Terror Mouse!

Building a better fight-mouse through brain injections of genes.

Much of our economic and political discussions are sublimated social dominance psychology ... who "deserves" to stand higher on the totem pole, who deserves what pay, which class should rule, which cultural myth should guide us into the future. These are not technocratic issues, but questions of value embedded in our social instincts. Up till quite recently, we were under the impression that our lives needed to be run by the nobilities of blood and church. And status archetypes like princess, knight, and king- reflected in popular literature like the Harry Potter series- continue to structure our political and social systems. For example, the king-like office of president.

Obviously, all this is extremly ancient and perhaps unavoidable. All animals with any kind of social system also have a social hierarchy so that most of the time, internal conflict can be avoided and members can get on with the common goals for which the social system exists. This includes mice, which are the subject of a recent paper in Science from a lab which investigated the neurological basis of their dominance hierarchy.

The tests of status were simple. In a tube test, two mice are put into opposite ends of a one-lane tube, and the one who backs out is the dominant mouse. The mice have been trained to run to the end of such tubes to get some food, and apparently were occasionally prodded along with sticks so that they met at the middle before deciding which mouse would back out.

A second test used a natural behavior where in nests, one mouse typically chews down the whiskers of the other mice, becomming the "barber" mouse. Other tests included measurements of weight gain after food was put in a common area in limited amounts, a urine marking assay of territory size, and a sound assay, where dominant males call out ultrasonically to females with more enthusiasm. The tests all correlated with each other, leading to a coherent score of social rank.

Previous clues had directed these researchers to the medial prefrontal cortex (MPFC) as an area that shows hightened activity during dominance-related behavior. So they looked for signs of social rank in their mice in this area of the brain by slicing up their research subjects and looking for electrical activty (live slices) and various molecular signatures (dead slices).

They found that the electrical activity of randomly tested neurons in this brain region, upon chemical stimulation of glutamate receptors, was somewhat higher in dominant mice vs the lowest ranked mice. Likewise, the c-Fos gene, which gets expressed after brain activity and is used as a marker for active brain regions, shows higher mRNA levels in higher-ranking mice (below). One wouldn't necessarily assume that the brains of dominant animals are more active than lower-ranking ones, but in any case, they would have different profiles of activity, so non-dominant mice may have higher activity elsewhere in the brain.

cFos gene expression in MPFC area of brain slices reflects social dominance.

Now for the exciting part. The researchers decided to test this correlation of brain activity with social status by direct action: increasing or decreasing glutamate receptor activity in the brains of living mice by injected gene therapy. Glutamate-sensitive neurons can be "tuned" by expression of proteins Ras or Rap,  which have opposite effects in the signalling cascade involved in recycling the synaptic vesicles that contain neurotransmitters. So the researchers injected the MPFC with a virus expressing either of these proteins. The affected neurons showed strong effects, with 179% of normal activity when infected by Ras-expressing virus, and 71% of normal activity when infected with Rap-expressing virus.

"Mice infected with the Ras virus moved upward in rank, starting a easrly as 12 hours after viral injection. In contrast, mice infected with the Rap virus moved down in rank. Infection of virus expression green fluorescent protein [GFP] alone did not result in any rank shift."

The average rank shift was only one unit, out of three possible units of rank from one end of the status scale to the other. So this treatment alone is not quite sufficient to produce the über-mouse. The treatment is also incredibly crude, perhaps providing an "injection" of confidence or slight craziness.

A small brain injection might do wonders for one's social status, if one wants to go beyond the steroid, testosterone and other injections people use currently. Less facetiously, it is another example of the brain basis of our thoughts, feelings, and behaviors.

• MPFC and the Self.
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• Incidentally, the GOP also has sex on the brain.
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• The stimulus should have been 1.8 trillion.
• A fascinating view of our recent debt history.
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• Discursive overview of modern monetary theory, money, banking, the Euro, and power.
• Our financial system is run by psychopaths.
• Economics quote of the week, by Adam Smith, courtesy Robert Skidelsky.

"The third and last duty of the sovereign....is that of erecting and maintaining those public institutions and those public works, which though they may be in the highest degree advantageous to a great society, are, however, of such a nature, that the profit could never repay the expense to any individual, or small number of individuals; and which it, therefore, cannot be expected that any individual, or small number of individuals, should erect or maintain."

Nowhere to hide- the megafauna refuge in Tibet

Where did wooly mammoths and wooly rhinoceri hang out in between ice ages?

