Adaptive Social Learning Strategies in Temporally and Spatially Varying Environments

Long before the origins of agriculture human ancestors had expanded across the globe into an immense variety of environments, from Australian deserts to Siberian tundra. Survival in these environments did not principally depend on genetic adaptations, but instead on evolved learning strategies that permitted the assembly of locally adaptive behavioral repertoires. To develop hypotheses about these learning strategies, we have modeled the evolution of learning strategies to assess what conditions and constraints favor which kinds of strategies. To build on prior work, we focus on clarifying how spatial variability, temporal variability, and the number of cultural traits influence the evolution of four types of strategies: (1) individual learning, (2) unbiased social learning, (3) payoff-biased social learning, and (4) conformist transmission. Using a combination of analytic and simulation methods, we show that spatial??but not temporal??variation strongly favors the emergence of conformist transmission. This effect intensifies when migration rates are relatively high and individual learning is costly. We also show that increasing the number of cultural traits above two favors the evolution of conformist transmission, which suggests that the assumption of only two traits in many models has been conservative. We close by discussing how (1) spatial variability represents only one way of introducing the low-level, nonadaptive phenotypic trait variation that so favors conformist transmission, the other obvious way being learning errors, and (2) our findings apply to the evolution of conformist transmission in social interactions. Throughout we emphasize how our models generate empirical predictions suitable for laboratory testing.     

Advantages and Limitations of the Use of Optogenetic Approach in Studying Fast-Scale Spike Encoding

Understanding single-neuron computations and encoding performed by spike-generation mechanisms of cortical neurons is one of the central challenges for cell electrophysiology and computational neuroscience. An established paradigm to study spike encoding in controlled conditions in vitro uses intracellular injection of a mixture of signals with fluctuating currents that mimic in vivo-like background activity. However this technique has two serious limitations: it uses current injection, while synaptic activation leads to changes of conductance, and current injection is technically most feasible in the soma, while the vast majority of synaptic inputs are located on the dendrites. Recent progress in optogenetics provides an opportunity to circumvent these limitations. Transgenic expression of light-activated ionic channels, such as Channelrhodopsin2 (ChR2), allows induction of controlled conductance changes even in thin distant dendrites. Here we show that photostimulation provides a useful extension of the tools to study neuronal encoding, but it has its own limitations. Optically induced fluctuating currents have a low cutoff (~70Hz), thus limiting the dynamic range of frequency response of cortical neurons. This leads to severe underestimation of the ability of neurons to phase-lock their firing to high frequency components of the input. This limitation could be worked around by using short (2 ms) light stimuli which produce membrane potential responses resembling EPSPs by their fast onset and prolonged decay kinetics. We show that combining application of short light stimuli to different parts of dendritic tree for mimicking distant EPSCs with somatic injection of fluctuating current that mimics fluctuations of membrane potential in vivo, allowed us to study fast encoding of artificial EPSPs photoinduced at different distances from the soma. We conclude that dendritic photostimulation of ChR2 with short light pulses provides a powerful tool to investigate population encoding of simulated synaptic potentials generated in dendrites at different distances from the soma.     

Encoding Stimulus Information by Spike Numbers and Mean Response Time in Primary Auditory Cortex

Neurons can transmit information about sensory stimuli via their firing rate, spike latency, or by the occurrence of complex spike patterns. Identifying which aspects of the neural responses actually encode sensory information remains a fundamental question in neuroscience. Here we compared various approaches for estimating the information transmitted by neurons in auditory cortex in two very different experimental paradigms, one measuring spatial tuning and the other responses to complex natural stimuli. We demonstrate that, in both cases, spike counts and mean response times jointly carry essentially all the available information about the stimuli. Thus, in auditory cortex, whereas spike counts carry only partial information about stimulus identity or location, the additional availability of relatively coarse temporal information is sufficient in order to extract essentially all the sensory information available in the spike discharge pattern, at least for the relatively short stimuli (< ∼ 100 ms) commonly used in auditory research.     

Mutual Temporal Relationships among Neuronal Spike Trains: Statistical Techniques for Display and Analysis

We describe a statistical technique, the joint peristimulus time (PST) scatter diagram, for the analysis of data from simultaneously recorded neurons subjected to repeated stimulation. Distinguishable features in the scatter diagram are related to effects of the stimulus on the observed neurons and to functional relations among the neurons. Properties of this measure and its variants are described and practical aspects of its application to experimental data are discussed.     

