Friday, October 2, 2015

Part III: Creativity, or Self-Organized Criticality, or the Brain's Cosmic Web

"To know subtle things, you must experience them directly; you become the truth you seek. Science raises doubts about anything that cannot be reduced to measurements, data, and factual findings. This sort of doubt doesn’t have to block us, however, since the very things described at the subtle level of existence, such as love and compassion, are desirable in everyday life already. They don’t need science to give them value; each person decides how valuable, or not, they are."
The Scientist:
In the early 1960s, MIT neurobiologist Joseph Altman used a hypodermic needle to induce lesions in rat brains, while simultaneously injecting tritiated thymidine, a radioactive form of the nucleoside commonly used for tracking DNA synthesis and cell proliferation. He found evidence of new brain cells that had been born at the time of injection, including some neurons and their neuroblast precursors.

Researchers were immediately skeptical of the results. Long-standing theory held that neurons in the brain that had been damaged or lost could not be replaced; Altman was suggesting the opposite. “They were really good, solid indications, but it was such a strong dogma that neurons couldn’t be generated in the adult brain,” says Frisén. “It wasn’t really until the ’90s, when new techniques came along, [that researchers] showed, yes, indeed, new neurons are added in the rodent brain.”

Those new techniques included BrdU, as well as neuron-specific protein markers and confocal imaging, which together enabled researchers to identify the newly generated cells. Multiple studies subsequently confirmed that neurogenesis occurs in limited regions of the rodent brain, specifically in the olfactory bulb and the dentate gyrus region of the hippocampus. Research also revealed that the rate of neurogenesis decreases with stress, depression, and anxiety, but increases with exercise and enrichment.

“The field grew enormously at this point,” says neuroscientist Fred Gage, of the Salk Institute for Biological Studies. And its focus began to shift from whether new neurons were being produced—they were—to whether those cells formed connections with existing networks to become functional—they do. Turns out, “these newly born cells have 5,000 synapses on their dendrites,” Gage says—well within the range of other neurons in the brain.

But would those rodent results hold up in primates? All signs pointed to yes. In March 1998, Princeton University’s Elizabeth Gould and colleagues found evidence of neurogenesis in the dentate gyrus of adult marmoset monkeys—and the researchers determined that the rate of cell proliferation was affected by stress, just as in rodents. Six months later, Gage’s group published its findings based on the clinical samples of human brain tissue. “It was a surprise to me, and I think to most people,” Frisén says. And the point was hammered home with the Frisén group’s analysis of 14C in human brain samples.

“The human evidence now unequivocally suggests that the dentate gyrus in humans undergoes turnover in our lifetime,” says Amar Sahay of Harvard University. “It really begs the question what the functions are of these adult-born neurons.”

Young and excitable

The first step in understanding the function of the new neurons in the adult brain was to characterize the cells themselves. In the late 1990s and early 2000s, researchers delved into the cell biology of neurogenesis, characterizing the populations of stem cells that give rise to the new neurons and the factors that dictate the differentiation of the cells. They also documented significant differences in the behavior of young and old neurons in the rodent brain. Most notably, young neurons are a lot more active than the cells of established hippocampal networks, which are largely inhibited.

“For a period of about four or five weeks, while [the newborn neurons] are maturing, they’re hyperexcitable,” says Gage. “They’ll fire at anything, because they’re young, they’re uninhibited, and they’re integrating into the circuit.”

To determine the functional role of the new, hyperactive neurons, researchers began inhibiting or promoting adult neurogenesis in rodents by various means, then testing the animals’ performance in various cognitive tasks. What they found was fairly consistent: the young neurons seemed to play a role in processing new stimuli and in distinguishing them from prior experiences. For example, if a mouse is placed in a new cage and given time to roam, then subjected to a mild shock, it will freeze for about 40 seconds the next time it is placed in that same environment, in anticipation of a shock. It has no such reaction to a second novel environment. But in an enclosure that has some features in common with the first, fear-inducing cage, the mouse freezes for 20 seconds before seemingly surmising that this is not the cage where it received the initial shock. Knock out the mouse’s ability to produce new neurons, however, and it will freeze for the full 40 seconds. The brain is not able to easily distinguish between the enclosures.

