Cholinergic modulation of synaptic integration and dendritic excitability in the striatum

Modulatory interneurons such as, the cholinergic interneuron, are always a perplexing subject to study. Far from clear-cut distinctions such as excitatory or inhibitory, modulating interneurons can have many, often contradictory effects. The striatum is one of the most densely expressing brain areas for cholinergic markers, and actylcholine (ACh) plays an important role in regulating synaptic transmission and cellular excitability. Every cell type in the striatum has receptors for ACh. Yet even for a given cell type, ACh affecting different receptors can have seemingly opposing roles. This review highlights relevant effects of ACh on medium spiny neurons (MSNs) of the striatum and suggests how its many effects may work in concert to modulate MSN firing properties.     

Responses of cortical neurons to local application of excitatory amino acids to their dendrites and soma

The efficacy of excitation induced by iontophoretic application of excitatory amino acids to the soma or different parts of the dendritic tree has been compared in experiments performed on parietal cortex slices. Spike activity was recorded extracellularly from single nerve cells of layer V. In total, the responses of 125 neurons were analyzed. Upon application of glutamate and aspartate to the neuronal soma and the majority of dendrites, latencies of excitatory responses did not exceed 500 msec. In 18% of cases, neuronal responses to transmitter application to basal and apical dendrites had longer (2–3 sec) latencies. The maximum intensity of responses was observed when excitatory amino acids had been applied to the soma or proximal parts of dendrites. If applied at a distance of over 100 µm to basal and 300 µm to apical dendrites, glutamate and aspartate elicited cellular responses whose intensity was 2–3 times lower than that of the responses induced by application to the soma. The maximum distances at which somatic spike responses could be recorded were 350 µm and 800 µm for basal and apical dendrites, respectively. Different latencies of the responses to somatic and dendritic applications of excitatory amino acids in some neurons, as well as high efficacy of responses to stimulation of remote parts of dendritic tree, may indicate nonidentity of electrical properties of dendritic and somatic membranes.Neirofiziologiya/Neurophysiology, Vol. 25, No. 6, pp. 437–446, November–December, 1993.     

The influences of somatic and dendritic inhibition on bursting patterns in a neuronal circuit model

The balance between inhibition and excitation plays a crucial role in the generation of synchronous bursting activity in neuronal circuits. In human and animal models of epilepsy, changes in both excitatory and inhibitory synaptic inputs are known to occur. Locations and distribution of these excitatory and inhibitory synaptic inputs on pyramidal cells play a role in the integrative properties of neuronal activity, e.g., epileptiform activity. Thus the location and distribution of the inputs onto pyramidal cells are important parameters that influence neuronal activity in epilepsy. However, the location and distribution of inhibitory synapses converging onto pyramidal cells have not been fully studied. The objectives of this study are to investigate the roles of the relative location of inhibitory synapses on the dendritic tree and soma in the generation of bursting activity. We investigate influences of somatic and dendritic inhibition on bursting activity patterns in several paradigms of potential connections using a simplified multicompartmental model. We also investigate the effects of distribution of fast and slow components of GABAergic inhibition in pyramidal cells. Interspike interval (ISI) analysis is used for examination of bursting patterns. Simulations show that the inhibitory interneuron regulates neuronal bursting activity. Bursting behavior patterns depend on the synaptic weight and delay of the inhibitory connection as well as the location of the synapse. When the inhibitory interneuron synapses on the pyramidal neuron, inhibitory action is stronger if the inhibitory synapse is close to the soma. Alterations of synaptic weight of the interneuron can be compensatory for changes in the location of synaptic input. The relative changes in these parameters exert a considerable influence on whether synchronous bursting activity is facilitated or reduced. Additional simulations show that the slow GABAergic inhibitory component is more effective than the fast component in distal dendrites. Taken together, these findings illustrate the potential for GABAergic inhibition in the soma and dendritic tree to play an important modulatory role in bursting activity patterns.     

