Lordosis after cerebellar damage in female rats

Massive destruction of the cerebellum is consistent with both the performance of lordosis by estrous female rats and the continuation of estrous cyclicity.     

alphaCaMKII Is essential for cerebellar LTD and motor learning

Activation of postsynaptic alpha-calcium/calmodulin-dependent protein kinase II (alphaCaMKII) by calcium influx is a prerequisite for the induction of long-term potentiation (LTP) at most excitatory synapses in the hippocampus and cortex. Here we show that postsynaptic LTP is unaffected at parallel fiber-Purkinje cell synapses in the cerebellum of alphaCaMKII(-/-) mice. In contrast, a long-term depression (LTD) protocol resulted in only transient depression in juvenile alphaCaMKII(-/-) mutants and in robust potentiation in adult mutants. This suggests that the function of alphaCaMKII in parallel fiber-Purkinje cell plasticity is opposite to its function at excitatory hippocampal and cortical synapses. Furthermore, alphaCaMKII(-/-) mice showed impaired gain-increase adaptation of both the vestibular ocular reflex and optokinetic reflex. Since Purkinje cells are the only cells in the cerebellum that express alphaCaMKII, our data suggest that an impairment of parallel fiber LTD, while leaving LTP intact, is sufficient to disrupt this form of cerebellar learning.     

Embarrassed,but not depressed: eye opening lessons for cerebellar learning

Cellular mechanisms of plasticity must be linked to circuit mechanisms of behavior to understand learning and memory. Studies of how learning occurs in cerebellar circuits for classical conditioning of eyeblinks are meeting this challenge admirably. Several recent papers have added to the richness of our understanding of cerebellar learning by correlating complex aspects of learned behaviors with hitherto underappreciated properties of the cerebellar circuit.     

The DNA damage response: sensing and signaling

The protein kinases ATM and ATR are central components of the checkpoint mechanisms that signal the presence of damaged DNA and stalled replication forks. Recent studies have provided important new insights into how these kinases work together with their regulatory subunits, DNA repair proteins and adaptor proteins to sense abnormal DNA structures and implement the appropriate DNA damage response. These advances have provided a more detailed understanding of the interface between damaged DNA and the checkpoint sensor proteins.     

Sterile inflammation: sensing and reacting to damage

Over the past several decades, much has been revealed about the nature of the host innate immune response to microorganisms, with the identification of pattern recognition receptors (PRRs) and pathogen-associated molecular patterns, which are the conserved microbial motifs sensed by these receptors. It is now apparent that these same PRRs can also be activated by non-microbial signals, many of which are considered as damage-associated molecular patterns. The sterile inflammation that ensues either resolves the initial insult or leads to disease. Here, we review the triggers and receptor pathways that result in sterile inflammation and its impact on human health.     

Mechanisms of cerebellar learning suggested by eyelid conditioning

Classical eyelid conditioning has been used to great advantage in demonstrating that the cerebellum helps to improve movements through experience, and in identifying the underlying mechanisms. Results from recent studies support the hypotheses that learning occurs in both the cerebellar nucleus and cortex, and that these sites make different contributions. Specifically, results indicate that the cerebellar cortex is responsible for temporally specific learning. A combination of experimental and computational studies has been important for arriving at these conclusions, which seem to be applicable to the broad range of movements to which the cerebellum contributes.     

Electrochemical sensing DNA damage with nano-titanium dioxide and repair with a medicinal herb species resveratrol

We have developed a simple electrochemical method to detect DNA damage caused by the photovoltaic effect of nano-TiO(2). Meanwhile, we have found that resveratrol, a Chinese Traditional Medicinal Herb species, can have a repairing effect to the oxidized DNA, which can also be detected with the proposed technique in this paper.     

Stability of complex spike timing-dependent plasticity in cerebellar learning

Dynamics of spike-timing dependent synaptic plasticity are analyzed for excitatory and inhibitory synapses onto cerebellar Purkinje cells. The purpose of this study is to place theoretical constraints on candidate synaptic learning rules that determine the changes in synaptic efficacy due to pairing complex spikes with presynaptic spikes in parallel fibers and inhibitory interneurons. Constraints are derived for the timing between complex spikes and presynaptic spikes, constraints that result from the stability of the learning dynamics of the learning rule. Potential instabilities in the parallel fiber synaptic learning rule are found to be stabilized by synaptic plasticity at inhibitory synapses if the inhibitory learning rules are stable, and conditions for stability of inhibitory plasticity are given. Combining excitatory with inhibitory plasticity provides a mechanism for minimizing the overall synaptic input. Stable learning rules are shown to be able to sculpt simple-spike patterns by regulating the excitability of neurons in the inferior olive that give rise to climbing fibers.     

