Progression of behavioral deficits during periadolescent development differs in female and male DISC1 knockout rats.

Mutations in the disrupted in schizophrenia-1 (DISC1) gene are associated with an increased risk of developing psychological disorders including schizophrenia, bipolar disorder, and depression. Assessing the impact of knocking out genes, like DISC1, in animal models provides valuable insights into the relationship between the gene and behavioral outcomes. Previous research has relied on mouse models to assess these impacts, however these may not yield as reliable or rich a behavioral analysis as can be obtained using rats. Thus, the goal of the present study was to characterize the behavioral effects of a biallelic functional deletion of the DISC1 gene in the Sprague Dawley rat. Female and male wild type and DISC1 knockout rats were assessed beginning just prior to weaning and during the post-weaning periadolescent period. The primary outcomes evaluated were activity, anxiety, responses to novel objects and conspecifics, and prepulse inhibition. These behaviors were selected as analogous indices of psychological dysfunction in humans. The DISC1 knockout had significant effects on behavior, although the kind and magnitude of deficits was different for females and males: in females, effects included hyperactivity, aversion to novelty, and a modest prepulse inhibition deficit; in males, effects in anxiety and neophobia were mild but their prepulse inhibition deficit was large. These data confirm that the DISC1 knockout rat model is an excellent way to reproduce and study symptoms of psychological disorders and provides compelling evidence for differential consequences of its dysfunction for females and males in the progression and emergence of specific behavioral deficits.

Overtraining Strengthens the Visual Discrimination Memory Trace Outside the Hippocampus in Male Rats.

The hippocampus (HPC) may compete with other memory systems when establishing a representation, a process termed overshadowing. However, this overshadowing may be mitigated by repeated learning episodes, making a memory resistant to post-training hippocampal damage. In the current study, we examined this overshadowing process for a hippocampal-dependent visual discrimination memory in rats. In Experiment 1, male rats were trained to criterion (80% accuracy on two consecutive days) on a visual discrimination and then given 50 additional trials distributed over 5 days or 10 weeks. Regardless of this additional learning, extensive damage to the HPC caused retrograde amnesia for the visual discrimination, suggesting that the memory remained hippocampal-dependent. In Experiment 2, rats received hippocampal damage before learning and required approximately twice as many trials to acquire the visual discrimination as control rats, suggesting that, when the overshadowing or competition is removed, the non-hippocampal memory systems only slowly acquires the discrimination. In Experiment 3, increasing the additional learning beyond criterion by 230 trials, the amount needed in Experiment 2 to train the non-hippocampal systems in absence of competition, successfully prevented the retrograde amnesic effects of post-training hippocampal damage. Combined, the findings suggest that a visual discrimination memory trace can be strengthened in non-hippocampal systems with overtraining and become independent of the HPC.

New method to induce mild traumatic brain injury in rodents produces differential outcomes in female and male Sprague Dawley rats.

BACKGROUND: Mild traumatic brain injuries (mTBI) are an increasing health concern due to persistent behavioral and neurological effects. To better understand these effects, researchers frequently rely on animal injury models. Existing models, however, may not adequately reproduce the mechanism of injury as it occurs in humans. NEW METHOD: Our new model for inducing mTBI in rodents entails acceleration of the animal toward a stationary impact zone to produce rapid rotational movement of the head. The aim of the present experiment was to characterize the effects of this injury in female and male rats on behavior, cognition, and neural plasticity. RESULTS: mTBI produced the most widespread effects in females: they were more active during recovery within minutes of mTBI and more active in the center of the open field 4days after mTBI. Spatial learning deficits in the water maze were mild but persistent and accompanied by reduced numbers of immature neurons in the hippocampus along with reductions in sera levels of the neurotrophin, BDNF. By contrast, male mTBI rats mainly exhibited mild spatial learning deficits, with no other observed effects. COMPARISON WITH EXISTING METHODS: Our model induced effects on behavior and biology in rats that aligned with existing models. However, new patterns were observed, particularly when comparing females and males. CONCLUSIONS: Taken together, these findings confirm the validity of this model and point to key differences between females and males in symptom severity and type. Additionally, our model adds a novel injury mechanism that complements existing rodent models.

