Electrophysiology publications

Intracortical microelectrodes are being developed to both record and stimulate neurons to understand brain circuitry or restore lost functions. However, the success of these probes is hampered partly due to the inflammatory host tissue responses to implants. To minimize the foreign body reactions, L1, a brain derived neuronal specific cell adhesion molecule, has been covalently bound to the neural electrode array surface. Here we evaluated the chronic recording performance of L1-coated silicon based laminar neural electrode arrays implanted into V1m cortex of mice. The L1 coating enhanced the overall visually evoked single-unit (SU) yield and SU amplitude, as well as signal-to-noise-ratio (SNR) in the mouse brain compared to the uncoated arrays across the 0-1500 μm depth. The improvement in recording is most dramatic in the hippocampus region, where the control group showed severe recording yield decrease after one week, while the L1 implants maintained a high SU yield throughout the 16 weeks. Immunohistological analysis revealed significant increases of axonal and neuronal density along with significantly lowered microglia activation around the L1 probe after 16 weeks. These results collectively confirm the effectiveness of L1 based biomimetic coating on minimizing inflammatory tissue response and improving neural recording quality and longevity. Improving chronic recording will benefit the brain-computer interface technologies and neuroscience studies involving chronic tracking of neural activities.

Disruption of cortical connectivity likely contributes to loss of consciousness (LOC) during both sleep and general anesthesia, but the degree of overlap in the underlying mechanisms is unclear. Both sleep and anesthesia comprise states of varying levels of arousal and consciousness, including states of largely maintained conscious experience (sleep: N1, REM; anesthesia: sedated but responsive) as well as states of substantially reduced conscious experience (sleep: N2/N3; anesthesia: unresponsive). Here, we tested the hypotheses that (1) cortical connectivity will exhibit clear changes when transitioning into states of reduced consciousness, and (2) these changes will be similar for arousal states of comparable levels of consciousness during sleep and anesthesia. Using intracranial recordings from five adult neurosurgical patients, we compared resting state cortical functional connectivity (as measured by weighted phase lag index, wPLI) in the same subjects across arousal states during natural sleep [wake (WS), N1, N2, N3, REM] and propofol anesthesia [pre-drug wake (WA), sedated/responsive (S), and unresponsive (U)]. Analysis of alpha-band connectivity indicated a transition boundary distinguishing states of maintained and reduced conscious experience in both sleep and anesthesia. In wake states WS and WA, alpha-band wPLI within the temporal lobe was dominant. This pattern was largely unchanged in N1, REM, and S. Transitions into states of reduced consciousness N2, N3, and U were characterized by dramatic changes in connectivity, with dominant connections shifting to prefrontal cortex. Secondary analyses indicated similarities in reorganization of cortical connectivity in sleep and anesthesia. Shifts from temporal to frontal cortical connectivity may reflect impaired sensory processing in states of reduced consciousness. The data indicate that functional connectivity can serve as a biomarker of arousal state and suggest common mechanisms of LOC in sleep and anesthesia.

Brain glucose-sensing neurons detect glucose fluctuations and prevent severe hypoglycemia, but mechanisms mediating functions of these glucose-sensing neurons are unclear. Here we report that estrogen receptor-α (ERα)-expressing neurons in the ventrolateral subdivision of the ventromedial hypothalamic nucleus (vlVMH) can sense glucose fluctuations, being glucose-inhibited neurons (GI-ERα vlVMH ) or glucose-excited neurons (GE-ERα vlVMH ). Hypoglycemia activates GI-ERα vlVMH neurons via the anoctamin 4 channel, and inhibits GE-ERα vlVMH neurons through opening the ATP-sensitive potassium channel. Further, we show that GI-ERα vlVMH neurons preferentially project to the medioposterior arcuate nucleus of the hypothalamus (mpARH) and GE-ERα vlVMH neurons preferentially project to the dorsal Raphe nuclei (DRN). Activation of ERα vlVMH to mpARH circuit and inhibition of ERα vlVMH to DRN circuit both increase blood glucose. Thus, our results indicate that ERα vlVMH neurons detect glucose fluctuations and prevent severe hypoglycemia in mice.

