Altered expression and chromatin structure of the hippocampal IGF1r gene is associated with impaired hippocampal function in the adult IUGR male rat.

Exposure to intrauterine growth restriction (IUGR) is an important risk factor for impaired learning and memory, particularly in males. Although the basis of IUGR-associated learning and memory dysfunction is unknown, potential molecular participants may be insulin-like growth factor 1 (Igf1) and its receptor, IGF1r. We hypothesized that transcript levels and protein abundance of Igf1 and IGF1r in the hippocampus, a brain region critical for learning and memory, would be lower in IUGR male rats than in age-matched male controls at birth (postnatal day 0, P0), at weaning (P21) and adulthood (P120). We also hypothesized that changes in messenger Ribonucleic acid (mRNA) transcript levels and protein abundance would be associated with specific histone marks in IUGR male rats. Lastly, we hypothesized that IUGR male rats would perform poorer on tests of hippocampal function at P120. IUGR was induced by bilateral ligation of the uterine arteries in pregnant dams at embryonic day 19 (term is 21 days). Hippocampal Igf1 mRNA transcript levels and protein abundance were unchanged in IUGR male rats at P0, P21 or P120. At P0 and P120, IGF1r expression was increased in IUGR male rats. At P21, IGF1r expression was decreased in IUGR male rats. Increased IGF1r expression was associated with more histone 3 lysine 4 dimethylation (H3K4Me2) in the promoter region. In addition, IUGR male rats performed poorer on intermediate-term spatial working memory testing at P120. We speculate that altered IGF1r expression in the hippocampus of IUGR male rats may play a role in learning and memory dysfunction later in life.

Arc mRNA induction in striatal efferent neurons associated with response learning.

The dorsal striatum is involved in motor-response learning, but the extent to which distinct populations of striatal efferent neurons are differentially involved in such learning is unknown. Activity-regulated, cytoskeleton-associated (Arc) protein is an effector immediate-early gene implicated in synaptic plasticity. We examined arc mRNA expression in striatopallidal vs. striatonigral efferent neurons in dorsomedial and dorsolateral striatum of rats engaged in reversal learning on a T-maze motor-response task. Male Sprague-Dawley rats learned to turn right or left for 3 days. Half of the rats then underwent reversal training. The remaining rats were yoked to rats undergoing reversal training, such that they ran the same number of trials but ran them as continued-acquisition trials. Brains were removed and processed using double-label fluorescent in situ hybridization for arc and preproenkephalin (PPE) mRNA. In the reversal, but not the continued-acquisition, group there was a significant relation between the overall arc mRNA signal in dorsomedial striatum and the number of trials run, with rats reaching criterion in fewer trials having higher levels of arc mRNA expression. A similar relation was seen between the numbers of PPE(+) and PPE(-) neurons in dorsomedial striatum with cytoplasmic arc mRNA expression. Interestingly, in behaviourally activated animals significantly more PPE(-) neurons had cytoplasmic arc mRNA expression. These data suggest that Arc in both striatonigral and striatopallidal efferent neurons is involved in striatal synaptic plasticity mediating motor-response learning in the T-maze and that there is differential processing of arc mRNA in distinct subpopulations of striatal efferent neurons.

Role of the medial and lateral caudate-putamen in mediating an auditory conditional response association.

Rats with quinolinic acid lesions of the medial or lateral caudate-putamen (CPu) and controls were tested for performance of a previously learned auditory conditional response association task. The task involved the selection of two possible responses when presented with one of two different tones. Results indicated that lesions of either the medial or the lateral CPu produced a sustained deficit in the auditory conditional response association task. Only the lateral CPu lesioned rats exhibited transient motor problems immediately following surgery, but these problems did not interfere with the execution of the appropriate responses. It is suggested that both the medial and the lateral CPu are involved in response selection and response separation within egocentric space.

The role of rat dorsomedial prefrontal cortex in working memory for egocentric responses.

