Nicotine attenuates spatial learning deficits induced in the rat by perinatal lead exposure

Maternally lead (Pb)-exposed, juvenile rats exhibit significant deficits in spatial reference memory acquisition and working memory performance in the Morris water maze (MWM). Acute systemic application of nicotine reverses these deficits without affecting behavioral performance of the age-matched, lead-unexposed control animals. These results suggest that nicotinic agonist treatments can ameliorate learning and memory impairments, presumably by compensating for deficient nicotinic function in developmentally lead-exposed animals.     

铅暴露对大鼠参考记忆和工作记忆的影响

BACKGROUND： Studies have demonstrated that lead exposure can result in cognitive dysfunction and behavior disorders. However, lead exposure impairments vary under different experimental conditions.
OBJECTIVE： To detect changes in spatial learning and memory following low-level lead exposure in rats, in Morris water maze test under the same experimental condition used to analyze lead exposure effects on various memory types and learning processes.
DESIGN AND SETTING： The experiment was conducted at the Animal Laboratory, Institute of Psychology, Chinese Academy of Science between February 2005 and March 2006. One-way analysis of variance （ANOVA） and behavioral observations were performed. MATERIALS： Sixteen male, healthy, adult, Sprague Dawley rats were randomized into normal con-trol and lead exposure groups （n = 8）.
METHODS： Rats in the normal control group were fed distilled water, and those in the lead exposure group were fed 250 mL of 0.05% lead acetate once per day. At day 28, all rats performed the Morris water maze test, consisting of four phases： space navigation, probe test, working memory test, and visual cue test.
MAIN OUTCOME MEASURES： Place navigation in the Morris water maze was used to evaluate spatial learning and memory, probe trials for spatial reference memory, working memory test for spatial working memory, and visual cue test for non-spatial cognitive function. Perkin-Elmer Model 300 Atomic Absorption Spectrometer was utilized to determine blood lead levels in rats.
RESULTS： （1） In the working memory test, the time to reach the platform remained unchanged between the control and lead exposure groups （F（1,1） = 0.007, P = 0.935）. A visible decrease in escape latencies was observed in each group （P = 0.028）. However, there was no significant difference between the two groups （F（1,1） = 1.869, P = 0.193）. The working memory probe test demonstrated no change between the two groups in the time spent in the target quadrant during the working memory probe test （F（1,1） = 1.869, P = 0.193）. However, by day 4, differences were observed in the working memory test （P 〈 0.01）. （2） Multivariate repetitive measure and ANOVA in place navigation presented no significant difference between the two groups （F（1,1） = 0.579, P = 0.459）. （3） Spatial probe test demonstrated that the time to reach the platform was significantly different between the two groups （F（1,1） = 4.587, P = 0.048）, and one-way ANOVA showed no significant difference in swimming speed between the two groups （F（1,1） = 1.528, P = 0.237）. （4） In the visual cue test, all rats reached the platform within 15 seconds, with no significant difference （F（1,1） = 0.579, P = 0.459）. （5） During experimentation, all rats increased in body mass, but there was no difference between the two groups （F（1,1） = 0.05, P = 0.943）. At day 28 of 0.05% lead exposure, the blood lead level was 29.72 μg/L in the lead exposure group and 5.86 μg/L in the control group （P 〈 0.01）.
CONCLUSION： The present results revealed low-level lead exposure significantly impaired spatial reference memory and spatial working memory, but had no effect on spatial learning.     

3,4-Methylenedioxymethamphetamine in adult rats produces deficits in path integration and spatial reference memory.

BACKGROUND: +/-3,4-Methylenedioxymethamphetamine (MDMA) is a recreational drug that causes cognitive deficits in humans. A rat model for learning and memory deficits has not been established, although some cognitive deficits have been reported. METHODS: Male Sprague-Dawley rats were treated with MDMA (15 mg/kg x 4 doses) or saline (SAL) (n = 20/treatment group) and tested in different learning paradigms: 1) path integration in the Cincinnati water maze (CWM), 2) spatial learning in the Morris water maze (MWM), and 3) novel object recognition (NOR). One week after drug administration, testing began in the CWM, then four phases of MWM, and finally NOR. Following behavioral testing, monoamine levels were assessed. RESULTS: +/-3,4-Methylenedioxymethamphetamine-treated rats committed more CWM errors than did SAL-treated rats. +/-3,4-Methylenedioxymethamphetamine-treated animals were further from the former platform position during each 30-second MWM probe trial but showed no differences during learning trials with the platform present. There were no group differences in NOR. +/-3,4-Methylenedioxymethamphetamine depleted serotonin in all brain regions and dopamine in the striatum. CONCLUSIONS: +/-3,4-Methylenedioxymethamphetamine produced MWM reference memory deficits even after complex learning in the CWM, where deficits in path integration learning occurred. Assessment of path integration may provide a sensitive index of MDMA-induced learning deficits.     

