Sunday, December 10, 2006

Organizations and cannabinoids   posted by amnestic @ 12/10/2006 03:18:00 PM

For theoretical and physiological reasons, there is a strain of neuroscience that considers the brain as something like a democracy. Consider as an example the decision that a neuron makes whether or not to fire an action potential. An action potential is sparked when the voltage difference between the inside and outside of the cell near a special portion of the axon reaches a threshold value. A given neuron receives thousands of inputs, some excitatory and some inhibitory. In a simplified view, excitatory inputs make the inside of the cell more positive, moving closer to the threshold, while inhibitory inputs move the cell further from action potential threshold. In a sense, each excitation is an 'aye' and each inhibition is a 'nay'. The axon hillock keeps a running tally of the votes and fires off a potential whenever the 'ayes have it'.

With neurons it isn't so much a sense of whether the ayes will win but when they will. How fast can the ayes get the potential all the way up to threshold? Well, if they act independently they may never get there. One of the best ways for a constituency to be heard is to all deliver the same message at once. The votes that arrive synchronously will certainly all be counted in the same tally. If I write my representative over and over again asking them to create a more rational marijuana policy, this might have some small effect on their thinking, but probably wouldn't convince them to vote my way even if I wrote them every day for 2 years. If those same 730 inputs came in all at once from different sources, the content would be a little less individual, but the policy effect would presumably be greater. That's why, even if I have my own individual perspective on the best policy, I get involved with and support larger organizations that can organize to achieve my goals.

Neurons achieve synchrony through oscillatory behavior. The most extensive study of neuronal oscillations has been in the hippocampus. If you stick an electrode into the extracellular space surrounding hippocampal neurons while rats engage in exploration of a novel space you will note that the potential fluctuates rhythmically at about 10 Hz. Neurons are most likely to fire when the extracellular potential is at its lowest (the trough). The source of these oscillations is an area of intense investigation and what is known already is more complicated than I want to go into here, but the effect of these oscillations is simple enough to understand: during the trough, many neurons are likely to fire at once. Thus, the oscillations provide an organization that neurons can join and add their voice to a larger consensus. If many of these neurons converge on a downstream target, they can greatly influence that target's firing behavior.

It has been very difficult to study these population/ensemble behaviors in the intact brain because you must record more than one neuron at once to ask whether they are synchronized. Recently a collaboration between the McNaughton and Buzsaki groups, two of the dopest labs in recording and analysis of many neurons at once, produced a report concerning the effect of cannabinoids on network activity in the hippocampus. The most prominent active ingredient in marijuana is a cannbinoid, delta-9-tetrahydrocannabinol (THC). It can bind two types of receptors in the brain: CB1 and CB2 receptors. There are synthetic agonists and antagonists that specifically affect CB1 allowing more in-depth analysis of this receptor subtype. Most of the experiments in the M&B paper were performed with a CB1 receptor agonist, but some of the effects were replicated using THC at "palliative and recreational" doses, suggesting that effects in this paper can be generalized to effects of actual marijuana use.

The major finding was that CB1 agonism (THC administration) disorganizes neuronal ensembles. The average firing rate is hardly affected. Neurons keep talking. They walk up the mall to the Lincoln memorial, but they do it one by one. This effect was initially detected as an across the board decrease in the power of oscillatory field potentials. The chants quieted down.
Crowd: Eat the cheeseburger, astro boy! Eat the cheeseburger, astro boy!
Trotter: Enough... if you're trying to start a riot, I suggest you choose a simpler chant.
Ensemble behavior can be analyzed using cross-correlograms. You use one neuron's spike as a reference, brand it as t=0, and then count the number of spikes from neuron 2 in time bins in relation to t=0. If two neurons are firing synchronously, there will be a large peak at 0 ms reflecting the large number of spikes from neuron 2 that coincide with spikes from neuron 1. Here is a rather dramatic visualization of a rat's hippocampus on a CB1 receptor agonist:

THC "destroys assembly organization". This is a very interesting subtle effect that couldn't have been detected using single neuron recordings. It doesn't effect the overall behavior of an individual neuron, but instead controls network-level phenomena. While the impulse may be to look at this report in terms of the effect of marijuana use, I think it is important to also understand that this receptor system provides the very unique potential of a tool for specifically understanding neuronal networks. Using these drugs we can begin to determine just exactly what behaviors and aspects of cognition rely on ensemble behavior rather than single neuron or simple population coding.

That said, I can't resist the metaphor. It is not clear exactly how CB1 receptor activation produces these network changes. What little is known suggest that cannabinoids may act presynaptically, perhaps reducing overall neurotransmitter release from the principal neurons of the hippocampus. It reduces their output and shuts them up. Likewise, the effect of on a drug law reform advocate is to effectively quiet their voice. In my experience, motivation, cognitive capacities, and credibility are reduced with any degree of extended use. The ability to organize and assemble is lost and some become so paranoid (imagining government lists of petition signatories and political organizers) that they refuse to speak up. To produce strong organizations capable of influencing a system, brain or otherwise, CB1 receptor agonism is to be avoided.