A triple dissociation of memory systems: Hippocampus, amygdala, and dorsal striatum.

A triple dissociation of memory systems: hippocampus, amygdala, and dorsal striatum.

Cognitive task performance after lidocaine-induced inactivation of different sites within the basolateral amygdala and dorsal striatum.

Spontaneously hypertensive, Wistar Kyoto and Sprague–Dawley rats differ in performance on a win-stay task and a conditioned cue preference task in the water radial arm maze

Middle-aged (12 month old) male rats show selective latent learning deficit

The influence of persistent cocaine self-administration on learning and memory has never been evaluated. Our objective was to isolate the effects of contingently administered cocaine from those of its general pharmacological or non-contingent actions on multiple memory system functioning. A triad design was used to yoke passive cocaine and saline administration to the behavior of rats who were actively self-administering cocaine. Following 4 weeks of cocaine or saline exposure in 2-h sessions, six triads were tested in the amygdala-dependent conditioned cue preference task and dorsal striatum-dependent win-stay task in an eight-arm radial maze environment. Drug or saline sessions continued throughout task testing. Throughout task testing, rats actively and passively exposed to cocaine sustained a total daily intake of approximately 15 mg/kg. During the conditioned cue preference task, saline-exposed rats showed robust conditioned preference for a Froot Loops-paired cue. Rats actively and passively exposed to cocaine showed no evidence of conditioning despite normal exploration in the maze during preference testing. For the win-stay task, no significant differences were found among the three groups in terms of the number of sessions to acquire the task or task accuracy at criterion. Rats actively or passively exposed to cocaine, however, completed sessions more quickly than saline-exposed rats at criterion. These findings suggest that contingent and non-contingent cocaine administration similarly disrupt stimulus-reward functions of the amygdala, but do not disrupt stimulus-response functions of the dorsal striatum. This dissociation may relate to differences in the rate by which dopamine is cleared from these tissues following cocaine exposure or possibly to cocaine-induced devaluation of natural rewards, which influences stimulus-reward learning, but not stimulus-response learning.

Dissociation of memory systems: The story unfolds.

Adult cocaine addicts, abstinent at the time of testing, show a variety of neurocognitive impairments. Less clear is whether there are differences in the degree of impairment if cocaine use is initiated during adolescence rather than adulthood. Using a preclinical model, we evaluated if stimulus-reward learning was impacted differently in rats exposed to cocaine during adolescence (beginning on postnatal day 37) vs adulthood (beginning on postnatal days 74-79) and then tested after a drug-free period. A yoked-triad design of intravenous cocaine self-administration in adult (n = 8 triads) and adolescent (n = 8 triads) rats was used. Sets of three animals either contingently self-administered cocaine or received cocaine or saline in a noncontingent manner. Rats self-administering 1-mg/kg doses of cocaine responded under a fixed-ratio 5, timeout 20-s schedule of reinforcement. After 18 2-h drug or saline sessions, all rats (now adults) began the drug-free period in their home environments. Testing in a stimulus-reward learning task (conditioned cue preference) began 19 days later. Self-administration behavior was similar in adolescent and adult rats. Lever responses were not significantly different, and both age groups averaged approximately 20 infusions per session. Rats contingently self-administering cocaine or passively exposed to cocaine during adulthood showed stimulus-reward learning deficits in the conditioned cue preference task. Rats exposed to contingent or noncontingent cocaine during adolescence had normal learning, showing strong preferences for a Froot Loops-paired cue. These findings suggest that adolescents are insensitive to cocaine-induced impairment of learning related to amygdala memory system functioning.

Reinforcer devaluation abolishes conditioned cue preference: evidence for stimulus-stimulus associations.

A number of aversive and appetitive unconditioned stimuli (such as shock and food) are known to produce memory enhancement when they occur during the post-training period. Post-training exposure to conditioned aversive stimuli has also been shown to enhance memory consolidation processes. The present study shows for the first time that post-training exposure to conditioned stimuli previously paired with consumption of a sucrose solution also enhances memory consolidation. Male Long Evans rats were trained on a one-session conditioned cue preference (CCP) task on a radial arm maze. Immediately or 2 hours after training, rats consumed a sucrose solution or were exposed to cues previously paired with consumption of sucrose or cues previously paired with water. Twenty-four hours later, the rats were tested for a CCP. Immediate, but not delayed, post-training consumption of sucrose enhanced memory for the CCP. Immediate, but not delayed, post-training exposure to cues previously paired with sucrose, but not with water, also enhanced CCP memory. The possibility that rewarding and aversive conditioned stimuli affect memory by a common physiological process is discussed.

