Intrinsic threshold plasticity: cholinergic activation and role in the neuronal recognition of incomplete input patterns.

Activity-dependent changes in membrane excitability are observed in neurons across brain areas and represent a cell-autonomous form of plasticity (intrinsic plasticity; IP) that in itself does not involve alterations in synaptic strength (synaptic plasticity; SP). Non-homeostatic IP may play an essential role in learning, e.g. by changing the action potential threshold near the soma. A computational problem, however, arises from the implication that such amplification does not discriminate between synaptic inputs and therefore may reduce the resolution of input representation. Here, we investigate consequences of IP for the performance of an artificial neural network in (a) the discrimination of unknown input patterns and (b) the recognition of known/learned patterns. While negative changes in threshold potentials in the output layer indeed reduce its ability to discriminate patterns, they benefit the recognition of known but incompletely presented patterns. An analysis of thresholds and IP-induced threshold changes in published sets of physiological data obtained from whole-cell patch-clamp recordings from L2/3 pyramidal neurons in (a) the primary visual cortex (V1) of awake macaques and (b) the primary somatosensory cortex (S1) of mice in vitro, respectively, reveals a difference between resting and threshold potentials of ∼15 mV for V1 and ∼25 mV for S1, and a total plasticity range of ∼10 mV (S1). The most efficient activity pattern to lower threshold is paired cholinergic and electric activation. Our findings show that threshold reduction promotes a shift in neural coding strategies from accurate faithful representation to interpretative assignment of input patterns to learned object categories. KEY POINTS: Intrinsic plasticity may change the action potential threshold near the soma of neurons (threshold plasticity), thus altering the input-output function for all synaptic inputs 'upstream' of the plasticity location. A potential problem arising from this shared amplification is that it may reduce the ability to discriminate between different input patterns. Here, we assess the performance of an artificial neural network in the discrimination of unknown input patterns as well as the recognition of known patterns subsequent to changes in the spike threshold. We observe that negative changes in threshold potentials do reduce discrimination performance, but at the same time improve performance in an object recognition task, in particular when patterns are incompletely presented. Analysis of whole-cell patch-clamp recordings from pyramidal neurons in the primary somatosensory cortex (S1) of mice reveals that negative threshold changes preferentially result from electric stimulation of neurons paired with the activation of muscarinic acetylcholine receptors.

Noise induced quiescence of epileptic spike generation in patients with epilepsy.

Clinical scalp electroencephalographic recordings from patients with epilepsy are distinguished by the presence of epileptic discharges i.e. spikes or sharp waves. These often occur randomly on a background of fluctuating potentials. The spike rate varies between different brain states (sleep and awake) and patients. Epileptogenic tissue and regions near these often show increased spike rates in comparison to other cortical regions. Several studies have shown a relation between spike rate and background activity although the underlying reason for this is still poorly understood. Both these processes, spike occurrence and background activity show evidence of being at least partly stochastic processes. In this study we show that epileptic discharges seen on scalp electroencephalographic recordings and background activity are driven at least partly by a common biological noise. Furthermore, our results indicate noise induced quiescence of spike generation which, in analogy with computational models of spiking, indicate spikes to be generated by transitions between semi-stable states of the brain, similar to the generation of epileptic seizure activity. The deepened physiological understanding of spike generation in epilepsy that this study provides could be useful in the electrophysiological assessment of different therapies for epilepsy including the effect of different drugs or electrical stimulation.

Rapid adaptation to elevated extracellular potassium in the pyloric circuit of the crab, Cancer borealis.

