Climbing fibers, the projections from the inferior olive to the cerebellar cortex, carry sensorimotor error and clock signals that trigger motor learning by controlling cerebellar Purkinje cell synaptic plasticity and discharge. Purkinje cells target the deep cerebellar nuclei, which are the output of the cerebellum and include an inhibitory GABAergic projection to the inferior olive. This pathway identifies a potential closed loop in the olivo-cortico-nuclear network. Therefore, sets of Purkinje cells may phasically control their own climbing fiber afferents. Here, using in vitro and in vivo recordings, we describe a genetically modified mouse model that allows the specific optogenetic control of Purkinje cell discharge. Tetrode recordings in the cerebellar nuclei demonstrate that focal stimulations of Purkinje cells strongly inhibit spatially restricted sets of cerebellar nuclear neurons. Strikingly, such stimulations trigger delayed climbing-fiber input signals in the stimulated Purkinje cells. Therefore, our results demonstrate that Purkinje cells phasically control the discharge of their own olivary afferents and thus might participate in the regulation of cerebellar motor learning.motor control | olivo-cerebellar loop | complex spikes T he cerebellar cortex is involved in a wealth of functions, from the control of posture to higher cognitive processes (1-3). Purkinje cells (PCs) are key processing units of the cerebellar cortex (4): each PC receives more than 175,000 parallel fiber synaptic inputs carrying information about the ongoing sensorymotor context. It also receives a single inferior olive afferent, the climbing fiber, which triggers a complex spike (CS), modulates PC firing (5), controls synaptic input plasticity, and has been proposed to carry error and clock signals to the cerebellum (2, 4-8). PCs are grouped in multiple parasagittal microzones, each receiving projections from separate areas of the inferior olive and projecting to subregions of the cerebellar nuclei (CN) (9-12). In the CN, PCs make inhibitory contacts on excitatory neurons that project to various premotor areas and propagate cerebellar computations to the motor system. Anatomical evidence indicates that PC terminals also contact CN inhibitory neurons that target inferior olive cells (13,14). This nucleoolivary pathway is topographically organized in multiple parallel projections to the inferior olive subnuclei (15), suggesting the existence of closed olivary-cortico-nuclear loops. Therefore, the discharge of a population of PCs in a microzone might not only shape the output of the cerebellum but also control its afferent climbing-fiber signal. Previous studies have shown that stimulation of the nucleo-olivary pathway significantly reduces olivary cell firing (16-18) and that pharmacological and genetic manipulations of PCs or olivary cell activity induce reciprocal modulations of the firing rate of PCs and climbing fibers (19, 20).These results indicate that PCs may tonically modulate the nucleo-olivary pathway. However, whether...

We injected a combination of the beta-amyloids (Abetas) Abeta40 and Abeta43 to "seed" formation of amyloid deposits in the dorsal dentate gyrus of rats in vivo, on the basis of a theory of Jarrett and Landsbury (1993). Rats were tested on several different learning tasks, and synaptic transmission and plasticity were assessed in vivo. Between 7 and 16 weeks after injection, we found aggregated amyloid material, reactive astrocytosis, microgliosis, and cell loss around the sites of injection. Rats were impaired specifically in working memory type tasks in accordance with the type of memory deficit observed in the early stages of Alzheimer's disease. Synaptic transmission and long-term potentiation, a candidate cellular mechanism for memory, were severely impaired in vivo. Injections of the same dose of fragments individually did not induce these effects. These findings suggest that aggregated amyloid material induces cognitive deficits similar to those observed in the early phases of Alzheimer's disease via an alteration in neuronal transmission and plasticity.

The memory deficits associated with Alzheimer's disease result to a great extent from hippocampal network dysfunction. The coordination of this network relies on theta () oscillations generated in the medial septum. Here, we investigated in rats the impact of hippocampal amyloid ␤ (A␤) injections on the physiological and cognitive functions that depend on the septohippocampal system. Hippocampal A␤ injections progressively impaired behavioral performances, the associated hippocampal power, and frequency response in a visuospatial recognition test. These alterations were associated with a specific reduction in the firing of the identified rhythmic bursting GABAergic neurons responsible for the propagation of the rhythm to the hippocampus, but without loss of medial septal neurons. Such results indicate that hippocampal A␤ treatment leads to a specific functional depression of inhibitory projection neurons of the medial septum, resulting in the functional impairment of the temporal network.