Publications using the RPvdsEx

Introduction Angelman syndrome (AS) is a neurodevelopmental disorder characterized by motor deficits, seizures, some autistic‐like behaviors, and severe impairment of speech. A dysfunction of the maternally imprinted UBE3A gene, coupled with a functional yet silenced paternal copy, results in AS. Although studies of transgenic mouse models have revealed a great deal about neural populations and rescue timeframes for specific features of AS, these studies have largely failed to examine intermediate phenotypes that contribute to the profound communicative disabilities associated with AS. Methods Here, we use a variety of tasks, including assessments of rapid auditory processing and social communication. Expressive vocalizations were directly assessed and correlated against other core behavioral measures (motor, social, acoustic perception) to model putative influences on communication. Results AS mice displayed the characteristic phenotypes associated with Angelman syndrome (i.e., social and motor deficits), as well as marginal enhancements in rapid auditory processing ability. Our characterization of adult ultrasonic vocalizations further showed that AS mice produce fewer vocalizations and vocalized for a shorter amount of time when compared to controls. Additionally, a strong correlation between motor indices and ultrasonic vocalization output was shown, suggesting that the motor impairments in AS may contribute heavily to communication impairments. Conclusion In summary, the combination of motor deficits, social impairment, marginal rapid auditory enhancements, and altered ultrasonic vocalizations reported in a mouse model of AS clearly parallel the human symptoms of the disorder. This mouse model offers a novel route to interrogate the underlying genetic, physiologic, and behavioral influences on the under‐studied topic of impaired communication in AS.

A GWAS study recently demonstrated single nucleotide polymorphisms (SNPs) in the human GLRB gene of individuals with a prevalence for agoraphobia. GLRB encodes the glycine receptor (GlyRs) β subunit. The identified SNPs are localized within the gene flanking regions (3' and 5' UTRs) and intronic regions. It was suggested that these nucleotide polymorphisms modify GlyRs expression and phenotypic behavior in humans contributing to an anxiety phenotype as a mild form of hyperekplexia. Hyperekplexia is a human neuromotor disorder with massive startle phenotypes due to mutations in genes encoding GlyRs subunits. GLRA1 mutations have been more commonly observed than GLRB mutations. If an anxiety phenotype contributes to the hyperekplexia disease pattern has not been investigated yet. Here, we compared two mouse models harboring either a mutation in the murine Glra1 or Glrb gene with regard to anxiety and startle phenotypes. Homozygous spasmodic animals carrying a Glra1 point mutation (alanine 52 to serine) displayed abnormally enhanced startle responses. Moreover, spasmodic mice exhibited significant changes in fear-related behaviors (freezing, rearing and time spent on back) analyzed during the startle paradigm, even in a neutral context. Spastic mice exhibit reduced expression levels of the full-length GlyRs β subunit due to aberrant splicing of the Glrb gene. Heterozygous animals appear normal without an obvious behavioral phenotype and thus might reflect the human situation analyzed in the GWAS study on agoraphobia and startle. In contrast to spasmodic mice, heterozygous spastic animals revealed no startle phenotype in a neutral as well as a conditioning context. Other mechanisms such as a modulatory function of the GlyRs β subunit within glycinergic circuits in neuronal networks important for fear and fear-related behavior may exist. Possibly, in human additional changes in fear and fear-related circuits either due to gene-gene interactions e.g., with GLRA1 genes or epigenetic factors are necessary to create the agoraphobia and in particular the startle phenotype.