Elevated potassium concentration ([K+]) is often used to alter excitability in neurons and networks by shifting the potassium equilibrium potential (EK) and, consequently, the resting membrane potential. We studied the effects of increased extracellular [K+] on the well-described pyloric circuit of the crab Cancer borealis. A 2.5-fold increase in extracellular [K+] (2.5×[K+]) depolarized pyloric dilator (PD) neurons and resulted in short-term loss of their normal bursting activity. This period of silence was followed within 5-10 min by the recovery of spiking and/or bursting activity during continued superfusion of 2.5×[K+] saline. In contrast, when PD neurons were pharmacologically isolated from pyloric presynaptic inputs, they exhibited no transient loss of spiking activity in 2.5×[K+], suggesting the presence of an acute inhibitory effect mediated by circuit interactions. Action potential threshold in PD neurons hyperpolarized during an hour-long exposure to 2.5×[K+] concurrent with the recovery of spiking and/or bursting activity. Thus the initial loss of activity appears to be mediated by synaptic interactions within the network, but the secondary adaptation depends on changes in the intrinsic excitability of the pacemaker neurons. The complex sequence of events in the responses of pyloric neurons to elevated [K+] demonstrates that electrophysiological recordings are necessary to determine both the transient and longer term effects of even modest alterations of K+ concentrations on neuronal activity.NEW & NOTEWORTHY Solutions with elevated extracellular potassium are commonly used as a depolarizing stimulus. We studied the effects of high potassium concentration ([K+]) on the pyloric circuit of the crab stomatogastric ganglion. A 2.5-fold increase in extracellular [K+] caused a transient loss of activity that was not due to depolarization block, followed by a rapid increase in excitability and recovery of spiking within minutes. This suggests that changing extracellular potassium can have complex and nonstationary effects on neuronal circuits.

Calcium stores regulate excitability in cultured rat hippocampal neurons.

Extracellular calcium ions support synaptic activity but also reduce excitability of central neurons. In the present study, the effect of calcium on excitability was explored in cultured hippocampal neurons. CaCl2 injected by pressure in the vicinity of a neuron that is bathed only in MgCl2 as the main divalent cation caused a depolarizing shift in action potential threshold and a reduction in excitability. This effect was not seen if the intracellular milieu consisted of Cs+ instead of K-gluconate as the main cation or when it contained ruthenium red, which blocks release of calcium from stores. The suppression of excitability by calcium was mimicked by caffeine, and calcium store antagonists cyclopiazonic acid or thapsigargin blocked this action. Neurons taken from synaptopodin-knockout mice show significantly reduced efficacy of calcium modulation of action potential threshold. Likewise, in Orai1 knockdown cells, calcium is less effective in modulating excitability of neurons. Activation of small-conductance K (SK) channels increased action potential threshold akin to that produced by calcium ions, whereas blockade of SK channels but not big K channels reduced the threshold for action potential discharge. These results indicate that calcium released from stores may suppress excitability of central neurons. NEW & NOTEWORTHY Extracellular calcium reduces excitability of cultured hippocampal neurons. This effect is mediated by calcium-gated potassium currents, possibly small-conductance K channels. Release of calcium from internal stores mimics the effect of extracellular calcium. It is proposed that calcium stores modulate excitability of central neurons.

Fluctuations in oscillation frequency control spike timing and coordinate neural networks.

Neuroscience research spans multiple spatiotemporal scales, from subsecond dynamics of individual neurons to the slow coordination of billions of neurons during resting state and sleep. Here it is shown that a single functional principle-temporal fluctuations in oscillation peak frequency ("frequency sliding")-can be used as a common analysis approach to bridge multiple scales within neuroscience. Frequency sliding is demonstrated in simulated neural networks and in human EEG data during a visual task. Simulations of biophysically detailed neuron models show that frequency sliding modulates spike threshold and timing variability, as well as coincidence detection. Finally, human resting-state EEG data demonstrate that frequency sliding occurs endogenously and can be used to identify large-scale networks. Frequency sliding appears to be a general principle that regulates brain function on multiple spatial and temporal scales, from modulating spike timing in individual neurons to coordinating large-scale brain networks during cognition and resting state.

An evaluation of paired motor unit estimates of persistent inward current in human motoneurons.

