Neuronal models for sleep-wake regulation and synaptic reorganization in the sleeping hippocampus

In this article, we discuss mathematical models that address the control of sleep-wake behavior in the infant and adult rodent and a model that addresses changes in single-cell firing patterns in the hippocampus across wake and rapid eye movement (REM) sleep states. Each of the models describes the dynamics of experimentally identified neuronal components--either the firing activity of wake-and sleep-promoting neuronal populations or the spiking activity of hippocampal pyramidal neurons. Our discussion of each model illustrates how a mathematical model that describes the temporal dynamics of the modeled neuronal components can reveal specifics about proposed neuronal mechanisms that underlie sleep-wake regulation or sleep-specific firing patterns. For example, the dynamics of the models developed for sleep-wake regulation in the infant rodent lend insight into the involved brain-stem neuronal populations and the evolution of the network during maturation. The results of the model for sleep-wake regulation in the adult rodent suggest distinct properties of the involved neuronal populations and their interactions that account for long-lasting and brief waking bouts. The dynamics of the model for sleep-specific hippocampal neural activity proposes neural mechanisms to account for observed activity changes that can invoke synaptic reorganization associated with learning and memory consolidation.     

Neuronal firing: Does function follow form?

Neurons generate diverse firing patterns to perform a range of specialized tasks. Experiments show that many features of these firing patterns arise from distinctive membrane properties, but theoretical work predicts that differences in neuronal morphology are also important.     

Timescales of multineuronal activity patterns reflect temporal structure of visual stimuli

The investigation of distributed coding across multiple neurons in the cortex remains to this date a challenge. Our current understanding of collective encoding of information and the relevant timescales is still limited. Most results are restricted to disparate timescales, focused on either very fast, e.g., spike-synchrony, or slow timescales, e.g., firing rate. Here, we investigated systematically multineuronal activity patterns evolving on different timescales, spanning the whole range from spike-synchrony to mean firing rate. Using multi-electrode recordings from cat visual cortex, we show that cortical responses can be described as trajectories in a high-dimensional pattern space. Patterns evolve on a continuum of coexisting timescales that strongly relate to the temporal properties of stimuli. Timescales consistent with the time constants of neuronal membranes and fast synaptic transmission (5-20 ms) play a particularly salient role in encoding a large amount of stimulus-related information. Thus, to faithfully encode the properties of visual stimuli the brain engages multiple neurons into activity patterns evolving on multiple timescales.     

Place-selective firing of CA1 pyramidal cells during sharp wave/ripple network patterns in exploratory behavior

We observed sharp wave/ripples (SWR) during exploration within brief (<2.4 s) interruptions of or during theta oscillations. CA1 network responses of SWRs occurring during exploration (eSWR) and SWRs detected in waking immobility or sleep were similar. However, neuronal activity during eSWR was location dependent, and eSWR-related firing was stronger inside the place field than outside. The eSPW-related firing increase was stronger than the baseline increase inside compared to outside, suggesting a "supralinear" summation of eSWR and place-selective inputs. Pairs of cells with similar place fields and/or correlated firing during exploration showed stronger coactivation during eSWRs and subsequent sleep-SWRs. Sequential activation of place cells was not required for the reactivation of waking co-firing patterns; cell pairs with symmetrical cross-correlations still showed reactivated waking co-firing patterns during sleep-SWRs. We suggest that place-selective firing during eSWRs facilitates initial associations between cells with similar place fields that enable place-related ensemble patterns to recur during subsequent sleep-SWRs.     

The analytical characteristics of the dynamics of interneuronal functional connections during conditioned-reflex activity]

The dynamics of functional relations between neurons was studied in the frontal cortex of dogs performing reversal conditioning task. To reveal the functionally relevant relationships between the temporal patterns of correlated firing and behavioral events, we developed an original processing technique. The technique included the following procedures: a) isolation of the "coupled spikes" (CS) from simultaneously recorded impulse trains: b) search for the temporal patterns of correlated firings and their classification by clustering single trials with similar temporal distribution of CS; c) assessment of behavioral significance of the identified patterns by evaluation of the probabilities of coincidence of behavioral events and different CS patterns. Significant correlations between impulse trains were revealed in 38 neuronal pairs of 456 analyzed. The effects of change in behavioral context on the CS dynamics during the task performance were found in 87% of neuronal pairs with correlated activity. In 17 pairs the behavioral conditions were identified, under which potentially connected neurons fired independently during all the periods of the behavioral task. The potentialities of the advanced processing technique are discussed. We suggest that this analysis can provide useful information about the temporal distribution of correlated firings under conditions of nonstereotyped behavior, when an animal reacts in the dynamically organized experimental context.     

