McIsaac, R.S.; Bedbrook, C.N.; Arnold, F.H. Recent advances in engineering microbial rhodopsins for optogenetics. Curr. Opin. Struct. Biol. 2015, 33, 8–15. [ Google Scholar] [ CrossRef] [ PubMed][ Green Version] Poulet, J.F.A.; Fernandez, L.M.J.; Crochet, S.; Petersen, C.C.H. Thalamic control of cortical states. Nat. Neurosci. 2012, 15, 370–372. [ Google Scholar] [ CrossRef] Li, N.; Gittelman, J.X.; Pollak, G.D. Intracellular Recordings Reveal Novel Features of Neurons That Code Interaural Intensity Disparities in the Inferior Colliculus. J. Neurosci. 2010, 30, 14573–14584. [ Google Scholar] [ CrossRef] [ PubMed][ Green Version] Wu, M.-C.; Bing, Y.-H.; Chu, C.-P.; Qiu, D.-L. Ethanol modulates facial stimulation-evoked outward currents in cerebellar Purkinje cells in vivo in mice. Sci. Rep. 2016, 6, 30857. [ Google Scholar] [ CrossRef][ Green Version]

Lee, A.K.; Brecht, M. Elucidating Neuronal Mechanisms Using Intracellular Recordings during Behavior. Trends Neurosci. 2018, 41, 385–403. [ Google Scholar] [ CrossRef] Windels, F.; Crane, J.W.; Sah, P. Inhibition Dominates the Early Phase of Up-States in the Basolateral Amygdala. J. Neurophysiol. 2010, 104, 3433–3438. [ Google Scholar] [ CrossRef] [ PubMed][ Green Version] Gentet, L.J.; Avermann, M.; Matyas, F.; Staiger, J.F.; Petersen, C.C.H. Membrane Potential Dynamics of GABAergic Neurons in the Barrel Cortex of Behaving Mice. Neuron 2010, 65, 422–435. [ Google Scholar] [ CrossRef] [ PubMed][ Green Version] Angle MR, Cui B, Melosh NA. Nanotechnology and neurophysiology. Curr Opin Neurobiol. 2015;32:132–40.Ding, R.; Liao, X.; Li, J.; Zhang, J.; Wang, M.; Guang, Y.; Qin, H.; Li, X.; Zhang, K.; Liang, S.; et al. Targeted Patching and Dendritic Ca2+ Imaging in Nonhuman Primate Brain in vivo. Sci. Rep. 2017, 7, 2873. [ Google Scholar] [ CrossRef] [ PubMed][ Green Version] In comparison, patch-clamps in vivo have even more limitations in terms of invasiveness than patch-clamps in vitro. The highly invasive injection of micropipettes in vivo also causes serious dialysis due to the intrinsic disruption of the natural intracellular environment, affecting the concentrations of ions and functional molecules. Additionally, rigid micropipettes need to be connected with other electronic devices during insertion into the nervous system with a high-volume requirement. Most of the electronics used in the in vivo patch-clamp systems are highly rigid, and a slight mechanical movement of the experimental animals could remove the resistance seal and cause unexpected and irreversible damage to the recorded tissue [ 36]. To date, patch-clamps in vivo have been applied in living and fixed small animals to avoid mechanical perturbation. Moreover, considering that the devices used in recording in vivo still need to be delivered to the target region of brain tissue through invasive surgery, the in vivo application of patch-clamps is highly invasive [ 20]. Spatial resolution Desbiolles BXE, de Coulon E, Bertsch A, Rohr S, Renaud P. Intracellular recording of cardiomyocyte action potentials with nanopatterned volcano-shaped microelectrode arrays. Nano Lett. 2019;19:6173–81. Zhang, G.-J.; Wu, M.-C.; Shi, J.-D.; Xu, Y.-H.; Chu, C.-P.; Cui, S.-B.; Qiu, D.-L. Ethanol Modulates the Spontaneous Complex Spike Waveform of Cerebellar Purkinje Cells Recorded in vivo in Mice. Front. Cell. Neurosci. 2017, 11. [ Google Scholar] [ CrossRef][ Green Version] Albisetti, G.W.; Ghanem, A.; Foster, E.; Conzelmann, K.-K.; Zeilhofer, H.U.; Wildner, H. Identification of Two Classes of Somatosensory Neurons That Display Resistance to Retrograde Infection by Rabies Virus. J. Neurosci. 2017, 37, 10358–10371. [ Google Scholar] [ CrossRef] [ PubMed]

Epsztein, J.; Lee, A.K.; Chorev, E.; Brecht, M. Impact of Spikelets on Hippocampal CA1 Pyramidal Cell Activity During Spatial Exploration. Science 2010, 327, 474–477. [ Google Scholar] [ CrossRef] [ PubMed] Hong G, Viveros RD, Zwang TJ, Yang X, Lieber CM. Tissue-like neural probes for understanding and modulating the brain. Biochemistry. 2018;57:3995–4004. Zhao Y, You SS, Zhang A, Lee JH, Huang J, Lieber CM. Scalable ultrasmall three-dimensional nanowire transistor probes for intracellular recording. Nat Nanotechnol. 2019;14:790.

