Developmental hearing loss-induced perceptual deficits are rescued by genetic restoration of cortical inhibition.

Even a transient period of hearing loss during the developmental critical period can induce long-lasting deficits in temporal and spectral perception. These perceptual deficits correlate with speech perception in humans. In gerbils, these hearing loss-induced perceptual deficits are correlated with a reduction of both ionotropic GABAA and metabotropic GABAB receptor-mediated synaptic inhibition in auditory cortex, but most research on critical period plasticity has focused on GABAA receptors. Therefore, we developed viral vectors to express proteins that would upregulate gerbil postsynaptic inhibitory receptor subunits (GABAA, Gabra1; GABAB, Gabbr1b) in pyramidal neurons, and an enzyme that mediates GABA synthesis (GAD65) presynaptically in parvalbumin-expressing interneurons. A transient period of developmental hearing loss during the auditory critical period significantly impaired perceptual performance on two auditory tasks: amplitude modulation depth detection and spectral modulation depth detection. We then tested the capacity of each vector to restore perceptual performance on these auditory tasks. While both GABA receptor vectors increased the amplitude of cortical inhibitory postsynaptic potentials, only viral expression of postsynaptic GABAB receptors improved perceptual thresholds to control levels. Similarly, presynaptic GAD65 expression improved perceptual performance on spectral modulation detection. These findings suggest that recovering performance on auditory perceptual tasks depends on GABAB receptor-dependent transmission at the auditory cortex parvalbumin to pyramidal synapse and point to potential therapeutic targets for developmental sensory disorders.

Superior semicircular canal dehiscence and subsequent closure induces reversible impaired decision-making.

Background: Vestibular loss and dysfunction has been associated with cognitive deficits, decreased spatial navigation, spatial memory, visuospatial ability, attention, executive function, and processing speed among others. Superior semicircular canal dehiscence (SSCD) is a vestibular-cochlear disorder in humans in which a pathological third mobile window of the otic capsule creates changes to the flow of sound pressure energy through the perilymph/endolymph. The primary symptoms include sound-induced dizziness/vertigo, inner ear conductive hearing loss, autophony, headaches, and visual problems; however, individuals also experience measurable deficits in basic decision-making, short-term memory, concentration, spatial cognition, and depression. These suggest central mechanisms of impairment are associated with vestibular disorders; therefore, we directly tested this hypothesis using both an auditory and visual decision-making task of varying difficulty levels in our model of SSCD. Methods: Adult Mongolian gerbils (n = 33) were trained on one of four versions of a Go-NoGo stimulus presentation rate discrimination task that included standard ("easy") or more difficult ("hard") auditory and visual stimuli. After 10 days of training, preoperative ABR and c+VEMP testing was followed by a surgical fenestration of the left superior semicircular canal. Animals with persistent circling or head tilt were excluded to minimize effects from acute vestibular injury. Testing recommenced at postoperative day 5 and continued through postoperative day 15 at which point final ABR and c+VEMP testing was carried out. Results: Behavioral data (d-primes) were compared between preoperative performance (training day 8-10) and postoperative days 6-8 and 13-15. Behavioral performance was measured during the peak of SSCD induced ABR and c + VEMP impairment and the return towards baseline as the dehiscence began to resurface by osteoneogenesis. There were significant differences in behavioral performance (d-prime) and its behavioral components (Hits, Misses, False Alarms, and Correct Rejections). These changes were highly correlated with persistent deficits in c + VEMPs at the end of training (postoperative day 15). The controls demonstrated additional learning post procedure that was absent in the SSCD group. Conclusion: These results suggest that aberrant asymmetric vestibular output results in decision-making impairments in these discrimination tasks and could be associated with the other cognitive impairments resulting from vestibular dysfunction.

An Animal Model of Neonatal Intensive Care Unit Exposure to Light and Sound in the Preterm Infant.

