Place Navigation In Rats Research Articles

Scopolamine disrupts place navigation in rats and humans: a translational validation of the Hidden Goal Task in the Morris water maze and a real maze for humans

Development of new drugs for treatment of Alzheimer's disease (AD) requires valid paradigms for testing their efficacy and sensitive tests validated in translational research. We present validation of a place-navigation task, a Hidden Goal Task (HGT) based on the Morris water maze (MWM), in comparable animal and human protocols. We used scopolamine to model cognitive dysfunction similar to that seen in AD and donepezil, a symptomatic medication for AD, to assess its potential reversible effect on this scopolamine-induced cognitive dysfunction. We tested the effects of scopolamine and the combination of scopolamine and donepezil on place navigation and compared their effects in human and rat versions of the HGT. Place navigation testing consisted of 4 sessions of HGT performed at baseline, 2, 4, and 8h after dosing in humans or 1, 2.5, and 5h in rats. Scopolamine worsened performance in both animals and humans. In the animal experiment, co-administration of donepezil alleviated the negative effect of scopolamine. In the human experiment, subjects co-administered with scopolamine and donepezil performed similarly to subjects on placebo and scopolamine, indicating a partial ameliorative effect of donepezil. In the task based on the MWM, scopolamine impaired place navigation, while co-administration of donepezil alleviated this effect in comparable animal and human protocols. Using scopolamine and donepezil to challenge place navigation testing can be studied concurrently in animals and humans and may be a valid and reliable model for translational research, as well as for preclinical and clinical phases of drug trials.

Evidence for a shift from place navigation to directional responding in one variant of the Morris water task.

Previous work from our laboratory has demonstrated that rats display a preference for directional responding over place navigation in a wide range of procedural variants of the Morris water task (Hamilton, Akers, Weisend, & Sutherland, 2007; Hamilton et al., 2008). A preference for place navigation has only been observed when the pool is reduced as a cue by filling it with water. Studies using dry land mazes have suggested that rats place navigate early in training and later switch to other forms of responding (e.g., motor). The present study evaluated whether rats switch from place navigation to directional responding in the "full-pool" variant of the water task. Rats were given 12, 24, or 36 hidden platform training trials. Probe trials with the pool repositioned in the room revealed a preference for place navigation in rats given 12 trials, an equal division of response preferences in rats given 24 trials, and a preference for directional responding in rats given 36 trials. These results indicate that the early preference for place navigation in the full-pool water task is transient and yields to a preference for directional responding with continued training.

Relative contribution of allothetic and idiothetic navigation to place avoidance on stable and rotating arenas in darkness

In the absence of useful visual or other exteroceptive cues, rats can orient in their environment using idiothetic navigation, the process in which the information generated during self-motion is integrated to yield a homing vector leading the animal back to a point of departure. If perceivable exteroceptive cues in the visited environment are available, their spatial relationship is integrated with idiothetic information and stored in a cognitive map of the environment. Our previous experiments demonstrated that place navigation in rats is severely impaired after devaluation of the intramaze substratal information by shuffling, i.e. by its random displacement relative to the already traversed track. Several interpretative difficulties of the previous study have been eliminated in the present study by the use of an advanced version of the shuffling apparatus. The results show that shuffling-induced impairment of substratal idiothesis depends on the salience of intramaze cues, that on a stable featureless arena, idiothesis can be updated by non-visual allothetic cues, and that shuffling exposing the animal to sudden accelerations and decelerations interferes with idiothetic navigation by the inherent conflict between substratal and inertial idiothesis. It is concluded that pure substratal idiothesis not updated by extramaze and intramaze cues cannot provide reliable navigation over distances longer than 5 m.

