Publications using TDT

Background: Science continues to search for a neuroprotective drug therapy to improve outcomes after cardiac arrest (CA). The use of glibenclamide (GBC) has shown promise in preclinical studies, but its effects on neuroprognostication tools are not well understood. We aimed to investigate the effect of GBC on somatosensory evoked potential (SSEP) waveform recovery post CA and how this relates to the early prediction of functional outcome, with close attention to arousal and somatosensory recovery, in a rodent model of CA. Methods: Sixteen male Wistar rats were subjected to 8-min asphyxia CA and assigned to GBC treatment (n = 8) or control (n = 8) groups. GBC was administered as a loading dose of 10 μg/kg intraperitoneally 10 min after the return of spontaneous circulation, followed by a maintenance dosage of 1.6 μg/kg every 8 h for 24 h. SSEPs were recorded from baseline until 150 min following CA. Coma recovery, arousal, and brainstem function, measured by subsets of the neurological deficit score (NDS), were compared between both groups. SSEP N10 amplitudes were compared between the two groups at 30, 60, 90, and 120 min post CA. Results: Rats treated with GBC had higher sub-NDS scores post CA, with improved arousal and brainstem function recovery (P = 0.007). Both groups showed a gradual improvement of SSEP N10 amplitude over time, from 30 to 120 min post CA. Rats treated with GBC showed significantly better SSEP recovery at every time point (P < 0.001 for 30, 60, and 90 min; P = 0.003 for 120 min). In the GBC group, the N10 amplitude recovered to baseline by 120 min post CA. Quantified Cresyl violet staining revealed a significantly greater percentage of damage in the control group compared with the GBC treatment group (P = 0.004). Conclusions: Glibenclamide improves coma recovery, arousal, and brainstem function after CA with decreased number of ischemic neurons in a rat model. GBC improves SSEP recovery post CA, with N10 amplitude reaching the baseline value by 120 min, suggesting early electrophysiologic recovery with this treatment. This medication warrants further exploration as a potential drug therapy to improve functional outcomes in patients after CA.

Objective. Gastric electrical stimulation (GES) is a bioelectric intervention for gastroparesis, obesity, and other functional gastrointestinal disorders. In a potential mechanism of action, GES activates the nerve endings of vagal afferent neurons and induces the vago-vagal reflex through the nucleus tractus solitarius (NTS) in the brainstem. However, it is unclear where and how to stimulate in order to optimize the vagal afferent responses. Approach. To address this question with electrophysiology in rats, we applied mild electrical currents to two serosal targets on the distal forestomach with dense distributions of vagal intramuscular arrays (IMAs) that innervated the circular and longitudinal smooth muscle layers. During stimulation, we recorded single and multi-unit responses from gastric neurons in NTS and evaluated how the recorded responses depended on the stimulus orientation and amplitude. Main results. We found that NTS responses were highly selective to the stimulus orientation for a range of stimulus amplitudes. The strongest responses were observed when the applied current flowed in the same direction as the IMAs in parallel with the underlying smooth muscle fibers. Our results suggest that gastric neurons in NTS may encode the orientation-specific activity of gastric smooth muscles relayed by vagal afferent neurons. Significance. This finding suggests that the orientation of GES is critical to effective engagement of vagal afferents and should be considered in light of the structural phenotypes of vagal terminals in the stomach.

It is generally assumed that listeners with normal audiograms have relatively symmetric hearing, and more specifically that diotic stimuli (having zero interaural differences) are heard as centered in the head. While measuring intracranial lateralization with a visual pointing task for tones and 50-Hz-wide narrowband noises from 300 to 700 Hz, examples of systematic and large (>50% from midline to the ear) lateralization biases were found. In a group of ten listeners, five showed consistent lateralization bias to the right or left side at all or a subset of frequencies. Asymmetries in hearing, not apparent in audiometric thresholds, may explain these lateralization biases.

