Friday Paper List – Posted Saturday Aug. 31st

You can quietly grab these papers and sneak out the back door…

Papers listed below:

1) A disinhibitory microcircuit initiates critical-period plasticity in the visual cortex Sandra J. Kuhlman, Nicholas D. Olivas, Elaine Tring, Taruna Ikrar, Xiangmin Xu & Joshua T. Trachtenberg ; Nature 2013 (link)

2) Optical control of mammalian endogenous transcription and epigenetic states Silvana Konermann, Mark D. Brigham, Alexandro E. Trevino, Patrick D. Hsu, Matthias Heidenreich, Le Cong, Randall J. Platt, David A. Scott, George M. Church & Feng Zhang ; Nature 2013 (link)

3) Cerebral organoids model human brain development and microcephaly Madeline A. Lancaster, Magdalena Renner, Carol-Anne Martin, Daniel Wenzel, Louise S. Bicknell, Matthew E. Hurles, Tessa Homfray, Josef M. Penninger, Andrew P. Jackson & Juergen A. Knoblich ; Nature 2013 (link)

  • Developmental Neuroscience: Miniature human brains Oliver Brustle ; Nature 2013 (link)

4) Molecular Mechanism for Age-Related Memory Loss: The Histone-Binding Protein RbAp48 Elias Pavlopoulos, Sidonie Jones, Stylianos Kosmidis, Maggie Close, Carla Kim, Olga Kovalerchik, Scott A. Small, Eric R. Kandel ; Science Translational Medicine 2013 (link)

5) Higher-Order Figure Discrimination in Fly and Human Vision Jacob W. Aptekar and Mark A. Frye ; Current Biology 2013 (link)

6) Building maps from maps in primary visual cortex Ian Nauhaus and Kristina J Nielsen ; Current Opinion in Neurobiology 2014 (link)

7) Temporally Precise Cell-Specific Coherence Develops in Corticostriatal Networks during Learning Aaron C. Koralek, Rui M. Costa, and Jose M. Carmena ; Neuron 2013 (link)

8) Scaling of Topologically Similar Functional Modules Defines Mouse Primary Auditory and Somatosensory Microcircuitry Alexander J. Sadovsky and Jason N. MacLean ; J Neurosci 2013 (link)

9) Theta Oscillations in the Medial Prefrontal Cortex Are Modulated by Spatial Working Memory and Synchronize with the Hippocampus through Its Ventral Subregion Pia-Kelsey O’Neill, Joshua A. Gordon, and Torfi Sigurdsson ; J Neurosci 2013 (link)

10) Joint Representation of Depth from Motion Parallax and Binocular Disparity Cues in Macaque Area MT Jacob W. Nadler, Daniel Barbash, HyungGoo R. Kim, Swati Shimpi, Dora E. Angelaki, and Gregory C. DeAngelis ; J Neurosci 2013 (link)

11) Reversible Information Flow across the Medial Temporal Lobe: The Hippocampus Links Cortical Modules during Memory Retrieval Bernhard P. Staresina, Elisa Cooper, and Richard N. Henson ; J Neurosci 2013 (link)

12) Rhythmic Whisking Area (RW) in Rat Primary Motor Cortex: An Internal Monitor of Movement-Related Signals? Todor V. Gerdjikov, Florent Haiss, Olga E. Rodriguez-Sierra, and Cornelius Schwarz ; J Neurosci 2013 (link)

13) An implantable neural probe with monolithically integrated dielectric waveguide and recording electrodes for optogenetics applications Fan Wu, Eran Stark, Maesoon Im, Il-Joo Cho, Eui-Sung Yoon, Gyorgy Buzsaki, Kensall D Wise and Euisik Yoon ; Journal of Neuroengineering 2013 (link)

14) Points of significance : Importance of being uncertain Martin Krzywinski & Naomi Altman ; Nature Methods 2013 (link)

Also the MIT Center for Neurobiological Engineering was just launched and you can check it out here. It looks pretty awesome.



Friday Paper List – August 23rd

I got wrapped up near the end of the week reading some back and forth in the “blogosphere” about some problems people have with optogenetics. As a card carrying member of the “I Love Optogenetics” fan club (don’t worry this is just a joke.. although I bet this could be a goldmine at SFN) it’s no surprise I was a bit flustered and defensive when I read this first blog entry:

Why “Optogenetic” Methods for Manipulating Brains Don’t Light Me Up* by John Horgan

I do wonder if the author is making a sincere argument or just kind of trolling optogenetics fanboys 🙂

Some of the reactions to that post lead me to this one:

On optogenetics by Mark Baxter

and then that lead me to this one:

Neurons do not have on/off switches by rxnm

I found all three interesting and definitely worth checking out!

Papers below:

1) Neuroscience thinks big (and collaboratively) Eric R. Kandel, Henry Markram, Paul M. Matthews, Rafael Yuste and Christof Koch ; Nature Reviews Neuroscience 2013 (link)

2) A visual motion detection circuit suggested by Drosophila connectomics Shin-ya Takemura, Arjun Bharioke, Zhiyuan Lu, Aljoscha Nern, Shiv Vitaladevuni, Patricia K. Rivlin, William T. Katz, Donald J. Olbris, Stephen M. Plaza, Philip Winston, Ting Zhao, Jane Anne Horne, Richard D. Fetter, Satoko Takemura, Katerina Blazek, Lei-Ann Chang, Omotara Ogundeyi, Mathew A. Saunders, Victor Shapiro, Christopher Sigmund, Gerald M. Rubin, Louis K. Scheffer, Ian A. Meinertzhagen & Dmitri B. Chklovskii ; Nature 2013 (link)

3) A directional tuning map of Drosophila elementary motion detectors Matthew S. Maisak, Juergen Haag, Georg Ammer, Etienne Serbe, Matthias Meier, Aljoscha Leonhardt, Tabea Schilling, Armin Bahl, Gerald M. Rubin, Aljoscha Nern, Barry J. Dickson, Dierk F. Reiff, Elisabeth Hopp & Alexander Borst ; Nature 2013 (link)

4) Connectomic reconstruction of the inner plexiform layer in the mouse retina Moritz Helmstaedter, Kevin L. Briggman, Srinivas C. Turaga, Viren Jain, H. Sebastian Seung & Winfried Denk ; Nature 2013 (link)

  • Commentary on the three papers above:
  • Accurate maps of visual circuitry Richard H. Masland ; Nature 2013 (link)

5) The First Stage of Cardinal Direction Selectivity Is Localized to the Dendrites of Retinal Ganglion Cells Keisuke Yonehara, Karl Farrow, Alexander Ghanem, Daniel Hillier, Kamill Balint, Miguel Teixeira, Josephine Juttner, Masaharu Noda, Rachael L. Neve, Karl-Klaus Conzelmann, and Botond Roska ; Neuron 2013 (link)

  • This paper above looks really good!

