memory formation

Two new studies uncover key players responsible for learning and memory formation

One of the most fascinating properties of the mammalian brain is its capacity to change throughout life. Experiences, whether studying for a test or experiencing a traumatic situation, alter our brains by modifying the activity and organization of specific neural circuitry, thereby modifying subsequent feelings, thoughts, and behavior. These changes take place in and among synapses, communication junctions between neurons. This experience-driven alteration of brain structure and function is called synaptic plasticity and it is considered the cellular basis for learning and memory.

Many research groups across the globe are dedicated to advancing our understanding of the fundamental principles of learning and memory formation. This understanding is dependent upon identifying the molecules involved in learning and memory and the roles they play in the process. Hundreds of molecules appear to be involved in the regulation of synaptic plasticity, and understanding the interactions among these molecules is crucial to fully understand how memory works.

There are several underlying mechanisms that work together to achieve synaptic plasticity, including changes in the amount of chemical signals released into a synapse and changes in how sensitive a cell’s response is to those signals. In particular, the protein BDNF, its receptor TrkB, and GTPase proteins are involved in some forms of synaptic plasticity, however, very little is known regarding when and where they are activated in the process.

By using sophisticated imaging techniques to monitor the spatiotemporal activation patterns of these molecules in single dendritic spines, the research group led by Dr. Ryohei Yasuda at Max Planck Florida Institute for Neuroscience and Dr. James McNamara at Duke University Medical Center have uncovered critical details of the interplay of these molecules during synaptic plasticity. These exciting findings were published online ahead of print in September 2016 as two independent publications in Nature (1, 2).

A surprising signaling system within the spine

In one of the publications (Harward and Hedrick et al.), the authors identified an autocrine signaling system – a system where molecules act on the same cells that produce them – within single dendritic spines. This autocrine signaling system is achieved by rapid release of the protein, BDNF, from a stimulated spine and subsequent activation of its receptor, TrkB, on the same spine, which further activates signaling inside the spine. This in turn leads to spine enlargement, the process essential for synaptic plasticity. In other words, signaling initiated inside the spine goes outside the spine and activates a receptor on the external surface of the spine, thereby evoking additional signals inside the spine. This finding of an autocrine signaling process within the dendritic spines surprised the scientists.

What are the consequences of the autocrine signaling within the spine?

The second publication (Hedrick and Harward et al.) reports that the autocrine signaling leads to activation of an additional set of signaling molecules called small GTPase proteins. The findings reveal a three-molecule model of structural plasticity, which implicates the localized, coincident activation of three GTPase proteins Rac1, Cdc42, and RhoA, as a causal feature of structural plasticity. It is known that these proteins regulate the shape of dendritic spines, however, how they work together to control spine structure has remained unclear. The researchers monitored the spatiotemporal activation patterns of these molecules in single dendritic spines during synaptic plasticity and found that all three proteins are activated simultaneously, but their activation patterns differed significantly. One of the differences is that RhoA and Rac1, when activated, spread beyond the stimulated spine to the surrounding dendrite, which facilitates plasticity of surrounding spines. Another difference is that Cdc42 activity was restricted to the stimulated spine, what seems to be necessary to produce spine-specific plasticity. Furthermore, the autocrine BDNF signaling is required for activation of Cdc42 and Rac1, but not for RhoA.

Unprecedented insights into the regulation of synaptic plasticity

These two studies provide unprecedented insights into the regulation of synaptic plasticity. One study revealed for the first time an autocrine signaling system and the second study presented a unique form of biochemical computation in dendrites involving the controlled complementation of three molecules. According to Dr. Yasuda, understanding the molecular mechanisms that are responsible for the regulation of synaptic strength is critical for understanding how neural circuits function, how they form, and how they are shaped by experience. Dr. McNamara noted that disorder of these signaling systems likely underlies dysfunction of synapses that cause epilepsy and a diversity of other diseases of the brain. Because hundreds of species of proteins are involved in the signal transduction that regulates synaptic plasticity, it is essential to investigate the dynamics of more proteins to better understand the signaling mechanisms in dendritic spines.

