Significance: Dopamine is an important neurotransmitter governing behavior and heavily implicated in a large range of neural disorders, including Parkinson’s disease, depression, and related mood and movement disorders. Methods allowing accurate monitoring of dopamine over long timescales have not been previously reported yet are crucial to enable improved diagnostics and therapeutics. We report a technical advance that allowed recording of dopamine from sensors implanted into the brains of nonhuman primates for over 100 days. Our integrated platform enabled monitoring fast changes in dopamine release in response to rewarding stimuli and the administration of dopamine-related drugs. These findings demonstrate the long-term feasibility and reproducibility of neurochemical measurements and strengthen their potential translation to human use.

Chemical signaling underlies both temporally phasic and extended activity in the brain. Phasic activity can be monitored by implanted sensors, but chronic recording of such chemical signals has been difficult because the capacity to measure them degrades over time. This degradation has been attributed to tissue damage progressively produced by the sensors and failure of the sensors themselves. We report methods that surmount these problems through the development of sensors having diameters as small as individual neuronal cell bodies (<10 µm). These micro-invasive probes (µIPs) markedly reduced expression of detectable markers of inflammation and tissue damage in a rodent test model. The chronically implanted µIPs provided stable operation in monitoring sub-second fluctuations in stimulation-evoked dopamine in anesthetized rats for over a year. These findings demonstrate that monitoring of chemical activity patterns in the brain over at least year-long periods, long a goal of both basic and clinical neuroscience, is achievable.

Cellular-scale (<10 μm) probes were developed for minimally invasive, subsecond, and multi-site monitoring of neurochemicals in rat brain.

The inverse relationship of dopamine and beta depends on their relative timing and site of origin, and on motivational parameters.

We developed a flexible "electrode-thread" array for recording dopamine neurochemicals from a lateral distribution of subcortical targets (up to 16) transverse to the axis of insertion. Ultrathin (∼10 μm diameter) carbon fiber (CF) electrode-threads (CFETs) are clustered into a tight bundle to introduce them into the brain from a single-entry point. The individual CFETs splay laterally in deep brain tissue during insertion due to their innate flexibility. This spatial redistribution allows navigation of the CFETs towards deep brain targets spreading horizontally from the axis of insertion. Commercial "linear" arrays provide single-entry insertion but only allow measurements along the axis of insertion. Horizontally configured arrays inflict separate penetrations for each individual channel. We tested functional performance of our CFET arrays in vivo for recording dopamine and for providing lateral spread to multiple distributed sites in the rat striatum. Spatial spread was further characterized in agar brain phantoms as a function of insertion depth. We also developed protocols to slice the embedded CFETs within fixed brain tissue using standard histology. This method allowed extraction of the precise spatial coordinates of the implanted CFETs and their recording sites as integrated with immunohistochemical staining for surrounding anatomical, cytological, and protein expression labels. Our CFET array has the potential to unlock a wide range of applications, from uncovering the role of neuromodulators in synaptic plasticity, to addressing critical safety barriers in clinical translation towards diagnostic and adaptive treatment in Parkinson's disease and major mood disorders.