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1.
Nano Lett ; 22(9): 3668-3677, 2022 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-35439419

RESUMO

The real-time monitoring of neurochemical release in vivo plays a critical role in understanding the biochemical process of the complex nervous system. Current technologies for such applications, including microdialysis and fast-scan cyclic voltammetry, suffer from limited spatiotemporal resolution or poor selectivity. Here, we report a soft implantable aptamer-graphene microtransistor probe for real-time monitoring of neurochemical release. As a demonstration, we show the monitoring of dopamine with nearly cellular-scale spatial resolution, high selectivity (dopamine sensor >19-fold over norepinephrine), and picomolar sensitivity, simultaneously. Systematic benchtop evaluations, ex vivo experiments, and in vivo studies in mice models highlight the key features and demonstrate the capability of capturing the dopamine release dynamics evoked by pharmacological stimulation, suggesting the potential applications in basic neuroscience studies and studying neurological disease-related processes. The developed system can be easily adapted for monitoring other neurochemicals and drugs by simply replacing the aptamers functionalized on the graphene microtransistors.


Assuntos
Dopamina , Grafite , Animais , Camundongos , Norepinefrina , Oligonucleotídeos
2.
Anal Chem ; 94(13): 5335-5343, 2022 04 05.
Artigo em Inglês | MEDLINE | ID: mdl-35324161

RESUMO

Mass spectrometry imaging (MSI) allows for untargeted mapping of the chemical composition of tissues with attomole detection limits. MSI using Fourier transform (FT)-based mass spectrometers, such as FT-ion cyclotron resonance (FT-ICR), grants the ability to examine the chemical space with unmatched mass resolution and mass accuracy. However, direct imaging of large tissue samples using FT-ICR is slow. In this work, we present an approach that combines the subspace modeling of ICR temporal signals with compressed sensing to accelerate high-resolution FT-ICR MSI. A joint subspace and spatial sparsity constrained model computationally reconstructs high-resolution MSI data from the sparsely sampled transients with reduced duration, allowing a significant reduction in imaging time. Simulation studies and experimental implementation of the proposed method in investigation of brain tissues demonstrate a 10-fold enhancement in throughput of FT-ICR MSI, without the need for instrumental or hardware modifications.


Assuntos
Ciclotrons , Diagnóstico por Imagem , Análise de Fourier , Espectrometria de Massas/métodos
3.
Nat Commun ; 13(1): 1161, 2022 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-35246539

RESUMO

Imperfections in data annotation, known as label noise, are detrimental to the training of machine learning models and have a confounding effect on the assessment of model performance. Nevertheless, employing experts to remove label noise by fully re-annotating large datasets is infeasible in resource-constrained settings, such as healthcare. This work advocates for a data-driven approach to prioritising samples for re-annotation-which we term "active label cleaning". We propose to rank instances according to estimated label correctness and labelling difficulty of each sample, and introduce a simulation framework to evaluate relabelling efficacy. Our experiments on natural images and on a specifically-devised medical imaging benchmark show that cleaning noisy labels mitigates their negative impact on model training, evaluation, and selection. Crucially, the proposed approach enables correcting labels up to 4 × more effectively than typical random selection in realistic conditions, making better use of experts' valuable time for improving dataset quality.


Assuntos
Diagnóstico por Imagem , Aprendizado de Máquina , Benchmarking , Curadoria de Dados , Atenção à Saúde
4.
Nat Methods ; 18(10): 1233-1238, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34594032

RESUMO

Peptidergic dense-core vesicles are involved in packaging and releasing neuropeptides and peptide hormones-critical processes underlying brain, endocrine and exocrine function. Yet, the heterogeneity within these organelles, even for morphologically defined vesicle types, is not well characterized because of their small volumes. We present image-guided, high-throughput mass spectrometry-based protocols to chemically profile large populations of both dense-core vesicles and lucent vesicles for their lipid and peptide contents, allowing observation of the chemical heterogeneity within and between these two vesicle populations. The proteolytic processing products of four prohormones are observed within the dense-core vesicles, and the mass spectral features corresponding to the specific peptide products suggest three distinct dense-core vesicle populations. Notable differences in the lipid mass range are observed between the dense-core and lucent vesicles. These single-organelle mass spectrometry approaches are adaptable to characterize a range of subcellular structures.


