Animals adapt their behavior in response to informative sensory cues using multiple brain circuits. The activity of midbrain dopaminergic neurons is thought to convey a critical teaching signal: ...reward-prediction error. Although reward-prediction error signals are thought to be essential to learning, little is known about the dynamic changes in the activity of midbrain dopaminergic neurons as animals learn about novel sensory cues and appetitive rewards. Here we describe a large dataset of cell-attached recordings of identified dopaminergic neurons as naive mice learned a novel cue-reward association. During learning midbrain dopaminergic neuron activity results from the summation of sensory cue-related and movement initiation-related response components. These components are both a function of reward expectation yet they are dissociable. Learning produces an increasingly precise coordination of action initiation following sensory cues that results in apparent reward-prediction error correlates. Our data thus provide new insights into the circuit mechanisms that underlie a critical computation in a highly conserved learning circuit.
For goal-directed behaviour it is critical that we can both select the appropriate action and learn to modify the underlying movements (for example, the pitch of a note or velocity of a reach) to ...improve outcomes. The basal ganglia are a critical nexus where circuits necessary for the production of behaviour, such as the neocortex and thalamus, are integrated with reward signalling to reinforce successful, purposive actions. The dorsal striatum, a major input structure of basal ganglia, is composed of two opponent pathways, direct and indirect, thought to select actions that elicit positive outcomes and suppress actions that do not, respectively. Activity-dependent plasticity modulated by reward is thought to be sufficient for selecting actions in the striatum. Although perturbations of basal ganglia function produce profound changes in movement, it remains unknown whether activity-dependent plasticity is sufficient to produce learned changes in movement kinematics, such as velocity. Here we use cell-type-specific stimulation in mice delivered in closed loop during movement to demonstrate that activity in either the direct or indirect pathway is sufficient to produce specific and sustained increases or decreases in velocity, without affecting action selection or motivation. These behavioural changes were a form of learning that accumulated over trials, persisted after the cessation of stimulation, and were abolished in the presence of dopamine antagonists. Our results reveal that the direct and indirect pathways can each bidirectionally control movement velocity, demonstrating unprecedented specificity and flexibility in the control of volition by the basal ganglia.
Animals infer when and where a reward is available from experience with informative sensory stimuli and their own actions. In vertebrates, this is thought to depend upon the release of dopamine from ...midbrain dopaminergic neurons. Studies of the role of dopamine have focused almost exclusively on their encoding of informative sensory stimuli; however, many dopaminergic neurons are active just prior to movement initiation, even in the absence of sensory stimuli. How should current frameworks for understanding the role of dopamine incorporate these observations? To address this question, we review recent anatomical and functional evidence for action-related dopamine signaling. We conclude by proposing a framework in which dopaminergic neurons encode subjective signals of action initiation to solve an internal credit assignment problem.
Coddington and Dudman review evidence for movement-related signaling in midbrain dopamine neurons. They outline a framework for understanding such signals in the context of anatomical connectivity with descending motor systems and propose roles of phasic dopamine activity in modulating action.
Highlights • Vertebrates are remarkable for their ability to select and execute motor skill. • Motor skill is defined by flexibility of execution while obtaining reliable outcomes. • Basal ganglia ...both command movement and control movement vigor in rodents. • Basal ganglia mediate implicit motivation in primates.
Efficient retrograde access to projection neurons for the delivery of sensors and effectors constitutes an important and enabling capability for neural circuit dissection. Such an approach would also ...be useful for gene therapy, including the treatment of neurodegenerative disorders characterized by pathological spread through functionally connected and highly distributed networks. Viral vectors, in particular, are powerful gene delivery vehicles for the nervous system, but all available tools suffer from inefficient retrograde transport or limited clinical potential. To address this need, we applied in vivo directed evolution to engineer potent retrograde functionality into the capsid of adeno-associated virus (AAV), a vector that has shown promise in neuroscience research and the clinic. A newly evolved variant, rAAV2-retro, permits robust retrograde access to projection neurons with efficiency comparable to classical synthetic retrograde tracers and enables sufficient sensor/effector expression for functional circuit interrogation and in vivo genome editing in targeted neuronal populations.
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•AAV can be endowed with robust retrograde functionality through directed evolution•Up to two orders of magnitude increase in retrograde transport over existing variants•Efficiency comparable to synthetic tracers•Sufficient payload expression for circuit interrogation and gene manipulation
Projection neurons are a critical component of large-scale networks distributing the results of local circuit computations between distant brain regions, but their specific contribution is often hard to pinpoint because of the difficulty of gaining selective genetic access. Tervo et al. introduce a designer variant of adeno-associated virus, rAAV2-retro, that allows for efficient mapping, monitoring, and manipulation of projection neurons.
