Dopamine neurons encode the difference between actual and predicted reward, or reward prediction error (RPE). Although many models have been proposed to account for this computation, it has ...been difficult to test these models experimentally. Here we established an awake electrophysiological recording system, combined with rabies virus and optogenetic cell-type identification, to characterize the firing patterns of monosynaptic inputs to dopamine neurons while mice performed classical conditioning tasks. We found that each variable required to compute RPE, including actual and predicted reward, was distributed in input neurons in multiple brain areas. Further, many input neurons across brain areas signaled combinations of these variables. These results demonstrate that even simple arithmetic computations such as RPE are not localized in specific brain areas but, rather, distributed across multiple nodes in a brain-wide network. Our systematic method to examine both activity and connectivity revealed unexpected redundancy for a simple computation in the brain.
•Electrophysiological recording from monosynaptic inputs of dopamine neurons was performed•Rabies virus tracing was combined with optogenetic tagging in awake recording•Information required to compute reward prediction errors (RPEs) was distributed•There are mixed representations of variables and partially computed RPEs in input neurons
Tian et al. combined rabies virus and photo-tagging to record from monosynaptic inputs to dopamine neurons. Information for reward prediction error computations is distributed and already mixed in input neurons, suggesting highly redundant and distributed computation for a simple arithmetic.
Dopamine has a central role in motivation and reward. Dopaminergic neurons in the ventral tegmental area (VTA) signal the discrepancy between expected and actual rewards (that is, reward prediction ...error), but how they compute such signals is unknown. We recorded the activity of VTA neurons while mice associated different odour cues with appetitive and aversive outcomes. We found three types of neuron based on responses to odours and outcomes: approximately half of the neurons (type I, 52%) showed phasic excitation after reward-predicting odours and rewards in a manner consistent with reward prediction error coding; the other half of neurons showed persistent activity during the delay between odour and outcome that was modulated positively (type II, 31%) or negatively (type III, 18%) by the value of outcomes. Whereas the activity of type I neurons was sensitive to actual outcomes (that is, when the reward was delivered as expected compared to when it was unexpectedly omitted), the activity of type II and type III neurons was determined predominantly by reward-predicting odours. We 'tagged' dopaminergic and GABAergic neurons with the light-sensitive protein channelrhodopsin-2 and identified them based on their responses to optical stimulation while recording. All identified dopaminergic neurons were of type I and all GABAergic neurons were of type II. These results show that VTA GABAergic neurons signal expected reward, a key variable for dopaminergic neurons to calculate reward prediction error.
Serotonin and dopamine are major neuromodulators. Here, we used a modified rabies virus to identify monosynaptic inputs to serotonin neurons in the dorsal and median raphe (DR and MR). We found that ...inputs to DR and MR serotonin neurons are spatially shifted in the forebrain, and MR serotonin neurons receive inputs from more medial structures. Then, we compared these data with inputs to dopamine neurons in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). We found that DR serotonin neurons receive inputs from a remarkably similar set of areas as VTA dopamine neurons apart from the striatum, which preferentially targets dopamine neurons. Our results suggest three major input streams: a medial stream regulates MR serotonin neurons, an intermediate stream regulates DR serotonin and VTA dopamine neurons, and a lateral stream regulates SNc dopamine neurons. These results provide fundamental organizational principles of afferent control for serotonin and dopamine.
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•Monosynaptic inputs to serotonin neurons in the DR and MR•Inputs to DR and MR serotonin neurons are spatially shifted in the forebrain•DR serotonin and VTA dopamine neurons receive similar inputs, except from striatum•Three input streams control serotonin and dopamine
Serotonin or dopamine neurons project throughout the brain and control many behaviors. Despite their importance, little is known about how serotonin and dopamine neurons are regulated, partly because of anatomical complexity. Here, Ogawa et al. used a modified rabies virus to systematically map direct inputs to serotonin neurons and found a surprising similarity of inputs between a group of serotonin neurons and a group of dopamine neurons. These results give a global picture of serotonin and dopamine neural circuits.