This type of assessment is called pattern separation. While some researchers quibble over the term, which is borrowed from computational neuroscience, most who study hippocampal neurogenesis agree that this is a primary role of new neurons in the adult brain. “While probably five or six different labs have been doing this over the last four or five years, basically everybody’s come to the same conclusion,” Gage says.

The basic idea is that, because young neurons are hyperexcitable and are still establishing their connectivity, they are amenable to incorporating information about the environment. If a mouse is placed in a new cage when young neurons are still growing and making connections, they may link up with the networks that encode a memory of the environment. Just a few months ago, researchers in Germany and Argentina published a mouse study demonstrating how, during a critical period of cellular maturation, new neurons’ connections with the entorhinal cortex, the main interface between the hippocampus and the cortex, and with the medial septum change in response to an enriched environment.

“The rate at which [new neurons] incorporate is dependent upon experience,” Gage says. “It’s amazing. It means that the new neurons are encoding things when they’re young and hyperexcitable that they can use as feature detectors when they’re mature. It’s like development is happening all the time in your brain.”

Adding support to the new neurons’ role in pattern separation, Sahay presented findings at the 2014 Society for Neuroscience conference that neurogenesis spurs circuit changes known as global remapping, in which overlap between the populations of neurons that encode two different inputs is minimized. “We have evidence now that enhancing neurogenesis does enhance global remapping in the dentate gyrus,” says Sahay. “It is important because it demonstrates that stimulating neurogenesis is sufficient to improve this very basic encoding mechanism that allows us to keep similar memories separate.”

Pattern separation is likely not the only role of new neurons in the adult hippocampus. Experiments that have suppressed neurogenesis in adult rats have revealed impairments in learning in a variety of other tasks. More broadly, “we think it has to do with the flexibility of learning,” says Gerd Kempermann of the Center for Regenerative Therapies at the Dresden University of Technology in Germany.

Last year, for example, neuroscientist Paul Frankland of the Hospital for Sick Children in Toronto and his colleagues found evidence that newly generated neurons play a role in forgetting, with increased neurogenesis resulting in greater forgetfulness among mice. “If you think about what you’ve done today, you can probably remember in a great deal of detail,” he says. “But if you go back a week or if you go back a month, unless something extraordinary happened, you probably won’t remember those everyday details. So there’s a constant sort of wiping of the slate.” New hippocampal neurons may serve as the “wiper,” he says, “cleaning out old information that, with time, becomes less relevant.”

Conversely, Frankland’s team found, suppressing neurogenesis seems to reinforce memories, making them difficult to unlearn. “We think that neurogenesis provides a way, a mechanism of living in the moment, if you like,” he says. “It clears out old memories and helps form new memories.”

Neurogenesis in the clinic

While studying the function of hippocampal neurogenesis in adult humans is logistically much more difficult than studying young neurons in mice, there is reason to believe that much of the rodent work may also apply to people—namely, that adult neurogenesis plays some role in learning and memory, says Kempermann. “Given that [the dentate gyrus] is so highly conserved and that the mechanisms of its function are so similar between the species—and given that neurogenesis is there in humans—I would predict that the general principle is the same.”

And if it’s true that hippocampal neurogenesis does contribute to aspects of learning involved in the contextualization of new information—an ability that is often impaired among people with neurodegenerative diseases—it’s natural to wonder whether promoting neurogenesis could affect the course of Alzheimer’s disease or other human brain disorders. Epidemiological studies have shown that people who lead an active life—known from animal models to increase neurogenesis—are at a reduced risk of developing dementia, and several studies have found reduced hippocampal neurogenesis in mouse models of Alzheimer’s. But researchers have yet to definitively prove whether neurogenesis, or lack thereof, plays a direct role in neurodegenerative disease progression. It may be that neurogenesis has “nothing to do with the pathology itself, but [with] the ability of our brain to cope with it,” says Kempermann.

