Termination Of Stimulus Research Articles

Stress relief as a natural resilience mechanism against depression-like behaviors

Relief, the appetitive state after the termination of aversive stimuli, is evolutionarily conserved. Understanding the behavioral role of this well-conserved phenomenon and its underlying neurobiological mechanisms are open and important questions. Here, we discover that the magnitude of relief from physical stress strongly correlates with individual resilience to depression-like behaviors in chronic stressed mice. Notably, blocking stress relief causes vulnerability to depression-like behaviors, whereas natural rewards supplied shortly after stress promotes resilience. Stress relief is mediated by reward-related mesolimbic dopamine neurons, which show minute-long, persistent activation after stress termination. Circuitry-wise, activation or inhibition of circuits downstream of the ventral tegmental area during the transient relief period bi-directionally regulates depression resilience. These results reveal an evolutionary function of stress relief in depression resilience and identify the neural substrate mediating this effect. Importantly, our data suggest a behavioral strategy of augmenting positive valence of stress relief with natural rewards to prevent depression.

Confirming an antiphasic bicyclic pattern of forward entrainment in signal detection: A reanalysis of Sun et al. (2021).

Forward entrainment refers to that part of the entrainment process that persists after termination of an entraining stimulus. Hickok et al. (2015) reported forward entrainment in signal detection that lasted for two post-stimulus cycles. In a recent paper, Sun et al. (2021) reported new data which suggested an absence of entrainment effects (Eur. J. Neurosci, 1-18, doi.org/10.1111/ejn.15367). Here we show that when Sun et al.'s data are analysed using unbiased detection-theoretic measures, a clear antiphasic bicyclic pattern of entrainment is observed. We further show that the measure of entrainment strength used by Sun et al., the normalized Fourier transform of performance curves, is not only erroneously calculated but is also unreliable in estimating entrainment strength due to signal-processing artifacts.

Aging-Related Alterations to Persistent Firing in the Lateral Entorhinal Cortex Contribute to Deficits in Temporal Associative Memory.

With aging comes a myriad of different disorders, and cognitive decline is one of them. Studies have consistently shown a decline amongst aged subjects in their ability to acquire and maintain temporal associative memory. Defined as the memory of the association between two objects that are separated in time, temporal associative memory is dependent on neocortical structures such as the prefrontal cortex and temporal lobe structures. For this memory to be acquired, a mental trace of the first stimulus is necessary to bridge the temporal gap so the two stimuli can be properly associated. Persistent firing, the ability of the neuron to continue to fire action potentials even after the termination of a triggering stimulus, is one mechanism that is posited to support this mental trace. A recent study demonstrated a decline in persistent firing ability in pyramidal neurons of layer III of the lateral entorhinal cortex with aging, contributing to learning impairments in temporal associative memory acquisition. In this work, we explore the potential ways persistent firing in lateral entorhinal cortex (LEC) III supports temporal associative memory, and how aging may disrupt this mechanism within the temporal lobe system, resulting in impairment in this crucial behavior.

Motivating Operations and Negative Reinforcement.

The motivating operations concept has improved the precision of our approach to analyzing behavior; it serves as a framework for classifying events that alter the reinforcing and punishing effectiveness of other events. Nevertheless, some aspects of the concept are seriously flawed, thereby limiting its utility. We contend in this article that the emphasis it places on the onset of some stimuli (putative motivating operations) making their offset a reinforcer in the absence of a learning history (i.e., in the case of unconditioned motivating operations), or because of such a history (i.e., in the case of reflexive conditioned motivating operations), is of no value in predicting or controlling behavior. It is unfortunate that this pseudo-analysis has been widely accepted, which has drawn attention away from actual motivating operations that are relevant to negative reinforcement, and led to conceptually flawed explanations of challenging human behaviors that are escape-maintained. When used appropriately, the motivating operations concept can help to clarify the conditions under which a stimulus change (in particular, stimulus termination) will function as a negative reinforcer. From both a theoretical and a practical perspective, rethinking the application of the motivating operations concept to negative reinforcement is advantageous. Herein, we explore the implications of doing so with the aim of encouraging relevant research and improving the practice of applied behavior analysis.

