Frequency-current Relationship Research Articles

Intrinsic and Extrinsic Tongue Muscles are Driven by Physiologically Distinct Motoneuron Pools

The hypoglossal motor nucleus innervates six of the seven tongue muscles responsible for wide-ranging behaviors including speech, breathing, and swallowing. Despite the task-specific nature of tongue movements, neurophysiologic research has historically treated hypoglossal motoneurons as a homogeneous population. Our previous work showed that hypoglossal motoneurons innervating specific tongue muscles had different firing thresholds and resting membrane potential. Here, we extend this work by comparing potassium conductance in motor neurons innervating the superior longitudinalis (SL; intrinsic) and genioglossus (GG; extrinsic), tongue muscles with opposing actions of tongue retraction and tongue protrusion, respectively. Experiments were performed using N=10 neonatal rat pups aged post-natal day 0-5 ( n=5 each of SL and GG). Motoneurons were back-labeled by injection of dextran rhodamine conjugated to Texas Red into either the SL or GG muscle. > 24-hours after injection, animals were anesthetized on ice and decapitated. The brainstem and spinal cord were removed and 250 μm transverse slices of the medulla containing the hypoglossal nucleus were obtained. SL or GG motor neurons were visualized under a fluorescence microscope and resting membrane potential, rheobase current, frequency-current relation and potassium currents were recorded using whole-cell patch clamp. Statistical analysis revealed that SL motoneurons were ~11 mV more depolarized than GG motoneurons (resting membrane potential of -49 vs -60 mV, p<0.05). Rheobase current (the minimal electrical current required to evoke an action potential) was greater in GG motoneurons than SL motoneurons (approximately 300 vs 150 pA, p<0.05). SL motoneurons had a higher firing rate than GG motoneurons in response to current injection ( p<0.05). Evaluation of neuronal potassium channel conductance showed that the magnitude of transient ( p < 0.01) and sustained (p < 0.01) potassium currents were greater in GG than SL motoneurons, consistent with our finding that resting membrane potential was more negative, and firing rate was slower, in GG than SL motoneurons. Finally, additional SL motoneuron recordings were performed to evaluate for potential sex differences in N=12 (6 male) rat pups aged post-natal day 0-5. Preliminary analysis revealed no significant difference in resting membrane potential between male (-49 mV) and female (-52 mV) SL motoneurons, suggesting that the properties of a specific hypoglossal motoneuron pool are consistent across sexes. Overall, these results demonstrate that GG motoneurons are less excitable than SL motoneurons, which supports the idea that intrinsic and extrinsic tongue muscles are driven by physiologically distinct motoneuron pools. This work has potential to guide development of therapeutics for disordered speech, breathing, and swallowing, all of which depend on proper neuromotor control of the tongue. This work was funded by NIH 5R01DC020889-02. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Analysis and Application of the Influence of Magnetic Material and Magnetic Gap on Electromagnetic Actuator

The impact of the actuator is examined in light of the properties of various materials. The features of the N48 material are examined when the N48 permanent magnet material is chosen. A novel magnetic steel construction for an electromagnetic actuator is built after analysis of the air gap structure. The functionality and nonlinear issues of the electromagnetic actuator are investigated in accordance with the properties of the materials and constructions. The link between electromagnetic output and current and frequency is investigated and determined using theoretical analysis, finite element analysis, and real test. The magnetic flux density distribution, electromagnetic dynamic response, current frequency relationship, and surface skin effect are derived using the electromagnetic simulation model built in COMSOL. Time domain simulation is used to determine the electromagnetic actuator’s static linearity. Simulation in a steady state is used to determine the operating linearity of an electromagnetic actuator. To confirm the accuracy of the theoretical and simulation results, the electromagnetic actuator prototype is put to the test. The simulation results demonstrate the high linearity and good performance of the electromagnetic actuator, with an average static linearity of 97.24%. To confirm the validity of the theory and simulation, an actual test is conducted on the structural prototype. The outcomes can not only serve as a guide for the best design of electromagnetic actuators but can also demonstrate the benefits and potential uses of various materials used in actuator construction.

