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How dynamic activity in neural circuits gives rise to behavior is a major area of interest in neuroscience. A key experimental approach for addressing this question involves measuring extracellular neuronal activity in awake, behaving animals. Recently developed Neuropixels probes have provided a step change in recording neural activity in large tissue volumes with high spatiotemporal resolution. This protocol describes the chronic implantation of Neuropixels probes in mice and rats using compact and reusable 3D-printed fixtures. The fixtures facilitate stable chronic in vivo recordings in freely behaving rats and mice. They consist of two parts: a covered main body and a skull connector. Single-, dual- and movable-probe fixture variants are available. After completing an experiment, probes are safely recovered for reimplantation by a dedicated retrieval mechanism. Fixture assembly and surgical implantation typically take 4–5 h, and probe retrieval takes ~30 min, followed by 12 h of incubation in probe cleaning agent. The duration of data acquisition depends on the type of behavioral experiment. Since our protocol enables stable, chronic recordings over weeks, it enables longitudinal large-scale single-unit data to be routinely obtained in a cost-efficient manner, which will facilitate many studies in systems neuroscience. This protocol describes the implantation of Neuropixels probes for chronic recording of neural activity in rats and mice using 3D-printed fixtures. The fixtures enable routine probe reuse, and single-, dual- and movable-probe variants are described.

Throughout the past decade, silicon-based neural probes have become a driving force in neural engineering. Such probes comprise sophisticated, integrated CMOS electronics which provide a large number of recording sites along slender probe shanks. Using such neural probes in a chronic setting often requires them to be mechanically anchored with respect to the skull. However, any relative motion between brain and implant causes recording instabilities and tissue responses such as glial scarring, thereby shielding recordable neurons from the recording sites integrated on the probe and thus decreasing the signal quality. In the current work, we present a comparison of results obtained using mechanically fixed and floating silicon neural probes chronically implanted into the cortex of a non-human primate. We demonstrate that the neural signal quality estimated by the quality of the spiking and local field potential (LFP) recordings over time is initially superior for the floating probe compared to the fixed device. Nonetheless, the skull-fixed probe also allowed long-term recording of multi-unit activity (MUA) and low frequency signals over several months, especially once pulsations of the brain were properly controlled.

One of the biggest challenges for neurotechnology is the design of devices that are tolerated well by brain tissue, without sacrificing functionality and implantability. This study examined which design choices mitigate tissue damage and improve longevity by varying probe features implanted in the cerebral cortex of mice. We report on a systematic, quantitative analysis of neuronal and inflammation markers across cortical depth. We implanted a total of 103 stiff silicon or flexible polyimide probes in 32 mice, varying their thicknesses and widths, and either attaching them to the skull or not. A new, automated workflow to quantify immunohistochemical data examines: 1) the tissue loss caused by the implant, 2) the cortical neuronal density, and 3) the immune response expressed by astrocytic and microglial reaction. Flexible polyimide probes exhibited a clear advantage, causing fewer lesions and weaker immune responses than stiff silicon probes. Furthermore, we observed a weak influence of the shank cross‐section. A cortical depth profile of immune reactivity revealed focal reactions at the device entry points in the superficial cortex and at the cortex‐white matter boundary. This study gives important insights on optimizing device design parameters as well as surgical insights for improved tissue integration of intracortical electrode arrays.

One of the biggest challenges for neurotechnology is the design of devices that are tolerated well by brain tissue, without sacrificing functionality and implantability. This study examined which design choices mitigate tissue damage and improve longevity, by varying probe features implanted in the cerebral cortex of mice. We report on a systematic, quantitative analysis of neuronal and inflammation markers across cortical depth. We implanted a total of 103 stiff silicon or flexible polyimide probes in 32 mice, varying their thicknesses and widths, which were either attached to the skull or not. A new, automated workflow to quantify immunohistochemical data examines: 1) the tissue loss caused by the implant, 2) the cortical neuronal density, and 3) the immune response expressed by astrocytic and microglial reaction. Flexible polyimide probes exhibited a clear advantage, with fewer lesions and weaker immune responses than stiff silicon probes. Furthermore, we observed a weaker influence of the shank cross-section. A cortical depth profile of immune reactivity revealed focal reactions at the device entry points in the superficial cortex and at the cortex-white matter boundary. This study gives important insights on optimizing device design parameters as well as surgical insights for improved tissue integration of intracortical electrode arrays.

