Electrophysiology publications

Receptive fields of sensory neurons are considered to be dynamic and depend on the stimulus history. In the auditory system, evidence of dynamic frequency-receptive fields has been found following stimulus-specific adaptation (SSA). However, the underlying mechanism and circuitry of SSA have not been fully elucidated. Here, we studied how frequency-receptive fields of neurons in rat inferior colliculus (IC) changed when exposed to a biased tone sequence. Pure tone with one specific frequency (adaptor) was presented markedly more often than others. The adapted tuning was compared with the original tuning measured with an unbiased sequence. We found inhomogeneous changes in frequency tuning in IC, exhibiting a center-surround pattern with respect to the neuron's best frequency. Central adaptors elicited strong suppressive and repulsive changes while flank adaptors induced facilitative and attractive changes. Moreover, we proposed a two-layer model of the underlying network, which not only reproduced the adaptive changes in the receptive fields but also predicted novelty responses to oddball sequences. These results suggest that frequency-specific adaptation in auditory midbrain can be accounted for by an adapted frequency channel and its lateral spreading of adaptation, which shed light on the organization of the underlying circuitry.

Spike rate adaptation (SRA) is a continuing change of responsiveness to ongoing stimuli, which is ubiquitous across species and levels of sensory systems. Under SRA, auditory responses to constant stimuli change over time, relaxing toward a long-term rate often over multiple timescales. With more variable stimuli, SRA causes the dependence of spike rate on sound pressure level to shift toward the mean level of recent stimulus history. A model based on subtractive adaptation (Benda J, Hennig RM. J Comput Neurosci 24: 113–136, 2008) shows that changes in spike rate and level dependence are mechanistically linked. Space-specific neurons in the barn owl's midbrain, when recorded under ketamine-diazepam anesthesia, showed these classical characteristics of SRA, while at the same time exhibiting changes in spike timing precision. Abrupt level increases of sinusoidally amplitude-modulated (SAM) noise initially led to spiking at higher rates with lower temporal precision. Spike rate and precision relaxed toward their long-term values with a time course similar to SRA, results that were also replicated by the subtractive model. Stimuli whose amplitude modulations (AMs) were not synchronous across carrier frequency evoked spikes in response to stimulus envelopes of a particular shape, characterized by the spectrotemporal receptive field (STRF). Again, abrupt stimulus level changes initially disrupted the temporal precision of spiking, which then relaxed along with SRA. We suggest that shifts in latency associated with stimulus level changes may differ between carrier frequency bands and underlie decreased spike precision. Thus SRA is manifest not simply as a change in spike rate but also as a change in the temporal precision of spiking.

Reliably interfacing a nerve with an electrode array is one of the approaches to restore motor and sensory functions after an injury to the peripheral nerve. Accomplishing this with current technologies is challenging as the electrode-neuron interface often degrades over time and surrounding myoelectric signals contaminate the neuro-signals in awake, moving animals. The purpose of this study was to evaluate the potential of microchannel electrode implants to monitor over time and in freely moving animals, neural activity from regenerating nerves. We designed and fabricated implants with silicone rubber and elastic thin-film metallization. Each implant carries an eight-by-twelve matrix of parallel microchannels (of 120 × 110 μm 2 cross-section and 4 mm length) and gold thin-film electrodes embedded in the floor of ten of the microchannels. After sterilization, the soft, multi-lumen electrode implant is sutured between the stumps of the sciatic nerve. Over a period of three months and in four rats, the microchannel electrodes recorded spike activity from the regenerating sciatic nerve. Histology indicates mini-nerves formed of axons and supporting cells regenerate robustly in the implants. Analysis of the recorded spikes and gait kinematics over the ten-week period suggests firing patterns collected with the microchannel electrode implant can be associated with different phases of gait.

Optogenetic techniques provide an unprecedented ability to precisely manipulate neural activity in the context of complex neural circuitry. Although the toolbox of optogenetic probes continues to expand at a rapid pace with more efficient and responsive reagents, hardware-based light delivery is still a major hurdle that limits its practical use in vivo . We have bypassed the challenges of external light delivery by directly coupling a bioluminescent light source (a genetically encoded luciferase) to an inhibitory opsin, which we term an inhibitory luminopsin (iLMO). iLMO was shown to suppress action potential firing and synchronous bursting activity in vitro in response to both external light and luciferase substrate. iLMO was further shown to suppress single-unit firing rate and local field potentials in the hippocampus of anesthetized rats. Finally, expression of iLMO was scaled up to multiple structures of the basal ganglia to modulate rotational behavior of freely moving animals in a hardware-independent fashion. This novel class of optogenetic probes demonstrates how non-invasive inhibition of neural activity can be achieved, which adds to the versatility, scalability and practicality of optogenetic applications in freely behaving animals.

