114 research outputs found
Lesson from the neuromuscular junction: role of pattern and timing of nerve activity in synaptic development
No full text[No abstract available
Enhanced thalamocortical synaptic transmission and dysregulation of the excitatory-inhibitory balance at the thalamocortical feed-forward inhibitory microcircuit in a genetic mouse model of migraine
No full textMigraine is a complex brain disorder, characterized by attacks of unilateral headache and global dysfunction in multisensory information processing, whose underlying cellular and circuit mechanisms remain unknown. The finding of enhanced excitatory, but unaltered inhibitory, neurotransmission at intracortical synapses in mouse models of familial hemiplegic migraine (FHM) suggested the hypothesis that dysregulation of the excitatory-inhibitory balance in specific circuits is a key pathogenic mechanism. Here, we investigated the thalamocortical (TC) feed-forward inhibitory microcircuit in FHM1 mice of both sexes carrying a gain-of-function mutation in CaV2.1. We show that TC synaptic transmission in somatosensory cortex is enhanced in FHM1 mice. Due to similar gain-of-function of TC excitation of layer 4 excitatory and fast-spiking inhibitory neurons elicited by single thalamic stimulations, neither the excitatory-inhibitory balance nor the integration time window set by the TC feed-forward inhibitory microcircuit were altered in FHM1 mice. However, during repetitive thalamic stimulation, the typical shift of the excitatory-inhibitory balance towards excitation and the widening of the integration time window were both smaller in FHM1 compared to wild-type mice, revealing a dysregulation of the excitatory-inhibitory balance, whereby the balance is relatively skewed towards inhibition. This is due to an unexpected differential effect of the FHM1 mutation on short-term synaptic plasticity at TC synapses on cortical excitatory and fast-spiking inhibitory neurons. Our findings point to enhanced transmission of sensory, including trigeminovascular nociceptive, signals from thalamic nuclei to cortex and TC excitatory-inhibitory imbalance as mechanisms that may contribute to headache, increased sensory gain, and sensory processing dysfunctions in migraine
Synaptic cooperativity regulates persistent network activity in neocortex
No full textDuring behavioral quiescence, the neocortex generates spontaneous slow oscillations, which may consist of up-states and down-states. Up-states are short epochs of persistent activity that resemble the activated neocortex during arousal and cognition. Neural activity in neocortical pathways can trigger up-states, but the variables that control their occurrence are poorly understood. We used thalamocortical slices from adult mice to explore the role of thalamocortical and intracortical synaptic cooperativity (the number of coincident afferents) in driving up-states. Cooperativity was adjusted by varying the intensity of electrical or blue-light stimuli in pathways that express channelrhodopsin-2. We found that optogenetics greatly improves the study of thalamocortical pathways in slices because it produces thalamocortical responses that resemble those observed in vivo. The results indicate that more synaptic cooperativity, caused by either thalamocortical or intracortical fast AMPA-receptor excitation, leads to more robust inhibition of up-states because it drives stronger feedforward inhibition. Conversely, during strong synaptic cooperativity that suppresses up-states, blocking fast excitation, and as a result the feedforward inhibition it drives, unmasks up-states entirely mediated by slow NMDA-receptor excitation. Regardless of the pathway's origin, cooperativity mediated by fast excitation is inversely related to the ability of excitatory synaptic pathways to trigger up-states in neocortex
Adult rat motor neurons do not re-establish electrical coupling during axonal regeneration and muscle reinnervation.
No full textGap junctions (GJs) between neurons are present in both the newborn and the adult nervous system, and although important roles have been suggested or demonstrated in a number of instances, in many other cases a full understanding of their physiological role is still missing. GJs are expressed in the rodent lumbar cord at birth and mediate both dye and electrical coupling between motor neurons. This expression has been proposed to mediate: (i) fast synchronization of motoneuronal spike activity, in turn linked to the process of refinement of neuromuscular connections, and (ii) slow synchronization of locomotor-like oscillatory activity. Soon after birth this coupling disappears. Since in the adult rat regeneration of motor fibers after peripheral nerve injury leads to a recapitulation of synaptic refinement at the target muscles, we tested whether GJs between motor neurons are transiently re-expressed. We found that in conditions of maximal responsiveness of lumbar motor neurons (such as no depression by anesthetics, decerebrate release of activity of subsets of motor neurons, use of temporal and spatial summation by antidromic and orthodromic stimulations, testing of large ensembles of motor neurons) no firing is observed in ventral root axons in response to antidromic spike invasion of nearby counterparts. We conclude that junctional coupling between motor neurons is not required for the refinement of neuromuscular innervation in the adult
Hebb-based rules of neural plasticity: are they ubiquitously important for the refinement of synaptic connections in development?
