A Method of Intermittently Increasing Neurogenesis in the Aging Mouse Brain is Shown to Improve Memory Function

In the paper I'll point out today, researchers use an intriguing method to transiently spur greater neurogenesis and integration of new neurons into neural circuits in older mice. Mice undergoing the procedure exhibited better memory function than those that did not. The interesting part of their approach is that it involves disrupting some fraction of the established neural connections between older neurons, a feat accomplished in a reversible way. During the period of time in which these connections between older neurons are somewhat disrupted, the surrounding tissue reacts by dialing up both the pace at which new neurons are created and also their integration into neural circuits. When the disruption is removed, the connections between older neurons reestablish themselves. So in this fashion the researchers get to have their cake and eat it too: the existing neural circuitry is preserved, but also expanded and strengthened by the newly created neurons.

This approach suggests it is possible that any method of temporarily interrupting neural connections might lead to the same outcome. Equally, the reaction observed may be very dependent on the specific part of the structure of the synapse that is suppressed, and thus on the specific few proteins involved. Hard to say at this point: there is still a great deal to be accomplished in terms of mapping the biochemistry of structures associated with neural function, and how that biochemistry relates to specific functions such as memory retrieval and discrimination. What is clear based on the past few decades of research is that a higher level of neurogenesis is beneficial across the board: it increases the ability of the adult and aging brain to heal, adapt, and learn. It most likely modestly postpones the progression and impact of age-related neurodegeneration, but beyond that it has the look of an enhancement that, if it could be achieved safely, every human being should undergo, leading to improved cognitive function at all ages. Just like artificially increased autophagy and calorie restriction and exercise mimetics, therapies to meaningfully increase neurogenesis are definitely on the to-do list for the research community, but nowhere near any form of practical clinical realization despite the many and varied demonstrations in laboratory animals that have taken place in past years.

Making memories stronger and more precise during aging

"The hippocampus allows us to form new memories of 'what, when and where' that help us navigate our lives, and neurogenesis - the generation of new neurons from stem cells - is critical for keeping similar memories separate." As the human brain matures, the connections between older neurons become stronger, more numerous, and more intertwined, making integration for the newly formed neurons more difficult. Neural stem cells become less productive, leading to a decline in neurogenesis. With fewer new neurons to help sort memories, the aging brain can become less efficient at keeping separate and faithfully retrieving memories.

The research team selectively overexpressed a transcription factor, Klf9, only in older neurons in mice, which eliminated more than one-fifth of their dendritic spines, increased the number of new neurons that integrated into the hippocampus circuitry by two-fold, and activated neural stem cells. When the researchers returned the expression of Klf9 back to normal, the old dendritic spines reformed, restoring competition. However, the previously integrated neurons remained. "Because we can do this reversibly, at any point in the animals life we can rejuvenate the hippocampus with extra, new, encoding units." The authors employed a complementary strategy in which they deleted a protein important for dendritic spines, Rac1, only in the old neurons and achieved a similar outcome, increasing the survival of the new neurons.

In order to keep two similar memories separate, the hippocampus activates two different populations of neurons to encode each memory in a process called pattern separation. When there is overlap between these two populations, researchers believe it is more difficult for an individual to distinguish between two similar memories formed in two different contexts. If the memories are encoded in overlapping populations of neurons, the hippocampus may inappropriately retrieve either. If the memories are encoded in non-overlapping populations of neurons, the hippocampus stores them separately and retrieves them only when appropriate. Mice with increased neurogenesis had less overlap between the two populations of neurons and had more precise and stronger memories, which, according to the researchers, demonstrates improved pattern separation. Mice with increased neurogenesis in middle age and aging exhibited better memory precision.

Modulating Neuronal Competition Dynamics in the Dentate Gyrus to Rejuvenate Aging Memory Circuits

The neural circuit mechanisms underlying the integration and functions of adult-born dentate granule cell (DGCs) are poorly understood. Adult-born DGCs are thought to compete with mature DGCs for inputs to integrate. Transient genetic overexpression of a negative regulator of dendritic spines, Kruppel-like factor 9 (Klf9), in mature DGCs enhanced integration of adult-born DGCs and increased neural stem cell activation. Reversal of Klf9 overexpression in mature DGCs restored spines and activity and reset neuronal competition dynamics and neural stem cell activation, leaving the dentate gyrus modified by a functionally integrated, expanded cohort of age-matched adult-born DGCs. Spine elimination by inducible deletion of Rac1 in mature DGCs increased survival of adult-born DGCs without affecting proliferation or DGC activity. Enhanced integration of adult-born DGCs transiently reorganized adult-born DGC local afferent connectivity and promoted global remapping in the dentate gyrus. Rejuvenation of the dentate gyrus by enhancing integration of adult-born DGCs in adulthood, middle age, and aging enhanced memory precision.

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