Publications using the RA16

The temporal frequency of sensory stimulation is a decisive factor in the plasticity of perceptual detection thresholds. However, surprisingly little is known about how distinct temporal parameters of sensory input differentially recruit activity of neuronal circuits in sensory cortices. Here we demonstrate that brief repetitive visual stimulation induces long-term plasticity of visual responses revealed 24 h after stimulation and that the location and generalization of visual response plasticity is determined by the temporal frequency of the visual stimulation. Brief repetitive low-frequency stimulation (2 Hz) is sufficient to induce a visual response potentiation that is expressed exclusively in visual cortex layer 4 and in response to a familiar stimulus. In contrast, brief, repetitive high-frequency stimulation (HFS, 20 Hz) is sufficient to induce a visual response potentiation that is expressed in all cortical layers and transfers to novel stimuli. HFS induces a long-term suppression of the activity of fast-spiking interneurons and primes ongoing gamma oscillatory rhythms for phase reset by subsequent visual stimulation. This novel form of generalized visual response enhancement induced by HFS is paralleled by an increase in visual acuity, measured as improved performance in a visual detection task.

The administration of immune checkpoint inhibitors (ICIs) often leads to immune-related adverse events. However, their effect on auditory function is largely unexplored. Thorough preclinical studies have not been published yet, only sporadic cases and pharmacovigilance reports suggest their significance. Here we investigated the effect of anti-PD-1 antibody treatment (4 weeks, intraperitoneally, 200 μg/mouse, 3 times/week) on hearing function and cochlear morphology in C57BL/6J mice. ICI treatment did not influence the hearing thresholds in click or tone burst stimuli at 4–32 kHz frequencies measured by auditory brainstem response. The number and morphology of spiral ganglion neurons were unaltered in all cochlear turns. The apical-middle turns (<32 kHz) showed preservation of the inner and outer hair cells (OHCs), whilst ICI treatment mitigated the age-related loss of OHCs in the basal turn (>32 kHz). The number of Iba1-positive macrophages has also increased moderately in this high frequency region. We conclude that a 4-week long ICI treatment does not affect functional and morphological integrity of the inner ear in the most relevant hearing range (4–32 kHz; apical-middle turns), but a noticeable preservation of OHCs and an increase in macrophage activity appeared in the >32 kHz basal part of the cochlea.

The nascent field of bioelectronic medicine seeks to decode and modulate peripheral nervous system signals to obtain therapeutic control of targeted end organs and effectors. Current approaches rely heavily on electrode-based devices, but size scalability, material and microfabrication challenges, limited surgical accessibility, and the biomechanically dynamic implantation environment are significant impediments to developing and deploying peripheral interfacing technologies. Here, we present a microscale implantable device – the nanoclip – for chronic interfacing with fine peripheral nerves in small animal models that begins to meet these constraints. We demonstrate the capability to make stable, high signal-to-noise ratio recordings of behaviorally-linked nerve activity over multi-week timescales. In addition, we show that multi-channel, current-steering-based stimulation within the confines of the small device can achieve multi-dimensional control of a small nerve. These results highlight the potential of new microscale design and fabrication techniques for realizing viable devices for long-term peripheral interfacing.

The neural mechanisms underlying forward suppression in the auditory cortex remain a puzzle. Little attention is paid to thalamic contribution despite the important fact that the thalamus gates upstreaming information to the auditory cortex. This study compared the time courses of forward suppression in the auditory thalamus, thalamocortical inputs and cortex using the two-tone stimulus paradigm. The preceding and succeeding tones were 20-ms long. Their frequency and amplitude were set at the characteristic frequency and 20 dB above the minimum threshold of given neurons, respectively. In the ventral division of the medial geniculate body of the thalamus, we found that the duration of complete forward suppression was about 75 ms and the duration of partial suppression was from 75 ms to about 300 ms after the onset of the preceding tone. We also found that during the partial suppression period, the responses to the succeeding tone were further suppressed in the primary auditory cortex. The forward suppression of thalamocortical field excitatory postsynaptic potentials was between those of thalamic and cortical neurons but much closer to that of thalamic ones. Our results indicate that early suppression in the cortex could result from complete suppression in the thalamus whereas later suppression may involve thalamocortical and intracortical circuitry. This suggests that the complete suppression that occurs in the thalamus provides the cortex with a "silence" window that could potentially benefit cortical processing and/or perception of the information carried by the preceding sound.

