Electrophysiology publications

What characteristics of neural activity distinguish the awake and anesthetized brain? Drugs such as isoflurane abolish behavioral responsiveness in all animals, implying evolutionarily conserved mechanisms. However, it is unclear whether this conservation is reflected at the level of neural activity. Studies in humans have shown that anesthesia is characterized by spatially distinct spectral and coherence signatures that have also been implicated in the global impairment of cortical communication. We questioned whether anesthesia has similar effects on global and local neural processing in one of the smallest brains, that of the fruit fly ( Drosophila melanogaster ). Using a recently developed multielectrode technique, we recorded local field potentials from different areas of the fly brain simultaneously, while manipulating the concentration of isoflurane. Flickering visual stimuli (‘frequency tags’) allowed us to track evoked responses in the frequency domain and measure the effects of isoflurane throughout the brain. We found that isoflurane reduced power and coherence at the tagging frequency (13 or 17 Hz) in central brain regions. Unexpectedly, isoflurane increased power and coherence at twice the tag frequency (26 or 34 Hz) in the optic lobes of the fly, but only for specific stimulus configurations. By modeling the periodic responses, we show that the increase in power in peripheral areas can be attributed to local neuroanatomy. We further show that the effects on coherence can be explained by impacted signal-to-noise ratios. Together, our results show that general anesthesia has distinct local and global effects on neuronal processing in the fruit fly brain.

Background: Current source density analysis of recordings from penetrating electrode arrays has traditionally been used to examine the layer- specific cortical activation and plastic changes associated with changed afferent input. We report on a related analysis, the second spatial derivative (SSD) of surface local field potentials (LFPs) recorded using custom designed thin-film polyimide substrate arrays. Results: SSD analysis of tone- evoked LFPs generated from the auditory cortex under the recording array demonstrated a stereotypical single local minimum, often flanked by maxima on both the caudal and rostral sides. In contrast, tone-pips at frequencies not represented in the region under the array, but known (on the basis of normal tonotopic organization) to be represented caudal to the recording array, had a more complex pattern of many sources and sinks. Comparison with existing methods: Compared to traditional analysis of LFPs, SSD analysis produced a tonotopic map that was more similar to that obtained with multi-unit recordings in a normal-hearing animal. Additionally, the statistically significant decrease in the number of acoustically responsive cortical locations in partially deafened cats following 6 months of cochlear implant use compared to unstimulated cases observed with multi-unit data (p=0.04) was also observed with SSD analysis (p=0.02), but was not apparent using traditional analysis of LFPs (p=0.6). Conclusions: SSD analysis of surface LFPs from the thin-film array provides a rapid and robust method for examining the spatial distribution of cortical activity with improved spatial resolution compared to more traditional LFP recordings.

Language tasks require the coordinated activation of multiple subnetworks-groups of related cortical interactions involved in specific components of task processing. Although electrocorticography (ECoG) has sufficient temporal and spatial resolution to capture the dynamics of event-related interactions between cortical sites, it is difficult to decompose these complex spatiotemporal patterns into functionally discrete subnetworks without explicit knowledge of each subnetwork's timing. We hypothesized that subnetworks corresponding to distinct components of task-related processing could be identified as groups of interactions with co-varying strengths. In this study, five subjects implanted with ECoG grids over language areas performed word repetition and picture naming. We estimated the interaction strength between each pair of electrodes during each task using a time-varying dynamic Bayesian network (tvDBN) model constructed from the power of high gamma (70-110Hz) activity, a surrogate for population firing rates. We then reduced the dimensionality of this model using principal component analysis (PCA) to identify groups of interactions with co-varying strengths, which we term functional network components (FNCs). This data-driven technique estimates both the weight of each interaction's contribution to a particular subnetwork, and the temporal profile of each subnetwork's activation during the task. We found FNCs with temporal and anatomical features consistent with articulatory preparation in both tasks, and with auditory and visual processing in the word repetition and picture naming tasks, respectively. These FNCs were highly consistent between subjects with similar electrode placement, and were robust enough to be characterized in single trials. Furthermore, the interaction patterns uncovered by FNC analysis correlated well with recent literature suggesting important functional-anatomical distinctions between processing external and self-produced speech. Our results demonstrate that subnetwork decomposition of event-related cortical interactions is a powerful paradigm for interpreting the rich dynamics of large-scale, distributed cortical networks during human cognitive tasks.

