Research ReportCA1 ischemic injury does not affect the ability of Mongolian gerbils to solve response, direction, or place problems
Introduction
The role of the dorsal hippocampus in various forms of spatial learning has been well documented in rats (Amsel, 1993, Bingman and Jones, 1994, Honey and Good, 1993, Jarrard, 1995, Morris et al., 1986, Moser et al., 1993, O'Keefe and Nadel, 1978). Previous lesion work does not suggest a role for the hippocampus in response learning (Kesner and Gilbert, 2006, Packard and McGaugh, 1996). Recently, we attempted to determine whether the dorsal hippocampus was necessary for rats to solve place and direction problems, which would confirm that these tasks require spatial memory (Stringer et al., 2005). Half of the rats were given N-methyl-d-aspartate (NMDA) lesions, which destroyed the dorsal CA1 and CA3 subfields and the dentate gyrus. Lesioned rats were impaired on both the direction and place but not response tasks whereas control rats mastered all three tasks. These findings confirmed that dorsal hippocampus is needed for rats to form a spatial map of their environment and to learn to go to a goal location or “place” relative to extramaze cues. In addition, the rats were also impaired in their ability to discriminate between two maze positions even when the start points were on different sides of the room. That is, the rats appeared to be impaired in their ability to map both global and local contexts. From these studies, we have confirmed that the dorsal hippocampus is necessary for discriminating among several local contexts within a global environment, in addition to mapping of the global environment as a whole.
Recent data from place cell recordings have suggested that CA1 and CA3 cells differ in terms of their responses to global versus local contexts (Gilbert and Kesner, 2006, Leutgeb et al., 2004, Rolls and Kesner, 2006). It appears that CA1 place cells are mainly responsive to global environmental cues and are relatively immune to changes in local context, whereas CA3 pyramidal cells are thought to encode an animal's location in terms of its current local context (Gilbert and Kesner, 2006, Leutgeb et al., 2004, Rolls and Kesner, 2006). This context-dependent representation in CA3 is thought to allow spatial memory to differentiate between different local environments (Leutgeb et al., 2004). Like rats, gerbils with dorsal CA1 lesions show deficits on tasks such as the Morris water maze, which are thought to require a stable global representation (Corbett et al., 1992, Block, 1999).
To further examine which subfield or subfields is or are necessary for each type of spatial learning in our place and direction tasks we used a gerbil model of global ischemia in which selective loss of CA1 neurons is produced following 5 min of bilateral carotid artery occlusion (Kirino, 1982, Colbourne and Corbett, 1995). Accordingly, we trained gerbils with and without CA1 ischemic injury on a response, direction, or one of two place problems. Previous studies have established that increased open field activity correlates with selective loss of hippocampal CA1 neurons and not neuronal loss from striatum or cortex (Gerhardt and Boast, 1988, Glickman et al., 1970, Mileson and Schwartz, 1991, Wang and Corbett, 1990, Babcock et al., 1993). However, when gerbils are exposed to an open field prior to ischemia, the usual pattern of hyperactivity is largely negated compared to gerbils that have not received previous exposure (Wang and Corbett, 1990, Babcock et al., 1993). This suggests that the increased locomotion after ischemia may be the result of a spatial mapping or a habituation deficit rather than a simple form of motor hyperactivity (Glickman et al., 1970, Wang and Corbett, 1990). In other words, if the animal has an impaired ability to form a spatial map of its environment, it may not readily recognize that environment as familiar on subsequent visits and will continue to explore. In the present experiment, we used an open field maze as a behavioural measure of CA1 injury.
Since a global representation of the entire test room, i.e. a stable place map, is not available to the gerbils because the place cells in dorsal CA1 have been destroyed, we predicted that the ischemic gerbils would be unable to solve the place and direction problems because they cannot differentiate between the two maze contexts (Fig. 1).