Selective enhancement of GABAergic inhibition is thought to impact many vital brain functions and interferes with the genesis and/or progression of numerous brain disorders. Here, we show that selectively increasing NMDA receptor activity in inhibitory neurons using an NMDAR positive allosteric modulator (PAM) elevates spiking activity of inhibitory neurons in vitro and in vivo. In vivo infusion of PAM increases spontaneous and sound-evoked spiking in inhibitory and decreases spiking in excitatory neurons, and increases signal-to-noise ratio in the primary auditory cortex. In addition, PAM infusion prior to noise trauma prevents the occurrence of tinnitus and reduction in GABAergic inhibition. These results reveal that selectively enhancing endogenous NMDAR activity on the GABAergic neurons can effectively enhance inhibitory activity and alter excitatory–inhibitory balance, and may be useful for preventing diseases that involve reduced inhibition as the major cause.

Many tasks demand that information is kept online for a few seconds before it is used to guide behavior. The information is kept in working memory as the persistent firing of neurons encoding the memorized information. The neural mechanisms responsible for persistent activity are not yet well understood. Theories attribute an important role to ionotropic glutamate receptors, and it has been suggested that NMDARs are particularly important for persistent firing because they exhibit long time constants. Ionotropic AMPARs have shorter time constants and have been suggested to play a smaller role in working memory. Here we compared the contribution of AMPARs and NMDARs to persistent firing in the dlPFC of male macaque monkeys performing a delayed saccade to a memorized spatial location. We used iontophoresis to eject small amounts of glutamate receptor antagonists, aiming to perturb, but not abolish, neuronal activity. We found that both AMPARs and NMDARs contributed to persistent activity. Blockers of the NMDARs decreased persistent firing associated with the memory of the neuron's preferred spatial location but had comparatively little effect on the representation of the antipreferred location. They therefore decreased the information conveyed by persistent firing about the memorized location. In contrast, AMPAR blockers decreased activity elicited by the memory of both the preferred and antipreferred location, with a smaller effect on the information conveyed by persistent activity. Our results provide new insights into the contribution of AMPARs and NMDARs to persistent activity during working memory tasks. SIGNIFICANCE STATEMENT Working memory enables us to hold on to information that is no longer available to the senses. It relies on the persistent activity of neurons that code for the memorized information, but the detailed mechanisms are not yet well understood. Here we investigated the role of NMDARs and AMPARs in working memory using iontophoresis of antagonists in the PFC of monkeys remembering the location of a visual stimulus for an eye movement response. AMPARs and NMDARs both contributed to persistent activity. NMDAR blockers mostly decreased persistent firing associated with the memory of the neuron's preferred spatial location, whereas AMPAR blockers caused a more general suppression. These results provide new insight into the contribution of AMPARs and NMDARs to working memory.

Objective: Reanimation of muscles paralyzed by disease states such as spinal cord injury remains a highly sought therapeutic goal of neuroprosthetic research. Optogenetic stimulation of peripheral motor nerves expressing light-sensitive opsins is a promising approach to muscle reanimation that may overcome several drawbacks of traditional methods such as functional electrical stimulation (FES). However, the utility of these methods has only been demonstrated in rodents to date, while translation to clinical practice will likely first require demonstration and refinement of these gene therapy techniques in non-human primates. Approach: Three rhesus macaques were injected intramuscularly with either one or both of two optogenetic constructs (AAV6-hSyn-ChR2-eYFP and/or AAV6-hSyn-Chronos-eYFP) to transduce opsin expression in the corresponding nerves. Neuromuscular junctions were targeted for virus delivery using an electrical stimulating injection technique. Functional opsin expression was periodically evaluated up to 13 weeks post-injection by optically stimulating targeted nerves with a 472 nm fiber-coupled laser while recording electromyographic (EMG) responses. Main Results: One monkey demonstrated functional expression of ChR2 at 8 weeks post-injection in each of two injected muscles, while the second monkey briefly exhibited contractions coupled to optical stimulation in a muscle injected with the Chronos construct at 10 weeks. A third monkey injected only in one muscle with the ChR2 construct showed strong optically coupled contractions at 5 ½ weeks which then disappeared by 9 weeks. EMG responses to optical stimulation of ChR2-transduced nerves demonstrated graded recruitment relative to both stimulus pulse-width and light intensity, and followed stimulus trains up to 16 Hz. In addition, the EMG response to prolonged stimulation showed delayed fatigue over several minutes. Significance: These results demonstrate the feasibility of viral transduction of peripheral motor nerves for functional optical stimulation of motor activity in non-human primates, a variable timeline of opsin expression in a animal model closer to humans, and fundamental EMG response characteristics to optical nerve stimulation. Together, they represent an important step in translating these optogenetic techniques as a clinically viable gene therapy.

