandya and Seltzer (1982), and Schmahmann and Pandya
(1989, 1991, 1993). The injection site in M-8L (Figs. 2A and 2B)
lies primarily in area 7a with minimal extension rostrally into area
7b. The injection in M-9R (Figs. 2D and 2E) is almost entirely
within the cytoarchitectural area 7b with minimal involvement of
adjoining area 7a. 3 H-leucine was also injected into LIP (Figs. 4A
and 4B), which is equivalent to the caudal part of area POa as
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Fig. 1. Corticopontine fiber projections were charted after 3 H-leucine injections into caudal areas of MT (A–C) and MST (D–F).
A: The MT injection site (crosshatch) is reflected onto the surface of the cerebrum from the depth of the superior temporal sulcus in
case M-7L. B: The MT injection site is shown in coronal sections with the core in black and the flare in stipple. C: The patches of
terminal axonal label within basal pontine gray were limited to dorsolateral (DL) and lateral (L) pontine gray. D: The MST injection
site, located in the superior temporal sulcus, is projected onto the cerebral surface in case M-8R. E: The MST injection site is depicted
in coronal sections with the core and flare indicated in black and stipple, respectively. F: Patches of terminal label were observed in
dorsal (D), dorsolateral (DL), lateral (L), and peduncular (P) pontine nuclei. The patches of label form a C-shaped lamella that is open
ventromedially. The box in section 445 denotes the pontine region corresponding to the photomicrograph shown in Figs. 3A and 3B.
Afferents to basal pons
Fig. 2. Corticopontine projections arising from areas 7a (A–C) and 7b (D–F). A: The 3 H-leucine injection was in area 7a and is
illustrated in black on the cerebral surface for case M-8L. There was minimal involvement of caudal area 7b. B: The core (black) and
flare (stipple) are indicated. C: Patches of terminal axonal label were distributed over a widespread region in the basal pontine gray,
which includes the dorsal (D), dorsolateral (DL), lateral (L), peduncular (P), and ventral (V) pontine nuclei. The patches of terminal
label form a prominent C-shaped lamella that is open medially. The box in section 455 denotes the pontine region corresponding to
the photomicrograph shown in Figs. 3C and 3D. D: Indicated in black is an injection centered predominantly in area 7b with slight
impingement on rostral area 7a in case M-9R). E: The injection site is seen in coronal sections with the core in black and flare in stipple.
F: Clusters of terminal axonal label were distributed over a large field of the basal pontine gray that included all sectors of the pontine
gray. Thus, the dorsomedial (DM) and paramedian (PM) pontine zones were added to the list of nuclei receiving inputs from area 7a
(see panels A–C). These patches were aligned in a circular lamella. The box in section 449 indicates the pontine zone corresponding
to the photomicrograph shown in Figs. 3E and 3F.
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cytoarchitecturally defined by Pandya and Seltzer (1982) and
Seltzer and Pandya (1986).
WGA-HRP
The injection site for WGA-HRP in NEM1 (Figs. 7B and 7C)
included NRTP, dorsomedial pontine nucleus (DM), dorsal pontine nucleus (D), and portions of peduncular pontine nucleus (P)
and probably the paramedian pontine nucleus (PM). The nomenclature of Nyby and Jansen (1951) was used to label regions of the
basal pontine gray, acknowledging that it is difficult to definitively
establish nuclear boundaries based upon neuronal size and shape,
neuronal packing density, intensity of Nissl staining, or pattern of
fascicles of the basis peduncularis. The results of our autoradiographic study are consistent with the exclusion of dorsolateral
(DL), lateral (L), and ventral pontine nucleus (V) from the HRP
uptake zone.
