Local memory allocation recruits memory ensembles across brain regions.

Memories are thought to be stored in ensembles of neurons across multiple brain regions. However, whether and how these ensembles are coordinated at the time of learning remains largely unknown. Here, we combined CREB-mediated memory allocation with transsynaptic retrograde tracing to demonstrate that the allocation of aversive memories to a group of neurons in one brain region directly affects the allocation of interconnected neurons in upstream brain regions in a behavioral- and brain region-specific manner in mice. Our analysis suggests that this cross-regional recruitment of presynaptic neurons is initiated by downstream memory neurons through a retrograde mechanism. Together with statistical modeling, our results indicate that in addition to the anterograde flow of information between brain regions, the establishment of interconnected, brain-wide memory traces relies on a retrograde mechanism that coordinates memory ensembles at the time of learning.

New research tools suggest a "levels-less" image of the behaving organism and dissolution of the reduction vs. anti-reduction dispute.

A kind of "ruthless reductionism" characterized the experimental practices of the first two decades of molecular and cellular cognition (MCC). More recently, new research tools have expanded experimental practices in this field, enabling researchers to image and manipulate individual molecular mechanisms in behaving organisms with an unprecedented temporal, sub-cellular, cellular, and even circuit-wide specificity. These tools dramatically expand the range and reach of experiments in MCC, and in doing so they may help us transcend the worn-out and counterproductive debates about "reductionism" and "emergence" that divide neuroscientists and philosophers alike. We describe examples of these new tools and illustrate their practical power by presenting an exemplary recent case of MCC research using them. From these tools and results, we provide an initial sketch of a new image of the behaving organism in its full causal-interactive complexity, with its molecules, cells, and circuits combined within the single system that it is. This new image stands in opposition to the traditional "levels" image of the behaving organism, and even the initial sketch we provide of it here offers hope for avoiding the dreary metaphysical debates about "emergence" and "downward causation," and even the reduction vs. anti-reduction dispute, all dependent upon the familiar "levels" image.

CCR5 closes the temporal window for memory linking.

Real-world memories are formed in a particular context and are often not acquired or recalled in isolation1-5. Time is a key variable in the organization of memories, as events that are experienced close in time are more likely to be meaningfully associated, whereas those that are experienced with a longer interval are not1-4. How the brain segregates events that are temporally distinct is unclear. Here we show that a delayed (12-24 h) increase in the expression of C-C chemokine receptor type 5 (CCR5)-an immune receptor that is well known as a co-receptor for HIV infection6,7-after the formation of a contextual memory determines the duration of the temporal window for associating or linking that memory with subsequent memories. This delayed expression of CCR5 in mouse dorsal CA1 neurons results in a decrease in neuronal excitability, which in turn negatively regulates neuronal memory allocation, thus reducing the overlap between dorsal CA1 memory ensembles. Lowering this overlap affects the ability of one memory to trigger the recall of the other, and therefore closes the temporal window for memory linking. Our findings also show that an age-related increase in the neuronal expression of CCR5 and its ligand CCL5 leads to impairments in memory linking in aged mice, which could be reversed with a Ccr5 knockout and a drug approved by the US Food and Drug Administration (FDA) that inhibits this receptor, a result with clinical implications. Altogether, the findings reported here provide insights into the molecular and cellular mechanisms that shape the temporal window for memory linking.

Dimensions and mechanisms of memory organization.

Memory formation is dynamic in nature, and acquisition of new information is often influenced by previous experiences. Memories sharing certain attributes are known to interact so that retrieval of one increases the likelihood of retrieving the other, raising the possibility that related memories are organized into associative mnemonic structures of interconnected representations. Although the formation and retrieval of single memories have been studied extensively, very little is known about the brain mechanisms that organize and link related memories. Here we review studies that suggest the existence of mnemonic structures in humans and animal models. These studies suggest three main dimensions of experience that can serve to organize related memories: time, space, and perceptual/conceptual similarities. We propose potential molecular, cellular, and systems mechanisms that might support organization of memories according to these dimensions.

Optogenetic reactivation of memory ensembles in the retrosplenial cortex induces systems consolidation.

The neural circuits underlying memory change over prolonged periods after learning, in a process known as systems consolidation. Postlearning spontaneous reactivation of memory-related neural ensembles is thought to mediate this process, although a causal link has not been established. Here we test this hypothesis in mice by using optogenetics to selectively reactivate neural ensembles representing a contextual fear memory (sometimes referred to as engram neurons). High-frequency stimulation of these ensembles in the retrosplenial cortex 1 day after learning produced a recent memory with features normally observed in consolidated remote memories, including higher engagement of neocortical areas during retrieval, contextual generalization, and decreased hippocampal dependence. Moreover, this effect was only present if memory ensembles were reactivated during sleep or light anesthesia. These results provide direct support for postlearning memory ensemble reactivation as a mechanism of systems consolidation, and show that this process can be accelerated by ensemble reactivation in an unconscious state.