plasticity

I just wrote about the alteration of a behavior pattern (decision-making) resulting from injury to the prefrontal cortex. That is the kind of functional specificity that might be expected as a result of "modularization" of mental functions. In that case, injuries to different people in the same place have the same kind of effect on behavior. Arguably, some part of the ventromedial prefrontal cortex functions as a module involved in moral decision-making (and as I noted, decision-making applied to gambling and other kinds of risks).

In a different study this week, a research team created knock-in mice, expressing the human photopigment allowing trichromatic vision in humans and other primates. They found that, even though mice belong to a lineage that hasn't had trichromatic vision for more than 100 million years, the mice immediately started perceiving the new color.

Here's an account from New Scientist, by Roxanne Khamsi:

The study demonstrates that the mouse brain is "primed" for expanded colour vision, the researchers say. It suggests that a simple mutation giving rise to the L receptor protein in our primate ancestors immediately expanded their visual perception.

"It has been unclear whether the simple addition of a photopigment is sufficient to yield a new dimension of colour vision, or whether you might need, in addition, some changes in the nervous system," says Gerald Jacobs, a vision researcher at the University of California, Santa Barbara, US, who took part in the study.

This is very interesting because it means that simple mutational changes in sensory systems are readily incorporated into sensory and cognitive processes by the brain. The paper suggests that the occurrence of novel sensory receptors might lead to selection for more and more efficient mechanisms for discriminating information, based on an initial, imperfect effect. That is basically the explanation for the evolution of all sensory systems, and is a powerful one.

The addition of new sensory receptors may be even more relevant for smell than for sight, since smell depends on hundreds of different olfactory receptor proteins, which originated by duplications and are eliminated by deactivations in different lineages of mammals. In retrospect, the idea that a novel sensory receptor might have immediate effects is sort of obvious, considering that humans are polymorphic for many olfactory receptors and some taste receptors. People with red-green colorblindness don't have catastrophic failure of their visual perception; instead, the perception system develops normally in the context of the lack of information from the missing receptor. Likewise, the senses of smell and taste bootstrap themselves based on the information present throughout development.

It's not remarkable that the brain should be plastic to new inputs; we would have noticed much sooner if it weren't!

References:

Jacobs GH, Williams GA, Cahill H, Nathans J. 2007. Emergence of novel color vision in mice engineered to express a human cone photopigment. Science 315:1723-1725. doi:10.1126/science.1138838

You are the captain of a military submarine travelling underneath a large iceberg. An onboard explosion has caused you to lose most of your oxygen supply and has injured one of your crew who is quickly losing blood. The injured crew member is going to die from his wounds no matter what happens.

The remaining oxygen is not sufficient for the entire crew to make it to the surface. The only way to save the other crew members is to shoot dead the injured crew member so that there will be just enough oxygen for the rest of the crew to survive.

Would you kill the fatally injured crew member in order to save the lives of the remaining crew members?

What would you do? What would you do!?? If it helps, you can imagine that Dennis Hopper is making you choose...

That scenario is from the New Scientist article by Roxanne Khamsi, covering the paper by Koenig and colleagues about the effects of ventromedial prefrontal cortex lesions on decision-making. She also finds the obvious analogy with the final scenes of Star Trek II: The Wrath of Khan.

The second paragraph of the article itself is the most enlightening, concerning the background of the study:

The basis of our moral judgements has been a long-standing focus of philosophical inquiry and, more recently, active empirical investigation. In a departure from traditional rationalist approaches to moral cognition that emphasize the role of conscious reasoning from explicit principles (15), modern accounts have proposed that emotional processes, conscious or unconscious, may also play an important role (16, 17). Emotion-based accounts draw support from multiple lines of empirical work: studies of clinical populations reveal an association between impaired emotional processing and disturbances in moral behaviour (1, 2, 3, 4); neuroimaging studies consistently show that tasks involving moral judgement activate brain areas known to process emotions (5, 6, 7, 8, 9); and behavioural studies demonstrate that manipulation of affective state can alter moral judgements (10, 11). However, neuroimaging studies do not settle whether putatively 'emotional' activations are a cause or consequence of moral judgement; behavioural studies in healthy individuals do not address the neural basis of moral judgement; and no clinical studies have specifically examined the moral judgements (as opposed to moral reasoning or moral behaviour) of patients with focal brain lesions. In brief, none of the existing studies establishes that brain areas integral to emotional processes are necessary for the generation of normal moral judgements. As a result, there remains a critical gap in the evidence relating moral judgement, emotion and the brain.

This study brings together two interesting subjects -- the role of emotion in decision-making, and the structure of the ventromedial prefrontal cortex (vmPFC). It has long been known that normal emotional cognition is necessary for decision-making -- people with brain injuries that interfere with normal emotional response often exhibit various degrees of inability to make decisions.