Confirmation of injection sites
The locations of the cortical areas injected in MT, MST, 7a, 7b,
and LIP were determined as closely as possible through examination of the cytoarchitecture of cortical areas. The cytoarchitecture
was difficult to make out within the core of the injections. However, in the flare regions of injections, and surrounding the injections (i.e. outside the core region), the cytoarchitecture was
discernible. Yet, at times, it was difficult to see where one cortical
area ended and an adjacent area began. In addition, there were
often wide transitional zones present between cortical areas. Thus,
we feel that the cortical boundaries depicted in broken lines in
Figs. 1, 2, 4, 6, and 8 present approximations for the boundaries of
the cortical areas injected with 3 H-leucine. To better establish the
location of tracer injections in functional areas of cortical areas, we
have relied heavily upon chartings made of the corticothalamic
projections (Figs. 5A–5E), which we compared with equivalent
chartings and descriptions from other studies in which the cortical
projections from areas MT, MST, 7a, 7b, and LIP to the dorsal
thalamus of monkeys had been studied using neuronal transport
techniques alone or combined with electrophysiology. Our results
thus show that (1) with an injection into caudal area MT (Figs. 1A
and 1B), we found terminal fields in the medial, lateral, and
inferior division of pulvinar (as defined by Olszewski, 1952) and
the midcaudal one-third of the thalamic reticular nucleus (Fig. 5A)
with a total pattern quite consistent with anterograde transport
studies performed by Maunsell and Van Essen (1983a, their Fig. 12),
and Ungerleider et al. (1984), in which electrophysiological identification of area MT had been performed prior to tracer injections.
(2) Our injection into caudal area MST (Figs. 1D and 1E) produced patches of terminal label in the medial, lateral, and inferior
pulvinar and, ventrally, in the thalamic reticular nucleus (Fig. 5B),
with the total pattern matching the descriptions of Boussaoud et al.
[1992, their Fig. (3)], who identified MST electrophysiologically
before making their injections of neuronal tracer. 3) After an
injection involving chiefly area 7a (Figs. 2A and 2B), we observed
terminal axonal fields in the medial division of the pulvinar and
dorsal part of the thalamic reticular nucleus (Fig. 5C), with an
organization that closely resembles that reported by Weber and Yin
(1984) following an area 7a injection. (4) In addition, after an
injection centered largely in area 7b (Figs. 2D and 2E), a pattern
of terminal fields is seen within the medial and oral divisions of
pulvinar and the dorsal-to-central part of the thalamic reticular
nucleus (Fig. 5D) that clearly matches descriptions of corticothalamic projections from area 7b by Weber and Yin (1984) and
R.A. Giolli et al.
Asanuma et al. (1985). (5) After an 3 H-leucine injection into
caudal area LIP (Figs. 4A and 4B), terminal fields were found in
the medial, lateral, and inferior divisions of pulvinar and the dorsal
segment of the thalamic reticular nucleus (Fig. 5E) exhibiting a
pattern paralleling the descriptions by Asanuma et al. (1985) and
Baizer et al. (1993) based on tracer injections into area LIP.
Termination sites
Autoradiography
In all cases, 3 H-leucine injections into parietal cortical areas
resulted in terminal axonal labeling in different sets of ipsilateral
pontine nuclei. By contrast, pontine terminations were not observed with 3 H-leucine injections within primary visual cortex
(cases M-1R and M-2R). Notably, in none of these cases was there
evidence of labeled axon terminals in NRTP. Thus, NRTP was
excluded as a terminus for these cortical neurons located in parietal
injection sites. On the other hand, each of these cases produced
characteristic multiple patches of cortico-pontine terminal labeling
within the basilar pontine nuclei. The individual patches usually
ranged in size from 40 mm to 60 mm in diameter up to 200–
300 mm in diameter.
The MT injection resulted in circumscribed pontine axonal
labeling in DL and dorsal portions of L (Fig. 1C). Labeled axon
terminals resulting from the MST injection were further identified
in pontine nuclei D and P, in addition to DL and L (Fig. 1F).