Earth was host to a magnificent ecosystem thousands of year ago- movingly drawn on the walls of Chauvet and other caves by our artistic ancestors. Wooly mammoths, wooly rhinoceri, aurochs, giant rhinoceri, and cave lions, among others. The ice ages ebbed and flowed, and these animals with them, until humans gave them nowhere to hide and upended the ages-old ecological order. Where did these animals stay during the warm periods? Where would they be now?

Wooly mammoths and rinoceri seem to have evolved in step with this era of ice ages, which began about 2.6 million years ago and rolled in 100,000 year cycles through the last million years. 100,000 years isn't enough time to evolve a wooly rhinocerous, but 3 million years is. A recent paper in Science tells of a new fossil found in Tibet of a proto-wooly rhinocerous from 3.7 million years ago, indicating that Tibet was the birthplace of at least some of the cold-adapted megafauna that was so successful during the ice ages. It notes also that the outer margins of Tibet where part of the known range of wooly rhinos, indicating that this area served as its refuge during warmer interglacial periods as well.

Elasmotherium, the giant rhinocerous.

It is worth noting that the Himalayas are thought to have begun exhibiting alpine conditions due to plate tectonics only from about 3 million years ago, contrary to earlier estimates, and closely consistent with the current paper's estimates. At any rate, once cold-adapted megafauna developed in Tibet, they found huge areas of the northern hemisphere hospitable during the ice ages, and were even able to meander over to North America. For instance, our bison diverged from the Tibeten yak only 2 million years ago.

How wonderful it would be to come upon these animals today. But of course Tibet has also been colonized by humans- the people of Tibet, who themselves became somwhat biologically adapted to the cold and altitude, and doubtless extirpated the rhinos, who with their formidable horns were so well-defended against all other predators.

Of the not-so-mega fauna that remain, do they have a chance? If we are not killing them directly, are we giving them wide landscapes to flourish in? Are we giving them millions of years to adapt to the climate change we are bringing on; even thousands?

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Star Wars and the hero's quest

The Star Wars mashup as a way to psychological, even spiritual, health.

I found the recent release of a full-length mashup version of Star Wars, composed of countless (actually, 473) clips from fan reenactments and animations, endlessly fascinating. As the Salon article that brought it to my attention mentions, it is a gloriously expressive outpouring of love. But is it healthy?

From the very first, Star Wars was an extraordinarily cheesy Hero tale. A journey by the fair-haired Luke from Potter-esque anonymity to savior of the galaxy, with a bit of magic (force) tossed in at highly convenient plot points, with luck and coincidence playing starring roles. Then the franchise went steadily downhill, but I won't go there!

As a fan of Jung, I respect the intricacies of the archetypal theory that surrounds this sort of tale, which goes into enormous detail about the typical hero, the helpers in the quest, the father-figure, the role of the underworld and its tests, the initiation ritual, the magic tools, and so forth. All this has its role. But one thing missing in the theory is its point ... why are these hero tales so gripping and perennial? Why do they emerge in every time and cuture? Joseph Campbell tries to explain it in his classic, the Hero with 1000 faces:

"The passage of the mythological hero ... fundamentally it is inward- into depths where obscure resistances are overcome, and long lost, forgotten powers are revivified, to be made available for the transfiguration of the world. This deed accomplished, life no longer suffers hopelessly under the terrible mutilations of ubiquitous disaster, battered by time, hideous throughout space, but with its horror visible still, its cries of anguish still tumultuous, it becomes penetrated by an all-suffusing love, and a knowledge of its own unconquered power." ...

"What, now, is the result of the miraculous passage and return? 

The battlefield is symbolic of the field of life, where every creature lives on the death of another. A realization of the inevitable guilt of life may so sicken the heart that, like Hamlet or Arjuna, one may refuse to go on with it. On the other hand, like most of the rest of us, one may invent a false, finally unjustified, image of oneself as an exceptional phenomenon in the world, not guilty as the others are, but justified in one's inevitable sinning because one represents the good. Such self-righteousness leads to a misunderstanding, not only of oneself but of the nature of both man and the cosmos. The goal of the myth is to dispel the need for such life ignorance by effecting a reconciliation of the individual consciousness with the universal will. And this is effected through a realization of the true relationship of the passing phenomena of time to the imperishable life that lives and dies in all."

In the spirit of simplification, what I would focus on is that the Hero tale, simply and plainly, is a way to model success. As Reagan said, nothing succeeds like success, and the psychological enactment of success- of reading the happy fairy tale, of cheering for a winning team, of watching the murder being solved on CSI, reading the superman comic book, and yes, wielding one's tin-foil light-saber, is more powerful than any Tony Robbins motivational pablum. Sure, actual success is the sweetest of all, but that is a rare experience, and anyway, we only know what to do with it and how to value it through the strenuous modelling of a childhood steeped in the hero tale (including Cindarella tales).

