3177 Determining mechanisms underlying hippocampal network disruption in early amyloid pathology

OBJECTIVES/SPECIFIC AIMS: Alzheimer’s disease (AD) is the leading cause of dementia, and a rapidly growing public health crisis as life expectancy increases. Two hallmark symptoms of the disease are memory impairment and the pathological accumulation of amyloid beta protein. The hippocampus is a brain region critical for the consolidation of new memories, and one of the first regions in which amyloid accumulation is observed. Our lab and others have observed a disruption to hippocampal network activity that is critical for memory consolidation in amyloid-accumulating mice. However, the mechanisms and neuronal micro-circuitry underlying this disruption are under-explored, a critical gap that warrants exploration if we are to understand memory disruption in the disease. In this study we have investigated the hypothesis that a preferential disruption to inhibitory PV neurons and the extracellular matrix that surrounds this cell type underlies downstream network alterations. METHODS/STUDY POPULATION: We have employed the 5xFAD mouse model of familial Alzheimer’s disease crossed with transgenic lines that selectively fluoresce in different neuronal sub-types. In a multi-modal approach, we have investigated behavioral, electrophysiological, and biochemical alterations between 3-month-old amyloid-accumulating 5xFAD mice and littermate controls. RESULTS/ANTICIPATED RESULTS: We observe a 35% increase in the incidence of synchronous hippocampal oscillations known as sharp wave ripples (SWRs) in amyloid-accumulating mice versus littermate controls (n = 28, p = 0.01), as well as a 95% increase in the power of slow gamma oscillations (p = 0.002). This hyperexcitability of the hippocampal network is correlated with an impairment in hippocampal-dependent memory, assayed with the Barnes Maze, a behavioral test of spatial memory (172% increase in latency to find escape hole, n = 8, p = 0.01). To elucidate the micro-circuitry that underlies this network disruption, we have investigated the integrity of peri-neuronal nets (PNNs), part of the extracellular matrix of proteins that preferentially ensheathe inhibitory PV neurons and support their function. We observe a 60% decrease in intensity of PNNs (n = 5, p = 0.005), suggesting PNN integrity is impaired in amyloid-accumulating mice. Ongoing experiments into the activity and synaptic input to both inhibitory PV and excitatory pyramidal neurons seek to determine the effects of this PNN disruption on downstream micro-circuitry. DISCUSSION/SIGNIFICANCE OF IMPACT: These findings suggest that a preferential impairment to PNNs and inhibitory PV cells underlie hippocampal hyperexcitability in a mouse model of AD. As hippocampal network activity is critical for memory consolidation, these effects contribute to our understanding of memory disruption during early disease progression, which has been poorly understood to date. These findings provide a foundation for future in vivo studies employing optogenetic stimulation to this neuronal sub-type, to determine if restoring physiological network balance can ameliorate memory decline.

Brief Inductions in Episodic Past or Future Thinking: Effects on Episodic Detail and Problem-Solving

Episodic specificity inductions, involving brief training in recollecting episodic details, have been shown to improve subsequent performance on tasks involving remembering the past, imagining the future and problem solving. The current study examined if specificity inductions targeting self-referential past or future episodic thinking would have dissociable effects on generating past and future episodic detail and problem solving. Sixty-three participants were randomised to either a past self-referential or future self-referential episodic induction. All participants also completed a control task. Participants randomised to the self-referential future thinking induction generated more episodic details on past and future narrative tasks compared to a control task, whereas participants randomised to a self-referential past thinking induction showed similar performance to the control task. When examining within-group performance of participants randomised to the past or future induction, we found some evidence of dissociable effects of inductions on narrative generation tasks, but not on problem solving outcomes. Our findings suggest that self-referential inductions may be useful for increasing episodic specificity, but that the temporal distance and direction of the induction matters. We discuss our results in the context of the potential clinical utility of this approach for populations vulnerable to autobiographical memory disruption.

Working-memory disruption by task-irrelevant talkers depends on degree of talker familiarity

When listening, familiarity with an attended talker’s voice improves speech comprehension. Here, we instead investigated the effect of familiarity with a distracting talker. In an irrelevant-speech task, we assessed listeners’ working memory for the serial order of spoken digits when a task-irrelevant, distracting sentence was produced by either a familiar or an unfamiliar talker (with rare omissions of the task-irrelevant sentence). We tested two groups of listeners using the same experimental procedure. The first group were undergraduate psychology students (N=66) who had attended an introductory statistics course. Critically, each student had been taught by one of two course instructors, whose voices served as familiar and unfamiliar task-irrelevant talkers. The second group of listeners were family members and friends (N=20) who had known either one of the two talkers for more than ten years. Students, but not family members and friends, made more errors when the task-irrelevant talker was familiar versus unfamiliar. Interestingly, the effect of talker familiarity was not modulated by the presence of task-irrelevant speech: students experienced stronger working-memory disruption by a familiar talker irrespective of whether they heard a task-irrelevant sentence during memory retention or merely expected it. While previous work has shown that familiarity with an attended talker benefits speech comprehension, our findings indicate that familiarity with an ignored talker deteriorates working memory for target speech. The absence of this effect in family members and friends suggests that the degree of familiarity modulates memory disruption.

Memory Guides the Comprehension of Event Changes for Older and Younger Adults

Two experiments examined adult age differences in the use of memory to comprehend changes in everyday activities. Participants viewed movies depicting an actor performing activities on two fictive days in her life. Some activities were repeated across days, other activities were repeated with a changed feature (e.g., waking up to an alarm clock or a phone alarm), and a final set of activities was performed on Day 2 only. After a one-week delay, participants completed a cued recall test for the activities of Day 2. Unsurprisingly, exact repetition boosted final recall. More surprising, features that changed from Day 1 to Day 2 were remembered approximately as well as features that were only presented on Day 2—showing an absence of proactive interference and in some cases proactive facilitation. Proactive facilitation was strongly related to participants’ ability to detect and recollect the changes. Younger adults detected and recollected more changes than older adults, which in part explained older adults’ differential deficit in memory for changed activity features. We propose that this pattern may reflect observers’ use of episodic memory to make predictions during the experience of a new activity, and that when predictions fail, this triggers processing that benefits subsequent episodic memory. Disruption of this chain of processing could play a role in age-related episodic memory deficits.