Concurrent Codes: A Holographic-Type Encoding Robust against Noise and Loss

Concurrent coding is an encoding scheme with ‘holographic’ type properties that are shown here to be robust against a significant amount of noise and signal loss. This single encoding scheme is able to correct for random errors and burst errors simultaneously, but does not rely on cyclic codes. A simple and practical scheme has been tested that displays perfect decoding when the signal to noise ratio is of order -18dB. The same scheme also displays perfect reconstruction when a contiguous block of 40% of the transmission is missing. In addition this scheme is 50% more efficient in terms of transmitted power requirements than equivalent cyclic codes. A simple model is presented that describes the process of decoding and can determine the computational load that would be expected, as well as describing the critical levels of noise and missing data at which false messages begin to be generated.     

Cloning and Tissue Expressional Characterization of a Full-Length cDNA Encoding Human Neuronal Protein P17.3

A full-length cDNA of 595 bp was isolated froma human fetal brain cDNA library. It contains an openreading frame encoding 153 amino acids, with an 18-bp5UTR and a 118-bp 3UTR in which there isan atypicalpolyadenylation signal (ATTAAA). The calculatedmolecular weight of the deduced protein is 17.3 kU. Thepredicted isoelectric point is 4.89. On account of itshigh homology to mouse neuronal protein NP15.6(81.2% identity), the deduced protein was namedneuronal protein 17.3 (NP17.3). When its secondarystructure was examined by the GGBSM program of PCGENEsoftware, it was found that 32.6 and 15.0% of itsamino acids are involved in formingalpha-helices and beta-sheets, respectively. Examinedwith the PESTFIND program, a typical PEST region foundin rapidly degraded proteins was found between residue48and residue 68.     

Optimal Information Representation and Criticality in an Adaptive Sensory Recurrent Neuronal Network

Recurrent connections play an important role in cortical function, yet their exact contribution to the network computation remains unknown. The principles guiding the long-term evolution of these connections are poorly understood as well. Therefore, gaining insight into their computational role and into the mechanism shaping their pattern would be of great importance. To that end, we studied the learning dynamics and emergent recurrent connectivity in a sensory network model based on a first-principle information theoretic approach. As a test case, we applied this framework to a model of a hypercolumn in the visual cortex and found that the evolved connections between orientation columns have a "Mexican hat" profile, consistent with empirical data and previous modeling work. Furthermore, we found that optimal information representation is achieved when the network operates near a critical point in its dynamics. Neuronal networks working near such a phase transition are most sensitive to their inputs and are thus optimal in terms of information representation. Nevertheless, a mild change in the pattern of interactions may cause such networks to undergo a transition into a different regime of behavior in which the network activity is dominated by its internal recurrent dynamics and does not reflect the objective input. We discuss several mechanisms by which the pattern of interactions can be driven into this supercritical regime and relate them to various neurological and neuropsychiatric phenomena.     

Lys842 in Neuronal Nitric-oxide Synthase Enables the Autoinhibitory Insert to Antagonize Calmodulin Binding, Increase FMN Shielding, and Suppress Interflavin Electron Transfer

Neuronal nitric-oxide synthase (nNOS) contains a unique autoinhibitory insert (AI) in its FMN subdomain that represses nNOS reductase activities and controls the calcium sensitivity of calmodulin (CaM) binding to nNOS. How the AI does this is unclear. A conserved charged residue (Lys⁸⁴²) lies within a putative CaM binding helix in the middle of the AI. We investigated its role by substituting residues that neutralize (Ala) or reverse (Glu) the charge at Lys⁸⁴². Compared with wild type nNOS, the mutant enzymes had greater cytochrome c reductase and NADPH oxidase activities in the CaM-free state, were able to bind CaM at lower calcium concentration, and had lower rates of heme reduction and NO synthesis in one case (K842A). Moreover, stopped-flow spectrophotometric experiments with the nNOS reductase domain indicate that the CaM-free mutants had faster flavin reduction kinetics and had less shielding of their FMN subdomains compared with wild type and no longer increased their level of FMN shielding in response to NADPH binding. Thus, Lys⁸⁴² is critical for the known functions of the AI and also enables two additional functions of the AI as newly identified here: suppression of electron transfer to FMN and control of the conformational equilibrium of the nNOS reductase domain. Its effect on the conformational equilibrium probably explains suppression of catalysis by the AI.     