Distinct set of kinases induced after retrieval of spatial memory discriminate memory modulation processes in the mouse hippocampus

Protein phosphorylation and dephosphorylation events play a key role in memory formation and various protein kinases and phosphatases have been firmly associated with memory performance. Here, we determined expression changes of protein kinases and phosphatases following retrieval of spatial memory in CD1 mice in a Morris Water Maze task, using antibody microarrays and confirmatory Western blot. Comparing changes following single and consecutive retrieval, we identified stably and differentially expressed kinases, some of which have never been implicated before in memory functions. On the basis of these findings we define a small signaling network associated with spatial memory retrieval. Moreover, we describe differential regulation and correlation of expression levels with behavioral performance of polo‐like kinase 1. Together with its recently observed genetic association to autism‐spectrum disorders our data suggest a role of this kinase in balancing preservation and flexibility of learned behavior. © 2013 Wiley Periodicals, Inc.     

亚甲二氧基甲基苯丙胺（迷魂药）对雄性大鼠空间记忆功能的非急性影响：Morris水迷宫试验

研究已证实,亚甲二氧基甲基苯丙胺（迷魂药）对成年和新生大鼠的学习记忆功能均有损害作用,且许多研究聚焦于MDMA的急性效应。实验为研究不同剂量MDMA对成年雄性大鼠空间记忆功能（Morris水迷宫试验）、体温、死亡率的影响,分别给予大鼠腹腔注射MDMA 0,5,10,20mg/kg,2次/d,共7d。结果发现,MDMA剂量依赖性损害大鼠空间记忆功能,以最高剂量（20mg/kg）作用最为明显。另外,MDMA还使大鼠出现体温过高和死亡增加。     

Effects of intrahippocampal injection of ghrelin on spatial memory in PTZ-induced seizures in male rats

Ghrelin (gh) is a peptide hormone that may affect learning and memory. There is some evidence that ghrelin can have antiepileptic effects. So we decided to investigate the possible effects of ghrelin on spatial memory following PTZ-induced seizures in male rats. Ninety male rats were divided into 9 groups including control, saline, ghrelin (0.3, 1.5 or 3 nmol) and pentylenetetrazol (PTZ, 50 mg/kg, i.p.) plus saline or ghrelin (0.3, 1.5 or 3 nmol). All groups were trained in Morris water maze (MWM) for two consecutive days. Our results showed that ghrelin significantly improves spatial memory at the doses of 1.5 or 3 nmol (P < 0.05) in normal rats. We also demonstrated the significant impairment of spatial memory in PTZ group (P < 0.05). Intrahippocampal injection of ghrelin at the dose of 3 nmol significantly improved spatial memory in PTZ + gh group compared to PTZ group (P < 0.05). These findings suggest that ghrelin as a neuropeptide can improve spatial memory in PTZ-treated rats.     

Neonatal hippocampal damage in rats: Long-term spatial memory deficits and associations with magnitude of hippocampal damage