Persistent inward current (PIC) plays an important role in setting the input-output gain of motoneurons. In humans, these currents are estimated by calculating the difference between synaptic input at motor unit recruitment and derecruitment (ΔF) derived from paired motor unit recordings. The primary objective of this study was to use the relationship between reciprocal inhibition (RI) and PIC to estimate the contribution of PIC relative to other motoneuron properties that result in nonlinear motor unit firing behavior. This study also assessed the contribution of other intrinsic properties (spike threshold accommodation and spike frequency adaptation) to ΔF estimates of PIC in human motor units by using ramps with varying rates of rise and duration. It was hypothesized that slower rates of ramp rise and longer ramp durations would inflate ΔF estimates of PIC, and RI and PIC values would only be correlated during the ramp with the fastest rate of rise and shortest duration when spike threshold accommodation and spike frequency adaptation is minimized. Fourteen university-aged participants took part in this study. Paired motor unit recordings were made from the right soleus muscle during ramp contractions of plantar flexors with three different rates of rise and durations. ΔF estimates of PIC increased with decreased rates of ramp rise (P < 0.01) and increased ramp durations (P < 0.01), most likely due to spike frequency adaptation. A correlation (r = 0.41; P < 0.03) between ΔF and RI provides evidence that PIC is the primary contributor to ΔF in shorter ramps with faster rates of rise.

Predicting spike timing in highly synchronous auditory neurons at different sound levels.

A challenge for sensory systems is to encode natural signals that vary in amplitude by orders of magnitude. The spike trains of neurons in the auditory system must represent the fine temporal structure of sounds despite a tremendous variation in sound level in natural environments. It has been shown in vitro that the transformation from dynamic signals into precise spike trains can be accurately captured by simple integrate-and-fire models. In this work, we show that the in vivo responses of cochlear nucleus bushy cells to sounds across a wide range of levels can be precisely predicted by deterministic integrate-and-fire models with adaptive spike threshold. Our model can predict both the spike timings and the firing rate in response to novel sounds, across a large input level range. A noisy version of the model accounts for the statistical structure of spike trains, including the reliability and temporal precision of responses. Spike threshold adaptation was critical to ensure that predictions remain accurate at different levels. These results confirm that simple integrate-and-fire models provide an accurate phenomenological account of spike train statistics and emphasize the functional relevance of spike threshold adaptation.

Cellular and Network Mechanisms May Generate Sparse Coding of Sequential Object Encounters in Hippocampal-Like Circuits.

The localization of distinct landmarks plays a crucial role in encoding new spatial memories. In mammals, this function is performed by hippocampal neurons that sparsely encode an animal's location relative to surrounding objects. Similarly, the dorsolateral pallium (DL) is essential for spatial learning in teleost fish. The DL of weakly electric gymnotiform fish receives both electrosensory and visual input from the preglomerular nucleus (PG), which has been hypothesized to encode the temporal sequence of electrosensory or visual landmark/food encounters. Here, we show that DL neurons in the Apteronotid fish and in the Carassius auratus (goldfish) have a hyperpolarized resting membrane potential (RMP) combined with a high and dynamic spike threshold that increases following each spike. Current-evoked spikes in DL cells are followed by a strong small-conductance calcium-activated potassium channel (SK)-mediated after-hyperpolarizing potential (AHP). Together, these properties prevent high frequency and continuous spiking. The resulting sparseness of discharge and dynamic threshold suggest that DL neurons meet theoretical requirements for generating spatial memory engrams by decoding the landmark/food encounter sequences encoded by PG neurons. Thus, DL neurons in teleost fish may provide a promising, simple system to study the core cell and network mechanisms underlying spatial memory.

The Changes of Intrinsic Excitability of Pyramidal Neurons in Anterior Cingulate Cortex in Neuropathic Pain.