According to the World Health Organization, ∼15 million children are born prematurely each year. Many of these infants end up spending days to weeks in a neonatal intensive care unit (NICU). Infants who are born prematurely are often exposed to noise and light levels that affect their auditory and visual development. Children often have long-term impairments in cognition, visuospatial processing, hearing, and language. We have developed a rodent model of NICU exposure to light and sound using the Mongolian gerbil (Meriones unguiculatus), which has a low-frequency human-like audiogram and is altricial. To simulate preterm infancy, the eyes and ears were opened prematurely, and animals were exposed to the NICU-like sensory environment throughout the gerbil's cortical critical period of auditory development. After the animals matured into adults, auditory perceptual testing was carried out followed by auditory brainstem response recordings and then histology to assess the white matter morphology of various brain regions. Compared to normal hearing control animals, NICU sensory-exposed animals had significant impairments in learning at later stages of training, increased auditory thresholds reflecting hearing loss, and smaller cerebellar white matter volumes. These have all been reported in longitudinal studies of preterm infants. These preliminary results suggest that this animal model could provide researchers with an ethical way to explore the effects of the sensory environment in the NICU on the preterm infant's brain development.

Developmental hearing loss-induced perceptual deficits are rescued by cortical expression of GABAB receptors.

Even transient periods of developmental hearing loss during the developmental critical period have been linked to long-lasting deficits in auditory perception, including temporal and spectral processing, which correlate with speech perception and educational attainment. In gerbils, hearing loss-induced perceptual deficits are correlated with a reduction of both ionotropic GABAA and metabotropic GABAB receptor-mediated synaptic inhibition in auditory cortex, but most research on critical period plasticity has focused on GABAA receptors. We developed viral vectors to express both endogenous GABAA or GABAB receptor subunits in auditory cortex and tested their capacity to restore perception of temporal and spectral auditory cues following critical period hearing loss in the Mongolian gerbil. HL significantly impaired perception of both temporal and spectral auditory cues. While both vectors similarly increased IPSCs in auditory cortex, only overexpression of GABAB receptors improved perceptual thresholds after HL to be similar to those of animals without developmental hearing loss. These findings identify the GABAB receptor as an important regulator of sensory perception in cortex and point to potential therapeutic targets for developmental sensory disorders.

Subtemporalis Muscle Middle Cranial Fossa Bone-Island Craniotomy Technique for Placement of an Active Transcutaneous Bone-Conduction Implant.

OBJECTIVE: Placement of an active transcutaneous bone-conduction implant (BCI) requires drilling of a precise bone bed to accommodate the device and allow for fixation points to make appropriate contact with bone, which can be difficult even when lifts are used. We describe a subtemporalis muscle middle cranial fossa bone-island craniotomy technique that simplifies the procedure and obviates the need for lifts in securing the device. STUDY DESIGN: Prospective case series. SETTING: Tertiary academic medical center. PATIENTS: Seventeen patients underwent surgery for placement of 18 transcutaneous BCIs, 14 for conductive or mixed hearing loss, and 4 for single-sided deafness. INTERVENTIONS: Surgical placement of a transcutaneous BCI with a bone-island craniotomy technique. MAIN OUTCOME MEASURES: Functional gain in air-conduction thresholds, aided air-bone gap, frequency of need for lifts, and minor and major complications. RESULTS: For the conductive or mixed hearing loss cohort, with the transcutaneous BCI in place, there was a highly statistically significant mean functional gain of 35.4 dB hearing level (HL) (range, 16.7-50.25 dB HL; standard deviation, 12.4 dB HL) compared with the unaided condition (p < 0.0001; 95% confidence interval, 36.6-51.6 dB HL). Lifts were not needed in any case. There was one minor complication requiring a second procedure in a patient who had previously received radiation and no major complications. There was no device loss or failure. CONCLUSIONS: A subtemporalis muscle middle cranial fossa bone-island craniotomy technique eliminates the need for lifts and is a safe and effective method for placement of a transcutaneous BCI.

Auditory processing remains sensitive to environmental experience during adolescence in a rodent model.

Elevated neural plasticity during development contributes to dramatic improvements in perceptual, motor, and cognitive skills. However, malleable neural circuits are vulnerable to environmental influences that may disrupt behavioral maturation. While these risks are well-established prior to sexual maturity (i.e., critical periods), the degree of neural vulnerability during adolescence remains uncertain. Here, we induce transient hearing loss (HL) spanning adolescence in gerbils, and ask whether behavioral and neural maturation are disrupted. We find that adolescent HL causes a significant perceptual deficit that can be attributed to degraded auditory cortex processing, as assessed with wireless single neuron recordings and within-session population-level analyses. Finally, auditory cortex brain slices from adolescent HL animals reveal synaptic deficits that are distinct from those typically observed after critical period deprivation. Taken together, these results show that diminished adolescent sensory experience can cause long-lasting behavioral deficits that originate, in part, from a dysfunctional cortical circuit.

