Deficits in landmark navigation and path integration after lesions of the interpeduncular nucleus.

Abstract

Experiments were designed to determine the role of the interpeduncular nucleus (IPN) in 3 forms of navigation: beacon, landmark, and path integration. In beacon navigation, animals reach goals using cues directly associated with them, whereas in landmark navigation animals use external cues to determine a direction and distance to goals. Path integration refers to the use of self-movement cues to obtain a trajectory to a goal. IPN-lesioned rats were tested in a food-carrying task in which they searched for food in an open field, and returned to a refuge after finding the food. Landmark navigation was evaluated during trials performed under lighted conditions and path integration was tested under darkened conditions, thus eliminating external cues. We report that IPN lesions increased the number of errors and reduced heading accuracy under both lighted and darkened conditions. Tests using a Morris water maze procedure indicated that IPN lesions produced moderate impairments in the landmark version of the water task, but left beacon navigation intact. These findings suggest that the IPN plays a fundamental role in landmark navigation and path integration.

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Deficits in Landmark Navigation and Path Integration After Lesions
of the Interpeduncular Nucleus
Benjamin J. Clark and Jeffrey S. Taube
Dartmouth College
Experiments were designed to determine the role of the interpeduncular nucleus (IPN) in 3 forms of
navigation: beacon, landmark, and path integration. In beacon navigation, animals reach goals using cues
directly associated with them, whereas in landmark navigation animals use external cues to determine a
direction and distance to goals. Path integration refers to the use of self-movement cues to obtain a
trajectory to a goal. IPN-lesioned rats were tested in a food-carrying task in which they searched for
food in an open field, and returned to a refuge after finding the food. Landmark navigation was evaluated
during trials performed under lighted conditions and path integration was tested under darkened
conditions, thus eliminating external cues. We report that IPN lesions increased the number of errors and
reduced heading accuracy under both lighted and darkened conditions. Tests using a Morris water maze
procedure indicated that IPN lesions produced moderate impairments in the landmark version of the
water task, but left beacon navigation intact. These findings suggest that the IPN plays a fundamental role
in landmark navigation and path integration.
Keywords: dorsal tegmental nucleus, habenula, head direction cells, navigation, spatial orientation
Animals can use a variety of distinct navigational strategies and
stimulus types to locate goals. For example, they can follow odor
paths deposited by themselves or by their conspecifics, or simply
move toward visual cues directly above or besides a goal location
(Redhead, Roberts, Good, & Pearce, 1997; Wallace, Gorny, &
Whishaw, 2002a). This form of navigation has been referred to as
beacon (or taxon) navigation (Gallistel, 1990; O’Keefe & Nadel,
1978). Alternatively, animals can learn the direction and distance
of a goal in relation to a visual cue or a configuration of several
visual cues, even if the goal is hidden (Morris, 1984; Prados &
Trobalon, 1998; Roberts & Pearce, 1998). Strategies based on such
cues are often referred to as landmark (or locale or piloting)
navigation (Gallistel, 1990; O’Keefe & Nadel, 1978). Although
beacon or landmark cues are generally reliable, they can become
unreliable if they change over a day or season and are also
uninformative if the animal is in a novel environment. Under these
circumstances, animals can keep track of their own self-movement
cues (i.e., vestibular, optic flow, motor efference copy, and pro-
prioceptive cues), which they can integrate in relation to a known
starting point to determine a current location or plot a trajectory to
a goal. This form of navigation is often called path integration (or
dead reckoning), and has been demonstrated in a wide range of
animals including humans (Etienne & Jeffery, 2004; Gallistel,
1990).
Research on the neurobiological basis of navigation has cen-
tered on the role of cortical and subcortical limbic brain regions,
mostly due to the findings of spatially responsive neurons in these
areas. For instance, the CA1 and CA3 subfields of the hippocam-
pus contain cells that are active when an animal is located in a
specific place in an environment (Best, White, & Minai, 2001;
O’Keefe & Dostrovsky, 1971). These neurons are termed place
cells and have been observed in rats, mice, and primates (Ekstrom
et al., 2003; Kentros, Agnihotri, Streater, Howkins, & Kandel,
2004; Ludvig, Tang, Gohil, & Botero, 2004; Ono, Nakamura,
Nishijo, & Eifuku, 1993). In recent years, Moser and colleagues
(Hafting, Fyhn, Molden, Moser, & Moser, 2005; Moser, Kropff, &
Moser, 2008; Sargolini et al., 2006) identified populations of
spatially responsive cells in the medial entorhinal cortex that
comprises the major cortical afferents of the rat hippocampus.
These neurons, which are known as grid cells, are active in
multiple locations of an environment such that their firing fields
form a grid-like pattern. A third class of spatial cells can be found
in the postsubiculum of the hippocampal formation (Taube, Mul-
ler, & Ranck, 1990a,b), as well as in several interconnected sub-
cortical limbic structures, including the anterior thalamus and
lateral mammillary nuclei (see Taube, 2007, for a review). These
cells discharge as a function of an animal’s head direction (HD),
but their activity is independent of the animal’s location and
ongoing behavior. HD cells have been observed in several species
including rats, mice, chinchillas, guinea pigs, and nonhuman pri-
mates (Robertson, Rolls, Georges-Franc ¸ois, & Panzeri, 1999;
Benjamin J. Clark and Jeffrey S. Taube, Department of Psychological
and Brain Sciences, Center for Cognitive Neuroscience, Dartmouth Col-
lege.
This work was supported through a National Institute of Health Grant
NS053907 to Jeffrey S. Taube and a PGS–D postgraduate scholarship from
the National Sciences and Engineering Research Council of Canada to
Benjamin J. Clark. A preliminary report of this research was presented at
the 37th annual Society for Neuroscience Meeting in San Diego, CA,
November 3–7, 2007. We thank Jennifer Rilling for technical assistance
and Stephane Valerio for helpful discussions concerning these experi-
ments.
Correspondence concerning this article should be addressed to Jeffrey S.
Taube, Department of Psychological and Brain Sciences, Dartmouth Col-
lege, Hanover, NH 03755. E-mail: jeffrey.taube@dartmouth.edu
Behavioral Neuroscience
2009, Vol. 123, No. 3, 490–503
© 2009 American Psychological Association
0735-7044/09/$12.00DOI: 10.1037/a0015477
490

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Taube, 2007). Collectively, place, grid, and HD cells provide
animals with an abundant source of spatial information for deter-
mining their current location and direction. It is well-known that
lesions of brain regions containing these cell types produce navi-
gational impairments in a wide range of path integration and
landmark-based spatial tasks (Aggleton, Hunt, Nagle, & Neave,
1996; Frohardt, Bassett, & Taube, 2006; Maaswinkel, Jarrard, &
Whishaw, 1999; Morris, Garrud, Rawlins, & O’Keefe, 1982; Par-
ron & Save, 2004; Steffenach, Witter, Moser, & Moser, 2005;
Taube, Kesslak, & Cotman, 1992; Whishaw, Hines, & Wallace,
2001). Thus, these findings suggest that the spatially modulated
place, grid, and HD cell systems likely play a fundamental role in
navigation.
