Brains work via their genes just as much as their neurons

Brains work via their genes just as much as their neurons
Don’t forget the genes! Credit: www.shutterstock.com

It's not headline news that our brains are the seat of our thoughts and feelings. The brain is a body's decision-maker, the pilot of its actions and the engineer that keeps all systems going. The brain suits the body's actions to its surroundings, taking in sensory details and sending out appropriate and timely responses. We've long attributed the marvelous workings of the brain to the intricate structures formed by its highly specialized cells, neurons. These structures constitute the hardware of the brain.

But new genomic research reveals that, at an even deeper level, emotions and are also shaped by a second layer of organization in the brain, one that we only recently created the tools to see. This one relies on genes.

We are beginning to appreciate how genes and work together, like software and hardware, to make brain function possible. Learning to understand this two-layer system can help us understand how the environment affects behavior, and how to hack the system to improve mental health.

It is time to fully recognize gene activity not as the background utility of the brain, but as an integral part of its operation.

Neurons in the driver's seat

The sheer complexity of the human brain became apparent in the late 19th century, when two skilled anatomists, Camillo Golgi of Italy and Santiago Ramón y Cajal of Spain, invented tissue-staining techniques that revealed intricate microscopic networks of neural cells.

We now know that about 100 billion neurons connect with each other in a to form complex circuits that carry electrical and chemical messages to make memories and govern behavior. This physical structure, the one that yielded itself to the scientific tools of the time, constitutes the hardware of our neural control system, which is uniquely rewireable by experience.

Throughout the 20th century, scores of scientists characterized the sugars, lipids, proteins and myriad other molecules that build, run and repair our brains. These molecules seemed to stay out of the limelight; they appeared to play a supporting role to the neurons that ostensibly controlled our behavior.

New appreciation of genes

Brains work via their genes just as much as their neurons
A cat’s neuron stained with Golgi’s technique as drawn by Santiago Ramón y Cajal. Credit: Santiago Ramón y Cajal

But the 21st-century science of genomics delivered a new surprise about the brain. Genomics examines the entire set of genetic information contained within cells, the activities of genes and the interactions between them. Genomics revealed that the brain's genes are considerably more involved in regulating behavior than ever imagined.

Genes direct the production of the above-mentioned brain molecules via intermediaries made of RNA. RNA molecules tell the machinery of the cell when and how to make the proteins it needs to grow and function. Technologies developed over the last 20 years have allowed researchers to monitor the ebbs and flows of RNA produced by every gene in the brain with increasing precision. These studies have unveiled a surprisingly close relationship between behavior and gene activity in the brain.

Some of the earliest insights into the close relationship between behavior and brain gene activity came from an unlikely source: the brain of the honeybee. Honeybees, like humans, live in a complex society, and they too are strongly influenced by what others around them are doing.

My laboratory discovered that changes in behavior are orchestrated by altered activity of thousands of genes in the bee brain. In some cases, the relationship between behavior and brain gene activity is so close that a computer program can accurately predict, from patterns of brain gene activity alone, the bee's behavior. It turns out that similar genomic responses are found in many other species, including human beings, a finding that reinforces the idea of genes within neurons as a driving force underlying behavior.

This discovery was surprising because neurons are known to adjust how they communicate with each other to cause changes in behavior via mechanisms that do not require immediate changes in gene activity. Although we knew the molecules of the brain must be continually manufactured to enable neuronal circuits to rewire as a result of age and accumulated experience, neuroscientists didn't anticipate that the relationship between brain gene activity and behavior would be so tightly coupled.

Genes in the brain exert their influence

Why is there such a close coupling of brain gene activity and behavior? One hint comes from another bee study. Honeybees respond aggressively and immediately to a threat to their hive; in nature any prolonged delay could prove fatal. This behavioral response is much faster than the time it takes to produce new molecules of RNA, suggesting the initial response is more dependent on the neural system than the genomic one. Nevertheless, my laboratory found changes in the activity of hundreds of genes in the brains of individual bees in response to an intruder in the hive, hours after the threat was neutralized. The threatening experience changed them, in both molecular and behavioral terms.

Coincident with the persistent changes in brain gene activity, which we could see via changes in amounts of each individual type of RNA molecule, was a persistent increase in the vigilance of the once-agitated bees. This makes good sense; while past performance does not necessarily predict future results on Wall Street, it is a safe bet in nature to remain vigilant after experiencing a threat. Experimental manipulations that simulated the gene activity profile of the post-intruder brain made naïve bees more aggressive, demonstrating a causal relationship between brain gene activity and behavior. The bee brain, confronted with a threat that might be recurring, has genomic apps that help it respond more effectively.

Brains work via their genes just as much as their neurons
Genes are translated to proteins that also play a major role in the brain. Credit: United States Department of Energy

My colleagues and I also showed that the same kinds of changes occur after stickleback fish and mice are threatened, suggesting that this slow, persistent, genomic response to experience is a universal property of brains.

Two systems working in concert

The brain's neurons and the genomes within them, the hardware and the software, together orchestrate one's response to a new situation, which can vary from person to person. The same dramatic event – a challenge at school or work, a new person in one's social circle – might cause a great deal of stress in one person, and very little in another. We now think that the neural systems of two such people are likely tuned differently by their genomic systems, perhaps as a consequence of differentially stressful past experiences. In the living brain, unlike a computer, the software can help modify the hardware, and as new situations are encountered, the functioning of the neural hardware continues to modify the genomic software. Nature has come up with a "smart" system in which hardware and software are adaptable and interact dynamically!