Auditory cues support place navigation in rats when associated with a visual cue

Rats, like other crepuscular animals, have excellent auditory capacities and they discriminate well between different sounds [Heffner HE, Heffner RS, Hearing in two cricetid rodents: wood rats ( Neotoma floridana) and grasshopper mouse ( Onychomys leucogaster). J Comp Psychol 1985;99(3):275–88]. However, most experimental literature concerning spatial orientation almost exclusively emphasizes the use of visual landmarks [Cressant A, Muller RU, Poucet B. Failure of centrally placed objects to control the firing fields of hippocampal place cells. J Neurosci 1997;17(7):2531–42; and Goodridge JP, Taube JS. Preferential use of the landmark navigational system by head direction cells in rats. Behav Neurosci 1995;109(1):49–61]. To address the important issue of whether rats are able to achieve a place navigation task relative to auditory beacons, we designed a place learning task in the water maze. We controlled cue availability by conducting the experiment in total darkness. Three auditory cues did not allow place navigation whereas three visual cues in the same positions did support place navigation. One auditory beacon directly associated with the goal location did not support taxon navigation (a beacon strategy allowing the animal to find the goal just by swimming toward the cue). Replacing the auditory beacons by one single visual beacon did support taxon navigation. A multimodal configuration of two auditory cues and one visual cue allowed correct place navigation. The deletion of the two auditory or of the one visual cue did disrupt the spatial performance. Thus rats can combine information from different sensory modalities to achieve a place navigation task. In particular, auditory cues support place navigation when associated with a visual one.

Place navigation in rats guided by a vestibular and kinesthetic orienting gradient.

The role of the slope of terrain in orientation was examined in rats trained to find, among 4 equidistant feeders, the 1 located in the upper left quadrant of a 10% tilted arena (1-m radius). Rats started from the center in light and with randomly changing slope direction reached the correct goal in 90% of 1st choices after 29 sessions. The same rats maintained 83% correct choices when the experiment was conducted in darkness. On a horizontal arena, their performance became random. After training, successful navigation was also observed (71% correct 1st choices) when the rats were started from different points at about 30 cm from the wall. This finding suggests that the slope of terrain may be used to establish a cognitive map based primarily on kinesthetic and vestibular signals. The flexibility of such a map seems to be rather limited, however, because changing the goal position with respect to inclination requires prolonged retraining.

Place navigation in rats guided by a vestibular and kinesthetic orienting gradient.

Place navigation in rats guided by a vestibular and kinesthetic orienting gradient.

P-19-18 - Differential effect of novel and reference antipsychotics on place navigation of rats in morris water maze

P-19-18 - Differential effect of novel and reference antipsychotics on place navigation of rats in morris water maze

Place navigation in rats with unilateral tetrodotoxin inactivation of the dorsal hippocampus: place but not procedural learning can be lateralized to one hippocampus.

Lateralization of the Morris water maze task was examined by injecting 5 ng of tetrodotoxin (TTX) into one dorsal hippocampus (HPC) of chronically cannulated rats (n = 20). The task, acquired (A) during unilateral HPC block, was retrieved (R) during TTX blockade of the ipsi- (I) or contralateral (C) HPC. Escape latencies (in seconds) at 3 levels of acquisition and in the first 4-trial block of I or C retrieval suggest lateralization was absent after the first block (A = 49, I = 40, C = 44), partial after training to an efficient search strategy (A = 6, I = 9, C = 14), and complete after overtraining to goal-directed escape (A = 4, I = 4, C = 12), as further indicated by comparisons of A vs. R behavior and probe trials. The analyses also indicate that (a) HPC contributes to the acquisition but is unnecessary for retrieval of the procedural engram, (b) overtrained learning with one HPC or intact brain is similar, and (c) there is no left-right hemispheric specialization for place learning.

Place navigation in rats with unilateral tetrodotoxin inactivation of the dorsal hippocampus: Place but not procedural learning can be lateralized to one hippocampus.

Place navigation in rats with unilateral tetrodotoxin inactivation of the dorsal hippocampus: Place but not procedural learning can be lateralized to one hippocampus.

Place navigation in rats is impaired by lesions of medial septum and diagonal band but not nucleus basalis magnocellularis

The role of forebrain cholinergic projections in place navigation learning was assessed in two experiments. Following surgery, rats were required to learn the spatial location of an underwater platform on the basis of distal room cues. Bilateral injections of ibotenic acid into the nucleus basalis magnocellularis depleted choline acetyltransferase (ChAT) from the anterior and temperoparietal cortex but not the hippocampus. Separate histological studies confirmed the accuracy of the lesions and demonstrated a marked loss of cortical acetylcholinesterase. These rats subsequently showed no deficits in spatial learning or memory. In a second experiment, bilateral lesions of the vertical limb of the diagonal band of Broca and medial septum depleted ChAT from the hippocampus and posterior cortex but not the anterior cortex. Histological studies confirmed the accuracy of the lesion and showed a pronounced loss of acetylcholinesterase from the hippocampus. These rats were deficient in spatial learning and showed reduced spatial bias during transfer tests. The data are discussed in the light of the hypothesis that the cholinergic innervation of the hippocampus plays a key role in spatial reference memory processes involved in place navigation.