Spinal cord injury usually occurs at the level of the cervical spine and results in profound impairment of forelimb function. In this study, we recorded awake behaving intramuscular electromyography (EMG) from the biceps and triceps muscles of the impaired forelimb during volitional and reflexive forelimb movements before and after unilateral cervical spinal cord injury (cSCI) in rats. C5/C6 hemicontusion reduced volitional forelimb strength by more than 50% despite weekly rehabilitation for one month post-injury. Triceps EMG during volitional strength assessment was reduced by more than 60% following injury, indicating reduced descending drive. Biceps EMG during reflexive withdrawal from a thermal stimulus was increased by 500% following injury, indicating flexor withdrawal hyperreflexia. The reduction in volitional forelimb strength was significantly correlated with volitional and reflexive biceps EMG activity. Our results support the hypothesis that biceps hyperreflexia and descending volitional drive both significantly contribute to forelimb strength deficits after cSCI and provide new insight into dynamic muscular dysfunction after cSCI. The use of multiple automated quantitative measures of forelimb dysfunction in the rodent cSCI model will likely aid the search for effective regenerative, pharmacological, and neuroprosthetic treatments for spinal cord injury.

Three-dimensional carbon nanotube frameworks favor spinal cord explant rewiring of motor outputs.

Precise temporal coding is necessary for proper acoustic analysis. However, at cortical level, forward suppression appears to limit the ability of neurons to extract temporal information from natural sound sequences. Here we studied how temporal processing can be maintained in the bats’ cortex in the presence of suppression evoked by natural echolocation streams that are relevant to the bats’ behavior. We show that cortical neurons tuned to target-distance actually profit from forward suppression induced by natural echolocation sequences. These neurons can more precisely extract target distance information when they are stimulated with natural echolocation sequences than during stimulation with isolated call-echo pairs. We conclude that forward suppression does for time domain tuning what lateral inhibition does for selectivity forms such as auditory frequency tuning and visual orientation tuning. When talking about cortical processing, suppression should be seen as a mechanistic tool rather than a limiting element.

Understanding the coding strategies used to process sensory input remains a central problem in neuroscience. Growing evidence suggests that sensory systems process natural stimuli efficiently by ensuring a close match between neural tuning and stimulus statistics through adaptation. However, adaptation causes ambiguity as the same response can be elicited by different stimuli. The mechanisms by which the brain resolves ambiguity remain poorly understood. Here we investigated adaptation in electrosensory pyramidal neurons within different parallel maps in the weakly electric fish Apteronotus leptorhynchus . In response to step increases in stimulus variance, we found that pyramidal neurons within the lateral segment (LS) displayed strong scale invariant adaptation whereas those within the centromedial segment (CMS) instead displayed weaker degrees of scale invariant adaptation. Signal detection analysis revealed that strong adaptation in LS neurons significantly reduced stimulus discriminability. In contrast, weaker adaptation displayed by CMS neurons led to significantly lesser impairment of discriminability. Thus, while LS neurons display adaptation that is matched to natural scene statistics, thereby optimizing information transmission, CMS neurons instead display weaker adaptation and would instead provide information about the context in which these statistics occur. We propose that such a scheme is necessary for decoding by higher brain structures.

Recently, we reported evidence for a novel mechanism of peripheral sensory coding based on oscillatory synchrony. Spontaneously oscillating electroreceptors in weakly electric fish (Mormyridae) respond to electrosensory stimuli with a phase reset that results in transient synchrony across the receptor population (Baker et al., 2015). Here, we asked whether the central electrosensory system actually detects the occurrence of synchronous oscillations among receptors. We found that electrosensory stimulation elicited evoked potentials in the midbrain exterolateral nucleus at a short latency following receptor synchronization. Frequency tuning in the midbrain resembled peripheral frequency tuning, which matches the intrinsic oscillation frequencies of the receptors. These frequencies are lower than those in individual conspecific signals, and instead match those found in collective signals produced by groups of conspecifics. Our results provide further support for a novel mechanism for sensory coding based on the detection of oscillatory synchrony among peripheral receptors.