Post-stimulatory activity in primate auditory cortex evoked by sensory stimulation during passive listening

Under certain circumstances, cortical neurons are capable of elevating their firing for long durations in the absence of a stimulus. Such activity has typically been observed and interpreted in the context of performance of a behavioural task. Here we investigated whether post-stimulatory activity is observed in auditory cortex and the medial geniculate body of the thalamus in the absence of any explicit behavioural task. We recorded spiking activity from single units in the auditory cortex (fields A1, R and RT) and auditory thalamus of awake, passively-listening marmosets. We observed post-stimulatory activity that lasted for hundreds of milliseconds following the termination of the acoustic stimulus. Post-stimulatory activity was observed following both adapting, sustained and suppressed response profiles during the stimulus. These response types were observed across all cortical fields tested, but were largely absent from the auditory thalamus. As well as being of shorter duration, thalamic post-stimulatory activity emerged following a longer latency than in cortex, indicating that post-stimulatory activity may be generated within auditory cortex during passive listening. Given that these responses were observed in the absence of an explicit behavioural task, post-stimulatory activity in sensory cortex may play a functional role in processes such as echoic memory and temporal integration that occur during passive listening.

Persistence of EEG Alpha Entrainment Depends on Stimulus Phase at Offset.

Neural entrainment is the synchronization of neural activity to the frequency of repetitive external stimuli, which can be observed as an increase in the electroencephalogram (EEG) power spectrum at the driving frequency, -also known as the steady-state response. Although it has been systematically reported that the entrained EEG oscillation persists for approximately three cycles after stimulus offset, the neural mechanisms underpinning it remain unknown. Focusing on alpha oscillations, we adopt the dynamical excitation/inhibition framework, which suggests that phases of entrained EEG signals correspond to alternating excitatory/inhibitory states of the neural circuitry. We hypothesize that the duration of the persistence of entrainment is determined by the specific functional state of the entrained neural network at the time the stimulus ends. Steady-state visually evoked potentials (SSVEP) were elicited in 19 healthy volunteers at the participants’ individual alpha peaks. Visual stimulation consisted of a sinusoidally-varying light terminating at one of four phases: 0, π/2, π, and 3π/2. The persistence duration of the oscillatory activity was analyzed as a function of the terminating phase of the stimulus. Phases of the SSVEP at the stimulus termination were distributed within a constant range of values relative to the phase of the stimulus. Longer persistence durations were obtained when visual stimulation terminated towards the troughs of the alpha oscillations, while shorter persistence durations occurred when stimuli terminated near the peaks. Source localization analysis suggests that the persistence of entrainment reflects the functioning of fronto-occipital neuronal circuits, which might prime the sensory representation of incoming visual stimuli based on predictions about stimulus rhythmicity. Consequently, different states of the network at the end of the stimulation, corresponding to different states of intrinsic neuronal coupling, may determine the time windows over which coding of incoming sensory stimulation is modulated by the preceding oscillatory activity.

Multisensory mechanisms of body perception in somatoform disorders

ObjectiveAccording to one of the hypotheses, somatoform disorders (SD) are related to disturbed perception of bodily signals. We suspect that the disturbances and abnormalities of multisensory integration dynamics may be an additional SD mechanism. The objective of the research was to investigate multisensory bodily illusion dynamics in SD patients. MethodsA clinical group of SD patients (n = 16) and a control group (n = 17) participated in experiments aimed at eliciting a visual-tactile rubber hand illusion (RHI) and a visual-kinesthetic virtual hand illusion (VHI). ResultsFor both illusions studied, the illusion dynamics in SD patients differed from those of healthy subjects. The visual-tactile illusion on the subjective level appeared to be less strong in SD patients, and no proprioceptive drift (PD) was detected. The subjective dynamics of the visual-kinesthetic illusion in patients were similar to those of the control group, but the PD dynamics were different: after the termination of stimuli from the artificial limb, the proprioceptive system did not return to its initial state; on the contrary, PD continued to increase. ConclusionIn comparison with the norm, patients with somatoform disorders display differences in multisensory mechanisms underlying the development of body perception. The results suggest that the disturbance of visual-tactile integration of the stimuli represents one of the mechanisms of body perception distortion in somatoform disorders. It may be assumed that one of the reasons for persistent symptom perception in SD patients is the rigidity of multisensory stimuli perception, at least in the visual-motor domain.