Effect of post-training administration of cocaine, diazepam and their combination on a win-stay task

Pure spatial learning occurs when rats acquire information about an environment while exploring it in the absence of reinforcers. We previously reported that voluntary, unreinforced exploration of a radial maze retards subsequent reinforced conditioned cue preference (CCP) learning in the same maze. In the present experiment, we examined the effects of involuntary, unreinforced pre-exposure to a radial maze. During pre-exposure, rats were moved by an experimenter between the ends of two arms of a radial maze five times in 30 min. This form of pre-exposure retarded CCP learning, whereas rats that were not pre-exposed and rats that were pre-exposed to a maze in a different room displayed normal CCP learning. These findings suggest that some information specific to the maze environment was acquired during involuntary unreinforced pre-exposure to it. In experiment 2, the retardation of reinforced CCP learning by involuntary unreinforced pre-exposure was eliminated by fimbria-fornix lesions made before pre-exposure but was unaffected by fimbria-fornix lesions made after pre-exposure but before training. Large neurotoxic lesions of the dorsal hippocampus made before pre-exposure had no effect on the retardation of CCP learning, but the rats with these lesions were impaired on a standard test of reinforced spatial learning in a water maze. The lesion effects in experiment 2 are similar to those previously reported for voluntary exploration and suggest that pure spatial learning may occur during both voluntary exploration of and involuntary exposure to an environment in the absence of reinforcers. Pure spatial learning can apparently occur with exposure to two different locations within an environment, but the rats do not have to move between the locations voluntarily. An intact fimbria-fornix is required for acquisition but not expression of this form of learning. The hippocampus is not involved in this form of learning.

Lesions of basolateral and central amygdala differentiate conditioned cue preference learning with and without unreinforced preexposure.

Substantial advances have been made in the last decade on our understanding of the basic physiology underlying neurogenesis in the postnatal mammalian brain. The bulk of the work in this area has been based on analysis of the adult brain. Relatively less is known about the capacity for neurogenesis in specific structures within the neonatal brain. Here we report that the production of medium spiny striatal projection neurons extends into the early neonatal period under normal physiological conditions in the rat brain. Birth-dating of newborn cells with bromodeoxyuridine at postnatal days 0, 2 and 5 showed a peak production close to birth, which sharply declined at the later time-points. Additionally, there was a low-level but stable contribution of neurons with interneuron identity over the same time-period. Importantly, retroviral labelling of new striatal projection neurons with green fluorescent protein showed long-term survival and terminal differentiation with characteristic morphology, including highly elaborated spiny dendrites, and appropriate axonal targeting of the globus pallidus and midbrain. This latent period of striatal neurogenesis in the early neonatal brain represents an interesting target for regenerative approaches aimed at restoring striatal circuitry in perinatal pathologies, such as hypoxic and ischaemic damage associated with cerebral palsy.

Neural circuits mediating latent learning and conditioning for salt in the rat

Two experiments were conducted to evaluate the effects of a high-fat diet (HFD) on two tasks that were either dependent on the dorsal hippocampus (DH) or independent of the DH. A total of 80 adult male Sprague Dawley rats were administered either a lard-based HFD (60% of calories from fat) or a control diet (10% of calories from fat) for 8 weeks, and then were trained and tested on either the latent cue preference (LCP) task or the conditioned cue preference (CCP) task in a 3-compartment box apparatus (2 end-compartments and 1 middle-compartment). The end compartments of the box apparatus contained either a single environmental cue (DH-independent) or multiple environmental cues (DH-dependent). During training trials for the LCP and CCP tasks, on alternating days, rats were given access to water in 1 of the 2 end compartments and no water in the opposite end compartment. Rats were water-replete during LCP training and were water-deprived during CCP training. During testing for both tasks, all rats were water-deprived and given free access to all compartments while the amounts of time spent in each compartment were recorded. Results showed that rats given the HFD demonstrated no compartment preferences during both LCP and CCP testing when the compartments contained multiple cues, while rats fed the control diet demonstrated normal compartment preference behavior. However, when the compartments contained a single environmental cue, rats given either the HFD and control diet demonstrated normal LCP and CCP learning. These results demonstrate that consumption of a HFD disrupted both LCP and CCP learning in a multiple-cue (DH-dependent) environment, but did not impair either type of learning in a single-cue (DH-independent) environment. This may be due to selective impairment of the DH caused by increased oxidative stress, inflammation, and/or disrupted neurotransmission produced by consumption of the HFD.