Many postnatal onset neurological disorders such as autism spectrum disorders (ASDs) and intellectual disability are thought to arise largely from disruption of excitatory/inhibitory homeostasis. Although mouse models of Rett syndrome (RTT), a postnatal neurological disorder caused by loss-of-function mutations in MECP2, display impaired excitatory neurotransmission, the RTT phenotype can be largely reproduced in mice simply by removing MeCP2 from inhibitory GABAergic neurons. To determine what role excitatory signaling impairment might play in RTT pathogenesis, we generated conditional mouse models with Mecp2 either removed from or expressed solely in glutamatergic neurons. MeCP2 deficiency in glutamatergic neurons leads to early lethality, obesity, tremor, altered anxiety-like behaviors, and impaired acoustic startle response, which is distinct from the phenotype of mice lacking MeCP2 only in inhibitory neurons. These findings reveal a role for excitatory signaling impairment in specific neurobehavioral abnormalities shared by RTT and other postnatal neurological disorders.

The degree of order versus randomness in mammalian cortical circuits has been the subject of much discussion. Previous reports showed that at a large scale there is smooth tonotopy in mouse auditory cortex, while at the single neuron level the representation is the traditional “salt and pepper” configuration attributed to rodent cortex. Here we show that at the micro columnar scale we find a large variety of response profiles, but neurons tend to share similar preference in terms of frequency, bandwidth and latency. However, this smooth representation was fractured and large differences were possible between neighbouring neurons. Despite the tendency of most groups of neurons to operate redundantly, high information gains were achieved between cells that had a high signal correlation. Connectivity between neurons was highly non-random, in agreement with a previous in-vitro report from layer five. Our results suggest the existence of functional clusters, connecting neighbouring mini-columns. This supports the idea of a “salt and pepper” configuration at the level of functional clusters of neurons rather than single units.

Objectives/Hypothesis Permanent facial nerve injury is a difficult challenge for both patients and physicians given its potential for debilitating functional, cosmetic, and psychological sequelae. Although current surgical interventions have provided considerable advancements in facial nerve rehabilitation, they often fail to fully address all impairments. We aim to introduce an alternative approach to facial nerve rehabilitation. Study Design Acute experiments in animals with normal facial function. Methods The study included three anesthetized cats. Four facial muscles ( levator auris longus, orbicularis oculi, nasalis, and orbicularis oris ) were monitored with a standard electromyographic (EMG) facial nerve monitoring system with needle electrodes. The main trunk of the facial nerve was exposed, and a 16‐channel penetrating electrode array was placed into the nerve. Electrical current pulses were delivered to each stimulating electrode individually. Elicited EMG voltage outputs were recorded for each muscle. Results Stimulation through individual channels selectively activated restricted nerve populations, resulting in selective contraction of individual muscles. Increasing stimulation current levels resulted in increasing EMG voltage responses. Typically, selective activation of two or more distinct muscles was successfully achieved via a single placement of the multi‐channel electrode array by selection of appropriate stimulation channels. Conclusion We have established in the animal model the ability of a penetrating electrode array to selectively stimulate restricted fiber populations within the facial nerve and to selectively elicit contractions in specific muscles and regions of the face. These results show promise for the development of a facial nerve implant system. Level of Evidence N/A. Laryngoscope , 2016 127:460–465, 2017

Sound-source localization in the horizontal plane relies on detecting small differences in the timing and level of the sound at the two ears, including differences in the timing of the modulated envelopes of high-frequency sounds (envelope interaural time differences (ITDs)). We investigated responses of single neurons in the inferior colliculus (IC) to a wide range of envelope ITDs and stimulus envelope shapes. By a novel means of visualizing neural activity relative to different portions of the periodic stimulus envelope at each ear, we demonstrate the role of neuron-specific excitatory and inhibitory inputs in creating ITD sensitivity (or the lack of it) depending on the specific shape of the stimulus envelope. The underlying binaural brain circuitry and synaptic parameters were modeled individually for each neuron to account for neuron-specific activity patterns. The model explains the effects of envelope shapes on sensitivity to envelope ITDs observed in both normal-hearing listeners and in neural data, and has consequences for understanding how ITD information in stimulus envelopes might be maximized in users of bilateral cochlear implants-for whom ITDs conveyed in the stimulus envelope are the only ITD cues available.

