Amnestic effect of intrahippocampal AM251, a CB1-selective blocker, in the inhibitory avoidance, but not in the open field habituation task, in rats

CB1 is the most abundant metabotropic receptor of the brain, being found in areas classically involved in learning and memory and present at higher density at presynaptic terminals. Different sets of evidence support the idea that endogenous ligands (endocannabinoids) to the CB1 receptors act as modulators of neurotransmission. In hippocampus, endocannabinoids seem to act as retrograde messengers mediating down-regulation of GABA release. Previous reports have described a cognitive impairment effect of cannabinoid agonists, or facilitation by antagonists. The scope of the present study is to investigate the effect of intrahippocampal administration of the CB1-selective antagonist, AM251, in two behavioral tasks. One hundred and twelve male Wistar rats with bilateral cannulae implanted in the CA1 region of the dorsal hippocampus were trained in a step-down inhibitory avoidance task (IA, footshock, 0.5 mA) or an open field habituation task (OF). Immediately, after training, animals received an infusion of 0.55, 5.5, and 55.5 ng/side of AM251 (Tocris), or its vehicle (DMSO/saline), via these cannulae. Our results show that AM251 disrupted memory consolidation of the IA task, but not the OF task, an effect that seems to be purely mnemonic since the drug showed no motor performance effects. Only the intermediate dose (5.5 ng/side) of AM251 was effective in IA and the absence of effect with the larger dose may be the consequence of non-specific binding. The fact that OF was not affected raises the possibility that this endogenous system requires some degree of aversiveness to be recruited. We propose that increased levels of endogenous cannabinoids in the hippocampus, following a training session, contribute to facilitate memory consolidation, a process that may have been disrupted with AM251.     

Glucocorticoid administration into the dorsal striatum [corrected] facilitates memory consolidation of inhibitory avoidance training but not of the context or footshock components

It is well established that glucocorticoid administration into a variety of brain regions facilitates memory consolidation of fear-conditioning tasks, including inhibitory avoidance. The present findings indicate that the natural glucocorticoid corticosterone administered into the dorsal striatum (i.e., caudate nucleus) of male Wistar rats produced dose- and time-dependent enhancement of inhibitory avoidance memory consolidation. However, as assessed with a modified inhibitory avoidance procedure that took place on two sequential days to separate context training from footshock training, corticosterone administration into the dorsal striatum did not enhance memory of either the contextual or aversively motivational aspects of the task.     

The effects of pretraining and reminder treatments on retrograde amnesia in rats: comparison of lesions to the fornix or perirhinal and entorhinal cortices

The present experiment examined the effects of pretraining and reminder treatments on the retention of a nonrelational odor-guided digging task following lesions to the hippocampal formation (i.e., fornix) or parahippocampal region (i.e., perirhinal and entorhinal cortices). The results showed that fornix-lesioned rats and control rats had good retention of the task and did not differ from each other; however, perirhinal- and entorhinal-lesioned rats were severely impaired and differed from fornix and control rats. The present experiment found no attenuation of amnesia following pretraining, which may be due to the lesion technique employed and the size of the resulting lesions. However, the experiment found a significant difference in performance following a reminder treatment, even in the severely impaired perirhinal- and entorhinal-lesioned group.     

Reversible disconnection of the hippocampal-prelimbic cortical circuit impairs spatial learning but not passive avoidance learning in rats

Wistar rats, treated with the GABA(A) receptor agonist muscimol, were used to investigate the role of the hippocampal-prelimbic cortical (Hip-PLC) circuit in spatial learning in the Morris water maze task, and in passive avoidance learning in the step-through task. In the water maze task, animals were trained for three consecutive days and tested 24 h after the end of training. In the step-through task, the animals were trained once and tested 24h after training. On the training days, daily infusion of muscimol (0.5 microg/0.25 microl) was given (1) bilaterally to the ventral hippocampus (vHip), (2) bilaterally to the prelimbic cortex (PLC), (3) to the unilateral vHip and the ipsilateral PLC, or (4) for disconnecting the Hip-PLC circuit, to both the unilateral vHip and the contralateral PLC 30 min before training. The results showed that inhibition of the vHip resulted in disruption of performance in both tasks. Inhibition of the PLC produced impaired water maze performance, but had no effect on the step-through task. Disconnection of the Hip-PLC circuit produced similar effects to PLC inhibition. However, simultaneous inhibition of the unilateral vHip and the ipsilateral PLC had little effect on performance of the water maze task. The results suggested that spatial learning depends on the Hip-PLC circuit, whereas passive avoidance learning is independent of this circuit.     