Variability and randomness in stationary neuronal activity

The patterns of neuronal activity can be different even if the mean firing rate is fixed. Investigating the variability of the firing may not be sufficient and we suggest to take into account the notion of randomness. The randomness is related to the entropy of the firing, which is bounded from above by the entropy of the Poisson process (given the mean interspike interval). Thus, we propose the Kullback-Leibler distance with respect to the Poisson process as a measure of randomness in a stationary neuronal activity. Under the condition of equal mean values the KL distance does not depend on the time scale and therefore can be compared to the coefficient of variation employed to measure the variability. Furthermore, this measure can be extended to account for correlated neuronal firing. Finally, we analyze the variability and randomness for three common ISI distributions in detail: gamma, lognormal and inverse Gaussian.     

Variability v.s. synchronicity of neuronal activity in local cortical network models with different wiring topologies

Dynamical behavior of a biological neuronal network depends significantly on the spatial pattern of synaptic connections among neurons. While neuronal network dynamics has extensively been studied with simple wiring patterns, such as all-to-all or random synaptic connections, not much is known about the activity of networks with more complicated wiring topologies. Here, we examined how different wiring topologies may influence the response properties of neuronal networks, paying attention to irregular spike firing, which is known as a characteristic of in vivo cortical neurons, and spike synchronicity. We constructed a recurrent network model of realistic neurons and systematically rewired the recurrent synapses to change the network topology, from a localized regular and a “small-world” network topology to a distributed random network topology. Regular and small-world wiring patterns greatly increased the irregularity or the coefficient of variation (Cv) of output spike trains, whereas such an increase was small in random connectivity patterns. For given strength of recurrent synapses, the firing irregularity exhibited monotonous decreases from the regular to the random network topology. By contrast, the spike coherence between an arbitrary neuron pair exhibited a non-monotonous dependence on the topological wiring pattern. More precisely, the wiring pattern to maximize the spike coherence varied with the strength of recurrent synapses. In a certain range of the synaptic strength, the spike coherence was maximal in the small-world network topology, and the long-range connections introduced in this wiring changed the dependence of spike synchrony on the synaptic strength moderately. However, the effects of this network topology were not really special in other properties of network activity. Action Editor: Xiao-Jing Wang     

周期激励下FHN模型的两种多峰分布放电节律

文章揭示了外界周期脉冲激励下神经元系统产生的随机整数倍和混沌多峰放电节律的关系.随机节律统计直方图呈多峰分布、峰值指数衰减、不可预报且复杂度接近1;混沌节律统计直方图呈不同的多峰分布,峰值非指数衰减、有一定的可预报性且复杂度小于1.混沌节律在激励脉冲周期小于系统内在周期且刺激强度较大时产生,参数范围较小;而随机节律在激励脉冲周期大于系统内在周期且脉冲刺激强度小时,可与随机因素共同作用而产生,产生的参数范围较大.上述结果揭示了两类节律的动力学特性,为区分两类节律提供了实用指标.     

Microarray Noninvasive Neuronal Seizure Recordings from Intact Larval Zebrafish

Zebrafish epilepsy models are emerging tools in experimental epilepsy. Zebrafish larvae, in particular, are advantageous because they can be easily genetically altered and used for developmental and drug studies since agents applied to the bath penetrate the organism easily. Methods for electrophysiological recordings in zebrafish are new and evolving. We present a novel multi-electrode array method to non-invasively record electrical activity from up to 61 locations of an intact larval zebrafish head. This method enables transcranial noninvasive recording of extracellular field potentials (which include multi-unit activity and EEG) to identify epileptic seizures. To record from the brains of zebrafish larvae, the dorsum of the head of an intact larva was secured onto a multi-electrode array. We recorded from individual electrodes for at least three hours and quantified neuronal firing frequency, spike patterns (continuous or bursting), and synchrony of neuronal firing. Following 15 mM potassium chloride- or pentylenetetrazole-infusion into the bath, spike and burst rate increased significantly. Additionally, synchrony of neuronal firing across channels, a hallmark of epileptic seizures, also increased. Notably, the fish survived the experiment. This non-invasive method complements present invasive zebrafish neurophysiological techniques: it affords the advantages of high spatial and temporal resolution, a capacity to measure multiregional activity and neuronal synchrony in seizures, and fish survival for future experiments, such as studies of epileptogenesis and development.     

