Reduce anxiety behavior by making more of a forebrain glucocorticoid receptor.

A paper from Rozeboom et al. whose abstract I reproduce here:

Although numerous stress-related molecules have been implicated in vulnerability to psychiatric illness, especially major depression and anxiety disorders, the role of the brain mineralocorticoid receptor (MR) in stress, depression, and affective function is not well defined. MR is a steroid hormone receptor that detects circulating glucocorticoids with high affinity and has been primarily implicated in controlling their basal level and circadian rhythm. To specifically address the role of MR in hypothalamic-pituitary-adrenal axis activity and anxiety-related behaviors, we generated transgenic mice with increased levels of MR in the forebrain (MRov mice) by using the forebrain-specific calcium/calmodulin-dependent protein kinase II {alpha} promoter to direct expression of MR cDNA. A mild but chronic elevation in forebrain MR results in decreased anxiety-like behavior in both male and female transgenic mice. Female MRov mice also exhibit a moderate suppression of the corticosterone response to restraint stress. Increased forebrain MR expression alters the expression of two genes associated with stress and anxiety, leading to a decrease in the hippocampal glucocorticoid receptor (GR) and an increase in serotonin receptor 5HT-1a, consistent with the decreased anxiety phenotype. These data suggest that the functions of forebrain MR may overlap with GR in hypothalamic-pituitary-adrenal axis regulation, but they dissociate significantly from GR in the modulation of affective responses, with GR overexpression increasing anxiety-like behavior and MR overexpression dampening it. These findings point to the importance of the MR:GR ratio in the control of emotional reactivity.

The whole paper, with an introduction that gives more context, can be downloaded HERE.

Motion aftereffect demonstration

I'm passing this on, a rather powerful (practically hallucinatory) demonstration. Look at the center of the moving lines for 20 seconds and then at a picture on the wall. DO NOT TRY THIS IF YOU HAVE PHOTOSENSITIVE EPILEPSY!

Primate beginnings of morality

Nicholas Wade, in the NY Times science section, presents a nice summary of the views of Franz de Waal, Marc Hauser, and other regarding moral behaviors in primates that are antecedent, and similar, to our own. Here is the PDF of the article, and I show the illustrations by Edel Rodriguez based on source material from Frans de Waal and legends below.

Chimpanzees have a sense of social structure and rules of behavior, most of which involve the hierarchy of a group, in which some animals rank higher than others. Social living demands a number of qualities that may be precursors of morality.


Frans de Waal argues that the building blocks of human morality can be seen in the behavior of nonhuman primates like himpanzees. Mutual grooming, for example, shows a sense of fairness or reciprocity.



Chimpanzees engage in both reconciliation and peacemaking. Male chimpanzees routinely reconcile after fights, which protects their group’s social fabric. And Dr. de Waal has described female chimpanzees removing stones from the hands of males about to fight.


The ability to understand the plight of others — empathy — is clearly an essential part of any moral system. Chimpanzees exhibit a variety of behaviors that suggest they have the capacity for empathy, such as helping a frightened young chimp down from a tree.

More on "gay" male fruit flies...

Ed Kravitz is an amazing guy who has made numerous major shifts in his research approach. I was a postdoctoral student with him in the 1960's in the Neurobiology Dept. at Harvard Med. Then we were working on the lobster nervous system and its GABA and glutamate neurotransmitters. Now the Kravitz laboratory is studying the genetics of aggressive and sexual behavior in Drosophila fruit flies. From his recent PNAS abstract:
legend: Drosophila courtship dance

The reproductive and defensive behaviors that are initiated in response to specific sensory cues can provide insight into how choices are made between different social behaviors. We manipulated both the activity and sex of a subset of neurons and found significant changes in male social behavior. Results from aggression assays indicate that the neuromodulator octopamine (OCT) is necessary for Drosophila males to coordinate sensory cue information presented by a second male and respond with the appropriate behavior: aggression rather than courtship. In competitive male courtship assays, males with no OCT or with low OCT levels do not adapt to changing sensory cues and court both males and females. We identified a small subset of neurons in the suboesophageal ganglion region of the adult male brain that coexpress OCT and male forms of the neural sex determination factor, Fruitless (FruM).