Fractal and nonfractal analysis of cell images: comparison and application to neuronal dendritic arborization

 Neurons of the rat spinal cord were stained using the Golgi impregnation method. Successfully impregnated neurons from laminae II, III, and VI were subjected to fractal and nonfractal analyses. Fractal analysis was performed using length-related techniques. Since an application of fractal methods to the analysis of dendrite arbor structures requires caution, we adopted as appropriate a nonfractal method proposing a generalized power-law model with two main nonfractal parameters: (i) the anfractuosity, characterizing the degree of dendritic deviation from straight lines; and (ii) an estimate of the total length of arbor dendrites. The anfractuosity can distinguish between two sets of drawings where the fractal methods failed. We also redefine some basic concepts of fractal geometry, present the ruler-counting method, and propose a new definition of fractal dimension. Received: 5 February 2002 / Accepted: 25 June 2002 Acknowledgement. We thank Ing. Dejan Ristanović for preparing the computer program used in this study. Correspondence to: D. Ristanović (e-mail: dusan@ristanovic.com, Tel.: +381-11-3615767)     

Cholinergic modulation of skill learning and plasticity

The basal forebrain cholinergic system strongly influences both cortical plasticity and learning. Directly relating these two roles has proven difficult. New results indicate that nucleus basalis lesions prevent motor cortex map plasticity and impair skill learning. These results strengthen the hypothesis that nucleus basalis gates neural plasticity necessary for instrumental learning.     

Alias-free sampling of neuronal spike trains

Summary Spectral analysis provides powerful techniques for describing the lower order moments of a stochastic process and interactions between two or more stochastic processes. A major problem in the application of spectral analysis to neuronal spike trains is how to obtain equispaced samples of the spike trains which will give unbiased and alias-free spectral estimates. Various sampling methods, which treat the spike train as a continuous signal, a point process and as a series of Dirac delta-functions, are reviewed and their limitations discussed. A new sampling technique, which gives unbiased and alias-free estimates, is described. This technique treats the spike train as a series of delta functions and generates samples by digital filtering. Implementation of this technique on a small computer is simple and virtually on-line.     

Recurrence plots of neuronal spike trains

The recently developed qualitative method of diagnosis of dynamical systems — recurrence plots has been applied to the analysis of dynamics of neuronal spike trains recorded from cerebellum and red nucleus of anesthetized cats. Recurrence plots revealed robust and common changes in the similarity structure of interspike interval sequences as well as significant deviations from randomness in serial ordering of intervals. Recurring episodes of alike, quasi-deterministic firing patterns suggest the spontaneous modulation of the dynamical complexity of the trajectories of observed neurons. These modulations are associated with changing dynamical properties of a neuronal spike-train-generating system. Their existence is compatible with the information processing paradigm of attractor neural networks.     

Use of `relative-phase' analysis to assess correlation between neuronal spike trains

 We propose a new method of studying the correlation between neuronal spike trains. This technique is based on the analysis of relative phase between two point processes. Relative phase here is defined as the relative timing difference between two spike trains normalized by the associated interspike interval of one cell. This phase measurement is intended to reveal the relative timing relationship between spike trains atdifferent firing rates. We apply this method to a numerical example and an example from two cerebellar neuronal spike trains of a behaving rat. The results are compared with classical cross-correlation analysis. We show that the technique can avoid some of the limitations of cross-correlation methods, reveal certain statistical dependencies that cannot be shown by cross correlation, and provide information as to the direction of influence between two spike trains. Received: 8 November 2001 / Accepted: 30 September 2002 / Published online: 24 January 2003 Correspondence to: Y. Chen (e-mail: chen@nsi.edu, Fax: + 1-858-626-2099) Acknowledgements. Research for this paper was supported by the Alafi Family Foundation and the Neurosciences Research Foundation.     

Behavior-related neuronal reactions and dynamics of neuronal activity

Functionally, behavior-related discharges of associative neurons are an efferent flow of pulses continuously generated over the course of each behavioral act of an animal. However, predominant research approaches are based on the "stimulus - reaction" principle. Analysis of the dynamics of unit activity in monkeys during performance of a multi-step behavioral complex showed that differences related to different behavioral acts consist in composition changes in the active neurons (or their recombination) rather than in a number of responsive cells or involvement of action-specific neurons. Each combination of active neurons ensures the distribution of efferent signals characteristic of the given combination. These findings suggest the addressing coding of the efferent neuronal signals.     

