Single Unit publications

Neural heterogeneities are seen ubiquitously within the brain and greatly complicate classification efforts. Here we tested whether the responses of an anatomically well-characterized sensory neuron population to natural stimuli could be used for functional classification. To do so, we recorded from pyramidal cells within the electrosensory lateral line lobe (ELL) of the weakly electric fish Apteronotus leptorhynchus in response to natural electro-communication stimuli as these cells can be anatomically classified into six different types. We then used two independent methodologies to functionally classify responses: one relies of reducing the dimensionality of a feature space while the other directly compares the responses themselves. Both methodologies gave rise to qualitatively similar results: while ON and OFF-type cells could easily be distinguished from one another, ELL pyramidal neuron responses are actually distributed along a continuum rather than forming distinct clusters due to heterogeneities. We discuss the implications of our results for neural coding and highlight some potential advantages.

Approximately 7% to 10% of patients develop a chronic pain syndrome after stroke. This chronic pain condition is called central poststroke pain (CPSP). Recent studies have observed an abnormal increase in the secretion of brain-derived neurotrophic factor (BDNF) in spinal cord tissue after spinal cord injury. An animal model of CPSP was established by an intrathalamus injection of collagenase. Mechanical and thermal allodynia was induced after lesions of the thalamic ventral basal complex in rats. Four weeks after the injection, the number of neurons decreased, the number of astrocytes, microglia, and P2X4 receptors increased, and BDNF mRNA expression increased in the brain lesion area. Nociceptive activity in the medial thalamus (MT) and the coherence coefficient of spontaneous field potential oscillations in the anterior cingulate cortex were enhanced in CPSP animals, and these enhancements were blocked by an acute injection of TrkB-Fc and TrkB antagonist Tat Cyclotraxin-B. Instead of being inhibited by the γ-aminobutyric acid (GABA) system in normal rats, multiunit activity in the MT was enhanced after a microinjection of muscimol, a GABA A receptor agonist, in CPSP animals. After CPSP, BDNF expression was enhanced in the MT, whereas the expression of GABA A channels and the cotransporter KCC2 decreased in the same area. These findings suggest that neuronal plasticity in the MT that was induced by BDNF overexpression after the thalamic lesion was a key factor in CPSP.

Inhibition plays an important role in creating the temporal response properties of duration-tuned neurons (DTNs) in the mammalian inferior colliculus (IC). Neurophysiological and computational studies indicate that duration selectivity in the IC is created through the convergence of excitatory and inhibitory synaptic inputs offset in time. We used paired-tone stimulation and extracellular recording to measure the frequency tuning of the inhibition acting on DTNs in the IC of the big brown bat ( Eptesicus fuscus). We stimulated DTNs with pairs of tones differing in duration, onset time, and frequency. The onset time of a short, best-duration (BD), probe tone set to the best excitatory frequency (BEF) was varied relative to the onset of a longer-duration, nonexcitatory (NE) tone whose frequency was varied. When the NE tone frequency was near or within the cell’s excitatory bandwidth (eBW), BD tone-evoked spikes were suppressed by an onset-evoked inhibition. The onset of the spike suppression was independent of stimulus frequency, but both the offset and duration of the suppression decreased as the NE tone frequency departed from the BEF. We measured the inhibitory frequency response area, best inhibitory frequency (BIF), and inhibitory bandwidth (iBW) of each cell. We found that the BIF closely matched the BEF, but the iBW was broader and usually overlapped the eBW measured from the same cell. These data suggest that temporal selectivity of midbrain DTNs is created and preserved by having cells receive an onset-evoked, constant-latency, broadband inhibition that largely overlaps the cell’s excitatory receptive field. We conclude by discussing possible neural sources of the inhibition. NEW & NOTEWORTHY Duration-tuned neurons (DTNs) arise from temporally offset excitatory and inhibitory synaptic inputs. We used single-unit recording and paired-tone stimulation to measure the spectral tuning of the inhibitory inputs to DTNs. The onset of inhibition was independent of stimulus frequency; the offset and duration of inhibition systematically decreased as the stimulus departed from the cell’s best excitatory frequency. Best inhibitory frequencies matched best excitatory frequencies; however, inhibitory bandwidths were more broadly tuned than excitatory bandwidths.

