Effect of High-Frequency Stimulation of the Perforant Path on Previously Acquired Spatial Memory in Rats: Influence of Memory Strength and Reactivation

<div><p>If memory depends on changes in synaptic strength, then manipulation of synaptic strength after learning should alter memory for what was learned. Here, we examined whether high frequency stimulation of the perforant path <i>in vivo</i> disrupts memory for a previously-learned hidden platform location in the Morris water task as well as whether this effect is modulated by memory strength or memory reactivation. We found that high frequency stimulation affected probe test performance regardless of memory strength or state of memory activation, although the precise nature of this effect differed depending on whether rats received minimal or extensive training prior to high frequency stimulation. These findings suggest that artificial manipulation of synaptic strength between the entorhinal cortex and hippocampus may destabilize memory for a previously-learned spatial location.</p></div

Retraining.

<p>Both rats that underwent 1 day of training (<b>AB</b>) and rats that underwent 4 days of training (<b>CD</b>) displayed a decrease in latency to reach the hidden platform across trials. Rats that underwent 4 days of training exhibited shorter latency than rats that underwent 1 day of training. £ denotes main effect of trial (collapsed across 1-day/4-day, reactivation/no reactivation, and HFS/control groups), <i>p</i><.05. ¥ denotes main effect of training (collapsed across reactivation/no reactivation and HFS/control groups and trial), <i>p</i><.05.</p

Training.

<p>Both rats that underwent 1 day of training (<b>AB</b>) and rats that underwent 4 days of training (<b>CD</b>) displayed a decrease in latency to reach the hidden platform across trials. £ denotes main effect of trial within 1-day training group (collapsed across reactivation/no reactivation and HFS/control groups), <i>p</i><.05. ¥ denotes main effect of trial within 4-day training group (collapsed across reactivation/no reactivation and HFS/control groups), <i>p</i><.05.</p

Experimental design and timeline.

<p>Rats were surgically (Sx) implanted with stimulating electrodes in the perforant path and recording electrodes in the dentate gyrus. After the acquisition of I/O curves, rats underwent either 1 day (upper timelines) or 4 consecutive days (lower timelines) of training in the hidden platform version of the Morris water task. Twenty-four hours after the completion of training, half of the rats received a memory reactivation treatment consisting of being briefly placed on the platform in its trained location in the pool (reactivation group), whereas the other half remained in their home cages (no reactivation group). Next, half of the rats received 10 HFS trains applied bilaterally to the perforant path (HFS group), whereas the other half received a matching number of test pulses (control group). Afterward, rats' memory for the platform location was assessed during two consecutive probe tests with the platform removed from the pool. Finally, rats underwent retraining with the platform returned to its trained location.</p

HFS.

<p>Across all experimental conditions, rats in the HFS group exhibited HFS-induced potentiation of evoked responses considering both EPSP slope (<b>ABEF</b>) and PS amplitude (<b>CDGH</b>), whereas rats in the control group exhibited no change in the size of evoked responses after a matching number of test pulses. Above graphs: representative traces of evoked responses from rats in the HFS group before (solid line) and after (dashed line) HFS. * denotes HFS-induced potentiation of evoked responses above baseline, <i>p</i><.05.</p

Probe tests.

<p>Among rats that underwent 1 day of training, rats in the HFS group exhibited a significant increase in latency (<b>AB</b>) and path length (<b>CD</b>) to the target location across consecutive probe tests, whereas rats in the control group exhibited no change across probe tests. HFS did not affect number of target crosses (<b>EF</b>), time spent in the target zone (<b>GH</b>), or time spent in the target quadrant (<b>IJ</b>). Among rats that underwent 4 days of training, HFS rats spent less time in the target zone than control rats during both probe tests (<b>QR</b>). Also, rats in the reactivation group exhibited short latency (<b>L</b>) and path length (<b>N</b>) during both probe tests, whereas rats in the no reactivation group exhibited a significant increase in latency (<b>K</b>) and path length (<b>M</b>) across consecutive probe tests. Rats in the reactivation group also spent more time in the target zone and target quadrant during both probe tests (<b>RT</b>) compared to rats in the no reactivation group (<b>QS</b>). Neither HFS nor reactivation affected number of target crosses (<b>OP</b>). * denotes main effect of probe test within HFS group (collapsed across reactivation/no reactivation groups), <i>p</i><.05.). # denotes main effect of HFS (collapsed across reactivation/no reactivation groups and probe tests), <i>p</i><.05. £ denotes main effect of probe test (collapsed across HFS/control and reactivation/no reactivation groups), <i>p</i><.05. § denotes main effect of probe test within no reactivation group (collapsed across HFS/control groups), <i>p</i><.05. ¥ denotes main effect of reactivation (collapsed across HFS/control groups and probe tests), <i>p</i><.05.</p

Experimental methods.