Pigeons (Columba livia) associate time intervals with symbols in a touch screen task: evidence for ordinality but not summation

The present experiments examined whether pigeons can sum symbols that are associated with various temporal consequences in a touch screen apparatus. Pigeons were trained to discriminate between two visual symbols that were associated with 0, 1, 2, 3, 4, or 5 s either of delay to 4 s of hopper access (delay group) or duration of hopper access (reward group). In Experiment 1, the pigeons in both groups learned to select the symbol associated with the more favorable outcome, and they successfully transferred this discrimination to novel symbol pairs. However, when tested with 2 pairs of symbols associated with different summed durations, they responded on the basis of a simple response rule rather than the sum of the symbol pair. In Experiment 2, the reward group was presented with four symbols at once and was allowed to successively choose one symbol at a time. All pigeons chose the symbols in order from largest to smallest. This indicates that pigeons formed an ordered representation of symbols associated with different time intervals, even though they did not sum the symbols.     

Post-training disruption of Arc protein expression in the anterior cingulate cortex impairs long-term memory for inhibitory avoidance training

The activity-regulated-cytoskeletal-associated protein (Arc) has a well established role in memory consolidation and synaptic plasticity in the hippocampus and amygdala. However the role of Arc within the anterior cingulate cortex (ACC), an area of the brain involved in processing memory for pain, has yet to be examined. Here we sought to determine if Arc protein within neurons of the rat ACC is necessary for the consolidation of a single-trial, contextual inhibitory avoidance (IA) task. Immunohistochemistry and western blotting revealed an increase in Arc protein within the ACC following IA training in a shock-specific manner, suggesting that ACC Arc expression may play a critical role in the consolidation of the aversive task. To directly test this hypothesis, male Sprague-Dawley rats were trained on the IA task and given post-training intra-ACC infusions of Arc antisense oligodeoxynucleotides (ODNs), designed to suppress Arc translation, or control scrambled ODNs that do not suppress Arc translation. Memory retention was tested 48h after training. Arc antisense-induced disruption of Arc protein expression in the ACC impaired long-term memory for the IA task as compared to rats given intra-ACC infusions of the scrambled control ODNS, suggesting that Arc expression in the ACC is important for the consolidation of emotional memory. Results further indicate that knock down of Arc 6h after training impairs IA memory. This is consistent with time course findings indicating elevated Arc expression at 3 and 6h after IA training but not 12 or 48h. Taken together, these findings support the hypothesis that Arc expression in the ACC participates in synaptic plasticity that underlies long-term memory.     

Improving postswitch performance in the dimensional change card-sorting task: the importance of the switch and of pretraining by redescribing the test cards

The dimensional change card-sorting task (DCCS) is used to assess the executive abilities of young children. Typically, 3-year-olds have difficulty in performing this task. However, the exact nature of this difficulty is still being debated. In the standard DCCS, children need to sort, for example, test cards with a blue flower or a red car into two boxes marked with the target cards. The 3-year-olds commonly have pronounced difficulty in switching from one sorting criterion (e.g., color) to another (e.g., shape). Here two experiments with 3-year-olds showed that making the transition between the sorting criteria more distinct improved performance significantly. This was achieved by taking away the target cards for a brief time period, asking a question irrelevant to the task, and pretraining the children by redescribing the test cards.     

Evidence for the automatic processing of prelexical codes in an orthographic but not a phonological task

The automatic activation of phonological and orthographic information in auditory and visual word processing was examined using a task-set procedure. Participants engaged in a phonological task (i.e., determining whether the letter “a” in a word sounded like /e/ or /æ/) or an orthographic task (i.e., determining whether the sound /s/ in a word was spelled with an “s” or a “c”). Participants were cued regarding which task to perform simultaneously with, or 750 ms before, a clear or degraded target. The stimulus clarity effect (i.e., clear words responded to faster than degraded words) was absorbed into the time that it took participants to identify the task on the basis of the cue in a simultaneous cue–target as compared to a delayed cue–target condition, but only for the orthographic task. These data are consistent with the claim that prelexical processing occurs in a capacity-free manner upon stimulus presentation when participants are trying to extract orthographic codes from words presented in the visual and auditory modalities. Such affirmative data were not obtained when participants attempted to extract phonological codes from words, since here the effects of stimulus clarity and cue delay were additive.     

Effect of arousal increase in predictable and random task switching: evidence for the involvement of the anterior attentional network in random but not in predictable task switching

Switch cost does not disappear as more preparation time for the next task is allowed. Tornay and Milán showed that the residual cost is smaller when tasks switch randomly than when they alternate in predictable sequences. They proposed that the difference was due to control mechanisms (anterior attentional network) being activated in the random condition because of its overall difficulty. Besides, it has been shown that increasing arousal levels inhibits the anterior attentional network. Therefore, Tornay and Milán's account predicts that high arousal should result in switch cost for the random condition increasing to the levels of predictable switching. In this work, this prediction was tested by assessing the interaction between increased arousal and switch cost with both predictable and random-task switching. The results may help to solve the ongoing controversy about the causes of switch cost.     