Coemergence of regularity and complexity during neural network development

With the growing recognition that rhythmic and oscillatory patterns are widespread in the brain and play important roles in all aspects of the function of our nervous system, there has been a resurgence of interest in neuronal synchronized bursting activity. Here, we were interested in understanding the development of synchronized bursts as information-bearing neuronal activity patterns. For that, we have monitored the morphological organization and spontaneous activity of neuronal networks cultured on multielectrode-arrays during their self-executed evolvement from a mixture of dissociated cells into an active network. Complex collective network electrical activity evolved from sporadic firing patterns of the single neurons. On the system (network) level, the activity was marked by bursting events with interneuronal synchronization and nonarbitrary temporal ordering. We quantified these individual-to-collective activity transitions using newly-developed system level quantitative measures of time series regularity and complexity. We found that individual neuronal activity before synchronization was characterized by high regularity and low complexity. During neuronal wiring, there was a transient period of reorganization marked by low regularity, which then leads to coemergence of elevated regularity and functional (nonstochastic) complexity. We further investigated the morphology-activity interplay by modeling artificial neuronal networks with different topological organizations and connectivity schemes. The simulations support our experimental results by showing increased levels of complexity of neuronal activity patterns when neurons are wired up and organized in clusters (similar to mature real networks), as well as network-level activity regulation once collective activity forms.     

Low dimensional model of bursting neurons

A computationally efficient, biophysically-based model of neuronal behavior is presented; it incorporates ion channel dynamics in its two fast ion channels while preserving simplicity by representing only one slow ion current. The model equations are shown to provide a wide array of physiological dynamics in terms of spiking patterns, bursting, subthreshold oscillations, and chaotic firing. Despite its simplicity, the model is capable of simulating an extensive range of spiking patterns. Several common neuronal behaviors observed in vivo are demonstrated by varying model parameters. These behaviors are classified into dynamical classes using phase diagrams whose boundaries in parameter space prove to be accurately delineated by linear stability analysis. This simple model is suitable for use in large scale simulations involving neural field theory or neuronal networks.     

The influence of early experience on the development of sensory systems

Once sensory stimuli become able to alter firing patterns in the developing brain, they can influence the maturation of neuronal circuits. Recent experimental studies add to our understanding of precisely which developmental events are affected by early experience. In particular, it appears that experience of the external environment can affect the brain earlier in development and at earlier stages of sensory processing than previously thought. These studies emphasise the developmental importance of the patterning of neuronal firing produced either by sensory stimuli or by spontaneous activity. The timing of action potentials is also an important aspect of several exciting studies describing the mechanisms - anatomical, synaptic, and molecular - by which early experience brings about alterations in the maturation of sensory circuitry. Importantly, this kind of approach can lead to predictions concerning the nature of sensory stimulation that is most effective in instructing brain development.     

Lipopolysaccharide effects on neuronal activity in rat basal forebrain and hypothalamus during sleep and waking

Peripheral administration of lipopolysaccharide (LPS) is associated with alterations in sleep and the electroencephalogram. To evaluate potential neuronal mechanisms for the somnogenic effects of LPS administration, we used unanesthetized rats to survey the firing patterns of neurons in various regions of rat basal forebrain (BF) and hypothalamus during spontaneous sleep and waking and during the epochs of sleep and waking that occurred after the intraperitoneal administration of LPS. In the brain regions studied, LPS administration was associated with altered firing rates in 39% of the neurons examined. A larger proportion of LPS-responsive units showed vigilance-related alterations in firing rates compared with nonresponsive units. Approximately equal proportions of LPS-responsive neurons showed increased and decreased firing rates after LPS administration, with some units in the lateral preoptic area of the hypothalamus showing particularly robust increases. These findings are consistent with other studies showing vigilance-related changes in neuronal activity in various regions of BF and hypothalamus and further demonstrate that peripheral LPS administration alters neuronal firing rates in these structures during both sleep and waking.     