Damasio and colleagues have been especially central to this area of neuroscience. My copy of Purves et al. (2004:708) has a nice paragraph summarizing their general idea:

Antonio Damasio and his colleagues at the University of Iowa have suggested that such decision-making entails the rapid evaluation of a set of possible outcomes with respect to the future consequences associated with each course of action. It seems plausible that the generation of conscious or subconscious mental images that represent the consequences of each contingency triggers emotional states that involve either alterations of somatic and visceral motor function, or the activation of neural representations of such activity. Whereas William James proposed that we are "afraid because we tremble," Damasio and his colleagues suggest a vicarious representation of motor action and sensory feedback in the neural circuits of the frontal and parietal lobes. It is these vicarious states, according to Damasio, that give metnal representations of contingencies the emotional valence that helps an individual to identify favorable or unfavorable outcomes.

This isn't the first study to examine decision-making in vmPFC patients. A 2000 paper by Bechara, Tranel, and Damasio described a gambling experiment, in which subjects were given an opportunity to risk high immediate punishment for a high long-term reward, or low punishment for a low long-term reward. They found that vmPFC subjects avoid the high short-term punishment, even after the already-high long-term reward is raised further.

The gambling result complicates matters somewhat, as far as interpreting the "moral quandary" experiments in the new research. Plausibly, the long-term versus short-term punishment factor is an important part of the "moral" decision: do you sacrifice many people immediately for a long-term relationship with a relative? That's backward from the way the question is usually asked, but it poses the same problem.

Tranel, Bechara, and Denberg (2002) found that patients with damage to the right vmPFC in particular had social and emotional deficits, in comparison to patients with left-only damage:

The aim of this study was to begin to parse the relative contributions of the right and left ventromedial prefrontal cortices (VMPC) in regard to social conduct, decision-making, and emotional processing. We hypothesized that the right VMPC is a critical component of the neural systems that subserve such functions, whereas the left VMPC is not. Seven participants with focal, stable unilateral lesions to the right (n = 4) or left (n = 3) VMPC were studied with procedures designed to measure social conduct, decision-making, and emotional processing and personality. The right-sided participants had profound disturbances of social and interpersonal behavior and of the ability to maintain gainful employment; they had defective performance and impaired anticipatory skin conductance responses during the Gambling Task; most had profound abnormalities of emotional processing and personality, and met criteria for "acquired sociopathy." By contrast, the left-sided participants had normal social and interpersonal behavior; they had stable employment; they performed normally and had normal skin conductance responses on the Gambling Task; they had normal emotional processing; and their personalities were unchanged from premorbid status. The marked deficits in social conduct, decision-making, and emotional processing in participants with unilateral right VMPC lesions are reminiscent in kind of those that have been reported in connection with bilateral VMPC lesions, albeit perhaps of lesser severity. The findings provide preliminary evidence that insofar as social, decision-making, and emotional functions are concerned, the right-sided component of the VMPC system may be critical, whereas the left-sided component may be less important.

Research in people without damage to their vmPFC has tried to determine the logical structure that the area uses to make decisions. For example, Alan Hampton and colleagues (2006) scanned people with an fMRI while they made different kinds of decisions. Here's the abstract:

Many real-life decision-making problems incorporate higher-order structure, involving interdependencies between different stimuli, actions, and subsequent rewards. It is not known whether brain regions implicated in decision making, such as the ventromedial prefrontal cortex (vmPFC), use a stored model of the task structure to guide choice (model-based decision making) or merely learn action or state values without assuming higher-order structure as in standard reinforcement learning. To discriminate between these possibilities, we scanned human subjects with functional magnetic resonance imaging while they performed a simple decision-making task with higher-order structure, probabilistic reversal learning. We found that neural activity in a key decision-making region, the vmPFC, was more consistent with a computational model that exploits higher-order structure than with simple reinforcement learning. These results suggest that brain regions, such as the vmPFC, use an abstract model of task structure to guide behavioral choice, computations that may underlie the human capacity for complex social interactions and abstract strategizing.

That paper argues for sophistication in the function of the vmPFC, which makes this area very interesting in the context of human evolution.

There is much more to say, here, but it's a post that has already gone on too long. The discussion at Neurophilosophy is definitely worthwhile. I especially found the comments interesting, where there is some consideration of what counts as "impaired". Considering prior research on VMPC lesions, together with this study, it is not obvious what "impaired" really means. Clearly, people with a brain injury and resulting behavior alterations are not quite the same. But when they become more rational, what does that mean about "normal"?