Future research in the Yasuda and McNamara Labs is expected to lead to significant advances in the understanding of intracellular signaling in neurons and will provide key insights into the mechanisms underlying synaptic plasticity and memory formation and brain diseases. These insights will hopefully lead to the development of drugs that could enhance memory and prevent or more effectively treat epilepsy and other brain disorders.

Whoever said INFPs were the emo ones

What not to do

Some of you may remember that my poor camera died in October, after four years of excellent service.  That was sad, but I was happy when my new camera (a Canon EOS Rebel SL1) arrived a few days later.  That part’s still happy; the new camera is great!

Yesterday I got home from my first trip with the new camera.  I dumped all the photos, went to format my memory card… and accidentally formatted the drive where all my recent photos live. 

This particular dumbness aside, I do back things up.  Not nearly as often as I should, naturally.  A recovery program was not especially successful.  So, there go a few weeks worth of photos, and I freely admit that there was some significant cursing when I realized what I’d done. 

On the bright side, I never actually formatted the card.  So I still have the photos from the trip, including some family pictures I would have been sorry to lose.

Anyway, I’ll be back in a few more days.  In the meantime, back up allllllll your shit, so you won’t be like a certain sad character of your acquaintance.

Phoenix Cluster Rebirth Spell

a spell for new beginnings and overcoming the past

One of the largest galaxy clusters in the known universe is the Phoenix Cluster. Galaxies at the center of the cluster may have been dormant for years, but the central galaxy has come to life with a burst of new star formation.

Old memories can sometimes keep us from making a new start. This little spell can help you burn off some of the excess baggage preventing you from moving forward. This is by no means a substitute for therapy or medication, just something to give you a little boost if you’re having trouble putting the past behind you.

What You’ll Need:

  • Red candle
  • Yellow candle
  • Orange candle
  • White candle
  • Time for visualization
  • Optional: your favorite bath mix, incense, or herbal tea


  1. Recite the following incantation, lighting one of your candles at the end of each couplet. You can light them in whatever order you like, but I prefer: red, yellow, orange, white.

    Light a fire to these memories,
    may only ashes and embers remain.
    I’m no longer a slave to their power,
    but I know I’m not done with their pain.
    Fire, awaken within me new growth,
    as would a cluster of stars in a herd.
    Newborn I stumble through the ash,
    I’m a golden firebird.

  2. Staying near your candles, visualize an object or a place that you associate with a negative experience in your life. When you can see it clearly in your mind, envision it catching on fire.
  3. Watch it burn. Where does the fire catch? At the top, in the center, at the foundation? How does the fire spread across the object or place? Does it melt? Does it crumble? Does it explode?
  4. When the fire has burned out completely, visualize yourself climbing up out of the ashes, dusting yourself off, then walking away.
  5. After your meditation, take a few moments for yourself. Soak in a hot bath while burning some incense, find a quiet space outside and take a few deep cleansing breaths, brew your favorite tea and curl up with a book; do anything that comforts you so you can enter your new life with something positive.

Basically The Reynolds Pamphlet just came out and Philip is drowning in a sea of depressing memories. I think the format went a bit weird, but the bits where it’s a flashback are supposed to be in italics.

Also, I was thinking of taking requests for oneshots if anybody doesn’t hate my writing too much. And, if you really don’t hate it, then check out The Trouble With College by KittyKat121213 on for total Lams fluff.

So, anyway, thanks for reading!

Philip Hamilton didn’t have a clue what had got into his father. It absolutely killed him to see his mother so broken.

The Reynolds Pamphlet. What a great idea. When somebody threatens to publish your sex scandal, make sure you beat them to it. Everybody had always said Alexander Hamilton was a genius, but Philip wasn’t so sure anymore.

