Review of the evidence for PKMzeta and CaMKII as "Memory Molecules"

February 15, 2019

John Lisman, a friend and scientific sparing partner, died on October 20, 2017. John proposed in 1985 that an autophosphorylating kinase could be the molecular mechanism for memory persistence. He then worked on CaMKII as a memory storage molecule. See John's lecture, a week before he died.

John submitted a manuscript to Molecular Brain comparing the evidence in support of CaMKII and PKMzeta but died before the reviews. The manuscript was published as is and Todd and I wrote an accompanying review, along with expert commentary.

John and I disagreed on PKMzeta and CaMKII as memory molecules, but I loved arguing with him during our summer lunches on the dock of the Captain Kidd in Wood Hole. Thank you John for the opportunity to write this PKMzeta and CaMKII review. Many of us miss you.

Image credit: Panos Tsokas - LTP-inducing Schaffer Collateral stimulation increases PKMzeta expression (red) and synaptic responses in CA1

Video on Cell Press' YouTube channel - we think of navigation in terms of location, because of the way we draw maps... there is another way!

January 16, 2020

Video explaining the essential head-direction cell findings, a introduction to etak navigation, and featuring wisdom from friend and mentor Jim Ranck - wonderful stuff! 

Head-direction cell paper with Jim Ranck - Neuron Cover

January 16, 2019

Exciting to see the Cover image of today's issue of Neuron featuring EunHye's artwork - adaptation of a photo inspired by etak navigation of the Pacific Islanders! 

EunHye's head-direction cell paper out in Neuron - Congratulations EunHye - a massive and difficult study to complete

December 03, 2018

We find that that the direction sense as measured by head-direction ensemble discharge is internally-organized, and intermittently registered to distinct environmental features, more like in etak navigation than in a GPS with a consistently anchored compass. The data just would not make sense until we abandoned the conventional 2-D spatial map framework! It is a good think that Jim rank gave me that "We the navigators book back about 1993 and it is lucky I opened it some time in 2012! Thanks to Jim and the genius navigators of the Caroline Islands. Shout out to Cristina Savin, marking the first publication of our collaboration - see her website:

September 03, 2018

This opinion piece discussed the significance of our first grant cycle of work with the Fmr1-null mouse model of Fragile X Syndrome. The findings show the importance of a systems neuroscience approach to understanding such a complex condition like FXS, even if the cause is a single gene mutation.

Milenna's dentate paper inspired a Preview commentary in Neuron and a LeBron James piece in the Washington Post

May 18, 2018

The findings in the dentate gyrus place cell paper, akin to how scale free correlations in a flock of starlings defines the state of the flock, seem to resonate within the community and the community is broad!  Xiaojing Chen and Jim Knierim do a nice job of explaining how the findings clarify and correct some long standing ideas. Their double entendre "It's about time" riffs on the finding that the signature of hippocampal memories is expressed in the relative timing of action potential discharge and not where the cells discharge, as has been thought and investigated for decades. It is also about time, that the field starts to think about discharge timing amongst neurons rather than just single cell tuning when we investigate cognitive variables and cognitive representations. Washington Post columnist Sally Jenkins was fantastic to talk with about how the brain builds models of what we know and can execute those models to remember, execute and plan. See how she uses these ideas to fathom Lebron James' genius. 

Check out André on Nova Wonders

May 02, 2018

Nova Wonders is a show about some of the really big questions that science is tackling. It was super interesting (and really hard) to do this show! The shows are beautiful and fascinating - the co-hosts, especially Talithia and Rana are really really good - watch Wednesday evenings.

Congrats to Dr. Milenna van Dijk on successfully defending her thesis and on her Neuron paper!

April 26, 2018

Dentate gyrus neurons signal distinct memories and memory-related information by sub-second patterns of strong, weak, and independent co-firing, that are transiently enhanced by increased co-firing between excitatory and inhibitory cells. They don't signal distinct memories by remapping.

This is conceptually similar to the behavior of a large flock of flying starlings. The flock can take on many complex patterns while maintaining its cohesion as a flock. Different flock patterns occur when just a small number of starlings change course, responding for example, to avoid a threat, such as a predatory hawk. Similarly, transient increases of excitatory-inhibitory co-firing can signal memory discrimination within the globally-maintained spatial tuning and scale-free correlation structure of the discharging population of dentate place cells.

Congrats to Dino on his new EEG paper

April 26, 2018

The brain generates all our thoughts with the electrical activity of neurons. We imagine it should be possible to use brain electrical activity to figure out what kinds of thinking someone is doing. If we could do this, it would be useful to decide if someone is using their brain to think in a neurotypical  or or a neurodiverse way, a way that is typical for the person or a way that is atypical for that individual. That type of measurement can objectively guide all sorts useful decisions. But what signals in the EEG are most informative? How can we evaluate brain signals that are often contaminated with noise? That's what Dino set out to assess. The answer is in this IEEE paper.