<p>A. Timeline. B. Sequential steps in carrying out the within-litter neonatal novelty exposure procedure: (i) Dam is removed from the home cage; (ii) Novel pups are transferred to individual non-home cages and yoked Home pups receive a matching amount of experimenter contact; (iii) After 3 min in the non-home cages, Novel pups are returned to the home cage in which the Home pups remain; (iv) Dam is returned to the home cage. C. Apparatus used to assess rats' ability to compete against a conspecific for exclusive access to chocolate rewards. Note that the runway was sufficiently narrow as to allow only one rat at a time to fully enter.</p

Maternal care during brief 10-min windows immediately after repeated novelty exposure predicts the effect of novelty exposure on CORT habituation among aged offspring.

<p>A. Greater average amount of maternal licking and grooming (LG) was associated with greater day-to-day variability in maternal LG (dots and bars indicate average and range, respectively, of LG across days for individual dams; <i>N</i> = 11 litters). B. Greater average amount of maternal LG was associated with negative novelty scores for CORT habituation (marginally significant). D. Smaller day-to-day variability in maternal LG was significantly correlated with positive novelty scores for CORT habituation.</p

Permanent effects of neonatal novelty exposure on social competitive success and stress response system function (24 months of age).

<p>AB. When trained individually, Novel and Home rats showed no difference in learning to obtain chocolate rewards nor did they differ in final level of performance (<i>N</i>_Novel = 11, <i>N</i>_Home = 11). C. During paired social competition testing, Novel rats won significantly more rewards than Home rats on Day 1 but not on Day 2 (<i>N</i> = 11 pairs of Novel and Home rats). D. Novel but not Home rats exhibited a significant reduction in wins from Day 1 to Day 2. E. Despite a significant difference between Novel and Home rats in wins on Day 1, there was no parallel difference in post-competition corticosterone (CORT) concentration. Overall, CORT response to social competition significantly decreased across testing days (<i>N</i> = 14 pairs of Novel and Home rats). F. Novel but not Home rats exhibited significant habituation of CORT response across days. In all panels, data are mean±SEM; * indicates <i>p</i><0.05; ns indicates <i>p</i>>0.05.</p

Clinical outcomes for previously treated patients with advanced biliary tract cancer - supplementary material

Supplemental Table 1: Search strategy for Embase (Embase 1974 to 2021 June 28)Supplemental Table 2: Search strategy for MEDLINE (Ovid MEDLINE In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) 1946 to June 28, 2021)Supplemental Table 3: Search strategy for CENTRAL (EBM Reviews - Cochrane Central Register of Controlled Trials May 2021)Supplemental Table 4: Search strategy for American Society of Clinical Oncology conference abstracts (Northern Light Life Sciences Conference Abstracts 2010 to 2021 Week 24)Supplemental Table 5: Search strategy for European Society for Medical Oncology conference abstracts (Northern Light Life Sciences Conference Abstracts 2010 to 2021 Week 24)Supplemental Table 6: Search strategy for ClinicalTrials.govSupplemental Table 7: Detailed study characteristics for trials included in the systematic reviewSupplemental Table 8: Detailed treatment characteristics for trials included in the systematic reviewSupplemental Table 9: Detailed patient characteristics for trials included in the systematic reviewSupplemental Table 10: Response outcomes for trials included in the systematic reviewSupplemental Table 11: Survival outcomes for trials included in the systematic reviewSupplemental Table 12: Safety outcomes for trials included in the systematic reviewSupplemental Table 13: Patient-reported outcomes for trials included in the systematic reviewSupplemental Table 14: Quality assessment of included single-arm and non-randomized trialsSupplemental Table 15: Summary of pooled KM estimates of OS Supplemental Table 16: Summary of KM estimates of PFS Supplemental Figure 1: Risk of bias assessment of included RCTs </p