The worst part was it all made sense. At first, when a smirking Theodosia had handed him a copy of it, he’d hoped it was all a joke. But it all fit.

Philip remembered that summer all too well. He’s been nine and they’d spent the summer upstate with his grandfather. His mother had begged his father to come for months beforehand.

“Alexander, take a break!” Eliza begged. She knew she loved this man, but he was so infuriating at times.

“Eliza, I have so much on my plate.”. That was the trouble with Alexander - he bit off more than he could chew. It had paid off for him in the war, but civilian life was different. Why couldn’t he settle with his family?

Philip remembered every argument his parents had had. He remembered the way his father had never stopped working, and his mother never stopped trying.

When his aunt came on the scene, Philip had assumed she’d get his father to come. Nobody said no to Angelica. Or so he’d thought.

“Alexander, I came all this way!” Angelica practically screamed. She’d loved this man for almost eleven years, but right now she was glad she wasn’t the one who had to put up with him every day.

“I have to get this plan through Congress.” was all Alexander responded with. That was the problem with him - his single tracked determination. He had to get his priorities straight.

It had been a great summer. Everything about it - apart from his father not being there. That summer was the first time Philip though that maybe his father cared more about his job than his family.

Apart from that it had been great. His grandfather had still been a Senator then, and he’d been friends with Theodosia. Maybe even a little more than friends, if he was being honest.

It had all gone wrong once they got back. It had felt a little weird - Philip had noticed his father had been on edge. He knew why now.

Thomas Jefferson had finally approved his father’s financial plan. When Alexander had heard it had gone through, he was like a new person.

“Alexander, slow down! I haven’t seen you so happy since Philip was born!” Eliza laughed. It was like having the man she fell in love with back. He hadn’t really been the same for a long time, always working himself too hard. Trying to prove himself to Washington.

Of course, it had all gone downhill after that. First, Aaron Burr had taken his grandfather’s Senate seat. He remembered it well.

“That jumped up, worthless, good-for-nothing…”.

“Alexander, slow down. What’s so bad about Aaron Burr? Didn’t he fight in the war with you?”.

“He doesn’t stand for anything, he doesn’t have opinions! You shouldn’t stick up for him, Eliza, he changed parties to run against your father!”.

“Well, maybe Dad was getting a bit old…”.

“He’s no better than Jefferson! Philip, I don’t want you speaking to that Theodosia, you hear me?”.

“Yes Father.” Philip sighed. It was a shame; he liked Theo. They were good friends.

Philip shuddered at the memory. He had been good friends with Theodosia, but everything had changed that day.

He’d lost his best friend. And a just over a year later, his father had changed. Changed too much.

“Eliza. Washington stepped down.”.


“And I don’t have a position in the Adams administration.”.

“Alexander. We don’t need money-”.

“We’re ruined, Eliza.”.


“Jefferson’s Vice President. If he fucks up the country, then I’m sorry.”.

Jefferson hadn’t done anything notable, at least not yet. But Alexander Hamilton apparently found it impossible to stay out of the spotlight for four years.

Philip knew he couldn’t do anything to change it. The Reynolds Pamphlet. Why was his father such an idiot?

There was nothing he could do that would comfort his mother, crying in her room. There was nothing he could do to calm down his aunt, yelling at his father in the lounge.

There was nothing he could do, full stop.


I know it’s been 2 days now since the #formationworldtour but here is @beyonce singing and performing one of my favorite songs from her #lemonade album #daddylessons 👯🐝🍋#formation #beyonce #yoncé #concert #rosebowl #pasadena #memories #takemeback (at Beyonce: Formation World Tour, Rose Bowl)

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Infantile Memory Study Points to Critical Periods in Early-Life Learning for Brain Development

A new study on infantile memory formation in rats points to the importance of critical periods in early-life learning on functional development of the brain. The research, conducted by scientists at New York University’s Center for Neural Science, reveals the significance of learning experiences over the first two to four years of human life; this is when memories are believed to be quickly forgotten—a phenomenon known as infantile amnesia.