Altered representation of the spatial code for odors after olfactory classical conditioning; memory trace formation by synaptic recruitment

In the olfactory bulb of vertebrates or the homologous antennal lobe of insects, odor quality is represented by stereotyped patterns of neuronal activity that are reproducible within and between individuals. Using optical imaging to monitor synaptic activity in the Drosophila antennal lobe, we show here that classical conditioning rapidly alters the neural code representing the learned odor by recruiting new synapses into that code. Pairing of an odor-conditioned stimulus with an electric shock-unconditioned stimulus causes new projection neuron synapses to respond to the odor along with those normally activated prior to conditioning. Different odors recruit different groups of projection neurons into the spatial code. The change in odor representation after conditioning appears to be intrinsic to projection neurons. The rapid recruitment by conditioning of new synapses into the representation of sensory information may be a general mechanism underlying many forms of short-term memory.     

Neurons in the amygdala with response-selectivity for anxiety in two ethologically based tests

The amygdala is a key area in the brain for detecting potential threats or dangers, and further mediating anxiety. However, the neuronal mechanisms of anxiety in the amygdala have not been well characterized. Here we report that in freely-behaving mice, a group of neurons in the basolateral amygdala (BLA) fires tonically under anxiety conditions in both open-field and elevated plus-maze tests. The firing patterns of these neurons displayed a characteristic slow onset and progressively increased firing rates. Specifically, these firing patterns were correlated to a gradual development of anxiety-like behaviors in the open-field test. Moreover, these neurons could be activated by any impoverished environment similar to an open-field; and introduction of both comfortable and uncomfortable stimuli temporarily suppressed the activity of these BLA neurons. Importantly, the excitability of these BLA neurons correlated well with levels of anxiety. These results demonstrate that this type of BLA neuron is likely to represent anxiety and/or emotional values of anxiety elicited by anxiogenic environmental stressors.     

Afferent modulation of dopamine neuron firing patterns

In recent studies examining the modulation of dopamine (DA) cell firing patterns, particular emphasis has been placed on excitatory afferents from the prefrontal cortex and the subthalamic nucleus. A number of inconsistencies in recently published reports, however, do not support the contention that tonic activation of NMDA receptors is the sole determinate of DA neuronal firing patterns. The results of work on the basic mechanism of DA firing and the action of apamin suggest that excitatory projections to DA neurons from cholinergic and glutamatergic neurons in the tegmental pedunculopontine nucleus, and/or inhibitory GABAergic projections, are also involved in modulating DA neuron firing behavior.     

帕金森病丘脑底核神经元的电活动特点

本研究探讨了帕金森病(Parkinson′s disease, PD)患者丘脑底核(subthalamic nucleus, STN)神经元电活动的特点及其与PD症状的关系. 35例PD患者在接受手术治疗的同时, 应用微电极细胞记录和EMG记录技术, 记录手术靶点STN及其周围结构神经元的电活动以及手术对侧肢体的EMG. 应用分析软件甄别单细胞电活动, 分析其特点及其与肢体EMG的关系. 结果表明, STN及其周围结构具有特征性放电活动.在36个记录针道中, 共发现436个STN神经元, 平均放电频率44.0±20.5 Hz. 其中, 56%的神经元呈不规则簇状放电; 15%呈紧张性放电; 29%呈规则的簇状放电, 其放电节律与肢体震颤的EMG高度一致(r2=0.66, P<0.01), 称之为震颤细胞. 在PD震颤型患者的STN中发现大量震颤细胞, 且80%位于STN中上部, 而在PD僵直型患者的STN中均发现与运动相关的细胞电活动. 本研究提示, 通过微电极记录技术可准确地判断STN的位置和范围; 与震颤活动相关的细胞放电和与运动相关细胞的放电与PD症状有内在关系; STN参与PD运动障碍的病理生理过程.     

Electrical synapses by guided growth of cultured neurons from the snail Lymnaea stagnalis

The ability to assemble neuronal networks with designed topology would allow uniquely defined experiments on neurocomputing. We describe a fundamental step, the controlled formation of synapses by guided outgrowth, in vitro for the first time combining simple neuritic geometry with predefined connectivity. We used neurons from the A-clusters in the pedal ganglia of the snail Lymnaea stagnalis. They were cultured on a substrate with linear patterns made by adsorption of brain-derived conditioning factors and photolithography. We induced and observed the frontal collision of two growth cones on narrow lanes. Following such encounters. individual electrical synapses formed that were sometimes strong enough for prolonged presynaptic stimulation to reach the threshold of postsynaptic firing.