The lateral amygdala (LA) acquires differential coding of predictive and non-predictive fear stimuli that is critical for proper fear memory assignment. The neurotransmitter dopamine is an important modulator of LA activity and facilitates fear memory formation, but whether dopamine neurons aid in the establishment of discriminative fear coding by the LA is unknown. NMDA-type glutamate receptors in dopamine neurons are critical for the prevention of generalized fear following an aversive experience, suggesting a potential link between a cell autonomous function of NMDAR in dopamine neurons and fear coding by the LA. Here, we utilized mice with a selective genetic inactivation functional NMDARs in dopamine neurons (DAT-NR1 KO mice) combined with behavior, in vivo electrophysiology, and ex vivo electrophysiology in LA neurons to demonstrate that plasticity underlying differential fear coding in the LA is regulated by NMDAR signaling in dopamine neurons and alterations in this plasticity is associated non-discriminative cued-fear responses.

Noise pollution from anthropogenic sources is an increasingly problematic challenge faced by many taxa, including fishes. Recent studies demonstrate that road traffic noise propagates effectively from bridge crossings into surrounding freshwater ecosystems; yet, its effect on the stress response and auditory function of freshwater stream fishes is unexamined. The blacktail shiner (Cyprinella venusta) was used as a model to investigate the degree to which traffic noise impacts stress and hearing in exposed fishes. Fish were exposed to an underwater recording of traffic noise played at approximately 140 dB re 1 μPa. Waterborne cortisol samples were collected and quantified using enzyme immunoassay (EIA). Auditory thresholds were assessed in control and traffic exposed groups by measuring auditory evoked potentials (AEPs). After acute exposure to traffic noise, fish exhibited a significant elevation in cortisol levels. Individuals exposed to 2 hours of traffic noise playback had elevated hearing thresholds at 300 and 400 Hz, corresponding to the most sensitive bandwidth for this species.

In Parkinson's disease patients in the OFF medication state, basal ganglia local field potentials exhibit changes in beta and gamma oscillations that correlate with reduced voluntary movement, manifested as rigidity and akinesia. However, magnetoencephalography and low-resolution electrocorticography (ECoG) studies in Parkinson's patients suggest that changes in sensorimotor cortical oscillations differ from those of the basal ganglia. To more clearly define the role of sensorimotor cortex oscillatory activity in Parkinson's, we performed intraoperative, high-resolution (4 mm spacing) ECoG recordings in 10 Parkinson's patients (2 females, ages 47-72) undergoing deep brain stimulation (DBS) lead placement in the awake, OFF medication state. We analyzed ECoG potentials during a computer-controlled reaching task designed to separate movement preparation from movement execution and compared findings to similar invasive recordings in eight patients with essential tremor (3 females, ages 59-78), a condition not associated with rigidity or akinesia. We show that (1) cortical beta spectral power at rest does not differ between Parkinson's and essential tremor patients (p = 0.85), (2) early motor preparation in Parkinson's patients in the OFF medication state is associated with a larger beta desynchronization compared to patients with essential tremor (p = 0.0061), and (3) cortical broadband gamma power is elevated in Parkinson's patients compared to essential tremor patients during both rest and task recordings (p = 0.004). Our findings suggest an oscillatory profile in sensorimotor cortex of Parkinson's patients that, in contrast to the basal ganglia, may act to promote movement to oppose the anti-kinetic bias of the dopamine-depleted state.

Despite many prior studies demonstrating offline behavioral gains in motor skills after sleep, the underlying neural mechanisms remain poorly understood. To investigate the neurophysiological basis for offline gains, we performed single-unit recordings in motor cortex as rats learned a skilled upper-limb task. We found that sleep improved movement speed with preservation of accuracy. These offline improvements were linked to both replay of task-related ensembles during non-rapid eye movement (NREM) sleep and temporal shifts that more tightly bound motor cortical ensembles to movements; such offline gains and temporal shifts were not evident with sleep restriction. Interestingly, replay was linked to the coincidence of slow-wave events and bursts of spindle activity. Neurons that experienced the most consistent replay also underwent the most significant temporal shift and binding to the motor task. Significantly, replay and the associated performance gains after sleep only occurred when animals first learned the skill; continued practice during later stages of learning (i.e., after motor kinematics had stabilized) did not show evidence of replay. Our results highlight how replay of synchronous neural activity during sleep mediates large-scale neural plasticity and stabilizes kinematics during early motor learning.

