The cerebellum has long been proposed to play a role in cognitive function, although this has remained controversial. This idea has received renewed support with the recent discovery that signals ...associated with reward can be observed in the cerebellar circuitry, particularly in goal-directed learning tasks involving an interplay between the cerebellar cortex, basal ganglia, and cerebral cortex. Remarkably, a wide range of reward contingencies—including reward expectation, delivery, size, and omission—can be encoded by specific circuit elements in a manner that reflects the microzonal organization of the cerebellar cortex. The facts that reward signals have been observed in both the mossy fiber and climbing fiber input pathways to the cerebellar cortex and that their convergence may trigger plasticity in Purkinje cells suggest that these interactions may be crucial for the role of the cerebellar cortex in learned behavior. These findings strengthen the emerging consensus that the cerebellum plays a pivotal role in shaping cognitive processing and suggest that the cerebellum may combine both supervised learning and reinforcement learning to optimize goal-directed action. We make specific predictions about how cerebellar circuits can work in concert with the basal ganglia to guide different stages of learning.
Kostadinov and Häusser describe recent evidence for reward-related signals in the cerebellum. They discuss the relationship between these new findings and canonical dopaminergic reward signals and speculate about how the cerebellum and basal ganglia may work together to facilitate learning.
The optogenetic revolution is transforming neuroscience. The dramatic recent progress in using light to both control and read out neural activity has highlighted the need for better probes, improved ...light delivery and more careful interpretation of results, which will all be required for optogenetics to fully realize its remarkable potential.
Neurons in the medial entorhinal cortex exhibit a grid-like spatial pattern of spike rates that has been proposed to represent a neural code for path integration. To understand how grid cell firing ...arises from the combination of intrinsic conductances and synaptic input in medial entorhinal stellate cells, we performed patch-clamp recordings in mice navigating in a virtual-reality environment. We found that the membrane potential signature of stellate cells during firing field crossings consisted of a slow depolarization driving spike output. This was best predicted by network models in which neurons receive sustained depolarizing synaptic input during a field crossing, such as continuous attractor network models of grid cell firing. Another key feature of the data, phase precession of intracellular theta oscillations and spiking with respect to extracellular theta oscillations, was best captured by an oscillatory interference model. Thus, these findings provide crucial new information for a quantitative understanding of the cellular basis of spatial navigation in the entorhinal cortex.
Cortical pyramidal neurons receive thousands of synaptic inputs arriving at different dendritic locations with varying degrees of temporal synchrony. It is not known if different locations along ...single cortical dendrites integrate excitatory inputs in different ways. Here we have used two-photon glutamate uncaging and compartmental modeling to reveal a gradient of nonlinear synaptic integration in basal and apical oblique dendrites of cortical pyramidal neurons. Excitatory inputs to the proximal dendrite sum linearly and require precise temporal coincidence for effective summation, whereas distal inputs are amplified with high gain and integrated over broader time windows. This allows distal inputs to overcome their electrotonic disadvantage, and become surprisingly more effective than proximal inputs at influencing action potential output. Thus, single dendritic branches can already exhibit nonuniform synaptic integration, with the computational strategy shifting from temporal coding to rate coding along the dendrite.
► Single cortical dendrites exhibit a gradient of nonlinear synaptic integration ► Input gain and temporal summation increase from proximal to distal locations ► Distal inputs can exert more influence on action AP output than proximal inputs ► Proximal inputs are more suited for temporal coding and distal inputs for rate coding
The activity of the cerebral cortex is thought to depend on the precise relationship between synaptic excitation and inhibition. In the visual cortex, in particular, intracellular measurements have ...related response selectivity to coordinated increases in excitation and inhibition. These measurements, however, have all been made during anaesthesia, which strongly influences cortical state and therefore sensory processing. The synaptic activity that is evoked by visual stimulation during wakefulness is unknown. Here we measured visually evoked responses--and the underlying synaptic conductances--in the visual cortex of anaesthetized and awake mice. Under anaesthesia, responses could be elicited from a large region of visual space and were prolonged. During wakefulness, responses were more spatially selective and much briefer. Whole-cell patch-clamp recordings of synaptic conductances showed a difference in synaptic inhibition between the two conditions. Under anaesthesia, inhibition tracked excitation in amplitude and spatial selectivity. By contrast, during wakefulness, inhibition was much stronger than excitation and had extremely broad spatial selectivity. We conclude that during wakefulness, cortical responses to visual stimulation are dominated by synaptic inhibition, restricting the spatial spread and temporal persistence of neural activity. These results provide a direct glimpse of synaptic mechanisms that control sensory responses in the awake cortex.
All-Optical Interrogation of Neural Circuits Emiliani, Valentina; Cohen, Adam E; Deisseroth, Karl ...