This study investigated the effects of neonatal hippocampal ablation on the development of spatial learning and memory abilities in rats. Newborn rats sustained bilateral electrolytic lesions of the hippocampus or were sham-operated on postnatal day 1 (PN1). At PN20–25, PN50–55, or PN90–95, separate groups of rats were tested in a Morris water maze on a visible “cue” condition (visible platform in a fixed location of the maze), a spatial “place” condition (submerged platform in a fixed location), or a no-contingency “random” condition (submerged platform in a random location). Rats were tested for 6 consecutive days, with 12 acquisition trials and 1 retention (probe) trial per day. During acquisition trials, the rat's latency to escape the maze was recorded. During retention trials (last trial for each day, no escape platform available), the total time the rat spent in the probe quadrant was recorded. Data from rats with hippocampal lesions tested as infants (PN20–25) or as adults (PN50–55 and PN90–95) converged across measures to reveal that 1) spatial (place) memory deficits were evident throughout developmental testing, suggesting that the deficits in spatial memory were long-lasting, if not permanent, and 2) behavioral performance measures under the spatial (place) condition were significantly correlated with total volume of hippocampal tissue damage, and with volume of damage to the right and anterior hippocampal regions. These results support the hypothesis that hippocampal integrity is important for the normal development of spatial learning and memory functions, and show that other brain structures do not assume hippocampal-spatial memory functions when the hippocampus is damaged during the neonatal period (even when testing is not begun until adulthood). Thus, neonatal hippocampal damage in rats may serve as a rodent model for assessing treatment strategies (e.g., pharmacological) relevant to human perinatal brain injury and developmental disabilities within the learning and memory realm. Hippocampus 7:403–415, 1997. © 1997 Wiley-Liss, Inc.     

Electrical induction of spikes in the hippocampus impairs recognition capacity and spatial memory in rats

In clinical studies, interictal EEG spikes (IS) have been associated with numerous neuropsychological abnormalities, ranging from transitory cognitive impairment to epileptic encephalopathies. Understanding the pathophysiological mechanisms of IS has been hampered by the lack of validated animal models. To mimic IS, a stimulating microelectrode was implanted in the ventral hippocampal commissure and a recording microelectrode in the CA1 region of the hippocampus of normal male rats. Spike patterns were induced using a series of electrical pulses 10-30 ms in duration with a frequency of 0.5-2Hz and a current of 0.2mA. The commissural stimulation-evoked population discharges in the hippocampus resembled naturally occurring IS in epileptic rats and, in no cases, resulted in behavioral seizures. For behavioral testing, the Morris water maze, radial arm maze, and object recognition tasks were used. Spikes were induced during sleep between the two sets of water maze trials; during the trials in the radial arm maze task; and prior to the sample phase and during the delay periods in the object recognition task. We demonstrated that rats that received spikes took longer to reach the escape platform in the second set of water maze trials; had significantly more reference errors and required more trials to complete the radial arm maze task; and had lower investigation ratios in the object recognition task. The results indicate that induction of spikes in the hippocampus results in impairment of spatial reference and nonspatial object recognition memory.     

Effect of chronic and acute low-frequency repetitive transcranial magnetic stimulation on spatial memory in rats

Repetitive transcranial magnetic stimulation (rTMS) is a novel, non-invasive neurological and psychiatric tool. The low-frequency (1 Hz or less) rTMS is likely to play a particular role in its mechanism of action with different effects in comparison with high-frequency (>1 Hz) rTMS. There is limited information regarding the effect of low-frequency rTMS on spatial memory. In our study, each male Wistar rat was daily given 300 stimuli (1.0 T, 200 micros) at a rate of 0.5 Hz or sham stimulation. We investigated the effects of chronic and acute rTMS on reference/working memory process in Morris water maze test with the hypothesis that the effect would differ by chronic or acute condition. Chronic low-frequency rTMS impaired the retrieval of spatial short- and long-term spatial reference memory but not acquisition process and working memory, whereas acute low-frequency rTMS predominantly induced no deficits in acquisition or short-term spatial reference memory as well as working memory except for long-term reference memory. In summary, chronic 0.5 Hz rTMS disrupts spatial short- and long-term reference memory function, but acute rTMS differently affects reference memory. Chronic low-frequency rTMS may be used to modulate reference memory. Treatment protocols using low-frequency rTMS in neurological and psychiatric disorders need to take into account the potential effect of chronic low-frequency rTMS on memory and other cognitive functions.     

Deprivation of endogenous brain-derived neurotrophic factor results in impairment of spatial learning and memory in adult rats

Brain-derived neurotrophic factor (BDNF) is abundantly expressed in the hippocampus and cerebral cortex and is involved in synaptic plasticity and long-term potentiation (LTP). The present study was under taken to investigate whether endogenous BDNF was required for spatial learning and memory in a rat model. Antibodies to BDNF (anti-BDNF, n=7) or control immunoglobulin G (control, n=6) were delivered into the rat brain continuously for 7 days with an osmotic pump. The rats were then subjected to a battery of behavioral tests. The results show that the average escape latencies in the BDNF antibody treated group were dramatically longer than those of the control (F=13.3, p<0.001). The rats treated with control IgG swam for a significantly longer distance in the P quadrant (where the escape plane had been placed) compared with the other three quadrants (p<0.05). In contrast, anti-BDNF-treated rats swam an equivalent distance in all four quadrants. The average percentage of swimming distance in the P quadrant by anti-BDNF-treated rats was much less than that by control IgG treated rats (p<0.001). These results suggest that endogenous BDNF is required for spatial learning and memory in adult rats.     