Key points Lateral superior olive (LSO) principal neurons receive AMPA receptor (AMPAR) ‐ and NMDA receptor (NMDAR)‐mediated EPSCs and glycinergic IPSCs. Both EPSCs and IPSCs have slow kinetics in prehearing animals, which during developmental maturation accelerate to sub‐millisecond decay time‐constants. This correlates with a change in glutamate and glycine receptor subunit composition quantified via mRNA levels. The NMDAR‐EPSCs accelerate over development to achieve decay time‐constants of 2.5 ms. This is the fastest NMDAR‐mediated EPSC reported. Acoustic trauma (AT, loud sounds) slow AMPAR‐EPSC decay times, increasing GluA1 and decreasing GluA4 mRNA. Modelling of interaural intensity difference suggests that the increased EPSC duration after AT shifts interaural level difference to the right and compensates for hearing loss. Two months after AT the EPSC decay times recovered to control values. Synaptic transmission in the LSO matures by postnatal day 20, with EPSCs and IPSCs having fast kinetics. AT changes the AMPAR subunits expressed and slows the EPSC time‐course at synapses in the central auditory system. Abstract Damaging levels of sound (acoustic trauma, AT) diminish peripheral synapses, but what is the impact on the central auditory pathway? Developmental maturation of synaptic function and hearing were characterized in the mouse lateral superior olive (LSO) from postnatal day 7 (P7) to P96 using voltage‐clamp and auditory brainstem responses. IPSCs and EPSCs show rapid acceleration during development, so that decay kinetics converge to similar sub‐millisecond time‐constants (τ, 0.87 ± 0.11 and 0.77 ± 0.08 ms, respectively) in adult mice. This correlated with LSO mRNA levels for glycinergic and glutamatergic ionotropic receptor subunits, confirming a switch from Glyα2 to Glyα1 for IPSCs and increased expression of GluA3 and GluA4 subunits for EPSCs. The NMDA receptor (NMDAR)‐EPSC decay τ accelerated from >40 ms in prehearing animals to 2.6 ± 0.4 ms in adults, as GluN2C expression increased. In vivo induction of AT at around P20 disrupted IPSC and EPSC integration in the LSO, so that 1 week later the AMPA receptor (AMPAR)‐EPSC decay was slowed and mRNA for GluA1 increased while GluA4 decreased. In contrast, GlyR IPSC and NMDAR‐EPSC decay times were unchanged. Computational modelling confirmed that matched IPSC and EPSC kinetics are required to generate mature interaural level difference functions, and that longer‐lasting EPSCs compensate to maintain binaural function with raised auditory thresholds after AT. We conclude that LSO excitatory and inhibitory synaptic drive matures to identical time‐courses, that AT changes synaptic AMPARs by expression of subunits with slow kinetics (which recover over 2 months) and that loud sounds reversibly modify excitatory synapses in the brain, changing synaptic function for several weeks after exposure.

How do you make a decision if you do not know the rules of the game? Models of sensory decision-making suggest that choices are slow if evidence is weak, but they may only apply if the subject knows the task rules. Here, we asked how the learning of a new rule influences neuronal activity in the visual (area V1) and frontal cortex (area FEF) of monkeys. We devised a new icon-selection task. On each day, the monkeys saw 2 new icons (small pictures) and learned which one was relevant. We rewarded eye movements to a saccade target connected to the relevant icon with a curve. Neurons in visual and frontal cortex coded the monkey's choice, because the representation of the selected curve was enhanced. Learning delayed the neuronal selection signals and we uncovered the cause of this delay in V1, where learning to select the relevant icon caused an early suppression of surrounding image elements. These results demonstrate that the learning of a new rule causes a transition from fast and random decisions to a more considerate strategy that takes additional time and they reveal the contribution of visual and frontal cortex to the learning process.

