Neuromodulatory systems exert profound influences on brain function. Understanding how these systems modify the operating mode of target circuits requires measuring spatiotemporally precise neuromodulator release. We developed dLight1, an intensity-based genetically encoded dopamine indicator, to enable optical recording of dopamine dynamics with high spatiotemporal resolution in behaving mice. We demonstrated the utility of dLight1 by imaging dopamine dynamics simultaneously with pharmacological manipulation, electrophysiological or optogenetic stimulation, and calcium imaging of local neuronal activity. dLight1 enabled chronic tracking of learning-induced changes in millisecond dopamine transients in striatum. Further, we used dLight1 to image spatially distinct, functionally heterogeneous dopamine transients relevant to learning and motor control in cortex. We also validated our sensor design platform for developing norepinephrine, serotonin, melatonin, and opioid neuropeptide indicators.

How single neurons represent information about the magnitude of a stimulus remains controversial. Neurons encoding purely sensory magnitude typically show monotonic response functions ("summation coding"), and summation units are usually implemented in models of numerosity representation. In contrast, cells representing numerical quantity exhibit nonmonotonic tuning functions that peak at their preferred numerosity ("labeled-line code"), but the restricted range of tested quantities in these studies did not permit a definite answer. Here, we analyzed both behavioral and neuronal representations of a broad range of numerosities from 1 to 30 in the prefrontal cortex of monkeys. Numerosity-selective neurons showed a clear and behaviorally relevant labeled-line code for all numerosities. Moreover, both the behavioral and neuronal tuning functions obeyed the Weber-Fechner Law and were best represented on a nonlinearly compressed scale. Our single-cell study is in good agreement with functional imaging data reporting peaked tuning functions in humans, demonstrating neuronal precursors for human number competence in a nonhuman primate. Our findings also emphasize that the manner in which neurons encode and maintain magnitude information may depend on the precise task at hand as well as the type of magnitude to represent and memorize.

Sensory information from mechanoreceptors and nociceptors in the skin plays key roles in adaptive and protective motor behaviours. To date, very little is known about how this information is encoded by spinal cord cell types and their activity patterns, particularly under freely behaving conditions. To enable stable measurement of neuronal and glial cell activity in behaving mice, we have developed fluorescence imaging approaches based on two-and miniaturized one-photon microscopy. We show that distinct cutaneous stimuli activate overlapping ensembles of dorsal horn neurons, and that stimulus type and intensity is encoded at the single-cell level. In contrast, astrocytes show large-scale coordinated calcium responses to intense but not weak sensory inputs. Sensory-evoked activity is potently suppressed by anaesthesia. By revealing the cellular and computational logic of spinal cord networks under behaving conditions, our approach holds promise for better understanding of healthy and aberrant spinal cord processes.

There is general agreement that nonverbal animals and humans endowed with language possess an evolutionary precursor system for representing and comparing numerical values. However, whether nonverbal numerical representations in human and nonhuman primates are quantitatively similar and whether linear or logarithmic coding underlies such magnitude judgments in both species remain elusive. To resolve these issues, we tested the numerical discrimination performance of human subjects and two rhesus monkeys (Macaca mulatta) in an identical delayed match-to-numerosity task for a broad range of numerosities from 1 to 30. The results demonstrate a noisy nonverbal estimation system obeying Weber's Law in both species. With average Weber fractions in the range of 0.51 and 0.60, nonverbal numerosity discriminations in humans and monkeys showed similar precision. Moreover, the detailed analysis of the performance distributions exhibited nonlinearly compressed numerosity representations in both primate species. However, the difference between linear and logarithmic scaling was less pronounced in humans. This may indicate a gradual transformation of a logarithmic to linear magnitude scale in human adults as the result of a cultural transformation process during the course of mathematical education.

SUMMARY Microglia are the intrinsic immune sentinels of the central nervous system. Their activation restricts tissue injury and pathogen spread, but in some settings, including viral infection, this response can contribute to cell death and disease. Identifying mechanisms that control microglial responses is therefore an important objective. Using replication-incompetent adenovirus 5 (Ad5)-based vectors as a model, we investigated the mechanisms through which microglia recognize and respond to viral uptake. Transgenic, immunohistochemical, molecular-genetic, and fluorescence imaging approaches revealed that phosphatidylserine (PtdSer) exposure on the outer leaflet of transduced cells triggers their engulfment by microglia through TAM receptor-dependent mechanisms. We show that inhibition of phospholipid scramblase 1 (PLSCR1) activity reduces intracellular calcium dysregulation, prevents PtdSer externalization, and enables months-long protection of vector-transduced, transgene-expressing cells from microglial phagocytosis. Our study identifies PLSCR1 as a potent target through which the innate immune response to viral vectors, and potentially other stimuli, may be controlled.