6) Distinct Basal Ganglia Circuits Controlling Behaviors Guided by Flexible and Stable Values Hyoung F. Kim, and Okihide Hikosaka ; Neuron 2013 (link)

7) BLA to vHPC Inputs Modulate Anxiety-Related Behaviors Ada C. Felix-Ortiz, Anna Beyeler, Changwoo Seo, Christopher A. Leppla, Craig P. Wildes, and Kay M. Tye ; Neuron 2013 (link)

8) Distinct Representations of Cognitive and Motivational Signals in Midbrain Dopamine Neurons Masayuki Matsumoto and Masahiko Takada ; Neuron 2013 (link)

9) The Sensory Neurons of Touch Victoria E. Abraira and David D. Ginty ; Neuron 2013 (link)

10) The Rodent Hippocampus Is Essential for Nonspatial Object Memory Sarah J. Cohen, Alcira H. Munchow, Lisa M. Rios, Gongliang Zhang, Herborg N. Asgeirsdottir, and Robert W. Stackman, Jr ; Current Biology 2013 (link)

11) The Head-Direction Signal Is Critical for Navigation Requiring a Cognitive Map but Not for Learning a Spatial Habit Brett Gibson, William N. Butler, and Jeffery S. Taube ; Current Biology 2013 (link)

12) Entrainment of the Human Circadian Clock to the Natural Light-Dark Cycle Kenneth P. Wright, Jr., Andrew W. McHill, Brian R. Birks, Brandon R. Griffin, Thomas Rusterholz, and Evan D. Chinoy ; Current Biology 2013 (link)

13) Probabilistic brains: knowns and unknowns Alexandre Pouget, Jeffrey M Beck, Wei Ji Ma & Peter E Latham ; Nature Neuroscience 2013 (link)

14) Balanced cortical microcircuitry for maintaining information in working memory Sukbin Lim & Mark S Goldman ; Nature Neuroscience 2013 (link)

15) Neural Correlates of Interval Timing in Rodent Prefrontal Cortex Jieun Kim, Jeong-Wook Ghim, Ji Hyun Lee, and Min Whan Jung ; J Neurosci 2013 (link)

16) CA1 Pyramidal Cell Theta-Burst Firing Triggers Endocannabinoid-Mediated Long-Term Depression at Both Somatic and Dendritic Inhibitory Synapses Thomas J. Younts, Vivien Chevaleyre, and Pablo E. Castillo ; J Neurosci 2013 (link)

17) Critical Role of the Hippocampus in Memory for Elapsed Time Nathan S. Jacobs, Timothy A. Allen, Natalie Nguyen, and Norbert J. Fortin ; J Neurosci 2013 (link)

18) Association Rules for Rat Spatial Learning: The Importance of the Hippocampus for Binding Item Identity With Item Location Mathieu M. Albasser, Julie R. Dumont, Eman Amin, Joshua D. Holmes, Murray R. Horne, John M. Pearce, and John P. Aggleton ; Hippocampus 2013 (link)

19) Speed Modulation of Hippocampal Theta Frequency Correlates With Spatial Memory Performance Gregory R. Richard, Ali Titiz, Anna Tyler, Gregory L. Holmes, Rod C. Scott, and Pierre-Pascal Lenck-Santini ; Hippocampus 2013 (link)

20) Imagining the Future: Evidence for a Hippocampal Contribution to Constructive Processing Brendan Gaesser, R. Nathan Spreng, Victoria C. McLelland, Donna Rose Addis, and Daniel L. Schacter ; Hippocampus 2013 (link)

21) Internal operations in the hippocampus: single cell and ensemble temporal coding George Dragoi ; Frontiers in Systems Neuroscience 2013 (link)

22) Competitive trace theory: a role for the hippocampus in contextual interference during retrieval Michael A. Yassa and Zachariah M. Reagh ; Frontiers in Behavioral Neuroscience 2013 (link)

I’ll let the band take us out….

One two three hit it !

Friday Paper List – Posted Saturday August 17th

It has been tough getting back into the swing of things, especially since I have recently moved. Hopefully my posts will become more consistent again. Plus Part 2 of the Special Blog Post on Magnificent Memory Manipulations  will come out eventually, I promise!

On to the papers:

1) Oxytocin enhances hippocampal spike transmission by modulating fast-spiking interneurons Scott F. Owen, Sebnem N. Tuncdemir, Patrick L. Bader, Natasha N. Tirko, Gord Fishell & Richard W. Tsien ; Nature 2013 (link)

2) Prolonged dopamine signalling in striatum signals proximity and value of distant rewards Mark W. Howe, Patrick L. Tierney, Stefan G. Sandberg, Paul E. M. Phillips & Ann M. Graybiel ; Nature 2013 (link)

3) Direct recordings of grid-like neuronal activity in human spatial navigation  Joshua Jacobs , Christoph T Weidemann , Jonathan F Miller , Alec Solway, John F Burke, Xue-Xin Wei, Nanthia Suthana, Michael R Sperling, Ashwini D Sharan, Itzhak Fried & Michael J Kahana ; Nature Neuroscience 2013 (link)

4) Septo-hippocampal GABAergic signaling across multiple modalities in awake mice Patrick Kaifosh, Matthew Lovett-Barron, Gergely F Turi, Thomas R Reardon & Attila Losonczy ; Nature Neuroscience 2013 (link)

For those of you interested in the transformation of sensory input from thalamus to cortex, three papers just came out in Nature Neuroscience on that topic!

