Making Memories Stronger and More Precise During Aging

Summary: Researchers report on the mechanism by which new neurons are able to sharpen memories.

Source: Harvard

Harvard researchers identify new mechanisms by which new neurons sharpen memories.

When it comes to the billions of neurons in your brain, what you see at birth is what get — except in the hippocampus. Buried deep underneath the folds of the cerebral cortex, neural stem cells in the hippocampus continue to generate new neurons, inciting a struggle between new and old as the new attempts to gain a foothold in memory-forming center of the brain.

In a study published online in Neuron, Harvard Stem Cell Institute (HSCI) researchers at Massachusetts General Hospital and the Broad Institute of Harvard and MIT in collaboration with an international team of scientists found they could bias the competition in favor of the newly generated neurons.

“The hippocampus allows us to form new memories of ‘what, when and where’ that help us navigate our lives,” said HSCI Principal Faculty member and the study’s corresponding author, Amar Sahay, PhD, “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,” Sahay said.

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.

Image shows hippocampal neurons.
Young neurons (pink), responsible for encoding new memories, must compete with mature neurons (green) to survive and integrate into the hippocampal circuit. image is credited to Kathleen McAvoy.

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, to discriminate between a Sunday afternoon stroll through the woods from a patrol through enemy territory in a forest, for example. 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 Sahay, demonstrates improved pattern separation.

Mice with increased neurogenesis in middle age and aging exhibited better memory precision.

“We believe that by increasing the hippocampus’s ability to do what it supposed to do and not retrieve past experiences when it shouldn’t can help,” said Sahay. This may be particularly useful for individuals suffering from post-traumatic stress disorder, mild cognitive impairment, or age-related memory loss.

About this memory research article

Funding: This work was done in collaboration with scientists from Harvard Stem Cell Institute, the Broad Institute of Harvard and MIT, Massachusetts General Hospital, Harvard Medical School, Columbia University, Heidelberg University, University Hospital of Cologne, Johannes Gutenberg University, and Echelon Bioscience and is supported by funding from the NIH, HSCI, and the Harvard Neurodiscovery Center/MADRC Center.

Source: Hannah L. Robbins – Harvard
Image Source: image is credited to Kathleen McAvoy.
Original Research: Abstract for “Modulating Neuronal Competition Dynamics in the Dentate Gyrus to Rejuvenate Aging Memory Circuits” by Kathleen M. McAvoy, Kimberly N. Scobie, Stefan Berger, Craig Russo, Nannan Guo, Pakanat Decharatanachart, Hugo Vega-Ramirez, Sam Miake-Lye, Michael Whalen, Mark Nelson, Matteo Bergami, Dusan Bartsch, Rene Hen, Benedikt Berninger, and Amar Sahay in Neuron. Published online September 1 2016 doi:10.1016/j.neuron.2016.08.009

Cite This Article

[cbtabs][cbtab title=”MLA”]Harvard “Making Memories Stronger and More Precise During Aging.” NeuroscienceNews. NeuroscienceNews, 1 September 2016.
<>.[/cbtab][cbtab title=”APA”]Harvard (2016, September 1). Making Memories Stronger and More Precise During Aging. NeuroscienceNew. Retrieved September 1, 2016 from[/cbtab][cbtab title=”Chicago”]Harvard “Making Memories Stronger and More Precise During Aging.” (accessed September 1, 2016).[/cbtab][/cbtabs]


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

•Mature DGC spine elimination enhances integration of adult-born DGCs
•Adult neurogenesis dictates population-based coding in the DG
•Integration of adult-born DGCs transiently reorganizes local afferent connectivity
•Rejuvenating the aged DG with adult-born DGCs promotes memory precision

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 NSC activation. Reversal of Klf9 overexpression in mature DGCs restored spines and activity and reset neuronal competition dynamics and NSC activation, leaving the DG 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 DG. Rejuvenation of the DG by enhancing integration of adult-born DGCs in adulthood, middle age, and aging enhanced memory precision.

