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1.
Nat Methods ; 21(4): 680-691, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38036855

RESUMEN

Dopamine (DA) plays multiple roles in a wide range of physiological and pathological processes via a large network of dopaminergic projections. To dissect the spatiotemporal dynamics of DA release in both dense and sparsely innervated brain regions, we developed a series of green and red fluorescent G-protein-coupled receptor activation-based DA (GRABDA) sensors using a variety of DA receptor subtypes. These sensors have high sensitivity, selectivity and signal-to-noise ratio with subsecond response kinetics and the ability to detect a wide range of DA concentrations. We then used these sensors in mice to measure both optogenetically evoked and behaviorally relevant DA release while measuring neurochemical signaling in the nucleus accumbens, amygdala and cortex. Using these sensors, we also detected spatially resolved heterogeneous cortical DA release in mice performing various behaviors. These next-generation GRABDA sensors provide a robust set of tools for imaging dopaminergic activity under a variety of physiological and pathological conditions.


Asunto(s)
Dopamina , Núcleo Accumbens , Ratones , Animales , Núcleo Accumbens/fisiología , Receptores Dopaminérgicos , Encéfalo , Receptores Acoplados a Proteínas G
2.
Nature ; 576(7785): 42-43, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31792416

Asunto(s)
Dípteros , Animales , Neuronas
3.
J Neurophysiol ; 120(4): 2091-2106, 2018 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-30089025

RESUMEN

The sensory signals generated by self-motion are complex and multimodal, but the ability to integrate these signals into a unified self-motion percept to guide navigation is essential for animal survival. Here, we summarize classic and recent work on self-motion coding in the visual and entorhinal cortices of the rodent brain. We compare motion processing in rodent and primate visual cortices, highlighting the strengths of classic primate work in establishing causal links between neural activity and perception, and discuss the integration of motor and visual signals in rodent visual cortex. We then turn to the medial entorhinal cortex (MEC), where calculations using self-motion to update position estimates are thought to occur. We focus on several key sources of self-motion information to MEC: the medial septum, which provides locomotor speed information; visual cortex, whose input has been increasingly recognized as essential to both position and speed-tuned MEC cells; and the head direction system, which is a major source of directional information for self-motion estimates. These inputs create a large and diverse group of self-motion codes in MEC, and great interest remains in how these self-motion codes might be integrated by MEC grid cells to estimate position. However, which signals are used in these calculations and the mechanisms by which they are integrated remain controversial. We end by proposing future experiments that could further our understanding of the interactions between MEC cells that code for self-motion and position and clarify the relationship between the activity of these cells and spatial perception.


Asunto(s)
Corteza Entorrinal/fisiología , Percepción de Movimiento , Corteza Visual/fisiología , Animales , Conectoma , Locomoción , Primates , Desempeño Psicomotor , Roedores
4.
bioRxiv ; 2023 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-37732217

RESUMEN

The ability to make advantageous decisions is critical for animals to ensure their survival. Patch foraging is a natural decision-making process in which animals decide when to leave a patch of depleting resources to search for a new one. To study the algorithmic and neural basis of patch foraging behavior in a controlled laboratory setting, we developed a virtual foraging task for head-fixed mice. Mouse behavior could be explained by ramp-to-threshold models integrating time and rewards antagonistically. Accurate behavioral modeling required inclusion of a slowly varying "patience" variable, which modulated sensitivity to time. To investigate the neural basis of this decision-making process, we performed dense electrophysiological recordings with Neuropixels probes broadly throughout frontal cortex and underlying subcortical areas. We found that decision variables from the reward integrator model were represented in neural activity, most robustly in frontal cortical areas. Regression modeling followed by unsupervised clustering identified a subset of neurons with ramping activity. These neurons' firing rates ramped up gradually in single trials over long time scales (up to tens of seconds), were inhibited by rewards, and were better described as being generated by a continuous ramp rather than a discrete stepping process. Together, these results identify reward integration via a continuous ramping process in frontal cortex as a likely candidate for the mechanism by which the mammalian brain solves patch foraging problems.