We are all by the nature of reality and life bound by countless fetters. Biological, physical, environmental, and above all social conditions hem us in on all sides. Life is an endless series of problems to be solved and desires to be satisfied in the teeth of implacable reality- even quite active competition & opposition. The mantra of "freedom" that rings through our political discourse is far from an existential promise, but a woefully limited proposition, relative only to our ur-political condition of total Hobbesian depotism. Now, we face, in political terms merely a tyranny of the majority, (or a majority of the money), moderated by a few constitutional rights, more or less observed.

Thus the sweetness and rarity of true success, where some magical tool or insight arises, perhaps spontaneously from the same place that is so insistent on the enactment of hero tales ... the unconscious, allowing us to cut an existential Gordian knot. While obedience to the ambient social norms may suffice for a "normal", discontented slave-like existence, we all aspire higher. Perhaps tragically, but also inevitably. The hero tale is the spur, the offering of hope, and the psychological preparation for that real quest.

How best to experience it? Clearly one gets out what one puts into it, psychologically speaking. Worst of all is the passive viewing experience, supine in front of a TV or theater screen. Next perhaps is the radio format, demanding substantially more mental attention and imagination. On par would be a live reading by a friend or parent, even if there are a few pictures involved. Somewhere in there would also come the solitary reading experience, which makes some imaginative demands, but is also a bit slow and dry. How about actual re-enactment and play? Here we get to some serious interactivity, intensity, mental involvement, and imagination. Indeed, the more crude the props and implements, the higher the imaginative involvement.

Lastly of course is actually carrying out a heroic experience, engaging in the hard work involved, the practice, the training, the schooling needed to be a professional musician, or join seal team 6, or cure cancer. But that takes forever!

One can easily imagine religion arising out of this process of devising and telling heroic tales. Adults and children alike thrive on such sagas. Perhaps one saga (Homer's, the Ramayana, the Mosaic tale, etc.) captures the mood and vitality of a culture particularly well, with close scrapes, awesome enemies, deep poetry, and triumphant successes. Perhaps, in its customary recognition of the overwhelming importance of the hero's unique inner resources (i.e. the unconscious), its heroes gain magical assistance or are themselves gods under mundane cover.

Perhaps this story becomes so psychologically compelling or ritualized in re-enactment that it turns from story into fact- a "believed" religious narrative. Some other ingredients may be added, such as a back-story about how the world is created, and some more or less rationalized doctrines about how the "super" powers and "super"-beings relate to each other to satisfy the more cerebral believers. But all these things can be added later on rather easily, as George Lucas has labored voluminously (if relatively vainly) to show. (L. Ron Hubbard had a great deal more success!)

And what about humor? In striking contrast to a story that evolves into religion, the Star Wars mashup is as much spoof as homage, yet is none the less loving for that. The original film used plenty of humor, particularly from C3PO, and the comically over-drawn villains. There are fine lines between modelling success and being successful, delicious in their plasticity. Also, fine lines between profundity and platitude, between bathos and tragedy, between meaningful myth and camp. Humor seems to signify our knowledge of those lines, our mutual conspiracy to experience greatness while wearing collanders on our heads. It also, in its better tenors, affirms existential hope over the various tragic means and ends of human life.

In this connection, Campbell tried to resurrect an ancient sense of comedy, far different from what is customary today:

"We are not disposed to assign to comedy the high rank of tragedy. Comedy as satire is acceptable, as fun it is a pleasant haven of escape, but the fairy tale of happiness ever after can not be taken seriously; it belongs to the never-never land of childhood, which is protected from the realities that will become terribly known soon enough; just as the myth of heaven ever after is for the old, whose lives are behind them and whose hearts have to be readied for the last portal of the transit into night - which sober, modern, Occidental judgement is founded on a total misunderstanding of the realities depicted in the fairy tale, the myth, and the divine comedies of redemption. These, in the ancient world, were regarded as of a higher rank than tragedy, of a deeper truth, of a more difficult realization, of a sounder structure, and of a revelation more complete. 

The happy ending of the fairy tale, the myth, and the divine comedy of the soul, is to be read, not as a contradiction, but as a transcendence of the universal tragedy of man. The objective world remains what it was, but, because of a shift of emphasis within the subject, is beheld as though transformed. ... Tragedy is the shattering of the forms and of our attachment to the forms; comedy, the wild and careless, inexhaustible joy of life invincible.
...
It is the business of mythology proper, and of the fairy tale, to reveal the specific dangers and techniques of the dark interior way from tragedy to comedy. Hence the incidents are fantastic and 'unreal': they represent psychological, not physical, triumphs."