Effect of reversible inactivation of the supramammillary nucleus on spatial learning and memory in rats

Memory includes processes such as acquisition, consolidation and retrieval. Reference memory (RM) and working memory (WM) are two kinds of memory that can be assessed in rodents using spatial tasks, especially using the Morris water maze. The Morris water maze is particularly sensitive to hippocampal lesions. The supramammillary nucleus (SuM) has strong links with the hippocampus and septum. The role of the SuM on spatial learning is controversial. In the present study, involvement of SuM in the different steps of spatial RM and WM was investigated in the Morris water maze using reversible inactivation of SuM with lidocaine. Lidocaine (0.5 microl, 4%) was injected into the SuM through a guide cannula implanted above the SuM. The rats were trained on RM and WM versions of the Morris water maze. SuM was inactivated before training or immediately after training or before the probe trial of retrieval tests. Reversible inactivation of the SuM impaired consolidation of RM, and of consolidation and retrieval of WM. Therefore, it seems that activity of SuM neurons plays a role in spatial RM and WM learning and memory in the rat.     

Post-training cocaine exposure facilitates spatial memory consolidation in C57BL/6 mice

In this study, we examined the ability of post-training injections of cocaine to facilitate spatial memory performance using the Morris water maze (MWM). We also investigated the role that hippocampal protein kinase A (PKA) and extracellular signal-regulated kinase 1/2 (ERK) signaling may play in cocaine-mediated spatial memory consolidation processes. Male and female C57BL/6 mice were first trained in a MWM task (eight consecutive trials) then injected with cocaine (0, 1.25, 2.5, 5, or 20 mg/kg), and memory for the platform location was retested after a 24 h delay. Cocaine had a dose-dependent effect on spatial memory performance because only the mice receiving 2.5 mg/kg cocaine displayed a significant reduction in latency to locate the platform. No sex differences in MWM performance were observed; however, females showed higher hippocampal levels of PKA when compared with males. A second experiment demonstrated that 2.5 mg/kg cocaine enhanced MWM performance only when administered within 2, but not 4 h after spatial training. We also found that cocaine (2.5 mg/kg) increased ERK2 phosphorylation within the hippocampus and one of its downstream targets (ribosomal S6 kinase), a mechanism that may be responsible, at least in part, for the enhanced cocaine-mediated spatial memory performance. Overall, these data demonstrate that a low dose of cocaine (2.5 mg/kg) administered within 2 h after training facilitates MWM spatial memory performance in C57BL/6 mice.     

Small lesions of the dorsal or ventral hippocampus subregions are associated with distinct impairments in working memory and reference memory retrieval,and combining them attenuates the acquisition rate of spatial reference memory

The importance of the hippocampus in spatial learning is well established, but the precise relative contributions by the dorsal (septal) and ventral (temporal) subregions remain unresolved. One debate revolves around the extent to which the ventral hippocampus contributes to spatial navigation and learning. Here, separate small subtotal lesions of dorsal hippocampus or ventral hippocampus alone (destroying 18.9 and 28.5% of total hippocampal volume, respectively) spared reference memory acquisition in the water maze. By contrast, combining the two subtotal lesions significantly reduced the rate of acquisition across days. This constitutes evidence for synergistic integration between dorsal and ventral hippocampus in mice. Evidence that ventral hippocampus contributes to spatial/navigation learning also emerged early on during the retention probe test as search preference was reduced in mice with ventral lesions alone or combined lesions. The small ventral lesions also led to anxiolysis in the elevated plus maze and over‐generalization of the conditioned freezing response to a neutral context. Similar effects of comparable magnitudes were seen in mice with combined lesions, suggesting that they were largely due to the small ventral damage. By contrast, small dorsal lesions were uniquely associated with a severe spatial working memory deficit in the water maze. Taken together, both dorsal and ventral poles of the hippocampus contribute to efficient spatial navigation in mice: While the integrity of dorsal hippocampus is necessary for spatial working memory, the acquisition and retrieval of spatial reference memory are modulated by the ventral hippocampus. Although the impairments following ventral damage (alone or in combination with dorsal damage) were less substantial, a wider spectrum of spatial learning, including context conditioning, was implicated. Our results encourage the search for integrative mechanism between dorsal and ventral hippocampus in spatial learning. Candidate neural substrates may include dorsoventral longitudinal connections and reciprocal modulation via overlapping polysynaptic networks beyond hippocampus.     

