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Wiring the Brain 2009—Kids in a Candy Store: New Methods Dazzle Researchers

Over the next weeks, we will be bringing you several reports from the Wiring the Brain: From Genetic to Neuronal Networks, a conference held 21-24 April 2009, in Adare, County Limerick, Ireland. We are very grateful to Aiden Corvin from the organizing committee and to reporter Victoria Heimer-Torres, a graduate student in Paul Young's laboratory at University College Cork, Ireland.


27 July 2009. Wiring the Brain covered neuronal networks across a variety of disciplines, from genes to disease. Each session was concise, relevant, and built seamlessly on the previous. The April 24 session titled “Rewiring the Adult Nervous System” described new and powerful methods that study neural circuitry at different levels. In this summary, I have chosen to focus on two that may be especially useful for the Young laboratory’s study of synaptic connectivity and neuronal morphology.

In his lecture, "Optogenetics: Development and Application," Karl Deisseroth of Stanford University, Palo Alto, California, focused on recent developments in optogenetics, a method that allows optical control of defined cell types in freely behaving animals. [Editor's note: see also a commentary by G. Gonzalez-Burgos on the application of these methods to parvalbumin-positive neurons in cortex.] This is made possible by microbial opsins that can fire or inhibit action potentials with millisecond precision and without the addition of chemical cofactors. The first opsin applied to neurobiology was channelrhodopsin-2 (ChR2), which Deisseroth and colleagues showed becomes permeable to cations in response to blue light in living neurons and can be used to drive precisely timed action potentials (Boyden et al., 2005). Deisseroth and colleagues followed up their initial work by next showing that when delivered to the hippocampus in vivo using a lentivirus, the channel provides optical control of neuronal firing in intact tissue and behaving mammals. This system is tolerated well by neurons, requires no added chemical cofactors, and allows for rapid, temporally precise spiking. It has since proven useful in many experimental systems, including deep brain stimulation, Parkinson disease models, and depression models.

Deisseroth and colleagues next found that the light-activated chloride pump halorhodopsin can inhibit action potentials in response to yellow/green light. These results were reproduced in both intact tissue and in behaving animals. Refinements included introducing an endoplasmic reticulum export motif into the expression sequence to prevent protein aggregates due to elevated expression levels (Gradinaru et al., 2007). Since the ChR2 and halorhodopsin channels are excited at different wavelengths, they can be used simultaneously in the same cell. They also discovered and investigated the cation channel VchR1-VolvoxChR1, whose absorption spectrum is red-shifted relative to ChR2 sufficiently to allow combinatorial expression and modulation (Zhang et al., 2008).

Subsequently, Deisseroth's group has developed step function opsins (SFOs), which are engineered bi-stable optical switches that allow “light-off” to be uncoupled from “channel-off” (a modification at the C128 position of the channel extends the open state conformation). This effect is triggered with blue light pulses but can be terminated with green pulses. This system facilitates control through precisely synchronizing pulses, is complementary to ChR2, and provides a good technology for long time-scale studies (Berndt et al., 2009).

Finally, Deisseroth presented recent work on ”optoXRs,” a novel light-activated G protein-coupled receptor (GPCR) produced by fusing a rhodopsin channel (extracellular and transmembrane domains) and an adrenergic receptor (AR) (intracellular domain). Cell culture analysis confirmed that opto-α1AR chimeras recruited the inositol phosphate signaling pathway when stimulated, while opto-β2AR chimeras increased cAMP production. Functional studies of optoXR activation in mouse nucleus accumbens showed increased firing in opto-α1AR-expressing neurons upon optical stimulation, in contrast to slightly reduced firing in opto-β2AR-expressing accumbens neurons. Furthermore, behavioral studies showed that opto-α1AR stimulation of accumbens neurons robustly affects reward-related behavior, whereas opto-β2AR and ChR2 are less effective in driving preference (Airan et al., 2009).

In his talk, "Corticopoiesis in a Dish: Intrinsic Mechanism of Specification of Cortical Neurons from Pluripotent Stem Cells," Pierre Vanderhaeghen of the University of Brussels, Belgium, showed that mouse embryonic stem (ES) cells can be used to reproduce in vitro the major milestones of cortical development. Without the need for exogenous morphogens, ES cells in culture adopt a forebrain fate. These forebrain-like progenitors differentiate further into either cortical or ventral progenitors. In mice, these give rise to both the cortex and the basal ganglia.

In order to increase the population of presumptive cortical progenitors, Vanderhaeghen and colleagues used sonic hedgehog (Shh) to inhibit the development of ventral progenitors. Once efficient production of cortical progenitors was established, they went on to show that these cells generate a diversity of neuronal subtypes that resemble authentic cortical pyramidal neurons that are glutamatergic and synaptically active. Furthermore, when grafted into the cerebral cortex of neonatal mice, these neurons developed layer-specific axonal projections, as well as area-specific projections, corresponding mainly to the visual and limbic occipital cortex. The discovery of intrinsic corticogenesis demonstrates that a specific cortical area can differentiate without any influence from the brain (Gaspard et al., 2008).—Victoria Heimer-Torres.

 
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