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• Economics quote, from Robert Solow, via Bill Mitchell, speaking of conventional micro-based macroeconomic modeling approaches (dynamic stochastic general equilibrium, or DSGE):

"An obvious example is that the DSGE story has no real room for unemployment of the kind we see most of the time, and especially now: unemployment that is pure waste. There are competent workers, willing to work at the prevailing wage or even a bit less, but the potential job is stymied by a market failure. The economy is unable to organize a win-win situation that is apparently there for the taking. This sort of outcome is incompatible with the notion that the economy is in rational pursuit of an intelligible goal. The only way that DSGE and related models can cope with unemployment is to make it somehow voluntary, a choice of current leisure or a desire to retain some kind of flexibility for the future or something like that. But this is exactly the sort of explanation that does not pass the smell test."

Neurons poised in meditation

Cortical neurons show exquisite balance between inhibitory and excitatory inputs, typically summing to zero.


Life wouldn't be quite as sweet without homeostatic mechanisms. From blood chemistry to the hedonic treadmill, our biology keeps things stable so we can sail through life on an even keel. As yet we have only a glimmer of appreciation for the many homeostatic mechanisms in the brain- for mood, activity, weight, temperature, introversion, sleep, and many more. While people differ in their settings for many of these systems, those settings tend to be extremely stable through life.

It's gradually become apparent that the basic workings of the brain rely on another homeostatic mechanism on the level of neurons and neural networks. The ability to shift attention, superimposed on a baseline brain rhythm / hum, indicates that the baseline condition of much of the brain is quasi-stability. Such shifts are detected in functional brain scanning as metabolic variations, (higher blood flow, among other signs), so there is real physiological change that follows what subjectively seems like effortless shifts of mental state.

So, most of the brain operates on a knife's edge / default / zero state which can be roped into active, attentive, ever-changing coalitions of neurons from all over the cortex to bring us the many and various conditions of thought, sensation, vision, emotional engagement, planning, etc. that are well-known to engage various specific parts of the brain.

For this important property of nerve cells in the brain, a recent paper provides a cellular rationale, which is that all information-carrying neurons in the brain typically get automatically balanced inhibitory and excitatory inputs through a feedback mechanism to inhibitory synapses. The idea is that each neuron connects as much to inhibitory interneurons as to excitatory information-carrying neurons, and those inhibitory neurons adjust their outputs over time in response to what is going on in the target cell so that its activity stays mostly quiescent. Most neurons thus spend most of their time in a calm, meditative state.

The paper leads with simulation experiments, and follows with supporting evidence from actual cells and networks. The hypothesis appears to go substantially beyond current knowledge, where inhibitory neurons are a well known component, but not a functionally well-understood part of the neural / cognitive landscape. The hypothesis provides a rationale, based on a relatively mindless cellular mechanism, for why the brain doesn't explode with activity, but rather keeps humming within relatively tight bounds, and as noted above, with the sort of knife-edge stability that lets us think with some degree of both focus and roving attention.

The story starts with Donald Hebb, who came up with perhaps the key insight to how neurons can learn as a network. The rule is commonly expressed as "cells that fire together wire together". Which is to say that in a neural network of cells, those that fire coincidently (one to the next) within some window of time (say <10 milliseconds), engage in a molecular process that strengthens their synaptic connections so that in the future, the downstream cell responds more strongly to firing of that upstream cell.

This basically mechanical process is the soul of associative learning, where a bell, say, is associated with the appearance of food. But lest everything become associated with everything else, countervailing mechanisms are needed to inhibit those connections that are not active, and keep overall activity at a low baseline so that only unusual occurences create signals. In this general respect, the role of inhibitory neurons (which generally use the neurotransmitter GABA in their synapses, in contrast to excitatory neurons that typically use glutamate) has been appreciated for some time.

The present authors take the extra step of simulating in detail specific rules of Hebbian learning and inhibition that seem to accurately account not only for the actual sensitivity of cortical neurons but, on a larger scale, for the operation of memory as an example of how all this adds up to collective neuronal & brain function.

The secret is a rule that generates detailed balance of excitatory and inhibitory inputs over time to each cell, leading the downstream (target) neuron to be mostly quiescent (also called by the authors asynchronous irregular activity, or AI). This rule operates on inhibitory interneurons that get the same upstream signals as excitatory neurons, adjusting their synaptic strengths towards the common downstream neuron.