Accurate sound localization requires normal binaural input and precise auditory neuronal representation of sound spatial locations. Previous studies showed that unilateral hearing loss profoundly impaired the sound localization abilities. However, the underlying neural mechanism is not fully understood. Here, we investigated how chronic unilateral conductive hearing loss (UCHL) affected the neural tuning to sound source azimuth in the primary auditory cortex (AI). The UCHL was manipulated by the removal of tympanic membrane and malleus in the right ear of young (P14) rats and adult (P57) rats. We recorded the azimuth tuning of neurons in the left AI contralateral to the operated ear in the two groups of rats that experienced 2 months of UCHL, and in the left AI of age-matched control rats. We found that AI neurons in control rats showed predominant preference to sound from contralateral azimuths. However, UCHL weakened the cortical neuronal representation of contralateral azimuths on the operated ear side and strengthened the cortical neuronal representation of ipsilateral azimuths on the intact ear side. This effect was stronger in rats with UCHL at young age than in rats with UCHL in adulthood. Moreover, UCHL degraded the azimuth selectivity and azimuth sensitivity of AI neurons, and this effect was stronger in rats with UCHL in adulthood than in rats with UCHL at young age. These findings highlight a remarkable age-related experience-dependent plasticity of neural tuning to sound source azimuth in AI, and imply a neural mechanism for the impacts of chronic UCHL on sound localization abilities.

To effectively interact with their environment, humans must often select actions from multiple incompatible options. Existing theories propose that during motoric response-conflict, inappropriate motor activity is actively (and perhaps non-selectively) suppressed by an inhibitory fronto-basal ganglia mechanism. We here tested this theory across three experiments. First, using scalp-EEG, we found that both outright action-stopping and response-conflict during action-selection invoke low-frequency activity of a common fronto-central source, whose activity relates to trial-by-trial behavioral indices of inhibition in both tasks. Second, using simultaneous intracranial recordings from the basal ganglia and motor cortex, we found that response-conflict increases the influence of the subthalamic nucleus on M1-representations of incorrect response-tendencies. Finally, using transcranial magnetic stimulation, we found that during the same time period when conflict-related STN-to-M1 communication is increased, cortico-spinal excitability is broadly suppressed. Together, these findings demonstrate that fronto-basal ganglia networks buttress action-selection under response-conflict by rapidly and non-selectively net-inhibiting inappropriate motor tendencies.