Cortical neurons remap their receptive fields and rescale sensitivity to spared peripheral inputs following sensory nerve damage. To address how these plasticity processes are coordinated over the course of functional recovery, we tracked receptive field reorganization, spontaneous activity, and response gain from individual principal neurons in the adult mouse auditory cortex over a 50-day period surrounding either moderate or massive auditory nerve damage. We related the day-by-day recovery of sound processing to dynamic changes in the strength of intracortical inhibition from parvalbumin-expressing (PV) inhibitory neurons. Whereas the status of brainstem-evoked potentials did not predict the recovery of sensory responses to surviving nerve fibers, homeostatic adjustments in PV-mediated inhibition during the first days following injury could predict the eventual recovery of cortical sound processing weeks later. These findings underscore the potential importance of self-regulated inhibitory dynamics for the restoration of sensory processing in excitatory neurons following peripheral nerve injuries.

The common marmoset (Callithrix jacchus) is one of the smallest species of primates, with high visual recognition abilities that allow them to judge the identity and quality of food and objects in their environment. To address the cortical processing of visual information related to material surface features in marmosets, we presented a set of stimuli that have identical three-dimensional shapes (bone, torus or amorphous) but different material appearances (ceramic, glass, fur, leather, metal, stone, wood, or matte) to anesthetized marmoset, and recorded multiunit activities from an area ventral to the superior temporal sulcus (STS) using multi-shanked, and depth resolved multi-electrode array. Out of 143 visually responsive multiunits recorded from four animals, 29% had significant main effect only of the material, 3% only of the shape and 43% of both the material and the shape. Furthermore, we found neuronal cluster(s), in which most cells: (1) showed a significant main effect in material appearance; (2) the best stimulus was a glossy material (glass or metal); and (3) had reduced response to the pixel-shuffled version of the glossy material images. The location of the gloss-selective area was in agreement with previous macaque studies, showing activation in the ventral bank of STS. Our results suggest that perception of gloss is an important ability preserved across wide range of primate species.

Vocal communication evokes robust responses in primary auditory cortex (A1) of songbirds, and single neurons from superficial and deep regions of A1 have been shown to respond selectively to songs over complex, synthetic sounds. However, little is known about how this song selectivity arises and manifests itself on the level of networks of neurons in songbird A1. Here, we examined the network-level coding of song and synthetic sounds in A1 by simultaneously recording the responses of multiple neurons in unanesthetized zebra finches. We developed a latent factor model of the joint simultaneous activity of these neural populations, and found that the shared variability in the activity has a surprisingly simple structure; it is dominated by an unobserved latent source with one degree-of-freedom. This simple model captures the structure of the correlated activity in these populations in both spontaneous and stimulus-driven conditions, and given both song and synthetic stimuli. The inferred latent variability is strongly suppressed under stimulation, consistent with similar observations in a range of mammalian cortical regions.

Stretchable optoelectronic fibers interrogate spinal cord circuits during free behavior.

