Gene expression provides the physiological underpinning for myriad biological processes, including those in the brain. However, monitoring the brain gene expression has been challenging due to the brain’s natural, confined architecture which restricts access to its thick, delicate tissue. Consequently, most existing approaches directly measure RNA abundance or transcriptional changes in an invasive manner, such as by histology or implanted optical devices, the result of which is irreversible physical damage to the brain. The aim of this thesis is to develop a new paradigm of molecular technology capable of measuring brain gene expression non-invasively, while ensuring high sensitivity, scalability, and precise spatial, temporal, and cellular resolution. As a first step towards this goal, we engineered a new class of synthetic, serum-based markers, called Released Markers of Activity (RMAs), that allows for non-invasive monitoring of gene expression with a simple blood test. Genetic tagging of specific genes of interest in the brain with RMA results in the release of RMA reporters from the brain into the bloodstream in response to the level of molecular activity of the gene. Once RMAs are deposited inside the blood, the blood samples can be analyzed using compatible biochemical techniques. Our initial readout method quantifies released RMAs in the blood by measuring luciferase activity, which provided high sensitivity with detectability down to approximately twelve labeled neurons in the mouse brain. Further, genetic tagging of RMAs to the neuronal activity-related gene Fos enabled the discrimination of brain activity through blood analysis. Because RMAs function as protein markers, this paradigm delivers greater scalability for measuring multiple genes or even enabling high-throughput gene analysis of the brain. The next devised strategy which combines the methods of nanopore protein sequencing and a machine learning-based classifier measures differentially barcoded RMAs for non-invasive, parallel readout of multiple genes in the brain. Taken together, our technology presents a novel and radical new reporter system for safe, repeatable, and multiplexed measurement of gene expression in an intact brain.