The effects of membrane potential oscillations on the excitability of rat hypoglossal motoneurons.

Oscillations in membrane potential induced by synaptic inputs and intrinsic ion channel activity play a role in regulating neuronal excitability, but the precise mechanisms underlying their contributions remain largely unknown. Here we used electrophysiological and modeling approaches to investigate the effects of Gaussian white noise injected currents on the membrane properties and discharge characteristics of hypoglossal (HG) motoneurons in P16-21 day old rats. We found that the noise-induced membrane potential oscillations facilitated spike initiation by hyperpolarizing the cells’ voltage threshold by 3.1 ± 1.0 mV and reducing the recruitment current for the tonic discharges by 0.26 ± 0.1 nA, on average (n = 59). Further analysis revealed that the noise reduced both recruitment and decruitment currents by 0.26 ± 0.13 and 0.33 ± 0.1 nA, respectively, and prolonged the repetitive firing. The noise also increased the slopes of frequency-current (F-I) relationships by 1.1 ± 0.2 Hz/nA. To investigate the potential mechanisms underlying these findings, we constructed a series of HG motoneuron models based on their electrophysiological properties. The models consisted of five compartments endowed with transient sodium (NaT), delayed-rectify potassium [K(DR)], persistent sodium (NaP), calcium-activated potassium [K(AHP)], L-type calcium (CaL) and H-current channels. In general, all our experimental results could be well fitted by the models, however, a modification of standard Hodgkin-Huxley kinetics was required to reproduce the changes in the F-I relationships and the prolonged discharge firing. This modification, corresponding to the noise generated by the stochastic flicker of voltage-gated ion channels (channel flicker, CF), was an adjustable sinusoidal function added to kinetics of the channels that increased their sensitivity to subthreshold membrane potential oscillations. Models with CF added to NaP and CaL channels mimicked the noise-induced alterations of membrane properties, whereas models with CF added to NaT and K(DR) were particularly effective in reproducing the noise-induced changes for repetitive firing observed in the real motoneurons. Further analysis indicated that the modified channel kinetics enhanced NaP- and CaL-mediated inward currents thus increasing the excitability and output of HG motoneurons, whereas they produced relatively small changes in NaT and K(DR), thus balancing these two currents and triggering variability of repetitive firing. This study provided insight into the types of membrane channel mechanisms that might underlie oscillation-induced alterations of neuronal excitability and motor output in rat HG motoneurons.

Persistent sodium conductance contributes to orexin-A-mediated modulation of membrane excitability in neonatal rat mesencephalic V neurons

Orexins are multifunctional hypothalamic neuropeptides that participate in the stimulation of feeding behavior and energy expenditure. However, little is known about their neuromodulatory effects in lower brainstem effector regions, including in the trigeminal neuronal system. The aim of this study was to examine the effects of orexin-A (Ox-A) on the membrane properties of mesencephalic trigeminal (Mes V) neurons that are critically involved in the generation and control of rhythmical oral motor activities. Whole-cell patch clamp recordings were obtained from Mes V neurons in coronal brain slices prepared from Sprague-Dawley rats (postnatal day 12–17). Bath application of Ox-A (100 nM) shortened the duration of the after-hyperpolarization following the action potential, while the interspike frequency of firings during repetitive discharge increased, together with a shift in the frequency-current relationship toward the left. In addition, Ox-A amplified the resonance at the depolarized membrane potential, accompanied with an increase in both Q-value and resonant frequency. A further voltage-clamp experiment demonstrated that Ox-A increased the peak current density of the persistent sodium current (INaP) and shifted its activation curve to the hyperpolarization direction. These results suggested that Ox-A may increase Mes V neuronal excitability by enhancing INaP, possibly sharing a common mechanism with another orexigenic hypothalamic neuropeptide, neuropeptide Y.

A Minimal Biophysical Model of Neocortical Pyramidal Cells: Implications for Frontal Cortex Microcircuitry and Field Potential Generation.