Assuntos
Aplysia/citologia , Ensaios de Triagem em Larga Escala/métodos , Aprendizado de Máquina , Organelas/fisiologia , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz , Animais
5.
Nature ; 598(7882): 646-651, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34646022

RESUMO

µ-Opioid peptide receptor (MOPR) stimulation alters respiration, analgesia and reward behaviour, and can induce substance abuse and overdose1-3. Despite its evident importance, the endogenous mechanisms for MOPR regulation of consummatory behaviour have remained unknown4. Here we report that endogenous MOPR regulation of reward consumption in mice acts through a specific dorsal raphe to nucleus accumbens projection. MOPR-mediated inhibition of raphe terminals is necessary and sufficient to determine consummatory response, while select enkephalin-containing nucleus accumbens ensembles are engaged prior to reward consumption, suggesting that local enkephalin release is the source of the endogenous MOPR ligand. Selective modulation of nucleus accumbens enkephalin neurons and CRISPR-Cas9-mediated disruption of enkephalin substantiate this finding. These results isolate a fundamental endogenous opioid circuit for state-dependent consumptive behaviour and suggest alternative mechanisms for opiate modulation of reward.


Assuntos
Analgésicos Opioides/farmacologia , Núcleo Accumbens/fisiologia , Receptores Opioides mu/fisiologia , Recompensa , Animais , Encefalinas , Feminino , Masculino , Camundongos , Camundongos Knockout
6.
J Am Soc Mass Spectrom ; 31(11): 2338-2347, 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33064944

RESUMO

We present a subspace method that accelerates data acquisition using Fourier transform-ion cyclotron resonance (FT-ICR) mass spectrometry imaging (MSI). For MSI of biological tissue samples, there is a finite number of heterogeneous tissue types with distinct chemical profiles that introduce redundancy in the high-dimensional measurements. Our subspace model exploits the redundancy in data measured from whole-slice tissue samples by decomposing the transient signals into linear combinations of a set of basis transients with the desired spectral resolution. This decomposition allowed us to design a strategy that acquires a subset of long transients for basis determination and short transients for the remaining pixels, drastically reducing the acquisition time. The computational reconstruction strategy can maintain high-mass-resolution and spatial-resolution MSI while providing a 10-fold improvement in throughput. We validated the capability of the subspace model using a rat sagittal brain slice imaging data set. Comprehensive evaluation of the quality of the mass spectral and ion images demonstrated that the reconstructed data produced by the reported method required only 15% of the typical acquisition time and exhibited both qualitative and quantitative consistency when compared to the original data. Our method enables either higher sample throughput or higher-resolution images at similar acquisition lengths, providing greater flexibility in obtaining FT-ICR MSI measurements.

7.
Nat Commun ; 11(1): 3673, 2020 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-32699250

RESUMO

Causal reasoning can shed new light on the major challenges in machine learning for medical imaging: scarcity of high-quality annotated data and mismatch between the development dataset and the target environment. A causal perspective on these issues allows decisions about data collection, annotation, preprocessing, and learning strategies to be made and scrutinized more transparently, while providing a detailed categorisation of potential biases and mitigation techniques. Along with worked clinical examples, we highlight the importance of establishing the causal relationship between images and their annotations, and offer step-by-step recommendations for future studies.