“What our findings tell us is that children’s brains need to get enough and healthy activation even before they enter pre-school,” explains Cristina Alberini, a professor in NYU’s Center for Neural Science, who led the study. “Without this, the neurological system runs the risk of not properly developing learning and memory functions.”

The other authors of the study, conducted in collaboration with the Icahn School of Medicine at Mt. Sinai, included: Alessio Travaglia, a post-doctoral researcher at NYU; Reto Bisaz, an NYU research scientist at the time of the study; Eric Sweet, a post-doctoral fellow at the Icahn School of Medicine at Mt. Sinai; and Robert Blitzer, a professor at the Icahn School of Medicine at Mt. Sinai.

In their study, which appears in the journal Nature Neuroscience, the researchers examined the mechanisms of infantile memory in rats—i.e., memories created 17 days after birth. This is the equivalent of humans under the age of three and when memories of who, what, when, and where–known as episodic memories–are rapidly forgotten. The phenomenon, referred as to “infantile or childhood amnesia,” is in fact the inability of adults to retrieve episodic memories that took place during the first two to four years of life.

In addressing this matter, Alberini and her colleagues compared rats’ infantile memory with that when they reached 24 days old—that is, when they are capable of forming and retaining long-term memories and at an age that roughly corresponds to humans at six to nine years old.

The episodic memory tested in the rodents was the memory of an aversive experience: a mild foot shock received upon entering in a new place. Adult rats, like humans, remember unpleasant or painful experiences that they had in specific places, and then avoid returning to them.  

To do so, rodents were placed in a box divided into two compartments: a “safe” compartment and a “shock” compartment. During the experiment, each rat was placed in the safe compartment with its head facing away from the door. After 10 seconds, the door separating the compartments was automatically opened, allowing the rat access to the shock compartment. If the rat entered the shock compartment, it received a mild foot shock.

The first set of results was not surprising. The authors found infantile amnesia for the 17 day-old rats, which showed avoidance of the “shock” compartment right after the experience, but lost this memory very rapidly: a day later these rats quickly returned to this compartment. In contrast, the rats exposed to the shock compartment at 24 days of life learned and retained the memory for a long time and avoided this place—revealing a memory similar to that of adult rats.

However, remarkably, the younger rats, which had apparently forgotten the initial experience, subsequently showed they actually had kept a trace of the memory. When, later in life, these rats were prompted with reminders—i.e., they were presented with recollections of the context and the foot shock—they indicated having a specific memory, which was revealed by their avoidance of the specific context in which they received a shock at day 17 of life. These findings show how early life experience, although not expressed or remembered, can influence adult life behavior.  

The findings raised the following question: what is occurring—neurologically—that explains why memories are retained by the younger rats only in a latent form but are stored and expressed long-term by older ones? Or, more specifically, what occurs during development that enhances the ability to form lasting memories?

To address this, the scientists focused on the brain’s hippocampus, which previous scholarship has shown is necessary for encoding new episodic memories. Here, in a series of experiments similar to the box tests, they found that if the hippocampus was inactive, the ability of younger rats to form latent memories and recall them later by reminders as they got older was diminished. They then found that mechanisms of “critical periods” are fundamental for establishing these infantile memories.  

A critical period is a developmental stage during which the nervous system is especially sensitive to environmental stimuli. If, during this period, the organism does not receive the appropriate stimuli required to develop a given function, it may be difficult or even impossible to develop that function later in life. Well-known examples of critical period-based functions are sensory functions, like vision, and language acquisition.

The study shows that there is a critical period for episodic learning and that during this period the hippocampus learns to become able to efficiently process and store memories long-term.