Spectro-Temporal Receptive Fields (STRFs) were estimated from both multi-unit sorted clusters and high-gamma power responses in human auditory cortex. Intracranial electrophysiological recordings were used to measure responses to a random chord sequence of Gammatone stimuli. Traditional methods for estimating STRFs from single-unit recordings, such as spike-triggered-averages, tend to be noisy and are less robust to other response signals such as local field potentials. We present an extension to recently advanced methods for estimating STRFs from generalized linear models (GLM). A new variant of regression using regularization that penalizes non-zero coefficients is described, which results in a sparse solution. The frequency-time structure of the STRF tends toward grouping in different areas of frequency-time and we demonstrate that group sparsity-inducing penalties applied to GLM estimates of STRFs reduces the background noise while preserving the complex internal structure. The contribution of local spiking activity to the high-gamma power signal was factored out of the STRF using the GLM method, and this contribution was significant in 85 percent of the cases. Although the GLM methods have been used to estimate STRFs in animals, this study examines the detailed structure directly from auditory cortex in the awake human brain. We used this approach to identify an abrupt change in the best frequency of estimated STRFs along posteromedial-to-anterolateral recording locations along the long axis of Heschl's gyrus. This change correlates well with a proposed transition from core to non-core auditory fields previously identified using the temporal response properties of Heschl's gyrus recordings elicited by click-train stimuli.

In a typical auditory scene, sounds from different sources and reflective surfaces summate in the ears, causing spatial cues to fluctuate. Prevailing hypotheses of how spatial locations may be encoded and represented across auditory neurons generally disregard these fluctuations and must therefore invoke additional mechanisms for detecting and representing them. Here, we consider a different hypothesis in which spatial perception corresponds to an intermediate or sub-maximal firing probability across spatially selective neurons within each hemisphere. The precedence or Haas effect presents an ideal opportunity for examining this hypothesis, since the temporal superposition of an acoustical reflection with sounds arriving directly from a source can cause otherwise stable cues to fluctuate. Our findings suggest that subjects' experiences may simply reflect the spatial cues that momentarily arise under various acoustical conditions and how these cues are represented. We further suggest that auditory objects may acquire "edges" under conditions when interaural time differences are broadly distributed.

Neuronal heterotopia refers to brain malformations resulting from deficits of neuronal migration. Individuals with heterotopias show a high incidence of neurological deficits, such as epilepsy. More recently, it has come to be recognized that focal heterotopias may also show a range of psychiatric problems, including cognitive and behavioral impairments. However, because focal heterotopias are not always located in the brain areas responsible for the symptoms, the causal relationship between the symptoms and heterotopias remains elusive. In this study, we showed that mice with focal heterotopias in the somatosensory cortex generated by in utero electroporation exhibited spatial working memory deficit and low competitive dominance behavior, which have been shown to be closely associated with the activity of the medial prefrontal cortex (mPFC) in rodents. Analysis of the mPFC activity revealed that the immediate-early gene expression was decreased and the local field potentials of the mPFC were altered in the mice with heterotopias compared with the control mice. Moreover, activation of these ectopic and overlying sister neurons using the DREADD (designer receptor exclusively activated by designer drug) system improved the working memory deficits. These findings suggest that cortical regions containing focal heterotopias can affect distant brain regions and give rise to behavioral abnormalities. Significance statement: Recent studies reported that patients with heterotopias have a variety of clinical symptoms, such as cognitive disturbance, psychiatric symptoms, and autistic behavior. However, the causal relationship between the symptoms and heterotopias remains elusive. Here we showed that mice with focal heterotopias in the somatosensory cortex generated by in utero electroporation exhibited behavioral deficits that have been shown to be associated with the mPFC activity in rodents. The existence of heterotopias indeed altered the neural activities of the mPFC, and direct manipulation of the neural activity of the ectopic neurons and their sister neurons in the overlying cortex improved the behavioral deficit. Thus, our results indicate that focal heterotopias could affect the activities of distant brain areas and cause behavioral abnormalities.