5) Tuned thalamic excitation is amplified by visual cortical circuits Anthony D Lien & Massimo Scanziani ; Nature Neuroscience 2013 (link)

6) Linear transformation of thalamocortical input by intracortical excitation Ya-tang Li, Leena A Ibrahim, Bao-hua Liu, Li I Zhang & Huizhong Whit Tao ; Nature Neuroscience 2013 (link)

7) Intracortical multiplication of thalamocortical signals in mouse auditory cortex Ling-yun Li1,, Ya-tang Li, Mu Zhou, Huizhong W Tao & Li I Zhang ; Nature Neuroscience 2013 (link)

8)  Lineage-specific laminar organization of cortical GABAergic interneurons Gabriele Ciceri, Nathalie Dehorter, Ignasi Sols, Josh Z Huang, Miguel Maravall & Oscar Marín ; Nature Neuroscience 2013 (link)

9) Extended practice of a motor skill is associated with reduced metabolic activity in M1 Nathalie Picard, Yoshiya Matsuzaka & Peter L Strick ; Nature Neuroscience 2013 (link)

10) Motor Cortex Feedback Influences Sensory Processing by Modulating Network State Edward Zagha, Amanda E. Casale, Robert N.S. Sachdev, Matthew J. McGinley, and David A. McCormick ; Neuron 2013 (link)

  • Top-Down Control of Cortical State Kenneth D. Harris ; Neuron 2013 (link)

11) Cellular and Synaptic Architecture of Multisensory Integration in the Mouse Neocortex Umberto Olcese, Giuliano Iurilli, and Paolo Medini ; Neuron 2013 (link)

12) Potassium Channels Control the Interaction between Active Dendritic Integration Compartments in Layer 5 Cortical Pyramidal Neurons Mark T. Harnett, Ning-Long Xu, Jeffrey C. Magee, and Stephen R. Williams ; Neuron 2013 (link)

13) Coding of Information in the Phase of Local Field Potentials within Human Medial Temporal Lobe Beth A. Lopour, Abtine Tavassoli, Itzhak Fried, and Dario L. Ringach ; Neuron 2013 (link)

14) Formation and Reverberation of Sequential Neural Activity Patterns Evoked by Sensory Stimulation Are Enhanced during Cortical Desynchronization Edgar J. Bermudez Contreras, Andrea Gomez Palacio Schjetnan, Arif Muhammad, Peter Bartho, Bruce L. McNaughton, Bryan Kolb, Aaron J. Gruber, and Artur Luczak ; Neuron 2013 (link)

15) The Need for Research Maps to Navigate Published Work and Inform Experiment Planning Anthony Landreth and Alcino J. Silva ; Neuron 2013 (link)

16) Genetically Targeted Optical Electrophysiology in Intact Neural Circuits Guan Cao, Jelena Platisa, Vincent A. Pieribone, Davide Raccuglia, Michael Kunst, and Michael N. Nitabach ; Neuron 2013 (link)

  • I have worked with Voltage Sensitive Dyes in the past and I strongly believe that a good GEVI (Genetically Encoded Voltage Indicator) is the future of neuroscience. So I find this work very very exciting!
  • I should also point out, the above image also does a good job of illustrating how I feel about being back in the lab after almost a year 🙂

17) Sparse reconstruction of brain circuits: Or, how to survive without a microscopic connectome Nuno Maçarico da Costa, Kevan A.C. Martin ; NeuroImage 2013 (link)

18) Noise focusing and the emergence of coherent activity in neuronal cultures Javier G. Orlandi, Jordi Soriano, Enrique Alvarez-Lacalle, Sara Teller and Jaume Casademunt ; Nature Physics 2013 (link)

19) Top-Down Beta Rhythms Support Selective Attention via Interlaminar Interaction: A Model Jung H. Lee, Miles A. Whittington, Nancy J. Kopell ; PLoS Computational Biology 2013 (link)

20)  Surge of neurophysiological coherence and connectivity in the dying brain Jimo Borjigin, UnCheol Leed, Tiecheng Liu, Dinesh Pal, Sean Huff, Daniel Klarr, Jennifer Sloboda, Jason Hernandez, Michael M. Wang, and George A. Mashour ; PNAS 2013 (link)

  • It looks like for about 30 seconds after death these rats temporarily turn into zombies. Luckily this is only temporary…

21)  Deep impact: unintended consequences of journal rank Björn Brembs, Katherine Button and Marcus Munafo ; Frontiers in Human Neuroscience 2013 (link)


A Special Blog Post: Magnificent Manipulations of Memory – Part 1

A little while ago the lab of Nobel Prize winner Dr. Susumu Tonegawa published a paper in Science (they also scored the cover for this issue):

Creating a False Memory in the Hippocampus Steve Ramirez,  Xu Liu,  Pei-Ann Lin, Junghyup Suh, Michele Pignatelli, Roger L. Redondo, Tomás J. Ryan, Susumu Tonegawa; Science 2013 (link)

After it came out you might have read about the paper in various news headlines all over the internet such as:

  • False memory planted in mouse’s brain –
  • Scientists can implant false memories into mice –
  • Scientists give mice false memories –

Or maybe from some more exciting ones like:

  • Nobel Prize Winning Scientist Recreates “Inception” in Mice –
  • ‘Total Recall’ for Mice –
  • Scientists create false memories in mice, cause rodent-style Inception –
  • Memory implantation is now officially real –

and there were some great pictures like these two:



So there was certainly plenty of hype about this new paper.

But when the paper came out I was puzzled because at first glance it wasn’t clear to me what was so new and exciting.