Convergence of forepaw somatosensory and motor cortical projections in the striatum, claustrum, thalamus, and pontine nuclei of cats.

The basal ganglia and pontocerebellar systems regulate somesthetic-guided motor behaviors and receive prominent inputs from sensorimotor cortex. In addition, the claustrum and thalamus are forebrain subcortical structures that have connections with somatosensory and motor cortices. Our previous studies in rats have shown that primary and secondary somatosensory cortex (S1 and S2) send overlapping projections to the neostriatum and pontine nuclei, whereas, overlap of primary motor cortex (M1) and S1 was much weaker. In addition, we have shown that M1, but not S1, projects to the claustrum in rats. The goal of the current study was to compare these rodent projection patterns with connections in cats, a mammalian species that evolved in a separate phylogenetic superorder. Three different anterograde tracers were injected into the physiologically identified forepaw representations of M1, S1, and S2 in cats. Labeled fibers terminated throughout the ipsilateral striatum (caudate and putamen), claustrum, thalamus, and pontine nuclei. Digital reconstructions of tracer labeling allowed us to quantify both the normalized distribution of labeling in each subcortical area from each tracer injection, as well as the amount of tracer overlap. Surprisingly, in contrast to our previous findings in rodents, we observed M1 and S1 projections converging prominently in striatum and pons, whereas, S1 and S2 overlap was much weaker. Furthermore, whereas, rat S1 does not project to claustrum, we confirmed dense claustral inputs from S1 in cats. These findings suggest that the basal ganglia, claustrum, and pontocerebellar systems in rat and cat have evolved distinct patterns of sensorimotor cortical convergence.

New model of superior semicircular canal dehiscence with reversible diagnostic findings characteristic of patients with the disorder.

Background: Third window syndrome is a vestibular-cochlear disorder in humans in which a third mobile window of the otic capsule creates changes to the flow of sound pressure energy through the perilymph/endolymph. The nature and location of this third mobile window can occur at many different sites (or multiple sites); however, the most common third mobile window is superior semicircular canal dehiscence (SSCD). There are two essential objective diagnostic characteristics needed to validate a model of SSCD: the creation of a pseudoconductive hearing loss and cVEMP increased amplitude and decreased threshold. Methods: Adult Mongolian gerbils (n = 36) received surgical fenestration of the superior semicircular canal of the left inner ear. ABR and c+VEMP testing were carried out prior to surgery and over acute (small 1 mm SSCD, 1-10 days) or prolonged (large 2 mm SSCD, 28 days) recovery. Because recovery of function occurred quickly, condenser brightfield stereomicroscopic examination of the dehiscence site was carried out for the small SSCD animals post-hoc and compared to both ABRs and c+VEMPs. Micro-CT analysis was also completed with representative samples of control, day 3 and 10 post-SSCD animals. Results: The SSCD created a significant worsening of hearing thresholds of the left ear; especially in the lower frequency domain (1-4 kHz). Left (EXP)/right (CTL) ear comparisons via ABR show significant worsening thresholds at the same frequency representations, which is a proxy for the human pseudoconductive hearing loss seen in SSCD. For the c+VEMP measurements, increased amplitude of the sound-induced response (N1 2.5 ms and P1 3.2 ms) was observed in animals that received larger fenestrations. As the bone regrew, the c+VEMP and ABR responses returned toward preoperative values. For small SSCD animals, micro-CT data show that progressive osteoneogenesis results in resurfacing of the SSCD without bony obliteration. Conclusion: The large (2 mm) SSCD used in our gerbil model results in similar electrophysiologic findings observed in patients with SSCD. The changes observed also reverse and return to baseline as the SSCD heals by bone resurfacing (with the lumen intact). Hence, this model does not require a second surgical procedure to plug the SSCD.

Adult neuroplasticity employs developmental mechanisms.