Background: Deficits in neuronal plasticity underlie many neurobehavioral and cognitive problems presented in fetal alcohol spectrum disorder (FASD). Our laboratory has developed a ferret model showing that early alcohol exposure leads to a persistent disruption in ocular dominance plasticity (ODP). For instance, a few days of monocular deprivation results in a robust reduction of visual cortex neurons' responsiveness to stimulation of the deprived eye in normal animals, but not in ferrets with early alcohol exposure. Previously our laboratory demonstrated that overexpression of serum response factor (SRF) exclusively in astrocytes can improve neuronal plasticity in FASD. Here, we test whether neuronal overexpression of SRF can achieve similar effects. Methods: Ferrets received 3.5 g/kg alcohol intraperitoneally (25% in saline) or saline as control every other day between postnatal day 10 to 30, which is roughly equivalent to the third trimester of human gestation. Animals were given intracortical injections of a Herpes Simplex Virus-based vector to express either green fluorescent protein or a constitutively active form of SRF in infected neurons. They were then monocularly deprived by eyelid suture for 4 to 5 days after which single-unit recordings were conducted to determine whether changes in ocular dominance had occurred. Results: Overexpression of a constitutively active form of SRF by neurons restored ODP in alcohol-treated animals. This effect was observed only in areas near the site of viral infection. Conclusions: Overexpression of SRF in neurons can restore plasticity in the ferret model of FASD, but only in areas near the site of infection. This contrasts with SRF overexpression in astrocytes which restored plasticity throughout the visual cortex.

We investigated the response of putative novelty-detecting neurons in the pallium of an electric fish to electrosensory and acoustic stimuli. Extracellular and whole cell patch recordings were made from neurons in the dorsal pallial nucleus (DD) of Apteronotus leptorhynchus. DD neurons were typically quiescent and exhibited hyperpolarized resting membrane potentials. Stimulation induced, with a variable long latency, rapid though transient depolarization and spike discharge. The transition between resting and depolarized/spiking states resembled the transition to Up states seen in mammalian telencephalic neurons.

Axons from the nucleus magnocellularis form a presynaptic map of interaural time differences (ITDs) in the nucleus laminaris (NL). These inputs generate a field potential that varies systematically with recording position and can be used to measure the map of ITDs. In the barn owl, the representation of best ITD shifts with mediolateral position in NL, so as to form continuous, smoothly overlapping maps of ITD with iso-ITD contours that are not parallel to the NL border. Frontal space (0°) is, however, represented throughout and thus overrepresented with respect to the periphery. Measurements of presynaptic conduction delay, combined with a model of delay line conduction velocity, reveal that conduction delays can account for the mediolateral shifts in the map of ITD.

The cerebellum is a critical sensorimotor structure that exhibits protracted postnatal development in mammals. Many aspects of cerebellar circuit development are activity dependent, but little is known about the nature and sources of the activity. Based on previous findings in 6-day-old rats, we proposed that myoclonic twitches, the spontaneous movements that occur exclusively during active sleep (AS), provide generalized as well as topographically precise activity to the developing cerebellum. Taking advantage of known stages of cerebellar cortical development, we examined the relationship between Purkinje cell activity (including complex and simple spikes), nuchal and hindlimb EMG activity, and behavioral state in unanesthetized 4-, 8-, and 12-day-old rats. AS-dependent increases in complex and simple spike activity peaked at 8 days of age, with 60% of units exhibiting significantly more activity during AS than wakefulness. Also, at all three ages, approximately one-third of complex and simple spikes significantly increased their activity within 100 ms of twitches in one of the two muscles from which we recorded. Finally, we observed rhythmicity of complex and simple spikes that was especially prominent at 8 days of age and was greatly diminished by 12 days of age, likely due to developmental changes in climbing fiber and mossy fiber innervation patterns. All together, these results indicate that the neurophysiological activity of the developing cerebellum can be used to make inferences about changes in its microcircuitry. They also support the hypothesis that sleep-related twitches are a prominent source of discrete climbing and mossy fiber activity that could contribute to the activity-dependent development of this critical sensorimotor structure.

A diversity of signals can be recorded with extracellular electrodes. It remains unclear whether different signal types convey similar or different information and whether they capture the same or different underlying neural phenomena. Some researchers focus on spiking activity, while others examine local field potentials, and still others posit that these are fundamentally the same signals. We examined the similarities and differences in the information contained in four signal types recorded simultaneously from multielectrode arrays implanted in primary motor cortex: well-isolated action potentials from putative single units, multiunit threshold crossings, and local field potentials (LFPs) at two distinct frequency bands. We quantified the tuning of these signal types to kinematic parameters of reaching movements. We found 1) threshold crossing activity is not a proxy for single-unit activity; 2) when examined on individual electrodes, threshold crossing activity more closely resembles LFP activity at frequencies between 100 and 300 Hz than it does single-unit activity; 3) when examined across multiple electrodes, threshold crossing activity and LFP integrate neural activity at different spatial scales; and 4) LFP power in the “beta band” (between 10 and 40 Hz) is a reliable indicator of movement onset but does not encode kinematic features on an instant-by-instant basis. These results show that the diverse signals recorded from extracellular electrodes provide somewhat distinct and complementary information. It may be that these signal types arise from biological phenomena that are partially distinct. These results also have practical implications for harnessing richer signals to improve brain-machine interface control.