Now you might be thinking I’m crazy. How could I possibly not be excited about this news? What could be more amazing than evidence for implanting a memory into a mouse using optogenetics? The line between science-fiction and reality is blurring more and more and you aren’t even impressed?!

Well I should make it clear- it wasn’t that I wasn’t impressed, amazed, and head over heels about the research and the paper- I was just confused because I thought I had already flipped out about how exciting this was a year ago! What I mean is, I was extremely excited about the paper published from Dr. Tonegawa’s lab last year in Nature. In fact it made the very top of my list of the Top Papers of 2012 !!!

So I wasn’t quite sure what was different about this new paper published in Science. Wasn’t this already shown? From the same lab? A year ago? Am I losing my mind? Was this time travel? Was this even a false memory?!

So with this in mind I pulled up the first publication:

Optogenetic stimulation of a hippocampal engram activates fear memory recall Xu Liu, Steve Ramirez, Petti T. Pang, Corey B. Puryear, Arvind Govindarajan, Karl Deisseroth & Susumu Tonegawa ; Nature 2012 (link)

and the new one:

Creating a False Memory in the Hippocampus Steve Ramirez,  Xu Liu,  Pei-Ann Lin, Junghyup Suh, Michele Pignatelli, Roger L. Redondo, Tomás J. Ryan, Susumu Tonegawa; Science 2013 (link)

Just reading the titles made it clear that the papers were in fact different. The first activates recall of a memory, while the second creates a false memory. But I wanted to make sure I was understanding what these differences actually were.

So I found myself posting figures from both papers in a powerpoint file to keep track of which paper did what and how it was done. While making notes about what each paper showed I started getting really excited about both papers, as well as the comparison between the two. This enthusiasm about both papers is what inspired me to write this incredibly long blog post about what each paper shows.

So below is my attempt to explain the findings from the Liu et al. 2012 Nature paper and the Ramirez et al. 2013 Science paper in clear and simple fashion. Hopefully it will be a fun read for folks who don’t normally read science publications and would like to understand what each paper shows. And for those who do, I hope you enjoy my attempt to give an overview of the findings in a way that is clear and easy to understand.

With that short introduction I now give you this very special blog post:

*                 *                 *

Magnificent Manipulations of Memory : an overview of two papers harnessing optogenetics for research on memory in the hippocampus.

 *                 *                 *

Embarking on any story about memory and the hippocampus almost always needs to start at the same place: with a 27 year old man named Henry Molaison also known as the infamous patient H.M.

Henry Molaison

Henry suffered from debilitating seizures and seeking treatment led him to Dr. William Scoville a neurosurgeon at Hartford Hospital in Connecticut. Dr. Scoville performed what was and in some cases still is considered a routine procedure to alleviate Henry’s seizures. The procedure is to open up the patient’s skull, find the area where the seizures are believed to be originating, and remove that part of the brain. In Henry’s case this meant removing, among other things, the hippocampus on both the left and right sides.

*As an important aside, when your typical neuroscientist hears about the Hippocampus he or she might think of a seahorse. This is because the name “hippocampus” originates from the Greek: ἵππος, “horse” and κάμπος, “coiled” – which referred to a seahorse.

Here is a hippocampus cut out of a brain next to a seahorse. They look the same.

However, for everyone else who is not a neuroscientist, when they hear the name hippocampus they think of a hippopotamus.


These do not look the same.

Back to our story…. In a nutshell, after having his hippocampus removed on both sides of his brain removed, Henry lost the ability to create new memories, which is called severe anterograde amnesia. This is a very rough approximation of what happened…but the point is Henry revealed the importance of the hippocampus with respect to memory. There is a long list of things we have learned from Henry and research with him after his surgery provided key insights into the existence of different types of memory in a complex memory system.  In general the field of memory research in neuroscience is built on a foundation of research from Henry Molaison and if you aren’t familiar with his story I highly recommend at least reading the wikipedia entry about him here

Mooving along, we now have the first building block of our story, that the hippocampus is important for memory. Insert a couple decades of neuroscience research and we arrive at the recent work from the Tonegawa lab in the Picower Institute for Learning and Memory at MIT.

Before being able to walk through the recent papers it is essential to cover some basics for memory research in the mouse hippocampus. Below is a cartoon “key” for this story.


In the key above you should be able to see that we have

  • a mouse
  • a window into this mouse’s hippocampus
  • inside the window to the hippocampus, several hippocampal neurons.
  • and finally the environment this mouse is in at this very moment. In this case a grey area that I will simple refer to as the Grey Place (creativity in names has never been my strength)

Now that we have gone over the key we can move on to our this cartoon. Below is a picture of what we think is happening in the mouse’s hippocampus when a mouse is exposed to a new environment. This roughly illustrates the current hypothesis of how memories are formed in the brain. So for our first cartoon we grab a mouse and move him from the Grey Place to a new environment for the first time, the Blue Place. formblueMemory Hopefully what you see above is that over time, as the mouse explores and hangs out in the Blue Place, a subset of active neurons in the hippocampus are encoding the mouse’s memory of this Blue Place.

…OK, that might be a complicated thing to see illustrated above…this is not a small or trivial concept and warrants further explanation…

What do I mean when I say these neurons in the hippocampus are, “encoding the mouse’s memory of this Blue Place” ? This question brings up an even more fundamental question: what is a memory? This is one of the most important questions in modern neuroscience, but on a basic and abstract level we have the following hypothesis:

Somehow a memory is made and stored in the brain.. and the brain is made up of neurons… so we think that a memory is in a way “made up” of neurons. More specifically we think that a memory might be made up of a specific set of neurons that are connected in a specific way. This entire abstract idea culminates in what is known as the Engram (you can read the basic stuff about the engram here).