Hearing is one of the five sensory organs that allows us to interact with society and our environment. However, one in eight Americans suffers from sensorineural hearing loss that is great enough to adversely impact their daily life. There is an urgent need to identify what part/degree of the auditory pathway (sensory or neural) is compromised so that appropriate treatment/intervention can be implemented. Single- or two-tone evoked potentials, the electrocochleography (eCochG), were measured along the auditory pathway, i.e., at the round window and remotely at the vertex, with simultaneous recordings of ear canal distortion product otoacoustic emissions. Sensory (cochlear) and neural components in the (remote-) eCochG responses showed distinct level- and frequency-dependent features allowing to be differentiated from each other. Specifically, the distortion products in the (remote-)eCochGs can precisely localize the sensory damage showing that they are effective to determine the sensory or neural damage along the auditory pathway.

In everyday life, predictable sensory stimuli are generally not ecologically informative. By contrast, novel or unexpected stimuli signal ecologically salient changes in the environment. This idea forms the basis of the predictive coding hypothesis: efficient sensory encoding minimizes neural activity associated with predictable backgrounds and emphasizes detection of changes in the environment. In real life, the brain must resolve multiple unexpected sensory events occurring over different time scales. The local/global deviant experimental paradigm examines auditory predictive coding over multiple time scales. For short-term novelty [hundreds of milliseconds; local deviance (LD)], sequences of identical sounds (/xxxxx/) are interspersed with sequences that contain deviants (/xxxxy/). Long-term novelty [several seconds; global deviance (GD)] is created using either (a) frequent /xxxxx/ and infrequent /xxxxy/ sequences, or (b) frequent /xxxxy/ and infrequent /xxxxx/ sequences. In scenario (a), there is both an LD and a GD effect (LDGD, “double surprise”). In (b), the global deviant is a local standard, i.e., sequence of identical sounds (LSGD). Cortical responses reflecting LD and GD originate in different brain areas, have a different time course, and are differentially sensitive to general anesthesia. Neural processes underlying LD and GD have been shown to interact, reflecting overlapping networks subserving the detection of novel auditory stimuli. This study examined these interactions using intracranial electroencephalography in neurosurgical patients. Subjects performed a GD target detection task before and during induction of anesthesia with propofol. Recordings were made from the auditory cortex, surrounding auditory-related and prefrontal cortex in awake, sedated, and unresponsive states. High gamma activity was used to measure the neural basis of local-by-global novelty interactions. Positive interaction was defined as a greater response to the double surprise LDGD condition compared to LSGD. Negative interaction was defined as a weaker response to LDGD. Positive interaction was more frequent than negative interaction and was primarily found in auditory cortex. Negative interaction typically occurred in prefrontal cortex and was more sensitive to general anesthesia. Temporo-parietal auditory-related areas exhibited both types of interaction. These interactions may have relevance in a clinical setting as biomarkers of conscious perception in the assessment of depth of anesthesia and disorders of consciousness.

There are psychoacoustic methods thought to measure gain reduction, which may be from the medial olivocochlear reflex (MOCR), a bilateral feedback loop that adjusts cochlear gain. Although studies have used ipsilateral and contralateral elicitors and have examined strength at different signal frequencies, these factors have not been examined within a single study. Therefore, basic questions about gain reduction, such as the relative strength of ipsilateral vs contralateral elicitation and the relative strength across signal frequency, are not known. In the current study, gain reduction from ipsilateral, contralateral, and bilateral elicitors was measured at 1-, 2-, and 4-kHz signal frequencies using forward masking paradigms at a range of elicitor levels in a repeated measures design. Ipsilateral and bilateral strengths were similar and significantly larger than contralateral strength across signal frequencies. Growth of gain reduction with precursor level tended to differ with signal frequency, although not significantly. Data from previous studies are considered in light of the results of this study. Behavioral results are also considered relative to anatomical and physiological data on the MOCR. These results indicate that, in humans, cochlear gain reduction is broad across frequencies and is robust for ipsilateral and bilateral elicitation but small for contralateral elicitation.