Cholinergic modulation contributes to adaptive sensory processing by controlling spontaneous and stimulus-evoked neural activity and long-term synaptic plasticity. In the dorsal cochlear nucleus (DCN), in vitro activation of muscarinic acetylcholine receptors (mAChRs) alters the spontaneous activity of DCN neurons and interacts with N-methyl-d-aspartate (NMDA) and endocannabinoid receptors to modulate the plasticity of parallel fiber synapses onto fusiform cells by converting Hebbian long-term potentiation to anti-Hebbian long-term depression. Because noise exposure and tinnitus are known to increase spontaneous activity in fusiform cells as well as alter stimulus timing-dependent plasticity (StTDP), it is important to understand the contribution of mAChRs to in vivo spontaneous activity and plasticity in fusiform cells. In the present study, we blocked mAChRs actions by infusing atropine, a mAChR antagonist, into the DCN fusiform cell layer in normal hearing guinea pigs. Atropine delivery leads to decreased spontaneous firing rates and increased synchronization of fusiform cell spiking activity. Consistent with StTDP alterations observed in tinnitus animals, atropine infusion induced a dominant pattern of inversion of StTDP mean population learning rule from a Hebbian to an anti-Hebbian profile. Units preserving their initial Hebbian learning rules shifted toward more excitatory changes in StTDP, whereas units with initial suppressive learning rules transitioned toward a Hebbian profile. Together, these results implicate muscarinic cholinergic modulation as a factor in controlling in vivo fusiform cell baseline activity and plasticity, suggesting a central role in the maladaptive plasticity associated with tinnitus pathology. NEW & NOTEWORTHY This study is the first to use a novel method of atropine infusion directly into the fusiform cell layer of the dorsal cochlear nucleus coupled with simultaneous recordings of neural activity to clarify the contribution of muscarinic acetylcholine receptors (mAChRs) to in vivo fusiform cell baseline activity and auditory-somatosensory plasticity. We have determined that blocking the mAChRs increases the synchronization of spiking activity across the fusiform cell population and induces a dominant pattern of inversion in their stimulus timing-dependent plasticity. These modifications are consistent with similar changes established in previous tinnitus studies, suggesting that mAChRs might have a critical contribution in mediating the maladaptive alterations associated with tinnitus pathology. Blocking mAChRs also resulted in decreased fusiform cell spontaneous firing rates, which is in contrast with their tinnitus hyperactivity, suggesting that changes in the interactions between the cholinergic and GABAergic systems might also be an underlying factor in tinnitus pathology.

Vagus nerve stimulation (VNS) has emerged as a therapy to treat a wide range of neurological disorders, including epilepsy, depression, stroke, and tinnitus. Activation of neurons in the locus coeruleus (LC) is believed to mediate many of the effects of VNS in the central nervous system. Despite the importance of the LC, there is a dearth of direct evidence characterizing neural activity in response to VNS. A detailed understanding of the brain activity evoked by VNS across a range of stimulation parameters may guide selection of stimulation regimens for therapeutic use. In this study, we recorded neural activity in the LC and the mesencephalic trigeminal nucleus (Me5) in response to VNS over a broad range of current amplitudes, pulse frequencies, train durations, inter-train intervals, and pulse widths. Brief 0.5s trains of VNS drive rapid, phasic firing of LC neurons at 0.1mA. Higher current intensities and longer pulse widths drive greater increases in LC firing rate. Varying the pulse frequency substantially affects the timing, but not the total amount, of phasic LC activity. VNS drives pulse-locked neural activity in the Me5 at current levels above 1.2mA. These results provide insight into VNS-evoked phasic neural activity in multiple neural structures and may be useful in guiding the selection of VNS parameters to enhance clinical efficacy.

The mammalian auditory cortex is necessary for spectral and spatial processing of acoustic stimuli. Most physiological studies of single neurons in the auditory cortex have focused on the onset and sustained portions of evoked responses, but there have been far fewer studies on the relationship between onset and offset responses. In the current study, we compared spectral and spatial tuning of onset and offset responses of neurons in primary auditory cortex (A1) and the caudolateral (CL) belt area of awake macaque monkeys. Several different metrics were used to determine the relationship between onset and offset response profiles in both frequency and space domains. In the frequency domain, a substantial proportion of neurons in A1 and CL displayed highly dissimilar best stimuli for onset- and offset-evoked responses, although even for these neurons, there was usually a large overlap in the range of frequencies that elicited onset, and offset responses and distributions of tuning overlap metrics were mostly unimodal. In the spatial domain, the vast majority of neurons displayed very similar best locations for onset- and offset-evoked responses, along with unimodal distributions of all tuning overlap metrics considered. Finally, for both spectral and spatial tuning, a slightly larger fraction of neurons in A1 displayed nonoverlapping onset and offset response profiles, relative to CL, which supports hierarchical differences in the processing of sounds in the two areas. However, these differences are small compared with differences in proportions of simple cells (low overlap) and complex cells (high overlap) in primary and secondary visual areas. NEW & NOTEWORTHY In the current study, we examine the relationship between the tuning of neural responses evoked by the onset and offset of acoustic stimuli in the primary auditory cortex, as well as a higher-order auditory area—the caudolateral belt field—in awake rhesus macaques. In these areas, the relationship between onset and offset response profiles in frequency and space domains formed a continuum, ranging from highly overlapping to highly nonoverlapping.