Effects of immune activation on the retrieval of spatial memory

Objective

It has been shown that there are extensive interactions between the central nervous system and the immune system. The present study focused on the effects of lipopolysaccharide (LPS) on memory retrieval, to explore the interaction between immune activation and memory.

Methods

C57BL/6J mice (8 weeks old) were first trained in the Morris water maze to reach asymptotic performance. Then mice were tested 24 h after the last training session and LPS was administered (1.25 mg/kg, i.p.) 4 h prior to the testing. The retrieval of spatial memory was tested by probe trial, and the time spent in the target quadrant and the number of platform location crosses were recorded. ELISA was performed to detect interleukin-1β (IL-1β) protein level in the hippocampus of mice tested in the water maze.

Results

Although LPS induced overt sickness behavior and a significant increase in the level of IL-1β in the hippocampus of mice, there was no significant difference in the time spent in the target quadrant or in the number of platform location crosses between LPS-treated and control groups in the probe trial testing.

Conclusion

Immune activation induced by LPS does not impair the retrieval of spatial memory.     

铅暴露鼠学习记忆障碍相关机制的研究

目的 研究铅暴露大鼠海马神经细胞精氨酸加压素(AVP)、生长抑素(SS)的阳性表达,及其与学习记忆障碍的关系.方法 将健康两月龄SD大鼠60只,随机分为对照组、染铅组,每组30只,染铅动物饮用0.1%醋酸铅去离子水3个月,制成慢性染铅大鼠模型;对照组饮用去离子水.Y-迷宫试验检测两组大鼠的学习和记忆能力,采用免疫组化方法测定大鼠海马AVP和SS阳性神经元数,观察铅暴露对其阳性表达的影响.结果 染铅组大鼠学习记忆能力较对照组明显减低(P<0.01),海马CA1区AVP 和SS阳性神经元数量均明显减少(均P<0.01),CA3区AVP(P<0.05)和SS(P>0.05)阳性神经元数量亦减少,但不如CA1区明显.结论 铅暴露大鼠学习记忆能力的减低可能与海马神经细胞AVP和SS的阳性表达减少有关.     

The neuroprotection of Rattin against amyloid β peptide in spatial memory and synaptic plasticity of rats

Rattin, a specific derivative of humanin in rats, shares the ability with HN to protect neurons against amyloid β (Aβ) peptide‐induced cellular toxicity. However, it is still unclear whether Rattin can protect against Aβ‐induced deficits in cognition and synaptic plasticity in rats. In the present study, we observed the effects of Rattin and Aβ31–35 on the spatial reference memory and in vivo hippocampal Long‐term potentiation of rats by using Morris water maze test and hippocampal field potential recording. Furthermore, the probable molecular mechanism underlying the neuroprotective roles of Rattin was investigated. We showed that intra‐hippocampal injection of Rattin effectively prevented the Aβ31–35‐induced spatial memory deficits and hippocampal LTP suppression in rats; the Aβ31–35‐induced activation of Caspase‐3 and inhibition of STAT3 in the hippocampus were also prevented by Rattin treatment. These findings indicate that Rattin treatment can protect spatial memory and synaptic plasticity of rats against Aβ31–35‐induced impairments, and the underlying protective mechanism of Rattin may be involved in STAT3 and Caspases‐3 pathways. Therefore, application of Rattin or activation of its signaling pathways in the brain might be beneficial to the prevention of Aβ‐related cognitive deficits. © 2013 Wiley Periodicals, Inc.     

