Melanie Sekeres

Memory consolidation or transformation: context manipulation and hippocampal representations of memory

The traditional view is that the hippocampus is necessary for retaining memories until they are consolidated in their original form in the neocortex. An alternative view is that the original memory, which is hippocampus- and context-dependent, becomes transformed with time to one that is more schematic and independent of the hippocampus. By manipulating context in two protocols that are widely used to investigate hippocampal-neocortical interactions in memory, we find evidence for the transformation view.

Preserved spatial memory after hippocampal lesions: effects of extensive experience in a complex environment

Damage to the hippocampus typically impairs spatial learning and memory in animals, but humans with hippocampal lesions retain spatial memories of premorbidly familiar environments. We showed that, like humans, normal rats reared in a complex environment and then given hippocampal lesions retained allocentric spatial memory for that environment. These results, which ruled out dependency on single cues, landmarks or specific routes, suggest that extensive premorbid experience leads to spatial representations that are independent of the hippocampus.

Changes in context-specificity during memory reconsolidation: Selective effects of hippocampal lesions

After acquisition, memories associated with contextual fear conditioning pass through a labile phase, in which they are vulnerable to hippocampal lesions, to a more stable state, via consolidation, in which they engage extrahippocampal structures and are resistant to such disruption. The process is accompanied by changes in the form of the memory from being context-specific to context-general. However, when revived by a reminder, stable memories once again become labile and susceptible to hippocampal disruption, and memory reconsolidation is needed to stabilize them. This study addressed two questions with respect to this reconsolidation phenomenon: (1) How do reminders reinstate a hippocampally dependent memory trace? (2) As the memory changes from a stable to a labile state after a reminder, does its form remain invariant, or does it also change? Using contextual manipulations at retrieval in a test of contextual fear conditioning, we showed that when the fear-conditioning environment served as a reminder, the reinstated memory regained its context specificity and, as a result, became vulnerable again to the effects of hippocampal lesions. By comparison, exposure to a different environment during the reminder session reinstated a version of the original memory that was dependent primarily on general features of the original context and, consequently, was less affected by hippocampal lesions. These findings, which relate loss of reactivated memories after hippocampal destruction (or inactivation) to changes in memory representation, are interpreted as consistent with the transformation hypothesis of memory processing.

Dorsal hippocampal CREB is both necessary and sufficient for spatial memory.

Although the transcription factor CREB has been widely implicated in memory, whether it is sufficient to produce spatial memory under conditions that do not normally support memory formation in mammals is unknown. We found that locally and acutely increasing CREB levels in the dorsal hippocampus using viral vectors is sufficient to induce robust spatial memory in two conditions that do not normally support spatial memory, weakly trained wild-type (WT) mice and strongly trained mutant mice with a brain-wide disruption of CREB function. Together with previous results, these findings indicate that CREB is both necessary and sufficient for spatial memory formation, and highlight its pivotal role in the hippocampal molecular machinery underlying the formation of spatial memory.

MEF2 negatively regulates learning-induced structural plasticity and memory formation

Memory formation is thought to be mediated by dendritic-spine growth and restructuring. Myocyte enhancer factor 2 (MEF2) restricts spine growth in vitro, suggesting that this transcription factor negatively regulates the spine remodeling necessary for memory formation. Here we show that memory formation in adult mice was associated with changes in endogenous MEF2 levels and function. Locally and acutely increasing MEF2 function in the dentate gyrus blocked both learning-induced increases in spine density and spatial-memory formation. Increasing MEF2 function in amygdala disrupted fear-memory formation. We rescued MEF2-induced memory disruption by interfering with AMPA receptor endocytosis, suggesting that AMPA receptor trafficking is a key mechanism underlying the effects of MEF2. In contrast, decreasing MEF2 function in dentate gyrus and amygdala facilitated the formation of spatial and fear memory, respectively. These bidirectional effects indicate that MEF2 is a key regulator of plasticity and that relieving the suppressive effects of MEF2-mediated transcription permits memory formation.

An investigation of the effects of hippocampal lesions in rats on pre‐ and postoperatively acquired spatial memory in a complex environment

In previous work, we showed that adult rats that were reared socially for 3 months in a complex (village) environment retained allocentric spatial memory for that environment following hippocampal lesions (Winocur et al., ( 2005 ) Nat Neurosci 8:273–275). In the present series of experiments, we showed that 3 months of postoperative rearing did not confer the same benefits (Experiment 1), although hippocampal groups, with or without rearing experience, exhibited spatial learning after extensive training (Experiments 1 and 2). Experiment 3 showed that as little as 2 weeks of preoperative rearing in the village was sufficient to retain acquired spatial memories after hippocampal lesions. Probe testing revealed that, although rats with hippocampal lesions exhibited remarkably good memory for preoperatively learned locations in the village, they were impaired when changes in task demands required flexible use of existing spatial representations. In a direct test of flexibility (Experiment 4), preoperatively reared rats were administered a blocked‐routes task in the original learning environment, in which on designated trials, a barrier was placed across one of the direct paths to the goal compartment. On encountering the barrier, control rats consistently selected the next most direct route, whereas rats with hippocampal lesions, despite using spatial strategies, made more errors and took longer to find the goal. The present results confirm that allocentric spatial memories can survive hippocampal damage but they are schematic in nature and less cohesive than those associated with cognitive maps in intact brains. As well, there was evidence that, although different processes are involved in their formation, the schematic memories that were acquired preoperatively and survived hippocampal lesions are essentially the same as those laboriously formed postoperatively after extensive training.