5.
bioRxiv ; 2023 Aug 25.
Artículo en Inglés | MEDLINE | ID: mdl-37662187

RESUMEN

Dopamine (DA) plays multiple roles in a wide range of physiological and pathological processes via a vast network of dopaminergic projections. To fully dissect the spatiotemporal dynamics of DA release in both dense and sparsely innervated brain regions, we developed a series of green and red fluorescent GPCR activation-based DA (GRABDA) sensors using a variety of DA receptor subtypes. These sensors have high sensitivity, selectivity, and signal-to-noise properties with subsecond response kinetics and the ability to detect a wide range of DA concentrations. We then used these sensors in freely moving mice to measure both optogenetically evoked and behaviorally relevant DA release while measuring neurochemical signaling in the nucleus accumbens, amygdala, and cortex. Using these sensors, we also detected spatially resolved heterogeneous cortical DA release in mice performing various behaviors. These next-generation GRABDA sensors provide a robust set of tools for imaging dopaminergic activity under a variety of physiological and pathological conditions.

6.
Cell Rep ; 36(10): 109669, 2021 09 07.
Artículo en Inglés | MEDLINE | ID: mdl-34496249

RESUMEN

During navigation, animals estimate their position using path integration and landmarks, engaging many brain areas. Whether these areas follow specialized or universal cue integration principles remains incompletely understood. We combine electrophysiology with virtual reality to quantify cue integration across thousands of neurons in three navigation-relevant areas: primary visual cortex (V1), retrosplenial cortex (RSC), and medial entorhinal cortex (MEC). Compared with V1 and RSC, path integration influences position estimates more in MEC, and conflicts between path integration and landmarks trigger remapping more readily. Whereas MEC codes position prospectively, V1 codes position retrospectively, and RSC is intermediate between the two. Lowered visual contrast increases the influence of path integration on position estimates only in MEC. These properties are most pronounced in a population of MEC neurons, overlapping with grid cells, tuned to distance run in darkness. These results demonstrate the specialized role that path integration plays in MEC compared with other navigation-relevant cortical areas.


Asunto(s)
Potenciales de Acción/fisiología , Corteza Entorrinal/fisiología , Giro del Cíngulo/fisiología , Percepción Visual/fisiología , Animales , Neuronas/fisiología , Corteza Visual Primaria/fisiología , Estudios Retrospectivos , Navegación Espacial/fisiología
7.
Neuron ; 109(18): 2967-2980.e11, 2021 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-34363753

RESUMEN

Neurons in the medial entorhinal cortex alter their firing properties in response to environmental changes. This flexibility in neural coding is hypothesized to support navigation and memory by dividing sensory experience into unique episodes. However, it is unknown how the entorhinal circuit as a whole transitions between different representations when sensory information is not delineated into discrete contexts. Here we describe rapid and reversible transitions between multiple spatial maps of an unchanging task and environment. These remapping events were synchronized across hundreds of neurons, differentially affected navigational cell types, and correlated with changes in running speed. Despite widespread changes in spatial coding, remapping comprised a translation along a single dimension in population-level activity space, enabling simple decoding strategies. These findings provoke reconsideration of how the medial entorhinal cortex dynamically represents space and suggest a remarkable capacity of cortical circuits to rapidly and substantially reorganize their neural representations.


Asunto(s)
Mapeo Encefálico/métodos , Corteza Entorrinal/fisiología , Red Nerviosa/fisiología , Percepción Espacial/fisiología , Conducta Espacial/fisiología , Animales , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL
8.
Nat Commun ; 12(1): 671, 2021 01 28.
Artículo en Inglés | MEDLINE | ID: mdl-33510164

RESUMEN

Neural circuits generate representations of the external world from multiple information streams. The navigation system provides an exceptional lens through which we may gain insights about how such computations are implemented. Neural circuits in the medial temporal lobe construct a map-like representation of space that supports navigation. This computation integrates multiple sensory cues, and, in addition, is thought to require cues related to the individual's movement through the environment. Here, we identify multiple self-motion signals, related to the position and velocity of the head and eyes, encoded by neurons in a key node of the navigation circuitry of mice, the medial entorhinal cortex (MEC). The representation of these signals is highly integrated with other cues in individual neurons. Such information could be used to compute the allocentric location of landmarks from visual cues and to generate internal representations of space.