The present experiment studied the effects of quinolinic acid (90 mM) lesions of the medial precentral and anterior cingulate on working memory for egocentric responses. Rats were trained on a delayed match-to-sample task that involved memory for a 90 degrees right or left turn. The results indicated that lesioned rats had significantly decreased scores during the 10 s delay condition compared to presurgery levels. An increase in the delay to 20 s significantly reduced working memory performance in the lesioned rats compared to that of controls. These findings suggest that the rat medial precentral and/or anterior cingulate area play an important role in working memory for egocentric responses.

A neural circuit analysis of visual recognition memory: role of perirhinal, medial, and lateral entorhinal cortex.

Using a continuous recognition memory procedure for visual object information, we sequentially presented rats with eight novel objects and four repeated objects (chosen from the 8). These were selected from 120 different three-dimensional objects of varying sizes, shapes, textures, and degree of brightness. Repeated objects had lags ranging from 0 to 4 (from 0 to 4 different objects between the first and repeated presentation). An object was presented on one side of a long table divided in half by an opaque Plexiglas guillotine door, and the latency between opening the door and the rat moving the object was measured. The first presentation of an object resulted in reinforcement, but repeated presentations did not result in a reinforcement. After completion of acquisition training (significantly longer latencies for repeated presentation compared with the first presentation of an object), rats received lesions of the perirhinal, medial, or lateral entorhinal cortex or served as sham operated controls. On the basis of postsurgery testing and additional tests, the results indicated that rats with perirhinal cortex lesions had a sustained impairment in performing the task. There were no sustained deficits with medial or lateral entorhinal cortex lesions. The data suggest that recognition memory for visual object information is mediated primarily by the perirhinal cortex but not by the medial or lateral entorhinal cortex.

Short-term memory for duration and distance in humans: role of the hippocampus.

Control participants and hypoxic participants with bilateral hippocampal damage were tested for short-term memory (STM) for presentation duration of a single object, STM for a single object, STM for spatial distance information, and time estimation. Delays of 1, 4, 8, 12, or 16 s were used for all the STM and time estimation tests. Results indicated that relative to controls, hypoxic participants were significantly impaired for STM for duration and distance information at the long but not short delays. Similarly, time estimation was accurate only to 8 s for hypoxic participants, but STM for a single object was only mildly affected. Results suggest that the hippocampus may be required for the processing of spatial and temporal STM information.

Long-term changes in basal ganglia function after a neurotoxic regimen of methamphetamine.

The abuse of psychostimulants, such as methamphetamine (METH), can cause long-lasting deficits in the dopamine (DA) innervation of the striatum. Although the consequences of large DA depletions on basal ganglia function have been well characterized, less is known about the alterations associated with smaller depletions, such as those produced by high doses of METH. The purpose of this study was to assess the long-term consequences of METH-induced DA depletion on basal ganglia function. Three weeks after rats were given multiple administrations of METH (5-10 mg/kg, four times at 2-h intervals), dose-related decreases in DA tissue content in striatum and tyrosine hydroxylase mRNA in the substantia nigra pars compacta were observed. In situ hybridization histochemistry revealed a selective decrease in preprotachykinin mRNA in striatum, predominantly at the highest dose of METH, and no change in striatal preprodynorphin, preproenkephalin, or neurotensin/neuromedin N mRNAs. Cytochrome oxidase activity was significantly elevated in the entopeduncular nucleus and substantia nigra pars reticulata of METH-treated rats, but not in the striatum, globus pallidus, or subthalamic nucleus, consistent with a selective decrease in striatonigral, but not striatopallidal, neuron function. Additionally, rats treated with a neurotoxic regimen of METH were impaired on a radial maze sequential learning task when tested 3 weeks following METH administration. These data indicate that exposure to a neurotoxic regimen of METH results in long-term changes in striatonigral, but not striatopallidal neuron function and, consequently, altered basal ganglia function.

Role of long-term synaptic modification in short-term memory.