Recent success in training artificial agents and robots derives from a combination of direct learning of behavioural policies and indirect learning through value functions
. Policy learning and value ...learning use distinct algorithms that optimize behavioural performance and reward prediction, respectively. In animals, behavioural learning and the role of mesolimbic dopamine signalling have been extensively evaluated with respect to reward prediction
; however, so far there has been little consideration of how direct policy learning might inform our understanding
. Here we used a comprehensive dataset of orofacial and body movements to understand how behavioural policies evolved as naive, head-restrained mice learned a trace conditioning paradigm. Individual differences in initial dopaminergic reward responses correlated with the emergence of learned behavioural policy, but not the emergence of putative value encoding for a predictive cue. Likewise, physiologically calibrated manipulations of mesolimbic dopamine produced several effects inconsistent with value learning but predicted by a neural-network-based model that used dopamine signals to set an adaptive rate, not an error signal, for behavioural policy learning. This work provides strong evidence that phasic dopamine activity can regulate direct learning of behavioural policies, expanding the explanatory power of reinforcement learning models for animal learning
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Progressive depletion of midbrain dopamine neurons (PDD) is associated with deficits in the initiation, speed, and fluidity of voluntary movement. Models of basal ganglia function focus on initiation ...deficits; however, it is unclear how they account for deficits in the speed or amplitude of movement (vigor). Using an effort-based operant conditioning task for head-fixed mice, we discovered distinct functional classes of neurons in the dorsal striatum that represent movement vigor. Mice with PDD exhibited a progressive reduction in vigor, along with a selective impairment of its neural representation in striatum. Restoration of dopaminergic tone with a synthetic precursor ameliorated deficits in movement vigor and its neural representation, while suppression of striatal activity during movement was sufficient to reduce vigor. Thus, dopaminergic input to the dorsal striatum is indispensable for the emergence of striatal activity that mediates adaptive changes in movement vigor. These results suggest refined intervention strategies for Parkinson’s disease.
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•A mouse model of Parkinson’s disease produces a persistent reduction in effort•The neural representation of movement vigor in striatum requires dopamine•Acute suppression of striatal activity during execution enervates movement•Dopamine repletion is sufficient to restore striatal activity and invigorate movement
Movement vigor, reduced in Parkinson’s disease, is regulated by dopamine-dependent activity in the striatum.
Neuronal cell types are the nodes of neural circuits that determine the flow of information within the brain. Neuronal morphology, especially the shape of the axonal arbor, provides an essential ...descriptor of cell type and reveals how individual neurons route their output across the brain. Despite the importance of morphology, few projection neurons in the mouse brain have been reconstructed in their entirety. Here we present a robust and efficient platform for imaging and reconstructing complete neuronal morphologies, including axonal arbors that span substantial portions of the brain. We used this platform to reconstruct more than 1,000 projection neurons in the motor cortex, thalamus, subiculum, and hypothalamus. Together, the reconstructed neurons constitute more than 85 meters of axonal length and are available in a searchable online database. Axonal shapes revealed previously unknown subtypes of projection neurons and suggest organizational principles of long-range connectivity.
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•Efficient pipeline for brain-wide imaging and reconstruction of individual neurons•Searchable database containing more than 1,000 fully reconstructed neurons•In some brain areas projection neurons fall into discrete classes•Other projection neurons form a continuum of projection types
An efficient pipeline for brain-wide imaging and morphological reconstruction of individual neurons, including long-range projection neurons, is presented along with a searchable database containing more than 1,000 fully reconstructed neurons in the mouse neocortex, hippocampus, thalamus, and hypothalamus.
The thalamus is the central communication hub of the forebrain and provides the cerebral cortex with inputs from sensory organs, subcortical systems and the cortex itself. Multiple thalamic regions ...send convergent information to each cortical region, but the organizational logic of thalamic projections has remained elusive. Through comprehensive transcriptional analyses of retrogradely labeled thalamic neurons in adult mice, we identify three major profiles of thalamic pathways. These profiles exist along a continuum that is repeated across all major projection systems, such as those for vision, motor control and cognition. The largest component of gene expression variation in the mouse thalamus is topographically organized, with features conserved in humans. Transcriptional differences between these thalamic neuronal identities are tied to cellular features that are critical for function, such as axonal morphology and membrane properties. Molecular profiling therefore reveals covariation in the properties of thalamic pathways serving all major input modalities and output targets, thus establishing a molecular framework for understanding the thalamus.
The ability to image neurons anywhere in the mammalian brain is a major goal of optical microscopy. Here we describe a minimally invasive microendoscopy system for studying the morphology and ...function of neurons at depth. Utilizing a guide cannula with an ultrathin wall, we demonstrated in vivo two-photon fluorescence imaging of deeply buried nuclei such as the striatum (2.5 mm depth), substantia nigra (4.4 mm depth) and lateral hypothalamus (5.0 mm depth) in mouse brain. We reported, for the first time, the observation of neuronal activity with subcellular resolution in the lateral hypothalamus and substantia nigra of head-fixed awake mice.
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