In recent years, research has focused on the role of subcortical
brain regions in spatial navigation and in the generation and
maintenance of hippocampal and limbic system place and HD cells
(Bassett, Tullman, & Taube, 2007; Blair, Cho, & Sharp, 1999;
Calton et al., 2003; Clark et al., 2009; Frohardt et al., 2006; Sharp
& Koester, 2008). The interpeduncular nucleus (IPN), a midline
structure located on the ventral surface of the midbrain, is of
particular interest because it occupies a pivotal position between
limbic midbrain and brainstem structures (Klemm, 2004; Morley,
1986; Sutherland, 1982). Interestingly, the IPN is reciprocally
connected to HD cell circuitry, specifically the dorsal tegmental
nuclei, and sends sparse inputs to the dentate and CA3 subfields of
the hippocampus (Baisden, Hoover, & Cowie, 1979; Groenewe-
gen, Ahlenius, Haber, Kowall, & Nauta, 1986; Montone, Fass,
Hamill, 1988; Segal, 1975; Shibata & Suzuki, 1984). Although
there has been no attention directed toward the role of the IPN in
navigation, large lesions of its primary afferent, the habenula,
produce impairments in landmark navigation tasks (Lecourtier,
Neijt, & Kelly, 2004). Furthermore, Sharp, Turner-Williams, and
Tuttle (2006) reported that some cells in the IPN and habenula
contained movement-related correlates associated with angular
head velocity or linear running speed. Moreover, we recently
found that selective lesions of the IPN significantly reduced the
extent of direction-specific firing of HD cells as well as lessened
the amount of control exerted by landmarks and self-movement
cues (Clark, Sarma, & Taube, 2009). Such findings indicate that
the IPN may convey spatially important information to HD cell
circuitry and may play a fundamental role in navigation.
Given the studies described above, we were interested in exam-
ining whether the IPN is involved in beacon, landmark, or path
integration based navigation. To address this issue we lesioned the
IPN in rats and tested them in two commonly used spatial tasks:
the food-carrying and Morris water tasks (Frohardt et al., 2006;
Maaswinkel et al., 1999; Morris, 1984; Parron & Save, 2004;
Whishaw et al., 2001; Whishaw & Tomie, 1997). First, we tested
IPN-lesioned and intact rats in the food-carrying paradigm in
which they searched for large food pellets in an open field, and
directly returned to their home refuge after finding the food. Using
this task, we evaluated the animal’s ability to return to the home
refuge when the testing room lights were turned off, thereby
removing visual landmark and optic flow information. Thus, be-
cause external cues were not useful in this version of the task, rats
had to rely on their ability to integrate self-movement information
from their starting location to return to the home refuge. Following
this path integration test, the room lights were turned back on and
the rats were then allowed to use the visual room cues to navigate
to the home refuge. Finally, we tested the same rats in a Morris
water maze procedure in which they were first trained to escape
from cool water by navigating toward a visual cue (a beacon)
marking a hidden platform. Rats were then tested in a standard
hidden platform procedure in which they were required to learn the
relationship between the visual room cues and the platform loca-
tion. This latter test provided a second evaluation of landmark
navigation. Below we report that IPN-lesioned rats were impaired
in both landmark navigation and path integration, but were unim-
paired in navigating to the goal when it was marked with a beacon.
Method
Subjects
Subjects were 19 female Long-Evans rats, weighing 250 to 300g
at the beginning of testing. Rats were singly housed in Plexiglas
cages and maintained on a 12-hr light–dark cycle. All procedures
involving the rats were performed in compliance with institutional
standards as set forth by the National Research Council’s (1996)
Guide for the Care and Use of Laboratory Animals and the Society
of Neuroscience.
Surgery
All animals were anesthetized with Nembutal (40 mg/kg ip) and
given atropine sulfate (5 mg/kg ip) to prevent respiratory distress.
The animals were placed in a Kopf stereotaxic instrument (David
Kopf Instruments, Tujunga, CA) and an incision was made to
expose the skull. Small holes were then drilled into the skull above
the IPN. Neurotoxic lesions of the IPN (n ? 10) were produced by
infusing 0.15 ?l of a 100 mM solution of N-methyl D-aspartate
(NMDA; dissolved in 0.9% saline) into six midline sites of the
brain. The solution was infused at a rate of 0.02 ?l/min through a
1 ?l Hamilton syringe (Hamilton Company, Reno, NV). Before
infusing the NMDA solution, the syringe rested at each injection
site for 3 min; this allowed the tissue to settle around the syringe
needle. After each injection, the syringe was left in place for 5 min
before being slowly removed. The needle was wiped with distilled
water in between each injection; this reduced overlying cortical
damage. Neurotoxic lesions were produced at six rostral-caudal
locations based on coordinates provided by Paxinos and Watson
(1998). Each site was 2.1 mm lateral to bregma and at a 14° angle
from vertical in the coronal plane: posterior (P) ? ?5.6 and
ventral (v) ? ?8.8 mm; P ? ?6.0 and v ? ?8.8 mm; P ? ?6.4
and v ? ?8.8 mm; P ? ?6.8 and v ? ?9.36 mm; P ? ?7.2 and
v ? ?9.36 mm; P ? ?7.4 and v ? ?9.36 mm. Sham rats (n ?
9) were given identical procedures but did not receive infusions of
NMDA into the IPN.
Feeding
Water was provided ad libitum while access to food was re-
stricted as necessary to maintain the animal’s body weight at 80%
of its free feeding weight. They were placed on an ad lib food diet
for a 1-week period immediately after surgery and during training
in the water task.
Apparatus
Foraging apparatus.
cal to that used by Frohardt et al. (2006). Briefly, the apparatus
The food-carrying apparatus was identi-
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consisted of a large, gray, circular (180 cm diameter) open field
with 16 symmetrically placed black food cups on the surface (see
Figure 1). Each food cup could be baited with a large 750 mg sugar
pellet (Bioserv, Frenchtown, NJ). Rats have a reliable proclivity to
carry these pellets back to their refuge for eating, rather than
consuming them at the food cup (Whishaw, Oddie, McNamara,
Harris, & Perry, 1990). Intact rats normally carry the food pellets
directly back to the refuge in a relatively straight line. The entire
field was supported by four rolling casters and was mounted on a
central bearing that allowed the field to be rotated around a central
platform. The central platform was slightly raised (1 cm thick, 53.3
cm in diameter) and remained stationary throughout the experi-
ment. The field was surrounded by a wall (38 cm high) containing
eight uniformly distributed doorways (each 13 cm wide) that were
covered by a black curtain that could be parted in the middle to
allow the rat to go through. There was a refuge behind one
doorway (13 cm wide, 40 cm long, 30.5 cm high) that was
completely covered with a cardboard lid, and served as a place of
safety and familiarity for the rat. The other seven doorways served
as false refuges and had wooden barriers behind the curtains. The
foraging apparatus was surrounded by black floor-to-ceiling cur-
tains (250 cm in diameter). A large white floor-to-ceiling curtain
that covered ? 80° of arc served as a visual landmark and was
placed ? 135° opposite the refuge. Four uniformly arranged lamps
were located above the apparatus to provide illumination. An
infrared video camera was located 3 m above the center of the field
so that the behavior of the rats could be videotaped when the room
was either illuminated or when the room lights were turned off.
Swimming pool.
The swimming pool was a 180 cm diameter
and 50 cm high round white tub positioned 14 cm above the floor.
The pool was filled to a depth of 23 cm with 21 to 22 °C water. The
water was made opaque by the addition of 750 ml of powdered
white paint. A clear Plexiglas platform with a 13 cm diameter top
was placed in the pool such that the top of the platform was 1 cm
below the surface of the water. A video camera was located above
the center of the swimming pool so that the behavior of the rats
could be videotaped and analyzed. The swimming pool was lo-
cated in a test room in which many cues, including counters,
cupboards, and posters were located; however, it was possible to
eliminate these cues by hanging black floor-to-ceiling curtains
around the pool (250 cm in diameter).
