Megan R. Carey

Activity-Dependent Regulation of Synapses by Retrograde Messengers

Throughout the brain, postsynaptic neurons release substances from their cell bodies and dendrites that regulate the strength of the synapses they receive. Diverse chemical messengers have been implicated in retrograde signaling from postsynaptic neurons to presynaptic boutons. Here, we provide an overview of the signaling systems that lead to rapid changes in synaptic strength. We consider the capabilities, specializations, and physiological roles of each type of signaling system.

The Representation of Time for Motor Learning

We have identified factors that control precise motor timing by studying learning in smooth pursuit eye movements. Monkeys tracked a target that moved horizontally for a fixed time interval before changing direction through the addition of a vertical component of motion. After repeated presentations of the same target trajectory, infrequent probe trials of purely horizontal target motion evoked a vertical eye movement around the time when the change in target direction would have occurred. The pursuit system timed the vertical eye movement by keeping track of the duration of horizontal target motion and by measuring the distance the target traveled before changing direction, but not by learning the position in space where the target changed direction. We conclude that high temporal precision in motor output relies on multiple signals whose contributions to timing vary according to task requirements.

Linking genetically defined neurons to behavior through a broadly applicable silencing allele.

Tools for suppressing synaptic transmission gain power when able to target highly selective neuron subtypes, thereby sharpening attainable links between neuron type, behavior, and disease; and when able to silence most any neuron subtype, thereby offering broad applicability. Here, we present such a tool, RC::PFtox, that harnesses breadth in scope along with high cell-type selection via combinatorial gene expression to deliver tetanus toxin light chain (tox), an inhibitor of vesicular neurotransmission. When applied in mice, we observed cell-type-specific disruption of vesicle exocytosis accompanied by loss of excitatory postsynaptic currents and commensurately perturbed behaviors. Among various test populations, we applied RC::PFtox to silence serotonergic neurons, en masse or a subset defined combinatorially. Of the behavioral phenotypes observed upon en masse serotonergic silencing, only one mapped to the combinatorially defined subset. These findings provide evidence for separability by genetic lineage of serotonin-modulated behaviors; collectively, these findings demonstrate broad utility of RC::PFtox for dissecting neuron functions.

Embarrassed, but Not Depressed: Eye Opening Lessons for Cerebellar Learning

Cellular mechanisms of plasticity must be linked to circuit mechanisms of behavior to understand learning and memory. Studies of how learning occurs in cerebellar circuits for classical conditioning of eyeblinks are meeting this challenge admirably. Several recent papers have added to the richness of our understanding of cerebellar learning by correlating complex aspects of learned behaviors with hitherto underappreciated properties of the cerebellar circuit.

Instructive signals for motor learning from visual cortical area MT.

Sensory error signals have long been proposed to act as instructive signals to guide motor learning. Here we have exploited the temporal specificity of learning in smooth pursuit eye movements and the well-defined anatomical structure of the neural circuit for pursuit to identify a part of sensory cortex that provides instructive signals for motor learning in monkeys. We show that electrical microstimulation in the motion-sensitive middle temporal area (MT) of extrastriate visual cortex instructs learning in smooth eye movements in a way that closely mimics the learning instructed by real visual motion. We conclude that MT provides instructive signals for motor learning in smooth pursuit eye movements under natural conditions, suggesting a similar role for sensory cortices in many kinds of learned behaviors.

Presynaptic CB1 Receptors Regulate Synaptic Plasticity at Cerebellar Parallel Fiber Synapses

Endocannabinoids are potent regulators of synaptic strength. They are generally thought to modify neurotransmitter release through retrograde activation of presynaptic type 1 cannabinoid receptors (CB1Rs). In the cerebellar cortex, CB1Rs regulate several forms of synaptic plasticity at synapses onto Purkinje cells, including presynaptically expressed short-term plasticity and, somewhat paradoxically, a postsynaptic form of long-term depression (LTD). Here we have generated mice in which CB1Rs were selectively eliminated from cerebellar granule cells, whose axons form parallel fibers. We find that in these mice, endocannabinoid-dependent short-term plasticity is eliminated at parallel fiber, but not inhibitory interneuron, synapses onto Purkinje cells. Further, parallel fiber LTD is not observed in these mice, indicating that presynaptic CB1Rs regulate long-term plasticity at this synapse.

Locomotor activity modulates associative learning in mouse cerebellum

Changes in behavioral state can profoundly influence brain function. Here we show that behavioral state modulates performance in delay eyeblink conditioning, a cerebellum-dependent form of associative learning. Increased locomotor speed in head-fixed mice drove earlier onset of learning and trial-by-trial enhancement of learned responses that were dissociable from changes in arousal and independent of sensory modality. Eyelid responses evoked by optogenetic stimulation of mossy fiber inputs to the cerebellum, but not at sites downstream, were positively modulated by ongoing locomotion. Substituting prolonged, low-intensity optogenetic mossy fiber stimulation for locomotion was sufficient to enhance conditioned responses. Our results suggest that locomotor activity modulates delay eyeblink conditioning through increased activation of the mossy fiber pathway within the cerebellum. Taken together, these results provide evidence for a novel role for behavioral state modulation in associative learning and suggest a potential mechanism through which engaging in movement can improve an individual’s ability to learn.Albergaria et al. demonstrate that ongoing locomotor activity modulates cerebellum-dependent associative learning. Optogenetic circuit dissection reveals a site of locomotor modulation within the mossy fiber pathway in the cerebellum.

Phosphatase Activity Controls the Ups and Downs of Cerebellar Learning

Investigations of the cellular substrate for cerebellar learning have focused largely on a single form of plasticity, kinase-dependent long-term depression (LTD). In this issue of Neuron, Schonewille et al. provide evidence that calcineurin, a protein phosphatase required for long-term potentiation (LTP) and other cellular processes, may be just as important.