The medial septum implements cortical theta oscillations, a 5-12 Hz rhythm associated with locomotion and paradoxical sleep reflecting synchronization of neuronal assemblies such as place cell sequence coding. Highly rhythmic burst-firing parvalbumin-positive GABAergic medial septal neurons are strongly coupled to theta oscillations and target cortical GABAergic interneurons, contributing to coordination within one or several cortical regions. However, a large population of medial septal neurons of unidentified neurotransmitter phenotype and with unknown axonal target areas fire with a low degree of rhythmicity. We investigated whether low-rhythmic-firing neurons (LRNs) innervated similar or different cortical regions to high-rhythmic-firing neurons (HRNs) and assessed their temporal dynamics in awake male mice. The majority of LRNs were GABAergic and parvalbumin-immunonegative, some expressing calbindin; they innervated interneurons mostly in the dentate gyrus (DG) and CA3. Individual LRNs showed several distinct firing patterns during immobility and locomotion, forming a parallel inhibitory stream for the modulation of cortical interneurons. Despite their fluctuating firing rates, the preferred firing phase of LRNs during theta oscillations matched the highest firing probability phase of principal cells in the DG and CA3. In addition, as a population, LRNs were markedly suppressed during hippocampal sharp-wave ripples, had a low burst incidence, and several of them did not fire on all theta cycles. Therefore, CA3 receives GABAergic input from both HRNs and LRNs, but the DG receives mainly LRN input. We propose that distinct GABAergic LRNs contribute to changing the excitability of the DG and CA3 during memory discrimination via transient disinhibition of principal cells.SIGNIFICANCE STATEMENT For the encoding and recall of episodic memories, nerve cells in the cerebral cortex are activated in precisely timed sequences. Rhythmicity facilitates the coordination of neuronal activity and these rhythms are detected as oscillations of different frequencies such as 5-12 Hz theta oscillations. Degradation of these rhythms, such as through neurodegeneration, causes memory deficits. The medial septum, a part of the basal forebrain that innervates the hippocampal formation, contains high- and low-rhythmic-firing neurons (HRNs and LRNs, respectively), which may contribute differentially to cortical neuronal coordination. We discovered that GABAergic LRNs preferentially innervate the dentate gyrus and the CA3 area of the hippocampus, regions important for episodic memory. These neurons act in parallel with the HRNs mostly via transient inhibition of inhibitory neurons.

The auditory system relies on binaural differences and spectral pinna cues to localize sounds in azimuth and elevation. However, the acoustic input can be unreliable, due to uncertainty about the environment, and neural noise. A possible strategy to reduce sound-location uncertainty is to integrate the sensory observations with sensorimotor information from previous experience, to infer where sounds are more likely to occur. We investigated whether and how human sound localization performance is affected by the spatial distribution of target sounds, and changes thereof. We tested three different open-loop paradigms, in which we varied the spatial range of sounds in different ways. For the narrowest ranges, target-response gains were highly idiosyncratic and deviated from an optimal gain predicted by error-minimization; in the horizontal plane the deviation typically consisted of a response overshoot. Moreover, participants adjusted their behavior by rapidly adapting their gain to the target range, both in elevation and in azimuth, yielding behavior closer to optimal for larger target ranges. Notably, gain changes occurred without any exogenous feedback about performance. We discuss how the findings can be explained by a sub-optimal model in which the motor-control system reduces its response error across trials to within an acceptable range, rather than strictly minimizing the error.

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.

Active mechanical amplification of sound occurs in cochlear outer hair cells (OHCs) that change their length with oscillations of their membrane potential. Such length changes are the proposed cellular source of the cochlear amplifier, and prestin is the motor protein responsible for OHC electromotility. Previous findings have shown that mice lacking prestin displayed a loss of OHC electromotility, subsequent loss of distortion-product otoacoustic emissions, and a 40-60 dB increase in hearing thresholds. In this study we were interested in studying the functional consequences of the complete loss of cochlear amplification on neural coding of frequency selectivity, tuning, and temporal processing in the auditory midbrain. We recorded near-field auditory evoked potentials and multi-unit activity from the inferior colliculus (IC) of prestin (-/-) null and prestin (+/+) wild-type control mice and determined frequency response areas (FRAs), tuning sharpness, and gap detection to tone bursts and silent gaps embedded in broadband noise. We were interested in determining if the moderate to severe sensorineural hearing loss associated with the loss of motor protein prestin would also impair auditory midbrain temporal-processing measures, or if compensatory mechanisms within the brainstem could compensate for the loss of prestin. In prestin knockout mice we observed that there are severe impairments in midbrain tuning, thresholds, excitatory drive, and gap detection suggesting that brainstem and midbrain processing could not overcome the auditory processing deficits afforded by the loss of OHC electromotility mediated by the prestin protein.

