Memory retrieval by activating engram cells in mouse models of early Alzheimer’s disease

By Dheeraj S. Roy, Autumn L Arons, Teryn Mitchell, Michele Pignatelli, T. Ryan, S. Tonegawa. 2016

505 citations recorded by the source corpus.

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive memory decline and subsequent loss of broader cognitive functions. Memory decline in the early stages of AD is mostly limited to episodic memory, for which the hippocampus has a crucial role. However, it has been uncertain whether the observed amnesia in the early stages of AD is due to disrupted encoding and consolidation of episodic information, or an impairment in the retrieval of stored memory information. Here we show that in transgenic mouse models of early AD, direct optogenetic activation of hippocampal memory engram cells results in memory retrieval despite the fact that these mice are amnesic in long-term memory tests when natural recall cues are used, revealing a retrieval, rather than a storage impairment. Before amyloid plaque deposition, the amnesia in these mice is age-dependent, which correlates with a progressive reduction in spine density of hippocampal dentate gyrus engram cells. We show that optogenetic induction of long-term potentiation at perforant path synapses of dentate gyrus engram cells restores both spine density and long-term memory. We also demonstrate that an ablation of dentate gyrus engram cells containing restored spine density prevents the rescue of long-term memory. Thus, selective rescue of spine density in engram cells may lead to an effective strategy for treating memory loss in the early stages of AD.

Subfields: Cellular and Molecular Neuroscience, Cognitive Neuroscience, Physiology

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Citations in the corpus

Dopamine Neurons Mediate Learning and Forgetting through Bidirectional Modulation of a Memory Trace (2018, unknown): “, 2015) or during Alzheimer’s disease (Roy et al., 2016) occurs through disruption of retrieval and not erasure of the engram.”
Aging and aging-related diseases: from molecular mechanisms to interventions and treatments (2022, background): “Neurofibrillary tangles gradually accumulate in the brain and are closely related to the prevalence of AD and the degree of disease.(211) Furthermore, dominant tau mutations lead to increased tau aggregation, neuroinflammation and neurodegeneration.”
The hippocampus and related neocortical structures in memory transformation. (2018, background): “By selectively reactivating these cells, they were able to elicit a fear response in animals that exhibited drug-induced retrograde amnesia [80], and in a mouse model of Alzheimer ’ s Disease [81].”
Memory engrams: Recalling the past and imagining the future (2020, background): “These transgenic mice [APP/ PS1 mice containing human transgenes with the familial ADmutation in both amyloid precursor protein (APP) and presenilin 1 (PSEN1)] showed contextual fear memory deficits (166).”