Browsing by Subject "Neural Inhibition"

Now showing 1 - 6 of 6
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    Acetylcholine Modulates Cerebellar Granule Cell Spiking by Regulating the Balance of Synaptic Excitation and Inhibition.
    (The Journal of neuroscience : the official journal of the Society for Neuroscience, 2020-04) Fore, Taylor R; Taylor, Benjamin N; Brunel, Nicolas; Hull, Court
    Sensorimotor integration in the cerebellum is essential for refining motor output, and the first stage of this processing occurs in the granule cell layer. Recent evidence suggests that granule cell layer synaptic integration can be contextually modified, although the circuit mechanisms that could mediate such modulation remain largely unknown. Here we investigate the role of ACh in regulating granule cell layer synaptic integration in male rats and mice of both sexes. We find that Golgi cells, interneurons that provide the sole source of inhibition to the granule cell layer, express both nicotinic and muscarinic cholinergic receptors. While acute ACh application can modestly depolarize some Golgi cells, the net effect of longer, optogenetically induced ACh release is to strongly hyperpolarize Golgi cells. Golgi cell hyperpolarization by ACh leads to a significant reduction in both tonic and evoked granule cell synaptic inhibition. ACh also reduces glutamate release from mossy fibers by acting on presynaptic muscarinic receptors. Surprisingly, despite these consistent effects on Golgi cells and mossy fibers, ACh can either increase or decrease the spike probability of granule cells as measured by noninvasive cell-attached recordings. By constructing an integrate-and-fire model of granule cell layer population activity, we find that the direction of spike rate modulation can be accounted for predominately by the initial balance of excitation and inhibition onto individual granule cells. Together, these experiments demonstrate that ACh can modulate population-level granule cell responses by altering the ratios of excitation and inhibition at the first stage of cerebellar processing.SIGNIFICANCE STATEMENT The cerebellum plays a key role in motor control and motor learning. While it is known that behavioral context can modify motor learning, the circuit basis of such modulation has remained unclear. Here we find that a key neuromodulator, ACh, can alter the balance of excitation and inhibition at the first stage of cerebellar processing. These results suggest that ACh could play a key role in altering cerebellar learning by modifying how sensorimotor input is represented at the input layer of the cerebellum.
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    Inhibition stabilization is a widespread property of cortical networks.
    (eLife, 2020-06-29) Sanzeni, Alessandro; Akitake, Bradley; Goldbach, Hannah C; Leedy, Caitlin E; Brunel, Nicolas; Histed, Mark H
    Many cortical network models use recurrent coupling strong enough to require inhibition for stabilization. Yet it has been experimentally unclear whether inhibition-stabilized network (ISN) models describe cortical function well across areas and states. Here, we test several ISN predictions, including the counterintuitive (paradoxical) suppression of inhibitory firing in response to optogenetic inhibitory stimulation. We find clear evidence for ISN operation in mouse visual, somatosensory, and motor cortex. Simple two-population ISN models describe the data well and let us quantify coupling strength. Although some models predict a non-ISN to ISN transition with increasingly strong sensory stimuli, we find ISN effects without sensory stimulation and even during light anesthesia. Additionally, average paradoxical effects result only with transgenic, not viral, opsin expression in parvalbumin (PV)-positive neurons; theory and expression data show this is consistent with ISN operation. Taken together, these results show strong coupling and inhibition stabilization are common features of the cortex.
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    Meclizine enhancement of sensorimotor gating in healthy male subjects with high startle responses and low prepulse inhibition.
    (Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 2014-02) Larrauri, José A; Kelley, Lisalynn D; Jenkins, Mason R; Westman, Eric C; Schmajuk, Nestor A; Rosenthal, M Zachary; Levin, Edward D
    Histamine H1 receptor systems have been shown in animal studies to have important roles in the reversal of sensorimotor gating deficits, as measured by prepulse inhibition (PPI). H1-antagonist treatment attenuates the PPI impairments caused by either blockade of NMDA glutamate receptors or facilitation of dopamine transmission. The current experiment brought the investigation of H1 effects on sensorimotor gating to human studies. The effects of the histamine H1 antagonist meclizine on the startle response and PPI were investigated in healthy male subjects with high baseline startle responses and low PPI levels. Meclizine was administered to participants (n=24) using a within-subjects design with each participant receiving 0, 12.5, and 25 mg of meclizine in a counterbalanced order. Startle response, PPI, heart rate response, galvanic skin response, and changes in self-report ratings of alertness levels and affective states (arousal and valence) were assessed. When compared with the control (placebo) condition, the two doses of meclizine analyzed (12.5 and 25 mg) produced significant increases in PPI without affecting the magnitude of the startle response or other physiological variables. Meclizine also caused a significant increase in overall self-reported arousal levels, which was not correlated with the observed increase in PPI. These results are in agreement with previous reports in the animal literature and suggest that H1 antagonists may have beneficial effects in the treatment of subjects with compromised sensorimotor gating and enhanced motor responses to sensory stimuli.
