Or: How to change your mind, with psychedelics and optogenetics.

Genevieve introduced the closing keynote for the PSFC Summit today: Karl Deisseroth is the pioneer of the mind-reading and writing tool (<a href="http://optogenetics.org" rel="noreferrer nofollow">optogenetics.org</a> at Stanford) that allows for individual neuron targeting and manipulation, and his new work looks at the effects of mind-altering drugs on brain function in detail.

For a sense of the power of his methods: he can take a pair of mice than were just mating happily, and with a flip of a switch, they become violent to each other. He made a mouse walk in an infinite left turn loop when a fiber optic is flipped on in the motor cortex (with no apparent awareness or distress at being controlled this way). Another team selectively turned on subsets of parenting behavior (like bringing wandering young back to the nest or grooming behaviors). They can also probe three different sub-states of anxiety that we only experience as a bundle.

How does this work? Before the plant kingdom evolved chlorophyll to harvest energy from sunlight, the more ancient bacteria used rhodopsins in a membrane-bound proton-pump to do the same. The rhodopsins captured a swath of the sun’s spectrum, tilting the algae to the leftover parts of the spectrum not yet absorbed, and this is why plants are green. Karl introduced these bacterial light-triggered elements into neurons of interest using a viral vector to the brain. He can then trigger neuronal firing optically, as the rhodopsin pump supplements the ion channels in the neuron. He can also trigger reporter molecules from the bacterial world to read out brain activity as the brain is functioning.

So, for example, he has observed a 3 Hz cycling in the retrosplenial cortex of a mouse brain on ketamine, and he has been able to reproduce the effects with optogenetic stimulation to achieve similar effects. He has also found that the dissociative drugs (ketamine and PCP) allow for reflexes to pain (e.g., heat on paw or puff of air to eyes) to continue normally, while the protective cognitive reactions (licking the paws after heat or squinting in anticipation of the next puff) disappear, a disassociation of mind and body reflexes.

He is diving deeper into the brain to investigate how this works, finding that the various subregions of the thalamus are regulated by disassociative drugs by overpowering the voting circuits with a pulsing 3 Hz modulation of the ketamine-enhanced circuits. The other nodes in the thalamus are operating as before, but do not achieve as powerful a consensus. The thalamus regulates where we spend our attention and conscious focus, to avoid doing everything we might be tempted to do simultaneously, and thereby not really doing any of them well.

In his latest work, he has found that MDMA operates very differently than Ketamine (work to be published later this year).