Hippocampal Lesions Produce Both Nongraded and Temporally Graded Retrograde Amnesia in the Same Rat

Rats were administered contextual fear conditioning and trained on a water‐maze, spatial memory task 28 days or 24 h before undergoing hippocampal lesion or control surgery. When tested postoperatively on both tasks, rats with hippocampal lesions exhibited retrograde amnesia for spatial memory at both delays but temporally graded retrograde amnesia for the contextual fear response. In demonstrating both types of retrograde amnesia in the same animals, the results parallel similar observations in human amnesics with hippocampal damage and provide compelling evidence that the nature of the task and the type of information being accessed are crucial factors in determining the pattern of retrograde memory loss associated with hippocampal damage. The results are interpreted as consistent with our transformation hypothesis (Winocur et al. (2010a) Neuropsychologia 48:2339–2356; Winocur and Moscovitch (2011) J Int Neuropsychol Soc 17:766–780) and at variance with standard consolidation theory and other theoretical models of memory.

Investigator experiences with financial conflicts of interest in clinical trials

BackgroundFinancial conflicts of interest (fCOI) can introduce actions that bias clinical trial results and reduce their objectivity. We obtained information from investigators about adherence to practices that minimize the introduction of such bias in their clinical trials experience.MethodsEmail survey of clinical trial investigators from Canadian sites to learn about adherence to practices that help maintain research independence across all stages of trial preparation, conduct, and dissemination. The main outcome was the proportion of investigators that reported full adherence to preferred trial practices for all of their trials conducted from 2001-2006, stratified by funding source.Results844 investigators responded (76%) and 732 (66%) provided useful information. Full adherence to preferred clinical trial practices was highest for institutional review of signed contracts and budgets (82% and 75% of investigators respectively). Lower rates of full adherence were reported for the other two practices in the trial preparation stage (avoidance of confidentiality clauses, 12%; trial registration after 2005, 39%). Lower rates of full adherence were reported for 7 practices in the trial conduct (35% to 43%) and dissemination (53% to 64%) stages, particularly in industry funded trials. 269 investigators personally experienced (n = 85) or witnessed (n = 236) a fCOI; over 70% of these situations related to industry trials.ConclusionFull adherence to practices designed to promote the objectivity of research varied across trial stages and was low overall, particularly for industry funded trials.

National Evaluation of Policies on Individual Financial Conflicts of Interest in Canadian Academic Health Science Centers

BackgroundConflicts of interest (COI) in research are an important emerging topic of investigation and are frequently cited as a serious threat to the integrity of human participant research.ObjectiveTo study financial conflicts of interest (FCOI) policies for individual investigators working in Canadian academic health centers.DesignSurvey instrument containing 61 items related to FCOI.SettingAll Canadian academic health science centers (universities with faculties of medicine, faculties of medicine and teaching hospitals) were requested to provide their three primary FCOI policies.MeasurementsNumber of all centers and teaching hospitals with policies addressing each of the 61 items related to FCOI.Main ResultsOnly one item was addressed by all 74 centers. Thirteen items were present in fewer than 25% of centers. Fewer than one-quarter of hospitals required researchers to disclose FCOI to research participants. The role of research ethics boards (REBs) in hospitals was marginal.LimitationsAsking centers to identify only three policies may not have inclusively identified all FCOI policies in use. Additionally, policies at other levels might apply. For instance, all institutions receiving federal grant money must comply with the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans.ConclusionsCanadian centers within the same level (for instance, teaching hospitals) differ significantly in the areas that their policies address and these policies differ widely in their coverage. Presently, no single policy in any Canadian center informs researchers about the broad range of individual FCOI issues. Canadian investigators need to understand the environment surrounding FCOI, be able to access and follow the relevant policies and be confident that they can avoid entering into a FCOI.

Factors affecting graded and ungraded memory loss following hippocampal lesions

This review evaluates three current theories--Standard Consolidation (Squire & Wixted, 2011), Overshadowing (Sutherland, Sparks, & Lehmann, 2010), and Multiple Trace-Transformation (Winocur, Moscovitch, & Bontempi, 2010)--in terms of their ability to account for the role of the hippocampus in recent and remote memory in animals. Evidence, based on consistent findings from tests of spatial memory and memory for acquired food preferences, favours the transformation account, but this conclusion is undermined by inconsistent results from studies that measured contextual fear memory, probably the most commonly used test of hippocampal involvement in anterograde and retrograde memory. Resolution of this issue may depend on exercising greater control over critical factors (e.g., contextual environment, amount of pre-exposure to the conditioning chamber, the number and distribution of foot-shocks) that can affect the representation of the memory shortly after learning and over the long-term. Research strategies aimed at characterizing the neural basis of long-term consolidation/transformation, as well as other outstanding issues are discussed.