STDP allows fast rate-modulated coding with Poisson-like spike trains

Spike timing-dependent plasticity (STDP) has been shown to enable single neurons to detect repeatedly presented spatiotemporal spike patterns. This holds even when such patterns are embedded in equally dense random spiking activity, that is, in the absence of external reference times such as a stimulus onset. Here we demonstrate, both analytically and numerically, that STDP can also learn repeating rate-modulated patterns, which have received more experimental evidence, for example, through post-stimulus time histograms (PSTHs). Each input spike train is generated from a rate function using a stochastic sampling mechanism, chosen to be an inhomogeneous Poisson process here. Learning is feasible provided significant covarying rate modulations occur within the typical timescale of STDP (~10-20 ms) for sufficiently many inputs (~100 among 1000 in our simulations), a condition that is met by many experimental PSTHs. Repeated pattern presentations induce spike-time correlations that are captured by STDP. Despite imprecise input spike times and even variable spike counts, a single trained neuron robustly detects the pattern just a few milliseconds after its presentation. Therefore, temporal imprecision and Poisson-like firing variability are not an obstacle to fast temporal coding. STDP provides an appealing mechanism to learn such rate patterns, which, beyond sensory processing, may also be involved in many cognitive tasks.     

Painful channels in sensory neurons

Pain is an unpleasant sensation experienced when tissues are damaged. Thus, pain sensation in some way protects body from imminent threat or injury. Peripheral sensory nerves innervated to peripheral tissues initially respond to multiple forms of noxious or strong stimuli, such as heat, mechanical and chemical stimuli. In response to these stimuli, electrical signals for conducting the nociceptive neural signals through axons are generated. These action potentials are then conveyed to specific areas in the spinal cord and in the brain. Sensory afferent fibers are heterogeneous in many aspects. For example, sensory nerves are classified as Aa, -b, -d and C-fibers according to their diameter and degree of myelination. It is widely accepted that small sensory fibers tend to respond to vigorous or noxious stimuli and related to nociception. Thus these fibers are specifically called nociceptors. Most of nociceptors respond to noxious mechanical stimuli and heat. In addition, these sensory fibers also respond to chemical stimuli [Davis et al. (1993)] such as capsaicin. Thus, nociceptors are considered polymodal. Recent advance in research on ion channels in sensory neurons reveals molecular mechanisms underlying how various types of stimuli can be transduced to neural signals transmitted to the brain for pain perception. In particular, electrophysiological studies on ion channels characterize biophysical properties of ion channels in sensory neurons. Furthermore, molecular biology leads to identification of genetic structures as well as molecular properties of ion channels in sensory neurons. These ion channels are expressed in axon terminals as well as in cell soma. When these channels are activated, inward currents or outward currents are generated, which will lead to depolarization or hyperpolarization of the membrane causing increased or decreased excitability of sensory neurons. In order to depolarize the membrane of nerve terminals, either inward currents should be generated or outward currents should be inhibited. So far, many cationic channels that are responsible for the excitation of sensory neurons are introduced recently. Activation of these channels in sensory neurons is evidently critical to the generation of nociceptive signals. The main channels responsible for inward membrane currents in nociceptors are voltage-activated sodium and calcium channels, while outward current is carried mainly by potassium ions. In addition, activation of non-selective cation channels is also responsible for the excitation of sensory neurons. Thus, excitability of neurons can be controlled by regulating expression or by modulating activity of these channels.     

Optogenetics and thermogenetics: technologies for controlling the activity of targeted cells within intact neural circuits

In recent years, interest has grown in the ability to manipulate, in a temporally precise fashion, the electrical activity of specific neurons embedded within densely wired brain circuits, in order to reveal how specific neurons subserve behaviors and neural computations, and to open up new horizons on the clinical treatment of brain disorders. Technologies that enable temporally precise control of electrical activity of specific neurons, and not these neurons' neighbors-whose cell bodies or processes might be just tens to hundreds of nanometers away-must involve two components. First, they require as a trigger a transient pulse of energy that supports the temporal precision of the control. Second, they require a molecular sensitizer that can be expressed in specific neurons and which renders those neurons specifically responsive to the triggering energy delivered. Optogenetic tools, such as microbial opsins, can be used to activate or silence neural activity with brief pulses of light. Thermogenetic tools, such as thermosensitive TRP channels, can be used to drive neural activity downstream of increases or decreases in temperature. We here discuss the principles underlying the operation of these two recently developed, but widely used, toolboxes, as well as the directions being taken in the use and improvement of these toolboxes.     