A Dynamic Window Recognition Algorithm for SSVEP-Based Brain-Computer Interfaces Using a Spatio-Temporal Equalizer.

The past decade has witnessed rapid development in the field of brain-computer interfaces (BCIs). While the performance is no longer the biggest bottleneck in the BCI application, the tedious training process and the poor ease-of-use have become the most significant challenges. In this study, a spatio-temporal equalization dynamic window (STE-DW) recognition algorithm is proposed for steady-state visual evoked potential (SSVEP)-based BCIs. The algorithm can adaptively control the stimulus time while maintaining the recognition accuracy, which significantly improves the information transfer rate (ITR) and enhances the adaptability of the system to different subjects. Specifically, a spatio-temporal equalization algorithm is used to reduce the adverse effects of spatial and temporal correlation of background noise. Based on the theory of multiple hypotheses testing, a stimulus termination criterion is used to adaptively control the dynamic window. The offline analysis which used a benchmark dataset and an offline dataset collected from 16 subjects demonstrated that the STE-DW algorithm is superior to the filter bank canonical correlation analysis (FBCCA), canonical variates with autoregressive spectral analysis (CVARS), canonical correlation analysis (CCA) and CCA reducing variation (CCA-RV) algorithms in terms of accuracy and ITR. The results show that in the benchmark dataset, the STE-DW algorithm achieved an average ITR of 134 bits/min, which exceeds the FBCCA, CVARS, CCA and CCA-RV. In off-line experiments, the STE-DW algorithm also achieved an average ITR of 116 bits/min. In addition, the online experiment also showed that the STE-DW algorithm can effectively expand the number of applicable users of the SSVEP-based BCI system. We suggest that the STE-DW algorithm can be used as a reliable identification algorithm for training-free SSVEP-based BCIs, because of the good balance between ease of use, recognition accuracy, ITR and user applicability.

Cerebellar Role in Predictive Control of Eye Velocity Initiation and Termination.

Predictive motor control is essential to achieve rapid and precise motor action in all vertebrates. Visuomotor transformations have been a popular model system to study the underlying neural mechanisms, in particular, the role of the cerebellum in both predictive and gain adaptations. In all species, large-field visual motion produces an involuntary conjugate ocular movement facilitating gaze stabilization called the optokinetic response. Gain adaptation can be induced by prolonged optokinetic visual stimulation; and if the visual stimulation is temporally periodic, predictive behavior emerges. Two predictive timing components were identifiable in this behavior. The first was prediction of stimulus initiation (when to move) and the other was stimulus termination (when to stop). We designed visual training that allowed us to evaluate initiation and termination independently that included the recording of cerebellar activity followed by acute and chronic cerebellar removal in goldfish of both sexes. We found that initiation and termination predictions were present in the cerebellum and more robust than conflicting visual sensory signals. Each prediction could be acquired independently, and both the acquisition and maintenance of each component were cerebellar-dependent. Subsequent analysis of the neuronal connectivity strongly supports the hypothesis that the acquired eye velocity behaviors were dependent on feedforward velocity buildup signals from the brainstem, but the adaptive timing mechanism itself originates within the circuitry of the cerebellum.SIGNIFICANCE STATEMENT Predictive and rapid motor control is essential in our daily life, such as in the playing of musical instruments or sports. The current work evaluates timing of a visuomotor behavior shown to be similar in humans as well as goldfish. Given the latter species' known brainstem cerebellar neuronal connectivity and experimental advantage, it was possible to demonstrate the cerebellum to be necessary for acquisition and maintenance of both the initiation and termination components of when to move and to stop. All evidence in this study points to the adaptive predictive control site to lie within the cerebellar circuitry.

