Intracellular recording is essential for investigating the electrical activity that occurs below a neuron’s threshold for AP generation, and so it is an important tool for elucidating the mechanisms by which synaptic inputs are transformed into AP output 
. Intracellular techniques have led to critical insights into the biophysics of dendritic integration 
and action potential generation 
, but measurements of the subthreshold activity underlying perception, memory and behavior have been limited due to the difficulty of establishing minimally invasive, stable intracellular recordings in vivo
Intracellular electrodes often cause biochemical and physiological perturbations in the cells from which they are recording. In whole-cell patch recording 
, for example, the patch pipette internal solution rapidly exchanges solutes with the cytoplasm. This allows for the experimental control of intracellular concentrations of ions and other molecules by using different pipette internal solutions 
, but it also leads to the disruption of biochemical processes that are necessary for normal cellular function 
. Dilution of freely diffusible cellular molecules occurs within a few minutes, making dialysis a limiting factor for reliable whole-cell recording 
. Using a variation of the whole-cell patch clamp technique, perforated patch recording 
, one can avoid the unwanted dialysis of biomolecules, but poor sealing, changing access resistance and spontaneous membrane ruptures have limited the in vivo
application of this technique (but see 
Another type of intracellular recording electrode, the sharp microelectrode, differs from a patch pipette in that it enters the cell by piercing through the plasma membrane 
. Sharp electrodes have smaller tips than patch pipettes and therefore dialyze the cytoplasm more slowly, but the impalement often results in irreparable membrane damage and shunting of the membrane potential 
. In a study where whole-cell recordings were established prior to sharp microelectrodes penetration, all neurons showed significant depolarization following impalement 
One way to avoid the dialysis of cellular molecules by electrode internal solution would be to replace the liquid, electrolytic conductor in the micropipette with a solid, metallic conductor 
. Incidentally, metallic microelectrodes aren’t new to intracellular recording 
, and their use actually precedes the first use of electrolyte-filled microelectrodes 
. The first in vivo
neuronal recordings using metal microelectrodes were probably the putative intracellular recordings that were reported by Hubel in 1957 
, which occurred occasionally while recording extracellular units with tungsten microelectrodes. Unfortunately, though solid-conductor intracellular microelectrodes would be non-dialyzing, they would be just as likely to introduce a leak current upon impalement as electrolyte-filled pipettes, thus mitigating their advantage over patch pipettes with respect to dialysis. To make solid-conductor intracellular electrodes practical for long-term neuronal recording, they must first be engineered in such a way as not to cause a membrane shunt upon insertion.
Developments in nanotechnology have prompted scientists to consider new, nanoengineered tools to access the interior of cells for intracellular electrical recording 
. The challenge to neurophysiologists has been to integrate these nanotechnologies into recording electrodes that are also resilient and maneuverable enough for use in brain tissue. This has proven difficult, largely because the wafer-based nanofabrication processes used to produce many nanostructured devices limit their use to flat preparations such as dissociated cell cultures. Only a few devices have been developed that would be suitable for being delivered into deep tissue (e.g. 
). Additionally, there has been no direct demonstration that any of these tools can be used to record from neurons without disrupting their physiology, which requires that properties such as resting membrane potential and input resistance be independently measured before and after membrane penetration by the nanoelectrode. Because reducing invasiveness is a key motivation behind developing new nanotechnology-based tools for electrophysiology, such tests will be critical in evaluating first-generation nanoelectrode technologies.
Here we describe Solid-Conductor Intracellular NanoElectrodes, or SCINES. We report their fabrication, electrical characterization, and use for recording neuronal transmembrane potentials in brain slices. We also perform simultaneous whole-cell recordings to independently assess the invasiveness of SCINE recording.