Age-related hearing loss (ARHL), clinically referred to as presbycusis, is one of the three most prevalent chronic medical conditions of our elderly, with the majority of persons over the age of 60 suffering from some degree of ARHL. The progressive loss of auditory sensitivity and perceptual capability results in significant declines in workplace productivity, quality of life, cognition and abilities to communicate effectively. Aldosterone is a mineralocorticoid hormone produced in the adrenal glands and plays a role in the maintenance of key ion pumps, including the Na-K(+)-Cl co-transporter 1 or NKCC1, which is involved in homeostatic maintenance of the endocochlear potential. Previously we reported that aldosterone (1 μM) increases NKCC1 protein expression in vitro and that this up-regulation of NKCC1 was not dose-dependent (dosing range from 1 nM to 100 μM). In the current study we measured behavioral and electrophysiological hearing function in middle-aged mice following long-term systemic treatment with aldosterone. We also confirmed that blood pressure remained stable during treatment and that NKCC1 protein expression was upregulated. Pre-pulse inhibition of the acoustic startle response was used as a functional measure of hearing, and the auditory brainstem response was used as an objective measure of peripheral sensitivity. Long-term treatment with aldosterone improved both behavioral and physiological measures of hearing (ABR thresholds). These results are the first to demonstrate a protective effect of aldosterone on age-related hearing loss and pave the way for translational drug development, using aldosterone as a key component to prevent or slow down the progression of ARHL.

Spike timing-dependent plasticity in the hippocampus has rarely been studied in vivo. Using extracellular potential and current source density analysis in urethane-anesthetized adult rats, we studied synaptic plasticity at the basal dendritic excitatory synapse in CA1 after excitation-spike (ES) pairing; E was a weak basal dendritic excitation evoked by stratum oriens stimulation, and S was a population spike evoked by stratum radiatum apical dendritic excitation. We hypothesize that positive ES pairing—generating synaptic excitation before a spike—results in long-term potentiation (LTP) while negative ES pairing results in long-term depression (LTD). Pairing (50 pairs at 5 Hz) at ES intervals of −10 to 0 ms resulted in significant input-specific LTP of the basal dendritic excitatory sink, lasting 60–120 min. Pairing at +10- to +20-ms ES intervals, or unpaired 5-Hz stimulation, did not induce significant basal dendritic or apical dendritic LTP or LTD. No basal dendritic LTD was found after stimulation of stratum oriens with 200 pairs of high-intensity pulses at 25-ms interval. Pairing-induced LTP was abolished by pretreatment with an N-methyl-d-aspartate receptor antagonist, 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), which also reduced spike bursting during 5-Hz pairing. Pairing at 0.5 Hz did not induce spike bursts or basal dendritic LTP. In conclusion, ES pairing at 5 Hz resulted in input-specific basal dendritic LTP at ES intervals of −10 ms to 0 ms but no LTD at ES intervals of −20 to +20 ms. Associative LTP likely occurred because of theta-rhythmic coincidence of subthreshold excitation with a backpropagated spike burst, which are conditions that can occur naturally in the hippocampus.

Accurate sound source localization of low-frequency sounds in the horizontal plane depends critically on the comparison of arrival times at both ears. A specialized brainstem circuit containing the principal neurons of the medial superior olive (MSO) is dedicated to this comparison. MSO neurons are innervated by segregated inputs from both ears. The coincident arrival of excitatory inputs from both ears is thought to trigger action potentials, with differences in internal delays creating a unique sensitivity to interaural time differences (ITDs) for each cell. How the inputs from both ears are integrated by the MSO neurons is still debated. Using juxtacellular recordings, we tested to what extent MSO neurons from anesthetized Mongolian gerbils function as simple cross-correlators of their bilateral inputs. From the measured subthreshold responses to monaural wideband stimuli we predicted the rate-ITD functions obtained from the same MSO neuron, which have a damped oscillatory shape. The rate of the oscillations and the position of the peaks and troughs were accurately predicted. The amplitude ratio between dominant and secondary peaks of the rate-ITD function, captured in the width of its envelope, was not always exactly reproduced. This minor imperfection pointed to the methodological limitation of using a linear representation of the monaural inputs, which disregards any temporal sharpening occurring in the cochlear nucleus. The successful prediction of the major aspects of rate-ITD curves supports a simple scheme in which the ITD sensitivity of MSO neurons is realized by the coincidence detection of excitatory monaural inputs.