Cerebral blood flow is not modulated following acute aerobic exercise in preadolescent children.

Cognitive enhancements following a single bout of exercise are frequently attributed to increases in cerebral blood flow, however to date we have little understanding of the extent to which such bouts of exercise actually even influence cerebral blood flow following the cessation of exercise. To gain such insight, both regional and global changes in cerebral blood flow were assessed using 3D pseudo-continuous arterial spin-labeled magnetic resonance imaging in a sample of 41 preadolescent children. Using a within-participants randomized crossover design, cerebral blood flow as assessed prior to and following 20-min of either aerobic exercise or an active-control condition during two separate, counterbalanced sessions. The aerobic exercise condition consisted of walking/jogging on a motor driven treadmill at an intensity of approximately 70% of age-predicted maximum heart rate (HR = 136.1 ± 11.1 bpm). The active control condition consisted of walking on the treadmill at the lowest possible intensity (0.5 mph and 0% grade; HR = 92.0 ± 12.2 bpm). Findings revealed no differences in cerebral blood flow following the cessation of exercise relative to the active control condition. These findings demonstrate that cerebral blood flow may not be altered in preadolescent children following the termination of the exercise stimulus during the period when cognitive enhancements have previously been observed.

Sensitivity of the circadian system to evening bright light in preschool-age children.

Although the light‐induced melatonin suppression response is well characterized in adults, studies examining the dynamics of this effect in children are scarce. The purpose of this study was to quantify the magnitude of evening light‐induced melatonin suppression in preschool‐age children. Healthy children (n = 10; 7 females; 4.3 ± 1.1 years) participated in a 7‐day protocol. On days 1–5, children followed a strict sleep schedule. On day 6, children entered a dim light environment (<15 lux) for 1‐h before providing salivary samples every 20‐ to 30‐min from the afternoon until 50‐min after scheduled bedtime. On day 7, subjects remained in dim light conditions until 1‐h before bedtime, at which time they were exposed to a bright light stimulus (~1000 lux) for 1‐h and then re‐entered dim light conditions. Saliva samples were obtained before, during, and after bright light exposure and were time anchored to samples taken the previous evening. We found robust melatonin suppression (87.6 ± 10.0%) in response to the bright light stimulus. Melatonin levels remained attenuated for 50‐min after termination of the light stimulus (P < 0.008). Furthermore, melatonin levels did not return to 50% of those observed in the dim light condition 50‐min after the light exposure for 7/10 children. Our findings demonstrate a robust light‐induced melatonin suppression response in preschool‐age children. These findings have implications for understanding the role of evening light exposure in the development of evening settling difficulties and may serve as experimental evidence to support recommendations regarding light exposure and sleep hygiene practices in early childhood.

Theoretical predication of temperature effects on accommodative processes in simulated amyotrophic lateral sclerosis during hypothermia and hyperthermia.

Electrotonic potentials allow the accommodative processes to long-lasting subthreshold polarizing stimuli to be assessed. The present study investigates such potentials in previously simulated cases of amyotrophic lateral sclerosis, termed as ALS1, ALS2 and ALS3, respectively, when the temperature is changed during hypothermia ([Formula: see text]C) and hyperthermia ([Formula: see text]C). The ALS cases are modeled as three progressively severe uniform axonal dysfunctions along the human motor nerve fiber which is simulated by our temperature-dependent multi-layered numerical model. The results show that the polarizing electrotonic potentials in the ALS1 case are quite similar to those in the normal case during hypothermia. Their defining currents are caused by the activation of potassium fast (K[Formula: see text]) and slow (K[Formula: see text]) channels in the nodal and internodal axolemma beneath the myelin sheath. Except in the ALS3 case at 20[Formula: see text]C, where the accommodative processes are blocked by depolarizing stimuli, in the ALS2 and ALS3 cases during hypothermia these stimuli activate the classical "transient" Na[Formula: see text] channels in the nodal and internodal axolemma beneath the myelin sheath. And this leads to action potential generations during the early parts of electrotonic responses in all compartments along the fiber length. Only in the ALS3 case after the termination of long-lasting subthreshold hyperpolarizing stimuli, action potential generations are obtained in the late parts of electrotonic potentials along the fiber length. In comparison to the normal case, in the gradually severe ALS cases, the depolarizing electrotonic potentials gradually increase, while the hyperpolarizing electrotonic potentials gradually decrease during hyperthermia. However, the repetitive firings are not obtained in these polarizing electrotonic potentials. The results show that the accommodative processes to depolarizing stimuli in the ALS3 case are more likely to be blocked during hypothermia than hyperthermia. The results also show that the polarizing electrotonic potentials in the three simulated ALS cases are specific indicators for the motor nerve disease ALS during hypothermia and hyperthermia.

