Dynamics of the reactivity of cortical neurons to repeated electrophoretic application of acetylcholine

Dynamics of reactivity was studied in 50 neurones of the rat sensorimotor cortex to repeated acetylcholine microiontophoresis. By the parameter of response plasticity the neurones are distributed into three groups--unchanging, decreasing and increasing the excitatory component of the reaction. A connection has been established of the type and rate of tonic and evoked activities dynamics with the duration of the excitatory component of neuronal reactions to acetylcholine. The highest probability of these dynamic activity changes manifestation is observed in cholinoceptive neurones with duration of excitatory reaction components to acetylcholine equal to 3.2, 8.1 and 13.5 s.     

Analysis of the reactivity of the sensorimotor neurons of the rat cerebral cortex to acetylcholine

Several types of cholinoceptive neurons have been identified in rat's sensomotor cortex according to response character to ionophoretical application of acetylcholine. The neurons investigated form continuous range according to duration of the excitatory component of reaction to transmitter application. It has been suggested that the duration of this component reflects the important functional properties of the nerve cell.     

Effect of morphine on the sensitivity of cerebral cortical neurons to acetylcholine

Sensitivity of sensorimotor cortical neurons to microiontophoretically applied morphine and acetylcholine has been studied in the experiments on unanesthetized rabbits. The predominant reaction to morphine and acetylcholine was decrease and increase in the rate of neuronal impulse activity, respectively. There was no correlation in the responses to morphine and acetylcholine. Atropine failed to influence the morphine effect. When both drugs are simultaneously applied to neurons, morphine decreases both excitatory and inhibitory responses to acetylcholine. This effect of morphine may occur in the case when the drug is applied in doses which do not change spontaneous neuronal activity. On the contrary, excitatory effect of glutamic acid decreased only when morphine was applied in doses causing local anesthetic effect and decreasing background neuronal activity. It is suggested that morphine can exercise a modulating influence on choline receptors of cortical neurons.     

Central cholinolytic effect of tropane derivatives: structure-activity relationship

The effect of two tropane derivatives on the electric neuronal activity in sensorimotor cortex was studied in rabbits using microiontophoretic method. Unlike atropine they lack aryl and hydroxyl, but possess morpholine and piperazine. The effects of both drugs were opposite to those of acetylcholine. Simultaneous application of tropane derivatives and acetylcholine to one neuron decreased both excitatory and inhibitory neuronal responses to acetylcholine. It is concluded that aryl and hydroxyl are not necessary for tropane derivatives to reveal their central cholinolytic activity.     

Plasticity and its physiological markers in the microsystem of cortical neurons during repeated local stimulation

Separate neuronal microsystems in the sensomotor cerebral cortex are able to exhibit the functional plasticity under conditions of repeated action of acetylcholine applied microiontophoretically. The characteristic properties of dynamics in activity of single cortex neurones are determined mainly by the initial reactivity to transmitter and by the state of nervous cells of the surrounding microsystem. The composition and succession of response components as well the duration of excitatory stage of reaction to acetylcholine serve as physiological markers of plastic properties of neurones in cortical microsystem.     

The cellular basis of cerebellar plasticity

Activity-dependent plasticity of the cerebellar neuronal circuitry is based on a unique synaptic plasticity known as long-term depression that occurs as a result of the interaction of two distinct types of excitatory synapses in Purkinje cells. A complex chain reaction of receptors and messengers has recently been revealed to underlie this phenomenon.     

Cellularly-driven differences in network synchronization propensity are differentially modulated by firing frequency

Spatiotemporal pattern formation in neuronal networks depends on the interplay between cellular and network synchronization properties. The neuronal phase response curve (PRC) is an experimentally obtainable measure that characterizes the cellular response to small perturbations, and can serve as an indicator of cellular propensity for synchronization. Two broad classes of PRCs have been identified for neurons: Type I, in which small excitatory perturbations induce only advances in firing, and Type II, in which small excitatory perturbations can induce both advances and delays in firing. Interestingly, neuronal PRCs are usually attenuated with increased spiking frequency, and Type II PRCs typically exhibit a greater attenuation of the phase delay region than of the phase advance region. We found that this phenomenon arises from an interplay between the time constants of active ionic currents and the interspike interval. As a result, excitatory networks consisting of neurons with Type I PRCs responded very differently to frequency modulation compared to excitatory networks composed of neurons with Type II PRCs. Specifically, increased frequency induced a sharp decrease in synchrony of networks of Type II neurons, while frequency increases only minimally affected synchrony in networks of Type I neurons. These results are demonstrated in networks in which both types of neurons were modeled generically with the Morris-Lecar model, as well as in networks consisting of Hodgkin-Huxley-based model cortical pyramidal cells in which simulated effects of acetylcholine changed PRC type. These results are robust to different network structures, synaptic strengths and modes of driving neuronal activity, and they indicate that Type I and Type II excitatory networks may display two distinct modes of processing information.     

