I recently had the opportunity to write a post for Nautilus on a subject that is dear to me - the use of crows and other intelligent members of the corvid family for neuroscience research. Corvid intelligence has been noticed by humans for millennia, and more recently by ethologists and psychologists. The fascinating thing about these animals is that like all birds, they do not have a neocortex - the part of the mammalian brain that has countless times been implicated in intelligence. Now, there is just one lab in the world - Andreas Nieder at the University of Tübingen - that has started peering into the brains of these fascinating creatures to try to understand how crows’ cortex-less brains enable them to perform amazing cognitive feats. You can read the full story on Nautilus.Read More
Today, let’s throwback to the multiple comparisons problem and relate it to something new: Open Science.
In the past years, more and more researchers, legislators and politicians have started to campaign for an open and transparent scientific conduct. The fact that the majority of scientific articles are locked behind the walls of expensive magazines and thus unreachable for the general tax payer (even though they funded the research) is upsetting. Moreover, the scientific community is struggling with reproducibility – the center for open science reproduced 100 psychology studies and found that only 39% of the effects were rated to have replicated the result of the original study! Sharing raw data and code, and publishing in open access journals can hopefully solve these problems.Read More
A few weeks ago, Vivian wrote a post about prion disease, discussing how understanding the mechanisms of Kuru could help us design treatments for other neurodegenerative disorders characterized by protein aggregations. The accumulation of protein as a pathological process has also been investigted outside the brain. Aging and degeneration are complex system-wide phenomena and studies like the one by Demontis and Perrimon (2011) show that by looking outside the brain we can unveil new whole-body regulatory mechanisms for neurodegeneration.Read More
This week I’m re-visiting adult human neurogenesis: the seminal neuroscience finding that new neuronal cells are born in adult human brains after the normal developmental period in which neurons are generated. This remarkable discovery was made by Peter Eriksson and colleagues in the lab of Fred Gage at The Salk Institute for Biological Studies. Prior consensus in the field was that once neurons died (a hallmark of neurodegenerative diseases such as Alzheimer’s and Parkinson’s) there was no regeneration of neurons. The view was that brains generated a finite number of neurons for the life of the organism, and these neurons networked to handle all learning of new knowledge and the making of new memories and associations—quite an incredible feat! However, the Gage group questioned the current model and found that there was neurogenesis in specific areas of rodent brains, a huge finding in and of itself. But this generated some controversy-- another group published that neurogenesis was not taking place in marmosets (a higher mammal than rodents) and therefore it was likely not happening in other primates, i.e., humans. Therefore, the publication of “Neurogenesis in the Adult Human Hippocampus” in Nature (Eriksson et al., 1998) helped to resolve what had become a contentious issue and definitively showed that indeed, new neurons are being born and incorporated into the hippocampal region of adult brains.Read More
If you aren’t asleep when the clock strikes three in the early morning, your eyelids get heavy and your brain feels like mush. You still have that paper to finish writing and you want to stay awake but staying awake is a struggle, a fight against our own brain. We have all been there (especially during finals week). With today’s post, lets look at how our brain regulates sleep and why we spend our days alternating between sleep and wakefulness?Read More
“Any way you can make love, somebody’s already thought of. Any crazy caper you can get up to, any great meal you can think of, any combination of children or idea of how to raise them – somebody’s already thought of. But nobody’s ever discovered an opiate receptor before.”