Effect of light level on the reference frames of visual motion processing.

It is empirically known that some action-related visual tasks, which may rely on the construction of spatiotopic coordinates, are not well conducted under mesopic vision. The aim of this study was to clarify the effect of light level on the reference frame, such as retinotopic and spatiotopic coordinate bases, associated with visual motion processing. For this purpose, we used a phenomenon called visual motion priming in which the perceived direction of a directionally ambiguous test stimulus is influenced by the moving direction of a priming stimulus. Previous studies have shown that negative and positive motion priming are conspicuously observed in retinotopic and spatiotopic coordinates, respectively. In the experiments, participants made a saccade after the termination of the priming stimulus and judged the perceived direction of the test stimulus presented subsequently in retinotopic or spatiotopic coordinates at different light levels. We found that in retinotopic coordinates, negative motion priming was observed at all light levels. In spatiotopic coordinates, positive motion priming was observed at photopic and scotopic light levels, whereas the strength of motion priming was greatly reduced at mesopic light levels. These results were robust to the change in the luminance contrast or the saccadic eye movement per se. Different spatiotemporal properties of cones and rods at mesopic light levels may disturb the construction of a spatiotopic representation of motion, which leads to the disappearance of visual motion priming in spatiotopic coordinates during mesopic vision.

Integrated Computational Model of Intracellular Signaling and microRNA Regulation Predicts the Network Balances and Timing Constraints Critical to the Hepatic Stellate Cell Activation Process

Activation and deactivation of hepatic stellate cells (HSCs) is an important mechanism contributing to both healthy liver function and development of liver diseases, which relies on the interplay between numerous signaling pathways. There is accumulating evidence for the regulatory role of microRNAs that are downstream from these pathways in HSC activation. However, the relative contribution of these pathways and interacting microRNA regulators to the activation process is unknown. We pursued a computational modeling approach to explore the timing and regulatory balances that are critical to HSC activation and quiescence. We developed an integrated model incorporating three signaling pathways with crosstalk (NF-κB, STAT3 and TGF-β) and two microRNAs (miR-146a, miR-21) that are differentially regulated by these pathways. Simulations demonstrated that TGF-β-mediated regulation of microRNAs is critical to drive the HSC phenotypic switch from quiescence (miR-146ahigh miR-21low) to an activated state (miR-146alow miR-21high). We found that the relative timing between peak NF-κB and STAT3 activation plays a key role driving the initial dynamics of miR-146a. We observed re-quiescence from the activated HSC state upon termination of cytokine stimuli. Our integrated model of signaling and microRNA regulation provides a new computational platform for investigating the mechanisms driving HSC molecular state phenotypes in normal and pathological liver physiology.

Generalization of negatively reinforced mands in children with autism.