Age-related hearing loss in humans (presbycusis) typically involves impairment of high frequency sensitivity before becoming progressively more severe at lower frequencies. Pathologies initially affecting lower frequency regions of hearing are less common. Here we describe a progressive, predominantly low-frequency recessive hearing impairment in two mutant mouse lines carrying different mutant alleles of the Klhl18 gene: a spontaneous missense mutation ( Klhl18 lowf ) and a targeted mutation ( Klhl18 tm1a(KOMP)Wtsi ). Both males and females were studied, and the two mutant lines showed similar phenotypes. Threshold for auditory brainstem responses (ABR; a measure of auditory nerve and brainstem neural activity) were normal at 3 weeks old but showed progressive increases from 4 weeks onwards. In contrast, distortion product otoacoustic emission (DPOAE) sensitivity and amplitudes (a reflection of cochlear outer hair cell function) remained normal in mutants. Electrophysiological recordings from the round window of Klhl18 lowf mutants at 6 weeks old revealed 1) raised compound action potential thresholds that were similar to ABR thresholds, 2) cochlear microphonic potentials that were normal compared with wildtype and heterozygous control mice and 3) summating potentials that were reduced in amplitude compared to control mice. Scanning electron microscopy showed that Klhl18 lowf mutant mice had abnormally tapering of the tips of inner hair cell stereocilia in the apical half of the cochlea while their synapses appeared normal. These results suggest that Klhl18 is necessary to maintain inner hair cell stereocilia and normal inner hair cell function at low frequencies.

Neuronal activation is often accompanied by the regulation of cerebral hemodynamics via a process known as neurovascular coupling (NVC) which is essential for proper brain function and has been observed to be disrupted in a variety of neuropathologies. A comprehensive understanding of NVC requires imaging capabilities with high spatiotemporal resolution and a field-of-view that spans different orders of magnitude. Here, we present an approach for concurrent multi-contrast mesoscopic and two-photon microscopic imaging of neurovascular dynamics in the cortices of live mice. We investigated the spatiotemporal correlation between sensory-evoked neuronal and vascular responses in the auditory cortices of living mice using four imaging modalities. Our findings unravel drastic differences in the NVC at the regional and microvascular levels and the distinctive effects of different brain states on NVC. We further investigated the brain-state-dependent changes of NVC in large cortical networks and revealed that anesthesia and sedation caused spatiotemporal disruption of NVC.

Individuals typically exhibit better cross-sensory perception following unisensory loss, demonstrating improved perception of information available from the remaining senses and increased cross-sensory use of neural resources. Even individuals with no sensory loss will exhibit such changes in cross-sensory processing following temporary sensory deprivation, suggesting that the brain's capacity for recruiting cross-sensory sources to compensate for degraded unisensory input is a general characteristic of the perceptual process. Many studies have investigated how auditory and visual neural structures respond to within- and cross-sensory input. However, little attention has been given to how general auditory and visual neural processing relates to within and cross-sensory perception. The current investigation examines the extent to which individual differences in general auditory neural processing accounts for variability in auditory, visual, and audiovisual speech perception in a sample of young healthy adults. Auditory neural processing was assessed using a simple click stimulus. We found that individuals with a smaller P1 peak amplitude in their auditory-evoked potential (AEP) had more difficulty identifying speech sounds in difficult listening conditions, but were better lipreaders. The results suggest that individual differences in the auditory neural processing of healthy adults can account for variability in the perception of information available from the auditory and visual modalities, similar to the cross-sensory perceptual compensation observed in individuals with sensory loss.

Algorithms that perform spike sorting depend on waveforms to cluster spikes. However, a cerebellar Purkinje-cell produces two types of spikes; simple and complex spikes. A complex spike coincides with the suppression of generating simple spikes. Here, we recorded neurophysiological data from three species and developed a spike analysis software named P-sort that relies on this statistical property to improve both the detection and the attribution of simple and complex spikes in the cerebellum.

Cannabis use disorder (CUD) has doubled in prevalence over the past decade as a nation-wide trend toward legalization allows for increased drug accessibility. As a result, marijuana has become the most commonly used illicit drug in the United States particularly among the adolescent population. This is especially concerning since there is greater risk for the harmful side effects of drug use during this developmental period due to ongoing brain maturation. Increasing evidence indicates that CUD often occurs along with other debilitating conditions including both alcohol use disorder (AUD) and anxiety disorders such post-traumatic stress disorder (PTSD). Additionally, exposure to cannabis, alcohol, and stress can induce alterations in glutamate regulation and homeostasis in the prefrontal cortex (PFC) that may lead to impairments in neuronal functioning and cognition. Therefore, in order to study the relationship between drug exposure and the development of PTSD, these studies utilized rodent models to determine the impact of adolescent exposure to delta-9-tetrahydrocannabinol (THC) and ethanol on responses to fear stimuli during fear conditioning and used calcium imaging to measure glutamate activity in the prelimbic cortex during this behavioral paradigm. The results from these experiments indicate that adolescent exposure to THC and ethanol leads to enhanced sensitivity to fear stimuli both behaviorally and neuronally. Additionally, these effects were attenuated when animals were treated with the glutamatergic modulator N-acetylcysteine (NAC). In summary, these studies support the hypothesis that adolescent exposure to THC and ethanol leads to alterations in fear stimuli processing through glutamatergic reliant modifications in PFC signaling.