“Early in life, while the brain cannot efficiently form long-term memories, it is ‘learning’ how to do so, making it possible to establish the abilities to memorize long-term,” explains Alberini. “However, the brain needs stimulation through learning so that it can get in the practice of memory formation—without these experiences, the ability of the neurological system to learn will be impaired.”  

These studies, the researchers observe, suggest that using learning and environmental interventions during a critical period may significantly help to address learning disabilities.

How Traumatic Memories Hide In The Brain, And How To Retrieve Them

Some stressful experiences – such as chronic childhood abuse – are so overwhelming and traumatic, the memories hide like a shadow in the brain.

At first, hidden memories that can’t be consciously accessed may protect the individual from the emotional pain of recalling the event. But eventually those suppressed memories can cause debilitating psychological problems, such as anxiety, depression, post-traumatic stress disorder or dissociative disorders.

A process known as state-dependent learning is believed to contribute to the formation of memories that are inaccessible to normal consciousness. Thus, memories formed in a particular mood, arousal or drug-induced state can best be retrieved when the brain is back in that state.

In a new study with mice, Northwestern Medicine scientists have discovered for the first time the mechanism by which state-dependent learning renders stressful fear-related memories consciously inaccessible.

“The findings show there are multiple pathways to storage of fear-inducing memories, and we identified an important one for fear-related memories,” said principal investigator Dr. Jelena Radulovic, the Dunbar Professor in Bipolar Disease at Northwestern University Feinberg School of Medicine. “This could eventually lead to new treatments for patients with psychiatric disorders for whom conscious access to their traumatic memories is needed if they are to recover.”

It’s difficult for therapists to help these patients, Radulovic said, because the patients themselves can’t remember their traumatic experiences that are the root cause of their symptoms.

The best way to access the memories in this system is to return the brain to the same state of consciousness as when the memory was encoded, the study showed.

The study was published August 17 in Nature Neuroscience.

Changing the Brain’s Radio Frequencies

Two amino acids, glutamate and GABA, are the yin and yang of the brain, directing its emotional tides and controlling whether nerve cells are excited or inhibited (calm). Under normal conditions the system is balanced. But when we are hyper-aroused and vigilant, glutamate surges. Glutamate is also the primary chemical that helps store memories in our neuronal networks in a way that they are easy to remember.

GABA, on the other hand, calms us and helps us sleep, blocking the action of the excitable glutamate. The most commonly used tranquilizing drug, benzodiazepine, activates GABA receptors in our brains.

There are two kinds of GABA receptors. One kind, synaptic GABA receptors, works in tandem with glutamate receptors to balance the excitation of the brain in response to external events such as stress.

The other population, extra-synaptic GABA receptors, are independent agents. They ignore the peppy glutamate. Instead, their job is internally focused, adjusting brain waves and mental states according to the levels of internal chemicals, such as GABA, sex hormones and micro RNAs. Extra-synaptic GABA receptors change the brain’s state to make us aroused, sleepy, alert, sedated, inebriated or even psychotic. However, Northwestern scientists discovered another critical role; these receptors also help encode memories of a fear-inducing event and then store them away, hidden from consciousness.

“The brain functions in different states, much like a radio operates at AM and FM frequency bands,” Radulovic said. “It’s as if the brain is normally tuned to FM stations to access memories, but needs to be tuned to AM stations to access subconscious memories. If a traumatic event occurs when these extra-synaptic GABA receptors are activated, the memory of this event cannot be accessed unless these receptors are activated once again, essentially tuning the brain into the AM stations.”

Retrieving Stressful Memories in Mice

In the experiment, scientists infused the hippocampus of mice with gaboxadol, a drug that stimulates extra-synaptic GABA receptors. “It’s like we got them a little inebriated, just enough to change their brain state,” Radulovic said.

Then the mice were put in a box and given a brief, mild electric shock. When the mice were returned to the same box the next day, they moved about freely and weren’t afraid, indicating they didn’t recall the earlier shock in the space. However, when scientists put the mice back on the drug and returned them to the box, they froze, fearfully anticipating another shock.

