SUMMARY The brain processes sensory inputs and contextualizes this information with internal brain states, generating the signals that drive motor and cognitive behaviors. The underlying computations are distributed across several anatomically and functionally distinct brain regions. Therefore, neuroscience requires tools to simultaneously investigate multiple brain regions at high spatial and temporal resolution in animals performing naturalistic behaviors. While remarkable progress has been made in technologies capable of large-scale neural recordings in rodents, most require restraining the head, significantly limiting the behavioral repertoire. Although several head-mounted, miniaturized recording devices have been developed, these devices are typically limited to ~10% (2-4g) of a mouse’s body weight that results in large tradeoffs in performance and capabilities. To solve this problem, we propose a fundamentally different approach that eliminates the need for ever-greater miniaturization of neural interfaces for use in freely behaving animals. We will engineer an exoskeleton that attaches to the animal’s head and is capable of maneuvering sophisticated neural recording hardware, weighing an order of magnitude higher than a mouse, in 6 degrees of freedom (DOF) in response to an animal’s movements. There are three Specific Aims. In Aim 1 we will engineer a 6 DOF Cranial-exoskeleton capable of manipulating a 1kg head stage docked to a freely behaving mouse. The exoskeleton will have an array of sensors to achieve 6 DOF force sensing at the 5 nM scale and use zero-impedance closed-loop control. For Aim 2 we will design and build a compatible Pixel-drive headstage and achieve efficient rodent-robot interfacing. The headstage will incorporate 6 DOF force-sensing hardware for neural probe manipulation and cameras for behavioral tracking. We will optimize the system by recording from a single Neuropixels probe in mice navigating an open field. In Aim 3 we will leverage the capabilities of the Cranial-exoskeleton and Pixel-drive for brain-wide recordings in mice performing novel object recognition and location tasks. This will include strategies for trajectory planning and introducing up to 6 Neuropixels probes with the headstage into the brain via polymer skulls and establish procedures for multi-site recordings in freely locomoting mice. The proposal brings together an interdisciplinary team of roboticists, neural engineers (Dr. Kodandaramaiah lab), and systems neuroscientist (Dr. Ebner lab) to tackle this pressing problem in neuroscience. When fully developed, the proposed Cranio-exoskeleton and Pixel- the drive will enable recordings from 1000s of contacts distributed throughout the brain, significantly enhancing the breadth and complexity of behaviors that can be studied using high performance, large scale neural recording, and behavior tracking devices.

NARRATIVE Currently available technologies for recording neural activity in freely behaving animals suffer reduced performance from miniaturization. We propose to engineer a cranial exoskeleton that attaches to the animal’s head and is capable of maneuvering neural recording hardware weighing orders of magnitude more than the animal subject, in 6 degrees of freedom in response to an animal’s movements. The cranial exoskeleton will reveal the mechanisms by which neural computations function normally to produce complex behaviors and how those computations go awry in neurological and neuropsychiatric diseases.