Ca2+ spikes initiated in the distal trunk of layer 5 pyramidal cells (PCs) underlie nonlinear dynamic changes in the gain of cellular response, critical for top-down control of cortical processing. Detailed models with many compartments and dozens of ionic channels can account for this Ca2+ spike-dependent gain and associated critical frequency. However, current models do not account for all known Ca2+-dependent features. Previous attempts to include more features have required increasing complexity, limiting their interpretability and utility for studying large population dynamics. We overcome these limitations in a minimal two-compartment biophysical model. In our model, a basal-dendrites/somatic compartment included fast-inactivating Na+ and delayed-rectifier K+ conductances, while an apical-dendrites/trunk compartment included persistent Na+, hyperpolarization-activated cation (I h ), slow-inactivating K+, muscarinic K+, and Ca2+ L-type. The model replicated the Ca2+ spike morphology and its critical frequency plus three other defining features of layer 5 PC synaptic integration: linear frequency-current relationships, back-propagation-activated Ca2+ spike firing, and a shift in the critical frequency by blocking I h Simulating 1000 synchronized layer 5 PCs, we reproduced the current source density patterns evoked by Ca2+ spikes and describe resulting medial-frontal EEG on a male macaque monkey. We reproduced changes in the current source density when I h was blocked. Thus, a two-compartment model with five crucial ionic currents in the apical dendrites reproduces all features of these neurons. We discuss the utility of this minimal model to study the microcircuitry of agranular areas of the frontal lobe involved in cognitive control and responsible for event-related potentials, such as the error-related negativity.SIGNIFICANCE STATEMENT A minimal model of layer 5 pyramidal cells replicates all known features crucial for distal synaptic integration in these neurons. By redistributing voltage-gated and returning transmembrane currents in the model, we establish a theoretical framework for the investigation of cortical microcircuit contribution to intracranial local field potentials and EEG. This tractable model will enable biophysical evaluation of multiscale electrophysiological signatures and computational investigation of cortical processing.

Orexins modulate membrane excitability in rat trigeminal motoneurons.

Orexins (Oxs) are multifunctional neuropeptides, secreted from the lateral hypothalamus, that stimulate feeding behavior and energy expenditure. In this study, the direct effects of Oxs on the membrane properties of trigeminal motoneurons (TMNs) were examined, which critically participate in the genesis of rhythmical oral motor activities underlying suckling and mastication. Sprague-Dawley rats (3-6 day-old) were used to obtain whole-cell patch-clamp recordings from TMNs. Bath application of Ox-A depolarized the membrane potential and induced inward current, wherein Na+ and Ca2+ were charge carriers. Transient receptor potential channel activation potentially contributed to current and voltage responses by way of Ox-A. Ox-A increased the peak amplitude and duration at half-amplitude of the medium-duration after hyperpolarization following the action potential. The interspike frequency of steady-state firings during repetitive discharge was increased, along with a shift in the frequency-current relationship occurring toward the left. Extracellular and intracellular Ca2+ were involved in regulating modulatory effects, but a requisite level of intracellular Ca2+ was not essential for Ox-induced upregulation of the interspike frequency. Ox-A also enhanced conditional bursting induced by N-methyl-d-aspartate and 5-HT, suggesting it participates in modulating TMNs' discharge patterns during various oral motor activities.

Morphological and electrophysiological properties of serotonin neurons with NMDA modulation in the mesencephalic locomotor region of neonatal ePet-EYFP mice.