Hyperbilirubinemia (jaundice) is caused by raised levels of unconjugated bilirubin in the blood. When severe, susceptible brain regions including the cerebellum and auditory brainstem are damaged causing neurological sequelae such as ataxia, hearing loss and kernicterus. The mechanism(s) by which bilirubin exerts its toxic effect have not been completely understood to date. In this study we investigated the acute mechanisms by which bilirubin causes the neurotoxicity that contributes to hearing loss. We developed a novel mouse model that exhibits the neurological features seen in human Bilirubin-Induced Neurological Dysfunction (BIND) syndrome that we assessed with a behavioural score and auditory brainstem responses (ABR). Guided by initial experiments applying bilirubin to cultured cells in vitro, we performed whole genome gene expression measurements on mouse brain tissue (cerebellum and auditory brainstem) following bilirubin exposure to gain mechanistic insights into biochemical processes affected, and investigated further using immunoblotting. We then compared the gene changes induced by bilirubin to bacterial lipopolysaccharide (LPS), a well characterized inducer of neuroinflammation, to assess the degree of similarity between them. Finally, we examined the extent to which genetic perturbation of inflammation and both known and novel anti-inflammatory drugs could protect hearing from bilirubin-induced toxicity. The in vitro results indicated that bilirubin induces changes in gene expression consistent with endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR). These gene changes were similar to the gene expression signature of thapsigargin-a known ER stress inducer. It also induced gene expression changes associated with inflammation and NF-κB activation. The in vivo model showed behavioural impairment and a raised auditory threshold. Whole genome gene expression analysis confirmed inflammation as a key mechanism of bilirubin neurotoxicity in the auditory pathway and shared gene expression hallmarks induced by exposure to bacterial lipopolysaccharide (LPS) a well-characterized inducer of neuroinflammation. Interestingly, bilirubin caused more severe damage to the auditory system than LPS in this model, but consistent with our hypothesis of neuroinflammation being a primary part of bilirubin toxicity, the hearing loss was protected by perturbing the inflammatory response. This was carried out genetically using lipocalin-2 (LCN2)-null mice, which is an inflammatory cytokine highly upregulated in response to bilirubin. Finally, we tested known and novel anti-inflammatory compounds (interfering with NF-κB and TNFα signalling), and also demonstrated protection of the auditory system from bilirubin toxicity. We have developed a novel, reversible, model for jaundice that shows movement impairment and auditory loss consistent with human symptoms. We used this model to establish ER-stress and inflammation as major contributors to bilirubin toxicity. Because of the rapid and reversible onset of toxicity in this novel model it represents a system to screen therapeutic compounds. We have demonstrated this by targeting inflammation genetically and with anti-inflammatory small molecules that offered protection against bilirubin toxicity. This also suggests that anti-inflammatory drugs could be of therapeutic use in hyperbilirubinemia.

Charles Darwin suggested the perception of rhythm to be common to all animals. While only recently experimental research is finding some support for this claim, there are also aspects of rhythm cognition that appear to be species-specific, such as the capability to perceive a regular pulse (or beat) in a varying rhythm. In the current study, using EEG, we adapted an auditory oddball paradigm that allows for disentangling the contributions of beat perception and isochrony to the temporal predictability of the stimulus. We presented two rhesus monkeys (Macaca mulatta) with a rhythmic sequence in two versions: an isochronous version, that was acoustically accented such that it could induce a duple meter (like a march), and a jittered version using the same acoustically accented sequence but that was presented in a randomly timed fashion, as such disabling beat induction. The results reveal that monkeys are sensitive to the isochrony of the stimulus, but not its metrical structure. The MMN was influenced by the isochrony of the stimulus, resulting in a larger MMN in the isochronous as opposed to the jittered condition. However, the MMN for both monkeys showed no interaction between metrical position and isochrony. So, while the monkey brain appears to be sensitive to the isochrony of the stimulus, we find no evidence in support of beat perception. We discuss these results in the context of the gradual audiomotor evolution (GAE) hypothesis (Merchant and Honing, 2014) that suggests beat-based timing to be omnipresent in humans but only weakly so or absent in non-human primates.

