Timing and Causality in the Generation of Learned Eyelid Responses

The cerebellum-red nucleus-facial motoneuron (Mn) pathway has been reported as being involved in the proper timing of classically conditioned eyelid responses. This special type of associative learning serves as a model of event timing for studying the role of the cerebellum in dynamic motor control. Here, we have re-analyzed the firing activities of cerebellar posterior interpositus (IP) neurons and orbicularis oculi (OO) Mns in alert behaving cats during classical eyeblink conditioning, using a delay paradigm. The aim was to revisit the hypothesis that the IP neurons (IPns) can be considered a neuronal phase-modulating device supporting OO Mns firing with an emergent timing mechanism and an explicit correlation code during learned eyelid movements. Optimized experimental and computational tools allowed us to determine the different causal relationships (temporal order and correlation code) during and between trials. These intra- and inter-trial timing strategies expanding from sub-second range (millisecond timing) to longer-lasting ranges (interval timing) expanded the functional domain of cerebellar timing beyond motor control. Interestingly, the results supported the above-mentioned hypothesis. The causal inferences were influenced by the precise motor and pre-motor spike timing in the cause-effect interval, and, in addition, the timing of the learned responses depended on cerebellar–Mn network causality. Furthermore, the timing of CRs depended upon the probability of simulated causal conditions in the cause-effect interval and not the mere duration of the inter-stimulus interval. In this work, the close relation between timing and causality was verified. It could thus be concluded that the firing activities of IPns may be related more to the proper performance of ongoing CRs (i.e., the proper timing as a consequence of the pertinent causality) than to their generation and/or initiation

An agonist–antagonist cerebellar nuclear system controlling eyelid kinematics during motor learning

The presence of two antagonistic groups of deep cerebellar nuclei neurons has been reported as necessary for a proper dynamic control of learned motor responses. Most models of cerebellar function seem to ignore the biomechanical need for a double activation–deactivation system controlling eyelid kinematics, since most of them accept that, for closing the eyelid, only the activation of the orbicularis oculi (OO) muscle (via the red nucleus to the facial motor nucleus) is necessary, without a simultaneous deactivation of levator palpebrae motoneurons (via unknown pathways projecting to the perioculomotor area). We have analyzed the kinetic neural commands of two antagonistic types of cerebellar posterior interpositus neuron (IPn) (types A and B), the electromyographic (EMG) activity of the OO muscle, and eyelid kinematic variables in alert behaving cats during classical eyeblink conditioning, using a delay paradigm. We addressed the hypothesis that the interpositus nucleus can be considered an agonist–antagonist system controlling eyelid kinematics during motor learning. To carry out a comparative study of the kinetic–kinematic relationships, we applied timing and dispersion pattern analyses. We concluded that, in accordance with a dominant role of cerebellar circuits for the facilitation of flexor responses, type A neurons fire during active eyelid downward displacements—i.e., during the active contraction of the OO muscle. In contrast, type B neurons present a high tonic rate when the eyelids are wide open, and stop firing during any active downward displacement of the upper eyelid. From a functional point of view, it could be suggested that type B neurons play a facilitative role for the antagonistic action of the levator palpebrae muscle. From an anatomical point of view, the possibility that cerebellar nuclear type B neurons project to the perioculomotor area—i.e., more or less directly onto levator palpebrae motoneurons—is highly appealing

The epigenetic factor CBP is required for the differentiation and function of medial ganglionic eminence-derived interneurons

The development of inhibitory circuits depends on the action of a network of transcription factors and epigenetic regulators that are critical for interneuron specification and differentiation. Although the identity of many of these transcription factors is well established, much less is known about the specific contribution of the chromatin-modifying enzymes that sculpt the interneuron epigenome. Here, we generated a mouse model in which the lysine acetyltransferase CBP is specifically removed from neural progenitors at the median ganglionic eminence (MGE), the structure where the most abundant types of cortical interneurons are born. Ablation of CBP interfered with the development of MGE-derived interneurons in both sexes, causing a reduction in the number of functionally mature interneurons in the adult forebrain. Genetic fate mapping experiments not only demonstrated that CBP ablation impacts on different interneuron classes, but also unveiled a compensatory increment of interneurons that escaped recombination and cushion the excitatory-inhibitory imbalance. Consistent with having a reduced number of interneurons, CBP-deficient mice exhibited a high incidence of spontaneous epileptic seizures, and alterations in brain rhythms and enhanced low gamma activity during status epilepticus. These perturbations led to abnormal behavior including hyperlocomotion, increased anxiety and cognitive impairments. Overall, our study demonstrates that CBP is essential for interneuron development and the proper functioning of inhibitory circuitry in vivo.A.M.F. is the recipient of a “Formación de Personal Investigador” fellowship from the Spanish Ministry of Economy and Competitivity (MINECO). B.d.B. is the recipient of a “Juan de La Cierva” contract from MINECO. A.B. research is supported by grants SAF2014-56197-R, PCIN-2015-192-C02-01 and SEV-2013-0317 from MINECO co-financed by ERDF, and grant PROMETEO/2016/006 from the Generalitat Valenciana. A.G. and J.M.D.G. research is supported by grants BFU2017-82375-R from MINECO and from the Tatiana Pérez de Guzman el Bueno Foundation. The Instituto de Neurociencias is a “Centre of Excellence Severo Ochoa.”Peer reviewe

