Perturbation to the cerebellum can lead to motor dysfunction, cognitive deficits, and behavioral inflexibility. Here we report that a cerebellum-specific transgenic mouse model with disrupted Purkinje cell function shows unexpectedly accelerated learning on a sensory evidence-accumulation task, as well as enhanced sensory reactivity to touch and auditory cues. Computational latent-state analysis of behavior revealed that accelerated learning was associated with enhanced focus on current over past trials. Learning was also accelerated by providing cue-locked optogenetic stimulation of Purkinje cells, but unaffected by continuous optogenetic interference with Purkinje cell activity. Both transgenic and optogenetically-boosted mice showed prolonged electrophysiological activity in Purkinje-cell complex spikes and anterior cingulate cortex. We suggest that cerebellar activity may shape evidence-accumulation learning by enhancing task focus and neocortical processing of current experience.

Cannibalism in the animal kingdom is widespread and well characterized, whereas the occurrence of human cannibalism has been controversial. Evidence points to cannibalism in aboriginal societies, prehistory, and the closely related chimpanzees. We assembled a non-comprehensive list (121 offenders, ~631 victims) of cannibalistic homicides in modern societies (since 1900) through internet-searches, publications, and expert questioning. Cannibalistic homicides were exceedingly rare, and often sex-related. Cannibalistic offenders were mainly men and older than offenders of non-cannibalistic homicides, whereas victims were comparatively young. Cannibalistic offenders typically killed manually (stabbing, strangulating, and beating) rather than using a gun. Furthermore, they killed more strangers and fewer intimates than conventional offenders. Human cannibals, similar to cannibalism in other species, killed and ate conspecifics, occasionally vomited and only rarely (2.5% of victims) ate kin. Interestingly, cannibalistic offenders who killed their blood relatives had more severe mental problems than non-kin-cannibals. We conclude that cannibalistic homicides have a unique pattern of murder methods, offenders, and victims.

To make successful evidence-based decisions, the brain must rapidly and accurately transform sensory inputs into specific goal-directed behaviors. Most experimental work on this subject has focused on forebrain mechanisms. Using a novel evidence-accumulation task for mice, we performed recording and perturbation studies of crus I of the lateral posterior cerebellum, which communicates bidirectionally with numerous forebrain regions. Cerebellar inactivation led to a reduction in the fraction of correct trials. Using two-photon fluorescence imaging of calcium, we found that Purkinje cell somatic activity contained choice/evidence-related information. Decision errors were represented by dendritic calcium spikes, which in other contexts are known to drive cerebellar plasticity. We propose that cerebellar circuitry may contribute to computations that support accurate performance in this perceptual decision-making task.

Cerebellar climbing-fiber-mediated complex spikes originate from neurons in the inferior olive (IO), are critical for motor coordination, and are central to theories of cerebellar learning. Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels expressed by IO neurons have been considered as pacemaker currents important for oscillatory and resonant dynamics. Here, we demonstrate that in vitro, network actions of HCN1 channels enable bidirectional glutamatergic synaptic responses, while local actions of HCN1 channels determine the timing and waveform of synaptically driven action potentials. These roles are distinct from, and may complement, proposed pacemaker functions of HCN channels. We find that in behaving animals HCN1 channels reduce variability in the timing of cerebellar complex spikes, which serve as a readout of IO spiking. Our results suggest that spatially distributed actions of HCN1 channels enable the IO to implement network-wide rules for synaptic integration that modulate the timing of cerebellar climbing fiber signals.

Serotonin plays an important role of controlling the physiology of the cerebellum. However, serotonin receptor expression has not been fully studied in the developing cerebellum. We have recently shown that cerebellar granule cells transiently express 5-HT3 receptors. In the present study, we investigate expression of 5-HT1 and 5-HT2 receptors in the mouse cerebellum both during postnatal development and in juvenile mice. Here, we show for the first time that 5-HT1A and 5-HT2A receptors are present on cerebellar granule cells with a distinct temporal expression pattern: 5-HT1A receptors are expressed only during the first 2 weeks, while 5-HT2A receptor expression persists until at least 8 weeks after birth. Because of its prolonged expression pattern, we investigated the electrophysiological properties of the 5-HT2A receptor. 5-HT2A receptors expressed by cerebellar granule cells promote stability by reducing variability of the synaptic response, and they modulate the paired-pulse ratio of the parallel fibre-Purkinje cell synapse. Furthermore, pharmacological block of 5-HT2A receptors enhances short-term synaptic plasticity at the parallel fibre-Purkinje cell synapse. We thus show a novel role for serotonin in controlling function of the cerebellum via 5-HT2A receptors expressed by cerebellar granule cells.

