Fear conditioning is a form of associative learning that is known to involve different brain areas, notably the amygdala, the prefrontal cortex and the periaqueductal grey (PAG). Here, we describe the functional role of pathways that link the cerebellum with the fear network. We found that the cerebellar fastigial nucleus (FN) sends glutamatergic projections to vlPAG that synapse onto glutamatergic and GABAergic vlPAG neurons. Chemogenetic and optogenetic manipulations revealed that the FN-vlPAG pathway controls bi-directionally the strength of the fear memories, indicating an important role in the association of the conditioned and unconditioned stimuli, a function consistent with vlPAG encoding of fear prediction error. Moreover, FN-vlPAG projections also modulate extinction learning. We also found a FN-parafascicular thalamus pathway, which may relay cerebellar influence to the amygdala and modulates anxiety behaviors. Overall, our results reveal multiple contributions of the cerebellum to the emotional system.

Microglia sense the changes in their environment. How microglia actively translate these changes into suitable cues to adapt brain physiology is unknown. We reveal an activity-dependent regulation of cortical inhibitory synapses plasticity by microglia, driven by purinergic signaling acting on P2RX7 and mediated by microglia-derived TNFα. We demonstrate that sleep induces this microglia-dependent inhibitory plasticity by promoting synaptic enrichment of GABAARs. We further show that in turn, microglia-specific depletion of TNFα alters slow waves during NREM sleep and blunts sleep-dependent memory consolidation. Together, our results reveal that microglia orchestrate sleep-intrinsic plasticity of inhibitory synapses, ultimately sculpting sleep slow waves and memory.

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Activation of NMDA receptors (NMDARs) has been proposed to be a key component of single neuron computations in vivo. However is unknown if specific mechanisms control the function of such receptors and modulate input-output transformations performed by cortical neurons under in vivo-like conditions. Here we found that in layer 2/3 pyramidal neurons (L2/3 PNs), repeated synaptic stimulation results in an activity-dependent decrease in NMDARs activity by vesicular zinc. Such a mechanism shifted the threshold for dendritic non-linearities and strongly reduced LTP induction. Modulation of NMDARs was cell- and pathway-specific, being present selectively in L2/3-L2/3 connections but absent in ascending bottom-up inputs originating from L4 neurons. Numerical simulations highlighted that activity-dependent modulation of NMDARs has an important influence in dendritic computations endowing L2/3 PN dendrites with the ability to sustain dendritic non-linear integrations constant across different regimes of synaptic activity like those found in vivo. The present results therefore provide a new perspective on the action of vesicular zinc in cortical circuits by highlighting the role of this endogenous ion in normalizing dendritic integration of PNs during a constantly changing synaptic input pattern.

Dystonia is often associated with functional alterations in the cerebello-thalamic pathways, which have been proposed to contribute to the disorder by propagating pathological firing patterns to the forebrain. Here, we examined the function of the cerebello-thalamic pathways in a model of DYT25 dystonia. DYT25 (Gnal+/−) mice carry a heterozygous knockout mutation of the Gnal gene, which notably disrupts striatal function, and systemic or striatal administration of oxotremorine to these mice triggers dystonic symptoms. Our results reveal an increased cerebello-thalamic excitability in the presymptomatic state. Following the first dystonic episode, Gnal+/- mice in the asymptomatic state exhibit a further increase of the cerebello-thalamo-cortical excitability, which is maintained after θ-burst stimulations of the cerebellum. When administered in the symptomatic state induced by a cholinergic activation, these stimulations decreased the cerebello-thalamic excitability and reduced dystonic symptoms. In agreement with dystonia being a multiregional circuit disorder, our results suggest that the increased cerebello-thalamic excitability constitutes an early endophenotype, and that the cerebellum is a gateway for corrective therapies via the depression of cerebello-thalamic pathways.

10Fear conditioning is a form of associative learning that is known to involve brain areas, notably the 11 amygdala, the prefrontal cortex and the periaqueductal grey (PAG). Here, we describe the functional 12 role of pathways that link the cerebellum with the fear network. We found that the cerebellar 13 fastigial nucleus (FN) sends glutamatergic projections to vlPAG that synapse onto glutamatergic and 14 GABAergic vlPAG neurons. Chemogenetic and optogenetic manipulations revealed that the FN-vlPAG 15 pathway controls bi-directionally the strength of the fear memory, indicating a role in the association 16 of the conditioned and unconditioned stimuli, a function consistent with vlPAG encoding of fear 17 prediction error. In addition, we found that a FN -thalamic parafascicular nucleus pathway, which 18 may relay cerebellar influence to the amygdala, is involved in anxiety and fear expression but not in 19 fear memory. Our results reveal the contributions to the emotional system of the cerebellum, which 20 exerts a potent control on the strength of the fear memory through excitatory FN-vlPAG projections. 21 22 23 Keywords: cerebellum; limbic circuits; fear memory, chemogenetics, electrophysiology 24 vermis, in relation to negative emotions (e.g. during recall of self-generated emotional episodes 20 ). 50 Consistent with this, localized cerebellar lesions, principally in the midline vermis, account in large 51 part for the emotional disturbances, inappropriate behavior and changes in affect, which are 52 collectively termed the "cerebellar cognitive affective syndrome" 21 and reported in cerebellar 53 patients. Several studies have shown that the cerebellum has functional connections from fear-54 related areas including the PAG, the amygdala, and the prefrontal cortex [22][23][24][25] . In accordance with the 55 existence of such connections, Pavlovian fear conditioning affects cerebellar plasticity 26 , post-56 conditioning cerebellar inactivation affects memory consolidation 27 , and cerebellar lesions -or 57 inactivation-modulate freezing 24,28 ; however, the pathways by which the cerebellum participates to 58 fear learning or expression remain undefined. 59. The cerebellar vermis, which is most consistently associated with emotional pathologies and fear 60 expression 20,24,29 , projects to the fastigial nucleus (FN), a deep cerebellar nucleus (DCN) which 61 projects to many targets from the spinal cord to the diencephalon 22 . The purpose of the present 62 study is to study the contribution of specific FN output pathways to fear learning. Using 63 neuroanatomical tracings, chemogenetic modulation of the cerebellar input to the vlPAG and to the 64 BLA during fear conditioning, optogenetics and extracellular electrophysiological recordings in awake 65 freely moving animals, we demonstrate the contribution of the cerebellum to fear learning through 66 its inputs to the vlPAG. 67 68 4 69 70Results 71 Neuroanatomical link between the cerebellum and vlPAG 72In order to examine cerebellar projections to areas involve...

SUMMARYThe contribution of cerebellum to motor learning is often considered to be limited to adaptation, a short-timescale tuning of reflexes and previous learned skills. Yet, the cerebellum is reciprocally connected to two main players of motor learning, the motor cortex and the basal ganglia, via the ventral and midline thalamus respectively. Here, we evaluated the contribution of cerebellar neurons projecting to these thalamic nuclei in a skilled locomotion task in mice. In the cerebellar nuclei, we found task-specific neuronal activities during the task, and lasting changes after the task suggesting an offline processing of task-related information. Using pathway-specific inhibition, we found that dentate neurons projecting to the midline thalamus contribute to learning and retrieval, while interposed neurons projecting to the ventral thalamus contribute to the offline consolidation of savings. Our results thus show that two parallel cerebello-thalamic pathways perform distinct computations operating on distinct timescales in motor learning.

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