Inactivation of the anterior cingulate reveals enhanced reliance on cortical networks for remote spatial memory retrieval after sequential memory processing.

One system consolidation model suggests that as time passes, ensembles of cortical neurons form strong connections to represent remote memories. In this model, the anterior cingulate cortex (ACC) serves as a cortical region that represents remote memories. However, there is debate as to whether remote spatial memories go through this systems consolidation process and come to rely on the ACC. The present experiment examined whether increasing the processing demand on the hippocampus, by sequential training on two spatial tasks, would more fully engage the ACC during retrieval of a remote spatial memory. In this scenario, inactivation of the ACC at a remote time point was hypothesized to produce a severe memory deficit if rats had been trained on two, sequential spatial tasks. Rats were trained on a water maze (WM) task only or a WM task followed by a radial arm maze task. A WM probe test was given recently or remotely to all rats. Prior to the probe test, rats received an injection of saline or muscimol into the ACC. A subtle deficit in probe performance was found at the remote time point in the group trained on only one spatial task and treated with muscimol. In the group trained on two spatial tasks and treated with muscimol, a subtle deficit in probe performance was noted at the recent time point and a substantial deficit in probe performance was observed at the remote time point. c-Fos labeling in the hippocampus revealed more labeling in the CA1 region in all remotely tested groups than recently tested groups. Findings suggest that spatial remote memories come to rely more fully on the ACC when hippocampal processing requirements are increased. Results also suggest continued involvement of the hippocampus in spatial memory retrieval along with a progressive strengthening of cortical connections as time progresses.

The impact of multiple memory formation on dendritic complexity in the hippocampus and anterior cingulate cortex assessed at recent and remote time points.

Consolidation processes, involving synaptic and systems level changes, are suggested to stabilize memories once they are formed. At the synaptic level, dendritic structural changes are associated with long-term memory storage. At the systems level, memory storage dynamics between the hippocampus and anterior cingulate cortex (ACC) may be influenced by the number of sequentially encoded memories. The present experiment utilized Golgi-Cox staining and neuron reconstruction to examine recent and remote structural changes in the hippocampus and ACC following training on three different behavioral procedures. Rats were trained on one hippocampal-dependent task only (a water maze task), two hippocampal-dependent tasks (a water maze task followed by a radial arm maze task), or one hippocampal-dependent and one non-hippocampal-dependent task (a water maze task followed by an operant conditioning task). Rats were euthanized recently or remotely. Brains underwent Golgi-Cox processing and neurons were reconstructed using Neurolucida software (MicroBrightField, Williston, VT, USA). Rats trained on two hippocampal-dependent tasks displayed increased dendritic complexity compared to control rats, in neurons examined in both the ACC and hippocampus at recent and remote time points. Importantly, this behavioral group showed consistent, significant structural differences in the ACC compared to the control group at the recent time point. These findings suggest that taxing the demand placed upon the hippocampus, by training rats on two hippocampal-dependent tasks, engages synaptic and systems consolidation processes in the ACC at an accelerated rate for recent and remote storage of spatial memories.

The use of sequential hippocampal-dependent and -non-dependent tasks to study the activation profile of the anterior cingulate cortex during recent and remote memory tests.

Recent findings suggest that as time passes, cortical networks become recruited for memory storage. In animal models, this has been studied by exposing rodents to one task, allowing them to form a memory representation for the task then waiting different periods of time to determine, either through brain imaging or region-specific inactivation, the location of the memory representation. A number of reports show that 30 days after a memory has been encoded, it comes to be stored in cortical areas such as the anterior cingulate cortex. The present study sought to determine what factors, in addition to the passage of time, would influence whether memory retrieval was associated with cortical activation. To this end, rats were assigned to one of three behavioural groups: (1) Training on one hippocampal-dependent memory task, the water maze (WM); (2) Training on two, different hippocampal-dependent memory tasks, the WM followed by the radial arm maze; (3) Training on one hippocampal-dependent memory task (WM) followed by training on one, non-hippocampal-dependent task, operant conditioning. After training, each group received a recent (2d) or remote (31d) water maze probe test. The group trained on two different hippocampal-dependent tasks and tested 2d later, showed the strongest preference for the platform location during the probe test. This group also displayed a pattern of c-Fos staining in the anterior cingulate cortex similar to the pattern of staining observed in the remotely-tested groups and different from that seen in the other recently-tested groups. These results suggest the formation of multiple hippocampal-dependent memories accelerate the speed at which cortical network recruitment is seen and leads to enhanced behavioural performance in the recent term.