So to illustrate the idea of the a memory or engram for the environment in the hippocampus we are going to move this mouse out of the Blue Place and place him back in the Grey Place.engramcomparison1

Now in the picture above we compare what we see when we look at our mouse before he had been to the Blue Place and after. When we look inside our special window into the hippocampus we can see that before we moved him, the mouse had no memory of the Blue Place. This should be fairly straightforward because the mouse had never been to this particular Blue Place.. sorry I forgot to mention it was his first time out and about 🙂 But if we look in the window to the hippocampus after the mouse has spent some time in the Blue Place we can see that there is a memory “trace” or engram inside the hippocampus- these are the cells that make up the memory of the Blue Place. 

It is very important to take this idea of the engram and what a memory is one step further in order to continue and make sure this concept is crystal clear!

Let’s look at our mouse, which is now sitting in the Grey Area just hanging out from a different perspective. On the right of the equals sign we have an illustration of what the mouse is thinking about at this particular moment in the typical cartoon style of a thought bubble. You can see on the left how this is translated into our cartoon with a window into the hippocampus. Both the left and the right represent the mouse sitting in the Grey Place thinking about nothing in particular, so for this reason the thought bubble is empty.


Now the key to the concept of an engram is in this next picture below!  What you should see is that in our typical cartoon on the left, inside the window into the hippocampus, the neurons which are marked in blue to represent the memory for the Blue Place are now activated (this is illustrated by lighting up the neurons with yellow to represent activity/ firing of action potentials). Now if you look at the equivalent cartoon on the right you can see that when the neurons that make up the engram / memory for the Blue Place are active this is equal to when the mouse is thinking about being in the Blue Place! So when the mouse has an experience, this is recorded as a memory in a specific set of cells that we call an engram. Then later if the mouse is recalling this memory he is activating the cells that make up the engram.


So I’ll rewrite this one more time. The very important point is that when the mouse is thinking about being in the Blue Place the memory or engram for the Blue Place is active!! So the memory for the Blue Place is a particular set of neurons in the hippocampus and when these neurons are active the memory itself is active.

Alright at this point we have completed the first big step in the story, so if you have made it this far congratulations! Now of course you may consider yourself an expert in modern neuroscience memory theory. Feel free to brag about how smart you are next time you get a chance.

For our next illustration and to gain a deeper understanding of the concepts above we are going to pick up our mouse and put him in another new environment, the Red Place. And as you expected after leaving the mouse there for a little bit to hang out and explore there is now a memory of the Red Place taking shape in his hippocampus. thingaboutRedPlace We can really drive home our understanding of what an engram is supposed to reperesent, meaning the neural substrate that is a memory, by looking at our mouse when we put him back in the Grey Place and watch as he thinks about /remembers his experience in the Blue Place (below)


as well as when he remembers that time he was in the Red Place :


Alright, at this point we should be pretty comfortable with the symbols in our cartoon and the idea of an engram. You noticed that in the cartoons above when the mouse was thinking about his memory of being in the Blue Place a specific subset of cells where active and when he though about his time in the Red Place a different subset of cells where active.

The next concept we need to quickly cover is about learning and associations. Learning is intrinsically tied to the concept of memory and in this case you might be more familiar with the name “Classical conditioning” , “Pavlovian leaning” or the anecdote about “Pavlov’s Dog”. Pavlov’s dog refers to the famous story about the Russian researcher Ivan Pavlov who demonstrated the principle of Classical Conditioning in his classic experiments. Pavlov trained his dog to associate the sound of a bell with being fed by ringing the bell right before he immediate gave him his food. So, after a while whenever the bell was sounded the dog’s mouth started watering in anticipation of the yummy food. In the experiments published in the two Tonegawa papers, the researchers use a particular type of classical conditioning called Fear Conditioning.

* as an important aside you should definitely check out this video for a great example of Pavlov’s dog! I found a copy of the clip on here.

So to go over how Fear Conditioning is used in memory research let’s get a brand new mouse and move him for the first time into the Red Place. This time though, after a short time we are going to provide a small shock of electrical current through the floor, a Foot Shock. firstFootShock As you can see, even though the shock was small and mostly harmless, the mouse did not enjoy being shocked and the shock certainly scared him quite a bit!

What is important in this example is that when we return the mouse to the Grey Place  below we can see that the mouse has a very distinct memory of the Red Place. The mouse doesn’t just remember the color of the floor but instead he also has a very strong memory that when he was in the Red Place he was shocked. This fear memory is so strong that we can see when we move the mouse from the Grey Place to the Red Place again the next day the mouse is noticeably scared and upset about being back in the Red Place. The Red Place is now associated in the mouse’s mind with a foot shock and even if there isn’t a foot shock provided the mouse will be very scared and uncomfortable because he has such a strong memory of being shocked last time he was in the Red Place.


At this point some readers might be a little upset and ask the question, “why do we have to shock this poor mouse? Do we have to do fear conditioning? Why not happy conditioning?”

The simple answer is that besides being the fact that they are very easy to quickly form and very strong when formed, fear memories are easier to detect that others, meaning it is easy to tell if the mouse is scared when you put him back in the Red Place. This is an important and reliable behavioral readout because it tells us that the mouse remembers being in the Red Place and having the foot shock in the past. So in experiments scientists need a good way to detect if the mouse has a memory or not and the Fear Conditioning paradigm provides a good behavioral readout for determining what the mouse does or does not remember.

Alright, now that we have gone over some basic theories about memory in the hippocampus, the engram, and fear conditioning, we can start to look at the first paper:

Optogenetic stimulation of a hippocampal engram activates fear memory recall Xu Liu, Steve Ramirez, Petti T. Pang, Corey B. Puryear, Arvind Govindarajan, Karl Deisseroth & Susumu Tonegawa ; Nature 2012 (link)

It is important to point out that the purpose of this post is to present the basic results and observations for a simple overview and comparison between the two papers. So in some cases I will be skipping over details or reducing complicated methods down to silly abstract ideas.  But for those who are interested in the details and methods of course read the papers!

Now the key to both of the Tonegawa papers rests on an amazing combination of modern genetic techniques, including  c-fos-tTA transgenic mice and AAV9-TRE-ChR2-EYFP viral injections! The special genetically engineered mice are super important in enabling the papers to ask the questions they ask!