Fragile X Syndrome (FXS) is a leading known genetic cause of intellectual disability. Many symptoms of FXS overlap with those in autism including repetitive behaviors, language delays, anxiety, social impairments and sensory processing deficits. Electroencephalogram (EEG) recordings from humans with FXS and an animal model, the Fmr1 knockout (KO) mouse, show remarkably similar phenotypes suggesting that EEG phenotypes can serve as biomarkers for developing treatments. This includes enhanced resting gamma band power and sound evoked total power, and reduced fidelity of temporal processing and habituation of responses to repeated sounds. Given the therapeutic potential of the antibiotic minocycline in humans with FXS and animal models, it is important to determine sensitivity and selectivity of EEG responses to minocycline. Therefore, in this study, we examined if a 10-day treatment of adult Fmr1 KO mice with minocycline (oral gavage, 30 mg/kg per day) would reduce EEG abnormalities. We tested if minocycline treatment has specific effects based on the EEG measurement type (e.g., resting versus sound-evoked) from the frontal and auditory cortex of the Fmr1 KO mice. We show increased resting EEG gamma power and reduced phase locking to time varying stimuli as well as the 40 Hz auditory steady state response in the Fmr1 KO mice in the pre-drug condition. Minocycline treatment increased gamma band phase locking in response to auditory stimuli, and reduced sound-evoked power of auditory event related potentials (ERP) in Fmr1 KO mice compared to vehicle treatment. Minocycline reduced resting EEG gamma power in Fmr1 KO mice, but this effect was similar to vehicle treatment. We also report frequency band-specific effects on EEG responses. Taken together, these data indicate that sound-evoked EEG responses may serve as more sensitive measures, compared to resting EEG measures, to isolate minocycline effects from placebo in humans with FXS. Given the use of minocycline and EEG recordings in a number of neurodegenerative and neurodevelopmental conditions, these findings may be more broadly applicable in translational neuroscience.

In birds the auditory system plays a key role in providing the sensory input used to discriminate between conspecific and heterospecific vocal signals. In those species that are known to learn their vocalizations, for example, songbirds, it is generally considered that this ability arises and is manifest in the forebrain, although there is no a priori reason why brainstem components of the auditory system could not also play an important part. To test this assumption, we used groups of normal reared and cross-fostered zebra finches that had previously been shown in behavioural experiments to reduce their preference for conspecific songs subsequent to cross fostering experience with Bengalese finches, a related species with a distinctly different song. The question we asked, therefore, is whether this experiential change also changes the bias in favour of conspecific song displayed by auditory midbrain units of normally raised zebra finches. By recording the responses of single units in MLd to a variety of zebra finch and Bengalese finch songs in both normally reared and cross-fostered zebra finches, we provide a positive answer to this question. That is, the difference in response to conspecific and heterospecific songs seen in normal reared zebra finches is reduced following cross-fostering. In birds the virtual absence of mammalian-like cortical projections upon auditory brainstem nuclei argues against the interpretation that MLd units change, as observed in the present experiments, as a result of top-down influences on sensory processing. Instead, it appears that MLd units can be influenced significantly by sensory inputs arising directly from a change in auditory experience during development.

Noise-induced hearing loss (NIHL) affects millions of people worldwide and presents a large social and personal burden. Pharmacological activation of SIRT3, a regulator of the mitochondrial oxidative stress response, has a protective effect on hearing thresholds after traumatic noise damage in mice. In contrast, the role of endogenously activated SIRT3 in hearing recovery has not been established. Here we tested the hypothesis that SIRT3 is required in mice for recovery of auditory thresholds after a noise exposure that confers a temporary threshold shift (TTS). SIRT3-specific immunoreactivity is present in outer hair cells, around the post-synaptic regions of inner hair cells, and faintly within inner hair cells. Prior to noise exposure, homozygous Sirt3-KO mice have slightly but significantly higher thresholds than their wild-type littermates measured by the auditory brainstem response (ABR), but not by distortion product otoacoustic emissions (DPOAE). Moreover, homozygous Sirt3-KO mice display a significant reduction in the progression of their peak 1 amplitude at higher frequencies prior to noise exposure. After exposure to a single sub-traumatic noise dose that does not permanently reduce cochlear function, compromise cell survival, or damage synaptic structures in wild-type mice, there was no difference in hearing function between the two genotypes, measured by ABR and DPOAE. The numbers of hair cells and auditory synapses were similar in both genotypes before and after noise exposure. These loss-of-function studies complement previously published gain-of-function studies and help refine our understanding of SIRT3's role in cochlear homeostasis under different damage paradigms. They suggest that SIRT3 may promote spiral ganglion neuron function. They imply that cellular mechanisms of homeostasis, in addition to the mitochondrial oxidative stress response, act to restore hearing after TTS. Finally, we present a novel application of a biomedical statistical analysis for identifying changes between peak 1 amplitude progressions in ABR waveforms after damage.