Latent learning in a swimming pool place task by rats: Evidence for the use of associative and not cognitive mapping processes

Using a latent learning paradigm, the experiments examine two hypotheses of how rats solve place navigation tasks. According to associative theory, experience with all relevant cues is required for accurate navigation. According to cognitive mapping theory, animals can generate novel trajectories from knowledge of spatial relations of objects in the environment. Rats that had been placed on a platform, which was submerged in a pool of opaque water and was moved each day, were tested later for their ability to find the platform using only surrounding room cues. One 30-sec exposure to a platform location was effective in improving performance. Improvement was greatest when tests were given within minutes of placement, but facilitation was obtained for as long as 4 hr. Improved performance was obtained as soon as rats acquired the procedural aspects of the task but did not increase with subsequent practice. Improved performance was also obtained when pre-trained rats were tested in a novel environment. Despite the advantage conferred by exposure to the target platform, test swims were not accurate, placement-induced improvement was not as great as that following a single swimming trial, and placement combined with a swim resulted in best performance. The results suggest that rats use associative learning processes rather than cognitive mapping to solve place problems in a swimming pool.     

Posttraining infusion of cholinergic drugs into the ventral subiculum modulated memory in an inhibitory avoidance task: Interaction with the bed nucleus of the stria terminalis

The ventral subiculum (vSUB), a hippocampal efferent target implicated in learning and stress coping, receives cholinergic input and sends glutamatergic output to the bed nucleus of the stria terminalis (BNST). This study examined the roles of vSUB muscarinic activation and its interaction with BNST N-methyl-d-aspartate and noradrenergic receptors in formation of aversive memory. Male Wistar rats with cannulae implanted into the vSUB or BNST were trained on a step-through inhibitory avoidance task. Shortly after training, they received cholinergic drugs infused into the vSUB and/or glutamatergic or noradrenergic drugs infused into the BNST. Results of the 1-day retention tests showed that intra-vSUB infusion of oxotremorine (0.01 μg) or scopolamine (0.3 or 3.0 μg) enhanced or impaired retention, respectively. Both effects were dose- and time-dependent, and 0.001 μg oxotremorine attenuated the amnesia induced by 3.0 μg scopolamine. The oxotremorine-induced memory enhancement was blocked by intra-BNST infusion of dl-2-amino-5-phosphonovaleric acid or propranolol at a dose not affecting retention; the amnesia induced by scopolamine was blunted by intra-BNST infusion of glutamate or norepinephrine at a dose with a negligible effect on retention. These data suggest that in an inhibitory avoidance task muscarinic activation of the vSUB modulated memory formation by interacting with the BNST glutamatergic and noradrenergic functions.     

Effect of a novel experience prior to training or testing on retention of an inhibitory avoidance response in mice: involvement of an opioid system

These experiments examined the effects of a novel experience prior to training or retention testing on 24-h retention of an inhibitory avoidance response in mice. The experiments were based on previous evidence that novel training experiences release hypothalamic beta-endorphin. When given 1 h prior to training, the novel experience (clinging to the wire-mesh ceiling and exploring a small box) attenuated the memory-enhancing effects of post-training administration of naloxone as well as the enhancing effects of beta-endorphin administered prior to the retention test. The novel experience given prior to training did not block the enhancing effects of post-training administration of epinephrine. beta-Endorphin and the novel experience both enhanced retention performance when administered 1 h (as well as 3 but not 6 h) prior to the retention test. The enhancement found with both treatments was blocked by simultaneous administration of naloxone or by administration of propranolol a few minutes prior to the retention test. The findings of these experiments are consistent with the view that the effects of the novel experience are due to a release of endogenous beta-endorphin and provide additional evidence that the effects, on retention, of naloxone given post-training and beta-endorphin given prior to a retention test, are based on training-induced release of beta-endorphin.     

Facilitation of acquisition and retention in preweanling but not postweanling rats by the presence of familiar home-nest material

A series of four experiments examined the effect of the presence of stimuli from the home nest on the acquisition and retention of aversively motivated behaviors in preweanling and adult rats. In Experiment 1, training in the presence of home-nest shavings facilitated acquisition of a T-maze discrimination to escape footshock for 16-day-old rats but not for adults. Experiment 2 demonstrated that the extent to which preweanlings were familiar with the home shavings determines the degree to which these stimuli facilitate spatial discrimination learning. When clean shavings were made more familiar than soiled home-nest stimuli (by changing the shavings every day) clean shavings enhanced discrimination performance, whereas no enhancement of learning by home shavings was observed. Experiment 3 extended the generality of the enhancement effect to a conditioned location aversion and examined the extent to which this facilitative effect was due to the tendency for home-nest shavings to elicit approach responses. Expression of the conditioned aversion was enhanced in subjects conditioned in the presence of home shavings, regardless of whether the home shavings were presented with the CS+, the CS-, or both. Experiment 4 determined that the enhanced expression of learning in the context of home-nest stimuli observed for preweanlings did not occur among subjects trained shortly after weaning. Collectively, these data suggest that whereas the enhancement of learning and retention by familiar home-nest stimuli enjoys generality across a number of conditioning situations, the effect may be limited to a relatively brief period during ontogeny.     

