Abstract
Mapping and decoding brain activity patterns underlying learning and memory represents both great interest and immense challenge. At present, very little is known regarding many of the very basic questions regarding the neural codes of memory: are fear memories retrieved during the freezing state or non-freezing state of the animals? How do individual memory traces give arise to a holistic, real-time associative memory engram? How are memory codes regulated by synaptic plasticity? Here, by applying high-density electrode arrays and dimensionality-reduction decoding algorithms, we investigate hippocampal CA1 activity patterns of trace fear conditioning memory code in inducible NMDA receptor knockout mice and their control littermates. Our analyses showed that the conditioned tone (CS) and unconditioned foot-shock (US) can evoke hippocampal ensemble responses in control and mutant mice. Yet, temporal formats and contents of CA1 fear memory engrams differ significantly between the genotypes. The mutant mice with disabled NMDA receptor plasticity failed to generate CS-to-US or US-to-CS associative memory traces. Moreover, the mutant CA1 region lacked memory traces for “what at when” information that predicts the timing relationship between the conditioned tone and the foot shock. The degraded associative fear memory engram is further manifested in its lack of intertwined and alternating temporal association between CS and US memory traces that are characteristic to the holistic memory recall in the wild-type animals. Therefore, our study has decoded real-time memory contents, timing relationship between CS and US, and temporal organizing patterns of fear memory engrams and demonstrated how hippocampal memory codes are regulated by NMDA receptor synaptic plasticity.
Highlights
The major obstacle in understanding of how memory works in the brain is the lack of description of the real-time brain activity patterns and its organizing principles underlying real-time memory process
We examined the genetic effects of forebrain-specific NMDA receptor deletion on trace fear conditioning by feeding the inducible knockout mice with doxycycline 5 days prior to fear conditioning
We found that many conditioned stimulus (CS) or unconditioned footshock (US) traces were retrieved in a temporally associational manner as evident from the three following analyses: 1) the intertwined retrieval pattern, again, it referred to the temporal format when a given CS or US simple memory trace was followed by a different memory trace
Summary
The major obstacle in understanding of how memory works in the brain is the lack of description of the real-time brain activity patterns and its organizing principles underlying real-time memory process. Most electrophysiological studies examined single unit activity using peri-event based data averaging methods over multiple trials to characterize response or tuning properties of the recording neurons. This data-averaging practice has, led to the loss of crucial information regarding transient activity patterns and fundamental dynamics that underlies realtime memory code. Little is known regarding the real-time brain activity patterns of associative memories and what real-time memory engram looks like and how they are organized. There is an emerging interest in applying large-scale neural recording and powerful mathematical decoding approaches to seek out brain activity patterns or brain activity maps hidden inside the large datasets [10,11,12,13]
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