In vivo loose patch and breakthrough whole-cell recordings are useful tools for investigating the intrinsic and synaptic properties of neurons. However, the correlation among pipette resistance, seal condition, and recording time is not thoroughly clear. Presently, we investigated the recording time of different pipette resistances and seal conditions in loose patch and breakthrough whole-cell recordings. The recording time did not change with pipette resistance for loose patch recording (Rp-loose) and first increased and then decreased as seal resistance for loose patch recording (Rs-loose) increased. For a high probability of a recording time ≥30 min, the low and high cutoff values of Rs-loose were 21.5 and 36 MΩ, respectively. For neurons with Rs-loose values of 21.5-36 MΩ, the action potential (AP) amplitudes changed slightly 30 min after the seal. The recording time increased as seal resistance for whole-cell recording (Rs-tight) increased and the zero-current membrane potential for breakthrough whole-cell recording (MPzero-current) decreased. For a high probability of a recording time ≥30 min, the cutoff values of Rs-tight and MPzero-current were 2.35 GΩ and -53.5 mV, respectively. The area under the curve (AUC) of the MPzero-current receiver operating characteristic (ROC) curve was larger than that of the Rs-tight ROC curve. For neurons with MPzero-current values ≤ -53.5 mV, the inhibitory or excitatory postsynaptic current amplitudes did not show significant changes 30 min after the seal. In neurons with Rs-tight values ≥2.35 GΩ, the recording time gradually increased and then decreased as the pipette resistance for whole-cell recording (Rp-tight) increased. For the high probability of a recording time ≥30 min, the low and high cutoff values of Rp-tight were 6.15 and 6.45 MΩ, respectively. Together, we concluded that the optimal Rs-loose range is 21.5-36 MΩ, the optimal Rp-tight range is 6.15-6.45 MΩ, and the optimal Rs-tight and MPzero-current values are ≥2.35 GΩ and ≤ -53.5 mV, respectively. Compared with Rs-tight, the MPzero-current value can more accurately discriminate recording times ≥30 min and <30 min.

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.

Language development builds upon a complex network of interacting subservient systems. It therefore follows that variations in, and subclinical disruptions of, these systems may have secondary effects on emergent language. In this paper, we consider the relationship between genetic variants, hearing, auditory processing and language development. We employ whole genome sequencing in a discovery family to target association and gene x environment interaction analyses in two large population cohorts; the Avon Longitudinal Study of Parents and Children (ALSPAC) and UK10K. These investigations indicate that USH2A variants are associated with altered low-frequency sound perception which, in turn, increases the risk of developmental language disorder. We further show that Ush2a heterozygote mice have low-level hearing impairments, persistent higher-order acoustic processing deficits and altered vocalizations. These findings provide new insights into the complexity of genetic mechanisms serving language development and disorders and the relationships between developmental auditory and neural systems.

The non-conventional neurotrophic factor mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER)-resident protein that promotes ER homeostasis. MANF has a cytoprotective function, shown in the central nervous system neurons and pancreatic beta cells. Here, we report that MANF is expressed in the hair cells and neurons and in selected non-sensory cells of the cochlea and that Manf inactivation triggers upregulation of the ER chaperones in these cells. However, Manf inactivation resulted in the death of only outer hair cells (OHCs), the cells responsible for sound amplification in the cochlea. All OHCs were formed in Manf -inactivated mice, but progressive OHC death started soon after the onset of hearing function. The robust OHC loss was accompanied by strongly elevated hearing thresholds. Conditional Manf inactivation demonstrated that MANF has a local function in the cochlea. Immunostainings revealed the upregulation of CHOP, the pro-apoptotic component of the unfolded protein response (UPR), in Manf -inactivated OHCs, linking the UPR to the loss of these cells. The phenotype of Manf -inactivated OHCs was distinctly dependent on the mouse strain, such that the strains characterized by early-onset age-related hearing loss (C57BL/6J and CD-1) were affected. These results suggest that Manf deficiency becomes detrimental when accompanied by gene mutations that predispose to hearing loss, by intensifying ER dyshomeostasis. Together, MANF is the first growth factor shown to antagonize ER stress-mediated OHC death. MANF might serve as a therapeutic candidate for protection against hearing loss induced by the ER-machinery-targeting stressors.