The mesencephalic locomotor region (MLR) is an essential area for initiation of locomotion. Its functional roles and circuits underlying locomotion have been studied intensively in many species. Studies suggest that cuneiform nucleus and pedunculopontine nucleus (PPN) are two core regions in the MLR for locomotion. However, it remains unclear about cellular components and morphological and intrinsic membrane properties of the neurons in these regions, especially the serotonergic neurons. Using neonatal ePet-EYFP transgenic mice and immunofluorescent technique, we demonstrated existence of 5-HT neurons in the MLR and discovered that 5-HT neurons distributed mainly in the caudal PPN. 5-HT neurons were heterogeneous in MLR and had three types of firing pattern (single spike, phasic and tonic) and two subtypes of morphology (pyramidal and stellate). We measured parameters of 5-HT neurons (n = 35) including resting membrane potential (- 69.2 ± 4.2mV), input resistance (1410.1 ± 616.9MΩ), membrane capacitance (36.4 ± 14.9 pF), time constant (49.7 ± 19.4ms), voltage threshold (- 32.1 ± 7.4mV), rheobase (21.3 ± 12.4 pA), action potential amplitude (58.9 ± 12.8mV) and half-width (4.7 ± 1.1ms), afterhyperpolarization amplitude (23.6 ± 10.4mV) and half-decay (331.6 ± 157.7ms). 5-HT neurons were intrinsically different from adjacent non-5-HT neurons and less excitable than them. Hyperpolarization-activated inward currents and persistent inward currents were recorded in 5-HT neurons. NMDA increased excitability of 5-HT neurons, especially the tonic-firing neurons, accompanied with depolarization of membrane potential, hyperpolarization of voltage threshold, reduction of afterhyperpolarization half-decay, and left-shift of frequency-current relationship. This study provided insight into the distribution and properties of 5-HT neurons in the MLR and interaction between serotonergic and glutamatergic modulations.

Motoneuron firing properties are modified by trans-spinal direct current stimulation in rats.

Spinal polarization evoked by direct current stimulation [trans-spinal direct current stimulation (tsDCS)] is a novel method for altering spinal network excitability; however, it remains not well understood. The aim of this study was to determine whether tsDCS influences spinal motoneuron activity. Twenty Wistar rats under general pentobarbital anesthesia were subjected to 15 min anodal (n = 10) or cathodal (n = 10) tsDCS of 0.1 mA intensity, and the electrophysiological properties of their motoneurons were intracellularly measured before, during, and after direct current application. The major effects of anodal intervention included increased minimum firing frequency and the slope of the frequency-current (f-I) relationship, as well as decreased rheobase and currents evoking steady-state firing (SSF). The effects of cathodal polarization included decreased maximum SSF frequency, decreased f-I slope, and decreased current evoking the maximum SSF. Notably, the majority of observed effects appeared immediately after the current onset, developed during polarization, and outlasted it for at least 15 min. Moreover, the effects of anodal polarization were generally more pronounced and uniform than those evoked by cathodal polarization. Our study is the first to present polarity-dependent, long-lasting changes in spinal motoneuron firing following tsDCS, which may aid in the development of more safe and accurate application protocols in medicine and sport. NEW & NOTEWORTHY Trans-spinal direct current stimulation induces significant polarity-dependent, long-lasting changes in the threshold and firing properties of spinal motoneurons. Anodal polarization potentiates motoneuron firing whereas cathodal polarization acts mainly toward firing inhibition. The alterations in rheobase and rhythmic firing properties are not restricted to the period of current application and can be observed long after the current offset.

Respiratory motoneuron properties during the transition from gill to lung breathing in the American bullfrog.

Amphibian respiratory development involves a dramatic metamorphic transition from gill to lung breathing and coordination of distinct motor outputs. To determine whether the emergence of adult respiratory motor patterns was associated with similarly dramatic changes in motoneuron (MN) properties, we characterized the intrinsic electrical properties of American bullfrog trigeminal MNs innervating respiratory muscles comprising the buccal pump. In premetamorphic tadpoles (TK stages IX-XVIII) and adult frogs, morphometric analyses and whole cell recordings were performed in trigeminal MNs identified by fluorescent retrograde labeling. Based on the amplitude of the depolarizing sag induced by hyperpolarizing voltage steps, two MN subtypes (I and II) were identified in tadpoles and adults. Compared with type II MNs, type I MNs had larger sag amplitudes (suggesting a larger hyperpolarization-activated inward current), greater input resistance, lower rheobase, hyperpolarized action potential threshold, steeper frequency-current relationships, and fast firing rates and received fewer excitatory postsynaptic currents. Postmetamorphosis, type I MNs exhibited similar sag, enhanced postinhibitory rebound, and increased action potential amplitude with a smaller-magnitude fast afterhyperpolarization. Compared with tadpoles, type II MNs from frogs received higher-frequency, larger-amplitude excitatory postsynaptic currents. Input resistance decreased and rheobase increased postmetamorphosis in all MNs, concurrent with increased soma area and hyperpolarized action potential threshold. We suggest that type I MNs are likely recruited in response to smaller, buccal-related synaptic inputs as well as larger lung-related inputs, whereas type II MNs are likely recruited in response to stronger synaptic inputs associated with larger buccal breaths, lung breaths, or nonrespiratory behaviors involving powerful muscle contractions.