Systemic treatment with GPI 1046 improves spatial memory and reverses cholinergic neuron atrophy in the medial septal nucleus of aged mice

Systemic treatment with GPI 1046, a non-immunosuppressive ligand of the immunophilin FKBP12 (FK-506-binding protein 12 kDa), has previously been shown to promote morphological recovery of the nigrostriatal dopaminergic projection after MPTP lesion in mice, and of lesioned sciatic nerve fibres after nerve crush in rats. In the present study, we investigated whether chronic systemic treatment with GPI 1046 could affect the decline of spatial learning and memory, and the atrophy of medial septal cholinergic neurons, associated with late senescence in C57 black mice. Three-month old (young) and 18-19-month old (aged) male C57BL/6N-Nia mice were first trained in a place learning task in the Morris water maze. Based on their performance relative to young controls, aged animals were then allocated to treatment groups (10 mg/kg GPI 1046, or vehicle). Retention of the spatial platform location was assessed after 3 weeks of dosing. We found that aged animals that had been dosed with GPI 1046 now performed at a significantly better level than their vehicle control group. Aged animals that had shown the greatest degree of impairment during training in the place learning task showed the greatest relative degree of improvement under treatment and were statistically indistinguishable from young, or aged unimpaired control animals. Cell volumes of cholinergic cells in the medial septal nucleus were assessed after an additional 10 months of dosing at 30 months of age, using stereological methods. We found that aged animals displayed a significant 34% decrease in volume of these cells relative to young controls. This atrophy was significantly reversed in aged GPI 1046-treated animals (13% shrinkage). We conclude that chronic systemic treatment with GPI 1046 positively affects memory mechanisms in the aged mouse, possibly by acting on the septohippocampal cholinergic system.     

Interleukin-1beta induces anorexia but not spatial learning and memory deficits in the rat

Sickness behaviors are a set of adaptive responses to infection that include lethargy, anorexia, and, of direct relevance to this work, learning and memory impairments. The proinflammatory cytokine, interleukin-1 beta (IL-1β) has been proposed as the primary peripheral mediator of these sickness behaviors, though few studies have investigated the effects of peripheral IL-1β on learning and memory. We used three different versions of the Morris water task (Morris water task), a spatial learning and memory task, to separately assess the effects of peripheral IL-1β on acquisition, consolidation, and retention of spatial location information. Using a dose that induced anorexia, assessed as a significant reduction in body weight, we observed no performance impairments in the IL-1β-treated rats across the different versions of the task, suggesting that peripheral IL-1β alone is insufficient to induce spatial learning and memory impairments in the rat. The observed dissociation of anorexia and cognitive dysfunction suggests that, either spatial learning and memory are not principal components of the sickness response, or cognitive dysfunction requires different or additional peripheral mediator(s).     

大鼠纹状体边缘区和海马空间学习功能比较的研究

目的　 研究纹状体边缘区和海马在空间学习功能方面有无区别。方法　 将大鼠穹隆海马伞切断及向边缘区注射海人藻酸 ,用Morris水迷宫测试两实验组和相应对照组的空间学习能力的变化。结果　 穹隆海马伞组和边缘区注射海人藻酸组的平均逃避潜伏期与对照组相比均有延长 ,而且延长幅度大致相同。穿环数均有所下降 ,幅度也大致相同。 结论　 纹状体边缘区同海马一样 ,与大鼠的空间学习功能有着密切关系。     

Disconnecting hippocampal projections to the anterior thalamus produces deficits on tests of spatial memory in rats

A disconnection procedure was used to test whether projections from the hippocampus to the anterior thalamic nuclei (AT), via the fimbria-fornix (FX), form functional components of a spatial memory system. The behavioural effects of combined unilateral lesions in the AT and FX were compared when they were either in contralateral hemispheres (AT-FX Contra) or the same hemisphere (AT-FX Ipsi). Other groups received bilateral FX lesions and Sham surgeries. Expt 1 demonstrated that none of these lesions affected performance of an object recognition task, while performance of an object location task, which tests the subjects' preference for an object that has changed location, was impaired in the AT-FX Contra and FX groups. In a T-maze alternation task, however, the FX group was severely impaired while both the AT-FX Ipsi and AT-FX Contra lesion groups showed only a mild impairment. In order to test whether spared crossed projections might support spatial performance in the AT-FX Contra group we then examined the effects of a combined AT-FX Contra lesion coupled with transection of the hippocampal commissure. This combination of lesions produced a severe disruption in spatial memory performance in the water maze, radial arm maze and T-maze, which was significantly greater than that produced by ipsilateral and contralateral AT-FX lesions alone. These results support the notion that disconnection of the AT from their hippocampal inputs produces impairments on a range of spatial memory tasks, but indicate that there are an array of different routes that can subserve this function.