Sex differences in synaptic plasticity underlying learning.

Although sex differences in learning behaviors are well documented, sexual dimorphism in the synaptic processes of encoding is only recently appreciated. Studies in male rodents have built upon the discovery of long-term potentiation (LTP), and acceptance of this activity-dependent increase in synaptic strength as a mechanism of encoding, to identify synaptic receptors and signaling activities that coordinate the activity-dependent remodeling of the subsynaptic actin cytoskeleton that is critical for enduring potentiation and memory. These molecular substrates together with other features of LTP, as characterized in males, have provided an explanation for a range of memory phenomena including multiple stages of consolidation, the efficacy of spaced training, and the location of engrams at the level of individual synapses. In the present report, we summarize these findings and describe more recent results from our laboratories showing that in females the same actin regulatory mechanisms are required for hippocampal LTP and memory but, in females only, the engagement of both modulatory receptors such as TrkB and synaptic signaling intermediaries including Src and ERK1/2 requires neuron-derived estrogen and signaling through membrane-associated estrogen receptor α (ERα). Moreover, in association with the additional ERα involvement, females exhibit a higher threshold for hippocampal LTP and spatial learning. We propose that the distinct LTP threshold in females contributes to as yet unappreciated sex differences in information processing and features of learning and memory.

Towards best practice in developing motor skills: a systematic review on spacing in VR simulator-based psychomotor training for surgical novices.

OBJECTIVE: Repeated practice, or spacing, can improve various types of skill acquisition. Similarly, virtual reality (VR) simulators have demonstrated their effectiveness in fostering surgical skill acquisition and provide a promising, realistic environment for spaced training. To explore how spacing impacts VR simulator-based acquisition of surgical psychomotor skills, we performed a systematic literature review. METHODS: We systematically searched the databases PubMed, PsycINFO, Psychology and Behavioral Sciences Collection, ERIC and CINAHL for studies investigating the influence of spacing on the effectiveness of VR simulator training focused on psychomotor skill acquisition in healthcare professionals. We assessed the quality of all included studies using the Medical Education Research Study Quality Instrument (MERSQI) and the risk of bias using the Cochrane Collaboration's risk of bias assessment tool. We extracted and aggregated qualitative data regarding spacing interval, psychomotor task performance and several other performance metrics. RESULTS: The searches yielded 1662 unique publications. After screening the titles and abstracts, 53 publications were retained for full text screening and 7 met the inclusion criteria. Spaced training resulted in better performance scores and faster skill acquisition when compared to control groups with a single day (massed) training session. Spacing across consecutive days seemed more effective than shorter or longer spacing intervals. However, the included studies were too heterogeneous in terms of spacing interval, obtained performance metrics and psychomotor skills analysed to allow for a meta-analysis to substantiate our outcomes. CONCLUSION: Spacing in VR simulator-based surgical training improved skill acquisition when compared to massed training. The overall number and quality of available studies were only moderate, limiting the validity and generalizability of our findings.

Does spaced education improve clinical knowledge among Family Medicine residents? A cluster randomized controlled trial.

Spaced education is a learning strategy to improve knowledge acquisition and retention. To date, no robust evidence exists to support the utility of spaced education in the Family Medicine residency. We aimed to test whether alerts to encourage spaced education can improve clinical knowledge as measured by scores on the Canadian Family Medicine certification examination. METHOD: We conducted a cluster randomized controlled trial to empirically and pragmatically test spaced education using two versions of the Family Medicine Study Guide mobile app. 12 residency training programs in Canada agreed to participate. At six intervention sites, we consented 335 of the 654 (51%) eligible residents. Residents in the intervention group were sent alerts through the app to encourage the answering of questions linked to clinical cases. At six control sites, 299 of 586 (51%) residents consented. Residents in the control group received the same app but with no alerts. Incidence rates of case completion between trial arms were compared using repeated measures analysis. We linked residents in both trial arms to their knowledge scores on the certification examination of the College of Family Physicians of Canada. RESULTS: Over 67 weeks, there was no statistically significant difference in the completion of clinical cases by participants. The difference in mean exam scores and the associated confidence interval did not exceed the pre-defined limit of 4 percentage points. CONCLUSION: Further research is recommended before deploying spaced educational interventions in the Family Medicine residency to improve knowledge.

Hippocampal and anterior cingulate cortex contribution to the processing of recently-acquired and remotely stored spatial memories in rats trained during preadolescence.