Selective attention and place navigation in rats treated prenatally with methylazoxymethanol

Prenatal treatment of rats on gestation day 15 with methylazoxymethanol (MAM) caused forebrain microencephaly. The behavioral analyses included measures of spontaneous motor activity and tests for cognitive deficits, and were performed when the rats had reached adult age. Female MAM-treated rats failed to demonstrate contextual control of latent inhibition, which confirms earlier findings with male rats. Male MAM-treated rats demonstrated a notable impairment of place navigation in a swim-maze, but showed as strong sensory preconditioning as the control animals. Biochemical analyses indicated considerable increases in catecholamine levels in the cerebral cortex, hippocampus and striatum. The cognitive deficits, characterised by the various conditioning (taste-aversion) and instrumental learning (swim-maze) tasks, suggested that the MAM rats are deficient in their capacity to attend selectively to the relevant stimulus in complex arrangements of the stimulus situation.

Selective attention and place navigation in rats treated prenatally with methylazoxymethanol.

Prenatal treatment of rats on gestation day 15 with methylazoxymethanol (MAM) caused forebrain microencephaly. The behavioral analyses included measures of spontaneous motor activity and tests for cognitive deficits, and were performed when the rats had reached adult age. Female MAM-treated rats failed to demonstrate contextual control of latent inhibition, which confirms earlier findings with male rats. Male MAM-treated rats demonstrated a notable impairment of place navigation in a swim-maze, but showed as strong sensory preconditioning as the control animals. Biochemical analyses indicated considerable increases in catecholamine levels in the cerebral cortex, hippocampus and striatum. The cognitive deficits, characterised by the various conditioning (taste-aversion) and instrumental learning (swim-maze) tasks, suggested that the MAM rats are deficient in their capacity to attend selectively to the relevant stimulus in complex arrangements of the stimulus situation.

Lack of task specificity and absence of posttraining effects of atropine on learning.

Three experiments are reported whose purpose was to examine the effect of the cholinergic antagonist atropine on the acquisition of different learning tasks known to be sensitive or insensitive to impairment by hippocampal lesions; on the retention of performance acquired in the absence of the drug; and on memory consolidation immediately after daily training trials. In Experiment 1, atropine sulfate (10 or 50 mg/kg, ip), injected 30 min prior to training, severely impaired learning of both spatial and nonspatial discrimination tasks when compared with saline or atropine methylnitrate (50 mg/kg). In Experiment 2, atropine sulfate (50 mg/kg) also impaired spatial discrimination accuracy in rats previously trained to asymptote under drug-free conditions. These deficits were not due to either peripheral drug effects or gross sensorimotor impairments. In Experiment 3, daily posttraining injections of atropine sulfate (50 mg/kg) failed to influence either learning or subsequent retention of place navigation in rats that were trained to find a single hidden escape platform. The data confirm that profound learning deficits occur when training is conducted under atropine but offer no support to the hypothesis that cholinergic neurons play an important role in memory consolidation or other posttraining processes. Furthermore, these results point to dissimilarities between the behavioral impairments induced by cholinergic blockade and hippocampal lesions under appropriate test regimes.

Development of place navigation in rats from weaning to puberty

Young hooded rats were trained to escape onto a hidden platform after swimming in a pool of opaque water. Subjects 21, 28, 35, 42, and 64 days of age on the first training day were given 28 trials on 5 consecutive days. Half of the rats were required to localize the platform in relation to external room cues only ("place only" condition) and the other half were helped by the presence of a visible cue on the platform ("cue + place" condition). A deficiency in place navigation was observed in the 21- and 28-day groups; they showed slow escape and took circuitous routes more often than older rats. This deficiency was related to a poor spatial bias toward the training position when the subjects were allowed to swim for 30 s in the absence of the platform, at the end of the 28-trial training period (probe trial). The 35-day group showed adult-like learning ability in both training conditions, but failed to show searching behavior during the probe trial after having been trained in the presence of the proximal cue. Only rats older than 40 days showed typical adult behavior such as swimming directly toward the platform from any starting position and localized searching around the absent platform's position during the probe trial, no matter what the training conditions were. These results suggest that central nervous system structures responsible for place learning in the rat are functional from around 32 days of age, but fail to trigger searching behavior following cued training before the sixth week.