Injection into area 7a produced labeled terminals in D, DL, L, P,
and V (Fig. 2C), whereas injection into area 7b resulted in terminal
labeling in these same pontine nuclei with the addition of DM and
PM (Fig. 2F). Fig. 3 shows the arrangements of patches of
terminal labeling within the pontine nuclei in three of the anterogradely injected cases. After a discrete 3 H-leucine injection into
LIP, patches of terminal labeling were found in DL, L, P, and D
(see Fig. 4C).
WGA-HRP
The retrograde neuronal labeling of cortical neurons following
injections of WGA-HRP into the basal pons was pertinent to the
anterograde studies described above. Thus, all of the corticopontine projectional data were confirmed by the retrograde studies,
except those from area MT (case M-7L) in which we believe that
the pontine nuclei receiving MT projection were not included in
the WGA-HRP injection sites in either NEM1 or FAS1. Specifically, retrograde labeling was observed in sections of cortex that
included MST, 7a, 7b, LIP, VIP, as well as the medial intraparietal
area, referred to as MIP by Colby et al. (1988), as located in the
medial bank of the intraparietal sulcus opposite to LIP (Fig. 8D).
Labeled cells were also observed in cortex lining the caudal
segment of the cingulate sulcus located on the medial surface of
the parietal cortex. No retrograde labeling was seen in MT which,
based upon the autoradiography findings described above, excluded DL and L from the WGA-HRP uptake zones in NEMI1 and
FAS1.
Contrasted with the pontine projections from parietal cortical
areas, projections of frontal areas have been shown by others to
include axonal terminations in NRTP (e.g. Shook et al., 1990).
With our WGA-HRP injections in NRTP and adjacent pontine gray
(Figs. 7B and 7C), retrograde neuronal labeling was found over a
broad area of frontal cortex extending well beyond the boundaries
of the frontal (FEF) and supplementary (SEF) eye fields (Figs. 8A–
8C). The retrograde neuronal labeling extended throughout much
Afferents to basal pons
Fig. 3. Matching bright- and dark-field photomicrographs show examples of the patches of terminal axonal label seen in the basal
pontine nuclei. Arrows in corresponding bright and dark photomicrographs point to equivalent structures as observed with bright- and
dark-field illuminations. Several of the patches of terminal labeling are not seen to good advantage in the bright-field photomicrographs
depicted in Figs. C and E, but the locations of these patches, as observed in the dark-field photomicrographs, has been determined and
shown in the corresponding bright-field pictures. A, B: (MST, case M-8R) The field is boxed in Fig. 1F, section 445 and includes
portions of dorsal, dorsolateral, lateral, and peduncular pontine gray. In this case, compared with the others depicted in these
photomicrographs, the size and shape of patches varied considerably and were of high density. C, D: (area 7a, case M-8L) This field
is enclosed by the box in Fig. 2C, section 455. E, F: (area 7b, case M-9R) The rectangular area viewed is indicated in Fig. 2F, section
449. The borders of the sections in C and E have been drawn in with pen. Calibration bars in B, D, and F ⫽ 500 mm.
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Fig. 4. Corticopontine fiber projections have been mapped after an injection into caudal area LIP in case M-4R. A: The injection site
in caudal LIP (crosshatch) is transferred onto the cerebral surface. B: Coronal sections reveal the core (black) and flare (stipple) of the
injection. C: The distribution and density of the patches of terminal label occupied portions of the dorsal (D), dorsolateral (DL), lateral
(L), and peduncular (P) pontine gray. The patches are seen to form a crude C-shaped lamella.
of the medial surfaces of frontal cortex including the cingulate
sulcus and the cingulate gyrus.