A single FruM-positive OCT neuron sends extensive bilateral arborizations to the suboesophageal ganglion [Su oes g in the image, click on image to enlarge], the lateral accessory lobe, and possibly the posterior antennal lobe, suggesting a mechanism for integrating multiple sensory modalities. Furthermore, eliminating the expression of FruM by transformer expression in OCT/tyramine neurons changes the aggression versus courtship response behavior. These results provide insight into how complex social behaviors are coordinated in the nervous system and suggest a role for neuromodulators in the functioning of male-specific circuitry relating to behavioral choice.

Heroes and Happiness

Here is a posting and an audio clip on the topic of happiness that you might find interesting. It includes material from Daniel Gilbert at Harvard, whose book "Stumbling Towards Happiness" I abstracted in earlier blog postings. There is a bit of rap music at the start of the audio, before the spoken text begins.

Most laughing has little to do with humor...

A nice piece by John Tierney (PDF download here) in the NY Times points out that

It’s an instinctual survival tool for social animals, not an intellectual response to wit. It’s not about getting the joke. It’s about getting along.

I recommend that you also have a look at an engaging article by Panksepp and Burgdorf: ‘‘Laughing’’ rats and the evolutionary antecedents of human joy? (PDF download here)

Temporal Lobe Seizures and God

Here are two engaging video clips from Ramachandran, who has also done fascinating work on the phantom limb syndrome and synesthesia.

Part I

Part II

Getting brain wiring correct during development...

During development optic nerve axons connect to cells in the lateral geniculate part of the thalamus, which then sends its axons on to the visual cortex. Inputs from the two eyes need to be sorted out from each other. Carla Shatz's laboratory in the Neurobiology Dept. at Harvard Med. reports very elegant experiments showing how how correct connections between retina and thalamus are reinforced.

Their summary:

The brain is comprised of an immense number of connections between neurons, and clever strategies are required to achieve the correct wiring during development. One common strategy uses neural activity itself as feedback to instruct individual connections (synapses) through synaptic learning rules that delineate which patterns of activity strengthen the synapse and which weaken it. Throughout life, such activity-dependent synaptic changes are likely driven by experience and are thought to underlie learning and memory, but during early stages of development, they are often driven by activity spontaneously generated within the brain. Here, we study connections in the visual pathway between the retina and lateral geniculate nucleus (LGN), which—to develop correctly—require spontaneous “retinal waves” before the eye is responsive to light. By replaying the retinal wave activity as it appears at single LGN synapses, we observe a novel learning rule that describes a relatively simple computation for the developing synapse in the context of retinal wave activity. We then demonstrate how this learning rule is matched to properties of the retinal waves in order to robustly drive the synaptic refinement that occurs in the visual system.

More specifically:

Retinogeniculate synapses have a novel learning rule that depends on the latencies between pre- and postsynaptic bursts on the order of one second: coincident bursts produce long-lasting synaptic enhancement, whereas non-overlapping bursts produce mild synaptic weakening. It is consistent with “Hebbian” development thought to exist at this synapse, and we demonstrate computationally that such a rule can robustly use retinal waves to drive eye segregation and retinotopic refinement. Thus, by measuring plasticity induced by natural activity patterns, synaptic learning rules can be linked directly to their larger role in instructing the patterning of neural connectivity.

How Lotto makes sense...

I've always thought of Lotto games as regressive taxation, and have been totally unable to understand why people would play them instead of socking the money away in a savings account. Benedict Carey has written a nice piece in the March 11 New York Times showing how I have completely missed the point.

...lottery tickets are not an investment but a disposable consumer purchase, which changes the equation radically. Like a throwaway lifestyle magazine, lottery tickets engage transforming fantasies: a wine cellar, a pool, a vision of tropical blues and white sand. The difference is that the ticket can deliver.