Preadolescent development is characterized by a reorganization of connectivity within and between brain regions that coincides with the emergence of more complex behaviors. The hippocampus is one such region that undergoes extensive preadolescent remodeling and as this process continues, spatial memory functions emerge. The current work investigated whether preadolescent spatial memories persist beyond 24 h and stabilize into the postadolescent period as remote memories supported by cortical networks in the anterior cingulate cortex (ACC). Male Long Evans rats were trained on the Morris water maze at different time frames from postnatal day (P) 18-26 and compared to P50 rats. Testing occurred at either a recent (24 h) or remote (3 weeks) timepoint. Spatial learning was evident in all age groups (P18, P20, P22, P24 and P50) across the 3 training days but only the P22 and P24 groups showed spatial learning that matched the P50 group. In light of this, the only group to show intact remote (3 week) memory was the P50 group. Spaced training in the P18 group did not improve retention at the recent or remote testing intervals. The P18 and P50 groups tested at 24 h showed more CA1 hippocampal c-Fos labeling than groups tested at 3 weeks. The P50 group tested at 3 weeks showed elevated c-Fos labeling in the anterior cingulate (ACC) compared to the P18 group tested at 3 weeks and the P50 group tested at 24 h. Spaced training in the P18 group was associated with elevated c-Fos labeling in the ACC at the 3-week test. Groups trained at P20, 22, and 24 showed more c-Fos labelling in the ACC than in the CA1. Results suggest that while spatial information processing emerges around P18/P20, remote spatial retention and the neural substrates that support retention are not in place until after P26 in rats.

Everyday memory: towards a translationally effective method of modelling the encoding, forgetting and enhancement of memory.

The testing of cognitive enhancers could benefit from the development of novel behavioural tasks that display better translational relevance for daily memory and permit the examination of potential targets in a within-subjects manner with less variability. We here outline an optimized spatial 'everyday memory' task. We calibrate it systematically by interrogating certain well-established determinants of memory and consider its potential for revealing novel features of encoding-related gene activation. Rats were trained in an event arena in which food was hidden in sandwells in a different location everyday. They found the food during an initial memory-encoding trial and were then required to remember the location in six alternative choice or probe trials at various time-points later. Training continued daily over a period of 4 months, realizing a stable high level of performance and characterized by delay-dependent forgetting over 24 h. Spaced but not massed access to multiple rewards enhanced the persistence of memory, as did post-encoding administration of the PDE4 inhibitor Rolipram. Quantitative PCR and then genome-wide analysis of gene expression led to a new observation - stronger gene-activation in hippocampus and retrosplenial cortex following spaced than massed training. In a subsidiary study, a separate group of animals replicated aspects of this training profile, going on to show enhanced memory when training was subject to post-encoding environmental novelty. Distinctive features of this protocol include its potential validity as a model of memory encoding used routinely by human subjects everyday, and the possibility of multiple within-subject comparisons to speed up assays of novel compounds.

Spaced taste avoidance conditioning in Lymnaea.

We succeeded in taste avoidance conditioning with sucrose as the conditional stimulus (CS) and an electrical stimulus (∼1000V, 80µA) as the unconditional stimulus (US). With 15 paired CS-US presentations on a single day, we were able to elicit both short-term memory (STM) and long-term memory (LTM) persisting for at least one week. However, while STM was elicited with 5, 8, 10, and 20 paired presentations of the CS-US on a single day, LTM was not. We found, however, that if we inserted a 3h interval between a first and a second set of CS-US pairings that both 8 and 20 paired CS-US presentations on a single day was now sufficient to cause LTM formation. Exposing snails to bryostatin before or during training enhanced LTM formation such that 8 paired presentations of the CS-US resulted in LTM.

Effective Delivery of Vagus Nerve Stimulation Requires Many Stimulations Per Session and Many Sessions Per Week Over Many Weeks to Improve Recovery of Somatosensation.

BACKGROUND: Chronic sensory loss is a common and undertreated consequence of many forms of neurological injury. Emerging evidence indicates that vagus nerve stimulation (VNS) delivered during tactile rehabilitation promotes recovery of somatosensation. OBJECTIVE: Here, we characterize the amount, intensity, frequency, and duration of VNS therapy paradigms to determine the optimal dosage for VNS-dependent enhancement of recovery in a model of peripheral nerve injury (PNI). METHODS: Rats underwent transection of the medial and ulnar nerves in the forelimb, resulting in chronic sensory loss in the paw. Eight weeks after injury, rats were implanted with a VNS cuff and received tactile rehabilitation sessions consisting of repeated mechanical stimulation of the previously denervated forepaw paired with short bursts of VNS. Rats received VNS therapy in 1 of 6 systematically varied dosing schedules to identify a paradigm that balanced therapy effectiveness with a shorter regimen. RESULTS: Delivering 200 VNS pairings a day 4 days a week for 4 weeks produced the greatest percent improvement in somatosensory function compared to any of the 6 other groups (One Way analysis of variance at the end of therapy, F[4 70] P = .005). CONCLUSIONS: Our findings demonstrate that an effective VNS therapy dosage delivers many stimulations per session, with many sessions per week, over many weeks. These results provide a framework to inform the development of VNS-based therapies for sensory restoration.

Adaptation of vestibulo-ocular and optokinetic reflexes after massed and spaced vestibulo-ocular motor learning.