Differential effects of post-training muscimol and AP5 infusions into different regions of the cingulate cortex on retention for inhibitory avoidance in rats.

Adult male Wistar rats were bilaterally implanted with indwelling cannulae in four different coordinates of the cingulate cortex: (1) the anterior cingulate (AC), (2) the rostral region of the posterior cingulate (RC), (3) the upper portion of the caudal region of the posterior cingulate (UC), and (4) the lower portion of the caudal region of the posterior cingulate (LC). After recovery, animals were trained in a step-down inhibitory avoidance task (3.0-s, 0.4-mA foot shock). Either immediately, or 90 or 180 min after training, animals received a 0.5-microl infusion of vehicle (phosphate buffer, pH 7.4), of muscimol (0.5 microg), or of AP5 (5.0 microg). Retention testing was carried out 24 h after training. Muscimol was amnestic when given into any of the three coordinates of the posterior cingulate cortex 90 min after training, and when given into LC immediately post-training. In addition, AP5 was amnestic when given into UC 90 min post-training, but not when given into any other region and/or at any other time. None of the treatments had any effect when given into AC. The results suggest that memory processing of the inhibitory avoidance task is regulated by the posterior but not by the anterior cingulate cortex, through muscimol-sensitive synapses, relatively late after training. AP5-sensitive synapses appear to play a very limited role in these processes, restricted to UC.     

On the failure of transfer of control from separately conducted Pavlovian conditioning to free-operant avoidance conditioning in rats

In Experiment 1, presentation of a tone previously correlated with foot shock produced an increase in the rate of rats' foot-shock avoidance responding, while presentation of a tone previously correlated with tail shock had no reliable effect on the rate of foot-shock avoidance responding. In Experiment 2, a tone correlated with tail shock elicited heart-rate conditioned responses, but had no reliable effect on the rate of subsequent foot-shock avoidance responding. In Experiment 3, presentation of a tone previously correlated with foot shock, and a tone previously correlated with tail shock in separate groups produced increases in the rate of tail-shock avoidance responding. In Experiment 4, a tone correlated with tail shock in one setting accelerated tail-shock avoidance responding in a second setting. Interaction between US and negative reinforcer modifiability by skeletal responding may contribute to the pattern of results obtained.     

Transection of direct anterior thalamic afferents from the hippocampus: effects on activity and active avoidance in rats

This investigation demonstrates the importance of the direct hippocampo-anterior thalamic component of the postcommissural fornix in the control of general locomotion and active avoidance. Transection of anterior thalamic afferents from the hippocampal formation (subicular cortex), at the point where they exit from the fornix posterior to the septum, is sufficient to enhance bidirectional active avoidance acquisition and increase general activity. This transection may also interrupt fibers to or from other thalamic nuclei and the anterior septum. However, destruction of connections of the anterior septum with the hippocampus, habenula, and thalamus by transection in the coronal plane anterior to the descending fornix columns, without damage to the subiculothalamic fibers, increases general activity levels without damage to the subiculothalamic fibers, increases general activity levels without affecting active avoidance behavior. The activity increase in this case resembles that seen after septal lesions rather than that seen after hippocampal lesions. Thus, destruction of a single fornix component contributing afferents to the anterior thalamic nuclei reproduces at least part of the hippocampal syndrome. This suggests that these fibers contribute significantly to the control of these behaviors and may mediate active avoidance changes resulting from hippocampal and fornix damage.     

A diffusion model account of response time and accuracy in a brightness discrimination task: fitting real data and failing to fit fake but plausible data

A brightness discrimination experiment was performed to examine how subjects decide whether a patch of pixels is “bright” or “dark,” and stimulus duration, brightness, and speed versus accuracy instructions were manipulated. The diffusion model (Ratcliff, 1978) was fit to the data, and it accounted for all the dependent variables: mean correct and error response times, the shapes of response time distributions for correct and error responses, and accuracy values. Speed-accuracy manipulations affected only boundary separation (response criteria settings) in the model. Drift rate (the rate of accumulation of evidence) in the diffusion model, which represents stimulus quality, increased as a function of stimulus duration and stimulus brightness but asymptoted as stimulus duration increased from 100 to 150 msec. To address the argument that the diffusion model can fit any pattern of data, simulated patterns of plausible data are presented that the model cannot fit.