Procedure
Food-carrying task.
carrying apparatus (see Figure 1) before surgery was performed.
At the start of training, all of the food cups were baited with
pellets, and each rat was placed in the refuge and allowed to forage
for the pellets. A single food-carrying trial consisted of the rat
leaving the refuge, finding the food pellet, and carrying it back to
the refuge to eat it. Similar to previous observations, once a rat
found a pellet it typically returned to the refuge to eat it (Frohardt
et al., 2006; Whishaw & Tomie, 1997). However, when rats tried
to eat a pellet in the open field, or search for another pellet during
a return path, the behavior was discouraged by making a startling
noise (shaking keys) or taking the food pellet away. Animals were
allowed to retrieve and eat four pellets per day. As the rats became
more proficient at the task, the number of baited food cups was
reduced daily until there was only one pellet available per trial in
one of four centrally located food dishes. Pretraining was complete
once the rats completed four successive retrieval trials and reliably
returned directly to the correct refuge for two consecutive days.
Once training was finished, rats were divided into two groups (IPN
lesion and sham) matched to minimize behavioral differences.
After recovery from surgery (?1 week), rats received food-
carrying trials first with the room lights turned off, and then with
the room lights turned back on.
Lights off.
This portion of the task assessed whether the IPN-
lesioned rats could accurately return to the refuge using path
All rats received training in the food-
Figure 1.
of a gray rotatable circular table with surrounding walls that contained
eight potential refuge locations hidden behind black curtains. A fixed
platform was mounted in the center of apparatus. Notice that a floor-to-
ceiling black curtain surrounds the maze apparatus and a white floor-to-
ceiling curtain hangs ?135° opposite to the refuge. (B) An overhead view
of the food-carrying apparatus. At the center of the apparatus is an example
sequence in which the central food dishes were baited during a single
testing day. The diagram also illustrated the four refuge locations (A, B, C,
or D) used during lights-off testing. Refuge location A was used throughout
lights-on testing.
(A) The food-carrying apparatus. The test apparatus consisted
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integration based processes. Thus, various attempts were made to
prevent the use of external allothetic information such as visual,
olfactory, and auditory cues. First, similar to several previous
studies (Wallace, Hines, & Whishaw, 2002b; Whishaw et al.,
2001), we prevented the use of visual cues by turning the room
lights off and sealing the room to block all visible light. In the
dark, an infrared camera was used to record behavior. Rats are
unable to see in the infared wavelength range (Neitz & Jacobs,
1986). Two infrared emitters were attached on different walls
providing sufficient infrared illumination in the room so the rat
was visible on the camera. To further ensure that the rats did not
use visual cues during lights-off sessions, the refuge was moved to
a different location at the beginning of each trial (Figure 1B). To
eliminate the use of olfactory cues as a source of guidance, the
floor of the open field was cleaned with 80% ethanol and rotated
after each trial. Previous reports have shown this procedure to be
an effective method for preventing the use of surface cues (Fro-
hardt et al., 2006; Maaswinkel et al., 1999). In addition, a radio
tuned to an FM station that played white noise was placed next to
the overhead camera. This provided background noise to eliminate
potential auditory cues. Under these conditions, rats performed 12
food-carrying trials across 3 consecutive days (4 trials/day). For
each trial, the food pellet was placed pseudorandomly in one of
four centrally located food dishes. The placement was consistent
between rats, but not between trials. Daily food-carrying sessions
were video recorded with the infrared camera and the behavioral
analysis was performed offline.
Lights-on test.
This portion of the task assessed whether the
IPN-lesioned rats could use landmarks to accurately return to the
refuge. Thus, in contrast to lights-off testing, the room lights were
left on, and the refuge remained in the same location throughout
testing (Figure 1B). Rats performed 12 trials across 3 consecutive
days under these conditions (4 trials/day). Similar to the trials
under the infrared condition, food pellets were placed pseudoran-
domly in one of four centrally located food dishes. Again, the
placement was consistent between rats, but not between trials. To
ensure that task difficulty did not vary, the pattern of food place-
ment in this version of the task was identical to that of the infrared
trials. Olfactory and auditory cues were again obscured by clean-
ing the floor of the open field with 80% ethanol and a dry cloth
after each trial and by using a radio tuned to an FM station placed
near the camera. Daily food-carrying sessions were recorded with
the overhead camera and the behavioral analysis was performed
offline.
Cued platform swimming task.
carrying tasks, rats were trained in a cued platform version of the
water task. This test examined the ability of the rats to swim
toward a cue directly associated with the platform location, that is,
beacon navigation. The visual cue used in the present study was a
flag mounted on a wooden dowel that stood 13 cm above the
platform (Taube et al., 1992). The flag consisted of four pieces of
black cardboard attached at 90° angles making it clearly visible
from any point in the pool. To ensure that only the flag was used
to locate the platform, various attempts were made to obscure the
room cues (i.e., posters, counters, cupboards, etc.) as well as the
apparatus cues (i.e., pool walls), which all can act as spatial cues
(Hamilton et al., 2008; Hamilton, Akers, Weisend, & Sutherland,
2007; Hoh & Cain, 1997; Morris, 1984). First, to prevent the use
of room cues, training took place with the black floor-to-ceiling
Following testing in the food-
curtains surrounding the swimming pool. To prevent the use of the
apparatus walls as a spatial cue, the platform was moved between
12 different pool locations after each swimming trial (e.g., the
center of the pool quadrants, center of the pool, and locations near
and away from the edge of the pool). Animals were trained for 2
days, each day consisting of two blocks of four consecutive trials
(4-hr interval between daily training blocks and 24 hr between
days). A trial consisted of placing a rat by hand into the water
facing the wall of the pool at one of four pseudorandomly selected
starting positions (North, South, East, and West) around the pe-
rimeter of the pool. Rats were allowed to swim until they found the
platform or until 60 s elapsed. If a rat found the platform in less
than 60 s, it was permitted to remain on the platform for 30 s. If
after 60 s the rat failed to find the platform, it was guided to the
platform and permitted to remain there for 30 s. At the end of the
trial the rat was returned to a holding cage, and approximately 10
to 20 min elapsed, during which the remaining rats in the cohort
were tested before beginning the next trial. After four trials, the
animals were returned to their home cages and the same procedure
was repeated for the next block of trials.
Hidden platform swimming task.
variant of the water maze task, rats were trained in a hidden
platform version. The purpose of this variant of the task was to
assess the rat’s ability to learn the fixed spatial relationship be-
tween the room/apparatus cues and the hidden platform. This task
provided a second assessment of landmark navigation. Thus, the
floor-to-ceiling curtains were removed to allow the animals to
view the distal room cues. Moreover, the flag was removed from
the platform and the platform remained in the same location
throughout training. Animals were trained for 4 days, each day
consisting of two blocks of four consecutive trials (4-hr interval
between daily training blocks and 24 hr between days). Trials were
similar to the nonspatial cued training, consisting of placing a rat
by hand into the water facing the wall of the pool at one of the four
starting positions (trial length 60 s; time on platform 30 s). Again,
at the end of each block of trials, rats were returned to their home
cages and the same procedure was repeated during the next train-
ing block. A probe trial with the platform removed from the
swimming pool was conducted for 60 s at the beginning of the fifth
day. For the probe trial, the rats were released from the side of the
pool opposite of the platform.