Prenatal choline supplementation attenuates MK-801-induced deficits in memory, motor function, and hippocampal plasticity in adult male rats.

Choline is essential to the development and function of the central nervous system and supplemental choline during development is neuroprotective against a variety of insults, including neurotoxins like dizocilpine (MK-801). MK-801 is an NMDA receptor antagonist that is frequently used in rodent models of psychological disorders, particularly schizophrenia. At low doses, it causes cognitive impairments, and at higher doses it induces motor deficits, anhedonia, and neuronal degeneration. The primary goals of the present study were to investigate whether prenatal choline supplementation protects against the cognitive impairments, motor deficits, and neuropathologies that are precipitated by MK-801 administration in adulthood. Adult male Sprague-Dawley rats were fed a standard or supplemented choline diet prenatally. Using the novelty preference test of object recognition, we found that only prenatal standard-fed rats displayed memory consolidation deficits induced by low-dose MK-801 administered immediately following study of sample objects; all other groups, including prenatal choline supplemented rats given MK-801, showed intact memory. Following high-dose MK-801, prenatal choline supplementation significantly alleviated rats' motor response to MK-801, particularly ataxia. Using doublecortin and Ki67 to mark neurogenesis and cell division, respectively, in the hippocampus, we found that prenatal choline supplementation, in the face of MK-801 toxicity, protected against reduced hippocampal plasticity. Taken together, the current findings suggest that prenatal choline supplementation protects against a variety of behavioral and neural pathologies induced by the neurotoxin, MK-801. This research contributes to the growing body of evidence supporting the robust neuroprotective capacity of choline.

Adult emotionality and neural plasticity as a function of adolescent nutrient supplementation in male rats.

The present study explored the effects of supplementing male rats with either choline, omega-3 fatty acids, or phytoestrogens, from weaning into early adulthood, on emotionality and hippocampal plasticity. Because of the neuroprotective properties of these nutrients, we hypothesized that they would positively affect both behavior and hippocampal function when compared to non-supplemented control rats. To test this hypothesis, male Sprague Dawley rats were assigned to one of four nutrient conditions after weaning: 1) control (normal rat chow); 2) choline (supplemented in drinking water); 3) omega 3 fatty acids (daily oral supplements); or 4) phytoestrogens (supplemented in chow). After 4weeks on their respective diets, a subset of rats began 3weeks of behavioral testing, while the remaining behaviorally naïve rats were sacrificed after 6weeks on the diets to assess numbers of adult-born hippocampal neurons using the immature neuron marker, doublecortin. The results revealed that choline supplementation affected emotional functioning; compared to rats in other diet conditions, rats in this group were less anxious in an open field and after exposure to predator odor and showed less behavioral despair after forced swimming. Similar behavioral findings were evident following supplementation with omega-3 fatty acids and phytoestrogen supplementation, though not on all tests and not to the same magnitude. Histological findings followed a pattern consistent with the behavioral findings: choline supplementation, followed by omega-3 fatty acid supplementation, but not phytoestrogen supplementation, significantly increased the numbers of new-born hippocampal neurons. Choline and omega-3 fatty acids have similar biological functions-affecting cell membranes, growth factor levels, and epigenetically altering gene transcription. Thus, the present findings suggest that targeting nutrients with these effects may be a viable strategy to combat adult psychopathologies.

Reduced cocaine-seeking behavior in heterozygous BDNF knockout rats.