Retrogradely labeled somata were observed in a variety of
subcortical nuclei and regions as demonstrated in Figs. 7A, 7D–7H
following the WGA-HRP injection into the pons (Figs. 7B and
7C). Densely labeled regions include portions of the zona incerta
(Figs. 7D–7F) and dorsomedial hypothalamic area adjacent to the
third ventricle (Fig. 7H). Moderately dense labeling was charted in
the ventral mesencephalic tegmentum dorsal to the substantia nigra
(Figs. 7F and 7G). Additionally, light but consistent neuronal
labeling was found within the rostral interstitial nucleus of the
medial longitudinal fasciculus (riMLF) (Figs. 7D–7G), red nucleus (Fig. 7D), and subthalamic nucleus (Figs. 7D, 7F, and 7G).
Discussion
The results of this study advance our understanding of the afferents
to some of the pontine nuclei that are involved in the processing of
sensori-motor signals. The most novel findings were the subcortical sources of inputs into the NRTP and0or adjacent pontine
nuclei, WGA-HRP uptake zone. These sources were the zona
incerta, riMLF, ventral mesencephalic tegmentum, red nucleus,
subthalamic nucleus, and dorsomedial hypothalamic area. In addition, the results provide more refined support for the existence of
projections to the macaque NRTP and0or adjacent pontine nuclei
from MIP (named by Colby et al., 1988), the cingulate cortex as
located in the depths of the cingulate sulcus and onto the cingulate
gyrus, premotor cortex on the medial part of the cerebrum, and a
significant area of frontal cortex. These cortical sources of pontine
projections are in addition to previously known projections from
extensive areas of the parietal and frontal cortices. While definitive
conclusions cannot be reached on the basis of the one or two
injections per area in this study, the results, combined with those of
others, support the notion that many cortical and subcortical
motor- and oculomotor-related structures send afferents to NRTP
and0or adjacent pontine nuclei. With respect to the NRTP, these
results are consistent with the evolving view of a global role for
NRTP in motor control and complement physiological observations that implicate the NRTP in eye and head movement control
(Crandall & Keller 1985; Gamlin & Clarke 1995; Suzuki et al.,
1997, 1999, 2001; Yamada et al., 1996).
The autoradiographic and retrograde tracer results are complementary and facilitate a comparison of “top–down” (i.e. anterograde tracers placed in cortex) versus “bottom–up” (i.e. retrograde
tracers placed in NRTP0pons) approaches to studying afferents to
pontine structures. The autoradiographic results indicated that
many of the visuo-motor-related parietal areas project to pontine
nuclei DL and L. In addition, MST and LIP also project to D and
P (Figs. 1F and 4C, respectively). Areas 7a and 7b project to all of
the above pontine nuclei and, additionally, target the ventral pontine nucleus (see Figs. 2C and 2F). Area 7b had the most widespread projection pattern of the cortical areas studied; its cortical
projections included all of the nuclei targeted by 7a, and it was the
sole source of afferents to DM and PM in the present study
Afferents to basal pons
Fig. 5. Chartings show the corticothalamic projections for each of the cortical injections illustrated in Figs. 1, 2, and 4. A–E indicate
the corticothalamic chartings, in order, for (A) Figs. 1A–1B, (B) Figs. 1D–1E, (C) Figs. 2A–2B, (D) Figs. 2D–2E, and (E)
Figs. 4A– 4B. Case descriptions are given on the left, and numbers of the individual coronal sections of brain are provided with each
section. Figs. 1A–1E have appeared as parts of Figs. 3–7 of Lui et al. (1995).
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Fig. 6. Semidiagrammatic representation of the cerebral cortical injections
of 3 H-leucine into functional areas of cerebral cortex in relationship to the
distribution of labeled pyramidal cells resulting from injection of WGAHRP into the NRTP0pontine nuclei as illustrated for cases NEMI1 and
FAS1 in Figs. 6B and 6C. Note the presence of retrogradely labeled cortical
neurons within zones for anterogradely injected 3 H-leucine in areas LIP,
7a, 7b, and MST as seen in a coronal section through the posterior parietal
cortex. The lack of retrograde neuronal labeling in area MT confirms that
the dorsolateral pontine nucleus was not in the WGA-HRP uptake zone.