Background Neurocognitive investigations suggest that conscious sensory perception depends on recurrent neuronal interactions among sensory, parietal, and frontal cortical regions, which are suppressed by general anesthetics. The purpose of this work was to investigate if local interactions in sensory cortex are also altered by anesthetics. The authors hypothesized that desflurane would reduce recurrent neuronal interactions in cortical layer–specific manner consistent with the anatomical disposition of feedforward and feedback pathways. Methods Single-unit neuronal activity was measured in freely moving adult male rats (268 units; 10 animals) using microelectrode arrays chronically implanted in primary and secondary visual cortex. Layer-specific directional interactions were estimated by mutual information and transfer entropy of multineuron spike patterns within and between cortical layers three and five. The effect of incrementally increasing and decreasing steady-state concentrations of desflurane (0 to 8% to 0%) was tested for statistically significant quadratic trend across the successive anesthetic states. Results Desflurane produced robust, state-dependent reduction ( P = 0.001) of neuronal interactions between primary and secondary visual areas and between layers three and five, as indicated by mutual information (37 and 41% decrease at 8% desflurane from wakeful baseline at [mean ± SD] 0.52 ± 0.51 and 0.53 ± 0.51 a.u., respectively) and transfer entropy (77 and 78% decrease at 8% desflurane from wakeful baseline at 1.86 ± 1.56 a.u. and 1.87 ± 1.67 a.u., respectively). In addition, a preferential suppression of feedback between secondary and primary visual cortex was suggested by the reduction of directional index of transfer entropy overall ( P = 0.001; 89% decrease at 8% desflurane from 0.11 ± 0.18 a.u. at baseline) and specifically, in layer five ( P = 0.001; 108% decrease at 8% desflurane from 0.12 ± 0.19 a.u. at baseline). Conclusions Desflurane anesthesia reduces neuronal interactions in visual cortex with a preferential effect on feedback. The findings suggest that neuronal disconnection occurs locally, among hierarchical sensory regions, which may contribute to global functional disconnection underlying anesthetic-induced unconsciousness. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

A “division of labor” has previously been assumed in which the directions of low- and high-frequency sound sources are thought to be encoded by neurons preferentially sensitive to low and high frequencies, respectively. Contrary to this, we found that auditory midbrain neurons encode the directions of both low- and high-frequency sounds regardless of their preferred frequencies. Neural responses were shaped by different sound localization cues depending on the stimulus spectrum—even within the same neuron.

Mutations in myosin-VIIa (MYO7A) cause Usher syndrome type 1, characterized by combined deafness and blindness. MYO7A is proposed to function as a motor that tensions the hair cell mechanotransduction (MET) complex, but conclusive evidence is lacking. Here we report that multiple MYO7A isoforms are expressed in the mouse cochlea. In mice with a specific deletion of the canonical isoform ( Myo7a-ΔC mouse), MYO7A is severely diminished in inner hair cells (IHCs), while expression in outer hair cells is affected tonotopically. IHCs of Myo7a-ΔC mice undergo normal development, but exhibit reduced resting open probability and slowed onset of MET currents, consistent with MYO7A’s proposed role in tensioning the tip link. Mature IHCs of Myo7a-ΔC mice degenerate over time, giving rise to progressive hearing loss. Taken together, our study reveals an unexpected isoform diversity of MYO7A expression in the cochlea and highlights MYO7A’s essential role in tensioning the hair cell MET complex.

An increase in circulating glucocorticoids (CORT) is an essential part of the response to stress. Sustained elevations of CORT, however, have dramatic consequences on behavior, endocrine systems and peripheral organs. Critically, they dampen the endocrine response to acute challenges and decrease intrinsic excitability of corticotropin-releasing hormone neurons in the paraventricular nucleus (CRH PVN ), suggesting key circuits may be less responsive to stress. Here, we make the surprising discovery that CRH PVN neurons harness a form of adaptive synaptic scaling to escape the persistent negative feedback pressure from CORT and maintain stable output in vivo . Specifically, there is an increase in glutamatergic drive to these cells that is mediated by a postsynaptic, multiplicative increase in synaptic strength. These findings suggest that dysfunctions associated with chronic stress may not be due to the primary actions of CORT, but instead reflect the emergence of synaptic adaptations as networks seek to re-establish intrinsic activity setpoints.