Modulation of NMDA-mediated intrinsic membrane properties of ascending commissural interneurons in neonatal rat spinal cord.

In this paper, the modulation of ascending commissural interneurons by N-methyl-D-aspartate was investigated in neonatal rats by using retrograde labeling and whole-cell patch clamp. Data shows these interneurons can be divided into three types (single spike, phasic, and tonic) based on their firing patterns. A hyperpolarization-activated nonselective cation current and persistent inward current are expressed in these interneurons. The parameters studied (n = 48) include: resting membrane potential (-59.2 ± 0.8 mV), input resistance (964.4 ± 49.3 MΩ), voltage threshold (-39.5 ± 0.6 mV), rheobase (13.5 ± 0.7 pA), action potential height (55.6 ± 2.2 mV), action potential half-width (2.8 ± 0.1 ms), afterhyperpolarization magnitude (16.1 ± 1.2 mV) and half-decay (217.9 ± 10.7 ms). 10 μM N-methyl-D-aspartate increases excitability of ascending commissural interneurons by depolarizing the membrane potential, hyperpolarizing voltage threshold, reducing rheobase, and shifting the frequency-current relationship to the left. N-methyl-Daspartate enhances persistent inward currents but reduces hyperpolarization-activated nonselective cation currents. This research uncovers unique ionic and intrinsic properties of ascending commissural interneurons which can be modulated by major excitatory neurotransmitters such as N-methyl-D-aspartate to potentially facilitate left-right alternation during locomotion.

Motoneuron output regulated by ionic channels: a modeling study of motoneuron frequency-current relationships during fictive locomotion.

Cat lumbar motoneurons display changes in membrane properties during fictive locomotion. These changes include reduction of input resistance and afterhyperpolarization, hyperpolarization of voltage threshold, and voltage-dependent excitation of the motoneurons. The state-dependent alteration of membrane properties leads to dramatic changes in frequency-current (F-I) relationship. The mechanism underlying these changes remains unknown. Using a motoneuron model combined with electrophysiological data, we investigated the channel mechanisms underlying the regulation of motoneuronal excitability and motor output. Simulation results showed that upregulation of transient sodium, persistent sodium, or Cav1.3 calcium conductances or downregulation of calcium-activated potassium or KCNQ/Kv7 potassium conductances could increase motoneuronal excitability and motor output through hyperpolarizing (left shifting) the F-I relationships or increasing the F-I slopes, whereas downregulation of input resistance or upregulation of potassium-mediated leak conductance produced the opposite effects. The excitatory phase of locomotor drive potentials (LDPs) also substantially hyperpolarized the F-I relationships and increased the F-I slopes, whereas the inhibitory phase of the LDPs had opposite effects to a similar extent. The simulation results also showed that none of the individual channel modulations could produce all the changes in the F-I relationships. The effects of modulation of Cav1.3 and KCNQ/Kv7 on F-I relationships were supported by slice experiments with the Cav1.3 agonist Bay K8644 and the KCNQ/Kv7 antagonist XE-991. The conclusion is that the varying changes in F-I relationships during fictive locomotion could be regulated by multichannel modulations. This study provides insight into the ionic basis for control of motor output in walking. NEW & NOTEWORTHY Mammalian spinal motoneurons have their excitability adapted to facilitate recruitment and firing during locomotion. Cat lumbar motoneurons display dramatic changes in membrane properties during fictive locomotion. These changes lead to a varying alteration of frequency-current relationship. The mechanisms underlying the changes remain unknown. In particular, little is known about the ionic basis for regulation of motoneuronal excitability and thus control of the motor output for walking by the spinal motor system.