(Fig. 2F, sections 418, 430, & 441). These corticopontine projections are essentially similar to those reported by other authors
studying nonhuman primates (Spatz & Tigges, 1973; Brodal, 1978;
Wiesendanger et al., 1979; Galletti et al., 1982; Maunsell & Van
Essen, 1983a; Ungerleider et al., 1984; Weber & Yin, 1984; May
& Andersen 1986; Schmahmann & Pandya, 1989, 1991, 1993;
Fries, 1990; Boussaoud et al., 1992; Baizer et al., 1993). Some
differences include the reports of Ungerleider et al. (1984) and
Maunsell and Van Essen (1983a) of additional MT projections to
peduncular pontine gray (P), and also Schmahmann and Pandya
(1989), Weber and Yin (1984), and Wiesendanger et al. (1979)
findings of a light area 7b projection to the DM with no projection
to the PM. With respect to the latter, our results are consistent with
those of May and Andersen (1986) in showing a more substantive
area 7b projection to DM and a light projection to PM. These
differences could be due to slightly differing determinations of
pontine nuclei borders or slight differences between injection sites
and amount of tracer injected.
The autoradiographic data were important in characterizing the
extent of the WGA-HRP uptake zones of the retrograde studies
(i.e. the NRTP0basal pontine uptake zones). The lack of retrograde
labeling in MT, following pontine WGA-HRP injections, was
interpreted as indicating that DL and L were excluded from the
uptake zone. The retrograde labeling in area 7b was presumably
due to tracer uptake in DM. Whether PM was also included in the
uptake zone could not be ruled out though the core of the WGAHRP injection site appears to be just dorsal to the edge of PM
R.A. Giolli et al.
(Figs. 7B and 7C). Although NRTP was included in the WGAHRP injection site, our autoradiographic results indicate that the
injected parietal vision- and visuo-motor-related cortical areas do
not project to NRTP. Similar results were implicit in the absence of
any statement that labeled cells were observed in NRTP in the
autoradiographic studies of others. Only May and Andersen (1986)
stated explicitly that area 7a, 7b, dorsal prelunate, and LIP do not
project to NRTP. Thus, we concluded that retrograde labeling of
cells in cortical areas MST, 7a, 7b, and LIP was due to uptake into
DM, D, and0or dorsal portion of P.
Leichnetz et al. (1984) and Glickstein et al. (1985) were, to our
knowledge, the earliest and only investigators to utilize a bottom–up
approach to identifying primate cortico-pontine pathways. Glickstein et al. sought to identify all the cortical areas projecting to the
pons and intentionally employed large HRP-injection volumes
designed to incorporate the entire pontine gray and NRTP on one
or both sides of the pons. Interestingly, our much more restricted
NRTP0pontine uptake zone resulted in a distribution of retrograde
labeling that was similar to that of Glickstein et al. (1985) with the
most notable difference being the lack of labeling of MT (due to
the exclusion of DL and L from our uptake zone). In Cebus, a New
World monkey, Leichnetz et al. (1984) placed HRP gel in NRTP
and observed retrograde labeling over much of frontal cortex and
in both banks of the intraparietal sulcus, LIP, and MIP. This latter
observation could reflect a species difference between capuchine
and macaque monkeys, but the labeling in LIP could suggest
spread of the HRP into pontine nucleus D making it uncertain if
the MIP labeling in Cebus was due to fiber projections to NRTP or
D or both nuclei.
The projections from cingulate sulcus to the pons have been
revealed only with the bottom–up approach used in this study and
by Glickstein et al. (1985). To be sure, Vilensky and Van Hoesen
(1981) conducted an autoradiographic study of cingulate-pontine
projections, but their tracer injection sites were limited to cingulate
gyrus and did not appear to invade the depths of the cingulate
sulcus. Thus, our observation of retrograde labeling in the depths
of the cingulate sulcus refine those of Glickstein et al. (1985) by
revealing projections to a constrained region of the pontine gray
near NRTP from cingulate cortex lying in the depths of the
cingulate sulcus and extending onto the cingulate gyrus.
