Norman M. White

A Triple Dissociation of Memory Systems: Hippocampus, Amygdala, and Dorsal Striatum

This study investigated the respective roles of the hippocampus, the amygdala, and the dorsal striatum in learning and memory. A standard set of experimental conditions for studying the effects of lesions to the three brain areas using an 8-arm radial maze was used: a win-shift version, a conditioned cue preference (CCP) version, and a win-stay version. Damage to the hippocampal system impaired acquisition of the win-shift task but not the CCP or win-stay tasks. Damage to the lateral amygdala impaired acquisition of the CCP task but not the win-shift or win-stay tasks. Damage to the dorsal striatum impaired acquisition of the win-stay task but not the win-shift or CCP tasks. These results are consistent with the hypothesis that the mammalian brain may be capable of acquiring different kinds of information with different, more-or-less independent neural systems. A neural system that includes the hippocampus may acquire information about the relationships among stimuli and events. A neural system that includes the amygdala may mediate the rapid acquisition of behaviors based on biologically significant events with affective properties. A neural system that includes the dorsal striatum may mediate the formation of reinforced stimulus-response associations.

Dissociation of hippocampus and caudate nucleus memory systems by posttraining intracerebral injection of dopamine agonists

The effect of posttraining intracerebral injections of the indirect dopamine (DA) agonist d-amphetamine, the direct D2 agonist LY 171555, and the direct D1 agonist SKF-38393 on the acquisition of two 8-arm radial maze tasks were examined. On a win-stay task, a light cue signaled the location of food in 4 randomly selected maze arms on each trial, and animals were required to visit each of the lit arms twice within a trial. Posttraining intracaudate injection of d-amphetamine (10.0 and 15.0 micrograms), LY 171555 (2.0 micrograms), and SKF-38393 (5.0 micrograms) all improved win-stay acquisition in relation to saline-injected controls. In contrast, posttraining intrahippocampal injection of DA agonists had no effect on win-stay acquisition. On a win-shift task, rats were allowed to obtain food from 4 randomly selected maze arms, followed by a delay period in which they were removed from the maze. They were returned to the maze for a retention test in which only those arms that had not been visited before the delay contained food. Posttraining intrahippocampal (but not intracaudate) injection of d-amphetamine (5.0 micrograms), LY 171555 (2.0 micrograms), and SKF-38393 (5.0 micrograms) all improved win-shift retention in relation to saline-injected controls. The results demonstrate a double dissociation of hippocampus and caudate nucleus memory functions and show that posttraining injection of both D1 and D2 agonists modulate the memory processes subserved by both hippocampus and caudate nucleus.

Parallel Information Processing in the Dorsal Striatum: Relation to Hippocampal Function

We investigated the effects of localized medial and lateral CPu lesions and fornix/fimbria lesions on responses to a local cue and to behavior based on cognitive–spatial information in the water maze. Rats were trained concurrently on the cue (visible platform) and spatial (submerged platform) components of the task, followed by a test in which responses to the two types of information were dissociated by a measure of competing response tendencies. Bilateral lesions of lateral CPu did not affect acquisition of either cue or spatial responding but produced a preference for the spatial response on the competition test. Bilateral lesions of the medial CPu retarded but did not prevent learning both components and produced a preference for the cue response on the competition test. The latter effect was accompanied by increased thigmotaxis (swimming in the periphery of the pool), primarily during the early acquisition trials, which was attributed to an impaired ability to respond to learned spatial information. Fornix/fimbria lesions prevented spatial but not cue learning and produced a preference for the cue response on the competition test. Asymmetric lesions (unilateral hippocampus and contralateral medial CPu) produced mild retardation of acquisition of both the cue and spatial tasks and a preference for the cue response on the competition test. These findings dissociate the functions of the lateral and medial CPu and suggest that the hippocampus and medial CPu may be parts of a system that promotes responding based on learned cognitive–spatial information, particularly in competitive cue–place response situations.