One way that some types of short-term or working memory may be implemented in the brain is by using autoassociation networks that recirculate information to maintain the firing of a subset of neurons in what is termed an attractor state. We describe how long-term synaptic modification is necessary to set up the appropriate stable attractors, each one of which corresponds to a memory of a particular item. Once the synapses have been modified, any of the short-term memory states may be triggered by an appropriate input which starts the neurons firing in one of the attractors, and then the firing is maintained in that attractor by the already modified synapses, with no further synaptic modification necessary. This analysis leads to the prediction that if this type of implementation is used for working memory, then long-term synaptic modification may be necessary only during an acquisition phase of a task, and once the task has been acquired, the performance of the working memory task should be unimpaired if no further synaptic modification is allowed. We show that a considerable body of research findings on the effects of agents that block synaptic modification on working memory tasks can be understood in this way. Many of the findings are consistent with the hypothesis that blocking synaptic modification in the hippocampus impairs the acquisition, but not the later performance, of hippocampal-dependent working memory tasks.

Spared discrimination and impaired reversal eyeblink conditioning in patients with temporal lobe amnesia.

The effect of medial temporal lobe damage on a 2-tone delay discrimination and reversal paradigm was examined in human classical eyeblink conditioning. Eight medial temporal lobe amnesic patients and their demographically matched controls were compared. Amnesic patients were able to distinguish between 2 tones during the initial discrimination phase of the experiment almost as well as control participants. Amnesic patients were not able to reverse the previously acquired 2-tone discrimination. In contrast, the control participants showed improved discrimination performance after the reversal of the tones. These findings support the hypothesis that the hippocampus and associated temporal lobe regions play a role in eyeblink conditioning that becomes essential in more complex versions of the task, such as the reversal of an acquired 2-tone discrimination.

Dissociating hippocampal subregions: double dissociation between dentate gyrus and CA1.

This study presents a double dissociation between the dentate gyrus (DG) and CA1. Rats with either DG or CA1 lesions were tested on tasks requiring either spatial or spatial temporal order pattern separation. To assess spatial pattern separation, rats were trained to displace an object which covered a baited food-well. The rats were then allowed to choose between two identical objects: one covered the same well as the sample phase object (correct choice), and a second object covered a different unbaited well (incorrect choice). Spatial separations of 15-105 cm were used to separate the correct object from the incorrect object. To assess spatial temporal order pattern separation, rats were allowed to visit each arm of a radial eight-arm maze once in a randomly determined sequence. The rats were then presented with two arms and were required to choose the arm which occurred earliest in the sequence. The choice arms varied according to temporal separation (0, 2, 4, or 6) or the number of arms that occurred between the two choice arms in the sample phase sequence. On each task, once a preoperative criterion was reached, each rat was given either a DG, CA1, or control lesion and then retested. The results demonstrated that DG lesions resulted in a deficit on the spatial task but not the temporal task. In contrast, CA1 lesions resulted in a deficit on the temporal task but not the spatial task. Results suggest that the DG supports spatial pattern separation, whereas CA1 supports temporal pattern separation.

Behavioral analysis of the contribution of the hippocampus and parietal cortex to the processing of information: interactions and dissociations.

The neurobiology of the attribute model of memory suggests that that there are potential interactions between the hippocampus and parietal cortex (PC) during learning, consolidation, and retrieval of spatial but not nonspatial information. In addition, the model suggests that there are double dissociations between the hippocampus and PC with respect to the intrinsic processes of spatial perceptual memory and spatial short-term or working memory. Data are presented that support both suggestions. There is a good possibility that spatial information is initially processed in parallel in the hippocampus and PC, followed by transfer of spatial information from the hippocampus to the PC for subsequent long-term storage.

Testing neural network models of memory with behavioral experiments.

In recent years, a number of computational neural networks have been proposed aimed at describing memory functions associated with different subregions of the hippocampus, namely dentate gyrus, CA3 and CA1. Recent evidence suggests that indeed specific subregions of the hippocampus may subserve different computational functions, such as spatial and temporal pattern separation, short-term or working memory, pattern association, and temporal pattern completion.

A double dissociation between the rat hippocampus and medial caudoputamen in processing two forms of knowledge.