Although the superiority of spaced training over massed training has been established in many forms of learning, the learning efficacy between the two with respect to time efficiency may not be simply compared because a longer total duration of learning is required in spaced training than massed training due to spacing intervals intervening between training sessions in the former. The purpose of the present study was to evaluate the differences in the adaptation of the vestibulo-ocular reflex (VOR) and optokinetic reflex (OKR) after visuo-vestibular training, and to investigate the efficacy of spaced and massed training in mice. Associative visuo-vestibular stimulation was applied to induce VOR and OKR motor learning. Training paradigms were categorized into five groups according to the duration of the spacing interval, keeping the total training time including spacing equal in all training paradigms. Both gain-up VOR training, which increased VOR gain and gain-down VOR training, which decreased VOR gain, increased OKR gain in the massed and spaced learning paradigms. While the increment in OKR gain after gain-up and gain-down training was maintained at 48 h after the end of the last training session, the change in VOR gain by gain-up or gain-down training recovered gradually after training. The OKR adaptation was still in progress during the spacing interval, and the amount of gain increase was greater with longer spacing interval. On the other hand, the VOR gain change after gain-up and gain-down training substantially recovered during the spacing interval. In conclusion, the present study, using learning paradigms with same total duration of training, demonstrated that the spacing effect was more robust in the adaptation of OKR than that of VOR, and the learning effect was maintained longer in OKR than in VOR. These differences in the adaptation of VOR and OKR following identical training conditions suggest that multiple plasticity mechanisms may be differentially involved in the gaze stabilization circuitry.

Efficacy of spaced learning in adaptation of optokinetic response.

INTRODUCTION: The superiority of spaced training, in which repeated training sessions are given with resting intervals, over massed training in learning efficacy has been well established. However, longer duration of total training time has been required for spaced training than massed training because spacing intervals intervene between training sessions in spaced training. Thus, the learning efficacy may not be simply compared between spaced and massed training in terms of "time efficiency." The aim of the present study was to investigate the efficacy of spaced and massed training using adaptation of horizontal optokinetic reflex (hOKR) in mice. METHODS: Training paradigms were categorized into seven groups according to the duration of spacing interval, keeping total duration of hOKR training including spacing almost equal in all training paradigms. RESULTS: The amount of short-term hOKR gain increase immediately after the 60 min hOKR training was not significantly different among seven training paradigms. The hOKR adaptation was still in progress during a spacing interval, and the increment in hOKR gain tended to be greater with the longer spacing interval. The increase in hOKR gain was maintained until 48 hr after the end of training in both massed and spaced training. CONCLUSION: The short-term learning effect was not significantly different among training paradigms regardless of spacing interval in hOKR adaptation, which suggests that the spacing effect is robust enough to overcome the shortage of optokinetic training cycles in hOKR adaptation.

Spaced Training Forms Complementary Long-Term Memories of Opposite Valence in Drosophila.

Forming long-term memory (LTM) often requires repetitive experience spread over time. Studies in Drosophila suggest aversive olfactory LTM is optimal after spaced training, multiple trials of differential odor conditioning with rest intervals. Memory after spaced training is frequently compared to that after the same number of trials without intervals. Here we show that, after spaced training, flies acquire additional information and form an aversive memory for the shock-paired odor and a slowly emerging and more persistent "safety-memory" for the explicitly unpaired odor. Safety-memory acquisition requires repetition, order, and spacing of the training trials and relies on triggering specific rewarding dopaminergic neurons. Co-existence of aversive and safety memories is evident as depression of odor-specific responses at different combinations of junctions in the mushroom body output network; combining two outputs appears to signal relative safety. Having complementary aversive and safety memories augments LTM performance after spaced training by making the odor preference more certain.

Pediatric resuscitation training-instruction all at once or spaced over time?

AIM: Healthcare providers demonstrate limited retention of knowledge and skills in the months following completion of a resuscitation course. Resuscitation courses are typically taught in a massed format (over 1-2 days) however studies in education psychology have suggested that spacing training may result in improved learning and retention. Our study explored the impact of spaced instruction compared to traditional massed instruction on learner knowledge and pediatric resuscitation skills. METHODS: Medical students completed a pediatric resuscitation course in either a spaced or massed format. Four weeks following course completion students completed a knowledge exam and blinded observers used expert-developed checklists to assess student performance of three skills (bag-valve mask ventilation (BVMV), intra-osseous insertion (IOI) and chest compressions (CC)). RESULTS: Forty-five out of 48 students completed the study protocol. Students in both groups had similar scores on the knowledge exam spaced: (37.8±6.1) vs. massed (34.3±7.6)(p<0.09) and overall global rating scale scores for IOI, BVMV and CC; however students in the spaced group also performed critical procedural elements more frequently than those in the massed training group CONCLUSION: Learner knowledge and performance of procedural skills in pediatric resuscitation taught in a spaced format is at least as good as learning in a massed format. Procedures learned in a spaced format may result in better retention of skills when compared to massed training.