A mathematical model of the effects of spatio-temporal patterns of dendritic input potentials on neuronal somatic potentials

A mathematical model of a neuron was developed to investigate the effects of various spatio-temporal patterns of miniature dendritic input potentials on neuronal somatic potentials. The model treats spatio-temporal dendritic activation patterns as the input or forcing function in the non-homogeneous cable equation. The theoretical somatic potentials resulting from several different spatio-temporal input patterns were generated on an IBM 360/75 computer. The model allows the investigation of the theoretical effects of activations at several different synaptic sites, of repeated activations at one or more sites, and of changes in various parameters. The time-to-peak and amplitude of individual excitatory postsynaptic potentials, distance of synapses from the soma, and interactivation interval for repeated activations at the same synapse were among the parameters investigated. Not only the order of activations at different synaptic sites was important, but the time intervals between activations were shown to be important. For a given order of activations at different synapses, optimum time intervals between activations were demonstrated, with respect to the resulting peak somatic potentials. Possible consequences of some hypothetical learning and memory mechanisms upon neuronal excitability were discussed. It was also shown that a deterministic model can generate theoretical curves which appear to be almost of a random nature with respect to the observed numbers and amplitudes of peaks of individual EPSPs. The conditions for the appearance of extra peaks were discussed.This paper describes work done as a portion of G.M.B.'s Ph. D. thesis in biomathematics at N.C. State University, and was supported by Public Health Service Grant No. GM-678 from the National Institute of General Medical Sciences.     

成年小鼠前脑NMDA受体参与神经元的动作电位发放

谷氨酸是中枢神经系统主要的快速兴奋性递质。AMPA受体和海人藻酸受体主要参与突触传递,而NMDA受体主要参与突触可塑性。基因操作的方法增强NMDA受体的功能,可以增强动物在正常生理状态下的学习能力,及在组织损伤情况下的反应敏感性。NMDA受体参与生理功能的主要机制是长时程增强（long—term potentiation,LTP）。我们的研究表明,NMDA受体不仅参与刺激前扣带皮层的第五层细胞或刺激白质诱导的突触反应,而且参与在胞体施加去极化跃阶电流诱导的动作电位的发放。钙一钙调蛋白敏感的腺苷酸环化酶1（adenylyl cyclase 1,AC1）和cAMP信号通路可能介导了这些反应。由于扣带皮层神经元在伤害性刺激和痛中发挥重要作用,我们的结果为前脑NMDA受体参与突触传递和动作电位发放,以及与前脑相关的行为,如感受伤害性刺激和痛,提供了一个新的机制。     

Synaptic modulation of neuronal coupling

Electrotonic coupling among neurons in the vertebrate, and more specifically the mammalian, brain has now been demonstrated to exist in all major brain subdivisions and in the spinal cord. For many of these brain areas, recent studies have investigated the possibilities of modulation of that coupling by synaptically released transmitters and/or neuromodulators. Reviewed here is the evidence for coupling, the synaptically related factors that play roles in up- or downregulation of this type of intercellular interaction and, to the extent that they have been investigated, the intracellular mechanisms operative in changing the extent of coupled networks in the brain. The functional significance of coupling and its modulation is discussed for some of these areas.     

Cholinergic modulation of experience-dependent plasticity in human auditory cortex

The factors that influence experience-dependent plasticity in the human brain are unknown. We used event-related functional magnetic resonance imaging (fMRI) and a pharmacological manipulation to measure cholinergic modulation of experience-dependent plasticity in human auditory cortex. In a differential aversive conditioning paradigm, subjects were presented with high (1600 Hz) and low tones (400 Hz), one of which was conditioned by pairing with an electrical shock. Prior to presentation, subjects were given either a placebo or an anticholinergic drug (0.4 mg iv scopolamine). Experience-dependent plasticity, expressed as a conditioning-specific enhanced BOLD response, was evident in auditory cortex in the placebo group, but not with scopolamine. This study provides in vivo evidence that experience-dependent plasticity, evident in hemodynamic changes in human auditory cortex, is modulated by acetylcholine.     