Somatostatin improves visual perception by reducing excitatory inputs to the parvalbumin-positive interneurons in the cortex.

Sensory information–driven spikes are synchronized across cortical layers by distinct subtypes of interneurons.

Time-dependent frequency trajectories are an inherent feature of many behaviorally relevant sounds, such as species-specific vocalizations. Dynamic frequency trajectories, even in short sounds, often convey meaningful information, which may be used to differentiate sound categories. However, it is not clear what and where neural responses in the auditory cortical pathway are critical for conveying information about behaviorally relevant frequency trajectories, and how these responses change with experience. Here, we uncover tuning to subtle variations in frequency trajectories in auditory cortex of female mice. We found that auditory cortical responses could be modulated by variations in a pure tone trajectory as small as 1/24th of an octave, comparable to what has been reported in primates. In particular, late spiking after the end of a sound stimulus was more often sensitive to the sound's subtle frequency variation compared with spiking during the sound. Such “Off” responses in the adult A2, but not those in core auditory cortex, were plastic in a way that may enhance the representation of a newly acquired, behaviorally relevant sound category. We illustrate this with the maternal mouse paradigm for natural vocalization learning. By using an ethologically inspired paradigm to drive auditory responses in higher-order neurons, our results demonstrate that mouse auditory cortex can track fine frequency changes, which allows A2 Off responses in particular to better respond to pitch trajectories that distinguish behaviorally relevant, natural sound categories. SIGNIFICANCE STATEMENT A whistle's pitch conveys meaning to its listener, as when dogs learn that distinct pitch trajectories whistled by their owner differentiate specific commands. Many species use pitch trajectories in their own vocalizations to distinguish sound categories, such as in human languages, such as Mandarin. How and where auditory neural activity encodes these pitch trajectories as their meaning is learned but not well understood, especially for short-duration sounds. We studied this in mice, where infants use ultrasonic whistles to communicate to adults. We found that late neural firing after a sound ends can be tuned to how the pitch changes in time, and that this response in a secondary auditory cortical field changes with experience to acquire a pitch change's meaning.

The current study aimed to resolve some of the inconsistencies in the literature on which mental processes affect auditory cortical activity. To this end, we studied auditory cortical firing in four monkeys with different experience while they were involved in six conditions with different arrangements of the task components sound, motor action, and water reward. Firing rates changed most strongly when a sound-only condition was compared to a condition in which sound was paired with water. Additional smaller changes occurred in more complex conditions in which the monkeys received water for motor actions before or after sounds. Our findings suggest that auditory cortex is most strongly modulated by the subjects' level of arousal, thus by a psychological concept related to motor activity triggered by reinforcers and to readiness for operant behavior. Our findings also suggest that auditory cortex is involved in associative and emotional functions, but not in agency and cognitive effort.

The taste of sugar is one of the most basic sensory percepts for humans and other animals. Animals can develop a strong preference for sugar even if they lack sweet taste receptors, indicating a mechanism independent of taste1-3. Here we examined the neural basis for sugar preference and demonstrate that a population of neurons in the vagal ganglia and brainstem are activated via the gut-brain axis to create preference for sugar. These neurons are stimulated in response to sugar but not artificial sweeteners, and are activated by direct delivery of sugar to the gut. Using functional imaging we monitored activity of the gut-brain axis, and identified the vagal neurons activated by intestinal delivery of glucose. Next, we engineered mice in which synaptic activity in this gut-to-brain circuit was genetically silenced, and prevented the development of behavioural preference for sugar. Moreover, we show that co-opting this circuit by chemogenetic activation can create preferences to otherwise less-preferred stimuli. Together, these findings reveal a gut-to-brain post-ingestive sugar-sensing pathway critical for the development of sugar preference. In addition, they explain the neural basis for differences in the behavioural effects of sweeteners versus sugar, and uncover an essential circuit underlying the highly appetitive effects of sugar.