Cholinergic modulation of neuronal spike reactions to dendritic and somatic application of excitatory acids

Acetylcholine effects on neuronal firing responses evoked by somatic or dendritic applications of excitatory amino acids were studied in slices of guinea-pig parietal cortex. Excitatory reactions initiated by dendritic activation were enhanced by acetylcholine wherever it was iontophoretically applied: either to soma or dendrites. The effect consisted in shortening spike response latencies and increasing response intensity and duration. The modified responses were recorded within 1-min interval after acetylcholine microinjections at a distance within 300 microns of the soma. Parameters of responses to somatic applications of excitatory amino acids were not significantly changed by acetylcholine. The results suggest that acetylcholine improves dendritic propagation rather than membrane excitability.     

Antagonism of N-methyl-D-aspartate (NMDA) evoked increases in cerebellar cGMP and striatal ACh release by phencyclidine (PCP) receptor agonists: evidence for possible allosteric coupling of NMDA and PCP receptors

A comparison was made of the actions of phencyclidine receptor agonists and N-methyl-D-aspartate (NMDA) receptor antagonists in two well-defined neurochemical test systems. These included (i) [3H]acetylcholine release from striatal cholinergic interneurons in vitro, a system known to be positively modulated by corticostriatal excitatory amino acid inputs in vivo; and (ii) cerebellar cGMP levels in vivo, an indicator of cerebellar Purkinje cell activity, which is also modulated by excitatory amino acid inputs. Using these neuronal systems, we report that phencyclidine receptor agonists demonstrated a noncompetitive antagonism of NMDA receptor agonist actions.     

Surprising Effects of Synaptic Excitation

Typically, excitatory synaptic coupling is thought of as an influence that accelerates and propagates firing in neuronal networks. This paper reviews recent results explaining how, contrary to these expectations, the presence of excitatory synaptic coupling can drastically slow oscillations in a network and how localized, sustained activity can arise in a network with purely excitatory coupling, without sustained inputs. These two effects stem from interactions of excitatory coupling with two different forms of intrinsic neuronal dynamics, and both serve to highlight the fact that the influence of synaptic coupling in a network depends strongly on the intrinsic properties of cells in the network.This work was partially supported by the National Science Foundation, under award DMS-0414023     

Identification and functional expression of a family of nicotinic acetylcholine receptor subunits in the central nervous system of the mollusc Lymnaea stagnalis

We described a family of nicotinic acetylcholine receptor (nAChR) subunits underlying cholinergic transmission in the central nervous system (CNS) of the mollusc Lymnaea stagnalis. By using degenerate PCR cloning, we identified 12 subunits that display a high sequence similarity to nAChR subunits, of which 10 are of the alpha-type, 1 is of the beta-type, and 1 was not classified because of insufficient sequence information. Heterologous expression of identified subunits confirms their capacity to form functional receptors responding to acetylcholine. The alpha-type subunits can be divided into groups that appear to underlie cation-conducting (excitatory) and anion-conducting (inhibitory) channels involved in synaptic cholinergic transmission. The expression of the Lymnaea nAChR subunits, assessed by real time quantitative PCR and in situ hybridization, indicates that it is localized to neurons and widespread in the CNS, with the number and localization of expressing neurons differing considerably between subunit types. At least 10% of the CNS neurons showed detectable nAChR subunit expression. In addition, cholinergic neurons, as indicated by the expression of the vesicular ACh transporter, comprise approximately 10% of the neurons in all ganglia. Together, our data suggested a prominent role for fast cholinergic transmission in the Lymnaea CNS by using a number of neuronal nAChR subtypes comparable with vertebrate species but with a functional complexity that may be much higher.     