And as long as the fantasy is possible, even a negligible probability of winning becomes paradoxically reinforcing...One is willing to pay hard cash that it be so real, so objective, that it is actually calculable — by someone, even if not oneself.

Because it is pure luck, the lottery is easy to grasp and allows for plenty of perfectly loopy — and very enjoyable — number superstitions. Your birthday digits never won you a dime? Try your marriage date; your favorite psalm verse; the day your bullying father-in-law died.... psychologists have found that ticket holders are very reluctant to trade their tickets for others, precisely because they have an illusion of control from having picked magical numbers.

This sense of power infuses the waiting period with purpose. And the hope of a huge payoff, however remote, is itself a source of pleasure. In brain-imaging studies of drug users, as well as healthy adults placing bets, neuroscientists have found that the prospect of a reward activates the same circuits in the brain that the payoffs themselves do.

The End Of The 'Natural'

This stimulating essay by Andy Clark I pass on in its entirety:

I am optimistic that the human race will continue to find ways of enhancing its own modes of thought, reason, and feeling. As flexible adaptive agents we are wide open to a surprising variety of transformative bodily and mental tricks and ploys, ranging from the use of software, sports regimes and meditational practice, to drug therapies, gene therapies, and direct brain-machine interfaces.

I am optimistic that, stimulated by this explosion of transformative opportunities, we will soon come to regard our selves as constantly negotiable collection of resources, easily able to straddle and criss-cross the boundaries between biology and artifact. In this hybrid vision of our own humanity I see increased potentials not just for repair but for empowerment, expansion, recreation, and growth. For some, this very same hybrid vision may raise specters of coercion, monstering and subjugation. For clearly, not all change is for the better, and hybridization (however naturally it may come to us) is neutral rather than an intrinsic good. But there is cause for (cautious) optimism.

First, there is nothing new about human enhancement. Ever since the dawn of language and self-conscious thought, the human species has been engaged in a unique 'natural experiment' in progressive niche construction. We engineer our own learning environments so as to create artificial developmental cocoons that impact our acquired capacities of thought and reason. Those enhanced minds then design new cognitive niches that train new generations of minds, and so on, in an empowering spiral of co-evolving complexity. The result is that, as Herbert Simon is reputed to have said, 'most human intelligence is artificial intelligence anyway'. New and emerging technologies of human cognitive enhancement are just one more step along this ancient path.

Second, the biological brain is itself populated by a vast number of hidden 'zombie processes' that underpin the skills and capacities upon which successful behavior depends. There are, for example, a plethora of such unconscious processes involved in activities from grasping an object all the way to the flashes of insight that characterize much daily skilful problem-solving. Technology and drug based enhancements add, to that standard mix, still more processes whose basic operating principles are not available for conscious inspection and control. The patient using a brain-computer interface to control a wheelchair will not typically know just how it all works, or be able to reconfigure the interface or software at will. But in this respect too, the new equipment is simply on a par with much of the old.

Finally, empirical science is at last beginning systematically to address the sources and wellsprings of human happiness and human flourishing, and the findings of these studies must themselves be taken as important data points for the design and marketing of (putative) technologies of enhancement.

In sum, I am optimistic that we will soon see the end of those over-used, and mostly ad hoc, appeals to the 'natural'...

Origins of Religious Violence

An essay by Ledford in the News section of the March 8 issue of Nature points out an interesting study on bad behavior that follows reading religious texts. A group of religious Mormon students in Utah and a group from the Free University in Amsterdam (in which only 50% believed in God and 27% in the Bible) read a passage from the Old Testament in which God commanded a tribe to "take arms against their brothers and chasten them before the Lord". Control groups did not read the passage, and then all participated in an exercise to measure aggression.

...whether the students were based in the Netherlands or the United States, and believed in God or not — the trend was the same: those who were told that God had sanctioned the violence against the Israelite were more likely to act aggressively in the subsequent exercise.

This simple experiment:

...does suggest that selective exposure to violent passages in a scriptural canon can promote aggression....That response probably reflects a long-standing finding in psychology that people respond more aggressively to a depiction of violence that they feel is justified.