Cocaine generates drug-seeking behavior by creating long-lasting changes in the reward pathway. The role of the growth factor, brain-derived neurotrophic factor (BDNF) in facilitating these changes was investigated in the present report with a genetic rat model. Using conditioned place preference, the current study investigated the hypothesis that a partial knockout of the BDNF gene in rats (BDNF(+/-)) would attenuate the rewarding effects of cocaine. Wildtype rats exposed to cocaine exhibited normal cocaine-seeking responses one day after conditioning and cocaine-seeking behavior was reinstated with drug priming following drug abstinence. In contrast, BDNF(+/-) rats did not show cocaine-seeking behavior one day after conditioning, nor did they respond to drug priming. A median split of rats based on BDNF levels in sera collected prior to behavioral procedures revealed that wildtype rats with high BDNF levels showed stronger conditioned place preference and reinstatement to cocaine. Together, the results support the hypothesis that a partial knockout of the BDNF gene attenuates the rewarding properties of cocaine. Additionally, individual differences in BDNF levels may predict future cocaine-seeking behavior. An underlying mechanism of these effects may be a reduction of the amount of synaptic changes made in the reward pathway.

Single session contextual fear conditioning remains dependent on the hippocampus despite an increase in the number of context-shock pairings during learning.

We examined if the strength of contextual fear learning determines whether remote memories become independent of the hippocampus. Rats received 3 or 10 shocks in a single contextual fear conditioning session and then received sham or complete neurotoxic lesions of the hippocampus 7, 50, or 100 days later. Following recovery from surgery, the rats were returned to the conditioning context for a 5-min retention test. During this test, freezing, complete immobility except for breathing, was used as an index of memory. Regardless of the learning-to-surgery interval, the rats with hippocampal damage from the 3-shock condition showed little and significantly less freezing than their respective control group, suggesting profound flat graded retrograde amnesia. Similarly, each group of hippocampal-damaged rats from the 10-shock condition froze significantly less than their respective control group. However, the rats that received hippocampal damage 50 days after learning froze significantly more than the rats that received the damage 7 days after learning. The latter gradient to the retrograde amnesia did not increase with more time as the freezing was not as high in the most remote memory group (100 days). Combined, these findings suggest that a contextual fear memory acquired in a single session under stronger learning parameters remains dependent on the hippocampus.

Postnatal choline levels mediate cognitive deficits in a rat model of schizophrenia.

In the present study, we investigated whether the essential nutrient choline may protect against schizophrenic-like cognitive deficits in a rat model. Theories regarding the etiology of schizophrenia suggest that early life events render an individual more vulnerable to adult challenges, and the combination may precipitate disease onset. To model this, the adult male offspring of dams who either experienced stress during late gestation or did not were given a 5 mg/kg dose of the NMDA antagonist,MK-801. The presence of both the prenatal challenge of stress and the adult challenge of MK-801 was expected to impair memory in these offspring. Memory was not expected to be impaired in rats that did not experience prenatal stress, but did receive MK-801 as adults. To study whether choline levels altered outcomes in these groups, rats were fed a choline-supplemented, -deficient, or standard diet during the period between the two challenges: beginning at weaning and continuing for 25 days. All rats consumed regular rat chow thereafter. The efficacy of the model was confirmed in the standard fed rats in that only those that were prenatally stressed and received MK-801 as adults displayed impaired memory on a novelty preference test of object recognition. Contrary to this finding and consistent with our hypothesis, choline-supplemented rats that were also both prenatally stressed and given MK-801 as adults showed intact memory. Choline deficiency impaired memory in rats that were just prenatally stressed, just given MK-801 as adults, and subjected to both. Thus, a choline deficient diet may render rats vulnerable to either challenge. Taken together, we offer evidence that developmental choline levels modulate the effects of prenatal stress and/or MK-801 and thereby alter the cognitive outcome in a rat model of schizophrenia.

Supplemental dietary choline during development exerts antidepressant-like effects in adult female rats.