Although neural plasticity is now widely studied, there was a time when the idea of adult plasticity was antithetical to the mainstream. The essential stumbling block arose from the seminal experiments of Hubel and Wiesel who presented convincing evidence that there existed a critical period for plasticity during development after which the brain lost its ability to change in accordance to shifts in sensory input. Despite the zeitgeist that mature brain is relatively immutable to change, there were a number of examples of adult neural plasticity emerging in the scientific literature. Interestingly, some of the earliest of these studies involved visual plasticity in the adult cat. Even earlier, there were reports of what appeared to be functional reorganization in adult rat somatosensory thalamus after dorsal column lesions, a finding that was confirmed and extended with additional experimentation. To demonstrate that these findings reflected more than a response to central injury, and to gain greater control of the extent of the sensory loss, peripheral nerve injuries were used that eliminated ascending sensory information while leaving central pathways intact. Merzenich, Kaas, and colleagues used peripheral nerve transections to reveal unambiguous reorganization in primate somatosensory cortex. Moreover, these same researchers showed that this plasticity proceeded in no less than two stages, one immediate, and one more protracted. These findings were confirmed and extended to more expansive cortical deprivations, and further extended to the thalamus and brainstem. There then began a series of experiments to reveal the physiological, morphological and neurochemical mechanisms that permitted this plasticity. Ultimately, Mowery and colleagues conducted a series of experiments that carefully tracked the levels of expression of several subunits of glutamate (AMPA and NMDA) and GABA (GABAA and GABAB) receptor complexes in primate somatosensory cortex at several time points after peripheral nerve injury. These receptor subunit mapping experiments revealed that membrane expression levels came to reflect those seen in early phases of critical period development. This suggested that under conditions of prolonged sensory deprivation the adult cells were returning to critical period like plastic states, i.e., developmental recapitulation. Here we outline the heuristics that drive this phenomenon.

Early Sensory Deprivation Leads to Differential Inhibitory Changes in the Striatum During Learning.

The corticostriatal circuit has been identified as a vital pathway for associative learning. However, how learning is implemented when the sensory striatum is permanently impaired remains unclear. Using chemogenetic techniques to suppress layer five auditory cortex (AC) input to the auditory striatum, learning of a sound discrimination task was significantly impacted in freely moving Mongolian gerbils, in particular when this suppression occurs early on during learning. Whole-cell recordings sampled throughout learning revealed a transient reduction in postsynaptic (GABAA) inhibition in both striatal D1 and D2 cells in normal-hearing gerbils during task acquisition. In contrast, when the baseline striatal inhibitory strengths and firing rates were permanently reduced by a transient period of developmental sensory deprivation, learning was accompanied by augmented inhibition and increased firing rates. Direct manipulation of striatal inhibition in vivo and in vitro revealed a key role of the transient inhibitory changes in task acquisition. Together, these results reveal a flexible corticostriatal inhibitory synaptic plasticity mechanism that accompanies associative auditory learning.

The Role of Motor and Environmental Visual Rhythms in Structuring Auditory Cortical Excitability.

Previous studies indicate that motor sampling patterns modulate neuronal excitability in sensory brain regions by entraining brain rhythms, a process termed motor-initiated entrainment. In addition, rhythms of the external environment are also capable of entraining brain rhythms. Our first goal was to investigate the properties of motor-initiated entrainment in the auditory system using a prominent visual motor sampling pattern in primates, saccades. Second, we wanted to determine whether/how motor-initiated entrainment interacts with visual environmental entrainment. We examined laminar profiles of neuronal ensemble activity in primary auditory cortex and found that whereas motor-initiated entrainment has a suppressive effect, visual environmental entrainment has an enhancive effect. We also found that these processes are temporally coupled, and their temporal relationship ensures that their effect on excitability is complementary rather than interfering. Altogether, our results demonstrate that motor and sensory systems continuously interact in orchestrating the brain's context for the optimal sampling of our multisensory environment.

Early life experiences selectively mature learning and memory abilities.

The mechanisms underlying the maturation of learning and memory abilities are poorly understood. Here we show that episodic learning produces unique biological changes in the hippocampus of infant rats and mice compared to juveniles and adults. These changes include persistent neuronal activation, BDNF-dependent increase in the excitatory synapse markers synaptophysin and PSD-95, and significant maturation of AMPA receptor synaptic responses. Inhibition of PSD-95 induction following learning impairs both AMPA receptor response maturation and infantile memory, indicating that the synapse formation/maturation is necessary for creating infantile memories. Conversely, capturing the learning-induced changes by presenting a subsequent learning experience or by chemogenetic activation of the neural ensembles tagged by learning matures memory functional competence. This memory competence is selective for the type of experience encountered, as it transfers within similar hippocampus-dependent learning domains but not to other hippocampus-dependent types of learning. Thus, experiences in early life produce selective maturation of memory abilities.