There is growing interest in the mechanisms for natural sensory learning in pro-social contexts. Studies using a maternal model of social behavior in the mouse have provided new insight into the auditory processing of behaviorally relevant pup vocalizations, which are used as communication signals to elicit pup retrieval behavior by adult females. Whether neural and behavioral plasticity in response to these vocalizations reflect auditory associative learning linking the sounds to pups, versus simply a change in maternal responsiveness to evolved vocal signals, remains an open question. Here we describe a T-maze paradigm to track auditory learning as we pair an initially neutral, non-ethological stimulus with delivery of a pup for retrieval, which is intrinsically reinforcing for rodents.•Training is rapid and completely appetitive.•Over a period of 7 × 50-minute daily training sessions, animals increasingly use the sound to guide their arm choice for pup retrieval, with an increase in performance from chance to an average of ~80% on day 7.•This pairing method establishes a newly-formed sensory association using a natural maternal behavioral response, and lays a solid foundation for studies into the neurochemical and circuit mechanisms that mediate auditory associative learning in natural social contexts.

Spasmodic dysphonia (SD) is an incurable focal dystonia of the larynx that impairs speech and communication. Vibro-tactile stimulation (VTS) alters afferent proprioceptive input to sensorimotor cortex that controls speech. This proof-of-concept study examined the effect of laryngeal VTS on speech quality and cortical activity in 13 SD participants who vocalized the vowel /a/ while receiving VTS for 29 minutes. In response to VTS, 9 participants (69%) exhibited a reduction of voice breaks and/or a meaningful increase in smoothed cepstral peak prominence , an acoustic measure of voice/speech quality. Symptom improvements persisted for 20 minutes past VTS. Application of VTS induced a significant suppression of theta band power over the left somatosensory-motor cortex and a significant rise of gamma rhythm over right somatosensory-motor cortex. Such suppression of theta oscillations is observed in patients with cervical dystonia who apply effective sensory tricks, suggesting that VTS in SD may activate a similar neurophysiological mechanism. Results of this feasibility study indicate that laryngeal VTS modulates neuronal synchronization over sensorimotor cortex, which can induce short-term improvements in voice quality. The effects of long-term VTS and its optimal dosage for treating voice symptoms in SD are still unknown and require further systematic study.

The amplitude of the brain response to a repeated auditory stimulus is diminished as compared to the response to the first tone (T1) for interstimulus intervals (ISI) lasting up to hundreds of milliseconds. This adaptation process, called auditory sensory gating (ASG), is altered in various psychiatric diseases including schizophrenia and is classically studied by focusing on early evoked cortical responses to the second tone (T2) using 500-ms ISI. However, mechanisms underlying ASG are still not well-understood. We investigated ASG in awake mice from the brainstem to cortex at variable ISIs (125–2000 ms) using high-density EEG and intracerebral recordings. While ASG decreases at longer ISIs, it is still present at durations (500–2000 ms) far beyond the time during which brain responses to T1 could still be detected. T1 induces a sequence of specific stable scalp EEG topographies that correspond to the successive activation of distinct neural networks lasting about 350 ms. These brain states remain unaltered if T2 is presented during this period, although T2 is processed by the brain, suggesting that ongoing networks of brain activity are active for longer than early evoked-potentials and are not overwritten by an upcoming new stimulus. Intracerebral recordings demonstrate that ASG is already present at the level of ventral cochlear nucleus (vCN) and inferior colliculus and is amplified across the hierarchy in bottom-up direction. This study uncovers the extended stability of sensory-evoked brain states and long duration of ASG, and sheds light on generators of ASG and possible interactions between bottom-up and top-down mechanisms.