To find satisfactory treatment strategies for neuropathic pain syndromes, the cellular mechanisms should be illuminated. Central sensitization is a generator of pain hypersensitivity, and is mainly reflected in neuronal hyperexcitability in pain pathway. Neuronal excitability depends on two components, the synaptic inputs and the intrinsic excitability. Previous studies have focused on the synaptic plasticity in different forms of pain. But little is known about the changes of neuronal intrinsic excitability in neuropathic pain. To address this question, whole-cell patch clamp recordings were performed to study the synaptic transmission and neuronal intrinsic excitability 1 week after spared nerve injury (SNI) or sham operation in male C57BL/6J mice. We found increased spontaneous excitatory postsynaptic currents (sEPSC) frequency in layer II/III pyramidal neurons of anterior cingulate cortex (ACC) from mice with neuropathic pain. Elevated intrinsic excitability of these neurons after nerve injury was also picked up, which was reflected in gain of input-output curve, inter-spike interval (ISI), spike threshold and Refractory period (RP). Besides firing rate related to neuronal intrinsic excitability, spike timing also plays an important role in neural information processing. The precision of spike timing measured by standard deviation of spike timing (SDST) was decreased in neuropathic pain state. The electrophysiological studies revealed the elevated intrinsic excitation in layer II/III pyramidal neurons of ACC in mice with neuropathic pain, which might contribute to central excitation.

Neural coding: A single neuron's perspective.

What any sensory neuron knows about the world is one of the cardinal questions in Neuroscience. Information from the sensory periphery travels across synaptically coupled neurons as each neuron encodes information by varying the rate and timing of its action potentials (spikes). Spatiotemporally correlated changes in this spiking regimen across neuronal populations are the neural basis of sensory representations. In the somatosensory cortex, however, spiking of individual (or pairs of) cortical neurons is only minimally informative about the world. Recent studies showed that one solution neurons implement to counteract this information loss is adapting their rate of information transfer to the ongoing synaptic activity by changing the membrane potential at which spike is generated. Here we first introduce the principles of information flow from the sensory periphery to the primary sensory cortex in a model sensory (whisker) system, and subsequently discuss how the adaptive spike threshold gates the intracellular information transfer from the somatic post-synaptic potential to action potentials, controlling the information content of communication across somatosensory cortical neurons.

Input-output relation and energy efficiency in the neuron with different spike threshold dynamics.

Neuron encodes and transmits information through generating sequences of output spikes, which is a high energy-consuming process. The spike is initiated when membrane depolarization reaches a threshold voltage. In many neurons, threshold is dynamic and depends on the rate of membrane depolarization (dV/dt) preceding a spike. Identifying the metabolic energy involved in neural coding and their relationship to threshold dynamic is critical to understanding neuronal function and evolution. Here, we use a modified Morris-Lecar model to investigate neuronal input-output property and energy efficiency associated with different spike threshold dynamics. We find that the neurons with dynamic threshold sensitive to dV/dt generate discontinuous frequency-current curve and type II phase response curve (PRC) through Hopf bifurcation, and weak noise could prohibit spiking when bifurcation just occurs. The threshold that is insensitive to dV/dt, instead, results in a continuous frequency-current curve, a type I PRC and a saddle-node on invariant circle bifurcation, and simultaneously weak noise cannot inhibit spiking. It is also shown that the bifurcation, frequency-current curve and PRC type associated with different threshold dynamics arise from the distinct subthreshold interactions of membrane currents. Further, we observe that the energy consumption of the neuron is related to its firing characteristics. The depolarization of spike threshold improves neuronal energy efficiency by reducing the overlap of Na(+) and K(+) currents during an action potential. The high energy efficiency is achieved at more depolarized spike threshold and high stimulus current. These results provide a fundamental biophysical connection that links spike threshold dynamics, input-output relation, energetics and spike initiation, which could contribute to uncover neural encoding mechanism.

A stimulus-dependent spike threshold is an optimal neural coder.