Is more always better? How different ‘doses’ of exercise after incomplete spinal cord injury affects the membrane properties of deep dorsal horn interneurons

Interneurons in the deep dorsal horn (DDH) of the spinal cord process somatosensory input, and form an important link between upper and lower motoneurons to subsequently shape motor output. Exercise training after SCI is known to improve functional motor recovery, but little is known about the mechanisms within spinal cord neurons that underlie these improvements. Here we investigate how the properties of DDH interneurons are affected by spinal cord injury (SCI) alone, and SCI in combination with different ‘doses’ of treadmill exercise training (3, 6, and 9wks). In an adult mouse hemisection model of SCI we used whole-cell patch-clamp electrophysiology to record intrinsic, AP firing and gain modulation properties from DDH interneurons in a horizontal spinal cord slice preparation. We find that neurons within two segments of the injury, both ipsi- and contralateral to the hemisection, are similarly affected by SCI and SCI plus exercise. The passive intrinsic membrane properties input resistance (Rin) and rheobase are sensitive to the effects of recovery time and exercise training after SCI thus altering DDH interneuron excitability. Conversely, select active membrane properties are largely unaffected by either SCI or exercise training. SCI itself causes a mismatch in the expression of voltage-gated subthreshold currents and AP discharge firing type. Over time after SCI, and especially with exercise training (9wks), this mismatched expression is exacerbated. Lastly, amplification properties (i.e. gain of frequency-current relationship) of DDH interneurons are altered by SCI alone and recover spontaneously with no clear effect of exercise training. These results suggest a larger ‘dose’ of exercise training (9wks) has a strong and selective effect on specific membrane properties, and on the output of interneurons in the vicinity of a SCI. These electrophysiological data provide new insights into the plasticity of DDH interneurons and the mechanisms by which exercise therapy after SCI can improve recovery.

Impact of the localization of dendritic calcium persistent inward current on the input-output properties of spinal motoneuron pool: a computational study.

The goal of this study is to investigate how the dendritic Ca-PIC location influences nonlinear input-output properties and depends on the type of motoneurons across the motoneuron pool. A model motoneuron pool consisting of 10 motoneurons was constructed using a recently developed two-compartment modeling approach that reflected key cell type-associated properties experimentally identified. The dendritic excitability and firing output depended systematically on both the PIC location and the motoneuron type. The PIC onset and offset in the current-voltage (I-V) relationship tended to occur at more hyperpolarized voltages as the path length to the PIC channels from the soma increased and as the cell type shifted from high- to low-threshold motoneurons. At the same time, the firing acceleration and frequency hysteresis in the frequency-current (F-I) relationship became faster and larger, respectively. However, the PIC onset-offset hysteresis increased as the path length and the recruitment threshold increased. Furthermore, the gain of frequency-current function before full PIC activation was larger for PIC channels located over distal dendritic regions in low- compared with high-threshold motoneurons. When compared with previously published experimental observations, the modeling concurred when Ca-PIC channels were placed closer to the soma in high- than low-threshold motoneurons in the model motoneuron pool. All of these results suggest that the negative relationship of Ca-PIC location and cell recruitment threshold may underlie the systematic variation in I-V and F-I transformation across the motoneuron pool.NEW & NOTEWORTHY How does the dendritic location of calcium persistent inward current (Ca-PIC) influence dendritic excitability and firing behavior across the spinal motoneuron pool? This issue was investigated developing a model motoneuron pool that reflected key motoneuron type-specific properties experimentally identified. The simulation results point out the negative relationship between the distance of Ca-PIC source from the soma and cell recruitment threshold as a basis underlying the systematic variation in input-output properties of motoneurons over the motoneuron pool.

Adaptations of motoneuron properties after weight-lifting training in rats.