Reevaluating the role of LTD in cerebellar motor learning

Long-term depression at parallel fiber-Purkinje cell synapses (PF-PC LTD) has been proposed to be required for cerebellar motor learning. To date, tests of this hypothesis have sought to interfere with receptors (mGluR1) and enzymes (PKC, PKG, or αCamKII) necessary for induction of PF-PC LTD and thereby determine if cerebellar motor learning is impaired. Here, we tested three mutant mice that target the expression of PF-PC LTD by blocking internalization of AMPA receptors. Using three different cerebellar coordination tasks (adaptation of the vestibulo-ocular reflex, eyeblink conditioning, and locomotion learning on the Erasmus Ladder), we show that there is no motor learning impairment in these mutant mice that lack PF-PC LTD. These findings demonstrate that PF-PC LTD is not essential for cerebellar motor learning.     

Role of olivary electrical coupling in cerebellar motor learning

The level of electrotonic coupling in the inferior olive is extremely high, but its functional role in cerebellar motor control remains elusive. Here, we subjected mice that lack olivary coupling to paradigms that require learning-dependent timing. Cx36-deficient mice showed impaired timing of both locomotion and eye-blink responses that were conditioned to a tone. The latencies of their olivary spike activities in response to the unconditioned stimulus were significantly more variable than those in wild-types. Whole-cell recordings of olivary neurons in vivo showed that these differences in spike timing result at least in part from altered interactions with their subthreshold oscillations. These results, combined with analyses of olivary activities in computer simulations at both the cellular and systems level, suggest that electrotonic coupling among olivary neurons by gap junctions is essential for proper timing of their action potentials and thereby for learning-dependent timing in cerebellar motor control.     

Wildfire damage evaluation by merging remote sensing with a fire area simulation model in Naoshima, Kagawa, Japan

Not only wildfire damage, but the failure of post-fire forest restoration is also one of the major threats for the conservation of forest ecosystems. Therefore, it is required to estimate wildfire damaged potential and recovery capacity to orientate the management of a post-fire community. The aim of our research is to estimate the resistibility against wildfire and the post-fire regeneration capacity by merging field observation data with Terra/ASTER Level1B satellite data and a fire area simulation model (FARSITE). As a result, the resistibility against wildfire and the post-fire regeneration capacity were high in the high prior-fire normalized differential vegetation index (NDVI) areas, where the trees had been thriving. Also, after the fire, the well developed surface soil (the A horizon) provided a good environment for resprouting from unburned stumps and the rhizome. It is suggested that the thriving forests have a strong resistance against wildfire and have large regeneration capacity.     

Linking active sensing and spatial learning in weakly electric fish

Weakly electric fish can learn the spatial layout of their environment using only their short-range electric sense. During spatial learning, active sensing motions are used to memorize landmark locations so that they can serve as anchors for idiothetic-based navigation. A hindbrain feedback circuit selectively amplifies the electrosensory input arising from these motions. The ascending electrolocation pathway preferentially transmits this information to the pallial regions involved in spatial learning and navigation. Similarities in both behavioral patterns and hindbrain circuitry of gymnotiform and mormyrid fish, two families that independently evolved their electrosense, suggest that amplification and transmission of active sensing motion inputs are fundamental mechanisms for spatial memory acquisition.     

Adaptive processing in electrosensory systems: Links to cerebellar plasticity and learning

The first central stage of electrosensory processing in fish takes place in structures with local circuitry that resembles the cerebellum. Cerebellum-like structures and the cerebellum itself share common patterns of gene expression and may also share developmental and evolutionary origins. Given these similarities it is natural to ask whether insights gleaned from the study of cerebellum-like structures might be useful for understanding aspects of cerebellar function and vice versa. Work from electrosensory systems has shown that cerebellum-like circuitry acts to generate learned predictions about the sensory consequences of the animals’ own behavior through a process of associative plasticity at parallel fiber synapses. Subtraction of these predictions from the actual sensory input serves to highlight unexpected and hence behaviorally relevant features. Learning and prediction are also central to many current ideas regarding the function of the cerebellum itself. The present review draws comparisons between cerebellum-like structures and the cerebellum focusing on the properties and sites of synaptic plasticity in these structures and on connections between plasticity and learning. Examples are drawn mainly from the electrosensory lobe (ELL) of mormyrid fish and from extensive work characterizing the role of the cerebellum in Pavlovian eyelid conditioning and vestibulo-ocular reflex (VOR) modification. Parallels with other cerebellum-like structures, including the gymnotid ELL, the elasmobranch dorsal octavolateral nucleus (DON), and the mammalian dorsal cochlear nucleus (DCN) are also discussed.     