Robust Brain-Machine Interface Design Using Optimal Feedback Control Modeling and Adaptive Point Process Filtering

Much progress has been made in brain-machine interfaces (BMI) using decoders such as Kalman filters and finding their parameters with closed-loop decoder adaptation (CLDA). However, current decoders do not model the spikes directly, and hence may limit the processing time-scale of BMI control and adaptation. Moreover, while specialized CLDA techniques for intention estimation and assisted training exist, a unified and systematic CLDA framework that generalizes across different setups is lacking. Here we develop a novel closed-loop BMI training architecture that allows for processing, control, and adaptation using spike events, enables robust control and extends to various tasks. Moreover, we develop a unified control-theoretic CLDA framework within which intention estimation, assisted training, and adaptation are performed. The architecture incorporates an infinite-horizon optimal feedback-control (OFC) model of the brain’s behavior in closed-loop BMI control, and a point process model of spikes. The OFC model infers the user’s motor intention during CLDA—a process termed intention estimation. OFC is also used to design an autonomous and dynamic assisted training technique. The point process model allows for neural processing, control and decoder adaptation with every spike event and at a faster time-scale than current decoders; it also enables dynamic spike-event-based parameter adaptation unlike current CLDA methods that use batch-based adaptation on much slower adaptation time-scales. We conducted closed-loop experiments in a non-human primate over tens of days to dissociate the effects of these novel CLDA components. The OFC intention estimation improved BMI performance compared with current intention estimation techniques. OFC assisted training allowed the subject to consistently achieve proficient control. Spike-event-based adaptation resulted in faster and more consistent performance convergence compared with batch-based methods, and was robust to parameter initialization. Finally, the architecture extended control to tasks beyond those used for CLDA training. These results have significant implications towards the development of clinically-viable neuroprosthetics.     

哺乳动物抗凝血酶基因的分子特征、微共线性与适应性进化

抗凝血酶(AT)是哺乳动物体内重要的天然抗凝血因子之一,它隶属于丝氨酸蛋白酶抑制物家族,主要参与并调节复杂的血凝过程。基于比较基因组学手段,共挖掘出17个哺乳动物抗凝血酶基因(AT),并剖析了它们的基因结构、微共线性、保守基序、功能结构域、以及系统进化关系。基因结构与微共线分析表明,哺乳动物AT基因具有5-12个外显子,大多数是7个外显子;不同物种AT基因所处区段之间具有较好的共线性。哺乳动物AT蛋白特征分析显示,SERPIN功能结构域与保守基序1、2、3、4、5、8和9存在相互重叠的部分。AT基因进化树揭示基因进化和通常认为的物种进化几乎一致。同时,利用PAML中Codeml的位点特异模型在AT基因中发掘了1个正选择位点328D。     

Energy Landscape Reveals That the Budding Yeast Cell Cycle Is a Robust and Adaptive Multi-stage Process

Quantitatively understanding the robustness, adaptivity and efficiency of cell cycle dynamics under the influence of noise is a fundamental but difficult question to answer for most eukaryotic organisms. Using a simplified budding yeast cell cycle model perturbed by intrinsic noise, we systematically explore these issues from an energy landscape point of view by constructing an energy landscape for the considered system based on large deviation theory. Analysis shows that the cell cycle trajectory is sharply confined by the ambient energy barrier, and the landscape along this trajectory exhibits a generally flat shape. We explain the evolution of the system on this flat path by incorporating its non-gradient nature. Furthermore, we illustrate how this global landscape changes in response to external signals, observing a nice transformation of the landscapes as the excitable system approaches a limit cycle system when nutrients are sufficient, as well as the formation of additional energy wells when the DNA replication checkpoint is activated. By taking into account the finite volume effect, we find additional pits along the flat cycle path in the landscape associated with the checkpoint mechanism of the cell cycle. The difference between the landscapes induced by intrinsic and extrinsic noise is also discussed. In our opinion, this meticulous structure of the energy landscape for our simplified model is of general interest to other cell cycle dynamics, and the proposed methods can be applied to study similar biological systems.     

