It is easy to underestimate the potential of today’s microelectronic technology, and we think that it will ultimately become feasible to deploy small wireless microcircuits, untethered in living brains, for direct monitoring of neuronal activity, although there are significant technological challenges. As an alternative to silicon VLSI, synthetic biology might provide an interesting set of novel techniques

to enable noninvasive recording of activity (Figure 2). This could be considered a wireless option, albeit a radically different one. For example, DNA polymerases could be used as spike sensors since their error rates are dependent on cation concentration. Prechosen DNA molecules could be synthesized DNA Damage inhibitor to record patterns of errors corresponding to the patterns of spikes in each cell, encoded as calcium-induced errors, serving as a “ticker-tape” record of the activity of the neuron. The capability of DNA for dense information storage is quite remarkable. In principle, a 5-μm-diameter synthetic cell could hold at least 6 billion base pairs of DNA, which could encode 7 days of spiking data at 100 Hz with 100-fold redundancy. For any given circuit, the reconstruction of activity might proceed in three steps. First, initial mapping could be done using

calcium imaging with spiking reconstruction carried out at 100 Hz. This could be performed with improvements to existing methods. The second step would involve voltage imaging of action potentials (and subthreshold electrical activity), ideally with a temporal resolution of 1 kHz. These first two steps could be carried out in PD0332991 purchase 3D yet they would be limited to superficial structures (<2 mm deep). In a third step, similar reconstructions of neuronal activity, but penetrating deep into brain circuits, could be performed. These would first be achieved with massively multiplexed nanoprobes, later complemented

by novel wireless approaches. Pregabalin But which circuits should be worked on, and in which order? We envision parallel efforts on several different preparations—progressing from reconstructing the activity of small, simple circuits to more complicated, larger ones. For example, in the short term (5 years), one could reconstruct the activity of a series of small circuits, all less than 70,000 neurons, from model organisms. C. elegans is the only complete connectome (302 neurons and 7,000 connections) ( White et al., 1986), and all of its neurons could be imaged simultaneously with two-photon imaging and genetic calcium indicators. In addition, one could reconstruct the entire activity pattern of a discrete region of the Drosophila brain, such as the medulla, with ∼15,000 neurons. The Drosophila connectome is currently 20% complete at the mesoscale ( Chiang et al., 2011), and could be finalized within three years.