“This establishes when the mice were returned to the same brain state created by the drug, they remembered the stressful experience of the shock,” Radulovic said.

The experiment showed when the extra-synaptic GABA receptors were activated with the drug, they changed the way the stressful event was encoded. In the drug-induced state, the brain used completely different molecular pathways and neuronal circuits to store the memory.

“It’s an entirely different system even at the genetic and molecular level than the one that encodes normal memories,” said lead study author Vladimir Jovasevic, who worked on the study when he was a postdoctoral fellow in Radulovic’s lab.

This different system is regulated by a small microRNA, miR-33, and may be the brain’s protective mechanism when an experience is overwhelmingly stressful.

The findings imply that in response to traumatic stress, some individuals, instead of activating the glutamate system to store memories, activate the extra-synaptic GABA system and form inaccessible traumatic memories.

Traumatic Memories Rerouted and Hidden Away

Memories are usually stored in distributed brain networks including the cortex, and can thus be readily accessed to consciously remember an event. But when the mice were in a different brain state induced by gaboxadol, the stressful event primarily activated subcortical memory regions of the brain. The drug rerouted the processing of stress-related memories within the brain circuits so that they couldn’t be consciously accessed.

Old Drug Offers New Hope to Treat Alzheimer’s Disease

Scientists from the Gladstone Institutes have discovered that salsalate, a drug used to treat rheumatoid arthritis, effectively reversed tau-related dysfunction in an animal model of frontotemporal dementia (FTD). Salsalate prevented the accumulation of tau in the brain and protected against cognitive impairments resembling impairments seen in Alzheimer’s disease and FTD.

Salsalate inhibits tau acetylation, a chemical process that can change the function and properties of a protein. Published in Nature Medicine, the researchers revealed that acetylated tau is a particularly toxic form of the protein, driving neurodegeneration and cognitive deficits. Salsalate successfully reversed these effects in a mouse model of FTD, lowering tau levels in the brain, rescuing memory impairments, and protecting against atrophy of the hippocampus—a brain region essential for memory formation that is impacted by dementia.

“We identified for the first time a pharmacological approach that reverses all aspects of tau toxicity,” says co-senior author Li Gan, PhD, an associate investigator at the Gladstone Institutes. “Remarkably, the profound protective effects of salsalate were achieved even though it was administered after disease onset, indicating that it may be an effective treatment option.”

Although tau has been a target in dementia research for some time, there are no tau-targeted drugs available for patients. Additionally, how the protein builds up in the brain, causing toxicity and contributing to disease, still remains largely a mystery.

By investigating post-mortem brains with Alzheimer’s disease, Dr. Gan’s team found that tau acetylation is one of the first signs of pathology, even before tau tangles are detectable. The acetylated form of tau not only marked disease progression, it also served as a driver for tau accumulation and toxicity. What’s more, in an animal model of FTD, when tau was acetylated, neurons had reduced ability to degrade the protein, causing it to build up in the brain. This in turn led to atrophy in the region and cognitive impairment in the mice on several different memory tests.

The Gladstone scientists discovered that salsalate can inhibit the enzyme p300 in the brain, which is elevated in Alzheimer’s disease and triggers acetylation. Blocking tau acetylation in this way enhanced tau turnover and effectively reduced tau levels in the brain. This reversed the tau-induced memory deficits and prevented loss of brain cells.

“Targeting tau acetylation could be a new therapeutic strategy against human tauopathies, like Alzheimer’s disease and FTD,” says co-senior author Eric Verdin, MD, a senior investigator at the Gladstone Institutes. “Given that salsalate is a prescription drug with a long-history of a reasonable safety profile, we believe it can have immediate clinical implications.”

The scientists say a clinical trial using salsalate to reduce tau levels in progressive supranuclear palsy, another tau-mediated neurological condition, has already been initiated.