S100β Increases Levels of β-Amyloid Precursor Protein and Its Encoding mRNA in Rat Neuronal Cultures

Abstract: S100β has been implicated in the formation of dystrophic neurites, overexpressing β-amyloid precursor protein (βAPP), in the β-amyloid plaques of Alzheimer's disease. We assessed the effects of S100β on cell viability of, neurite outgrowth from, and βAPP expression by neurons in primary cultures from fetal rat cortex. S100β (1–10 ng/ml) enhanced neuronal viability (as assessed by increased mitochondrial activity and decreased lactic acid dehydrogenase release) and promoted neurite outgrowth. Higher levels of S100β (100 ng/ml, but not 1 µg/ml) produced qualitatively similar, but less marked, effects. S100β also induced increased neuronal expression of the microtubule-associated protein MAP2, an effect that is consistent with trophic effects of S100β on neurite outgrowth. S100β (10 and 100 ng/ml) induced graded increases in neuronal expression of βAPP and of βAPP mRNA. These results support our previous suggestion that excessive expression of S100β by activated, plaque-associated astrocytes in Alzheimer's disease contributes to the appearance of dystrophic neurites overexpressing βAPP in diffuse amyloid deposits, and thus to the conversion of these deposits into the diagnostic neuritic β-amyloid plaques.     

Expression of mRNA Encoding Mcu and Other Mitochondrial Calcium Regulatory Genes Depends on Cell Type,Neuronal Subtype,and Ca2+ Signaling

Uptake of Ca²⁺ into the mitochondrial matrix controls cellular metabolism and survival-death pathways. Several genes are implicated in controlling mitochondrial Ca²⁺ uptake (mitochondrial calcium regulatory genes, MCRGs), however, less is known about the factors which influence their expression level. Here we have compared MCRG mRNA expression, in neural cells of differing type (cortical neurons vs. astrocytes), differing neuronal subtype (CA3 vs. CA1 hippocampus) and in response to Ca²⁺ influx, using a combination of qPCR and RNA-seq analysis. Of note, we find that the Mcu-regulating Micu gene family profile differs substantially between neurons and astrocytes, while expression of Mcu itself is markedly different between CA3 and CA1 regions in the adult hippocampus. Moreover, dynamic control of MCRG mRNA expression in response to membrane depolarization-induced Ca²⁺ influx is also apparent, resulting in repression of Letm1, as well as Mcu. Thus, the mRNA expression profile of MCRGs is not fixed, which may cause differences in the coupling between cytoplasmic and mitochondrial Ca²⁺, as well as diversity of mitochondrial Ca²⁺ uptake mechanisms.     

Induction of Robust Cellular and Humoral Virus-Specific Adaptive Immune Responses in Human Immunodeficiency Virus-Infected Humanized BLT Mice