Perinatal choline supplementation in rats is neuroprotective against insults such as fetal alcohol exposure, seizures, and advanced age. In the present study we explored whether dietary choline supplementation may also confer protection from psychological challenges, like stress, and act as a natural buffer against stress-linked psychological disorders, like depression. We previously found that choline supplementation increased adult hippocampal neurogenesis, a function compromised by stress, lowered in depression, and boosted by antidepressants; and increased levels of growth factors linked to depression, like brain-derived neurotrophic factor. Together, these were compelling reasons to study the role of choline in depressed mood. To do this, we treated rats with a choline supplemented diet (5 mg/kg choline chloride in AIN76A) prenatally on embryonic days 10-22, on postnatal days (PD) 25-50, or as adults from PD75 onward. Outside of these treatment periods rats were fed a standard diet (1.1 mg/kg choline chloride in AIN76A); control rats consumed only this diet throughout the study. Starting on PD100 rats' anxiety-like responses to an open field, learning in a water maze, and reactivity to forced swimming were assessed. Rats given choline supplementation during pre- or post-natal development, but not adult-treated rats, were less anxious in the open field and less immobile in the forced swim test than control rats. These effects were not mediated by a learning deficit as all groups performed comparably and well in the water maze. Thus, we offer compelling support for the hypothesis that supplemental dietary choline, at least when given during development, may inoculate an individual against stress and major psychological disorders, like depression.

Prenatal choline deficiency does not enhance hippocampal vulnerability after kainic acid-induced seizures in adulthood.

Choline is a vital nutrient needed during early development for both humans and rodents. Severe dietary choline deficiency during pregnancy leads to birth defects, while more limited deficiency during mid- to late pregnancy causes deficits in hippocampal plasticity in adult rodent offspring that are accompanied by cognitive deficits only when task demands are high. Because prenatal choline supplementation confers neuroprotection of the adult hippocampus against a variety of neural insults and aids memory, we hypothesized that prenatal choline deficiency may enhance vulnerability to neural injury. To examine this, adult offspring of rat dams either fed a control diet (CON) or one deficient in choline (DEF) during embryonic days 12-17 were given multiple injections (i.p.) of saline (control) or kainic acid to induce seizures and were euthanized 16 days later. Perhaps somewhat surprisingly, DEF rats were not more susceptible to seizure induction and showed similar levels of seizure-induced hippocampal histopathology, GAD expression loss, upregulated hippocampal GFAP and growth factor expression, and increased dentate cell and neuronal proliferation as that seen in CON rats. Although prenatal choline deficiency compromises adult hippocampal plasticity in the intact brain, it does not appear to exacerbate the neuropathological response to seizures in the adult hippocampus at least shortly after excitotoxic injury.

Estradiol alters Fos-immunoreactivity in the hippocampus and dorsal striatum during place and response learning in middle-aged but not young adult female rats.

Evidence from lesion and inactivation studies suggests that the hippocampus (HPC) and dorsal striatum compete for control over navigation behavior, and there is some evidence in males that the structure with greater relative activation controls behavior. Estradiol has been shown to enhance HPC-dependent place learning and impair dorsal striatum-dependent response learning in female rats, possibly by increasing hippocampal activation and/or decreasing striatal activation. We used Fos-immunoreactivity (Fos-IR) to examine the activation of several subregions of the HPC and striatum in ovariectomized female rats with or without estradiol replacement 30 min after place or response learning. In 4-month-old rats, neither task nor estradiol increased Fos-IR above explore control levels in any subregion analyzed, even though estradiol impaired response learning. In 12-month-old rats, estradiol increased Fos-IR in the dentate gyrus, dorsal medial striatum, and dorsal lateral striatum in place task learners, while the absence of estradiol increased Fos-IR in these regions in response task learners. However, learning rate was not affected by estradiol in either task. We also included a group of long-term ovariectomized 12-month-old rats that displayed impaired place learning and altered Fos-IR in CA1 of the HPC. These results suggest that task-specific effects of estradiol on hippocampal and striatal activation emerge across age but that relative hippocampal and striatal activation are not related to learning rate during spatial navigation learning.

Water maze experience and prenatal choline supplementation differentially promote long-term hippocampal recovery from seizures in adulthood.