References:

Koenigs M, Young L, Adolphs R, Tranel D, Cushman F, Hauser M, Damasio A. 2007. Damage to the prefrontal cortex increases utilitarian social judgements. Nature (advance online) doi:10.1038/nature05631

Bechara A, Tranel D, Damasio H. 2000. Characterization of the decision-making deficit of patients with ventromedial prefrontal cortex lesions. Brain 123:2189-2202. Free full text

Tranel D, Bechara A, Denberg NL. 2002. Asymmetric functional roles of right and left ventromedial prefrontal cortices in social conduct, decision-making, and emotional processing. Cortex 38:589-612.

Hampton AN, Bossaerts P, O'Doherty JP. 2006. The role of the ventromedial prefrontal cortex in abstract state-based inference during decision making in humans. J Neurosci 26:8360-8367. doi:10.1523/JNEUROSCI.1010-06.2006

Purves D, Augustine GF, Fitzpatrick D, Hall WC, LaMantia A-S, McNamara JO, Williams SM. 2004. Neuroscience. 3 ed. Sinauer, Sunderland MA.

Neurophilosophy has this nice post reviewing work by Curtis and colleagues in Science. The main idea of the paper is that a neural migratory pathway in rats and mice, which enables neurons to migrate into the olfactory bulb from the subventricular zone, also exists in humans -- even though nobody noticed it before.

To me, the interesting part is the description of how they noticed the new neurons. In this case, cancer treatment had left the new cells with a flag showing that their DNA had been recently synthesized:

Maurice Curtis and his colleagues examined the brains of deceased cancer patients who had previously been injected with bromo- deoxyuridine (BrdU), a chemical which is incorporated into newly-synthesized DNA, and which is therefore used by oncologists to visualize and monitor the growth of tumours. To their surprise, they found BrdU-positive cells in the olfactory bulbs of the patients' brains, suggesting that it contained newly-generated neurons. Curtis's team then used antibody staining to show that the cells begin to differentiate into olfactory neurons while migrating through the rostral migratory stream. Upon arriving at the bulb, the cells continued to differentiate, forming mature olfactory neurons. Using electron microscopy, they also showed that this 'tube' is 3.5 mm long and 1.5 mm in diameter.

I like the "natural experiment" aspect of this. We'll have to see if other instances of adult neurogenesis can also be highlighted in this way, particularly among younger adults (this is a group where the minimum age was 38), but also in older adults with neurodegeneration.

References:

Curtis, M. A. et al. (2007). Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension. Science (Online early) doi:10.1126/science.1136281

A Harvard Medical School press release (via Science Blog) describes a study by Majdan and Shatz in the current Nature Neuroscience:

A new study focusing on the molecular roots of plasticity has found that visual stimulus turns up the expression of some genes and turns down the expression of others, somewhat like a conductor cueing the members of an orchestra. The study also found that during different stages of life in rodents, distinct sets of genes spring into action in response to visual input. These gene sets may work in concert to allow synapses and neural circuits to respond to visual activity and shape the brain, reports the May issue of Nature Neuroscience.

The investigators' identification of many distinct sets of activity-dependent genes follows a shift in neuroscience research toward a more holistic view of the role of genes in neural development and plasticity.

"What we found opens science up to a more global look at genes, from studying one gene at a time to looking at families of genes acting together," said first author Marta Majdan, Harvard Medical School research fellow in neurobiology. These findings suggest that genetic therapies for neurodegenerative diseases, some of which are largely limited to treatment focused on a single gene, will require more extensive knowledge of molecular pathways and gene interactions to be successful.

Why is this interesting? We have known for a long time that there is a critical period of development of visual cortex. If mammals are light deprived during this time period, their cortex will not develop properly. In other words, an environmental stimulus in a critical window is necessary for the "wiring" of neural circuits related to visual perception.

This study examined gene expression in mouse cortex during those time periods to find out which genes are activated at the critical times:

There are critical periods in development when sensory experience directs the maturation of synapses and circuits within neocortex. We report that the critical period in mouse visual cortex has a specific molecular logic of gene regulation. Four days of visual deprivation regulated one set of genes during the critical period, and different sets before or after. Dark rearing perturbed the regulation of these age-specific gene sets. In addition, a 'common gene set', comprised of target genes belonging to a mitogen-activated protein (MAP) kinase signaling pathway, was regulated by vision at all ages but was impervious to prior history of sensory experience. Together, our results demonstrate that vision has dual effects on gene regulation in visual cortex and that sensory experience is needed for the sequential acquisition of age-specific, but not common, gene sets. Thus, a dynamic interplay between experience and gene expression drives activity-dependent circuit maturation (Majdan and Shatz 2006:650).

This has a couple of implications. One is that a deactivation of one or more of the genes that are activated during the developmental window may have the same effect as depriving the individual of the environmental stimulus. So some variation in the development of visual perception might be attributable to variation in this system of genes.