Each day, people encounter stimuli they find unpleasant. Some children with autism may require systematic instruction to acquire the communication skills necessary to request the termination of such aversive stimuli. We taught 2 school-aged boys with autism a mand (e.g., signing "stop") that could be used to escape a variety of aversive stimuli. First, we employed a systematic assessment to identify aversive stimuli to use during training. We then conducted mand training sequentially across those stimuli until sufficient exemplars were trained for generalization to occur to untrained stimuli. For both participants, cross-stimulus generalization was observed after training with 2 stimuli. Participants manded for escape in the presence of aversive stimuli, but almost never manded in the presence of preferred stimuli or when the programmed stimuli were absent. In addition, we found an inverse relation between acquisition of the mand and engagement in problem behavior and evidence of generalization to nontraining contexts.

Pain Does Not Follow the Boxcar Model: Temporal Dynamics of the BOLD fMRI Signal During Constant Current Painful Electric Nerve Stimulation

The temporal dynamics of the blood oxygen level–dependent (BOLD) signal, especially for painful stimulations, is not completely understood. In this study, the BOLD signal response to a long painful electrical stimulation (a continuous painful stimulation of 2 minutes) is directly compared to that of a short painful stimulation (four 30-second periods of painful stimulation interleaved with 30-second rest) in an effort to further probe the relationship between the temporal dynamics of the BOLD signal during constant-intensity pain stimulation. Time course analysis showed that both stimulation protocols produced 3 similarly timed peaks in both data sets, suggesting an early and delayed BOLD response to painful stimulation initiation, and a response related to stimulus termination. Despite the continuous stimulation, the BOLD signal returned to baseline in the 2-minute task. Even with this signal discrepancy, however, the activation maps of the 2 pain tasks differed only slightly, suggesting that the bulk of the activation is determined by the sharp rise in BOLD signal with stimulus onset. These findings imply that the BOLD signal response time course is not directly reflective of pain perception. PerspectiveThis article demonstrates that the BOLD signal for a painful stimulation contains multiple peaks and does not maintain the constant level during stimulation that is assumed in typical analysis. Although these dynamics should be accounted for in future studies because of their ability to confound results, their presence did not significantly alter the overall group maps.

Neon color spreading in dynamic displays: Temporal factors

When a red star is placed in the middle of an Ehrenstein figure so as to be collinear with the surrounding black rays, a reddish veil is perceived to fill the white center. This is called neon color spreading. To better understand the processes that give rise to this phenomenon, we studied the temporal properties of the effect. Specifically, we presented a "sustained" black Ehrenstein figure (rays) for 600 ms and a "transient" red star for 48 ms, or the converse pattern, at various stimulus onset asynchronies (-100-700 ms) and asked subjects to compare the strength of the neon color in the test stimulus to that of a reference pattern in which the transient star had an onset asynchrony of 300 ms. Additional exposure durations of 24 and 96 ms were used for each transient stimulus in order to study the effect of temporal integration. Simultaneity of the on- and off-transients of the star and the Ehrenstein rays were found to optimize neon color spreading, especially when both stimuli terminated together. Longer exposure durations of the transient stimulus up to 96 ms further improved the effect. Neon color spreading was much reduced when the transient stimulus was presented soon after the beginning of the sustained stimulus, with a gradual build-up towards the end. These results emphasize the importance of stimulus onset asynchrony (SOA) and stimulus termination asynchrony (STA) for the perception of neon color spreading.

The Serotonin 2C Receptor Antagonist SB 242084 Exhibits Abuse-Related Effects Typical of Stimulants in Squirrel Monkeys