Assuntos
Diagnóstico por Imagem/métodos , Interpretação de Imagem Assistida por Computador/métodos , Aprendizado de Máquina , Causalidade , Humanos
8.
Anal Chem ; 92(13): 9338-9347, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32519839

RESUMO

The brain consists of organized ensembles of cells that exhibit distinct morphologies, cellular connectivity, and dynamic biochemistries that control the executive functions of an organism. However, the relationships between chemical heterogeneity, cell function, and phenotype are not always understood. Recent advancements in matrix-assisted laser desorption/ionization mass spectrometry have enabled the high-throughput, multiplexed chemical analysis of single cells, capable of resolving hundreds of molecules in each mass spectrum. We developed a machine learning workflow to classify single cells according to their mass spectra based on cell groups of interest (GOI), e.g., neurons vs astrocytes. Three data sets from various cell groups were acquired on three different mass spectrometer platforms representing thousands of individual cell spectra that were collected and used to validate the single cell classification workflow. The trained models achieved >80% classification accuracy and were subjected to the recently developed instance-based model interpretation framework, SHapley Additive exPlanations (SHAP), which locally assigns feature importance for each single-cell spectrum. SHAP values were used for both local and global interpretations of our data sets, preserving the chemical heterogeneity uncovered by the single-cell analysis while offering the ability to perform supervised analysis. The top contributing mass features to each of the GOI were ranked and selected using mean absolute SHAP values, highlighting the features that are specific to the defined GOI. Our approach provides insight into discriminating the chemical profiles of the single cells through interpretable machine learning, facilitating downstream analysis and validation.


Assuntos
Aprendizado de Máquina , Espectrometria de Massas/métodos , Animais , Área Sob a Curva , Cerebelo/citologia , Cerebelo/metabolismo , Hipocampo/citologia , Hipocampo/metabolismo , Análise de Componente Principal , Curva ROC , Ratos , Análise de Célula Única , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz
9.
Proc Natl Acad Sci U S A ; 116(43): 21427-21437, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31601737

RESUMO

Pharmacology and optogenetics are widely used in neuroscience research to study the central and peripheral nervous systems. While both approaches allow for sophisticated studies of neural circuitry, continued advances are, in part, hampered by technology limitations associated with requirements for physical tethers that connect external equipment to rigid probes inserted into delicate regions of the brain. The results can lead to tissue damage and alterations in behavioral tasks and natural movements, with additional difficulties in use for studies that involve social interactions and/or motions in complex 3-dimensional environments. These disadvantages are particularly pronounced in research that demands combined optogenetic and pharmacological functions in a single experiment. Here, we present a lightweight, wireless, battery-free injectable microsystem that combines soft microfluidic and microscale inorganic light-emitting diode probes for programmable pharmacology and optogenetics, designed to offer the features of drug refillability and adjustable flow rates, together with programmable control over the temporal profiles. The technology has potential for large-scale manufacturing and broad distribution to the neuroscience community, with capabilities in targeting specific neuronal populations in freely moving animals. In addition, the same platform can easily be adapted for a wide range of other types of passive or active electronic functions, including electrical stimulation.


Assuntos
Optogenética/métodos , Farmacologia/métodos , Animais , Encéfalo/metabolismo , Química Encefálica , Channelrhodopsins/metabolismo , Estimulação Elétrica , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Optogenética/instrumentação , Farmacologia/instrumentação , Próteses e Implantes , Tecnologia sem Fio/instrumentação
10.
Nat Biomed Eng ; 3(8): 655-669, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31384010

RESUMO

Both in vivo neuropharmacology and optogenetic stimulation can be used to decode neural circuitry, and can provide therapeutic strategies for brain disorders. However, current neuronal interfaces hinder long-term studies in awake and freely behaving animals, as they are limited in their ability to provide simultaneous and prolonged delivery of multiple drugs, are often bulky and lack multifunctionality, and employ custom control systems with insufficiently versatile selectivity for output mode, animal selection and target brain circuits. Here, we describe smartphone-controlled, minimally invasive, soft optofluidic probes with replaceable plug-like drug cartridges for chronic in vivo pharmacology and optogenetics with selective manipulation of brain circuits. We demonstrate the use of the probes for the control of the locomotor activity of mice for over four weeks via programmable wireless drug delivery and photostimulation. Owing to their ability to deliver both drugs and photopharmacology into the brain repeatedly over long time periods, the probes may contribute to uncovering the basis of neuropsychiatric diseases.