Coherence Potentials: Loss-Less,All-or-None Network Events in the Cortex

Transient associations among neurons are thought to underlie memory and behavior. However, little is known about how such associations occur or how they can be identified. Here we recorded ongoing local field potential (LFP) activity at multiple sites within the cortex of awake monkeys and organotypic cultures of cortex. We show that when the composite activity of a local neuronal group exceeds a threshold, its activity pattern, as reflected in the LFP, occurs without distortion at other cortex sites via fast synaptic transmission. These large-amplitude LFPs, which we call coherence potentials, extend up to hundreds of milliseconds and mark periods of loss-less spread of temporal and amplitude information much like action potentials at the single-cell level. However, coherence potentials have an additional degree of freedom in the diversity of their waveforms, which provides a high-dimensional parameter for encoding information and allows identification of particular associations. Such nonlinear behavior is analogous to the spread of ideas and behaviors in social networks.     

Flight-correlated activity changes in neurons of the lateral accessory lobes in the brain of the locust Schistocerca gregaria

The study investigates activity changes in neurons of the lateral accessory lobes in the brain of the locust Schistocerca gregaria during wind-elicited tethered flight. Neurons with ascending projections from the ventral nerve cord to the lateral accessory lobes showed flight-associated excitations which were modulated in the flight motor rhythm. Descending neurons with ramifications in the lateral accessory lobes were tonically excited corresponding to flight duration. The onset of wind-elicited responses in the descending neurons preceded the onset of flight motor activity by 22–60 milliseconds. Neurons connecting the lateral accessory lobes with the central body, the anterior optic tubercles, or other brain areas showed a variety of responses including activity changes during flight initiation and flight termination. Activity in many of these neurons was less tightly coupled to the flight situation and often returned to background levels before flight was terminated. Most of the recorded neurons responded, in addition, to stationary visual stimuli. The results suggest that the lateral accessory lobes in the locust brain are integrative links between the central body, visual pathways, and the ventral nerve cord. The possible involvement of these brain areas in flight control is discussed.     

Timing as an intrinsic property of neural networks: evidence from in vivo and in vitro experiments

The discrimination and production of temporal patterns on the scale of hundreds of milliseconds are critical to sensory and motor processing. Indeed, most complex behaviours, such as speech comprehension and production, would be impossible in the absence of sophisticated timing mechanisms. Despite the importance of timing to human learning and cognition, little is known about the underlying mechanisms, in particular whether timing relies on specialized dedicated circuits and mechanisms or on general and intrinsic properties of neurons and neural circuits. Here, we review experimental data describing timing and interval-selective neurons in vivo and in vitro. We also review theoretical models of timing, focusing primarily on the state-dependent network model, which proposes that timing in the subsecond range relies on the inherent time-dependent properties of neurons and the active neural dynamics within recurrent circuits. Within this framework, time is naturally encoded in populations of neurons whose pattern of activity is dynamically changing in time. Together, we argue that current experimental and theoretical studies provide sufficient evidence to conclude that at least some forms of temporal processing reflect intrinsic computations based on local neural network dynamics.     

Synaptic modification in neural circuits: a timely action

Long-term modification of synaptic strength is thought to be the basic mechanism underlying the activity-dependent refinement of neural circuits and the formation of memories engrammed on them. Studies ranging from cell culture preparations to humans subjects indicate that the decision of whether a synapse will undergo strengthening or weakening critically depends on the temporal order of presynaptic and postsynaptic activity. At many synapses, potentiation will be induced only when the presynaptic neuron fires an action potential within milliseconds before the postsynaptic neuron fires, whereas weakening will occur when it is the postsynaptic neuron that fires first. Such processes might be important for the remodeling of neural circuits by activity during development and for network functions such as sequence learning and prediction. Ultimately, this synaptic property might also be fundamental for the cognitive process by which we structure our experience through cause and effect relations.     