Antagonists of the serotonin (5-hydroxytryptamine; 5-HT) type 2C receptor (5-HT(2C)R) are being considered as potential pharmacotherapeutics for various affective disorders, but evidence suggests that these compounds enhance the effects of cocaine and related psychostimulants in rodents. However, the effects of selective 5-HT(2C)R antagonists have not been evaluated in nonhuman primates. The present studies used operant-behavioral and in vivo microdialysis techniques to assess the impact of 5-HT(2C)R antagonism on the behavioral and neurochemical effects of cocaine in squirrel monkeys. In subjects trained to lever-press on a fixed-interval schedule of stimulus termination, pretreatment with the highly selective 5-HT(2C)R antagonist 6-chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-1H-indole-1-carboxyamide dihydrochloride (SB 242084) (vehicle, 0.01-0.1 mg/kg) produced behavioral-stimulant effects alone and interacted with cocaine in an apparently additive manner. In monkeys trained to self-administer intravenous cocaine according to a second-order schedule of drug delivery, SB 242084 (vehicle, 0.03-0.1 mg/kg) modulated cocaine-induced reinstatement of previously extinguished responding and maintained self-administration behavior when substituted for cocaine availability. These studies are the first to assess the direct reinforcing effects of a 5-HT(2C)R-selective antagonist in any species. Finally, in vivo microdialysis studies revealed that pretreatment with SB 242084 (0.1 mg/kg) modulated cocaine-induced dopamine increases within the nucleus accumbens, but not the caudate nucleus, of awake subjects. Taken together, the results suggest that SB 242084 exhibits a behavioral profile that is qualitatively similar to other psychostimulants, although its efficacy is modest compared with cocaine. The observed interactions with cocaine and the substitution for cocaine self-administration may be indicative of some degree of abuse potential in humans.

Mechanisms defining the electrotonic potential abnormalities in simulated amyotrophic lateral sclerosis

Electrotonic potentials allow the accommodative processes to polarizing stimuli to be assessed. Electrotonic potential transients in response to applied polarizing stimuli are caused by the kinetics of underlying axonal conductances. Here, we study these transients using our multi-layered model of the human motor nerve, in three simulated cases of the motor neuron disease amyotrophic lateral sclerosis (ALS): ALS1, ALS2 and ALS3 are three consecutively greater degrees of uniform axonal dysfunctions along the human motor nerve fibre. The results show that the responses in the ALS1 case are quite similar to the normal case. In contrast, in the ALS2 and ALS3 cases, long-lasting (100 ms) subthreshold depolarizing stimuli activate the classical "transient" Na(+) channels in the nodal and in the internodal axolemma beneath the myelin sheath; this leads to action potential generation during the early parts of the electrotonic responses in all compartments along the fibre length. The results also show that the electrotonic potentials in response to long-lasting (100 ms) subthreshold hyperpolarizing stimuli in the ALS1 and ALS2 cases are quiet similar to those of the normal case. However, the current kinetics in the ALS3 case differs from the normal case after the termination of the long-lasting hyperpolarizing stimuli. In the most abnormal ALS3 case, the activation of the Na(+) channels in the nodal and in the internodal axolemma leads to repetitive action potential generation in the late parts (100-200 ms) of the hyperpolarizing electrotonic responses. The results show that the repetitive firing, due to the progressively increased nodal and internodal ion channel dysfunction, are consistent with the loss of functional potassium channels involving both the fast and the slow potassium channel types. The results confirm that the electrotonic potentials in the three simulated ALS cases are specific indicators for the motor neuron disease ALS. The mechanisms underlying the simulated ALS are also discussed.

Distinct neural firing mechanisms to tonal stimuli offset in the inferior colliculus of mice in vivo

Offset neurons, which fire at the termination of sound, likely encode sound duration and serve to process temporal information. Offset neurons are found in most ascending auditory nuclei; however, the neural mechanisms that evoke offset responses are not well understood. In this study, we examined offset neural responses to tonal stimuli in the inferior colliculus (IC) in vivo with extracellular and intracellular recording techniques in mice. Based on peristimulus time histogram (PSTH) patterns, we classified extracellular offset responses into four types: Offset, Onset–Offset, Onset–Sustained-Offset and Inhibition-Offset types. Moreover, using in vivo whole-cell recording techniques, we found that offset responses were generated in most cells through the excitatory and inhibitory synaptic inputs. However, in a small number of cells, the offset responses were generated as a rebound to hyperpolarization during tonal stimulation. Many offset neurons fired robustly at a preferred duration of tonal stimulus, which corresponded with the timing of rich excitatory synaptic inputs. We concluded that most IC offset neurons encode the termination of the tone stimulus by responding to inherited ascending synaptic information, which is tuned to sound duration. The remainder generates offset spikes de novo through a post-inhibitory rebound mechanism.