High gamma power has become the principal means of assessing auditory cortical activation in human intracranial studies, albeit at the expense of low frequency local field potentials (LFPs). It is unclear whether limiting analyses to high gamma impedes ability of clarifying auditory cortical organization. We compared the two measures obtained from posterolateral superior temporal gyrus (PLST) and evaluated their relative utility in sound categorization. Subjects were neurosurgical patients undergoing invasive monitoring for medically refractory epilepsy. Stimuli (consonant-vowel syllables varying in voicing and place of articulation and control tones) elicited robust evoked potentials and high gamma activity on PLST. LFPs had greater across-subject variability, yet yielded higher classification accuracy, relative to high gamma power. Classification was enhanced by including temporal detail of LFPs and combining LFP and high gamma. We conclude that future studies should consider utilizing both LFP and high gamma when investigating the functional organization of human auditory cortex.

Vulnerability to noise-induced tinnitus is associated with increased spontaneous firing rate in dorsal cochlear nucleus principal neurons, fusiform cells. This hyperactivity is caused, at least in part, by decreased Kv7.2/3 (KCNQ2/3) potassium currents. However, the biophysical mechanisms underlying resilience to tinnitus, which is observed in noise-exposed mice that do not develop tinnitus (non-tinnitus mice), remain unknown. Our results show that noise exposure induces, on average, a reduction in KCNQ2/3 channel activity in fusiform cells in noise-exposed mice by 4 days after exposure. Tinnitus is developed in mice that do not compensate for this reduction within the next 3 days. Resilience to tinnitus is developed in mice that show a re-emergence of KCNQ2/3 channel activity and a reduction in HCN channel activity. Our results highlight KCNQ2/3 and HCN channels as potential targets for designing novel therapeutics that may promote resilience to tinnitus.

Interaural time differences (ITDs) are an important cue for the localization of sounds in azimuthal space. Both birds and mammals have specialized, tonotopically organized nuclei in the brain stem for the processing of ITD: medial superior olive in mammals and nucleus laminaris (NL) in birds. The specific way in which ITDs are derived was long assumed to conform to a delay-line model in which arrays of systematically arranged cells create a representation of auditory space with different cells responding maximally to specific ITDs. This model was supported by data from barn owl NL taken from regions above 3 kHz and from chicken above 1 kHz. However, data from mammals often do not show defining features of the Jeffress model such as a systematic topographic representation of best ITDs or the presence of axonal delay lines, and an alternative has been proposed in which neurons are not topographically arranged with respect to ITD and coding occurs through the assessment of the overall response of two large neuron populations, one in each hemisphere. Modeling studies have suggested that the presence of different coding systems could be related to the animal's head size and frequency range rather than their phylogenetic group. Testing this hypothesis requires data from across the tonotopic range of both birds and mammals. The aim of this study was to obtain in vivo recordings from neurons in the low-frequency range (<1000 Hz) of chicken NL. Our data argues for the presence of a modified Jeffress system that uses the slopes of ITD-selective response functions instead of their peaks to topographically represent ITD at mid- to high frequencies. At low frequencies, below several 100 Hz, the data did not support any current model of ITD coding. This is different to what was previously shown in the barn owl and suggests that constraints in optimal ITD processing may be associated with the particular demands on sound localization determined by the animal's ecological niche in the same way as other perceptual systems such as field of best vision.

Significance Over the past decade, human posterior parietal cortex (PPC) has been unexpectedly implicated in remembering and memory-related decision making. Functional neuroimaging indicates that memory-related responses differ across PPC, and patients with PPC lesions show subtle to significant changes in memory behavior. These surprising observations have motivated novel theorizing, yet current understanding of PPC contributions to memory is limited by the absence of temporal information about activity in PPC subregions as retrieval decisions unfold. In this study, recordings from the human brain show for the first time that distinct temporal and functional profiles of activity are present in PPC subregions as participants make recognition memory decisions. These new findings inform theories of parietal functional contributions to memory, decision making, and attention.