23 research outputs found
Jahrestagung der Gesellschaft für Medizinische Ausbildung ; Medizinische Fakultät der Ludwig-Maximilians-Universität München ; 05.-08. Oktober 2011 ; Tagungsband ; [Lehren - Lernen - Prüfen ; von der Dissonanz zum Dreiklang? ; abstracts] ; Lehren - Lernen - Prüfen
No full textBook of Abstracts: Jahrestagung der Gesellschaft für Medizinische Ausbildung (GMA): 05.10. - 08.10.2011, Münche
Quasiperiodic rhythms of the inferior olive
Get PDFInferior olivary activity causes both short-term and long-term changes in cerebellar output underlying motor performance and motor learning. Many of its neurons engage in coherent subthreshold oscillations and are extensively coupled via gap junctions. Studies in reduced preparations suggest that these properties promote rhythmic, synchronized output. However, the interaction of these properties with torrential synaptic inputs in awake behaving animals is not well understood. Here we combine electrophysiological recordings in awake mice with a realistic tissue-scale computational model of the inferior olive to study the relative impact of intrinsic and extrinsic mechanisms governing its activity. Our data and model suggest that if subthreshold oscillations are present in the awake state, the period of these oscillations will be transient and variable. Accordingly, by using different temporal patterns of sensory stimulation, we found that complex spike rhythmicity was readily evoked but limited to short intervals of no more than a few hundred milliseconds and that the periodicity of this rhythmic activity was not fixed but dynamically related to the synaptic input to the inferior olive as well as to motor output. In contrast, in the long-term, the average olivary spiking activity was not affected by the strength and duration of the sensory stimulation, while the level of gap junctional coupling determined the stiffness of the rhythmic activity in the olivary network during its dynamic response to sensory modulation. Thus, interactions between intrinsic properties and extrinsic inputs can explain the variations of spiking activity of olivary neurons, providing a temporal framework for the creation of both the short-term and long-term changes in cerebellar output
Cerebellar Output Controls Generalized Spike-and-Wave Discharge Occurrence
Get PDFObjective Disrupting thalamocortical activity patterns has proven to be a promising approach to stop generalized spike-and-wave discharges (GSWDs) characteristic of absence seizures. Here, we investigated to what extent modulation of neuronal firing in cerebellar nuclei (CN), which are anatomically in an advantageous position to disrupt cortical oscillations through their innervation of a wide variety of thalamic nuclei, is effective in controlling absence seizures. Methods Two unrelated mouse models of generalized absence seizures were used: the natural mutant tottering, which is characterized by a missense mutation in Cacna1a, and inbred C3H/HeOuJ. While simultaneously recording single CN neuron activity and electrocorticogram in awake animals, we investigated to what extent pharmacologically increased or decreased CN neuron activity could modulate GSWD occurrence as well as short-lasting, on-demand CN stimulation could disrupt epileptic seizures. Results We found that a subset of CN neurons show phase-locked oscillatory firing during GSWDs and that manipulating this activity modulates GSWD occurrence. Inhibiting CN neuron action potential firing by local application of the ?-aminobutyric acid type A (GABA-A) agonist muscimol increased GSWD occurrence up to 37-fold, whereas increasing the frequency and regularity of CN neuron firing with the use of GABA-A antagonist gabazine decimated its occurrence. A single short-lasting (30–300 milliseconds) optogenetic stimulation of CN neuron activity abruptly stopped GSWDs, even when applied unilaterally. Using a closed-loop system, GSWDs were detected and stopped within 500 milliseconds. Interpretation CN neurons are potent modulators of pathological oscillations in thalamocortical network activity during absence seizures, and their potential therapeutic benefit for controlling other types of generalized epilepsies should be evaluated. Ann Neurol 2015;77:1027–1049MicroelectronicsElectrical Engineering, Mathematics and Computer Scienc
A tissue-scale network model of the inferior olive.