Understanding the function of brain cortices requires simultaneous investigation at multiple spatial and temporal scales and to link neural activity to an animal's behavior. A major challenge is to measure within- and across-layer information in actively behaving animals, in particular in mice that have become a major species in neuroscience due to an extensive genetic toolkit. Here we describe the Hybrid Drive, a new chronic implant for mice that combines tetrode arrays to record within-layer information with silicon probes to simultaneously measure across-layer information. The design of our device combines up to 14 tetrodes and 2 silicon probes, that can be arranged in custom arrays to generate unique areas-specific (and multi-area) layouts. We show that large numbers of neurons and layer-resolved local field potentials can be recorded from the same brain region across weeks without loss in electrophysiological signal quality. The drive's lightweight structure ( $\\approx$3.5 g) leaves animal behavior largely unchanged during a variety of experimental paradigms. We demonstrate how the data collected with the Hybrid Drive allow state-of-the-art analysis in a series of experiments linking the spiking activity of CA1 pyramidal layer neurons to the oscillatory activity across hippocampal layers. Our new device fits a gap in the existing technology and increases the range and precision of questions that can be addressed about neural computations in freely behaving mice. Competing Interest Statement A.A. is managing director of ATLAS Neuroengineering, Leuven, Belgium; ATLAS develops silicon-based neural probes which have been used in this study. The remaining authors declare no conflict of interests. Footnotes * https://github.com/MatteoGuardamagna/Hybrid_drive

Abstract It is an uninformative truism to state that the brain operates at multiple spatial and temporal scales, each with each own set of emergent phenomena. More worthy of attention is the point that our current understanding of it cannot clearly indicate which of these phenomenological scales are the significant contributors to the brain’s function and primary output (i.e. behaviour). Apart from the sheer complexity of the problem, a major contributing factor to this state of affairs is the lack of instrumentation that can simultaneously address these multiple scales without causing function altering damages to the underlying tissue. One important facet of this problem is that standard neural recording devices normally require one output connection per electrode. This limits the number of electrodes that can fit along the thin shafts of implantable probes generating a limiting balance between density and spread. Sharing a single output connection between multiple electrodes relaxes this constraint and permits designs of ultra-high density probes. Here we report the design and in-vivo validation of such a device, a complementary metal-oxide-semiconductor (CMOS) scanning probe with 1344 electrodes; the outcome of the European research project NeuroSeeker. We show that this design targets both local and global spatial scales by allowing the simultaneous recording of more than 1000 neurons spanning 7 functional regions with a single shaft. The neurons show similar recording longevity and signal to noise ratio to passive probes of comparable size and no adverse effects in awake or anesthetized animals. Addressing the data management of this device we also present novel visualization and monitoring methods. Using the probe with freely moving animals we show how accessing a number of cortical and subcortical brain regions offers a novel perspective on how the brain operates around salient behavioural events. Finally, we compare this probe with lower density, non CMOS designs (which have to adhere to the one electrode per output line rule). We show that an increase in density results in capturing neural firing patterns, undetectable by lower density devices, which correlate to self-similar structures inherent in complex naturalistic behaviour. To help design electrode configurations for future, even higher density, CMOS probes, recordings from many different brain regions were obtained with an ultra-dense passive probe. Footnotes * Added more animals results for the analysis presented

Cross-validating new methods for recording neural activity is necessary to accurately interpret and compare the signals they measure. Here we describe a procedure for precisely aligning two probes for in vivo paired-recordings such that the spiking activity of a single neuron is monitored with both a dense extracellular silicon polytrode and a juxtacellular micro-pipette. Our new method allows for efficient, reliable, and automated guidance of both probes to the same neural structure with micron resolution. We also describe a new dataset of paired-recordings, which is available online. We propose that our novel targeting system, and ever expanding cross-validation dataset, will be vital to the development of new algorithms for automatically detecting/sorting single-units, characterizing new electrode materials/designs, and resolving nagging questions regarding the origin and nature of extracellular neural signals.