Ok.. ok.. now there is a chance this is what happened to several people when they read ” c-fos-tTA transgenic mice and AAV9-TRE-ChR2-EYFP viral injections”


or just

.. but don’t worry! I promise to walk through whatever you need to know and make things simple. And in general we don’t need to go over the details of what most of that means!

So back to the paper. Why don’t we ignore the real name and just lump together all of these terms to make a name for these special mice:

c-Fos-tTA -AAV9-TRE-ChR2-EYFP …….

Then as scientists often do, why don’t we take the first letter of each term and try to make a shorter nickname?

cFos-tTA –AAV9-TRE-ChR2-EYFP mice = cFtTATCE mice?

OK… that looks horrible and even more confusing.. how about we just go with calling the genetically engineered mice, MightyMice?

Ok, so what does it mean for the mouse to be a MightyMouse? In this case the Tonegawa lab’s MightyMouse has a very important super power. We can deconstruct what this super power is by looking at two important terms in the complicated scientific mumbo jumbo.

The first is the c-fos at the beginning : c-Fos-tTA -AAV9-TRE-ChR2-EYFP.

c-Fos is the name of a gene that is expressed when neurons fire lots of action potentials- meaning when they are very active.

The next important part is the ChR2 which you can see near the end of the mumbo jumbo here: c-Fos-tTA -AAV9-TRE-ChR2-EYFP

ChR2 stands for channelrhodopsin 2 and this is the name of our favorite optogenetic protein channel. In other words this is our light activated switch!

So the super power for the MightyMouse is that when neurons in the MightyMouse’s hippocampus are highly active they express genes that make optogenetic switches!

Because this is so important for both papers I’ll explain this in more detail. Let’s review what happens during the formation of a memory.

When the mouse is placed in any given environment there is a particular sub-set of neurons that are highly active in that environment. Those highly active neurons are the ones that become the special sub-set of neurons that represent that environment- they form / become the memory / engram for that experience in that environment. So when the mouse is in the environment, those cells fire a lot. When the mouse is off somewhere thinking about the environment – remembering it –  those cells again are being activated and firing  – essentially “replaying” the memory.

Now remember what makes these MightyMice so cool is that when neurons are highly active they start to express a gene that inserts a switch into their cell membrane (the optogenetic switch)! This allows the scientists to control these cells later.

So below we can see the difference between a normal mouse and the MightyMouse used in these studies:


You can see in the cartoon above some of the neurons in the hippocampus of the normal mouse are more active in this Blue Place than others.  This is because over time this neurons are becoming the memory for that place. So blown up in size on the far right we can see in the normal mouse both a neuron that is part of the memory / engram for the Blue Place on the top and blown up in size below it is just another neuron that is not part of that memory / engram.

Now if we look below at the same situation in the MightyMouse we can see the exact same parts except for one simple but very important difference. In the MightyMouse, the neurons that were more active also express the optogenetic switch. So as you can see the MightyMouse is a very special mouse because they allow the scientists to activate this very specific sub-set of neurons in the hippocampus whenever they want! In the example above, scientists would be able to switch on only the neurons that make up the memory/engram for the Blue Place without affecting the other surrounding neurons.

OK, so I’m sure you are getting excited and are very eager to get to the actual experiment from the first paper. Before we do I have to introduce two final pieces to the puzzle. These are the last two I promise!

The first is MightyMouse kryptonite. Yes you read that right. The MightyMouse from the Tonegawa lab does have one weakness! There is a chemical that we will refer to as Dox. If the MightyMice eat Dox it will temporarily suppress their super powers. Observe below!


Now for the last and final piece of the puzzle before we get to the experiment. This is just a quick and simple refresher on optogenetics. Chances are if you are reading this blog, then like me you are already familar with how optogenetics works, but just in case here we go:  Channelrhodopsin 2 (ChR2) is an optogenetic tool that we can use to control neurons with light. With ChR2 we can switch neurons ON and make them active / fire action potentials by shining blue light on them! Demonstrated below:


Alright, we have arrived at last! Now I mean it! We can really start to go over the experiment and results presented in the first paper:

Optogenetic stimulation of a hippocampal engram activates fear memory recall Xu Liu, Steve Ramirez, Petti T. Pang, Corey B. Puryear, Arvind Govindarajan, Karl Deisseroth & Susumu Tonegawa ; Nature 2012 (link)

The experiment in this paper has basically three steps. Yeah I know.. all of this just for an experiment with three lousy steps?! What’s the deal? Before you get upset and throw your computer on the ground let me say this- in my opinion a well designed experiment should be as simple as possible, so trust me this paper packs plenty of power in this simple three step experiment.

Step 1

For the first part of the experiment Liu et al. take their MightyMouse (who has been eating food mixed with Dox) and place him in a environment we will call Place A. The mouse hangs out in Place A for 5 days becoming familiar and comfortable with the new environment. As you know from above while he is in Place A the MightyMouse will be forming a memory in his hippocampus of Place A.


Over these 5 days the MightyMouse spends  in Place A Liu et al. would occasionally flashed blue light on his hippocampus.

This is a very important control. Liu et al. demonstrate in this first step that at this point the MightyMouse is very comfortable in Place A and he never really cares that Liu et al. occasionally flashes blue light onto his hippocampus. It doesn’t really bother him and when you think about it why should it? Shining blue light on neurons doesn’t do anything. If you want you can test this out for yourself at home. Go buy a flashlight that emits blue light and shine it on your brain..nothing happens. Trust me 🙂

So you can see this important control illustrated below.


Step 2

For the next step things get exciting! To begin with Liu et al. stop mixing Dox with MightyMouse’s food! As the Dox clears away from MightyMouse’s system his powers are activated and he becomes the MightyMouse we all know and love, HOORAY!

Once the MightyMouse is no longer eating Dox he is now placed in a brand new environment, Place B for 2 days. Over these two days, with his super powers unleashed, the MightyMouse explores the new environment and a new set of neurons in the hippocampus are active in Place B, forming the memory of Place B. It is important to remember that the MightyMouse has a hippocampus that has super powers! Not only are there neurons firing in this new environment, becoming associated with Place B and forming the memory/engram for Place B, but they are also  starting to express the optogenetic switch ChR2 in their cell membranes!

