Explore the vast range of titles available.

Sensory cortices modulate innate behaviors through corticofugal projections targeting phylogenetically-old brainstem nuclei. However, the principles behind the functional connectivity of these projections remain poorly understood. Here, we show that in mice visual cortical neurons projecting to the optic-tract and dorsal-terminal nuclei (NOT-DTN) possess distinct response properties and anatomical connectivity, supporting the adaption of an essential innate eye movement, the optokinetic reflex (OKR). We find that these corticofugal neurons are enriched in specific visual areas, and they prefer temporo-nasal visual motion, matching the direction bias of downstream NOT-DTN neurons. Remarkably, continuous OKR stimulation selectively enhances the activity of these temporo-nasally biased cortical neurons, which can efficiently promote OKR plasticity. Lastly, we demonstrate that silencing downstream NOT-DTN neurons, which project specifically to the inferior olive—a key structure in oculomotor plasticity, impairs the cortical modulation of OKR and OKR plasticity. Our results unveil a direction-selective cortico-brainstem pathway that adaptively modulates innate behaviors. The visual cortex adapts innate behaviors through its corticofugal projections to the brainstem. Here, authors show that this pathway sends unique brainstem neurons distinct behaviorally relevant signals, whose strength can plastically change to promote behavioral adaptation.

Organisms must learn new strategies to adapt to changing environments. Activity in different neurons often exhibits synchronization that can dynamically enhance their communication and might create flexible brain states that facilitate changes in behavior. We studied the role of gamma-frequency (~40 Hz) synchrony between prefrontal parvalbumin (PV) interneurons in mice learning multiple new cue–reward associations. Voltage indicators revealed cell-type-specific increases of cross-hemispheric gamma synchrony between PV interneurons when mice received feedback that previously learned associations were no longer valid. Disrupting this synchronization by delivering out-of-phase optogenetic stimulation caused mice to perseverate on outdated associations, an effect not reproduced by in-phase stimulation or out-of-phase stimulation at other frequencies. Gamma synchrony was specifically required when new associations used familiar cues that were previously irrelevant to behavioral outcomes, not when associations involved new cues or for reversing previously learned associations. Thus, gamma synchrony is indispensable for reappraising the behavioral salience of external cues.Learning new associations that reappraise the behavioral significance of previously irrelevant cues requires gamma-frequency synchronization between parvalbumin interneurons in the left and right prefrontal cortex.

Long-term synaptic plasticity is believed to be the cellular substrate of learning and memory. Synaptic plasticity rules are defined by the specific complement of receptors at the synapse and the associated downstream signaling mechanisms. In young rodents, at the cerebellar synapse between granule cells (GC) and Purkinje cells (PC), bidirectional plasticity is shaped by the balance between transcellular nitric oxide (NO) driven by presynaptic N-methyl-D-aspartate receptor (NMDAR) activation and postsynaptic calcium dynamics. However, the role and the location of NMDAR activation in these pathways is still debated in mature animals. Here, we show in adult rodents that NMDARs are present and functional in presynaptic terminals where their activation triggers NO signaling. In addition, we find that selective genetic deletion of presynaptic, but not postsynaptic, NMDARs prevents synaptic plasticity at parallel fiber-PC (PF-PC) synapses. Consistent with this finding, the selective deletion of GC NMDARs affects adaptation of the vestibulo-ocular reflex. Thus, NMDARs presynaptic to PCs are required for bidirectional synaptic plasticity and cerebellar motor learning.

The cerebellum aids the learning of fast, coordinated movements. According to current consensus, erroneously active parallel fibre synapses are depressed by complex spikes signalling movement errors. However, this theory cannot solve the credit assignment problem of processing a global movement evaluation into multiple cell-specific error signals. We identify a possible implementation of an algorithm solving this problem, whereby spontaneous complex spikes perturb ongoing movements, create eligibility traces and signal error changes guiding plasticity. Error changes are extracted by adaptively cancelling the average error. This framework, stochastic gradient descent with estimated global errors (SGDEGE), predicts synaptic plasticity rules that apparently contradict the current consensus but were supported by plasticity experiments in slices from mice under conditions designed to be physiological, highlighting the sensitivity of plasticity studies to experimental conditions. We analyse the algorithm’s convergence and capacity. Finally, we suggest SGDEGE may also operate in the basal ganglia.