Asunto(s)
Corteza Entorrinal/fisiología , Red Nerviosa/fisiología , Neuronas/fisiología , Navegación Espacial/fisiología , Percepción Visual/fisiología , Algoritmos , Animales , Señales (Psicología) , Corteza Entorrinal/citología , Movimientos Oculares/fisiología , Femenino , Movimientos de la Cabeza/fisiología , Masculino , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Modelos Neurológicos , Red Nerviosa/citología
9.
Nat Neurosci ; 21(8): 1096-1106, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-30038279

RESUMEN

To guide navigation, the nervous system integrates multisensory self-motion and landmark information. We dissected how these inputs generate spatial representations by recording entorhinal grid, border and speed cells in mice navigating virtual environments. Manipulating the gain between the animal's locomotion and the visual scene revealed that border cells responded to landmark cues while grid and speed cells responded to combinations of locomotion, optic flow and landmark cues in a context-dependent manner, with optic flow becoming more influential when it was faster than expected. A network model explained these results by revealing a phase transition between two regimes in which grid cells remain coherent with or break away from the landmark reference frame. Moreover, during path-integration-based navigation, mice estimated their position following principles predicted by our recordings. Together, these results provide a theoretical framework for understanding how landmark and self-motion cues combine during navigation to generate spatial representations and guide behavior.


Asunto(s)
Señales (Psicología) , Corteza Entorrinal/fisiología , Movimiento/fisiología , Orientación/fisiología , Percepción Espacial/fisiología , Animales , Corteza Entorrinal/citología , Potenciales Evocados/fisiología , Femenino , Locomoción/fisiología , Ratones , Ratones Endogámicos C57BL , Redes Neurales de la Computación , Neuronas/clasificación , Desempeño Psicomotor/fisiología , Realidad Virtual , Percepción Visual/fisiología
11.
Mol Autism ; 5(1): 16, 2014 Feb 24.
Artículo en Inglés | MEDLINE | ID: mdl-24564913

RESUMEN

BACKGROUND: Fragile X syndrome and tuberous sclerosis are genetic syndromes that both have a high rate of comorbidity with autism spectrum disorder (ASD). Several lines of evidence suggest that these two monogenic disorders may converge at a molecular level through the dysfunction of activity-dependent synaptic plasticity. METHODS: To explore the characteristics of transcriptomic changes in these monogenic disorders, we profiled genome-wide gene expression levels in cerebellum and blood from murine models of fragile X syndrome and tuberous sclerosis. RESULTS: Differentially expressed genes and enriched pathways were distinct for the two murine models examined, with the exception of immune response-related pathways. In the cerebellum of the Fmr1 knockout (Fmr1-KO) model, the neuroactive ligand receptor interaction pathway and gene sets associated with synaptic plasticity such as long-term potentiation, gap junction, and axon guidance were the most significantly perturbed pathways. The phosphatidylinositol signaling pathway was significantly dysregulated in both cerebellum and blood of Fmr1-KO mice. In Tsc2 heterozygous (+/-) mice, immune system-related pathways, genes encoding ribosomal proteins, and glycolipid metabolism pathways were significantly changed in both tissues. CONCLUSIONS: Our data suggest that distinct molecular pathways may be involved in ASD with known but different genetic causes and that blood gene expression profiles of Fmr1-KO and Tsc2+/- mice mirror some, but not all, of the perturbed molecular pathways in the brain.