Inhibition of excitatory neuronal cell death by cell-permeable calcineurin autoinhibitory peptide

In glutamate-mediated excitatory neuronal cell death, immunosuppressants (FK506, Cys-A) are powerful agents that protect neurons from apoptosis. Immunosuppressants inhibit two types of enzyme, calcium/calmodulin-dependent protein phosphatase (calcineurin: CaN), and peptidyl-prolyl cis-trans-isomerase (PPIase) activity such as the FKBP family. In this study, we used a protein transduction approach to determine the functional role of CaN and to produce a potential therapeutic agent for glutamate-mediated neuronal cell death. We created a novel cell-permeable CaN autoinhibitory peptide using the 11 arginine protein transduction domain. This peptide was highly efficient at transducing into primary culture neurons, potently inhibited CaN phosphatase activities, and inhibited glutamate-mediated neuronal cell death. These results showed that CaN plays an important role in excitatory neuronal cell death and cell-permeable CaN autoinhibitory peptide could be a new drug to protect neurons from excitatory neuronal death.     

Reactions of neurons in the sensory-motor cortex on different amounts of administered acetylcholine

As a result of acetylcholine iontophoresis with different currents 3-fold increase of transmitter compared with the threshold one for reaction has been shown not to result in change of a type of reaction pattern more than in 80.3% of neurones. Such increase of action force is quite enough for the significant lengthening of the reaction excitatory components in the most of investigated neurones. After the following repeated application of smaller quantity of transmitter the number of neurones with growth of frequency of excited impulsive activity recovers as well as the level of firing frequency decrease in the course of repetitive administration of transmitter. The effect of large doses of transmitter results in aftereffect expressed by increasing probability of excitatory component reduction during the repetitive applications of acetylcholine.     

Functionally opposite receptors on neurones.

According to the second general principle of chemical neurotransmission, formulated by Eccles, a neurotransmitter released from the axonal terminals of a neurone has only one and the same effect on all the follower cells: all the follower cells are either excited or inhibited by it. The evidence reviewed in this paper suggests that there may be some exceptions to this general pattern of synaptic organisation. The co-existence of both excitatory and inhibitory receptors for the same transmitter substance on the same neuronal membrane has been described in invertebrates: ‘opposite receptors’ can occur for acetylcholine, dopamine and glutamate. There is also evidence suggesting the existence of opposite receptors for acetylcholine and nonadrenaline on neurones in the mammalian brain. The activation of functionally opposite receptors results in ‘antagonistic agonism’: the net pharmacological effect is obtained by the algebraic summation of the two opposing component effects. Both the time-course and the polarity of neuronal responses to a given neurotransmitter is influenced by the relationship between the two kinds of receptor. It is suggested that both pre-synaptic and post-synaptic factors may modify this relationship.     

Signal propagation in feedforward neuronal networks with unreliable synapses

In this paper, we systematically investigate both the synfire propagation and firing rate propagation in feedforward neuronal network coupled in an all-to-all fashion. In contrast to most earlier work, where only reliable synaptic connections are considered, we mainly examine the effects of unreliable synapses on both types of neural activity propagation in this work. We first study networks composed of purely excitatory neurons. Our results show that both the successful transmission probability and excitatory synaptic strength largely influence the propagation of these two types of neural activities, and better tuning of these synaptic parameters makes the considered network support stable signal propagation. It is also found that noise has significant but different impacts on these two types of propagation. The additive Gaussian white noise has the tendency to reduce the precision of the synfire activity, whereas noise with appropriate intensity can enhance the performance of firing rate propagation. Further simulations indicate that the propagation dynamics of the considered neuronal network is not simply determined by the average amount of received neurotransmitter for each neuron in a time instant, but also largely influenced by the stochastic effect of neurotransmitter release. Second, we compare our results with those obtained in corresponding feedforward neuronal networks connected with reliable synapses but in a random coupling fashion. We confirm that some differences can be observed in these two different feedforward neuronal network models. Finally, we study the signal propagation in feedforward neuronal networks consisting of both excitatory and inhibitory neurons, and demonstrate that inhibition also plays an important role in signal propagation in the considered networks.     

Genetic basis of autosomal dominant nocturnal frontal lobe epilepsy

In this review the current literature regarding autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is presented and discussed. This disease is caused by mutations of genes coding for subunits of neuronal acetylcholine receptor comprising the sodium/potassium ion channel. To date, three types of mutations of the gene encoding alpha4 subunit of acetylcholine receptor were described in multi-generation families in Australia, Spain, Norway and Japan. Two other types of mutations of the beta2 subunit were also reported in two families, one from Italy and the other from Scotland. Mutations were caused by substitutions of a single nucleotide or by several-nucleotide insertions and result in a decrease or an increase in the activity of the receptor, or its changes in the affinity to the ligand. Recent advances in molecular genetics have provided the means for a better understanding of human epileptogenesis at a molecular level, which facilitates clinical diagnosis and provides a more rational basis of therapy of this form of epilepsy.     