Tripathy, S.J.; Toker, L.; Bomkamp, C.; Mancarci, B.O.; Belmadani, M.; Pavlidis, P. Assessing Transcriptome Quality in Patch-Seq Datasets. Front. Mol. Neurosci. 2018, 11, 363. [ Google Scholar] [ CrossRef] [ PubMed] Van Hook, M.J.; Thoreson, W.B. Whole-Cell Patch-Clamp Recording. In Current Laboratory Methods in Neuroscience Research; Springer: New York, NY, USA, 2014; pp. 353–367. [ Google Scholar] Funayama, K.; Hagura, N.; Ban, H.; Ikegaya, Y. Functional Organization of Flash-Induced V1 Offline Reactivation. J. Neurosci. 2016, 36, 11727–11738. [ Google Scholar] [ CrossRef][ Green Version] Fairfield JA. Nanostructured materials for neural electrical interfaces. Adv Funct Mater. 2018;28:1701145.

Grienberger, C.; Milstein, A.D.; Bittner, K.C.; Romani, S.; Magee, J.C. Inhibitory suppression of heterogeneously tuned excitation enhances spatial coding in CA1 place cells. Nat. Neurosci. 2017, 20, 417–426. [ Google Scholar] [ CrossRef] [ PubMed] Witter, L.; De Zeeuw, C.I. In Vivo Differences in Inputs and Spiking Between Neurons in Lobules VI/VII of Neocerebellum and Lobule X of Archaeocerebellum. Cerebellum 2015, 14, 506–515. [ Google Scholar] [ CrossRef][ Green Version] Salzberg, B.M.; Davila, H.V.; Cohen, L.B. Optical Recording of Impulses in Individual Neurones of an Invertebrate Central Nervous System. Nature 1973, 246, 508–509. [ Google Scholar] [ CrossRef]

Article Menu

Lee, A.K.; Manns, I.D.; Sakmann, B.; Brecht, M. Whole-Cell Recordings in Freely Moving Rats. Neuron 2006, 51, 399–407. [ Google Scholar] [ CrossRef][ Green Version] Berenyi A, Somogyvari Z, Nagy AJ, Roux L, Long JD, Fujisawa S, Stark E, Leonardo A, Harris TD, Buzsaki G. Large-scale, high-density (up to 512 channels) recording of local circuits in behaving animals. J Neurophysiol. 2014;111:1132–49.

Rastegar S, Stadlbauer J, Pandhi T, Karriem L, Fujimoto K, Kramer K, Estrada D, Cantley KD. Measurement of signal-to‐noise ratio in graphene‐based passive microelectrode arrays. Electroanal. 2019;31:991–1001. Jayant K, Wenzel M, Bando Y, Hamm JP, Mandriota N, Rabinowitz JH, Plante IJ, Owen JS, Sahin O, Shepard KL, Yuste R. Flexible nanopipettes for minimally invasive intracellular electrophysiology in vivo. Cell Rep. 2019;26:266–78.

Over the past few decades, several new intracellular recording techniques based on the development of nanofabrication and nanopatterning have been proposed, and these techniques have achieved success compared to conventional techniques at various levels. These approaches can be classified into three major groups according to the principles behind their recordings, which are the nanoelectrodes exchanging ions with the cytoplasm, the nanoscale FETs with a specific detection area, and the extracellular recording electrodes that output attenuated intracellular-like signals. Nanoelectrodes obtain intracellular access by directly penetrating the cell or electroporation and optoporation. The reduced disruption of the cell physiology by nanoelectrodes is attributed to the small electrode tip size, but the design of smaller electrodes faces compromises between the signal quality and reduced electrode size. The performance of nanowire FETs is not limited by the impedance, thus achieving significant advantages in long-term recording and parallelization. However, the fabrication of this device is complex and costly, and the reagent delivery and stimulation activation functions are limited. The extracellular recording electrode maintains the completeness of the cell membrane and simultaneously can obtain attenuated intracellular signals by forming a tight seal with the cell. This is an interesting and promising strategy, especially for those cases in which the cellular physiological status must be protected, such as recordings that last for days and weeks. However, the signals obtained by this technique were weakened, and the technique is therefore not suitable for studies during which the amplitude frequently changes because of the reduced precision. The design of 3D structures of the nanoelectrode arrays attracts much attention, attempting to make new recording devices ultra-flexible and biofriendly [ 58]. These devices are expected to be easy to implant and be friendly to the nervous system, avoiding the potential immune reaction to the utmost extent [ 59]. Based on the discussion above, all these approaches have achieved various advances over the conventional patch-clamp technique, representing new developments in recording methods for transmembrane potential measurement. Domnisoru, C.; Kinkhabwala, A.A.; Tank, D.W. Membrane potential dynamics of grid cells. Nature 2013, 495, 199–204. [ Google Scholar] [ CrossRef][ Green Version]