The generation of humanized BLT mice by the cotransplantation of human fetal thymus and liver tissues and CD34⁺ fetal liver cells into nonobese diabetic/severe combined immunodeficiency mice allows for the long-term reconstitution of a functional human immune system, with human T cells, B cells, dendritic cells, and monocytes/macrophages repopulating mouse tissues. Here, we show that humanized BLT mice sustained high-level disseminated human immunodeficiency virus (HIV) infection, resulting in CD4⁺ T-cell depletion and generalized immune activation. Following infection, HIV-specific humoral responses were present in all mice by 3 months, and HIV-specific CD4⁺ and CD8⁺ T-cell responses were detected in the majority of mice tested after 9 weeks of infection. Despite robust HIV-specific responses, however, viral loads remained elevated in infected BLT mice, raising the possibility that these responses are dysfunctional. The increased T-cell expression of the negative costimulator PD-1 recently has been postulated to contribute to T-cell dysfunction in chronic HIV infection. As seen in human infection, both CD4⁺ and CD8⁺ T cells demonstrated increased PD-1 expression in HIV-infected BLT mice, and PD-1 levels in these cells correlated positively with viral load and inversely with CD4⁺ cell levels. The ability of humanized BLT mice to generate both cellular and humoral immune responses to HIV will allow the further investigation of human HIV-specific immune responses in vivo and suggests that these mice are able to provide a platform to assess candidate HIV vaccines and other immunotherapeutic strategies.An ideal animal model of human immunodeficiency virus (HIV) infection remains elusive. Nonhuman primates that are susceptible to HIV infection typically do not develop immunodeficiency (63), and although the simian immunodeficiency virus (SIV) infection of rhesus macaques has provided many critically important insights into retroviral pathogenesis (30), biological and financial considerations have created some limitations to the wide dissemination of this model. The great need for an improved animal model of HIV itself recently has been underscored by the disappointing results of human trials of MRKAd5, an adenovirus-based HIV type 1 (HIV-1) vaccine. This vaccine was not effective and actually may have increased some subjects'' risk of acquiring HIV (53). In the wake of these disappointing results, there has been increased interest in humanized mouse models of HIV infection (54). The ability of humanized mouse models to test candidate vaccines or other immunomodulatory strategies will depend critically on the ability of these mice to generate robust anti-HIV human immune responses.Mice have provided important model systems for the study of many human diseases, but they are unable to support productive HIV infection, even when made to express human coreceptors for the virus (7, 37, 52). A more successful strategy to humanize mice has been to engraft human immune cells and/or tissues into immunodeficient severe combined immunodeficiency (SCID) or nonobese diabetic (NOD)/SCID mice that are unable to reject xenogeneic grafts (39, 42, 57). Early versions of humanized mice supported productive HIV infection and allowed investigators to begin to address important questions in HIV biology in vivo (23, 40, 43-45). More recently, human cord blood or fetal liver CD34⁺ cells have been used to reconstitute Rag2^−/− interleukin-2 receptor γ chain-deficient (γ_c^−/−) and NOD/SCID/γ_c^−/− mice, resulting in higher levels of sustained human immune cell engraftment (27, 29, 61). These mice have allowed for stable, disseminated HIV infection (2, 4, 24, 65, 67), including mucosal transmission via vaginal and rectal routes (3). These mice recently have been used to demonstrate an important role for Treg cells in acute HIV infection (29) and to demonstrate that the T-cell-specific delivery of antiviral small interfering RNA is able to suppress HIV replication in vivo (31). These mice also have demonstrated some evidence of adaptive human immune responses, including the generation of HIV-specific antibody responses in some infected mice (2, 65), and some evidence of humoral and cell-mediated responses to non-HIV antigens or pathogens (24, 61). Most impressively, Rag2^−/− γ_c^−/− mice reconstituted with human fetal liver-derived CD34⁺ cells have generated humoral responses to dengue virus infection that demonstrated both class switching and neutralizing capacity (32). In spite of these advances, however, these models have not yet been reported to generate de novo HIV-specific cell-mediated immune responses, which are considered to be a crucial arm of host defense against HIV infection in humans.In contrast to humanized mouse models in which only human hematopoietic cells are transferred into immunodeficient mice, the surgical implantation of human fetal thymic and liver tissue has been performed in addition to the transfer of human hematopoietic stem cells (HSC) to generate mice in which human T cells are educated by autologous human thymic tissue rather than by the xenogeneic mouse thymus. Melkus and colleagues refer to mice they have reconstituted in this way as NOD/SCID-hu BLT (for bone marrow, liver, and thymus), or simply BLT, mice (41). We previously referred to mice that we have humanized in a similar way as NOD/SCID mice cotransplanted with human fetal thymic and liver tissues (Thy/Liv) and CD34⁺ fetal liver cells (FLC) (33, 60) but now adopt the designation BLT mice as well. BLT mice demonstrate the robust repopulation of mouse lymphoid tissues with functional human T lymphocytes (33, 41, 60) and can support the rectal and vaginal transmission of HIV (13, 59). Further, BLT mice demonstrate antigen-specific human immune responses against non-HIV antigens and/or pathogens (41, 60). The ability of these mice to generate human immune responses against HIV, however, has not yet been reported. In this study, we investigated whether the provision of autologous human thymic tissue in BLT mice generated by the cotransplantion of human fetal Thy/Liv tissues and CD34⁺ FLC would allow for the maturation of human T cells in humanized mice capable of providing improved cellular responses to HIV as well as providing adequate help for improved humoral responses. To describe the cells contributing to human immune responses in BLT mice, we also characterized the phenotypes of multiple subsets of T cells, B cells, dendritic cells (DCs), and monocytes/macrophages present in uninfected humanized mice. The generation of robust HIV-directed human cellular and humoral immune responses in these mice would further demonstrate the ability of humanized mice to provide a much needed platform for the evaluation of HIV vaccines and other novel immunomodulatory strategies.     