Objective: The ability to record and to control action potential firing in neuronal circuits is critical to understand how the brain functions. The objective of this study is to develop a monolithic integrated circuit (IC) to record action potentials and simultaneously control action potential firing using optogenetics. Methods: A low-noise and high input impedance (or low input capacitance) neural recording amplifier is combined with a high current laser/light-emitting diode (LED) driver in a single IC. Results: The low input capacitance of the amplifier (9.7 pF) was achieved by adding a dedicated unity gain stage optimized for high impedance metal electrodes. The input referred noise of the amplifier is [Formula: see text], which is lower than the estimated thermal noise of the metal electrode. Thus, the action potentials originating from a single neuron can be recorded with a signal-to-noise ratio of at least 6.6. The LED/laser current driver delivers a maximum current of 330 mA, which is adequate for optogenetic control. The functionality of the IC was tested with an anesthetized Mongolian gerbil and auditory stimulated action potentials were recorded from the inferior colliculus. Spontaneous firings of fifth (trigeminal) nerve fibers were also inhibited using the optogenetic protein Halorhodopsin. Moreover, a noise model of the system was derived to guide the design. Significance: A single IC to measure and control action potentials using optogenetic proteins is realized so that more complicated behavioral neuroscience research and the translational neural disorder treatments become possible in the future.

One of the most complex tasks performed by sensory systems is “scene analysis”: the interpretation of complex signals as behaviorally relevant objects. The study of this problem, universal to species and sensory modalities, is particularly challenging in audition, where sounds from various sources and localizations, degraded by propagation through the environment, sum to form a single acoustical signal. Here we investigated in a songbird model, the zebra finch, the neural substrate for ranging and identifying a single source. We relied on ecologically and behaviorally relevant stimuli, contact calls, to investigate the neural discrimination of individual vocal signature as well as sound source distance when calls have been degraded through propagation in a natural environment. Performing electrophysiological recordings in anesthetized birds, we found neurons in the auditory forebrain that discriminate individual vocal signatures despite long-range degradation, as well as neurons discriminating propagation distance, with varying degrees of multiplexing between both information types. Moreover, the neural discrimination performance of individual identity was not affected by propagation-induced degradation beyond what was induced by the decreased intensity. For the first time, neurons with distance-invariant identity discrimination properties as well as distance-discriminant neurons are revealed in the avian auditory cortex. Because these neurons were recorded in animals that had prior experience neither with the vocalizers of the stimuli nor with long-range propagation of calls, we suggest that this neural population is part of a general-purpose system for vocalizer discrimination and ranging. SIGNIFICANCE STATEMENT Understanding how the brain makes sense of the multitude of stimuli that it continually receives in natural conditions is a challenge for scientists. Here we provide a new understanding of how the auditory system extracts behaviorally relevant information, the vocalizer identity and its distance to the listener, from acoustic signals that have been degraded by long-range propagation in natural conditions. We show, for the first time, that single neurons, in the auditory cortex of zebra finches, are capable of discriminating the individual identity and sound source distance in conspecific communication calls. The discrimination of identity in propagated calls relies on a neural coding that is robust to intensity changes, signals' quality, and decreases in the signal-to-noise ratio.

Rodent organotypic hippocampal cultures spontaneously develop epileptiform activity after approximately 2 weeks in vitro and are increasingly used as a model of chronic post-traumatic epilepsy. However, organotypic cultures are maintained in an artificial environment (culture medium), which contains electrolytes, glucose, amino acids and other components that are not present at the same concentrations in cerebrospinal fluid (CSF). Therefore, it is possible that epileptogenesis in organotypic cultures is driven by these components. We examined the influence of medium composition on epileptogenesis. Epileptogenesis was evaluated by measurements of lactate and lactate dehydrogenase (LDH) levels (biomarkers of ictal activity and cell death, respectively) in spent culture media, immunohistochemistry and automated 3-D cell counts, and extracellular recordings from CA3 regions. Changes in culture medium components moderately influenced lactate and LDH levels as well as electrographic seizure burden and cell death. However, epileptogenesis occurred in any culture medium that was capable of supporting neural survival. We conclude that medium composition is unlikely to be the cause of epileptogenesis in the organotypic hippocampal culture model of chronic post-traumatic epilepsy.