No full text(A) To study the relative impact of the different components of the inferior olive we employed a biologically realistic network consisting of 200 model neurons embedded in a 3D grid of 10 x 10 x 2. The model neurons received input from two sources: a phasic input dubbed "sensory input" and a continuous fluctuating current, emulating a "contextual input". The “sensory input” reaches a subset of neurons synchronously and is modeled as an activation of glutamate receptor channels with a peak amplitude of 5 pA/cm2. The “sensory input” is complemented with a continuous input that is a mixture of excitatory and inhibitory synapses representing signals from different sources (see Fig 1A). The “contextual input” is modeled as an Ornstein-Uhlenbeck noise process delivered to all neurons in the model network, with a 20 ms decay, representing temporally correlated input. The model neurons are interconnected by gap junctions. (B) The model neurons display subthreshold membrane oscillations (STOs), represented by the lower circle, and spiking, represented by the upper circle. The colors indicate which current dominates which part of the activity pattern. An Ih current (green), a hyperpolarization-activated cation current, underlies a rise in membrane potential; the IT current (red), mediated by low threshold T-type Ca2+ channels (Cav3.1), further drives up the membrane potential and from here either the subthreshold oscillation continues (lower circle) or a spike is generated (upper circle), mediated through INa and IK currents (yellow and blue, respectively); both after a spike or a subthreshold peak, influx of Ca2+ through the P/Q-type type Ca2+ channels (Cav2.1) leads to a hyperpolarization due to Ca2+-dependent K+ channels (blue); this hyperpolarization in turn will activate the Ih current resuming the oscillation cycle. A resulting trace of the STO punctuated with one spike is diagrammatically displayed on the right. For a full description of currents, consult methods. (C) 3D connectivity scheme of the 200 neurons in the network model. Links indicate gap junctional interconnections; the color of each neuron in the model represents the number of neurons to which that cell is connected. The thick green lines indicate first order neighbors of the center cell. (D-E) Membrane potential of cells in the absence of input, for networks with and without gap junctional coupling. (F-G) Cell activity sorted by amplitude, indicating that coupling the neurons of the network brings non-oscillating cells into the synchronous oscillation. (H-I) Distribution of STO frequency and amplitude for coupled and uncoupled model networks.</p
Evolving Models of Pavlovian Conditioning: Cerebellar Cortical Dynamics in Awake Behaving Mice
No full textSummaryThree decades of electrophysiological research on cerebellar cortical activity underlying Pavlovian conditioning have expanded our understanding of motor learning in the brain. Purkinje cell simple spike suppression is considered to be crucial in the expression of conditional blink responses (CRs). However, trial-by-trial quantification of this link in awake behaving animals is lacking, and current hypotheses regarding the underlying plasticity mechanisms have diverged from the classical parallel fiber one to the Purkinje cell synapse LTD hypothesis. Here, we establish that acquired simple spike suppression, acquired conditioned stimulus (CS)-related complex spike responses, and molecular layer interneuron (MLI) activity predict the expression of CRs on a trial-by-trial basis using awake behaving mice. Additionally, we show that two independent transgenic mouse mutants with impaired MLI function exhibit motor learning deficits. Our findings suggest multiple cerebellar cortical plasticity mechanisms underlying simple spike suppression, and they implicate the broader involvement of the olivocerebellar module within the interstimulus interval
Cerebellar potentiation and learning a whisker-based object localization task with a time response window
Get PDFWhisker-based object localization requires activation and plasticity of somatosensory and motor cortex. These parts of the cerebral cortex receive strong projections from the cerebellum via the thalamus, but it is unclear whether and to what extent cerebellar processing may contribute to such a sensorimotor task. Here, we subjected knock-out mice, which suffer from impaired intrinsic plasticity in their Purkinje cells and long-term potentiation at their parallel fiber-to-Purkinje cell synapses (L7-PP2B), to an object localization task with a time response window (RW). Water-deprived animals had to learn to localize an object with their whiskers, and based upon this location they were trained to lick within a particular period ("go" trial) or refrain from licking ("no-go" trial). L7-PP2B mice were not ataxic and showed proper basic motor performance during whisking