Assuntos
Neurofarmacologia/métodos , Optogenética/instrumentação , Tecnologia sem Fio/instrumentação , Animais , Encéfalo/fisiologia , Encefalopatias , Estimulação Encefálica Profunda/métodos , Sistemas de Liberação de Medicamentos/instrumentação , Sistemas de Liberação de Medicamentos/métodos , Implantes Experimentais , Dispositivos Lab-On-A-Chip , Locomoção , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Neurofarmacologia/instrumentação , Optogenética/métodos
11.
Neuron ; 102(3): 529-552, 2019 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-31071288

RESUMO

The mesocorticolimbic pathway is canonically known as the "reward pathway." Embedded within the center of this circuit is the striatum, a massive and complex network hub that synthesizes motivation, affect, learning, cognition, stress, and sensorimotor information. Although striatal subregions collectively share many anatomical and functional similarities, it has become increasingly clear that it is an extraordinarily heterogeneous region. In particular, the nucleus accumbens (NAc) medial shell has repeatedly demonstrated that the rules dictated by more dorsal aspects of the striatum do not apply or are even reversed in functional logic. These discrepancies are perhaps most easily captured when isolating the functions of various neuromodulatory peptide systems within the striatum. Endogenous peptides are thought to play a critical role in modulating striatal signals to either amplify or dampen evoked behaviors. Here we describe the anatomical-functional backdrop upon which several neuropeptides act within the NAc to modulate behavior, with a specific emphasis on nucleus accumbens medial shell and stress responsivity. Additionally, we propose that, as the field continues to dissect fast neurotransmitter systems within the NAc, we must also provide considerable contextual weight to the roles local peptides play in modulating these circuits to more comprehensively understand how this important subregion gates motivated behaviors.


Assuntos
Motivação/fisiologia , Neuropeptídeos/metabolismo , Núcleo Accumbens/metabolismo , Corpo Estriado/metabolismo , Corpo Estriado/fisiologia , Humanos , Interneurônios , Neurônios , Núcleo Accumbens/fisiologia
12.
Annu Rev Neurosci ; 41: 453-473, 2018 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-29852083

RESUMO

Opioids are the most commonly used and effective analgesic treatments for severe pain, but they have recently come under scrutiny owing to epidemic levels of abuse and overdose. These compounds act on the endogenous opioid system, which comprises four G protein-coupled receptors (mu, delta, kappa, and nociceptin) and four major peptide families (ß-endorphin, enkephalins, dynorphins, and nociceptin/orphanin FQ). In this review, we first describe the functional organization and pharmacology of the endogenous opioid system. We then summarize current knowledge on the signaling mechanisms by which opioids regulate neuronal function and neurotransmission. Finally, we discuss the loci of opioid analgesic action along peripheral and central pain pathways, emphasizing the pain-relieving properties of opioids against the affective dimension of the pain experience.


Assuntos
Analgésicos Opioides/metabolismo , Analgésicos Opioides/uso terapêutico , Dor/tratamento farmacológico , Dor/metabolismo , Animais , Humanos , Percepção da Dor , Receptores Acoplados a Proteínas G/metabolismo
13.
Proc Natl Acad Sci U S A ; 114(43): E9125-E9134, 2017 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-29073109