Environmental cues affect place cells responses, but whether this information is integrated versus segregated in distinct hippocampal cell populations is unclear. Here, we show that, in mice running on a treadmill enriched with visual-tactile landmarks, place cells are more strongly controlled by landmark-associated sensory inputs in deeper regions of CA1 pyramidal layer (CA1d). Many cells in CA1d display several firing fields correlated with landmarks, mapping positions slightly before or within the landmarks. Supporting direct involvement of sensory inputs, their firing fields show instantaneous responses to landmark manipulations, persist through change of context, and encode landmark identity and saliency. In contrast, cells located superficially in the pyramidal layer have single firing fields, are context specific and respond with slow dynamics to landmark manipulations. These findings suggest parallel and anatomically segregated circuits within CA1 pyramidal layer, with variable ties to landmarks, allowing flexible representation of spatial and non-spatial information.

Optogenetic interrogation of neural pathways relies on delivery of light-sensitive opsins into tissue and subsequent optical illumination and electrical recording from the regions of interest. Despite the recent development of multifunctional neural probes, integration of these modalities in a single biocompatible platform remains a challenge. We developed a device composed of an optical waveguide, six electrodes and two microfluidic channels produced via fiber drawing. Our probes facilitated injections of viral vectors carrying opsin genes while providing collocated neural recording and optical stimulation. The miniature (<200 μm) footprint and modest weight (<0.5 g) of these probes allowed for multiple implantations into the mouse brain, which enabled opto-electrophysiological investigation of projections from the basolateral amygdala to the medial prefrontal cortex and ventral hippocampus during behavioral experiments. Fabricated solely from polymers and polymer composites, these flexible probes minimized tissue response to achieve chronic multimodal interrogation of brain circuits with high fidelity.

Retinal electrostimulation is promising a successful therapy to restore functional vision. However, a narrow stimulating current range exists between retinal neuron excitation and inhibition which may lead to misperformance of visual prostheses. As the conveyance of representation of complex visual scenes may require neighbouring electrodes to be activated simultaneously, electric field summation may contribute to reach this inhibitory threshold. This study used three approaches to assess the implications of relatively high stimulating conditions in visual prostheses: (1) in vivo , using a suprachoroidal prosthesis implanted in a feline model, (2) in vitro through electrostimulation of murine retinal preparations, and (3) in silico by computing the response of a population of retinal ganglion cells. Inhibitory stimulating conditions led to diminished cortical activity in the cat. Stimulus-response relationships showed non-monotonic profiles to increasing stimulating current. This was observed in vitro and in silico as the combined response of groups of neurons (close to the stimulating electrode) being inhibited at certain stimulating amplitudes, whilst other groups (far from the stimulating electrode) being recruited. These findings may explain the halo-like phosphene shapes reported in clinical trials and suggest that simultaneous stimulation in retinal prostheses is limited by the inhibitory threshold of the retinal ganglion cells.

Robust auditory perception plays a pivotal function for processing behaviorally relevant sounds, particularly with distractions from the environment. The neuronal coding enabling this ability, however, is still not well understood. In this study, we recorded single-unit activity from the primary auditory cortex (A1) of awake marmoset monkeys ( Callithrix jacchus) while delivering conspecific vocalizations degraded by two different background noises: broadband white noise and vocalization babble. Noise effects on neural representation of target vocalizations were quantified by measuring the responses' similarity to those elicited by natural vocalizations as a function of signal-to-noise ratio. A clustering approach was used to describe the range of response profiles by reducing the population responses to a summary of four response classes (robust, balanced, insensitive, and brittle) under both noise conditions. This clustering approach revealed that, on average, approximately two-thirds of the neurons change their response class when encountering different noises. Therefore, the distortion induced by one particular masking background in single-unit responses is not necessarily predictable from that induced by another, suggesting the low likelihood of a unique group of noise-invariant neurons across different background conditions in A1. Regarding noise influence on neural activities, the brittle response group showed addition of spiking activity both within and between phrases of vocalizations relative to clean vocalizations, whereas the other groups generally showed spiking activity suppression within phrases, and the alteration between phrases was noise dependent. Overall, the variable single-unit responses, yet consistent response types, imply that primate A1 performs scene analysis through the collective activity of multiple neurons. NEW & NOTEWORTHY The understanding of where and how auditory scene analysis is accomplished is of broad interest to neuroscientists. In this paper, we systematically investigated neuronal coding of multiple vocalizations degraded by two distinct noises at various signal-to-noise ratios in nonhuman primates. In the process, we uncovered heterogeneity of single-unit representations for different auditory scenes yet homogeneity of responses across the population.