In contrast to findings concerning parieto-pontine projections,
the subcortical projections of frontal cortical areas include NRTP
as a terminus. In the macaque monkey, frontal and supplementary
eye fields (FEF and SEF, respectively) have been shown to project
to NRTP as well as to neighboring pontine nuclei (Künzel & Akert,
1977; Brodal, 1980; Huerta et al., 1986; Stanton et al., 1988;
Shook et al., 1990). In these studies, the use of quite circumscribed
tracer injections or lesions did not give any indication of the extent
of frontal cortex projecting to NRTP and basilar pontine gray. The
retrograde neuronal labeling seen in Figs. 8A–8C, together with
the section indicators in Fig. 8 (upper right insert), allows for an
appreciation of the large amount of frontal cortex targeting the
macaque NRTP0pontine region. These results are similar to those
of Glickstein et al. (1985) obtained with massive HRP uptake sites
and of Leichnetz et al. (1984) for the Cebus monkey. The sources
of cortical projections to the NRTP0pontine region included much
of the frontal cortex extending onto the medial wall and continuing
into the cingulate sulcus and over the cingulate cortex (Figs. 8A–
8C). The Cebus monkey appears to be similar to the macaque, as
comparable results were obtained in Cebus monkeys with HRP-gel
implants in NRTP (Leichnetz et al., 1984). The results of our
combined autoradiographic and retrograde studies for cortical
Afferents to basal pons
Fig. 7. Retrograde labeling of subcortical neurons was charted following an injection of WGA-HRP into the NRTP0pontine region in
case NEM1. A: The locations of the planes of section for the chartings as depicted in B–H. B,C: Coronal sections through the injection
site with section B rostral to C and the approximate plane of sections for B–C indicated by an asterisk in A. D–H: Mappings of
subcortical afferents to the NRTP0pontine nuclei. Retrogradely labeled neurons were present in section D: red nucleus (RN); D–F: zona
incerta (ZI); F, G: ventral mesencephalic tegmentum (VMT); D–F: rostral interstitial nucleus of the medial longitudinal fasciculus
(riMLF); D–G: subthalamic nucleus (St); and H: dorsomedial hypothalamic area (DMH). Each dot represents one retrogradely labeled
neuron.
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R.A. Giolli et al.
Fig. 8. Cerebrocortical neuronal labeling is seen following the injection of WGA-HRP into the NRTP and neighboring pontine gray
in case NEM1 (see Figs. 6B– 6C for injection site). The plane of section for A–D is shown on lateral and medial views of the surface
of cerebrum at upper right. Chartings A–D are in rostro-caudal sequence, and these gauge the density and distribution of retrogradely
labeled pyramidal cells after the injection into the NRTP0pontine area. Each dot equals one labeled cortical neuron.
projections to the NRTP0pontine region are summarized in Fig. 9A.
Area MT was not included as retrograde labeling was not observed
in area MT, and the anterograde results indicate an MT projection
to pontine nuclei DL and L, which are not depicted in Fig. 9A.