After training in the cued
Behavioral Analysis
Food-carrying task.
mented into searches and returns (Frohardt et al., 2006; Wallace et
al., 2002b; Whishaw & Tomie, 1997). Searches were defined as
the moment the rat left the refuge to the point at which the rat finds
and picks up the food pellet. The return segment was defined as the
point in which the rat picks up the food pellet and carries it back
to the refuge. Using a stopwatch, the duration of searches and
returns were measured in seconds. Because some recent evidence
suggests that rats can use other sources of information to correct
and/or change their trajectory after initially orienting to a goal
(Hamilton, Rosenfelt, & Whishaw, 2004), returns were further
analyzed by measuring the initial and final heading angles. The
initial heading angle was defined as the angle between the refuge
and the rat’s directional heading when the rat picked up the food
pellet and was one body length away from the food cup. The final
Individual food-carrying trials were seg-
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heading angle was defined as the angle between the refuge and the
rat’s directional heading when the rat approached the refuge and
crossed a “virtual finish line” that was 2 cm from the outside wall
of the apparatus. Each angle was measured with a resolution of 6°
that was either clockwise or counterclockwise from the refuge. For
analysis, the initial and final heading angles were converted to
absolute values; thus, the maximum deviation was 180°. Finally,
returns were measured for accuracy by indicating the first doorway
the rat entered. A measure of choice accuracy was calculated by
counting the number of times the rat chose the correct refuge
location. Mean search duration, return duration, initial heading,
final heading, and the number of correct choices were calculated
for each testing day and animal.
Swimming task.
Each training trial for the cued and hidden
platform tasks was measured for duration (seconds) using a stop-
watch. Mean escape latencies for each animal were calculated for
each block of four trials. For the probe trial, the pool was divided
into four equal quadrants (see inset of Figure 8A) and the percent-
age of time that rats spent in each quadrant was measured. Because
previous work has shown that rats can use the distance from the
pool wall to localize the platform position (Hamilton et al., 2007;
2008; Hoh & Cain, 1997), we calculated the percentage of time
that rats spent in an annulus marking the platform positions rela-
tive to the pool wall and two other equal annuli marking the middle
and outer segments of the swimming pool (see inset of Figure 8B).
Thus, if the animals generally learned that the platform was a
particular distance from the pool wall, then we would see a greater
percentage of swim time in the platform annulus.
Statistics
Analysis in the food-carrying and water maze tasks was per-
formed using a two-factor repeated measures analysis of variance
(ANOVA) with group as between-subjects factors and days/block
as within-subjects factors. Follow-up simple contrasts as well as
mean comparisons were also performed (Tabachnick & Fidell,
2007).
Histological Analysis
At the completion of the experiments, animals were deeply
anesthetized with sodium pentobarbital. The rats were then per-
fused intracardially with saline followed by a 10% formalin solu-
tion. Each brain was removed from the skull and was postfixed in
a 10% formalin solution for at least 24 hr. The brains were then
cryoprotected in a 20% sucrose solution for 24 hr, and were then
frozen and cut coronally at 30 ?m sections with a cryostat. Every
third section was taken through the IPN and mounted on glass
microscope slides. Sections were stained with thionin, and exam-
ined under light microscopy to evaluate the lesions. To quantify
the extent of electrolytic and neurotoxic damage to the IPN, digital
images were captured at three rostral-caudal levels (?5.8 mm,
?6.3 mm, and ?6.8 mm posterior to bregma) provided by Paxinos
and Watson (1998). The area of undamaged tissue in the IPN was
calculated at each rostral-caudal level using Image-J software
(http://rsb.info.nih.gov/ij/index.html). Tissue was considered un-
damaged if it contained healthy neurons and few glial cells. Once
the area of undamaged tissue was calculated, the area of spared
tissue was summed across the three sections and compared with an
average area measured in the control rats. The total amount of
damage was calculated using the following formula: Tissue dam-
aged ? [average area of IPN in control rats (pixels2) – total area
of spared IPN tissue in lesioned rats (pixels2)/average area of IPN
in control rats (pixels2)] ? 100%.
Results
Histology
Figure 2A shows the rostral-caudal extent of the largest and
smallest IPN lesions at select plates from Paxinos and Watson
(1998). Representative sections from sham and IPN-lesioned rats
are shown in Figure 2B and 2C, respectively. Overall, the amount
of damage to the IPN varied from 78% to 100%. Seven rats
sustained a 90 to 100% complete lesion of the IPN, whereas three
rats had 78, 84, and 88% damage, respectively. The variability in
the lesions was mainly due to the fact that the rats had some
sparing in the most caudal regions of the IPN. Inspection of the
histology indicated that all of the lesioned rats showed complete
damage to the rostral region of the IPN, and all but three animals
had complete damage to the caudal portions of the IPN. It was
particularly important that rostral areas were completely lesioned
because the rostral subnuclei of the IPN are prominently connected
with the dorsal tegmental nuclei and thus capable of influencing
HD cell activity (Groenewegen et al., 1986; Hemmendinger &
Moore, 1984; Liu, Chang, & Wickern, 1984). Because there were
no observable behavioral differences (i.e., measures of return
accuracy) between the animals with smaller lesions and those with
larger lesions, we pooled all of the lesioned rats into one group.
The lesions typically extended into lateral and dorsal structures,
including the paranigral nucleus, interfascicular nucleus, caudal
linear nucleus of the raphe, and the ventral tegmental area (see
Figure 2C). However, in all cases, damage to these adjacent
structures was incomplete and unilateral (?20%). Three IPN-
lesioned and four sham animals had minor unilateral damage
(?30%) to the overlying cortex bordering the dysgranular region
of the retrosplenial and the medial subregions of the parietal
cortex. Previous studies have reported that neurotoxic damage to
the retrosplenial or parietal cortices can produce impairments in
spatial tasks (Aggleton & Vann, 2004; Harker & Whishaw, 2004;
Parron & Save, 2004). However, because very large lesions of
these cortical structures are required to produce impairments, it is
unlikely that our ? 30% damage contributed to the results in the
present study. Nevertheless, to rule out this possibility, we com-
pared the pre- and postsurgical behavioral data to each other from
the food-carrying task for the four cortically damaged sham ani-
mals. This analysis did not reveal any significant differences on
any of our behavioral measures (p ? .05). Thus, we argue that
lesions specific to the IPN are the most likely cause of our
experimental findings.
Lights-Off Test
The purpose of the lights-off task was to evaluate the naviga-
tional accuracy of IPN-lesioned rats when they are limited to using
a path integration based strategy. We first examined the search
patterns of rats during infrared conditions. Because one of the
sham rats failed to carry food on the final lights-off testing day,
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data from this animal’s final testing session was excluded from
statistical analysis. The left panels in Figure 3 show the search
paths of representative rats from sham and IPN-lesioned groups for
the first infrared test trial. Notice that the search paths of rats from
both groups have similar circuitous patterns that reach large por-
tions of the apparatus. The time taken to locate a food pellet was
used to measure performance during searches and is shown in
Table 1. On average, the search times of IPN-lesioned rats were
similar to that of sham animals. A repeated measures ANOVA on
the search times did not indicate any group, F(1, 16) ? .142, p ?
.711, day, F(2, 32) ? 1.02, p ? .371, or group by day interactions,
F(2, 32) ? 1.82, p ? .179.