A: Diagram of the inhibitory neuron (light gray), getting excitatory inputs and acting in parallel with excitatory stimulation to a balanced target (green). B: Diagram of simulations, where 25 inhibitory and 100 excitatory neurons with distinct signal trains, feed into a target neuron. C: Relation of the learning rule with time. Only coincident firing (inhibitory and target neurons) within ~20 milliseconds is supposed to strengthen synapses.

What's the rule?

∆w = µ( (pre * post) - (p0 * pre) )

w is synaptic efficiency, pre is the presynaptic activity, post is postsynaptic activity, p0 is a constant that targets the postsynaptic neuron to low average activity (zero most of the time), and µ is the learning rate: the key factor for how quickly coincident firing strengthens inhibitory synapses.

Course of simulations, where the net membrane current on the target neuron is green, the excitatory current is black, and inhibitory current on the target cell (from the inhibitory synaptic firing) is gray. Note that the target ends up (after) at zero most of the time.

Clearly this is a flexible rule, where constants can be plugged in to approximate what is empirically observed. Yet its simplicity, once set up, is very impressive. A time course of simulation samples is shown above. The inhibitory activity starts at zero, (before), and due to frequent co-firing of the inhibitory and target neurons, (due to their common excitatory input), their connections progressively strengthen to the point that net firing of the target cell goes down close to zero (after) for all but unusual excitatory inputs that vary faster than the rule-based learning rate.

Different values for µ, or the learning rate, (apologies.. I use greek mu in the text in place of eta) make relatively little difference to system behavior, after perturbing the excitatory input (red line), compared to the background activity (black line).

As the authors put it: "In the detailed balanced state, the response of the cell was sparse and reminiscent of experimental observations across many sensory systems. Spikes were caused primarily by transients in the input signals, during which the faster dynamics of the excitatory synapses momentarily overcame inhibition." Thus from a very simple cellular structure is born a sophisticated information processing system.

Comparison of simulation (lines) to experiments (blocks) cited from other researchers on rat auditory cortex single-neuron learning curves in response to a shift in sensory (sound) signal frequency. The X-axis is in minutes, and the Y axis is excitatory : inhibitory current ratio, taken from two different cells- a cell tuned to the prior frequency (blue) or a cell tuned to a newly introduced frequency (red).

Lastly, the researchers turn to what this kind of circuit / rule can do in a larger scale neural system, using memory as an example. They simulate a matrix of 100 X 100 cells made up of mostly excitatory cells (Ex in the figure below) and 25% inhibitory cells (In). Unlike the determined circuits simulated above, here the cells randomly connect to 2% of the other cells in the population. The researchers assumed that enough inhibitory connections would be sprinkled throughout so that, given enough learning time, the network as a whole would behave in the balanced way they expect.

The graphs above follow the evolution of this system in time, with A showing the initial state where all the excitatory cells fire at full blast, and the inhibitory cells fire randomly. After a simulated hour of internal learning, (B), the network has indeed settled down to a baseline balanced, or AI state of very low output activity, shown by the dark snowy pattern, despite the excitatory cells still firing at the original rate.

At time C, the researchers introduced a permanent five-fold increased excitatory synapse strength within two patches of the matrix (red and blue squares in A; the unaffected control patch is black). The graphs underneath sample a few random cells from either the red or black (control) areas of the matrix. The transient activation / recognition of the introduced signal is clearly apparent (C). Yet after another simulated hour, (D), the inhibitory circuits have adjusted and the overall network is back to a baseline, quiescent state. The patches of prior high activity are completely invisible.

No measure of ambient neural activity would detect a memory engram here. Yet when a quarter of the red patch excitatory neurons were driven with extra activity, the full red patch lit up again, (E), showing that a full memory could be re-activated from a partial input. The cleanliness of this process, not overlapping the blue patch at all, indeed forming a slight negative image over it, is astonishing. This constitutes an extremely interesting and promising model for how information can be tucked away and later retrieved out of our brains.. a loosely constructed tangle of neurons and their ~100 trillion synapses.

What can I add? Perhaps that simulation is an increasingly essential element in biology, as in so many other fields. We are dealing with such complexity that it is hopeless to formulate comprehendable representations of this reality in prose form, or even graphs, charts, or other tools of presentation. To get at the dynamics of complex systems, critical and simple insights like that of Hebbs and the inhibitory neuron balancing rule promoted here remain essential. But to demonstrate what such insights really mean for complex systems, mental extrapolation is not enough- computer simulation is needed.

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