Resistance training, with repeated short-term and high-intensity exercises, is responsible for an increase in muscle mass and force. The aim of this study was to determine whether such training induces adaptations in the electrophysiological properties of motoneurons innervating the trained muscles and to relate these adaptive changes to previous observations made on motor unit contractile properties. The study was performed on adult male Wistar rats. Animals from the training group were subjected to a 5-wk voluntary progressive weight-lifting program, whereas control rats were restricted to standard cage activity. Intracellular recordings from lumbar spinal motoneurons were made under pentobarbital anesthesia. Membrane properties were measured, and rhythmic firing of motoneurons was analyzed. Strength training evoked adaptive changes in both slow- and fast-type motoneurons, indicating their increased excitability. A shorter spike duration, a higher input resistance, a lower rheobase, a decrease in the minimum current required to evoke rhythmic firing, an increase in the maximum frequencies of the early-state firing (ESF) and the steady-state firing (SSF), and an increase in the respective slopes of the frequency-current (f/I) relationship were observed in fast motoneurons of the trained group. The increase in the maximum ESF and SSF frequencies and an increase in the SSF f/I slope were also present in slow motoneurons. Higher maximum firing rates of motoneurons as well as higher discharge frequencies evoked at the same level of intracellular depolarization current imply higher levels of tetanic forces developed by motor units over the operating range of force production after strength training.NEW & NOTEWORTHY Neuronal responses to weight-lifting training can be observed in altered properties of both slow and fast motoneurons. Motoneurons of trained animals are more excitable, require lower intracellular currents to evoke rhythmic firing, and have the ability to evoke higher maximum discharge frequencies during repetitive firing.

Distinct response properties of rat prepositus hypoglossi nucleus neurons classified on the basis of firing patterns

Neurons in the prepositus hypoglossi nucleus (PHN), which is involved in controlling horizontal gaze, show distinct firing patterns in response to depolarizing current pulses. Although the firing patterns are commonly used to classify neuron types, whether the classified PHN neurons show differences in voltage response properties when stimulated with various types of current inputs remains unclear. In this study, we investigated the response properties of PHN neurons to various current stimuli using whole-cell recordings in rat brainstem slices. In response to pulse currents, neurons that exhibited oscillatory firing (OSC type) showed greater gain than other types, and neurons with a low firing rate (LFR type) showed strong overshooting firing responses to ramp currents. In response to triangular ramp currents, the late-spiking type and the LFR type showed a marked hysteretic frequency-current relationship. In response to sinusoidal currents, the gain was larger in the OSC type than in the other types, although the gain and phase of all types of neurons were similarly modulated by an increase in the input frequency. These findings suggest that distinct neuron types show distinct response properties, depending on the type of stimulus. These neuron types may represent the functionally different populations in the PHN.

Cell-Autonomous Excitation of Midbrain Dopamine Neurons by Endocannabinoid-Dependent Lipid Signaling

The major endocannabinoid in the mammalian brain is the bioactive lipid 2-arachidonoylglycerol (2-AG). The best-known effects of 2-AG are mediated by G-protein-coupled cannabinoid receptors. In principle, 2-AG could modify neuronal excitability by acting directly on ion channels, but such mechanisms are poorly understood. Using a preparation of dissociated mouse midbrain dopamine neurons to isolate effects on intrinsic excitability, we found that 100nM 2-AG accelerated pacemaking and steepened the frequency-current relationship for burst-like firing. In voltage-clamp experiments, 2-AG reduced A-type potassium current (IA) through a cannabinoid receptor-independent mechanism mimicked by arachidonic acid, which has no activityon cannabinoid receptors. Activation of orexin, neurotensin, and metabotropic glutamate Gq/11-linked receptors mimicked the effects of exogenous2-AG and their actions were prevented by inhibiting the 2-AG-synthesizing enzyme diacylglycerol lipaseα. The results show that 2-AG and related lipid signaling molecules can directly tune neuronal excitability in a cell-autonomous manner by modulating IA.