Key points Ongoing, moderate noise exposure does not instantly damage the auditory system but may cause lasting deficits, such as elevated thresholds and accelerated ageing of the auditory system. The neuromodulatory peptide urocortin‐3 (UCN3) is involved in the body's recovery from a stress response, and is also expressed in the cochlea and the auditory brainstem. Lack of UCN3 facilitates age‐induced hearing loss and causes permanently elevated auditory thresholds following a single 2 h noise exposure at moderate intensities. Outer hair cell function in mice lacking UCN3 is unaffected, so that the observed auditory deficits are most likely due to inner hair cell function or central mechanisms. Highly specific, rather than ubiquitous, expression of UCN3 in the brain renders it a promising candidate for designing drugs to ameliorate stress‐related auditory deficits, including recovery from acoustic trauma. Abstract Environmental acoustic noise is omnipresent in our modern society, with sound levels that are considered non‐damaging still causing long‐lasting or permanent changes in the auditory system. The small neuromodulatory peptide urocortin‐3 (UCN3) is the endogenous ligand for corticotropin‐releasing factor receptor type 2 and together they are known to play an important role in stress recovery. UCN3 expression has been observed in the auditory brainstem, but its role remains unclear. Here we describe the detailed distribution of UCN3 expression in the murine auditory brainstem and provide evidence that UCN3 is expressed in the synaptic region of inner hair cells in the cochlea. We also show that mice with deficient UCN3 signalling experience premature ageing of the auditory system starting at an age of 4.7 months with significantly elevated thresholds of auditory brainstem responses (ABRs) compared to age‐matched wild‐type mice. Following a single, 2 h exposure to moderate (84 or 94 dB SPL) noise, UCN3‐deficient mice exhibited significantly larger shifts in ABR thresholds combined with maladaptive recovery. In wild‐type mice, the same noise exposure did not cause lasting changes to auditory thresholds. The presence of UCN3‐expressing neurons throughout the auditory brainstem and the predisposition to hearing loss caused by preventing its normal expression suggests UCN3 as an important neuromodulatory peptide in the auditory system's response to loud sounds.

Partial hearing loss can cause neurons in the auditory and audiovisual cortices to increase their responsiveness to visual stimuli; however, behavioral studies in hearing-impaired humans and rats have found that the perceptual ability to accurately judge the relative timing of auditory and visual stimuli is largely unaffected. To investigate the neurophysiological basis of how audiovisual temporal acuity may be preserved in the presence of hearing loss-induced crossmodal plasticity, we exposed adult rats to loud noise and two weeks later performed in vivo electrophysiological recordings in two neighboring regions within the lateral extrastriate visual (V2L) cortex—a multisensory zone known to be responsive to audiovisual stimuli (V2L-Mz) and a predominantly auditory zone (V2L-Az). To examine the cortical layer-specific effects at the level of postsynaptic potentials, a current source density (CSD) analysis was applied to the local field potential (LFP) data recorded in response to auditory and visual stimuli presented at various stimulus onset asynchronies (SOAs). As predicted, differential effects were observed in the neighboring cortical regions’ postnoise exposure. Most notably, an analysis of the strength of multisensory response interactions revealed that V2L-Mz lost its sensitivity to the relative timing of the auditory and visual stimuli, due to an increased responsiveness to visual stimulation that produced a prominent audiovisual response irrespective of the SOA. In contrast, not only did the V2L-Az in noise-exposed rats become more responsive to visual stimuli but neurons in this region also inherited the capacity to process audiovisual stimuli with the temporal precision and specificity that was previously restricted to the V2L-Mz. Thus, the present study provides the first demonstration that audiovisual temporal processing can be preserved following moderate hearing loss via compensatory plasticity in the higher-order sensory cortices that is ultimately characterized by a functional transition in the cortical region capable of temporal sensitivity.