The cartoon below illustrates what is happening so far in Step 2.


Now for two days the MightyMouse wakes up in his home cage and is moved into Place B to hang out and explore. On the third day after MightyMouse is placed in Place B Liu et al. apply a Foot Shock through the floor of Place B. This is illustrated below.


As you know from earlier, this type of Fear Conditioning has a very powerful effect on the memory MightyMouse has for Place B. You can see that when the Foot Shock is applied MightyMouse integrates the vivid experience of being shocked into his memory of Place B In other words from now on MightyMouse will associate Place B as the place he was shocked. And MightyMouse did not like being shocked. Overall if you were to ask this MightyMouse about Place B after this third day, he would probably say,

“I have a very bad memory of that awful Place B. Last time I was in Place B I had these awful shocks. Place B is not a happy place.” 

Now if you were a particularly inquisitive news reporter for the local paper, you might even ask this MightyMouse to compare his memories and feelings about Place B with those of Place A. In this case the MightyMouse would probably say something like,

“Well gosh, I have very different memories of those two places. In fact, they couldn’t be more different. I mean Place A was a pretty nice spot. Besides the occasional strange flash of blue light I found it to be fairly pleasant. It had nice blue floors and was a nice square shaped place. I’ve always liked square shaped places.

Now Place B is an entirely different story. Place B was all round and had very red floors. And let me tell you, I’ll never forget the last time I was in Place B! I was shocked a whole bunch! I really didn’t like that. In fact I really don’t ever want to go back to Place B if I can help it. I have nothing but bad memories of my time spent in Place B.  Just thinking about that awful place sends shivers down my tail. 

Step 3

At last we are at the last step of the experiment in this first paper. FYI – the mouse interview above was not included in the actual experiment. After Step 2 was over Liu et al started mixing Dox back into MightyMouse’s food. So MightyMouse no longer has a hippocampus with activity-dependent expression of ChR2 super powers.

Now for the big moment and final step the next day Liu et al. placed the MightyMouse into Place A. As expected, the MightyMouse went about his usual business and sniffed around the area, just hanging out in Place A like any other time when he used to hang out in Place A.

Then Liu et al. flashed blue light on MightyMouse’s hippocampus …..

…. and MightyMouse immediately froze. Whenever Liu et al. flashed blue light onto MightyMouse’s hippocampus, he showed signs of freaking out and being scared. You can see this illustrated below.


So what’s happening here? Why is this such a big deal?

Let’s go over the state of MightyMouse’s hippocampus. After being exposed to Place B while off Dox – MightyMouse formed a distinct memory of Place B and this memory was associated with a Foot Shock. After being put back on Dox, we have a MightyMouse that had an memory of being shocked in Place B that can be switched on by blue light via optogenetics. So this is exactly what this paper shows. MightyMouse was shown relaxing in the normal Place A minding his own business, and then when blue light was flashed over his hippocampus, the neurons that encoded for the memory of Place B was activated, causing him to freeze, almost an identical response to what would happen if you placed MightyMouse back into Place B.


So there you have it… Liu et al. were able to selectively tag a specific memory of a specific place and then reactivate that memory with a flash of blue light. They evoked the fear response in a non-threatening environment (Place A) by optogenetically activating the memory of a scary place (Place B).

* as a small aside – for those who enjoy finding flaws in everything you read (the perpetually skeptical) you might be thinking, “wait what about possibility X? or condition Y?” I’m not going to take the time to cover all of the controls that were explored to confirm this is what was actually happening, but they are all in the paper. So of course read the paper!

Now this is a big deal. As the title says, the authors demonstrate optogenetic activation of an engram representing a fear memory! So on the most basic level let’s just look at what the researchers did one more time:

They activated a specific memory in a mouse’s brain using blue light.

I think it’s kind of neat to take a step back now to get some perspective. Let’s go back a couple decades around the time Dr. Scoville was performing neurosurgery on Henry Molaison. At about the same time there was another very famous neurosurgeon by the name of Dr. Wilder Penfield. Dr. Penfield would perform several procedures similar to the one carried out on Henry Molaison, but he also published research from electrical stimulation of cortex in awake patients during procedures. There really is no way I can do justice to covering all of the important contributions Dr. Penfield made to the field of neuroscience (read more about him here), but let’s focus on his reports following electrical stimulation of the temporal lobe. Dr. Penfield wrote that stimulation of the temporal lobe in awake patients over what he deemed, “memory cortex” caused patients to experience a memory:

Recollections which are clearly derived from a patient’s past memory can sometimes be forced upon him by the stimulating electrode. The psychical experience, thus produced, stops when the electrode is withdrawn and may repeat itself when the electrode is reapplied. Such psychical results have been obtained from stimulation of certain areas of the temporal cortex, but from no other areas of the brain. – Memory Mechanisms, Wilder Penfield, Archives of Neurology and Psychiatry 1952

So for example you can see in figure 4 below a diagram of electrical stimulation mapping of patient R.W. The electrode was added by me if you couldn’t tell. Penfield wrote that when he stimulated site #31 and #30 the patient said he had a vivid experience of listening to his mother talk on the phone with his aunt- which was a memory from earlier that day.


One important point is that these stimulations in what Penfield referred to as “memory cortex” were very different from the evoked responses reported when stimulating areas of the primary sensory cortices. For instance if you stimulated in the visual cortex, say in area #20 in the diagram above, the patent might report seeing a twinkling white spot in their visual field. Or if he stimulated somatosensory cortex, a patient might report feeling a tingling sensation over a specific part of their body. But when the “memory cortex” was stimulated, patients reported very vivid re-experiencing of memories.

So now we can look at Penfield’s historic experiments from the 1950’s where he was occasionally able to evoke memories with electrical stimulation in the cartoon below. We can see when the brain is stimulated it evoked a vivid memory of watching a mother speak on the phone.