The retrograde axonal labeling that we found in subcortical
nuclei raises the possibility of parallel, direct, and indirect path-
ways from frontal cortical areas to the NRTP0basal pons. As
indicated by the broken lines in Fig. 9B, axonal projections have
been demonstrated from FEF to the superior colliculus, red nucleus, riMLF, zona incerta, and subthalamic nucleus (Künzle &
Akert 1977; Huerta et al., 1986; Stanton et al., 1988; Shook et al.,
1990). As we observed retrograde neuronal labeling in these
Afferents to basal pons
737
Fig. 9. The afferents to the NRTP0pontine region are shown in “neuronal flow diagrams” A and B. As per the reasons given in the text,
it is probable that the WGA-HRP uptake zone in cases NEM1 and FAS1 included NRTP, the dorsomedial (DMPN), dorsal (DPN), and
sectors of the peduncular (PPN) pontine gray. A: Summarizes the cortical sources of afferents to the NRTP0pontine nuclei. The
projections that are either novel or refinements in the macaque are shown in bold type, whereas previously known sources of
cortico-pontine fibers are indicated in regular-size type. B: Provides summaries of the subcortical sources of inputs to the
NRTP0pontine nuclei. Findings from the present research are depicted in bold type with previously observed sources of input shown
in regular type. Thicker arrows denote more substantial inputs to the pontine complex than do thinner arrows. Dashed lines indicate
cortical inputs targeting subcortical pontine afferents. Note the potential for indirect cortico-subcortical-NRTP0pontine region
pathways that parallel direct pathways demonstrated in A. The dotted lines around DPN and PPN attest to the common pontine terminal
axonal zones for projections from LIP, VIP, 7a, 7b, and MST.
structures (with the exception of the superior colliculus which was
not examined), indirect pathways from FEF to NRTP via these
structures may parallel the direct FEF-NRTP pathways noted
above. Similarly, FEF and SEF projections to superior colliculus
(Shook et al., 1990) may be part of a FEF0SEF-SC-NRTP path that
parallels the direct FEF0SEF-NRTP pathway uncovered by Shook
et al. (1990) and demonstrated in the present study (Figs. 7 and 8).
Furthermore, it is known that motor cortex (M1) projects directly
upon NRTP and, also, the red nucleus (Hartmann-von Monakow
et al., 1979, 1981; Leichnetz, 1986), therefore, the M1-NRTP
direct path parallels an M1-red nucleus-NRTP pathway. These
possibilities are intriguing, though the existence of parallel direct
and indirect pathways requires that the cortical inputs to red
nucleus, riMLF, zona incerta, subthalamic nucleus, and superior
colliculus terminate on exactly those neurons that project onto
NRTP. Whether the cortical inputs to these subcortical structures
do make these requisite connections remains to be determined. The
present findings, combined with the potential indirect pathways,
738
are summarized in Fig. 9B, in which notable data from the present
study are indicated in bold lettering.
Functional considerations
Much is known about the visual, oculomotor, and0or motor properties of cells in most of the parietal areas wherein retrograde
labeling was observed and will not be reviewed here (for reviews
see Andersen et al., 1997 and Colby & Goldberg, 1999). The
finding of retrograde labeling in the MIP, the cingulate cortex
(lining the cingulate sulcus and continuing inferiorly onto the
cingulate gyrus and superiorly onto the superior parietal lobule),
and a myriad of areas in the frontal lobe raises questions about the
functions that may be mediated by the cortico-pontine fibers
arising in these areas. Somatosensory, visual, and reaching responses have been recorded in MIP cells (Colby & Duhamel,
1991; Johnson et al., 1996). MIP receives inputs from visual area
PO and projects to frontal, motor-related cortices (Colby et al.,
1988; Matelli et al., 1998). Motor-related activity has been recorded in portions of the medial extensions of supplementary and
presupplementary motor areas referred to as the “cingulate motor
area” (Shima & Tanji, 1998) and the “medial wall” (Picard &
Strick, 1996). Recording sites for motor-related activity extended
into the cingulate sulcus, but not more ventrally. The functions of
retrogradely labeled frontal areas exclusive of FEF, SEF, premotor,
and motor cortices remain to be determined.