GABA_B1a^-/- mice exhibit a drastic increase in the spectral power of LFP activity in the presence of kainate.

<p>(<i>A</i>) Scheme of the experimental protocol used. LFP activity in the CA1 area was recorded for 30 min to establish a baseline. Then, a HFS protocol (consisting of five 200 Hz, 100 ms trains of pulses at a rate of 1/s) was presented and the evoked LFP activity was recorded for another 30 min. After that, mice were injected with kainate (8 mg/kg), and 60 min later LFP activity was recorded again. Calibration for the selected LFP traces is indicated on the right. (<i>B-G</i>) Histograms representing the maximum values of the spectral power of LFP activity recorded during baseline (BL) recordings, and before and after kainate injection into WT (green histograms) and GABA_B1a^-/- (red histograms) mice. Values of all spectral bands (1–100 Hz) are depicted in <i>B</i>, selected spectral bands in <i>C-G</i> (1–3 Hz in <i>C</i>, 3–8 Hz in <i>D</i>, 8–12 Hz in <i>E</i>, 12–30 Hz in <i>F</i>, and 30–100 Hz in <i>G</i>). Note that for all spectral bands the maximum values of the spectral power were seen in GABA_B1a^-/- mice in the presence of kainate and the second HFS.*, <i>P</i> < 0.05; **, <i>P</i> < 0.01; ***, <i>P</i> < 0.001.</p

GABA_B1a^-/- mice exhibit increased LTP of evoked fEPSPs in the CA1 area while input/output curves and paired-pulse facilitation are normal.

<p>(<i>A</i>) Input/output curves for the CA3-CA1 synapse. A single (100 μs, biphasic) pulse was presented to Schaffer collaterals at increasing intensities (from 0.02 mA to 0.4 mA, in steps of 0.02 mA) while recording evoked fEPSPs in the CA1 area for WT (open circles) and GABA_B1a^-/- (closed circles) mice. Representative fEPSPs recorded from the stratum radiatum evoked with the intensities indicated in the graph (1, 2, 3) are shown at the top for each genotype. Equations corresponding to the best (<i>r</i> ≥ 0.996; <i>P</i> < 0.0001) sigmoid fits of the data [mean ± SEM; n ≥ 8 mice and ≥ 40 measurements for each of the 20 different stimulus intensities applied] are indicated. (<i>B</i>) Paired-pulse facilitation at the CA3-CA1 synapse. The graph shows the slopes of the second fEPSPs expressed as a percentage of the first (mean ± SEM) for six inter-stimulus intervals (10, 20, 40, 100, 200, and 500 ms). WT and GABA_B1a^-/- mice exhibited paired-pulse facilitation at intervals of 10–200 ms (<i>P</i> < 0.01) that was not significantly different between the genotypes (<i>P</i> = 0.342). Representative recordings at 20 ms (top) and 200 ms (bottom) of inter-stimulus interval are shown on top (open circles for WT and closed circles for GABA_B1a^-/-). (<i>C</i>) Time course of LTP in the CA1 area (fEPSP mean ± SEM) following HFS. The HFS was presented after 15 min of baseline recording, at the time marked by the dashed line. The fEPSP is given as a percentage of the baseline (100%) slope. WT and GABA_B1a^-/- mice showed a significant increase (ANOVA, two-tailed) in fEPSP slope following HFS when compared to baseline at day 1 (<i>P</i> < 0.001). fEPSP slope values were significantly (*, <i>P</i> ≤ 0.03) larger for GABA_B1a^-/- than WT mice during the 5 days of recording. fEPSPs collected from WT (open circles) and GABA_B1a^-/- (closed circles) mice before (baseline, B) and after (1, 2) HFS of Schaffer collaterals are shown on top.</p