Serotonin's function in the brain is unclear. One challenge in testing the numerous hypotheses about serotonin's function has been observing the activity of identified serotonergic neurons in animals ...engaged in behavioral tasks. We recorded the activity of dorsal raphe neurons while mice experienced a task in which rewards and punishments varied across blocks of trials. We 'tagged' serotonergic neurons with the light-sensitive protein channelrhodopsin-2 and identified them based on their responses to light. We found three main features of serotonergic neuron activity: (1) a large fraction of serotonergic neurons modulated their tonic firing rates over the course of minutes during reward vs punishment blocks; (2) most were phasically excited by punishments; and (3) a subset was phasically excited by reward-predicting cues. By contrast, dopaminergic neurons did not show firing rate changes across blocks of trials. These results suggest that serotonergic neurons signal information about reward and punishment on multiple timescales.
Aging leads to a gradual decline in physical activity and disrupted energy homeostasis. The NAD
-dependent SIRT6 deacylase regulates aging and metabolism through mechanisms that largely remain ...unknown. Here, we show that SIRT6 overexpression leads to a reduction in frailty and lifespan extension in both male and female B6 mice. A combination of physiological assays, in vivo multi-omics analyses and
C lactate tracing identified an age-dependent decline in glucose homeostasis and hepatic glucose output in wild type mice. In contrast, aged SIRT6-transgenic mice preserve hepatic glucose output and glucose homeostasis through an improvement in the utilization of two major gluconeogenic precursors, lactate and glycerol. To mediate these changes, mechanistically, SIRT6 increases hepatic gluconeogenic gene expression, de novo NAD
synthesis, and systemically enhances glycerol release from adipose tissue. These findings show that SIRT6 optimizes energy homeostasis in old age to delay frailty and preserve healthy aging.
Mice deficient for SIRT6 exhibit a severely shortened lifespan, growth retardation, and highly elevated LINE1 (L1) activity. Here we report that SIRT6-deficient cells and tissues accumulate abundant ...cytoplasmic L1 cDNA, which triggers strong type I interferon response via activation of cGAS. Remarkably, nucleoside reverse-transcriptase inhibitors (NRTIs), which inhibit L1 retrotransposition, significantly improved health and lifespan of SIRT6 knockout mice and completely rescued type I interferon response. In tissue culture, inhibition of L1 with siRNA or NRTIs abrogated type I interferon response, in addition to a significant reduction of DNA damage markers. These results indicate that L1 activation contributes to the pathologies of SIRT6 knockout mice. Similarly, L1 transcription, cytoplasmic cDNA copy number, and type I interferons were elevated in the wild-type aged mice. As sterile inflammation is a hallmark of aging, we propose that modulating L1 activity may be an important strategy for attenuating age-related pathologies.
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•SIRT6 KO mice accumulate L1 cDNA, triggering interferon response via cGAS pathway•Wild-type aged mice accumulate L1 cDNA and display type I interferon response•Reverse-transcriptase inhibitors rescue type I interferon response and DNA damage•Reverse-transcriptase inhibitors extend lifespan and improve health of SIRT6 KO mice
Simon et al. show that LINE1 retrotransposon elements are derepressed in aged and progeroid mice. Cytoplasmic accumulation of LINE1 cDNA copies induced a type I interferon response, through the cGAS DNA sensing pathway, resulting in pathological inflammation. Inhibiting L1 replication significantly improved the health and lifespan of aged mice.
In diverse organisms, calorie restriction slows the pace of ageing and increases maximum lifespan. In the budding yeast Saccharomyces cerevisiae, calorie restriction extends lifespan by increasing ...the activity of Sir2 (ref. 1), a member of the conserved sirtuin family of NAD+-dependent protein deacetylases. Included in this family are SIR-2.1, a Caenorhabditis elegans enzyme that regulates lifespan, and SIRT1, a human deacetylase that promotes cell survival by negatively regulating the p53 tumour suppressor. Here we report the discovery of three classes of small molecules that activate sirtuins. We show that the potent activator resveratrol, a polyphenol found in red wine, lowers the Michaelis constant of SIRT1 for both the acetylated substrate and NAD+, and increases cell survival by stimulating SIRT1-dependent deacetylation of p53. In yeast, resveratrol mimics calorie restriction by stimulating Sir2, increasing DNA stability and extending lifespan by 70%. We discuss possible evolutionary origins of this phenomenon and suggest new lines of research into the therapeutic use of sirtuin activators.
Telomeres and Longevity: A Cause or an Effect? Adwan Shekhidem, Huda; Sharvit, Lital; Leman, Eva ...