In adult animals, the cerebellum is richly innervated by serotonin: serotonergic fibres are the third main afferent fibres into the cerebellum. However, the physiology of the serotonergic system and its functional significance are not fully known during development in the cerebellum. In this review we will focus on the serotonergic regulation of the cerebellum during postnatal development. We hypothesize a powerful role for serotonin in the physiology of the developing cerebellum. A presumably tonic activation of serotonin receptors by binding of serotonin becomes specific by temporally and spatially restricted expression of different serotonin receptors, each with their own (sometimes antagonizing) functions. During the first postnatal week, activation of 5-HT₁ receptors expressed by both granule cells and Purkinje cells stimulates dendritic growth and synapse formation. Later, activation of 5-HT₃ receptors expressed by granule cells limits dendritic growth of Purkinje cells via mediating the secretion of reelin, influences physiological maturation of Purkinje cells, modulates synaptic plasticity at parallel fibre-Purkinje cell synapses and thereby affects competition with the climbing fibres on Purkinje cell dendrites resulting in proper climbing fibre elimination. Last, activation of 5-HT₂ receptors expressed by granule cells and Purkinje cells both during late postnatal development and in the mature cerebellum promotes the stability of synaptic activity. Thus, we propose that serotonin controls cerebellar development in three phases: (1) stimulation of dendritic growth and formation of synapses, (2) hard-wiring of neuronal connections with limits to dendritic growth but ensuring synaptic plasticity, and (3) stabilization of synapses. Taken together, serotonin receptors expressed by different cells in the cerebellum have a specialized role during postnatal development, but with some similar main effects. Distinct spatial and temporal expression of these receptors gives serotonin a powerful and specific role in cerebellar development.

Functional serotonin 3 (5-HT3) receptors are transiently expressed by cerebellar granule cells during early postnatal development, where they modulate short-term synaptic plasticity at the parallel fibre-Purkinje cell synapse. Here, we show that serotonin controls maturation of Purkinje cells in the mouse cerebellum. The 5-HT3 receptors regulate morphological maturation of Purkinje cells during early postnatal development, and this effect is mediated by the glycoprotein reelin. Using whole-cell patch-clamp recordings we also investigated physiological development of Purkinje cells in 5-HT3A receptor knockout mice during early postnatal development, and found abnormal physiological maturation, characterized by a more depolarized resting membrane potential, an increased input resistance and the ability to fire action potentials upon injection of a depolarizing current at an earlier age. Furthermore, short-term synaptic plasticity was impaired at both the parallel fibre-Purkinje cell and the climbing fibre-Purkinje cell synapses, and both the amplitude and the frequency of spontaneous miniature events recorded from Purkinje cells were increased. The expedited morphological and physiological maturation affects the whole cerebellar cortical network, as indicated by delayed climbing fibre elimination in 5-HT3A receptor knockout mice. There was no difference between wild-type and 5-HT3A receptor knockout mice in any of the morphological or physiological properties described above at later ages, indicating a specific time window during which serotonin regulates postnatal development of the cerebellum via 5-HT3 receptors expressed by granule cells.

The serotonin 5-HT(3) receptor is the only ligand-gated ion channel activated by serotonin and is expressed by GABAergic interneurons in many brain regions, including the cortex, amygdala and hippocampus. Furthermore, 5-HT(3) receptors are expressed by glutamatergic Cajal-Retzius cells in the cerebral cortex. We used 5-HT(3A)/enhanced green fluorescent protein (EGFP) transgenic mice to show that 5-HT(3) receptors are also ubiquitously expressed by glutamatergic granule cells in the cerebellum during the first three postnatal weeks. Using whole-cell patch clamp recordings, we show that local application of either serotonin or the selective 5-HT(3) receptor agonist SR57227A to granule cells results in a small inward current, demonstrating a post- and/or extrasynaptic localisation of the 5-HT(3) receptors. Functional 5-HT(3) receptors were also observed presynaptically at the parallel fibre-Purkinje cell synapse. Pharmacological block using the selective 5-HT(3) receptor antagonist tropisetron induced a reduction in the frequency of miniature synaptic events recorded from Purkinje cells. Paired-pulse stimulation of parallel fibres on whole-cell voltage clamped Purkinje cells from 1-week-old mice did not yet show synaptic plasticity. In the presence of tropisetron, the parallel fibre-Purkinje cell synapse showed paired-pulse depression. Taken together, these results show that functional 5-HT(3) receptors are present during early postnatal development in the cerebellum, where they modulate synaptic plasticity.