G protein-coupled receptors (GPCRs) are classically characterized as cell-surface receptors transmitting extracellular signals into cells. Here we show that central components of a GPCR signaling system comprised of the melatonin type 1 receptor (MT), its associated G protein, and β-arrestins are on and within neuronal mitochondria. We discovered that the ligand melatonin is exclusively synthesized in the mitochondrial matrix and released by the organelle activating the mitochondrial MT signal-transduction pathway inhibiting stress-mediated cytochrome release and caspase activation. These findings coupled with our observation that mitochondrial MT overexpression reduces ischemic brain injury in mice delineate a mitochondrial GPCR mechanism contributing to the neuroprotective action of melatonin. We propose a new term, "automitocrine," analogous to "autocrine" when a similar phenomenon occurs at the cellular level, to describe this unexpected intracellular organelle ligand-receptor pathway that opens a new research avenue investigating mitochondrial GPCR biology.

Objective To understand the safety, putaminal coverage, and enzyme expression of adeno‐associated viral vector serotype‐2 encoding the complementary DNA for the enzyme, aromatic L‐amino acid decarboxylase (VY‐AADC01), delivered using novel intraoperative monitoring to optimize delivery. Methods Fifteen subjects (three cohorts of 5) with moderately advanced Parkinson's disease and medically refractory motor fluctuations received VY‐AADC01 bilaterally coadministered with gadoteridol to the putamen using intraoperative magnetic resonance imaging (MRI) guidance to visualize the anatomic spread of the infusate and calculate coverage. Cohort 1 received 8.3 × 10 11 vg/ml and ≤450 μl per putamen (total dose, ≤7.5 × 10 11 vg); cohort 2 received the same concentration (8.3 × 10 11 vg/ml) and ≤900 μl per putamen (total dose, ≤1.5 × 10 12 vg); and cohort 3 received 2.6 × 10 12 vg/ml and ≤900 μl per putamen (total dose, ≤4.7 × 10 12 vg). (18)F‐fluoro‐L‐dihydroxyphenylalanine positron emission tomography (PET) at baseline and 6 months postprocedure assessed enzyme activity; standard assessments measured clinical outcomes. Results MRI‐guided administration of ascending VY‐AADC01 doses resulted in putaminal coverage of 21% (cohort 1), 34% (cohort 2), and 42% (cohort 3). Cohorts 1, 2, and 3 showed corresponding increases in enzyme activity assessed by PET of 13%, 56%, and 79%, and reductions in antiparkinsonian medication of –15%, –33%, and –42%, respectively, at 6 months. At 12 months, there were dose‐related improvements in clinical outcomes, including increases in patient‐reported ON‐time without troublesome dyskinesia (1.6, 3.3, and 1.5 hours, respectively) and quality of life. Interpretation Novel intraoperative monitoring of administration facilitated targeted delivery of VY‐AADC01 in this phase 1 study, which was well tolerated. Increases in enzyme expression and clinical improvements were dose dependent. ClinicalTrials.gov Identifier: NCT01973543 Ann Neurol 2019;85:704–714

Recent advances in multi-electrode array technology have made it possible to monitor large neuronal ensembles at cellular resolution. In humans, however, current approaches either restrict recordings to only a few neurons per penetrating electrode or combine the signals of thousands of neurons in local field potential (LFP) recordings. Here, we describe a new probe variant and set of techniques which enable simultaneous recording from over 200 well-isolated cortical single units in human participants during intraoperative neurosurgical procedures using silicon Neuropixels probes. We characterized a diversity of extracellular waveforms with eight separable single unit classes, with differing firing rates, positions along the length of the linear electrode array, spatial spread of the waveform, and modulation by LFP events such as interictal discharges and burst suppression. While some additional challenges remain in creating a turn-key recording system, high-density silicon arrays provide a path for studying humanspecific cognitive processes and their dysfunction at unprecedented spatiotemporal resolution.Major technological advances in the past decade have led to a revolution in the neurosciences.Many research programs now routinely rely on the analysis of single-neuron action potentials from hundreds and even thousands of neurons, which provide a rich understanding of the coordinated activity of large neuronal ensembles that underlie sensory, motor, and cognitive operations [1][2][3][4] . While these developments have been most pronounced in animal models, there have been parallel, albeit slower, advances in the ability to record from single neurons in humans. Single-unit recordings in humans have been performed since the mid-1950s 5-8 , and were foundational in understanding the role of neural circuits in neurologic disease. For example, such techniques helped to establish an understanding of the relationship between .