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August 11, 2004

Behavior Genetic Engineering

via [email protected]: A new PNAS paper describes a successful attempt to engineer behavior with gene therapy in primates. (GNXP mirrored full PDF). The temporary effect:

Like many humans, monkeys tend to slack off when their goal is distant, then work harder as a deadline looms. But when a key gene is turned off, the primates work hard from the word go, researchers report in PNAS Online1.

"The gene knockdown triggered a remarkable transformation in the simian work ethic," says Barry Richmond of the National Institute of Mental Health in Bethesda, Maryland, who studied the animals.

With the gene turned off, the monkeys were unable to anticipate how many trials were left before the reward was given. They stopped procrastinating and worked hard throughout the task, making consistently fewer errors at every stage. The monkeys became extreme workaholics ... This was conspicuously out-of-character for these animals.

Beyond the cool factor, this technique could be applied widely to associate genes with cognitive functions.

Godless comments:

First, I think this paper should have gone to Science/Nature/Cell. It's that good. Some of the more interesting aspects:

  1. Their use of antisense DNA (not RNAi) means that this method is generalizable - any neural genes whose expression you wish to reduce can be potentially affected even if all you have is the base pair sequence. While this has been worked on for some time (as far back as 1998), this is probably the most spectacular example to date. (I'm open to corrections from someone more familiar with the neuropharmacology literature.)

    What's so cool about this? Well, classical pharmacological techniques rely on the difficult, time consuming, and imprecise approach of finding compounds that will bind to a desired gene product (often by trying out chemical analogs of known interacting proteins). This requires lots of experiments; though guys like Stuart Schreiber at Harvard are working on high-throughput screening methods for chemical genomics, rapidly finding specific and consistent small molecular agonists of particular gene products is still an open problem.

    Antisense-based pharmacology is a major advance as it throws open the doors to immediate, precise, "digital" gene knockdown. All you need is the base-pair sequence of the gene to get a potentially surgical, targeted antigene agent.

  2. This may have implications for the momentum towards more use of RNAi and antisense based drugs - something I've heard about but haven't done much reading on. But see here.
  3. On a less technical note, it's clear that this sort of thing could be done with humans. The obstacles to studying human cognition in this fashion are ethical - not technical.

Here's the full PDF, from lead author Zheng Liu. Most interesting clips:

When schedules of several operant trials must be successfully completed to obtain a reward, monkeys quickly learn to adjust their behavioral performance by using visual cues that signal how many trials have been completed and how many remain in the current schedule. Bilateral rhinal (perirhinal and entorhinal) cortex ablations irreversibly prevent this learning. Here, we apply a recombinant DNA technique to investigate the role of dopamine D2 receptor in rhinal cortex for this type of learning...

These results suggest that the D2 receptor in primate rhinal cortex is essential for learning to relate the visual cues to the schedules. The specificity of the receptor manipulation reported here suggests that this approach could be generalized in this or other brain pathways to relate molecular mechanisms to cognitive functions...

Monkeys, as do humans, quickly learn to use visual cues to adjust their behavior based on how much work has been completed and how much remains (the relative workload) before reaching a goal or obtaining a reward (1–4). Because of its strong inputs from the ventral visual pathway and projections to the hippocampal formation (5–13), the rhinal (perirhinal and entorhinal) cortex has been heavily investigated for its role in visual recognition memory (14) and acquisition of stimulus–stimulus associations (15–18). In addition, we became interested in its role in reward-related learning because of its dense innervation by dopamine-rich fibers (19–22), which presumably arise in the substantia nigra pars compactaventral tegmental area complex (23). Using a behavioral task, visually cued reward schedules, in which the monkeys are required to perform multiple operant trials to obtain a reward at the end of a schedule, we previously demonstrated that bilateral rhinal cortex ablations prevent monkeys from learning to use visual cues to make the behavioral adjustments in the schedule task (2) and that responses of single neurons in monkey perirhinal cortex reflect a visual cue’s relation to the progress through a schedule, i.e., relative workload (3). These latter two studies led us to conclude that monkey rhinal cortex has a critical role in establishing the associations between visual cues and this form of reward contingency...

After regaining the ability to use the cues, the behavior was stable; the relationships between theaverage error rates and schedule states were the same from the first to the third week after cues were learned...Thus, although the effect of this treatment lasts for several weeks, it is nonetheless temporary. This finding, that the ability to learn new cues recovered after treatment and proceeded at the same rate as before DNA treatment, strongly suggests that the D2 receptor targeted DNA treatment had a time-limited, reversible effect on cognitive behavior.

We have shown that direct injection of a DNA construct interfering with the function of the D2 receptor in the rhinal cortex temporarily leads to a complete inability to learn associations between visual cues and the workload remaining before reward. Thus, it appears that dopamine D2-mediated mechanisms underlie the functional role that monkey rhinal cortex plays in learning this type of association. Future studies can determine whether other types of cognitive behavior dependent on the rhinal cortex likewise depend on D2-mediated mechanisms and also clarify the precise molecular mechanism(s) by which DNA constructs interfere with behavior and receptor ligand binding. Our findings offer a strong incentive for pursuing this recombinant DNA approach as a means to interrogate and modulate the roles of specific components of the molecular pathways underlying behavior.

There are of course also possibilities for agricultural engineering: stud bulls who never get tired, horses who run till their last breath, greyhounds who "run through the line" rather than slowing down as the finish approaches.

Update:

Also see Randall Parker's comments.

Posted by rikurzhen at 01:22 PM