Typical frequency-current curves of neurons obtained from a model based on cellular automaton

Usually, neurons stimulated by constant current exhibit one of two types of behavior: for type-1 neurons, the curve representing “firing frequency versus input current” is continuous; for type-2 neurons, there is a discontinuity in such a curve. Here, we reproduce these typical behaviors from a discrete-time model based on the dynamics of ion channels. In this model, the axonal membrane is considered as a lattice and each patch of this lattice contains a set of ion channels. The state transitions of the voltage-gated ion channels are governed by deterministic rules. We show that the frequency-current relationship obtained from this model is similar to the one derived from the Hodgkin–Huxley equations, which are commonly used to describe type-2 neurons. We also show that our approach can be convenient to model type-1 neurons.

Optimizing computer models of corticospinal neurons to replicate in vitro dynamics.

We developed models of motor cortex corticospinal neurons that replicate in vitro dynamics, including hyperpolarization-induced sag and realistic firing patterns. Models demonstrated resonance in response to synaptic stimulation, with resonance frequency increasing in apical dendrites with increasing distance from soma, matching the increasing oscillation frequencies spanning deep to superficial cortical layers. This gradient may enable specific corticospinal neuron dendrites to entrain to relevant oscillations in different cortical layers, contributing to appropriate motor output commands.

The influence of increased membrane conductance on response properties of spinal motoneurons

During functional spinal neural network activity motoneurons receive massive synaptic excitation and inhibition, and their membrane conductance increases considerably – they are switched to a high-conductance state. High-conductance states can substantially alter response properties of motoneurons. In the present study we investigated how an increase in membrane conductance affects spike frequency adaptation, the gain (i.e., the slope of the frequency-current relationship) and the threshold for action potential generation. We used intracellular recordings from adult turtle motoneurons in spinal cord slices. Membrane conductance was increased pharmacologically by extracellular application of the GABAA receptor agonist muscimol. Our findings suggest that an increase in membrane conductance of about 40–50% increases the magnitude of spike frequency adaptation, but does not change the threshold for action potential generation. Increased conductance causes a subtractive rather than a divisive effect on the initial and the early frequency-current relationships and may have not only a subtractive but also a divisive effect on the steady-state frequency-current relationship.

Neuromodulation of fast-spiking and non-fast-spiking hippocampal CA1 interneurons by human cerebrospinal fluid.

How the brain extracellular fluid influences the activity of GABAergic interneurons in vivo is not known. This issue is examined in the hippocampal brain slice by comparing GABAergic interneuron activity in human versus artificial cerebrospinal fluid. Human cerebrospinal fluid (hCSF) substantially increases the excitability of fast-spiking and non-fast-spiking CA1 interneurons. CA1 pyramidal cells are even more strongly excited by hCSF. The tonic excitation of pyramidal cells, in combination with an increased responsiveness of interneurons to excitatory input, is likely to promote the generation of synchronized network activity in the hippocampus. GABAergic interneurons intricately regulate the activity of hippocampal and neocortical networks. Their function in vivo is likely to be tuned by neuromodulatory substances in the brain extracellular fluid. However, in vitro investigations of GABAergic interneuron function do not account for such effects, as neurons are kept in artificial extracellular fluid. To examine the neuromodulatory influence of brain extracellular fluid on GABAergic activity, we recorded from fast-spiking and non-fast-spiking CA1 interneurons, as well as from pyramidal cells, in the presence of human cerebrospinal fluid (hCSF), using a matched artificial cerebrospinal fluid (aCSF) as control. We found that hCSF increased the frequency of spontaneous firing more than twofold in the two groups of interneurons, and more than fourfold in CA1 pyramidal cells. hCSF did not affect the resting membrane potential of CA1 interneurons but caused depolarization in pyramidal cells. The increased excitability of interneurons and pyramidal cells was accompanied by reductions in after-hyperpolarization amplitudes and a left-shift in the frequency-current relationships. Our results suggest that ambient concentrations of neuromodulators in the brain extracellular fluid powerfully influence the excitability of neuronal networks.