Status epilepticus (SE) in adulthood dramatically alters the hippocampus and produces spatial learning and memory deficits. Some factors, like environmental enrichment and exercise, may promote functional recovery from SE. Prenatal choline supplementation (SUP) also protects against spatial memory deficits observed shortly after SE in adulthood, and we have previously reported that SUP attenuates the neuropathological response to SE in the adult hippocampus just 16 days after SE. It is unknown whether SUP can ameliorate longer-term cognitive and neuropathological consequences of SE, whether repeatedly engaging the injured hippocampus in a cognitive task might facilitate recovery from SE, and whether our prophylactic prenatal dietary treatment would enable the injured hippocampus to more effectively benefit from cognitive rehabilitation. To address these issues, adult offspring from rat dams that received either a control (CON) or SUP diet on embryonic days 12-17 first received training on a place learning water maze task (WM) and were then administered saline or kainic acid (KA) to induce SE. Rats then either remained in their home cage, or received three additional WM sessions at 3, 6.5, and 10 weeks after SE to test spatial learning and memory retention. Eleven weeks after SE, the brains were analyzed for several hippocampal markers known to be altered by SE. SUP attenuated SE-induced spatial learning deficits and completely rescued spatial memory retention by 10 weeks post-SE. Repeated WM experience prevented SE-induced declines in glutamic acid decarboxylase (GAD) and dentate gyrus neurogenesis, and attenuated increased glial fibrilary acidic protein (GFAP) levels. Remarkably, SUP alone was similarly protective to an even greater extent, and SUP rats that were water maze trained after SE showed reduced hilar migration of newborn neurons. These findings suggest that prophylactic SUP is protective against the long-term cognitive and neuropathological effects of KA-induced SE, and that rehabilitative cognitive enrichment may be partially beneficial.

Spatial memory and hippocampal plasticity are differentially sensitive to the availability of choline in adulthood as a function of choline supply in utero.

Altered dietary choline availability early in life leads to persistent changes in spatial memory and hippocampal plasticity in adulthood. Developmental programming by early choline nutrition may determine the range of adult choline intake that is optimal for the types of neural plasticity involved in cognitive function. To test this, male Sprague-Dawley rats were exposed to a choline chloride deficient (DEF), sufficient (CON), or supplemented (SUP) diet during embryonic days 12-17 and then returned to a control diet (1.1 g choline chloride/kg). At 70 days of age, we found that DEF and SUP rats required fewer choices to locate 8 baited arms of a 12-arm radial maze than CON rats. When switched to a choline-deficient diet (0 g/kg), SUP rats showed impaired performance while CON and DEF rats were unaffected. In contrast, when switched to a choline-supplemented diet (5.0 g/kg), DEF rats' performance was significantly impaired while CON and SUP rats were less affected. These changes in performance were reversible when the rats were switched back to a control diet. In a second experiment, DEF, CON, and SUP rats were either maintained on a control diet, or the choline-supplemented diet. After 12 weeks, DEF rats were significantly impaired by choline supplementation on a matching-to-place water-maze task, which was also accompanied by a decrease in dentate cell proliferation in DEF rats only. IGF-1 levels were elevated by both prenatal and adult choline supplementation. Taken together, these findings suggest that the in utero availability of an essential nutrient, choline, causes differential behavioral and neuroplastic sensitivity to the adult choline supply.

Age-related declines in exploratory behavior and markers of hippocampal plasticity are attenuated by prenatal choline supplementation in rats.