No full textNeuronal death and suppression of functional synaptic inputs are well-known regressive events characterizing PNS and CNS development. In the CNS, participation of activity in synapse elimination has been known ever since the pioneering studies of Hubel and Wiesel, but only recently has a Hebb-based mechanism of spike synchrony versus asynchrony received unequivocal experimental support in the visual system. At the neuromuscular junction (NMJ), where synapse elimination was discovered, the specific function of the "timing of activity" was addressed by only one group of studies and did not receive widespread attention. Here we critically review the latest NMJ investigation advocating an "activity-independent" mechanism for synapse elimination and contrast it with an equally recent study demonstrating a key role for spike timing. Finally, we highlight how the striking similarities between the two mentioned studies on spike timing (visual system and NMJ) establish conclusively its role in the development of the nervous system in general
Whisker-related afferents in superior colliculus
No full textWhisker-related afferents in superior colliculus. J Neurophysiol 115: 2265–2279, 2016. First published February 10, 2016; doi:10.1152/jn.00028.2016.—Rodents use their whiskers to explore the environment, and the superior colliculus is part of the neural circuits that process this sensorimotor information. Cells in the intermediate layers of the superior colliculus integrate trigeminotectal afferents from trigeminal complex and corticotectal afferents from barrel cortex. Using histological methods in mice, we found that trigeminotectal and corticotectal synapses overlap somewhat as they innervate the lower and upper portions of the intermediate granular layer, respectively. Using electrophysiological recordings and optogenetics in anesthetized mice in vivo, we showed that, similar to rats, whisker deflections produce two successive responses that are driven by trigeminotectal and corticotectal afferents. We then employed in vivo and slice experiments to characterize the response properties of these afferents. In vivo, corticotectal responses triggered by electrical stimulation of the barrel cortex evoke activity in the superior colliculus that increases with stimulus intensity and depresses with increasing frequency. In slices from adult mice, optogenetic activation of channelrhodopsin-expressing trigeminotectal and corticotectal fibers revealed that cells in the intermediate layers receive more efficacious trigeminotectal, than corticotectal, synaptic inputs. Moreover, the efficacy of trigeminotectal inputs depresses more strongly with increasing frequency than that of corticotectal inputs. The intermediate layers of superior colliculus appear to be tuned to process strong but infrequent trigeminal inputs and weak but more persistent cortical inputs, which explains features of sensory responsiveness, such as the robust rapid sensory adaptation of whisker responses in the superior colliculus
The timing of activity is a regulatory signal during development of neural connections.
No full textIn PNS and CNS remarkable rearrangements occur soon after the connections are laid down in the course of embryonic life. These processes clearly follow the period of developmental cell death and mostly take place during the very beginning of postnatal life. They consist in changes of the peripheral fields of neurons, marked by elimination of many inputs, while others undergo further maturation and strengthening. Along the efforts to uncover the signals that regulate development, it turned out that while the initial construction of the circuits is heavily based on chemical cues, the subsequent rearrangement is markedly influence by activity. Here we describe experiments testing the influence on developmental plasticity of a particular aspect of activity, the timing of nerve impulses in the competing inputs. Two recent investigations are reviewed, indicating strikingly similar developmental features in quite different systems, neuromuscular and visual. A sharp contrast between the effects of synchrony and asynchrony emerges, indicating that Hebb-related activity rules are important not only for learning but also for development
Spike timing plays a key role in synapse elimination at the neuromuscular junction.
No full textNerve impulse activity produces both developmental and adult plastic changes in neural networks. For development, however, its precise role and the mechanisms involved remain elusive. Using the classic model of synapse competition and elimination at newly formed neuromuscular junctions, we asked whether spike timing is the instructive signal at inputs competing for synaptic space. Using a rat strain whose soleus muscle is innervated by two nerves, we chronically evoked different temporal spike patterns in the two nerves during synapse formation in the adult. We found that asynchronous activity imposed upon the two nerves promotes synapse elimination, provided that their relative spikes are separated by 25 ms or more; remarkably, this elimination occurs even though an equal number of spikes were evoked in the competing axons. On the other hand, when spikes are separated by 20 ms or less, activity is perceived as synchronous, and elimination is prevented. Thus, in development, as in adult plasticity, precise spike timing plays an instructive role in synaptic modification
NMDA receptors are the basis of persistent network activity in neocortex slices
No full textDuring behavioral quiescence the neocortex generates spontaneous slow oscillations that consist of Up and Down states. Up states are short epochs of persistent activity but their underlying source is unclear. In neocortex slices of adult mice, we monitored several cellular and network variables during the transition between a traditional buffer, that does not cause Up states, and a lower divalent cation buffer, that leads to the generation of Up states. We found that the resting Vm and input resistance of cortical cells did not change with the development of Up states. The synaptic efficacy of excitatory postsynaptic potentials mediated by non-NMDA receptors was slightly reduced but this is unlikely to facilitate the generation of Up states. On the other hand, we identified two variables that are associated with the generation of Up states; an enhancement of the intrinsic firing excitability of cortical cells and an enhancement of NMDA mediated responses evoked by electrical or optogenetic stimulation. The fact that blocking NMDA receptors abolishes Up states indicates that the enhancement in intrinsic firing excitability alone is insufficient to generate Up states. NMDA receptors have a crucial role in the generation of Up states in neocortex slices
The state of somatosensory cortex during neuromodulation.
No full textDuring behavioral quiescence, such as slow-wave sleep and anesthesia, the neocortex is in a deactivated state characterized by the presence of slow oscillations. During arousal, slow oscillations are absent and the neocortex is in an activated state that greatly impacts information processing. Neuromodulators acting in neocortex are believed to mediate these state changes, but the mechanisms are poorly understood. We investigated the actions of noradrenergic and cholinergic activation on slow oscillations, cellular excitability, and synaptic inputs in thalamocortical slices of somatosensory cortex. The results show that neuromodulation abolishes slow oscillations, dampens the excitability of principal cells, and rebalances excitatory and inhibitory synaptic inputs in thalamocortical-recipient layers IV–III. Sensory cortex is much more selective about the inputs that can drive it. The source of neuromodulation is critically important in determining this selectivity. Cholinergic activation suppresses the excitatory and inhibitory conductances driven by thalamocortical and intracortical inputs. Noradrenergic activation suppresses the excitatory conductance driven by intracortical inputs but not by thalamocortical inputs and enhances the inhibitory conductance driven by thalamocortical inputs but not by intracortical inputs. Thus noradrenergic activation emphasizes thalamocortical (sensory) inputs relative to intracortical inputs, while cholinergic activation suppresses both
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