Plasticity of dendritic excitability

Dendrites are equipped with a plethora of voltage-gated ion channels that greatly enrich the computational and storage capacity of neurons. The excitability of dendrites and dendritic function display plasticity under diverse circumstances such as neuromodulation, adaptation, learning and memory, trauma, or disorders. This adaptability arises from alterations in the biophysical properties or the expression levels of voltage-gated ion channels-induced by the activity of neurotransmitters, neuromodulators, and second-messenger cascades. In this review we discuss how this plasticity of dendritic excitability could alter information transfer and processing within dendrites, neurons, and neural networks under physiological and pathological conditions.     

Dynamic patterns of correlated activity in the prefrontal cortex encode information about social behavior

New technologies make it possible to measure activity from many neurons simultaneously. One approach is to analyze simultaneously recorded neurons individually, then group together neurons which increase their activity during similar behaviors into an “ensemble.” However, this notion of an ensemble ignores the ability of neurons to act collectively and encode and transmit information in ways that are not reflected by their individual activity levels. We used microendoscopic GCaMP imaging to measure prefrontal activity while mice were either alone or engaged in social interaction. We developed an approach that combines a neural network classifier and surrogate (shuffled) datasets to characterize how neurons synergistically transmit information about social behavior. Notably, unlike optimal linear classifiers, a neural network classifier with a single linear hidden layer can discriminate network states which differ solely in patterns of coactivity, and not in the activity levels of individual neurons. Using this approach, we found that surrogate datasets which preserve behaviorally specific patterns of coactivity (correlations) outperform those which preserve behaviorally driven changes in activity levels but not correlated activity. Thus, social behavior elicits increases in correlated activity that are not explained simply by the activity levels of the underlying neurons, and prefrontal neurons act collectively to transmit information about socialization via these correlations. Notably, this ability of correlated activity to enhance the information transmitted by neuronal ensembles is diminished in mice lacking the autism-associated gene Shank3. These results show that synergy is an important concept for the coding of social behavior which can be disrupted in disease states, reveal a specific mechanism underlying this synergy (social behavior increases correlated activity within specific ensembles), and outline methods for studying how neurons within an ensemble can work together to encode information.

Behaviorally-specific patterns of correlated activity between prefrontal neurons normally enhance the information that neuronal ensembles transmit about social behavior. This study shows that in a mouse model of autism, individual neurons continue to encode social information, but this additional information carried by patterns of correlated activity is lost.     

Olfactory learning

The olfactory nervous systems of insects and mammals exhibit many similarities, suggesting that the mechanisms for olfactory learning may be shared. Neural correlates of olfactory memory are distributed among many neurons within the olfactory nervous system. Perceptual olfactory learning may be mediated by alterations in the odorant receptive fields of second and/or third order olfactory neurons, and by increases in the coherency of activity among ensembles of second order neurons. Operant olfactory conditioning is associated with an increase in the coherent population activity of these neurons. Olfactory classical conditioning increases the odor responsiveness and synaptic activity of second and perhaps third order neurons. Operant and classical conditioning both produce an increased responsiveness to conditioned odors in neurons of the basolateral amygdala. Molecular genetic studies of olfactory learning in Drosophila have revealed numerous molecules that function within the third order olfactory neurons for normal olfactory learning.     

How silent is the brain: is there a “dark matter” problem in neuroscience?

Evidence from a variety of recording methods suggests that many areas of the brain are far more sparsely active than commonly thought. Here, we review experimental findings pointing to the existence of neurons which fire action potentials rarely or only to very specific stimuli. Because such neurons would be difficult to detect with the most common method of monitoring neural activity in vivo—extracellular electrode recording—they could be referred to as “dark neurons,” in analogy to the astrophysical observation that much of the matter in the universe is undetectable, or dark. In addition to discussing the evidence for largely silent neurons, we review technical advances that will ultimately answer the question: how silent is the brain?     

Development of neural circuitry for precise temporal sequences through spontaneous activity, axon remodeling, and synaptic plasticity

Temporally precise sequences of neuronal spikes that span hundreds of milliseconds are observed in many brain areas, including songbird premotor nucleus, cat visual cortex, and primary motor cortex. Synfire chains-networks in which groups of neurons are connected via excitatory synapses into a unidirectional chain-are thought to underlie the generation of such sequences. It is unknown, however, how synfire chains can form in local neural circuits, especially for long chains. Here, we show through computer simulation that long synfire chains can develop through spike-time dependent synaptic plasticity and axon remodeling-the pruning of prolific weak connections that follows the emergence of a finite number of strong connections. The formation process begins with a random network. A subset of neurons, called training neurons, intermittently receive superthreshold external input. Gradually, a synfire chain emerges through a recruiting process, in which neurons within the network connect to the tail of the chain started by the training neurons. The model is robust to varying parameters, as well as natural events like neuronal turnover and massive lesions. Our model suggests that long synfire chain can form during the development through self-organization, and axon remodeling, ubiquitous in developing neural circuits, is essential in the process.     