- Candace Pert1
Shortly before starting graduate school in pharmacology at Johns Hopkins University in 1970, Candace Pert broke her back in a riding accident2. She took morphine to treat the pain, and subsequently became curious as to how this miraculous drug acted to produce such profound analgesic effects.Read More
In 2015 The Danish Girl, Ruby Rose, Caitlyn Jenner, and Transparent paved the road for trans-visibility in mainstream media. This has brought a great deal of attention and debate to the medical and political scene, but a large gap still remains between policy making and our understanding of how trans-sexuality develops through childhood and adolescence, and how we can alleviate the pain and discomfort for trans-adolescents of going through the physical changes puberty. This year the NIH launched the largest longitudinal study on long-term psychological and medical effects of puberty suppressors, a drug for sex reassignment therapy for adolescents with gender dysphoria1.Read More
This episode of Brain Celebrities will take us to the mountainous highlands of New Guinea, where the Fore people live. Until the 1960’s, the Fore had an interesting habit: they ate their dead. This gruesome tradition might help us understand neurological diseases such as Creutzfeldt-Jakob and Alzheimer’s disease.Read More
Patients with a damaged retina or visual cortex often report hole(s) in their sight. However inconvenient they may seem, these holes in many cases do not bother the patients and are sometimes not noticed at all. How do they block these holes from their awareness? In fact, this is a question that we should all ask ourselves, because we all have natural blind spots in our visual perception. This blind spot is caused by a small region in the back of our eyes that contains no retinal neurons. Instead, this region is dedicated for the retinal output neurons to send signals to the brain. Therefore, we walk around with two holes (one on each side) in our visual field. How do we not notice them, even when we try seeing with only one eye at a time?Read More
What are dreams, and why do we have them? People have probably been asking these questions since the dawn of reflective thought, but it wasn’t until the 1950s that scientists first identified neurophysiological correlates of dreaming. A classic paper by Aserinsky and Kleitman1 in 1953 marked the discovery of what we now refer to as Rapid Eye Movement (REM) sleep (Figure 1). Together with non-Rapid Eye Movement (NREM) sleep, REM sleep if one of the two major sleep states that humans and other mammals pass through multiple times during each sleep episode. REM sleep is the state associated with the vivid, hallucinatory dream experiences that we (sometimes) remember after waking.Read More
Not all drugs can completely change who we are. Cocaine is one of the few with this power. Like many other psychoactive drugs, cocaine was first used as an anesthetic, but its potential effect on one’s mind and will was soon discovered and overshadowed its original usage. Cocaine’s power does not lie within the molecule itself, but rather in its interaction with the brain’s reward system (see a previous TBT post for the discovery of this system).Read More
“February is my favorite month.” said no one living in Boston ever. The short days, cold temperatures, and repetitive snow really throw a dagger (presumably made of ice) into good times. I tend to think of Dec-Feb as my hibernating months; I am more lethargic, less motivated, and my fiancé and labmates can vouch for the fact that I am slightly more irritable than the good natured loving person I always am in better weather. I’ve come to attribute my noticeable seasonal downswing to Seasonal Affective Disorder, or SAD (an acronym that ironically makes me quite happy), a self-diagnosis I probably made from seeing a commercial. Being the curious graduate student that I am I decided to do a little research on the subject and see what I could learn—really trying to go above and beyond what pharmaceutical advertising taught me.Read More
How do we learn and remember? How does our nervous system change to allow learning and memory? These are questions that neuroscientists are still tackling to this very day. Today we will go back to 1973 and look at one of the first papers by Thomas Carew and Eric Kandel addressing these questions.Read More
It is no linguistic coincidence that high temperature and spiciness share the same word in the English dictionary: they induce the same burning sensation. The biological basis for this commonality was discovered in 1997 by David Julius’s group at UCSF1.Read More
Here’s to a relatively recent TBT! In 2010, Craig Bennett and colleagues submitted a poster with the following title:
"Neural Correlates of Interspecies Perspective Taking in the Post-Mortem Atlantic Salmon: An Argument For Proper Multiple Comparisons Correction"
Yes, you are reading it right, it is about the neural correlates of a dead fish!Read More
Late one night, a woman strolls through an urban park, and a belligerent man yells at her to come to the bench where he is sitting. The woman casually walks over to the man, who puts a knife to her throat. In a gentle voice she tells him, "If you're going to kill me, you're gonna have to go through my God's angels first." The man is so freaked out by this statement and the women's calm demeanor that he immediately lets her go. The next day, she takes another solitary walk through the park, as if nothing had happened.1 The woman described above, who is still alive today, is a famous case study in the neuroscience of human emotion. If you didn't know any better, little about her would strike you as odd - extremely outgoing and somewhat coquettish, but certainly not pathological. In fact, professional psychologists naive to her case don't seem to notice much about her that is strange. After speaking to her about her life and experiences, which include many personal hardships, they describe her as being a "survivor" with "exceptional coping skills." After learning that this woman is patient S.M., the same psychologists reinterpret their assessments of the woman: she is now said to display, "an abnormally low level of negative emotional phenomenology".2Read More
“As you know, in most areas of science, there are long periods of beginning before we really make progress.” – Eric Kandel
In a typical maze experiment, a hungry rat enters a moderately complicated maze, in which it does its best to find a “reward room” with food. After some guesses, the rat finds its way, consumes the food, and is returned to the entrance of the maze. From then on, the rat makes fewer bad guesses and finds the food faster after each round. Eventually, it completely masters the maze layout and finds the perfect route every time. To explain this improvement, scientists have coined the term reward reinforcement, which essentially suggests that the reward that the rat collects at the end reinforces its correct choices, until it eventually learns a perfect route. This model may sound very simple, but is it?