Dopamine D3 receptor mutant mice exhibit increased behavioral sensitivity to concurrent stimulation of D1 and D2 receptors

The dopamine D3 receptor is expressed primarily in regions of the brain that are thought to influence motivation and motor functions. To specify in vivo D3 receptor function, we generated mutant mice lacking this receptor. Our analysis indicates that in a novel environment, D3 mutant mice are transiently more active than wild-type mice, an effect not associated with anxiety state. Moreover, D3 mutant mice exhibit enhanced behavioral sensitivity to combined injections of D1 and D2 class receptor agonists, cocaine and amphetamine. However, the combined electrophysiological effects of the same D1 and D2 agonists on single neurons within the nucleus accumbens were not altered by the D3 receptor mutation. We conclude that one function of the D3 receptor is to modulate behaviors by inhibiting the cooperative effects of postsynaptic D1 and other D2 class receptors at systems level.

Effects of medial and lateral caudate-putamen lesions on place- and cue-guided behaviors in the water maze: relation to thigmotaxis

Rats with dorsomedial or dorsolateral caudate-putamen lesions and sham-operated controls were trained on the standard hidden platform (place) task in the water maze. Compared to controls, rats with dorsomedial, but not dorsolateral lesions were slower to escape to the hidden platform and spent significantly more time swimming near the wall of the pool (thigmotaxis) on the early trials, but eventually achieved control levels of performance. When the platform was removed from the pool, all groups exhibited a significant bias for swimming in the training quadrant and crossing the former location of the platform. In the second phase of the experiment rats were given visible platform (cue) training in a different room/pool with the platform moved to a new location each day. Rats with dorsomedial, but not dorsolateral lesions required more trials to reach criterion; again, thigmotaxis was observed on the early trials. The third phase, carried out in the original room/pool, included a place-retention trial followed by a place-cue competition test, (i.e. a choice between the learned spatial location of the hidden platform and the visible platform in a new location). The rats with dorsomedial, but not dorsolateral lesions swam to the visible platform more frequently than the controls. In the final phase, the rats in both lesion groups exhibited slightly lower thigmotactic tendencies than controls in a standard dry-land open field, a finding inconsistent with the hypothesis that thigmotaxis in the water maze is due to increased fear or anxiety. Taken together with other behavioral and anatomical findings, the results suggest that the dorsomedial caudate-putamen, by virtue of its connections with limbic and prefrontal cortical regions, may mediate a response selection process that integrates cognitive information with stimulus-response tendencies.

Conditioned place preference from intra-accumbens but not intra-caudate amphetamine injections

Rats received injections of d-amphetamine sulphate (10 micrograms in 0.5 ul) in nucleus accumbens and were placed into one of two (randomly assigned) distinctive environments. The next day the rats were placed into the other environment and received either a saline injection or no treatment. This procedure was repeated six times. When the rats were allowed a free choice between the two environments they showed a significant preference for the one that had been paired with amphetamine. This finding suggests that amphetamine-stimulated release of dopamine in nucleus accumbens can increase the incentive value of neutral stimuli with which it is paired. When the same procedure was carried out with a group of rats that received amphetamine injections in the dorsolateral caudate nucleus, no preference for the side paired with the drug was evident. This suggests that there is functional differentiation between different parts of the dopaminergic terminal system.

Anatomical disassociation of amphetamine's rewarding and aversive effects: An intracranial microinjection study

Amphetamine has rewarding properties in some behavioral paradigms, such as self-administration and conditioned place preference (CPP), but an aversive component is also apparent when the drug is tested with the conditioned taste aversion (CTA) paradigm. The persent study was an attempt to determine the neuroanatomical substrates of the drugs rewarding and aversive effects. Previous evidence suggested that amphetamines stimulation of activity in dopaminergic synapses is critical for both effects. Amphetamine was therefore micro-injected bilaterally (10 μg/0.5 μl per side) into six different dopaminergic sites, each in a different group of animals: the medial prefrontal cortex, nucleus accumbens, anteromedial caudate nucleus, lateroventral caudate nucleus, amygdala, and the region subjacent to the area postrema (AP region). The effects of these injections in both the taste and place conditioning paradigms were examined in separate experiments. Of the six sites, a significant CPP was observed only with accumbens injections and a significant CTA was observed only with AP region injections. It was concluded that the accumbens plays a primary role in mediating the rewarding effects of amphetamine and that the AP region plays a primary role in mediating the CTA. This constitutes an anatomical disassociation of amphetamines rewarding and aversive effects. The differential associative bias of place-reward and taste-aversion learning apparent in the results is discussed.

