Cerebellar and Extracerebellar Involvement in Mouse Eyeblink Conditioning: the ACDC Model

Over the past decade the advent of mouse transgenics has generated new perspectives on the study of cerebellar molecular mechanisms that are essential for eyeblink conditioning. However, it also appears that results from eyeblink conditioning experiments done in mice differ in some aspects from results previously obtained in other mammals. In this review article we will, based on studies using (cell-specific) mouse mutants and region-specific lesions, re-examine the general eyeblink behavior in mice and the neuro-anatomical circuits that might contribute to the different peaks in the conditioned eyeblink trace. We conclude that the learning process in mice has at least two stages: An early stage, which includes short-latency responses that are at least partly controlled by extracerebellar structures such as the amygdala, and a later stage, which is represented by well-timed conditioned responses that are mainly controlled by the pontocerebellar and olivocerebellar systems. We refer to this overall concept as the Amygdala-Cerebellum-Dynamic-Conditioning Model (ACDC model)

High frequency burst firing of granule cells ensures transmission at the parallel fiber to purkinje cell synapse at the cost of temporal coding.

Cerebellar granule cells (GrCs) convey information from mossy fibers (MFs) to Purkinje cells (PCs) via their parallel fibers (PFs). MF to GrC signaling allows transmission of frequencies up to 1 kHz and GrCs themselves can also fire bursts of action potentials with instantaneous frequencies up to 1 kHz. So far, in the scientific literature no evidence has been shown that these high-frequency bursts also exist in awake, behaving animals. More so, it remains to be shown whether such high-frequency bursts can transmit temporally coded information from MFs to PCs and/or whether these patterns of activity contribute to the spatiotemporal filtering properties of the GrC layer. Here, we show that, upon sensory stimulation in both un-anesthetized rabbits and mice, GrCs can show bursts that consist of tens of spikes at instantaneous frequencies over 800 Hz. In vitro recordings from individual GrC-PC pairs following high-frequency stimulation revealed an overall low initial release probability of ~0.17. Nevertheless, high-frequency burst activity induced a short-lived facilitation to ensure signaling within the first few spikes, which was rapidly followed by a reduction in transmitter release. The facilitation rate among individual GrC-PC pairs was heterogeneously distributed and could be classified as either "reluctant" or "responsive" according to their release characteristics. Despite the variety of efficacy at individual connections, grouped activity in GrCs resulted in a linear relationship between PC response and PF burst duration at frequencies up to 300 Hz allowing rate coding to persist at the network level. Together, these findings support the hypothesis that the cerebellar granular layer acts as a spatiotemporal filter between MF input and PC output (D'Angelo and De Zeeuw, 2009)

Sleep deprivation directly following eyeblink-conditioning impairs memory consolidation

The relation between sleep and different forms of memory formation continues to be a relevant topic in our daily life. Sleep has been found to affect cerebellum-dependent procedural memory formation, but it remains to be elucidated to what extent the level of sleep deprivation directly after motor training also influences our ability to store and retrieve memories. Here, we studied the effect of disturbed sleep in mice during two different time-windows, one covering the first four hours following eyeblink conditioning (EBC) and another window following the next period of four hours. Compared to control mice with sleep ad libitum, the percentage of conditioned responses and their amplitude were impaired when mice were deprived of sleep directly after conditioning

Cerebellum: What is in a Name? Historical Origins and First Use of This Anatomical Term

In this paper, we study who first used the Latin anatomical term “cerebellum” for the posterior part of the brain. The suggestion that this term was introduced by Leonardo da Vinci is unlikely. Just before the start of the da Vinci era in the fifteenth century, several authors referred to the cerebellum as “cerebri posteriorus.” Instead, in his translation of Galen’s anatomical text De utilitare particularum of 1307, Nicolo da Reggio used the Latinized Greek word “parencephalon.” More peculiar was the Latin nautical term “puppi,” referring to the stern of a ship, that was applied to the cerebellum by Constantine the African in his translation of the Arabic Liber regius in the eleventh century. The first to use the term “cerebellum” appears to be Magnus Hundt in his Anthropologia from 1501. Like many of the anatomists of this period, he was a humanist with an interest in classical literature. They may have encountered the term “cerebellum” in the writings by classical authors such as Celsus, where it was used as the diminutive of “cerebrum” for the small brains of small animals, and, subsequently, applied the term to the posterior part of the brain. In the subsequent decades of the sixteenth century, an increasing number of pre-Vesalian authors of anatomical texts started to use the name “cerebellum,” initially often combined with one or more of the earlier terms, but eventually more frequently in isolation. We found that a woodcut in Dryander’s Anatomia capitis humani of 1536 is the first realistic picture of the cerebellum

