Nancy S. Hong

A role for adult neurogenesis in spatial long-term memory.

Adult hippocampal neurogenesis has been linked to learning but details of the relationship between neuronal production and memory formation remain unknown. Using low dose irradiation to inhibit adult hippocampal neurogenesis we show that new neurons aged 4-28 days old at the time of training are required for long-term memory in a spatial version of the water maze. This effect of irradiation was specific since long-term memory for a visibly cued platform remained intact. Furthermore, irradiation just before or after water maze training had no effect on learning or long-term memory. Relationships between learning and new neuron survival, as well as proliferation, were investigated but found non-significant. These results suggest a new role for adult neurogenesis in the formation and/or consolidation of long-term, hippocampus-dependent, spatial memories.

Multiple memory systems: The power of interactions

Two relatively simple theories of brain function will be used to demonstrate the explanatory power of multiple memory systems in your brain interacting cooperatively or competitively to directly or indirectly influence cognition and behaviour. The view put forth in this mini-review is that interactions between memory systems produce normal and abnormal manifestations of behaviour, and by logical extension, an understanding of these complex interactions holds the key to understanding debilitating brain and psychiatric disorders.

Parallel associative processing in the dorsal striatum: segregation of stimulus-response and cognitive control subregions.

Although evidence suggests that the dorsal striatum contributes to multiple learning and memory functions, there nevertheless remains considerable disagreement on the specific associative roles of different neuroanatomical subregions. We review evidence indicating that the dorsolateral striatum (DLS) is a substrate for stimulus-response habit formation - incremental strengthening of simple S-R bonds - via input from sensorimotor neocortex while the dorsomedial striatum (DMS) contributes to behavioral flexibility - the cognitive control of behavior - via prefrontal and limbic circuits engaged in relational and spatial information processing. The parallel circuits through dorsal striatum interact with incentive/affective motivational processing in the ventral striatum and portions of the prefrontal cortex leading to overt responding under specific testing conditions. Converging evidence obtained through a detailed task analysis and neurobehavioral assessment is beginning to illuminate striatal subregional interactions and relations to the rest of the mammalian brain.

The challenges of understanding mammalian cognition and memory-based behaviours: an interactive learning and memory systems approach

Various research problems are presented to illustrate the utility of using the interactive multiple learning and memory systems view to better understand normal and abnormal manifestations of mammalian behaviour. Evidence for incidental learning and memory processes is presented and various implications of this work are discussed. Empirical and theoretical work directed at understanding the cognitive and non-cognitive processes associated with place learning in the water task and context conditioning during aversive events is also presented.

A dissociation of dorso-lateral striatum and amygdala function on the same stimulus–response habit task

This experiment tested the idea that the amygdala-based learning and memory system covertly acquires a stimulus-reward (stimulus-outcome) association during acquisition of a stimulus-response (S-R) habit task developed for the eight-arm radial maze. Groups of rats were given dorso-lateral striatal or amygdala lesions and then trained on the S-R habit task on the eight-arm radial maze. Rats with neurotoxic damage to the dorso-lateral striatum were severely impaired on the acquisition of the S-R habit task but showed a conditioned-cue preference for the stimulus reinforced during S-R habit training. Rats with neurotoxic damage to the amygdala were able to acquire the S-R habit task but did not show a conditioned-cue preference for the stimulus reinforced during S-R habit training. This pattern of results represents a dissociation of learning and memory functions of the dorsal striatum and amygdala on the same task.

NMDA-receptor blockade by CPP impairs post-training consolidation of a rapidly acquired spatial representation in rat hippocampus

Recent evidence suggests that N‐methyl‐d‐aspartate (NMDA)‐receptor mediated plasticity in hippocampus has a more subtle role in memory‐based behaviours than originally thought. One idea is that NMDA‐based plasticity is essential for the consolidation of post‐training memory but not for the initial encoding or for short‐term memory. To further test this idea we used a three‐phase variant of the hidden goal water maze task. In the first phase, rats were pretrained to an initial location. Next, intense, massed training was done in a 2‐h interval to teach the rats to go to a new location after either an injection of the NMDA receptor antagonist (6)‐3‐(2‐carboxypiperazin‐4‐yl)propyl‐1‐phosphonic acid (CPP) or of vehicle. Finally, under drug‐free conditions 24 h after new location training, a competition test was done between the original and new locations. We find that N‐methyl‐d‐aspartate (NMDA)‐receptor blockade has little or no effect on new location training. In contrast, when tested 24 h later, the strength of the trace for the new location learned during NMDA‐receptor blockade was much weaker compared with the trace for the new location learned after saline injection. Further experiments showed similar effects when NMDA‐receptors were blocked immediately after the new location training, suggesting that this is a memory consolidation effect. Our results therefore reinforce the notion that hippocampal NMDA‐receptors participate in post‐training memory consolidation but are not essential for the processes necessary to learn or retain navigational information in the short term.