and licking, but were severely impaired in learning this task compared with wild-type littermates. Significantly fewer L7-PP2B mice were able to learn the task at long RWs. Those L7-PP2B mice that eventually learned the task made unstable progress, were significantly slower in learning, and showed deficiencies in temporal tuning. These differences became greater as the RW became narrower. Trained wild-type mice, but not L7-PP2B mice, showed a net increase in simple spikes and complex spikes of their Purkinje cells during the task. We conclude that cerebellar processing, and potentiation in particular, can contribute to learning a whisker-based object localization task when timing is relevant. This study points toward a relevant role of cerebellum-cerebrum interaction in a sophisticated cognitive task requiring strict temporal processing
Potentiation of cerebellar Purkinje cells facilitates whisker reflex adaptation through increased simple spike activity
No full textCerebellar plasticity underlies motor learning. However, how the cerebellum operates to enable learned changes in motor output is largely unknown. We developed a sensory-driven adaptation protocol for reflexive whisker protraction and recorded Purkinje cell activity from crus 1 and 2 of awake mice. Before training, simple spikes of individual Purkinje cells correlated during reflexive protraction with the whisker position without lead or lag. After training, simple spikes and whisker protractions were both enhanced with the spiking activity now leading behavioral responses. Neuronal and behavioral changes did not occur in two cell-specific mouse models with impaired long-term potentiation at their parallel fiber to Purkinje cell synapses. Consistent with cerebellar plasticity rules, increased simple spike activity was prominent in cells with low complex spike response probability. Thus, potentiation at parallel fiber to Purkinje cell synapses may contribute to reflex adaptation and enable expression of cerebellar learning through increases in simple spike activity
No phase-dependent spiking probabilities observed <i>in vivo</i>.
No full text(A) In order to test the impact of the presumed phase of the inferior olivary neurons in vivo, we applied a “gallop” stimulation pattern, alternating short (250 ms) and long (400 ms) intervals. Air puffs were delivered to the whisker pad. Complex spikes were counted in response windows (RWs) 20–200 ms post-stimulus and cells were sorted as a function of the ratio between the numbers of complex spikes in short and long intervals (indicated as horizontal dash between filled and empty bars). In this analysis, we included only the RWs that followed an RW with at least one complex spike; i.e. the RWs indicated by a dashed border were ignored. For each Purkinje cell the relative response probabilities for the long and short intervals are illustrated as the length of the filled and open bars, respectively. None of the Purkinje cells showed a significant difference in the response probability between the two intervals (all p > 0.05 on Fisher’s exact test). (B) The same for the alternation of 250 and 300 ms intervals, showing even less response bias than in A. (C) If sensory stimulation triggers complex spikes, one would expect that a higher frequency of stimulation would lead to a higher frequency of complex spikes. However, such a relation was absent. For this analysis, we included only sensory-responsive Purkinje cells of which the complex spike response exceeded a bootstrap-derived 99% probability threshold. The gray scaling of the symbols indicates the response probability. Purkinje cells displaying a higher complex spike response rate had a slightly increased firing rate upon higher stimulus frequencies, but this was far from the expected increase (based upon a linear relationship; the shaded area indicates the 25–75% range).</p
Oscillatory dynamics in spontaneous firing <i>in vivo</i> in the presence and absence of gap junctions.
No full text(A) Color-coded inter-complex spike-interval (ICSI) histogram of spontaneous firing of 60 Gjd2-/- and 52 wild-type Purkinje cells, normalized to the bin with the highest complex spike count per Purkinje cell. (B) The Gdj2-/- Purkinje cell distribution shows higher Z-scores than the wild-type population, indicating a stronger rhythmicity during spontaneous firing in the absence of gap junctions (p = 0.003; Kolmogorov-Smirnov test). A Z-score >3 was taken as sign for the presence of rhythmicity–which occurred more often in the Gjd2 KO than in the WT Purkinje cells (colored fraction in the pie diagrams; p = 0.005; Fisher’s exact test). In the absence of gap junctions, rhythmic firing was more stereotypical, as illustrated by less variation in the time to peak (C; p = 0.0431; U = 1030.0; Mann-Whitney test). Note that the left panel of A is a copy of Fig 2B and presented here to facilitate comparison.</p