Although no group differences were observed during search
behavior in the infrared test, the accuracy of returns varied across
the groups. As shown in the right panels of Figure 3, the return
paths of IPN-lesioned rats were less accurate, less direct, and
longer than the return segments of sham rats. Indeed, IPN-lesioned
rats chose the correct refuge 1.83 ? .24 times out of four possible
attempts, while sham animals chose the correct refuge nearly twice
as often 3.33 ? .13 times (Figure 4A). An ANOVA confirmed that
the IPN-lesioned rats chose the correct refuge significantly less
than shams, F(1, 16) ? 17.5, p ? .001. The ANOVA did not
AA
BB
DD
-5.8mm
-6.3mm
-6.8mm
C
E
Figure 2.
(gray) and smallest (black) IPN lesions at relative coordinates from bregma. (B) An enlarged view of the boxed
area in A in a representative section from a sham rat. (C) A representative section from a rat with neurotoxic
damage in the IPN. Note the glial scar that passes through the IPN. The black arrows point to damage extending
into structures dorsal to the IPN (paranigral nucleus and interfascicular nucleus). (D) and (E) show close-up
images of the sections from a representative control and IPN-lesioned rat at the location indicated by the black
box in sections B and C, respectively. Note the absence of neurons and the greater number of glial cells in the
section from the IPN-lesioned rat (E). Panel A is adapted from The Rat Brain in Stereotaxic Coordinates (4th
ed.), G. Paxinos and C. Watson, 1998. Copyright 1998, with permission from Elsevier.
(A) Select plates from Paxinos and Watson (1998) showing the rostral-caudal extent of the largest
S Searchh R t Return
Sham
IPN
Figure 3.
(bottom) rats on their search (left panels) and return (right panels) trips
during the first trial of lights-off testing. The black box represents the
refuge location and the open circle represents the food pellet location. Note
the increased path length and incorrect initial directional heading on the
return trip for the IPN-lesioned rat.
Representative paths taken by sham (top) and IPN-lesioned
495
IMPAIRED NAVIGATION FOLLOWING IPN LESIONS

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indicate a day, F(2, 32) ? .711, p ? .499, or group by day
interaction, F(2, 32) ? 1.12, p ? .338. A similar result was
obtained when evaluating the time taken to return to the refuge
with the food pellet (Figure 4B). A repeated measures ANOVA
conducted on return time revealed that the lesioned animals had
greater return durations, as indicated by a significant group effect,
F(1, 16) ? 21.2, p ? .001. An ANOVA did not indicate any
significant day, F(2, 32) ? 1.32, p ? .282, or group by day
interactions, F(2, 32) ? 1.12, p ? .339. Measures of the initial and
final heading had similar patterns. Figure 4C and 4D show that the
absolute initial and final heading angles of the IPN-lesioned rats
(initial: 69.5 ? 5.5°; final: 61.7 ? 5.8°) deviated further from the
refuge than that of sham rats (initial: 31.7 ? 2.9°; final: 22.9 ?
2.5°). This finding was confirmed by significant group effects,
initial: F(1, 16) ? 17, p ? .001; final: F(1, 16) ? 14.3, p ? .002.
Nevertheless, the ANOVAs did not indicate day, initial: F(2,
32) ? .159, p ? .854; final: F(2, 32) ? .855, p ? .435; or group
by day interactions, initial: F(2, 32) ? .226, p ? .799; final: F(2,
32) ? .169, p ? .846. Taken together, the results are consistent
with the interpretation that IPN-lesioned rats are unable to use path
integration processes to accurately return to the refuge.
Lights-On Test
The purpose of the lights-on version of the food-carrying task
was to assess the ability of rats to navigate using a landmark
navigation strategy. First, we examined the measures of search
behavior during this version of the task. The left panels in
Figure 5 show the search paths of representative rats from IPN-
lesioned and sham groups for the first trial of lights-on training. As
observed during lights-off trials, rats from both groups made
circuitous searches before finding the food pellets. The groups did
not differ in search duration (see Table 1) as indicated by a
nonsignificant group effect, F(1, 17) ? .889, p ? .359. Moreover,
the ANOVA did not reveal any significant day, F(2, 34) ? .065,
p ? .937, or group by day interactions for search duration, F(2,
34) ? .122, p ? .885.
The right panels in Figure 5 show representative return paths
made by sham and IPN-lesioned rats. Note that the return path
made by the IPN-lesioned rat was less accurate, less direct, and
longer than that of the sham rat. Indeed, Figure 6A shows that on
average IPN-lesioned rats chose the correct refuge (2.50 ? .20)
less than sham animals (3.81 ? .08). A significant group effect for
the ANOVA conducted on the number of correct choices con-
firmed this observation, F(1, 17) ? 19.4, p ? .001. The ANOVA
did not indicate a day effect, F(2, 34) ? 1.06, p ? .359, or a group
by day interaction, F(2, 34) ? 1.52, p ? .234. Analysis on the
duration to return to the refuge after finding the food pellet show
that IPN-lesioned rats take longer to find the refuge than sham rats
(Figure 6B). An ANOVA confirmed a significant group effect,
F(1, 17) ? 15.7, p ? .001. Interestingly, the ANOVA revealed
significant day, F(2, 34) ? 17.5, p ? .001, and group by day
interactions, F(2, 34) ? 3.73, p ? .03. Inspection of Figure 6B
ices
ber of Correct Choi
Numb
4
c)
eturn Duration (sec
Re
20
AA
B
1
2
3
Sham
IPN-Lesion
5
10
15
0
0
(degrees)
Initial Heading (
80
100
120
(degrees)
Final Heading (
80
100
120
C
D
Day 1
y
Day 2
y
Day 3
y
0
20
40
60
Day 1yDay 2yDay 3y
0
20
40
60
Figure 4.
IPN-lesioned (closed circles) for each day of lights-off testing. (A) Number
of correct refuge choices (M ? SEM). (B) The time taken to return to the
refuge (M ? SEM). (C) The initial (M ? SEM) and (D) final heading angle
(M ? SEM) from the refuge location. A perfect return heading to the refuge
would be 0°.
Return trip dependent measures for sham (open circles) and
S Searchh R tReturn
Sham
IPN
Figure 5.
(bottom) rats on their search (left panels) and return (right panels) trips
during the first trial of lights-on testing. The black box represents the
refuge location and the open circle represents the food pellet location. Note
the increased path length and incorrect initial directional heading on the
return trip for the IPN-lesioned rat.
Representative paths taken by sham (top) and IPN-lesioned
Table 1
Average (?SEM) Search Duration
GroupCondition DaySearch durationa
Sham Infrared One
Two
Three
One
Two
Three
One
Two
Three
One
Two
Three
11.84 ? 1.88
13.03 ? 2.88
15.88 ? 3.04
15.93 ? 3.36
12.53 ? 1.47
12.10 ? 1.55
10.94 ? 1.63
12.28 ? 3.07
11.19 ? 2.43
9.58 ? 1.72
9.25 ? 1.26
9.23 ? 2.24
IPN lesionInfrared
Sham Lights on
IPN lesionLights on
aGiven in seconds.
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shows that the IPN-lesioned rats reduced their return latencies
from Day 1 (7.72 ? .62 sec) to Day 3 (4.78 ? .52 sec), although
the daily return latencies remained the same for sham rats. Further
analysis with planned contrasts confirmed this observation (p ?