Mnemonic functions of the basal ganglia.

A synthesis of older and recent work on mnemonic functions of the basal ganglia in rats, monkeys and humans emphasizes a reciprocal relationship of the caudate nucleus and putamen with the cerebral cortex, which mediates the memory of consistent relationships between stimuli and responses (sometimes called habits) that often involve relationships between the individual and its environment (egocentric memory). Evidence at several levels of analysis (including neuroplastic synaptic changes, activity of single neurons, and behavioral changes caused by lesions or neurochemical manipulations) implicate dopamine release from nigro-striatal neurons in the reinforcement, or strengthening, of neural representations in the basal ganglia.

The amphetamine conditioned place preference: differential involvement of dopamine receptor subtypes and two dopaminergic terminal areas

We investigated involvement of dopamine receptor subtypes and two dopaminergic terminal areas in the acquisition and the expression of the amphetamine conditioned place preference (CPP). When injected systemically before conditioning, both D1 and D2 dopamine antagonists blocked acquisition in a dose-dependent manner. When injected systemically before testing, the effects of the same D1 and D2 antagonists differed. The selective D1 antagonist SCH23390 dose-dependently blocked expression of the previously established conditioned behavior within the dose range that also blocked acquisition. In contrast, D2 antagonists failed to block expression of the amphetamine CPP at doses which blocked acquisition. Expression was, however, blocked by higher doses of D2 antagonists, which may have lost their selectivity for the D2 dopamine receptor. The expression of the CPP was also blocked by microinjections of SCH23390 or sulpiride into nucleus accumbens, but not into striatum. In a control experiment, sodium pentobarbital, which significantly reduced spontaneous locomotor activity in a manner similar to the higher doses of the dopamine antagonists, had no effect on the expression of the amphetamine CPP when given before testing. Finally, electrolytic lesions of the dorsal striatum potentiated the amphetamine CPP. These findings indicate that the dopamine released by amphetamine interacts with both D1 and D2 dopamine receptors to establish a CPP, but that the expression of the CPP may involve activation of the D1 dopamine receptor in the nucleus accumbens.

Memory facilitation produced by dopamine agonists: role of receptor subtype and mnemonic requirements.

The role of dopamine (DA) receptor subtypes in the acquisition of two memory tasks in the 8-arm radial maze was examined. The receptors were manipulated with posttraining, subcutaneous injections of an indirect DA receptor agonist (D-amphetamine), a selective D2 receptor agonist (LY171555), and a selective D1 receptor agonist (SKF-38393). On a win-stay task (sensitive to caudate nucleus lesions) a light cue signalled the location of food in 4 randomly selected arms on each trial. Rats were given one trial per day and injected after training on day 5. D-Amphetamine (2.0 mg/kg) and LY171555 (2.0 mg/kg) improved performance relative to controls; however SKF-38393 (1-4 mg/kg) had no effect on the acquisition of win-stay behavior. On a win-shift task (sensitive to fornix/hippocampal lesions) a delay of 18 hr was imposed between the first 4 and second 4 choices; drugs were injected after the first 4 choices. D-Amphetamine (1.0 mg/kg) and LY171555 (2.0 mg/kg) significantly improved retention relative to controls. SKF-38393 (1-4 mg/kg) had no effect on win-shift retention. These results suggest that the memory-improving properties of DA agonists on tasks sensitive to both hippocampal and caudate lesions are mediated by the D2 receptor.