Site of resting state inhibition of the nicotinic acetylcholine receptor by a hydrophobic inhibitor

The lipophilic photoactivatable probe 3-(trifluoromethyl)-3-(m-iodophenyl) diazirine (TID) is a noncompetitive, resting-state inhibitor of the nicotinic acetylcholine receptor (nAChR) that requires tens of milliseconds of preincubation to inhibit agonist-induced cation efflux. At equilibrium, [(125)I]TID photoincorporates into both the ion channel and the lipid-protein interface of the Torpedo nAChR. To determine which of these regions is responsible for resting-state inhibition, we characterized the interactions between [(125)I]TID and nAChR-rich membranes milliseconds after mixing, by use of time-resolved photolabeling. Photolabeling was performed after preincubation times of 2 ms or 600 s (equilibrium), and the efficiencies of incorporation at specific residues were determined by amino-terminal sequence analysis of nAChR-subunit proteolytic fragments isolated by SDS-PAGE and/or reversed-phase HPLC. Equilibration of TID with lipid was complete within a millisecond as determined by both stopped-flow fluorescence quenching of diphenylhexatriene in lipid bilayers and photoincorporation into nAChR-rich membrane phospholipids. Equilibration with the lipid-protein interface (alphaM4) was slightly slower, reaching approximately 50% that at equilibrium after 2 ms preincubation. In contrast, equilibration with the channel region (alpha 2 and deltaM2) was much slower, reaching only 10% that at equilibrium after 2 ms preincubation. Within the ion channel, the ratio of [(125)I]TID incorporation between M2 residues 9', 13', and 16' was independent of preincubation time. We conclude that TID's access to the ion channel is more restricted than to the lipid-protein interface and that TID bound within the ion channel is responsible for flux inhibition upon activation of the nAChR.     

Mechanisms of establishing long-term fluctuations in neuronal networks. II. Networks with pre- and postsynaptic inhibition

The role of pre- and postsynaptic inhibitory processes in establishing long-term activity measuring hundreds of milliseconds in neuronal networks was investigated on a simulated (mathematical) model. Additional factors appear in networks with pre- and postsynaptic inhibition which are responsible for terminating this long-term network activity, either owing to depolarization setting in at the neuronal terminals reaching a critical level together with marked suppression of the effects of synaptic excitation, or else due to activation of inhibitory neurons exerting a powerful hyperpolarizing action on other neurons of the network. It is deduced that introducing additional negative feedback circuits in the form of pre- or post-synaptic inhibition renders the workings of this mechanism for terminating activity within the neuronal network more reliable, less subject to disruptive action, and more accurate.A. A. Bogomolets Institute of Physiology, Academy of Sciences of the Ukrainian SSR, Kiev. Translated from Neirofiziologiya, Vol. 18, No. 3, pp. 392–402, May–June, 1986.     

A neural correlate of oculomotor sequences in supplementary eye field

Complex learned motor sequences can be composed of a combination of a small number of elementary actions. To investigate how the brain represents such sequences, we devised an oculomotor sequence task in which the monkey had to choose the target solely by the sequential context, not by the current stimulus combination. We found that many neurons in the supplementary eye field (SEF) became active with a specific target direction (D neuron) or a specific target/distractor combination (C neuron). Furthermore, such activity was often selective for one among several sequences that included the combination (S neuron). These results suggest that the SEF contributes to the generation of saccades in many learned sequences.     