The rat collects its food in the reward room, not during the navigation or decision-making. Therefore, the brain’s reward system does not turn on until the end of each run. How, then, does the reward system backtrack in time and selectively reinforce choices made in the past? If we had the ability to look into the rat’s brain and watch the activities of the synapses (the connections between neurons), we would find, as the rat navigates through the maze, millions of synapses flash on and off, while millions more remain silent. How does the brain keep track of this enormous, evolving constellation of synaptic activity, so that only the appropriate ones can be tuned up and down by the reward in the end?
One way to solve this problem is to have a logging system, in which individual synapses log their activity over time, like hourglasses that are flipped on (to let sand through) only when their corresponding synapses are active and flipped upside-down when inactive. In this way, when the reward arrives, the active synapses can be singled out by reading the hourglasses. This idea is called synaptic tagging.
What is the nature of this activity tag? One strong candidate arises from work done by Kausik Si (pronounced “See”) and Nobel Laureate Eric Kandel. It’s an RNA binding protein called CPEB (not to be confused with CREB, which is a different protein that is also important for memory). CPEB is turned on in active synapses and is necessary for maintaining long-term memory in different animal species1,2.
How does CPEB tag synaptic activity? Si and Kandel’s answer initially flabbergasted the entire neuroscience community: it is a prion. Prions are most famous for causing spongy brains in the mad cow disease. Many proteins can be prions, as long as they spontaneously form strong aggregates (i.e. clumps) and expand the aggregates by converting single proteins into the self-aggregating form. Proteins involved in many neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases, have recently been thought to resemble prions. However, the CPEB aggregates are not the harbingers of disease but rather the functional essence of the protein. The aggregation of CPEB only happens in active synapses, and blocking the aggregation, either by antibody neutralization or by mutation of the gene, reduces synaptic plasticity and the animal’s ability to form long-term memory3–5.
Initial insights into the function of CPEB come from the observation that its aggregate binds RNA4. A recent paper by the Si group proposes that the aggregation of CPEB promotes memory formation by switching CPEB’s function from suppressing to promoting protein translation6. This switching phenomenon depends on CPEB’s ability to recruit other protein complexes to modify the stability of RNAs.
Is CPEB the only mechanism for synaptic tagging? Probably not. Studies of CPEB indicate that it is essential for long-term memory, on the timescale from hours to days. However, tagging synapses on a shorter time scale is also needed to explain problems such as delayed reinforcement (described above). There is strong evidence that synapses can be tagged and tuned concertedly within a much shorter timeframe, although scientists do not yet know how this happens7. When this mystery is revealed, another gasp of surprise will be heard reverberating across the neuroscience community.
- Si, K. et al. A neuronal isoform of CPEB regulates local protein synthesis and stabilizes synapse-specific long-term facilitation in aplysia. Cell 115, 893–904 (2003).
- Keleman, K., Krüttner, S., Alenius, M. & Dickson, B. J. Function of the Drosophila CPEB protein Orb2 in long-term courtship memory. Nat. Neurosci. 10, 1587–93 (2007).
- Majumdar, A. et al. Critical role of amyloid-like oligomers of Drosophila Orb2 in the persistence of memory. Cell 148, 515–29 (2012).
- Si, K., Lindquist, S. & Kandel, E. R. A Neuronal Isoform of the Aplysia CPEB Has Prion-Like Properties. Cell 115, 879–891 (2003).
- Si, K., Choi, Y.-B., White-Grindley, E., Majumdar, A. & Kandel, E. R. Aplysia CPEB Can Form Prion-like Multimers in Sensory Neurons that Contribute to Long-Term Facilitation. Cell 140, 421–435 (2010).
- Khan, M. R. et al. Amyloidogenic Oligomerization Transforms Drosophila Orb2 from a Translation Repressor to an Activator. Cell 163, 1468–1483 (2015).
- He, K. et al. Distinct Eligibility Traces for LTP and LTD in Cortical Synapses. Neuron 88, 528–538 (2015).