“Modulating Neuronal Competition Dynamics in the Dentate Gyrus to Rejuvenate Aging Memory Circuits” by Kathleen M. McAvoy, Kimberly N. Scobie, Stefan Berger, Craig Russo, Nannan Guo, Pakanat Decharatanachart, Hugo Vega-Ramirez, Sam Miake-Lye, Michael Whalen, Mark Nelson, Matteo Bergami, Dusan Bartsch, Rene Hen, Benedikt Berninger, and Amar Sahay in Neuron. Published online September 1 2016 doi:10.1016/j.neuron.2016.08.009

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  1. When one chooses to examine the threads, which, once woven together, have formed the “tapestry” of scientific psychology, in terms of specific influential psychologists and specific scientific discoveries, the student of this historical narrative, often takes one of two approaches.

    The first (known as the personalistic, or “great person”), approach assumes that progress is the result of the periodic appearance of a “visionary genius” who proposes a completely novel paradigm or “lens”, within which to frame the nature of questions asked; an approach which results in testable hypotheses which bear an extraordinary amount of “fruit” (explanations to phenomena which had perplexed previous psychologists for a considerable length of time).

    The second (known as the naturalistic) approach posits that progress which appears to “lurch forward erratically” (consistent with what one would expect if stagnation were “interrupted” by the periodic yet random arrivals of such “geniuses”) is actually a dynamic epiphenomenon or “by product” reflective of a confluence of myriad influences, as well as a fortuitous zeitgeist (intellectual climate), in which a socio cultural openness to novel approaches is the norm, and in fact, many individuals are utilizing those approaches. Some of these individuals, will, through charisma, a high profile media presence, will end up “getting the credit” …thus creating the “illusion of genius”.

    The reality is very rarely (if ever) an either/or case.
    In describing the progression in schools of thought (paradigms) in psychology, the philosopher Thomas Kuhn (1970), suggests that the criterion for the “maturation” of psychology (or any science) is a succession of common paradigms, each of which (while it is dominant) defines the entire field, and is marked by agreement on all major relevant theoretical and methodological issues.

    At some point after a paradigm is recognized, it may (it will) be replaced by a new one that accounts for all existing findings AS WELL as an inevitable increase in observed anomalies which cannot be accounted for by the current paradigm.

    Thus, each paradigm (school) of psychology, after occupying “center stage” for a brief, shining, “superstar moment”..will inevitably give way to a new paradigm –one which can account for current phenomena, AND those “pesky anomalies”, which inevitably creep in, upon both technological advances, and too much time “under the microscope”
    While this may be a frustration for (sometimes several generations) of psychologists, who may have spent their entire careers, and indeed, LIVES, invested in a paradigm which is “falling apart”…SUCH IS LIFE; To be a “real” Psychologist (or scientist of any type) is to sign on for a combat mission of sorts; IT IS NOT FOR THE FAINT OF HEART WHO CAN’T DEAL WITH “THEIR RECORDS BEING BROKEN”…many non-scientists really have no clue as to how this feels
    NONETHELESS, in psychology, as in any other science, this, and only this, reflects the health, vitality, and diversity that are required for a successful evolution of the field
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    David Kessler is a physician (Psychiatrist and Pediatrician) and a former FDA Commissioner who became immersed in the issue of addiction while working to curb tobacco use. He later wrote the bestselling The End of Overeating as he expanded his research into addiction
    He has now at the tip of the spear in a (currently underway) PARADIGM SHIFT in Psychology.
    A unified field theory that links anxiety, obsession, impulse disorder, phobia, panic, addiction, depression, mania, hypochondriasis, and even some aspects of psychosis under a single term he coins as “capture.”
    An actual example as stated by Kessler in his recent (4.15.16) book: “You are settling down to work in a coffee shop or on an airplane. Lots of noise around you but a single loud voice in conversation captures you attention. You notice it, you determine to ignore it and get back to work but you can’t. Your will simply can’t make your mind let drop its attention to that loud (and by now surely obnoxious) voice. That’s capture.”
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    Drawing on his two decades of research, Kessler calls this underlying mechanism “capture” and reveals its three basic elements: ‘narrowing of attention, perceived lack of control, and change in affect, or emotional state.’ He devotes considerable attention to David Foster Wallace in a “Psychiatric Autopsy” of the worst case scenario: “capture turning on the self”…. He also carefully demonstrates how capture can lead to violence as well as exalted spiritual experiences. Kessler does ends on a note of hope, presenting a range of possible ways that people can potentially gain more control of their lives through an understanding of capture.”

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