Until recently, hypocretin (Hcrt) neurons were the only known wake-promoting neuronal population in the lateral hypothalamus (LH), but subpopulations of inhibitory neurons in this area and glutamatergic neurons in the nearby supramammillary nucleus (SuM) have recently been found that also promote wakefulness. We performed chemogenetic excitation of LH neurons in mice and observed increased wakefulness that lasted more than 4 h without unusual behavior or EEG anomalies. The increased wakefulness was similar in the presence or absence of the dual orexin receptor blocker almorexant (ALM). Analysis of hM3Dq transfection and c-FOS expression in LH inhibitory neurons and in the SuM failed to confirm that the increased wakefulness was due to these wake-promoting populations, although this possibility cannot be completely excluded. To evaluate the relationship to the Hcrt system, we repeated the study in Orexin-tTA mice in the presence or absence of dietary doxycycline (DOX), which enabled us to manipulate the percentage of Hcrt neurons that expressed hM3Dq. In DOX-fed mice, 18% of Hcrt neurons as well as many other LH neurons expressed hM3Dq; these mice showed a profound increase in wake after hM3Dq activation even in the presence of ALM. In mice switched to normal chow, 62% of Hcrt neurons expressed hM3Dq along with other LH cells; chemogenetic activation produced even more sustained arousal which could be reduced to previous levels by ALM treatment. Together, these results indicate an LH neuron population that promotes wakefulness through an Hcrt-independent pathway that can act synergistically with the Hcrt system to prolong arousal.

Two synchronous sounds at different locations in the midsagittal plane induce a fused percept at a weighted-average position, with weights depending on relative sound intensities. In the horizontal plane, sound fusion (stereophony) disappears with a small onset asynchrony of 1–4 ms. The leading sound then fully determines the spatial percept (the precedence effect). Given that accurate localisation in the median plane requires an analysis of pinna-related spectral-shape cues, which takes ~25–30 ms of sound input to complete, we wondered at what time scale a precedence effect for elevation would manifest. Listeners localised the first of two sounds, with spatial disparities between 10–80 deg, and inter-stimulus delays between 0–320 ms. We demonstrate full fusion (averaging), and largest response variability, for onset asynchronies up to at least 40 ms for all spatial disparities. Weighted averaging persisted, and gradually decayed, for delays >160 ms, suggesting considerable backward masking. Moreover, response variability decreased with increasing delays. These results demonstrate that localisation undergoes substantial spatial blurring in the median plane by lagging sounds. Thus, the human auditory system, despite its high temporal resolution, is unable to spatially dissociate sounds in the midsagittal plane that co-occur within a time window of at least 160 ms.

Introduction It is known that an interruption of acoustic input in early life will result in abnormal development of the auditory system. Here, we further show that this negative impact actually spans beyond the auditory system to the hippocampus, a system critical for spatial memory. Methods We induced a temporary conductive hearing loss (TCHL) in P14 rats by perforating the eardrum and allowing it to heal. The Morris water maze and Y‐maze tests were deployed to evaluate spatial memory of the rats. Electrophysiological recordings and anatomical analysis were made to evaluate functional and structural changes in the hippocampus following TCHL. Results The rats with the TCHL had nearly normal hearing at P42, but had a decreased performance with the Morris water maze and Y‐maze tests compared with the control group. A functional deficit in the hippocampus of the rats with the TCHL was found as revealed by the depressed long‐term potentiation and the reduced NMDA receptor‐mediated postsynaptic current. A structural deficit in the hippocampus of those animals was also found as revealed the abnormal expression of the NMDA receptors, the decreased number of dendritic spines, the reduced postsynaptic density and the reduced level of neurogenesis. Conclusions Our study demonstrates that even temporary auditory sensory deprivation in early life of rats results in abnormal development of the hippocampus and consequently impairs spatial memory in adulthood.

Models of firing rate homeostasis such as synaptic scaling and the sliding synaptic plasticity modification threshold predict that decreasing neuronal activity (for example, by sensory deprivation) will enhance synaptic function. Manipulations of cortical activity during two forms of visual deprivation, dark exposure (DE) and binocular lid suture, revealed that, contrary to expectations, spontaneous firing in conjunction with loss of visual input is necessary to lower the threshold for Hebbian plasticity and increase miniature excitatory postsynaptic current (mEPSC) amplitude. Blocking activation of GluN2B receptors, which are upregulated by DE, also prevented the increase in mEPSC amplitude, suggesting that DE potentiates mEPSCs primarily through a Hebbian mechanism, not through synaptic scaling. Nevertheless, NMDA-receptor-independent changes in mEPSC amplitude consistent with synaptic scaling could be induced by extreme reductions of activity. Therefore, two distinct mechanisms operate within different ranges of neuronal activity to homeostatically regulate synaptic strength.