Predation risk induces broad behavioral and physiological responses that have traditionally been considered acute and transitory. However, prolonged or frequent exposure to predators and the sensory cues of their presence they broadcast to the environment impact long-term prey physiology and demographics. Though several studies have assessed acute and chronic stress responses in varied taxa, these attempts have often involved a priori expectations of the molecular pathways involved in physiological responses, such as glucocorticoid pathways and neurohormone production in vertebrates. While relatively little is known about physiological and molecular predator-induced stress in insects, many dramatic insect defensive behaviors have evolved to combat selection by predators. For instance, several moth families, such as Noctuidae, include members equipped with tympanic organs that allow the perception of ultrasonic bat calls and facilitate predation avoidance by eliciting evasive aerial flight maneuvers. In this study, we exposed adult male fall armyworm (Spodoptera frugiperda) moths to recorded ultrasonic bat foraging and attack calls for a prolonged period and constructed a de novo transcriptome based on brain tissue from predator cue-exposed relative to control moths kept in silence. Differential expression analysis revealed that 290 transcripts were highly up- or down-regulated among treatment tissues, with many annotating to noteworthy proteins, including a heat shock protein and an antioxidant enzyme involved in cellular stress. Though nearly 50% of differentially expressed transcripts were unannotated, those that were are implied in a broad range of cellular functions within the insect brain, including neurotransmitter metabolism, ionotropic receptor expression, mitochondrial metabolism, heat shock protein activity, antioxidant enzyme activity, actin cytoskeleton dynamics, chromatin binding, methylation, axonal guidance, cilia development, and several signaling pathways. The five most significantly overrepresented Gene Ontology terms included chromatin binding, macromolecular complex binding, glutamate synthase activity, glutamate metabolic process, and glutamate biosynthetic process. As a first assessment of transcriptional responses to ecologically relevant auditory predator cues in the brain of moth prey, this study lays the foundation for examining the influence of these differentially expressed transcripts on insect behavior, physiology, and life history within the framework of predation risk, as observed in ultrasound-sensitive Lepidoptera and other 'eared' insects.

Over the past decade, numerous neuroimaging studies based on hemodynamic markers of brain activity have examined the feeling of body ownership using perceptual body-illusions in humans. However, the direct electrophysiological correlates of body ownership at the cortical level remain unexplored. To address this, we studied the rubber hand illusion in 5 patients (3 males and 2 females) implanted with intracranial electrodes measuring cortical surface potentials. Increased high-γ (70–200 Hz) activity, an index of neuronal firing rate, in premotor and intraparietal cortices reflected the feeling of ownership. In both areas, high-γ increases were intimately coupled with the subjective illusion onset and sustained both during and in-between touches. However, intraparietal activity was modulated by tactile stimulation to a higher degree than the premotor cortex through effective connectivity with the hand-somatosensory cortex, which suggests different functional roles. These findings constitute the first intracranial electrophysiological characterization of the rubber hand illusion and extend our understanding of the dynamic mechanisms of body ownership.

Oscillations in the brain facilitate neural processing and cognitive functions. This study investigated the dependence of long-term potentiation (LTP), a neural correlate of memory, on the phase of the hippocampal θ rhythm, a prominent brain oscillation. Multichannel field potentials and current source-sinks were analyzed in hippocampal CA1 of adult male rats under urethane anesthesia. A single burst (five pulses at 200 Hz) stimulation of stratum oriens (OR) induced LTP of the basal dendritic excitatory sink (ES), which was maximal when the burst was delivered at ∼340° and ∼160° of the distal dendritic θ rhythm. Apical dendritic sink evoked by stratum radiatum (RAD) stimulation also showed biphasic maxima at ∼30° and ∼210° of the distal dendritic θ rhythm, about 50° phase delay to basal dendritic LTP. By contrast, maximal population spike (PS) excitability, following single-pulse excitation of the basal or mid-apical dendrites, occurred at a θ phase of ∼140°, and maximal basal dendritic ES occurred at ∼20°; γ (30–57 Hz) activity recorded in CA1 RAD had maximal power at ∼300° of the distal dendritic θ rhythm, different from the phases of maximal LTP. LTP induced during the rising θ phase was NMDA receptor sensitive. It is suggested that the θ phase modulation of CA1 PS excitability is mainly provided by θ-rhythmic proximal inhibition, while dendritic LTP is also modulated by dendritic inhibition and excitation, specific to basal and apical dendrites. In summary, basal and apical dendritic synaptic plasticity and spike excitability are facilitated at different θ phases in a compartmental fashion.