.01). A similar pattern of results was obtained for the absolute
initial heading (Figure 6C) and absolute final heading angles
(Figure 6D). The ANOVAs for these measures showed that the
initial and final heading angles deviated further from the refuge
than that of sham rats, initial: F(1, 17) ? 36.5, p ? .001; final: F(1,
17) ? 20.3, p ? .001. In addition, significant day, initial: F(2,
34) ? 7.96, p ? .001; final: F(2, 34) ? 9.35, p ? .001; and group
by day effects, initial: F(2, 34) ? 6.67, p ? .004; final: F(2, 34) ?
12.5, p ? .001; were indicated by the ANOVAs. Further analysis
with planned contrasts confirmed a significant reduction across
days in the initial (p ? .003) and final (p ? .001) headings for the
IPN-lesioned rats. Again, inspection of Figure 6C and 6D clearly
show that the IPN-lesioned rats reduced their initial and final
heading angles from Day 1 (initial: 81.0 ? 9.4°; final: 71.4 ?
13.5°) to Day 3 (initial: 51.7 ? 9.5°; final: 39.0 ? 8.8°), although
the daily initial and final heading angles remained the same for
sham rats. Taken together, the results demonstrate that an intact
IPN is required for accurate landmark navigation. Nonetheless, the
impairments were significantly reduced by the final testing day
suggesting that some recovery of navigational accuracy is possible
after several trials in the landmark navigation task.
Cued Platform Swimming Task
This version of the water maze was used to assess whether the
lesioned animals could navigate using a beacon. Two rats from the
IPN-lesioned group were excluded from the analysis because they
demonstrated poor swimming marked by the absence of movement
or floating when placed in the water. These animals were excluded
from testing in the subsequent hidden platform version of the task.
All other animals in both groups demonstrated that they could
accurately navigate toward the cued platform (Figure 7A). This
result was confirmed by a significant block effect, F(3, 45) ? 47.7,
p ? .001; as indicated by a repeated measures ANOVA. In
addition, the ANOVA showed that the group effect approached
significance, F(1, 15) ? 3.79, p ? .07; but was not significant for
the group by block interaction, F(3, 45) ? .580, p ? .361. It is
possible that the higher mean latencies for the IPN-lesioned group
during the second and third training block resulted in the near
significant group effect (see Figure 7A). Mean comparisons
showed that significant group differences occurred during the third
block (p ? .018), but not for Blocks 1, 2, or 4 (p ? .05),
suggesting that the greater swim latencies for IPN-lesioned rats
during the third block contributed to the near significant group
effects. In sum, although IPN-lesioned rats had significantly higher
latencies during the third training block, they were capable of
accurately navigating toward the cued platform by the fourth
testing block. Thus, the results suggest that IPN lesions do not
interfere with accurate beacon navigation.
Hidden Platform Swimming Task
The hidden platform version of the water maze was used to
further evaluate the landmark navigation abilities of the IPN-
lesioned animals. Specifically, the task requires that the animals
learn the spatial relationship between the fixed room/apparatus
cues and the platform location. Figure 7B plots the swim latencies
es
of Correct Choice
Number o
55
2020
AA
2
3
4
n Duration (sec)
Return
10
15
B
0
1
Sham
IPN-Lesion
0
5
rees)
tial Heading (degr
Init
100100
120
ees)
nal Heading (degre
Fin
100 100
120DC
20
40
60
80
20
40
60
80
Day 1 Day 2Day 3
0
Day 1Day 2Day 3
0
Figure 6.
IPN-lesioned (closed circles) rats for each day of lights-on testing. (A)
Number of correct refuge choices (M ? SEM). (B) The time taken to return
to the refuge (M ? SEM). (C) The initial (M ? SEM) and (D) final heading
angle (M ? SEM) from the refuge location. A perfect return heading to the
refuge would be 0°.
Return trip dependent measures for sham (open circles) and
Figure 7.
navigate to the cued platform during the four training blocks (4 trials each).
(B) Latency (M ? SEM) for the sham and IPN-lesioned rats to navigate to
the hidden uncued platform during the eight training blocks (four trials
each).
(A) Latency (M ? SEM) for the sham and IPN-lesioned rats to
497
IMPAIRED NAVIGATION FOLLOWING IPN LESIONS

Page 9

of animals in IPN-lesioned and sham groups. Overall, rats from
both groups showed reduced swim latencies across training, as
indicated by a significant block effect, F(7, 105) ? 11.6, p ? .001.
Despite the observation that the IPN-lesioned group had numeri-
cally greater mean swim latencies (16.4 ? 1.4 sec) than the sham
group (11.0 ? 1.2 sec), the ANOVA did not indicate a significant
group effect, F(1, 15) ? 3.51, p ? .08. Similarly, the group by
block interaction did not reach statistical significance, F(7, 105) ?
.863, p ? .539. It is noteworthy, however, that the IPN-lesioned
group had higher swim latencies during Blocks 3 to 8 as compared
to control rats. Mean comparisons showed that IPN-lesioned rats
had significantly greater escape latencies during Blocks 6 and 7
(p ? .01, .046, respectively), but not during Blocks 3, 4, and 8
(p ? .05). A comparison of Block 5 latencies approached signif-
icance (p ? .059). In sum, these results suggest that IPN-lesioned
animals can learn the position of the platform after 8 blocks of
training, but do not reach the same level of performance as sham
rats.
Given the findings described above, it is important to note that
several studies have demonstrated that rats can solve the water
maze task using a number of spatial cues including the fixed
relationship of the platform with the pool walls and the distal room
cues (Hamilton et al., 2007; 2008; Hoh & Cain, 1997; Morris,
1984). Thus, it is possible that the IPN lesions may have impaired
navigation based on a particular information source although spar-
ing other cue sources, resulting in the mild training impairment
described above. To determine what spatial information the ani-
mals in the present study acquired during training, we further
tested the rats in a probe trial 24 hr after the final training block of
the hidden platform task. For this probe test, the platform was
removed from the pool and the rats were released from the oppo-
site side of the swimming pool and allowed to swim for 60 s. If
during training our rats used the distal room cues to orient and
swim to the hidden platform, we would expect that the animals
would initially swim toward the platform’s previous location and
spend a disproportionate amount of time searching at that location
during the probe trial. Inspection of the video files revealed that
although all 9 of the sham animals swam directly to the platforms
previous location, only 3 out of the 8 IPN-lesioned rats swam
directly toward the correct location. To assess this difference
further, we calculated the percentage of time each rat swam in the
four pool quadrants (see Figure 8A). In general, sham rats spent
more time than IPN-lesioned rats in the quadrant that previously
contained the platform (sham: 58.5 ? 2.25%; IPN: 37.3 ? 4.88%).
An ANOVA confirmed this general observation by showing a
significant group by quadrant interaction, F(3, 45) ? 8.62, p ?
.001; with a significant group difference in the target quadrant
(p ? .01). Inspection of Figure 8A suggests that although the
IPN-lesioned rats showed poorer retention for the platforms pre-
vious location, the IPN-lesioned animals spent more time swim-
ming in the correct quadrant than in other quadrants. Confirming
this observation, an ANOVA on the quadrant times for IPN-
lesioned rats showed a significant effect of quadrant, F(3, 21) ?
4.27, p ? .02. On average, IPN-lesioned rats spent a greater
percentage of time in the target quadrant (37.3 ? 4.88%) than in
the other quadrants (average time in other quadrants: 20.6 ?
1.6%). A mean comparison demonstrated that this difference
reached statistical significance (p ? .04). Taken together, these
data suggest that the IPN-lesioned rats showed some retention for
the platform’s previous location, however, their performance did
not reach the level of the sham rats.