Focusing attention on the neural substrate for the smoothpursuit eye movement system, two parallel cortico-ponto-cerebellar
pathways have been implicated: one involving neurons in the
pontine nuclei proper and the other incorporating the NRTP. Our
autoradiographic results are consistent with an MT0MST-pontine
nucleus DL-cerebellum pathway that bypasses the NRTP. Visual
motion signals of utility for guiding pursuit and pursuit-related
modulations in activity have been recorded in structures of the
MT0MST-pontine nucleus DL-cerebellum (e.g. Miles & Fuller,
1975; Lisberger & Fuchs, 1978; Maunsell & Van Essen, 1983b;
Komatsu & Wurtz, 1988; Mustari et al., 1988; Newsome et al.,
1988; Suzuki & Keller, 1988a,b; Thier et al., 1988; Suzuki et al.,
1990), yet bilateral lesions of DL did not abolish pursuit behavior
(May & Keller, 1988) suggesting a parallel pathway involved with
pursuit. Our WGA-HRP results are consistent with an FEF-NRTPcerebellum route. Activity related to smooth-pursuit eye movements have been noted in these structures (Miles & Fuller, 1975;
Lisberger & Fuchs, 1978; Suzuki & Keller, 1988a,b; Gottlieb
et al., 1994; Suzuki et al., 1999) adding support to the validity of
this second cortico-ponto-cerebellar pathway as a component of
the neural substrate regulating pursuit behavior.
The functions of certain of the subcortical sources of inputs to
the NRTP0basal pontine gray have not been completely characterized. However, the red nucleus and rostral interstitial nucleus of
MLF are well known to be involved with motor and oculomotor
functions, respectively (see, e.g. King & Fuchs, 1979; Gibson
et al., 1985). Saccade-related pauses in activity have been recorded
in zona incerta implicating its role in oculomotor control (Ma,
1996). The subthalamic nucleus, as part of the basal ganglia
circuitry, may permit the NRTP0pontine nuclei to monitor the
function of the basal ganglia. However, we are uncertain about the
functional significance of the dorsomedial hypothalamic area and
ventral mesencephalic tegmental with their afferents to the NRTP0
pontine nuclei. Though understanding awaits further investigations, the known functional attributes of subcortical structures
R.A. Giolli et al.
projecting to the NRTP0pontine nuclei are consistent with oculomotor and0or motor-related roles.
Taken together, our results and the results of others implicate
the existence of three parallel cortico-ponto-cerebellar systems, a
parieto-ponto-cerebellar system, and two fronto-ponto-cerebellar
systems. The massive HRP volumes that Glickstein et al. (1985)
injected into the pontine gray including NRTP had the advantage
of labeling all the cerebral cortical sources of pontine afferents.
Large portions of the parietal and frontal cortices were retrogradely labeled. Our autoradiographic and WGA-HRP results provided a finer resolution of the view of cortico-pontine connectivity
and, combined with the results of others, implicate a parieto-pontocerebellum and a fronto-ponto-cerebellum system of connections
that exclude NRTP, and a fronto-NRTP-cerebellum set of connections. Whether the patches of pontine nuclei cells receiving inputs
from parietal cortex are the same as those receiving inputs from
frontal cortex remains to be determined. The challenge will be to
clarify the functional differences between these three systems of
cortico-NRTP0ponto-cerebellum connections. A hint may be available from the nature of the parallel MT0MST-pontine and FEF0
SEF-NRTP substrates for smooth-pursuit eye movement control
discussed above. Without excluding significant motor-related parietal responses, one wonders if the sensory information in the
sensori-motor, parieto-pontine pathways might distinguish these
connections from more “motor” related fronto-NRTP0pontine connections. An added complication is the possibility that the three
direct cortico-NRTP0ponto-cerebellum systems may be paralleled
by indirect cortico-pontine pathways through subcortical structures to NRTP0pontine nuclei that were implicated in the current
study.
Acknowledgments
We wish to gratefully acknowledge the expert technical contributions of
Mr. Shag Van Pham. This research was supported by NSF Grant #
IBN-9121376 (to R.A.G.), NIH Grant EY09082 (to D.A.S.), and part of an
unrestricted departmental award from Research to Prevent Blindness to the
Department of Ophthalmology, Indiana University School of Medicine (for
K.F.B.).
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