Forward Signaling by Unipolar Brush Cells in the Mouse Cerebellum

Unipolar brush cells (UBCs) are glutamatergic interneurons prominently present in the granular layer of the vestibulocerebellum. UBCs engage in extensive synaptic contact with a single presynaptic mossy fiber and signal to downstream granule cells through an elaborate network of mossy fiber-like axons. Ultrastructural examinations and electrophysiological recordings in organotypic slice cultures have indicated that UBCs target not only granule cells but also other UBCs, thus forming chains of two or perhaps more interconnected UBCs. In this report, we show recordings of spontaneous and evoked (di)synaptic events in granule cells and UBCs in fresh cerebellar slices from juvenile mice (5–7 weeks). The patterns of arrival of synaptic events were consistent with the presence of a presynaptic UBC, and recordings from UBCs displayed spontaneous protracted synaptic events characteristic of UBC excitatory synaptic transmission. These results highlight that chains of UBCs could further extend the temporal range of delayed and protracted signaling in the cerebellar cortical network

Ultrastructure of the cat inferior olive : an anatomical study using three new combination techniques

The present ultrastructural study focuses on two of the subnuclei of the IO: The medial accessory olive (MAO) and the principal olive (PO). These subnuclei, which are predominantly innervated by descending systems and by a recurrent pathway from the central cerebellar nuclei, may be involved in the preparation and execution of movements. Accurate timing obviously is essential in these processes. The morphological observations of this study will be discussed in relation to the electrophysiological properties of the olivary neurons (Chapter V). It will be attempted to show that the specific formation of the dendritic elements of these cells together with their synaptic input are well suited to serve as a timing devic

Repeated mild injury causes cumulative damage to hippocampal cells

An interesting hypothesis in the study of neurotrauma is that repeated traumatic brain injury may result in cumulative damage to cells of the brain. However, post-injury sequelae are difficult to address at the cellular level in vivo. Therefore, it is necessary to complement these studies with experiments conducted in vitro. In this report, the effects of single and repeated traumatic injury in vitro were investigated in cultured mouse hippocampal cells using a well characterized model of stretch-induced injury. Cell damage was assessed by the level of propidium iodide (PrI) uptake and retention of fluorescein diacetate (FDA). Uninjured control wells displayed minimal PrI uptake and high levels of FDA retention. Mild, moderate and severe levels of stretch caused increasing amounts of PrI uptake, respectively, when measured at 15 min and 24 h post-injury, indicating increased cellular damage with increasing amounts of stretch. For repeated injury studies, cultures received a second injury 1 h after the initial insult. Repeated mild injury caused a slight increase in PrI uptake compared with single injury at 15 min and 24 h post-injury, which was evident primarily in glial cells. However, the neurites of neurones in cultures that received repeated insults showed signs of damage that were not evident after a single mild injury. The release of neurone-specific enolase (NSE) and S-100beta protein, two common clinical markers of CNS damage, was also measured following the repeated injuries paradigm. When measured at 6 h post-injury, both NSE and S-100beta were found to be elevated after repeated mild injuries when compared with the single injury group. These results suggest that cells of the hippocampus may be susceptible to cumulative damage following repeated mild traumatic insults. Both glial cells and neurones appear to exhibit increased signs of damage after repetitive injury. To our knowledge, this study represents the first report on the effects of repeated mechanical insults on specific cells of the brain using an in vitro model system. The biochemical pathways of cellular degradation following repeated mild injuries may differ considerably from those that are activated by a single mild insult. Therefore, we hope to use this model in order to investigate secondary pathways of cellular damage after repeated mild traumatic injury, and as a rapid and economical means of screening possibilities for treatment strategies, including pharmaceutical intervention