Population calcium responses of Purkinje cells in the oculomotor cerebellum driven by nonvisual input.

The climbing fiber input to the cerebellum conveys instructive signals that can induce synaptic plasticity and learning by triggering complex spikes accompanied by large calcium transients in Purkinje cells. In the cerebellar flocculus, which supports oculomotor learning, complex spikes are driven by image motion on the retina, which could indicate an oculomotor error. In the same neurons, complex spikes also can be driven by nonvisual signals. It has been shown that the calcium transients accompanying each complex spike can vary in amplitude, even within a given cell, therefore, we compared the calcium responses associated with the visual and nonvisual inputs to floccular Purkinje cells. The calcium indicator GCaMP6f was selectively expressed in Purkinje cells, and fiber photometry was used to record the calcium responses from a population of Purkinje cells in the flocculus of awake behaving mice. During visual (optokinetic) stimuli and pairing of vestibular and visual stimuli, the calcium level increased during contraversive retinal image motion. During performance of the vestibulo-ocular reflex in the dark, calcium increased during contraversive head rotation and the associated ipsiverse eye movements. The amplitude of this nonvisual calcium response was comparable to that during conditions with retinal image motion present that induce oculomotor learning. Thus, population calcium responses of Purkinje cells in the cerebellar flocculus to visual and nonvisual input are similar to what has been reported previously for complex spikes, suggesting that multimodal instructive signals control the synaptic plasticity supporting oculomotor learning.NEW & NOTEWORTHY It was long known that the climbing fiber input to Purkinje cells in the cerebellar flocculus conveys visual feedback about the accuracy of image-stabilizing oculomotor reflexes. More recently, the same climbing fibers were reported to carry nonvisual signals. Here, we report that both visual and nonvisual inputs can elicit robust calcium responses in the Purkinje cells, suggesting that the instructive signals guiding oculomotor plasticity are multimodal.

Arc visualization of odor objects reveals experience-dependent ensemble sharpening, separation, and merging in anterior piriform cortex in adult rat.

Visualization using the immediate early gene Arc revealed sparser and more robust odor representations in the anterior piriform cortex of adult rats when odor was associated with water reward over 2-3 d. Rewarded odor "mixtures" resulted in rats responding to either component odor similarly, and, correspondingly, the odor representations became more similar as indexed by increased overlap in piriform Arc-expressing (Arc(+)) pyramidal neurons. The increased overlap was consistent with the rats' generalization from component odors. Discriminating among highly similar odor mixtures for reward led to increased differentiation of the neural representations as indexed by a reduction in overlap for piriform Arc(+) pyramidal neurons after training. Similar odor mixture discrimination also required more trials to criterion. The visible reduction in the overlap of odor representations indexes pattern separation. The Arc visualization of odor representations in the anterior piriform network suggests that odor objects are widely distributed representations and can be rapidly modified by reward training in adult rats. We suggest that dynamic changes such as those observed here in piriform odor encoding are at the heart of perceptual learning and reflect the continuing plastic nature of mature associative cortex as an outcome of successful problem solving.

Systemic pharmacological suppression of neural activity reverses learning impairment in a mouse model of Fragile X syndrome.

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-Kb and H2Db (MH-CI KbDb-/-), 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 KbDb-/-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.