International journal of molecular sciences,
2019-Jul-01, 2019-07-01, 20190701, Letnik:
20, Številka:
13
Journal Article
Recenzirano
Odprti dostop
Telomere dynamics have been found to be better predictors of survival and mortality than chronological age. Telomeres, the caps that protect the end of linear chromosomes, are known to shorten with ...age, inducing cell senescence and aging. Furthermore, differences in age-related telomere attrition were established between short-lived and long-lived organisms. However, whether telomere length is a "biological thermometer" that reflects the biological state at a certain point in life or a biomarker that can influence biological conditions, delay senescence and promote longevity is still an ongoing debate. We cross-sectionally tested telomere length in different tissues of two long-lived (naked mole-rat and
) and two short-lived (rat and mice) species to tease out this enigma. While blood telomere length of the naked mole-rat (NMR) did not shorten with age but rather showed a mild elongation, telomere length in three tissues tested in the Spalax declined with age, just like in short-lived rodents. These findings in the NMR, suggest an age buffering mechanism, while in
tissues the shortening of the telomeres are in spite of its extreme longevity traits. Therefore, using long-lived species as models for understanding the role of telomeres in longevity is of great importance since they may encompass mechanisms that postpone aging.
Decisions occur in dynamic environments. In the framework of reinforcement learning, the probability of performing an action is influenced by decision variables. Discrepancies between predicted and ...obtained rewards (reward prediction errors) update these variables, but they are otherwise stable between decisions. Although reward prediction errors have been mapped to midbrain dopamine neurons, it is unclear how the brain represents decision variables themselves. We trained mice on a dynamic foraging task in which they chose between alternatives that delivered reward with changing probabilities. Neurons in the medial prefrontal cortex, including projections to the dorsomedial striatum, maintained persistent firing rate changes over long timescales. These changes stably represented relative action values (to bias choices) and total action values (to bias response times) with slow decay. In contrast, decision variables were weakly represented in the anterolateral motor cortex, a region necessary for generating choices. Thus, we define a stable neural mechanism to drive flexible behavior.
•Medial prefrontal cortex (mPFC) persistently encodes value-based decision variables•Relative value signals are stable, and total value signals decay•Persistent decision variables are weakly represented in premotor cortex•mPFC projections to dorsomedial striatum persistently represent decision variables
Flexible behavior requires a memory of previous interactions with the environment. The medial prefrontal cortex persistently represents value-based decision variables, bridging the time between choices. These decision variables are sent to the dorsomedial striatum to bias action selection.
The efficacy of venovenous extracorporeal membrane oxygenation (ECMO) in patients with severe acute respiratory distress syndrome (ARDS) remains controversial.
In an international clinical trial, we ...randomly assigned patients with very severe ARDS, as indicated by one of three criteria - a ratio of partial pressure of arterial oxygen (Pao
) to the fraction of inspired oxygen (Fio
) of less than 50 mm Hg for more than 3 hours; a Pao
:Fio
of less than 80 mm Hg for more than 6 hours; or an arterial blood pH of less than 7.25 with a partial pressure of arterial carbon dioxide of at least 60 mm Hg for more than 6 hours - to receive immediate venovenous ECMO (ECMO group) or continued conventional treatment (control group). Crossover to ECMO was possible for patients in the control group who had refractory hypoxemia. The primary end point was mortality at 60 days.
At 60 days, 44 of 124 patients (35%) in the ECMO group and 57 of 125 (46%) in the control group had died (relative risk, 0.76; 95% confidence interval CI, 0.55 to 1.04; P=0.09). Crossover to ECMO occurred a mean (±SD) of 6.5±9.7 days after randomization in 35 patients (28%) in the control group, with 20 of these patients (57%) dying. The frequency of complications did not differ significantly between groups, except that there were more bleeding events leading to transfusion in the ECMO group than in the control group (in 46% vs. 28% of patients; absolute risk difference, 18 percentage points; 95% CI, 6 to 30) as well as more cases of severe thrombocytopenia (in 27% vs. 16%; absolute risk difference, 11 percentage points; 95% CI, 0 to 21) and fewer cases of ischemic stroke (in no patients vs. 5%; absolute risk difference, -5 percentage points; 95% CI, -10 to -2).
Among patients with very severe ARDS, 60-day mortality was not significantly lower with ECMO than with a strategy of conventional mechanical ventilation that included ECMO as rescue therapy. (Funded by the Direction de la Recherche Clinique et du Développement and the French Ministry of Health; EOLIA ClinicalTrials.gov number, NCT01470703 .).
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