Noise-induced hearing loss has gained relevance as one of the most common forms of hearing impairment. The anatomical correlates of hearing loss, principally cell damage and/or death, are relatively well-understood histologically. However, much less is known about the physiological aspects of damaged, surviving cells. Here we addressed the functional consequences of noise exposure on the capacity of inner hair cells (IHCs) to release synaptic vesicles at synapses with spiral ganglion neurons (SGNs). Mice of either sex at postnatal day (P) 15–16 were exposed to 1–12 kHz noise at 120 dB sound pressure level (SPL), for 1 h. Exocytosis was measured by tracking changes in membrane capacitance (ΔCm) from IHCs of the apical cochlea. Upon IHC depolarization to different membrane potentials, ΔC m showed the typical bell-shaped curve that mirrors the voltage dependence of Ca 2+ influx, in both exposed and unexposed cells. Surprisingly, from IHCs at 1-day after exposure (d.a.e.), we found potentiation of exocytosis at the peak of the bell-shaped curve. The increase in exocytosis was not accompanied by changes in whole-cell Ca 2+ influx, suggesting a modification in coupling between Ca 2+ channels and synaptic vesicles. Consistent with this notion, noise exposure also changed the Ca 2+ -dependence of exocytosis from linear to supralinear. Noise exposure did not cause loss of IHCs, but did result in a small reduction in the number of IHC-SGN synapses at 1-d.a.e. which recovered by 14-d.a.e. In contrast, a strong reduction in auditory brainstem response wave-I amplitude (representing synchronous firing of SGNs) and distortion product otoacoustic emissions (reflecting outer hair cell function) indicated a profound hearing loss at 1- and 14-d.a.e. To determine the role of glutamate release in the noise-induced potentiation of exocytosis, we evaluated vesicular glutamate transporter-3 ( Vglut3 ) knock-out (KO) mice. Unlike WT, IHCs from Vglut3 KO mice showed a noise-induced reduction in ΔC m and Ca 2+ influx with no change in the Ca 2+ -dependence of exocytosis. Together, these results indicate that traumatic noise exposure triggers changes of IHC synaptic function including a Vglut3 -dependent potentiation of exocytosis.

Significance To gain better hearing sensitivity, the energetic and metabolic supplies are crucial for cochlea to develop a blood-labyrinth barrier containing abundant capillaries and cellular compartments. For example, the stria vascularis, the power plant of the cochlea, generates a +80 mV endocochlear potential and a 150 mM potassium concentration in the scala media. Previous studies of stria vascularis development and function have been largely focused on characterizing transcription factors, channels, and transporters. In our study, we identify a retrotransposon insertion mutation responsible for complete stria vascularis loss of function. Our study further highlights the diversity of genetic mutations capable of inducing inherited deafness.

Neurophysiological studies depend on a reliable quantification of whether and when a neuron responds to stimulation. Simple methods to determine responsiveness require arbitrary parameter choices, such as binning size, while more advanced model-based methods require fitting and hyperparameter tuning. These parameter choices can change the results, which invites bad statistical practice and reduces the replicability. New recording techniques that yield increasingly large numbers of cells would benefit from a test for cell-inclusion that requires no manual curation. Here, we present the parameter-free ZETA-test, which outperforms t-tests, ANOVAs, and renewal-process-based methods by including more cells at a similar false-positive rate. We show that our procedure works across brain regions and recording techniques, including calcium imaging and Neuropixels data. Furthermore, in illustration of the method, we show in mouse visual cortex that (1) visuomotor-mismatch and spatial location are encoded by different neuronal subpopulations and (2) optogenetic stimulation of VIP cells leads to early inhibition and subsequent disinhibition.

