A universal and 3D-printed rat calvarium replacement system to enable for pan-cortical and sub-cortical recordings and optogenetics

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Abstract While altered broad-scale brain dynamics are a key brain signature of major depressive disorder (MDD) and despite the plethora of powerful neuroscientific tools available in rodents, we actually do not currently have the capacity to assess these broad-scale neocortical dynamics in rodents with synaptic-timescale temporal and single neuron resolution. This is a key gap in the capacity of neuroscientists to study MDD-related biology via rodent models including the sustained threat model. Electrophysiologic and optogenetic approaches would be ideal to study how neocortical dynamics are orchestrated at baseline and are perturbed in disease, since many mechanisms may be synaptic in nature and both methods can operate at synaptic-timescales. We are a team of neuroscientists and mechanical engineers and we aim to develop a system to allow implantation of previously- impractical complex combinations of electrodes and optic fibers to record and manipulate the rat brain. The basis of our approach is a 3-dimensionally printed (3D printed) replacement for the dorsal rat skull – an “Interface Plate” - which we have already successfully attached to two rats with good survival. Unlike a natural skull the Interface Plate is custom designed and fabricated and so can be adapted to guide and secure many devices to the animal using a novel surgical approach including pre-surgical assembly. We aim to optimize our design for the Interface Plate to enable two experiments that will be novel and crucial to studies of sustained threat-related disturbances in neocortical dynamics. The first aim will use our 3D printed positioning and guide system to place 128 electrodes broadly across the entire dorsal neocortex. This will enable the first ever mapping of electrical activity at sub-millisecond resolution across the entire dorsal neocortex enabling us to capture events ranging from synaptic transmission to oscillations to neuromodulation, behavior and brain state transitions. We will additionally place electrodes at both superficial and deep layers to gather data about relative roles of these evolutionarily-conserved anatomical layers. In a second aim we will adapt our Interface Plate to enable recording in neocortex while simultaneously recording and optogenetically stimulating regions that play key roles in coordinating neocortex including the dorsal hippocampus, the medial dorsal nucleus of the thalamus (MDN) and the thalamic reticular nucleus (TRN). In this aim, 8 (and later 32) electrodes will be implanted in cortex for recording while into dorsal hippocampal CA1, MDN and TRN we will implant silicon probes with 64 recording channels and a coupled optic fiber. This will facilitate experiments examining and testing the roles of non- neocortical structures in coordinating the cortex both in and out of sustained threat conditions. The experiments enabled here will provide fundamental new data regarding the neocortex in health and disease. This work will also lead to the creation of a customizable and flexible new tool which we will make openly available to enable complex experiments in freely behaving animals for anyone in the neuroscience community.