Print journal: Optogenetics as a medical treatment—and a barrier to metaphysics

By: Aleksandra Augustynowicz, writing for The Science in Society Review

Imagine a healing pinpoint of light, fixed in the center of your forehead, radiating beams of energy throughout your body—a snippet from your local meditation class, or a clairvoyant glimpse of the future. About 121 million people worldwide suffer from depression, and in 2000, the illness was 4th in the global burden of disease.  It is expected to rise to second place in 2020, affecting both sexes of all ages. Seven out of every thousand adults worldwide have Schizophrenia [1]. Millions are struggling with anxiety, while others are battling neurodegenerative diseases. Current treatments are not always effective due to the brain’s many still-unresolved mysteries. But the new field of optogenetics can now tease apart the workings of the nervous system.

Neuron-SEMOptogenetics depends on transfecting target cells with viral vectors to express protein ion channels that respond to different wavelengths of light. Blue light stimulates proteins taken from freshwater algae Chlamydomans Reinhardtii, green light affects those from its relative Volvox Carteri, and yellow works on those of the archaebacteria Natronomona Pharaonis. Once the proteins are expressed on the target cell membrane, a wire ending in a small light is guided to the desired area of the brain. Turning on the light stimulates the proteins. When activated, they regulate the electrical activity of cells. Pulses of blue, green, or yellow wavelengths can be used to select and excite the desired cells without affecting the functions of their neighboring cells [2]. In this way, optogenetics give a way to modulate specific neuronal pathways as appropriate stimulations evoke responses like movement, altered behavior, or even memory retrieval. Studying these selective pathways and observing their effects brings us ever closer to understanding brain function. Though optogenetics can prove to be a powerful tool in medicine, this new dawn for mental health studies and the unveiled brain could bring on blindingly bright discoveries about ourselves—it could upset the way we think of emotions and interpersonal relations. It debunks ontological questions of identity and existence.

Optogenetics could be the new treatment therapy for depression or addiction. It provides insight into pleasure-system pathologies and mechanisms of substance abuse by facilitating the study of groups of dopaminergic and cholinergic neurons. Dopamine plays an important role in the control of movement, emotion, and pleasure or pain sensations [3], while cholinergic receptor activation modulates numerous complex and often opposing biological processes [4]. Studying these pathways requires a method that is selective and temporally precise. Ilana Witten and colleagues from Princeton University have identified patterns in reward pathways by pulsing light onto chosen receptors in transfected mice. The neurons selected were sensitive to cocaine, and the study suggests that optogenetics can block cocaine conditioning in mammals. The control of the microcircuit disrupts the effects of drug abuse [4]. The same reward pathway might be turned off in a mother with a cocaine addiction, and allow her to focus on those she loves, making optogenetics a potent tool.

This tool was used to probe the mechanism behind depression with a study of the prefrontal cortex neurons in mice; humans have corresponding neurons that are thought to contribute to the disease. The mice were subjected to chronic social defeat stress—a model of bullying—by being exposed to an aggressive mouse. After repeated contact, the stressed mice showed social avoidance—a sign of depression. Neurons in the mouse brain showed gene expression that mimicked tissues from the prefrontal cortex of clinically depressed postmortem human patients. A fiber was inserted to light up and stimulate the pre-frontal cortex, and the mice fully recovered from depression symptoms—they began to interact with other mice. The optogenetic manipulation of cortical neuron firing highlighted the key activity of the prefrontal cortex in depression-like behavior and showed the possibility of counteracting depression symptoms. Evidence suggested that electrical stimulation can relieve depression that is resistant to other treatments [5].

Anxiety, the most common among psychiatric disorders, has been linked to the amygdala—a region in the brain associated with emotional processing. The neural mechanisms behind the condition, however, were unknown until precise optogenetic stimulation of mouse basolateral amygdala terminals showed a reversal of anxiety symptoms. Conversely, when the cells in this region were optogenetically inhibited through glutamate receptor antagonism, anxious behavior increased [6]. Could the calming effect of waving lighters during a Pink Floyd concert be optogenetics’ new color in the band’s iconic prism?

Because of the brain’s complexity, chemical treatments are limited for psychiatric disorders that are due to chemical imbalances in the brain. The networks of synapses stretch far beyond local chemical composition. Medications acting to restore the chemical balances affect neuron firing in the whole circuitry of the brain rather than solely targeting the defective link. Treatment effectiveness varies. Optogenetic targeting, on the other hand, allows for selective control with exceptional temporal precision—the stimulus does not affect nearby cells that are not meant to be excited [7]. Thanks to this method, we can start to hone in on the mechanisms within the mysterious brain.