We further assessed the ability of the animals to use the pool
walls as a spatial cue by dividing the maze into three annuli (see
inset of Figure 8B). We reasoned that if the rats were capable of
using the pool walls as a cue, we would observe a greater amount
of search time in the annulus marking the platform position rela-
tive to the wall (the middle annulus). Inspection of the video files
showed that sham rats generally searched in the correct quadrant
and annulus, whereas IPN-lesioned rats generally searched in the
correct middle annulus but not in the correct quadrant. That is,
lesioned rats generally swam along the middle annulus. As shown
in Figure 8B, search preference for the middle annulus was greater
than the other annuli for both groups of animals, and did not vary
between the IPN-lesioned and sham groups (mean for middle
annulus, IPN: 47.5 ? 5.2%; sham: 46.7 ? 3.69%). Confirming this
observation, an ANOVA on the percentage of swim time in each
pool annuli did not reveal group, F(1, 15) ? .882, p ? .362, or
group by annuli effects, F(2, 30) ? .078, p ? .925, but did reveal
a significant annuli effect, F(2, 30) ? 12.3, p ? .001. This latter
Figure 8.
animals spent swimming in the four swimming pool quadrants during the
probe trial. The black bars indicate the quadrant that contained the platform
during training (see inset). (B) Bar graph showing the percentage of time
(M ? SEM) that animals spent swimming in the three pool annuli. Black
bars indicate the annulus that contained the platform during training (see
inset). The white circle in the inset indicates the platform location.
(A) Bar graph showing the percentage of time (M ? SEM) that
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significant result reflects the search preference of both groups of
animals for the middle annulus over the other two annuli. Consid-
ering this finding with that of the quadrant analysis, our results
collectively demonstrate that IPN-lesioned rats were capable of
learning the distance from the swimming pool walls to the plat-
form, but were impaired at using the distal visual cues to disam-
biguate the correct quadrant for a focused search.
Discussion
The IPN has been linked to a variety of behaviors including
homeostasis, olfaction, stress, sleep, nociception, and avoidance
learning (reviewed in Klemm, 2004; Morley, 1986). This impli-
cation in a wide range of behaviors may stem from the fact that it
contains several morphologically distinct subnuclei and discrete
subregional distributions of neurotransmitters (Groenewegen et al.,
1986). At present, it is unknown whether the IPN has a role in
navigation. Thus, the purpose of the present study was to deter-
mine whether the IPN is involved in three forms of navigation:
beacon, landmark, and path integration. IPN lesions were produced
by infusing the neurotoxin NMDA into the IPN at six rostral-
caudal levels. After the rats recovered from the surgery, they were
tested in a food-carrying paradigm that they had acquired before
surgery and then a standard cued platform and hidden platform
Morris water maze procedure that they had to acquire postsurgery
(Frohardt et al., 2006; Morris et al., 1982; Whishaw et al., 2001).
Our findings demonstrate that IPN lesions impair accurate navi-
gation in tasks evaluating landmark navigation and path integra-
tion, but not in tasks assessing beacon navigation. Impairments in
landmark navigation were milder than path integration deficits, as
IPN-lesioned rats showed some recovery of navigational accuracy
across testing trials. In sum, these results suggest that the IPN
serves a fundamental role in navigation.
IPN Lesions and Path Integration
The path integration task given to rats with IPN damage was
similar to that given previously to rats with lesions of place cell
(hippocampus), grid cell (entorhinal cortex), and HD cell circuitry
(anterior thalamus and dorsal tegmental nuclei; Frohardt et al.,
2006; Maaswinkel et al., 1999; Parron & Save, 2004; Save, Guaz-
zelli, & Poucet, 2001; Whishaw et al., 2001). Sham and IPN-
lesioned rats were trained in the food-carrying paradigm in which
they searched for food pellets in an open field, and directly
returned to their home refuge after finding the food. We evaluated
the animal’s ability to use self-movement cues to accurately return
to the home refuge by turning the room lights off and monitoring
their behavior under infrared light, a wavelength that rats cannot
see (Neitz & Jacobs, 1986). Olfactory and auditory cues were
displaced by cleaning the apparatus and refuge between foraging
trials and playing white noise from a radio above the table. To
further ensure that room cues were not used, the home refuge was
moved to a different doorway at the beginning of each trial.
Previous work has shown that similar testing conditions promote
the use of path integration rather than landmark or beacon based
navigational strategies (Forhardt et al., 2006; Maaswinkel et al.,
1999). Under these conditions, sham rats were able to return
accurately to the home refuge, suggesting that they were capable of
integrating self-movement information to determine a direct return
to the refuge (Frohardt et al., 2006; Maaswinkel et al., 1999;
Parron & Save, 2004; Whishaw et al., 2001; Whishaw & Tomie,
1997). In contrast, rats with lesions of the IPN were less accurate
and less direct when returning to the refuge under infrared condi-
tions. This result suggests that the IPN lesions interfered with
accurate path integration.
Navigation based on path integration likely involves several
computational and behavioral characteristics including: (a) the
establishment of an initial starting point or home base, (b) the
computation of a current orientation (direction, location, and dis-
tance) relative to a starting point, and (c) the computation of a
direct trajectory back to the starting point or some other goal. This
last computational step requires that the animal compute the an-
gular distance it must turn to embark on the correct trajectory.
These steps are often described in terms of a vector-based system
in which, (a) the path integration vector is reset or nulled before the
animal leaves the home base; (b) the vector pointing to the home
base is updated by integrating speed, distance, and directional
changes while the animal moves through its environment; and (c)
the vector is decoded so as to select a proper homing direction for
return (Etienne & Jeffery, 2004). However path integration is
defined, it is unlikely that IPN lesions interfered with the estab-
lishment of the refuge as a reference point because animals from
both groups spent most of their time in the refuge during food-
carrying trials and persistently searched and eventually located the
refuge after finding the food pellet. Thus, it is likely that the IPN
influences one or more of the other subsequent steps.
One possibility is that the IPN contributes to path integration
through its dense inputs to the HD cell circuit via the dorsal
tegmental nuclei. Indeed, researchers have proposed that the cells
and pathways comprising the HD cell circuit are used to compute
the directional component of path integration (Burgess, Barry, &
O’keefe, 2007; McNaughton et al., 1996; Redish, 1999). Consis-
tent with this view is a recent report from our laboratory in which
the activity of anterior thalamic HD cells was monitored in animals
that had large neurotoxic or electrolytic lesions of the IPN (Clark
et al., 2009). HD cells were recorded during conditions that re-
quired the integration of self-movement cues to maintain their
preferred firing directions as the animal locomoted from a familiar
enclosure to a novel one. In these path integration-dependent tests,
HD cells in intact animals maintained their preferred firing direc-
tion, whereas HD cells in IPN-lesioned animals failed to accurately
maintain their preferred directions. Thus, directional path integra-
tion was impaired in rats with IPN lesions.
We have suggested that the IPN conveys motor information to
the HD cell circuit because of its intimate connectivity with the
habenula, which receives motor information from basal ganglia
output structures (Contestabile & Flumerfelt, 1981; Groenewegen
et al., 1986; van der Kooy & Carter, 1981), and the finding that the
IPN contains cells sensitive to the animal’s movement speed
(Sharp et al., 2006). Thus, it is possible that the path integration
impairments observed in the present study stem from depriving the
HD cell circuit of motor based self-movement cues. The IPN may
alternatively influence path integration processes via its well doc-
umented projections to the dentate and CA3 subfields of the
hippocampus (Baisden et al., 1979; Groenewegen et al., 1986;
Montone et al., 1988; Segal, 1975; Shibata & Suzuki, 1984), which
along with CA1 area have been linked to path integration process-
ing (Golob & Taube, 1999; McNaughton et al., 1996; Whishaw et
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IMPAIRED NAVIGATION FOLLOWING IPN LESIONS

Page 11

al., 2001). Future work investigating hippocampal place cell ac-
tivity in animals with IPN lesions may shed light on this issue.