The calcium‐sensing receptor and integrins modulate cerebellar granule cell precursor differentiation and migration

In the developing cerebellum granule cell precursors (GCPs) proliferate in the external granule cell layer before differentiating and migrating to the inner granule cell layer. Aberrant GCP proliferation leads to medulloblastoma, the most prevalent form of childhood brain cancer. Here, we demonstrate that the calcium‐sensing receptor (CaSR), a homodimeric G‐protein coupled receptor, functions in conjunction with cell adhesion proteins, the integrins, to enhance GCP migration and cell homing by promoting GCP differentiation. During the second postnatal week a robust peak in CaSR expression was observed in GCPs; reciprocal immunoprecipitation experiments conducted during this period established that the CaSR and β1 integrins are present together in a macromolecular protein complex. Analysis of cell‐surface proteins demonstrated that activation of the CaSR by positive allosteric modulators promoted plasma membrane expression of β1 integrins via ERK2 and AKT phosphorylation and resulted in increased GCP migration toward an extracellular matrix protein. The results of in vivo experiments whereby CaSR modulators were injected i.c.v. revealed that CaSR activation promoted radial migration of GCPs by enhancing GCP differentiation, and conversely, a CaSR inhibitor disrupted GCP differentiation and promoted GCP proliferation. Our results demonstrate that an ion‐sensing G‐protein coupled receptor acts to promote neuronal differentiation and homing during cerebellar maturation. These findings together with those of others also suggest that CaSR/integrin complexes act to transduce extracellular calcium signals into cellular movement, and may function in this capacity as a universal cell migration/homing complex in the developing brain. © 2015 Wiley Periodicals, Inc. Develop Neurobiol 76: 375–389, 2016     

Raising cytosolic Cl- in cerebellar granule cells affects their excitability and vestibulo-ocular learning

Cerebellar cortical throughput involved in motor control comprises granule cells (GCs) and Purkinje cells (PCs), both of which receive inhibitory GABAergic input from interneurons. The GABAergic input to PCs is essential for learning and consolidation of the vestibulo-ocular reflex, but the role of GC excitability remains unclear. We now disrupted the Kcc2 K-Cl cotransporter specifically in either cell type to manipulate their excitability and inhibition by GABA(A)-receptor Cl(-) channels. Although Kcc2 may have a morphogenic role in synapse development, Kcc2 disruption neither changed synapse density nor spine morphology. In both GCs and PCs, disruption of Kcc2, but not Kcc3, increased [Cl(-)](i) roughly two-fold. The reduced Cl(-) gradient nearly abolished GABA-induced hyperpolarization in PCs, but in GCs it merely affected excitability by membrane depolarization. Ablation of Kcc2 from GCs impaired consolidation of long-term phase learning of the vestibulo-ocular reflex, whereas baseline performance, short-term gain-decrease learning and gain consolidation remained intact. These functions, however, were affected by disruption of Kcc2 in PCs. GC excitability plays a previously unknown, but specific role in consolidation of phase learning.     

Statistical characteristics of climbing fiber spikes necessary for efficient cerebellar learning

 Mean firing rates (MFRs), with analogue values, have thus far been used as information carriers of neurons in most brain theories of learning. However, the neurons transmit the signal by spikes, which are discrete events. The climbing fibers (CFs), which are known to be essential for cerebellar motor learning, fire at the ultra-low firing rates (around 1 Hz), and it is not yet understood theoretically how high-frequency information can be conveyed and how learning of smooth and fast movements can be achieved. Here we address whether cerebellar learning can be achieved by CF spikes instead of conventional MFR in an eye movement task, such as the ocular following response (OFR), and an arm movement task. There are two major afferents into cerebellar Purkinje cells: parallel fiber (PF) and CF, and the synaptic weights between PFs and Purkinje cells have been shown to be modulated by the stimulation of both types of fiber. The modulation of the synaptic weights is regulated by the cerebellar synaptic plasticity. In this study we simulated cerebellar learning using CF signals as spikes instead of conventional MFR. To generate the spikes we used the following four spike generation models: (1) a Poisson model in which the spike interval probability follows a Poisson distribution, (2) a gamma model in which the spike interval probability follows the gamma distribution, (3) a max model in which a spike is generated when a synaptic input reaches maximum, and (4) a threshold model in which a spike is generated when the input crosses a certain small threshold. We found that, in an OFR task with a constant visual velocity, learning was successful with stochastic models, such as Poisson and gamma models, but not in the deterministic models, such as max and threshold models. In an OFR with a stepwise velocity change and an arm movement task, learning could be achieved only in the Poisson model. In addition, for efficient cerebellar learning, the distribution of CF spike-occurrence time after stimulus onset must capture at least the first, second and third moments of the temporal distribution of error signals. Received: 28 January 2000 / Accepted in revised form: 2 August 2000     

On the role of anatomy in learning by the cerebellar cortex

The properties due to the location of neurons, synapses, and possibly even synaptic channels, in neuron networks are still unknown. Our preliminary results suggest that not only the interconnections but also the relative positions of the different elements in the network are of importance in the learning process in the cerebellar cortex. We have used neural field equations to investigate the mechanisms of learning in the hierarchical neural network. The numerical resolution of these equations reveals two important properties: (i) The hierarchical structure of this network has the expected effect on learning because the flow of information at the neuronal level is controlled by the heterosynaptic effect through the synaptic density-connectivity function, i.e. the action potential field variable is controlled by the synaptic efficacy field variable at different points of the neuron. (ii) The geometry of the system involves different velocities of propagation along different fibers, i.e. different delays between cells, and thus has a stabilizing effect on the dynamics, allowing the Purkinje output to reach a given value. The field model proposed should be useful in the study of the spatial properties of hierarchical biological systems.