This reciprocity between and neurons continually builds on an interwoven history that stretches all the way back to inherited individual differences in temperament, which also influence . And while an acute stress might cause genomic changes that provoke fear and anger for a few hours, chronic stress due to deprivation or violence can cause debilitating health effects because it activates genomic changes in the brain that do not dissipate. In some cases, it induces long-lasting changes to the chemical structure of DNA; these changes, referred to as epigenetic, might even be passed down from one generation to the next.

Brains work via their genes just as much as their neurons
Neurons got the early glory, but don’t forget the genes. Credit: ZEISS Microscopy, CC BY-NC-ND

We need to learn how to better read the genomic record of changes left by experience in order to predict future outcomes. Not only would this deepen our fundamental understanding of the , but it would also help us understand how socioeconomic stresses "get under the skin" to negatively affect health and well-being.

Research efforts, including the exciting new federal Brain Initiative, must focus on developing new technologies – both to measure neuronal activity with greater precision and to explore how the neuronal and genomic systems communicate with each other.

Brains do more than direct our behavior. They build our experiences into a coherent perception of the world. This world will be as unique for each of us as our personal history, with the potential to be sunny, or cloudy, or filled with shadows. If we can become proficient in the code our brains run on, perhaps we can learn to give these narratives a nudge in the right direction, and flood every person's world with light.


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JVK
Oct 14, 2015
See also: Pheromones in action http://bioscience...154.full by Gene E. Robinson and Organizational and activational effects of hormones on insect behavior by Elekonich and Gene E. Robinson

Now that others have linked nutrient-dependent changes in base pairs to RNA-mediated amino acid substitutions that stabilize the organized genomes of all living genera in the context of their physiology of reproduction, what aspect of hormone-organized and hormone-activated behavior in insects cannot be extended to humans via the honeybee model organism?

Nutrient-dependent/pheromone-controlled adaptive evolution: a model. http://www.ncbi.n...24693353
Excerpt: "The honeybee already serves as a model organism for studying human immunity, disease resistance, allergic reaction, circadian rhythms, antibiotic resistance, the development of the brain and behavior, mental health, longevity, diseases of the X chromosome, learning and memory..."

Oct 14, 2015
Nutrient-dependent/pheromone-controlled adaptive evolution: a model. http://www.ncbi.n...24693353

Criticisms of the nutrient-dependent pheromone-controlled evolutionary model
http://www.ncbi.n...4049134/

JVK
Oct 14, 2015
Structural diversity of supercoiled DNA http://dx.doi.org...omms9440
Video representation (fun): https://www.youtu...youtu.be All About that Base (Meghan Trainor Parody)

The Meghan Trainor was about the size of the "ass." In the end, the video representation reasserts that fact that Neil deGrasse Tyson is one.

See also: Scientific method: Defend the integrity of physics http://www.nature...-1.16535

A more technical representation of my model is here: Nutrient-dependent / Pheromone-controlled thermodynamics and thermoregulation http://youtu.be/DbH_Rj9U524

The text of my atoms to ecosystems model is here: Nutrient-dependent pheromone-controlled ecological adaptations: from atoms to ecosystems http://figshare.c...s/994281

JVK
Oct 14, 2015
Also co-authored by Gene Robinson:
Behavioral plasticity in honey bees is associated with differences in brain microRNA transcriptome http://dx.doi.org....00782.x

For comparison to the first and last sentence of the abstract from my atoms to ecosystems model:

"This atoms to ecosystems model of ecological adaptations links nutrient-dependent epigenetic effects on base pairs and amino acid substitutions to pheromone-controlled changes in the microRNA / messenger RNA balance and chromosomal rearrangements."

"Olfactory/pheromonal input links food odors and social odors from the epigenetic landscape to the physical landscape of DNA in the organized genomes of species from microbes to man during their development." --
http://figshare.c...s/994281

JVK
Oct 15, 2015
See also: A sex pheromone assembly line in Manduca sexta http://phys.org/n...xta.html and Towards a new moth perfume http://phys.org/n...tml#nwlt

Until researchers learn the difference between mutations that perturb protein folding and amino acid substitutions that stabilize the organized genomes of species from microbes to man, we will continue to see the pseudoscientific nonsense of neo-Darwinian theory incorporated into research reports that do not make sense to serious scientists.

Oct 15, 2015
Mutational 'hot spot' leads to adaptation in high-altitude birds
http://phys.org/n...html#jCp

Significance

"Within a given gene, there may be many possible mutations that are capable of producing a particular change in phenotype. However, if some sites have especially high rates of mutation to function-altering alleles, then such mutations may make disproportionate contributions to phenotypic evolution. We report the discovery that a point mutation at a highly mutable site in the β-globin gene of Andean house wrens has produced a physiologically important change in the oxygenation properties of hemoglobin (Hb). The mutant allele that confers an increased Hb–O2 affinity is present at an unusually high frequency at high altitude. These findings suggest that site-specific variation in mutation rate may exert a strong influence on the genetic basis of phenotypic evolution."
http://www.pnas.o...07300112

Oct 15, 2015
@JVK

Beneficial genetic mutations by natural selection---is your head exploding?

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