High performance miniaturized microscopes for through skull cortex-wide imaging in freely behaving mice

The National Institutes of Health Office of the Director awarded $803,099 to Objective Biotechnology, Inc. on September 15, 2025, under the Research Infrastructure Programs (CFDA 93.351) to develop and advance the mini-mscope, a 3.8-gram miniaturized imaging device for mesoscale cortex-wide neural activity measurement in freely behaving mice.

The Phase I Small Business Technology Transfer (STTR) project addresses limitations identified in beta testing by engineering a mini-mscope with a highly sensitive imaging CMOS sensor, evaluating its performance for through-skull imaging without craniotomy, and comprehensively assessing its imaging capabilities across diverse behavioral contexts. Work includes integrating a novel CMOS sensor into the existing device footprint, increasing effective resolution, and developing an intact skull preparation to enable brain imaging through the skull. The award supports commercialization and wider adoption of the device for neuroscientific research.

Objective Biotechnology, Inc., a Minneapolis-based minority-owned biotechnology company and University of Minnesota spin-out, receives the award. Performance occurs in Minneapolis, Minnesota, with a period of performance running through August 31, 2027.

Abstract

The mammalian cerebral cortex plays a crucial role in learned and adaptive sensory-motor behaviors, with its evolutionary expansion contributing to advanced cognitive abilities in humans and primates. While progress has been made in understanding regional cortical computations, the coordination of neural activity across the cortex for unified behavioral outputs remains poorly understood. The innovation described involves the development of the mini-mscope, a miniature imaging device capable of mesoscale dynamic measurements across the cortex in freely behaving mice. Weighing 3.8G, the mini-mscope has been distributed to several laboratories globally, demonstrating its efficacy in dorsal cortical activity imaging during various behaviors. Beta testing revealed two key issues: limited behavior testing and a challenging implantation procedure. The proposed phase I, small business technology transfer (STTR) project aims to address these concerns by engineering a mini-mscope with a highly sensitive imaging cmos sensor, evaluating its performance in through-skull imaging, and comprehensively assessing its imaging capabilities across diverse behavioral contexts. Successful outcomes are expected to enhance the mini-mscope's commercial viability, facilitating wider adoption for neuroscientific research. In aim 1 of this proposal, we will engineer a mini-mscope with highly sensitive imaging cmos sensor and evaluate the imaging performance of the mini-mscope through an intact skull preparation. This will involve integrating a novel cmos sensor into the existing device footprint, increasing the effective resolution of the device, and developing an intact skull preparation to image the brain through the skull without the need for a craniotomy. The new mini-mscope will be benchtop tested against the device performance of the extensively validated lab prototype of the mini-mscope. In aim 2 of this proposal we will perform comprehensive in-vivo evaluation of the mini-mscope in a broad spectrum of behavioral contexts and to optimize the opto-mechanical design to perform artifact free imaging. The in-vivo performance of the mini-mscope will be evaluated in 5 behavioral assays that capture a wide range of behavioral paradigms used in traditional neuroscience. In conjunction, the opto-mechanical stability of the device will be optimized to ensure stable, motion-artifact free imaging in all plausible behavioral conditions.