RESUMO

Hedonic hotspots are brain sites where particular neurochemical stimulations causally amplify the hedonic impact of sensory rewards, such as "liking" for sweetness. Here, we report the mapping of two hedonic hotspots in cortex, where mu opioid or orexin stimulations enhance the hedonic impact of sucrose taste. One hedonic hotspot was found in anterior orbitofrontal cortex (OFC), and another was found in posterior insula. A suppressive hedonic coldspot was also found in the form of an intervening strip stretching from the posterior OFC through the anterior and middle insula, bracketed by the two cortical hotspots. Opioid/orexin stimulations in either cortical hotspot activated Fos throughout a distributed "hedonic circuit" involving cortical and subcortical structures. Conversely, cortical coldspot stimulation activated circuitry for "hedonic suppression." Finally, food intake was increased by stimulations at several prefrontal cortical sites, indicating that the anatomical substrates in cortex for enhancing the motivation to eat are discriminable from those for hedonic impact.


Assuntos
Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiologia , Ala(2)-MePhe(4)-Gly(5)-Encefalina/farmacologia , Proteínas Oncogênicas v-fos/metabolismo , Orexinas/farmacologia , Analgésicos Opioides/farmacologia , Animais , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Masculino , Microinjeções , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiologia , Ratos Sprague-Dawley , Sacarose/farmacologia
14.
Neuropsychopharmacology ; 41(8): 2101-11, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26787120

RESUMO

The nucleus accumbens (NAc) contains a hedonic hotspot in the rostral half of medial shell, where opioid agonist microinjections are known to enhance positive hedonic orofacial reactions to the taste of sucrose ('liking' reactions). Within NAc shell, orexin/hypocretin also has been reported to stimulate food intake and is implicated in reward, whereas blockade of muscarinic acetylcholine receptors by scopolamine suppresses intake and may have anti-reward effects. Here, we show that NAc microinjection of orexin-A in medial shell amplifies the hedonic impact of sucrose taste, but only within the same anatomically rostral site, identical to the opioid hotspot. By comparison, at all sites throughout medial shell, orexin microinjections stimulated 'wanting' to eat, as reflected by increases in intake of palatable sweet chocolates. At NAc shell sites outside the hotspot, orexin selectively enhanced 'wanting' to eat without enhancing sweetness 'liking' reactions. In contrast, microinjections of the antagonist scopolamine at all sites in NAc shell suppressed sucrose 'liking' reactions as well as suppressing intake of palatable food. Conversely, scopolamine increased aversive 'disgust' reactions elicited by bitter quinine at all NAc shell sites. Finally, scopolamine microinjections localized to the caudal half of medial shell additionally generated a fear-related anti-predator reaction of defensive treading and burying directed toward the corners of the transparent chamber. Together, these results confirm a rostral hotspot in NAc medial shell as a unique site for orexin induction of hedonic 'liking' enhancement, similar to opioid enhancement. They also reveal distinct roles for orexin and acetylcholine signals in NAc shell for hedonic reactions and motivated behaviors.


Assuntos
Afeto , Ingestão de Alimentos , Medo , Núcleo Accumbens/fisiologia , Orexinas/fisiologia , Receptores Muscarínicos/fisiologia , Animais , Feminino , Masculino , Antagonistas Muscarínicos/administração & dosagem , Núcleo Accumbens/efeitos dos fármacos , Orexinas/administração & dosagem , Ratos Sprague-Dawley , Escopolamina/administração & dosagem , Sacarose/administração & dosagem , Paladar
15.
Front Syst Neurosci ; 9: 90, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26124708

RESUMO

The study of the neural bases of eating behavior, hunger, and reward has consistently implicated the lateral hypothalamus (LH) and its interactions with mesocorticolimbic circuitry, such as mesolimbic dopamine projections to nucleus accumbens (NAc) and ventral pallidum (VP), in controlling motivation to eat. The NAc and VP play special roles in mediating the hedonic impact ("liking") and motivational incentive salience ("wanting") of food rewards, and their interactions with LH help permit regulatory hunger/satiety modulation of food motivation and reward. Here, we review some progress that has been made regarding this circuitry and its functions: the identification of localized anatomical hedonic hotspots within NAc and VP for enhancing hedonic impact; interactions of NAc/VP hedonic hotspots with specific LH signals such as orexin; an anterior-posterior gradient of sites in NAc shell for producing intense appetitive eating vs. intense fearful reactions; and anatomically distributed appetitive functions of dopamine and mu opioid signals in NAc shell and related structures. Such findings help improve our understanding of NAc, VP, and LH interactions in mediating affective and motivation functions, including "liking" and "wanting" for food rewards.

