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Serotonin neurons of the dorsal and median raphe nuclei (DR, MR) collectively innervate the entire forebrain and midbrain, modulating diverse physiology and behavior. To gain a fundamental understanding of their molecular heterogeneity, we used plate-based single-cell RNA-sequencing to generate a comprehensive dataset comprising eleven transcriptomically distinct serotonin neuron clusters. Systematic in situ hybridization mapped specific clusters to the principal DR, caudal DR, or MR. These transcriptomic clusters differentially express a rich repertoire of neuropeptides, receptors, ion channels, and transcription factors. We generated novel intersectional viral-genetic tools to access specific subpopulations. Whole-brain axonal projection mapping revealed that DR serotonin neurons co-expressing vesicular glutamate transporter-3 preferentially innervate the cortex, whereas those co-expressing thyrotropin-releasing hormone innervate subcortical regions in particular the hypothalamus. Reconstruction of 50 individual DR serotonin neurons revealed diverse and segregated axonal projection patterns at the single-cell level. Together, these results provide a molecular foundation of the heterogenous serotonin neuronal phenotypes.

Eye movements provide insights about a wide range of brain functions, from sensorimotor integration to cognition; hence, the measurement of eye movements is an important tool in neuroscience research. We describe a method, based on magnetic sensing, for measuring eye movements in head-fixed and freely moving mice. A small magnet was surgically implanted on the eye, and changes in the magnet angle as the eye rotated were detected by a magnetic field sensor. Systematic testing demonstrated high resolution measurements of eye position of <0.1°. Magnetic eye tracking offers several advantages over the well-established eye coil and video-oculography methods. Most notably, it provides the first method for reliable, high-resolution measurement of eye movements in freely moving mice, revealing increased eye movements and altered binocular coordination compared to head-fixed mice. Overall, magnetic eye tracking provides a lightweight, inexpensive, easily implemented, and high-resolution method suitable for a wide range of applications.

Determining the sites and directions of plasticity underlying changes in neural activity and behavior is critical for understanding mechanisms of learning. Identifying such plasticity from neural recording data can be challenging due to feedback pathways that impede reasoning about cause and effect. We studied interactions between feedback, neural activity, and plasticity in the context of a closed-loop motor learning task for which there is disagreement about the loci and directions of plasticity: vestibulo-ocular reflex learning. We constructed a set of circuit models that differed in the strength of their recurrent feedback, from no feedback to very strong feedback. Despite these differences, each model successfully fit a large set of neural and behavioral data. However, the patterns of plasticity predicted by the models fundamentally differed, with the direction of plasticity at a key site changing from depression to potentiation as feedback strength increased. Guided by our analysis, we suggest how such models can be experimentally disambiguated. Our results address a long-standing debate regarding cerebellum-dependent motor learning, suggesting a reconciliation in which learning-related changes in the strength of synaptic inputs to Purkinje cells are compatible with seemingly oppositely directed changes in Purkinje cell spiking activity. More broadly, these results demonstrate how changes in neural activity over learning can appear to contradict the sign of the underlying plasticity when either internal feedback or feedback through the environment is present.

Climbing fiber-driven long-term depression (LTD) of parallel fiber synapses onto cerebellar Purkinje cells has long been investigated as a putative mechanism of motor learning. We recently discovered that the rules governing the induction of LTD at these synapses vary across different regions of the cerebellum. Here, we discuss the design of LTD induction protocols in light of this heterogeneity in plasticity rules. The analytical advantages of the cerebellum provide an opportunity to develop a deeper understanding of how the specific plasticity rules at synapses support the implementation of learning.

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. Here, the authors show that mouse medial entorhinal cortex encodes three-dimensional head movement as well as eye position and velocity. These self-motion signals are represented conjunctively in individual neurons alongside body position, running speed, and azimuthal head direction.

The rate and temporal pattern of neural spiking each have the potential to influence computation. In the cerebellum, it has been hypothesized that the irregularity of interspike intervals in Purkinje cells affects their ability to transmit information to downstream neurons. Accordingly, during oculomotor behavior in mice and rhesus monkeys, mean irregularity of Purkinje cell spiking varied with mean eye velocity. However, moment-to-moment variations revealed a tight correlation between eye velocity and spike rate, with no additional information conveyed by spike irregularity. Moreover, when spike rate and irregularity were independently controlled using optogenetic stimulation, the eye movements elicited were well-described by a linear population rate code with 3–5 ms temporal precision. Biophysical and random-walk models identified biologically realistic parameter ranges that determine whether spike irregularity influences responses downstream. The results demonstrate cerebellar control of movements through a remarkably rapid rate code, with no evidence for an additional contribution of spike irregularity.