Routine OGTT: A Robust Model Including Incretin Effect for Precise Identification of Insulin Sensitivity and Secretion in a Single Individual

In order to provide a method for precise identification of insulin sensitivity from clinical Oral Glucose Tolerance Test (OGTT) observations, a relatively simple mathematical model (Simple Interdependent glucose/insulin MOdel SIMO) for the OGTT, which coherently incorporates commonly accepted physiological assumptions (incretin effect and saturating glucose-driven insulin secretion) has been developed. OGTT data from 78 patients in five different glucose tolerance groups were analyzed: normal glucose tolerance (NGT), impaired glucose tolerance (IGT), impaired fasting glucose (IFG), IFG+IGT, and Type 2 Diabetes Mellitus (T2DM). A comparison with the 2011 Salinari (COntinuos GI tract MOdel, COMO) and the 2002 Dalla Man (Dalla Man MOdel, DMMO) models was made with particular attention to insulin sensitivity indices IS_COMO, IS_DMMO and k_xgi (the insulin sensitivity index for SIMO). ANOVA on k_xgi values across groups resulted significant overall (P<0.001), and post-hoc comparisons highlighted the presence of three different groups: NGT (8.62×10⁻⁵±9.36×10⁻⁵ min⁻¹pM⁻¹), IFG (5.30×10⁻⁵±5.18×10⁻⁵) and combined IGT, IFG+IGT and T2DM (2.09×10⁻⁵±1.95×10⁻⁵, 2.38×10⁻⁵±2.28×10⁻⁵ and 2.38×10⁻⁵±2.09×10⁻⁵ respectively). No significance was obtained when comparing IS_COMO or IS_DMMO across groups. Moreover, k_xgi presented the lowest sample average coefficient of variation over the five groups (25.43%), with average CVs for IS_COMO and IS_DMMO of 70.32% and 57.75% respectively; k_xgi also presented the strongest correlations with all considered empirical measures of insulin sensitivity. While COMO and DMMO appear over-parameterized for fitting single-subject clinical OGTT data, SIMO provides a robust, precise, physiologically plausible estimate of insulin sensitivity, with which habitual empirical insulin sensitivity indices correlate well. The k_xgi index, reflecting insulin secretion dependency on glycemia, also significantly differentiates clinically diverse subject groups. The SIMO model may therefore be of value for the quantification of glucose homeostasis from clinical OGTT data.     

Dopamine as a Potent Inducer of Cellular Glutathione and NAD(P)H:Quinone Oxidoreductase 1 in PC12 Neuronal Cells: A Potential Adaptive Mechanism for Dopaminergic Neuroprotection

Dopamine auto-oxidation and the consequent formation of reactive oxygen species and electrophilic quinone molecules have been implicated in dopaminergic neuronal cell death in Parkinson’s disease. We reported here that in PC12 dopaminergic neuronal cells dopamine at noncytotoxic concentrations (50–150 μM) potently induced cellular glutathione (GSH) and the phase 2 enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1), two critical cellular defenses in detoxification of ROS and electrophilic quinone molecules. Incubation of PC12 cells with dopamine also led to a marked increase in the mRNA levels for γ-glutamylcysteine ligase catalytic subunit (GCLC) and NQO1. In addition, treatment of PC12 cells with dopamine resulted in a significant elevation of GSH content in the mitochondrial compartment. To determine whether treatment with dopamine at noncytotoxic concentrations, which upregulated the cellular defenses could protect the neuronal cells against subsequent lethal oxidative and electrophilic injury, PC12 cells were pretreated with dopamine (150 μM) for 24 h and then exposed to various cytotoxic concentrations of dopamine or 6-hydroxydopamine (6-OHDA). We found that pretreatment of PC12 cells with dopamine at a noncytotoxic concentration led to a remarkable protection against cytotoxicity caused by dopamine or 6-OHDA at lethal concentrations, as detected by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium reduction assay. In view of the critical roles of GSH and NQO1 in protecting against dopaminergic neuron degeneration, the above findings implicate that upregulation of both GSH and NQO1 by dopamine at noncytotoxic concentrations may serve as an important adaptive mechanism for dopaminergic neuroprotection.