Objective: Top-down spatial attention is effective at selecting a target sound from a mixture. However, nonspatial features often distinguish sources in addition to location. This study explores whether redundant nonspatial features are used to maintain selective auditory attention for a spatially defined target. Design: We recorded electroencephalography while subjects focused attention on one of three simultaneous melodies. In one experiment, subjects (n = 17) were given an auditory cue indicating both the location and pitch of the target melody. In a second experiment (n = 17 subjects), the cue only indicated target location, and we compared two conditions: one in which the pitch separation of competing melodies was large, and one in which this separation was small. Results: In both experiments, responses evoked by onsets of events in sound streams were modulated by attention, and we found no significant difference in this modulation between small and large pitch separation conditions. Therefore, the evoked response reflected that target stimuli were the focus of attention, and distractors were suppressed successfully for all experimental conditions. In all cases, parietal alpha was lateralized following the cue, but before melody onset, indicating that subjects initially focused attention in space. During the stimulus presentation, this lateralization disappeared when pitch cues were strong but remained significant when pitch cues were weak, suggesting that strong pitch cues reduced reliance on sustained spatial attention. Conclusions: These results demonstrate that once a well-defined target stream at a known location is selected, top-down spatial attention plays a weak role in filtering out a segregated competing stream.

Vocal production is a sensory-motor process in which auditory self-monitoring is used to ensure accurate communication. During vocal production, the auditory cortex of both humans and animals is suppressed, a phenomenon that plays an important role in self-monitoring and vocal motor control. However, the underlying neural mechanisms of this vocalization-induced suppression are unknown. γ-band oscillations (>25 Hz) have been implicated a variety of cortical functions and are thought to arise from activity of local inhibitory interneurons, but have not been studied during vocal production. We therefore examined γ-band activity in the auditory cortex of vocalizing marmoset monkeys, of either sex, and found that γ responses increased during vocal production. This increase in γ contrasts with simultaneously recorded suppression of single-unit and multiunit responses. Recorded vocal γ oscillations exhibited two separable components: a vocalization-specific nonsynchronized (“induced”) response correlating with vocal suppression, and a synchronized (“evoked”) response that was also present during passive sound playback. These results provide evidence for the role of cortical γ oscillations during inhibitory processing. Furthermore, the two distinct components of the γ response suggest possible mechanisms for vocalization-induced suppression, and may correspond to the sensory-motor integration of top-down and bottom-up inputs to the auditory cortex during vocal production. SIGNIFICANCE STATEMENT Vocal communication is important to both humans and animals. In order to ensure accurate information transmission, we must monitor our own vocal output. Surprisingly, spiking activity in the auditory cortex is suppressed during vocal production yet maintains sensitivity to the sound of our own voice (“feedback”). The mechanisms of this vocalization-induced suppression are unknown. Here we show that auditory cortical γ oscillations, which reflect interneuron activity, are actually increased during vocal production, the opposite response of that seen in spiking units. We discuss these results with proposed functions of γ activity during inhibitory sensory processing and coordination of different brain regions, suggesting a role in sensory-motor integration.

There are several technical challenges to obtaining high-quality recordings of cochlear potentials in human electrocochleography (ECochG). These challenges include electrical artifacts from devices such as acoustic transducers, biological artifacts from excessive myogenic and electroencephalographic potentials, and issues associated with the placement of a tympanic membrane (TM) electrode on the eardrum. This article presents approaches for dealing with these challenges for ECochG measurement using a TM electrode. Emphasis is placed on eliminating stimulus artifact, optimizing the placement of the electrode, and comparing a custom-made electrode with a commercially-available electrode. This comparison revealed that the custom-made electrode results in greater subject comfort, superior ease of placing the electrode on the eardrum, and larger compound action potential (CAP) amplitudes.