Section snippets
Results
Data from four gerbils were omitted from the analysis. Two of the gerbils damaged their teeth and were unable to continue the experiment (both were ischemic, one from the response group and one from the place 2 group). One animal from the response group had unilateral ischemic injury, while the other from the direction group showed evidence of highly abnormal dentate and CA3 cytoarchitecture, which suggested a genetic or birth defect. Both histological data and the activity measure confirmed
Discussion
Histological analysis revealed that cell loss was restricted exclusively to the dorsal CA1 hippocampal subregion as noted previously in this model (Kirino, 1982, Colbourne and Corbett, 1995). Ischemic gerbils showed significantly greater open field activity than controls, which is consistent with earlier reports that dorsal CA1 hippocampal damage is correlated with hyperactivity (Gerhardt and Boast, 1988, Wang and Corbett, 1990, Mileson and Schwartz, 1991, Babcock et al., 1993). This finding is
Subjects
Subjects were 40 female Mongolian gerbils (Meriones unguiculatus), approximately 5 months old and weighing 52.0–67.0 g at the start of the experiment. Gerbils were housed in pairs upon arrival. After surgery, ischemic gerbils were housed individually in transparent plastic cages (45 cm × 24 cm × 20 cm). Controls were likewise separated from their cagemates to coincide with separation of the operated animals. The gerbils were maintained in controlled conditions (temperature: 20 ± 2 °C; 12-h light/dark
Acknowledgments
Special thanks to Suzanne Evans for performing the surgeries and helping with the data collection. Kristopher Langdon and Krista Hewlett provided helpful comments on the manuscript. This work was supported by NSERC grants to DMS and GMM and CIHR to DC.
References (31)
- et al.
Locomotor activity in the ischemic gerbil
Brain Res.
(1993) - et al.
Grating acuity of the Mongolian gerbil (Meriones unguiculatus)
Behav. Brain Res.
(1983) Global ischemia and behavioral deficits
Prog. Neurobiol.
(1999)- et al.
Dynamic changes in CA1 dendritic spines associated with ischemic tolerance
Exp. Neurol.
(2006) - et al.
The role of the dorsal CA3 hippocampal subregion in spatial working memory and pattern separation
Behav. Brain Res.
(2006) - et al.
Some effects of hippocampal lesions on the behavior of Mongolian gerbils
Physiol. Behav.
(1970) What does the hippocampus really do?
Behav. Brain Res.
(1995)Delayed neuronal death in the gerbil hippocampus following ischemia
Brain Res.
(1982)- et al.
Temporal profile of magnetic resonance imaging changes following forebrain ischemia in the gerbil
Neurosci. Lett.
(1998) - et al.
The use of locomotor activity as a behavioral screen for neuronal damage following transient forebrain ischemia in gerbils
Neurosci. Lett.
(1991)
Inactivation of hippocampus or caudate nucleus with lidocaine differentially affects expression of place and response learning
Neurobiol. Learn. Mem.
Characterization of anxiety and habituation profile following global ischemia in rats
Physiol. Behav.
Variation in visual acuity within pigmented, and between pigmented and albino rat strains
Behav. Brain Res.
A computational theory of hippocampal function, and empirical tests of the theory
Prog. Neurobiol.
Cerebral ischemia, locomotor activity and spatial mapping
Brain Res.
Cited by (9)
Rats' orientation at the start point is important for spatial learning in a water T-maze
2013, Learning and MotivationCitation Excerpt :The impairment in place learning on the translation task, relative to place learning on the rotation task and relative to response and direction learning, has been reported across task, motivational condition and species (Skinner et al., 2003; Walsh et al., 2008; Whyte et al., 2009).
Changes in HPA reactivity and noradrenergic functions regulate spatial memory impairments at delayed time intervals following cerebral ischemia
2011, Hormones and BehaviorCitation Excerpt :The current study supports such interpretation and show that ischemic rats can perform well on spatial memory tasks if the dysregulation of stress hormones is attenuated. Extra-CA1 structures and/or brain circuits including the hippocampal subfield CA3 and the frontal cortex are important for spatial memory (Walsh et al., 2008; Dalley et al., 2004) and minimally damaged by 10 min of cerebral ischemia (Nunn et al., 1994). The observation of attenuated spatial memory deficits in clonidine and metyrapone-treated ischemic rats in spite of important CA1 neuronal damage suggests that activation of these (or other) brain areas were sufficient to maintain intact spatial memory capabilities.
An assessment of response, direction and place learning by rats in a water T-maze
2009, Learning and MotivationRats' Orientation Is More Important Than Start Point Location for Successful Place Learning
2010, Journal of Experimental Psychology: Animal Behavior ProcessesThe domestic piglet: An important model for investigating the neurodevelopmental consequences of early life insults
2015, Annual Review of Animal Biosciences