Optognetic potential to treat neurological diseases was shown in mice with Autism and Schizophrenia, which correspond to defects in neural interactions. Elevated ratio of cortical cellular excitation to inhibition (E/I balance) in cells contributes to disease symptoms. After activation of their prefrontal cortical excitatory neurons with light, autistic mice showed an increased preference for social interaction [8]. This study gave insight to cell and circuit level changes that would not have been possible with just pharmacological manipulation. It leads us closer to understanding the pathophysiology behind social and information-processing dysfunctions.

We’ve come far in our Odyssey across the nervous system, hacking away, shocking, dousing, and stimulating. We know the general architecture of the brain and the responsibilities of each part.  With time, instead of just knowing the area of the brain responsible for a reaction, we can now target the specific subgroups of neurons. These can be studied with temporal specificity and spatial selection. The new method provides insight into how neural circuits coordinate reward-driven learning and decision making. The promising knowledge we gain through these studies has a price: our current understanding of ourselves. We could end up classifying love as just a series of equations and cellular events—a pleasure-reward pathway. Our perception of the feeling would become a collection of electrical signals in determined cells. The knowledge may cause disillusion: what would happen to the magical mystery that moved Petrarch to compose? What makes a human special apart from his physical being is his love, his desire to philosophize, his ability to dream and imagine. Reducing the metaphysical qualities to electrical calculations might upset the classic idea of “man.” An optogenetic dissection of the amygdala, hypothalamus and orbifrontal cortex to discover treatment for mental illnesses could also mean a dehumanization of emotions: chemical and physical processes. Psychopathologies arise with a lack of empathy [9], but their study would expose biological motivations behind the feeling.  We have to understand that as the ultimate Homo sapiens, literally the ‘knowing man’—having insight into the very organ that allows us to see within ourselves—we gain knowledge that comes with the price of the magic of individualism.

Looking into the future of neuroscience, Francis Crick predicted “When we finally understand scientifically our perceptions, our thoughts, our emotions and our actions—hopefully sometime in the 21st century—it is more than likely that our view of ourselves, and our place in the universe will be totally transformed” [10]. Our possibilities will have transformed along with our views. Despite our immense progress we still have a long way to go. As of right now, if Francis Crick had read enough Sir Arthur Conan Doyle, perhaps he might have quoted Sherlock Holmes: “I am a brain Watson. The rest of me is a mere appendix.”

References

  1. Mental Health: Depression. World Health Organization. [Online]. Available: http://www.who.int/mental_health/management/depression/definition/en/. [2012, July 09].
  2. Deisseroth, K. “Controlling the Brain with Light.”  Scientific American. November 2010. 49-51.
  3. Best, J.A., Nijhout, F.H., Reed, M.C. Homeostatic mechanisms in dopamine synthesis and release: a mathematical model. Theoretical Biology and Medical Modeling. September 2009; 6:21.
  4. Witten, IB. et al Cholinergic interneurons control local circuit activity and cocaine conditioning. Science. December 17 2010; 330 (6011):1677-1681.
  5. Covington, H et al. Antidepressant effect of optogenetic stimulation of the medial prefrontal cortex. The Journal of Neuroscience, December 1 2010; 30(48):16082–16090
  6. Tae KM et al. Amygdala circuitry mediating reversible and bidirectional control of anxiety. Nature Mar 17 2011; 471: 358-362.
  7. Witten, IB et al. Recombinase-driver rat lines: tools, techniques, and optogenetic application to dopamine mediated reinforcement. Neuron, December 8 2011; 72: 721-733.
  8. Yizhar O, et al. Neocortical Excitation/Inhibition balance in information processing and social dysfunction. Nature September 08 2011; 477: 171-178.
  9. Decety, J. Dissecting the neural mechanisms mediating empathy. Emotion Review 2011; 3:92
  10. Crick F. The impact of molecular biology on neuroscience. The Royal Society 1999; 354: 021-025.
  11. Image credit (GNU GPL): Rougier, N. Neuron. Wikimedia Commons. 2005.

This is an excerpt of an article that was originally published in The Science in Society Review, a sister publication of The Triple Helix Online. Aleksandra Augustynowicz is a student at the University of Chicago. Contact us to read the original article, and follow us on Facebook.

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