Scientific Understanding of Consciousness
Memory Formation and Recall via Competition between Engrams
Nature 536, 405–407 (25 August 2016)
Neuroscience: Memories linked within a window of time
Center for Memory and Brain, Boston University, Boston, Massachusetts 02215, USA.
In mice, two fear-associated memories that are created close in time are represented in the brain's amygdala by the activation of overlapping ensembles of neurons. As a result, eliminating the fear of one memory also extinguishes fear of the other.
Two of my strongest memories are of emotional but unrelated events that occurred on the same day. On 20 July 1969, I successfully finished a gruelling month-long, round-the-clock experiment. That evening, I saw men first walk on the Moon. These two events are, for me, forever connected. Why? Writing in Science, Rashid et al. (see below) offer an explanation — emotionally charged events that occur close in time are bound together because of an overlap between the ensembles of neurons that are excited when the memories are laid down.
In their study, Rashid and colleagues trained mice to fear a particular tone (tone 1) by pairing the sound with a mild electric shock. Then, after an interval of between 1.5 and 24 hours, they trained the same animals to fear a different tone (tone 2). If the authors subsequently extinguished the animals' fear of tone 2, by repeatedly using it without shock, fear responses to tone 1 also decreased — but only if the initial training events had occurred within 6 hours of each other. Thus, a selective link forms between memories of fear-associated events that occur close together.
A brain region called the amygdala is essential for associating cues with shock. Select ensembles of neurons in this region are activated in mice during fear-associated training, and are then reactivated when the animal recalls the event. Using a sophisticated method for marking neurons activated during each event, Rashid et al. found a high degree of overlap (co-allocation) between the neurons activated by the two memories if the memories were created within 6 hours of each other, but not when created 24 hours apart.
The authors used elegant genetic tools to force activation of a common set of amygdala neurons during both learning events — a trick that artificially linked memories that occurred outside the 6-hour window. By contrast, when they inhibited excitation of the same population, preventing co-allocation of neuronal ensembles, memories that occurred within the 6-hour window were separated. These experiments confirm that common excitability of neurons in the amygdala is responsible for co-allocating neurons to memories within a window of time.
Brain-imaging studies in humans have also documented a gradual evolution of hippocampal neuronal activity associated with successful recall of the temporal order of events and with distinguishing events that occur at different times. Thus, in addition to the role of time in linking and separating memories described in the current studies, time can also sequentially organize memories.
Of course, time is only one variable that can link and separate memory representations. Previous studies have demonstrated that other types of contextual manipulation, such as shared or distinct stimuli and consistent or opposing reward associations for the same stimulus, can link or separate neural representations of memories that occur close in time. Nonetheless, Rashid et al. extend our understanding of the role of time in integrating and separating emotional and spatial memories, and reveal that allocation of neural ensembles underlies the powerful role of evolving temporal contexts in linking and separating memories.
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Science 22 Jul 2016: Vol. 353, Issue 6297, pp. 383-387
Competition between engrams influences fear memory formation and recall
Asim J. Rashid, et.al.
Program in Neurosciences and Mental Health, Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada.
Department of Psychology, University of Toronto, Toronto, ON M5G 3G3, Canada.
Institute of Medical Sciences, University of Toronto, Toronto, ON M5S 1A8, Canada.
Department of Physiology, University of Toronto, Toronto, ON M5G 1X8, Canada.
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA.
Engrams are the changes in brain tissue that store single memories. Neuroscientists can localize and manipulate them, but until now, little was known about how multiple engrams interact to influence memories. Rashid et al. examined how neural assemblies in an area called the lateral amygdala interact. If two frightening events occurred within 6 hours, the same set of neurons was used to express fear memories for both events. However, if the events were separated by 24 hours, distinct memory traces were formed.
Collections of cells called engrams are thought to represent memories. Although there has been progress in identifying and manipulating single engrams, little is known about how multiple engrams interact to influence memory. In lateral amygdala (LA), neurons with increased excitability during training outcompete their neighbors for allocation to an engram. We examined whether competition based on neuronal excitability also governs the interaction between engrams. Mice received two distinct fear conditioning events separated by different intervals. LA neuron excitability was optogenetically manipulated and revealed a transient competitive process that integrates memories for events occurring closely in time (coallocating overlapping populations of neurons to both engrams) and separates memories for events occurring at distal times (disallocating nonoverlapping populations to each engram).
Memory of an event is thought to be represented by an ensemble of neurons, referred to as its memory trace or engram. Despite recent advances in localizing and manipulating single engrams, little is known about how multiple engrams interact to influence memory function. Two engrams may engage nonoverlapping neuronal populations, thus minimizing interference between distinct memory representations. Alternatively, engrams may engage overlapping neuronal populations to functionally link those memories. Here, we examined the rules governing engram interaction.
In lateral amygdala (LA), a region critical for conditioned fear memory, eligible neurons compete for engram allocation. Neurons with relatively higher function of transcription factor CREB or increased excitability at training preferentially win this competition and are allocated to an engram. Silencing these neurons prevents memory expression, whereas their activation artificially elicits memory expression, indicating that these allocated neurons are both necessary and sufficient for expression of that memory. Similar competition governs engram allocation in mice without experimental manipulation of CREB or excitability.
These results reveal that, in the LA, a transient competitive process governs the interaction between engrams to integrate memories for events occurring closely in time and distinguish memories for events occurring farther apart in time. Coallocation is not limited to linking memories at encoding. Memory recall may engage a similar process to link new with old memories. We trained mice on event 1, 2 days before event 2. Event 2 memory was enhanced if event 1 was recalled 6 hours, not 24 hours, before event 2. Here, we find that excitatory-inhibitory balance determines whether memories are bound or, alternately, segregated in the LA. More broadly, these principles provide a foundation for understanding how memories are organized within associative networks. During final preparation of this manuscript, a notable study showing time-limited coallocation of hippocampal memory traces was published.
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