Neurotoxic lesions of the medial prefrontal cortex or medial striatum impair multiple-location place learning in the water task: evidence for neural structures with complementary roles in behavioural flexibility

This series of experiments assessed the effects of neurotoxic damage to either the medial prefrontal cortex or the medial striatum on the acquisition of multiple-location place learning in the water task. During training, normal subjects learn to search for a new hidden platform location at the beginning of each training session and to continue to swim to that location until the end of training during that session. By the end of training, normal subjects show one-trail place learning in which they find the new location on the first trial and swim directly to that location on the second swim. Rats with damage to either the medial prefrontal cortex or dorso-medial striatum showed deficits in learning to swim to the new location each day. These deficits were interpreted as impairments in behavioural flexibility. The lesion-induced impairment was not caused by perseverative errors but was manifested in an inability to rapidly acquire a new spatial position in conflict with the previous position. Interestingly, the subjects from both lesion groups were able to show normal place learning and memory after repeated training within a session. The results were interpreted as suggestive of a complementary role of these neural structures in behavioural flexibility.

POST-TRAINING CB1 CANNABINOID RECEPTOR AGONIST ACTIVATION DISRUPTS LONG-TERM CONSOLIDATION OF SPATIAL MEMORIES IN THE HIPPOCAMPUS

Cannabinoids have long been associated with mnemonic deficits. However, existing evidence has generally focused on the effect of cannabinoids when they are delivered prior to task-training, and such findings are confounded by possible drug effects on sensory, motor, and/or motivational systems that support the acquisition and the expression of learning. The present study investigated the effects of the CB1-receptor agonist WIN 55,212-2 (WIN) on memory consolidation in the Morris water maze. In experiment 1, systemic injections of either WIN or DMSO vehicle were given daily following each training day (post-training), and rats were probe-tested 1 week or 4 weeks later. Rats injected with 1 mg/kg and 3 mg/kg of WIN spent significantly less time in the target quadrant compared with controls 4 weeks later, while no difference was observed at 1-week retention. In experiment 2, intrahippocampal injections of WIN were administered to the dorsal hippocampus following each training day and rats were again probe-tested 1 week or 4 weeks later. Rats bilaterally infused with WIN at 2.5 microg and 5 microg (per side) during training spent significantly less time in the target quadrant than vehicle controls on probe trial 4 weeks later, while no difference was seen at 1-week retention. Taken together, our results showed that post-training activation of CB1 receptors in the hippocampus disrupts long-term memory consolidation but has no effect on acquisition and short-term retention. Plausible pharmacological interactions between cannabinoids and other neurotransmitter systems and associated plasticity mechanisms are discussed.

Context-specific interference on reversal learning of a stimulus-response habit

Learning occurs in a particular place and time. In most learning situations, information about the training context is encoded along with the task demands and solution. However, the extent to which context contributes to the acquisition and expression of a particular learned response is unclear. In the present paper we examined two fundamental issues underlying the importance of context information and its role in expression of discrimination learning and reversal learning. Rats were trained on a stimulus-response (S-R) habit task designed for the eight-arm radial maze and after reaching a set criterion different context manipulations were performed. Results from Section 2.2.1 revealed that although rats detected a change in context, the learning was not context specific. Results from Section 2.2.2 showed that S-R reversal learning was enhanced when animals were reversed in a context that was different from the one used during original training. Animals that were reversed in a different context showed a renewal effect to the initial S-R when brought back to the original training context.

Attenuation of context-specific inhibition on reversal learning of a stimulus-response task in rats with neurotoxic hippocampal damage.

Rats with hippocampal or sham lesions were trained on a stimulus-response task developed for the 8-arm radial maze. After reaching a stringent learning criterion, different context manipulations were performed. In Experiment I, the different groups were transferred to an identical radial maze in a different room to determine the context specificity of the discrimination learning. Experiment I revealed that although rats with hippocampal lesions did not show a normal context detection effect, the expression of the discrimination was not context dependent for either the lesion or sham groups. In Experiment II, animals were trained to criterion on the discrimination task and then both groups were divided into sub-groups based on whether they would experience reversal training in the same or different context from original training. Experiment II indicated that animals with hippocampal lesions and shams reversed in a different context were significantly enhanced in reaching the learning criterion compared to either counterparts that were reversed in the same context. Reversal learning in rats with hippocampal lesions was faster than sham animals in the same context suggesting that the context-specific inhibition effect was hippocampal-based. After learning the reversal task, the groups of animals trained and reversed in different contexts were brought back into the original training context to test for competitive effects. Animals with hippocampal lesions that were reversed in the different context, did not show a competition between the most recently acquired discrimination and a context-specific association acquired during original training whereas sham animals in the same condition did. Taken together these results suggest that rats with hippocampal lesions do not acquire normal context-specific inhibition during discrimination learning.