Identification of Specific Sensory Neuron Populations for Study of Expressed Ion Channels

Sensory neurons transmit signals from various parts of the body to the central nervous system. The soma for these neurons are located in the dorsal root ganglia that line the spinal column. Understanding the receptors and channels expressed by these sensory afferent neurons could lead to novel therapies for disease. The initial step is to identify the specific subset of sensory neurons of interest. Here we describe a method to identify afferent neurons innervating the muscles by retrograde labeling using a fluorescent dye DiI (1,1''-dioctadecyl-3,3,3'',3''-tetramethylindocarbocyanine perchlorate). Understanding the contribution of ion channels to excitation of muscle afferents could help to better control excessive excitability induced by certain disease states such as peripheral vascular disease or heart failure. We used two approaches to identify the voltage dependent ion channels expressed by these neurons, patch clamp electrophysiology and immunocytochemistry. While electrophysiology plus pharmacological blockers can identify functional ion channel types, we used immunocytochemistry to identify channels for which specific blockers were unavailable and to better understand the ion channel distribution pattern in the cell population. These techniques can be applied to other areas of the nervous system to study specific neuronal groups.     

Correlations in Ion Channel mRNA in Rhythmically Active Neurons

Background

To what extent do identified neurons from different animals vary in their expression of ion channel genes? In neurons of the same type, is ion channel expression highly variable and/or is there any relationship between ion channel expression that is conserved?

Methodology/Principal Findings

To address these questions we measured ion channel mRNA in large cells (LCs) of the crab cardiac ganglion. We cloned a calcium channel, caco, and a potassium channel, shaker. Using single-cell quantitative PCR, we measured levels of mRNA for these and 6 other different ion channels in cardiac ganglion LCs. Across the population of LCs we measured 3–9 fold ranges of mRNA levels, and we found correlations in the expression of many pairs of conductances

Conclusions/Significance

In previous measurements from the crab stomatogastric ganglion (STG), ion channel expression was variable, but many pairs of channels had correlated expression. However, each STG cell type had a unique combination of ion channel correlations. Our findings from the crab cardiac ganglion are similar, but the correlations in the LCs are different from those in STG neurons, supporting the idea that such correlations could be markers of cell identity or activity.     

Associative short-term synaptic plasticity mediated by endocannabinoids

Associative learning is important on rapid timescales, but no suitable form of short-term plasticity has been identified that is both associative and synapse specific. Here, we assess whether endocannabinoids can mediate such plasticity. In the cerebellum, bursts of parallel fiber (PF) activity evoke endocannabinoid release from Purkinje cell dendrites that results in retrograde synaptic inhibition lasting seconds. We find that the powerful climbing fiber (CF) to Purkinje cell synapse regulates this inhibition. Compared to PF stimulation alone, coactivation of PF and CF synapses greatly enhanced endocannabinoid-mediated inhibition of PF synapses. Retrograde inhibition was restricted to PFs activated within several hundred milliseconds of CF activation. This associative plasticity reflects two aspects of calcium-dependent endocannabinoid release. First, PF-mediated activation of metabotropic glutamate receptors locally reduced the dendritic calcium levels required for endocannabinoid release. Second, CF and PF coactivation evoked localized supralinear dendritic calcium signals. Thus, endocannabinoids mediate transient associative synaptic plasticity.     

Single-channel recordings from cultured human retinal pigment epithelial cells

We have applied patch-clamp techniques to on-cell and excised-membrane patches from human retinal pigment epithelial cells in tissue culture. Single-channel currents from at least four ion channel types were observed: three or more potassium-selective channels with single-channel slope conductances near 100, 45, and 25 pS as measured in on-cell patches with physiological saline in the pipette, and a relatively nonselective channel with subconductance states, which has a main-state conductance of approximately 300 pS at physiological ion concentrations. The permeability ratios, PK/PNa, measured in excised patches were 21 for the 100-pS channels, 3 for the 25-pS channels, and 0.8 for the 300-pS nonselective channel. The 45-pS channels appeared to be of at least two types, with PK/PNa's of approximately 41 for one type and 3 for the other. The potassium-selective channels were spontaneously active at all potentials examined. The average open time for these channels ranged from a few milliseconds to many tens of milliseconds. No consistent trend relating potassium-selective channel kinetics to membrane potential was apparent, which suggests that channel activity was not regulated by the membrane potential. In contrast to the potassium-selective channels, the activity of the nonselective channel was voltage dependent: the open probability of this channel declined to low values at large positive or negative membrane potentials and was maximal near zero. Single-channel conductances observed at several symmetrical KCl concentrations have been fitted with Michaelis-Menten curves in order to estimate maximum channel conductances and ion-binding constants for the different channel types. The channels we have recorded are probably responsible for the previously observed potassium permeability of the retinal pigment epithelium apical membrane.