Temporal envelope processing is critical for speech comprehension, which is known to be affected by normal aging. Whereas the macaque is an excellent animal model for human cerebral cortical function, few studies have investigated neural processing in the auditory cortex of aged, nonhuman primates. Therefore, we investigated age-related changes in the spiking activity of neurons in primary auditory cortex (A1) of two aged macaque monkeys using amplitude-modulated (AM) noise and compared these responses with data from a similar study in young monkeys (Yin P, Johnson JS, O'Connor KN, Sutter ML. J Neurophysiol 105: 582–600, 2011). For each neuron, we calculated firing rate (rate code) and phase-locking using phase-projected vector strength (temporal code). We made several key findings where neurons in old monkeys differed from those in young monkeys. Old monkeys had higher spontaneous and driven firing rates, fewer neurons that synchronized with the AM stimulus, and fewer neurons that had differential responses to AM stimuli with both a rate and temporal code. Finally, whereas rate and temporal tuning functions were positively correlated in young monkeys, this relationship was lost in older monkeys at both the population and single neuron levels. These results are consistent with considerable evidence from rodents and primates of an age-related decrease in inhibition throughout the auditory pathway. Furthermore, this dual coding in A1 is thought to underlie the capacity to encode multiple features of an acoustic stimulus. The apparent loss of ability to encode AM with both rate and temporal codes may have consequences for stream segregation and effective speech comprehension in complex listening environments.

The anterior hypothalamic area (AHA) is an important integrative relay structure for a variety of autonomic, endocrine, and behavioral responses including feeding behavior and response to stress. However, changes in the activity of the AHA neurons during stress and feeding in freely moving rats are not clear. The present study investigated the firing rate and burst activity of neurons in the central nucleus of the AHA (cAHA) during sucrose intake in non-stressful conditions and after acute stress in freely behaving rats. Rats were implanted with micro-electrodes into the cAHA, and extracellular multi-unit activity was recorded during 1-h access to 10% sucrose in non-stressful conditions or after acute foot shock stress. Acute stress significantly reduced sucrose intake, total sucrose lick number, and lick frequency in licking clusters, and increased inter-lick intervals. At the cluster start (CS) of sucrose licking, the cAHA neurons increased (CS-excited, 20% of the recorded neurons), decreased (CS-inhibited, 42% of the neurons) or did not change (CS-nonresponsive, 38% of the neurons) their firing rate. Stress resulted in a significant increase in the firing rate of the CS-inhibited neurons by decreasing inter-spike intervals within the burst firing of these neurons. This increase in the stress-induced firing rate of the CS-inhibited neurons was accompanied by a disruption of the correlation between the firing rate of CS-inhibited and CS-nonresponsive neurons that was observed in non-stressful conditions. Stress did not affect the firing rate of the CS-excited and CS-nonresponsive neurons. However, stress changed the pattern of burst firing of the CS-excited and CS-nonresponsive neurons by decreasing and increasing the burst number in the CS-excited and CS-nonresponsive neurons, respectively. These results suggest that the cAHA neurons integrate the signals related to stress and intake of palatable food and play a role in the stress- and eating-related circuitry.

Implantable biomedical microdevices enable the restoration of body function and improvement of health condition. As the interface between artificial machines and natural tissue, various kinds of microelectrodes with high density and tiny size were developed to undertake precise and complex medical tasks through electrical stimulation and electrophysiological recording. However, if only the electrical interaction existed between electrodes and muscle or nerve tissue without nutrition factor delivery, it would eventually lead to a significant symptom of denervation-induced skeletal muscle atrophy. In this paper, we developed a novel flexible tubular microelectrode integrated with fluidic drug delivery channel for dynamic tissue implant. First, the whole microelectrode was made of biocompatible polymers, which could avoid the drawbacks of the stiff microelectrodes that are easy to be broken and damage tissue. Moreover, the microelectrode sites were circumferentially distributed on the surface of polymer microtube in three dimensions, which would be beneficial to the spatial selectivity. Finally, the in vivo results confirmed that our implantable tubular microelectrodes were suitable for dynamic electrophysiological recording and simultaneous fluidic drug delivery, and the electrode performance was further enhanced by the conducting polymer modification.