16.
J Neurosci ; 34(12): 4239-50, 2014 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-24647944

RESUMO

A specialized cubic-millimeter hotspot in the rostrodorsal quadrant of medial shell in nucleus accumbens (NAc) of rats may mediate opioid enhancement of gustatory hedonic impact or "liking". Here, we selectively stimulated the three major subtypes of opioid receptors via agonist microinjections [mu (DAMGO), delta (DPDPE), or kappa (U50488H)] and constructed anatomical maps for functional localizations of consequent changes in hedonic "liking" (assessed by affective orofacial reactions to sucrose taste) versus "wanting" (assessed by changes in food intake). Results indicated that the NAc rostrodorsal quadrant contains a shared opioid hedonic hotspot that similarly mediates enhancements of sucrose "liking" for mu, delta, and kappa stimulations. Within the rostrodorsal hotspot boundaries each type of stimulation generated at least a doubling or higher enhancement of hedonic reactions, with comparable intensities for all three types of opioid stimulation. By contrast, a negative hedonic coldspot was mapped in the caudal half of medial shell, where all three types of opioid stimulation suppressed "liking" reactions to approximately one-half normal levels. Different anatomical patterns were produced for stimulation of food "wanting", reflected in food intake. Altogether, these results indicate that the rostrodorsal hotspot in medial shell is unique for generating opioid-induced hedonic enhancement, and add delta and kappa signals to mu as hedonic generators within the hotspot. Also, the identification of a separable NAc caudal coldspot for hedonic suppression, and separate NAc opioid mechanisms for controlling food "liking" versus "wanting" further highlights NAc anatomical heterogeneity and localizations of function within subregions of medial shell.


Assuntos
Ingestão de Alimentos/fisiologia , Núcleo Accumbens/metabolismo , Receptores Opioides/metabolismo , Recompensa , Paladar/fisiologia , Analgésicos Opioides/farmacologia , Animais , Mapeamento Encefálico , Ingestão de Alimentos/efeitos dos fármacos , Ala(2)-MePhe(4)-Gly(5)-Encefalina/farmacologia , Masculino , Núcleo Accumbens/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores Opioides/agonistas , Paladar/efeitos dos fármacos
17.
Neurosci Biobehav Rev ; 37(9 Pt A): 1919-31, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23261404

RESUMO

Ann Kelley was a scientific pioneer in reward neuroscience. Her many notable discoveries included demonstrations of accumbens/striatal circuitry roles in eating behavior and in food reward, explorations of limbic interactions with hypothalamic regulatory circuits, and additional interactions of motivation circuits with learning functions. Ann Kelley's accomplishments inspired other researchers to follow in her footsteps, including our own laboratory group. Here we describe results from several lines of our research that sprang in part from earlier findings by Kelley and colleagues. We describe hedonic hotspots for generating intense pleasure 'liking', separate identities of 'wanting' versus 'liking' systems, a novel role for dorsal neostriatum in generating motivation to eat, a limbic keyboard mechanism in nucleus accumbens for generating intense desire versus intense dread, and dynamic limbic transformations of learned memories into motivation. We describe how origins for each of these themes can be traced to fundamental contributions by Ann Kelley.


Assuntos
Encéfalo/fisiologia , Comportamento Alimentar/fisiologia , Motivação/fisiologia , Recompensa , Animais , Humanos , Aprendizagem/fisiologia
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