Preserving Inhibition during Developmental Hearing Loss Rescues Auditory Learning and Perception.

Transient periods of childhood hearing loss can induce deficits in aural communication that persist long after auditory thresholds have returned to normal, reflecting long-lasting impairments to the auditory CNS. Here, we asked whether these behavioral deficits could be reversed by treating one of the central impairments: reduction of inhibitory strength. Male and female gerbils received bilateral earplugs to induce a mild, reversible hearing loss during the critical period of auditory cortex development. After earplug removal and the return of normal auditory thresholds, we trained and tested animals on an amplitude modulation detection task. Transient developmental hearing loss induced both learning and perceptual deficits, which were entirely corrected by treatment with a selective GABA reuptake inhibitor (SGRI). To explore the mechanistic basis for these behavioral findings, we recorded the amplitudes of GABAA and GABAB receptor-mediated IPSPs in auditory cortical and thalamic brain slices. In hearing loss-reared animals, cortical IPSP amplitudes were significantly reduced within a few days of hearing loss onset, and this reduction persisted into adulthood. SGRI treatment during the critical period prevented the hearing loss-induced reduction of IPSP amplitudes; but when administered after the critical period, it only restored GABAB receptor-mediated IPSP amplitudes. These effects were driven, in part, by the ability of SGRI to upregulate α1 subunit-dependent GABAA responses. Similarly, SGRI prevented the hearing loss-induced reduction of GABAA and GABAB IPSPs in the ventral nucleus of the medial geniculate body. Thus, by maintaining, or subsequently rescuing, GABAergic transmission in the central auditory thalamocortical pathway, some perceptual and cognitive deficits induced by developmental hearing loss can be prevented.SIGNIFICANCE STATEMENT Even a temporary period of childhood hearing loss can induce communication deficits that persist long after auditory thresholds return to normal. These deficits may arise from long-lasting central impairments, including the loss of synaptic inhibition. Here, we asked whether hearing loss-induced behavioral deficits could be reversed by reinstating normal inhibitory strength. Gerbils reared with transient hearing loss displayed both learning and perceptual deficits. However, when animals were treated with a selective GABA reuptake inhibitor during or after hearing loss, behavioral deficits were entirely corrected. This behavioral recovery was correlated with the return of normal thalamic and cortical inhibitory function. Thus, some perceptual and cognitive deficits induced by developmental hearing loss were prevented with a treatment that rescues a central synaptic property.

Top-down, contextual entrainment of neuronal oscillations in the auditory thalamocortical circuit.

Prior studies have shown that repetitive presentation of acoustic stimuli results in an alignment of ongoing neuronal oscillations to the sequence rhythm via oscillatory entrainment by external cues. Our study aimed to explore the neural correlates of the perceptual parsing and grouping of complex repeating auditory patterns that occur based solely on statistical regularities, or context. Human psychophysical studies suggest that the recognition of novel auditory patterns amid a continuous auditory stimulus sequence occurs automatically halfway through the first repetition. We hypothesized that once repeating patterns were detected by the brain, internal rhythms would become entrained, demarcating the temporal structure of these repetitions despite lacking external cues defining pattern on- or offsets. To examine the neural correlates of pattern perception, neuroelectric activity of primary auditory cortex (A1) and thalamic nuclei was recorded while nonhuman primates passively listened to streams of rapidly presented pure tones and bandpass noise bursts. At arbitrary intervals, random acoustic patterns composed of 11 stimuli were repeated five times without any perturbance of the constant stimulus flow. We found significant delta entrainment by these patterns in the A1, medial geniculate body, and medial pulvinar. In A1 and pulvinar, we observed a statistically significant, pattern structure-aligned modulation of neuronal firing that occurred earliest in the pulvinar, supporting the idea that grouping and detecting complex auditory patterns is a top-down, context-driven process. Besides electrophysiological measures, a pattern-related modulation of pupil diameter verified that, like humans, nonhuman primates consciously detect complex repetitive patterns that lack physical boundaries.