Rats with hippocampus, medial caudoputamen (CPU), lateral CPU, or control lesions were trained on declarative and procedural knowledge variants of a novel rodent sequential learning task. Medial CPU lesions impaired rats' ability to learn the procedure of running through a sequence of open maze arms but did not disrupt their capacity to explicitly generate (i.e.. "declare") maze arm sequences. Hippocampus lesions produced the opposite set of results. Rats with lateral CPU lesions were not impaired on either version of the task. Transfer tests indicated that control rats predominantly used egocentric cues to solve the procedural task and allocentric spatial cues to solve the declarative task. These findings suggest a double dissociation between the medial CPU and hippocampus in processing egocentric-procedural and allocentric-declarative sequential information, respectively.

Involvement of the prelimbic-infralimbic areas of the rodent prefrontal cortex in behavioral flexibility for place and response learning.

The present experiments investigated the role of the prelimbic-infralimbic areas in behavioral flexibility using a place-response learning paradigm. All rats received a bilateral cannula implant aimed at the prelimbic-infralimbic areas. To examine the role of the prelimbic-infralimbic areas in shifting strategies, rats were tested on a place and a response discrimination in a cross-maze. Some rats were tested on the place version first followed by the response version. The procedure for the other rats was reversed. Infusions of 2% tetracaine into the prelimbic-infralimbic areas did not impair acquisition of the place or response discriminations. Prelimbic-infralimbic inactivation did impair learning when rats were switched from one discrimination to the other (cross-modal shift). To investigate the role of the prelimbic-infralimbic areas in intramodal shifts (reversal learning), one group of rats was tested on a place reversal and another group tested on a response reversal. Prelimbic-infralimbic inactivation did not impair place or response intramodal shifts. Some rats that completed testing on a particular version in the cross-modal and intramodal experiments were tested on the same version in a new room for 3 d. The transfer tests revealed that rats use a spatial strategy on the place version and an egocentric response strategy on the response version. Overall, these results suggest that the prelimbic-infralimbic areas are important for behavioral flexibility involving cross-modal but not intramodal shifts.

The role of the agranular insular cortex in working memory for food reward value and allocentric space in rats.

The present experiment examined the effects of quinolinic acid (125 mM) lesions of the agranular insular area on working memory for food reward value and working memory for spatial locations. In both tasks a go/no-go procedure was used. Working memory for food reward value was assessed using a delayed conditional discrimination in which either a 20% or 45% sugar content cereal was associated with a reinforcement and the other cereal was not. In the spatial locations task, rats were allowed to enter 12 arms in a radial maze for a food reinforcement. Of the 12 arm presentations, three or four arms were presented for a second time in a session which did not contain a reinforcement. The number of trials between the 1st and 2nd presentation of an arm ranged from 0 to 6 (lags). Working memory was assessed by the latency to enter an arm during the 2nd presentation. In the food reward value task, agranular insular lesions produced memory deficits in a delay-dependent manner. In contrast, agranular insular lesions did not impair working memory for spatial locations. These results add to accumulating evidence suggesting that different types of working memory are distributed across separate prefrontal subregions.

Involvement of rodent prefrontal cortex subregions in strategy switching.

The present study examined whether inactivation of the prelimbic-infralimbic areas or the dorsal anterior cingulate area impairs strategy switching in the cheeseboard task. After implantation of a cannula aimed at either the prelimbic-infralimbic or dorsal anterior cingulate areas, all rats were tested in a spatial and a visual-cued version of the task. Some of the rats received the spatial version first, followed by the visual-cued version. The procedure for the other rats was reversed. Infusions of 2% tetracaine into the prelimbic-infralimbic or dorsal anterior cingulate areas did not impair acquisition of the spatial or visual-cued versions. However, inactivation of the prelimbic-infralimbic areas, but not the dorsal anterior cingulate area, impaired learning when rats were switched from one version to the other. These findings suggest that the prelimbic-infralimbic areas are involved in switching to new behavior-guiding strategies.

Memory for duration: role of hippocampus and medial prefrontal cortex.