Cholinergic modulation of anaphylactic shock: plasma proteins influence

Cholinergic drugs can modulate anaphylactic shock and change lymphocyte functions. Plasma proteins modulate effects of muscarinic antagonists during anaphylactic shock. The present investigation was carried out to study the antianaphylactic activity of methacine (antagonist at muscarinic receptors) in combination with neostigmine (anticholinesterase drug). However, it is not known whether plasma proteins-albumin, C-reactive protein (CRP) and immunoglobulin G (IgG) - modify the effects of cholinergic drugs like methacine, serotonin (5-HT) level in the lymphoid organs and quantity of antibody-forming cells (AFC) in the spleen of guinea pigs during experimental anaphylactic shock. It was shown that administration of methacine with neostigmine (40 min and 15 min prior to shock induction, accordingly) at the pathochemical stage revokes shock development. By blocking cholinesterase endogenous acetylcholine is increased and methacine blocks muscarinic receptors and therewith unwanted side effects in the airways (bronchoconstriction) and heart (bradycardia). Administration of the combination of methacine with neostigmine at the immunological stage (guinea pig sensitization) does not affect the course of anaphylactic shock. Administration of methacine with IgG at the pathochemical stage of shock significantly decreases shock intensity, while administration of methacine with CRP or albumin has no influence on the shock. Administration of IgG or CRP (not albumin) at the immunological stage of shock and albumin or IgG (not CRP) at the pathochemical stage leads to reduction of the anaphylactic reaction. Application of methacine with neostigmine or IgG (effective combinations of drugs) results in normalization of antibody response in the spleen and 5-HT level in the lymphoid organs. Administration of methacine with CRP or albumin (ineffective combinations of drugs) leads to increase of antibody response in the spleen and 5-HT level in the lymphoid organs. Administration of hexamethonium or aceclidine aggravated anaphylactic shock reaction. Thus, the combination of methacine with neostigmine can regulate the pathochemical stage of shock and the 5-HT release. At the pathochemical stage of shock IgG increases the antianaphylactic activity of methacine, but albumin and CRP abolish it.     

The mouse neocortical slice: preparation and responses to excitatory amino acids

1. An improved method of preparing wedges of cerebral cortex and corpus callosum from 500 microM thick coronal sections using mouse brain is described. 2. The characteristics of mixing in the two compartment baths is fully reported. 3. Cortical tissue could be depolarized relative to callosal tissue by superfusion of N-methyl-D-aspartate (NMDA), quinolinate, kainate or quisqualate. 4. At higher concentrations of agonists the depolarization was followed by a small hyperpolarization. This hyperpolarization was abolished by 5 microM ouabain. 5. Neither TTX (1 microM) nor bicuculline (50-62.5 microM) significantly affected the amplitude of the responses to the excitatory amino acids. 6. Responses to NMDA and quinolinate were selectively reduced by magnesium ions, 2-amino-5-phosphonovalerate or ketamine.     

Pooling of impulse sequences,with emphasis on applications to neuronal spike data

Summary A mathematical model is presented that is supposed to describe those types of neuronal discharges which show a preponderance of short intervals, as well as one or more preferred intervals of a longer duration. It is assumed that via two channels impulses impinge upon a nerve cell and that each impulse gives rise to a response. The intervals between impulses in one channel are distributed according to an exponential, or an exponential-like, function; those in the other channel are distributed according to a monomodal, or a multimodal, function.The interval distributions and the expectation density (auto-correlation) functions of the model are in particular compared with data on thalamic neuron discharge patterns reported in the literature.The properties of superimposed time series of events would seem to be of a wider interest, stretching beyond the field of theoretical neurophysiology. It is indicated how the theory is of use in the detection of hidden rhythms in records which are composed of a mixture of different signals.