Either way, the research suggests that “the identification of pro-neurogenic compounds would have a therapeutic impact on cognitive dysfunction, specifically, pattern separation alterations in aging and early stages of Alzheimer’s disease,” notes Harvard’s Sahay. “There’s a growing list of genes that encode secreted factors or other molecules that stimulate neurogenesis. Identifying compounds that harness these pathways—that’s the challenge.”

The birth of new neurons in the adult hippocampus may also influence the development and progression of mood disorders. Several studies have suggested that reduced neurogenesis may be involved in depression, for instance, and have revealed evidence that antidepressants act, in part, by promoting neurogenesis in the hippocampus. When Columbia University’s René Hen and colleagues short-circuited neurogenesis in mice, the animals no longer responded to the antidepressant fluoxetine.10 “It was a very big surprise,” Hen says. “The hippocampus has really been always thought of as critical for learning and memory, and it is, but we still don’t understand well the connection to mood.”

Adult neurogenesis has also been linked to post-traumatic stress disorder (PTSD). While it is perhaps less obvious how young neurons might influence the expression of fear, Sahay says it makes complete sense, given the emerging importance of neurogenesis in distinguishing among similar experiences. “In a way, the hippocampus acts as a gate,” he says, with connections to the amygdala, which is important for processing fear, and the hypothalamus, which triggers the production of stress hormones, among other brain regions. “It determines when [these] other parts of the brain should be brought online.” If new neurons are not being formed in the hippocampus, a person suffering from PTSD may be less able to distinguish a new experience from the traumatic one that is at the root of his disorder, Sahay and his colleagues proposed earlier this year. “We think neurogenesis affects the contextual processing, which then dictates the recruitment of stress and fear circuits.”

Of course, the big question is whether researchers might one day be able to harness neurogenesis in a therapeutic capacity. Some scientists, such as Hongjun Song of Johns Hopkins School of Medicine, say yes. “I think the field is moving toward [that],” he says. “[Neurogenesis] is not something de novo that we don’t have at all—that [would be] much harder. Here, we know it happens; we just need to enhance it.”

The researchers highlight the role of the "cosmic web" - a large-scale web-like structure comprised of galaxies - on the evolution of galaxies that took place in the distant universe, a few billion years after the Big Bang. In their paper, published Nov. 20 in the Astrophysical Journal, they present observations showing that thread-like "filaments" in the cosmic web played an important role in this evolution. "The filaments are like bridges connecting the denser regions in the cosmic web," Behnam Darvish, at the Department of Physics and Astronomy at UC Riverside explained. "Imagine threads woven into the web."

"We were surprised by the crucial role the filaments play in galaxy formation and evolution," Mobasher said. "Star formation is enhanced in them. The filaments likely increase the chance of gravitational interaction between galaxies, which, in turn, results in this star-formation enhancement. There is evidence in our local universe that this process in filaments also continues to occur at the present time."

A complex system that hovers between “boring randomness and boring regularity” is surprisingly stable overall, said Olaf Sporns, a cognitive neuroscientist at Indiana University. “Boring is bad,” he said, at least for a critical system. In fact, “if you try to avoid ever sparking an avalanche, eventually when one does occur, it is likely to be really large,” said Raissa D’Souza, a complex systems scientist at the University of California, Davis, who simulated just such a generic system last year. “If you spark avalanches all the time, you’ve used up all the fuel, so to speak, and so there is no opportunity for large avalanches.”

Continue to Part IV: How Art Evolves Consciousness.

More information:
» The Scientist: Each person has a unique activity correlation matrix, or connectome
» Convozine: "One is a Neuron. The Other is the Structure of the Universe."
» Inceptionism: Going Deeper into Neural Networks
» Mathematics, Cities, and Brains: What Can A Highway Engineer Learn From A Neuroscientist?
» Astronomers Capture The First Image Of The Mysterious Web That Connects All Galaxies In The Universe

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