12.
BMC Med Genomics ; 6: 34, 2013 Sep 24.
Artículo en Inglés | MEDLINE | ID: mdl-24063311

RESUMEN

BACKGROUND: Decades of research strongly suggest that the genetic etiology of autism spectrum disorders (ASDs) is heterogeneous. However, most published studies focus on group differences between cases and controls. In contrast, we hypothesized that the heterogeneity of the disorder could be characterized by identifying pathways for which individuals are outliers rather than pathways representative of shared group differences of the ASD diagnosis. METHODS: Two previously published blood gene expression data sets--the Translational Genetics Research Institute (TGen) dataset (70 cases and 60 unrelated controls) and the Simons Simplex Consortium (Simons) dataset (221 probands and 191 unaffected family members)--were analyzed. All individuals of each dataset were projected to biological pathways, and each sample's Mahalanobis distance from a pooled centroid was calculated to compare the number of case and control outliers for each pathway. RESULTS: Analysis of a set of blood gene expression profiles from 70 ASD and 60 unrelated controls revealed three pathways whose outliers were significantly overrepresented in the ASD cases: neuron development including axonogenesis and neurite development (29% of ASD, 3% of control), nitric oxide signaling (29%, 3%), and skeletal development (27%, 3%). Overall, 50% of cases and 8% of controls were outliers in one of these three pathways, which could not be identified using group comparison or gene-level outlier methods. In an independently collected data set consisting of 221 ASD and 191 unaffected family members, outliers in the neurogenesis pathway were heavily biased towards cases (20.8% of ASD, 12.0% of control). Interestingly, neurogenesis outliers were more common among unaffected family members (Simons) than unrelated controls (TGen), but the statistical significance of this effect was marginal (Chi squared P < 0.09). CONCLUSIONS: Unlike group difference approaches, our analysis identified the samples within the case and control groups that manifested each expression signal, and showed that outlier groups were distinct for each implicated pathway. Moreover, our results suggest that by seeking heterogeneity, pathway-based outlier analysis can reveal expression signals that are not apparent when considering only shared group differences.


Asunto(s)
Trastornos Generalizados del Desarrollo Infantil/sangre , Trastornos Generalizados del Desarrollo Infantil/genética , Perfilación de la Expresión Génica , Genómica/métodos , Estudios de Casos y Controles , Humanos , Reproducibilidad de los Resultados
13.
PLoS One ; 7(12): e49475, 2012.
Artículo en Inglés | MEDLINE | ID: mdl-23227143

RESUMEN

Autism Spectrum Disorders (ASD) is a spectrum of highly heritable neurodevelopmental disorders in which known mutations contribute to disease risk in 20% of cases. Here, we report the results of the largest blood transcriptome study to date that aims to identify differences in 170 ASD cases and 115 age/sex-matched controls and to evaluate the utility of gene expression profiling as a tool to aid in the diagnosis of ASD. The differentially expressed genes were enriched for the neurotrophin signaling, long-term potentiation/depression, and notch signaling pathways. We developed a 55-gene prediction model, using a cross-validation strategy, on a sample cohort of 66 male ASD cases and 33 age-matched male controls (P1). Subsequently, 104 ASD cases and 82 controls were recruited and used as a validation set (P2). This 55-gene expression signature achieved 68% classification accuracy with the validation cohort (area under the receiver operating characteristic curve (AUC): 0.70 [95% confidence interval [CI]: 0.62-0.77]). Not surprisingly, our prediction model that was built and trained with male samples performed well for males (AUC 0.73, 95% CI 0.65-0.82), but not for female samples (AUC 0.51, 95% CI 0.36-0.67). The 55-gene signature also performed robustly when the prediction model was trained with P2 male samples to classify P1 samples (AUC 0.69, 95% CI 0.58-0.80). Our result suggests that the use of blood expression profiling for ASD detection may be feasible. Further study is required to determine the age at which such a test should be deployed, and what genetic characteristics of ASD can be identified.


Asunto(s)
Trastornos Generalizados del Desarrollo Infantil/genética , Transcriptoma , Niño , Trastornos Generalizados del Desarrollo Infantil/sangre , Estudios de Cohortes , Perfilación de la Expresión Génica , Humanos , Masculino , Modelos Genéticos , Análisis de Secuencia por Matrices de Oligonucleótidos
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