What about:

...a radical solution to theologically inspired violence — cut the violent passages out of the scripture....It's a wildly controversial idea that ought not to be...because spiritual leaders effectively do that on a regular basis. "A lot of churches have a series of passages that they read during the year," says Avalos. "And usually they don't choose the passages involving genocide."

And, speaking of musicians...

Haydn Fantasia in C Major:

The brains of musicians are different...

When asked to mark the center of a horizontal line, neurologically intact right-handers show a slight yet reliable tendency to bisect about 2% to the left of the true center. Patston et al show that that musicians show a slight rightward bias, suggesting left pseudoneglect, and also that musicians bisect the lines more accurately than nonmusicians.


Figure: Mean percentage deviation from the true center in the line-bisection task according to group (musicians vs. nonmusicians) and hand used. Negative numbers denote leftward bias, and positive numbers denote rightward bias. Error bars represent mean standard error.

Currently, there is considerable interest in the musical brain as a window into neurodevelopmental plasticity, with reports of both white-matter and gray-matter differences between musicians and nonmusicians. This work suggests that musicians may develop an increased ability for the left hemisphere to perform cognitive functions that are usually right-hemisphere dominant, and is consistent with the idea that musical training can have perceptual and cognitive effects beyond the auditory modality.

Brain response to threat - reduced by holding hands

Coan, Schaeffer, and Davidson show how social support reduces brain arousal in response to threat. Their abstract:

Social contact promotes enhanced health and well-being, likely as a function of the social regulation of emotional responding in the face of various life stressors. For this functional magnetic resonance imaging (fMRI) study, 16 married women were subjected to the threat of electric shock while holding their husband's hand, the hand of an anonymous male experimenter, or no hand at all. Results indicated a pervasive attenuation of activation in the neural systems supporting emotional and behavioral threat responses when the women held their husband's hand. A more limited attenuation of activation in these systems occurred when they held the hand of a stranger. Most strikingly, the effects of spousal hand-holding on neural threat responses varied as a function of marital quality, with higher marital quality predicting less threat-related neural activation in the right anterior insula, superior frontal gyrus, and hypothalamus during spousal, but not stranger, hand-holding.

A figure from the paper (click on figure to enlarge it):

Legend - Threat-responsive regions of interest affected by hand-holding condition. Green clusters highlighting right dorsolateral prefrontal cortex (rDLPFC), left caudate–nucleus accumbens (lCd/Na), and superior colliculus (SC) indicate spouse-related attenuation. Blue clusters highlighting the ventral anterior cingulate cortex (vACC), posterior cingulate (PC), right postcentral gyrus (rPG), and left supramarginal gyrus (lSMG) indicate attenuation associated with both spouse and stranger hand-holding.

Conscious Reasoning and Intuition in Moral Judgment

Cushman, Young, and Hauser. at Harvard, ask...

Is moral judgment accomplished by intuition or conscious reasoning?

They

...investigated three principles that guide moral judgments: (a) Harm caused by action is worse than harm caused by omission, (b) harm intended as the means to a goal is worse than harm foreseen as the side effect of a goal, and (c) harm involving physical contact with the victim is worse than harm involving no physical contact.

They note that

A critical ingredient missing from the current debate is an experimental method that clearly links data on moral judgment with data on moral justification. Without establishing that an individual uses a specific moral principle, it makes little sense to ask whether the content of that principle is directly available to conscious reasoning. Therefore, in the present study, we first identified three moral principles used by subjects in the judgment of moral dilemmas, and then explored the extent to which subjects generated justifications based on these principles....Asking whether these principles are invoked to explain moral judgments, we found that subjects generally appealed to the first and third principles in their justifications, but not to the second.

These experiments support the view:

that moral judgment can be accomplished by multiple systems: Some moral principles are available to conscious reflection—permitting but not guaranteeing a role for conscious reasoning—whereas others are better characterized by an intuitionist model.