In this task rats had to learn that a three-dimensional object stimulus (a rectangle) that was visible for 2 s would result in a positive (go) reinforcement for one object (a ball) and no reinforcement (no go) for a different object (a bottle). However, if the rectangle stimulus was visible for 8 s then there would be no reinforcement for the ball (no go), but a reinforcement for the bottle (go). After rats learned this conditional discrimination by responding differentially in terms of latency to approach the object, they received large (dorsal and ventral) lesions of the hippocampus, lesions of the medial prefrontal cortex (anterior cingulate and precentral cortex), lesions of the cortex dorsal to the dorsal hippocampus, or served as sham-operated controls. Following recovery from surgery they were retested. The results indicate that there were major impairments following hippocampal lesions, in contrast to cortical control and medial prefrontal cortex lesions, as indicated by smaller latency differences between positive and negative trials on postsurgery tests. In order to ensure that the deficits observed with hippocampal lesions were not due to a discrimination problem, new rats were trained in an object (gray cylinder) duration discrimination task. In this go/no go procedure, the rats were reinforced for a 2-s exposure (duration) of the gray cylinder, but not a 10-s duration, or vice versa. The results indicate that after hippocampal lesions, there was an initial deficit followed by complete recovery. There were no significant changes for the medial prefrontal, cortical control, or sham-operated animals. It appears that the hippocampus, but not the medial prefrontal cortex, is actively involved in representing in short-term memory temporal attribute information based on the use of markers for the beginning and end of the presence (duration) of a stimulus (object).

Neural circuit analysis of spatial working memory: role of pre- and parasubiculum, medial and lateral entorhinal cortex.

Using a continuous recognition memory procedure for spatial location information, rats were given sequential presentation of individual arms on a 12-arm maze. Each arm contained a Froot Loop reinforcement the first time it was presented, and latency to traverse the arm was measured. A subset of the arms were repeated, but did not contain reinforcement. Repeated arms were presented with lags ranging from zero to six (from zero to six different arm presentations occurred between the first and repeated presentation). After completion of acquisition training (significantly longer latencies for repeated arms in comparison with the first presentation of an arm), rats received lesions of the medial or lateral entorhinal cortex, pre- and parasubiculum, or served as sham-operated controls. Based on continued postsurgery training and additional tests, the results indicated that rats with pre- and parasubiculum or pre- and parasubiculum plus medial entorhinal cortex produced sustained impairment in performing the task. Medial or lateral entorhinal cortex and control lesions did not display any sustained deficits. The data suggest that working memory for spatial location information is mediated primarily by the pre- and parasubiculum, but not medial entorhinal and lateral entorhinal cortex.

The effects of muscarinic cholinergic receptor blockade in the rat anterior cingulate and Prelimbic/Infralimbic cortices on spatial working memory.

Previous findings indicate that cholinergic input to the medial prefrontal cortex may modulate mnemonic processes. The present experiment determined whether blockade of muscarinic cholinergic receptors in the rodent anterior cingulate and prelimbic/infralimbic cortices impairs spatial working memory. In a 12-arm radial maze, a working memory for spatial locations task was employed using a continuous recognition go/no-go procedure. Rats were allowed to enter 12 arms for a reinforcement. Of the 12 arm presentations, 3 or 4 arms were presented for a second time in a session that did not contain a reinforcement. The number of trials between the first and second presentations of an arm ranged from 0 to 6 (lags). Infusions of scopolamine (1, 5, and 10 microgram), a muscarinic cholinergic antagonist, into the prelimbic/infralimbic cortices, but not the anterior cingulate cortex, significantly impaired spatial working memory in a lag- and dose-dependent manner. The deficit induced by scopolamine (10 microgram) was attenuated by concomitant intraprelimbic/infralimbic injections of oxotremorine (2 microgram) a muscarinic cholinergic agonist. A separate group of rats was tested on a successive spatial discrimination task. Injections of scopolamine (1, 5, and 10 microgram) into the prelimbic/infralimbic cortices did not impair performance on the spatial discrimination task. These findings suggest that muscarinic transmission in the prelimbic/infralimbic cortices, but not the anterior cingulate cortex, is important for spatial working memory.