Now we can compare this with the Liu et al. paper, where scientists were now able to evoke a specific memory in a MightyMouse using optogenetics!


Pretty amazing when you think about it. Especially when you consider that Dr. Penfield was just randomly stimulating areas and the memory he got was up to chance as he was activating thousands of neurons. In the Liu et al. experiment a specific memory was evoked by activating a sparse sub-set of hippocampal neurons, demonstrating that these few neurons were sufficient to evoke a memory and fear response. This paper is very strong evidence for the idea of the existence of an engram in the hippocampus and it’s really beautiful work!

But of course there is the next paper, which is even more important and amazing….

* Because this post ended up being the longest thing ever.. I will bring the epic conclusion where I walk through the even more exciting and more recent second paper from the Tonegawa lab in the Part 2  for this post. Besides walking through the experiment and results I will explain the difference between the two papers and why the second one is such a big deal!

I hope you enjoyed reading this post as much as I enjoyed writing it. Please I encourage you to make any comments or ask any questions in the comments section below. There really is nothing better than going over a paper and then discussing it with others! So please let me know what you think!

P.S. I would like to thank my amazing younger brother for being kind enough to read over this lengthy blog post and give me much needed feedback. I especially appreciate that he brought to my attention my severe inability to properly use the words “where” and “were”.

Posting a list of papers every week is child’s play compared to actually writing something. This post would be much worse without my brother’s help. Thank you.

Friday Paper List – posted Monday August 5th?!

Well hello there!

It has been two whole weeks since my last post. Sorry about that. Besides being busy with things in the real world, I have been working on and off on a SUPER BIG SPECIAL blog post!

So I am almost done with Part 1 of the super special giant sized blog post and should be posting it either late tonight or sometime tomorrow.

I know what you are thinking, “Part 1 you say? So this super special blog post is so big it has more than one part to it?”

Well the answer is yes! It will be a very big blog post. So get excited. I know I am excited to share it with everyone.

In the meantime I just wanted to quickly confirm that I am not dead and throw up some papers from weeks ago.

As I mentioned I am very excited about this special blog post and I’ll go ahead and tell you that it was inspired by #1 on this list.. so please stay tuned!

1) Creating a False Memory in the Hippocampus Steve Ramirez,  Xu Liu,  Pei-Ann Lin, Junghyup Suh, Michele Pignatelli, Roger L. Redondo, Tomás J. Ryan, Susumu Tonegawa; Science 2013 (link)

2)  An ultra-lightweight design for imperceptible plastic electronics Martin Kaltenbrunner, Tsuyoshi Sekitani, Jonathan Reeder, Tomoyuki Yokota, Kazunori Kuribara, Takeyoshi Tokuhara, Michael Drack, Reinhard Schwo ̈diauer, Ingrid Graz, Simona Bauer-Gogonea, Siegfried Bauer & Takao Someya ; Nature 2013 (link)

3) Cellular mechanisms of brain state–dependent gain modulation in visual cortex Pierre-Olivier Polack, Jonathan Friedman1 & Peyman Golshani; Nature Neuroscience 2013 (link)

4) Steady or changing? Long-term monitoring of neuronal population activity Henry Lutcke, David J. Margolis, and Fritjof Helmchen ; Trends in Neuroscience 2013 (link)

5) A Biophysically Detailed Model of Neocortical Local Field Potentials Predicts the Critical Role of Active Membrane Currents Michael W. Reimann, Costas A. Anastassiou, Rodrigo Perin, Sean L. Hill, Henry Markram, and Christof Koch ; Nature Neuroscience 2013 (link)

6) Optogenetic Inhibition of Synaptic Release with Chromophore-Assisted Light Inactivation (CALI) John Y. Lin, Sharon B. Sann, Keming Zhou, Sadegh Nabavi, Christophe D. Proulx, Roberto Malinow, Yishi Jin, and Roger Y. Tsien ; Nature Neuroscience 2013 (link)

7) Oscillatory activity in the monkey hippocampus during visual exploration and memory formation Michael J. Jutras, Pascal Fries, and Elizabeth A. Buffalo ; PNAS 2013 (link)

8) In vivo synaptic recovery following optogenetic hyperstimulation Maike Kittelmann, Jana F. Liewald, Jan Hegermann, Christian Schultheis, Martin Braunerd, Wagner Steuer Costa, Sebastian Wabnig, Stefan Eimer, and Alexander Gottschalk ; PNAS 2013 (link)

9) Synthesizing cognition in neuromorphic electronic systems Emre Neftci, Jonathan Binas, Ueli Rutishauser, Elisabetta Chicca, Giacomo Indiveri, and Rodney J. Douglas ; PNAS 2012 (link)

10) How the Visual Brain Encodes and Keeps Track of Time Paolo Salvioni, Micah M. Murray, Lysiann Kalmbach, and Domenica Bueti ; J Neuroscience 2013 (link)

11) Developmental Changes in Structural and Functional Properties of Hippocampal AMPARs Parallels the Emergence of Deliberative Spatial Navigation in Juvenile Rats Margaret G. Blair, Nhu N.-Q. Nguyen, Sarah H. Albani, Matthew M. L’Etoile, Marina M. Andrawis, Leanna M. Owen, Rodrigo F. Oliveira, Matthew W. Johnson, Dianna L. Purvis, Erin M. Sanders, Emily T. Stoneham, Huaying Xu, and Theodore C. Dumas ; J Neuroscience 2013 (link)

12) Feedforward Inhibition Underlies the Propagation of Cholinergically Induced Gamma Oscillations from Hippocampal CA3 to CA1 Rita Zemankovics, Judit M. Veres, Iris Oren, and Norbert Ha ́jos ; J Neuroscience 2013 (link)

13) Key Features of Human Episodic Recollection in the Cross-Episode Retrieval of Rat Hippocampus Representations of Space Eduard Kelemen, Andre ́ A. Fenton ; PLoS Biolody 2013 (link)