Another is that it takes the coordination of several developmentally relevant genes to introduce this window of plasticity. There may be underlying commonalities -- perhaps these sets of genes that differ in timing may be regulated by a few genes that determine timing. That may imply that changes in life history that impact the timing of environmental cues -- such as changes in gestation lengths, for instance -- may incur a lot of pushback on the part of gene sets that respond to timing. Or it may mean that there are a few underlying genes related to life history timing that can pull effects along with them easily.

And of course, it makes a model for the development of other brain processes where there may be developmental windows, such as language.

The next paper in the issue, by Daniela Tropea and colleagues, is also related to plasticity of the visual cortex and gene regulation. Here's the abstract:

Two key models for examining activity-dependent development of primary visual cortex (V1) involve either reduction of activity in both eyes via dark-rearing (DR) or imbalance of activity between the two eyes via monocular deprivation (MD). Combining DNA microarray analysis with computational approaches, RT-PCR, immunohistochemistry and physiological imaging, we find that DR leads to (i) upregulation of genes subserving synaptic transmission and electrical activity, consistent with a coordinated response of cortical neurons to reduction of visual drive, and (ii) downregulation of parvalbumin expression, implicating parvalbumin-expressing interneurons as underlying the delay in cortical maturation after DR. MD partially activates homeostatic mechanisms but differentially upregulates molecular pathways related to growth factors and neuronal degeneration, consistent with reorganization of connections after MD. Expression of a binding protein of insulin-like growth factor-1 (IGF1) is highly upregulated after MD, and exogenous application of IGF1 prevents the physiological effects of MD on ocular dominance plasticity examined in vivo.

So fiddling with the genes does generate changes to plasticity responses after environmental alterations. And Harvard does have a better PR department than MIT...

References:

Majdan M, Shatz CJ. 2006. Effects of visual experience on activity-dependent gene regulation in cortex. Nature Neurosci 9:650-659. DOI link

Tropea D, Kreiman G, Lyckman A, Mukherjee S, Yu H, Horng S, Sur M. 2006. Gene expression changes and molecular pathways mediating activity-dependent plasticity in visual cortex. Nature Neurosci 9:660-668. DOI link

A literature search for another topic brought me this article from 2004 by Suk Jin Hong and colleagues (Johns Hopkins):

Identification and analysis of plasticity-induced late-response genes

The excitatory neurotransmitter, glutamate, activates N-methyl-D-aspartate (NMDA) receptors to induce long-lasting synaptic changes through alterations in gene expression. It is believed that these long-lasting changes contribute to learning and memory, drug tolerance, and ischemic preconditioning. To identify NMDA-induced late-response genes, we used a powerful gene-identification method, differential analysis of primary cDNA library expression (DAzLE), and cDNA microarray from primary cortical neurons. We report here that a variety of genes, which we have named plasticity-induced genes (PLINGs), are up-regulated with differential expression patterns after NMDA receptor activation, indicating that there is a broad and dynamic range of long-lasting neuronal responses that occur through NMDA receptor activation. Our results provide a molecular dissection of the activity-dependent long-lasting neuronal responses induced by NMDA receptor activation.

As you might predict from the prose, this is a pretty technical paper: all about microarrays and upregulation. But there is some very interesting stuff in here.

First, the study looked for late response genes: those who showed changes in expression between 6 and 24 hours after the stimulation of the NMDA receptors. NMDA glutamate is a neurotransmitter; brain researchers have studied it because it appears to play an important role in the survival of neurons, and problems with NMDA signalling are associated with neuron damage after a stroke. By looking for late responses, the study was attempting to identify the genes that might be involved in neuron growth, including the strengthening of connections between neurons. These changes are necessary for learning, memory, and other so-called "plastic" responses in the nervous system.

So in other words, this is an attempt to find some of the genes that allow our brains to change. The research was done with rat brains.

The study found hundreds of genes (661, to be exact) that are up-regulated late after NMDA receptor stimulation. Up-regulation means that the genes are producing mRNA transcripts in greater numbers than without the stimulation. According to the paper, this number excludes those genes that produce only immediate effects but return to baseline levels by 6 hours. It includes over 150 previously unidentified genes.

This is too many genes to find a clear pathway for neuronal changes, at least not yet. But it shows that neurotransmitters exert lots of changes on neurons. Many of them certainly cause dendrite growth, alterations in synapse sensitivity, production of more (or less) receptors, and other changes.

And all of these are possible targets of selection in human evolution. Culture and learning are incredibly important to human behavior, and our brains do not develop normally in the absence of cultural and other environmental stimuli. Thus, culture cannot involve merely intrinsic structural genes. It must influence brain structure via hormonal and neurotransmitter pathways. The responses to these culture-mediated influences must be among the most important determinants of what makes us human.

References:

Hong SJ, Li H, Becker KG, Dawson VL, Dawson TM. 2004. Identification and analysis of plasticity-induced late-response genes. Proc Nat Acad Sci USA 101:2145-2150. Free full text online