The neurochemical serotonin (5-hydroxytryptamine, 5-HT) is involved in a variety of behavioral functions including arousal, reward, and attention, and has a role in several complex disorders of the brain. In the auditory system, 5-HT fibers innervate a number of subcortical nuclei, yet the modulatory role of 5-HT in nearly all of these areas remains poorly understood. In this study, we examined spiking activity of neurons in the dorsal cochlear nucleus (DCN) following iontophoretic application of 5-HT. The DCN is an early site in the auditory pathway that receives dense 5-HT fiber input from the raphe nuclei and has been implicated in the generation of auditory disorders marked by neuronal hyperexcitability. Recordings from the DCN in awake mice demonstrated that iontophoretic application of 5-HT had heterogeneous effects on spiking rate, spike timing, and evoked spiking threshold. We found that 56% of neurons exhibited increases in spiking rate during 5-HT delivery, while 22% had decreases in rate and the remaining neurons had no change. These changes were similar for spontaneous and evoked spiking and were typically accompanied by changes in spike timing. Spiking increases were associated with lower first spike latencies and jitter, while decreases in spiking generally had opposing effects on spike timing. Cases in which 5-HT application resulted in increased spiking also exhibited lower thresholds compared to the control condition, while cases of decreased spiking had no threshold change. We also found that the 5-HT2 receptor subtype likely has a role in mediating increased excitability. Our results demonstrate that 5-HT can modulate activity in the DCN of awake animals and that it primarily acts to increase neuronal excitability, in contrast to other auditory regions where it largely has a suppressive role. Modulation of DCN function by 5-HT has implications for auditory processing in both normal hearing and disordered states.

Impaired motivation is present in a variety of neurological disorders, suggesting that decreased motivation is caused by broad dysfunction of the nervous system across a variety of circuits. Based on evidence that impaired motivation is a major symptom in the early stages of Huntington’s disease, when dopamine receptor type 2-expressing striatal medium spiny neurons (D2-MSNs) are particularly affected, we hypothesize that degeneration of these neurons would be a key node regulating motivational status. Using a progressive, time-controllable, diphtheria toxin-mediated cell ablation/dysfunction technique, we find that loss-of-function of D2-MSNs within ventrolateral striatum (VLS) is sufficient to reduce goal-directed behaviours without impairing reward preference or spontaneous behaviour. Moreover, optogenetic inhibition and ablation of VLS D2-MSNs causes, respectively, transient and chronic reductions of goal-directed behaviours. Our data demonstrate that the circuitry containing VLS D2-MSNs control motivated behaviours and that VLS D2-MSN loss-of-function is a possible cause of motivation deficits in neurodegenerative diseases.

Embodied theories of cognition emphasize the central role of sensorimotor transformations in the representation of others' actions. Support for these theories is derived from the discovery of the mirror neuron system (MNS) in primates, from noninvasive techniques in humans, and from a limited number of intracranial studies. To understand the neural dynamics of the human MNS, more studies with precise spatial and temporal resolutions are essential. We used electrocorticography to define activation patterns in sensorimotor, parietal and/or frontal neuronal populations, during a viewing and grasping task. Our results show robust high gamma activation for both conditions in classic MNS sites. Furthermore, we provide novel evidence for 2 different populations of neurons: sites that were only active for viewing and grasping ("pure mirroring") and sites that were also active between viewing and grasping, and perhaps serve a more general attentional role. Lastly, a subgroup of parietal electrodes showed earlier peaks than all other regions. These results highlight the complexity of spatial-temporal patterns within the MNS and provide a critical link between single-unit research in monkeys and noninvasive techniques in human.