Interestingly, anatomical evidence indicates that the caudal sub-
nuclei of the IPN projects to the hippocampus, whereas the rostral
subnuclei of the IPN project most prominently to the dorsal teg-
mental nuclei (DTN) (Groenewegen et al., 1986; Hemmendinger
& Moore, 1984; Liu et al., 1984). It will be important for future
experiments to examine this distinct anatomical relationship as
well as the functional role served by the connections between the
different IPN subnuclei.
IPN Lesions and Landmark Navigation
Rats from sham and IPN-lesioned groups were given two
tests to evaluate their landmark navigation abilities. First, rats
were tested in the food-carrying task with the room illuminated
and the refuge left in a consistent location. Like the lights-off
version of the food-carry task, olfactory and auditory cues were
obscured by washing the open-field between trials and playing
white noise from a radio above the table. Under these testing
conditions, sham rats returned to the refuge accurately and
directly, whereas IPN-lesioned rats were less accurate, less
direct, and took longer to find the refuge location. Although this
finding suggests that IPN lesions interfere with the ability to
navigate based on visual landmarks, it is possible that the rats
elected to use path integration rather than landmark based
strategies when the room lights were turned on. We addressed
this possibility by testing the rats in a standard hidden platform
version of the Morris water maze (Morris, 1984; Morris et al.,
1982). In this task, the rats were pseudorandomly placed at one
of four start points at the periphery of the swimming pool and
were required to swim and climb a platform that was submerged
just below the surface of cool opaque water. To reliably locate
the hidden platform, the task requires that the rats learn the
relationship between the visual room cues and the platform
location. By the end of testing, sham rats readily localized the
position of the hidden platform and showed retention for the
platform position in a probe test. In contrast, IPN-lesioned rats
had longer latencies to find the hidden platform and showed less
retention for the platform location during the probe test. Col-
lectively, the results from both tests suggest that IPN lesions
interfere with accurate landmark navigation.
Conceptually, learning can be divided between task acquisi-
tion and accurate performance. For spatial tasks involving land-
mark navigation this first entails learning the procedural aspects
of the task, followed by learning the relationship between the
goal and ambient room cues (Bannerman, Good, Butcher, Ram-
say, & Morris, 1995; Saucier & Cain, 1995). For instance, in the
hidden platform variant of the Morris water maze, the rat must
learn how to swim, learn that it cannot escape by searching at
the sides of the pool, learn that escape is possible by obtaining
purchase on the pool platform, and learn to wait on the platform
until it is removed and placed back in the home cage. After the
rat is familiar with these procedural demands, it can then learn
the location of the platform in relation to the room/apparatus
cues. Because interpretations of landmark navigation deficits
are confounded if procedural and landmark learning are not
distinguished, we elected to test sham and lesioned rats in a
cued (beacon navigation) variant of the Morris water task
before testing their navigation in the hidden (landmark naviga-
tion) variant. Thus, the cued platform task not only evaluated
beacon navigation, but was also used to ensure that the animals
could learn the procedural demands of the Morris water task
before assessing landmark navigation. As a consequence, two
lesioned rats were removed from the experiment because they
displayed marked swimming impairments characterized by long
bouts of floating and the absence of movement. For the remain-
ing rats, it was clear that IPN lesions spared the ability to
accurately swim to a cued platform, but impaired navigation to
the hidden platform, suggesting that the lesions impaired land-
mark learning rather than the acquisition of the task procedures.
Like the water maze, the food-carrying task requires that
animals learn to search and find a large food-pellet and then
carry it to the refuge location. It is unlikely that IPN lesions
interfered with the performance of the procedural elements of
the task. First, animals in both groups were presurgically fa-
miliarized with both lights-off and light-on testing conditions.
Furthermore, after recovery from surgery, animals from both
groups displayed reliable food carrying by exiting the refuge
rapidly (?3 to 5 s), searching the open-field for food, and
carrying the food pellet to a doorway. When an incorrect
doorway was selected, animals from both groups visited other
doorways until they found the correct one. Thus, the deficits
observed in IPN-lesioned rats during lights-on and lights-off
testing are more likely to involve impairments of landmark
navigation and path integration, respectively.
Although the results of the present study suggest that the IPN
has a role in landmark navigation, it is unclear whether the struc-
ture is differentially involved in the acquisition, retention, or
retrieval of landmark information. Lesions of the IPN clearly
disrupted the retention of the presurgically acquired lights-on task,
but had a weaker effect on new learning. For example, IPN-
lesioned rats showed significant improvements in landmark navi-
gation across testing days in the food-carrying task and the hidden
platform task. During the water maze probe trials, lesioned rats
searched in the correct pool quadrant more than the other quad-
rants, although not nearly as accurately as sham rats. In addition,
we noted that many of the lesioned rats swam in circles at a fixed
distance from the pool wall such that their swim paths crossed the
platforms previous position. This finding indicates that although
the lesioned rats were poorer than shams at using the distal visual
cues to focus their search, the rats were capable of estimating the
distance of the platform position from the pool wall. Similar
observations have been made in rats with hippocampal and ento-
rhinal cortex lesions (Morris, Schenk, Tweedie, & Jarrad, 1990;
Schenk & Morris, 1985). These results suggest that while their
landmark navigational abilities were generally impaired, other
strategies and sources of information are available through path-
ways independent of the IPN.
The results of the landmark navigation tests demonstrate that
IPN lesions produce mild impairments in landmark navigation,
despite the fact that the IPN is several synapses removed from
the cortical circuitry often linked to the processing of landmark
information. Given the fact that IPN lesions severely impair
path integration, perhaps by removing the normal flow of motor
information to limbic brain areas, one possible explanation for
the landmark navigation deficits is that a stable spatial frame-
work based on path integration information is required for
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landmark cue learning (Alyan & Jander, 1994; McNaughton et
al., 1996). In other words, landmark learning may occur in
relation to path integration, and not independent of it. Although
work by some investigators supports this view (Dudchenko,
Goodridge, Seiterle, & Taube, 1997; Gibson, Shettleworth, &
McDonald, 2002; Knierim, Kudrimoti, & McNaughton, 1995;
Martin, Harley, Smith, Hoyles, & Hunes, 1997), it is still
currently unclear whether path integration and landmark navi-
gation is subserved by independent neural structures or whether
they are mediated by a common neural substrate. Future work
should be directed at this issue.
Conclusions
In summary, IPN lesions impair accurate navigation in tasks
evaluating landmark navigation and path integration, but not in
tasks assessing beacon navigation. Landmark navigation impair-
ments were generally mild, as lesioned rats showed marked im-
provements in navigation accuracy across testing days in both the
food-carrying and water maze spatial tasks. The IPN and its related
circuitry comprise a major link between limbic forebrain, striatum,
and brainstem structures (Klemm, 2004; Lecourtier & Kelley,
2007; Sutherland, 1982). Future work should be directed at eluci-
dating the precise role this circuitry has on spatial behavior and in
learning and memory in general.
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Received September 4, 2008
Revision received January 16, 2009
Accepted January 26, 2009 ?
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