Enhanced adolescent learning and hippocampal axonal projections following preadolescent spatial exposure to a water or dry maze.

The present work sought to determine whether preadolescent exposure to a different task in the same spatial environment would lead to enhancement of water-maze performance and changes in hippocampal connectivity. Separate groups of preadolescent (p16-p26) Long Evans rats (LER) were exposed to the same room and arena using either a water-maze (WM) or a dry-maze (DM), while a third group received no exposure to the spatial cues (NT) but were handled. Three weeks later, rats were tested on the WM or DM task in the same room where preadolescent exposure took place. This set up conditions where the DM/WM and WM/DM groups were exposed to the same spatial cues during the preadolescent and adolescent (p40-p44) phases but performed different tests allowing for the dissociation of spatial cue exposure and task familiarity on adolescent performance. When animals experienced similar preadolescent and adolescent conditions (WM/WM or DM/DM), there was improved performance over animals with no preadolescent spatial exposure (NT/WM or NT/DM). In group DM/WM, there was enhanced adolescent performance compared to group NT/WM. In contrast, group WM/DM did not show enhanced adolescent performance. Compared to groups with no preadolescent spatial exposure, groups with both preadolescent and adolescent spatial exposure showed elevated synaptophysin staining in the hippocampal CA3 region indicating an expanded axonal projection in this region. These data suggest the possibility that exposure to spatial cues during the preadolescent period, independent from task-specific requirements, contributes to enhanced adolescent spatial performance on the WM. This appears to be linked with the reorganization of axonal inputs to the CA3 region.

Estradiol treatment in preadolescent females enhances adolescent spatial memory and differentially modulates hippocampal region-specific phosphorylated ERK labeling.

Estrogen levels in rats are positively correlated with enhanced memory function and hippocampal dendritic spine density. There is much less work on the long-term effects of estradiol manipulation in preadolescent rats. The present work examined how injections of estradiol during postnatal days 19-22 (p19-22; preadolescence) affected water maze performance and hippocampal phosphorylated ERK labeling. To investigate this, half of the estradiol- and vehicle-treated female rats were trained on a water maze task 24h after the end of estradiol treatment (p23-27) while the other half was not trained. All female rats were tested on the water maze from p40 to p44 (adolescence) and hippocampal pERK1/2 labeling was assessed as a putative marker of neuronal plasticity. During adolescence, preadolescent-trained groups showed lower latencies than groups without preadolescent training. Retention data revealed lower latencies in both estradiol groups, whether preadolescent trained or not. Immunohistochemical detection of hippocampal pERK1/2 revealed elevations in granule cell labeling associated with the preadolescent trained groups and reductions in CA1 labeling associated with estradiol treatment. These results show a latent beneficial effect of preadolescent estradiol treatment on adolescent spatial performance and suggest an organizational effect of prepubescent exogenously applied estradiol.

Effect of juvenile pretraining on adolescent structural hippocampal attributes as a substrate for enhanced spatial performance.

Research has demonstrated that Long-Evans rats (LER) display superior mnemonic function over Wistar rats (WR). These differences are correlated with endogenous and input-dependent properties of the hippocampus. The present work sought to determine if juvenile pretraining might enhance hippocampal structural markers and if this would be associated with spatial processing improvements. Male and female WR and LER were either handled or trained on a water maze task from postnatal day 16 (p16) to p26 (pretraining). All animals were then trained on the task from p40 to p44 followed by immunohistochemical assessment of synaptophysin (to mark presynaptic terminals), MAP-2 (to mark dendrites), and the phosphorylated (activated) form of the extracellular signal-regulated kinase-1 (pERK1) in the hippocampus. From p19 to p20, LER (both male and female) showed a dramatic improvement in locating the hidden platform compared to their WR counterparts. On the first day of training at p40, all pretrained groups showed shorter latencies to locate the platform compared to groups without pretraining. Over the next 4 d, only pretrained male LER showed enhanced memory. Immunohistochemical analysis revealed fewer pERK1-labeled neurons in the CA3 hippocampal region in all pretrained groups and fewer pERK1-labeled neurons in the CA1 region of pretrained male LER. Pretrained male LER also showed more MAP-2 staining in CA1 and dentate gyrus regions. Synaptophysin staining revealed a pattern of axonal redistribution in the CA3 region in the pretrained groups. Results suggest a pattern of structural hippocampal alterations that may help to identify network malleability following pretraining protocols.