Noise exposure represents the second most common cause of acquired sensorineural hearing loss and we observed that tumor necrosis factor α (TNFα) was involved in this context. The effect of Tnfα gene silencing on the expression profile related to the TNFα metabolic pathway in an experimental model of noise-induced hearing loss had not previously been studied. Methods: Single ears of Wistar rats were pretreated with Tnfα small interfering RNA (siRNA) by trans-tympanic administration 24 h before they were exposed to white noise (120 dBSPL for three hours). After 24 h of noise exposure, we analyzed the electrophysiological threshold and the amplitude of waves I, II, III, and IV in the auditory brain response click. In addition, qRT-PCR was performed to evaluate the TNFα metabolic pathway in the ears submitted or not to gene silencing. Results: Preservation of the electrophysiological threshold and the amplitude of waves was observed in the ears submitted to gene silencing compared to the ears not treated. Increased anti-apoptotic gene expression and decreased pro-apoptotic gene expression were found in the treated ears. Conclusion: Our results allow us to suggest that the blockade of TNFα by gene silencing was useful to prevent noise-induced hearing loss.

Heightened aggression is characteristic of multiple neuropsychiatric disorders and can have various negative effects on patients, their families and the public. Recent studies in humans and animals have implicated brain reward circuits in aggression and suggest that, in subsets of aggressive individuals, domination of subordinate social targets is reinforcing. In this study, we showed that, in male mice, orexin neurons in the lateral hypothalamus activated a small population of glutamic acid decarboxylase 2 (GAD2)-expressing neurons in the lateral habenula (LHb) via orexin receptor 2 (OxR2) and that activation of these GAD2 neurons promoted male-male aggression and conditioned place preference for aggression-paired contexts. Moreover, LHb GAD2 neurons were inhibitory within the LHb and dampened the activity of the LHb as a whole. These results suggest that the orexin system is important for the regulation of inter-male aggressive behavior and provide the first functional evidence of a local inhibitory circuit within the LHb.

Excitatory signaling mediated by NMDARs has been shown to regulate mood disorders. However, current treatments targeting NMDAR subtypes have shown limited success in treating patients, highlighting a need for alternative therapeutic targets. Here, we identify a role for GluN2D-containing NMDARs in modulating emotional behaviors and neural activity in the bed nucleus of the stria terminalis (BNST). Using a GluN2D KO mouse line (GluN2D −/− ), we assessed behavioral phenotypes across tasks modeling emotional behavior. We then used a combination of ex vivo electrophysiology and in vivo fiber photometry to assess changes in BNST plasticity, cell-specific physiology, and cellular activity profiles. GluN2D −/− male mice exhibit evidence of exacerbated negative emotional behavior, and a deficit in BNST synaptic potentiation. We also found that GluN2D is functionally expressed on corticotropin-releasing factor (CRF)-positive BNST cells implicated in driving negative emotional states, and recordings in mice of both sexes revealed increased excitatory and reduced inhibitory drive onto GluN2D −/− BNST-CRF cells ex vivo and increased activity in vivo . Using a GluN2D conditional KO line (GluN2D flx/flx ) to selectively delete the subunit from the BNST, we find that BNST-GluN2D flx/flx male mice exhibit increased depressive-like behaviors, as well as altered NMDAR function and increased excitatory drive onto BNST-CRF neurons. Together, this study supports a role for GluN2D-NMDARs in regulating emotional behavior through their influence on excitatory signaling in a region-specific manner, and suggests that these NMDARs may serve as a novel target for selectively modulating glutamate signaling in stress-responsive structures and cell populations. SIGNIFICANCE STATEMENT Excitatory signaling mediated through NMDARs plays an important role in shaping emotional behavior; however, the receptor subtypes/brain regions through which this occurs are poorly understood. Here, we demonstrate that loss of GluN2D-containing NMDARs produces an increase in anxiety- and depressive-like behaviors in mice, deficits in BNST synaptic potentiation, and increased activity in BNST-CRF neurons known to drive negative emotional behavior. Further, we determine that deleting GluN2D in the BNST leads to increased depressive-like behaviors and increased excitatory drive onto BNST-CRF cells. Collectively, these results demonstrate a role for GluN2D-NMDARs in regulating the activity of stress-responsive structures and neuronal populations in the adult brain, suggesting them as a potential target for treating negative emotional states in mood-related disorders.

Do noises wake you up at night? Blame your locus coeruleus.