A neural code based on sequences of spikes can consume a significant portion of the brain's energy budget. Thus, energy considerations would dictate that spiking activity be kept as low as possible. However, a high spike-rate improves the coding and representation of signals in spike trains, particularly in sensory systems. These are competing demands, and selective pressure has presumably worked to optimize coding by apportioning a minimum number of spikes so as to maximize coding fidelity. The mechanisms by which a neuron generates spikes while maintaining a fidelity criterion are not known. Here, we show that a signal-dependent neural threshold, similar to a dynamic or adapting threshold, optimizes the trade-off between spike generation (encoding) and fidelity (decoding). The threshold mimics a post-synaptic membrane (a low-pass filter) and serves as an internal decoder. Further, it sets the average firing rate (the energy constraint). The decoding process provides an internal copy of the coding error to the spike-generator which emits a spike when the error equals or exceeds a spike threshold. When optimized, the trade-off leads to a deterministic spike firing-rule that generates optimally timed spikes so as to maximize fidelity. The optimal coder is derived in closed-form in the limit of high spike-rates, when the signal can be approximated as a piece-wise constant signal. The predicted spike-times are close to those obtained experimentally in the primary electrosensory afferent neurons of weakly electric fish (Apteronotus leptorhynchus) and pyramidal neurons from the somatosensory cortex of the rat. We suggest that KCNQ/Kv7 channels (underlying the M-current) are good candidates for the decoder. They are widely coupled to metabolic processes and do not inactivate. We conclude that the neural threshold is optimized to generate an energy-efficient and high-fidelity neural code.

Alterations in membrane and firing properties of layer 2/3 pyramidal neurons following focal laser lesions in rat visual cortex.

Focal cortical injuries are well known to cause changes in function and excitability of the surviving cortical areas but the cellular correlates of these physiological alterations are not fully understood. In the present study we employed a well established ex vivo-in vitro model of focal laser lesions in the rat visual cortex and we studied membrane and firing properties of the surviving layer 2/3 pyramidal neurons. Patch-clamp recordings, performed in the first week post-injury, revealed an increased input resistance, a depolarized spike threshold as well as alterations in the firing pattern of neurons in the cortex ipsilateral to the lesion. Notably, the reported lesion-induced alterations emerged or became more evident when an exciting perfusing solution, known as modified artificial cerebrospinal fluid, was used to increase the ongoing synaptic activity in cortical slices. Conversely, application of glutamatergic or GABAA receptor blockers reduced the observed alterations and GABAB receptor blockers abolished the differences completely. All together the present findings suggest that changes in synaptic receptors function, following focal cortical injuries, can modulate membrane and firing properties of layer 2/3 pyramidal neurons. This previously unknown functional interplay between synaptic and membrane properties may constitute a novel cellular mechanism to explain alterations in neuronal network function and excitability following focal cortical injuries.

Inhibition shapes response selectivity in the inferior colliculus by gain modulation.

Pharmacological block of inhibition is often used to determine if inhibition contributes to spike selectivity, in which a preferred stimulus evokes more spikes than a null stimulus. When inhibitory block reduces spike selectivity, a common interpretation is that differences between the preferred- and null-evoked inhibitions created the selectivity from less-selective excitatory inputs. In models based on empirical properties of cells from the inferior colliculus (IC) of awake bats, we show that inhibitory differences are not required. Instead, inhibition can enhance spike selectivity by changing the gain, the ratio of output spikes to input current. Within the model, we made preferred stimuli that evoked more spikes than null stimuli using five distinct synaptic mechanisms. In two cases, synaptic selectivity (the differences between the preferred and null inputs) was entirely excitatory, and in two it was entirely inhibitory. In each case, blocking inhibition eliminated spike selectivity. Thus, observing spike rates following inhibitory block did not distinguish among the cases where synaptic selectivity was entirely excitatory or inhibitory. We then did the same modeling experiment using empirical synaptic conductances derived from responses to preferred and null sounds. In most cases, inhibition in the model enhanced spike selectivity mainly by gain modulation and firing rate reduction. Sometimes, inhibition reduced the null gain to zero, eliminating null-evoked spikes. In some cases, inhibition increased the preferred gain more than the null gain, enhancing the difference between the preferred- and null-evoked spikes. Finally, inhibition kept firing rates low. When selectivity is quantified by the selectivity index (SI, the ratio of the difference to the sum of the spikes evoked by the preferred and null stimuli), inhibitory block reduced the SI by increasing overall firing rates. These results are consistent with inhibition shaping spike selectivity by gain control.