Our new place cell papers on Fragile X Mice are online this week

January 18, 2018

Our latest work with hippocampus place cells in Fmr1 knockout mice published in two papers this week.

Congratulations especially to Dino, Zoe (who's a new mom!!), and Fraser (who's a new dad!! - unrelated to Zoe). It's been  a productive season!

Hippocampus electrophysiological signature of recollection and cognitive representational inflexibility in fragile X mice

January 18, 2018

Congratulations to the team on this meaty PLoS Biology paper. Special kudos to Dino for leading this from start to finish! 

Image: credit Dino Dvorak

To discover how knowledge inflexibility manifests in FXS, we took advantage of hippocampus place cells that typically discharge action potentials in discrete places (3 example place cell blue-to-red activity maps of a circular environment are shown). Moment-to-moment, place cell action potentials (black ticks) that occur during medium-frequency gamma inputs to hippocampus (yellow) encode the mouse’s current “local” position, and spiking that occurs during slow gamma activity (blue) encodes recollected “distal” positions. This occurs even when wild-type mice are challenged to use their knowledge flexibly by recollecting recent updated information (solid red) such as the current location of shock) instead of older outdated information (dotted red) such as the former location of shock, whereas FXS mice show cognitive inflexibility because their place cells discharge too often during slow gamma, causing the mice to recollect the outdated instead of the current information.

Our new PCP paper is out in Journal of Neuroscience

November 08, 2017

Maddy's tour de force on PCP disruption of spatial cognition and place cell discharge coordination with minimal impact on place fields. Although the spatial tuning of individual cells is undisturbed, their sub-second action potential discharge correlations are discoordinated by PCP. Specifically, PCP causes the cells that did not previously discharge together, to discharge together and this seems to produce the cognitive disturbance.  

Our new paper on the effects of deleting BC1 RNA is out in Learning & Memory

November 15, 2017

Genetic deletion of BC1 a non-protein coding RNA enhances group 1 mGluR-stimulated LTD and impairs active place avoidance learning, but the magnitude of these effects depend on the background strain of the mice. This is Ain's rotation project, when she was just trying out the lab. This was the cover story at Learning & Memory - Congratulations Ain!

New paper is out online showing that active place avoidance is neither stressful nor fear conditioning. Hopefully this paper will set the record straight.

October 18, 2016

We use the active place avoidance paradigm to investigate the neurobiological basis of memory and cognitive control because the paradigm is one of the most sensitive assays for hippocampus function in rodents. Mice and rats show task deficits after virtually any manipulation designed to disrupt hippocampus function, including partial and unilateral inactivation of hippocampus, ischemic stroke, silencing or ablation of adult born granule cells, and manipulation of synaptic plasticity molecular function. 


However, especially in reviews of our grants and those of colleagues, the active place avoidance task is assumed to be stressful and a form of fear conditioning. Unlike the water maze, inhibitory avoidance, and fear conditioning paradigms that are more commonly used to study the neurobiology of memory, active place avoidance is minimally stressful. In prior work, we have not been able to distinguish animals trained in the task from controls that never receive or avoid shock, using behavior and defecation as measures of responses to stress and fear. That work seems to not have convinced many in the community, who may be more familiar with the far more intense shock of other memory paradigms, and not appreciate how mild a 500 ms 0.2-0.3 mA shock feels.

In Edith's new paper we tried to address this concern of the community by measuring the stress hormone corticosterone in mice across learning the standard version of the active place avoidance task. Corticosterone levels were no different from control animals that explored the environment without receiving shock. Hopefully, this evidence will be compelling and allow the community to more accurately assess data collected within the paradigm, without the interpretational bias that can come from assumptions that are not supported by evidence, despite their intuitive appeal. As a final note, we always try to rely on experimental design, to control for factors we do not know, which is why depending on the question being addressed, we sometimes use untrained subjects or yoked-shock subjects to compare to subjects that perform active place avoidance.


Thank you Edith and the team for pulling together to hopefully clarify this issue for the community!

André talks to children about discovery, science and memory in a Tumble podcast

September 08, 2017

Tumble has terrific podcasts for children motivated by the children's questions. It was fun and surprisingly challenging to talk about the process of discovery science and memory in a way that was comprehensible and not boring. The picture show expansion microscopic images of learning-stimulated genetically-tagged (green = ChR2.0-eYFP) dendrites of hippocampus neurons with PKMzeta (red) co-localized to a select, sparse number of spines in the lower image. This image was created by Edith during her studies of the place avoidance PKMzeta engram.  

Rising Star: André Fenton, playful problem-solver

May 27, 2017

On the Fourth of July in Woods Hole, Massachusetts, you might find André Fenton dressed up as a neuron, surrounded by students pretending to be calcium ions and electrical signals. You might also find him quietly pondering the meaning of ‘reality.’


Fenton, professor of neural science at New York University (NYU), is equal parts fun and philosophical. At the Marine Biological Laboratory in Woods Hole, where he co-directs an eight-week course on the neural basis of behavior, he mixes deep discussions of the mind with water-balloon fights.

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