Scientific Understanding of Consciousness
Consciousness as an Emergent Property of Thalamocortical Activity

Thalamus in Fear and Memory


Science 15 March 2013: Vol. 339 no. 6125 pp. 1290-1295

A Neural Circuit for Memory Specificity and Generalization

Wei Xu, Thomas C. Südhof

Department of Molecular and Cellular Physiology and Howard Hughes Medical Institute, Stanford University, 265 Campus Drive, Stanford, CA 94304–5453, USA.


Increased fear memory generalization is associated with posttraumatic stress disorder, but the circuit mechanisms that regulate memory specificity remain unclear. Here, we define a neural circuit—composed of the medial prefrontal cortex, the nucleus reuniens (NR) of the thalamus, and the hippocampus—that controls fear memory generalization. Inactivation of prefrontal inputs into the NR or direct silencing of NR projections enhanced fear memory generalization, whereas constitutive activation of NR neurons decreased memory generalization. Direct optogenetic activation of phasic and tonic action-potential firing of NR neurons during memory acquisition enhanced or reduced memory generalization, respectively. We propose that the NR determines the specificity and generalization of memory attributes for a particular context by processing information from the medial prefrontal cortex en route to the hippocampus.

Memories allow animals to adapt to a constantly changing environment. Memories are never completely precise but always partially generalized, which enables an animal to quickly and appropriately respond to novel stimuli that resemble a previous experience. The level of memory specificity and the degree of generalization are normally balanced. Generalization of fear memories protects animals by alerting them to potential dangers when animals are exposed to situations that are similar to previously experienced harmful circumstances, but overgeneralization of fear memories can lead to inappropriate anxiety. This is evident with posttraumatic stress disorder (PTSD), in which the reexperiencing of a past trauma is triggered by cues existing in a normally safe environment. Similarly, overgeneralization of episodic memories is a consistent problem in patients with severe depression. Since its initial demonstration, memory generalization has been extensively characterized, and multiple theories have been developed to explain it. In addition to the hippocampus, which is critical for maintaining the specificity of memories, we recently found that the medial prefrontal cortex (mPFC) is essential for memory generalization. Specifically, we observed that global impairment of synaptic transmission in the mPFC unexpectedly caused overgeneralization of contextual fear memories. This observation is potentially interesting, because functional abnormalities of the mPFC have been consistently observed in patients with PTSD and other psychiatric disorders.

The mPFC mediates the cognitive control of many high-level brain functions. However, it is unclear which synaptic projections from the mPFC to subcortical regions are critical for maintaining the proper balance between retention and generalization of fear memory details.

To quantitatively map the projections from the mPFC to subcortical regions, we developed a "SynaptoTag" adeno-associated virus (AAV), which coexpresses red fluorescent mCherry protein and enhanced green fluorescent protein (EGFP) fused to the synaptic vesicle protein.

Here, we establish that the mPFC controls memory specificity via signaling to the NR that, in turn, signals to the hippocampus and also back to the mPFC. The generalization of hippocampus-dependent memories is often discussed in the framework of complementary learning systems theory. In this theory, the hippocampus keeps separate representations of individual memory episodes (specific memories), whereas the cortex abstracts common features from multiple memories. Through systems consolidation, in which memories are transferred from the hippocampus to the cortex, memories become generalized. Highly specific memories are proposed to be maintained through "pattern separation," but can be generalized during retrieval through "pattern completion.” Complementary learning systems theory provides a plausible account of the time-dependent generalization of memories after memory acquisition and their generalization upon memory retrieval, but this theory does not explain how memory generalization is controlled during acquisition. Taking advantage of the temporal precision of optogenetic stimulations, we found that the mPFC-NR-hippocampus circuit controls memory specificity and generalization during acquisition.

Because memories are not composed of simple unitary traces but rather of flexible combinations of attributes or features of the remembered objects or situations, generalization of memories may stem from overlap between the representations of the attributes and/or features of memories. Studies of hippocampal place cells indicate that these cells undergo substantial "remapping" when encoding similar memories, especially in the CA3 region. Through remapping, subtle changes in the environment could produce profound alterations of a memory representation in the hippocampus, thereby increasing the distinction between similar memories. Thus, the mPFC-NR-hippocampus circuit may regulate memory generalization by actively controlling remapping. Notably, hippocampal remapping is modulated by motivational and emotional states. Because the mPFC is centrally involved in the motivational and emotional states of an animal,  the mPFC-NR pathway may convey the motivational and emotional value of the attributes of a memory to the hippocampus for memory encoding, which, in turn, may underlie the regulation of memory generalization during acquisition.

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