The ability to accurately integrate or bind stimuli from more than one sensory modality is highly dependent on the features of the stimuli, such as their intensity and relative timing. Previous studies have demonstrated that the ability to perceptually bind stimuli is impaired in various clinical conditions such as autism, dyslexia, schizophrenia, as well as aging. However, it remains unknown if adult-onset hearing loss, separate from aging, influences audiovisual temporal acuity. In the present study, rats were trained using appetitive operant conditioning to perform an audiovisual temporal order judgment (TOJ) task or synchrony judgment (SJ) task in order to investigate the nature and extent that audiovisual temporal acuity is affected by adult-onset hearing loss, with a specific focus on the time-course of perceptual changes following loud noise exposure. In our first series of experiments, we found that audiovisual temporal acuity in normal-hearing rats was influenced by sound intensity, such that when a quieter sound was presented, the rats were biased to perceive the audiovisual stimuli as asynchronous (SJ task), or as though the visual stimulus was presented first (TOJ task). Psychophysical testing demonstrated that noise-induced hearing loss did not alter the rats' temporal sensitivity 2-3 weeks post-noise exposure, despite rats showing an initial difficulty in differentiating the temporal order of audiovisual stimuli. Furthermore, consistent with normal-hearing rats, the timing at which the stimuli were perceived as simultaneous (i.e., the point of subjective simultaneity, PSS) remained sensitive to sound intensity following hearing loss. Contrary to the TOJ task, hearing loss resulted in persistent impairments in asynchrony detection during the SJ task, such that a greater proportion of trials were now perceived as synchronous. Moreover, psychophysical testing found that noise-exposed rats had altered audiovisual synchrony perception, consistent with impaired audiovisual perceptual binding (e.g., an increase in the temporal window of integration on the right side of simultaneity; right temporal binding window (TBW)). Ultimately, our collective results show for the first time that adult-onset hearing loss leads to behavioral plasticity of audiovisual perception, characterized by a rapid recalibration of temporal sensitivity but a persistent impairment in the perceptual binding of audiovisual stimuli.

Learning drives behavioral adaptations necessary for survival. While plasticity of excitatory projection neurons during associative learning is studied extensively, little is known about the contributions of local interneurons. Using fear conditioning as a model for associative learning, we find that behaviorally relevant, salient stimuli cause learning by tapping into a local microcircuit consisting of precisely connected subtypes of inhibitory interneurons. By employing calcium imaging and optogenetics, we demonstrate that vasoactive intestinal peptide (VIP)-expressing interneurons in the basolateral amygdala are activated by aversive events and provide an instructive disinhibitory signal for associative learning. Notably, VIP interneuron responses are plastic and shift from the instructive to the predictive cue upon memory formation. We describe a novel form of adaptive disinhibitory gating by VIP interneurons that allows to discriminate unexpected, important from irrelevant information, and might be a general dynamic circuit motif to trigger stimulus-specific learning, thereby ensuring appropriate behavioral adaptations to salient events.

Auditory streaming is the process by which environmental sound is segregated into discrete perceptual objects. The auditory system has a remarkable capability in this regard as revealed in psychophysical experiments in humans and other primates. However, little is known about the underlying neuronal mechanisms, in part because of the lack of suitable behavioural paradigms in non-primate species. The mouse is an increasingly popular model for studying the neural mechanisms of perception and action because of the range of molecular tools enabling precise manipulation of neural circuitry. Here we present a novel behavioural task that can be used to assess perceptual aspects of auditory streaming in head-fixed mice. Animals were trained to detect a target sound in a one of two simultaneously presented, isochronous pure tone sequences. Temporal expectation was manipulated by presenting the target sound in a particular stream either early (~2 s) or late (~4 s) with respect to trial onset in blocks of 25-30 trials. Animals reached high performance on this task (d' > 1 overall), and notably their false alarms were very instructive of their behavioural state. Indeed, false alarm timing was markedly delayed for late blocks compared to early ones, indicating that the animals associated a different context to an otherwise identical stimulus. More finely, we observed that the false alarms were timed to the onset of the sounds present in the target stream. This suggests that the animals could selectively follow the target stream despite the presence of a distractor stream. Extracellular electrophysiological recordings during the task revealed that sound processing is flexibly modulated in a manner consistent with the optimisation of behavioural outcome. Together, these results indicate that the perceptual streaming can be inferred via the timing of false alarms in mice, and provide a new paradigm with which to investigate neuronal mechanisms of selective attention.