Supplemental choline in the maternal diet produces a lasting enhancement in memory in offspring that resists age-related decline and is accompanied by neuroanatomical, neurophysiological and neurochemical changes in the hippocampus. The present study was designed to examine: 1) if prenatal choline supplementation alters behaviors that contribute to risk or resilience in cognitive aging, and 2) whether, at old age (25 months), prenatally choline-supplemented rats show evidence of preserved hippocampal plasticity. A longitudinal design was used to look at exploration of an open field, with and without objects, at 1 and 24 months of age in male and female rats whose mothers were fed a diet supplemented with choline (SUP; 5 mg/kg choline chloride) or not supplemented (CON; 1.1 mg/kg choline chloride) on embryonic days 12-17. Aging caused a significant decline in open field exploration that was more pronounced in males but interest in novel objects was maintained in both sexes. Prenatal choline supplementation attenuated, but did not prevent age-related decline in exploration in males and increased object exploration in young females. Following behavioral assessment, rats were euthanized to assess markers of hippocampal plasticity. Aged SUP males and females had more newly proliferated cells in the hippocampal dentate gyrus and protein levels of vascular endothelial growth factor (VEGF) and neurotrophin-3 (NT-3) were significantly elevated in female SUP rats in comparison to all other groups. Taken together, these findings provide the first evidence that prenatal choline supplementation causes changes in exploratory behaviors over the lifespan and preserves some features of hippocampal plasticity that can be seen even at 2 years of age.

Prenatal choline supplementation attenuates neuropathological response to status epilepticus in the adult rat hippocampus.

Prenatal choline supplementation (SUP) protects adult rats against spatial memory deficits observed after excitotoxin-induced status epilepticus (SE). To examine the mechanism underlying this neuroprotection, we determined the effects of SUP on a variety of hippocampal markers known to change in response to SE and thought to underlie ensuing cognitive deficits. Adult offspring from rat dams that received either a control or SUP diet on embryonic days 12-17 were administered saline or kainic acid (i.p.) to induce SE and were euthanized 16 days later. SUP markedly attenuated seizure-induced hippocampal neurodegeneration, dentate cell proliferation, and hippocampal GFAP mRNA expression levels, prevented the loss of hippocampal GAD65 protein and mRNA expression, and altered growth factor expression patterns. SUP also enhanced pre-seizure hippocampal levels of BDNF, NGF, and IGF-1, which may confer a neuroprotective hippocampal microenvironment that dampens the neuropathological response to and/or helps facilitate recovery from SE to protect cognitive function.

Prenatal choline availability modulates hippocampal neurogenesis and neurogenic responses to enriching experiences in adult female rats.

Increased dietary intake of choline early in life improves performance of adult rats on memory tasks and prevents their age-related memory decline. Because neurogenesis in the adult hippocampus also declines with age, we investigated whether prenatal choline availability affects hippocampal neurogenesis in adult Sprague-Dawley rats and modifies their neurogenic response to environmental stimulation. On embryonic days (ED) 12-17, pregnant rats ate a choline-supplemented (SUP-5 g/kg), choline sufficient (SFF-1.1 g/kg), or choline-free (DEF) semisynthetic diet. Adult offspring either remained in standard housing or were given 21 daily visits to explore a maze. On the last ten exploration days, all rats received daily injections of 5-bromo-2-deoxyuridine (BrdU, 100 mg/kg). The number of BrdU+ cells was significantly greater in the dentate gyrus in SUP rats compared to SFF or DEF rats. While maze experience increased the number of BrdU+ cells in SFF rats to the level seen in the SUP rats, this enriching experience did not alter cell proliferation in DEF rats. Similar patterns of cell proliferation were obtained with immunohistochemical staining for neuronal marker doublecortin, confirming that diet and exploration affected hippocampal neurogenesis. Moreover, hippocampal levels of the brain-derived neurotrophic factor (BDNF) were increased in SUP rats as compared to SFF and DEF animals. We conclude that prenatal choline intake has enduring effects on adult hippocampal neurogenesis, possibly via up-regulation of BDNF levels, and suggest that these alterations of neurogenesis may contribute to the mechanism of life-long changes in cognitive function governed by the availability of choline during gestation.

Consolidation of object-discrimination memory is independent of the hippocampus in rats.