▪ Abstract  The cerebellum is an evolutionarily conserved structure critical for motor learning in vertebrates. The model that has influenced much of the work in the field for the past 30 years suggests that motor learning is mediated by a single plasticity mechanism in the cerebellum: long-term depression (LTD) of parallel fiber synapses onto Purkinje cells. However, recent studies of simple behaviors such as the vestibulo-ocular reflex (VOR) indicate that multiple plasticity mechanisms contribute to cerebellum-dependent learning. Multiple plasticity mechanisms may provide the flexibility required to store memories over different timescales, regulate the dynamics of movement, and allow bidirectional changes in movement amplitude. These plasticity mechanisms must act in combination with appropriate information-coding strategies to equip motor-learning systems with the ability to express learning in correct contexts. Studies of the patterns of generalization of motor learning in the VOR provide insight about the coding of information in neurons at sites of plasticity. These principles emerging from studies of the VOR are consistent with results concerning more complex behaviors and thus may reflect general principles of cerebellar function.

Climbing fiber input to the cerebellum is thought to control the induction of motor learning. Here, the authors use a new behavioral training procedure in which climbing fiber signals are eliminated, but learning still occurs. This suggests that other neural signals, possibly Purkinje cell simple spike activity, are sufficient to induce motor learning. The climbing fiber input to the cerebellum from the inferior olive is thought to act as a teacher whose activity controls the induction of motor learning. We designed training conditions that did not elicit instructive signals in the climbing fibers, but nevertheless induced robust and consistent motor learning in the vestibulo-ocular reflex of rhesus monkeys. Our results indicate that instructive signals in the climbing fibers are not necessary for cerebellum-dependent learning. Instead, instructive signals carried by either the climbing fibers or Purkinje cell simple spikes may be sufficient to induce motor learning, with additive effects occurring when both instructive signals are present during training.

The enhancement of associative synaptic plasticity often results in impaired rather than enhanced learning. Previously, we proposed that such learning impairments can result from saturation of the plasticity mechanism (Nguyen-Vu et al., 2017), or, more generally, from a history-dependent change in the threshold for plasticity. This hypothesis was based on experimental results from mice lacking two class I major histocompatibility molecules, MHCI H2-K b and H2-D b (MHCI K b D b−/− ), which have enhanced associative long-term depression at the parallel fiber-Purkinje cell synapses in the cerebellum (PF-Purkinje cell LTD). Here, we extend this work by testing predictions of the threshold metaplasticity hypothesis in a second mouse line with enhanced PF-Purkinje cell LTD, the Fmr1 knockout mouse model of Fragile X syndrome (FXS). Mice lacking Fmr1 gene expression in cerebellar Purkinje cells (L7- Fmr1 KO) were selectively impaired on two oculomotor learning tasks in which PF-Purkinje cell LTD has been implicated, with no impairment on LTD-independent oculomotor learning tasks. Consistent with the threshold metaplasticity hypothesis, behavioral pre-training designed to reverse LTD at the PF-Purkinje cell synapses eliminated the oculomotor learning deficit in the L7- Fmr1 KO mice, as previously reported in MHCI K b D b−/− mice. In addition, diazepam treatment to suppress neural activity and thereby limit the induction of associative LTD during the pre-training period also eliminated the learning deficits in L7- Fmr1 KO mice. These results support the hypothesis that cerebellar LTD-dependent learning is governed by an experience-dependent sliding threshold for plasticity. An increased threshold for LTD in response to elevated neural activity would tend to oppose firing rate stability, but could serve to stabilize synaptic weights and recently acquired memories. The metaplasticity perspective could inform the development of new clinical approaches for addressing learning impairments in autism and other disorders of the nervous system.

The past several years have brought revelations and paradigm shifts in research on the cerebellum. Historically viewed as a simple sensorimotor controller with homogeneous architecture, the cerebellum is increasingly implicated in cognitive functions. It possesses an impressive diversity of molecular, cellular and circuit mechanisms, embedded in a dynamic, recurrent circuit architecture. Recent insights about the diversity and dynamism of the cerebellum provide a roadmap for the next decade of cerebellar research, challenging some old concepts, reinvigorating others and defining major new research directions. Recent research has discovered new connections between cerebellar neurons, revealed abundant inputs related to reward, demonstrated a cellular solution for the temporal credit assignment problem and restructured theories of cerebellar learning.