Take Marc Hauser's Moral Sense Test

NeuroLaw

The March 11 Sunday Times Magazine has an excellent article on the impact of neuroscience research on assigning guilt or innocence in criminal cases. I am posting only a few clips from the article and recommend that you read the entire piece, which you can download here.

THE RISE OF NEUROLAW....

Some sort of organic brain defense has become de rigueur in any sort of capital defense...Lawyers routinely order scans of convicted defendants’ brains and argue that a neurological impairment prevented them from controlling themselves. The prosecution counters that the evidence shouldn’t be admitted, but under the relaxed standards for mitigating evidence during capital sentencing, it usually is. Indeed, a Florida court has held that the failure to admit neuroscience evidence during capital sentencing is grounds for a reversal.

THE END OF RESPONSIBILITY?

In a landmark case the landmark case a divided Supreme Court struck down the death penalty for offenders who committed crimes when they were under the age of 18.

The leading neurolaw brief in the case, filed by the American Medical Association and other groups, argued that because “adolescent brains are not fully developed” in the prefrontal regions, adolescents are less able than adults to control their impulses and should not be held fully accountable “for the immaturity of their neural anatomy.” In his majority decision, Justice Anthony Kennedy declared that “as any parent knows and as the scientific and sociological studies” cited in the briefs “tend to confirm, ‘[a] lack of maturity and an underdeveloped sense of responsibility are found in youth more often than in adults.’ ” Although Kennedy did not cite the neuroscience evidence specifically, his indirect reference to the scientific studies in the briefs led some supporters and critics to view the decision as the Brown v. Board of Education of neurolaw.

PUTTING THE UNCONSCIOUS ON TRIAL...

Two companies, No Lie MRI and Cephos, are now competing to refine f.M.R.I. lie-detection technology so that it can be admitted in court and commercially marketed.

ARE YOU RESPONSIBLE FOR WHAT YOU MIGHT DO?....

Neuroscience, it seems, points two ways: it can absolve individuals of responsibility for acts they’ve committed, but it can also place individuals in jeopardy for acts they haven’t committed — but might someday.

WHAT IS AHEAD?

As the new technologies proliferate, even the neurolaw experts themselves have only begun to think about the questions that lie ahead. Can the police get a search warrant for someone’s brain? Should the Fourth Amendment protect our minds in the same way that it protects our houses? Can courts order tests of suspects’ memories to determine whether they are gang members or police informers, or would this violate the Fifth Amendment’s ban on compulsory self-incrimination? Would punishing people for their thoughts rather than for their actions violate the Eighth Amendment’s ban on cruel and unusual punishment? However astonishing our machines may become, they cannot tell us how to answer these perplexing questions. We must instead look to our own powers of reasoning and intuition, relatively primitive as they may be....neuroscience itself can never identify the mysterious point at which people should be excused from responsibility for their actions because they are not able, in some sense, to control themselves. That question, he suggests, is “moral and ultimately legal,” and it must be answered not in laboratories but in courtrooms and legislatures. In other words, we must answer it ourselves.

Making Us/Them Dichotomies More Benign.

Interesting thoughts from Robert Sapolsky:

A truly discouraging thing to me is how easily humans see the world as dichotomized between Us and Them. This comes through in all sorts of ways —social anthropology, lord of the flies, prison experiments, linguistics (all those cultures where the word for the members of that culture translates into "People," thus making a contrast with the non-people living in the next valley). As a neurobiologist, I'm particularly impressed with and discouraged by one finding relevant to this. There's a part of the brain called the amygdala that has lots to do with fear and anxiety and aggression. Functional brain imaging studies of humans show that the amygdala becomes metabolically active when we look at a scary face (even when the face is flashed up so quickly that we aren't consciously aware of seeing it). And some recent work—solid, done by top people, independently replicated — suggests that the amygdala can become activated when we view the face of someone from another race. The Them as scary, and the Them being someone whose skin color is real different from our own. Damn, that's an upsetting finding. But right on the heels of those studies are follow-ups showing that the picture is more complicated. The "Other skin color = scared activated amygdala = the Other" can be modified by experience. "Experience," can be how diverse of a world you grew up in. More diversity, and the amygdala is likely to become activated in that circumstance. And also, "experience," can be whether, shortly before your amygdala is put through the brain imaging paces, you are subtly biased to think about people categorically or as individuals. If you're cued towards individuating, your amygdala doesn't light up. Thus, it seems quite plausible to me that we are hard-wired towards making Us/Them distinctions and not being all that nice to the Them. But what is anything but hard-wired is who counts as an Us and as a Them —we are so easily manipulated into changing those categories. So, I'm optimistic that with the right sort of priorities and human engineering (whatever that phrase means), we can be biased towards making Us/Them dichotomies far more benign than they tend to be now. Say, by making all of us collectively feel like an Us with Them being the space aliens that may attack us some day. Or making the Them to be mean, shitty, intolerant people without compassion. But, I'm sure not optimistic that we'll soon be having political, religious or cultural leaders likely to move us effectively in that direction. Just to deflate that optimism.