GABAergic inhibition gates excitatory LTP in perirhinal cortex.

The perirhinal cortex (PRh) is a key region downstream of auditory cortex (ACx) that processes familiarity linked mnemonic signaling. In gerbils, ACx-driven EPSPs recorded in PRh neurons are largely shunted by GABAergic inhibition (Kotak et al., 2015, Frontiers in Neural Circuits, 9). To determine whether inhibitory shunting prevents the induction of excitatory long-term potentiation (e-LTP), we stimulated ACx-recipient PRh in a brain slice preparation using theta burst stimulation (TBS). Under control conditions, without GABA blockers, the majority of PRh neurons exhibited long-term depression. A very low concentration of bicuculline increased EPSP amplitude, but under this condition TBS did not significantly increase e-LTP induction. Since PRh synaptic inhibition included a GABAB receptor-mediated component, we added a GABAB receptor antagonist. When both GABAA and GABAB receptors were blocked, TBS reliably induced e-LTP in a majority of PRh neurons. We conclude that GABAergic transmission is a vital mechanism regulating e-LTP induction in the PRh, and may be associated with auditory learning.

Sensory Processing in the Dorsolateral Striatum: The Contribution of Thalamostriatal Pathways.

The dorsal striatum has two functionally-defined subdivisions: a dorsomedial striatum (DMS) region involved in mediating goal-directed behaviors that require conscious effort, and a dorsolateral striatum (DLS) region involved in the execution of habitual behaviors in a familiar sensory context. Consistent with its presumed role in forming stimulus-response (S-R) associations, neurons in DLS receive massive inputs from sensorimotor cortex and are responsive to both active and passive sensory stimulation. While several studies have established that corticostriatal inputs contribute to the stimulus-induced responses observed in the DLS, there is growing awareness that the thalamus has a significant role in conveying sensory-related information to DLS and other parts of the striatum. The thalamostriatal projections to DLS originate mainly from the caudal intralaminar region, which contains the parafascicular (Pf) nucleus, and from higher-order thalamic nuclei such as the medial part of the posterior (POm) nucleus. Based on recent findings, we hypothesize that the thalamostriatal projections from these two regions exert opposing influences on the expression of behavioral habits. This article reviews the subcortical circuits that regulate the transmission of sensory information through these thalamostriatal projection systems, and describes the evidence that indicates these circuits could be manipulated to ameliorate the symptoms of Parkinson's disease (PD) and related neurological disorders.

The Sensory Striatum Is Permanently Impaired by Transient Developmental Deprivation.

Corticostriatal circuits play a fundamental role in regulating many behaviors, and their dysfunction is associated with many neurological disorders. In contrast, sensory disorders, like hearing loss (HL), are commonly linked with processing deficits at or below the level of the auditory cortex (ACx). However, HL can be accompanied by non-sensory deficits, such as learning delays, suggesting the involvement of regions downstream of ACx. Here, we show that transient developmental HL differentially affected the ACx and its downstream target, the sensory striatum. Following HL, both juvenile ACx layer 5 and striatal neurons displayed an excitatory-inhibitory imbalance and lower firing rates. After hearing was restored, adult ACx neurons recovered balanced excitatory-inhibitory synaptic gain and control-like firing rates, but striatal neuron synapses and firing properties did not recover. Thus, a brief period of abnormal cortical activity may induce cellular impairments that persist into adulthood and contribute to neurological disorders that are striatal in origin.

A viral strategy for targeting and manipulating interneurons across vertebrate species.

A fundamental impediment to understanding the brain is the availability of inexpensive and robust methods for targeting and manipulating specific neuronal populations. The need to overcome this barrier is pressing because there are considerable anatomical, physiological, cognitive and behavioral differences between mice and higher mammalian species in which it is difficult to specifically target and manipulate genetically defined functional cell types. In particular, it is unclear the degree to which insights from mouse models can shed light on the neural mechanisms that mediate cognitive functions in higher species, including humans. Here we describe a novel recombinant adeno-associated virus that restricts gene expression to GABAergic interneurons within the telencephalon. We demonstrate that the viral expression is specific and robust, allowing for morphological visualization, activity monitoring and functional manipulation of interneurons in both mice and non-genetically tractable species, thus opening the possibility to study GABAergic function in virtually any vertebrate species.