Ca V3.1 T-type channels are abundant at the cerebellar synapse between parallel fibers and Purkinje cells where they contribute to synaptic depolarization. So far, no specific physiological function has been attributed to these channels neither as charge carriers nor more specifically as Ca ²⁺ carriers. Here we analyze their incidence on synaptic plasticity, motor behavior, and cerebellar motor learning, comparing WT animals and mice where T-type channel function has been abolished either by gene deletion or by acute pharmacological blockade. At the cellular level, we show that Ca V3.1 channels are required for long-term potentiation at parallel fiber–Purkinje cell synapses. Moreover, basal simple spike discharge of the Purkinje cell in KO mice is modified. Acute or chronic T-type current blockade results in impaired motor performance in particular when a good body balance is required. Because motor behavior integrates reflexes and past memories of learned behavior, this suggests impaired learning. Indeed, subjecting the KO mice to a vestibulo-ocular reflex phase reversal test reveals impaired cerebellum-dependent motor learning. These data identify a role of low-voltage activated calcium channels in synaptic plasticity and establish a role for Ca V3.1 channels in cerebellar learning.

Plasticity at the cerebellar parallel fiber to Purkinje cell synapse may underlie information processing and motor learning. In vivo, parallel fibers appear to fire in short high frequency bursts likely to activate sparsely distributed synapses over the Purkinje cell dendritic tree. Here, we report that short parallel fiber tetanic stimulation evokes a ∼7-15% depression which develops over 2 min and lasts for at least 20 min. In contrast to the concomitantly evoked short-term endocannabinoid-mediated depression, this persistent posttetanic depression (PTD) does not exhibit a dependency on the spatial pattern of synapse activation and is not caused by any detectable change in presynaptic calcium signaling. This persistent PTD is however associated with increased paired-pulse facilitation and coefficient of variation of synaptic responses, suggesting that its expression is presynaptic. The chelation of postsynaptic calcium prevents its induction, suggesting that post- to presynaptic (retrograde) signaling is required. We rule out endocannabinoid signaling since the inhibition of type 1 cannabinoid receptors, monoacylglycerol lipase or vanilloid receptor 1, or incubation with anandamide had no detectable effect. The persistent PTD is maximal in pre-adolescent mice, abolished by adrenergic and dopaminergic receptors block, but unaffected by adrenergic and dopaminergic agonists. Our data unveils a novel form of plasticity at parallel fiber synapses: a persistent PTD induced by physiologically relevant input patterns, age-dependent, and strongly modulated by the monoaminergic system. We further provide evidence supporting that the plasticity mechanism involves retrograde signaling and presynaptic diacylglycerol.

In our study, we presented functional and immunohistochemical evidence for the presence of presynaptic N-methyl-D-aspartate receptors (pre-NMDARs) at parallel fiber–Purkinje cell (PF-PC) synapses in the adult cerebellum. As in young rodents, pre-NMDARs are required to induce PF-PC synaptic plasticity. Using cell-specific deletion of NMDARs in granule cells (GCs) or PCs, we demonstrated that only GC NMDARs are robustly involved in PF-PC synaptic plasticity and vestibuloocular reflex (VOR) adaptation.

[...]a two-fold higher absorption by the dermal route for nickel and platinum (Pt) justified decreasing the dPDE for each element. [...]the PDE for mercury (Hg) is 30 pg/day; thus, the daily exposure from a dermatological DP should not exceed 30% (e.g., 9 pg/day) and the concentration limit of 10 pg/g. [...]up to a posology in DP of 0.9 g/day, the dermal concentration limit for Hg (10 pg/g) must be applied; whereas above 0.9 g/day the 30% PDE (9 pg/ day) will be the applicable limit. [...]these dermal concentration limits and revised PDE are not applicable for topical DP applied on skin requiring preparations, like curettage, keratolytic pretreatment, or abrasion, for which a case-by-case evaluation should be performed, taking into account changes in dermal penetration. [...]the authors propose the establishment of dPDEs for some EIs to take into consideration differences between oral and dermal penetration levels and to set dermal concentration limits for some EIs due to their significant skin sensitization risk.

Significance T-type calcium channels are present in the spines of a number of principal neurons. In absence of specific antagonists, their function has been difficult to elucidate. At the cerebellar synapse between parallel fiber (PF) and Purkinje cell (PC), postsynaptic Ca 2+ signaling is not the result of ionotropic glutamatergic receptor activation, while T-type Ca V 3.1 channels are abundantly expressed in PCs. We show that they are required for long-term potentiation but not for long-term depression at PF–PC synapses. Because plasticity at this site has long been proposed to be important for cerebellar forms of motor learning, we have checked the behavioral incidence of acute or chronic blockade of T-type channels. In this condition, we show impairment of demanding cerebellar motor learning tasks.