The Journal of neuroscience,
10/2015, Letnik:
35, Številka:
41
Journal Article
Recenzirano
Odprti dostop
There have been two recent revolutionary advances in neuroscience: First, genetically encoded activity sensors have brought the goal of optical detection of single action potentials in vivo within ...reach. Second, optogenetic actuators now allow the activity of neurons to be controlled with millisecond precision. These revolutions have now been combined, together with advanced microscopies, to allow "all-optical" readout and manipulation of activity in neural circuits with single-spike and single-neuron precision. This is a transformational advance that will open new frontiers in neuroscience research. Harnessing the power of light in the all-optical approach requires coexpression of genetically encoded activity sensors and optogenetic probes in the same neurons, as well as the ability to simultaneously target and record the light from the selected neurons. It has recently become possible to combine sensors and optical strategies that are sufficiently sensitive and cross talk free to enable single-action-potential sensitivity and precision for both readout and manipulation in the intact brain. The combination of simultaneous readout and manipulation from the same genetically defined cells will enable a wide range of new experiments as well as inspire new technologies for interacting with the brain. The advances described in this review herald a future where the traditional tools used for generations by physiologists to study and interact with the brain-stimulation and recording electrodes-can largely be replaced by light. We outline potential future developments in this field and discuss how the all-optical strategy can be applied to solve fundamental problems in neuroscience.
This review describes the nexus of dramatic recent developments in optogenetic probes, genetically encoded activity sensors, and novel microscopies, which together allow the activity of neural circuits to be recorded and manipulated entirely using light. The optical and protein engineering strategies that form the basis of this "all-optical" approach are now sufficiently advanced to enable single-neuron and single-action potential precision for simultaneous readout and manipulation from the same functionally defined neurons in the intact brain. These advances promise to illuminate many fundamental challenges in neuroscience, including transforming our search for the neural code and the links between neural circuit activity and behavior.
The functional impact of single interneurons on neuronal output in vivo and how interneurons are recruited by physiological activity patterns remain poorly understood. In the cerebellar cortex, ...molecular layer interneurons and their targets, Purkinje cells, receive excitatory inputs from granule cells and climbing fibers. Using dual patch-clamp recordings from interneurons and Purkinje cells in vivo, we probe the spatiotemporal interactions between these circuit elements. We show that single interneuron spikes can potently inhibit Purkinje cell output, depending on interneuron location. Climbing fiber input activates many interneurons via glutamate spillover but results in inhibition of those interneurons that inhibit the same Purkinje cell receiving the climbing fiber input, forming a disinhibitory motif. These interneuron circuits are engaged during sensory processing, creating diverse pathway-specific response functions. These findings demonstrate how the powerful effect of single interneurons on Purkinje cell output can be sculpted by various interneuron circuit motifs to diversify cerebellar computations.
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•Single spikes in single interneurons can inhibit Purkinje cell firing in vivo•Climbing fiber input excites or inhibits interneurons via glutamate spillover in vivo•Interneuron circuit motifs are spatially organized by depth in the molecular layer•These direct and disinhibitory motifs can explain the responses to sensory stimulation
Using dual two-photon guided patch-clamp recordings from molecular-layer interneurons and Purkinje cells in vivo, Arlt and Häusser show that single-interneuron spikes can potently inhibit Purkinje cell output and uncover the microcircuit logic by which interneurons and their targets are recruited by different excitatory afferents.
Information processing in the brain depends on the integration of synaptic input distributed throughout neuronal dendrites. Dendritic integration is a hierarchical process, proposed to be equivalent ...to integration by a multilayer network, potentially endowing single neurons with substantial computational power. However, whether neurons can learn to harness dendritic properties to realize this potential is unknown. Here, we develop a learning rule from dendritic cable theory and use it to investigate the processing capacity of a detailed pyramidal neuron model. We show that computations using spatial or temporal features of synaptic input patterns can be learned, and even synergistically combined, to solve a canonical nonlinear feature-binding problem. The voltage dependence of the learning rule drives coactive synapses to engage dendritic nonlinearities, whereas spike-timing dependence shapes the time course of subthreshold potentials. Dendritic input-output relationships can therefore be flexibly tuned through synaptic plasticity, allowing optimal implementation of nonlinear functions by single neurons.
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•A learning rule derived from cable theory is used in biophysical simulations•Pyramidal cell I/O functions can be optimized for computation by synaptic plasticity•Active and passive dendritic mechanisms enhance input pattern discrimination•Single neurons can learn network-level computations simply by tuning synaptic weights
Bicknell and Häusser develop a theoretical approach for investigating single-neuron computation and learning. By deriving a plasticity rule that optimally adjusts the strengths of interacting synapses to control somatic spiking, they show that neurons can learn to harness the biophysical properties of their dendrites to perform nonlinear computations.
The conventional view of dendritic function is that dendrites collect synaptic input and deliver it to the soma. This view has been challenged in recent years by new results demonstrating that ...dendrites can act as independent processing and signalling units, performing local computations that are then broadcast to the rest of the neuron, or to other neurons via dendritic transmitter and neuromodulator release. Here we describe these findings and discuss the notion that the single dendritic branch may represent a fundamental unit of signalling in the mammalian nervous system. This view proposes that the dendritic branch is a basic organizational unit for integrating synaptic input, implementing synaptic and homeostatic plasticity, and controlling local cellular processes such as protein translation.
Optogenetics — The Might of Light Hausser, Michael
The New England journal of medicine,
10/2021, Letnik:
385, Številka:
17
Journal Article
Recenzirano
This year’s Lasker Basic Medical Research Award goes to Drs. Deisseroth, Hegemann, and Oesterhelt for their contributions to developing optogenetics: a means of activating or suppressing neuronal ...activity and thus an indispensable tool for neuroscientists.
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