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    On the distribution of firing rates in networks of cortical neurons.
    (The Journal of neuroscience : the official journal of the Society for Neuroscience, 2011-11) Roxin, Alex; Brunel, Nicolas; Hansel, David; Mongillo, Gianluigi; van Vreeswijk, Carl
    The distribution of in vivo average firing rates within local cortical networks has been reported to be highly skewed and long tailed. The distribution of average single-cell inputs, conversely, is expected to be Gaussian by the central limit theorem. This raises the issue of how a skewed distribution of firing rates might result from a symmetric distribution of inputs. We argue that skewed rate distributions are a signature of the nonlinearity of the in vivo f-I curve. During in vivo conditions, ongoing synaptic activity produces significant fluctuations in the membrane potential of neurons, resulting in an expansive nonlinearity of the f-I curve for low and moderate inputs. Here, we investigate the effects of single-cell and network parameters on the shape of the f-I curve and, by extension, on the distribution of firing rates in randomly connected networks.
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    Pinning down response inhibition in the brain--conjunction analyses of the Stop-signal task.
    (Neuroimage, 2010-10-01) Boehler, CN; Appelbaum, LG; Krebs, RM; Hopf, JM; Woldorff, MG
    Successful behavior requires a finely-tuned interplay of initiating and inhibiting motor programs to react effectively to constantly changing environmental demands. One particularly useful paradigm for investigating inhibitory motor control is the Stop-signal task, where already-initiated responses to Go-stimuli are to be inhibited upon the rapid subsequent presentation of a Stop-stimulus (yielding successful and unsuccessful Stop-trials). Despite the extensive use of this paradigm in functional neuroimaging, there is no consensus on which functional comparison to use to characterize response-inhibition-related brain activity. Here, we utilize conjunction analyses of successful and unsuccessful Stop-trials that are each contrasted against a reference condition. This conjunction approach identifies processes common to both Stop-trial types while excluding processes specific to either, thereby capitalizing on the presence of some response-inhibition-related activity in both conditions. Using this approach on fMRI data from human subjects, we identify a network of brain structures that was linked to both types of Stop-trials, including lateral-inferior frontal and medial frontal cortical areas and the caudate nucleus. In addition, comparisons with a reference condition matched for visual stimulation identified additional activity in the right inferior parietal cortex that may play a role in enhancing the processing of the Stop-stimuli. Finally, differences in stopping efficacy across subjects were associated with variations in activity in the left anterior insula. However, this region was also associated with general task accuracy (which furthermore correlated directly with stopping efficacy), suggesting that it might actually reflect a more general mechanism of performance control that supports response inhibition in a relatively nonspecific way.
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    Regulation of DLK-1 kinase activity by calcium-mediated dissociation from an inhibitory isoform.
    (Neuron, 2012-11-08) Yan, Dong; Jin, Yishi
    MAPKKK dual leucine zipper-bearing kinases (DLKs) are regulators of synaptic development and axon regeneration. The mechanisms underlying their activation are not fully understood. Here, we show that C. elegans DLK-1 is activated by a Ca(2+)-dependent switch from inactive heteromeric to active homomeric protein complexes. We identify a DLK-1 isoform, DLK-1S, that shares identical kinase and leucine zipper domains with the previously described long isoform DLK-1L but acts to inhibit DLK-1 function by binding to DLK-1L. The switch between homo- or heteromeric DLK-1 complexes is influenced by Ca(2+) concentration. A conserved hexapeptide in the DLK-1L C terminus is essential for DLK-1 activity and is required for Ca(2+) regulation. The mammalian DLK-1 homolog MAP3K13 contains an identical C-terminal hexapeptide and can functionally complement dlk-1 mutants, suggesting that the DLK activation mechanism is conserved. The DLK activation mechanism is ideally suited for rapid and spatially controlled signal transduction in response to axonal injury and synaptic activity.