We examined whether retrograde amnesia would be more likely for object discriminations learned an hour before hippocampal damage than object discriminations learned days before. Specifically, rats were trained on two object-discrimination problems 72 h before surgery and another discrimination problem and the reversal of one of the previously learned problems 1 h before surgery. Importantly, novel procedures that minimized overtraining on the object discriminations were used to increase the possibility of the lesions causing amnesia. After either receiving sham or neurotoxic-induced hippocampal damage, rats were tested for retention using an extinction procedure. Control rats and rats with extensive hippocampal damage displayed a strong bias for the rewarded object on each object-discrimination problem and a significant bias for the most recent contingency learned on the reversal problem. These results suggest that, despite the use of very sensitive training and testing procedures, hippocampal damage did not cause retrograde amnesia. The findings imply that the hippocampus is not critical for the consolidation, storage, or retrieval of object-reward associations, or any other information required for accurate performance of an object discrimination.

Differential fos expression following aspiration, electrolytic, or excitotoxic lesions of the perirhinal cortex in rats.

The authors explored the possibility that there are different neural consequences, beyond the primary site of brain damage, following perirhinal cortex (PRh) lesions made in different ways. Fos expression was used as a marker for neuronal activation and compared across the forebrains of rats that underwent the different types of surgery. Electrolytic and excitotoxic PRh lesions produced dramatic increases in Fos expression in the cortex, and excitotoxic and aspiration PRh lesions increased Fos expression in the dentate gyrus. These data are consistent with the hypothesis that different lesion methods have separable effects on neural function in regions outside the lesion site that could account for inconsistencies in the literature regarding the behavioral effects of PRh lesions on tests of spatial memory.

Perirhinal cortex lesions produce variable patterns of retrograde amnesia in rats.

Two experiments examined the contribution of the perirhinal cortex (PRh) to retrograde memory for the location of a platform in a water maze. In a previous study, we found that electrolytic lesions of the PRh produced retrograde amnesia, without a temporal gradient, for water-maze problems acquired 4 weeks and 2 days before surgery [Behav. Brain. Res. 114 (2000) 119]. In Experiment 1, we used the same mixed design as in our previous report (time of learning was a within-subjects factor), but PRh lesions were made by aspiration. Contrary to our earlier report, these PRh rats displayed good retention of both platform locations. Combined, these findings indicate that the lesion method may contribute importantly to the pattern of deficits observed. Experiment 2 was conducted similar to Experiment 1, except that a completely between-subjects design was used (time of learning was a between-subjects factor). Rats that received PRh lesions approximately 2 days after the last training session displayed impaired retention of the platform's location, whereas rats that received PRh lesions 4 weeks after training did not. This finding of a temporally graded retrograde amnesia is consistent with our earlier report, and further suggests that the involvement of the PRh in the retention of water-maze problems is time-limited. However, also consistent with our earlier report, the PRh-lesioned rats in Experiment 2 that displayed a retention deficit rapidly reacquired the task. This finding, combined with the negative findings in Experiment 1, suggests that the contribution of the PRh to retrograde memory for platform locations is subtle and may not be due to impaired spatial memory abilities. Additionally, the conflicting results of Experiments 1 and 2 underscore the importance of the design employed in studies of retrograde amnesia in animals.

Hippocampal damage and exploratory preferences in rats: memory for objects, places, and contexts.

Rats have a natural tendency to spend more time exploring novel objects than familiar objects, and this preference can be used as an index of object recognition. Rats also show an exploratory preference for objects in locations where they have not previously encountered objects (an index of place memory) and for familiar objects in contexts different from those in which the objects were originally encountered (an index of context memory). In this experiment, rats with cytotoxic lesions of the hippocampal formation were tested on all three versions of the novelty-preference paradigm, with a 5-min retention interval between the familiarization and test phases. Rats with sham lesions displayed a novelty preference on all three trial types, whereas the rats with hippocampal lesions displayed a novelty preference on Object trials but did not discriminate between the objects on Place trials or Context trials. The findings indicate that hippocampal damage impairs memory for contextual or spatial aspects of an experience, whereas memory for objects that were part of the same experience are left relatively intact.