Primary structure of a developmentally regulated nicotinic acetylcholine receptor protein from Drosophila

Acetylcholine is a major excitatory neurotransmitter in the central nervous system of insects. Using DNA probes of the Torpedo nicotinic acetylcholine receptor (AChR) we have isolated two overlapping cDNA clones encoding a putative neuronal AChR protein from the fruitfly, Drosophila melanogaster. The predicted mature protein consists of 497 amino acids, has a calculated mol. wt of 57 340 and shows extensive homology to known AChR subunits from different species along its entire amino acid sequence. Northern analysis revealed a hybridizing mRNA of 3.2 kb in late embryo and in pupae. Expression of the corresponding AChR gene thus characterizes periods of neuronal differentiation in Drosophila.     

Dynamic Excitatory and Inhibitory Gain Modulation Can Produce Flexible,Robust and Optimal Decision-making

Behavioural and neurophysiological studies in primates have increasingly shown the involvement of urgency signals during the temporal integration of sensory evidence in perceptual decision-making. Neuronal correlates of such signals have been found in the parietal cortex, and in separate studies, demonstrated attention-induced gain modulation of both excitatory and inhibitory neurons. Although previous computational models of decision-making have incorporated gain modulation, their abstract forms do not permit an understanding of the contribution of inhibitory gain modulation. Thus, the effects of co-modulating both excitatory and inhibitory neuronal gains on decision-making dynamics and behavioural performance remain unclear. In this work, we incorporate time-dependent co-modulation of the gains of both excitatory and inhibitory neurons into our previous biologically based decision circuit model. We base our computational study in the context of two classic motion-discrimination tasks performed in animals. Our model shows that by simultaneously increasing the gains of both excitatory and inhibitory neurons, a variety of the observed dynamic neuronal firing activities can be replicated. In particular, the model can exhibit winner-take-all decision-making behaviour with higher firing rates and within a significantly more robust model parameter range. It also exhibits short-tailed reaction time distributions even when operating near a dynamical bifurcation point. The model further shows that neuronal gain modulation can compensate for weaker recurrent excitation in a decision neural circuit, and support decision formation and storage. Higher neuronal gain is also suggested in the more cognitively demanding reaction time than in the fixed delay version of the task. Using the exact temporal delays from the animal experiments, fast recruitment of gain co-modulation is shown to maximize reward rate, with a timescale that is surprisingly near the experimentally fitted value. Our work provides insights into the simultaneous and rapid modulation of excitatory and inhibitory neuronal gains, which enables flexible, robust, and optimal decision-making.     

Fasciculin II,a protein inhibitor of acetylcholinesterase,tested on central synapses ofAplysia

Fasciculin II, a potential inhibitor of acetylcholinesterase (AChE), was tested on two types of Aplysia cholinergic receptors: H type, opening Cl- channels; and D type, opening cationic channels. Evoked postsynaptic inhibitory responses and responses to ionophoretic application of acetylcholine (ACh) or carbachol onto H-type receptors were potentiated in the presence of fasciculin II at 10(-9) M, whereas the same concentration of this drug was without effect on the evoked postsynaptic excitatory responses or on the application of ACh or carbachol on D-type receptors. The observed effects of fasciculin II were identical to those obtained with other inhibitors of AChE on the same preparation. The facilitatory effect on the carbachol response in H-type cells indicates that fasciculin II, as other AChE inhibitors, does not act on H-type synapses solely by blocking the hydrolysis of ACh. We concluded that fasciculin II was a good inhibitor of acetylcholinesterase on neuronal preparations in vivo. The results are further discussed as a new element in favor of a previously proposed hypothesis of a molecular interaction between AChE and ACh H-type receptors.     

Spatiotemporal organization of unit activity in the frog tectum and its modification by visual stimuli

Unit activity was recorded in the tectum of curarized frogs during presentation of various visual stimuli (on- and off-responses to diffuse illumination and movement of an object of recognizable shape). It was shown that different types of stimulation lead to the organization of a different distribution of unit activity in the tectum, in the form of excitatory-inhibitory neuronal mosaics; inhibitory responses, limiting and exacerbating the excitatory responses of other neurons, predominate. The differences observed in the spatiotemporal characteristics of the neuronal mosaics under the influence of different stimuli may be evidence of specificity of coding of visual impulses carrying different information from the retina in the tectum.