Brain cells and arrangements unique to human cerebral cortex

A New Focus article in the March 2 issue of Science by Michael Balter reviews work on several brain neuronal types and arrangements that are distinctive to humans and great apes.

Spindle neurons (also called Von Economo or VEN neurons after their Austrain discoverer) are provide one example (credit J. Allman):

...these neurons are located in only two parts of the brain: the anterior cingulate cortex, deep in the center of the brain, and the frontoinsular cortex, located inside the frontal lobes. In humans, both of these structures appear to be involved in aspects of social cognition such as trust, empathy, and feelings of guilt and embarrassment. Not only were VENs unique to great apes, but humans had many more VENs than other apes. And the human VENs were markedly larger.

John Allman of Cal Tech suggests that

...the large VENs might relay information rapidly from the anterior cingulate and frontoinsular cortices to other parts of the brain....They are really stripped-down, high-performance kinds of cells...the big VENs might help humans adjust behavior swiftly in response to rapidly changing social situations....

New data on dementia seem to fit that notion.

Last December, a team led by William Seeley at UC San Francisco reported in Annals of Neurology that subjects afflicted with a type of dementia that causes inappropriate and impulsive social behavior had 74% fewer VENs in their anterior cingulate cortex compared to normal controls.

The article goes on to discuss the fact that minicolumns of the, groups of 80 to 100 nerve cells bundled together vertically in the cerebral cortex are much wider in humans than in chimps and monkeys (average of 51 versus 36 micrometers) due to an increase in the space taken up by neuropil (the axons, dendrites, and synapses that make neural connections). That is, there are many more connections.

Astrocyte Cells: (Credit: Oberheim et al. Univ. Rochester)

It also turns out that that levels of the messenger RNA that makes thrombospondins - large proteins released by astrocytes which trigger synapse formation - are six times higher in human cerebral cortex than in chimps or monkeys. The differences were seen in the cerebral cortex but not in the cerebellum and nonbrain tissues. (Astrocytes are support cells that make up nearly half the cells in the human brain, but their functions have remained a mystery.)

Alter a gene - make more fearless mice

Here is a brief clip on material I have mentioned previously...

Odor cues during sleep stimulate memory.

The March 9 issue of Science has an interesting report by Rasch et al. and commentary by Miller on experiments demonstrating that pulses of an odor (rose scent) given during a learning task, improve consolidation of the memory of that task if given also during slow-wave sleep. The abstract:

Sleep facilitates memory consolidation. A widely held model assumes that this is because newly encoded memories undergo covert reactivation during sleep. We cued new memories in humans during sleep by presenting an odor that had been presented as context during prior learning, and so showed that reactivation indeed causes memory consolidation during sleep. Re-exposure to the odor during slow-wave sleep (SWS) improved the retention of hippocampus-dependent declarative memories but not of hippocampus-independent procedural memories. Odor re-exposure was ineffective during rapid eye movement sleep or wakefulness or when the odor had been omitted during prior learning. Concurring with these findings, functional magnetic resonance imaging revealed significant hippocampal activation in response to odor re-exposure during SWS.