The basolateral amygdala (BLA) is obligatory for fear learning. This learning is linked to BLA excitatory projection neurons whose activity is regulated by complex networks of inhibitory interneurons, dominated by parvalbumin (PV)-expressing GABAergic neurons. The roles of these GABAergic interneurons in learning to fear and learning not to fear, activity profiles of these interneurons across the course of fear learning, and whether or how these change across the course of learning all remain poorly understood. Here, we used PV cell-type-specific recording and manipulation approaches in male transgenic PV-Cre rats during pavlovian fear conditioning to address these issues. We show that activity of BLA PV neurons during the moments of aversive reinforcement controls fear learning about aversive events, but activity during moments of nonreinforcement does not control fear extinction learning. Furthermore, we show expectation-modulation of BLA PV neurons during fear learning, with greater activity to an unexpected than expected aversive unconditioned stimulus (US). This expectation-modulation was specifically because of BLA PV neuron sensitivity to aversive prediction error. Finally, we show that BLA PV neuron function in fear learning is conserved across these variations in prediction error. We suggest that aversive prediction-error modulation of PV neurons could enable BLA fear-learning circuits to retain selectivity for specific sensory features of aversive USs despite variations in the strength of US inputs, thereby permitting the rapid updating of fear associations when these sensory features change. SIGNIFICANCE STATEMENT The capacity to learn about sources of danger in the environment is essential for survival. This learning depends on complex microcircuitries of inhibitory interneurons in the basolateral amygdala. Here, we show that parvalbumin-positive GABAergic interneurons in the rat basolateral amygdala are important for fear learning during moments of danger, but not for extinction learning during moments of safety, and that the activity of these neurons is modulated by expectation of danger. This may enable fear-learning circuits to retain selectivity for specific aversive events across variations in expectation, permitting the rapid updating of learning when aversive events change.

Mitochondrial dynamics are essential for maintaining the physiological function of the mitochondrial network, and the disorder of mitochondrial dynamics leads to neurodegenerative diseases. However, how mitochondrial dynamics affects auditory function in the inner ear remains unclear. FAM73a and FAM73b are mitochondrial outer membrane proteins that mediate mitochondrial fusion. Here, we found that FAM73a or FAM73b deficiency resulted in elevated oxidative stress and apoptosis of hair cells. Additionally, mitochondrial fission also causes an increase expression of IL-12 in basilar membrane macrophages through accumulating IRF1. As a bridge between innate and adaptive immune responses, hyperproduction of IL-12 further promoted the polarization of Th1 and tissue damage. Our data highlighted an important role of mitochondrial dynamics in maintaining cochlear homeostasis and hair cell survival. Mitochondrial dynamics not only disturbed hair cell function, but also induced the disorder of immune responses.

Chronically implanted neural probes are powerful tools to decode brain activity however, recording population and spiking activity over long periods remains a major challenge. Here, we designed and fabricated flexible intracortical Michigan-style arrays with a shank cross-section per electrode of 250 μm $$^2$$ 2 utilizing the polymer paryleneC with the goal to improve the immune acceptance. As flexible neural probes are unable to penetrate the brain due to the low buckling force threshold, a tissue-friendly insertion system was developed by reducing the effective shank length. The insertion strategy enabled the implantation of the four, bare, flexible shanks up to 2 mm into the mouse brain without increasing the implantation footprint and therefore, minimizing the acute trauma. In acute recordings from the mouse somatosensory cortex and the olfactory bulb, we demonstrated that the flexible probes were able to simultaneously detect local field potentials as well as single and multi-unit activity. Additionally, the flexible arrays outperformed stiff probes with respect to yield of single unit activity. Following the successful in vivo validation, we further improved the microfabrication towards a double-metal-layer process, and were able to double the number of electrodes per shank by keeping the shank width resulting in a cross-section per electrode of 118 μm $$^2$$ 2 .

Brain injuries cause hemodynamic changes in several distant, spared areas from the lesion. Our objective was to better understand the neuronal correlates of this reorganization in awake, behaving female monkeys. We used reversible inactivation techniques to “injure” the primary motor cortex, while continuously recording neuronal activity of the ventral premotor cortex in the two hemispheres, before and after the onset of behavioral impairments. Inactivation rapidly induced profound alterations of neuronal discharges that were heterogeneous within each and across the two hemispheres, occurred during movements of either the affected or nonaffected arm, and varied during different phases of grasping. Our results support that extensive, and much more complex than expected, neuronal reorganization takes place in spared areas of the bihemispheric cortical network involved in the control of hand movements. This broad pattern of reorganization offers potential targets that should be considered for the development of neuromodulation protocols applied early after brain injury. SIGNIFICANCE STATEMENT It is well known that brain injuries cause changes in several distant, spared areas of the network, often in the premotor cortex. This reorganization is greater early after the injury and the magnitude of early changes correlates with impairments. However, studies to date have used noninvasive brain imaging approaches or have been conducted in sedated animals. Therefore, we do not know how brain injuries specifically affect the activity of neurons during the generation of movements. Our study clearly shows how a lesion rapidly impacts neurons in the premotor cortex of both hemispheres. A better understanding of these complex changes can help formulate hypotheses for the development of new treatments that specifically target neuronal reorganization induced by lesions in the brain.

Hearing loss is a common disability affecting the world’s population today. While several studies have shown that inner ear gene therapy can be successfully applied to mouse models of hereditary hearing loss to improve hearing, most of these studies rely on inner ear gene delivery in the neonatal age, when mouse inner ear has not fully developed. However, the human inner ear is fully developed at birth. Therefore, in order for inner ear gene therapy to be successfully applied in patients with hearing loss, one must demonstrate that gene delivery can be safely and reliably performed in the mature mammalian inner ear. In this study, we examine the steps involved in posterior semicircular canal gene delivery in the adult mouse inner ear. We find that the duration of perilymphatic leakage and injection rate have a significant effect on the post-surgical hearing outcome. Our results show that although AAV2.7m8 has a lower hair cell transduction rate in adult mice compared to neonatal mice at equivalent viral load, AAV2.7m8 is capable of transducing the adult mouse inner and outer hair cells with high efficiency in a dose-dependent manner.

Recent investigation of memory-related functions in the auditory system have capitalized on the use of memory-modulating molecules to probe the relationship between memory and substrates of memory in auditory system coding. For example, epigenetic mechanisms, which regulate gene expression necessary for memory consolidation, are powerful modulators of learning-induced neuroplasticity and long-term memory (LTM) formation. Inhibition of the epigenetic regulator histone deacetylase 3 (HDAC3) promotes LTM, which is highly specific for spectral features of sound. The present work demonstrates for the first time that HDAC3 inhibition also enables memory for temporal features of sound. Adult male rats trained in an amplitude modulation (AM) rate discrimination task and treated with a selective inhibitor of HDAC3 formed memory that was highly specific to the AM rate paired with reward. Sound-specific memory revealed behaviorally was associated with a signal-specific enhancement in temporal coding in the auditory system; stronger phase locking that was specific to the rewarded AM rate was revealed in both the surface-recorded frequency following response and auditory cortical multiunit activity in rats treated with the HDAC3 inhibitor. Furthermore, HDAC3 inhibition increased trial-to-trial cortical response consistency (relative to naive and trained vehicle-treated rats), which generalized across different AM rates. Stronger signal-specific phase locking correlated with individual behavioral differences in memory specificity for the AM signal. These findings support that epigenetic mechanisms regulate activity-dependent processes that enhance discriminability of sensory cues encoded into LTM in both spectral and temporal domains, which may be important for remembering spectrotemporal features of sounds, for example, as in human voices and speech. SIGNIFICANCE STATEMENT Epigenetic mechanisms have recently been implicated in memory and information processing. Here, we use a pharmacological inhibitor of HDAC3 in a sensory model of learning to reveal the ability of HDAC3 to enable precise memory for amplitude-modulated sound cues. In so doing, we uncover neural substrates for memory's specificity for temporal sound cues. Memory specificity was supported by auditory cortical changes in temporal coding, including greater response consistency and stronger phase locking. HDAC3 appears to regulate effects across domains that determine specific cue saliency for behavior. Thus, epigenetic players may gate how sensory information is stored in long-term memory and can be leveraged to reveal the neural substrates of sensory details stored in memory.